Long-chain polyunsaturated fatty acid synthesis in fish: Comparative analysis of Atlantic salmon (Salmo salar L.) and Atlantic cod (Gadus morhua L.) Delta 6 fatty acyl desaturase gene promoters

Fish vary in ability to biosynthesise n-3 long-chain polyunsaturated fatty acids (LC-PUFA), with marine fish such as cod being inefficient in comparison to freshwater and salmonid fish. We investigated differences in the gene promoters of Δ6 fatty acyl desaturase (Δ6 FAD), a critical enzyme in LC-PUFA biosynthesis, in cod and salmon. Progressive deletions and targeted mutations of the promoters were tested for activity in a transfected fish cell line under low or high LC-PUFA treatment, and regions sufficient to direct transcription were identified. Comparison of these regions with sequences of corresponding regions of Δ6 FAD genes from mammals, amphibians and fish indicated a remarkable conservation of binding sites for SREBPs and NF-Y. In addition to these sites, a site was identified in salmon with similarity to that recognised by Sp1 transcription factor, and which was required for full expression of the salmon Δ6 FAD gene. The cod promoter was less active and lacked the Sp1 site. Eicosapentaenoic acid suppressed LC-PUFA synthesis in AS cells and also suppressed activity of the salmon Δ6 FAD promoter although this activity was likely mediated through sites other than Sp1, possibly similar to those recognised by NF-Y and SREBP transcription factors

Integrated mapping of pharmacokinetics and pharmacodynamics in a patient-derived xenograft model of glioblastoma

Therapeutic options for the treatment of glioblastoma remain inadequate despite concerted research efforts in drug development. Therapeutic failure can result from poor permeability of the blood-brain barrier, heterogeneous drug distribution, and development of resistance. Elucidation of relationships among such parameters could enable the development of predictive models of drug response in patients and inform drug development. Complementary analyses were applied to a glioblastoma patient-derived xenograft model in order to quantitatively map distribution and resulting cellular response to the EGFR inhibitor erlotinib. Mass spectrometry images of erlotinib were registered to histology and magnetic resonance images in order to correlate drug distribution with tumor characteristics. Phosphoproteomics and immunohistochemistry were used to assess protein signaling in response to drug, and integrated with transcriptional response using mRNA sequencing. This comprehensive dataset provides simultaneous insight into pharmacokinetics and pharmacodynamics and indicates that erlotinib delivery to intracranial tumors is insufficient to inhibit EGFR tyrosine kinase signaling.National Institutes of Health (U.S.) (U54 CA210180)MIT/Mayo Physical Sciences Center for Drug Distribution and Drug Efficacy in Brain TumorsDana-Farber Cancer Institute (PLGA Fund)Lundbeck FoundationNovo Nordisk Foundatio

Type of calcineurin inhibitor and long-term outcomes following liver transplantation in patients with primary biliary cholangitis – an ELTR study

Background &amp; Aims: Tacrolimus has been associated with recurrence of primary biliary cholangitis (PBC) after liver transplantation (LT), which in turn may reduce survival. This study aimed to assess the association between the type of calcineurin inhibitor used and long-term outcomes following LT in patients with PBC. Methods: Survival analyses were used to assess the association between immunosuppressive drugs and graft or patient survival among adult patients with PBC in the European Liver Transplant Registry. Patients who received a donation after brain death graft between 1990 and 2021 with at least 1 year of event-free follow-up were included. Results: In total, 3,175 patients with PBC were followed for a median duration of 11.4 years (IQR 5.9–17.9) after LT. Tacrolimus (Tac) was registered in 2,056 (64.8%) and cyclosporin in 819 (25.8%) patients. Following adjustment for recipient age, recipient sex, donor age, and year of LT, Tac was not associated with higher risk of graft loss (adjusted hazard ratio [aHR] 1.07, 95% CI 0.92-1.25, p = 0.402) or death (aHR 1.06, 95% CI 0.90-1.24, p = 0.473) over cyclosporin. In this model, maintenance mycophenolate mofetil (MMF) was associated with a lower risk of graft loss (aHR 0.72, 95% CI 0.60-0.87, p &lt;0.001) or death (aHR 0.72, 95% CI 0.59-0.87, p &lt;0.001), while these risks were higher with use of steroids (aHR 1.31, 95% CI 1.13-1.52, p &lt;0.001, and aHR 1.34, 95% CI 1.15-1.56, p &lt;0.001, respectively). Conclusions: In this large LT registry, type of calcineurin inhibitor was not associated with long-term graft or recipient survival, providing reassurance regarding the use of Tac post LT in the population with PBC. Patients using MMF had a lower risk of graft loss and death, indicating that the threshold for combination treatment with Tac and MMF should be low. Impact and implications: This study investigated the association between immunosuppressive drugs and the long-term survival of patients with primary biliary cholangitis (PBC) following donation after brain death liver transplantation. While tacrolimus has previously been related to a higher risk of PBC recurrence, the type of calcineurin inhibitor was not related to graft or patient survival among patients transplanted for PBC in the European Liver Transplant Registry. Additionally, maintenance use of mycophenolate was linked to lower risks of graft loss and death, while these risks were higher with maintenance use of steroids. Our findings should provide reassurance for physicians regarding the continued use of Tac after liver transplantation in the population with PBC, and suggest potential benefit from combination therapy with mycophenolate.</p

Priority focus areas for a sub-national response to climate change and health: A South African provincial case study

Introduction: The intersection of health and climate change is often absent or under-represented in sub-national government strategies. This analysis of the literature, using a new methodological framework, highlights priority focus areas for a sub-national government response to health and climate change, using the Western Cape (WC) province of South Africa as a case study. Methods: A methodological framework was created to conduct a review of priority focus areas relevant for sub-national governments. The framework encompassed the establishment of a Project Steering Group consisting of relevant, sub-national stakeholders (e.g. provincial officials, public and environmental health specialists and academics); an analysis of local climatic projections as well as an analysis of global, national and sub-national health risk factors and impacts. Results: Globally, the discussion of health and climate change adaptation strategies in sub-national, or provincial government is often limited. For the case study presented, multiple health risk factors were identified. WC climatic projections include a warmer and potentially drier future with an increased frequency and intensity of extreme weather events. WC government priority focus areas requiring further research on health risk factors include: population migration and environmental refugees, land use change, violence and human conflict and vulnerable groups. WC government priority focus areas for further research on health impacts include: mental ill-health, non-communicable diseases, injuries, poisonings (e.g. pesticides), food and nutrition insecurity-related diseases, water- and food-borne diseases and reproductive health. These areas are currently under-addressed, or not addressed at all, in the current provincial climate change strategy. Conclusions: Sub-national government adaptation strategies often display limited discussion on the health and climate change intersect. The methodological framework presented in this case study can be globally utilized by other sub-national governments for decision-making and development of climate change and health adaptation strategies. Additionally, due to the broad range of sectoral issues identified, a primary recommendation from this study is that sub-national governments internationally should consider a “health and climate change in all policies” approach when developing adaptation and mitigation strategies to address climate change

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice