Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients.

BACKGROUND: Remdesivir improves clinical outcomes in patients hospitalized with moderate-to-severe coronavirus disease 2019 (Covid-19). Whether the use of remdesivir in symptomatic, nonhospitalized patients with Covid-19 who are at high risk for disease progression prevents hospitalization is uncertain. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving nonhospitalized patients with Covid-19 who had symptom onset within the previous 7 days and who had at least one risk factor for disease progression (age ≥60 years, obesity, or certain coexisting medical conditions). Patients were randomly assigned to receive intravenous remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. The primary efficacy end point was a composite of Covid-19-related hospitalization or death from any cause by day 28. The primary safety end point was any adverse event. A secondary end point was a composite of a Covid-19-related medically attended visit or death from any cause by day 28. RESULTS: A total of 562 patients who underwent randomization and received at least one dose of remdesivir or placebo were included in the analyses: 279 patients in the remdesivir group and 283 in the placebo group. The mean age was 50 years, 47.9% of the patients were women, and 41.8% were Hispanic or Latinx. The most common coexisting conditions were diabetes mellitus (61.6%), obesity (55.2%), and hypertension (47.7%). Covid-19-related hospitalization or death from any cause occurred in 2 patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.03 to 0.59; P = 0.008). A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a Covid-19-related medically attended visit by day 28 (hazard ratio, 0.19; 95% CI, 0.07 to 0.56). No patients had died by day 28. Adverse events occurred in 42.3% of the patients in the remdesivir group and in 46.3% of those in the placebo group. CONCLUSIONS: Among nonhospitalized patients who were at high risk for Covid-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalization or death than placebo. (Funded by Gilead Sciences; PINETREE ClinicalTrials.gov number, NCT04501952; EudraCT number, 2020-003510-12.).

Blood Pressure Management After Endovascular Therapy for Acute Ischemic Stroke: The BEST-II Randomized Clinical Trial.

Importance: The effects of moderate systolic blood pressure (SBP) lowering after successful recanalization with endovascular therapy for acute ischemic stroke are uncertain. Objective: To determine the futility of lower SBP targets after endovascular therapy (<140 mm Hg or 160 mm Hg) compared with a higher target (≤180 mm Hg). Design, Setting, and Participants: Randomized, open-label, blinded end point, phase 2, futility clinical trial that enrolled 120 patients with acute ischemic stroke who had undergone successful endovascular therapy at 3 US comprehensive stroke centers from January 2020 to March 2022 (final follow-up, June 2022). Intervention: After undergoing endovascular therapy, participants were randomized to 1 of 3 SBP targets: 40 to less than 140 mm Hg, 40 to less than 160 mm Hg, and 40 to 180 mm Hg or less (guideline recommended) group, initiated within 60 minutes of recanalization and maintained for 24 hours. Main Outcomes and Measures: Prespecified multiple primary outcomes for the primary futility analysis were follow-up infarct volume measured at 36 (±12) hours and utility-weighted modified Rankin Scale (mRS) score (range, 0 [worst] to 1 [best]) at 90 (±14) days. Linear regression models were used to test the harm-futility boundaries of a 10-mL increase (slope of 0.5) in the follow-up infarct volume or a 0.10 decrease (slope of -0.005) in the utility-weighted mRS score with each 20-mm Hg SBP target reduction after endovascular therapy (1-sided α = .05). Additional prespecified futility criterion was a less than 25% predicted probability of success for a future 2-group, superiority trial comparing SBP targets of the low- and mid-thresholds with the high-threshold (maximum sample size, 1500 with respect to the utility-weighted mRS score outcome). Results: Among 120 patients randomized (mean [SD] age, 69.6 [14.5] years; 69 females [58%]), 113 (94.2%) completed the trial. The mean follow-up infarct volume was 32.4 mL (95% CI, 18.0 to 46.7 mL) for the less than 140-mm Hg group, 50.7 mL (95% CI, 33.7 to 67.7 mL), for the less than 160-mm Hg group, and 46.4 mL (95% CI, 24.5 to 68.2 mL) for the 180-mm Hg or less group. The mean utility-weighted mRS score was 0.51 (95% CI, 0.38 to 0.63) for the less than 140-mm Hg group, 0.47 (95% CI, 0.35 to 0.60) for the less than 160-mm Hg group, and 0.58 (95% CI, 0.46 to 0.71) for the high-target group. The slope of the follow-up infarct volume for each mm Hg decrease in the SBP target, adjusted for the baseline Alberta Stroke Program Early CT score, was -0.29 (95% CI, -0.81 to ∞; futility P = .99). The slope of the utility-weighted mRS score for each mm Hg decrease in the SBP target after endovascular therapy, adjusted for baseline utility-weighted mRS score, was -0.0019 (95% CI, -∞ to 0.0017; futility P = .93). Comparing the high-target SBP group with the lower-target groups, the predicted probability of success for a future trial was 25% for the less than 140-mm Hg group and 14% for the 160-mm Hg group. Conclusions and Relevance: Among patients with acute ischemic stroke, lower SBP targets less than either 140 mm Hg or 160 mm Hg after successful endovascular therapy did not meet prespecified criteria for futility compared with an SBP target of 180 mm Hg or less. However, the findings suggested a low probability of benefit from lower SBP targets after endovascular therapy if tested in a future larger trial. Trial Registration: ClinicalTrials.gov Identifier: NCT04116112.

