Annual risk of hepatitis E virus infection and seroreversion: Insights from a serological cohort in Sitakunda, Bangladesh.

Hepatitis E virus (HEV) is a major cause of acute jaundice in South Asia. Gaps in our understanding of transmission are driven by non-specific symptoms and scarcity of diagnostics, impeding rational control strategies. In this context, serological data can provide important proxy measures of infection. We enrolled a population-representative serological cohort of 2,337 individuals in Sitakunda, Bangladesh. We estimated the annual risks of HEV infection and seroreversion both using serostatus changes between paired serum samples collected 9 months apart, and by fitting catalytic models to the age-stratified cross-sectional seroprevalence. At baseline, 15% (95 CI: 14-17%) of people were seropositive, with seroprevalence highest in the relatively urban south. During the study, 27 individuals seroreverted (annual seroreversion risk: 15%, 95 CI: 10-21%), and 38 seroconverted (annual infection risk: 3%, 95CI: 2-5%). Relying on cross-sectional seroprevalence data alone, and ignoring seroreversion, underestimated the annual infection risk five-fold (0.6%, 95 CrI: 0.5-0.6%). When we accounted for the observed seroreversion in a reversible catalytic model, infection risk was more consistent with measured seroincidence. Our results quantify HEV infection risk in Sitakunda and highlight the importance of accounting for seroreversion when estimating infection incidence from cross-sectional seroprevalence data.

Religiosity, Financial Risk Taking, and Reward Processing: An Experimental Study.

The present study investigated the extent to which financial risk-taking (FRT) perspectives and religiosity influenced an individual's performance on financial decision-making tasks under risk and/or uncertainty. It further investigated the potential to measure this interaction using electro-encephalogram (EEG) assessments through reward-related event-related potentials (P3 and FRN). EEG data were collected from 37 participants undergoing four decision-making tasks comprising the Balloon Analogue Risk Task (BART), Iowa Gambling Test (IGT), Mixed-Gamble Loss-Aversion Task (MGLAT), and MGLA-Success Task (MGLAST). The present study found that BART performance may be affected by an interaction of FRT perspectives and religiosity. The physiological effects of task feedback were also distinguished between religious and non-religious individuals objectively with EEG data. Overall, while religiosity and FRT may not significantly influence IGT and MGLA performance, and interact with BART in a complex way, physiological reaction towards feedback after BART performance appears to be strongly affected by religiosity and FRT perspectives.

Increasing physical activity using an just-in-time adaptive digital assistant supported by machine learning: A novel approach for hyper-personalised mHealth interventions.

OBJECTIVE: Physical inactivity is a leading modifiable cause of death and disease worldwide. Population-based interventions to increase physical activity are needed. Existing automated expert systems (e.g., computer-tailored interventions) have significant limitations that result in low long-term effectiveness. Therefore, innovative approaches are needed. This special communication aims to describe and discuss a novel mHealth intervention approach that proactively offers participants with hyper-personalised intervention content adjusted in real-time. METHODS: Using machine learning approaches, we propose a novel physical activity intervention approach that can learn and adapt in real-time to achieve high levels of personalisation and user engagement, underpinned by a likeable digital assistant. It will consist of three major components: (1) conversations: to increase user's knowledge on a wide range of activity-related topics underpinned by Natural Language Processing; (2) nudge engine: to provide users with hyper-personalised cues to action underpinned by reinforcement learning (i.e., contextual bandit) and integrating real-time data from activity tracking, GPS, GIS, weather, and user provided data; (3) Q&A: to facilitate users asking any physical activity related questions underpinned by generative AI (e.g., ChatGPT, Bard) for content generation. RESULTS: The detailed concept of the proposed physical activity intervention platform demonstrates the practical application of a just-in-time adaptive intervention applying various machine learning techniques to deliver a hyper-personalised physical activity intervention in an engaging way. Compared to traditional interventions, the novel platform is expected to show potential for increased user engagement and long-term effectiveness due to: (1) using new variables to personalise content (e.g., GPS, weather), (2) providing behavioural support at the right time in real-time, (3) implementing an engaging digital assistant and (4) improving the relevance of content through applying machine learning algorithms. CONCLUSION: The use of machine learning is on the rise in every aspect of today's society, however few attempts have been undertaken to harness its potential to achieve health behaviour change. By sharing our intervention concept, we contribute to the ongoing dialogue on creating effective methods for promoting health and well-being in the informatics research community. Future research should focus on refining these techniques and evaluating their effectiveness in controlled and real-world circumstances.

Adverse childhood experiences and association with poorer health and health-harming behaviours in adulthood among the Americans.

BACKGROUND: Adverse childhood experiences (ACEs) such as abuse and neglect have an immediate impact on children and are associated with poorer health and behavioural outcomes in adulthood. This study examined the prevalence of ACEs and their association with socio-demographic factors, physical and mental health, morbidity and health-harming behaviours in adulthood among Americans. METHOD: Data for the study come from the 2019 Behavioral Risk Factor Surveillance System (BRFSS), covering a sample of 116 032 adult respondents from 22 states of the United States. Descriptive and inferential statistical techniques, including multiple logistic regression models, were employed to analyse the data. RESULTS: At least one kind of ACE was found to be quite common among American adults, as 60% of adults had at least one kind of ACE, 22.5% had one ACE and 17% had four or more ACEs during 0-17 years of life. Of the total ACEs, 42.2% were due to abuse (physical, emotional or sexual), and 46% were due to any kind of household dysfunction. There is an increasing trend in ACEs in the United States. Adults with low socio-economic status, female, living in urban areas, gay or bisexual orientation, minority other than White and unemployed had a significantly higher prevalence of ACEs than their counterparts. ACEs were found to be significantly associated with poor physical and mental health; health-harming behaviours such as binge drinking, heavy drinking and smoking; and chronic morbidities. CONCLUSION: Programmes aimed at reducing ACEs and mitigating the harms of ACEs among those who have already experienced them should be strengthened to improve public health and quality of life and reduce health-harming behaviours.

Generation and Characterization of CYP2E1-Overexpressing HepG2 Cells to Study the Role of CYP2E1 in Hepatic Hypoxia-Reoxygenation Injury.

The mechanisms of hepatic ischemia/reperfusion (I/R) injury, which occurs during liver transplantation or surgery, are poorly understood. The purpose of the current study was to generate and characterize a HepG2 cell line with a stable overexpression of CYP2E1 to investigate the role of the enzyme in hypoxia/reperfusion (H/R) injury in an ex vivo setting. GFP-tagged CYP2E1 and control clones were developed, and their gene expression and protein levels of GFP and CYP2E1 were determined using RT-PCR and ELISA/Western blot analysis, respectively. Additionally, the CYP2E1 catalytic activity was determined by UPLC-MS/MS analysis of 6-hydroxychlorzoxazone formed from the chlorzoxazone substrate. The CYP2E1 and control clones were subjected to hypoxia (10 h) and reoxygenation (0.5 h), and cell death and reactive oxygen species (ROS) generation were quantitated using LDH and flow cytometry, respectively. Compared with the control clone, the selected CYP2E1 clone showed a 720-fold increase in CYP2E1 expression and a prominent band in the western blot analysis, which was associated with a 150-fold increase in CYP2E1 catalytic activity. The CYP2E1 clone produced 2.3-fold more ROS and 1.9-fold more cell death in the H/R model. It is concluded that the constitutive CYP2E1 in the liver may play a detrimental role in hepatic I/R injury.

Interpersonal Violence Is Associated with Self-Reported Stress, Anxiety and Depression among Men in East-Central Sweden: Results of a Population-Based Survey.

Background and Objectives: Interpersonal violence is a social and public health problem globally, and though it is related to poor health outcomes across all genders, most research has been directed towards violence against women. As a result, the health consequences of men's victimization may be underreported and unaddressed. The purpose of this study was to assess the relationship between interpersonal violence and the psychological health outcomes of self-reported stress, anxiety, and depression among men. Materials and Methods: The study used data from the male sample (n = 2597) of the 2018 Health on Equal Terms Survey conducted in Gävleborg County in East-Central Sweden. Regression analysis was carried out to study the relationship between interpersonal violence and self-reported stress, anxiety, and depression. Results: The bivariate analysis showed that there was a statistically significant association between interpersonal violence and self-reported stress (OR 2.35; CI 1.45-3.81), anxiety (OR 1.54; CI 1.06-2.25), and depression (OR 2.30; CI 1.48-3.57). Controlling for other variables in the multivariate analysis removed the statistically significant relationship and reduced the odds ratios for stress (OR 1.46; CI 0.57-3.74), anxiety (OR 0.86; 0.40-1.84), and depression (OR 1.40; CI 0.67-3.32) respectively. Conclusions: The study found that interpersonal violence among men was associated with stress, anxiety and depression which was largely explained by demographic, socioeconomic, and health/behavior-related factors. The findings suggest the need for longitudinal studies to assess causal links between male victimization and psychological health outcomes at the county level.

