Virtual reality-empowered deep-learning analysis of brain cells.

Automated detection of specific cells in three-dimensional datasets such as whole-brain light-sheet image stacks is challenging. Here, we present DELiVR, a virtual reality-trained deep-learning pipeline for detecting c-Fos+ cells as markers for neuronal activity in cleared mouse brains. Virtual reality annotation substantially accelerated training data generation, enabling DELiVR to outperform state-of-the-art cell-segmenting approaches. Our pipeline is available in a user-friendly Docker container that runs with a standalone Fiji plugin. DELiVR features a comprehensive toolkit for data visualization and can be customized to other cell types of interest, as we did here for microglia somata, using Fiji for dataset-specific training. We applied DELiVR to investigate cancer-related brain activity, unveiling an activation pattern that distinguishes weight-stable cancer from cancers associated with weight loss. Overall, DELiVR is a robust deep-learning tool that does not require advanced coding skills to analyze whole-brain imaging data in health and disease.

Inorganic Polyphosphate Affects Biofilm Assembly, Capsule Formation, and Virulence of Hypervirulent ST23 Klebsiella pneumoniae.

The emergence of hypervirulent Klebsiella pneumoniae (hvKP) strains poses a significant threat to public health due to high mortality rates and propensity to cause severe community-acquired infections in healthy individuals. The ability to form biofilms and produce a protective capsule contributes to its enhanced virulence and is a significant challenge to effective antibiotic treatment. Polyphosphate kinase 1 (PPK1) is an enzyme responsible for inorganic polyphosphate synthesis and plays a vital role in regulating various physiological processes in bacteria. In this study, we investigated the impact of polyP metabolism on the biofilm and capsule formation and virulence traits in hvKP using Dictyostelium discoideum amoeba as a model host. We found that the PPK1 null mutant was impaired in biofilm and capsule formation and showed attenuated virulence in D. discoideum compared to the wild-type strain. We performed a proteomic analysis to gain further insights into the underlying molecular mechanism. The results revealed that the PPK1 mutant had a differential expression of proteins involved in capsule synthesis (Wzi-Ugd), biofilm formation (MrkC-D-H), synthesis of the colibactin genotoxin precursor (ClbB), as well as proteins associated with the synthesis and modification of lipid A (ArnB-LpxC-PagP). These proteomic findings corroborate the phenotypic observations and indicate that the PPK1 mutation is associated with impaired biofilm and capsule formation and attenuated virulence in hvKP. Overall, our study highlights the importance of polyP synthesis in regulating extracellular biomolecules and virulence in K. pneumoniae and provides insights into potential therapeutic targets for treating K. pneumoniae infections.

Caracterización sociodemográfica y alimentaria de personas vegetarianas chilenas en el año 2022

Actualmente, en Chile se ha evidenciado un aumento de la población vegetariana, sin embargo, existen escasos datos sociodemográficos, por lo cual, el objetivo del presente estudio es caracterizar, según antecedentes sociodemográficos y alimentarios a personas vegetarianas chilenas en el año 2022. Se utilizó el paradigma cuantitativo y el diseño metodológico fue no experimental, descriptivo, exploratorio de corte transversal. Se aplicó una encuesta de caracterización mediante Google Forms a 504 personas y para el análisis de la información se utilizó el programa SPSS v. 24. El 85,7% declaró ser de género femenino, la edad promedio fue 26,3 ± 5,7 años, 45,5% de los encuestados se declararon ovolactovegetarianos, seguido por vegetarianos estrictos (38,7%) y la principal motivación fue principios animalistas (68,7%). El 87,8% cursó educación superior y el 36,5% correspondió al área de salud. El principal motivo de asistencia al nutricionista fue el asesoramiento con un 80%. Se destacó que la población vegetariana consideró que es fundamental la asistencia a un profesional nutricionista para practicar este estilo de vida de forma óptima, por lo que es fundamental que los profesionales de salud se involucren en conocer a esta población, con el objetivo de otorgar una atención más cercana e integral. Finalmente, la presente investigación corresponde al primer estudio que permite caracterizar a la población vegetariana en Chile.

