Miracle-dz/UniFAR-FTUs huggingface dataset:
Discovery and pharmacological characterization of AZD3229, a potent KIT/PDGFRα inhibitor for treatment of gastrointestinal stromal tumors

AZD3229 demonstrates pan-KIT/PDGFRα activity in several preclinical models and is a promising agent for the treatment of GIST. Getting the GIST of treatment Gastrointestinal stromal tumor, or GIST, can be targeted by inhibiting KIT and platelet-derived growth factor α (PDGFRα). Unfortunately, the therapeutic effects do not always last, as the tumors develop resistance mutations that are not susceptible to existing drugs. Banks et al. report the design of AZD3229, a compound that combines selectivity for KIT and PDGFRα with broad activity against a variety of disease-causing mutations. Its selectivity decreases the risk of off-target toxicity, which has been a problem for multiple other KIT/PDGFRα inhibitors. AZD3229 showed promising activity and safety in a range of drug-resistant GIST mouse models, suggesting its potential for clinical translation. Gastrointestinal stromal tumor (GIST) is the most common human sarcoma driven by mutations in KIT or platelet-derived growth factor α (PDGFRα). Although first-line treatment, imatinib, has revolutionized GIST treatment, drug resistance due to acquisition of secondary KIT/PDGFRα mutations develops in a majority of patients. Second- and third-line treatments, sunitinib and regorafenib, lack activity against a plethora of mutations in KIT/PDGFRα in GIST, with median time to disease progression of 4 to 6 months and inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) causing high-grade hypertension. Patients with GIST have an unmet need for a well-tolerated drug that robustly inhibits a range of KIT/PDGFRα mutations. Here, we report the discovery and pharmacological characterization of AZD3229, a potent and selective small-molecule inhibitor of KIT and PDGFRα designed to inhibit a broad range of primary and imatinib-resistant secondary mutations seen in GIST. In engineered and GIST-derived cell lines, AZD3229 is 15 to 60 times more potent than imatinib in inhibiting KIT primary mutations and has low nanomolar activity against a wide spectrum of secondary mutations. AZD3229 causes durable inhibition of KIT signaling in patient-derived xenograft (PDX) models of GIST, leading to tumor regressions at doses that showed no changes in arterial blood pressure (BP) in rat telemetry studies. AZD3229 has a superior potency and selectivity profile to standard of care (SoC) agents—imatinib, sunitinib, and regorafenib, as well as investigational agents, avapritinib (BLU-285) and ripretinib (DCC-2618). AZD3229 has the potential to be a best-in-class inhibitor for clinically relevant KIT/PDGFRα mutations in GIST.
A Graph Convolutional Network–Based Method for Chemical-Protein Interaction Extraction: Algorithm Development

Background Extracting the interactions between chemicals and proteins from the biomedical literature is important for many biomedical tasks such as drug discovery, medicine precision, and knowledge graph construction. Several computational methods have been proposed for automatic chemical-protein interaction (CPI) extraction. However, the majority of these proposed models cannot effectively learn semantic and syntactic information from complex sentences in biomedical texts. Objective To relieve this problem, we propose a method to effectively encode syntactic information from long text for CPI extraction. Methods Since syntactic information can be captured from dependency graphs, graph convolutional networks (GCNs) have recently drawn increasing attention in natural language processing. To investigate the performance of a GCN on CPI extraction, this paper proposes a novel GCN-based model. The model can effectively capture sequential information and long-range syntactic relations between words by using the dependency structure of input sentences. Results We evaluated our model on the ChemProt corpus released by BioCreative VI; it achieved an F-score of 65.17%, which is 1.07% higher than that of the state-of-the-art system proposed by Peng et al. As indicated by the significance test (P<.001), the improvement is significant. It indicates that our model is effective in extracting CPIs. The GCN-based model can better capture the semantic and syntactic information of the sentence compared to other models, therefore alleviating the problems associated with the complexity of biomedical literature. Conclusions Our model can obtain more information from the dependency graph than previously proposed models. Experimental results suggest that it is competitive to state-of-the-art methods and significantly outperforms other methods on the ChemProt corpus, which is the benchmark data set for CPI extraction.
SKAP2 is required for defense against K. pneumoniae infection and neutrophil respiratory burst