SARS-CoV-2 Seroprevalence before Delta Variant Surge, Chattogram, Bangladesh, March-June 2021.

A March-June 2021 representative serosurvey among Sitakunda subdistrict (Chattogram, Bangladesh) residents found an adjusted prevalence of severe acute respiratory syndrome coronavirus 2 antibodies of 64.1% (95% credible interval 60.0%-68.1%). Before the Delta variant surge, most residents had been infected, although cumulative confirmed coronavirus disease incidence was low.

Multimodal Hybrid Deep Learning Approach to Detect Tomato Leaf Disease Using Attention Based Dilated Convolution Feature Extractor with Logistic Regression Classification.

Automatic leaf disease detection techniques are effective for reducing the time-consuming effort of monitoring large crop farms and early identification of disease symptoms of plant leaves. Although crop tomatoes are seen to be susceptible to a variety of diseases that can reduce the production of the crop. In recent years, advanced deep learning methods show successful applications for plant disease detection based on observed symptoms on leaves. However, these methods have some limitations. This study proposed a high-performance tomato leaf disease detection approach, namely attention-based dilated CNN logistic regression (ADCLR). Firstly, we develop a new feature extraction method using attention-based dilated CNN to extract most relevant features in a faster time. In our preprocessing, we use Bilateral filtering to handle larger features to make the image smoother and the Ostu image segmentation process to remove noise in a fast and simple way. In this proposed method, we preprocess the image with bilateral filtering and Otsu segmentation. Then, we use the Conditional Generative Adversarial Network (CGAN) model to generate a synthetic image from the image which is preprocessed in the previous stage. The synthetic image is generated to handle imbalance and noisy or wrongly labeled data to obtain good prediction results. Then, the extracted features are normalized to lower the dimensionality. Finally, extracted features from preprocessed data are combined and then classified using fast and simple logistic regression (LR) classifier. The experimental outcomes show the state-of-the-art performance on the Plant Village database of tomato leaf disease by achieving 100%, 100%, 96.6% training, testing, and validation accuracy, respectively, for multiclass. From the experimental analysis, it is clearly demonstrated that the proposed multimodal approach can be utilized to detect tomato leaf disease precisely, simply and quickly. We have a potential plan to improve the model to make it cloud-based automated leaf disease classification for different plants.

The mutational landscapes of genetic and chemical models of Kras-driven lung cancer.

Next-generation sequencing of human tumours has refined our understanding of the mutational processes operative in cancer initiation and progression, yet major questions remain regarding the factors that induce driver mutations and the processes that shape mutation selection during tumorigenesis. Here we performed whole-exome sequencing on adenomas from three mouse models of non-small-cell lung cancer, which were induced either by exposure to carcinogens (methyl-nitrosourea (MNU) and urethane) or by genetic activation of Kras (Kras(LA2)). Although the MNU-induced tumours carried exactly the same initiating mutation in Kras as seen in the Kras(LA2) model (G12D), MNU tumours had an average of 192 non-synonymous, somatic single-nucleotide variants, compared with only six in tumours from the Kras(LA2) model. By contrast, the Kras(LA2) tumours exhibited a significantly higher level of aneuploidy and copy number alterations compared with the carcinogen-induced tumours, suggesting that carcinogen-induced and genetically engineered models lead to tumour development through different routes. The wild-type allele of Kras has been shown to act as a tumour suppressor in mouse models of non-small-cell lung cancer. We demonstrate that urethane-induced tumours from wild-type mice carry mostly (94%) Kras Q61R mutations, whereas those from Kras heterozygous animals carry mostly (92%) Kras Q61L mutations, indicating a major role for germline Kras status in mutation selection during initiation. The exome-wide mutation spectra in carcinogen-induced tumours overwhelmingly display signatures of the initiating carcinogen, while adenocarcinomas acquire additional C > T mutations at CpG sites. These data provide a basis for understanding results from human tumour genome sequencing, which has identified two broad categories of tumours based on the relative frequency of single-nucleotide variations and copy number alterations, and underline the importance of carcinogen models for understanding the complex mutation spectra seen in human cancers.

