PARP-1 regulates DNA repair factor availability.

PARP-1 holds major functions on chromatin, DNA damage repair and transcriptional regulation, both of which are relevant in the context of cancer. Here, unbiased transcriptional profiling revealed the downstream transcriptional profile of PARP-1 enzymatic activity. Further investigation of the PARP-1-regulated transcriptome and secondary strategies for assessing PARP-1 activity in patient tissues revealed that PARP-1 activity was unexpectedly enriched as a function of disease progression and was associated with poor outcome independent of DNA double-strand breaks, suggesting that enhanced PARP-1 activity may promote aggressive phenotypes. Mechanistic investigation revealed that active PARP-1 served to enhance E2F1 transcription factor activity, and specifically promoted E2F1-mediated induction of DNA repair factors involved in homologous recombination (HR). Conversely, PARP-1 inhibition reduced HR factor availability and thus acted to induce or enhance BRCA-ness . These observations bring new understanding of PARP-1 function in cancer and have significant ramifications on predicting PARP-1 inhibitor function in the clinical setting

Quantum Electronics

Contains thirteen research projects split into three sections.U.S. Air Force - Rome Air Development Center (Contract F19628-80-C-0077)National Science Foundation (Grant PHY79-09739)Joint Services Electronics Program (Contract DAAG29-78-C-0020)Joint Services Electronics Program (Contract DAAG29-80-C-0104)U.S. Air Force Geophysics Laboratory (AFSC) (Contract F19628-79-C-0082)National Science Foundation (Grant ECS79-19475)National Science Foundation (Grant DAR80-08752)National Science Foundation (Grant ENG79-09980

Structure-Based Screen Identifies a Potent Small Molecule Inhibitor of Stat5a/b with Therapeutic Potential for Prostate Cancer and Chronic Myeloid Leukemia.

Bypassing tyrosine kinases responsible for Stat5a/b phosphorylation would be advantageous for therapy development for Stat5a/b-regulated cancers. Here, we sought to identify small molecule inhibitors of Stat5a/b for lead optimization and therapy development for prostate cancer and Bcr-Abl-driven leukemias. In silico screening of chemical structure databases combined with medicinal chemistry was used for identification of a panel of small molecule inhibitors to block SH2 domain-mediated docking of Stat5a/b to the receptor-kinase complex and subsequent phosphorylation and dimerization. We tested the efficacy of the lead compound IST5-002 in experimental models and patient samples of two known Stat5a/b-driven cancers, prostate cancer and chronic myeloid leukemia (CML). The lead compound inhibitor of Stat5-002 (IST5-002) prevented both Jak2 and Bcr-Abl-mediated phosphorylation and dimerization of Stat5a/b, and selectively inhibited transcriptional activity of Stat5a (IC50 = 1.5μmol/L) and Stat5b (IC50 = 3.5 μmol/L). IST5-002 suppressed nuclear translocation of Stat5a/b, binding to DNA and Stat5a/b target gene expression. IST5-002 induced extensive apoptosis of prostate cancer cells, impaired growth of prostate cancer xenograft tumors, and induced cell death in patient-derived prostate cancers when tested ex vivo in explant organ cultures. Importantly, IST5-002 induced robust apoptotic death not only of imatinib-sensitive but also of imatinib-resistant CML cell lines and primary CML cells from patients. IST5-002 provides a lead structure for further chemical modifications for clinical development for Stat5a/b-driven solid tumors and hematologic malignancies

A ‘living fossil’ eel (Anguilliformes: Protanguillidae, fam. nov.) from an undersea cave in Palau

We report the discovery of an enigmatic, small eel-like fish from a 35 m-deep fringing-reef cave in the western Pacific Ocean Republic of Palau that exhibits an unusual suite of morphological characters. Many of these uniquely characterize the Recent members of the 19 families comprising the elopomorph order Anguilliformes, the true eels. Others are found among anguilliforms only in the Cretaceous fossils, and still others are primitive with respect to both Recent and fossil eels. Thus, morphological evidence explicitly places it as the most basal lineage (i.e. the sister group of extant anguilliforms). Phylogenetic analysis and divergence time estimation based on whole mitogenome sequences from various actinopterygians, including representatives of all eel families, demonstrate that this fish represents one of the most basal, independent lineages of the true eels, with a long evolutionary history comparable to that of the entire Anguilliformes (approx. 200 Myr). Such a long, independent evolutionary history dating back to the early Mesozoic and a retention of primitive morphological features (e.g. the presence of a premaxilla, metapterygoid, free symplectic, gill rakers, pseudobranch and distinct caudal fin rays) warrant recognition of this species as a ‘living fossil’ of the true eels, herein described as Protanguilla palau genus et species nov. in the new family Protanguillidae

Is there a role for the quantification of RRM1 and ERCC1 expression in pancreatic ductal adenocarcinoma?

