Development of a Culture-Common Formal Characteristics of Behavior - Temperament Markers Inventory (FCB-TMI-CC).

The goal was to create a brief temperament inventory grounded in the Regulative Theory of Temperament (FCB-TMI-CC), with a user-friendly, online applicability for studies in different cultures. As the regulative role of temperament is strongly revealed under meaningful stress, the study was planned within the time of the COVID-19 pandemic. To ensure high diversity in terms of culture, economic and environmental conditions, data from nine countries (Poland, United States of America, Italy, Japan, Argentina, South Korea, Ireland, United Kingdom and Kazakhstan) were utilized (min. N = 200 per country). Validation data were gathered on the level of COVID-19 stressors, posttraumatic stress disorder (PTSD), depression, anxiety and stress symptoms, and Big Five personality traits. Multigroup confirmatory factor analysis served as the basis for the inventory's construction. The final culture-common version includes 37 items (5-6 in each of the 7 scales) and covers the core aspects of temperament dimensions. Temperament structure was confirmed to be equivalent across measured cultures. The measurement is invariant at the level of factor loadings and the reliability (internal consistency) and theoretical validity of the scales were at least acceptable. Therefore, the FCB-TMI-CC may serve as a valuable tool for studying temperament across diverse cultures and facilitate cross-cultural comparisons.

Hemiptera-induced galls of Sapium glandulosum have histological and cytological compartmentalization created with a large amount of carbohydrate.

Gall formation impacts the development of plant species by altering the structure and mobilization of reserves, and the functional and physiological patterns of the host organ. The current study aimed to evaluate the impact generated by the Neolithus fasciatus galling insect (Hemiptera: Triozidae) in Sapium glandulosum leaves (Euphorbiaceae) at the cytological, histological, histochemical, and biochemical levels. Non-galled leaves and galls in the young, mature, and senescent stages were evaluated. The non-galled leaf has a uniseriate epidermis, stomata only on the abaxial side, a dorsiventral mesophyll, and parenchyma cells with thin primary walls containing chloroplasts with plastoglobules. The gall has a parenchymatous compartmentalized cortex. The young and mature galls already have a dense cytoplasm, especially in the inner cells of the cortex, with chloroplasts, mitochondria, Golgi complex, and large and evident nuclei. In senescent galls, there are signs of organelle degradation and cell digestion. Carbohydrates occur in greater amounts in the mature gall, mainly in the starch grain form, while proteins and lipids predominate in non-galled leaves. Secondary metabolites occur mainly in the young gall and may be related to its protection and to the signaling of its development. Sapium glandulosum galls have histological and cytological compartmentalization of the cortex with a large amount of carbohydrates, which supply energy to maintain the development of the structure.

A Novel Gemcitabine-Resistant Gallbladder Cancer Model Provides Insights into Molecular Changes Occurring during Acquired Resistance.

Treatment options for advanced gallbladder cancer (GBC) are scarce and usually rely on cytotoxic chemotherapy, but the effectiveness of any regimen is limited and recurrence rates are high. Here, we investigated the molecular mechanisms of acquired resistance in GBC through the development and characterization of two gemcitabine-resistant GBC cell sublines (NOZ GemR and TGBC1 GemR). Morphological changes, cross-resistance, and migratory/invasive capabilities were evaluated. Then, microarray-based transcriptome profiling and quantitative SILAC-based phosphotyrosine proteomic analyses were performed to identify biological processes and signaling pathways dysregulated in gemcitabine-resistant GBC cells. The transcriptome profiling of parental and gemcitabine-resistant cells revealed the dysregulation of protein-coding genes that promote the enrichment of biological processes such as epithelial-to-mesenchymal transition and drug metabolism. On the other hand, the phosphoproteomics analysis of NOZ GemR identified aberrantly dysregulated signaling pathways in resistant cells as well as active kinases, such as ABL1, PDGFRA, and LYN, which could be novel therapeutic targets in GBC. Accordingly, NOZ GemR showed increased sensitivity toward the multikinase inhibitor dasatinib compared to parental cells. Our study describes transcriptome changes and altered signaling pathways occurring in gemcitabine-resistant GBC cells, which greatly expands our understanding of the underlying mechanisms of acquired drug resistance in GBC.