Currently, in Chile there has been an increase in the vegetarian population; however, there are few sociodemographic data, therefore, the objective of this study is to characterise, according to sociodemographic and dietary background, Chilean vegetarians in the year 2022. The quantitative paradigm was used and the methodological design was non-experimental, descriptive, exploratory cross-section. A characterisation survey was applied using Google Forms to 504 people and SPSS v. 24. 85.7% declared to be female, the average age was 26.3 ± 5.7 years, 45.5% of those surveyed declared themselves lacto-ovo vegetarians, followed by strict vegetarians (38.7%) and the main motivation was animalistic principles (68.7%). 87.8% attended higher education and 36.5% corresponded to the health area. The main reason for helping the nutritionist was the advice with 80%. It was highlighted that the vegetarian population considered that it is essential to assist a professional nutritionist in practising this lifestyle optimally, so it is essential that health professionals get involved in getting to know this population, with the aim of providing closer and more comprehensive care. Finally, this research corresponds to the first study that allows characterising the vegetarian population in Chile.

Endothelial Notch1 signaling in white adipose tissue promotes cancer cachexia.

Cachexia is a major cause of morbidity and mortality in individuals with cancer and is characterized by weight loss due to adipose and muscle tissue wasting. Hallmarks of white adipose tissue (WAT) remodeling, which often precedes weight loss, are impaired lipid storage, inflammation and eventually fibrosis. Tissue wasting occurs in response to tumor-secreted factors. Considering that the continuous endothelium in WAT is the first line of contact with circulating factors, we postulated whether the endothelium itself may orchestrate tissue remodeling. Here, we show using human and mouse cancer models that during precachexia, tumors overactivate Notch1 signaling in distant WAT endothelium. Sustained endothelial Notch1 signaling induces a WAT wasting phenotype in male mice through excessive retinoic acid production. Pharmacological blockade of retinoic acid signaling was sufficient to inhibit WAT wasting in a mouse cancer cachexia model. This demonstrates that cancer manipulates the endothelium at distant sites to mediate WAT wasting by altering angiocrine signals.

Fasting-sensitive SUMO-switch on Prox1 controls hepatic cholesterol metabolism.

Accumulation of excess nutrients hampers proper liver function and is linked to nonalcoholic fatty liver disease (NAFLD) in obesity. However, the signals responsible for an impaired adaptation of hepatocytes to obesogenic dietary cues remain still largely unknown. Post-translational modification by the small ubiquitin-like modifier (SUMO) allows for a dynamic regulation of numerous processes including transcriptional reprogramming. We demonstrate that specific SUMOylation of transcription factor Prox1 represents a nutrient-sensitive determinant of hepatic fasting metabolism. Prox1 is highly SUMOylated on lysine 556 in the liver of ad libitum and refed mice, while this modification is abolished upon fasting. In the context of diet-induced obesity, Prox1 SUMOylation becomes less sensitive to fasting cues. The hepatocyte-selective knock-in of a SUMOylation-deficient Prox1 mutant into mice fed a high-fat/high-fructose diet leads to a reduction of systemic cholesterol levels, associated with the induction of liver bile acid detoxifying pathways during fasting. The generation of tools to maintain the nutrient-sensitive SUMO-switch on Prox1 may thus contribute to the development of "fasting-based" approaches for the preservation of metabolic health.

Development of a peptide drug restoring AMPK and adipose tissue functionality in cancer cachexia.

Cancer cachexia is a severe systemic wasting disease that negatively affects quality of life and survival in patients with cancer. To date, treating cancer cachexia is still a major unmet clinical need. We recently discovered the destabilization of the AMP-activated protein kinase (AMPK) complex in adipose tissue as a key event in cachexia-related adipose tissue dysfunction and developed an adeno-associated virus (AAV)-based approach to prevent AMPK degradation and prolong cachexia-free survival. Here, we show the development and optimization of a prototypic peptide, Pen-X-ACIP, where the AMPK-stabilizing peptide ACIP is fused to the cell-penetrating peptide moiety penetratin via a propargylic glycine linker to enable late-stage functionalization using click chemistry. Pen-X-ACIP was efficiently taken up by adipocytes, inhibited lipolysis, and restored AMPK signaling. Tissue uptake assays showed a favorable uptake profile into adipose tissue upon intraperitoneal injection. Systemic delivery of Pen-X-ACIP into tumor-bearing animals prevented the progression of cancer cachexia without affecting tumor growth and preserved body weight and adipose tissue mass with no discernable side effects in other peripheral organs, thereby achieving proof of concept. As Pen-X-ACIP also exerted its anti-lipolytic activity in human adipocytes, it now provides a promising platform for further (pre)clinical development toward a novel, first-in-class approach against cancer cachexia.

Obesity and cancer-extracellular matrix, angiogenesis, and adrenergic signaling as unusual suspects linking the two diseases.

Obesity is an established risk factor for several human cancers. Given the association between excess body weight and cancer, the increasing rates of obesity worldwide are worrisome. A variety of obesity-related factors has been implicated in cancer initiation, progression, and response to therapy. These factors include circulating nutritional factors, hormones, and cytokines, causing hyperinsulinemia, inflammation, and adipose tissue dysfunction. The impact of these conditions on cancer development and progression has been the focus of extensive literature. In this review, we concentrate on processes that can link obesity and cancer, and which provide a novel perspective: extracellular matrix remodeling, angiogenesis, and adrenergic signaling. We describe molecular mechanisms involved in these processes, which represent putative targets for intervention. Liver, pancreas, and breast cancers were chosen as exemplary disease models. In view of the expanding epidemic of obesity, a better understanding of the tumorigenic process in obese individuals might lead to more effective treatments and preventive measures.

Trip13 Depletion in Liver Cancer Induces a Lipogenic Response Contributing to Plin2-Dependent Mitotic Cell Death.

Aberrant energy metabolism and cell cycle regulation both critically contribute to malignant cell growth and both processes represent targets for anticancer therapy. It is shown here that depletion of the AAA+-ATPase thyroid hormone receptor interacting protein 13 (Trip13) results in mitotic cell death through a combined mechanism linking lipid metabolism to aberrant mitosis. Diminished Trip13 levels in hepatocellular carcinoma cells result in insulin-receptor-/Akt-pathway-dependent accumulation of lipid droplets, which act as functional acentriolar microtubule organizing centers disturbing mitotic spindle polarity. Specifically, the lipid-droplet-coating protein perilipin 2 (Plin2) is required for multipolar spindle formation, induction of DNA damage, and mitotic cell death. Plin2 expression in different tumor cells confers susceptibility to cell death induced by Trip13 depletion as well as treatment with paclitaxel, a spindle-interfering drug commonly used against different cancers. Thus, assessment of Plin2 levels enables the stratification of tumor responsiveness to mitosis-targeting drugs, including clinically approved paclitaxel and Trip13 inhibitors currently under development.

ClinicaDL: An open-source deep learning software for reproducible neuroimaging processing.

BACKGROUND AND OBJECTIVE: As deep learning faces a reproducibility crisis and studies on deep learning applied to neuroimaging are contaminated by methodological flaws, there is an urgent need to provide a safe environment for deep learning users to help them avoid common pitfalls that will bias and discredit their results. Several tools have been proposed to help deep learning users design their framework for neuroimaging data sets. Software overview: We present here ClinicaDL, one of these software tools. ClinicaDL interacts with BIDS, a standard format in the neuroimaging field, and its derivatives, so it can be used with a large variety of data sets. Moreover, it checks the absence of data leakage when inferring the results of new data with trained networks, and saves all necessary information to guarantee the reproducibility of results. The combination of ClinicaDL and its companion project Clinica allows performing an end-to-end neuroimaging analysis, from the download of raw data sets to the interpretation of trained networks, including neuroimaging preprocessing, quality check, label definition, architecture search, and network training and evaluation. CONCLUSIONS: We implemented ClinicaDL to bring answers to three common issues encountered by deep learning users who are not always familiar with neuroimaging data: (1) the format and preprocessing of neuroimaging data sets, (2) the contamination of the evaluation procedure by data leakage and (3) a lack of reproducibility. We hope that its use by researchers will allow producing more reliable and thus valuable scientific studies in our field.

Relatos de vida que elaboran personas vegetarianas sobre el acompañamiento y planificación nutricional

RESUMEN Las dietas vegetarianas pueden proveer beneficios para la salud, prevención y tratamiento de enfermedades, siendo adecuadas en todas las etapas del ciclo vital cuando es correctamente asesorada por un profesional especialista en nutrición, entre los que se encuentran las nutricionistas, a fin de prevenir déficits en nutrientes críticos. Debido a esto, resulta relevante identificar la percepción que elaboran sobre el rol del nutricionista las personas vegetarianas que no han contado con asesoría y planificación nutricional profesional. Se realizó un estudio cualitativo centrado en los relatos de vida, donde participaron 10 personas vegetarianas residentes de Coquimbo y La Serena durante el año 2019, seleccionados mediante un muestreo bola de nieve, lo que implicó producir información cualitativa a través de una entrevista semi estructurada. Posteriormente se utilizó análisis cualitativo de contenido, producto de este análisis surgen dos grandes categorías. Como primera categoría el rol biopsicosocial del profesional nutricionista y segunda categoría sugerencias desde los vegetarianos para la atención. Del análisis se destaca la importancia del profesional nutricionista en el abordaje de personas vegetarianas o veganas, quienes esperan de los profesionales un vínculo efectivo con su comunidad mediante instancias de educación alimentaria, asesorías a bajo costo, el desarrollo de competencias técnicas y personales tales como, la actualización continua y la atención empática. Los hallazgos de este estudio pueden ser tomados como guía para la formación y actualización de profesionales, además de proponer medidas nutricionales en el campo de la salud pública y atención contextualizada a personas vegetarianas.

