Mechanistic Modeling Quantifies The Influence Of Tumor Growth Kinetics On The Response To Anti-Angiogenic Treatment        

Mechanistic Modeling Quantifies The Influence Of Tumor Growth Kinetics On The Response To Anti-Angiogenic Treatment

Thomas D. Gaddy, Stacey D. Finley

Abstract

Tumors exploit angiogenesis, the formation of new blood vessels from pre-existing vasculature, in order to obtain nutrients required for continued growth and proliferation. Targeting factors that regulate angiogenesis, including the potent promoter vascular endothelial growth factor (VEGF), is therefore an attractive strategy for inhibiting tumor growth. Systems biology modeling enables us to identify tumor-specific properties that influence the response to those anti-angiogenic strategies. Here, we build on our previous systems biology model of VEGF transport and kinetics in tumor-bearing mice to include a tumor compartment whose volume depends on the “angiogenic signal” produced when VEGF binds to its receptors on tumor endothelial cells. We trained and validated the model using in vivo measurements of xenograft tumor volume to produce a model that accurately predicts the tumor's response to anti-angiogenic treatment. We applied the model to investigate how tumor growth kinetics influence the response to anti-angiogenic treatment targeting VEGF. Based on multivariate regression analysis, we found that certain intrinsic kinetic parameters that characterize the growth of tumors could successfully predict response to anti-VEGF treatment. This model is a useful tool for predicting which tumors will respond to anti-VEGF treatment, complementing pre-clinical in vivo studies.


          (USA-CT-RIDGEFIELD) Scientist III, Immune Modulation        
Boehringer Ingelheim is an equal opportunity global employer who takes pride in maintaining a diverse and inclusive culture. We embrace diversity of perspectives and strive for an inclusive environment which benefits our employees, patients and communities. **Description:** We are seeking a highly motivated scientist with strong interpersonal communication skills to join the newly created Immune Modulation (IM) Research Group at Boehringer Ingelheim’s US research facility in Ridgefield, CT. The successful candidate will work within the CI&IM _in vivo_ pharmacology group to advance both exploratory and drug candidate discovery programs and provide target discovery/validation, in-vivo efficacy, mechanism of action (MOA) and pharmacodynamic data essential to drive projects into clinical development. The ideal candidate will collaborate with other members of in-vivo teams and with key responsibilities involving primarily designing and conducting in vivo pharmacology models of inflammation and oncology, as well as establishing early PK/PD for lead progression. **Responsibilities:** + Execute research projects according to the experimental design, ensure technically capable and provide accurate, reliable and reproducible data. + Independently perform in vivo studies, proficient in data collection/documentation, interpret data and with mentorship, present to project teams. + Collaborate extensively with other members of the Immune Modulation Group in Ridgefield, while synergizing effectively with the in vivo pharmacology group in the Inflammation & Respiratory therapeutic area. + Expand scientific/technical knowledge and skill sets by regularly reading relevant scientific literature and implement learnings in the study designs or project strategies. + Ensure that the highest standard of animal welfare is maintained in all studies involving experimental animals. + Understand and implement study protocol according to AAALAC and IACUC guidelines. **Qualifications:** + BS in Immunology,Pharmacology or related discipline with minimum 6 years of industry experience. Candidates with other degrees and significant experience considered. + Extensive hands-on experience on conducting rodent experiments including preparation of test compounds, handling and dosing mice by various routes (IP, SC, IV or PO), collection of blood and tissues for PK and PD biomarker analysis. + Familiar with human or murine primary cell isolation, cytokine profiling by ELISA or MSD, T cell and/or myeloid cell functional assays, Western blot, and qPCR. Experience in using multi-color flow cytometry (FACS) to evaluate immune cell biomarkers and data analysis software is a plus. + Past experience with syngeneic or xenograft tumor models or PDX models is preferred. Familiarity with hydrodynamic tail vein injection is a plus but not required. + Excellent oral and written communication skills. Proficiency in all common Microsoft Office and Graphpad Prism software. + Strong ability to multi-task and willingness to work effectively in a fast-paced, highly collaborative, and diverse research environment. + The ability to both work independent and being a team player. **Eligibility Requirements:** + Must be legally authorized to work in the United States without restriction. + Must be willing to take a drug test and post-offer physical (if required) + Must be 18 years of age or older **Our Culture:** Boehringer Ingelheim is one of the world’s top 20 pharmaceutical companies and operates globally with approximately 50,000 employees. Since our founding in 1885, the company has remained family-owned and today we are committed to creating value through innovation in three business areas including human pharmaceuticals, animal health and biopharmaceutical contract manufacturing. Since we are privately held, we have the ability to take an innovative, long-term view. Our focus is on scientific discoveries and the introduction of truly novel medicines that improve lives and provide valuable services and support to patients and their families. Employees are challenged to take initiative and achieve outstanding results. Ultimately, our culture and drive allows us to maintain one of the highest levels of excellence in our industry. We are also deeply committed to our communities and our employees create and engage in programs that strengthen the neighborhoods where we live and work. Boehringer Ingelheim, including Boehringer Ingelheim Pharmaceuticals, Inc., Boehringer Ingelheim USA, Boehringer Ingelheim Animal Health USA, Inc., Merial Barceloneta, LLC and Boehringer Ingelheim Fremont, Inc. is an equal opportunity and affirmative action employer committed to a culturally diverse workforce. All qualified applicants will receive consideration for employment without regard to race; color; creed; religion; national origin; age; ancestry; nationality; marital, domestic partnership or civil union status; sex, gender identity or expression; affectional or sexual orientation; disability; veteran or military status, including protected veteran status; domestic violence victim status; atypical cellular or blood trait; genetic information (including the refusal to submit to genetic testing) or any other characteristic protected by law. Boehringer Ingelheim is firmly committed to ensuring a safe, healthy, productive and efficient work environment for our employees, partners and customers. As part of that commitment, Boehringer Ingelheim conducts pre-employment verifications and drug screenings. **Organization:** _US-BI Pharma/BI USA_ **Title:** _Scientist III, Immune Modulation_ **Location:** _Americas-United States-CT-Ridgefield_ **Requisition ID:** _178469_
           Manipulation of tumour blood flow by 5,6-dimethylxanthenone-4-acetic acid enhances radioimmunotherapy in a colonic xenograft model.         
Pedley, RB; Boden, JA; Boxer, GM; Boden, RB; R, HJ; (1995) Manipulation of tumour blood flow by 5,6-dimethylxanthenone-4-acetic acid enhances radioimmunotherapy in a colonic xenograft model. In: (pp. 75-).
          COX-2 Inhibitors May Reverse IDO1-mediated Immunosuppression in Some Cancers        

​PHILADELPHIA — In preclinical studies, tumors that consitutively expressed the protein indoleamine 2,3-dioxygenase (IDO1) responded to the cyclooxygenase-2 (COX-2) inhibitor celecoxib (Celebrex) and had improved infiltration of certain subsets of T cells, making them more likely to respond to anti-PD1 therapies, according to data published in Cancer Immunology Research, a journal of the American Association for Cancer Research.

“A key challenge in cancer immunotherapy is to understand why some patients respond to immunotherapy but many others do not,” said Benoit J. Van den Eynde, MD, PhD, professor at Ludwig Institute for Cancer Research at de Duve Institute and Université catholique de Louvain in Brussels, Belgium. “If we understand why, we can then select and treat only those patients who will benefit from the treatment, but most importantly, we can devise strategies to make immunotherapy work in those who are not currently responding.” Benoit J. Van den Eynde, MD, PhD

Many tumors use IDO1 as a shield to protect themselves from immune attack, explained Van den Eynde. Some of them start building and raising their shields when they are being attacked by T cells, which is called adaptive resistance. In such tumors, IDO1 expression is associated with inflammation and T-cell infiltration.

However, some tumors produce IDO1 constitutively (continuously) and have their shields ready and raised before any immune attack. Such tumors are fully protected and can prevent T-cell attack by disabling the T cells right away. “This is what we call intrinsic resistance and may explain why some tumors are ‘cold,’ meaning, not infiltrated by T cells,” Van den Eynde said.

“We wanted to understand the molecular mechanisms that make some tumors express IDO1 constitutively,” he added.

Using two human melanoma cell lines, Van den Eynde and colleagues first demonstrated that COX-2 and its product, prostaglandin E2 (PGE2), caused the constitutive expression of IDO1 by utilizing the MAPK, PKC, and PI3K cell-signaling pathways. These results held true in other human tumor cell lines as well, including lung, ovarian, and head and neck cancer cell lines. “These data provide evidence that COX-2 drives tumor-induced immunosuppression through constitutive expression of IDO1,” Van den Eynde noted.

Next, they showed that immunodeficient mice reconstituted with human lymphocytes and bearing human ovarian tumor xenografts with constitutive IDO1 expression responded to celecoxib as well as the IDO1 inhibitor, epacadostat. “The outcomes we observed with COX-2 inhibitors and IDO1 inhibitors were identical, which came as a surprise,” Van den Eynde said. “It is always very useful to have two compounds acting on the same pathway with two different modes of action: In case tumors start resisting one compound, they may still be sensitive to the other.”

By mining the transcriptomics data of 1,041 different human tumor cell lines from the Broad Institute, the researchers found a correlation between IDO1 expression and activation of the COX-2/PGE2 axis in several cancer types, including stomach, pancreatic, liver, and lung cancers, and sarcoma.

“Our studies provide a clear rationale to test, in the clinics, combinations of anti-PD1 immunotherapy and COX-2 inhibitors,” Van den Eynde said. “This should be straightforward given the fact that both anti-PD1 and COX-2 inhibitors are already approved for clinical use in different contexts.” Initial analysis by the team indicated that about 10 to 50 percent of human tumors express IDO1 constitutively, depending on tumor type.

This study was funded by Ludwig Institute for Cancer Research, Walloon Excellence in Life Sciences and Biotechnology (WELBIO, Belgium), FNRS-Télévie (Belgium), Foundation Against Cancer (Belgium), de Duve Institute and Université catholique de Louvain. Van den Eynde has ownership interest in iTeos Therapeutics, a biotechnology company developing IDO1 inhibitors.

Press Release Published Date: 7/20/2017 8:05 PM
Display on Homepage: Yes

          Estrogen receptor coregulator binding modulators (ERXs) effectively target estrogen receptor positive human breast cancers.        

Estrogen receptor coregulator binding modulators (ERXs) effectively target estrogen receptor positive human breast cancers.

Elife. 2017 Aug 08;6:

Authors: Raj GV, Sareddy GR, Ma S, Lee TK, Viswanadhapalli S, Li R, Liu X, Murakami S, Chen CC, Lee WR, Mann M, Krishnan SR, Manandhar B, Gonugunta VK, Strand D, Tekmal RR, Ahn JM, Vadlamudi RK

Abstract
The majority of human breast cancer is estrogen receptor alpha (ER) positive. While anti-estrogens/aromatase inhibitors are initially effective, resistance to these drugs commonly develops. Therapy-resistant tumors often retain ER signaling, via interaction with critical oncogenic coregulator proteins. To address these mechanisms of resistance, we have developed a novel ER coregulator binding modulator, ERX-11. ERX-11 interacts directly with ER and blocks the interaction between a subset of coregulators with both native and mutant forms of ER. ERX-11 effectively blocks ER-mediated oncogenic signaling and has potent anti-proliferative activity against therapy-sensitive and therapy-resistant human breast cancer cells. ERX-11 is orally bioavailable, with no overt signs of toxicity and potent activity in both murine xenograft and patient-derived breast tumor explant models. This first-in-class agent, with its novel mechanism of action of disrupting critical protein-protein interactions, overcomes the limitations of current therapies and may be clinically translatable for patients with therapy-sensitive and therapy-resistant breast cancers.

PMID: 28786813 [PubMed - in process]


           A distribution study at sub-millimetre resolution of a recombinant MFE-23 : CPG(2) fusion protein in a colorectal cancer xenograft model         
Bhatia, J; Pedley, RB; Sharma, SK; Boxer, GM; Read, DA; Boden, RW; Michael, P; ... Begent, RHJ; + view all <#> Bhatia, J; Pedley, RB; Sharma, SK; Boxer, GM; Read, DA; Boden, RW; Michael, P; Chester, KA; Begent, RHJ; - view fewer <#> (1998) A distribution study at sub-millimetre resolution of a recombinant MFE-23 : CPG(2) fusion protein in a colorectal cancer xenograft model. BRIT J CANCER , 78 61 - 61.
           Enhancement of adept with anti-vasculature drugs in a xenograft model.         
Pedley, RB; Sharma, SK; Boden, R; Boxer, GM; Springer, CJ; Begent, RHJ; (1998) Enhancement of adept with anti-vasculature drugs in a xenograft model. BRIT J CANCER , 78 51 - 51.
           A distribution study at sub-millimetre resolution of a recombinant MFE:CPG2 fusion protein in a colorectal cancer xenograft model.         
Bhatia, J; Pedley, RB; Sharma, SK; Boxer, GM; Read, DA; Michael, P; Boden, RW; ... R, HJ; + view all <#> Bhatia, J; Pedley, RB; Sharma, SK; Boxer, GM; Read, DA; Michael, P; Boden, RW; Chester, KAAB; R, HJ; - view fewer <#> (1998) A distribution study at sub-millimetre resolution of a recombinant MFE:CPG2 fusion protein in a colorectal cancer xenograft model. In: (Proceedings) Proceedings BACR, Br J Cancer. (pp. 61-).
           A distribution study at sub-millimetre resolution of a recombinant MFE-23:CPG(2) fusion protein in a colorectal cancer xenograft model         
Bhatia, J; Pedley, RB; Sharma, SK; Boxer, GM; Read, DA; Boden, RW; Michael, P; ... Begent, RHJ; + view all <#> Bhatia, J; Pedley, RB; Sharma, SK; Boxer, GM; Read, DA; Boden, RW; Michael, P; Chester, KA; Begent, RHJ; - view fewer <#> (1998) A distribution study at sub-millimetre resolution of a recombinant MFE-23:CPG(2) fusion protein in a colorectal cancer xenograft model. British Journal of Cancer , 78 p. 147.
          Debio 0617B Inhibits Growth of STAT3-Driven Solid Tumors through Combined Inhibition of JAK, SRC, and Class III/V Receptor Tyrosine Kinases        
Tumor survival, metastases, chemoresistance, and escape from immune responses have been associated with inappropriate activation of STAT3 and/or STAT5 in various cancers, including solid tumors. Debio 0617B has been developed as a first-in-class kinase inhibitor with a unique profile targeting phospho-STAT3 (pSTAT3) and/or pSTAT5 in tumors through combined inhibition of JAK, SRC, ABL, and class III/V receptor tyrosine kinases (RTK). Debio 0617B showed dose-dependent inhibition of pSTAT3 in STAT3-activated carcinoma cell lines; Debio 0617B also showed potent antiproliferative activity in a panel of cancer cell lines and in patient-derived tumor xenografts tested in an in vitro clonogenic assay. Debio 0617B showed in vivo efficacy by inhibiting tumor growth in several mouse xenograft models. To increase in vivo efficacy and STAT3 inhibition, Debio 0617B was tested in combination with the EGFR inhibitor erlotinib in a non-small cell lung cancer xenograft model. To evaluate the impact of in vivo STAT3 blockade on metastases, Debio 0617B was tested in an orthotopic tumor model. Measurement of primary tumor weight and metastatic counts in lung tissue demonstrated therapeutic efficacy of Debio 0617B in this model. These data show potent activity of Debio 0617B on a broad spectrum of STAT3-driven solid tumors and synergistic activity in combination with EGFR inhibition. (C) 2016 AACR.
           Recombinant human erythropoietin alpha targets intratumoral blood vessels, improving chemotherapy in human xenograft models         
Tóvári, József and Gilly, R. and Rásó, Erzsébet and Paku, Sándor and Bereczky, Bíborka and Tímár, József (2005) Recombinant human erythropoietin alpha targets intratumoral blood vessels, improving chemotherapy in human xenograft models. CANCER RESEARCH, 65 (16). pp. 7186-7193. ISSN 0008-5472
          Nobiletin might have a great potential for treating glioblastoma.        
PMID:  Oncol Rep. 2017 May ;37(5):2847-2856. Epub 2017 Mar 23. PMID: 28339056 Abstract Title:  Nobiletin inhibits invasion via inhibiting AKT/GSK3β/β-catenin signaling pathway in Slug-expressing glioma cells. Abstract:  Epithelial-mesenchymal transition (EMT) is a pivotal event in tumor progression during which cancer cells undergo dramatic changes acquiring highly invasive properties. In this study, we found that nobiletin, a polymethoxylated flavone, suppressed migration and invasion in both U87 and U251 glioma cells. Expression of epithelial markers (E-cadherin and occludin) was upregulated; mesenchymal markers (N-cadherin, fibronectin) and the transcriptional factor Slug were downregulated after nobiletin treatment. Transforming growth factorβ (TGF-β) was applied to stimulate EMT and the results showed that nobiletin not only influenced basal level cell migration but also prevented TGF-β-triggered migration and EMT, with the AKT/GSK3β/β-catenin signaling pathway greatly involved. Furthermore, nobiletin remarkably diminished TGF-β-induced β-catenin nuclear translocation and the binding to the Slug promoter. It is worth noting that nobiletin almost blocked invasion in Slug-expressing U87 and U251 cells, and only exhibiting faint effect on non-Slug-expressing U343 glioma cells. Reinforced Slug expression in U343 cells by transfecting Slug plasmid was significantly attenuated by nobiletin, demonstrating the essential role of Slug in the anti-metastasis effect of nobiletin. Nobiletin repressed tumor growth in vivo and abrogated EMT in nude mice bearing U87-Luc xenografts, as demonstrated by Xenogen IVIS imaging and immunohistochemistry assay. Our findings suggested that nobiletin might have a great potential for treating glioblastoma.

