Miracle-dz/UniFAR-FTUs huggingface dataset:
A Next-Generation Risk Assessment Case Study for Coumarin in Cosmetic Products

Abstract Next-Generation Risk Assessment is defined as an exposure-led, hypothesis-driven risk assessment approach that integrates new approach methodologies (NAMs) to assure safety without the use of animal testing. These principles were applied to a hypothetical safety assessment of 0.1% coumarin in face cream and body lotion. For the purpose of evaluating the use of NAMs, existing animal and human data on coumarin were excluded. Internal concentrations (plasma Cmax) were estimated using a physiologically based kinetic model for dermally applied coumarin. Systemic toxicity was assessed using a battery of in vitro NAMs to identify points of departure (PoDs) for a variety of biological effects such as receptor-mediated and immunomodulatory effects (Eurofins SafetyScreen44 and BioMap Diversity 8 Panel, respectively), and general bioactivity (ToxCast data, an in vitro cell stress panel and high-throughput transcriptomics). In addition, in silico alerts for genotoxicity were followed up with the ToxTracker tool. The PoDs from the in vitro assays were plotted against the calculated in vivo exposure to calculate a margin of safety with associated uncertainty. The predicted Cmax values for face cream and body lotion were lower than all PoDs with margin of safety higher than 100. Furthermore, coumarin was not genotoxic, did not bind to any of the 44 receptors tested and did not show any immunomodulatory effects at consumer-relevant exposures. In conclusion, this case study demonstrated the value of integrating exposure science, computational modeling and in vitro bioactivity data, to reach a safety decision without animal data.
Antiproliferative potential of piperine and curcumin in drug-resistant human leukemia cancer cells are mediated via autophagy and apoptosis induction, S-phase cell cycle arrest and inhibition of cell invasion and migration.

PURPOSE Leukemia causes annually a significant number of deaths. The main objective of this study was to investigate the anticancer properties of piperine and curcumin against HL60 leukemia cells and to elucidate the underlying mechanism. METHODS Antiproliferative effects were assessed by WST-1 cell viability assay. Cell apoptotic effects were studied by DAPI staining assay. Annexin V/propidium iodide (PI) assay was used to assess apoptosis. Electron microscopy was used for detection of autophagy and flow cytometry for cell cycle analysis, while transwell migration assay was used to study the effects on cell migration and invasion. Protein expression was estimated by western blot. RESULTS The results showed that both piperine and curcumin inhibited significantly the growth of the HL60 cells and exhibited an IC50 of 25 and 30 µM respectively. Further, it was observed that the anticancer effects of piperine and curcumin were due to the induction of mitochondrial-mediated apoptosis which was also associated with enhancement of the Bax expression. Transmission electron microscopy also showed that both curcumin and piperine induced autophagy in the HL-60 leukemia cells. Flow cytometry showed that piperine and curcumin also caused arrest of the HL-60 cells at the S-phase of the cell cycle. Finally wound healing and transwell assays showed that piperine and curcumin suppressed the migration and invasive potential of the HL60 cells. CONCLUSIONS The present study reveals that piperine and curcumin exhibit significant antitumor activity in human leukemia HL60 cells via multiple mechanisms and may prove promising in the development of systemic therapy for leukemia.
Uncertainty in Blood Pressure Measurement Estimated Using Ensemble-Based Recursive Methodology

Automated oscillometric blood pressure monitors are commonly used to measure blood pressure for many patients at home, office, and medical centers, and they have been actively studied recently. These devices usually provide a single blood pressure point and they are not able to indicate the uncertainty of the measured quantity. We propose a new technique using an ensemble-based recursive methodology to measure uncertainty for oscillometric blood pressure measurements. There are three stages we consider: the first stage is pre-learning to initialize good parameters using the bagging technique. In the second stage, we fine-tune the parameters using the ensemble-based recursive methodology that is used to accurately estimate blood pressure and then measure the uncertainty for the systolic blood pressure and diastolic blood pressure in the third stage.
Which is the best neoadjuvant (pre-surgery) chemoradiation regimen for locally advanced rectal carcinoma? Short or long course of radiation therapy? Do we have new data?

PURPOSE Surgical resection is the cornerstone of curative treatment for rectal adenocarcinomas. For extensive invasive tumors, preoperative radiotherapy and chemoradiotherapy have been utilized to promote tumor regression in an attempt to convert a planned abdominoperineal resection to a sphincter-sparing surgical procedure. In order to find out which of the currently radiation therapy treatment regimen used preoperatively for rectal cancer is the best we conducted a comprehensive literature search. METHODS We searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE database up to December 2018 for trials comparing the short and long term radiation therapy regimens for rectal carcinoma associated or not with chemotherapy. RESULTS The search of the literature identified 38 papers related to the subject. After analysis and evaluation, 11 eligible trials were included for review. The optimal fractionation and timing of surgery in relation to radiotherapy was still controversial. Randomized trials showed that if surgery is delayed after 5×5 Gy and consolidation chemotherapy is added between 5×5 Gy and surgery, such a combination results in better short term overall survival and lower acute toxicity. CONCLUSION Long-course radiotherapy with delay seems not to be different than short-course radiotherapy with delay, but prolongs substantially the treatment time.
The Sacred Power of Beauty: Examining the Perceptual Effect of Buddhist Symbols on Happiness and Life Satisfaction in China

The theoretical relationship between Buddhism and subjective well-being has gained much academic attention in recent decades. However, the prominent determinants of religiosity remain limited for researchers to understand a holistic picture of religion-informed subjective well-being, particularly in the context of Buddhism. This study has applied a quantitative survey to verify the impact of the aesthetic effects of the Buddhist gesture symbol on Chinese people’s subjective happiness through sequential mediators of life satisfaction and the perceived religiosity. The significance of this study is threefold. Firstly, it aims to enrich the current academic understanding of the religion-informed subjective well-being by introducing a new determinant of the Buddhist symbols. Secondly, the current study investigates the mechanism of how Buddhist symbols could influence happiness by analyzing the sequential mediating roles of religiosity and life satisfaction. Thirdly, this study empirically examines the topic in the context of China to confirm and underpin the theoretical relationship between Buddhism and subjective well-being in relevant research, which has previously focused on Western culture. Our results indicated that the aesthetic perception of the Buddhist gesture symbol positively influenced perceived happiness and life satisfaction. In addition, perceived religiosity and life satisfaction sequentially mediated the perceived happiness after seeing the Buddhist gesture symbol. Our findings contribute to the current academic understanding of religious symbols and their impacts on subjective well-being.
Targeted PARP Inhibition Combined with FGFR1 Blockade is Synthetically Lethal to Malignant Cells in Patients with Pancreatic Cancer

