Metformin inhibits melanoma development through autophagy and apoptosis mechanisms

Metformin is the most widely used antidiabetic drug because of its proven efficacy and limited secondary effects. Interestingly, recent studies have reported that metformin can block the growth of different tumor types. Here, we show that metformin exerts antiproliferative effects on melanoma cells, whereas normal human melanocytes are resistant to these metformin-induced effects. To better understand the basis of this antiproliferative effect of metformin in melanoma, we characterized the sequence of events underlying metformin action. We showed that 24 h metformin treatment induced a cell cycle arrest in G0/G1 phases, while after 72 h, melanoma cells underwent autophagy as demonstrated by electron microscopy, immunochemistry, and by quantification of the autolysosome-associated LC3 and Beclin1 proteins. In addition, 96 h post metformin treatment we observed robust apoptosis of melanoma cells. Interestingly, inhibition of autophagy by knocking down LC3 or ATG5 decreased the extent of apoptosis, and suppressed the antiproliferative effect of metformin on melanoma cells, suggesting that apoptosis is a consequence of autophagy. The relevance of these observations were confirmed in vivo, as we showed that metformin treatment impaired the melanoma tumor growth in mice, and induced autophagy and apoptosis markers. Taken together, our data suggest that metformin has an important impact on melanoma growth, and may therefore be beneficial in patients with melanoma

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background: Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods: The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results: A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P < 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion: Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)

BRD4 connects enhancer remodeling to senescence immune surveillance

Oncogene-induced senescence is a potent barrier to tumorigenesis that limits cellular expansion following certain oncogenic events. Senescent cells display a repressive chromatin configuration thought to stably silence proliferation-promoting genes, while simultaneously activating an unusual form of immune surveillance involving a secretory program referred to as the senescence-associated secretory phenotype (SASP). Here we demonstrate that senescence also involves a global remodeling of the enhancer landscape with recruitment of the chromatin reader BRD4 to newly activated super-enhancers adjacent to key SASP genes. Transcriptional profiling and functional studies indicate that BRD4 is required for the SASP and downstream paracrine signaling. Consequently, BRD4 inhibition disrupts immune cell mediated targeting and elimination of premalignant senescent cells in vitro and in vivo. Our results identify a critical role for BRD4-bound super-enhancers in senescence immune surveillance and in the proper execution of a tumor-suppressive program

Absence of latitudinal gradient in oligoclonal bands prevalence in Argentina

Background: Like MS prevalence, oligoclonal bands (OCB) frequency seems to follow a latitudinal gradient. Argentina is extensive, latitude-wise, and previous studies have not found an MS prevalence latitudinal gradient. Our aim is to describe OCB prevalence in MS, clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS) patients included in the Argentinean MS and NMOSD registry (RelevarEM) and to investigate if it follows a latitudinal gradient. Methods: For each province, an average latitude was calculated, and OCB frequency was investigated. Multivariate logistical regression analysis and linear correlation were performed. Statistical analysis was repeated after excluding patients from centers using isoelectric focusing (IEF) in less than 95% of patients (CwIEF<95). Results: We included 2866 patients. OCB where positive in 73.9% of patients. No association or correlation were found between OCB and latitude of residence, even after excluding patients from (CwIEF<95). Conclusion: OCB positivity does not follow a latitudinal gradient in Argentina. Also, OCB positivity is lower than described in other world regions.Fil: Correale, Jorge. Fleni. Departamento de Neurología. Servicio de Neuroinmunología y Enfermedades Desmielinizantes; Argentina.Fil: Negrotto, Laura. Fleni. Departamento de Neurología. Servicio de Neuroinmunología y Enfermedades Desmielinizantes; Argentina.Fil: Marrodán, Mariano. Fleni. Departamento de Neurología. Servicio de Neuroinmunología y Enfermedades Desmielinizantes; Argentina.Fil: Fiol, Marcela Paula. Fleni. Departamento de Neurología. Servicio de Neuroinmunología y Enfermedades Desmielinizantes; Argentina.Fil: Gaitán, María Inés. Fleni. Departamento de Neurología. Servicio de Neuroinmunología y Enfermedades Desmielinizantes; Argentina.Fil: Ysrraelit, María Célica. Fleni. Departamento de Neurología. Servicio de Neuroinmunología y Enfermedades Desmielinizantes; Argentina.Fil: Vrech, Carlos. Sanatorio Allende. Departamento de Enfermedades desmielinizantes; Argentina.Fil: Pappolla, Agustín. Hospital Italiano de Buenos Aires. Servicio de Neurología; Argentina.Fil: Miguez, Jimena. Hospital Italiano de Buenos Aires. Servicio de Neurología; Argentina.Fil: Patrucco, Liliana. Hospital Italiano de Buenos Aires. Servicio de Neurología; Argentina.Fil: Cristiano, Edgardo. Centro de esclerosis múltiple de Buenos Aires; Argentina.Fil: Rojas, Juan I. Centro de esclerosis múltiple de Buenos Aires; Argentina. Hospital Universitario de CEMIC. Servicio de Neurología; Argentina.Fil: Carrá, Adriana. Hospital Británico. Sección de Enfermedades Desmielinizantes; Argentina. Fundación Favaloro/INECO. Instituto de Neurociencias; Argentina.Fil: Chertcoff, Aníbal. Fundación Favaloro/INECO. Instituto de Neurociencias; Argentina.Fil: Steinberg, Judith. Hospital Británico. Sección de Enfermedades Desmielinizantes; Argentina.Fil: Martinez, Alejandra D. Hospital Británico. Sección de Enfermedades Desmielinizantes; Argentina.Fil: Curbelo, María Celeste. Hospital Británico. Sección de Enfermedades Desmielinizantes; Argentina.Fil: Cohen, Leila. Hospital Dr. J. M. Ramos Mejía. Centro Universitario de Esclerosis Múltiple; Argentina.Fil: Alonso, Ricardo. Hospital Dr. J. M. Ramos Mejía. Centro Universitario de Esclerosis Múltiple; Argentina.Fil: Garcea, Orlando. Hospital Dr. J. M. Ramos Mejía. Centro Universitario de Esclerosis Múltiple; Argentina

