The Dual Delivery of Y15 and Metformin in a PLGA Scaffold for the Treatment of Platinum Resistant Ovarian Cancer

Background: Ovarian cancer is the fifth leading cause of cancer mortality among women in the US. High mortality is linked to resistance to platinum compounds. Currently there is no treatment for platinum resistant ovarian cancer (OCpt). Platinum resistance shows increased activity of focal adhesion kinase (FAK). Y15 is a FAK inhibitor and increases OCpt sensitivity to chemotherapy. Metformin induces apoptosis, has no increased cytotoxicity, and works synergistically with Y15 in OCpt cells. Biomaterial scaffolds deliver drugs locally, maximizing drug concentration and bioavailability while minimizing systemic toxicity. PLGA copolymer has excellent biocompatibility, versatility, and a tailorable degradation rate. The objective of this study is to utilize biomaterials as a dual drug delivery system and investigate if the combined delivery of Y15 and Metformin would result in synergistic effects on cell viability. Methods: A mold-less technique combining PLGA and the drugs in tetraglycol were injected into PBS to form a globular scaffold. An MTT assay was used to analyze cell viability in OCpt OVCAR3 cells at an absorbance of 570 nm with a microplate reader. Results: Metformin and Y15 resulted in cell viabilities of 66% and 54%, respectively. When combined, the viability decreased to 23%. In studies with the fabricated PLGA scaffolds, cell viabilities were 74% and 89% for Metformin and Y15. When combined, cell viability decreased significantly to 5%. Conclusions: The delivery of Y15 and Metformin in a biomaterial scaffold can result in a synergistic effect on cell viability and thus, can be a promising approach for the treatment of OCpt

Complex Biventricular Pacing - A Case Series

AbstractIt is established that cardiac resynchronisation therapy (CRT) reduces mortality and hospitalisation and improves functional class in patients with NYHA class 3-4 heart failure, an ejection fraction of ≤ 35% and a QRS duration of ≥ 120ms. Recent updates in the American guidelines have expanded the demographic of patients in whom CRT may be appropriate. Here we present two cases of complex CRT; one with a conventional indication but occluded central veins and the second with a novel indication for CRT post cardiac transplant

SMART: An Open Source Data Labeling Platform for Supervised Learning

SMART is an open source web application designed to help data scientists and research teams efficiently build labeled training data sets for supervised machine learning tasks. SMART provides users with an intuitive interface for creating labeled data sets, supports active learning to help reduce the required amount of labeled data, and incorporates inter-rater reliability statistics to provide insight into label quality. SMART is designed to be platform agnostic and easily deployable to meet the needs of as many different research teams as possible. The project website contains links to the code repository and extensive user documentation.Comment: 5 pages, 1 figur

Using Environmental DNA to Detect Whales and Dolphins in the New York Bight

Determining how cetaceans and other threatened marine animals use coastal habitats is critical to the effective conservation of these species. Environmental DNA (eDNA) is an emerging tool that can potentially be used to detect cetaceans over broad spatial and temporal scales. In particular, eDNA may present a useful complementary method for monitoring their presence during visual surveys in nearshore areas, and for co-detecting prey. In conjunction with ongoing visual surveys, we tested the ability of eDNA metabarcoding to detect the presence and identity of cetaceans in the New York Bight (NYB), and to identify fish species (potential prey) present in the area. In almost all cases in which humpback whales and dolphins were visually observed, DNA from these species was also detected in water samples. To assess eDNA degradation over time, we took samples in the same location 15 and 30min after a sighting in seven instances, and found that eDNA often, but not always, dropped to low levels after 30min. Atlantic menhaden were detected in all samples and comprised the majority of fish sequences in most samples, in agreement with observations of large aggregations of this important prey species in the NYB. While additional data are needed to better understand how factors such as behavior and oceanographic conditions contribute to the longevity of eDNA signals, these results add to a growing body of work indicating that eDNA is a promising tool to complement visual and acoustic surveys of marine megafauna

Progression of Age-Related Macular Degeneration Among Individuals Homozygous for Risk Alleles on Chromosome 1 (CFH-CFHR5) or Chromosome 10 (ARMS2/HTRA1) or Both

Importance: Age-related macular degeneration (AMD) is a common cause of irreversible vision loss among individuals older than 50 years. Although considerable advances have been made in our understanding of AMD genetics, the differential effects of major associated loci on disease manifestation and progression may not be well characterized. Objective: To elucidate the specific associations of the 2 most common genetic risk loci for AMD, the CFH-CFHR5 locus on chromosome 1q32 (Chr1) and the ARMS2/HTRA1 locus on chromosome 10q26 (Chr10)-independent of one another and in combination-with time to conversion to late-stage disease and to visual acuity loss. Design, Setting, and Participants: This case series study included 502 individuals who were homozygous for risk variants at both Chr1 and Chr10 (termed Chr1&10-risk) or at either Chr1 (Chr1-risk) or Chr10 (Chr10-risk) and who had enrolled in Genetic and Molecular Studies of Eye Diseases at the Sharon Eccles Steele Center for Translational Medicine between September 2009 and March 2020. Multimodal imaging data were reviewed for AMD staging, including grading of incomplete and complete retinal pigment epithelium and outer retinal atrophy. Main Outcomes and Measures: Hazard ratios and survival times for conversion to any late-stage AMD, atrophic or neovascular, and associated vision loss of 2 or more lines. Results: In total, 317 participants in the Chr1-risk group (median [IQR] age at first visit, 75.6 [69.5-81.7] years; 193 women [60.9%]), 93 participants in the Chr10-risk group (median [IQR] age at first visit, 77.5 [72.2-84.2] years; 62 women [66.7%]), and 92 participants in the Chr1&10-risk group (median [IQR] age at first visit, 71.7 [68.0-76.3] years; 62 women [67.4%]) were included in the analyses. After adjusting for age and AMD grade at first visit, compared with 257 participants in the Chr1-risk group, 56 participants in the Chr1&10-risk group (factor of 3.3 [95% CI, 1.6-6.8]; P < .001) and 58 participants in the Chr10-risk group (factor of 2.6 [95% CI, 1.3-5.2]; P = .007) were more likely to convert to a late-stage phenotype during follow-up. This difference was mostly associated with conversion to macular neovascularization, which occurred earlier in participants with Chr1&10-risk and Chr10-risk. Eyes in the Chr1&10-risk group (median [IQR] survival, 5.7 [2.1-11.1] years) were 2.1 (95% CI, 1.1-3.9; P = .03) times as likely and eyes in the Chr10-risk group (median [IQR] survival, 6.3 [2.7-11.3] years) were 1.8 (95% CI, 1.0-3.1; P = .05) times as likely to experience a visual acuity loss of 2 or more lines compared with eyes of the Chr1-risk group (median [IQR] survival, 9.4 [4.1-* (asterisk indicates event rate did not reach 75%)] years). Conclusions and Relevance: These findings suggest differential associations of the 2 major AMD-related risk loci with structural and functional disease progression and suggest distinct underlying biological mechanisms associated with these 2 loci. These genotype-phenotype associations may warrant consideration when designing and interpreting AMD research studies and clinical trials