Improvised rental housing to make cities COVID safe in India.

•COVID-19 necessitates relook at existing living conditions in the developing countries, with Indian cities as case study•With 3935 persons per hectare, Dharavi is one of the most crowded slums in the world, with 80% households on rent•Living conditions-socio-economics, neighbourhood circumstances and household crowding significantly abet the pandemic•As COVID recovery, Indian government on July 8, initiated affordable rental housing complexes for urban poor and migrants.•We recommend land monetization, real estate trusts, progressive designs, digital lease management, and tax on second house.

The role of intraoperative fluid optimization using the esophageal Doppler in advanced gynecological cancer: early postoperative recovery and fitness for discharge.

OBJECTIVE: To determine the effect of fluid optimization using esophageal Doppler monitoring (EDM) when compared to standard fluid management in women who undergo major gynecological cancer surgery and whether its use is associated with reduced postoperative morbidity. METHODS: From January 2009 to December 2010, women undergoing laparotomy for pelvic masses or uterine cancer had either fluid optimization using intraoperative EDM or standard fluid replacement without using EDM. Cases were selected from 2 surgeons to control for variability in surgical practice. Demographic and surgical details were collected prospectively. Univariate and multivariate analyses were performed to quantify the association between the use of EDM with "early postoperative recovery" and "early fitness for discharge." RESULTS: A total of 198 women were operated by the 2 prespecified surgeons; 79 women had fluid optimization with EDM, whereas 119 women had standard anesthetic care. The use of ODM was associated with earlier postoperative recovery (adjusted odds ratio, 2.83; 95% confidence interval, 1.20-6.68; P = 0.02) and earlier fitness for discharge (adjusted odds ratio, 2.81; 95% confidence interval, 1.01-7.78; P = 0.05). Women with advanced-stage disease in the "EDM" group resumed oral diet earlier than women in the "no EDM" group (median, 1 day vs 2 days; P = 0.02). These benefits with EDM did not extend to women with early-stage disease/benign/borderline tumors. No significant difference in postoperative complications was noted. CONCLUSIONS: Intraoperative fluid optimization with EDM in women with advanced gynecological cancer may be associated with improved postoperative recovery and early fitness for discharge. Studies with adequate power are needed to investigate its role in reducing postoperative complications.

How to tackle complexity in urban climate resilience? Negotiating climate science, adaptation and multi-level governance in India.

