Engineered Platform for Immune Isolation and Modulation in Pancreatic Islet Transplantation For Type-1 Diabetes

Islet microencapsulation through permselective hydrogels may improve safety and efficacy of transplantation, maintain immunoisolation, and offer metabolic control without chronic and systemic immunosuppression. Impaired transport of glucose/insulin and/or inflammatory responses by the host immune system to the capsules may decrease encapsulated islet functionality. I engineered a platform for immune isolation and modulation of pancreatic islets combining microencapsulation with targeted delivery of immunomodulatory drugs to increase their functionality after transplantation. I performed parallel evaluations of alginate single and double capsules (SC, DC) versus polyethylene glycol (PEG) conformal coating (CC) of human islets. With data obtained in silico and in vivo, I concluded that minimal capsule size is critical for metabolic control and improving the biocompatibility of CC grafts in the site of transplantation using localized and targeted immunomodulation may be beneficial to increase the efficacy of CC grafts. To improve CC biocompatibility, I tested anti-inflammatory dexamethasone (Dex) and cyclosporine A (CsA) loading efficiency and release kinetics in Drug-Integrating Amphiphilic Nanoassemblies (DIANA) and efficacy in decreasing inflammatory cytokine secretion by activated macrophages while maintaining islet functionality in vitro and in vivo. DIANAs loaded Dex increased water solubility by ~15 times and released it within 8 hours. nFIB localize in the site of inflammation when added locally, and nMIC target the graft after IV injection. Local and IV Dex- and CsA-DIANAs decreased inflammation three days post transplantation of CC grafts in mice. This approach can be applied to islet transplantation for improving CC biocompatibility providing optimal metabolic control without chronic systemic immunosuppression.</p

Age and Growth of Atlantic Blue Marlin (Makaira nigricans) Larvae from the Coastal Waters of Cuba

Atlantic blue marlin (Makaira nigricans) are the largest species among the Istiophorids in the Atlantic Ocean with primary spawning grounds in the northern Caribbean and Bahamas. We examined the early life history dynamics of blue marlin relating to growth, distribution, and habitat conditions. Although larval growth has been described from adjacent areas in the Atlantic, this study sourced larvae from Cuba, one of the hotspots of the distribution of the species. Blue marlin larvae were collected in 2015 and 2016, were genetically identified, and 157 sagittal otoliths were aged. Larval growth rates (mm day-1) are reported for the first two weeks by examining the number of daily increments and relating these to the standard larval length (mm). Although linear and exponential models were used to estimate the rate of growth between years (2015 & 2016) and regions (north and south), the exponential growth model was a better fit. The instantaneous growth rates for samples collected in Cuba were very similar (North 2015: 0.099; South 2015: 0.124; North 2016: 0.116). However, larvae collected in the North of Cuba were larger at age than the South, yet their instantaneous growth rates were very similar, and no statistical differences in growth rates were detected between these two regions. When examining environmental conditions between regions (North & South) chlorophyll differed and between years (2015 & 2016) salinity differed. Understanding larval distribution and larval growth variability can influence blue marlin recruitment and may be related to environmental conditions in the Atlantic Basin

P285. Radiographic predictors of instability vs composite clinical success of spondyloplasty of TLIF for degenerative spondylolisthesis. Analysis of results from a prospective FDA IDE trial

Blumenthal et al (2013) found that segmental facet joint angle (FJA) >50°, disc height (DH) >6.5mm and segmental translation (ST) >1.25mm were associated with higher rates of reoperation in patients who had decompression only, without fusion, for symptomatic degenerative spondylolisthesis (DS). An ongoing FDA IDE study (NCT03115983) is comparing spondyloplasty (decompression and dynamic sagittal tether (DST) stabilization vs decompression and transforaminal lumbar interbody fusion (TLIF) for symptomatic DS. Radiographic measures including those identified by Blumenthal may identify signals among subgroups with clinical success or failure. The purpose of this analysis is to assess composite clinical success (CCS) among spondyloplasty and TLIF subjects having a PDI. Post-hoc analysis of data from a multi-center, prospective IDE study of spondyloplasty vs TLIF for symptomatic DS (NCT03115983). A total of 299 subjects enrolled in the IDE trial of spondyloplasty (N=140) vs TLIF (N=159). Full study inclusion criteria provided at clinicaltrials.gov (NCT03115983). Primary outcome measure CCS was defined as patients meeting all of the following through 24-months: successful index implantation; 15-point improvement on the Oswestry Disability Index (ODI); no device integrity failure defined as device breakage, separation, dislocation or disassembly; no subsequent surgical intervention (SSI) at the index or adjacent segments; and no decrease in neurologic status unless attributable to a concurrent medical condition or other unrelated cause. PDI were defined as ST>1.25mm, FJA>50° or DH>6.5mm as measured on preoperative radiographs. CCS rates were calculated for each subgroup of patients having or not having each individual PDI, all PDI, any PDI or no PDI in each of the two treatment arms. Influence of each PDI was assessed using student's t-test to compare subjects with and without the PDI. Too Long Text characters = 69300 max allowed in xls 32,250. There was no identifiable relationship between any of the preoperative radiographic parameters and clinical success in either the spondyloplasty or TLIF groups. Notably, failures in the spondyloplasty group were not associated with higher preoperative mobility, disc height, anterolisthesis or FJ angle, as has been seen in decompression alone. LimiFlex Dynamic Sagittal Tether (Investigational/Not Approved), Standard of Care TLIF instrumentation and graft materials (Approved for this indication