Abstract Vegetarian diets can provide benefits for health, prevention, and treatment of diseases and are appropriate at all stages of the life, when properly advised by specialists in nutrition, to prevent deficits in critical nutrients. Because of this, it is relevant to identify the perception of the role of the nutritionist among vegetarians who have not received professional nutritional advice and planning. A qualitative study focused on life stories was conducted, where 10 vegetarians living in Coquimbo and La Serena participated during 2019, selected through snowball sampling, which involved producing qualitative information through a semi-structured interview. Subsequently, qualitative content analysis was used, and two main categories emerged from this analysis. The first category was the biopsychosocial role of the professional nutritionist, and the second category was suggestions from vegetarians for care. The analysis highlights the importance of the professional nutritionist in the approach to vegetarians or vegans, who expect from professionals an effective link with their community through instances of food education, low-cost advice, the development of technical and personal skills such as continuous updating and empathetic care. The findings of this study can be taken as a guide for the training and updating of professionals, in addition to proposing nutritional measures in the field of public health and contextualized care for vegetarians.

Coaxial fibers of poly(styrene-co-maleic anhydride)@poly(vinyl alcohol) for wound dressing applications: Dual and sustained delivery of bioactive agents promoting fibroblast proliferation with reduced cell adherence.

The prevalence of chronic and acute wounds, as well as the complexity of their treatment represent a great challenge for health systems around the world. In this context, the development of bioactive wound dressings that release active agents to prevent infections and promote wound healing, appears as the most promising solution. In this work, we develop an antibacterial and biocompatible wound dressing material made from coaxial electrospun fibers of poly(styrene-co-maleic anhydride) and poly(vinyl alcohol) (PSMA@PVA). The coaxial configuration of the fibers consists of a shell of poly (styrene-co-maleic anhydride) containing a variable concentration of silver nanoparticles (AgNPs) 0.1-0.6 wt% as antibacterial agent, and a core of PVA containing 1 wt% allantoin as healing agent. The fibers present diameters between 0.72 and 1.7 µm. The release of Ag+ in a physiological medium was studied for 72 h, observing a burst release during the first 14 h and then a sustained and controlled release during the remaining 58 h. Allantoin release curves showed significant release only after 14 h. The meshes showed an antibacterial activity against Pseudomonas aeruginosa and Bacillus subtilis that correlates with the amount of AgNPs incorporated and the release rate of Ag+. Indeed, meshes containing 0.3 and 0.6 wt% of AgNPs showed a 99.99% inhibition against both bacteria. The adherence and cell viability of the meshes were evaluated in mouse embryonic fibroblasts NIH/3T3, observing a significant increase in cell viability after 72 h of incubation accompanied by a reduced adhesion of fibroblasts that decreased in the presence of the active agents. These results show that the material prepared here is capable of significantly promoting fibroblast cell proliferation but without strong adherence, which makes it an ideal material for wound dressings with non-adherent characteristics and with potential for wound healing.

Therapy-Related Transcriptional Subtypes in Matched Primary and Recurrent Head and Neck Cancer.

PURPOSE: The genetic relatedness between primary and recurrent head and neck squamous cell carcinomas (HNSCC) reflects the extent of heterogeneity and therapy-driven selection of tumor subpopulations. Yet, current treatment of recurrent HNSCC ignores the molecular characteristics of therapy-resistant tumor populations. EXPERIMENTAL DESIGN: From 150 tumors, 74 primary HNSCCs were RNA sequenced and 38 matched primary/recurrent tumor pairs were both whole-exome and RNA sequenced. Transcriptome analysis determined the predominant classical (CL), basal (BA), and inflamed-mesenchymal (IMS) transcriptional subtypes according to an established classification. Genomic alterations and clonal compositions of tumors were evaluated from whole-exome data. RESULTS: Although CL and IMS subtypes were more common in primary HNSCC with low recurrence rates, the BA subtype was more prevalent and stable in recurrent tumors. The BA subtype was associated with a transcriptional signature of partial epithelial-to-mesenchymal transition (p-EMT) and early recurrence. In 44% of matched cases, the dominant subtype changed from primary to recurrent tumors, preferably from IMS to BA or CL. Expression analysis of prognostic gene sets identified upregulation of hypoxia, p-emt, and radiotherapy resistance signatures and downregulation of tumor inflammation in recurrences compared with index tumors. A relevant subset of primary/recurrent tumor pairs presented no evidence for a common clonal origin. CONCLUSIONS: Our study showed a high degree of genetic and transcriptional heterogeneity between primary/recurrent tumors, suggesting therapy-related selection of a transcriptional subtype with characteristics unfavorable for therapy. We conclude that therapy decisions should be based on genetic and transcriptional characteristics of recurrences rather than primary tumors to enable optimally tailored treatment strategies.

