Miracle-dz/UniFAR-FTUs huggingface dataset:
Isolation and Characterization of Two Novel Colorectal Cancer Cell Lines, Containing a Subpopulation with Potential Stem-Like Properties: Treatment Options by MYC/NMYC Inhibition

Simple Summary The aim of this study was to gain a better understanding of cancer stem cells, which are a small subpopulation of tumor cells with high plasticity driving tumor growth and metastasis. Here we isolated two novel colorectal cancer cell lines originating from a rectal neuroendocrine carcinoma and a colorectal adenocarcinoma, depicting stem-like properties. These in vitro models offer the possibility to evaluate pathophysiological mechanisms in order to develop tailored therapeutic strategies for distinct colorectal malignancies. Investigations revealed gene copy number gain of the N-myc proto-oncogene for both. Accordingly, inhibition of the protein–protein interaction of myc and N-myc proto-oncogenes with the myc-associated factor X utilizing small molecule KJ-Pyr-9, exhibited a significant reduction in survival of both cell lines by the induction of apoptosis. Consequently, the blockage of these interactions may serve as a possible treatment strategy for colorectal cancer cell lines with gene copy number gain of the N-myc proto-oncogene. Abstract Cancer stem cells (CSC) are crucial mediators of cancer relapse. Here, we isolated two primary human colorectal cancer cell lines derived from a rectal neuroendocrine carcinoma (BKZ-2) and a colorectal adenocarcinoma (BKZ-3), both containing subpopulations with potential stem-like properties. Protein expression of CSC-markers prominin-1 and CD44 antigen was significantly higher for BKZ-2 and BKZ-3 in comparison to well-established colon carcinoma cell lines. High sphere-formation capacity further confirmed the existence of a subpopulation with potential stem-like phenotype. Epithelial–mesenchymal transition markers as well as immune checkpoint ligands were expressed more pronounced in BKZ-2. Both cell populations demonstrated N-myc proto-oncogene (NMYC) copy number gain. Myc proto-oncogene (MYC)/NMYC activity inhibitor all-trans retinoic acid (ATRA) significantly reduced the number of tumor spheres for both and the volume of BKZ-2 spheres. In contrast, the sphere volume of ATRA-treated BKZ-3 was increased, and only BKZ-2 cell proliferation was reduced in monolayer culture. Treatment with KJ-Pyr-9, a specific inhibitor of MYC/NMYC-myc-associated factor X interaction, decreased survival by the induction of apoptosis of both. In summary, here, we present the novel colorectal cancer cell lines BKZ-2 and BKZ-3 as promising cellular in vitro models for colorectal carcinomas and identify the MYC/NMYC molecular pathway involved in CSC-induced carcinogenesis with relevant therapeutic potential.
Machine Learning-Based DNA Methylation Score for Fetal Exposure to Maternal Smoking: Development and Validation in Samples Collected from Adolescents and Adults

Background: Fetal exposure to maternal smoking during pregnancy is associated with the development of noncommunicable diseases in the offspring. Maternal smoking may induce such long-term effects through persistent changes in the DNA methylome, which therefore hold the potential to be used as a biomarker of this early life exposure. With declining costs for measuring DNA methylation, we aimed to develop a DNA methylation score that can be used on adolescent DNA methylation data and thereby generate a score for in utero cigarette smoke exposure. Methods: We used machine learning methods to create a score reflecting exposure to maternal smoking during pregnancy. This score is based on peripheral blood measurements of DNA methylation (Illumina’s Infinium HumanMethylation450K BeadChip). The score was developed and tested in the Raine Study with data from 995 white 17-y-old participants using 10-fold cross-validation. The score was further tested and validated in independent data from the Northern Finland Birth Cohort 1986 (NFBC1986) (16-y-olds) and 1966 (NFBC1966) (31-y-olds). Further, three previously proposed DNA methylation scores were applied for comparison. The final score was developed with 204 CpGs using elastic net regression. Results: Sensitivity and specificity values for the best performing previously developed classifier (“Reese Score”) were 88% and 72% for Raine, 87% and 61% for NFBC1986 and 72% and 70% for NFBC1966, respectively; corresponding figures using the elastic net regression approach were 91% and 76% (Raine), 87% and 75% (NFBC1986), and 72% and 78% for NFBC1966. Conclusion: We have developed a DNA methylation score for exposure to maternal smoking during pregnancy, outperforming the three previously developed scores. One possible application of the current score could be for model adjustment purposes or to assess its association with distal health outcomes where part of the effect can be attributed to maternal smoking. Further, it may provide a biomarker for fetal exposure to maternal smoking. https://doi.org/10.1289/EHP6076
Use of End-of-Class Quizzes to Promote Pharmacy Student Self-Reflection, Motivate Students to Improve Study Habits, and to Improve Performance on Summative Examinations

Underperforming students are often unaware of deficiencies requiring improvement until after poor performance on summative exams. The goal of the current study was to determine whether inclusion of individual end-of-class formative quizzes, which comprise of higher level Bloom’s questions, could encourage students to reflect on and address deficiencies and improve academic performance. Ninety-seven out of 123 first-year pharmacy students (79%) enrolled in a Biochemistry and Cell & Molecular Biology course participated in a single-blinded, randomized, controlled, crossover study. Paired t-test analyses demonstrated that that implementation of individual end-of-class formative quizzes resulted in significantly higher summative exam scores for below average students (p = 0.029). Notably, inclusion of quizzes significantly improved performance on higher Bloom’s questions for these students (p = 0.006). Analysis of surveys completed by students prior to summative exam indicate that the formative end-of-class quizzes helped students identify deficiencies (89%) and making them feel compelled to study more (83%) and attend review sessions (61%). Many students indicated that quizzes increased stress levels (45%). Our collective data indicate that quizzes can improve summative exam performance for below average first year pharmacy students, and improve self-reflection and student motivation to study. However, the impact on student stress levels should be considered.
Implementing high‐dimensional propensity score principles to improve confounder adjustment in UK electronic health records

Recent evidence from US claims data suggests use of high‐dimensional propensity score (hd‐PS) methods improve adjustment for confounding in non‐randomised studies of interventions. However, it is unclear how best to apply hd‐PS principles outside their original setting, given important differences between claims data and electronic health records (EHRs). We aimed to implement the hd‐PS in the setting of United Kingdom (UK) EHRs.
Diosgenin inhibits TGF-β1/Smad signaling and regulates epithelial mesenchymal transition in experimental pulmonary fibrosis

Abstract Idiopathic Pulmonary Fibrosis (IPF) is a grave disease characterized by abnormal wound healing associated with chronic, progressive, irreversible fatal lung disease, leading to persistent injuries to the alveolar epithelium. A consequent disturbance of fibroblast proliferation and apoptosis results in subsequent release of pro-inflammatory and pro-fibrotic mediators coupled with accumulation of extracellular matrix within the interstitium. Inexorable distortion of lung alveolar architecture leads to respiratory failure with a median survival rate of 3–5 years. Currently available drugs can only slowdown the progression of fibrosis and novel drugs are warranted to treat this disease. In this study, we demonstrate the fibro-protective effect of diosgenin in experimental lung fibrosis through regulation of Epithelial Mesenchymal Transition (EMT). A single dose of 3 U/kg body weight (b.wt) Bleomycin (BLM) was administered intratracheally in Wistar male albino rats and fibrotic animals were treated with diosgenin (100 mg/kg b.wt) orally for 28 days. BLM administered rat show histological alteration with increased mast cell and collagen accumulation. BLM induced abnormalities were significantly reduced upon treatment with diosgenin. Western blot analysis revealed an increased level of pro-inflammatory and pro-fibrotic molecules such as IL-1β and TGF-β in BLM induced rats. Rats supplemented with diosgenin showed a decreased expression of inflammatory and pro-fibrotic mediators. Markers of EMT molecules were evaluated by immunoblot. The results of immunoblot demonstrate that diosgenin regulated the expression of TGF-β mediated EMT. Hence, from the overall study, administration of diosgenin prevents pulmonary fibrosis by restraint inflammation and EMT.
Clinical characteristics and outcome of hemodialysis patients with COVID-19: a large cohort study in a single Chinese center

Abstract Background Novel coronavirus disease (COVID-19) is spreading rapidly, which poses great challenges to patients on maintenance hemodialysis. Here we report the clinical features of 66 hemodialysis patients with laboratory confirmed COVID-19 infection. Design, setting, participants, and measurements Retrospective, single-center case series of the 66 hemodialysis patients with confirmed COVID-19 from 1 January to 5 March 2020; the final date of follow-up was 25 March 2020. Results The clinical data were collected from 66 hemodialysis patients with confirmed COVID-19. The incidence of COVID-19 in our center was 11.0% (66/602), of which 18 patients died. According to different prognosis, hemodialysis patients with COVID-19 were divided into the survival and death group. A higher incidence of fever and dyspnea was found in the death group compared with the survival group. Meanwhile, patients in the death group were often accompanied by higher white blood cell count, prolonged PT time, increased D-dimer (p < .05). More patients in the death group showed hepatocytes and cardiomyocytes damage. Furthermore, logistic regression analysis suggested that fever, dyspnea, and elevated D-dimer were independent risk factors for death in hemodialysis patients with COVID-19 (OR, 1.077; 95% CI, 1.014 to 1.439; p = .044; OR, 1.146; 95% CI, 1.026 to 1.875; p = .034, OR, 4.974; 95% CI, 3.315 to 6.263; p = .007, respectively). Conclusions The potential risk factors of fever, dyspnea, and elevated D-dimer could help clinicians to identify hemodialysis patients with poor prognosis at an early stage of COVID-19 infection.
Diabetic Ketoacidosis and Related Events With Sotagliflozin Added to Insulin in Adults With Type 1 Diabetes: A Pooled Analysis of the inTandem 1 and 2 Studies

OBJECTIVE To evaluate the incidence and risk factors for diabetic ketoacidosis (DKA) and related adverse events (AEs) in adults with type 1 diabetes treated with sotagliflozin adjunctive to insulin. RESEARCH DESIGN AND METHODS Data from two identically designed, 52-week, randomized studies were pooled and analyzed for DKA, changes in β-hydroxybutyrate (BHB), and percentage of patients with BHB >0.6 and >1.5 mmol/L. The patients were administered placebo, sotagliflozin 200 mg, or sotagliflozin 400 mg once daily. RESULTS A total of 191 ketosis-related AEs were reported, and 98 underwent adjudication. Of these, 37 events (36 patients) were adjudicated as DKA, with an exposure-adjusted incidence rate of 0.2, 3.1, and 4.2 events per 100 patient-years for placebo, sotagliflozin 200 mg, and sotagliflozin 400 mg, respectively. No patient died of a DKA event. From a baseline BHB of ∼0.13 mmol/L, sotagliflozin treatment led to a small median increase over 52 weeks (≤0.05 mmol/L at all time points). Of sotagliflozin-treated patients, approximately 47% and 7% had ≥1 BHB measurement >0.6 mmol/L and >1.5 mmol/L, respectively (vs. 20% and 2%, respectively, of placebo-treated patients). Subsequent to the implementation of a risk mitigation plan, annualized DKA incidence was lower versus preimplementation in both the sotagliflozin 200 and 400 mg groups. CONCLUSIONS In patients with type 1 diabetes, confirmed DKA incidence increased when sotagliflozin was added to insulin compared with insulin alone. A lower incidence of DKA was observed following the implementation of an enhanced risk mitigation plan, suggesting that this risk can be managed with patient education.
Give Intravenous Bolus Overdose a Brake: User Experience and Perception of Safety Device

Objectives Drugs can come in concentrated solutions that require dilution before intravenous bolus administration. Upon dilution, the syringe can contain more than the required amount of drug. The user may mistakenly administer the full contents of the syringe, resulting in an overdose. In this cross-sectional study, we evaluated user experience and perception of Syringe Brake, a dosage flow restrictor device, as part of the intravenous morphine bolus administration workflow. Methods From December 2018 to January 2019, doctors and nurses working in the emergency department of 3 public tertiary hospitals in Singapore were invited to complete a paper-based 11-item 5-point Likert scale survey questionnaire after 3 months of Syringe Brake implementation. Results Overall, 77.5% (290/374; 4.11 ± 0.83) of participants were satisfied with the use of Syringe Brake to prevent medication error. Our survey results showed that the top features of Syringe Brake were ease of setting the desired volume to be administered (86.1%; 4.21 ± 0.72), allowing the drug to be titrated safely (84.8%; 4.26 ± 0.77), and giving users the confidence to avoid overdosing the patient (82.1%; 4.21 ± 0.78). Those with hands-on experience with Syringe Brake rated significantly higher for all survey statements except on the perceived ability to prevent error arising from miscommunication (adjusted odds ratio, 1.58 [0.98–2.57]; P = 0.062). Conclusions Syringe Brake shows promising potential for adoption to prevent medication errors. The device serves as a constraint to prevent accidental overdose, caused by user unfamiliarity or autopilot administration.
Association of blood pressure with mortality in hemodialysis patients with a tunneled cuffed catheter

Abstract The use of tunneled cuffed catheters (TCCs) for permanent blood access is increasing as the hemodialysis population ages. However, the higher mortality and complication rates associated with their use have been significant concerns. This single-center observational cohort study aimed to investigate clinical factors affecting mortality and complications in Japanese hemodialysis patients with a TCC. We enrolled 64 consecutive patients receiving hemodialysis through a TCC between 2012 and 2019. The primary outcome was all-cause mortality and the secondary outcome was the incidence of catheter-related complications at 2 years. Cox proportional hazards models were used to examine variables associated with these outcomes. At 2 years, death from any cause and catheter-related complications occurred in 27/64 (42%) and 23/64 (36%) patients, respectively. There were 14 bacteremia events, 7 catheter obstructions, and 8 instances of restricted blood flow. Multivariate analysis showed that systolic blood pressure (SBP) < 100 mm Hg at the time of catheter insertion was associated with higher all-cause mortality (hazard ratio, 2.59; 95% confidence interval, 1.05–6.41) and catheter-related complications (hazard ratio, 2.57; 95% confidence interval, 1.52–22.2). The Kaplan–Meier analyses also showed that patients with SBP <100 mm Hg had higher mortality (P = .001) and a higher incidence of catheter-related complications (P = .0068). SBP <100 mm Hg at the time of catheter insertion is associated with mortality and catheter-related complications in hemodialysis patients using a TCC. Further multi-center studies are required to validate our results.
Injuries and rapid weight loss in elite Korean wrestlers: an epidemiological study

ABSTRACT Objectives The purpose of this study was to reveal the relationship between rapid weight loss and injury patterns during the training of elite wrestlers, expected to represent South Korea. Methods Since 2019, data for elite wrestlers have been collected prospectively by the Korean Training Center. The data were stratified by sex, wrestling style, weight class, injury location, injuries during the weight-loss period, and weight loss method. The χ2 test was used to compare groups. The risk of injury was indicated by the Poisson rate with a 95% confidence interval (95% CI). Results There were 120 male Greco-Roman, 120 male freestyle, and 100 female freestyle wrestling. The mean weight loss among wrestlers was 5.52 (±1.44) kg, and the mean duration of weight loss was 7.96 (±3.31) days. In general, all wrestlers used similar weight loss methods. We recorded 914 injuries in 340 athletes. Wrestlers had significantly higher injury rates during weight loss periods than during other periods of training (23.18 VS 11.93; p < 0.001). Most injuries occurred in the lower extremities (38.0%), followed by the upper extremities (25.9%), trunk (24.8%), and the head and neck area (11.3%). The injury severity was significantly influenced by sex, wrestling style, and weight class. Conclusion Rapid weight loss is related to the incidence of sports injuries in wrestlers. Most injuries occur during rapid weight loss periods in South Korean elite wrestlers. Moreover, the injury site and injury severity depend on sex, wrestling style, and weight class.
Development of a pathogenesis‐based therapy for peeling skin syndrome type 1 *

Peeling skin syndrome type 1 (PSS1) is a rare and severe autosomal recessive form of congenital ichthyosis. Patients are affected by pronounced erythroderma accompanied by pruritus and superficial generalized peeling of the skin. The disease is caused by nonsense mutations or complete deletion of the CDSN gene encoding for corneodesmosin (CDSN). PSS1 severely impairs quality of life and therapeutic approaches are totally unsatisfactory.
Reassessment of the risk of narcolepsy in children in England 8 years after receipt of the AS03-adjuvanted H1N1 pandemic vaccine: A case-coverage study

Background Early studies of narcolepsy after AS03-adjuvanted pandemic A/H1N12009 vaccine (Pandemrix) could not define the duration of elevated risk post-vaccination nor the risk in children aged under 5 years who may not present until much older. Methods/Findings Clinical information and sleep test results, extracted from hospital notes at 3 large pediatric sleep centers in England between September 2017 and June 2018 for narcolepsy cases aged 4–19 years with symptom onset since January 2009, were reviewed by an expert panel to confirm the diagnosis. Vaccination histories were independently obtained from general practitioners (GPs). The odds of vaccination in narcolepsy cases compared with the age-matched English population was calculated after adjustment for clinical conditions that were indications for vaccination. GP questionnaires were returned for 242 of the 244 children with confirmed narcolepsy. Of these 5 were under 5 years, 118 were 5–11 years, and 119 were 12–19 years old at diagnosis; 39 were vaccinated with Pandemrix before onset. The odds ratio (OR) for onset at any time after vaccination was 1.94 (95% confidence interval [CI] 1.30–2.89), The elevated risk period was restricted to onsets within 12 months of vaccination (OR 6.65 [3.44–12.85]) and was highest within the first 6 months. After one year, ORs were not significantly different from 1 up to 8 years after vaccination. The ORs were similar in under five-year-olds and older ages. The estimated attributable risk was 1 in 34,500 doses. Our study is limited by including cases from only 3 sleep centers, who may differ from cases diagnosed in nonparticipating centers, and by imprecision in defining the centers’ catchment population. The potential for biased recall of onset shortly after vaccination in cases aware of the association cannot be excluded. Conclusions In this study, we found that vaccine-attributable cases have onset of narcolepsy within 12 months of Pandemrix vaccination. The attributable risk is higher than previously estimated in England because of identification of vaccine-attributable cases with late diagnoses. Absence of a compensatory drop in risk 1–8 years after vaccination suggests that Pandemrix does not trigger onsets in those in whom narcolepsy would have occurred later.
No need to use both Disabilities of the Arm, Shoulder and Hand and Constant–Murley score in studies of midshaft clavicular fractures

Background and purpose Most newer randomized studies examining plate fixation and nonoperative treatment of midshaft clavicular fractures utilize both Disabilities of the Arm, Shoulder and Hand (DASH) and Constant–Murley score (CS) in the evaluation of patient outcomes. Compared with DASH, the use of CS requires on-site trained personnel and patient visits to obtain the score. The use of both DASH and CS should provide extra value compared with the use of a single functional outcome score; if this value is not provided, the combined use is not necessary. We evaluated the agreement between DASH and CS in patients with displaced midshaft clavicular fractures. Patients and methods We used prospectively collected data from 146 patients enrolled in a randomized study comparing operative and nonoperative treatment of midshaft clavicular fractures. We determined correlation between DASH and CS at all follow-up points and calculated mean bias in the Bland–Altman plot. Results We found moderate to high correlation (from 0.82 at 6 weeks’ follow-up to 0.58 at 1-year follow-up) between DASH and CS score, and a small bias (2.21 [95% CI 0.22–4.20]) in the Bland–Altman plot. Interpretation In patients with displaced midshaft clavicular fractures DASH and CS measures the same degree of disability. Unless specifically studying strength and range of motion, we recommend the sole use of DASH as it would eliminate potential observer-induced bias along with removing the economic and logistic burden of obtaining CS without compromising the value of the collected data.
The Effect of Nickel on the Microstructure, Mechanical Properties and Corrosion Properties of Niobium–Vanadium Microalloyed Powder Metallurgy Steels

In this study, the effects of adding Ni in different ratios to Fe-matrix material containing C-Nb-V produced by powder metallurgy on microstructure, tensile strength, hardness and corrosion behaviors were investigated. Fe-C and Fe-C-Nb-V powders containing 5%, 10%, 13%, 15%, 20%, 30% and 40% nickel were pressed at 700 MPa and then sintered in an Ar atmosphere at 1400 °C. Microstructures of the samples were characterized with optical microscope, scanning electron microscope (SEM) and XRD. Corrosion behaviors were investigated by obtaining Tafel curves in an aqueous solution containing 3.5% NaCl. Mechanical properties were determined by hardness and tensile testing. While Fe-C alloy and Fe-C-Nb-V microalloyed steel without Ni typically have a ferrite-pearlite microstructure, the austenite phase has been observed in the microstructures of the alloys with 10% nickel and further. Yield and tensile strength increased with nickel content and reached the highest strength values with 13% Ni content. The addition of more nickel led to decrease the strength. Analysis of Tafel curves showed that corrosion resistance of alloys increased with increasing nickel concentration.