Biliary pancreatic diversion and laparoscopic adjustable gastric banding in morbid obesity: their long-term effects on metabolic syndrome and on cardiovascular parameters

<p>Abstract</p> <p>Background</p> <p>Bariatric surgery is able to improve glucose and lipid metabolism, and cardiovascular function in morbid obesity. Aim of this study was to compare the long-term effects of malabsorptive (biliary pancreatic diversion, BPD), and restrictive (laparoscopic gastric banding, LAGB) procedures on metabolic and cardiovascular parameters, as well as on metabolic syndrome in morbidly obese patients.</p> <p>Methods</p> <p>170 patients studied between 1989 and 2001 were called back after a mean period of 65 months. 138 patients undergoing BPD (n = 23) or LAGB (n = 78), and control patients (refusing surgery and treated with diet, n = 37) were analysed for body mass index (BMI), blood glucose, cholesterol, and triglycerides, blood pressure, heart rate, and ECG indexes (QTc, Cornell voltage-duration product, and rate-pressure-product).</p> <p>Results</p> <p>After a mean 65 months period, surgery was more effective than diet on all items under evaluation; diabetes, hypertension, and metabolic syndrome disappeared more in surgery than in control patients, and new cases appeared only in controls. BPD was more effective than LAGB on BMI, on almost all cardiovascular parameters, and on cholesterol, not on triglyceride and blood glucose. Disappearance of diabetes, hypertension, and metabolic syndrome was similar with BPD and with LAGB, and no new cases were observed.</p> <p>Conclusion</p> <p>These data indicate that BPD, likely due to a greater BMI decrease, is more effective than LAGB in improving cardiovascular parameters, and similar to LAGB on metabolic parameters, in obese patients. The greater effect on cholesterol levels is probably due to the different mechanism of action.</p

In vivo temporal resolution of acute promyelocytic leukemia progression reveals a role of Klf4 in suppressing early leukemic transformation

Genome organization plays a pivotal role in transcription, but how transcription factors (TFs) rewire the structure of the genome to initiate and maintain the programs that lead to oncogenic transformation remains poorly understood. Acute promyelocytic leukemia (APL) is a fatal subtype of leukemia driven by a chromosomal translocation between the promyelocytic leukemia (PML) and retinoic acid receptor α (RARα) genes. We used primary hematopoietic stem and progenitor cells (HSPCs) and leukemic blasts that express the fusion protein PML-RARα as a paradigm to temporally dissect the dynamic changes in the epigenome, transcriptome, and genome architecture induced during oncogenic transformation. We found that PML-RARα initiates a continuum of topologic alterations, including switches from A to B compartments, transcriptional repression, loss of active histone marks, and gain of repressive histone marks. Our multiomics-integrated analysis identifies Klf4 as an early down-regulated gene in PML-RARα-driven leukemogenesis. Furthermore, we characterized the dynamic alterations in the Klf4 cis-regulatory network during APL progression and demonstrated that ectopic Klf4 overexpression can suppress self-renewal and reverse the differentiation block induced by PML-RARα. Our study provides a comprehensive in vivo temporal dissection of the epigenomic and topological reprogramming induced by an oncogenic TF and illustrates how topological architecture can be used to identify new drivers of malignant transformation.Funding: G.M. conducted this work with support from “Becas Leonardo a Investigadores y Creadores Culturales” from the Banco Bilbao Vizcaya Argentaria Foundation. The work in the Di Croce laboratory is supported by grants from the Spanish Ministry of Science and Innovation (PID2019-108322GB-100), “Fundación Vencer El Cancer” (VEC), the European Regional Development Fund (ERDF), Secretaria d'Universitats i Recerca del Departament d'Economia I Coneixement de la Generalitat de Catalunya (Programa Operatiu FEDER de Catalunya 2014-2020; AGAUR, 2017 SGR and 2019 FI_B 00426), the European Union's Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement number 713673 “ChromDesign,” and the Fondo Social Europeo (FSE). A.S. is supported by a fellowship from “la Caixa” Foundation (ID 100010434). The work was partially supported by awards from the European Research Council under the 7th Framework Program (FP7/2007-2013 609989), the European Union's Horizon 2020 Research and Innovation Program (676556), and the Spanish Ministerio de Ciencia, Innovación y Universidades (BFU2017-85926-P) to M.A.M.-R. We acknowledge support of the Spanish Ministry of Science and Innovation through the Instituto de Salud Carlos III, the EMBL partnership, and the cofinancing with funds from the European Regional Development Fund (FEDER), Centro de Excelencia Severo Ochoa; Centres de Recerca de Catalunya Programme/Generalitat de Cataluny