Clinica: An Open-Source Software Platform for Reproducible Clinical Neuroscience Studies.

We present Clinica (www.clinica.run), an open-source software platform designed to make clinical neuroscience studies easier and more reproducible. Clinica aims for researchers to (i) spend less time on data management and processing, (ii) perform reproducible evaluations of their methods, and (iii) easily share data and results within their institution and with external collaborators. The core of Clinica is a set of automatic pipelines for processing and analysis of multimodal neuroimaging data (currently, T1-weighted MRI, diffusion MRI, and PET data), as well as tools for statistics, machine learning, and deep learning. It relies on the brain imaging data structure (BIDS) for the organization of raw neuroimaging datasets and on established tools written by the community to build its pipelines. It also provides converters of public neuroimaging datasets to BIDS (currently ADNI, AIBL, OASIS, and NIFD). Processed data include image-valued scalar fields (e.g., tissue probability maps), meshes, surface-based scalar fields (e.g., cortical thickness maps), or scalar outputs (e.g., regional averages). These data follow the ClinicA Processed Structure (CAPS) format which shares the same philosophy as BIDS. Consistent organization of raw and processed neuroimaging files facilitates the execution of single pipelines and of sequences of pipelines, as well as the integration of processed data into statistics or machine learning frameworks. The target audience of Clinica is neuroscientists or clinicians conducting clinical neuroscience studies involving multimodal imaging, and researchers developing advanced machine learning algorithms applied to neuroimaging data.

MRI-Determined Psoas Muscle Fat Infiltration Correlates with Severity of Weight Loss during Cancer Cachexia.

PURPOSE: To evaluate the suitability of psoas and erector spinae muscle proton density fat fraction (PDFF) and fat volume as biomarkers for monitoring cachexia severity in an oncological cohort, and to evaluate regional variances in muscle parameters over time. METHODS: In this prospective study, 58 oncological patients were examined by a 3 T MRI receiving between one and five scans. Muscle volume and PDFF were measured, segmentation masks were divided into proximal, middle and distal muscle section. RESULTS: A regional variation of fat distribution in erector spinae muscle at baseline was found (p < 0.01). During follow-ups significant relative change of muscle parameters was observed. Relative maximum change of erector spinae muscle showed a significant regional variation. Correlation testing with age as a covariate revealed significant correlations for baseline psoas fat volume (r = -0.55, p < 0.01) and baseline psoas PDFF (r = -0.52, p = 0.02) with maximum BMI change during the course of the disease. CONCLUSION: In erector spinae muscles, a regional variation of fat distribution at baseline and relative maximum change of muscle parameters was observed. Our results indicate that psoas muscle PDFF and fat volume could serve as MRI-determined biomarkers for early risk stratification and disease monitoring regarding progression and severity of weight loss in cancer cachexia.

Imaging modalities for diagnosis and monitoring of cancer cachexia.

Cachexia, a multifactorial wasting syndrome, is highly prevalent among advanced-stage cancer patients. Unlike weight loss in healthy humans, the progressive loss of body weight in cancer cachexia primarily implicates lean body mass, caused by an aberrant metabolism and systemic inflammation. This may lead to disease aggravation, poorer quality of life, and increased mortality. Timely detection is, therefore, crucial, as is the careful monitoring of cancer progression, in an effort to improve management, facilitate individual treatment and minimize disease complications. A detailed analysis of body composition and tissue changes using imaging modalities-that is, computed tomography, magnetic resonance imaging, (18F) fluoro-2-deoxy-D-glucose (18FDG) PET and dual-energy X-ray absorptiometry-shows great premise for charting the course of cachexia. Quantitative and qualitative changes to adipose tissue, organs, and muscle compartments, particularly of the trunk and extremities, could present important biomarkers for phenotyping cachexia and determining its onset in patients. In this review, we present and compare the imaging techniques that have been used in the setting of cancer cachexia. Their individual limitations, drawbacks in the face of clinical routine care, and relevance in oncology are also discussed.

Epidemiology of anal human papillomavirus infection and high-grade squamous intraepithelial lesions in 29 900 men according to HIV status, sexuality, and age: a collaborative pooled analysis of 64 studies.

BACKGROUND: Robust age-specific estimates of anal human papillomavirus (HPV) and high-grade squamous intraepithelial lesions (HSIL) in men can inform anal cancer prevention efforts. We aimed to evaluate the age-specific prevalence of anal HPV, HSIL, and their combination, in men, stratified by HIV status and sexuality. METHODS: We did a systematic review for studies on anal HPV infection in men and a pooled analysis of individual-level data from eligible studies across four groups: HIV-positive men who have sex with men (MSM), HIV-negative MSM, HIV-positive men who have sex with women (MSW), and HIV-negative MSW. Studies were required to inform on type-specific HPV infection (at least HPV16), detected by use of a PCR-based test from anal swabs, HIV status, sexuality (MSM, including those who have sex with men only or also with women, or MSW), and age. Authors of eligible studies with a sample size of 200 participants or more were invited to share deidentified individual-level data on the above four variables. Authors of studies including 40 or more HIV-positive MSW or 40 or more men from Africa (irrespective of HIV status and sexuality) were also invited to share these data. Pooled estimates of anal high-risk HPV (HR-HPV, including HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68), and HSIL or worse (HSIL+), were compared by use of adjusted prevalence ratios (aPRs) from generalised linear models. FINDINGS: The systematic review identified 93 eligible studies, of which 64 contributed data on 29 900 men to the pooled analysis. Among HIV-negative MSW anal HPV16 prevalence was 1·8% (91 of 5190) and HR-HPV prevalence was 6·9% (345 of 5003); among HIV-positive MSW the prevalences were 8·7% (59 of 682) and 26·9% (179 of 666); among HIV-negative MSM they were 13·7% (1455 of 10 617) and 41·2% (3798 of 9215), and among HIV-positive MSM 28·5% (3819 of 13 411) and 74·3% (8765 of 11 803). In HIV-positive MSM, HPV16 prevalence was 5·6% (two of 36) among those age 15-18 years and 28·8% (141 of 490) among those age 23-24 years (ptrend=0·0091); prevalence was 31·7% (1057 of 3337) among those age 25-34 years and 22·8% (451 of 1979) among those age 55 and older (ptrend<0·0001). HPV16 prevalence in HIV-negative MSM was 6·7% (15 of 223) among those age 15-18 and 13·9% (166 of 1192) among those age 23-24 years (ptrend=0·0076); the prevalence plateaued thereafter (ptrend=0·72). Similar age-specific patterns were observed for HR-HPV. No significant differences for HPV16 or HR-HPV were found by age for either HIV-positive or HIV-negative MSW. HSIL+ detection ranged from 7·5% (12 of 160) to 54·5% (61 of 112) in HIV-positive MSM; after adjustment for heterogeneity, HIV was a significant predictor of HSIL+ (aPR 1·54, 95% CI 1·36-1·73), HPV16-positive HSIL+ (1·66, 1·36-2·03), and HSIL+ in HPV16-positive MSM (1·19, 1·04-1·37). Among HPV16-positive MSM, HSIL+ prevalence increased with age. INTERPRETATION: High anal HPV prevalence among young HIV-positive and HIV-negative MSM highlights the benefits of gender-neutral HPV vaccination before sexual activity over catch-up vaccination. HIV-positive MSM are a priority for anal cancer screening research and initiatives targeting HPV16-positive HSIL+. FUNDING: International Agency for Research on Cancer.

Association of circulating PLA2G7 levels with cancer cachexia and assessment of darapladib as a therapy.