Klebsiella pneumoniae is a respiratory, blood, liver, and bladder pathogen of significant clinical concern. We show that the adaptor protein, SKAP2, is required for protection against K. pneumoniae (ATCC 43816) pulmonary infections. Skap2-/- mice had 100-fold higher bacterial burden when compared to wild-type and burden was controlled by SKAP2 expression in innate immune cells. Skap2-/- neutrophils and monocytes were present in infected lungs, and the neutrophils degranulated normally in response to K. pneumoniae infection in mice; however, K. pneumoniae-stimulated reactive oxygen species (ROS) production in vitro was abolished. K. pneumoniae-induced neutrophil ROS response required the activity of SFKs, Syk, Btk, PLCγ2, and PKC. The loss of SKAP2 significantly hindered the K. pneumoniae-induced phosphorylation of SFKs, Syk, and Pyk2 implicating SKAP2 as proximal to their activation in pathogen-signaling pathways. In conclusion, SKAP2-dependent signaling in neutrophils is essential for K. pneumoniae-activated ROS production and for promoting bacterial clearance during infection.
Digital Biomarkers of Social Anxiety Severity: Digital Phenotyping Using Passive Smartphone Sensors

Background Social anxiety disorder is a highly prevalent and burdensome condition. Persons with social anxiety frequently avoid seeking physician support and rarely receive treatment. Social anxiety symptoms are frequently underreported and underrecognized, creating a barrier to the accurate assessment of these symptoms. Consequently, more research is needed to identify passive biomarkers of social anxiety symptom severity. Digital phenotyping, the use of passive sensor data to inform health care decisions, offers a possible method of addressing this assessment barrier. Objective This study aims to determine whether passive sensor data acquired from smartphone data can accurately predict social anxiety symptom severity using a publicly available dataset. Methods In this study, participants (n=59) completed self-report assessments of their social anxiety symptom severity, depressive symptom severity, positive affect, and negative affect. Next, participants installed an app, which passively collected data about their movement (accelerometers) and social contact (incoming and outgoing calls and texts) over 2 weeks. Afterward, these passive sensor data were used to form digital biomarkers, which were paired with machine learning models to predict participants’ social anxiety symptom severity. Results The results suggested that these passive sensor data could be utilized to accurately predict participants’ social anxiety symptom severity (r=0.702 between predicted and observed symptom severity) and demonstrated discriminant validity between depression, negative affect, and positive affect. Conclusions These results suggest that smartphone sensor data may be utilized to accurately detect social anxiety symptom severity and discriminate social anxiety symptom severity from depressive symptoms, negative affect, and positive affect.
A Randomized Controlled Comparison of Epidural Analgesia Onset Time and Adverse Reactions During Labor With Different Dose Combinations of Bupivacaine and Sufentanil

Objectives: The purpose was to compare the effects of 3 different dose combinations of bupivacaine and sufentanil on the onset of analgesia and the occurrence of side effects. Materials and Methods: One hundred sixty-nine pregnant women were randomly assigned to 3 groups: the B1S5 group received 0.1% bupivacaine+5 μg sufentanil in 15 mL; the B125S5 group received 0.125% bupivacaine+5 μg sufentanil in 15 mL; and the B1S10 group received 0.1% bupivacaine+10 μg sufentanil in 15 mL. The primary outcome was the analgesic onset time, and the secondary outcomes were mode of delivery, patient satisfaction, maternal and neonatal side effects (pruritus, hypotension, sedation, motor block, decreased fetal heart rate, fever, and interference with breastfeeding). Results: The median (inter-quartile range) time to achieve effective analgesia was significantly faster in the B125S5 group than in the B1S5 group (10 [11-14 {4-30}] min vs. 15 [17-20 {5-30}] min, P<0.001). There was no significant difference in the analgesia onset time between the B1S10 and B125S5 groups (10 [11-14 {4-30}] min vs. 12 [13-15 {3-30}] min, P=0.202). Pruritus, hypotension, motor block, maternal satisfaction, delivery mode, decreased fetal heart rate, total bupivacaine dose and breastfeeding scores were not significantly different among the 3 groups except the sufentanil dosage and incidence of mild drowsiness and fever (the B1S10 group had significantly higher fever than the other groups). Discussion: The B125S5 combination may be superior to the B1S5 and B1S10 combinations as an initial dose for epidural analgesia to achieve rapid effective analgesia with minimal side effects.
Estimating local government efficiency using a panel data parametric approach: the case of Chilean municipalities