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          The DNA Network        
The DNA Network

The DNA Network

Gene for the placebo response? Not even close. [Genetic Future]

Posted: 03 Dec 2008 07:45 PM CST

head_meet_wall.jpgNew Scientist trumpets the discovery of "the first placebo gene". The study in question is here.

I usually don't comment on this type of study, but this time the hype is just too much for me: New Scientist describes the study as "a milestone in the quest to understand" the placebo effect; an article in ScienceNow quotes a psychiatrist saying that "the findings could have major implications for research design". The article itself certainly doesn't talk down its results, with the first sentence of the discussion stating:

The present study demonstrates that the magnitude of the placebo response [...] is tied to attenuated amygdala excitability, which in turn is linked to serotonergic genetic variation.

The problem? The study examined just 25 subjects, and if there's one clear lesson from the history of candidate gene asociation studies it's that such tiny studies are essentially worthless: systematic reviews of the field (e.g. here, here and here) have consistently found that the majority of such associations are never replicated, suggesting that positive results in small studies are substantially more likely to arise through a combination of chance, error and publication bias than through a genuine causal link.

It's only relatively recently that genetic association studies have come of age, with the advent of agnostic genome-wide association studies, massive sample sizes, rigorous statistical frameworks and the use of independent replication cohorts. Unfortunately, it appears that such novelties haven't yet permeated Uppsala University's Department of Psychology - but that hasn't stopped their study from generating media attention, in publications that should really have known better.

So don't believe the hype: as a good rule of thumb, if a genetic association study contains fewer than 100 subjects, it's not a "milestone" with "major implications" - in fact, you might as well simply pretend it doesn't exist at all. (Many studies with more than 100 subjects are also crap, but at least there's a chance they're capturing a genuine causal variant.) I'm deadly serious about this. The field is so littered with the stinking carcasses of unreplicated candidate gene associations that it's a reasonable default to simply assume that any small, unreplicated study is false.

Now, if only there was a way to get some science journalists to internalise that little rule of thumb...

Read the comments on this post...

Paralogous genes and disease alleles [Yann Klimentidis' Weblog]

Posted: 03 Dec 2008 06:38 PM CST

I don't quite fully get this, but the point of the method that they propose is to look at paralogous genes to more efficiently pinpoint the actual causal variants from among the many "hits" that pop up in GWASs.

Genome-Wide Analysis of Human Disease Alleles Reveals That Their Locations Are Correlated in Paralogous Proteins
Mark Yandell, Barry Moore, Fidel Salas, Chris Mungall, Andrew MacBride, Charles White, Martin G. Reese
PLoS Comput Biol 4(11): e1000218
Abstract: The millions of mutations and polymorphisms that occur in human populations are potential predictors of disease, of our reactions to drugs, of predisposition to microbial infections, and of age-related conditions such as impaired brain and cardiovascular functions. However, predicting the phenotypic consequences and eventual clinical significance of a sequence variant is not an easy task. Computational approaches have found perturbation of conserved amino acids to be a useful criterion for identifying variants likely to have phenotypic consequences. To our knowledge, however, no study to date has explored the potential of variants that occur at homologous positions within paralogous human proteins as a means of identifying polymorphisms with likely phenotypic consequences. In order to investigate the potential of this approach, we have assembled a unique collection of known disease-causing variants from OMIM and the Human Genome Mutation Database (HGMD) and used them to identify and characterize pairs of sequence variants that occur at homologous positions within paralogous human proteins. Our analyses demonstrate that the locations of variants are correlated in paralogous proteins. Moreover, if one member of a variant-pair is disease-causing, its partner is likely to be disease-causing as well. Thus, information about variant-pairs can be used to identify potentially disease-causing variants, extend existing procedures for polymorphism prioritization, and provide a suite of candidates for further diagnostic and therapeutic purposes.

Mendel's Garden [Genetic Future]

Posted: 03 Dec 2008 06:04 PM CST

Chris over at A Free Man has done a great job putting together the latest issue of genetics blog carnival Mendel's Garden - check it out.

Read the comments on this post...

Activating a gene through pioneer transcripts [The Daily Transcript]

Posted: 03 Dec 2008 05:47 PM CST

First up read yesterday's entry on Genomic Organization.

Now that you've done that, let's talk about a paper that appeared in Nature about a month ago. The article is entitled:

Stepwise chromatin remodelling by a cascade of transcription initiation of non-coding RNAs (link)

Superficially you would look at this title and exclaim Wow another function for non-coding RNAs! Well not exactly. It would seem that everyone is going ga-ga over these non-coding RNAs, but if you dig deeper, something else is going on. Note that I'm not saying that the paper is crap, in fact the results are VERY interesting, but you have to keep in mind that this paper is describing is how the act of transcribing non-coding RNA affects genomic organization.

But before we begin, let's dust off our lexicon. Here are some definitions that I did not bring up yesterday. Chromatin can be thought of as the configuration of DNA with its associated proteins, mainly nucleosomes. Chromatin remodelling refers to alterations in the packaging of this DNA so that the tightness and location of nucleosomes have been altered. As I described yesterday, these changes will affect how DNA binding proteins associate with the genome, which in turn modifies what regions are transcribed into RNA.You'll also remember that the theme of that post was that RNA Polymerase II (aka Pol II) and nucleosomes have a strange relationship. In fact Pol II can directly alter the modifications found on histones and can also influence how DNA is bound to its nucleosomes. So there is a constant conversation between chromatin structure and Pol II.

The Nature paper illustrates this principle nicely. It demonstrates how one gene, fbp1, is activated in response to glucose deprivation. Strangely, Pol II plays a big part in initiating gene activation by allowing the chromatin to be remodelled.

You see it would seem that when the gene is "inactive", Pol II transcribes very long RNAs that start well before the fbp1 gene. These "pioneer" transcripts cover a whole section just before and then continue past the gene and end at the normal termination site. These long mRNAs are even polyadenylated at their end. But they are weird. These RNAs are neither spliced nor translated into protein. The transcripts are found at a very low level and seem to be unstable (I'm inferring that the transcripts have a short half-life from some of their gels, but unfortunately the authors don't measure this parameter). When glucose levels are lowered, the long transcripts disappear and instead new shorter RNAs are made by Pol II molecules. These shorter RNAs begin at points closer to the gene's start site but again end at the gene's termination site. The short guys are however much more numerous as compared to the initial pioneer transcripts. Eventually very short transcripts are made. These transcripts start at the "consensus start site" of the fbp1 gene and are not only properly spliced but are translated into protein.

Now here is the cool part, if you genetically modify the yeast genome so that a transcriptional terminator is introduced in front of the fbp1 gene, you not only prematurely truncate these long pioneer transcripts but you prevent the production of all the shorter transcripts. Yes you prevent the stepwise activation of the gene.

So what is happening?

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Ethics of Genetic Testing: Part 1 [Mary Meets Dolly]

Posted: 03 Dec 2008 04:02 PM CST


I have found that many Catholics are confused about genetic testing and the ethical issues that surround it.  So I have decided to write a two part series on the ethics of genetic testing.

Part 1: Genetic testing is not all bad.

DNA11.com
And yet many Catholics are wary of the Human Genome Project (HGP) and genetic testing, and the knowledge they provide.  Of course, there are serious ethical implications, but the HGP has provided a wonderful opportunity to prevent and even cure disease.  As genetic testing becomes more commonplace, we will have more information on diseases that one may be at risk to develop.  If discovered early enough, we can make choices to help prevent or delay the onset of that disease.

A colleague's battle with cancer is a good example of the use of genetic testing to prevent disease.  We now know that mutations in the BCRA1 or BCRA2 gene put a woman at high risk of developing breast or ovarian cancer.  My colleague's mother, aunts, and cousin had breast or ovarian cancer.  She, herself, was an ovarian cancer survivor.  When the test for mutations in the BCRA1 gene became available, she found that she did have the mutation.  Her sister was also tested, had the mutation, but had yet to develop cancer.  Knowing she was at high risk, the sister underwent preventive surgery and now regularly gets screened for tumors.  Hopefully, she will never develop cancer, but, if she does, it will be caught early, increasing her chances for survival.

Doctors often use genetic testing to help treat their patients.  A good example is the test for a mutation in the
Factor V Leiden gene.  Factor V Leiden is the most common hereditary blood coagulation disorder in the United States.  Patients with a mutation in this gene are at greater risk of developing potentially deadly blood clots.  If a doctor knows that a patient has an increased risk of developing a clot, they can prescribe medication or monitor the patient closely after surgery. 

Genetic testing also provides information on Hereditary Hemochromatosis (HHC), the most common form of iron overload disease.  HHC is an inherited disorder that causes the body to absorb and store too much iron.  If the disease is not detected early and treated, iron will accumulate in body tissues and may eventually lead to serious problems.  Mutations in the HFE gene are the thought to be the cause of HHC.  A genetic test can identify patients who are at risk for developing HHC before they begin to have symptoms.   In fact, there are countless such conditions and diseases, linked to genetic factors, that will be positively impacted by genetic testing, including diabetes and Alzheimer's disease.

Genetic testing has also created an exciting new field called pharmacogenetics.  Pharmacogenetics is the study of how
DNAStore.com
people's genetic make-up affects their response to medicines.  Because each person metabolizes drugs differently, it can take a lot of trial and error before a doctor will find the right drug or combination of drugs and dosage(s) for a particular patient.  Scientists continue to find genes that regulate the metabolism of drugs.  Discovering the genetic profile of how a patient may react to a class of drugs will facilitate the doctor's decision on which drug and what dosage is appropriate for that patient.  Recently, a sales representative showed me a microarray DNA chip that tests the genes responsible for the metabolism of psychiatric drugs.  This test will provide psychiatrists with valuable information, so they can better prescribe medications, increasing effectiveness and reducing side effects.

Prenatal diagnosis of the unborn, using genetic testing, is always an ethically sticky subject.  There are several immoral uses of prenatal genetic testing that I address in Unethical Uses of Genetic Testing, but, as Catholics, we cannot automatically assume that prenatal genetic testing is immoral.  An obstetrician opposed to abortion once told me that, in his observation, genetic testing has often prevented a couple from aborting their child.  He said that not knowing is often more scary than knowing, and couples may be more likely to abort if they do not have all of the information available.  In the future, with the perfection of surgery on the unborn in the womb, prenatal genetic testing may actually save unborn lives.  The Vatican Congregation of the Doctrine of the Faith has made a statement on prenatal diagnosis:

"Is prenatal diagnosis morally licit?  If prenatal diagnosis respects the life and the integrity of the embryo and the human fetus and is directed toward safeguarding or healing as an individual, then the answer is affirmative."
All of the benefits of genetic testing are too numerous to list here.  The Catholic Church welcomes genetic testing when its function is to improve sound medical practice.  The possibilities of genetic testing prompted John Paul II to make the following statement:
Indeed, the biomedical sciences are currently experiencing a period of rapid and marvelous growth, especially with regard to new discoveries in the areas of genetics….  But if scientific research is to be directed toward respect for personal dignity and support of human life, its scientific validity according to the rules of each discipline is not enough. It must also qualify positively from the ethical point of view, and this presupposes that from the outset it endeavors to promote the true good of human beings as individuals and as a community. This happens when efforts are made to eliminate the causes of disease by putting real prevention into practice, or whenever more effective therapies are sought for the treatment of serious illnesses.

Stephen Hawking coming to Ontario. [Genomicron]

Posted: 03 Dec 2008 03:57 PM CST

JoVE: Video-publication in Medicine and Psychology [ScienceRoll]

Posted: 03 Dec 2008 01:50 PM CST


JoVE is the Journal of Visualized Experiments, a journal of videos indexed by Pubmed as well. Now, they expanded their video-based model of scientific publishing to include medicine and psychology protocols. We had to wait for this improvement, but now it happened.

The first two videos:

jove-medicine

      

College Tuition is a Scandal [adaptivecomplexity's blog]

Posted: 03 Dec 2008 09:52 AM CST


College tuition has increased 439% since 1984, and the net yearly cost of college at a 4-year public university is 76% of the median family income, according to a story in today's NY Times. Even community colleges don't end up being a much better deal. It's a scandal. We're pricing most people out of college at a time when middle-class income is stagnating and education is more critical than ever for career success.

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Sing this! [ScienceRoll]

Posted: 03 Dec 2008 09:25 AM CST


      

Shedding Light on Neon Signs [Sciencebase Science Blog]

Posted: 03 Dec 2008 07:00 AM CST

neon-signAs regular readers know, I like to keep a fairly close eye on what Sciencebase visitors are searching for so that I can put together new posts that provide answers to the questions readers want answering. Recently, there has been a spate of search queries related to neon signs. Perhaps not the most exciting of subjects, but there is some nice chemistry to be learned from all the different colours available, so I thought I’d shed some light on the subject of noble gas illumination.

Incidentally, for those unaware of the history of noble gases, they were at one time known as inert gases because chemists though their full outer shell of electrons made them unreactive. As more and more reactions for these so-called inert gases were discovered, it became necessary to give them another label, hence noble.

A neon light is not really much more than a fluorescent tube (actually, it’s less as it needs no phosphor coating on the inside), but instead of containing mercury vapour to give a bright “white” light, neon tubes contain the noble gas neon, surprise, surprise. Pass an electric discharge through a tube containing low pressure neon and it will glow with that familiar orange-red glow, so evocative of late-night bars and sleazy movies.

A neon light uses a very high voltage to propel an electric current through a low-density gas of neon atoms held in a glass tube. Charges from the electrode at each end of the tube fly through the gas colliding frequently with neon atoms and transferring some of their energy to the neon atoms. This kicks the neon atoms into a higher energy, excited state, with an electron in a higher orbital than normal. This excited state does not last and as the electron loses energy the atom drops back to a lower energy state and releases a photon of light. The energy of this photon is equivalent to the energy fall and for neon atoms that coincides with an energy that produces a reddish glow.

Many people, unfamiliar with the noble gas group of the periodic table - the p-block, assume that all coloured fluorescent tubes used in signage are neon signs. However, there are two ways to produce other colours - paint a standard mercury tube with the colour you want or far more effectively use a different noble gas in the tube instead of neon, perhaps together with mercury vapour to give a stronger glow. Here’s a break down of the discharge colours for each noble gas.

Helium (He) - Orangey white, usually
Neon (Ne) - Orange-red glow
Argon (Ar) - Violet, pale lavender blue
Krypton (Kr) - Grayish dim off-white
Xenon (Xe) - Blue-grey
Radon (Rn) - radioactive, not used in lighting

Of course, it is not only the noble gases and mercury vapour that can be added to lighting tubes. Nitrogen produces a slightly pinker glow than argon, oxygen glows violet-lavender but dimly. Hydrogen glows lavender at low currents, but pinkish magenta above 10 milliAmps, while carbon dioxide produces a slight bluish-white. Mercury can be made to glow in the ultraviolet, and is used in so-called black lights. Sodium vapour at low pressure glows the bright yellow of street lighting, particularly in England. And, even water vapour produces a glow similar to hydrogen, only dimmer .

Shedding Light on Neon Signs

Increased Secretion in Senescent Cells [The Daily Transcript]

Posted: 03 Dec 2008 06:57 AM CST

I just read a paper that features fellow science blogger Chris Patil as an author (although he would be the first to state that he was second on the author's list). The manuscript, which appeared in yesterday's edition of PLoS Biology, describes senescence-associated secretory phenotype (aka SASP), a phenomenon that is associated with cancer cells treated with chemotherapeutic reagents that cause DNA-damage and with cells undergoing senescence. From the paper:

Despite support for the idea that senescence is a beneficial anticancer mechanism, indirect evidence suggests that senescent cells can also be deleterious and might contribute to age-related pathologies [10,23-25]. The apparent paradox of contributing to both tumor suppression and aging is consistent with an evolutionary theory of aging, termed antagonistic pleiotropy [26]. Organisms generally evolve in environments that are replete with extrinsic hazards, and so old individuals tend to be rare in natural populations. Therefore, there is little selective pressure for tumor suppressor mechanisms to be effective well into old age; rather, these mechanisms need to be sufficiently effective only to ensure successful reproduction. Further, tumor suppressor mechanisms could in principle even be deleterious at advanced ages, as predicted by evolutionary antagonistic pleiotropy. Consistent with this view, senescent cells increase with age in mammalian tissues [27], and have been found at sites of age-related pathologies such as osteoarthritis and atherosclerosis [28-30]. Moreover, in mice, chronically active p53 both promotes cellular senescence and accelerates aging phenotypes [31,32].

How might senescent cells be deleterious? Senescent cells acquire many changes in gene expression, mostly documented as altered mRNA abundance, including increased expression of secreted proteins [33-41]. Some of these secreted proteins act in an autocrine manner to reinforce the senescence growth arrest [37,38,40,41]. Moreover, cell culture and mouse xenograft studies suggest that proteins secreted by senescent cells can promote degenerative or hyperproliferative changes in neighboring cells [35,39,42,43]. Thus, although the cell-autonomous senescence growth arrest suppresses cancer, factors secreted by senescent cells might have deleterious cell-nonautonomous effects that alter the tissue microenvironment.

It turns out that SASP is responsive to oncogenic forms of RAS and loss of p53, two of the most important genetic contributors to cancer.

It will be interesting to tease out whether SASP is solely due to an increase in transcription of a select group of secreted proteins or whether some other aspect of mRNA metabolism is altered (such as a decrease in mRNA turnover). After all, there seems to be a tight connection between stress and mRNA metabolism (see this post). Also it is likely that the secretory potential of the endoplasmic reticulum has to be upregulated and this clearly requires certain branches of the UPR gene regulatory program (unfolded protein response - again another stress response pathway - see this post) to be activated.

Abel Pharmboy has a great post on the article, that I strongly encourage you to go over and check it out.

I should also add that one of the benefits of blogging as a scientist is that it gives you a forum to discuss your published results. In this spirit, I encourage you to head over to Ouroboros and ask Chris about SASP and his latest findings.

Read the comments on this post...

Top 10 Innovations In Life Science [Bitesize Bio]

Posted: 03 Dec 2008 05:30 AM CST

The Scientist magazine has published a list of the top 10 innovations in life science in 2008, as judged by their panel of expert judges.

Among the chosen highlights are:

An in-vivo multispectral imaging system
that provides fluorescence, luminescence, and radioisotopic imaging overlayed onto anatomical X-ray, which can be used to view molecular movement in small animals in nearly real time.

A Fucci (Fluorescent ubiquitination-based cell cycle indicator)-based system that allows real-time, in vivo imaging of the cell cycle.

A service that allows end users to order customised zinc finger proteins to snip genomic DNA at the precise location they desire for knocking-out, or in, genes.

And a low-cost DNA sequencing system that can sequence the entire human genome for just $60K… and they aim to reduce the cost to $10K by the end of 2008.

Check out the whole list at The Scientist Magazine.

Is It Heritable? Twin Study Evidence Suggests Eyeball (aka Intraocular) Pressure is Substantially Affected by Genetics [DNA and You]

Posted: 03 Dec 2008 01:14 AM CST

As I've previously mentioned, twin studies allow an estimation of the heritability of a trait by comparing the degree of concordance in a given phenotype between MZ (identical) twins and DZ (fraternal) twins.

Eye examI recently came across a fascinating study looking at the heritability of intraocular pressure - that is -the pressure on the inside of the eyeball that ophthalmologists and optometrists measure when screening for glaucoma.  Carbonaro and colleagues, from the Twin Research and Genetic Epidemiology Unit at King's College London School of Medicine, performed a classical twin study to estimate intraocular pressure (IOP) heritability1.  Although there was some modest variability in the heritability estimates depending on which of 3 instruments was utilized to measure IOP, the results suggested that genetic factors explain about 62 percent of the variation in IOP, with individual environmental factors and/or stochastic factors accounting for the remainder.

62 percent is impressively high, but of course does not tell us anything about the genetic architecture of the trait.  Although some progress has been made in understanding the genetics of congenital glaucoma, we have much further to go with adult glaucoma/IOP elevation.  Despite the existence of a few clues2-4, much work remains to be done. 

Photo: By ninjapoodles via Creative Commons.


Cited References

1. Carbonaro F, Andrew T, Mackey DA, Spector TD, Hammond CJ.  Heritability of intraocular pressure: a classical twin study.  Br J Ophthalmol 92:1125-8, 2008.

2. Duggal P et al.  Identification of novel genetic loci for intraocular pressure: a genomewide scan of the Beaver Dam Eye Study.  Arch Ophthalmol 125:74-9, 2007.

3. Wiggs JL et al.  Genome-wide scan for adult onset primary open angle glaucoma.  Hum Mol Genet 9:1109-17, 2000.

4. Nemesure B et al.  A genome-wide scan for primary open-angle glaucoma (POAG): the Barbados Family Study of Open-Angle Glaucoma.  Hum Genet 112:600-9, 2003.

A few questions for Governor Palin [Omics! Omics!]

Posted: 02 Dec 2008 11:03 PM CST

It's hard to believe that it's been a full month since the historic election. Well, depends on how you count a month, but today is the first Tuesday after the first Monday in December.

I was more of a political junkie in my youth, but I haven't sworn off the habit. Only in the last few days was I attempting to handicap the electoral college. TNG was a huge Obama fan, asking every adult in sight whether they would be voting for him. On the flip side, the other ticket had Miss Amanda quite charged up -- the idea of a Canino-American being one heartbeat from the presidency was too much to resist (though she has declared she will nip any groomer who attempts to apply lipstick to her!). Her disappointment that night was quickly salved by Obama's first major policy declaration in his celebratory speech. Alas, her closest kin have not been mentioned as in the running for the White House staff position.

Speaking of Governor Palin, it seems she will not be fading from the limelight. No, indeed it looks like her personal Iditarod will be going for the nomination in 2012. Alaska's chief executive made a number of comments during the campaign which induced consternation in the scientific community. Granted, the fruit fly remark was specifically about research on a totally different bug than Drosophila in a completely agriculturally-targeted setting, but it didn't endear her to the fans of Morgan & Bridges. Given she has four years to prepare, it wouldn't hurt to start now. And, in the spirit of reuse, should she not run it would seem the majority of these queries would apply to the majority of other Republicans who went for the high office this year.

1) You have publically taken stands that some views held by a minority (or less) of the scientific community should be accepted and used as the basis for policy decisions (e.g. the existance and/or cause of global warming trends) and/or taught in public schools as viable alternatives to the majority view (e.g. creationism). How do you choose which 'maverick' scientific theories have merit and which do not?

2) Which of the following maverick theories, relevant to major issues in this country today, should be taught in public schools or used to guide policy:

2.1) Healthcare (research priorities, Medicare/Medicaid reimbursement policy)

2.1.1) Childhood vaccines cause autism

2.1.2) AIDS can be treated more effectively with vitamin combinations than antiretrovirals

2.1.3) AIDS is caused by lifestyle factors and not the virus HIV

2.1.4) High cholesterol levels do not cause heart disease; cholesterol lowering using drugs risks cancer & depression

2.2) Physical sciences

2.2.1) Petroleum is not a limited supply of fossil remains of ancient lifeforms but rather is constantly created by processes deep in the earth (clearly an area where Ms. Palin has declared as in her sphere of expertise)

2.2.2) Manned space travel through the van Allen belts is guaranteed to be lethal; funding an attempt to land on the moon should be cancelled.

2.2.3) Einstein's Theory of Relativity is clearly wrong, as the concept of time dilation is so opposed to normal experience as to be laughable.



3) Should the U.S. government ever fund research outside its borders? Under what conditions should such operations be funded, if ever?


4) To what degree should non-expert politicians alter the research funding priorities set by experts in the field?

5) What, if any, useful science has come from studying fruit flies? Should the U.S. fund any further research? What other organisms do you also feel are not worth researching?


This is just a draft; readers are invited to submit further questions via the comments

Mendel’s Garden #26: A Few of My Favorite Things [A Free Man » Science]

Posted: 02 Dec 2008 10:28 PM CST

I’m quite pleased to host this month’s Mendel’s Garden - a blog carnival featuring the best genetics writing on the internets for the last month. Since it’s my party, I’ve picked out a few of my favorite topics to feature. But in the way of introduction for the neophytes in the crowd, let’s define our terms. The first question I ask my students on their first exam is “What is a gene and how is it regulated?”. I’m looking for them to talk about Mendel’s description of units of inheritance and the modern DNA based definition. Well, RPM of Evolgen thinks that it’s time to expand our definition or throw the word out entirely. He makes a solid argument, based on the fact that a lot of things that are transcribed in the genome wouldn’t be considered ‘genes’ by most of us. But if we trash the word, what would geneticists call themselves?

For a perfect example of the beautiful complexity of genetics illustrated, check out this father-son photo from Not Afraid To Use It. About says it all. Without further ado, a few of my favorite things genetical:

I found a couple of great posts about the genetics of autism. Now, to clarify, I’m not a big fan of autism per se, but I got embroiled (in a minor way) in the controversy with this post on the autism-MMR vaccine sham. Since then, I’ve followed the new research on autism with some interest. A post over at Highlight Health describes two genome-wide genetic analyses that identified five genetic loci that contribute to autism susceptibility, lending more support to the argument that autism is largely a heritable disorder. Kristina Chew, of AutismVox, thinks that geneticists sometimes go a bit far, however. Her response to a “sweeping” new theory that an evolutionary tug-of-war between parental genetic contributions is astutely skeptical. And of course, As is the case with any genetic disorder, there is an environmental component to consider. Reviewing an odd study out of Cornell, the Great Beyond details an assertion that autism rates are higher in rainy parts of the world. Take of it what you will, folks.

I’ve become increasingly fascinated with human evolution and in the genomic era research into our roots is just burgeoning. This month, Daniel McArthur at Genetic Future writes about one of the new tools available to evolutionary geneticists and gives an example of its use to look at positive selection at certain human genetic loci. One of the more interesting stories from this field is of the pair of skeletons found in a mass grave in Germany locked in an intimate embrace. The Great Beyond describes the DNA analysis that revealed that the 4600 year old remains were of a parent and child  and appear, with fractured skulls and an arrowhead in the spine, to have been unfortunate victims of humanity’s penchant for genocide. Of course, none of this may matter according to UCL’s Steve Jones (as reported on Dick Dawkins dot net) who says that human evolution is done due to a dearth of older fathers. Jones argues that genetic variation comes, in part, from mutations that men accumulateas they get older. Don’t worry, Steve, I think there are plenty of toxins about to keep us mutating.

Speaking of junk science,  there was some new junk on junk DNA released as a press release from the Genome Institute of Singapore. As Bayblab points out, this is a new and disturbing way of publishing your results - skip all the hassle of peer review and editing and just throw it out there to the mainstream press. Shame really, because this is my third topic of choice - epigenetics. Yann Klimentidis, on his blog, recounts some recent research looking at epigenetic changes in utero brought on by environmental stress. Zamp Bionews has more about epigenetic control of offspring fertility, which in this case is regulated by small RNAs apparently passed on maternally. Alex at The Daily Transcript has RNA, if not epigenetic, regulation in his post describing how each RNA binding protein in yeast tends to associate with mRNAs of a particular type. He hypothesizes that the expression of entire classes of genes may be subject to coordinated regulation at the level of mRNA metabolism.

And finally this month, a technical brief for those of you doing the hard work of science rather than just writing about it.  Sandra, who blogs at Discovering Biology in a Digital World, tells us about a new BLAST feature that allows users to create a custom database. Sandra goes through a step-by-step tut and generates a viral phylogeny. For those Ph.D. students out there in the “Nothing Works Doldrums”, Nick at Bite Size Bio has some reassuring words for you - sometimes things just don’t work. That’s biology.

Next month’s Mendel’s Garden will be hosted by Another Blasted Weblog. If you’re interested in submitting, you can do so here.

This posting includes an audio/video/photo media file: Download Now

How Transcription Affects Genomic Organization and Vice Versa [The Daily Transcript]

Posted: 02 Dec 2008 06:15 PM CST

Recently there has been a flood of press about epigenetics and non-coding RNA. What is lacking from these articles is a description of how DNA is packaged and what DNA elements such as promoters and enhancers do. Today I would like to touch upon all of these subjects with a post on how DNA is organized and how this affects the turning on or off of genes.

OK here we go ...

One of the biggest findings over the past couple of years is how the act of transcription feeds back onto the organization of DNA.

What do I mean by that?

Read the rest of this post... | Read the comments on this post...

UC Davis giving further props to blogs (mine that is) [The Tree of Life]

Vancouver, BC jobs

          KIST/PU Nanostructured Heparin Derivatives as an Angiogenesis Inhibitor        
Although low molecular weight heparin (LMWH) has been known to regulate angiogenesis, tumor growth and metastasis, the administration of heparin for treating cancer is limited in clinical application due to its unsatisfactory therapeutic effects and a strong anticoagulant activity, which induces hemorrhages. LMWH-Taurocholate conjugate (HT10), which has low anticoagulant activity as well as a number of sulfations was prepared. Circular dichroism method was used to evaluate a structural property of heparin derivatives. Lactate dehydrogenase (LDH) test was carried out in order to evaluate cytotoxic effects of HT10 on human umbilical vein endothelial cells (HUVECs) and squamous cell carcinoma cells (SCC7). Vascular endothelial growth factor 165 (VEGF165) dependent Matrigel plug assay and bFGF dependent HUVECs tubular formation test were performed to verify the antiangiogenic potential of HT10 as an VEGF165 and bFGF inhibitor. Finally tumor growth inhibition effects of HT10 were investigated in SCC7 and MDA-MB231 xenograft mouse models.Apart from other heparin derivatives, HT10 which has 12.7% of anticoagulant activity showed peculiar polyproline–helical structure. The results of HUVECs tubular formation and Matrigel plug assay bolstered the action of HT10 as an antiangiogenic agent inhibiting VEGF165 as well as bFGF functions. In tumor growth inhibition experiments, HT10 showed a significant tumor growth inhibition potential on SCC7; moreover it delayed a development of MDA-MB231 effectively. Polyproline-helical structured HT10 showed significant antiangiogenic potential and tumor growth inhibitory effect.
          Research Assistant - BRI Biopharmaceutical Research Inc. - Vancouver, BC        
Being one of the few privately owned CRO with capabilities in bioanalytical, in-vivo and in-vitro DMPK and xenograft animal models in Western Canada, BRI's
From Indeed - Fri, 07 Jul 2017 20:19:04 GMT - View all Vancouver, BC jobs
          Cannabis and Cannabinoids, Cancer Antitumor Effects, Prion prevention, Pain management, Muscle relaxer, and Palliative Medicine        
National Cancer Institute at the National Institutes of Health

Cannabis and Cannabinoids (PDQ®), Cancer Antitumor Effects, Prion prevention, Pain management, muscle relaxer, and Palliative Medicine

Cannabis and Cannabinoids (PDQ®)

Laboratory/Animal/Preclinical Studies

Antitumor Effects Appetite Stimulation Analgesia

Cannabinoids are a group of 21-carbon–containing terpenophenolic compounds produced uniquely by Cannabis sativa and Cannabis indica species.[1,2] These plant-derived compounds may be referred to as phytocannabinoids. Although delta-9-tetrahydrocannabinol (THC) is the primary psychoactive ingredient, other known compounds with biologic activity are cannabinol, cannabidiol (CBD), cannabichromene, cannabigerol, tetrahydrocannabivarin, and delta-8-THC. CBD, in particular, is thought to have significant analgesic and anti-inflammatory activity without the psychoactive effect (high) of delta-9-THC.

Antitumor Effects

One study in mice and rats suggested that cannabinoids may have a protective effect against the development of certain types of tumors.[3] During this 2-year study, groups of mice and rats were given various doses of THC by gavage. A dose-related decrease in the incidence of hepatic adenoma tumors and hepatocellular carcinoma was observed in the mice. Decreased incidences of benign tumors (polyps and adenomas) in other organs (mammary gland, uterus, pituitary, testis, and pancreas) were also noted in the rats. In another study, delta-9-THC, delta-8-THC, and cannabinol were found to inhibit the growth of Lewis lung adenocarcinoma cells in vitro and in vivo .[4] In addition, other tumors have been shown to be sensitive to cannabinoid-induced growth inhibition.[5-8]

Cannabinoids may cause antitumor effects by various mechanisms, including induction of cell death, inhibition of cell growth, and inhibition of tumor angiogenesis and metastasis.[9-11] Cannabinoids appear to kill tumor cells but do not affect their nontransformed counterparts and may even protect them from cell death. These compounds have been shown to induce apoptosis in glioma cells in culture and induce regression of glioma tumors in mice and rats. Cannabinoids protect normal glial cells of astroglial and oligodendroglial lineages from apoptosis mediated by the CB1 receptor.[12]

The effects of delta-9-THC and a synthetic agonist of the CB2 receptor were investigated in hepatocellular carcinoma (HCC).[13] Both agents reduced the viability of hepatocellular carcinoma cells in vitro and demonstrated antitumor effects in hepatocellular carcinoma subcutaneous xenografts in nude mice. The investigations documented that the anti-HCC effects are mediated by way of the CB2 receptor. Similar to findings in glioma cells, the cannabinoids were shown to trigger cell death through stimulation of an endoplasmic reticulum stress pathway that activates autophagy and promotes apoptosis. Other investigations have confirmed that CB1 and CB2 receptors may be potential targets in non-small cell lung carcinoma[14] and breast cancer.[15]

In an in vivo model using severe combined immunodeficient mice, subcutaneous tumors were generated by inoculating the animals with cells from human non-small cell lung carcinoma cell lines.[16] Tumor growth was inhibited by 60% in THC-treated mice compared with vehicle-treated control mice. Tumor specimens revealed that THC had antiangiogenic and antiproliferative effects. However, research with immunocompetent murine tumor models has demonstrated immunosuppression and enhanced tumor growth in mice treated with THC.[17,18]

In addition, both plant-derived and endogenous cannabinoids have been studied for anti-inflammatory effects. A mouse study demonstrated that endogenous cannabinoid system signaling is likely to provide intrinsic protection against colonic inflammation.[19] As a result, a hypothesis that phytocannabinoids and endocannabinoids may be useful in the risk reduction and treatment of colorectal cancer has been developed.[20-23]

Appetite Stimulation
Many animal studies have previously demonstrated that delta-9-THC and other cannabinoids have a stimulatory effect on appetite and increase food intake. It is believed that the endogenous cannabinoid system may serve as a regulator of feeding behavior. The endogenous cannabinoid anandamide potently enhances appetite in mice.[24] Moreover, CB1 receptors in the hypothalamus may be involved in the motivational or reward aspects of eating.[25]

Analgesia
Understanding the mechanism of cannabinoid-induced analgesia has been increased through the study of cannabinoid receptors, endocannabinoids, and synthetic agonists and antagonists. The CB1 receptor is found in both the central nervous system (CNS) and in peripheral nerve terminals. Similar to opioid receptors, increased levels of the CB1 receptor are found in regions of the brain that regulate nociceptive processing.[26] CB2 receptors, located predominantly in peripheral tissue, exist at very low levels in the CNS. With the development of receptor-specific antagonists, additional information about the roles of the receptors and endogenous cannabinoids in the modulation of pain has been obtained.[27,28]

Cannabinoids may also contribute to pain modulation through an anti-inflammatory mechanism; a CB2 effect with cannabinoids acting on mast cell receptors to attenuate the release of inflammatory agents, such as histamine and serotonin, and on keratinocytes to enhance the release of analgesic opioids has been described.[29-31]

References

1.Adams IB, Martin BR: Cannabis: pharmacology and toxicology in animals and humans. Addiction 91 (11): 1585-614, 1996. [PUBMED Abstract]

2.Grotenhermen F, Russo E, eds.: Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential. Binghamton, NY: The Haworth Press, 2002.