BACKGROUND: Cancer cachexia (CCx) is a multifactorial wasting disorder characterized by involuntary loss of body weight that affects many cancer patients and implies a poor prognosis, reducing both tolerance to and efficiency of anticancer therapies. Actual challenges in management of CCx remain in the identification of tumour-derived and host-derived mediators involved in systemic inflammation and tissue wasting and in the discovery of biomarkers that would allow for an earlier and personalized care of cancer patients. The aim of this study was to identify new markers of CCx across different species and tumour entities. METHODS: Quantitative secretome analysis was performed to identify specific factors characteristic of cachexia-inducing cancer cell lines. To establish the subsequently identified phospholipase PLA2G7 as a marker of CCx, plasma PLA2G7 activity and/or protein levels were measured in well-established mouse models of CCx and in different cohorts of weight-stable and weight-losing cancer patients with different tumour entities. Genetic PLA2G7 knock-down in tumours and pharmacological treatment using the well-studied PLA2G7 inhibitor darapladib were performed to assess its implication in the pathogenesis of CCx in C26 tumour-bearing mice. RESULTS: High expression and secretion of PLA2G7 were hallmarks of cachexia-inducing cancer cell lines. Circulating PLA2G7 activity was increased in different mouse models of CCx with various tumour entities and was associated with the severity of body wasting. Circulating PLA2G7 levels gradually rose during cachexia development. Genetic PLA2G7 knock-down in C26 tumours only partially reduced plasma PLA2G7 levels, suggesting that the host is also an important contributor. Chronic treatment with darapladib was not sufficient to counteract inflammation and tissue wasting despite a strong inhibition of the circulating PLA2G7 activity. Importantly, PLA2G7 levels were also increased in colorectal and pancreatic cancer patients with CCx. CONCLUSIONS: Overall, our data show that despite no immediate pathogenic role, at least when targeted as a single entity, PLA2G7 is a consistent marker of CCx in both mice and humans. The early increase in circulating PLA2G7 levels in pre-cachectic mice supports future prospective studies to assess its potential as biomarker for cancer patients.

Liver-fibrosis-activated transcriptional networks govern hepatocyte reprogramming and intra-hepatic communication.

Liver fibrosis is a strong predictor of long-term mortality in individuals with metabolic-associated fatty liver disease; yet, the mechanisms underlying the progression from the comparatively benign fatty liver state to advanced non-alcoholic steatohepatitis (NASH) and liver fibrosis are incompletely understood. Using cell-type-resolved genomics, we show that comprehensive alterations in hepatocyte genomic and transcriptional settings during NASH progression, led to a loss of hepatocyte identity. The hepatocyte reprogramming was under tight cooperative control of a network of fibrosis-activated transcription factors, as exemplified by the transcription factor Elf-3 (ELF3) and zinc finger protein GLIS2 (GLIS2). Indeed, ELF3- and GLIS2-controlled fibrosis-dependent hepatokine genes targeting disease-associated hepatic stellate cell gene programs. Thus, interconnected transcription factor networks not only promoted hepatocyte dysfunction but also directed the intra-hepatic crosstalk necessary for NASH and fibrosis progression, implying that molecular "hub-centered" targeting strategies are superior to existing mono-target approaches as currently used in NASH therapy.

Resección intestinal por endometriosis severa, diagnóstico y tratamiento luego de la introducción de la Unidad de Endometriosis: revisión de 18 años en el Hospital Clínico de la Universidad de Chile / Bowel resection for severe endometriosis, diagnosis and treatment after the introduction of Endometriosis Unit: 18 years review, Clinical Hospital of the University of Chile

INTRODUCCIÓN: La endometriosis intestinal afecta en gran medida la calidad de vida de una mujer joven y habitualmente requiere un tratamiento quirúrgico con resección intestinal. Esta cirugía es técnicamente compleja por las adherencias firmes del intestino a la vagina, el útero y los ovarios. OBJETIVO: Describir y analizar los resultados quirúrgicos e histopatológicos de las resecciones intestinales por endometriosis grave durante los últimos 18 años en el Hospital Clínico de la Universidad de Chile, en relación con la introducción de la unidad multidisciplinaria de endometriosis, a partir del año 2011, y las experiencias publicadas en la literatura chilena y extranjera. MÉTODO: Trabajo retrospectivo realizado en un hospital terciario desde el año 2001 hasta el año 2019. Las pacientes se asignaron a dos grupos según el período de cirugía: grupo 2001-2010 y grupo 2011-2019, luego de la introducción de la unidad de endometriosis. Se recopilaron todas las pacientes a las que se realizó una resección intestinal (discoidal o segmentaria) por endometriosis, por laparotomía o laparoscopía. Los datos distribuidos normalmente se presentan como promedio ± DE y los datos no paramétricos como mediana (rango). Las comparaciones demográficas de variables continuas se hicieron con la prueba t de Student y las de las variables categóricas con las pruebas de ji al cuadrado o de Fisher. La significación estadística se estableció en p < 0,05. RESULTADOS: Se recopilaron 52 casos. El 94,2% de las cirugías fueron electivas. El 5,8% fueron de urgencia por obstrucción intestinal (todas entre 2001 y 2010). Un 75% de las cirugías fueron laparoscópicas. Se realizó resección segmentaria en el 67,3%, resección discoidal simple en el 28,8%, resección discoidal doble en el 1,9% y resección segmentaria y una discoidal en el 1,9%. La histopatología demostró compromiso de la lesión hasta la mucosa intestinal en un 7,7%. Hubo franca disminución del dolor en el seguimiento de las pacientes. El 24% de las pacientes con deseo de embarazo y endometriosis intestinal lograron un parto de término mediante fecundación in vitro o espontáneamente. Hubo cuatro complicaciones posoperatorias, tres de ellas de categoría II según la clasificación de Clavien-Dindo y una de categoría IV A con reintervención a las 72 horas. Al comparar ambos periodos, en 2001-2010 los exámenes diagnósticos utilizados fueron ecografía transvaginal (0%), enema baritado (60%), tomografía computarizada de abdomen y pelvis (45%) y resonancia magnética pelviana (20%), mientras que en 2011-2019 fueron ecografía transvaginal (100%), enema baritado (3%), tomografía computarizada (3%) y resonancia magnética pelviana (66%). En 2001-2010, las lesiones fueron más más infiltrativas (mayor compromiso mucoso y submucoso) (75 vs. 16% de las resecciones intestinales; p < 0,05), estenóticas (cirugías de urgencia por obstrucción), con mayor porcentaje de resecciones segmentarias (100 vs. 46,9%; p < 0,05) y más días de hospitalización (5,8 ± 2,3 vs. 4,1 ± 0,9 días) que en 2011-2019. CONCLUSIONES: A nuestro entender, esta es la serie más grande publicada en Chile de resecciones intestinales por endometriosis. Estos hallazgos demuestran cómo la introducción de la unidad multidisciplinaria de endometriosis permite un diagnóstico precoz y un tratamiento quirúrgico eficaz y oportuno, tal como se decribe en la literatura.

INTRODUCTION: Bowel endometriosis severely affects a young woman's quality of life and often requires surgical treatment with bowel resection. This surgery is technically complex due to the tight adhesions of the intestine to the vagina, uterus, and ovaries. The objective of this work is to describe and analyze the surgical and histopathological results of intestinal resections for severe endometriosis during the last 18 years at the Clinical Hospital University of Chile, in relation to the implementation of the multidisciplinary endometriosis unit, based on the year 2011 and the experiences published in Chilean and foreign literature. METHOD: Retrospective work carried out in a tertiary hospital from 2001 to 2019. The patients were assigned to two groups according to the surgery period: group 2001-2010 and group 2011-2019, after endometriosis unit formation. All patients who underwent bowel resection (discoidal or segmental) for endometriosis by laparotomy or laparoscopy were collected. Normally distributed data are presented as mean ± SD and nonparametric data as median (range). Demographic comparisons of continuous variables are compared using Student's t test and categorical variables using chi squared or Fisher's test. Statistical significance was established at p < 0.05. RESULTS: 52 cases were collected. 94.2% of the surgeries were elective. 5.8% were urgent due to intestinal obstruction (all between 2001 and 2010). 75% of the surgeries were laparoscopic. Segmental resection 67.3%, simple discoidal resection 28.8%, double discoidal resection 1.9% and segmental resection and a discoidal resection 1.9%. Histopathology showed involvement of the lesion up to the intestinal mucosa in 7.7%. A marked decrease in pain in the follow-up of the patients. 24% of the patients with a desire for pregnancy and intestinal endometriosis achieved a full-term delivery by IVF or spontaneously. There were four postoperative complications, three of them category II according to the Clavien-Dindo classification, and one category IV A complication with reoperation at 72 h. When comparing both periods, between 2001-2010 the diagnostic tests used were: transvaginal ultrasound (ECO TV) (0%), barium enema (BE) (60%), abdomen pelvis CT (45%) and pelvic resonance (MRI) (20%). Between 2011 and 2019 ECO TV (100%), EB (3%), TAC (3%) RM (66%). In the period 2001 to 2010, the lesions were more infiltrative (greater mucosal and submucosal involvement) (75% vs 16% of intestinal resections (P <0.05)), stenotic (urgent surgery for obstruction), with a higher percentage of resections segmental (100% vs 46.9% (P <0.05) and more days of hospitalization (5.8 ± 2.3 SD vs 4.1 ± 0.9 SD) than in the period from 2011 to 2019. CONCLUSIONS: To our knowledge, this is the largest series published in Chile of intestinal resections for endometriosis. These findings demonstrate how the introduction of the multidisciplinary endometriosis unit allows early diagnosis and effective and timely surgical treatment as described in the literature.

Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism.

By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi-agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high-throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation-like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including imipramine, induced cancer cell death in combination with the mitochondrial uncoupler niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors CHOP and TFE3, which resulted in cell death through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard-of-care chemotherapy paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing.