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Abstract Background Metabolic dysfunction associated steatotic liver disease (MASLD) is associated with increased cardiovascular disease (CVD) risk in persons with HIV (PWH). The lipidomic and metabolomic alterations contributing to this risk are poorly understood. We aimed to characterize the advanced lipoprotein and targeted metabolomic profiles in PWH and assess if the presence and severity of MASLD influence these profiles. Methods This is a cross-sectional analysis of a prospectively enrolled multicenter cohort. PWH without alcohol abuse or known liver disease underwent vibration-controlled transient elastography for controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). Lipidomic and metabolomic profiling was undertaken with nuclear magnetic resonance (NMR) spectroscopy. Hepatic steatosis was defined as CAP ≥ 263 dB/m and clinically significant fibrosis (CSF) as LSM ≥ 8 kPa. Logistic regression models assessed associations between MASLD, CSF and lipidomic and metabolic parameters. Results Of 190 participants (71% cisgender male, 96% on antiretroviral therapy), 58% had MASLD and 12% CSF. Mean (SD) age was 48.9 (12.1) years and body mass index (BMI) 29.9 (6.4) kg/m2. Compared to PWH without MASLD (controls), PWH with MASLD had lower HDL-C but higher total triglyceride, VLDL-C, branched-chain amino acids, GlycA, trimethylamine N-oxide levels, Lipoprotein-Insulin Resistance and Diabetes Risk Indices. There were no significant differences in these parameters between participants with MASLD with or without CSF. In a multivariable regression analysis, MASLD was independently associated with changes in most of these parameters after adjustment for age, gender, race/ethnicity, type 2 diabetes mellitus, BMI, and lipid lowering medications use. Conclusions MASLD in PWH is independently associated with altered advanced lipoprotein and targeted metabolic profiles, indicating a higher CVD risk in this population.

BackgroundMicrosatellite instability (MSI) secondary to mismatch repair (MMR) deficiency is characterized by insertions and deletions (indels) in short DNA sequences across the genome. These indels can generate neoantigens, which are ideal targets for precision immune interception. However, current neoantigen databases lack information on neoantigens arising from coding microsatellites. To address this gap, we introduce The MicrOsatellite Neoantigen Discovery Tool (MONET).MethodMONET identifies potential mutated tumor-specific neoantigens (neoAgs) by predicting frameshift mutations in coding microsatellite sequences of the human genome. Then MONET annotates these neoAgs with key features such as binding affinity, stability, expression, frequency, and potential pathogenicity using established algorithms, tools, and public databases. A user-friendly web interface (https://monet.mdanderson.org/) facilitates access to these predictions.ResultsMONET predicts over 4 million and 15 million Class I and Class II potential frameshift neoAgs, respectively. Compared to existing databases, MONET demonstrates superior coverage (>85% vs.

Cronkhite-Canada Syndrome (CCS) is a rare, noninherited polyposis syndrome affecting 1 in every million individuals. Despite over 50 years of CCS cases, the etiopathogenesis and optimal treatment for CCS remains unknown due to the rarity of the disease and lack of model systems. To better understand the etiology of CCS, we generated human intestinal organoids (HIOs) from intestinal stem cells isolated from 2 patients. We discovered that CCS HIOs are highly proliferative and have increased numbers of enteroendocrine cells producing serotonin (also known as 5-hydroxytryptamine or 5HT). These features were also confirmed in patient tissue biopsies. Recombinant 5HT increased proliferation of non-CCS donor HIOs and inhibition of 5HT production in the CCS HIOs resulted in decreased proliferation, suggesting a link between local epithelial 5HT production and control of epithelial stem cell proliferation. This link was confirmed in genetically engineered HIOs with an increased number of enteroendocrine cells. This work provides a new mechanism to explain the pathogenesis of CCS and illustrates the important contribution of HIO cultures to understanding disease etiology and in the identification of novel therapies. Our work demonstrates the principle of using organoids for personalized medicine and sheds light on how intestinal hormones can play a role in intestinal epithelial proliferation.

BackgroundInternational chemoprevention preferences and approaches in Lynch syndrome (LS) and APC-associated polyposis, including Familial adenomatous polyposis (FAP) and attenuated FAP (AFAP) have not been previously explored.AimTo describe current chemoprevention strategies for patients with LS or FAP/AFAP (referred to collectively as FAP) practiced by members of four international hereditary cancer societies through administration of a survey.ResultsNinety-six participants across four hereditary gastrointestinal cancer societies responded to the survey. Most respondents (91%, 87/96) completed information regarding their demographics and practice characteristics relating to hereditary gastrointestinal cancer and chemoprevention clinical practices. Sixty-nine percent (60/87) of respondents offer chemoprevention for FAP and/or LS as a part of their practice. Of the 75% (72/96) of survey respondents who were eligible to answer practice-based clinical vignettes based off of their responses to ten barrier questions regarding chemoprevention, 88% (63/72) of those participants completed at least one case vignette question to further characterize chemoprevention practices in FAP and/or LS. In FAP, 51% (32/63) would offer chemoprevention for rectal polyposis, with sulindac - 300 mg (18%, 10/56) and aspirin (16%, 9/56) being the most frequently selected options. In LS, 93% (55/59) of professionals discuss chemoprevention and 59% (35/59) frequently recommend chemoprevention. Close to half of the respondents (47%, 26/55) would recommend beginning aspirin at time of commencement of the patient’s first screening colonoscopy (usually at age 25yrs). Ninety-four percent (47/50) of respondents would consider a patient’s diagnosis of LS as an influential factor for aspirin use. There was no consensus on the dose of aspirin (≤100 mg, >100 mg - 325 mg or 600 mg) to offer patients with LS and there was no agreement on how other factors, such as BMI, hypertension, family history of colorectal cancer, and family history of heart disease, would affect the recommendation for aspirin use. Possible harm among older patients (>70 years) was identified as the most common reason to discourage aspirin use.ConclusionAlthough chemoprevention is widely discussed and offered to patients with FAP and LS by an international group of hereditary gastrointestinal cancer experts, there is significant heterogeneity in how it is applied in clinical practice.

BackgroundRecent clinical trial data from Lynch Syndrome (LS) carriers demonstrated that naproxen administered for 6-months is a safe primary chemoprevention that promotes activation of different resident immune cell types without increasing lymphoid cellularity. While intriguing, the precise immune cell types enriched by naproxen remained unanswered. Here, we have utilized cutting-edge technology to elucidate the immune cell types activated by naproxen in mucosal tissue of LS patients.MethodsNormal colorectal mucosa samples (pre- and post-treatment) from a subset of patients enrolled in the randomized and placebo-controlled ‘Naproxen Study’ were obtained and subjected to a tissue microarray for image mass cytometry (IMC) analysis. IMC data was processed using tissue segmentation and functional markers to ascertain cell type abundance. Computational outputs were then used to quantitatively compare immune cell abundance in pre- and post-naproxen specimens.ResultsUsing data-driven exploration, unsupervised clustering identified four populations of immune cell types with statistically significant changes between treatment and control groups. These four populations collectively describe a unique cell population of proliferating lymphocytes within mucosal samples from LS patients exposed to naproxen.ConclusionsOur findings show that daily exposure of naproxen promotes T-cell proliferation in the colonic mucosa, which paves way for developing combination of immunoprevention strategies including naproxen for LS patients.

Deregulation of the BCL-2 family interactions ensures cancer resistance to apoptosis and is a major challenge to current treatments. Here the authors describe a novel therapeutic strategy to overcome two anti-apoptotic mechanisms for cancer therapy.

ObjectiveLynch Syndrome (LS) carriers have a significantly increased risk of developing colorectal cancer (CRC) during their lifetimes. Further stratification of this patient population may help in identifying additional risk factors that predispose to colorectal carcinogenesis. In most LS patients CRC may arise from adenomas, although an alternative non-polypoid carcinogenesis pathway has been proposed for PMS2 carriers. Using data from our institutional LS cohort, our aim was to describe our current colorectal screening outcomes with a focus on the incidence of adenomas in the context of different MMR genotypes and patient demographics such as gender, race, and ethnicity.DesignWe collected demographics, genetic, colonoscopy, and pathology results from a total of 163 LS carriers who obtained regular screening care at MD Anderson Cancer Center. Data were extracted from the electronic health records into a REDCap database for analysis. Logistic regressions were performed to measure the association between MMR variants and the likelihood of adenomas, advanced adenomas, and CRC. Then, we analyzed the cumulative incidences of these outcomes for the first 36 months following enrollment using Kaplan-Meier incidence curves, and Cox proportional hazard regressions.ResultsOn multivariate analysis, age (≥45 years old) was associated with an increased risk of developing adenomas (P=0.034). Patients with a prior or active cancer status were less likely to develop adenomas (P=0.015), despite of the lack of association between surgical history with this outcome (P=0.868). We found no statistically significant difference in likelihood of adenoma development between MLH1 and MSH2/EPCAM, MSH6, and PMS2 carriers. Moreover, we observed no statistically significant difference in the likelihood of advanced adenomas or CRC for any measured covariates. On Cox proportional hazard, compared to MLH1 carriers, the incidence of adenomas was highest among MSH2/EPCAM carriers during for the first 36-months of follow-up (P

Abstract Cellular heterogeneity underlies cancer evolution and metastasis. Advances in single-cell technologies such as single-cell RNA sequencing and mass cytometry have enabled interrogation of cell type-specific expression profiles and abundance across heterogeneous cancer samples obtained from clinical trials and preclinical studies. However, challenges remain in determining sample sizes needed for ascertaining changes in cell type abundances in a controlled study. To address this statistical challenge, we have developed a new approach, named Sensei, to determine the number of samples and the number of cells that are required to ascertain such changes between two groups of samples in single-cell studies. Sensei expands the t-test and models the cell abundances using a beta-binomial distribution. We evaluate the mathematical accuracy of Sensei and provide practical guidelines on over 20 cell types in over 30 cancer types based on knowledge acquired from the cancer cell atlas (TCGA) and prior single-cell studies. We provide a web application to enable user-friendly study design via https://kchen-lab.github.io/sensei/table_beta.html .

Background Monotherapy with immune checkpoint blockade is ineffective for patients (pts) with microsatellite stable (MSS) metastatic colorectal cancer (mCRC). This study investigates whether the combination of trametinib (T) with durvalumab (D) can alter the immune tumor microenvironment (TME) by successfully priming and activating T-cells.Methods Open-label, single-center, phase II trial with primary endpoint of immune-related response rate for combination of T+D in refractory MSS mCRC pts (NCT03428126). T is 2 mg/day orally starting 1 week prior to D, which is given 1500 mg intravenously every 4 weeks. Simon 2-stage design used to enroll 29 pts into first stage, requiring a response in two or more pts to proceed to stage 2. Tumor biopsies were collected at baseline (BL) and early on-treatment (OT) at week 4.Results Twenty nine treated pts include 48% females, median age 48 years (range 28–75), and median prior therapies 2 (range 1–5). No grade (G) 4 or 5 treatment-related adverse events (TRAE). The most common TRAE of any grade was acneiform rash, 17% being G3. One of 29 pts had confirmed partial response (PR) lasting 9.3 months (mo) for an overall response rate of 3.4%. Seven pts had stable disease (SD) and five pts (1 PR, 4 SD) demonstrated decrease in total carcinoembryonic antigen ng/mL (best percentage reduction: 94%, 95%, 42%, 34%, and 22%, respectively). Median progression-free survival was 3.2 mo (range 1.1–9.3 months). Three pts with both liver and lung metastases demonstrated discrepant responses in which clinical benefit was present in the lung metastases but not liver metastases. Comparison of BL and 4-week OT tumor tissue flow cytometry demonstrated no changes in T-cell infiltration but upregulation expression of PD-1 and Tim3 on CD8 T cells. However, expression of PD-1 and Tim3 as single markers and as coexpressed markers was observed to increase OT relative to BL (p=0.03, p=0.06 and p=0.06, respectively).Conclusions T+D demonstrated acceptable tolerability in pts with refractory MSS mCRC. The response rate in the first stage of the study did not meet efficacy criteria to proceed to the second stage. Specific site of metastatic disease may impact outcomes in novel immunotherapy combination trials.Trial registration number NCT03428126.

Enhanced liver fibrosis score (ELF) and one of its components, amino‐terminal propeptide of type III procollagen (PIIINP) are promising noninvasive biomarkers of liver histology in patients with nonalcoholic steatohepatitis (NASH). We evaluated the association of ELF and PIIINP with fibrosis stages at baseline and end of treatment (EOT) with vitamin E or pioglitazone in the PIVENS trial (Pioglitazone vs. Vitamin E vs. Placebo for the Treatment of Nondiabetic Patients With NASH) and characterized ELF and PIIINP changes and their associations with changes in the histological endpoints. ELF and PIIINP were measured at baseline and weeks 16, 48, and 96 on sera from 243 PIVENS participants. Baseline and EOT ELF were significantly associated with fibrosis stage (P

Non-alcoholic fatty liver disease (NAFLD) currently represents an epidemic worldwide. NAFLD is the most frequently diagnosed chronic liver disease, affecting 20–30% of the general population. Furthermore, its prevalence is predicted to increase exponentially in the next decades, concomitantly with the global epidemic of obesity, type 2 diabetes mellitus (T2DM), and sedentary lifestyle. NAFLD is a clinical syndrome that encompasses a wide spectrum of associated diseases and hepatic complications such as hepatocellular carcinoma (HCC). Moreover, this disease is believed to become the main indication for liver transplantation in the near future. Since NAFLD management represents a growing challenge for primary care physicians, the Asociación Latinoamericana para el Estudio del Hígado (ALEH) has decided to organize this Practice Guidance for the Diagnosis and Treatment of Non-Alcoholic Fatty Liver Disease, written by Latin-American specialists in different clinical areas, and destined to general practitioners, internal medicine specialists, endocrinologists, diabetologists, gastroenterologists, and hepatologists. The main purpose of this document is to improve patient care and awareness of NAFLD. The information provided in this guidance may also be useful in assisting stakeholders in the decision-making process related to NAFLD. Since new evidence is constantly emerging on different aspects of the disease, updates to this guideline will be required in future.

How telomere dysfunction is directly linked to inflammation in humans is currently unclear. Here the authors reveal that telomere dysfunction drives activation of the YAP1 transcription factor, up-regulating the pro inflammatory factor, pro-IL-18 thus revealing a link between telomere dysfunction and initiation of intestinal inflammation.

Abstract Background Individuals who have colorectal or endometrial cancers displaying loss of immunohistochemical staining of one or more mismatch repair proteins without an identifiable causative germline pathogenic variant have unexplained mismatch repair deficiency (UMMRD). Comprehensive germline genetic testing for Lynch syndrome (LS) includes sequencing and deletion/duplication analysis of MLH1, MSH2, MSH6, and PMS2, deletion analysis of EPCAM, and MSH2 inversion analysis. Updated genetic testing to include elements of comprehensive LS testing not previously completed could further clarify LS status in individuals with UMMRD, allowing for tailored screening guidelines for affected individuals and their family members. However, patient understanding of the potential impact of updated genetic testing for LS is unclear. This study aimed to evaluate the interest in and perceived impact of updated genetic testing among individuals with UMMRD at a tertiary academic center. Methods A survey evaluating interest in and perceived impact of updated genetic testing was mailed to 98 potential participants. Electronic health record review was completed for all individuals meeting eligibility criteria. Thirty-one individuals responded to the survey. Results Results indicate this population is highly interested in updated genetic testing with the perceived impact being primarily for family members to have appropriate genetic testing and screening. Electronic health record review indicates that clinicians have an evolving understanding of causes of UMMRD, representing a potential change in assessment of cancer risk. Conclusions Updated risk assessment and genetic counseling with a discussion of the benefits and limitations of germline and somatic genetic testing, is essential as the understanding of UMMRD and genetic testing recommendations for this population evolve.

Abstract Background We examined how extra-hepatic comorbidity burden impacts mortality in patients with cirrhosis referred for liver transplantation (LT). Methods Adults with cirrhosis evaluated for their first LT in 2012 were followed through their clinical course with last follow up in 2019. Extra-hepatic comorbidity burden was measured using the Charlson Comorbidity Index (CCI). The endpoints were 90-day transplant free survival (Cox-Proportional Hazard regression), and overall mortality (competing risk analysis). Results The study included 340 patients, mean age 56 ± 11, 63% male and MELD-Na 17.2 ± 6.6. The CCI was 0 (no comorbidities) in 44%, 1–2 in 44% and > 2 (highest decile) in 12%, with no differences based on gender but higher CCI in patients with fatty and cryptogenic liver disease. Thirty-three (10%) of 332 patients not receiving LT within 90 days died. Beyond MELD-Na, the CCI was independently associated with 90-day mortality (hazard ratio (HR), 1.32 (95% confidence interval (CI) 1.02–1.72). Ninety-day mortality was specifically increased with higher CCI category and MELD ≥18 (12% (CCI = 0), 22% (CCI = 1–2) and 33% (CCI > 2), (p = 0.002)) but not MELD-Na ≤17. At last follow-up, 69 patients were alive, 100 underwent LT and 171 died without LT. CCI was associated with increased overall mortality in the competing risk analysis (Sub-HR 1.24, 95%CI 1.1–1.4). Conclusions Extra-hepatic comorbidity burden significantly impacts short-term mortality in patients with cirrhosis and high MELD-Na. This has implications in determining urgency of LT and mortality models in cirrhosis and LT waitlisting, especially with an ageing population with increasing prevalence of fatty liver disease.

Colorectal cancer (CRC) remains the third most common cancer in the US with 15% of cases displaying Microsatellite Instability (MSI) secondary to Lynch Syndrome (LS) or somatic hypermethylation of the MLH1 promoter. A cohort of rhesus macaques from our institution developed spontaneous mismatch repair deficient (MMRd) CRC with a notable fraction harboring a pathogenic germline mutation in MLH1 (c.1029C

Abstract Background Recent evidence cautions against the use of non-selective beta-blockers (NSBB) in patients with refractory ascites or spontaneous bacterial peritonitis while other data suggests a survival benefit in patients with advanced liver disease. The aim of this study was to describe the use and impact of NSBB in patients with cirrhosis referred for liver transplantation. Methods A single-center cohort of patients with cirrhosis, who were referred and evaluated for liver transplantation between January and June 2012 were studied for baseline characteristics and clinical outcomes. Patients were grouped according to the use of NSBB at initial evaluation, with the endpoint of 90-day mortality. Results Sixty-five (38%) of 170 consecutive patients evaluated for liver transplantation were taking NSBB. Patients taking NSBB had higher MELD and Child Pugh score. NSBB use was associated with lower 90-day mortality (6% vs. 15%) with a risk adjusted hazard ratio of 0.27 (95%CI .09–0.88, p = .03). Patients taking NSBB developed acute kidney injury (AKI) within 90 days more frequently than patients not taking NSBB (22% vs 11%), p = 0.048). However, this was related to increased stage 1 AKI episodes, all of which resolved. Twelve (27%) of 45 patients with > 90 day follow up discontinued NSBB, most commonly for hypotension and AKI, had increased subsequent MELD and mortality. Conclusions NSBB use in patients with cirrhosis undergoing liver transplant evaluation is associated with better short-term survival. Nevertheless, ongoing tolerance of NSBB in this population is dynamic and may select a subset of patients with better hemodynamic reserve.

This article aims at reconstructing the social, educational and academic trajectories of graduates in Social Sciences, at our university, from a material of twelve in-depth interviews with such graduates during 2000s. Firstly, we discuss the different dynamics and paths to ‘choosing’ the degree in Social Sciences among interviewees from different sociocultural backgrounds, considering, as the literature points out, both the “expectations readjustments” that can lead to careers of lesser social prestige, as well as the unique socialization experiences that inculcate, in some of our interviewees, specific propensities and interests towards our career. Subsequently, we discuss some issues that were indistinctly thematized by interviewees from different sociocultural backgrounds, as, for instance, the theme of the “non-material gains” that interviewees routinely associate to their degree in Social Sciences despite the difficulties of professionalization frequently narrated by them.

Despite regulatory approval of several immune-based treatments for cancer in the past decade, a number of barriers remain to be addressed in order to fully harness the therapeutic potential of the immune system and provide benefits for patients with cancer. As part of the Cancer Moonshot initiative, the Immuno-Oncology Translational Network (IOTN) was established to accelerate the translation of basic discoveries to improve immunotherapy outcomes across the spectrum of adult cancers and to develop immune-based approaches that prevent cancers before they occur. The IOTN currently consists of 32 academic institutions in the USA. By leveraging cutting-edge preclinical research in immunotherapy and immunoprevention, open data and resource sharing, and fostering highly collaborative team science across the immuno-oncology ecosystem, the IOTN is designed to accelerate the generation of novel mechanism-driven immune-based cancer prevention and therapies, and the development of safe and effective personalized immuno-oncology approaches.

This text aims at exploring the analytical dimension ignited by the notion of “social capital” on the reconstitution of educational trajectories among underprivileged students from urban backgrounds. Drawing on both the national and the international literatures, it seeks to evidence not only the relevance of the social networks that diffuse informational flows on institutions, careers and modes of selection of the Brazilian system of higher education (a fact which tends to reduce both the social and the cultural distances between underprivileged students, engaged within such networks), as well as how such networks may operate as the relational instances that support the projection of juvenile life styles which symbolize and express the incorporation of dispositions towards the prolongation of the educational trajectories among underprivileged students.

BackgroundSafety-net hospitals provide care for racially/ethnically diverse and disadvantaged urban populations. Their hospitalized patients with cirrhosis are relatively understudied and may be vulnerable to poor outcomes and racial/ethnic disparities.AimsTo examine the outcomes of patients with cirrhosis hospitalized at regionally diverse safety-net hospitals and the impact of race/ethnicity.MethodsA study of patients with cirrhosis hospitalized at 4 safety-net hospitals in 2012 was conducted. Demographic, clinical factors, and outcomes were compared between centers and racial/ethnic groups. Study endpoints included mortality and 30-day readmission.ResultsIn 2012, 733 of 1,212 patients with cirrhosis were hospitalized for liver-related indications (median age 55 years, 65% male). The cohort was racially diverse (43% White, 25% black, 22% Hispanic, 3% Asian) with cirrhosis related to alcohol and viral hepatitis in 635 (87%) patients. Patients were hospitalized mainly for ascites (35%), hepatic encephalopathy (20%) and gastrointestinal bleeding (GIB) (17%). Fifty-four (7%) patients died during hospitalization and 145 (21%) survivors were readmitted within 30 days. Mortality rates ranged from 4 to 15% by center (p = .007) and from 3 to 10% by race/ethnicity (p = .03), but 30-day readmission rates were similar. Mortality was associated with Model for End-stage Liver Disease (MELD), acute-on-chronic liver failure, hepatocellular carcinoma, sodium and white blood cell count. Thirty-day readmission was associated with MELD and Charlson Comorbidity Index >4, with lower risk for GIB. We did not observe geographic or racial/ethnic differences in hospital outcomes in the risk-adjusted analysis.ConclusionsHospital mortality and 30-day readmission in patients with cirrhosis at safety-net hospitals are associated with disease severity and comorbidities, with lower readmissions in patients admitted for GIB. Despite geographic and racial/ethnic differences in hospital mortality, these factors were not independently associated with mortality.

Este artigo busca argumentar que toda relação de "comunicação pedagógica" revela-se sob a forma de uma interação face a face. Não obstante, a sociologia da educação tem evidenciado, desde sua emergência, que as condições que regem a potencial eficácia de uma relação de comunicação pedagógica não são completamente endógenas ao contexto interativo em que esta relação se desdobra, uma vez que ela depende decisivamente da socialização e da escolarização prévia dos agentes em interação. Sendo assim, através da observação de uma situação de comunicação pedagógica cujos agentes em interação têm suas trajetórias sociais reconstruídas previamente por meio de entrevistas em profundidade, o artigo propõe um quadro de pesquisa original para possível orientação de estudos na sociologia da educação que, conforme as tendências recentes da área, sejam direcionados à abordagem de dinâmicas e processos transcorridos no interior de instituições de ensino através da articulação dos níveis micro e macrossociológico da análise.

SMAD4 is an essential mediator in the transforming growth factor-β pathway. Sporadic mutations of SMAD4 are present in 2.1-20.0% of colorectal cancers (CRCs) but data are limited. In this study, we aimed to evaluate clinicopathologic characteristics, prognosis, and clinical outcome associated with this mutation in CRC cases. Data for patients with metastatic or unresectable CRC who underwent genotyping for SMAD4 mutation and received treatment at The University of Texas MD Anderson Cancer Center from 2000 to 2014 were reviewed. Their tumors were sequenced using a hotspot panel predicted to cover 80% of the reported SMAD4 mutations, and further targeted resequencing that included full-length SMAD4 was performed on mutated tumors using a HiSeq sequencing system. Using The Cancer Genome Atlas data on CRC, the characteristics of SMAD4 and transforming growth factor-β pathway mutations were evaluated according to different consensus molecular subtypes of CRC. Among 734 patients with CRC, 90 (12%) had SMAD4 mutations according to hotspot testing. SMAD4 mutation was associated with colon cancer more so than with rectal cancer (odds ratio 2.85; p

Circulating cell-free DNA (cfDNA) isolated from the plasma of cancer patients (pts) has been shown to reflect the genomic mutation profile of the tumor. However, physician and patient assessment of clinical utility of these assays in patients with metastatic colorectal cancer (mCRC) has not been previously described.Patients were prospectively consented to a prospective genomic matching protocol (Assessment of Targeted Therapies Against Colorectal Cancer [ATTACC]), with collection of blood for cfDNA extraction and sequencing of a 54-gene panel in a CLIA-certified lab. Formalin-fixed, paraffin-embedded (FFPE) tissue from prior resections or biopsies underwent 50-gene sequencing. Results from both assays were returned to the treating physicians for patient care and clinical trial selection. Follow-up surveys of treating physicians and chart reviews assessed clinical utility.128 mCRC pts were enrolled between 6/2014 and 1/2015. Results were returned in median of 13 and 26 days for cfDNA and FFPE sequencing, respectively. With cfDNA sequencing, 78% (100/128) of samples had a detectable somatic genomic alteration. 50% of cfDNA cases had potentially actionable alterations, and 60% of these could be genomically matched to at least one clinical trial in our institution. 50% (15/30) of these pts enrolled onto an identified matched trial. Physicians reported that the cfDNA testing improved the quality of care they could provide in 73% of the cases, and that 89% of pts reported greater satisfaction with the efforts to personalize experimental therapeutic agents.cfDNA sequencing can provide timely information on potentially actionable mutations and amplifications, thereby facilitating clinical trial enrollment and improving the perceived quality of care.

Se presenta una revisión sobre la enfermedad hepática no alcohólica, teniendo en cuenta los aspectos más actuales de la fisiopatología, el diagnóstico y el tratamiento de la enfermedad.

Los modelos pronósticos representan un pilar importante en la evaluación de los pacientes con cirrosis hepática, sobre todo a la hora de tomar decisiones como el trasplante hepático. Los 2 modelos más utilizados al nivel mundial, el Child Pugh Turcotte y el Model for end stage liver disease (MELD), presentan ventajas y desventajas en su aproximación a los pacientes. El objetivo de este trabajo fue revisar estos modelos pronósticos utilizados en la enfermedad hepática terminal, así como comparar el modelo MELD y el Child Pugh Turcotte sobre la base del diseño, eficacia predictiva y aplicación practica. Se concluye que ambos modelos son útiles para predecir la mortalidad en los pacientes con cirrosis hepática y que se deben realizar futuras investigaciones para mejorar su poder discriminativo.The prognostic models are a significant pillar in assessment of patients presenting hepatic cirrhosis, mainly at moment to make a decision related to liver transplantation. The two more used models at international level, the Child Pugh Turcotte and the Model for end stage liver disease ( MELD) have advantages and disadvantages in its approximation to patients. The aim of present paper was to review these prognostic models used in the end-terminal liver disease, as well as to compare the above mentioned models on the base of the design, predictive effectiveness and practical application. We conclude that both models are useful to predict mortality in patients presenting with hepatic cirrhosis and also that more future researches must to be performed to improve its discriminatory power.

BACKGROUND: Arterial blood pressure (BP) is a reliable marker of circulatory dysfunction in cirrhotic patients. There are no prospective studies evaluating the association between different levels of arterial BP and ascites development in compensated cirrhotic patients. Therefore, we evaluated the relationship between arterial BP and ascites development in compensated cirrhotic patients. MATERIALS AND METHODS: A total of 402 patients with compensated HCV-related cirrhosis were prospectively followed during 6 years to identify ascites development. At baseline, patients underwent systolic, diastolic and mean arterial pressure (MAP) measurements. Any history of arterial hypertension was also recorded. The occurrence of events such as bleeding, hepatocellular carcinoma, death and liver transplantation prior to ascites development were considered as competing risk events. RESULTS: Over a median of 156 weeks, ascites occurred in 54 patients (13%). At baseline, MAP was significantly lower in patients with ascites development (75.9 mm/Hg [95%CI, 70.3-84.3]) than those without ascites (93.6 mm/Hg [95% CI: 86.6-102.3]). After adjusting for covariates, the 6-year cumulative incidence of ascites was 40% (95%CI, 34%-48%) for patients with MAP

Las tasas de seroconversión del antígeno e alcanzadas con los antivirales actuales no sobrepasan el 35 %. La combinación de inmunomodulador y antiviviral ha sido teóricamente la estrategia más aceptada en los últimos años; sin embargo, los resultados en la práctica clínica han sido contradictorios. Se realizó el presente trabajo para evaluar la eficacia y seguridad de un esquema de tratamiento prolongado durante 52 sem con interferón alfa-2b más lamivudina en pacientes con hepatitis crónica B y antígeno e positivo. Se estudiaron 46 pacientes asignados aleatoriamente: 23 recibieron 150 mg diarios de lamivudina por 4 sem, lamivudina más interferón alfa-2b (10 MU en días alternos) por 24 sem, seguido de lamivudina en la misma dosis y frecuencia hasta completar las 52 sem. Otros 23 recibieron 150 mg diarios de lamivudina por 4 sem y lamivudina más interferón alfa-2b (5 MU en días alternos) durante 52 sem. Se encontró que las tasas de seroconversión del antígeno fueron similares en ambos grupos. Una proporción significativa de pacientes con tratamiento combinado prolongado logró negativizar el ADN viral (52 % frente al 26 %, p=0,06) y el antígeno de superficie (48 % frente al 26 %, p=0,11), comparado con los controles. La mejoría en el índice de actividad histológica fue observada en el 48 % de los pacientes tratados con tratamiento combinado prolongado frente al 22 % de los controles (p=0,06). Se concluyó que el tratamiento prolongado deerferón y lamivudina durante 52 sem puede brindar beneficios clínicos en las tasas de pérdida sostenida del ADN viral, el antígeno de superficie y en el índice de actividad histológica.The seroconversion rates of e antigen attained with the current antivirals do not exceed 35 %. The combination of immunomodulator and antiviral has been theoretically the most accepted strategy in the last five years; however, the results in clinical practice have been contradictory. This paper is aimed at evaluating the efficacy and security of a treatment scheme prolonged for 52 weeks with alpha-2b interferon plus lamivudine in patients with e antigen positive chronic hepatitis B. 46 patients selected at random were studied: 23 received 150 mg of lamivudine daily during 4 weeks, lamivudine plus alpha-2b (10 MU every other day) for 24 weeks, followed by lamivudine in the same dose and frequency until completing the 52 weeks. Other 23 were administered 150 mg of lamivudine daily for 4 weeks plus alpha 2b interferon (5 MU every other day) during 52 weeks. It was found that the antigen seroconversion rates were similar in both groups. A marked proportion of patients with combined prolonged treatment proved to be negative to the viral DNA (52 % vs. 26p = 0.06) and the surface antigen (48 % vs. 26 %, p = 0.11) compared with the controls. The improvement in the histological activity rate was observed in 48 % of the patients treated with combined prolonged treatment against 22 % of the controls (p = 0.06) It was concluded that the prolonged treatment of interferon and lamivudine during 52 weeks may have clinical benefits on the rates of sustained viral DNA loss, surface antigen and the histological activity index.