The role and therapeutic promise of poly-ADP ribose polymerase (PARP) inhibitors in anticancer chemotherapy are increasingly being explored, particularly in adjuvant or maintenance therapy, considering their low efficacy as monotherapy agents and their potentiating effects on concurrently administered contemporary chemotherapeutics. Against the background of increasing acquired resistance to FGFR1 inhibitors and our previous work, which partially demonstrated the caspase-3/PARP-mediated antitumor and antimetastatic efficacy of PD173074, a selective FGFR1 inhibitor, against ALDH-high/FGFR1-rich pancreatic ductal adenocarcinoma (PDAC) cells, we investigated the probable synthetic lethality and therapeutic efficacy of targeted PARP inhibition combined with FGFR1 blockade in patients with PDAC. Using bioinformatics-based analyses of gene expression profiles, co-occurrence and mutual exclusivity, molecular docking, immunofluorescence staining, clonogenicity, Western blotting, cell viability or cytotoxicity screening, and tumorsphere formation assays, we demonstrated that FGFR1 and PARP co-occur, form a complex, and reduce survival in patients with PDAC. Furthermore, FGFR1 and PARP expression was upregulated in FGFR1 inhibitor (dasatinib)-resistant PDAC cell lines SU8686, MiaPaCa2, and PANC-1 compared with that in sensitive cell lines Panc0403, Panc0504, Panc1005, and SUIT-2. Compared with the limited effect of single-agent olaparib (PARP inhibitor) or PD173074 on PANC-1 and SUIT-2 cells, low-dose combination (olaparib + PD173074) treatment significantly, dose-dependently, and synergistically reduced cell viability, upregulated cleaved PARP, pro-caspase (CASP)-9, cleaved-CASP9, and cleaved-CASP3 protein expression, and downregulated Bcl-xL protein expression. Furthermore, combination treatment markedly suppressed the clonogenicity and tumorsphere formation efficiency of PDAC cells regardless of FGFR1 inhibitor-resistance status and enhanced RAD51 and γ-H2AX immunoreactivity. In vivo studies have shown that both early and late initiation of combination therapy markedly suppressed tumor xenograft growth and increase in weight, although the effect was more pronounced in the early initiation group. In conclusion, FGFR1 inhibitor-resistant PDAC cells exhibited sensitivity to PD173074 after olaparib-mediated loss of PARP signaling. The present FGFR1/PARP-mediated synthetic lethality proof-of-concept study provided preclinical evidence of the feasibility and therapeutic efficacy of combinatorial FGFR1/PARP1 inhibition in human PDAC cell lines.
Analysis of BRCA1 and RAD51C Promoter Methylation in Italian Families at High-Risk of Breast and Ovarian Cancer

Previous studies on breast and ovarian carcinoma (BC and OC) revealed constitutional BRCA1 and RAD51C promoter hypermethylation as epigenetic alterations leading to tumor predisposition. Nevertheless, the impact of epimutations at these genes is still debated. One hundred and eight women affected by BC, OC, or both and considered at very high risk of carrying BRCA1 germline mutations were studied. All samples were negative for pathogenic variants or variants of uncertain significance at BRCA testing. Quantitative BRCA1 and RAD51C promoter methylation analyses were performed by Epityper mass spectrometry on peripheral blood samples and results were compared with those in controls. All the 108 analyzed cases showed methylation levels at the BRCA1/RAD51C promoter comparable with controls. Mean methylation levels (± stdev) at the BRCA1 promoter were 4.3% (± 1.4%) and 4.4% (± 1.4%) in controls and patients, respectively (p > 0.05; t-test); mean methylation levels (± stdev) at the RAD51C promoter were 4.3% (± 0.9%) and 3.7% (± 0.9%) in controls and patients, respectively (p > 0.05; t-test). Based on these observations; the analysis of constitutional methylation at promoters of these genes does not seem to substantially improve the definition of cancer risks in patients. These data support the idea that epimutations represent a very rare event in high-risk BC/OC populations.
A Phosphite Dehydrogenase Variant with Promiscuous Access to Nicotinamide Cofactor Pools Sustains Fast Phosphite-Dependent Growth of Transplastomic Chlamydomonas reinhardtii

Heterologous expression of the NAD+-dependent phosphite dehydrogenase (PTXD) bacterial enzyme from Pseudomonas stutzerii enables selective growth of transgenic organisms by using phosphite as sole phosphorous source. Combining phosphite fertilization with nuclear expression of the ptxD transgene was shown to be an alternative to herbicides in controlling weeds and contamination of algal cultures. Chloroplast expression of ptxD in Chlamydomonas reinhardtii was proposed as an environmentally friendly alternative to antibiotic resistance genes for plastid transformation. However, PTXD activity in the chloroplast is low, possibly due to the low NAD+/NADP+ ratio, limiting the efficiency of phosphite assimilation. We addressed the intrinsic constraints of the PTXD activity in the chloroplast and improved its catalytic efficiency in vivo via rational mutagenesis of key residues involved in cofactor binding. Transplastomic lines carrying a mutagenized PTXD version promiscuously used NADP+ and NAD+ for converting phosphite into phosphate and grew faster compared to those expressing the wild type protein. The modified PTXD enzyme also enabled faster and reproducible selection of transplastomic colonies by directly plating on phosphite-containing medium. These results allow using phosphite as selective agent for chloroplast transformation and for controlling biological contaminants when expressing heterologous proteins in algal chloroplasts, without compromising on culture performance.
The use of mental health services by Australian adolescents with mental disorders and suicidality: Findings from a nationwide cross-sectional survey

Objectives Mental disorders and suicidality among adolescents have been identified as a major public health concern worldwide; however, they often do not get the necessary attention from parents, school and health professional, and therefore are left untreated. This study aimed to investigate the factors associated with the use of mental health services among Australian adolescents aged 13–17 with mental disorders and/or suicidality. Methods Adolescents aged 13–17 (n = 2134) from Young Minds Matter (YMM): the Second Australian Child and Adolescent Survey of Mental Health and Wellbeing were included in this study. The YMM is a cross-sectional nationwide survey, in which information was collected from both parents and adolescents (aged 13–17 years). Both bivariate and multivariate analyses were conducted to identify the factors that have an impact on the use of mental health services (outcome variable) in two subsamples: (1) adolescents with mental disorder and (2) adolescents with suicidality. Results Overall, 740 (34.7%) and 168 (7.9%) adolescents reported a mental disorder and/or suicidality, respectively. The incidence of seeking any service was higher among adolescents with suicidality (approximately 50%) compared to those with a mental disorder (about 30%). Girls, older age-group (15–17), adolescents living with disadvantaged families (lower-income, less educated and unemployed parents), those who had multiple mental disorders and history of substance use were most likely to use mental health services regardless of mental disorder and suicidality. Health services and online services were the most popular type of mental health service among adolescents aged 13–17 across two subgroups, while, school and telephone services were less utilized. Conclusions Many adolescents with mental disorders and/or suicidality do not use mental health services. The findings indicate differences in factors associated with the use of mental health services among adolescents with mental disorder and suicidality. Further research is needed to address the specific barriers that limit the use of the services.
Frequency and Causes of Burnout in US Community Oncologists in the Era of Electronic Health Records.

BACKGROUND Physician burnout, characterized by exhaustion of physical or emotional strength, cynicism, and lack of achievement, has become a worsening phenomenon in medicine, contributing to higher health care costs and patient/physician dissatisfaction. How burnout has affected hematologists and oncologists is not well studied. METHODS US community oncologists/hematologists were queried via a Web-based survey from September-November 2018. Physicians were asked about frequency of burnout symptoms, drivers of work-related stress, and their perceptions on management of workload. RESULTS Among the 163 physicians surveyed, 46% felt a substantial amount of stress at work. Most physicians felt emotionally (85%) and physically (87%) exhausted. A majority of physicians felt lethargic (67%), ineffective (64%), and/or detached (63%). In a typical workweek, 93% needed time beyond time allocated to clinical care to complete work responsibilities. Electronic health record (EHR) responsibilities caused moderate to excessive stress at work for 67% of physicians; 79% of physicians worked on EHRs outside of clinic hours. Other sources of excessive stress were changing reimbursement models (33%), interactions with payers (31%), and increasing patient and caregiver demands (31%). A third of physicians have considered retiring early or changing their career path to cope. To combat burnout, physicians' practices have used advanced practice providers, invested in information technology, and/or hired additional administrative staff. However, the majority of physicians stated they had optimal or good control over their workload. CONCLUSION Most oncologists experience burnout symptoms and require additional time beyond that allocated to clinical care to complete their workload. The discordance between oncologists' admission of stress and exhaustion while claiming good control over those same burdens warrants exploration in future research.
Non-genetic risk factors for atrial fibrillation are equally important in both young and old age: A nationwide population-based study.

AIMS There are several non-genetic risk factors for new-onset atrial fibrillation, including age, sex, obesity, hypertension, diabetes, and alcohol consumption. However, whether these non-genetic risk factors have equal significance among different age groups is not known. We performed a nationwide population-based analysis to compare the clinical significance of non-genetic risk factors for new-onset atrial fibrillation in various age groups. METHODS AND RESULTS A total of 9,797,409 people without a prior diagnosis of atrial fibrillation who underwent a national health check-up in 2009 were included. During 80,130,090 person-years of follow-up, a total of 196,136 people were diagnosed with new-onset atrial fibrillation. The impact of non-genetic risk factors on new-onset atrial fibrillation was examined in different age groups. Obesity, male sex, heavy alcohol consumption, smoking, hypertension, diabetes and chronic kidney disease were associated with an increased risk of new-onset atrial fibrillation. With minor variations, these risk factors were consistently associated with the risk of new-onset atrial fibrillation among various age groups. Using these risk factors, we created a scoring system to predict future risk of new-onset atrial fibrillation in different age groups. In receiver operating characteristic curve analysis, the predictive value of these risk factors ranged between 0.556 and 0.603, and no significant trends were observed. CONCLUSIONS Non-genetic risk factors for new-onset atrial fibrillation may have a similar impact on different age groups. Except for sex, these non-genetic risk factors can be modifiable. Therefore, efforts to control non-genetic risk factors might have relevance for both the young and old.
Random Sketching for Neural Networks With ReLU

Training neural networks is recently a hot topic in machine learning due to its great success in many applications. Since the neural networks’ training usually involves a highly nonconvex optimization problem, it is difficult to design optimization algorithms with perfect convergence guarantees to derive a neural network estimator of high quality. In this article, we borrow the well-known random sketching strategy from kernel methods to transform the training of shallow rectified linear unit (ReLU) nets into a linear least-squares problem. Using the localized approximation property of shallow ReLU nets and a recently developed dimensionality-leveraging scheme, we succeed in equipping shallow ReLU nets with a specific random sketching scheme. The efficiency of the suggested random sketching strategy is guaranteed by theoretical analysis and also verified via a series of numerical experiments. Theoretically, we show that the proposed random sketching is almost optimal in terms of both approximation capability and learning performance. This implies that random sketching does not degenerate the performance of shallow ReLU nets. Numerically, we show that random sketching can significantly reduce the computational burden of numerous backpropagation (BP) algorithms while maintaining their learning performance.
Psychosocial Working Conditions and Well-Being of Migrant Workers in Spain

This study examines the relationship beween employment and psychosocial working conditions and well-being of native and migrant workers in the working population of Spain. Data from the 7th Spanish Survey of Working Conditions was used to conduct a confirmatory factor analysis (n = 8508) to identify the main latent variables that influenced well-being. Using structural equation modeling and multivariate analysis, we found different patterns and perceptions of well-being and working conditions in these two groups. We discuss the reasons for these differences and suggest directions for further research in this area.
“When you first walk out the gates…where do [you] go?”: Barriers and opportunities to achieving continuity of health care at the time of release from a provincial jail in Ontario

We aimed to explore continuity of health care and health barriers, facilitators, and opportunities for people at the time of release from a provincial correctional facility in Ontario, Canada. We conducted focus groups in community-based organizations in a city in Ontario, Canada: a men’s homeless shelter, a mental health service organization, and a social service agency with programs for people with substance use disorders. We included adults who spoke English well enough to participate in the discussion and who had been released from the provincial correctional facility in the previous year. We conducted three focus groups with 18 total participants. Participants had complex health needs on release, including ongoing physical and psychological impacts of time in custody. They identified lack of access to high quality health care; lack of housing, employment, social services, and social supports; and discrimination on the basis of incarceration history as barriers to health on release. Access to health care, housing, social services, and social supports all facilitated health on release. To address health needs on release, participants suggested providing health information in jail, improving discharge planning, and developing accessible clinics in the community. This pilot study identified opportunities to support health at the time of release from jail, including delivery of programs in jail, linkage with and development of programs in the community, and efforts to support structural changes to prevent and address discrimination. These data will inform ongoing work to support health and continuity of care on release from a provincial correctional facility.