https://pubs.rsc.org/en/content/articlepdf/2013/cc/c3cc41143e

Exploration of the medical periodic table: towards new targets

Object Gliadel (BCNU) wafer and concomitant temozolomide (TMZ) therapy, when used individually as adjuvant therapies, extend survival from that achieved by resection and radiation therapy (XRT) for glioblastoma multiforme (GBM). It remains unstudied whether combining Gliadel and TMZ therapy is safe or further improves survival in patients with newly diagnosed GBM. The authors reviewed their initial experience utilizing combined Gliadel, TMZ, and radiation therapy for the treatment of GBM. Methods All cases involving patients undergoing primary resection of GBM with or without Gliadel wafer (3.85% BCNU) implantation and adjuvant XRT over a 10-year period (1997–2006) were retrospectively reviewed. Beginning in 2004, concomitant TMZ became the standard of care at the authors' institution and all patients with Gliadel implantation also received concomitant TMZ (Stupp protocol). Overall survival and treatment-related morbidity were assessed for all patients treated with Gliadel plus concomitant TMZ (XRT + Glia...

Gliadel (BCNU) wafer plus concomitant temozolomide therapy after primary resection of glioblastoma multiforme

Glioblastoma (GBM) is the most common and aggressive primary brain tumor with very poor patient median survival. To identify a microRNA (miRNA) expression signature that can predict GBM patient survival, we analyzed the miRNA expression data of GBM patients (n=222) derived from The Cancer Genome Atlas (TCGA) dataset. We divided the patients randomly into training and testing sets with equal number in each group. We identified 10 significant miRNAs using Cox regression analysis on the training set and formulated a risk score based on the expression signature of these miRNAs that segregated the patients into high and low risk groups with significantly different survival times (hazard ratio [HR]=2.4; 95% CI=1.4-3.8; p<0.0001). Of these 10 miRNAs, 7 were found to be risky miRNAs and 3 were found to be protective. This signature was independently validated in the testing set (HR=1.7; 95% CI=1.1-2.8; p=0.002). GBM patients with high risk scores had overall poor survival compared to the patients with low risk scores. Overall survival among the entire patient set was 35.0% at 2 years, 21.5% at 3 years, 18.5% at 4 years and 11.8% at 5 years in the low risk group, versus 11.0%, 5.5%, 0.0 and 0.0% respectively in the high risk group (HR=2.0; 95% CI=1.4-2.8; p<0.0001). Cox multivariate analysis with patient age as a covariate on the entire patient set identified risk score based on the 10 miRNA expression signature to be an independent predictor of patient survival (HR=1.120; 95% CI=1.04-1.20; p=0.003). Thus we have identified a miRNA expression signature that can predict GBM patient survival. These findings may have implications in the understanding of gliomagenesis, development of targeted therapy and selection of high risk cancer patients for adjuvant therapy.

/pdf/a-ten-microrna-expression-signature-predicts-survival-in-4yaitobg2u.pdf

A ten-microRNA expression signature predicts survival in glioblastoma.

http://csmres.co.uk/cs.public.upd/article-downloads/Challenges-and-opportunities-for-non-antibody-scaffold-drugs.pdf

Challenges and opportunities for non-antibody scaffold drugs.

Aims/hypothesis: Obesity is an independent risk factor for heart diseases but the underlying mechanism is not clear. This study examined cardiac contraction, oxidative stress, oxidative modification of sarco(endo) plasmic reticulum Ca 2+ -ATPase (SERCA) and the myosin heavy chain (MHC) isoform switch in obese mice. Methods: Mechanical properties were evaluated in ven- tricular myocytes from C57BL/6J lean and Lep/Lep obese mice (formerly known as ob/ob mice), including peak shortening (PS), time to 50 or 90% PS, time to 50 or 90% relengthening (TR50 ,T R 90), maximal velocity of short- ening/relengthening (±dL/dt), intracellular Ca 2+ and its decay (τ). Oxidative stress, lipid peroxidation, protein damage and SERCA activity were assessed by glutathi- one/glutathione disulfide, malondialdehyde, protein car- bonyl and 45 Ca 2+ uptake, respectively. NADPH oxidase was determined by immunoblotting. Results: Myocytes from Lep/Lep mice displayed depressed PS and ± dL/dt, prolonged TR50 ,T R90, elevated resting (Ca 2+ )i, prolonged τ, reduced contractile capacity at high stimulus frequen- cies and diminished responsiveness to extracellular Ca 2+ compared with lean controls. Cardiac glutathione/gluta- thione disulfide was decreased whereas malondialdehyde, protein carbonyl, membrane p47 phox and membrane gp91 phox were increased in the Lep/Lep group. SERCA isoenzyme 2a was markedly modified by oxidation in Lep/ Lep hearts and associated with decreased 45 Ca 2+ uptake. The MHC isozyme displayed a shift from the α to the β isoform in Lep/Lep hearts. Short-term incubation of angiotensin II with myocytes mimicked the mechanical defects, SERCA oxidation and 45 Ca 2+ uptake seen in Lep/ Lep myocytes. Incubation of the NADPH oxidase inhib- itor apocynin with Lep/Lep myocytes alleviated contractile defects without reversing SERCA oxidation or activity. Conclusions/interpretation: These data indicate that obe- sity-related cardiac defects may be related to NADPH oxidase activation, oxidative damage to SERCA and the MHC isozyme switch.

/pdf/cardiac-contractile-dysfunction-in-lep-lep-obesity-is-sdzothxqar.pdf

Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca2+-ATPase and myosin heavy chain isozyme switch.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/j.febslet.2005.01.049

A newly synthetic chromium complex – chromium(phenylalanine)3 improves insulin responsiveness and reduces whole body glucose tolerance

Glioblastomas (GBMs) are among the most aggressive of all known human tumors. The median survival times remain in the 12- to 15-month range despite aggressive surgery, radiation, and chemotherapy. Through molecular and genetic profiling efforts, underlying mechanisms of resistance to these therapies are becoming better understood. The present standard of care has been shaped by the recently reported phase III study by the European Organisation for Research and Treatment of Cancer and the National Cancer Institute of Canada, which found that the addition of temozolomide (TMZ) to radiation therapy significantly improved outcome compared with radiation alone. However, careful examination of these data reveals that not all GBM patients benefited from the addition of TMZ to radiation therapy. A companion correlative study found that GBM patients with tumors with MGMT promoter methylation appeared to derive the greatest benefit from the addition of TMZ to radiation therapy. Although this finding is provocative, it should be kept in mind that this study was performed retrospectively and that prospective validation is required before MGMT methylation can be used for clinical stratification purposes. However, this study does show promise for the tailoring of future treatments according to the molecular and genetic profiles of an individual's tumor rather than using the "one-glove-fits-all" approach that is currently being followed. As more effective "smart drugs" are developed, molecular and genetic profiling will assume even greater importance in this regard.

Predictive and prognostic markers in human glioblastomas.

Synthesis, characterization, and aqueous chemistry of cytotoxic Au(III) polypyridyl complexes

Malignant gliomas remain among the most treatment-refractory tumors. Traditional upfront treatment regimens have incorporated nitrosurea-based chemotherapy. This strategy has evolved to include temozolomide-based approaches. Promising Phase I/II data with TMZ in the recurrent setting prompted a Phase III EORTC study of TMZ in combination with RT for patients with newly diagnosed GBM. The landmark EORTC 26981-22981/NCIC CE3 study demonstrated a significant improvement in not only median survival, but also in terms of 2-year survival. Given that over one-quarter of the patients enrolled on the TMZ + RT arm survived beyond 2-years, there appears to be a finite percentage of patients who derive long-term benefit from this treatment regimen. Given that the EORTC-based regimen represents an incremental improvement in the standard of care, rather than a truly curative solution for most patients, further efforts must be expended to identify novel therapeutic approaches. To this end, targeted therapies have emerged as an attractive option. Accumulating evidence suggests that certain molecular pathways are selectively upregulated in tumor vs. normal cells. Some of these pathways have been shown to be instrumental in proliferation, migration, invasion, angiogenesis, and/or survival in preclinical models. These would appear to represent ideal therapeutic targets, as their antagonism may lead to an improvement in the therapeutic ratio of radiation. Emerging data from clinical studies on "first generation" targeted therapies appear to demonstrate benefit for select patients. Further molecular/genetic profiling must be undertaken to identify exactly which patients benefit.

Kamalakannan Palanichamy

Papers

A newly synthetic chromium complex – chromium(phenylalanine)3 improves insulin responsiveness and reduces whole body glucose tolerance

Predictive and prognostic markers in human glioblastomas.

Synthesis, characterization, and aqueous chemistry of cytotoxic Au(III) polypyridyl complexes

Overcoming therapeutic resistance in malignant gliomas: current practices and future directions.

Antioxidant properties of argpyrimidine