<p>Abstract</p> <p>Background</p> <p>RRM1 and ERCC1 overexpression has been extensively investigated as potential predictive markers of tumor sensitivity to conventional chemotherapy agents, most thoroughly in lung cancer. However, data in pancreatic cancer are scarce.</p> <p>Methods</p> <p>We investigated the mRNA and protein expression of ERCC1 and RRM1 by RT-PCR and immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded pancreatic ductal carcinoma (PDA) tissues. The primary outcome investigated was the association between RRM1 and ERCC1 expression and overall survival (OS) or disease-free survival (DFS).</p> <p>Results</p> <p>A total of 94 patients with resected PDA were included in this study. Most of them (87%) received gemcitabine based chemotherapy. Data for OS analysis was available in all cases but only 68% had enough information to estimate DFS. IHC analysis revealed information for 99% (93/94) and 100% of the cases for RRM1 and ERCC1 expression respectively. However, PCR data interpretation was possible in only 49 (52%) and 79 (84%) cases respectively. There was no significant association between high or low expression of either RRM1 or ERCC1, detected by IHC and OS (14.4 vs. 19.9 months; <it>P </it>= 0.5 and 17.1 vs. 19.9; <it>P </it>= 0.83 respectively) or PCR and OS (48.0 vs. 24.1 months; <it>P </it>= 0.21 and 22.0 vs. 16.0 months; <it>P </it>= 0.39 respectively). Similar results were obtained for DFS.</p> <p>Conclusions</p> <p>RRM1 and ERCC1 expression does not seem to have a clear predictive or prognostic value in pancreatic cancer. Our data raise some questions regarding the real clinical and practical significance of analyzing these molecules as predictors of outcomes.</p

Mast Cell-Derived Histamine Mediates Cystitis Pain

Background: Mast cells trigger inflammation that is associated with local pain, but the mechanisms mediating pain are unclear. Interstitial cystitis (IC) is a bladder disease that causes debilitating pelvic pain of unknown origin and without consistent inflammation, but IC symptoms correlate with elevated bladder lamina propria mast cell counts. We hypothesized that mast cells mediate pelvic pain directly and examined pain behavior using a murine model that recapitulates key aspects of IC. Methods and Findings: Infection of mice with pseudorabies virus (PRV) induces a neurogenic cystitis associated with lamina propria mast cell accumulation dependent upon tumor necrosis factor alpha (TNF), TNF-mediated bladder barrier dysfunction, and pelvic pain behavior, but the molecular basis for pelvic pain is unknown. In this study, both PRV-induced pelvic pain and bladder pathophysiology were abrogated in mast cell-deficient mice but were restored by reconstitution with wild type bone marrow. Pelvic pain developed normally in TNF- and TNF receptor-deficient mice, while bladder pathophysiology was abrogated. Conversely, genetic or pharmacologic disruption of histamine receptor H1R or H2R attenuated pelvic pain without altering pathophysiology. Conclusions: These data demonstrate that mast cells promote cystitis pain and bladder pathophysiology through the separable actions of histamine and TNF, respectively. Therefore, pain is independent of pathology and inflammation, an

Path dependence in energy systems and economic development

Energy systems are subject to strong and long-lived path dependence, owing to technological, infrastructural, institutional and behavioural lock-ins. Yet, with the prospect of providing accessible cheap energy to stimulate economic development and reduce poverty, governments often invest in large engineering projects and subsidy policies. Here, I argue that while these may achieve their objectives, they risk locking their economies onto energy-intensive pathways. Thus, particularly when economies are industrializing, and their energy systems are being transformed and are not yet fully locked-in, policymakers should take care before directing their economies onto energy-intensive pathways that are likely to be detrimental to their long-run prosperity

Transfusion-transmitted infections

Although the risk of transfusion-transmitted infections today is lower than ever, the supply of safe blood products remains subject to contamination with known and yet to be identified human pathogens. Only continuous improvement and implementation of donor selection, sensitive screening tests and effective inactivation procedures can ensure the elimination, or at least reduction, of the risk of acquiring transfusion transmitted infections. In addition, ongoing education and up-to-date information regarding infectious agents that are potentially transmitted via blood components is necessary to promote the reporting of adverse events, an important component of transfusion transmitted disease surveillance. Thus, the collaboration of all parties involved in transfusion medicine, including national haemovigilance systems, is crucial for protecting a secure blood product supply from known and emerging blood-borne pathogens

T. cruzi OligoC-TesT: A Simplified and Standardized Polymerase Chain Reaction Format for Diagnosis of Chagas Disease

Chagas disease (American trypanosomiasis) is caused by the protozoan parasite Trypanosoma cruzi and represents a major public health problem in Latin America. Furthermore, growing human population movements extend the disease distribution to regions outside the South American continent. Accurate diagnosis is crucial in patient care and in preventing transmission through blood transfusion, organ transplantation, or vertical transmission from mother to child. Routine diagnosis of Trypanosoma cruzi infection generally is based on detection of the host's antibodies against the parasite. However, antibody detection tests are liable to specificity problems and are of limited use in assessing treatment outcome and congenital infections. The introduction of the polymerase chain reaction (PCR) to amplify specific DNA sequences opened promising diagnostic perspectives. Despite its reported high sensitivity and specificity, broad use of the PCR technique in diagnosis of Chagas disease is hampered by its complexity and the lack of any standardization. We here present the development and evaluation of the T. cruzi OligoC-TesT, a simple and standardized dipstick format for detection of PCR amplified T. cruzi DNA. The new tool is an important step towards simplified and standardized molecular diagnosis of Chagas disease