Do work ability and life satisfaction matter for return to work? Predictive ability of the work ability index and life satisfaction questionnaire among women with long-term musculoskeletal pain.

BACKGROUND: Impaired work ability and reduced life satisfaction due to long-term musculoskeletal pain, particularly in neck, shoulders and back, are considered occupational health problems that can result in workers taking sick leave. The aim of the study was to determine whether work ability and life satisfaction predict return to work (RTW) among women with long-term neck/shoulder and/or back pain, and to assess the ability of the Work Ability Index (WAI) and the Life Satisfaction Questionnaire (LiSat-11) to discriminate between those who did RTW and those who did not RTW (NRTW). METHODS: This is a cohort study with 1-year follow-up. A survey was sent to 600 women receiving sick leave benefits from the Swedish Social Insurance Agency. In total, 208 women responded at baseline, and 141 at a 1-year follow-up. To identify whether work ability and life satisfaction predicted RTW, multiple logistic regression analyses were performed with and without adjustment for type of work and pain intensity. To assess the discriminative ability of the WAI and the LiSat-11 for women who did RTW and those who did NRTW, receiver operating characteristic curves were fitted. RESULTS: Work ability predicted RTW, and the results remained significant after adjusting for type of work and pain intensity (OR 1.12, 95% CI: 1.04-1.22). Life satisfaction was not significant. The WAI at baseline adequately discriminated between RTW and NRTW after 1 year (Area under curve 0.78, 95% CI: 0.70-0.86), but the LiSat-11 did not. CONCLUSIONS: This study supports a relationship between work ability and RTW among women on sick leave for long-term neck/shoulder and/or back pain. The results indicate that the WAI, but not the LiSat-11, can discriminate between RTW and NRTW in the population under study. Although the discriminative ability of the WAI needs to be verified in new samples before it can be recommended for use in rehabilitation settings, we suggest that healthcare professionals consider how women perceive their work ability in order to better support them in their RTW.

Neural-specific deletion of the focal adhesion adaptor protein paxillin slows migration speed and delays cortical layer formation.

Paxillin and Hic-5 are homologous focal adhesion adaptor proteins that coordinate cytoskeletal rearrangements in response to integrin signaling, but their role(s) in cortical development are unknown. Here, we find that Hic-5-deficient mice are postnatal viable with normal cortical layering. Mice with a neural-specific deletion of paxillin are also postnatal viable, but show evidence of a cortical neuron migration delay that is evident pre- and perinatally, but is not detected at postnatal day 35 (P35). This phenotype is not modified by Hic-5 deficiency (double knockout). Specific deletion of paxillin in postmitotic neurons using Nex-Cre-mediated recombination as well as in utero electroporation of a Cre-expression construct identified a cell-autonomous requirement for paxillin in migrating neurons. Paxillin-deficient neurons have shorter leading processes that exhibited multiple swellings in comparison with control. Multiphoton imaging revealed that paxillin-deficient neurons migrate ∼30% slower than control neurons. This phenotype is similar to that produced by deletion of focal adhesion kinase (FAK), a signaling partner of paxillin, and suggests that paxillin and FAK function cell-autonomously to control migrating neuron morphology and speed during cortical development.

Reversal of Osteopenia in Ovariectomized Rats by Pentoxifylline: Evidence of Osteogenic and Osteo-Angiogenic Roles of the Drug.