As the world's population is expected to be over 2/3rd urban by 2050, climate action in cities is a growing area of interest in the inter-disciplines of development policy, disaster mitigation and environmental governance. The climate impacts are expected to be quite severe in the developing world, given its urban societies are densely packed, vastly exposed to natural elements while possessing limited capabilities. There is a notable ambiguity and complexity that inhibits a methodical approach in identifying urban resilience measures. The complexity is due to intersection of large number of distinct variables in climate geoscience (precipitation and temperature anomalies at different locations, RCPs, timeline), adaptation alternatives (approach, priority, intervention level) and urban governance (functional mandate, institutional capacity, and plans & policies). This research examines how disparate and complex knowledge and information in these inter-disciplines can be processed for systematic 'negotiation' to situate, ground and operationalize resilience in cities. With India as a case, we test this by simulating mid-term and long-run climate scenarios (2050 & 2080) to map regional climate impacts that shows escalation in the intensity of climate events like heat waves, urban flooding, landslides and sea level rise. We draw on suitable adaptation measures for five key urban sectors- water, infrastructure (including energy), building, urban planning, health and conclude a sleuth of climate resilience building measures for policy application through national/ state policies, local urban plans and preparation of city resilience strategy, as well as advance the research on 'negotiated resilience' in urban areas.

Challenges in managing ST elevation myocardial infarction during the COVID-19 pandemic.

BACKGROUND: Coronavirus disease 2019 (COVID-19) may contribute to delayed presentations of acute myocardial infarction. Delayed presentation with late reperfusion is often associated with an increased risk of mechanical complications and adverse outcomes. Inherent delays are possible as every patient who is acutely sick is being considered a potential case or a career of COVID-19. Also, standardized personal protective equipment precautions are established for all members of the team, regardless of pending COVID-19 testing which might further add to delays. AIM: To compare performance measures and clinical outcomes of all patients who presented to our facility with ST elevation myocardial infarction (STEMI) during the COVID-19 pandemic to same time cohort from 2019. METHODS: All patients who presented to our facility with STEMI during the pandemic were compared to a matched cohort during the same time period in 2019. STEMI with unknown time of symptom onset and inpatient STEMI patients were excluded. Primary outcome was major adverse cardiac events (MACE) in-hospital and up to 14 d after STEMI, including death, myocardial infarction, cardiac arrest, or stroke. Significant differences among groups for continuous variables were tested through ANOVA, using SYSTAT, version 13. Chi-square tests of association were used to compare patient characteristics among groups using SYSTAT. Relative risk scores and associated tests for significance were calculated for discrete variables using MedCalc (MedCalc Software, Ostend, Belgium). RESULTS: There was a significantly longer time interval from symptom onset to first medical contact (FMC) in the COVID-19 group (P < 0.02). Time to first electrocardiogram, door-to-balloon time, and FMC to balloon time were not significantly affected. The right coronary artery was the most common culprit for STEMI in both the cohorts. Over 60% of patients had one or more obstructive (> 50%) lesion(s) remote from the culprit site. In-hospital and 14 d MACE were more prevalent in the COVID-19 group (P < 0.01 and P < 0.001). CONCLUSION: This single academic center study in the United States suggests that there is a delay in patients with STEMI seeking medical attention during the COVID-19 pandemic which could be translating into worse clinical outcomes.

Patient Perspectives With Telehealth Visits in Cardiology During COVID-19: Online Patient Survey Study.