3. National Toxicology Program .: NTP toxicology and carcinogenesis studies of 1-trans-delta(9)-tetrahydrocannabinol (CAS No. 1972-08-3) in F344 rats and B6C3F1 mice (gavage studies). Natl Toxicol Program Tech Rep Ser 446 (): 1-317, 1996. [PUBMED Abstract]

4.Bifulco M, Laezza C, Pisanti S, et al.: Cannabinoids and cancer: pros and cons of an antitumour strategy. Br J Pharmacol 148 (2): 123-35, 2006. [PUBMED Abstract]

5.Sánchez C, de Ceballos ML, Gomez del Pulgar T, et al.: Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res 61 (15): 5784-9, 2001. [PUBMED Abstract]

6.McKallip RJ, Lombard C, Fisher M, et al.: Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. Blood 100 (2): 627-34, 2002. [PUBMED Abstract]

7.Casanova ML, Blázquez C, Martínez-Palacio J, et al.: Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J Clin Invest 111 (1): 43-50, 2003. [PUBMED Abstract]

8.Blázquez C, González-Feria L, Alvarez L, et al.: Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas. Cancer Res 64 (16): 5617-23, 2004. [PUBMED Abstract]

9.Guzmán M: Cannabinoids: potential anticancer agents. Nat Rev Cancer 3 (10): 745-55, 2003. [PUBMED Abstract]

10.Blázquez C, Casanova ML, Planas A, et al.: Inhibition of tumor angiogenesis by cannabinoids. FASEB J 17 (3): 529-31, 2003. [PUBMED Abstract]

11.Vaccani A, Massi P, Colombo A, et al.: Cannabidiol inhibits human glioma cell migration through a cannabinoid receptor-independent mechanism. Br J Pharmacol 144 (8): 1032-6, 2005. [PUBMED Abstract]

12.Torres S, Lorente M, Rodríguez-Fornés F, et al.: A combined preclinical therapy of cannabinoids and temozolomide against glioma. Mol Cancer Ther 10 (1): 90-103, 2011. [PUBMED Abstract]

13.Vara D, Salazar M, Olea-Herrero N, et al.: Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy. Cell Death Differ 18 (7): 1099-111, 2011. [PUBMED Abstract]

14.Preet A, Qamri Z, Nasser MW, et al.: Cannabinoid receptors, CB1 and CB2, as novel targets for inhibition of non-small cell lung cancer growth and metastasis. Cancer Prev Res (Phila) 4 (1): 65-75, 2011. [PUBMED Abstract]

15.Nasser MW, Qamri Z, Deol YS, et al.: Crosstalk between chemokine receptor CXCR4 and cannabinoid receptor CB2 in modulating breast cancer growth and invasion. PLoS One 6 (9): e23901, 2011. [PUBMED Abstract]

16.Preet A, Ganju RK, Groopman JE: Delta9-Tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo. Oncogene 27 (3): 339-46, 2008. [PUBMED Abstract]

17.Zhu LX, Sharma S, Stolina M, et al.: Delta-9-tetrahydrocannabinol inhibits antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway. J Immunol 165 (1): 373-80, 2000. [PUBMED Abstract]

18.McKallip RJ, Nagarkatti M, Nagarkatti PS: Delta-9-tetrahydrocannabinol enhances breast cancer growth and metastasis by suppression of the antitumor immune response. J Immunol 174 (6): 3281-9, 2005. [PUBMED Abstract]

19.Massa F, Marsicano G, Hermann H, et al.: The endogenous cannabinoid system protects against colonic inflammation. J Clin Invest 113 (8): 1202-9, 2004. [PUBMED Abstract]

20.Patsos HA, Hicks DJ, Greenhough A, et al.: Cannabinoids and cancer: potential for colorectal cancer therapy. Biochem Soc Trans 33 (Pt 4): 712-4, 2005. [PUBMED Abstract]

21.Liu WM, Fowler DW, Dalgleish AG: Cannabis-derived substances in cancer therapy--an emerging anti-inflammatory role for the cannabinoids. Curr Clin Pharmacol 5 (4): 281-7, 2010. [PUBMED Abstract]

22.Malfitano AM, Ciaglia E, Gangemi G, et al.: Update on the endocannabinoid system as an anticancer target. Expert Opin Ther Targets 15 (3): 297-308, 2011. [PUBMED Abstract]

23.Sarfaraz S, Adhami VM, Syed DN, et al.: Cannabinoids for cancer treatment: progress and promise. Cancer Res 68 (2): 339-42, 2008. [PUBMED Abstract]

24.Mechoulam R, Berry EM, Avraham Y, et al.: Endocannabinoids, feeding and suckling--from our perspective. Int J Obes (Lond) 30 (Suppl 1): S24-8, 2006. [PUBMED Abstract]

25.Fride E, Bregman T, Kirkham TC: Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood. Exp Biol Med (Maywood) 230 (4): 225-34, 2005. [PUBMED Abstract]

26.Walker JM, Hohmann AG, Martin WJ, et al.: The neurobiology of cannabinoid analgesia. Life Sci 65 (6-7): 665-73, 1999. [PUBMED Abstract]

27.Meng ID, Manning BH, Martin WJ, et al.: An analgesia circuit activated by cannabinoids. Nature 395 (6700): 381-3, 1998. [PUBMED Abstract]

28.Walker JM, Huang SM, Strangman NM, et al.: Pain modulation by release of the endogenous cannabinoid anandamide. Proc Natl Acad Sci U S A 96 (21): 12198-203, 1999. [PUBMED Abstract]
29.Facci L, Dal Toso R, Romanello S, et al.: Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc Natl Acad Sci U S A 92 (8): 3376-80, 1995. [PUBMED Abstract]

30.Ibrahim MM, Porreca F, Lai J, et al.: CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci U S A 102 (8): 3093-8, 2005. [PUBMED Abstract]

31.Richardson JD, Kilo S, Hargreaves KM: Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain 75 (1): 111-9, 1998. [PUBMED Abstract]

Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1
Robert Ramer*, Katharina Bublitz*, Nadine Freimuth*, Jutta Merkord*, Helga Rohde*, Maria Haustein*, Philipp Borchert*, Ellen Schmuhl*, Michael Linnebacher† and Burkhard Hinz*,1

+ Author Affiliations

*Institute of Toxicology and Pharmacology and

†Section of Molecular Oncology and Immunotherapy, Department of General Surgery, University of Rostock, Rostock, Germany

↵1Correspondence: Institute of Toxicology and Pharmacology, University of Rostock, Schillingallee 70, D-18057 Rostock, Germany. E-mail: burkhard.hinz@med.uni-rostock.de

Abstract

Cannabinoids inhibit cancer cell invasion via increasing tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). This study investigates the role of intercellular adhesion molecule-1 (ICAM-1) within this action. In the lung cancer cell lines A549, H358, and H460, cannabidiol (CBD; 0.001–3 μM) elicited concentration-dependent ICAM-1 up-regulation compared to vehicle via cannabinoid receptors, transient receptor potential vanilloid 1, and p42/44 mitogen-activated protein kinase. Up-regulation of ICAM-1 mRNA by CBD in A549 was 4-fold at 3 μM, with significant effects already evident at 0.01 μM. ICAM-1 induction became significant after 2 h, whereas significant TIMP-1 mRNA increases were observed only after 48 h. Inhibition of ICAM-1 by antibody or siRNA approaches reversed the anti-invasive and TIMP-1-upregulating action of CBD and the likewise ICAM-1-inducing cannabinoids Δ9-tetrahydrocannabinol and R(+)-methanandamide when compared to isotype or nonsilencing siRNA controls. ICAM-1-dependent anti-invasive cannabinoid effects were confirmed in primary tumor cells from a lung cancer patient. In athymic nude mice, CBD elicited a 2.6- and 3.0-fold increase of ICAM-1 and TIMP-1 protein in A549 xenografts, as compared to vehicle-treated animals, and an antimetastatic effect that was fully reversed by a neutralizing antibody against ICAM-1 [% metastatic lung nodules vs. isotype control (100%): 47.7% for CBD + isotype antibody and 106.6% for CBD + ICAM-1 antibody]. Overall, our data indicate that cannabinoids induce ICAM-1, thereby conferring TIMP-1 induction and subsequent decreased cancer cell invasiveness.

—Ramer, R., Bublitz, K., Freimuth, N., Merkord, J., Rohde, H., Haustein, M., Borchert, P., Schmuhl, E., Linnebacher, M., Hinz, B. Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1. cannabinoids tissue inhibitor of metalloproteinases-1 experimental metastasis ICAM-1 Received October 17, 2011. Accepted December 5, 2011.

Cannabis in Palliative Medicine: Improving Care and Reducing Opioid-Rel­ated Morbidity

Published online before print March 28, 2011, J HOSP PALLIAT CARE August 2011 vol. 28 no. 5 297-303

Cannabis in Palliative Medicine: Improving Care and Reducing Opioid-Related Morbidity


Gregory T. Carter, MD, MS Hospice Services, Providence Medical Group, Olympia, WA, USA, gtcarter@uw.edu Aaron M. Flanagan, MD Providence Medical Group, Olympia, WA, USA Mitchell Earleywine, PhD Department of Psychology, University at Albany State University of New York, Albany, NY, USA Donald I. Abrams, MD University of California, San Francisco, CA, USA Sunil K. Aggarwal, MD, PhD Physical Medicine and Rehabilitation, The Rusk Institute of Rehabilitation Medicine, New York University, USA Lester Grinspoon, MD Department of Psychiatry, Harvard Medical School, USA, Massachusetts Mental Health Center, Boston, MA, USA



Abstract


Unlike hospice, long-term drug safety is an important issue in palliative medicine. Opioids may produce significant morbidity. Cannabis is a safer alternative with broad applicability for palliative care. Yet the Drug Enforcement Agency (DEA) classifies cannabis as Schedule I (dangerous, without medical uses). Dronabinol, a Schedule III prescription drug, is 100% tetrahydrocannabinol (THC), the most psychoactive ingredient in cannabis. Cannabis contains 20% THC or less but has other therapeutic cannabinoids, all working together to produce therapeutic effects. As palliative medicine grows, so does the need to reclassify cannabis. This article provides an evidence-based overview and comparison of cannabis and opioids. Using this foundation, an argument is made for reclassifying cannabis in the context of improving palliative care and reducing opioid-related morbidity.
cannabis medical marijuana opioids hospice chronic pain palliative medicine


Published online ahead of print August 30, 2010 CMAJ 10.1503/cm­aj.091414

Smoked cannabis for chronic neuropathi­c pain: a randomized controlled trial

Abstract

Background: Chronic neuropathic pain affects 1%–2% of the adult population and is often refractory to standard pharmacologic treatment. Patients with chronic pain have reported using smoked cannabis to relieve pain, improve sleep and improve mood.

Methods: Adults with post-traumatic or postsurgical neuropathic pain were randomly assigned to receive cannabis at four potencies (0%, 2.5%, 6% and 9.4% tetrahydrocannabinol) over four 14-day periods in a crossover trial. Participants inhaled a single 25-mg dose through a pipe three times daily for the first five days in each cycle, followed by a nine-day washout period. Daily average pain intensity was measured using an 11-point numeric rating scale. We recorded effects on mood, sleep and quality of life, as well as adverse events.

Results: We recruited 23 participants (mean age 45.4 [standard deviation 12.3] years, 12 women [52%]), of whom 21 completed the trial. The average daily pain intensity, measured on the 11-point numeric rating scale, was lower on the prespecified primary contrast of 9.4% v. 0% tetrahydrocannabinol (5.4 v. 6.1, respectively; difference = 0.7, 95% confidence interval [CI] 0.02–1.4). Preparations with intermediate potency yielded intermediate but nonsignificant degrees of relief. Participants receiving 9.4% tetrahydrocannabinol reported improved ability to fall asleep (easier, p = 0.001; faster, p < 0.001; more drowsy, p = 0.003) and improved quality of sleep (less wakefulness, p = 0.01) relative to 0% tetrahydrocannabinol. We found no differences in mood or quality of life. The most common drug-related adverse events during the period when participants received 9.4% tetrahydrocannabinol were headache, dry eyes, burning sensation in areas of neuropathic pain, dizziness, numbness and cough.

Conclusion­:: A single inhalation of 25 mg of 9.4% tetrahydro­cannabinol herbal cannabis three times daily for five days reduced the intensity of pain, improved sleep and was well tolerated. Further long-term safety and efficacy studies are indicated. (Internati­onal Standard Randomised Controlled Trial Register no. ISRCTN6831­4063)

Conclusion
Our results support the claim that smoked cannabis reduces pain, improves mood and helps sleep. We believe that our trial provides a methodological approach that may be considered for further research. Clinical studies using inhaled delivery systems, such as vaporizers,32,33 are needed.

Cases J. 2009; 2: 7487.
Published online 2009 May 18

Standardiz­ed natural product cannabis in pain management and observatio­ns at a Canadian compassion society: a case report

Cases J. 2009; 2: 7487. Published online 2009 May 18. doi: 10.1186/1757-1626-2-7487 PMCID: PMC2740265

Copyright © 2009 Hornby et al.; licensee Cases Network Ltd.

Standardized natural product cannabis in pain management and observations at a Canadian compassion society: a case report

A Paul Hornby,1 Manju Sharma,2 and Bree Stegman3 1Department of Medial Cannabis Research, The Green Cross Society of BC, 2127 Kingsway, Vancouver, B.C., V5N 2T4, Canada 2Department of Pathology and Laboratory Medicine, Heather Pavilion, Vancouver General Hospital, Vancouver, B.C., Canada 3Canadian Registered Nurses Association of B.C., Vancouver Coastal Health Authority, 2755 Arbutus Street, Vancouver, B.C., Canada Corresponding author. A Paul Hornby: paul@hedron.ca ; Manju Sharma: manjusharma49@gmail.com ; Bree Stegman: breestegman@hotmail.com

Received November 5, 2008; Accepted February 13, 2009.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

This article has been cited by other articles in PMC.

Abstract

An adult Caucasian male with excruciating pains following multiple traumas was monitored, daily, over one year while managing chronic pain by self-administering quantifiable amounts of natural cannabis. Tetrahydrocannabinol, Cannabidiol, and Cannabinol were all measured in tinctures, capsules, smoke-able product plus some baked goods, prior to their administration. By allowing standardization, the subject was able to develop a daily regimen of pain management that was resistant to a battery of most patent analgesics.

snip...

Conclusions

The case reported here represents one of many observed at the Green Cross Society. With 70% of the members treating chronic pain the same phenomenon is observed over and over that people achieve a significant degree of pain management using standardized natural product cannabis. Often a better quality of life is attained with cannabis use only, or in conjunction with reduced opiate consumption. The subject in this study is nearly one year using only natural product cannabis plus supplements for his severe pain. He recently went through yet another two surgeries to back and hand using only cannabis for post-operative pain.

The roughly 4000 members of the Green Cross Society find similar benefit from standardized natural product cannabis medicine. To follow, will be publication of the Society's demographic data regarding use for various conditions such as arthritis, fybromyalgia, HIV/AIDS, and chronic pain, to name a few. A breakdown of the illnesses, what strains (cannabinoid profiles) is most effective, and at what dosages will be published at a later time.



RESEARCH PAPER
Effect of D9-tetrahydrocannabinol, a cannabinoid receptor agonist, on the triggering of transient lower oesophageal sphincter relaxations in dogs and humans
H Beaumont1, J Jensen2, A Carlsson2, M Ruth3, A Lehmann2 and GE Boeckxstaens1,4 1Academic Medical Centre, Department of Gastroenterology and Hepatology, Amsterdam, the Netherlands, 2AstraZeneca R&D, Integrative Pharmacology, Mölndal, Sweden 3Discovery Medicine, Mölndal, Sweden, and 4University Hospital Leuven, Catholic University of Leuven, Department of Gastroenterology, Leuven, Belgium

Background and purpose: Transient lower oesophageal sphincter relaxations (TLESRs) are the main mechanism underlying gastro-oesophageal reflux and are a potential pharmacological treatment target. We evaluated the effect of the CB1/CB2 receptor agonist D9-tetrahydrocannabinol (D9-THC) on TLESRs in dogs. Based on these findings, the effect of D9-THC was studied in healthy volunteers.