ABSTRACT Previous empirical evidence on municipal efficiency mostly uses cross-sectional data which makes it impossible to separate unobserved heterogeneity from inefficiency. Furthermore, they also typically use a two-stage approach which has been widely criticized as the assumptions in the first stage are violated in the second stage, generating biased results. We contribute to the literature by putting forward a one stage approach with parametric models and panel data to estimate municipal efficiency of 324 Chilean municipalities for the period 2008–2018. We take into account observed and unobserved heterogeneity, incorporating them both into the frontier and jointly estimating efficiency of all the municipalities in the sample. Our results suggest that Chilean municipalities have a relevant degree of inefficiency as they could achieve the same provision of services with 53% −61% less resources, depending on the specification, and that there is large heterogeneity in their level of efficiency. Finally, we also find that municipalities with a high dependency on the Municipal Common Fund are less efficient supporting the notion of local governments fiscal laziness present in the literature …
The pharmacist's role in disaster research response.

PURPOSE The need for high-quality research during disaster responses has been well described in the literature, and such research is supported by efforts at the federal level through the National Institutes of Health Disaster Research Response (DR2) Program. This article describes the fourth DR2 workshop with a specific focus on opportunities for pharmacists to get involved with disaster research efforts. SUMMARY Pharmacists have historically played a significant role in disaster planning and response, and there are a number of opportunities for pharmacists to bring their unique perspective, positioning, and skills to disaster research response (ie, onsite and other research on the medical and public health aspects of disasters and public health emergencies). In February 2019, the fourth DR2 workshop was held in Tucson, AZ, in conjunction with the University of Arizona College of Medicine-Tucson, the university's Mel and Enid Zuckerman College of Public Health, University of Arizona College of Pharmacy, and the university's Bio5 Institute to explore clinical and population-based research in a simulated disaster setting. This article describes the workshop and discusses several opportunities for pharmacists to design, lead, and support research efforts during disaster scenarios through involvement in research areas including clinical, operational, educational, and logistic aspects of pharmacy practice. CONCLUSION Due to their positioning throughout health systems, unique perspective, training, and skills, pharmacists are uniquely situated to play an important role in disaster research response.
Agile Requirements Engineering and Software Planning for a Digital Health Platform to Engage the Effects of Isolation Caused by Social Distancing: Case Study

Background Social distancing and shielding measures have been put in place to reduce social interaction and slow the transmission of the coronavirus disease (COVID-19). For older people, self-isolation presents particular challenges for mental health and social relationships. As time progresses, continued social distancing could have a compounding impact on these concerns. Objective This project aims to provide a tool for older people and their families and peers to improve their well-being and health during and after regulated social distancing. First, we will evaluate the tool’s feasibility, acceptability, and usability to encourage positive nutrition, enhance physical activity, and enable virtual interaction while social distancing. Second, we will be implementing the app to provide an online community to assist families and peer groups in maintaining contact with older people using goal setting. Anonymized data from the app will be aggregated with other real-world data sources to develop a machine learning algorithm to improve the identification of patients with COVID-19 and track for real time use by health systems. Methods Development of this project is occurring at the time of publication, and therefore, a case study design was selected to provide a systematic means of capturing software engineering in progress. The app development framework for software design was based on agile methods. The evaluation of the app’s feasibility, acceptability and usability shall be conducted using Public Health England's guidance on evaluating digital health products, Bandura’s model of health promotion, the Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) framework and the Nonadoption, Abandonment and Challenges to the Scale-up, Spread and Suitability (NASSS) framework. Results Making use of a pre-existing software framework for health behavior change, a proof of concept was developed, and a multistage app development and deployment for the solution was created. Grant submissions to fund the project and study execution have been sought at the time of publication, and prediscovery iteration of the solution has begun. Ethical approval for a feasibility study design is being sought. Conclusions This case study lays the foundations for future app development to combat mental and societal issues arising from social distancing measures. The app will be tested and evaluated in future studies to allow continuous improvement of the app. This novel contribution will provide an evidence-based exemplar for future app development in the space of social isolation and loneliness.
Food-Safe Process for High Recovery of Flavonoids from Cocoa Beans: Antioxidant and HPLC-DAD-ESI-MS/MS Analysis

Considering the increasing interest in the incorporation of natural antioxidants in enriched foods, this work aimed to establish a food-grade and suitable procedure for the recovery of polyphenols from cocoa beans avoiding the degreasing process. The results showed that ultrasound for 30 min with particle sample size < 0.18 mm changed the microstructure of the cell, thus increasing the diffusion pathway of polyphenols and avoiding the degreasing process. The effect of temperature, pH, and concentration of ethanol and solute on the extraction of polyphenols was evaluated. Through a 24 full factorial design, a maximum recovery of 122.34 ± 2.35 mg GAE/g, 88.87 ± 0.78 mg ECE/g, and 62.57 ± 3.37 mg ECE/g cocoa beans, for total concentration of polyphenols (TP), flavonoids (TF), and flavan-3-ols (TF3), respectively, was obtained. Based on mathematical models, the kinetics of the solid–liquid extraction process indicates a maximum equilibrium time of 45 min. Analysis by HPLC-DAD-ESI-MS/MS showed that our process allowed a high amount of methylxanthines (10.43 mg/g), catechins (7.92 mg/g), and procyanidins (34.0 mg/g) with a degree of polymerization >7, as well as high antioxidant activity determined by Oxygen Radical Absorbance Capacity (1149.85 ± 25.10 µMTrolox eq/g) and radical scavenging activity (DPPH•, 120.60 ± 0.50 µM Trolox eq/g). Overall, the recovery method made possible increases of 59.7% and 12.8% in cocoa polyphenols content and extraction yield, respectively. This study showed an effective, suitable and cost-effective process for the extraction of bioactive compounds from cocoa beans without degreasing.
The Association Between Cholecystectomy, Metabolic Syndrome, and Nonalcoholic Fatty Liver Disease: A Population-Based Study

OBJECTIVES: Obesity is a risk factor for several phenotypes such as gallstones, metabolic syndrome (MS), and nonalcoholic fatty liver disease (NAFLD). It has been suggested that cholecystectomy is a risk factor for metabolic abnormalities and NAFLD. We aimed to determine whether cholecystectomy is associated with MS or NAFLD in a Dutch population-based study. METHODS: The Rotterdam Study is an ongoing prospective population-based cohort. We included participants who underwent a liver ultrasound between 2009 and 2014 to assess steatosis. The prevalence of MS and NAFLD was calculated, and we performed regression analyses relating cholecystectomy with MS and NAFLD and adjusted for age, sex, study cohort, education level, physical activity, energy intake, time since cholecystectomy, body mass index, presence of hypertension, diabetes mellitus, and steatosis/MS. RESULTS: We included 4,307 participants (57.5% women, median age 66.0 years [interquartile range 58–74]). In total, 265 participants (6.2%) underwent a cholecystectomy. The median age at the time of cholecystectomy was 57.0 years (47.5–66.5), and the median time from cholecystectomy to imaging of the liver was 10.0 years (0.5–19.5). The prevalence of MS in participants with cholecystectomy was 67.2% and 51.9% in participants without cholecystectomy (P < 0.001). Ultrasound diagnosed moderate/severe NAFLD was present in, respectively, 42.7% and 34.2% of the participants (P = 0.008). After multivariable adjustments for metabolic factors, cholecystectomy was no longer associated with the presence of MS or NAFLD. DISCUSSION: The prevalence of MS and NAFLD is higher in participants after cholecystectomy. However, our trial shows that cholecystectomy may not be independently associated with the presence of MS and NAFLD after correction for metabolic factors.
Airway organoids as models of human disease

