Miracle-dz/UniFAR-FTUs huggingface dataset:
Clinical Utility of CDK4/6 Inhibitors in Sarcoma: Successes and Future Challenges

PURPOSE Soft tissue and bone sarcomas are rare malignancies that exhibit significant pathologic and molecular heterogeneity. Deregulation of the CDKN2A-CCND-CDK4/6-retinoblastoma 1 (Rb) pathway is frequently observed in about 25% of unselected sarcomas and is pathognomonic for specific sarcoma subtypes. This genomic specificity has fueled the clinical evaluation of selective CDK4/6 inhibitors in sarcomas. Here, we highlight successes, opportunities, and future challenges for using CDK4/6 inhibitors to treat sarcoma. MATERIALS AND METHODS This review summarizes the current evidence for the use of CDK4/6 inhibitors in sarcoma while identifying molecular rationale and predictive biomarkers that provide the foundation for targeting the CDK4/6 pathway in sarcoma. A systematic review was performed of articles indexed in the PubMed database and the National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov). For each sarcoma subtype, we discuss the preclinical rationale, case reports, and available clinical trials data. RESULTS Despite promising clinical outcomes in a subset of sarcomas, resistance to CDK4/6 inhibitors results in highly heterogeneous clinical outcomes. Current clinical data support the use of CDK4/6 inhibitors in subsets of sarcoma primarily driven by CDK4/6 deregulation. When dysregulation of the Rb pathway is a secondary driver of sarcoma, combination therapy with CDK4/6 inhibition may be an option. Developing strategies to identify responders and the mechanisms that drive resistance is important to maximize the clinical utility of these drugs in patients with sarcoma. Potential biomarkers that indicate CDK4/6 inhibitor sensitivity in sarcoma include CDK4, CCND, CCNE, RB1, E2F1, and CDKN2A. CONCLUSION CDK4/6 inhibitors represent a major breakthrough for targeted cancer treatment. CDK4/6 inhibitor use in sarcoma has led to limited, but significant, early clinical success. Targeted future clinical research will be key to unlocking the potential of CDK4/6 inhibition in sarcoma. Response to CDK4/6-inhibitors in sarcomas indicate the need for predictive biomarkers specific to this disease.
Age-specific incidence, treatment, and survival trends in esophageal cancer: a Dutch population-based cohort study

Abstract Background Data on the age-specific incidence of esophageal cancer are lacking. Our aim was to investigate the age-stratified incidence, treatment, and survival trends of esophageal cancer in the Netherlands, with a focus on adults <50 years. Material and methods Patients diagnosed with esophageal cancer were included from the nationwide Netherlands Cancer Registry (1989–2018). Follow-up data were available until 31 December 2018. Annual percentage changes of incidence were analyzed according to age group (<50, 50–74, and ≥75 years) and histology type: adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). Treatment trends and relative survival rates (RSR) were estimated by age and stage grouping. Results A total 59,584 patients were included. In adults <50 years, EAC incidence tripled (mean increase per year: males 1.5%, females 3%), while the incidence of ESCC decreased (mean decrease per year: males −5.3%, females −4.3%). Patients <50 years more often presented with advanced disease stages compared to older patients and were more likely to receive multimodality treatments. Most patients <50 years with potentially curable disease were treated with neoadjuvant chemoradiotherapy followed by surgery compared to patients 50–74 and ≥75 years (74% vs. 55% vs. 15%, respectively; p < .001), and received more frequent systemic therapy once staged with palliative disease (72% vs. 54% vs. 19%, respectively; p < .001). The largest RSR improvement was seen in patients <50 years with early-stage (five years: +47%), potentially curable (five years: +22%), and palliative disease (one year: +11%). Over time, a trend of increasing survival difference was seen between patients <50 and ≥75 years with potentially curable (five-year difference: 17% to 27%) and palliative disease (one-year difference: 11% to 20%). Conclusion The incidence of EAC is increasing in adults <50 years in the Netherlands. Differences in the use of multimodality treatments with curative or life-prolonging intent in different age categories may account for increasing survival gaps.
Prolonged Glycemic Adaptation Following Transition From a Low- to High-Carbohydrate Diet: A Randomized Controlled Feeding Trial

OBJECTIVE Consuming ≥150 g/day carbohydrate is recommended for 3 days before an oral glucose tolerance test (OGTT) for diabetes diagnosis. For evaluation of this recommendation, time courses of glycemic changes following transition from a very-low-carbohydrate (VLC) to high-carbohydrate diet were assessed with continuous glucose monitoring (CGM). RESEARCH DESIGN AND METHODS After achieving a weight loss target of 15% (±3%) on the run-in VLC diet, participants (18–50 years old, BMI ≥27 kg/m2) were randomly assigned for 10 weeks to one of three isoenergetic diets: VLC (5% carbohydrate and 77% fat); high carbohydrate, high starch (HC-Starch) (57% carbohydrate and 25% fat, including 20% refined grains); and high carbohydrate, high sugar (HC-Sugar) (57% carbohydrate and 25% fat, including 20% sugar). CGM was done throughout the trial (n = 64) and OGTT at start and end (n = 41). All food was prepared in a metabolic kitchen and consumed under observation. RESULTS Glucose metrics continued to decline after week 1 in the HC-Starch and HC-Sugar groups (P < 0.05) but not VLC. During weeks 2–5, fasting and 2-h glucose (millimoles per liter per week) decreased in HC-Starch (fasting −0.10, P = 0.001; 2 h −0.10, P = 0.04). During weeks 6–9, 2-h glucose decreased in HC-Starch (−0.07, P = 0.01) and fasting and 2-h glucose decreased in HC-Sugar (fasting −0.09, P = 0.001; 2 h −0.09, P = 0.003). The number of participants with abnormal glucose tolerance by OGTT remained 10 (of 16) in VLC at start and end but decreased from 17 to 9 (of 25) in both high-carbohydrate groups. CONCLUSIONS Physiological adaptation from a low- to high-carbohydrate diet may require many weeks, with implications for the accuracy of diabetes tests, interpretation of macronutrient trials, and risks of periodic planned deviations from a VLC diet.
Speciation of heavy metals in the ore scattering in the harbor yard and their simulated acid rain leaching behaviors

In this paper,we would like to bring forward the results of our investigation for predicting the potential risk from the rain leachingwith heavy metal ingredients due to the rain leaching in the copper ore and lead ore in the harbor stockyard.The results of ourinvestigation have shown that the leaching behaviors of Zn and Cd in the copperore prove to be similar.The cumulative amounts of Zn and Cd that are released in the leaching period could be divided into two stages,namely,a rapid leaching stage(within 1 d)and a slow leaching stage(after1 d). The amounts of Zn and Cd released in the rapid leaching stage turn to account for 98.29%and 98.02%of the total amounts released in the said leaching period.The cumulative amounts of Zn and Pb released in the lead ore prove to increase linearly with the time passing on.The speciation results of heavy metals in the ore further reveal that the water soluble fraction of Zn and Cd in the copperore both takes quite a large proportion.In addition,the water soluble fraction of heavy metals has a high mobility,which is likely to be released in a short time.Therefore,whenever it rains,the water soluble fraction of heavy metalswould leach in a shorttime,leading to a high environment risk.However,itis comparable for the amounts of water soluble fraction of Zn and Cd in the copper ore to those released in the rapid leaching stage.The proportions of water soluble fraction of Zn and Pb in the lead ore aswell as their cumulative amounts released in the leaching period were small.In particular,Pb and SO2-4can form precipitate which has a low mobility.Thus,leaching of Zn and Pb in the lead ore can merely lead to a minor environment risk.
Immature Granulocyte Count and Delta Neutrophil Index as New Predictive Factors for Axillary Metastasis of Breast Cancer.

OBJECTIVE To determine the diagnostic value of preoperative immature granulocyte (IG) count and delta neutrophil index (DNI) level before clinical detection of axillary lymph node metastasis. STUDY DESIGN Cohort study. PLACE AND DURATION OF STUDY Department of General Surgery, Kahramanmaras Sutcu Imam University, Onikisubat, Turkey from February 2015 to February 2020. METHODOLOGY Patients older than 18 years and operated for breast pathologies in the study period were evaluated retrospectively. Patients without axillary or distant organ metastasis, and who did not receive neoadjuvant chemotherapy were examined by dividing them into two groups as pathologically non-metastatic axilla (Group NM) and metastatic axilla (Group M). They were retrospectively evaluated for DNI, IG, white blood cell count (WBC), neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and mean platelet volumes (MPV). RESULTS All of the 83 patients, who met the inclusion criteria, were females (100%). Forty-six patients (55.42%) were in the Group-NM and 37 (44.58%) were in Group-M. Statistically significant difference was observed between the groups in terms of WBC, NLR, PLR, MPV, DNI and IG count (p<0.05), while there was no difference in age (p = 0.862). As a result of the univariate and multivariate analysis, WBC, NLR, PLR, MPV, DNI and IG count were determined as predictive factors. The discriminatory power of the DNI for diagnosing clinically negative pathologically positive axillary metastasis of breast cancer at the cut-off value ≥0.35% (ARUC:0.903; 95% confidence interval [CI]: 0.84-0.967) showed 86.5% sensitivity, 80.4% specificity, positive predictive value (PPV) 86.5%, negative predictive value (NPV) 80.4%. The discriminatory power of the IG count for diagnosing clinically negative pathologically positive axillary metastasis of breast cancer, at the cut-off value ≥25/mm3 (ARUC:0.976; 95% CI:0.953-1.000) showed 100% sensitivity, 82.6% specificity, 100% PPV, and 82.6% NPV. CONCLUSION DNI and IG count may be new predictive factors with high sensitivity and specificity in detecting axillary metastasis of breast cancer. Key Words: Delta neutrophil index, Immature granulocyte count, Neutrophil lymphocyte ratio, Breast cancer, Axillary metastasis.
Widespread genetic heterogeneity of human ribosomal RNA genes

Polymorphism drives survival under stress and provides adaptability. Genetic polymorphism of ribosomal RNA (rRNA) genes derives from internal repeat variation of this multicopy gene, and from interindividual variation. A considerable amount of rRNA sequence heterogeneity has been proposed but has been challenging to estimate given the scarcity of accurate reference sequences. We identified four rDNA copies on chromosome 21 (GRCh38) with 99% similarity to recently introduced reference sequence KY962518.1. We customized a GATK bioinformatics pipeline using the four rDNA loci, spanning a total 145 kb, for variant calling and used high-coverage whole-genome sequencing (WGS) data from the 1000 Genomes Project to analyze variants in 2504 individuals from 26 populations. We identified a total of 3791 variant positions. The variants positioned nonrandomly on the rRNA gene. Invariant regions included the promoter, early 5′ ETS, most of 18S, 5.8S, ITS1, and large areas of the intragenic spacer. A total of 470 variant positions were observed on 28S rRNA. The majority of the 28S rRNA variants were located on highly flexible human-expanded rRNA helical folds ES7L and ES27L, suggesting that these represent positions of diversity and are potentially under continuous evolution. Several variants were validated based on RNA-seq analyses. Population analyses showed remarkable ancestry-linked genetic variance and the presence of both high penetrance and frequent variants in the 5′ ETS, ITS2, and 28S regions segregating according to the continental populations. These findings provide a genetic view of rRNA gene array heterogeneity and raise the need to functionally assess how the 28S rRNA variants affect ribosome functions.
Towards range-guidance in proton therapy to detect organ motion-induced dose degradations

Introduction. Internal organ motion and deformations may cause dose degradations in proton therapy (PT) that are challenging to resolve using conventional image-guidance strategies. This study aimed to investigate the potential of range guidance using water-equivalent path length (WEPL) calculations to detect dose degradations occurring in PT. Materials and methods. Proton ranges were estimated using WEPL calculations. Field-specific isodose surfaces in the planning CT (pCT), from robustly optimised five-field proton plans (opposing lateral and three posterior/posterior oblique beams) for locally advanced prostate cancer patients, were used as starting points. WEPLs to each point on the field-specific isodoses in the pCT were calculated. The corresponding range for each point was found in the repeat CTs (rCTs). The spatial agreement between the resulting surfaces in the rCTs (hereafter referred to as iso-WEPLs) and the isodoses re-calculated in rCTs was evaluated for different dose levels and Hausdorff thresholds (2–5 mm). Finally, the sensitivity and specificity of detecting target dose degradation (V95% < 95%) using spatial agreement measures between the iso-WEPLs and isodoses in the pCT was evaluated. Results. The spatial agreement between the iso-WEPLs and isodoses in the rCTs depended on the Hausdorff threshold. The agreement was 65%–88% for a 2 mm threshold, 83%–96% for 3 mm, 90%–99% for 4 mm, and 94%–99% for 5 mm, across all fields and isodose levels. Minor differences were observed between the different isodose levels investigated. Target dose degradations were detected with 82%–100% sensitivity and 75%–80% specificity using a 2 mm Hausdorff threshold for the lateral fields. Conclusion. Iso-WEPLs were comparable to isodoses re-calculated in the rCTs. The proposed strategy could detect target dose degradations occurring in the rCTs and could be an alternative to a fully-fledged dose re-calculation to detect anatomical variations severely influencing the proton range.
Three heads are better than one: Psychiatry trainees’ experiences of a psychotherapy written case supervision group with three co-supervisors

Objective The aim of this project was to evaluate the experiences of Royal Australian and New Zealand College of Psychiatrists (RANZCP) trainees in a regional centre who participated in a psychodynamic psychotherapy written case supervision group with three co-supervisors. Method A web-based survey was sent to RANZCP trainees. Descriptive statistics were performed, and written feedback was analysed. Results A total of 8 of 10 eligible trainees completed the survey. All respondents stated that the group met their training needs. The average rating of feeling understood by supervisors was 91 (maximum 100). Positive feedback was received about the variety and breadth of experience provided by the co-supervisors. Trainees felt that 1:1 supervision was important to complement group supervision. Conclusions The supervision group model with three co-supervisors is competently meeting the training needs of RANZCP trainees as well as providing a deep learning experience. This model may be of use in other services, particularly in regional settings.
The Associations between Dietary Supplement Use, Diet Quality, and Health-Related Quality of Life among Older Female Cancer Survivors

Abstract Evidence-based guidelines for cancer survivorship do not recommend dietary supplementation, yet older cancer survivors report high prevalence of dietary supplement use, specifically multivitamin (MVM), calcium, and vitamin D. Female cancer survivors (≥65 years) who were ≤5 years post-cancer diagnosis completed questionnaires assessing health-related quality of life (HRQoL), diet quality, and supplement intake. Intakes of MVM, calcium, and vitamin D supplementation were 61.4%, 76.9%, and 35.3%, respectively. Women who used MVM supplements had significantly higher dietary quality mean scores for total vegetables (4.5 ± 0.9 to 4.1 ± 1.1), greens and beans (4.1 ± 1.3 to 3.6 ± 1.6), whole fruit (4.7 ± 0.8 to 4.3 ± 1.3), and whole grains (2.9 ± 1.8 to 2.3 ± 1.6) than those who did not use these supplements. After controlling for demographic and clinical variables, the odds of MVM use was 1.07 times greater among those women who had higher total HEI scores. Participants with lower HRQoL were 4% more likely to take an MVM. Understanding the prevalence of supplementation, associations with diet quality, and perceived benefits of supplementation may help healthcare providers in educating survivors and promoting adherence to the evidence-based guidelines.
Risk of new‐onset type 2 diabetes in 600 055 people after COVID‐19: A cohort study

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may increase the risk of new-onset type 2 diabetes (T2D) with a few observations substantiating concern. SARS-CoV-2 can infect pancreatic islet cells and metabolic complications can occur in people with coronavirus disease 2019 (COVID-19) who have no prior history of diabetes. Currently, there is limited epidemiological evidence to suggest a temporal association between SARS-CoV-2 infection and new-onset T2D.
Deeply conserved synteny and the evolution of metazoan chromosomes

Animal genomes show networks of deeply conserved gene linkages whose phylogenetic scope and chromosomal context remain unclear. Here, we report chromosome-scale conservation of synteny among bilaterians, cnidarians, and sponges and use comparative analysis to reconstruct ancestral chromosomes across major animal groups. Comparisons among diverse metazoans reveal the processes of chromosome evolution that produced contemporary karyotypes from their Precambrian progenitors. On the basis of these findings, we introduce a simple algebraic representation of chromosomal change and use it to establish a unified systematic framework for metazoan chromosome evolution. We find that fusion-with-mixing, a previously unappreciated mode of chromosome change, has played a central role. We find that relicts of several metazoan chromosomal units are preserved in unicellular eukaryotes. These conserved pre-metazoan linkages include the chromosomal unit that encodes the most diverse set of metazoan homeobox genes, suggesting a candidate genomic context for the early diversification of this key gene family.
Improving Pelvic Floor Muscle Training Adherence Among Pregnant Women: Validation Study

Background Mobile health apps, for example, the Tät, have been shown to be potentially effective in improving pelvic floor muscle training (PFMT) among women, but they have not yet been studied among pregnant women. Adherence to daily PFMT will improve pelvic floor muscle strength leading to urinary incontinence (UI) improvement during the pregnancy. Objective This study aims to document the validation process in developing the Kegel Exercise Pregnancy Training app, which was designed to improve the PFMT adherence among pregnant women. Methods We utilized an intervention mapping approach incorporated within the mobile health development and evaluation framework. The framework involved the following steps: (1) conceptualization, (2) formative research, (3) pretesting, (4) pilot testing, (5) randomized controlled trial, and (6) qualitative research. The user-centered design-11 checklist was used to evaluate the user-centeredness properties of the app. Results A cross-sectional study was conducted to better understand PFMT and UI among 440 pregnant women. The study reported a UI prevalence of 40.9% (180/440), with less than half having good PFMT practice despite their good knowledge. Five focus group discussions were conducted to understand the app design preferred by pregnant women. They agreed a more straightforward design should be used for better app usability. From these findings, a prototype was designed and developed accordingly, and the process conformed to the user-centered design–11 (UCD-11) checklist. A PFMT app was developed based on the mHealth development and evaluation framework model, emphasizing higher user involvement in the application design and development. The application was expected to improve its usability, acceptability, and ease of use. Conclusions The Kegel Exercise Pregnancy Training app was validated using a thorough design and development process to ensure its effectiveness in evaluating the usability of the final prototype in our future randomized control trial study.
Kink-Oriented People and Exogenous Oppressions: Understanding Mental Health and Related Service Use in a Rural Context

ABSTRACT Rural, kink-oriented people experience much exogenous oppression and yet related research is scarce. This study examined the risk and protective factors of kink-oriented rural Tasmanian Australians with preexisting mental health conditions and help-seeking barriers and facilitators. Participants completed either an online survey (n = 42), an interview (n = 10), or both. Thematic analysis and descriptive statistics were used to analyze the qualitative and quantitative data, respectively. Participants aged 18 to 61 were gender and sexually diverse and better educated but had more lifetime suicide attempts than the general public. Despite the increasing normalization of kink, 90.5% of participants have never seen a kink-aware mental health professional (MHP) and nearly 83.0% did not disclose to an MHP for fear of stigma or discrimination. Self-awareness, resilience, social support and kink improved participants’ mental health. Tailored support from trained MHP is vital to improve the mental health of kink-oriented people in rural areas.