Experimental approach: In dogs, manometry was used to evaluate the effect of D9-THC in the presence and absence of the CB1 receptor antagonist SR141716A on TLESRs induced by gastric distension. Secondly, the effect of 10 and 20 mg D9-THC was studied in 18 healthy volunteers in a placebo-controlled study. Manometry was performed before and for 3 h after meal ingestion on three occasions.
Key results: In dogs, D9-THC dose-dependently inhibited TLESRs and reduced acid reflux rate. SR141716A significantly reversed the effects of D9-THC on TLESRs. Similarly, in healthy volunteers, D9-THC significantly reduced the number of TLESRs and caused a non-significant reduction of acid reflux episodes in the first postprandial hour. In addition, lower oesophageal sphincter pressure and swallowing were significantly reduced by D9-THC. After intake of 20 mg, half of the subjects experienced nausea and vomiting leading to premature termination of the study. Other side-effects were hypotension, tachycardia and central effects. Conclusions and implications: D9-THC significantly inhibited the increase in meal-induced TLESRs and reduced spontaneous swallowing in both dogs and humans. In humans, D9-THC significantly reduced basal lower oesophageal sphincter pressure. These findings confirm previous observations in dogs and indicate that cannabinoid receptors are also involved in the triggering of TLESRs in humans.

snip...
In conclusion, the present study demonstrates that D9-THC significantly inhibits the increase in TLESRs evoked by meal ingestion and reduces spontaneous swallowing in both dogs and humans. Furthermore, D9-THC reduces basal LES pressure in humans. These findings confirm previous findings in dogs and indicate that CB receptors are also involved in the triggering of TLESRs in humans.

British Journal of Pharmacology (2009) 156, 153–162; doi:10.1111/j.1476-5381.2008.00010.x; published online 5 December 2008

Keywords: gastro-oesophageal reflux disease; cannabinoid; transient lower oesophageal sphincter relaxation; D9-tetrahydrocannabinol

Abbreviations: GERD, gastro-oesophageal reflux disease; LES, lower oesophageal sphincter; TLESRs, transient lower oesophageal sphincter relaxations; CB, cannabinoid; D9-THC, D9-tetrahydrocannabinol; DMN, dorsal motor nucleus of the vagus; NTS, nucleus tractus solitarius; PPIs, proton pump inhibitors


J Neurosci. 2007 Sep 5;27(36):9­537-44.

Nonpsychoa­ctive cannabidio­l prevents prion accumulati­on and protects neurons against prion toxicity.
Dirikoc S, Priola SA, Marella M, Zsürger N, Chabry J.

Institut de Pharmacolo­gie Moléculair­e et Cellulaire­, Unité Mixte de Recherche 6097, Centre National de la Recherche Scientifiq­ue, 06560 Valbonne, France.

Abstract

Prion diseases are transmissible neurodegenerative disorders characterized by the accumulation in the CNS of the protease-resistant prion protein (PrPres), a structurally misfolded isoform of its physiological counterpart PrPsen. Both neuropathogenesis and prion infectivity are related to PrPres formation. Here, we report that the nonpsychoactive cannabis constituent cannabidiol (CBD) inhibited PrPres accumulation in both mouse and sheep scrapie-infected cells, whereas other structurally related cannabinoid analogs were either weak inhibitors or noninhibitory. Moreover, after intraperitoneal infection with murine scrapie, peripheral injection of CBD limited cerebral accumulation of PrPres and significantly increased the survival time of infected mice. Mechanistically, CBD did not appear to inhibit PrPres accumulation via direct interactions with PrP, destabilization of PrPres aggregates, or alteration of the expression level or subcellular localization of PrPsen. However, CBD did inhibit the neurotoxic effects of PrPres and affected PrPres-induced microglial cell migration in a concentration-dependent manner. Our results suggest that CBD may protect neurons against the multiple molecular and cellular factors involved in the different steps of the neurodegenerative process, which takes place during prion infection. When combined with its ability to target the brain and its lack of toxic side effects, CBD may represent a promising new anti-prion drug.


Drugs: 9 July 2010 - Volume 70 - Issue 10 - pp 1245-1254 doi: 10.2165/11537930-000000000-00000 Review Articles Pharmacological Management of Pain in Patients with Multiple Sclerosis
Solaro, Claudio1; Messmer Uccelli, Michele2
Abstract
Multiple sclerosis (MS) is an inflammatory, demyelinating, autoimmune disease of the CNS. There are currently a number of disease-modifying medications for MS that modulate or suppress the immune system; however, these medications do not directly relieve MS symptoms, which include visual deficits, gait problems, sensory deficits, weakness, tremor, spasticity and pain, among others.
Pain is a common symptom in MS which has recently been estimated to be experienced by more than 40% of patients. Nociceptive pain occurs as an appropriate physiological response transmitted to a conscious level when nociceptors in bone, muscle or any body tissue are activated, warning the organism of tissue damage. Neuropathic pain is initiated as a direct consequence of a lesion or disease affecting the somatosensory system, with no physiological advantage. Nociceptive and neuropathic pain in MS may be present concurrently and at different stages of the disease, and may be associated with other symptoms. Central neuropathic pain has been reported to be among the most common pain syndromes in MS. It is described as constant, often spontaneous, burning occurring more frequently in the lower limbs. Treatment typically includes tricyclic antidepressants and antiepileptic medications, although studies have been conducted in relatively small samples and optimal dosing has not been confirmed. Cannabinoids have been among the few treatments studied in well designed, randomized, placebo-controlled trials for central neuropathic pain. In the largest of these trials, which included 630 subjects, a 15-week comparison between Δ9-tetrahydrocannabinol and placebo was performed. More patients receiving active treatment perceived an improvement in pain than those receiving placebo, although approximately 20% of subjects reported worsening of pain while on active treatment.
Trigeminal neuralgia, while affecting less than 5% of patients with MS, is the most studied pain syndrome. The pain can be extreme and is typically treated with carbamazepine, although adverse effects can mimic an MS exacerbation. Painful topic spasms occur in approximately 11% of the MS population and are treated with antispasticity medications such as baclofen and benzodiazepines. Gabapentin has also demonstrated efficacy, but all studies have included small sample sizes.
In general, evidence for treating pain in MS is limited. Many clinical features of pain are often unrecognized by clinicians and are difficult for patients to describe. Treatment is often based on anecdotal reports and clinical experience. We present a review of treatment options for pain in MS, which should serve to update current knowledge, highlight shortcomings in clinical research and provide indications towards achieving evidence-based treatment of pain in MS.
Cannabinoids control spasticity and tremor in a multiple sclerosis model



David Baker1, Gareth Pryce1, J. Ludovic Croxford1, Peter Brown2, Roger G. Pertwee3, John W. Huffman4 & Lorna Layward
Neuroinflammation Group, Department of Neurochemistry, Institute of Neurology, University College London, 1 Wakefield Street, London WC1N 1PJ and the Institute of Ophthalmology, UCL, London EC1V 9EL, UK




The Medical Research Council Human Movement and Balance Unit, National Hospital for Neurology and Neurosurgery , Queen Square, London, WC1N 3BG, UK

Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill , Aberdeen AB25 2ZD, UK


Department of Chemistry, Clemson University, Clemson, South Carolina 29634-1905 , USA
Multiple Sclerosis Society of Great Britain and Northern Ireland , 25 Effie Road, London SW6 1EE, UK Correspondence to: Correspondence and requests for materials should be addressed to D.B. (e-mail: Email: D.Baker@ion.ucl.ac.uk).
Abstract
Chronic relapsing experimental allergic encephalomyelitis (CREAE) is an autoimmune model of multiple sclerosis1. Although both these diseases are typified by relapsing-remitting paralytic episodes, after CREAE induction by sensitization to myelin antigens1 Biozzi ABH mice also develop spasticity and tremor. These symptoms also occur during multiple sclerosis and are difficult to control. This has prompted some patients to find alternative medicines, and to perceive benefit from cannabis use2. Although this benefit has been backed up by small clinical studies, mainly with non-quantifiable outcomes3, 4, 5, 6, 7, the value of cannabis use in multiple sclerosis remains anecdotal. Here we show that cannabinoid (CB) receptor agonism using R(+)-WIN 55,212, 9-tetrahydrocannabinol, methanandamide and JWH-133 (ref. 8) quantitatively ameliorated both tremor and spasticity in diseased mice. The exacerbation of these signs after antagonism of the CB1 and CB2 receptors, notably the CB1 receptor, using SR141716A and SR144528 (ref. 8) indicate that the endogenous cannabinoid system may be tonically active in the control of tremor and spasticity. This provides a rationale for patients' indications of the therapeutic potential of cannabis in the control of the symptoms of multiple sclerosis2, and provides a means of evaluating more selective cannabinoids in the future.
 
 
Association Between Marijuana Exposure and Pulmonary Function Over 20 Years
 
 
Mark J. Pletcher, MD, MPH; Eric Vittinghoff, PhD; Ravi Kalhan, MD, MS; Joshua Richman, MD, PhD; Monika Safford, MD; Stephen Sidney, MD, MPH; Feng Lin, MS; Stefan Kertesz, MD
[+] Author Affiliations
Author Affiliations: Department of Epidemiology and Biostatistics (Drs Pletcher and Vittinghoff and Mr Lin) and Division of General Internal Medicine, Department of Medicine (Dr Pletcher), University of California, San Francisco; Asthma-COPD Program, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois (Dr Kalhan); Department of Surgery (Dr Richman) and Division of Preventive Medicine (Drs Safford and Kertesz), University of Alabama at Birmingham; Center for Surgical, Medical and Acute Care Research and Transitions, Veterans Affairs Medical Center, Birmingham (Drs Richman and Kertesz); and Division of Research, Kaiser Permanente of Northern California, Oakland (Dr Sidney). Abstract Context Marijuana smoke contains many of the same constituents as tobacco smoke, but whether it has similar adverse effects on pulmonary function is unclear.
Objective To analyze associations between marijuana (both current and lifetime exposure) and pulmonary function.
Design, Setting, and Participants The Coronary Artery Risk Development in Young Adults (CARDIA) study, a longitudinal study collecting repeated measurements of pulmonary function and smoking over 20 years (March 26, 1985-August 19, 2006) in a cohort of 5115 men and women in 4 US cities. Mixed linear modeling was used to account for individual age-based trajectories of pulmonary function and other covariates including tobacco use, which was analyzed in parallel as a positive control. Lifetime exposure to marijuana joints was expressed in joint-years, with 1 joint-year of exposure equivalent to smoking 365 joints or filled pipe bowls.
Main Outcome Measures Forced expiratory volume in the first second of expiration (FEV1) and forced vital capacity (FVC).
Results Marijuana exposure was nearly as common as tobacco exposure but was mostly light (median, 2-3 episodes per month). Tobacco exposure, both current and lifetime, was linearly associated with lower FEV1 and FVC. In contrast, the association between marijuana exposure and pulmonary function was nonlinear (P < .001): at low levels of exposure, FEV1 increased by 13 mL/joint-year (95% CI, 6.4 to 20; P < .001) and FVC by 20 mL/joint-year (95% CI, 12 to 27; P < .001), but at higher levels of exposure, these associations leveled or even reversed. The slope for FEV1 was −2.2 mL/joint-year (95% CI, −4.6 to 0.3; P = .08) at more than 10 joint-years and −3.2 mL per marijuana smoking episode/mo (95% CI, −5.8 to −0.6; P = .02) at more than 20 episodes/mo. With very heavy marijuana use, the net association with FEV1 was not significantly different from baseline, and the net association with FVC remained significantly greater than baseline (eg, at 20 joint-years, 76 mL [95% CI, 34 to 117]; P < .001).
Conclusion Occasional and low cumulative marijuana use was not associated with adverse effects on pulmonary function.
KEYWORDS: FORCED EXPIRATORY VOLUME,
LUNG VOLUME MEASUREMENTS,
MARIJUANA SMOKING,
RESPIRATORY FUNCTION TESTS,
SMOKING,
SUBSTANCE-RELATED DISORDERS,
TOBACCO,
VITAL CAPACITY.
 
bottom line, big brother and pharmaceutical companies i.e. $$$ i.e. Washington. ...
TSS

          Chimeric antigen receptor modified T cells that target chemokine receptor CCR4 as a therapeutic modality for T-cell malignancies.        
Related Articles

Chimeric antigen receptor modified T cells that target chemokine receptor CCR4 as a therapeutic modality for T-cell malignancies.

Am J Hematol. 2017 Sep;92(9):892-901

Authors: Perera LP, Zhang M, Nakagawa M, Petrus MN, Maeda M, Kadin ME, Waldmann TA, Perera PY

Abstract
With the emerging success of treating CD19 expressing B cell malignancies with ex vivo modified, autologous T cells that express CD19-directed chimeric antigen receptors (CAR), there is intense interest in expanding this evolving technology to develop effective modalities to treat other malignancies including solid tumors. Exploiting this approach to develop a therapeutic modality for T cell malignancies for which the available regimens are neither curative, nor confer long term survival we generated a lentivirus-based CAR gene transfer system to target the chemokine receptor CCR4 that is over-expressed in a spectrum of T cell malignancies as well as in CD4(+) CD25(+) Foxp3(+) T regulatory cells that accumulate in the tumor microenvironment constituting a barrier against anti-tumor immunity. Ex vivo modified, donor-derived T cells that expressed CCR4 directed CAR displayed antigen-dependent potent cytotoxicity against patient-derived cell lines representing ATL, CTCL, ALCL and a subset of HDL. Furthermore, these CAR T cells also eradicated leukemia in a mouse xenograft model of ATL illustrating the potential utility of this modality in the treatment of a wide spectrum of T cell malignancies.

PMID: 28543380 [PubMed - indexed for MEDLINE]


          In Vivo 3T Magnetic Resonance Imaging Using a Biologically Specific Contrast Agent for Prostate Cancer: A Nude Mouse Model        
We characterized in vivo a functional superparamagnetic iron-oxide magnetic resonance contrast agent that shortens the relaxation time in magnetic resonance imaging (MRI) of prostate cancer xenografts. The agent was developed by conjugating Molday ION™ carboxyl-6 (MIC6), with a deimmunized mouse monoclonal antibody (muJ591) targeting prostate-specific membrane antigen (PSMA). This functional contrast agent could be used as a noninvasive method to detect prostate cancer cells that are PSMA positive and more readily differentiate them from surrounding tissues for treatment. The functional contrast agent was injected intravenously into mice and its effect was compared to both MIC6 (without conjugated antibody) and phosphate-buffered saline (PBS) injection controls. MR imaging was performed on a clinical 3T MRI scanner using a multiecho spin echo (MESE) sequence to obtain relaxation time values. Inductively coupled plasma atomic emission spectroscopy was used to confirm an increase in elemental iron in injected mice tumours relative to controls. Histological examination of H&E stained tissues showed normal morphology of the tissues collected.
          Discovery and Characterization of R/S-N-3-Cyanophenyl-N'-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea, a New Histone Deacetylase Class III Inhibitor Exerting Antiproliferative Activity against Cancer Cell Lines        
Title: Discovery and Characterization of R/S-N-3-Cyanophenyl-N'-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea, a New Histone Deacetylase Class III Inhibitor Exerting Antiproliferative Activity against Cancer Cell Lines

Author, co-author: Schnekenburger, M; Goffin, Eric; Lee, J-Y; Jang, J.Y; Mazumder, A; Ji, S; Rogister, Bernard; Bouider, N; Lefranc, F; Miklos, W; Mathieu, V; De Tullio, Pascal; Kim, K-W; Dicato, M; Berger, W; Han, BW; Kiss, R; Pirotte, Bernard; Diederich, M