BACKGROUND: The rise of COVID-19 and the issue of a mandatory stay-at-home order in March 2020 led to the use of a direct-to-consumer model for cardiology telehealth in Kentucky. Kentucky has poor health outcomes and limited broadband connectivity. Given these and other practice-specific constraints, the region serves as a unique context to explore the efficacy of telehealth in cardiology. OBJECTIVE: This study aims to determine the limitations of telehealth accessibility, patient satisfaction with telehealth relative to in-person visits, and the perceived advantages and disadvantages to telehealth. Our intent was two-fold. First, we wanted to conduct a rapid postassessment of the mandated overhaul of the health care delivery system, focusing on a representative specialty field, and how it was affecting patients. Second, we intend to use our findings to make suggestions about the future application of a telehealth model in specialty fields such as cardiology. METHODS: We constructed an online survey in Qualtrics following the Patient Assessment of Communication During Telemedicine, a patient self-report questionnaire that has been previously developed and validated. We invited all patients who had a visit scheduled during the COVID-19 telehealth-only time frame to participate. Questions included factors for declining telehealth, patient satisfaction ratings of telehealth and in-person visits, and perceived advantages and disadvantages associated with telehealth. We also used electronic medical records to collect no-show data for in-person versus telehealth visits to check for nonresponse bias. RESULTS: A total of 224 respondents began our survey (11% of our sample of 2019 patients). Our recruitment rate was 86% (n=193) and our completion rate was 62% (n=120). The no-show rate for telehealth visits (345/2019, 17%) was nearly identical to the typical no-show rate for in-person appointments. Among the 32 respondents who declined a telehealth visit, 20 (63%) cited not being aware of their appointment as a primary factor, and 15 (47%) respondents cited their opinion that a telehealth appointment was not medically necessary as at least somewhat of a factor in their decision. Both in-person and telehealth were viewed favorably, but in-person was rated higher across all domains of patient satisfaction. The only significantly lower mean score for telehealth (3.7 vs 4.2, P=.007) was in the clinical competence domain. Reduced travel time, lower visit wait time, and cost savings were seen as big advantages. Poor internet connectivity was rated as at least somewhat of a factor by 33.0% (35/106) of respondents. CONCLUSIONS: This study takes advantage of the natural experiment provided by the COVID-19 pandemic to assess the efficacy of telehealth in cardiology. Patterns of satisfaction are consistent across modalities and show that telehealth appears to be a viable alternative to in-person appointments. However, we found evidence that scheduling of telehealth visits may be problematic and needs additional attention. Additionally, we include a note of caution that patient satisfaction with telehealth may be artificially inflated during COVID-19 due to external health concerns connected with in-person visits.

Association of asymptomatic hemorrhage after endovascular stroke treatment with outcomes.

BACKGROUND: Intracerebral hemorrhage (ICH) occurs in ~20%-30% of stroke patients undergoing endovascular therapy (EVT). However, there is conflicting evidence regarding the effect of asymptomatic ICH (aICH) on post-EVT outcomes. We sought to evaluate the effect of aICH on immediate and 90-day post-EVT neurological outcomes. METHODS: In this post-hoc analysis of the multicenter, prospective Blood Pressure after Endovascular Therapy (BEST) study we identified subjects with ICH following EVT. This population was divided into no ICH, aICH, and symptomatic ICH (sICH). Associations with 90-day modified Rankin Scale (mRS) dichotomized by functional independence (0-2 vs 3-6) and early neurological recovery (ENR) were determined using univariate/multivariate logistic regression models. RESULTS: Of 485 patients enrolled in BEST, 446 had 90-day follow-up data available. 92 (20.6%) developed aICH, and 18 (4%) developed sICH. Compared with those without ICH, aICH was not associated with worse 90-day outcome or lower ENR (OR 0.84 [0.53-1.35], P=0.55, aOR 0.84 [0.48-1.44], P=0.53 for 90-day mRS 0-2; OR 0.77 [0.48-1.23], P=0.34, aOR 0.72 [0.43-1.22] for ENR). aICH was not associated with 90-day outcome or ENR in patients with mTICI ≥2 b (OR 0.78 [0.48-1.26], P=0.33 for 90-day mRS 0-2; OR 0.89 [0.69-1.12], P=0.15 for ENR). A higher proportion of patients with aICH had mTICI ≥2 b than those without ICH (97%vs 87%, P=0.01). CONCLUSIONS: aICH was not associated with worse outcomes in patients with large-vessel stroke treated with EVT. aICH was more frequent in patients with successful recanalization. Further validation of our findings in large cohort studies of EVT-treated patients is warranted.