Is Primary Breast Melanoma a True Pathological Entity? The Argument against it

Previous studies have reported cases of primary melanoma of the breast parenchyma (PMBP), but the pathogenesis of this disease remains poorly understood. We review the presentation and outcomes of reported cases and provide detailed pathological analysis of four additional cases. Furthermore, we discuss potential theories regarding the pathogenesis of this clinical presentation. We identified 29 published studies (n=95 patients) and report four new cases (n=99). Ninety-one (92%) patients were female, with a median age of 50 years. Previous skin melanomas were reported by 56% of patients, with the trunk being the most common location (32.7%) followed by the upper extremities (20%). The most common tumor location reported (n=73) was the right (49%) upper outer quadrant (56%). The median time from skin melanoma diagnosis to the presence of a breast mass was 65 months (1-192). Nodal status at presentation was reported in n=67 (68%) patients. Of these, positive nodal metastases were seen in 40.3%, while distant metastatic disease at presentation was reported in 30% of patients. Surgery was performed in 66%, being partial mastectomy (PM) the most common procedure in 82 %. Adjuvant therapy was described in 38 patients. The reported (n=12) median survival was 11.5 (1-70) months. Melanomas identified in the breast parenchyma are likely the result of nodal or hematogenous spread from previously known or unknown melanomas, and should not be considered as PMBP. Management should be multidisciplinary, including surgical excision aimed at obtaining negative margins with lymphadenectomy of clinically positive nodes and neoadjuvant/adjuvant immunotherapy

Liraglutide effects on epicardial adipose tissue micro-RNAs and intra-operative glucose control

Epicardial adipose tissue (EAT) plays a role in coronary artery disease (CAD). EAT has regional distribution throughout the heart and each location may have a different genetic profile and function. Glucagon like peptide-1 receptor analogs (GLP-1RAs) reduce cardiovascular risk. However, the short-term effects of GLP-1RA on microRNA (miRNA) profile of each EAT location is unknown. Objective was to evaluate if EAT miRNAs were different between coronary (CORO-EAT), left atrial EAT (LA-EAT) and subcutaneous fat (SAT), and liraglutide can modulate EAT miRNAs expression. This was a 12-week randomized, double-blind, placebo-controlled study in 38 patients with type 2 diabetes (T2DM) and coronary artery disease (CAD) who were started on either liraglutide or placebo for a minimum of 4 up to 12 weeks prior to coronary artery by-pass grafting (CABG). Fat samples were collected during CABG. miR16, miR155 and miR181a were significantly higher in CORO-EAT and in LA-EAT than SAT (p < 0.01 and p < 0.05) in overall patients. miR16 and miR181-a were significantly higher in CORO-EAT than SAT (p < 0.01), and miR155 and miR181a were higher in LA-EAT than SAT (p < 0.05) in the liraglutide group. Liraglutide-treated patients had better intra-op glucose control than placebo (146 ± 21 vs 160 ± 21 mg/dl, p < 0.01). Our study shows that CORO- and LA-miRNAs profiles were significantly different than SAT miRNAs in overall patients and miRNAs were significantly higher in CORO-EAT and LA-EAT than SAT in the liraglutide group. Pre-op liraglutide was also associated with better intra operative glucose control than placebo independently of weight loss. •Epicardial adipose tissue (EAT) plays a role in coronary artery disease (CAD).•EAT has regional distribution throughout the heart and each location may have a different genetic profile and function.•Glucagon like peptide-1 receptor analogs (GLP-1RAs) reduce cardiovascular risk. However, the short-term effects of GLP-1RA on microRNA (miRNA) profile of each EAT location is unknown.•Coronary (CORO-EAT) and left atrial EAT (LA-EAT) miRNAs profiles were significantly different than subcutaneous fat (SAT), in overall patients.•miR16 and miR181-a were significantly higher in CORO-EAT than SAT and miR155 and miR181a were higher in LA-EAT than SAT in the liraglutide group.•Pre-op liraglutide treatment was also associated with better intra operative glucose control than placebo independently of weight loss

Unique Signatures of Highly Constrained Genes Across Publicly Available Genomic Databases

Publicly available genomic databases and genetic constraint scores are crucial in understanding human population variation and the identification of variants that are likely to have a deleterious impact causing human disease. We utilized the one of largest publicly available databases, gnomAD, to determine genes that are highly constrained for only LoF, only missense, and both LoF/missense variants, identified their unique signatures, and explored their causal relationship with human conditions. Those genes were evaluated for unique patterns including their chromosomal location, tissue level expression, gene ontology analysis, and gene family categorization using multiple publicly available databases. Those highly constrained genes associated with human disease, we identified unique patterns of inheritance, protein size, and enrichment in distinct molecular pathways. In addition, we identified a cohort of highly constrained genes that are currently not known to cause human disease, that we suggest will be candidates to pursue as novel disease-associated genes. In summary, these insights not only elucidate biological pathways of highly constrained genes that expand our understanding of critical cellular proteins but also advance research in rare diseases.Publicly available genomic databases and genetic constraint scores are crucial in understanding human population variation and the identification of variants that are likely to have a deleterious impact causing human disease. We utilized the one of largest publicly available databases, gnomAD, to determine genes that are highly constrained for only LoF, only missense, and both LoF/missense variants, identified their unique signatures, and explored their causal relationship with human conditions. Those genes were evaluated for unique patterns including their chromosomal location, tissue level expression, gene ontology analysis, and gene family categorization using multiple publicly available databases. Those highly constrained genes associated with human disease, we identified unique patterns of inheritance, protein size, and enrichment in distinct molecular pathways. In addition, we identified a cohort of highly constrained genes that are currently not known to cause human disease, that we suggest will be candidates to pursue as novel disease-associated genes. In summary, these insights not only elucidate biological pathways of highly constrained genes that expand our understanding of critical cellular proteins but also advance research in rare diseases