Identifying Senescence as a Mode of Chemo Resistance in Ovarian Cancer

Current treatments of ovarian and breast cancer result in chemo resistance all too often. It has been hypothesized that senescence-a dormant condition associated with increased age and apoptosis- may play a role in the development of chemo resistance. We performed an in-vitro study with HOSE (carboplatin-sensitive), SKOV3 (chemo resistant ovarian cancer), and CAMA1 (chemo resistant breast cancer) cell lines, which were exposed to a variety of platinum-based treatments meant to model current cover clinically relevant scenarios in terms of tumor hypoxia. They were then stained for senescence in-vitro using B-gal, and analyzed for proliferation using the Cell Counting Kit 8, trypan blue dye exclusion, and survival plating, among other methods. Real-time quantitative PCR was used to determine relative levels of gene expression for classical apoptotic and senescent markers. Our results indicate that proliferation was temporarily halted in SKOV3 and CAMA1 after treatment. Cell proliferation later resumed in these cell lines while HOSE cell underwent apoptosis. Analysis of genetic tests (such as qPCR) also revealed that SKOV3 and CAMA1 had decreased gene expression of key genes that regulate apoptosis and senescence (such as p53 and CDK2). It can be concluded from this data that senescence was in fact a mode of chemoresistance and that future treatments may want to focus on disabling cancerous cells’ senescent stage

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

Traversing the Labyrinth: A Comprehensive Analysis of Pedestrian Traffic in Venice

The purpose of this project was to contribute to the development of a computer model to assist the City of Venice in the management of pedestrian traffic congestion. In collaboration with the Santa Fe Complex, the team confirmed the feasibility of the model by producing a prototype that effectively simulates pedestrian mobility in western San Marco. Additionally, the team determined that the existing networks of surveillance cameras could be leveraged to automatically feed the model in future years

The Cancer Stem Cell Marker GSK3b, a Gene involved in Oxidative Stress, Modulates Chemoresistance in Ovarian Cancer

The leading cause of death from gynecologic malignancies is epithelial ovarian cancer. These tumors are comprised of a highly heterogeneous population of cells, of which only a small subset of stem-like cells possess the ability to regenerate tumors in vivo. These cancer stem cells (CSCs) represent a significant clinical challenge as they are resistant to conventional cancer therapies and play essential roles in metastasis and tumor relapse. While chemotherapy is the preferred treatment modality, chemoresistance severely limits treatment success. It has been hypothesized that cancer stem cells are at the root of this problem. Their ability to self-renew and proliferate is what causes a large number of ovarian cancers to recur and not respond to normal chemotherapeutic treatments. Recent evidence suggests that deregulation of stem cell pathways is a key factor in the onset and maintenance of chemoresistance. Several key markers such as BMI1, FZD1, GGSK3b, NANOG, TWIST1, and OCT4 (POU5F1) are hypothesized to play a central role in the development and differentiation of multiple cell lineages. Recent studies have demonstrated that these markers is required for the carcinogenesis in several cancer types. The aim of this study was to investigate the significance of CSC expression in chemoresistant and sensitive ovarian cancer cancer cell lines. Through the analysis of gene expression in these cell lines, CSC markers could be identified. CSC mRNA expression was detected by real-time quantitative PCR and by gel electrophoresis of PCR products in sensitive and resistant ovarian cell lines. The objective of such an improved delineation is to develop targeted therapy for selective elimination of cancer stem cells with minimal toxicity to normal stem cells. Our research indicates that there were novel changes in gene expression in the chemoresistant cell lines, specifically involving GSK3b. Further research is needed to gain better understanding of the role that these genes specifically play in cancer survival, metastasis, and chemo resistance

The Effects of DNA Methylation on Medulloblastoma Cell Survivability and Development

Establish the role epigenetic methylation plays in the segregation of Medulloblastoma subgroups, through pathway analysis in the literature and cancer genome Atlas publicly available data. The goal is to develop an in-vitro assay to study therapeutic responses for subgroups 3 and 4. Functional analysis assays will be used to determine a mechanism for chemoresistance in specific subgroups. In the current study, we assessed Medulloblastoma group 3 (D341) and Group 4 (D283) cell lines using the DNA isolation kit and angiogenesis kits which allows for amplification via PCR and visualize tube formation for tumor nutrients. Twist 1 fended were measured and recorded with the methylation Gold. Group 3 MB cell lines treated with chemotherapy reagents demonstrate altered methylation profiles, angiogenic tube formation increase, a decrease in apoptosis, and underwent phenotypic changes to overcome resistance. Gel electrophoresis results indicated consistent Twist-1 expression in the DAOY+cisplatin cell line in comparison to the control. Cells treated with chemotherapeutic agents evade the mechanisms of apoptosis resulting in angiogenesis. We identified a possible correlation between cisplatin treatment, alteration of methylation patterns, and an increase of Twist-1 gene expression. Twist-1 previously identified to be involved in angiogenesis and cisplatin resistance (Roberts et al. 2016), this supports our hypothesis that alterations in methylation patterns result in an increase in overall chemoresistance

Defining the Feeding Value of Moldy Corn Selected for Low Mycotoxin Content

Cool, wet conditions during the 2009 growing season resulted in mold infestation of corn before it was mature. This experiment determined the total tract digestibility of energy and dry matter in 7 corn samples, selected for the presence of mold by with low mycotoxin content (< 1.0 ppm DON). Sixteen finishing barrows weighing an average of 99 kg were housed individually and fed experimental diets contained 96.9% of the corn sample. Pigs were fed twice a day for 3 feeding periods of 14 days each. Corn test weight, kernel damage and mold count all varied among sources (P < 0.001) and there were also differences in DM and GE digestibility for the most compromised corn sources. We concluded that mold infestation may negatively affect the feeding value of corn. Therefore, the practice of blending moldy corn with clean corn may adversely affect its feeding value for pigs.</p

Uncovering emergent interactions in three-way combinations of stressors

Understanding how multiple stressors interact is needed to predict the dynamical outcomes of diverse biological systems, ranging from drug-resistant pathogens that are combated and treated with combination drug therapies to ecosystems impacted by environmental toxicants or disturbances. Nevertheless, extensive studies of higher-order (more than two component) interactions have been lacking. Here, we conduct experiments using 20 three-drug combinations and their effects on the bacterial growth of Escherichia coli. We report our measurements of growth rates in single, pairwise and triple-drug combinations. To uncover emergent interactions, we derive a simple framework to calculate expectations for three-way interactions based on the measured impact of each individual stressor and of each pairwise interaction. Using our framework, we find that (i) emergent antagonisms are more common than emergent synergies and (ii) emergent antagonisms are more common and emergent synergies are more rare than would be inferred from measures of net effects that do not disentangle pairwise interactions from three-way interactions