Experimental evaluation of the anti-ulcer activity of the ethanolic extract of grape (Vitis vinifera) seed in wistar albino rats against aspirin plus pylorus ligation induced gastric ulcer model

Background: There is an increased demand for newer safer drugs for the treatment of peptic ulcer disease as its incidence is increasing gradually in view of changing lifestyle and stress. The objective of this study was to evaluate the anti-ulcer activity of ethanol extract of seeds of Vitis vinifera.Methods: The ethanol extract of Vitis vinifera was investigated for its anti-ulcer activity in rats against Aspirin plus Pylorus ligation induced gastric ulcer.The antiulcer activity was assessed by determining and comparing gastric volume, pH, free and total acidity; ulcer number and its inhibition, ulcer severity and ulcer index.Results: A significant antiulcer activity was observed. Pylorus ligation model showed significant (p<0.01) reduction in gastric volume, free acidity and ulcer index as compared to control.Conclusions: This present study indicates that Vitis vinifera seed extract have potential anti-ulcer activity in the model tested

EXPERIMENTAL EVALUATION OF THE ANTI-ULCER ACTIVITY OF GRAPE (VITIS VINIFERA) SEED EXTRACT IN WISTAR ALBINO RATS AGAINST HYDROCHLORIC ACID – ETHANOL INDUCED ULCER MODEL

Background:Herbal products are finding increasing demand in the treatment of Peptic ulcer, on account of their better safety and efficacy.Objectives:To evaluate the anti-ulcer activity of ethanolic extract of seeds of Vitis Vinifera in Wistar albino rats.Methods:The ethanolic extract of Vitis Vinifera was investigated for its anti-ulcer activity in rats against HCl – Ethanol induced ulcer model. The antiulcer activity was assessed by determining and comparing gastric volume, pH, free and total acidity; ulcer number and its inhibition, ulcer severity and ulcer index.Results:A significant antiulcer activity was observed. The grape seed 100mg/kg group showed significant [p &lt; 0.05] reduction in ulcer number 30.00 ± 3.23 as compared to the control. The grape seed 200mg/kg showed significant [p &lt; 0.05] reduction in ulcer number 27.33 ± 2.97, free acidity 20.00 ± 2.26, and gastric lesion18.00 ± 2.96 as compared to the control.Conclusion:This present study indicates that Vitis vinifera seed extract has potential anti ulcer activity in the model tested. Keywords: Vitis vinifera, Anti-ulcer, Ethanol, Free acidity, Total acidit

Generations and Gender Survey (GGS)

The Generations and Gender Survey (GGS) is one of the two pillars of the Generations and Gender Programme designed to improve understanding of demographic and social development and of the factors that influence these developments. This article describes how the theoretical perspectives applied in the survey, the survey design and the questionnaire are related to this objective. The key features of the survey include panel design, multidisciplinarity, comparability, context-sensitivity, inter-generational and gender relationships. The survey applies the life course approach, focussing on the processes of childbearing, partnership dynamics, home leaving, and retiring. The selection of topics for data collection mainly follows the criterion of theoretically grounded relevance to explaining one or more of the mentioned processes. A large portion of the survey deals with economic aspects of life, such as economic activity, income, and economic well-being; a comparably large section is devoted to values and attitudes. Other domains covered by the survey include gender relationships, household composition and housing, residential mobility, social networks and private transfers, education, health, and public transfers. The third chapter of the article describes the motivations for their inclusion. The GGS questionnaire is designed for a face-to-face interview. It includes the core that each participating country needs to implement in full, and four optional sub-modules on nationality and ethnicity, on previous partners, on intentions of breaking up, and on housing, respectively. The participating countries are encouraged to include also the optional sub-modules to facilitate comparative research on these topics.economic activity, event history, family, fertility, gender, generation, household, panel studies, survey, values

Unusual CD4+CD28nullT Lymphocytes and Recurrence of Acute Coronary Events

ObjectivesWe hypothesized that the expansion of unusual T lymphocytes, CD4+CD28nullT cells, might represent a key pathogenetic mechanism of recurrent instability.BackgroundClinical presentation of acute coronary syndromes (ACS) is variable. Some patients have recurrent episodes of instability, despite optimal treatment, whereas others have a single acute event in their life. The CD4+CD28nullT cells, with a functional profile that favors vascular injury, have recently been found both in peripheral blood and in unstable coronary plaques of patients with ACS.MethodsPeripheral blood T cells from 120 consecutive unstable angina (UA) patients were analyzed for the distribution of T-cell subsets by flow cytometry. Patients were subgrouped according to the occurrence of prior (during the 24 months before the study enrollment) and subsequent (during the 24 months of follow-up) acute coronary events. For 51 patients, the index event was the first ever (G1); 30 patients had prior events (G2); and 39 patients had further events at follow-up (death, myocardial infarction, or UA) or both before and after the index event (G3).ResultsThe CD4+CD28nullT-cell frequency was higher in G3 than in G2 and G1 (median 9.5% [range 2.4% to 48.0%] vs. 5.1% [range 0.4% to 27.8%] and 2.3% [range 0.2% to 22.8%], respectively; p < 0.001). The expansion of these unusual T lymphocytes was higher in patients with elevated C-reactive protein levels, and it was reduced by statin therapy. On multivariate logistic regression analysis, CD4+CD28nullT-cell frequency was an independent predictor of future acute coronary events (odds ratio 3.01, 95% confidence interval 1.1 to 8.25; p = 0.023).ConclusionsA perturbation of T-cell repertoire is strongly associated with the recurrence of acute coronary events, conceivably playing a key pathogenetic role

po 049 egfr blockade induces a paneth cell like phenotype with rewired signalling dependencies in crc tumoursat maximal response

Introduction Anti-EGFR therapies with the monoclonal antibodies cetuximab and panitumumab have improved survival in colorectal cancer (CRC) patients; nevertheless, incomplete mass obliteration and eventual relapse are a common setback, even after a plateau of maximal response. Preclinical data suggest that tumour recurrence may be fueled by a reservoir of so-called 'drug-tolerant persisters' that engage non-mutational routes of adaptation to therapy. Yet, the molecular underpinnings that sustain residual disease, as well as the strategies to oppose it, are largely unexplored. Material and methods The effects of targeted therapies were evaluated in patient-derived xenografts. The biochemical and biological consequences of drug exposure were gauged by immunohistochemistry and morphometric analyses (in vivo), and by time-lapse imaging, Western Blot, Cell Titer-Glo and Caspase-Glo assays (in vitro). Transcriptional perturbations were assessed by microarray analysis and/or RT-qPCR. The activity of transcriptional modulators was measured by reporter assays in vitro. Results and discussions Residual tumours surviving cetuximab treatment exhibited a quiescent, Wnt-high, and secretory/Paneth cell-like state as a distinctive trait. This pattern outlines that of EGFR-inhibited quiescent stem cells of the normal intestine, suggesting that developmental trajectories are somehow coopted by cancer cells to face external insults. Such phenotype was reversible with drug suspension, pointing to non-genetic plasticity as a determinant of cancer cell reprogramming. Residual tumours also displayed lower expression of EGFR-activating ligands, congruent with reduced EGFR dependency, and showed rewired reliance on compensatory HER2/HER3 activity, as well as persistent PI3K signalling. Mechanistically, the acquisition of Paneth cell-like features was mediated, at least partly, by inactivation of YAP – a key driver of intestinal cell regeneration. Therapeutically, combined blockade of EGFR and PI3K/AKT lessened residual disease burden, but did not lead to long-term disease control. However, treatment with panHER, a mixture of antibodies concurrently targeting EGFR, HER2, and HER3, reduced tumour volumes and delayed tumour relapse after therapy cessation. Conclusion Drug tolerance in cetuximab-sensitive CRC models involves a switch towards a Paneth-cell like state typified by sustained HER2/HER3 and PI3K signalling. Treatment with panHER effectively exhausted residual tumour burden and impeded/delayed late relapse