Pentoxifylline (PTX) is a non-selective phosphodiesterase inhibitor and is used for the management of intermittent claudication. We tested whether PTX has oral efficacy in stimulating new bone formation. Rat calvarial osteoblasts (RCO) were used to study the effect of PTX on osteoblast differentiation and angiogenesis. Pharmacokinetic and pharmacodynamic studies were carried out in rats to determine an oral dose of PTX. In ovariectomized (OVX) rats with osteopenia, the effect of PTX on various skeletal parameters was studied, and compared with teriparatide. Effect of PTX on angiogenic signaling was studied by immunoblotting and relevant pharmacologic inhibitors. Bone vascularity was measured by intravenous injection of polystyrene fluorospheres followed by in vivo imaging, and angiogenesis was studied in vitro by tubulogenesis of endothelial cells and in vivo by Matrigel plug assay. Effective concentration (EC50) of PTX in RCO was 8.2 nM and plasma PTX level was 7 nM/mL after single oral dosing of 25 mg/kg, which was 1/6th the clinically used dose. At this dose, PTX enhanced bone regeneration at femur osteotomy site and completely restored bone mass, microarchitecture, and strength in OVX rats. Furthermore, PTX increased surface referent bone formation parameters and serum bone formation marker (PINP) without affecting the resorption marker (CTX-1). PTX increased the expression of vascular endothelial growth factor and its receptor in bones and osteoblasts. PTX also increased skeletal vascularity, tubulogenesis of endothelial cells and in vivo angiogenesis. Taken together, our study suggested that PTX at 16% of adult human oral dose completely reversed osteopenia in OVX rats by osteogenic and osteo-angiogenic mechanisms.

Clinical Predictors of Regression of Choroidal Melanomas after Brachytherapy: A Growth Curve Model.

PURPOSE: To build multivariate models to assess correctly and efficiently the contribution of tumor characteristics on the rate of regression of choroidal melanomas after brachytherapy in a way that adjusts for confounding and takes into account variation in tumor regression patterns. DESIGN: Modeling of longitudinal observational data. PARTICIPANTS: Ultrasound images from 330 of 388 consecutive choroidal melanomas (87%) irradiated from 2000 through 2008 at the Helsinki University Hospital, Helsinki, Finland, a national referral center. METHODS: Images were obtained with a 10-MHz B-scan during 3 years of follow-up. Change in tumor thickness and cross-sectional area were modeled using a polynomial growth-curve function in a nested mixed linear regression model considering regression pattern and tumor levels. Initial tumor dimensions, tumor-node-metastasis (TNM) stage, shape, ciliary body involvement, pigmentation, isotope, plaque size, detached muscles, and radiation parameters were considered as covariates. MAIN OUTCOME MEASURES: Covariates that independently predict tumor regression. RESULTS: Initial tumor thickness, largest basal diameter, ciliary body involvement, TNM stage, tumor shape group, break in Bruch's membrane, having muscles detached, and radiation dose to tumor base predicted faster regression, whether considering all tumors or those that regressed in a pattern compatible with exponential decay. Dark brown pigmentation was associated with slower regression. In multivariate modeling, initial tumor thickness remained the predominant and robust predictor of tumor regression (P < 0.0001). In addition, use of ruthenium isotope as opposed to iodine isotope (P = 0.018) independently contributed to faster regression of tumor thickness. For both isotopes considered alone, initial tumor thickness was the sole clinical predictor of regression (P < 0.0001). CONCLUSIONS: Regression of choroidal melanoma after brachytherapy was associated with several clinical tumor and treatment parameters, most of which were shown to reflect initial tumor size. An independent predictor of regression of tumor thickness was the isotope used. These 2 covariates need to be adjusted for when exploring the associations with the rate of regression of histopathologic or genetic features of the tumor. Our model allows such future analyses efficiently without matching.

Vitamin A Supplementation during Pregnancy Enhances Pandemic H1N1 Vaccine Response in Mothers, but Enhancement of Transplacental Antibody Transfer May Depend on When Mothers Are Vaccinated during Pregnancy.

Background: In the growing embryo, the vitamin A requirement is tightly regulated. Maternal vitamin A deficiency during pregnancy may alter maternal immune function to accommodate the fetus. Objective: Our primary objective was to determine the effect of oral vitamin A supplementation (VAS) during pregnancy and until 6 mo postpartum on pandemic H1N1-vaccine responses in mothers and their infants at 6 mo of age. Methods: In this randomized controlled clinical trial, pregnant women (n = 112) during the second trimester (mean ± SD: 14 ± 1 wk) were assigned to receive either an oral dose of 10,000 IU vitamin A or placebo weekly until 6 mo postpartum. During the third trimester, mothers received a single dose of inactivated pandemic H1N1-influenza vaccine. Hemagglutination-inhibition (HAI) titer was measured in cord, infant, and maternal blood samples. Multivariate regressions with adjustments were used for data analysis. Results: Seventy-six percent of women had low plasma retinol concentrations (<1.05 µmol/L) in their second trimester. VAS of mothers increased vitamin A concentrations in cord blood by 21.4% and in colostrum by 40.7%. At 6 mo postpartum, women in the vitamin A group had 38.7% higher HAI titers and a higher proportion of HAI titer of ≥1:40 of the cutoff compared with the placebo group. A total of 54.5% of infants had an HAI titer ≥1:40 at 6 mo of age, but there was no difference in HAI titer in infants between groups. Overall, HAI in cord blood did not differ between groups, but in the placebo group, cord blood HAI was negatively associated with maternal "vaccination-to-delivery intervals" (rs = -0.401; P = 0.5), and maternal VAS increased cord blood HAI 6-fold if antenatal immunization was administered ≥10 wk before delivery. Conclusions: In a community with low vitamin A status, weekly maternal VAS during pregnancy and postpartum increases the breast-milk vitamin A concentration and enhances prenatal H1N1-vaccine responses in mothers, but the benefits of maternal VAS in transplacental antibody transfer may depend on the time of gestation when mothers were vaccinated. This trial was registered at clinicaltrials.gov as NCT00817661.

Factors related to work ability and well-being among women on sick leave due to long-term pain in the neck/shoulders and/or back: a cross-sectional study.

BACKGROUND: Musculoskeletal pain is one of the leading causes of sick leave, especially among women, in Western countries. The aim of the present study was to identify factors associated with work ability and well-being, respectively, among women on sick leave due to long-term pain in the neck/shoulders and/or back. METHODS: A cross-sectional study with a correlational design was conducted on women who were sick-listed due to long-term pain in the neck/shoulders and/or back. A total of 208 participants responded to a survey comprising eight instruments: Multidimensional Pain Inventory scale, General Self-Efficacy scale, Sense of Coherence scale, Coping Strategies Questionnaire, Demand-Control-Support Questionnaire, Hospital Anxiety and Depression Scale, Work Ability Index and Life Satisfaction questionnaire. Multiple linear regression analyses were performed to identify factors associated with work ability and well-being, respectively. RESULTS: Women who more strongly believed they would return to the same work had greater work ability (ß = 0.39, p < 0.001), whereas women with higher pain intensity (ß = - 0.30, p < 0.001) and higher job strain (ß = - 0.12, p < 0.05) had lower work ability. Women with higher self-efficacy rated greater well-being (ß = 0.14, p < 0.05). As the women's scores for depression increased, their well-being decreased by 48%, which was statistically significant (p < 0.001). The regression models for work ability and well-being were significant (p < 0.001), and their adjusted R- square values were 48% and 59%, respectively. CONCLUSIONS: The study suggests that the factors beliefs to be back at the same work, pain intensity and job strain are predictive of work ability. Moreover, the factors self-efficacy and depression seem to be predictive of well-being. The findings highlight factors that should be considered by health care professionals and policy-makers to guide attempts to reduce sick leave.

BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model.

BRAF (v-raf murine sarcoma viral oncogene homolog B) inhibitors elicit a transient anti-tumor response in ∼ 80% of BRAF(V600)-mutant melanoma patients that almost uniformly precedes the emergence of resistance. Here we used a mouse model of melanoma in which melanocyte-specific expression of Braf(V618E) (analogous to the human BRAF(V600E) mutation) led to the development of skin hyperpigmentation and nevi, as well as melanoma formation with incomplete penetrance. Sleeping Beauty insertional mutagenesis in this model led to accelerated and fully penetrant melanomagenesis and synchronous tumor formation. Treatment of Braf(V618E) transposon mice with the BRAF inhibitor PLX4720 resulted in tumor regression followed by relapse. Analysis of transposon insertions identified eight genes including Braf, Mitf, and ERas (ES-cell expressed Ras) as candidate resistance genes. Expression of ERAS in human melanoma cell lines conferred resistance to PLX4720 and induced hyperphosphorylation of AKT (v-akt murine thymoma viral oncogene homolog 1), a phenotype reverted by combinatorial treatment with PLX4720 and the AKT inhibitor MK2206. We show that ERAS expression elicits a prosurvival signal associated with phosphorylation/inactivation of BAD, and that the resistance of hepatocyte growth factor-treated human melanoma cells to PLX4720 can be reverted by treatment with the BAD-like BH3 mimetic ABT-737. Thus, we define a role for the AKT/BAD pathway in resistance to BRAF inhibition and illustrate an in vivo approach for finding drug resistance genes.