Abstract: A new series of N-aryl-N'-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)ureas bearing an alkoxycarbonylamino group at the 6-position were synthesized and examined as putative anticancer agents targeting sirtuins in glioma cells. On the basis of computational docking combined to in vitro sirtuin 1/2 inhibition assays, we selected compound 18 [R/S-N-3-cyanophenyl-N'-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea] which displays a potent antiproliferative activity on various glioma cell types, assessed by quantitative videomicroscopy, eventually triggering senescence. The impact on normal glial cells was lower with a selectivity index of >10. Furthermore, human U373 and Hs683 glioblastoma cell lines served to demonstrate the inhibitory activity of 18 against histone deacetylase (HDAC) class III sirtuins 1 and 2 (SIRT1/2) by quantifying acetylation levels of histone and non-histone proteins. The translational potential of 18 was validated by an NCI-60 cell line screen and validation of growth inhibition of drug resistant cancer cell models. Eventually, the anticancer potential of 18 was validated in 3D glioblastoma spheroids and in vivo by zebrafish xenografts. In summary, compound 18 is the first representative of a new class of SIRT inhibitors opening new perspectives in the medicinal chemistry of HDAC inhibitors.
          Role of Neuraminidase-1 in Cancer Development and Clinical Implications        
Role of Neuraminidase-1 in Cancer Development and Clinical Implications Haxho, Fiona The abnormal expression of cell surface sialic acid has recently been identified as an important trait of cancer cells. The main sialylation-modifying enzyme in mammalian cells, neuraminidase-1 (Neu1), has been shown to positively regulate several receptors and their activation, including the epidermal growth factor receptor (EGFR), insulin receptor (IR), and a number of TOLL-like receptors (TLR). Notably, these receptors each play unique and profound roles in tumor development and progression via promotion of cell proliferation and survival pathways, cell growth and metabolism, and immune-mediated tumorigenesis, respectively. Here, we further characterize the role of Neu1 in cancer cell signaling, as well as tumor growth, neovascularization and metastasis. Furthermore, the molecular targeting of Neu1 using competitive inhibitor and sialic acid analog oseltamivir phosphate (OP) has been evaluated for its therapeutic role in suppressing tumor progression. This report uncovers the molecular mechanisms that regulate the role of Neu1 sialidase in insulin receptor activation. Specifically, we show that GPCR agonists bombesin, bradykinin, angiotensin I and angiotensin II can stimulate Neu1 sialidase activity to induce IR activation (phosphorylation) in the absence of insulin. Furthermore, this effect can be blocked by GPCR inhibitor BIM-23127 as well as OP. The studies in this report also investigated the effect of OP in murine models of human triple-negative breast cancer (MDA-MB-231), ovarian endometrial cancer (A2780), and pancreatic ductal adenocarcinoma (PANC1) tumor xenografts growing in RAGxCγ mice. In comparison to untreated groups, OP treatment resulted in a significant reduction in tumor volume, metastatic spread to the mouse liver and lungs, as well as a reduction in tumor-associated neovascularization and recruitment of host endothelial cells. In conclusion, these findings provide insight into the novel targeting of tumor-promoting pathways via Neu1 sialidase and implicate OP as a novel agent in cancer therapy.
          Overexpression of progesterone receptor membrane component 1: possible mechanism for increased breast cancer risk with norethisterone in hormone therapy        
imageObjective: Clinical trials have demonstrated an increased risk of breast cancer during estrogen/norethisterone (NET) therapy. With this in mind, the effects of estrogen/NET combination on the proliferation of breast cancer cells overexpressing the progesterone receptor membrane component 1 (PGRMC1) were examined. The same combination was used for the first time in a mouse xenograft model to determine its effects on tumor development. Methods: MCF-7 cells were stably transfected with PGRMC1 expression plasmid (WT-12 cells) or empty vector control (pcDNA-3HA). NET, medroxyprogesterone acetate (MPA), and progesterone were tested alone and sequentially and continuously combined with estradiol (E2). Six-week-old nude mice were inoculated with E2 pellets 24 hours before the injection of tumor cells into both flanks (n = 5-6 mice per group). After 8 days, animals were inoculated with a NET pellet or with placebo pellets, and tumor volumes were recorded twice a week. Results: NET alone significantly increased the proliferation of WT-12 cells, MPA was effective only at the two highest concentrations, and progesterone had no effect. The twofold to threefold E2-induced increase (10−10 M) was not significantly influenced by the addition of the various progestogens. In contrast, 10−12 M E2 had no effect; however, addition of MPA and NET triggered a significant proliferative response. In vivo, a sequential combination of NET and E2 also significantly increased the tumor growth of WT-12 cells; empty vector cells did not respond to NET. Conclusions: We have demonstrated for the first time that an E2/NET combination increases the proliferation of PGRMC1-overexpressing breast cancer cells, both in vivo and in vitro. Our results suggest that undetected tumor cells overexpressing PGRMC1 may be more likely to develop into frank tumor cells in women undergoing E2/NET hormone therapy.
           ANTIBODY DIRECTED ENZYME PRODRUG THERAPY (ADEPT) IN HUMAN TUMOR XENOGRAFT MODELS         
SHARMA, SK; BAGSHAWE, KD; ROGERS, GT; BURKE, PJ; SPRINGER, CJ; ANTONIW, P; BODEN, RW; ... SHERWOOD, R; + view all <#> SHARMA, SK; BAGSHAWE, KD; ROGERS, GT; BURKE, PJ; SPRINGER, CJ; ANTONIW, P; BODEN, RW; SEARLE, F; MELTON, R; SHERWOOD, R; - view fewer <#> (1990) ANTIBODY DIRECTED ENZYME PRODRUG THERAPY (ADEPT) IN HUMAN TUMOR XENOGRAFT MODELS. BRITISH JOURNAL OF CANCER , 62 (3) p. 487.
           INACTIVATION AND CLEARANCE OF AN ANTI-CEA CARBOXYPEPTIDASE-G2 CONJUGATE IN BLOOD AFTER LOCALIZATION IN A XENOGRAFT MODEL         
SHARMA, SK; BAGSHAWE, KD; BURKE, PJ; BODEN, RW; ROGERS, GT; (1990) INACTIVATION AND CLEARANCE OF AN ANTI-CEA CARBOXYPEPTIDASE-G2 CONJUGATE IN BLOOD AFTER LOCALIZATION IN A XENOGRAFT MODEL. BRITISH JOURNAL OF CANCER , 61 (5) pp. 659-662. 10.1038/bjc.1990.149 .
           PRELIMINARY-OBSERVATIONS ON THE MICRODISTRIBUTION OF LABELED ANTIBODIES IN HUMAN COLONIC ADENOCARCINOMA XENOGRAFTS - RELEVANCE TO MICRODOSIMETRY         
PEDLEY, RB; BOXER, GM; BODEN, JA; SOUTHALL, PJ; BEGENT, RHJ; BAGSHAWE, KD; HUMM, J; PEDLEY, RB; BOXER, GM; BODEN, JA; SOUTHALL, PJ; BEGENT, RHJ; BAGSHAWE, KD; HUMM, J; SEARLE, F; - view fewer <#> (1990) PRELIMINARY-OBSERVATIONS ON THE MICRODISTRIBUTION OF LABELED ANTIBODIES IN HUMAN COLONIC ADENOCARCINOMA XENOGRAFTS - RELEVANCE TO MICRODOSIMETRY. BRIT J CANCER , 61 (2) 218 - 220.
          Gold nanoparticles as multimodality imaging agents for brain gliomas        
Background: Nanoparticles can be used for targeted drug delivery, in particular for brain cancer therapy. However, this requires a detailed analysis of nanoparticles from the associated microvasculature to the tumor, not easy because of the required high spatial resolution. The objective of this study is to demonstrate an experimental solution of this problem, based in vivo and post-mortem whole organ imaging plus nanoscale 3-dimensional (3D) X-ray microscopy. Results: The use of gold nanoparticles (AuNPs) as contrast agents paved the way to a detailed high-resolution three dimensional (3D) X-ray and fluorescence imaging analysis of the relation between xenografted glioma cells and the tumor-induced angiogenic microvasculature. The images of the angiogenic microvessels revealed nanoparticle leakage. Complementary tests showed that after endocytotic internalization fluorescent AuNPs allow the visible-light detection of cells. Conclusions: AuNP-loading of cells could be extended from the case presented here to other imaging techniques. In our study, they enabled us to (1) identify primary glioma cells at inoculation sites in mice brains; (2) follow the subsequent development of gliomas. (3) Detect the full details of the tumor-related microvasculature; (4) Finding leakage of AuNPs from the tumor-related vasculature, in contrast to no leakage from normal vasculature.
          Complete microscale profiling of tumor microangiogenesis A microradiological methodology reveals fundamental aspects of tumor angiogenesis and yields an array of quantitative parameters for its characterization        
Complete profiling would substantially facilitate the fundamental understanding of tumor angiogenesis and of possible anti-angiogenesis cancer treatments. We developed an integrated synchrotron-based methodology with excellent performances: detection of very small vessels by high spatial resolution (-1 mu m) and nanoparticle contrast enhancement, in vivo dynamics investigations with high temporal resolution (-1 ms), and three-dimensional quantitative morphology parametrization by computer tracing. The smallest (3-10 mu m) microvessels were found to constitute >80% of the tumor vasculature and exhibit many structural anomalies. Practical applications are presented, including vessel microanalysis in xenografted tumors, monitoring the effects of anti-angiogenetic agents and in vivo detection of tumor vascular rheological properties. (C) 2011 Elsevier Inc. All rights reserved.
          An end to Alzheimer’s disease, TSE Prion Research, and the Honorable Hillary Clinton        
An end to Alzheimer’s disease

 

We can prevent, effectively treat, and make an Alzheimer’s cure possible by 2025.

 

An end to Alzheimer’s disease

 

“If we’re the kind of nation that cares for its citizens and supports families, respects our elders, and takes care of our neighbors, then we’ve got work to do. And we need to do better when it comes to diseases like Alzheimer’s.”

 

Hillary, December 22, 2015

 

Alzheimer’s disease is the sixth leading cause of death in the United States. It’s the only cause of death in the top 10 that we can’t prevent, cure, or even delay.

 

As the population of our country ages, the number of people suffering from Alzheimer’s is expected to grow to nearly 15 million Americans—and could cost more than $1 trillion per year—by 2050.

 

As president, Hillary will: Commit to preventing, effectively treating, and making a cure possible for Alzheimer’s disease by 2025. Invest $2 billion per year in research for Alzheimer’s and related disorders, the level leading researchers have determined necessary to prevent and effectively treat Alzheimer’s and make a cure possible by 2025. Make sure that funding is reliable and consistent so researchers can work steadily toward effective treatment. Put the best and brightest on the case. Hillary will appoint a top-flight team of research and health experts to oversee this ambitious initiative.

 

Alzheimer’s disease affects a growing number of Americans and their families. To support those families, Hillary will: Make it easier for families and individuals with Alzheimer’s to get the care they need. Medicare should cover comprehensive Alzheimer’s care-planning sessions and the cost of properly documenting every diagnosis and care plan. Help protect loved ones who wander. Hillary will work with Congress to reauthorize the Missing Alzheimer’s Disease Patient Alert Program to help find individuals who are reported missing. Ensure our seniors are aware and can take advantage of their Medicare benefits. Hillary will direct the Social Security Administration to raise awareness about the wellness visits, cognitive screenings, and other preventive benefits covered by Medicare.

 

Hillary’s plan builds on her long record of working across the aisle on behalf of patients and families dealing with Alzheimer’s disease: In the U.S. Senate, she consistently pushed for greater funding for Alzheimer’s research, including federally funded stem cell research. She also co-chaired the Congressional Task Force on Alzheimer’s Disease and introduced legislation to restore funding for the Alzheimer’s Association 24/7 Contact Center and for Alzheimer’s disease demonstration grants.

 


 

Greetings Madam Secretary Clinton et al,

 

I WOULD KINDLY LIKE TO ANALYZE THIS STATEMENT MA’AM ;

 

>>> We can prevent, effectively treat, and make an Alzheimer’s cure possible by 2025.

 

PREVENT

 

this must be on the forefront of research i.e. ‘iatrogenic’ transmission.

 

Alzheimer’s disease, iatrogenic, and Transmissible Spongiform Encephalopathy TSE Prion disease, that is the question ???

 

>>> The only tenable public line will be that "more research is required’’ <<<

 

>>> possibility on a transmissible prion remains open<<<

 

O.K., so it’s about 23 years later, so somebody please tell me, when is "more research is required’’ enough time for evaluation ?

 


 


 

SWISS MEDICAL WEEKLY

 

Alzheimer-type brain pathology may be transmitted by grafts of dura mater 26/01/2016 Singeltary comment ;

 


 

re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy

 

Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015)

 

snip...see full Singeltary Nature comment here;

 


 

Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease

 

*** Singeltary comment PLoS ***

 

Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?

 

Posted by flounder on 05 Nov 2014 at 21:27 GMT

 


 

Sunday, November 22, 2015

 

*** Effect of heating on the stability of amyloid A (AA) fibrils and the intra- and cross-species transmission of AA amyloidosis Abstract

 

Amyloid A (AA) amyloidosis is a protein misfolding disease characterized by extracellular deposition of AA fibrils. AA fibrils are found in several tissues from food animals with AA amyloidosis. For hygienic purposes, heating is widely used to inactivate microbes in food, but it is uncertain whether heating is sufficient to inactivate AA fibrils and prevent intra- or cross-species transmission. We examined the effect of heating (at 60 °C or 100 °C) and autoclaving (at 121 °C or 135 °C) on murine and bovine AA fibrils using Western blot analysis, transmission electron microscopy (TEM), and mouse model transmission experiments. TEM revealed that a mixture of AA fibrils and amorphous aggregates appeared after heating at 100 °C, whereas autoclaving at 135 °C produced large amorphous aggregates. AA fibrils retained antigen specificity in Western blot analysis when heated at 100 °C or autoclaved at 121 °C, but not when autoclaved at 135 °C. Transmissible pathogenicity of murine and bovine AA fibrils subjected to heating (at 60 °C or 100 °C) was significantly stimulated and resulted in amyloid deposition in mice. Autoclaving of murine AA fibrils at 121 °C or 135 °C significantly decreased amyloid deposition. Moreover, amyloid deposition in mice injected with murine AA fibrils was more severe than that in mice injected with bovine AA fibrils. Bovine AA fibrils autoclaved at 121 °C or 135 °C did not induce amyloid deposition in mice. These results suggest that AA fibrils are relatively heat stable and that similar to prions, autoclaving at 135 °C is required to destroy the pathogenicity of AA fibrils. These findings may contribute to the prevention of AA fibril transmission through food materials to different animals and especially to humans.

 

Purchase options Price * Issue Purchase USD 511.00 Article Purchase USD 54.00

 


 


 

*** Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes contaminated during neurosurgery ***

 

Gibbs CJ Jr, Asher DM, Kobrine A, Amyx HL, Sulima MP, Gajdusek DC. Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.

 

Stereotactic multicontact electrodes used to probe the cerebral cortex of a middle aged woman with progressive dementia were previously implicated in the accidental transmission of Creutzfeldt-Jakob disease (CJD) to two younger patients. The diagnoses of CJD have been confirmed for all three cases. More than two years after their last use in humans, after three cleanings and repeated sterilisation in ethanol and formaldehyde vapour, the electrodes were implanted in the cortex of a chimpanzee. Eighteen months later the animal became ill with CJD. This finding serves to re-emphasise the potential danger posed by reuse of instruments contaminated with the agents of spongiform encephalopathies, even after scrupulous attempts to clean them.

 


 

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

 

Singeltary, Sr et al. JAMA.2001; 285: 733-734. Vol. 285 No. 6, February 14, 2001 JAMA

 

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

 

To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.

 

Terry S. Singeltary, Sr Bacliff, Tex

 

1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323.

 


 

Transmissible Spongiform Encephalopathy TSE PRION UPDATE

 

Saturday, July 23, 2016

 

BOVINE SPONGIFORM ENCEPHALOPATHY BSE TSE PRION SURVEILLANCE, TESTING, AND SRM REMOVAL UNITED STATE OF AMERICA UPDATE JULY 2016

 


 

Tuesday, July 26, 2016

 

Atypical Bovine Spongiform Encephalopathy BSE TSE Prion UPDATE JULY 2016

 


 

Sunday, July 17, 2016

 

CHRONIC WASTING DISEASE CWD TSE PRION GLOBAL REPORT UPDATE JULY 17 2016

 


 

Monday, May 02, 2016

 

*** Zoonotic Potential of CWD Prions: An Update Prion 2016 Tokyo ***

 


 

*** NIH awards $11 million to UTHealth researchers to study deadly CWD prion diseases Claudio Soto, Ph.D. ***

 

Public Release: 29-Jun-2016

 


 

Tuesday, July 12, 2016

 

Chronic Wasting Disease CWD, Scrapie, Bovine Spongiform Encephalopathy BSE, TSE, Prion Zoonosis Science History

 

see history of NIH may destroy human brain collection

 


 

I urge everyone to watch this video closely...terry

 

*** you can see video here and interview with Jeff's Mom, and scientist telling you to test everything and potential risk factors for humans ***

 


 

Sunday, July 24, 2016

 

Chronic Wasting Disease Prions in Elk Antler Velvet and Marketing of this Product in Nutritional Supplements for Humans?

 

Research Project: TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES: THE ROLE OF GENETICS, STRAIN VARIATION, AND ENVIRONMENTAL CONTAMINATION IN DISEASE CONTROL

 


 

Saturday, April 23, 2016

 

SCRAPIE WS-01: Prion diseases in animals and zoonotic potential 2016

 

Prion. 10:S15-S21. 2016 ISSN: 1933-6896 printl 1933-690X

 


 

Saturday, July 16, 2016

 

Importation of Sheep, Goats, and Certain Other Ruminants [Docket No. APHIS-2009-0095]RIN 0579-AD10

 

WITH great disgust and concern, I report to you that the OIE, USDA, APHIS, are working to further legalize the trading of Transmissible Spongiform Encephalopathy TSE Pion disease around the globe.

 

THIS is absolutely insane. it’s USDA INC.

 


 

Saturday, May 28, 2016

 

*** Infection and detection of PrPCWD in soil from CWD infected farm in Korea Prion 2016 Tokyo ***

 


 

Thursday, June 9, 2016

 

Advisory Committee; Transmissible Spongiform Encephalopathies Advisory Committee; Termination

 


 

TREATMENT

 

However, this is where Confucius is confused Ma’am, see my letter to President Clinton and his response back in 1997 ;

 

THE WHITE HOUSE

 

WASHINGTON

 

July 3, 1997

 

Mr. Terry S. Singletary, Sr.

 

xxx

 

Bacliff, Texas 77518

 

Dear Terry:

 

Thank you for writing to me regarding the use of marijuana for medical purposes. I appreciate knowing your views. My Administration has worked very hard to ensure that Americans have access to safe and effective medicine.

 

My Administration strongly opposes the California and Arizona drug legalization measures because they contradict our federal law and our national drug control strategy. They disregard the medical and scientific process by which our nation evaluates and approves safe and effective medicines. And, most important, they send the wrong message to our children -- undermining the efforts of parents, educators, elected leaders, and countless others who are working to ensure a healthy, drug-free society.

 

However, in response to anecdotal claims about marijuana's medical benefits, the Office of National Drug Control Policy is funding a comprehensive research review by the National Academy of Science's Institute of Medicine. The purpose of this study is to ensure that good science remains the basis of our drug control policy.

 

As we work to protect the health of children and our nation, I appreciate your interest in this issue.

 

Sincerely,

 

Bill Clinton

 

end

 

1-7-97

 

Mr. President,

 

Hello, I’m writing in concern with the issues around the use of Medical Marijuana for people suffering from Aids, Cancer, Glaucoma, Chronic Pain, Muscle Spasms, and Multiple Sclerosis, and also Spinal Cord Injury.

 

I’m very concerned about the stance you and your...my administration has taken against this. Somebody needs to wake up and read the medical findings over the past years. Look at how it has helped people. ...

 

snip...(I get a bit long winded here)...snip

 

But what has disturbed me the most, is what happened in California and Arizona, how our appointed federal government bureaucrats and law enforcement agencies openly and actively engaged in a campaign to undermine, subvert and ultimately destroy the voters decision to enact laws of their choosing.

 

If this keeps happening, you will destroy the voters hope of ever changing anything. You will destroy the Democratic process.

 

Come on Bill, we all know you inhaled and I still voted for you twice. Change this Refer Madness. We don’t need the politicians writing prescriptions...

 

P.S. just think of the jail space you could use for murderers and rapist.

 

Very Sincere,

 

Terry S. Singeltary Sr.

 

END

 

ALZHEIMER’S TREATMENT SEE UPDATED SCIENCE 2016

 

Public Release: 28-Jun-2016 Cannabinoids remove plaque-forming Alzheimer's proteins from brain cells

 

Salk Institute

 

IMAGE: Preliminary lab studies by Salk Professor David Schubert suggest that the molecule THC reduces beta amyloid proteins in human neurons. view more

 

Credit: Salk Institute

 

LA JOLLA -- Salk Institute scientists have found preliminary evidence that tetrahydrocannabinol (THC) and other compounds found in marijuana can promote the cellular removal of amyloid beta, a toxic protein associated with Alzheimer's disease.

 

While these exploratory studies were conducted in neurons grown in the laboratory, they may offer insight into the role of inflammation in Alzheimer's disease and could provide clues to developing novel therapeutics for the disorder.

 

"Although other studies have offered evidence that cannabinoids might be neuroprotective against the symptoms of Alzheimer's, we believe our study is the first to demonstrate that cannabinoids affect both inflammation and amyloid beta accumulation in nerve cells," says Salk Professor David Schubert, the senior author of the paper.

 

Alzheimer's disease is a progressive brain disorder that leads to memory loss and can seriously impair a person's ability to carry out daily tasks. It affects more than five million Americans according to the National Institutes of Health, and is a leading cause of death. It is also the most common cause of dementia and its incidence is expected to triple during the next 50 years.

 

It has long been known that amyloid beta accumulates within the nerve cells of the aging brain well before the appearance of Alzheimer's disease symptoms and plaques. Amyloid beta is a major component of the plaque deposits that are a hallmark of the disease. But the precise role of amyloid beta and the plaques it forms in the disease process remains unclear.

 

In a manuscript published in June 2016's Aging and Mechanisms of Disease, Salk team studied nerve cells altered to produce high levels of amyloid beta to mimic aspects of Alzheimer's disease.

 

The researchers found that high levels of amyloid beta were associated with cellular inflammation and higher rates of neuron death. They demonstrated that exposing the cells to THC reduced amyloid beta protein levels and eliminated the inflammatory response from the nerve cells caused by the protein, thereby allowing the nerve cells to survive.

 

"Inflammation within the brain is a major component of the damage associated with Alzheimer's disease, but it has always been assumed that this response was coming from immune-like cells in the brain, not the nerve cells themselves," says Antonio Currais, a postdoctoral researcher in Schubert's laboratory and first author of the paper. "When we were able to identify the molecular basis of the inflammatory response to amyloid beta, it became clear that THC-like compounds that the nerve cells make themselves may be involved in protecting the cells from dying."

 

Brain cells have switches known as receptors that can be activated by endocannabinoids, a class of lipid molecules made by the body that are used for intercellular signaling in the brain. The psychoactive effects of marijuana are caused by THC, a molecule similar in activity to endocannabinoids that can activate the same receptors. Physical activity results in the production of endocannabinoids and some studies have shown that exercise may slow the progression of Alzheimer's disease.

 

Schubert emphasized that his team's findings were conducted in exploratory laboratory models, and that the use of THC-like compounds as a therapy would need to be tested in clinical trials.

 

In separate but related research, his lab found an Alzheimer's drug candidate called J147 that also removes amyloid beta from nerve cells and reduces the inflammatory response in both nerve cells and the brain. It was the study of J147 that led the scientists to discover that endocannabinoids are involved in the removal of amyloid beta and the reduction of inflammation.

 

###

 

Other authors on the paper include Oswald Quehenberger and Aaron Armando at the University of California, San Diego; and Pamela Maher and Daniel Daughtery at the Salk Institute.

 

The study was supported by the National Institutes of Health, The Burns Foundation and The Bundy Foundation.

 

About Salk Institute:

 

Every cure has a starting point. The Salk Institute embodies Jonas Salk's mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is where cures begin. Learn more at: salk.edu.

 

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

 


 

*** National Cancer Institute at the National Institutes of Health ***

 

Cannabis and Cannabinoids (PDQ®), Cancer Antitumor Effects, Prion prevention, Pain management, muscle relaxer, and Palliative Medicine

 

Cannabis and Cannabinoids (PDQ®)

 

Laboratory/Animal/Preclinical Studies

 

Antitumor Effects Appetite Stimulation Analgesia

 

Laboratory/Animal/Preclinical Studies

 

Antitumor Effects

 

Appetite Stimulation

 

Analgesia

 

Cannabinoids are a group of 21-carbon–containing terpenophenolic compounds produced uniquely by Cannabis sativa and Cannabis indica species.[1,2] These plant-derived compounds may be referred to as phytocannabinoids. Although delta-9-tetrahydrocannabinol (THC) is the primary psychoactive ingredient, other known compounds with biologic activity are cannabinol, cannabidiol (CBD), cannabichromene, cannabigerol, tetrahydrocannabivarin, and delta-8-THC. CBD, in particular, is thought to have significant analgesic and anti-inflammatory activity without the psychoactive effect (high) of delta-9-THC.

 

Antitumor Effects One study in mice and rats suggested that cannabinoids may have a protective effect against the development of certain types of tumors.[3] During this 2-year study, groups of mice and rats were given various doses of THC by gavage. A dose-related decrease in the incidence of hepatic adenoma tumors and hepatocellular carcinoma was observed in the mice. Decreased incidences of benign tumors (polyps and adenomas) in other organs (mammary gland, uterus, pituitary, testis, and pancreas) were also noted in the rats. In another study, delta-9-THC, delta-8-THC, and cannabinol were found to inhibit the growth of Lewis lung adenocarcinoma cells in vitro and in vivo .[4] In addition, other tumors have been shown to be sensitive to cannabinoid-induced growth inhibition.[5-8]

 

Cannabinoids may cause antitumor effects by various mechanisms, including induction of cell death, inhibition of cell growth, and inhibition of tumor angiogenesis invasion and metastasis.[9-12] One review summarizes the molecular mechanisms of action of cannabinoids as antitumor agents.[13] Cannabinoids appear to kill tumor cells but do not affect their nontransformed counterparts and may even protect them from cell death. These compounds have been shown to induce apoptosis in glioma cells in culture and induce regression of glioma tumors in mice and rats. Cannabinoids protect normal glial cells of astroglial and oligodendroglial lineages from apoptosis mediated by the CB1 receptor.[14]

 

The effects of delta-9-THC and a synthetic agonist of the CB2 receptor were investigated in hepatocellular carcinoma (HCC).[15] Both agents reduced the viability of hepatocellular carcinoma cells in vitro and demonstrated antitumor effects in hepatocellular carcinoma subcutaneous xenografts in nude mice. The investigations documented that the anti-HCC effects are mediated by way of the CB2 receptor. Similar to findings in glioma cells, the cannabinoids were shown to trigger cell death through stimulation of an endoplasmic reticulum stress pathway that activates autophagy and promotes apoptosis. Other investigations have confirmed that CB1 and CB2 receptors may be potential targets in non-small cell lung carcinoma [16] and breast cancer.[17]

 

An in vitro study of the effect of CBD on programmed cell death in breast cancer cell lines found that CBD induced programmed cell death, independent of the CB1, CB2, or vanilloid receptors. CBD inhibited the survival of both estrogen receptor–positive and estrogen receptor–negative breast cancer cell lines, inducing apoptosis in a concentration-dependent manner while having little effect on nontumorigenic, mammary cells.[18]

 

CBD has also been demonstrated to exert a chemopreventive effect in a mouse model of colon cancer.[19] In the experimental system, azoxymethane increased premalignant and malignant lesions in the mouse colon. Animals treated with azoxymethane and CBD concurrently were protected from developing premalignant and malignant lesions. In in vitro experiments involving colorectal cancer cell lines, the investigators found that CBD protected DNA from oxidative damage, increased endocannabinoid levels, and reduced cell proliferation.

 

Another investigation into the antitumor effects of CBD examined the role of intercellular adhesion molecule-1 (ICAM-1).[12] ICAM-1 expression has been reported to be negatively correlated with cancer metastasis. In lung cancer cell lines, CBD upregulated ICAM-1, leading to decreased cancer cell invasiveness.

 

In an in vivo model using severe combined immunodeficient mice, subcutaneous tumors were generated by inoculating the animals with cells from human non-small cell lung carcinoma cell lines.[20] Tumor growth was inhibited by 60% in THC-treated mice compared with vehicle-treated control mice. Tumor specimens revealed that THC had antiangiogenic and antiproliferative effects. However, research with immunocompetent murine tumor models has demonstrated immunosuppression and enhanced tumor growth in mice treated with THC.[21,22]

 

In addition, both plant-derived and endogenous cannabinoids have been studied for anti-inflammatory effects. A mouse study demonstrated that endogenous cannabinoid system signaling is likely to provide intrinsic protection against colonic inflammation.[23] As a result, a hypothesis that phytocannabinoids and endocannabinoids may be useful in the risk reduction and treatment of colorectal cancer has been developed.[24-27]

 

Appetite Stimulation Many animal studies have previously demonstrated that delta-9-THC and other cannabinoids have a stimulatory effect on appetite and increase food intake. It is believed that the endogenous cannabinoid system may serve as a regulator of feeding behavior. The endogenous cannabinoid anandamide potently enhances appetite in mice.[28] Moreover, CB1 receptors in the hypothalamus may be involved in the motivational or reward aspects of eating.[29]

 

Analgesia Understanding the mechanism of cannabinoid-induced analgesia has been increased through the study of cannabinoid receptors, endocannabinoids, and synthetic agonists and antagonists. The CB1 receptor is found in both the central nervous system (CNS) and in peripheral nerve terminals. Similar to opioid receptors, increased levels of the CB1 receptor are found in regions of the brain that regulate nociceptive processing.[30] CB2 receptors, located predominantly in peripheral tissue, exist at very low levels in the CNS. With the development of receptor-specific antagonists, additional information about the roles of the receptors and endogenous cannabinoids in the modulation of pain has been obtained.[31,32]

 

Cannabinoids may also contribute to pain modulation through an anti-inflammatory mechanism; a CB2 effect with cannabinoids acting on mast cell receptors to attenuate the release of inflammatory agents, such as histamine and serotonin, and on keratinocytes to enhance the release of analgesic opioids has been described.[33-35] One study reported that the efficacy of synthetic CB1- and CB2-receptor agonists were comparable with the efficacy of morphine in a murine model of tumor pain.[36]

 

References

 

snip...

 


 

J Neurosci. 2007 Sep 5;27(36):9­537-44.

 

Nonpsychoa­ctive cannabidio­l prevents prion accumulati­on and protects neurons against ***prion*** toxicity.

 

*** Our results suggest that CBD may protect neurons against the multiple molecular and cellular factors involved in the different steps of the neurodegenerative process, which takes place during prion infection. When combined with its ability to target the brain and its lack of toxic side effects, CBD may represent a promising new anti-prion drug.

 


 

Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy

 

Brenda E. Porter x Brenda E. Porter Search for articles by this author , Catherine Jacobson x Catherine Jacobson Search for articles by this author Correspondence Corresponding author. email Received: May 24, 2013; Received in revised form: July 23, 2013; Accepted: August 30, 2013; DOI: http://dx.doi.org/10.1016/j.yebeh.2013.08.037 Abstract Full Text Images/Data References Related Articles To view the full text, please login as a subscribed user or purchase a subscription. Click here to view the full text on ScienceDirect.

 

Abstract

 

Severe childhood epilepsies are characterized by frequent seizures, neurodevelopmental delays, and impaired quality of life. In these treatment-resistant epilepsies, families often seek alternative treatments. This survey explored the use of cannabidiol-enriched cannabis in children with treatment-resistant epilepsy. The survey was presented to parents belonging to a Facebook group dedicated to sharing information about the use of cannabidiol-enriched cannabis to treat their child's seizures. Nineteen responses met the following inclusion criteria for the study: a diagnosis of epilepsy and current use of cannabidiol-enriched cannabis. Thirteen children had Dravet syndrome, four had Doose syndrome, and one each had Lennox–Gastaut syndrome and idiopathic epilepsy. The average number of antiepileptic drugs (AEDs) tried before using cannabidiol-enriched cannabis was 12. Sixteen (84%) of the 19 parents reported a reduction in their child's seizure frequency while taking cannabidiol-enriched cannabis. Of these, two (11%) reported complete seizure freedom, eight (42%) reported a greater than 80% reduction in seizure frequency, and six (32%) reported a 25–60% seizure reduction. Other beneficial effects included increased alertness, better mood, and improved sleep. Side effects included drowsiness and fatigue. Our survey shows that parents are using cannabidiol-enriched cannabis as a treatment for their children with treatment-resistant epilepsy. Because of the increasing number of states that allow access to medical cannabis, its use will likely be a growing concern for the epilepsy community. Safety and tolerability data for cannabidiol-enriched cannabis use among children are not available. Objective measurements of a standardized preparation of pure cannabidiol are needed to determine whether it is safe, well tolerated, and efficacious at controlling seizures in this pediatric population with difficult-to-treat seizures.

 


 

Marijuana and Epilepsy

 


 

Original Contribution| January 11, 2012 Association Between Marijuana Exposure and Pulmonary Function Over 20 Years

 

Conclusion Occasional and low cumulative marijuana use was not associated with adverse effects on pulmonary function.

 


 

Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1

 

Cannabinoids inhibit cancer cell invasion via increasing tissue inhibitor of matrix metalloproteinases-1 (TIMP-1).

 


 


 

Cannabis in Palliative Medicine: Improving Care and Reducing Opioid-Rel­ated Morbidity

 

Published online before print March 28, 2011, J HOSP PALLIAT CARE August 2011 vol. 28 no. 5 297-303

 


 

Published online ahead of print August 30, 2010 CMAJ 10.1503/cm­aj.091414

 

Smoked cannabis for chronic neuropathi­c pain: a randomized controlled trial

 

Conclusion

 

Our results support the claim that smoked cannabis reduces pain, improves mood and helps sleep. We believe that our trial provides a methodological approach that may be considered for further research. Clinical studies using inhaled delivery systems, such as vaporizers,32,33 are needed.

 


 

Cases J. 2009; 2: 7487.

 

Published online 2009 May 18

 

Standardiz­ed natural product cannabis in pain management and observatio­ns at a Canadian compassion society: a case report

 

The roughly 4000 members of the Green Cross Society find similar benefit from standardized natural product cannabis medicine. To follow, will be publication of the Society's demographic data regarding use for various conditions such as arthritis, fybromyalgia, HIV/AIDS, and chronic pain, to name a few. A breakdown of the illnesses, what strains (cannabinoid profiles) is most effective, and at what dosages will be published at a later time.

 


 

Effect of D9-tetrahydrocannabinol, a cannabinoid receptor agonist, on the triggering of transient lower oesophageal sphincter relaxations in dogs and humans

 

These findings confirm previous findings in dogs and indicate that CB receptors are also involved in the triggering of TLESRs in humans.

 


 

Drugs: 9 July 2010 - Volume 70 - Issue 10 - pp 1245-1254

 

Pharmacological Management of Pain in Patients with Multiple Sclerosis

 

Cannabinoids have been among the few treatments studied in well designed, randomized, placebo-controlled trials for central neuropathic pain. In the largest of these trials, which included 630 subjects, a 15-week comparison between Δ9-tetrahydrocannabinol and placebo was performed. More patients receiving active treatment perceived an improvement in pain than those receiving placebo, although approximately 20% of subjects reported worsening of pain while on active treatment.

 


 

Cannabinoids control spasticity and tremor in a multiple sclerosis model

 

The exacerbation of these signs after antagonism of the CB1 and CB2 receptors, notably the CB1 receptor, using SR141716A and SR144528 (ref. 8) indicate that the endogenous cannabinoid system may be tonically active in the control of tremor and spasticity. This provides a rationale for patients' indications of the therapeutic potential of cannabis in the control of the symptoms of multiple sclerosis2, and provides a means of evaluating more selective cannabinoids in the future.

 


 


 

Thursday, June 30, 2016 Cannabinoids remove plaque-forming Alzheimer's proteins from brain cells

 


 


 

CURE?

 

we will never cure anything if we can never see the forest for the trees $$$

 

we must get corporate political science, god save the industry at all cost mentality, out of sound scientific policy making.

 

NEEDLESS CONFLICT

 


 


 


 

Evidence That Transmissible Mink Encephalopathy Results from Feeding Infected Cattle

 

Over the next 8-10 weeks, approximately 40% of all the adult mink on the farm died from TME.

 

snip...

 

The rancher was a ''dead stock'' feeder using mostly (>95%) downer or dead dairy cattle...

 


 


 


 

In Confidence - Perceptions of unconventional slow virus diseases of animals in the USA - APRIL-MAY 1989 - G A H Wells

 

3. Prof. A. Robertson gave a brief account of BSE. The US approach was to accord it a very low profile indeed. Dr. A Thiermann showed the picture in the ''Independent'' with cattle being incinerated and thought this was a fanatical incident to be avoided in the US at all costs. ...

 


 

”The occurrence of CWD must be viewed against the contest of the locations in which it occurred. It was an incidental and unwelcome complication of the respective wildlife research programmes. Despite it’s subsequent recognition as a new disease of cervids, therefore justifying direct investigation, no specific research funding was forthcoming. The USDA veiwed it as a wildlife problem and consequently not their province!” ...page 26.

 


 

*** Spraker suggested an interesting explanation for the occurrence of CWD. The deer pens at the Foot Hills Campus were built some 30-40 years ago by a Dr. Bob Davis. At or abut that time, allegedly, some scrapie work was conducted at this site. When deer were introduced to the pens they occupied ground that had previously been occupied by sheep.

 


 

2016

 

What say ye Ma’am ?

 

Terry S. Singeltary Sr. Bacliff, Texas USA 77518 flounder9@verizon.net

          Cannabinoids remove plaque-forming Alzheimer's proteins from brain cells         
Cannabinoids remove plaque-forming Alzheimer's proteins from brain cells
 
 
Public Release: 28-Jun-2016 Cannabinoids remove plaque-forming Alzheimer's proteins from brain cells
 
Salk Institute
 
IMAGE: Preliminary lab studies by Salk Professor David Schubert suggest that the molecule THC reduces beta amyloid proteins in human neurons. view more
 
Credit: Salk Institute
 
LA JOLLA -- Salk Institute scientists have found preliminary evidence that tetrahydrocannabinol (THC) and other compounds found in marijuana can promote the cellular removal of amyloid beta, a toxic protein associated with Alzheimer's disease.
 
While these exploratory studies were conducted in neurons grown in the laboratory, they may offer insight into the role of inflammation in Alzheimer's disease and could provide clues to developing novel therapeutics for the disorder.
 
"Although other studies have offered evidence that cannabinoids might be neuroprotective against the symptoms of Alzheimer's, we believe our study is the first to demonstrate that cannabinoids affect both inflammation and amyloid beta accumulation in nerve cells," says Salk Professor David Schubert, the senior author of the paper.
 
Alzheimer's disease is a progressive brain disorder that leads to memory loss and can seriously impair a person's ability to carry out daily tasks. It affects more than five million Americans according to the National Institutes of Health, and is a leading cause of death. It is also the most common cause of dementia and its incidence is expected to triple during the next 50 years.
 
It has long been known that amyloid beta accumulates within the nerve cells of the aging brain well before the appearance of Alzheimer's disease symptoms and plaques. Amyloid beta is a major component of the plaque deposits that are a hallmark of the disease. But the precise role of amyloid beta and the plaques it forms in the disease process remains unclear.
 
In a manuscript published in June 2016's Aging and Mechanisms of Disease, Salk team studied nerve cells altered to produce high levels of amyloid beta to mimic aspects of Alzheimer's disease.
 
The researchers found that high levels of amyloid beta were associated with cellular inflammation and higher rates of neuron death. They demonstrated that exposing the cells to THC reduced amyloid beta protein levels and eliminated the inflammatory response from the nerve cells caused by the protein, thereby allowing the nerve cells to survive.
 
"Inflammation within the brain is a major component of the damage associated with Alzheimer's disease, but it has always been assumed that this response was coming from immune-like cells in the brain, not the nerve cells themselves," says Antonio Currais, a postdoctoral researcher in Schubert's laboratory and first author of the paper. "When we were able to identify the molecular basis of the inflammatory response to amyloid beta, it became clear that THC-like compounds that the nerve cells make themselves may be involved in protecting the cells from dying."
 
Brain cells have switches known as receptors that can be activated by endocannabinoids, a class of lipid molecules made by the body that are used for intercellular signaling in the brain. The psychoactive effects of marijuana are caused by THC, a molecule similar in activity to endocannabinoids that can activate the same receptors. Physical activity results in the production of endocannabinoids and some studies have shown that exercise may slow the progression of Alzheimer's disease.
 
Schubert emphasized that his team's findings were conducted in exploratory laboratory models, and that the use of THC-like compounds as a therapy would need to be tested in clinical trials.
 
In separate but related research, his lab found an Alzheimer's drug candidate called J147 that also removes amyloid beta from nerve cells and reduces the inflammatory response in both nerve cells and the brain. It was the study of J147 that led the scientists to discover that endocannabinoids are involved in the removal of amyloid beta and the reduction of inflammation.
 
###
 
Other authors on the paper include Oswald Quehenberger and Aaron Armando at the University of California, San Diego; and Pamela Maher and Daniel Daughtery at the Salk Institute.
 
The study was supported by the National Institutes of Health, The Burns Foundation and The Bundy Foundation.
 
About Salk Institute:
 
Every cure has a starting point. The Salk Institute embodies Jonas Salk's mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is where cures begin. Learn more at: salk.edu.
 
Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.
 
 
*** National Cancer Institute at the National Institutes of Health ***
 
Cannabis and Cannabinoids (PDQ®), Cancer Antitumor Effects, Prion prevention, Pain management, muscle relaxer, and Palliative Medicine
 
Cannabis and Cannabinoids (PDQ®)
 
Laboratory/Animal/Preclinical Studies
 
Antitumor Effects Appetite Stimulation Analgesia
 
Laboratory/Animal/Preclinical Studies
 
Antitumor Effects
 
Appetite Stimulation
 
Analgesia
 
Cannabinoids are a group of 21-carbon–containing terpenophenolic compounds produced uniquely by Cannabis sativa and Cannabis indica species.[1,2] These plant-derived compounds may be referred to as phytocannabinoids. Although delta-9-tetrahydrocannabinol (THC) is the primary psychoactive ingredient, other known compounds with biologic activity are cannabinol, cannabidiol (CBD), cannabichromene, cannabigerol, tetrahydrocannabivarin, and delta-8-THC. CBD, in particular, is thought to have significant analgesic and anti-inflammatory activity without the psychoactive effect (high) of delta-9-THC.
 
Antitumor Effects One study in mice and rats suggested that cannabinoids may have a protective effect against the development of certain types of tumors.[3] During this 2-year study, groups of mice and rats were given various doses of THC by gavage. A dose-related decrease in the incidence of hepatic adenoma tumors and hepatocellular carcinoma was observed in the mice. Decreased incidences of benign tumors (polyps and adenomas) in other organs (mammary gland, uterus, pituitary, testis, and pancreas) were also noted in the rats. In another study, delta-9-THC, delta-8-THC, and cannabinol were found to inhibit the growth of Lewis lung adenocarcinoma cells in vitro and in vivo .[4] In addition, other tumors have been shown to be sensitive to cannabinoid-induced growth inhibition.[5-8]
 
Cannabinoids may cause antitumor effects by various mechanisms, including induction of cell death, inhibition of cell growth, and inhibition of tumor angiogenesis invasion and metastasis.[9-12] One review summarizes the molecular mechanisms of action of cannabinoids as antitumor agents.[13] Cannabinoids appear to kill tumor cells but do not affect their nontransformed counterparts and may even protect them from cell death. These compounds have been shown to induce apoptosis in glioma cells in culture and induce regression of glioma tumors in mice and rats. Cannabinoids protect normal glial cells of astroglial and oligodendroglial lineages from apoptosis mediated by the CB1 receptor.[14]
 
The effects of delta-9-THC and a synthetic agonist of the CB2 receptor were investigated in hepatocellular carcinoma (HCC).[15] Both agents reduced the viability of hepatocellular carcinoma cells in vitro and demonstrated antitumor effects in hepatocellular carcinoma subcutaneous xenografts in nude mice. The investigations documented that the anti-HCC effects are mediated by way of the CB2 receptor. Similar to findings in glioma cells, the cannabinoids were shown to trigger cell death through stimulation of an endoplasmic reticulum stress pathway that activates autophagy and promotes apoptosis. Other investigations have confirmed that CB1 and CB2 receptors may be potential targets in non-small cell lung carcinoma [16] and breast cancer.[17]
 
An in vitro study of the effect of CBD on programmed cell death in breast cancer cell lines found that CBD induced programmed cell death, independent of the CB1, CB2, or vanilloid receptors. CBD inhibited the survival of both estrogen receptor–positive and estrogen receptor–negative breast cancer cell lines, inducing apoptosis in a concentration-dependent manner while having little effect on nontumorigenic, mammary cells.[18]
 
CBD has also been demonstrated to exert a chemopreventive effect in a mouse model of colon cancer.[19] In the experimental system, azoxymethane increased premalignant and malignant lesions in the mouse colon. Animals treated with azoxymethane and CBD concurrently were protected from developing premalignant and malignant lesions. In in vitro experiments involving colorectal cancer cell lines, the investigators found that CBD protected DNA from oxidative damage, increased endocannabinoid levels, and reduced cell proliferation.
 
Another investigation into the antitumor effects of CBD examined the role of intercellular adhesion molecule-1 (ICAM-1).[12] ICAM-1 expression has been reported to be negatively correlated with cancer metastasis. In lung cancer cell lines, CBD upregulated ICAM-1, leading to decreased cancer cell invasiveness.
 
In an in vivo model using severe combined immunodeficient mice, subcutaneous tumors were generated by inoculating the animals with cells from human non-small cell lung carcinoma cell lines.[20] Tumor growth was inhibited by 60% in THC-treated mice compared with vehicle-treated control mice. Tumor specimens revealed that THC had antiangiogenic and antiproliferative effects. However, research with immunocompetent murine tumor models has demonstrated immunosuppression and enhanced tumor growth in mice treated with THC.[21,22]
 
In addition, both plant-derived and endogenous cannabinoids have been studied for anti-inflammatory effects. A mouse study demonstrated that endogenous cannabinoid system signaling is likely to provide intrinsic protection against colonic inflammation.[23] As a result, a hypothesis that phytocannabinoids and endocannabinoids may be useful in the risk reduction and treatment of colorectal cancer has been developed.[24-27]
 
Appetite Stimulation Many animal studies have previously demonstrated that delta-9-THC and other cannabinoids have a stimulatory effect on appetite and increase food intake. It is believed that the endogenous cannabinoid system may serve as a regulator of feeding behavior. The endogenous cannabinoid anandamide potently enhances appetite in mice.[28] Moreover, CB1 receptors in the hypothalamus may be involved in the motivational or reward aspects of eating.[29]
 
Analgesia Understanding the mechanism of cannabinoid-induced analgesia has been increased through the study of cannabinoid receptors, endocannabinoids, and synthetic agonists and antagonists. The CB1 receptor is found in both the central nervous system (CNS) and in peripheral nerve terminals. Similar to opioid receptors, increased levels of the CB1 receptor are found in regions of the brain that regulate nociceptive processing.[30] CB2 receptors, located predominantly in peripheral tissue, exist at very low levels in the CNS. With the development of receptor-specific antagonists, additional information about the roles of the receptors and endogenous cannabinoids in the modulation of pain has been obtained.[31,32]
 
Cannabinoids may also contribute to pain modulation through an anti-inflammatory mechanism; a CB2 effect with cannabinoids acting on mast cell receptors to attenuate the release of inflammatory agents, such as histamine and serotonin, and on keratinocytes to enhance the release of analgesic opioids has been described.[33-35] One study reported that the efficacy of synthetic CB1- and CB2-receptor agonists were comparable with the efficacy of morphine in a murine model of tumor pain.[36]
 
References
 
snip...
 
 
J Neurosci. 2007 Sep 5;27(36):9­537-44.
 
Nonpsychoa­ctive cannabidio­l prevents prion accumulati­on and protects neurons against ***prion*** toxicity.
 
*** Our results suggest that CBD may protect neurons against the multiple molecular and cellular factors involved in the different steps of the neurodegenerative process, which takes place during prion infection. When combined with its ability to target the brain and its lack of toxic side effects, CBD may represent a promising new anti-prion drug.
 
 
Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy
 
Brenda E. Porter x Brenda E. Porter Search for articles by this author , Catherine Jacobson x Catherine Jacobson Search for articles by this author Correspondence Corresponding author. email Received: May 24, 2013; Received in revised form: July 23, 2013; Accepted: August 30, 2013; DOI: http://dx.doi.org/10.1016/j.yebeh.2013.08.037 Abstract Full Text Images/Data References Related Articles To view the full text, please login as a subscribed user or purchase a subscription. Click here to view the full text on ScienceDirect.
 
Abstract
 
Severe childhood epilepsies are characterized by frequent seizures, neurodevelopmental delays, and impaired quality of life. In these treatment-resistant epilepsies, families often seek alternative treatments. This survey explored the use of cannabidiol-enriched cannabis in children with treatment-resistant epilepsy. The survey was presented to parents belonging to a Facebook group dedicated to sharing information about the use of cannabidiol-enriched cannabis to treat their child's seizures. Nineteen responses met the following inclusion criteria for the study: a diagnosis of epilepsy and current use of cannabidiol-enriched cannabis. Thirteen children had Dravet syndrome, four had Doose syndrome, and one each had Lennox–Gastaut syndrome and idiopathic epilepsy. The average number of antiepileptic drugs (AEDs) tried before using cannabidiol-enriched cannabis was 12. Sixteen (84%) of the 19 parents reported a reduction in their child's seizure frequency while taking cannabidiol-enriched cannabis. Of these, two (11%) reported complete seizure freedom, eight (42%) reported a greater than 80% reduction in seizure frequency, and six (32%) reported a 25–60% seizure reduction. Other beneficial effects included increased alertness, better mood, and improved sleep. Side effects included drowsiness and fatigue. Our survey shows that parents are using cannabidiol-enriched cannabis as a treatment for their children with treatment-resistant epilepsy. Because of the increasing number of states that allow access to medical cannabis, its use will likely be a growing concern for the epilepsy community. Safety and tolerability data for cannabidiol-enriched cannabis use among children are not available. Objective measurements of a standardized preparation of pure cannabidiol are needed to determine whether it is safe, well tolerated, and efficacious at controlling seizures in this pediatric population with difficult-to-treat seizures.
 
 
Marijuana and Epilepsy
 
 
Original Contribution| January 11, 2012 Association Between Marijuana Exposure and Pulmonary Function Over 20 Years
 
Conclusion Occasional and low cumulative marijuana use was not associated with adverse effects on pulmonary function.
 
 
Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1
 
Cannabinoids inhibit cancer cell invasion via increasing tissue inhibitor of matrix metalloproteinases-1 (TIMP-1).
 
 
 
Cannabis in Palliative Medicine: Improving Care and Reducing Opioid-Rel­ated Morbidity
 
Published online before print March 28, 2011, J HOSP PALLIAT CARE August 2011 vol. 28 no. 5 297-303
 
 
Published online ahead of print August 30, 2010 CMAJ 10.1503/cm­aj.091414
 
Smoked cannabis for chronic neuropathi­c pain: a randomized controlled trial
 
Conclusion
 
Our results support the claim that smoked cannabis reduces pain, improves mood and helps sleep. We believe that our trial provides a methodological approach that may be considered for further research. Clinical studies using inhaled delivery systems, such as vaporizers,32,33 are needed.
 
 
Cases J. 2009; 2: 7487.
 
Published online 2009 May 18
 
Standardiz­ed natural product cannabis in pain management and observatio­ns at a Canadian compassion society: a case report
 
The roughly 4000 members of the Green Cross Society find similar benefit from standardized natural product cannabis medicine. To follow, will be publication of the Society's demographic data regarding use for various conditions such as arthritis, fybromyalgia, HIV/AIDS, and chronic pain, to name a few. A breakdown of the illnesses, what strains (cannabinoid profiles) is most effective, and at what dosages will be published at a later time.
 
 
Effect of D9-tetrahydrocannabinol, a cannabinoid receptor agonist, on the triggering of transient lower oesophageal sphincter relaxations in dogs and humans
 
These findings confirm previous findings in dogs and indicate that CB receptors are also involved in the triggering of TLESRs in humans.
 
 
Drugs: 9 July 2010 - Volume 70 - Issue 10 - pp 1245-1254
 
Pharmacological Management of Pain in Patients with Multiple Sclerosis
 
Cannabinoids have been among the few treatments studied in well designed, randomized, placebo-controlled trials for central neuropathic pain. In the largest of these trials, which included 630 subjects, a 15-week comparison between Δ9-tetrahydrocannabinol and placebo was performed. More patients receiving active treatment perceived an improvement in pain than those receiving placebo, although approximately 20% of subjects reported worsening of pain while on active treatment.
 
 
Cannabinoids control spasticity and tremor in a multiple sclerosis model
 
The exacerbation of these signs after antagonism of the CB1 and CB2 receptors, notably the CB1 receptor, using SR141716A and SR144528 (ref. 8) indicate that the endogenous cannabinoid system may be tonically active in the control of tremor and spasticity. This provides a rationale for patients' indications of the therapeutic potential of cannabis in the control of the symptoms of multiple sclerosis2, and provides a means of evaluating more selective cannabinoids in the future.
 
 
 
 

           AT7867 Is a Potent and Oral Inhibitor of AKT and p70 S6 Kinase That Induces Pharmacodynamic Changes and Inhibits Human Tumor Xenograft Growth         
Grimshaw, K. M. and Hunter, L.-J. K. and Yap, T. A. and Heaton, S. P. and Walton, M. I. and Woodhead, S. J. and Fazal, L. and Reule, M. and Davies, T. G. and Seavers, L. C. and Lock, V. and Lyons, J. F. and Thompson, N. T. and Workman, P. and Garrett, Michelle D. (2010) AT7867 Is a Potent and Oral Inhibitor of AKT and p70 S6 Kinase That Induces Pharmacodynamic Changes and Inhibits Human Tumor Xenograft Growth. Molecular Cancer Therapeutics, 9 (5). pp. 1100-1110. ISSN 1535-7163. (doi:https://doi.org/10.1158/1535-7163.MCT-09-0986 ) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)