Characteristics of beta-lactamases and their genes (blaA and blaB) in Yersinia intermedia and Y. frederiksenii.

BACKGROUND: The presence of beta-lactamases in Y. enterocolitica has been reported to vary with serovars, biovars and geographical origin of the isolates. An understanding of the beta-lactamases in other related species is important for an overall perception of antibiotic resistance in yersiniae. The objective of this work was to study the characteristics of beta-lactamases and their genes in strains of Y. intermedia and Y. frederiksenii, isolated from clinical and non-clinical sources in India. RESULTS: The enzymes, Bla-A (a constitutive class A penicillinase) and Bla-B (an inducible class C cephalosporinase) were found to be present in all the clinical and non-clinical strains of Y. intermedia and Y. frederiksenii by double disc diffusion method. The results showed differential expression of Bla-A as indicated by presence/absence of synergy whereas expression of Bla-B was quite consistent. The presence of these enzymes was also reflected in the high minimum inhibitory concentrations, MIC50 (126-1024 mg/L) and MIC90 (256-1024 mg/L) of beta-lactam antibiotics against these species. Restriction fragment length polymorphism (RFLP) revealed heterogeneity in both blaA and blaB genes of Y. intermedia and Y. frederiksenii. The blaA gene of Y. intermedia shared significant sequence identity (87-96%) with blaA of Y. enterocolitica biovars 1A, 1B and 4. The sequence identity of blaA of Y. frederiksenii with these biovars was 77-79%. The sequence identity of blaB gene of Y. intermedia and Y. frederiksenii was more (85%) with that of Y. enterocolitica biovars 1A, 1B and 2 compared to other species viz., Y. bercovieri, Y. aldovae and Y. ruckeri. Isoelectric focusing data further revealed that both Y. intermedia and Y. frederiksenii produced Bla-A (pI 8.7) and "Bla-B like" (pI 5.5-7.1) enzymes. CONCLUSION: Both Y. intermedia and Y. frederiksenii showed presence of blaA and blaB genes and unequivocal expression of the two beta-lactamases. Limited heterogeneity was detected in blaA and blaB genes as judged by PCR-RFLP. Phylogenetic relationships showed that the two species shared a high degree of identity in their bla genes. This is the first study reporting characteristics of beta-lactamases and their genes in strains of Y. intermedia and Y. frederiksenii isolated from Asian region.

Molecular characterization of beta-lactamase genes blaA and blaB of Yersinia enterocolitica biovar 1A.

The beta-lactamase genes blaA and blaB were detected by PCR amplification in strains of Yersinia enterocolitica biovar 1A isolated from India, Germany, France and the USA. Both genes were detected in all strains. Polymerase chain reaction-restriction fragment length polymorphism revealed genetic heterogeneity in blaA but not in blaB. Cluster analysis of blaA restriction profiles grouped the strains into three groups. The blaA gene of Y. enterocolitica biovar 1A showed a high degree of sequence homology to that of Y. enterocolitica 8081 (biovar 1B) and Y. enterocolitica Y-56 (biovar 4), whereas homology was low with class A beta-lactamase genes of other members of the family Enterobacteriaceae. The pI 8.7 of enzyme Bla-A of Y. enterocolitica biovar 1A was similar to that of biovars 2, 3 and 4. The enzyme Bla-B focused at 6.8 and 7.1, indicating that biovar 1A strains produced a 'B-like' enzyme. This is the first study to have investigated the genetic heterogeneity of the beta-lactamase genes of Y. enterocolitica.

Stress-mediated Sin3B activation leads to negative regulation of subset of p53 target genes.

The multiprotein SWI-independent 3 (Sin3)-HDAC (histone deacetylase) corepressor complex mediates gene repression through its interaction with DNA-binding factors and recruitment of chromatin-modifying proteins on to the promoters of target gene. Previously, an increased expression of Sin3B and tumour suppressor protein, p53 has been established upon adriamycin treatment. We, now provide evidence that Sin3B expression is significantly up-regulated under variety of stress conditions and this response is not stress-type specific. We observed that Sin3B expression is significantly up-regulated both at transcript and at protein level upon DNA damage induced by bleomycin drug, a radiomimetic agent. This increase in Sin3B expression upon stress is found to be p53-dependent and is associated with enhanced interaction of Sin3B with Ser(15) phosphorylated p53. Binding of Sin3-HDAC repressor complex on to the promoters of p53 target genes influences gene regulation by altering histone modifications (H3K9me3 and H3K27me3) at target genes. Furthermore, knockdown of Sin3B by shRNA severely compromises p53-mediated gene repression under stress conditions. Taken together, these results suggest that stress-induced Sin3B activation is p53-dependent and is essential for p53-mediated repression of its selective target genes. The present study has an implication in understanding the transrepression mechanism of p53 under DNA damaging conditions.

Sin3: insight into its transcription regulatory functions.

Sin3, a large acidic protein, shares structural similarity with the helix-loop-helix dimerization domain of proteins of the Myc family of transcription factors. Sin3/HDAC corepressor complex functions in transcriptional regulation of several genes and is therefore implicated in the regulation of key biological processes. Knockdown studies have confirmed the role of Sin3 in cellular proliferation, differentiation, apoptosis and cell cycle regulation, emphasizing Sin3 as an essential regulator of critical cellular events in normal and pathological processes. The present review covers the diverse functions of this master transcriptional regulator as well as illustrates the redundant and distinct functions of its two mammalian isoforms.

Outcome of midurethral tape continence surgery in patients with and without urodynamically confirmed stress incontinence.

OBJECTIVE: To compare the outcomes of midurethral tape continence surgery in patients with urodynamically confirmed stress incontinence (USI) and patients with symptoms of stress urinary incontinence but normal urodynamic studies (NUDS) and a positive 1-h pad test. STUDY DESIGN: Analysis of data collected prospectively from 356 women who underwent tension-free vaginal tape (TVT) surgery from June 1998 to September 2009. There were 25 women with NUDS but a positive pad test. Outcome measures in these 25 women were compared with 65 women with urodynamically confirmed stress incontinence. These 65 women were chosen as suitable controls from the group of 331 potential controls. All the women underwent TVT surgery under local or spinal anaesthesia. RESULTS: The outcome measures were: (1) absence of stress urinary incontinence symptoms, (2) new occurrence of lower urinary tract irritative symptoms (LUTS), (3) persistent voiding dysfunction (VD), and (4) recurrent urinary tract infections (UTIs). Following TVT, stress incontinence was absent in 100% and 97% of patients in the NUDS and USI groups respectively. The occurrence of LUTS was 4% and 4.6% in the NUDS and USI groups, while VD was found in 4% and 4.6% and recurrent UTIs in 8% and 6.1% of the groups respectively. CONCLUSION: There were no significant differences in outcomes following TVT in patients with and without urodynamically confirmed stress urinary incontinence.

Deletion of tuberous sclerosis 1 in somatic cells of the murine reproductive tract causes female infertility.

Tumors develop with dysregulated activation of mammalian target of rapamycin (mTOR), the kinase activity of which is kept in an inactive state by a tumor suppressor dimer containing tuberous sclerosis 1 (TSC1) and TSC2. We examined whether conditional deletion of TSC1 by a knock-in allele of the anti-Müllerian hormone type 2 receptor (Amhr2) driving Cre expression and subsequent activation of mTOR in granulosa cells and in oviductal and uterine stromal cells affects fertility in female mice. Increased phosphorylation of ribosomal protein S6, a downstream target of activated mTOR, was observed in all AMHR2-expressing tissues examined, indicating loss of TSC1 activity. TSC1 deletion in granulosa cells led to the detection of significantly fewer primordial follicles in mutant mice at 12 wk, suggesting premature ovarian insufficiency, which might be related to the significantly increased time mutant mice spent in estrus. Although the number of good-quality ovulated oocytes was not significantly different compared with controls, there was a significantly higher number of degenerated oocytes after normal and superovulation, suggesting compromised oocyte quality, as well. Natural mating also showed severalfold higher numbers of degenerate bodies in the mutants that collected in bilateral swellings resembling hydrosalpinges that formed in all mice examined because of occlusion of the proximal oviduct. Attempts to transfer control embryos into mutant uteri also failed, indicating that implantation was compromised. Endometrial epithelial cells continued to proliferate, and quantitative RT-PCR showed that mucin 1 expression persisted during the window of implantation in mutant uteri, without any changes in progesterone receptor mRNA expression, suggesting a mechanism that does not involve disrupted estradiol-regulated progesterone receptor expression. Homozygous deletion of TSC1 in reproductive tract somatic tissues of mice rendered females completely infertile, which is likely due to these pleiotropic effects on follicle recruitment, oviductal development, and blastocyst implantation.

Tumor suppressor protein p53 recruits human Sin3B/HDAC1 complex for down-regulation of its target promoters in response to genotoxic stress.

Master regulator protein p53, popularly known as the "guardian of genome" is the hub for regulation of diverse cellular pathways. Depending on the cell type and severity of DNA damage, p53 protein mediates cell cycle arrest or apoptosis, besides activating DNA repair, which is apparently achieved by regulation of its target genes, as well as direct interaction with other proteins. p53 is known to repress target genes via multiple mechanisms one of which is via recruitment of chromatin remodelling Sin3/HDAC1/2 complex. Sin3 proteins (Sin3A and Sin3B) regulate gene expression at the chromatin-level by serving as an anchor onto which the core Sin3/HDAC complex is assembled. The Sin3/HDAC co-repressor complex can be recruited by a large number of DNA-binding transcription factors. Sin3A has been closely linked to p53 while Sin3B is considered to be a close associate of E2Fs. The theme of this study was to establish the role of Sin3B in p53-mediated gene repression. We demonstrate a direct protein-protein interaction between human p53 and Sin3B (hSin3B). Amino acids 1-399 of hSin3B protein are involved in its interaction with N-terminal region (amino acids 1-108) of p53. Genotoxic stress induced by Adriamycin treatment increases the levels of hSin3B that is recruited to the promoters of p53-target genes (HSPA8, MAD1 and CRYZ). More importantly recruitment of hSin3B and repression of the three p53-target promoters upon Adriamycin treatment were observed only in p53(+/+) cell lines. Additionally an increased tri-methylation of the H3K9 residue at the promoters of HSPA8 and CRYZ was also observed following Adriamycin treatment. The present study highlights for the first time the essential role of Sin3B as an important associate of p53 in mediating the cellular responses to stress and in the transcriptional repression of genes encoding for heat shock proteins or proteins involved in regulation of cell cycle and apoptosis.

Synthesis and evaluation of S-4-(3-thienyl)phenyl-alpha-methylacetic acid.

Herein we report an efficient procedure to synthesize S-4-(3-thienyl)phenyl-alpha-methylacetic acid, an enantiomerically pure intermediate of a recently approved nonsteroidal antiinflammatory cyclooxygenase inhibitor, atliprofen [methyl RS-4-(3-thienyl)phenyl-alpha-methylacetate]. The interactions of the active S-isomer of the acid were theoretically compared with those of S-ibuprofen through molecular docking studies using COX-1 and COX-2 protein structures. The results were corroborated by in vitro and in vivo studies.