Se hace una revisión para explicar cómo influyen y la estrecha relación que tienen los diversos procesos celulares que ocurren en el tejido hepático, severamente dañado, y en la circulación mesentérica con las distintas alteraciones sistémicas que aparecen en la insuficiencia hepática aguda, síndrome clínico resultado de una necrosis hepática masiva que genera disfunción progresiva del órgano con la presencia de profundas alteraciones en sus funciones detoxificadora, metabólica, sintetizadora y excretora. La hipótesis de la masa crítica, así como la de las endotoxinas-citoquinas y sustancias vasoactivas explican de cierta forma los diferentes cambios moleculares que sustentan las bases fisiopatológicas de esta compleja entidad.A review was made to explain how the diverse cellular processes occurring in the severely damaged liver tissue and in the mesenteric circulation influence on the different systemic alterations appearing in acute liver failure, and the close relation existing among them. The acute liver failure is a clinical syndrome resulting from a mass liver necrosis generating progressive dysfunction of the organ with the presence of deep alterations in its detoxicating, metabolic, sinthesizing and excreting functions.The hypothesis of critical mass, as well as that on endotoxins-cytokines and vasoactive substances explain somehow the different molecular changes supporting the physiopathological bases of this complex entity.

Aproximadamente 80 % de la hepatitis C evoluciona a la cronicidad. Factores como los epidemiológicos, virales y del huésped intervienen en la progresión de la enfermedad. Se describió el comportamiento de variables epidemiológicas asociadas a la hepatitis crónica C y se identificó la posible asociación de estas con la intensidad de la fibrosis. Se estudiaron 80 pacientes con hepatitis C. Se determinó la intensidad de la fibrosis por el sistema de puntuación METAVIR. Se agruparon en: ausencia o poca fibrosis (F0-F1) y fibrosis marcada (F2 a F4) buscando la posible asociación estadística con los factores epidemiológicos. Se halló asociación significativa entre el estimado de antigüedad de la infección, la vía de adquisición y la edad al contraerla con la intensidad de la fibrosis. La progresión de la hepatitis C puede estar determinada por algunos factores epidemiológicos que influyen de forma decisiva en la historia natural de la enfermedad.Approximately 80 % of hepatitis C evolves to chronicity. The epidemiological and viral factors as well as those of the guest take part in the progression of the disease. The behavior of the epidemiological variables associated with chronic hepatitis C was described and the possible association of these ones with the intensity of fibrosis was identified. 80 patients with hepatitis C were studied and the intensity of fibrosis was determined by the METAVIR scoring system. They were grouped into absence or little fibrosis (f0-F1) and marked fibrosis (F2-F4) seeking for the possible statistical association with the epidemiological factors. A significant association was found among the infection's oldness estimate, the way it was acquired, the patient's age on catching it and the intensity of fibrosis. The progression of hepatits C may be determined by some epidemiological factors influencing decisively the natural history of the disease.

Resumo Este artigo retrata o caso de jovens de camadas populares que buscam alcançar o ensino superior com base em uma iniciativa de “cursinho popular” organizada na cidade de São Paulo. O texto busca caracterizar e evidenciar, primeiramente, os agenciamentos de socialização a partir dos quais esses jovens são investidos de disposições ao alongamento de suas expectativas escolares, incorporando o ensino superior como destino educacional pressentido como “possível” por eles. Em seguida, o artigo busca esclarecer como esses agenciamentos se desdobram, no entanto, em desajustes, limites e inadequações entre as disposições incorporadas por esses jovens e as exigências dos modos de seleção próprios às instituições de ensino superior público, que passam a ser valorizadas e pretendidas por eles a partir de suas passagens pelo cursinho popular.