A MicroRNA Linking Human Positive Selection and Metabolic Disorders

Postponed access: the file will be accessible after 2021-10-14Positive selection in Europeans at the 2q21.3 locus harboring the lactase gene has been attributed to selection for the ability of adults to digest milk to survive famine in ancient times. However, the 2q21.3 locus is also associated with obesity and type 2 diabetes in humans, raising the possibility that additional genetic elements in the locus may have contributed to evolutionary adaptation to famine by promoting energy storage, but which now confer susceptibility to metabolic diseases. We show here that the miR-128-1 microRNA, located at the center of the positively selected locus, represents a crucial metabolic regulator in mammals. Antisense targeting and genetic ablation of miR-128-1 in mouse metabolic disease models result in increased energy expenditure and amelioration of high-fat-diet-induced obesity and markedly improved glucose tolerance. A thrifty phenotype connected to miR-128-1-dependent energy storage may link ancient adaptation to famine and modern metabolic maladaptation associated with nutritional overabundance.acceptedVersio

A MicroRNA Linking Human Positive Selection and Metabolic Disorders

Positive selection in Europeans at the 2q21.3 locus harboring the lactase gene has been attributed to selection for the ability of adults to digest milk to survive famine in ancient times. However, the 2q21.3 locus is also associated with obesity and type 2 diabetes in humans, raising the possibility that additional genetic elements in the locus may have contributed to evolutionary adaptation to famine by promoting energy storage, but which now confer susceptibility to metabolic diseases. We show here that the miR-128-1 microRNA, located at the center of the positively selected locus, represents a crucial metabolic regulator in mammals. Antisense targeting and genetic ablation of miR-128-1 in mouse metabolic disease models result in increased energy expenditure and amelioration of high-fat-diet-induced obesity and markedly improved glucose tolerance. A thrifty phenotype connected to miR-128-1-dependent energy storage may link ancient adaptation to famine and modern metabolic maladaptation associated with nutritional overabundance

A single-cell atlas of human and mouse white adipose tissue

none38noneMargo P. Emont, Christopher Jacobs, Adam L. Essene, Deepti Pant, Danielle Tenen, Georgia Colleluori, Angelica Di Vincenzo, Anja M. Jørgensen, Hesam Dashti, Adam Stefek, Elizabeth McGonagle, Sophie Strobel, Samantha Laber, Saaket Agrawal,Gregory P. Westcott, Amrita Kar, Molly L. Veregge, Anton Gulko, Harini Srinivasan, Zachary Kramer, Eleanna De Filippis, Erin Merkel, Jennifer Ducie, Christopher G. Boyd, William Gourash, Anita Courcoulas, Samuel J. Lin, Bernard T. Lee, Donald Morris, Adam Tobias, Amit V. Khera, Melina Claussnitzer, Tune H. Pers, Antonio Giordano, Orr Ashenberg, Aviv Regev, Linus T. Tsai & Evan D. RosenEmont, Margo P.; Jacobs, Christopher; Essene, Adam L.; Pant, Deepti; Tenen, Danielle; Colleluori, Georgia; DI VINCENZO, Angelica; Jørgensen, Anja M.; Dashti, Hesam; Stefek, Adam; Mcgonagle, Elizabeth; Strobel, Sophie; Laber, Samantha; Agrawal, Saaket; Westcott, Gregory P.; Kar, Amrita; Veregge, Molly L.; Gulko, Anton; Srinivasan, Harini; Kramer, Zachary; De Filippis, Eleanna; Merkel, Erin; Ducie, Jennifer; Boyd, Christopher G.; Gourash, William; Courcoulas, Anita; Lin, Samuel J.; Lee, Bernard T.; Morris, Donald; Tobias, Adam; Khera, Amit V.; Claussnitzer, Melina; Pers, Tune H.; Giordano, Antonio; Ashenberg, Orr; Regev, Aviv; Tsai &, Linus T.; Rosen, Evan D

Opportunistic infections and AIDS malignancies early after initiating combination antiretroviral therapy in high-income countries

Background: There is little information on the incidence of AIDS-defining events which have been reported in the literature to be associated with immune reconstitution inflammatory syndrome (IRIS) after combined antiretroviral therapy (cART) initiation. These events include tuberculosis, mycobacterium avium complex (MAC), cytomegalovirus (CMV) retinitis, progressive multifocal leukoencephalopathy (PML), herpes simplex virus (HSV), Kaposi sarcoma, non-Hodgkin lymphoma (NHL), cryptococcosis and candidiasis. Methods: We identified individuals in the HIV-CAUSAL Collaboration, which includes data from six European countries and the US, who were HIV-positive between 1996 and 2013, antiretroviral therapy naive, aged at least 18 years, hadCD4+ cell count and HIV-RNA measurements and had been AIDS-free for at least 1 month between those measurements and the start of follow-up. For each AIDS-defining event, we estimated the hazard ratio for no cART versus less than 3 and at least 3 months since cART initiation, adjusting for time-varying CD4+ cell count and HIV-RNA via inverse probability weighting. Results: Out of 96 562 eligible individuals (78% men) with median (interquantile range) follow-up of 31 [13,65] months, 55 144 initiated cART. The number of cases varied between 898 for tuberculosis and 113 for PML. Compared with non-cART initiation, the hazard ratio (95% confidence intervals) up to 3 months after cART initiation were 1.21 (0.90-1.63) for tuberculosis, 2.61 (1.05-6.49) for MAC, 1.17 (0.34-4.08) for CMV retinitis, 1.18 (0.62-2.26) for PML, 1.21 (0.83-1.75) for HSV, 1.18 (0.87-1.58) for Kaposi sarcoma, 1.56 (0.82-2.95) for NHL, 1.11 (0.56-2.18) for cryptococcosis and 0.77 (0.40-1.49) for candidiasis. Conclusion: With the potential exception of mycobacterial infections, unmasking IRIS does not appear to be a common complication of cART initiation in high-income countries

Surgical outcomes of gallbladder cancer: the OMEGA retrospective, multicentre, international cohort study

Background Gallbladder cancer (GBC) is rare but aggressive. The extent of surgical intervention for different GBC stages is non-uniform, ranging from cholecystectomy alone to extended resections including major hepatectomy, resection of adjacent organs and routine extrahepatic bile duct resection (EBDR). Robust evidence here is lacking, however, and survival benefit poorly defined. This study assesses factors associated with recurrence-free survival (RFS), overall survival (OS) and morbidity and mortality following GBC surgery in high income countries (HIC) and low and middle income countries (LMIC).Methods The multicentre, retrospective Operative Management of Gallbladder Cancer (OMEGA) cohort study included all patients who underwent GBC resection across 133 centres between 1st January 2010 and 31st December 2020. Regression analyses assessed factors associated with OS, RFS and morbidity.Findings On multivariable analysis of all 3676 patients, wedge resection and segment IVb/V resection failed to improve RFS (HR 1.04 [0.84-1.29], p = 0.711 and HR 1.18 [0.95-1.46], p = 0.13 respectively) or OS (HR 0.96 [0.79-1.17], p = 0.67 and HR 1.48 [1.16-1.88], p = 0.49 respectively), while major hepatectomy was associated with worse RFS (HR 1.33 [1.02-1.74], p = 0.037) and OS (HR 1.26 [1.03-1.53], p = 0.022). Furthermore, EBDR (OR 2.86 [2.3-3.52], p < 0.0010), resection of additional organs (OR 2.22 [1.62-3.02], p < 0.0010) and major hepatectomy (OR 3.81 [2.55-5.73], p < 0.0010) were all associated with increased morbidity and mortality. Compared to LMIC, patients in HIC were associated with poorer RFS (HR 1.18 [1.02-1.37], p = 0.031) but not OS (HR 1.05 [0.91-1.22], p = 0.48). Adjuvant and neoadjuvant treatments were infrequently used.Interpretation In this large, multicentre analysis of GBC surgical outcomes, liver resection was not conclusively associated with improved survival, and extended resections were associated with greater morbidity and mortality without oncological benefit. Aggressive upfront resections do not benefit higher stage GBC, and international col-laborations are needed to develop evidence-based neoadjuvant and adjuvant treatment strategies to minimise surgical morbidity and prioritise prognostic benefit.Funding Cambridge Hepatopancreatobiliary Department Research Fund.Copyright & COPY; 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)