Aggressive multiple sclerosis in Argentina: Data from the nationwide registry RelevarEM

The objectives of the present study were to describe the frequency of aggressive multiple sclerosis (aMS) as well as to compare clinical and radiological characteristics in aMS and non-aMS patients included in RelevarEM (NCT 03375177). Methods The eligible study population and cohort selection included adult-onset patients (≥18 years) with definite MS. AMS were defined as those reaching confirmed EDSS ≥ 6 within 5 years from symptom onset. Confirmation was achieved when a subsequent EDSS ≥ 6 was recorded at least six months later but within 5 years of the first clinical presentation. AMS and non-aMS were compared using the χ2 test for categorical and the Mann-Whitney for continuous variables at MS onset and multivariable analysis was performed using forward stepwise logistic regression with baseline characteristics at disease onset. Results A total of 2158 patients with MS were included: 74 aMS and 2084 non-aMS. The prevalence of aMS in our cohort was 3.4% (95%CI 2.7–4.2). AMS were more likely to be male (p = 0.003), older at MS onset (p < 0.001), have primary progressive MS (PPMS) phenotype (p = 0.03), multifocal presentation (p < 0.001), and spinal cord as well as infratentorial lesions at MRI during disease onset (p = 0.004 and p = 0.002, respectively). Conclusion 3.4% of our patient population could be considered aMS. Men, patients older at symptom onset, multifocal presentation, PPMS phenotype, and spinal cord as well as brainstem lesions on MRI at clinical presentation all had higher odds of having aMS.Fil: Kohler, Matías. Fundación Sinapsis Santa Rosa; Argentina.Fil: Kohler, Eduardo. Fundación Sinapsis Santa Rosa; Argentina.Fil: Vrech, Carlos. Sanatorio Allende; Argentina.Fil: Pappolla, Agustín. Hospital Italiano de Buenos Aires; Argentina.Fil: Miguez, Jimena. Hospital Italiano de Buenos Aires; Argentina.Fil: Patrucco, Liliana. Hospital Italiano de Buenos Aires; Argentina.Fil: Correale, Jorge. Fleni. Departamento de Neurología. Servicio de Neuroinmunología y Enfermedades Desmielinizantes; ArgentinaFil: Marrodan, Mariano. Fleni. Departamento de Neurología. Servicio de Neuroinmunología y Enfermedades Desmielinizantes; ArgentinaFil: Gaitán, María Inés. Fleni. Departamento de Neurología. Servicio de Neuroinmunología y Enfermedades Desmielinizantes; Argentina.Fil: Fiol, Marcela. Fleni. Departamento de Neurología. Servicio de Neuroinmunología y Enfermedades Desmielinizantes; Argentina.Fil: Negrotto, Laura. Fleni. Departamento de Neurología. Servicio de Neuroinmunología y Enfermedades Desmielinizantes; Argentina.Fil: Ysrraelit, María Célica. Fleni. Departamento de Neurología. Servicio de Neuroinmunología y Enfermedades Desmielinizantes; Argentina.Fil: Cristiano, Edgardo. Centro de esclerosis múltiple de Buenos Aires; Argentina.Fil: Carrá, Adriana. Hospital Británico; Argentina.Fil: Steinberg, Judith. Hospital Británico; Argentina.Fil: Martinez, Alejandra D. Hospital Británico; Argentina.Fil: Curbelo, María Celeste. Hospital Británico; Argentina.Fil: Cohen, Leila. Hospital Dr. J. M. Ramos Mejía; Argentina.Fil: Alonso, Ricardo. Hospital Dr. J. M. Ramos Mejía; Argentina.Fil: Garcea, Orlando. Hospital Dr. J. M. Ramos Mejía; Argentina