Sedentary behavior, physical inactivity, abdominal obesity and obesity in adults and older adults: A systematic review and meta-analysis.

BACKGROUND: Sedentary behavior and physical inactivity may increase the risk of obesity. This systematic review and meta-analysis aimed to investigate: i) the prevalence/incidence of sedentary behavior and physical inactivity, ii) the association of sedentary behavior and physical inactivity with obesity, and iii) the objective and subjective measures, diagnostic criteria, and cut-off points to estimate sedentary behavior and physical inactivity in adults and older adults with obesity. METHODS: We conducted a systematic review and meta-analysis in PubMed, Scielo, Lilacs, and Cochrane Library databases. A meta-analysis of a random-effects model was performed to estimate the combined prevalence of sedentary behavior and physical inactivity and their association with obesity. RESULTS: Twenty-three studies involving 638,000 adults and older adults were included in the systematic review. A meta-analysis was conducted with 111,851 individuals with obesity. The combined prevalence of sedentary behavior was 31% (95% CI, 23-41%), and physical inactivity was 43% (95% CI, 31-55%). Significant associations between obesity and sedentary behavior (OR 1.45, 95% CI, 1.21-1.75) and physical inactivity (OR 1.52, 95% CI, 1.23-1.87) were found. Nine studies have used objective measures to assess physical activity levels, such as accelerometers and pedometers, whereas fourteen applied subjective methods and self-reported questionnaires. CONCLUSIONS: As expected, we found elevated rates of sedentary behavior and physical inactivity in individuals with obesity and a positive risk association. The wide range of objective and subjective measures, methods and cut-offs resulted in great variations of physical inactivity and sedentary behavior estimates. TRIAL REGISTRATION: PROSPERO (CRD42016037747).

Evolución del perfil clínico y pronóstico de pacientes con alta hospitalaria por insuficiencia cardíaca en las dos primeras décadas del sigloxxi. El Registro INCA-Ex / Clinical and prognostic profile evolution of patients discharged from hospital due to heart failure in the first two decades of the 21st century. The INCA-Ex Registry

Objetivo: Estudiar la evolución del perfil clínico de una población dada de alta con diagnóstico principal de insuficiencia cardíaca (IC) en las dos primeras décadas del siglo y las variables predictoras de mortalidad y reingreso en el primer año de alta. Diseño: Estudio observacional, retrospectivo, longitudinal. Emplazamiento: Área de salud Don Benito-Villanueva de la Serena, Badajoz, España. Participantes: Todos los pacientes dados de alta con diagnóstico principal de IC entre 2000 y 2019 en un complejo hospitalario general.Mediciones principalesSe recogieron variables sociodemográficas y clínicas, y se realizó un seguimiento de un año; la variable resultado fue un compuesto de mortalidad y/o reingreso. Resultados: Se incluyeron 4.107 altas, edad media 77,1 (DE 10,5) años, 53,1% de mujeres. El número de ingresos, la edad, los antecedentes de neoplasias, los ictus, la insuficiencia renal y la anemia fueron en aumento, así como los reingresos (p de tendencias <0,001), mientras permaneció constante la mortalidad. Fueron variables predictoras de reingreso y/o muerte HR (IC95%): edad (por año) 1,04 (1,03-1,04), diabetes: 1,11 (1,01-1,24), IC previa 1,41 (1,28-1,57), variable compuesta infarto, ictus y/o arteriopatía periférica 1,24 (1,11-1,38), enfermedad pulmonar obstructiva crónica (EPOC) 1,29 (1,15-1,44), neoplasia 1,33 (1,16-1,53), anemia 1,63 (1,41-1,86), insuficiencia renal 1,42 (1,26-1,60). Conclusiones: En los últimos 20años se han incrementado los ingresos de pacientes por IC, su edad y la comorbilidad. Fueron variables predictoras de mortalidad y/o reingreso la edad, la diabetes, la enfermedad cardiovascular previa, las neoplasias, la EPOC, la insuficiencia renal y la anemia; sin embargo, la mortalidad al año se mantuvo constante.(AU)

