Miracle-dz/UniFAR-FTUs huggingface dataset:
Activation of the EGFR/PI3K/AKT pathway limits the efficacy of trametinib treatment in head and neck cancer

Blocking the mitogen‐activated protein kinase (MAPK) pathway with the MEK1/2 inhibitor trametinib has produced promising results in patients with head and neck squamous cell carcinoma (HNSCC). In the current study, we showed that trametinib treatment leads to overexpression and activation of the epidermal growth factor receptor (EGFR) in HNSCC cell lines and patient‐derived xenografts. Knockdown of EGFR improved trametinib treatment efficacy both in vitro and in vivo. Mechanistically, we demonstrated that trametinib‐induced EGFR overexpression hyperactivates the phosphatidylinositol 3‐kinase (PI3K)/AKT pathway. In vitro, blocking the PI3K pathway with GDC‐0941 (pictilisib), or BYL719 (alpelisib), prevented AKT pathway hyperactivation and enhanced the efficacy of trametinib in a synergistic manner. In vivo, a combination of trametinib and BYL719 showed superior antitumor efficacy vs. the single agents, leading to tumor growth arrest. We confirmed our findings in a syngeneic murine head and neck cancer cell line in vitro and in vivo. Taken together, our findings show that trametinib treatment induces hyperactivation of EGFR/PI3K/AKT; thus, blocking of the EGFR/PI3K pathway is required to improve trametinib efficacy in HNSCC.
First Application of the Zeeman Technique to Remotely Measure Auroral Electrojet Intensity From Space

Using the O2 118 GHz spectral radiance measurements obtained by the Microwave Limb Sounder instrument on board the Aura spacecraft, we demonstrate that the Zeeman effect can be used to remotely measure the magnetic field perturbations produced by the auroral electrojet near the Hall current closure altitudes. Our derived current‐induced magnetic field perturbations are found to be highly correlated with those coincidently obtained by ground magnetometers. These perturbations are also found to be linearly correlated with auroral electrojet strength. The statistically derived polar maps of our measured magnetic field perturbation reveal a spatial‐temporal morphology consistent with that produced by the Hall current during substorms and storms. With today's technology, a constellation of compact, low‐power, high‐spectral‐resolution cubesats would have the capability to provide high precision and spatiotemporal magnetic field samplings needed for auroral electrojet measurements to gain insights into the spatiotemporal behavior of the auroral electrojet system.
Extension of a theorem of J. C. C. Nitsche on the Gaussian curvature equation and higher-order versions of the Ahlfors-Schwarz lemma

A classical result of Nitsche (21) about the behaviour of the solu- tions to the Liouville equationu = 4 e 2u near isolated singularities is gener- alized to solutions of the Gaussian curvature equationu = −κ(z) e 2u where κ is a negative Holder continuous function. As an application a higher-order version of the Yau-Ahlfors-Schwarz lemma for complete conformal Rieman- nian metrics is obtained.
Exercise-based cardiac rehabilitation programmers for patients after transcatheter aortic valve implantation: A systematic review and meta-analysis

Background: Currently, transcatheter aortic valve implantation (TAVI) is presently a recognized treatment modality for patients with severe aortic stenosis who are often old, disabled, frail, and have low exercise capacity (ExCap). It is further expected from this therapy to improve quality of life by improving of the cardio function performance. The aim of this study is to evaluate the effect of exercise-based cardiac rehabilitation (CR) on patients after TAVI. Methods: PubMed, Embase, Cochrane Library, and Web of Science were searched from inception to December 10, 2022 for relevant studies that evaluated the effect of CR on patients after TAVI. The primary outcome was the improvement of 6-minute walked distance and Barthel index score after CR. The secondary outcomes included other parameters such as SF-12 scale, HADS score, Morse Fall Scale, Frailty-Index, ExCap, and FIM score. All statistical analyses were performed using the standard statistical procedures provided in Review Manager 5.2. Results: A total of 12 observational studies were identified, with 2365 participants. Pooled data indicated that CR programmers significantly improved the 6-minute walked distance (SMD 0.65; 95% confidence intervals [CI] 0.51–0.79) and Barthel index score (SMD 0.83; 95% CI 0.61–1.06). In addition, compared with admission, patients experienced significant improvement in SF-12 scale at CR discharge, with a pooled mean differences (MD) of 2.74 (95% CI 0.86–4.61) in physical component score and 2.76 (95% CI 0.59–4.93) in mental component score. Similar results were also observed in ExCap (MD 8.10 W; 95% CI 1.57 W–14.63 W) and FIM score (MD 11.0; 95% CI 6.22–15.78). Conclusions: Our analysis indicated that exercise-based CR programmers had significant effect on patients after TAVI in improving exercise tolerance and functional independence.
Engineering Undergraduates' Views of A-Level Mathematics and Further Mathematics as Preparation for Their Degree.

An ongoing reform programme of the post-16 Advanced ‘A’-level qualifications in England and Wales means that pre-university mathematics content and assessment will change from 2017. Undergraduate engineering is a subject that relies heavily on mathematics, and applicants to engineering degree programmes in the UK are required to have studied A-level Mathematics in order to be accepted. Therefore, the planned reforms are likely to have an impact on students’ transition to undergraduate engineering. To investi-gate this, we conducted an online questionnaire survey of 462 current undergraduate engineering students who had taken A-levels. Participants reported on their experiences of studying post-compulsory mathematics and the preparation it provided for their degrees. Those who had studied the more advanced A-levelçFurther Mathematicsçin addition to A-level Mathematics, considered it to be good preparation. They also believed that the A-level structure, which allows specialization in certain areas of applied mathematics, to be advantageous. In particular, possibilities for in-depth study of mechanics and pure mathematics were highly valued by participants. It is recommended that university engineering departments do more to encourage prospective students to study Further Mathematics. However, it should not necessarily be made compulsory because of con-straints regardingaccess, uptake and provisionof FurtherMathematics in certain schools.
A Comprehensive Review of Cervical Cancer Screening Devices: The Pros and the Cons

Objective: The low screening coverage and reluctance of women in participation lead to low uptake in cervical screening tests. Hence the majority of cervical cancer patients visiting the hospitals are diagnosed at advanced stage, often leading to poor survival rate. This paper aims to review and compile available cancer screening devices so that more people in this field will adopt suitable devices in cervical cancer screening routine depending on requirements which may encourage the uptake in cervical screening tests. Methods: This paper reviews devices invented for different cervical cancer screening methods, which are Pap smear test, visual inspection with acetic acid (VIA) or Lugol’s iodine (VILI), and HPV (human papillomavirus)-DNA (deoxyribonucleic acid) self-test in terms of functionality, performance in solving the limitations of screening procedure and additionally where applicable, the cervical cell collection efficacy and abnormality detection accuracy. The devices are either available in the market, published in research articles or published in international patent databases. Result: The reviewed devices either simplified the screening procedure to improve the clinical efficiency and accuracy in screening, reduced the pain and discomfort experienced by women during screening procedures, or achieved both outcomes. Conclusion: Many devices have been invented to improve the screening procedures which may potentially improve the uptake in cervical screening tests and encourage the organization of screening campaigns to reduce cervical cancer incidence.
Analysis of AlN monolayer as a prospective cathode for aluminum-ion batteries

Developing cathode materials with high specific capability and excellent electrochemical performance is crucial for the advancement of aluminum-ion batteries, which leverage the high theoretical energy density of aluminum metal anodes. In this paper, we investigated the interaction of AlCl4 cluster and Al atom with AlN (−100) and (001) monolayer using density functional theory to assess the applicability of AlN as cathode material for aluminum-ion batteries. The results show that the AlN (001) monolayer is the most effective for adsorbing and accommodating AlCl4 clusters. Moreover, the AlN (001) monolayer maintains metallic behavior at different concentrations of the AlCl4 cluster, laying the foundation for its battery application. The theoretical storage capacity of the AlCl4 cluster is 105.93 mAhg−1, which exceeds that of the Al/graphite battery. The formation energy of AlCl4 -intercalated AlN compounds is −2.74 eV, and the intercalant gallery height is moderate. Furthermore, the diffusion barrier of 0.19 eV for AlCl4 cluster between the AlN (001) monolayer provides high rate capability. The results indicate that AlN monolayer may be a potential cathode material for aluminum-ion batteries.
Performance assessment of variant UNet-based deep-learning dose engines for MR-Linac-based prostate IMRT plans

Objective. UNet-based deep-learning (DL) architectures are promising dose engines for traditional linear accelerator (Linac) models. Current UNet-based engines, however, were designed differently with various strategies, making it challenging to fairly compare the results from different studies. The objective of this study is to thoroughly evaluate the performance of UNet-based models on magnetic-resonance (MR)-Linac-based intensity-modulated radiation therapy (IMRT) dose calculations. Approach. The UNet-based models, including the standard-UNet, cascaded-UNet, dense-dilated-UNet, residual-UNet, HD-UNet, and attention-aware-UNet, were implemented. The model input is patient CT and IMRT field dose in water, and the output is patient dose calculated by DL model. The reference dose was calculated by the Monaco Monte Carlo module. Twenty training and ten test cases of prostate patients were included. The accuracy of the DL-calculated doses was measured using gamma analysis, and the calculation efficiency was evaluated by inference time. Results. All the studied models effectively corrected low-accuracy doses in water to high-accuracy patient doses in a magnetic field. The gamma passing rates between reference and DL-calculated doses were over 86% (1%/1 mm), 98% (2%/2 mm), and 99% (3%/3 mm) for all the models. The inference times ranged from 0.03 (graphics processing unit) to 7.5 (central processing unit) seconds. Each model demonstrated different strengths in calculation accuracy and efficiency; Res-UNet achieved the highest accuracy, HD-UNet offered high accuracy with the fewest parameters but the longest inference, dense-dilated-UNet was consistently accurate regardless of model levels, standard-UNet had the shortest inference but relatively lower accuracy, and the others showed average performance. Therefore, the best-performing model would depend on the specific clinical needs and available computational resources. Significance. The feasibility of using common UNet-based models for MR-Linac-based dose calculations has been explored in this study. By using the same model input type, patient training data, and computing environment, a fair assessment of the models’ performance was present.
Prioritization of Monogenic Congenital Anomalies of the Kidney and Urinary Tract Candidate Genes with Existing Single-Cell Transcriptomics Data of the Human Fetal Kidney

Introduction: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first 3 decades of life. Over 40 genes have been identified as causative for isolated human CAKUT. However, many genes remain unknown, and the prioritization of potential CAKUT candidate genes is challenging. To develop an independent approach to prioritize CAKUT candidate genes, we hypothesized that monogenic CAKUT genes are most likely co-expressed along a temporal axis during kidney development and that genes with coinciding high expression may represent strong novel CAKUT candidate genes. Methods: We analyzed single-cell mRNA (sc-mRNA) transcriptomics data of human fetal kidney for temporal sc-mRNA co-expression of 40 known CAKUT genes. A maximum of high expression in consecutive timepoints of kidney development was found for four of the 40 genes (EYA1, SIX1, SIX2, and ITGA8) in nephron progenitor cells a, b, c, d (NPCa–d). We concluded that NPCa–d are relevant for CAKUT pathogenesis and intersected two lists of CAKUT candidate genes resulting from unbiased whole-exome sequencing (WES) with the 100 highest expressed genes in NPCa–d. Results: Intersection of the 100 highest expressed genes in NPCa–d with WES-derived CAKUT candidate genes identified an overlap with the candidate genes KIF19, TRIM36, USP35, CHTF18, in each of which a biallelic variant was detected in different families with CAKUT. Conclusion: Sc-mRNA expression data of human fetal kidney can be utilized to prioritize WES-derived CAKUT candidate genes. KIF19, TRIM36, USP35, and CHTF18 may represent strong novel candidate genes for CAKUT.
Update on autoantibodies and related biomarkers in autoimmune inflammatory myopathies

Purpose of review This manuscript reviews recently published advances in the identification of autoimmune inflammatory myopathies (AIM)-specific and AIM-related autoantibodies considered of value in the workup of patients suspected of having AIM. Newer autoantibodies, developments, and advances in the methodology of testing, the gaps and pitfalls in using these assays as diagnostic biomarkers, and the importance of considering overlap diseases and unique clinical AIM phenotypes are discussed. Recent findings a) studies of the various diagnostic platforms (e.g., line immunoassays [LIA]) have clarified their limitations and raise cautions in the interpretation of the results.b) particle based solid phase multianalyte technology (PMAT) is a promising newer diagnostic platform.c) elucidation of older and descriptions of newer AIM autoantibody markers provide increasing clinical value by revealing novel clinical features (including AIM subsets and overlap syndromes [OS]) and co-existing malignancies. Summary The spectrum of autoantibodies and related biomarkers in AIM continues to expand. Many of these have clear clinical implications in regard to subsets and overlap conditions of AIM, associated malignancy and pathological findings.
Pan-cancer analysis of the prognostic and immunological role of matrix metalloproteinase 9

Matrix metalloproteinase 9 (MMP9), a zinc ion-dependent endopeptidase, is one of the most complex matrix metalloproteinases in the gelatinase family. During tissue remodeling, MMP9 leads to gelatin and collagen degradation, which in turn promotes tumor invasion and metastasis. However, comprehensive pan-cancer analysis has not been performed for MMP9. In addition, the diagnostic and prognostic value of MMP9 as a cancer biomarker remain poorly understood, as well as the utility of MMP9 expression as a predictor of immunological responses. Based on a comprehensive analysis of bioinformatics information, we investigated MMP9 expression in different cancers, correlations between MMP9 expression and cancer prognosis and gene mutations, and relationships between MMP9 expression and immune cell infiltration. Our results indicated that MMP9 was highly expressed in most malignant cancers. MMP9 expression was significantly positively or negatively associated with the clinical prognoses of patients with different kinds of cancer. Furthermore, MMP9 expression significantly correlated with infiltrating cells and the expression levels of immune checkpoint genes. This pan-cancer analysis provides comprehensive information on the potential value of MMP9 as a theranostic biomarker.
Development and validation of a prognostic nomogram for predicting cancer-specific survival in lymph node-negative elderly esophageal cancer patients: A SEER-based study

In this study, we explored the prognostic risk factors of elderly patients (≥65 years old) with lymph node-negative esophageal cancer (EC) and established a nomogram to evaluate the cancer-specific survival of patients. The surveillance, epidemiology, and end results database was used to collect data on patients diagnosed with EC. Univariate and multivariate Cox analyses were used to determine independent prognostic factors, and the nomogram for predicting cancer-specific survival of EC patients was constructed based on the independent prognostic factors obtained from the multivariate Cox analysis. To evaluate the predictive ability of the nomogram, calibration curves, concordance index (C-index), receiver operating characteristic curves, and decision curve analysis were conducted. Kaplan–Meier method was used to analyze the long-term outcomes of EC patients with different risk stratifications. A total of 3050 cases with lymph node-negative EC were randomized into the training cohort (1525) and the validation cohort (1525). Cancer-specific mortality at 1, 3, and 5 years in the entire cohort was 30.7%, 41.8%, and 59.2%, respectively. In multivariate Cox analysis, age (P < .001), marital status (P < .001), tumor size (P < .001), Tumor-node-metastasis stage (P < .001), chemotherapy (P = .011), radiotherapy (P < .001), and surgery (P < .001) were independent prognostic factors. The C-index for the training cohort was 0.740 (95% confidence interval [CI]: 0.722–0.758), and the C-index for the validation cohort was 0.738 (95% CI: 0.722–0.754). The calibration curve demonstrated the great calibration ability of the nomogram. Based on the area under the receiver operating characteristic curve, the nomogram demonstrated a higher sensitivity than the tumor-node-metastasis stage. Decision curve analysis showed the good clinical utility of the nomogram. The risk stratification system was established using the Kaplan–Meier curve and verified by the log-rank test (P < .001). The nomogram and risk stratification system can improve the accuracy of prediction to help clinicians identify high-risk patients and make treatment decisions.
Men, testosterone and Covid‐19

Men have more severe Coronavirus disease 2019 (Covid‐19) outcomes and higher mortality rates than women, and it was suggested that testosterone levels might promote severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection and Covid‐19 severity. However, clinical studies have not supported this theory. Studies have consistently shown that serum testosterone concentrations during acute Covid‐19 in men are inversely proportional to the inflammatory cytokines and severity of illness. It is likely that lower testosterone concentrations in this setting are a result of acute Covid‐19 illness on the hypothalamic–pituitary–testicular axis. Clinical trials that attempted to lower testosterone concentrations further or block androgen signaling acutely during Covid‐19 in men did not result in improved Covid‐19 outcomes. Additionally, pre‐existing male hypogonadism, diagnosed before Covid‐19 pandemic, was found to be a risk factor for hospitalization from Covid‐19. In this review, we also discuss the preclinical and mechanistic studies that have evaluated the role of androgens in SARS‐CoV‐2 infection and illness. Finally, long‐term consequences of Covid‐19 on male reproductive health are reviewed. SARS‐CoV‐2 virus is known to infiltrate testis and induce orchitis in men, but it is unclear if Covid‐19 leads to an increase in incidence of male hypogonadism.
An evaluation of clinical presentation and genetic testing approaches for patients with neuromuscular disorders

Inherited neuromuscular disorders (NMDs) are a large group of genetic conditions characterized by impaired peripheral nerve, motor neuron, neuromuscular junction, or skeletal muscle function. These conditions are also known to have clinical and genetic heterogeneity and variable ages of onset. Clinical evaluation for NMDs has increasingly incorporated molecular genetics. However, genetic testing is complicated by the variety of testing options and the ambiguity of NMD phenotypes. Examining test selection and yield may elucidate testing recommendations and improve the diagnostic journey for these patients. This retrospective chart review evaluated the clinical presentations, genetic testing approaches, and diagnostic outcomes of 155 patients with suspected NMDs at Cincinnati Children's Hospital Medical Center. A total of 262 individual tests were ordered, averaging 1.7 tests per patient. The clinic utilized 26 separate genetic tests, with test yields ranging from 0% to 66%. Overall, 21% of patients received a genetic diagnosis. Of all the clinical findings evaluated, elevated CPK levels with or without muscle weakness were the most informative symptoms correlated with a diagnostic result. This study highlights several genetic testing considerations for NMDs, including the variability of diagnostic outcomes. This knowledge is relevant to clinicians and patients, especially during the pretest counseling and consenting process.
Assessment of HBV infection and inter‐host cellular responses using intrahepatic cholangiocyte organoids

Intrahepatic cholangiocyte organoids (ICOs) model was evaluated for host differences in hepatitis B virus (HBV) infection, cellular responses, antiviral, and immunomodulator responses. Twelve ICOs generated from liver resections and biopsies were assessed for metabolic markers and functional HBV entry receptor expression throughout differentiation. Structural changes relevant to HBV infection were characterized using histology, confocal, and electron microscopy examinations. Optimal ICO culture conditions for HBV infection using HepAD38 (genotype D) and plasma derived HBV (genotype B & C) were described. HBV infection was confirmed using HBcAg immunostaining, qRT‐PCR (RNA, cccDNA, extracellular DNA), and ELISA (HBsAg and HBeAg). Drug response to antiviral and immunosuppressive agent, and cellular responses (interferon‐stimulated genes [ISG]) to interferon‐α and viral mimic (PolyI:C) were assessed. ICOs underwent metabolic and structural remodeling following differentiation. Optimal HBV infection was achieved in well‐differentiated ICOs using spinoculation, with time and donor dependent increase in HBV RNA, cccDNA, extracellular DNA, HBeAg, and HBsAg. Donor dependent drug‐responsiveness to entry inhibitor and JAK inhibitor was observed. Despite having a robust ISG response to interferon‐α and PolyI:C, HBV infection in ICOs did not upregulate ISGs. Human ICOs support HBV infection and replication with donor dependent variation in viral dynamics and cellular responses. These features can be utilized for development of personalized drug testing platform for antivirals.