Synthesis and Evaluation of Chirally Defined Side Chain Variants of 7-Chloro-4-Aminoquinoline To Overcome Drug Resistance in Malaria Chemotherapy.

A novel 4-aminoquinoline derivative [(S)-7-chloro-N-(4-methyl-1-(4-methylpiperazin-1-yl)pentan-2-yl)-quinolin-4-amine triphosphate] exhibiting curative activity against chloroquine-resistant malaria parasites has been identified for preclinical development as a blood schizonticidal agent. The lead molecule selected after detailed structure-activity relationship (SAR) studies has good solid-state properties and promising activity against in vitro and in vivo experimental malaria models. The in vitro absorption, distribution, metabolism, and excretion (ADME) parameters indicate a favorable drug-like profile.

Pharmacological activation of aldehyde dehydrogenase 2 promotes osteoblast differentiation via bone morphogenetic protein-2 and induces bone anabolic effect.

Aldehyde dehydrogenases (ALDHs) are a family of enzymes involved in detoxifying aldehydes. Previously, we reported that an ALDH inhibitor, disulfiram caused bone loss in rats and among ALDHs, osteoblast expressed only ALDH2. Loss-of-function mutation in ALDH2 gene is reported to cause bone loss in humans which suggested its importance in skeletal homeostasis. We thus studied whether activating ALDH2 by N-(1, 3-benzodioxol-5-ylmethyl)-2, 6-dichlorobenzamide (alda-1) had osteogenic effect. We found that alda-1 increased and acetaldehyde decreased the differentiation of rat primary osteoblasts and expressions of ALDH2 and bone morphogenetic protein-2 (BMP-2). Silencing ALDH2 in osteoblasts abolished the alda-1 effects. Further, alda-1 attenuated the acetaldehyde-induced lipid-peroxidation and oxidative stress. BMP-2 is essential for bone regeneration and alda-1 increased its expression in osteoblasts. We then showed that alda-1 (40mg/kg dose) augmented bone regeneration at the fracture site with concomitant increase in BMP-2 protein compared with control. The osteogenic dose (40mg/kg) of alda-1 attained a bone marrow concentration that was stimulatory for osteoblast differentiation, suggesting that the tissue concentration of alda-1 matched its pharmacologic effect. In addition, alda-1 promoted modeling-directed bone growth and peak bone mass achievement, and increased bone mass in adult rats which reiterated its osteogenic effect. In osteopenic ovariectomized (OVX) rats, alda-1 reversed trabecular osteopenia with attendant increase in serum osteogenic marker (procollagen type I N-terminal peptide) and decrease in oxidative stress. Alda-1 has no effect on liver and kidney function. We conclude that activating ALDH2 by alda-1 had an osteoanabolic effect involving increased osteoblastic BMP-2 production and decreased OVX-induced oxidative stress.

Adenoma development in familial adenomatous polyposis and MUTYH-associated polyposis: somatic landscape and driver genes.

Familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) are inherited disorders associated with multiple colorectal adenomas that lead to a very high risk of colorectal cancer. The somatic mutations that drive adenoma development in these conditions have not been investigated comprehensively. In this study we performed analysis of paired colorectal adenoma and normal tissue DNA from individuals with FAP or MAP, sequencing 14 adenoma whole exomes (eight MAP, six FAP), 55 adenoma targeted exomes (33 MAP, 22 FAP) and germline DNA from each patient, and a further 63 adenomas by capillary sequencing (41 FAP, 22 MAP). With these data we examined the profile of mutated genes, the mutational signatures and the somatic mutation rates, observing significant diversity in the constellations of mutated driver genes in different adenomas, and loss-of-function mutations in WTX (9%; p < 9.99e-06), a gene implicated in regulation of the WNT pathway and p53 acetylation. These data extend our understanding of the early events in colorectal tumourigenesis in the polyposis syndromes.