Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Ichthyological Bulletin J.L.B. Smith Institute of Ichthyology; No. 71

The present study was undertaken to describe the species composition, size composition and distribution of the fish fauna associated with the temporarily open/closed East Kleinemonde Estuary on the southeast coast of South Africa. Data collected on the estuary mouth condition from March 1993 to August 1997 indicated that this system was predominantly closed, while open mouth conditions were unseasonal and prevailed for only a short duration following periods of high rainfall. Fishes were sampled throughout the estuary between April 1993 and January 1997 using seine and gill nets. A total of 30 species belonging to 17 families were recorded, including the critically endangered estuarine pipefish Syngnathus watermeyeri. Besides the estuarine pipefish, an additional five species capable of completing their life cycle within the estuary were recorded. The ichthyofaunal community was dominated by 18 marine-spawning species with varying degrees of dependence on estuaries as nursery areas. The marine species that are not dependent on estuaries as nursery areas were represented by three species, while the euryhaline freshwater species, obligate catadromous species and facultative catadromous species were each represented by one species. The dominant members of the estuarine-spawning group were well represented by all post-larval life-history stages, whereas the mean size of each marine-spawning species indicated that juvenile size classes dominated this group. Classification and ordination of both the small- and large-mesh seine net fish assemblages revealed a high degree of similarity throughout the estuary, with the exception of a distinct grouping associated with sandy substrata in the lower reaches of the system. Catch per unit effort (CPUE) data provided evidence of spatial segregation by several species as well as within some families (e.g. Gobiidae).Rhodes University Libraries (Digitisation

Recent disclosures of clinical drug candidates

On December 6, 2007, the Society for Medicines Research held a one-day meeting entitled Recent Disclosures of Clinical Drug Candidates. The meeting brought together speakers from around the world representing both the pharmaceutical industry and academia. The meeting provided an overview of some of the latest approaches being taken in a range of therapeutic areas such as oncology, immunology, central nervous system disease, gastroenterology and antiviral research. Copyright 2008 Prous Science, S.A.U. or its licensors. All rights reserved

Herboxidiene: Determination of absolute configuration by degradation and synthetic studies

Degradation of the novel polyketide herbicide herboxidiene leads to useful fragments for further analogue synthesis and also enabled determination of the absolute configuration of the natural product via asymmetric synthesis of the respective fragments. A combination of degradation, and asymmetric synthetic studies enabled the absolute configuration of herboxidiene to be determined. The fragments obtained from degradation are useful for the preparation of semi-synthetic herboxidiene analogues

On the effectiveness of supplemental instruction: a systematic review of supplemental instruction and peer-assisted study sessions literature between 2001 and 2010

Supplemental instruction (SI)—variously known as peer-assisted learning, peer-assisted study sessions, and other names—is a type of academic support intervention popular in higher education. In SI sessions, a senior student facilitates peer learning between undergraduates studying a high-risk course. This article presents a systematic review of the literature between 2001 and 2010 regarding the effectiveness of SI. Twenty-nine studies met the inclusion criteria. Due to methodological heterogeneity and lack of consistency defining the SI treatment, qualitative synthesis methods were applied. For seven included studies, however, an effect size of SI participation on final grades was calculated, ranging from d = 0.29 to d = 0.60. The findings of the review are consistent with claims validated by the U.S. Department of Education in the 1990s that participation in SI is correlated with higher mean grades, lower failure and withdrawal rates, and higher retention and graduation rates

Aldosterone Secretagogues Increase Adrenal Blood Flow in Male Rats

Small and medium enterprises (SMEs) that make alpaca fiber products, require a model of partnership that enables dynamic and efficient care in the short term, demand for their goods, these requirements are the result of international treaties the country has signed. This model takes into account the particular characteristics that markets have, commons and key stakeholders, so that in this way succeeds in raising the competitiveness of domestic products in the international market and thus the development and improvement of quality of life.Las pequeñas y medianas empresas (PYMES) que elaboran productos con fibra de alpaca, requieren de un modelo de asociatividad dinámico y eficiente que permita atender, en el corto plazo, la gran demanda de sus artículos; dichos requerimientos son fruto de los tratados internacionales que el país viene firmando. Este modelo toma en consideración las características particulares que tienen los mercados, los bienes comunes (7) y los actores clave; para que de este modo se logre elevar el nivel de competitividad de los productos nacionales en el mercado internacional y con ello el desarrollo y la mejora de calidad de vid