Aim: To study the evolution of the clinical profile of a population discharged with a main diagnosis of heart failure (HF) in the first two decades of the century and the predictive variables of mortality and readmission in the first year of discharge. Design: Observational, retrospective, longitudinal study. Site: Don Benito Villanueva de la Serena Badajoz health area. Participants: All patients discharged with a main diagnosis of HF between 2000 and 2019 in a general hospital complex were included. Main measurements: Sociodemographic and clinical variables were collected, and a one-year follow-up; the result variable was a composite of mortality and/or readmission. Results: A total of 4107 discharges were included, mean age 77.1 (SD±10.5) years, 53.1% women. The number of admissions, age, history of neoplasms, stroke, kidney failure, and anemia increased, as did readmissions (P for trends <.001), while mortality remained constant. Predictive variables for readmission and/or death were HR (95%CI): age (per year) 1.04 (1.03-1.04), diabetes: 1.11 (1.01-1.24), previous HF 1.41 (1.28-1.57), composite variable myocardial infarction, stroke and/or peripheral artery disease 1.24 (1.11-1.38), chronic obstructive pulmonary disease (COPD) 1.29 (1.15-1.44), neoplasia 1.33 (1.16-1.53), anemia 1.63 (1.41-1.86), chronic kidney failure 1.42 (1.26-1.60). Conclusions: In the last 20 years, admissions for heart failure, patient age, and comorbidity have increased. Predictive variables for mortality and/or readmission were age, diabetes, previous cardiovascular disease, neoplasms, COPD, kidney failure, and anemia; however, mortality at one year remained constant.(AU)

[Clinical and prognostic profile evolution of patients discharged from hospital due to heart failure in the first two decades of the 21st century. The INCA-Ex Registry]. / Evolución del perfil clínico y pronóstico de pacientes con alta hospitalaria por insuficiencia cardíaca en las dos primeras décadas del sigloxxi. El Registro INCA-Ex.

AIM: To study the evolution of the clinical profile of a population discharged with a main diagnosis of heart failure (HF) in the first two decades of the century and the predictive variables of mortality and readmission in the first year of discharge. DESIGN: Observational, retrospective, longitudinal study. SITE: Don Benito Villanueva de la Serena Badajoz health area. PARTICIPANTS: All patients discharged with a main diagnosis of HF between 2000 and 2019 in a general hospital complex were included. MAIN MEASUREMENTS: Sociodemographic and clinical variables were collected, and a one-year follow-up; the result variable was a composite of mortality and/or readmission. RESULTS: A total of 4107 discharges were included, mean age 77.1 (SD±10.5) years, 53.1% women. The number of admissions, age, history of neoplasms, stroke, kidney failure, and anemia increased, as did readmissions (P for trends <.001), while mortality remained constant. Predictive variables for readmission and/or death were HR (95%CI): age (per year) 1.04 (1.03-1.04), diabetes: 1.11 (1.01-1.24), previous HF 1.41 (1.28-1.57), composite variable myocardial infarction, stroke and/or peripheral artery disease 1.24 (1.11-1.38), chronic obstructive pulmonary disease (COPD) 1.29 (1.15-1.44), neoplasia 1.33 (1.16-1.53), anemia 1.63 (1.41-1.86), chronic kidney failure 1.42 (1.26-1.60). CONCLUSIONS: In the last 20 years, admissions for heart failure, patient age, and comorbidity have increased. Predictive variables for mortality and/or readmission were age, diabetes, previous cardiovascular disease, neoplasms, COPD, kidney failure, and anemia; however, mortality at one year remained constant.

Positive Effects of Extra-Virgin Olive Oil Supplementation and DietBra on Inflammation and Glycemic Profiles in Adults With Type 2 Diabetes and Class II/III Obesity: A Randomized Clinical Trial.

Background: Evidence on the effects of dietary interventions on inflammatory markers in individuals with obesity and type 2 diabetes mellitus (T2DM) is scarce. Our study evaluated the effects of extra-virgin olive oil alone and in combination with a traditional Brazilian diet on inflammatory markers and glycemic profiles in adults with both T2DM and class II/III obesity. Methods: Adults aged 18-64 years with T2DM and class II/III obesity were randomized into two intervention groups: 1) extra-virgin olive oil only and 2) extra-virgin olive oil + a traditional Brazilian diet (OliveOil+DietBra). Data on sociodemographic characteristics, lifestyle, anthropometry, biochemical markers and inflammatory markers were collected. The primary outcomes were glycemic parameters and inflammatory markers. The body mass index (BMI) and weight were the secondary outcomes. Results: Forty individuals with T2DM and class II/III obesity were enrolled, and 34 (85%) completed the intervention course. The intake of olive oil was 37.88 ± 12.50 mL/day in the olive oil group and 37.71 ± 12.23 mL/day in the OliveOil+DietBra group, with no significant difference between groups (p = 0.484). Compared to the olive oil only group, the OliveOil+DietBra group had significantly lower levels of fasting insulin (p = 0.047) at the end of the intervention, whereas the other glycemic parameters were not altered. In the OliveOil+DietBra group, serum levels of inflammatory cytokines, IL-1α (p = 0.006) and adiponectin (p = 0.049) were lower and those of TNFα were higher (p = 0.037). There was a significant reduction in BMI and weight compared to the baseline values in the OliveOil+DietBra group (p = 0.015). Conclusions: The intervention with OliveOil+DietBra effectively decreased the levels of fasting insulin, IL-1α and adiponectin, suggesting its beneficial role in improving the inflammatory profiles and fasting insulin levels in adults with class II/III obesity and T2DM. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT02463435.

Síndrome de epidermólisis ampollosa juntural-atresia pilórica con aplasia cutis congénita extensa / Junctional epidermolysis bullosa-pyloric atresia syndrome with extensive congenital aplasia cutis

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Assessment of the Cost of the Mediterranean Diet in a Low-Income Region: Adherence and Relationship with Available Incomes.

BACKGROUND: The Mediterranean Diet (MD) is recognized as heart-healthy, but the economic cost associated with this type of diet has scarcely been studied. The objective of the present study is to explore the cost and adherence of a low-income region population to the MD and its relationship with income. METHODS: A population-based study was carried out on 2,833 subjects between 25 and 79 years of age, 54% women, selected at random from the municipalities of Vegas Altas, La Siberia and La Serena in the province of Badajoz, Extremadura (Spain). Average monthly cost of each product included in the MD was computed and related to adherence to the MD using the Panagiotakos Index and average disposable income. RESULTS: The monthly median cost was 203.6€ (IQR: 154.04-265.37). Food-related expenditure was higher for men (p<0.001), age cohort between 45 and 54 years (p<0.013) and those living in urban areas (p<0.001). A positive correlation between food-related expenditure and the MD adherence was found. Monthly median cost represents 15% of average disposable income, ranging between 11% for the group with low MD adherence and 17% for the group with high MD adherence. CONCLUSIONS: The monthly cost of the MD was positively correlated with the degree of adherence to this dietary pattern. Given that the estimated monthly cost is similar to that of other Spanish regions with a higher income level, the economic effort required to be able to afford the Mediterranean diet is higher. This may represent a barrier to access, which should be analyzed in detail by public decision-makers.

Dissolution test for oral suspension: an overview about use and importance

Abstract This work aims to ascertain the comprehensiveness of dissolution tests for oral suspensions registered in Brazil and the USA. After consulting literature since 1994, a paucity of information about dissolution methods for suspensions was detected. It makes it difficult to establish the most appropriate test parameters. In January, 2019, there were 46 drugs registered in Anvisa (Brazil) as oral suspension, being 47 reference, 173 generic and 114 interchangeable similar (IS) medicines; while in the USA, 90 drugs were registered as oral suspension by FDA, 235 Abreviatted New Drug Application and 111 New Drug Application medicines. Out of 46 and 90, only six and 15 drugs as oral suspension had a pharmacopeial dissolution test, corresponding to 70 (20.9%) and 82 (23.7%) products in Brazil and the USA, respectively. Dissolution studies were found for 17 drugs as oral suspension in the non-compendial literature. Dissolution test conditions were established to few marketable oral suspension drugs, most of which are BCS class II or IV. Thus, investing in dissolution studies could subsidize the registration of these products by regulators, especially for generic and IS drugs, by comparing dissolution profiles, and predicting their in vivo behavior to avoid exposure of healthy individuals to clinical research.

Evaluation of the chemopreventive potentials of ezetimibe and aspirin in a novel mouse model of gallbladder preneoplasia.

Gallbladder stones (cholecystolithiasis) are the main risk factor for gallbladder cancer (GBC), a lethal biliary malignancy with poor survival rates worldwide. Gallbladder stones are thought to damage the gallbladder epithelium and trigger chronic inflammation. Preneoplastic lesions that arise in such an inflammatory microenvironment can eventually develop into invasive carcinoma, through mechanisms that are not fully understood. Here, we developed a novel gallbladder preneoplasia mouse model through the administration of two lithogenic diets (a low- or a high-cholesterol diet) in wild-type C57BL/6 mice over a period of 9 months. Additionally, we evaluated the chemopreventive potentials of the anti-inflammatory drug aspirin and the cholesterol absorption inhibitor ezetimibe. Both lithogenic diets induced early formation of gallbladder stones, together with extensive inflammatory changes and widespread induction of metaplasia, an epithelial adaptation to tissue injury. Dysplastic lesions were presented only in mice fed with high-cholesterol diet (62.5%) in late stages (9th month), and no invasive carcinoma was observed at any stage. The cholesterol absorption inhibitor ezetimibe inhibited gallbladder stone formation and completely prevented the onset of metaplasia and dysplasia in both lithogenic diets, whereas aspirin partially reduced metaplasia development only in the low-cholesterol diet setting. This model recapitulates several of the structural and inflammatory findings observed in human cholecystolithiasic gallbladders, making it relevant for the study of gallbladder carcinogenesis. In addition, our results suggest that the use of cholesterol absorption inhibitors and anti-inflammatory drugs can be evaluated as chemopreventive strategies to reduce the burden of GBC among high-risk populations.

Integrated genomic analysis reveals mutated ELF3 as a potential gallbladder cancer vaccine candidate.

Gallbladder cancer (GBC) is an aggressive gastrointestinal malignancy with no approved targeted therapy. Here, we analyze exomes (n = 160), transcriptomes (n = 115), and low pass whole genomes (n = 146) from 167 gallbladder cancers (GBCs) from patients in Korea, India and Chile. In addition, we also sequence samples from 39 GBC high-risk patients and detect evidence of early cancer-related genomic lesions. Among the several significantly mutated genes not previously linked to GBC are ETS domain genes ELF3 and EHF, CTNNB1, APC, NSD1, KAT8, STK11 and NFE2L2. A majority of ELF3 alterations are frame-shift mutations that result in several cancer-specific neoantigens that activate T-cells indicating that they are cancer vaccine candidates. In addition, we identify recurrent alterations in KEAP1/NFE2L2 and WNT pathway in GBC. Taken together, these define multiple targetable therapeutic interventions opportunities for GBC treatment and management.

Type 2 Diabetes Mellitus in Class II and III Obesity: Prevalence, Associated Factors, and Correlation between Glycemic Parameters and Body Mass Index.

Despite the worldwide growth of class II and III obesity, the factors associated with type 2 diabetes mellitus (T2DM) in these obese individuals are not widely understood. Moreover, no study has investigated these associations in South America. Our study aimed to investigate the prevalence of T2DM and its associated factors, with an emphasis on biochemical parameters and eating habits, in class II and III obese individuals. We also aimed to analyze the correlation between glycemic parameters and body mass index (BMI). Baseline data from a randomized clinical trial (DieTBra Trial) of 150 class II and III obese individuals (BMI > 35 kg/m2) was used. An accelerometer, Food Frequency Questionnaire, and bioimpedance analysis were used to assess physical activity levels, eating habits, and body composition, respectively. Blood was collected after 12 h of fasting. Hierarchical multivariate Poisson regression was performed, and prevalence ratios (PRs) were calculated. Correlations between glycemic parameters (fasting blood glucose, glycosylated hemoglobin, homeostasis model assessment of insulin resistance (HOMA-IR), and insulin) and BMI were also analyzed. The prevalence of T2DM was 40.0% (95% CI, 32.1-48.3), high fasting blood glucose level was 19.33% (95% CI, 13.3-26.6), and high glycosylated hemoglobin was 32.67% (95% CI, 25.2-40.8). Age ≥ 50 years (PR = 3.17, 95% CI, 1.26-7.98) was significantly associated with T2DM; there was a positive linear trend between age and T2DM (p = 0.011). Multivariate analysis showed an association with educational level (PR = 1.49, 1.07-2.09, p = 0.018), nonconsumption of whole grains daily (PR = 1.67, 1.00-2.80, p = 0.049), and high HOMA-IR (PR = 1.54, 1.08-2.18, p = 0.016). We found a high prevalence of T2DM and no significant correlations between BMI and glycemic parameters.

Traditional Brazilian Diet and Olive Oil Reduce Cardiometabolic Risk Factors in Severely Obese Individuals: A Randomized Trial.

Cardioprotective effects associated with extra virgin olive oil (EVOO) have been studied within the Mediterranean diet. However, little is known about its consumption in the traditional Brazilian diet (DieTBra) or without any dietary prescription, particularly in severely obese individuals. This study aimed to assess the effectiveness of DieTBra and EVOO in cardiometabolic risk factor (CMRF) reduction in severely obese individuals. We conducted a parallel randomized clinical trial with 149 severely obese individuals (body mass index ≥ 35.0 kg/m2) aged 18-65 years, assigned to three groups: 52 mL/day of EVOO (n = 50), DieTBra (n = 49), and DieTBra + 52 mL/day of EVOO (n = 50). Participants were followed up for 12 weeks. Low-density lipoprotein cholesterol (LDL-c) was the primary endpoint and several cardiometabolic parameters were secondary endpoints. Endpoints were compared at baseline and at the end of the study using analysis of variance, the Kruskal-Wallis test, and Student's t-test. The TC/High-density lipoprotein (HDL) ratio (-0.33 ± 0.68, p = 0.002) and LDL/HDL ratio (-0.26 ± 0.59, p = 0.005) decreased in the EVOO group. Delta values for all variables showed no significant statistical difference between groups. However, we highlight the clinical significance of LDL-c reduction in the EVOO group by 5.11 ± 21.79 mg/dL and in the DieTBra group by 4.27 ± 23.84 mg/dL. We also found a mean reduction of around 10% for Castelli II (LDL/HDL) and homocysteine in the EVOO group and TG and the TG/HDL ratio in the DieTBra group. EVOO or DieTBra when administered alone lead to reduction in some cardiometabolic risk parameters in severely obese individuals.

Risk Factors Associated with Cardiac Autonomic Modulation in Obese Individuals.

Obesity leads to an imbalance in the autonomic nervous system, especially in increased sympathetic modulation and decreased vagal tone, and some anthropometric, metabolic, and lifestyle variables may increase the risk of developing cardiovascular disease. Objective. To analyze the association between cardiovascular autonomic modulation and biochemical and anthropometric markers, food intake, and physical activity level in severely obese individuals. Methodology. The present study is a cutout of a randomized clinical trial "Effect of nutritional intervention and olive oil in severe obesity" (DieTBra Trial), where the baseline data were analyzed. Anthropometric data, biochemical exams, heart rate variability (HRV), accelerometry, and 24 h recall (R24H) of obese patients (body mass index BMI ≥35 kg/m2) were collected. Results. 64 obese patients were analyzed, with a mean age of 39.10 ± 7.74 years (27 to 58 years). By HRV analysis, in the frequency domain, the obese had a higher predominance of sympathetic autonomic modulation (low frequency (LF) 56.44 ± 20.31 nu) and lower parasympathetic modulation (high frequency (HF) 42.52 ± 19.18 nu). A negative association was observed between the variables Homeostasis Evaluation Model (HOMA-IR) and HF (p = 0.049). In the physical activity analysis, there was a negative association between moderate to vigorous physical activity and the sympathetic component (p = 0.043), and for sedentary time (ST), there was a negative association with HF (p = 0.049) and LF/HF (p = 0.036) and a positive association with LF (p = 0.014). For multiple linear regression, waist circumference (WC) and HOMA-IR values were negatively associated with HF (ß = -0.685, p = 0.010; ß = -14.989, p = 0.010; respectively). HOMA-IR (ß = 0.141, p = 0.003) and the percentage of lipids ingested (ß = -0.030, p = 0.043) were negatively associated with LF/HF. Conclusion. Among the cardiovascular risk variables studied, insulin resistance and central adiposity showed the greatest influence on cardiac autonomic modulation of obese, increasing the risk for cardiovascular disease.

Functional and genomic characterization of three novel cell lines derived from a metastatic gallbladder cancer tumor.

BACKGROUND: Gallbladder cancer (GBC) is the most common tumor of the biliary tract. The incidence of GBC shows a large geographic variability, being particularly frequent in Native American populations. In Chile, GBC represents the second cause of cancer-related death among women. We describe here the establishment of three novel cell lines derived from the ascitic fluid of a Chilean GBC patient, who presented 46% European, 36% Mapuche, 12% Aymara and 6% African ancestry. RESULTS: After immunocytochemical staining of the primary cell culture, we isolated and comprehensively characterized three independent clones (PUC-GBC1, PUC-GBC2 and PUC-GBC3) by short tandem repeat DNA profiling and RNA sequencing as well as karyotype, doubling time, chemosensitivity, in vitro migration capability and in vivo tumorigenicity assay. Primary culture cells showed high expression of CK7, CK19, CA 19-9, MUC1 and MUC16, and negative expression of mesothelial markers. The three isolated clones displayed an epithelial phenotype and an abnormal structure and number of chromosomes. RNA sequencing confirmed the increased expression of cytokeratin and mucin genes, and also of TP53 and ERBB2 with some differences among the three cells lines, and revealed a novel exonic mutation in NF1. The PUC-GBC3 clone was the most aggressive according to histopathological features and the tumorigenic capacity in NSG mice. CONCLUSIONS: The first cell lines established from a Chilean GBC patient represent a new model for studying GBC in patients of Native American descent.

Hippo-YAP1 Is a Prognosis Marker and Potentially Targetable Pathway in Advanced Gallbladder Cancer.

Gallbladder cancer is an aggressive disease with late diagnosis and no efficacious treatment. The Hippo-Yes-associated protein 1 (YAP1) signaling pathway has emerged as a target for the development of new therapeutic interventions in cancers. However, the role of the Hippo-targeted therapy has not been addressed in advanced gallbladder cancer (GBC). This study aimed to evaluate the expression of the major Hippo pathway components mammalian Ste20-like protein kinase 1 (MST1), YAP1 and transcriptional coactivator with PDZ-binding motif (TAZ) and examined the effects of Verteporfin (VP), a small molecular inhibitor of YAP1-TEA domain transcription factor (TEAD) protein interaction, in metastatic GBC cell lines and patient-derived organoids (PDOs). Immunohistochemical analysis revealed that advanced GBC patients had high nuclear expression of YAP1. High nuclear expression of YAP1 was associated with poor survival in GBC patients with subserosal invasion (pT2). Additionally, advanced GBC cases showed reduced expression of MST1 compared to chronic cholecystitis. Both VP treatment and YAP1 siRNA inhibited the migration ability in GBC cell lines. Interestingly, gemcitabine resistant PDOs with high nuclear expression of YAP1 were sensitive to VP treatment. Taken together, our results suggest that key components of the Hippo-YAP1 signaling pathway are dysregulated in advanced gallbladder cancer and reveal that the inhibition YAP1 may be a candidate for targeted therapy.

Effect of Extra Virgin Olive Oil and Traditional Brazilian Diet on the Bone Health Parameters of Severely Obese Adults: A Randomized Controlled Trial.

Dietary interventions can stabilize and/or reverse bone mass loss. However, there are no reports on its effects on bone mineral density (BMD) in severely obese people, despite the vulnerability of this group to bone loss. We examine the effect of extra virgin olive oil supplementation and the traditional Brazilian diet (DieTBra) on BMD and levels of calcium, vitamin D, and parathyroid hormone (PTH) in severely obese adults. A randomized controlled trial followed-up with severely obese adults (n = 111, with mean body mass index 43.6 kg/m2 ± 4.5 kg/m2) for 12 weeks. Study participants received either olive oil (52 mL/day), DieTBra, or olive oil + DieTBra (52 mL/day + DieTBra). BMD was assessed by total spine and hip dual-energy X-ray absorptiometry. After interventions, BMD means for total spine (p = 0.016) and total hip (p = 0.029) were higher in the DieTBra group than in the olive oil + DieTBra group. Final mean calcium levels were higher in the olive oil group compared to the olive oil + DieTBra group (p = 0.026). Findings suggest that DieTBra and extra virgin olive oil have positive effects on bone health in severely obese adults. The major study was registered at ClinicalTrials.gov (NCT02463435).