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Nature jobs - a look to the future ahead of time

March 16, 2010

Nature jobs.com is the premier science recruitment website listing > 6000 jobs across all scientific disciplines from both academic and commercial research centers. Its free, making it the site of choice for many institutions.

Silence therapeutics: a PKN3 specific RNAi patent - But how good is the target?

February 9, 2010

Analysis of:Silence Therapeutics to get RNAi patent covering novel cancer target | www.pharmabiz.com

Dosing has begun in a phase I study of Atu027, the RNAi molecule that specifically targets protein kinase N3 (PKN3) for the treatment of advanced solid tumors. The study should be completed in another 12 months.

B cells promote solid tumor formation - another use for Rituximab?

February 6, 2010

Analysis of:FcRγ Activation Regulates Inflammation-Associated Squamous Carcinogenesis | www.cell.com

Using a mouse model of squamous carcinogenesis, Andreu and colleagues showed a functional role for B cells in defining a pro tumor micro environment in premalignant tissue.  In mice deplete of B cells, this process was effectively stalled.  The authors speculate that targeting B lymphocytes or their downstream effectors could therefore offer a rationale anti cancer therapeutic approach.

Epigenomics: PRESEPT Study – Septin 9 methylation in colon cancer

February 4, 2010

Analysis of:Epigenomics AG Reports Conclusions from PRESEPT Study Audit | www.epigenomics.com

Epigenomics is a molecular diagnostics company with a focus on DNA methylation biomarkers aimed at diagnosing cancer before symptoms occur. Its product portfolio includes the detection of colorectal cancer in blood that is based on methylation status of the biomarker Septin9. Two of the three testing laboratories that performed Septin9 analysis achieved cancer detection rates of 62.5% and a third laboratory a somewhat lower rate of 28%. This may be due to an instrument malfunction.

Bayer: Follicular Lymphoma - Idiotype Vaccination versus R maintenance

February 2, 2010

Analysis of:Bayer begins phase-I study with Idiotype vaccination, a personalized vaccine from tobacco plants to treat non-Hodgkin's lymphoma | www.pharmabiz.com

The natural history of Follicular lymphoma is characteristic of so called ‘indolent’ lymphomas, with a relatively prolonged survival (10 yrs) and a pattern of repeat responses to treatment and subsequent recurrences. The presence of residual tumor following therapy is associated with shorter time to relapse. Treatment of patients in complete remission with a personalized vaccine that directly targets these residual tumor cells may offer an alternative to  'maintenance Rituximab' approaches.

Phase I of PKN3 silencing: how will this compare with PI3K-mTOR inhibition

December 22, 2009

Analysis of:Silence Therapeutics merges with Intradigm Corp to form RNAi therapeutics company | www.pharmabiz.com

RNAi is a competitive arena. The planned merger increases the choice of technologies on offer to pharmaceutical industry  to deliver RNAi molecules. This is recognized as one of the main challenges in the emerging field of RNAi therapeutics.

Biomarkers - Capturing Long Distant DNA Interactions by Parallel Sequencing

December 18, 2009

Analysis of:Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human Genome | www.sciencemag.org

The compaction of DNA within the nucleus is non random bringing disparate genes and promotor regions in much closer proximity to each other than their linear distance would suggest.  These interactions can be frozen within the nucleus and the interacting DNA catalogued by massive parallel sequence analysis (Illumina). In essence, we can now detect long distant DNA interactions that were previously out of reach.

Epigenetics - Aberrant Control of H3K27me3 - mutations in both EZH2 and UTX

December 16, 2009

Analysis of:Tyrosine 641 of the EZH2 Oncogene Is Frequently Mutated in Follicular and Diffuse Large B-Cell Lymphomas of Germinal Center Origin | ash.confex.com

EZH2, part of the polycomb repressive complex 2 (PRC2), which trimethylates lysine 27 of histone H3 (H3K27me3) plays an essential role in the epigenetic maintenance of this repressive chromatin mark . Mutations in EZH2 have now been reported in 10-20% of germinal center lymphomas, specifically targeting Tyrosine 641 within the catalytic domain and near abolishing its trimethylating potential.

DLBCL - Millennium - Bortezomib - know your ABCs from your GCBs

December 14, 2009

Analysis of:Differential efficacy of Bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. | www.ncbi.nlm.nih.gov

Diffuse Large B cell Lymphoma (DLBCL) can be divided into 2 distinct genetic entities referred to as Germinal Center B cell-like (GCB) and Activated B cell-like (ABC) forms, as defined by their gene expression profiles. The ABC type is characterized by constitutive activation of the NF-kappa B pathway. The data by Dunleavy and colleagues suggest that Bortezomib (Millennium) enhances the activity of chemotherapy in ABC but not GCB DLBCL by specifically targeting this pathway.

Metabolomics: Agios Pharmaceuticals - 2HG production in brain cancers

December 12, 2009

Analysis of:Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. | www.ncbi.nlm.nih.gov

Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a feature of primary human brain cancers. These mutations result in loss of the enzyme's ability to catalyse conversion of isocitrate to alpha-ketoglutarate. Recent studies by Agios Pharmaceuticals (Nature. 2009 Nov 22) have demonstrated that these cancer-associated IDH1 mutations result in a novel gain in function and lead to the accumulation of an onco-metabolite called hydroxyglutarate (2HG).

New Cancer Drugs: Distinguishing between genes 'sinning' and those 'sinned against'.

February 29, 2008

Analysis of:Cancer drugs should be tailored to fit patient | www.fiercebioresearcher.com

In the accident of the cancer genome there will always be collateral damage. The difficulty is therefore distinguishing between mutations that are driving cell survival and proliferation (sinners) versus those which merely are passengers, neutral changes (sinned against) that arose at precisely the same time or as a consequence of the main cancer causing events. Brute force sequencing becomes the easy part and functional studies will be necessary to identify the fraction of mutations that have any relevant.

No increased risk of haematopoietic malignancies and solid cancers after treatment with TNF antagonists

February 29, 2008

Analysis of:Hematologic Malignant Neoplasms After Drug Exposure in Rheumatoid Arthritis | archinte.ama-assn.org

The Quebec study did not examine the effect of TNF antogonists on cancer incidence. Two recent studies followed an antagonist (Etanercept, Infliximab, Adalimumab) treated cohort (n=4160) from 1999-2003 (Askling et al Ann Rheum Dis. 2005 Oct;64(10):1414-20 and 1421-26). Risk of solid cancer or lymphoma was no higher in TNF treated RA patients  than other RA cohorts.

Drivers and Passengers: The complexity and heterogeneity of mutational signatures in cancer means that sequencing becomes the easy part.

February 26, 2008

Analysis of:Study: More Complexity In Tailoring Cancer Drugs | online.wsj.com

In the accident of the cancer genome there will always be collateral damage. The difficulty is therefore distinguishing between mutations that are driving cell survival and proliferation versus those which merely are passengers, neutral changes that arose at precisely the same time or as a consequence of the main cancer causing events. This is summed up perfectly by a recent quote by Bert Vogelstein “ what’s clear now that wasn’t clear at the beginning of the Cancer Genome Atlas is the complexity and heterogeneity of the mutational signatures that are going to be found in most cancers………… the sequencing becomes the easy part – the harder and longer road is going to be to figure out what it all means in functional studies”. We are certainly on the right road – no one however can say for sure how long this road will be and what lies in store at the end of it.

Padova Italy - 10 years on : Patient Safety: Things are getting better!

February 25, 2008

Analysis of:Managing Preanalytical Processes for Patient Safety | www.medcompare.com

Carraro P and Plebani M have recently updated their 1997 study; Errors in a stat laboratory: types and frequencies 10 years later: Clin Chem. 2007 Jul;53(7):1338-42. http://www.ncbi.nlm.nih.gov/pubmed/17525103?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum Of 51,746 analyses 160 findings were confirmed as laboratory errors.

SNPing to identify the genetic basis of prostate cancer

February 18, 2008

Analysis of:Prostate Cancer Genetics | www.nhs.uk

Genome wide association studies compare the incidence of DNA sequence variants in large cohorts of patients and controls as a strategy to identify common genetic factors responsible for disease.  In three recent reports in Nature Genetics (Gudmundsson, Thomas and Eeles: 10 February 08) the Illumina SNP chip platforms were utilised to compare DNA variants in >50,000 patients and controls. The studies identified new disease variants on several chromosomes and confirmed previously reported associations. Of particular note, the gene encoding beta-microseminoprotein, a protein synthesised by the epithelial cells of the prostate and a primary constituent of semen was independently identified in 2 studies. The tedious process of combing genomic regions for the precise causal variants in other locations is underway.

Drop outs: a new key to unlocking cell survival and proliferation pathways in cancer

February 14, 2008

Analysis of:Gene discovery through functional genomics | www.ncbi.nlm.nih.gov

In papers by Silva and Schlabach published in Science (1st Feb 08) RNA silencing was used to selectively remove genes, one at a time, from cancer cell lines in order to measure their influence on cell survival and proliferation. The beauty of the approach is that 1000s of genes can be assayed simultaneously but only those genes affecting the cancer's ability to survive or its proliferation capacity are 'deselected' (drop out) and can be readily identified. These genes or their corresponding proteins may therefore represent a cancer's achilles heal and offer a means by which the cancer cell can be efficiently targeted.

Hair follicle gene expression profiling as a means of assessing new cancer treatments

February 11, 2008

Analysis of:Epistem plc and AstraZeneca Complete Plucked Hair Biomarker Study for Oncology Drug Development | www.foxbusiness.com

The key to the current study is whether sequential gene expression profiling of hair follicles before and during the course of a patient's treatment can be 'linked to changes in tumours' and act therefore 'to determine drug exposure, toxicity and dose response'. The authors, and indeed previous studies, have shown (Ann Clin Lab Sci. 2006 Spring;36(2):115-26) the technical feasibility of this approach.   The success of the study depends therefore on normal variability between individuals and characterising a meaningful 'core gene sets' that are have sufficent predictive power to infer that the drug is actually hitting its target. It will be interesting to follow the 'checks and balances' that will be used to test the validity of this approach.    

Genetic risk stratification in intermediate risk AML

February 4, 2008

Analysis of:MolMed's actue leukemia drug receives approval to start phase III | www.checkbiotech.org

Mutation profiling in large series of patients with acute myeloid leukemia has identified particular genes and patterns of mutation (FLT3, NPM, MLL, WT1) that confer poor outcome in intermediate/normal cytogenetic risk AML groups. This groups represents >50% of AMLs. Improvements in transplant-related mortality through TK008 would be valuable, not only in high risk poor cytogenetic group cases but also in deciding on treatment options for this intermediate group.

Such partnerships may become the norm following the '1000 Genomes Project' :

February 4, 2008

Analysis of:World class researchers in gene tie-up | www.businessweekly.co.uk

The success of the planned studies on depression and obesity to search for genetic variants associated with these diseases, announced in the collaboration between MRC and GSK in the UK, is dependant on having sufficiently large cohorts of patients with allied clinical information and long term follow for meaningful analysis. New drug development is aways off. Any short-term success Target will be dependent on the variants or pathways identified and if compounds targeting these pathways are already in play.

Is the efficacy of a molecule with two antibody functions <, >, or = to administering two antibody therapies separately?

November 1, 2007

Analysis of:Abbott Scientists Create One Molecule With Two Antibody Functions | www.pipelinereview.com

The manuscript by Wu and colleagues published in Nature Biotechnology online: 14 October 2007 could lead the way for 'simultaneous blockade of multiple targets'  to 'yield better therapeutic efficacy than inhibition of a single target' throught the development of a 'dual-variable-domain immunoglobulin (DVD-Ig)— that can be engineered from any two monoclonal antibodies while preserving activities of the parental antibodies'.

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