The Melanocortin-4 Receptor Integrates Circadian Light Cues and Metabolism

The melanocortin system directs diverse physiological functions from coat color to body weight homoeostasis. A commonality among melanocortin-mediated processes is that many animals modulate similar processes on a circannual basis in response to longer, summer days, suggesting an underlying link between circadian biology and the melanocortin system. Despite key neuroanatomical substrates shared by both circadian and melanocortin-signaling pathways, little is known about the relationship between the two. Here we identify a link between circadian disruption and the control of glucose homeostasis mediated through the melanocortin-4 receptor (Mc4r). Mc4r-deficient mice exhibit exaggerated circadian fluctuations in baseline blood glucose and glucose tolerance. Interestingly, exposure to lighting conditions that disrupt circadian rhythms improve their glucose tolerance. This improvement occurs through an increase in glucose clearance by skeletal muscle and is food intake and body weight independent. Restoring Mc4r expression to the paraventricular nucleus prevents the improvement in glucose tolerance, supporting a role for the paraventricular nucleus in the integration of circadian light cues and metabolism. Altogether these data suggest that Mc4r signaling plays a protective role in minimizing glucose fluctuations due to circadian rhythms and environmental light cues and demonstrate a previously undiscovered connection between circadian biology and glucose metabolism mediated through the melanocortin system

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant

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

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

COVID-19 Through Nepali Teachers’ Perspectives

The Nepali education system has been affected by the extensive spread of COVID-19. Before the pandemic, Nepal was in a period of growth regarding educational policy after suffering from a civil conflict that lasted 10 years (Valente 2015; Parker et al. 2013). Although Nepal was in the process of recovering, they have a considerable digital divide with a lack of Internet access for many citizens (Mandal, 2020). Nepal has supplemented the lack of Internet access with TVs, radios, and phones (Dhamala 2020; Radhakrishnan-Nair et al. 2020; UNESCO 2020). Because the pandemic is current, there is a lack of research on how COVID-19 and the lack of Internet access have affected the teachers in the Nepali education system. In our research, we investigate Nepali teachers’ perspectives of COVID-19 affecting the education system

Customer Segmentation Using Exploratory Data Analysis and Clustering Methods: A Grocery Store Case Study

Customer segmentation is the process of uncovering behavioral patterns and characteristics that various customer groups may share. This process makes it easier to create marketing, service and sales efforts tailored to the needs of a specific group and enables marketers to better understand their audience, increase revenue, and earn greater market share. The goal of this study is to identify customer segments for a retail grocery store. We use the data set from Kaggle that contains information about customers’ purchasing behavior and monetary value, shopping modality, recency, as well as their campaign response patterns. We use exploratory data analysis and a modified version of the RMF segmentation technique to identify customer tiers within each shopping modality and use customer demographic characteristics to create customer profiles for each tier. In the next step we employ K-means clustering to create customer segments based on customer monetary value and recency. We then evaluate the responsiveness of each cluster to marketing campaigns and discounts

Signs of Humanity – a researcher-artist collaboration

A team of Jefferson students, alumni and faculty in collaboration with artist Willie Baronet, employed qualitative methods to explore poverty in Philadelphia. Background The Signs of Humanity (SOH) Project is a researcher-artist collaboration. This joint venture was designed to explore the interactions between people using signs to ask for help and those who pass by with the goal of reducing the dehumanization of this community. The research arm was designed to qualitatively explore the experiences of people who seek financial support or in-kind help from passersby. This is referred to as panhandling in the literature and that term will be used going forward. While not everyone who panhandles is experiencing homelessness, these situations frequently co-occur in Philadelphia. People who panhandle are a very visible fraction of a city\u27s homeless population and while they are often counted there are few opportunities to hear from them about their lived experiences. The signs they carry point to common hardships such as housing and food insecurity and substance abuse disorders: however, they do not tell the complete story. A team of Jefferson researchers, MPH and MD students (and alumni) along with Willie Baronet, a Dallas Artist, conducted interviews with 41 people over the course of 1 week. Questions explored the lived experience of people in need here in Philadelphia, including their interactions with passersby, their opinions about how money collected is used by their counterparts, their experiences with housing insecurity and their perception of how the opioid crisis has affected them. The research team performed intercept interviews that including freelisting and open-ended questions

The Chronic Effect of Interval Training on Energy Intake: A Systematic Review and Meta-Analysis

Single bouts of acute exercise do not appear to increase subsequent energy intake (EI), even when energy deficit is large. However, studies have shown a compensatory effect on EI following chronic exercise, and it remains unclear whether this is affected by exercise intensity. We investigated the chronic effect of high-intensity interval training (HIIT) and sprint interval training (SIT) on EI when compared with moderate-intensity continuous training (MICT) or no exercise (CON). Databases were searched until 13 March 2017 for studies measuring EI in response to chronic exercise (>= 4 weeks of duration) of a high-intensity interval nature. Meta-analysis was conducted for between-group comparisons on EI (kilojoules) and bodyweight (kg). Results showed large heterogeneity, and therefore, metaregression analyses were conducted. There were no significant differences in EI between HIIT/SIT versus MICT (P = 0.282), HIIT/SIT versus CON (P = 0.398), or MICT versus CON (P = 0.329). Although bodyweight was significantly reduced after HIIT/SIT versus CON but not HIIT/SIT versus MICT (in studies measuring EI), this was not clinically meaningful