Studies developing and applying organoid technology have greatly increased in volume and visibility over the past decade. Organoids are three‐dimensional structures that are established from pluripotent stem cells (PSCs) or adult tissue stem cells (ASCs). They consist of organ‐specific cell types that self‐organize through cell sorting and spatially restricted lineage commitment to generate architectural and functional characteristics of the tissue of interest. The field of respiratory development and disease has been particularly productive in this regard. Starting from human cells (PSCs or ASCs), models of the two segments of the lung, the airways and the alveoli, can be built. Such organoids allow the study of development, physiology and disease and thus bridge the gap between animal models and clinical studies. This review discusses current developments in the pulmonary organoid field, highlighting the potential and limitations of current models.
Physical activity and successful aging among middle-aged and older adults: a systematic review and meta-analysis of cohort studies

Background: We aimed to investigate the association between physical activity and successful aging among middle-aged and older adults and study how this association changes with age and time. Results: The mean score of Newcastle-Ottawa Scale assessment was 8.0±0.8. Physically active middle-aged and older adults were more likely to age successfully than sedentary adults (OR=1.64, 95%CI: 1.40–1.94). The effect of physical activity was stronger in the younger group (OR=1.71, 95%CI: 1.41–2.08) than on the older group (OR=1.54, 95%CI: 1.13–2.08). However, the protective effect of physical activity reduced annually by approximately 3%. Conclusions: Physical activity promotes successful aging among middle-aged and older adults especially in the younger population. Being physically active at middle and old age is beneficial to successful aging. Methods: We searched for the relevant studies in three online databases: Pubmed, Web of Science, and Embase. Fifteen community-based cohort studies were included. The Newcastle-Ottawa Scale assessment Form was used for quality assessment. Overall, 189,192 participants aged 43.9-79.0 years were analyzed. The odds ratio for successful aging of the most physically active group compared with sedentary group was analyzed. Subgroup analysis was conducted by age group. Univariate Meta-regression was performed according to follow-up years.
A RETROSPECTIVE SUMMARY OF CERVID MORBIDITY AND MORTALITY IN ONTARIO AND NUNAVUT REGIONS OF CANADA (1991–2017)

Abstract: Free-ranging cervids in Canada face diverse threats such as climate change, human population expansion, and the northward spread of vector-borne pathogens. However, we currently have a limited understanding of the impacts of these health challenges in Ontario cervids. Our objective was to identify and characterize causes of morbidity and mortality in free-ranging cervids submitted to the Ontario and Nunavut node of the Canadian Wildlife Health Cooperative (CWHC) over a 27-yr period (1991 to 2017). Submissions included carcasses submitted for full postmortem examination (gross and histopathology; n=196) and field-collected tissues (n=384). Ancillary tests were performed on a case-by-case basis. Univariable logistic regression was used to test for associations between select causes of morbidity and mortality, and factors such as sex, age, and season. Four cervid species were examined: white-tailed deer (Odocoileus virginianus; n=211), moose (Alces alces; n=140), elk (Cervus canadensis; n=136), and caribou (Rangifer tarandus caribou; n=93). Noninfectious disease was the most common general cause of morbidity and mortality (38.1%; 221/580) and was most commonly attributed to trauma (49.7%; 110/221). Deaths attributed to infectious diseases (34.3%; 199/580) were most often bacterial in etiology (45.7%; 91/199). The most common primary infectious disease diagnosed in caribou was digital limb infection, and moose were most commonly diagnosed with parasitic causes, including meningeal worm (Parelaphostrongylus tenuis) and winter tick (Dermacentor albipictus). Chronic wasting disease was not diagnosed among cervids tested during the study period, consistent with the previous lack of detection of the disease in Ontario. These results reveal that anthropogenic, infectious, and environmentally associated causes of morbidity and mortality are commonly diagnosed in cervids submitted to the CWHC Ontario and Nunavut regions, and represent potential population threats that should continue to be monitored.