EGFR blockade reverts resistance to KRAS G12C inhibition in colorectal cancer

Most patients with KRAS G12C-mutant non-small cell lung cancer (NSCLC) experience clinical benefit from selective KRASG12C inhibition, whereas patients with colorectal cancer bearing the same mutation rarely respond. To investigate the cause of the limited efficacy of KRASG12C inhibitors in colorectal cancer, we examined the effects of AMG510 in KRAS G12C colorectal cancer cell lines. Unlike NSCLC cell lines, KRAS G12C colorectal cancer models have high basal receptor tyrosine kinase (RTK) activation and are responsive to growth factor stimulation. In colorectal cancer lines, KRASG12C inhibition induces higher phospho-ERK rebound than in NSCLC cells. Although upstream activation of several RTKs interferes with KRASG12C blockade, we identify EGFR signaling as the dominant mechanism of colorectal cancer resistance to KRASG12C inhibitors. The combinatorial targeting of EGFR and KRASG12C is highly effective in colorectal cancer cells and patient-derived organoids and xenografts, suggesting a novel therapeutic strategy to treat patients with KRAS G12C colorectal cancer. SIGNIFICANCE: The efficacy of KRASG12C inhibitors in NSCLC and colorectal cancer is lineage-specific. RTK dependency and signaling rebound kinetics are responsible for sensitivity or resistance to KRASG12C inhibition in colorectal cancer. EGFR and KRASG12C should be concomitantly inhibited to overcome resistance to KRASG12C blockade in colorectal tumors.See related commentary by Koleilat and Kwong, p. 1094.This article is highlighted in the In This Issue feature, p. 1079

Colorectal cancer residual disease at maximal response to EGFR blockade displays a druggable Paneth cell–like phenotype

Blockade of epidermal growth factor receptor (EGFR) causes tumor regression in some patients with metastatic colorectal cancer (mCRC). However, residual disease reservoirs typically remain even after maximal response to therapy, leading to relapse. Using patient-derived xenografts (PDXs), we observed that mCRC cells surviving EGFR inhibition exhibited gene expression patterns similar to those of a quiescent subpopulation of normal intestinal secretory precursors with Paneth cell characteristics. Compared with untreated tumors, these pseudodifferentiated tumor remnants had reduced expression of genes encoding EGFR-activating ligands, enhanced activity of human epidermal growth factor receptor 2 (HER2) and HER3, and persistent signaling along the phosphatidylinositol 3-kinase (PI3K) pathway. Clinically, properties of residual disease cells from the PDX models were detected in lingering tumors of responsive patients and in tumors of individuals who had experienced early recurrence. Mechanistically, residual tumor reprogramming after EGFR neutralization was mediated by inactivation of Yes-associated protein (YAP), a master regulator of intestinal epithelium recovery from injury. In preclinical trials, Pan-HER antibodies minimized residual disease, blunted PI3K signaling, and induced long-term tumor control after treatment discontinuation. We found that tolerance to EGFR inhibition is characterized by inactivation of an intrinsic lineage program that drives both regenerative signaling during intestinal repair and EGFR-dependent tumorigenesis. Thus, our results shed light on CRC lineage plasticity as an adaptive escape mechanism from EGFR-targeted therapy and suggest opportunities to preemptively target residual disease

Human fertility: sociodemographic aspects

This study analyzes the sociodemographic factors at the root of the reduction in fertility in developed countries and the way in which these are correlated to the increase in levels of infertility. The postponement of marriage and of bearing the first child, the transition still underway toward nontraditional family forms and unfavorable economic and institutional factors explain a considerable part of the increase in levels of infertility