Miracle-dz/UniFAR-FTUs huggingface dataset:
Efficacy of Sirolimus Treatment in PEComa–10 Years of Practice Perspective

Perivascular epithelioid cell tumors (PEComa) represent a family of rare mesenchymal tumors resultant from deregulation in mTOR pathway activity. The aim of this study is to evaluate the long-term efficacy of targeted PEComa treatment. We reviewed all consecutive patients with PEComa who started systemic treatment with sirolimus in our reference sarcoma center between January 2011 and August 2020. Histopathology of PEComa was reviewed and confirmed in all cases by a designated sarcoma pathologist. Any surviving progression-free patients were censored at the last follow-up (31 March 2021). Survival curves were calculated according to Kaplan–Meier method and compared with the log-rank test or a Cox proportional hazard model. Fifteen (12 females and 3 males) consecutive PEComa patients were treated. The median age of patients treated systemically was 50 years. Median progression-free survival (PFS) was 4.9 months (95% CI: 3.8-NA) for first-line chemotherapy and was not reached (95% CI: 42.0-NA) for sirolimus as first-line therapy. There was one objective response (OR) in the chemotherapy group. The OR rate reached 73% (11/15 cases) for sirolimus regardless of the treatment line. All patients archived disease control. Three patients died due to disease progression after 55, 32, and 32 months since metastatic disease diagnosis. After a median follow-up of 55.7 (range: 3.2–220) months, the 5 yr OS was 65% (CI 95% 39–100). Our study is the largest single-institution report on PEComa systemic targeted therapy and fills the gap in the field of advanced PEComa care since the FDA/EMEA approval of sirolimus.
Does Each Menstrual Cycle Elicit a Distinct Effect on Olfactory and Gustatory Perception?

The obesity pandemic has brought forth a scientific interest in food intake and sensory perception interactions. Olfactory perception and gustatory perception are very complex and under the influence of many factors, including the menstrual cycle. This study aims to clarify conflicting findings on the influence of the menstrual cycle on olfactory and gustatory perception. Women were assessed during four consecutive phases of one complete cycle (mid-follicular, ovulatory, mid-luteal, and late luteal phases (N = 21)), in contrast to women measured across the same phases belonging to two menstrual cycles (N = 29). Additional control groups were men (N = 17), postmenopausal women (N = 14), oral contraceptive users (N = 10), and women with an anovulatory cycle (N = 8). Olfactory threshold, odor discrimination, and identification were tested using the “Sniffin Sticks“ test kit. Suprathreshold intensity and hedonic ratings for sweet, salty, sour, and bitter solutions were assessed. One-way ANOVA and ANOVA for repeated measurements was applied in the analysis, along with linear and trigonometric data fitting and linear mixed models. Linear increases in olfactory discrimination, identification, and overall olfactory performance were observed only in women followed across a complete menstrual cycle. Compared to other groups, these women displayed a cyclic pattern characterized by a predilection for sweet solution; reduced distaste for salty and sour solutions; and increased intensity perception of salty, sour, and bitter solutions towards the end of the cycle. These results suggest that a distinct hormonal milieu of a complete menstrual cycle may be affecting both olfactory and gustatory perception.
Long COVID and the mental and physical health of children and young people: national matched cohort study protocol (the CLoCk study)

Introduction There is uncertainty surrounding the diagnosis, prevalence, phenotype, duration and treatment of Long COVID. This study aims to (A) describe the clinical phenotype of post-COVID symptomatology in children and young people (CYP) with laboratory-confirmed SARS-CoV-2 infection compared with test-negative controls, (B) produce an operational definition of Long COVID in CYP, and (C) establish its prevalence in CYP. Methods and analysis A cohort study of SARS-CoV-2-positive CYP aged 11–17 years compared with age, sex and geographically matched SARS-CoV-2 test-negative CYP. CYP aged 11–17 testing positive and negative for SARS-CoV-2 infection will be identified and contacted 3, 6, 12 and 24 months after the test date. Consenting CYP will complete an online questionnaire. We initially planned to recruit 3000 test positives and 3000 test negatives but have since extended our target. Data visualisation techniques will be used to examine trajectories over time for symptoms and variables measured repeatedly, separately by original test status. Summary measures of fatigue and mental health dimensions will be generated using dimension reduction methods such as latent variables/latent class/principal component analysis methods. Cross-tabulation of collected and derived variables against test status and discriminant analysis will help operationalise preliminary definitions of Long COVID. Ethics and dissemination Research Ethics Committee approval granted. Data will be stored in secure Public Health England servers or University College London’s Data Safe Haven. Risks of harm will be minimised by providing information on where to seek support. Results will be published on a preprint server followed by journal publication, with reuse of articles under a CC BY licence. Data will be published with protection against identification when there are small frequencies involved. Trial registration number ISRCTN34804192; Pre-results.
Assessing EFL learners’ written performance: The case of task repetition

Abstract Previous second language acquisition (SLA) research on task repetition has mainly addressed oral production, and the contribution of task repetition to various aspects of writing has received scant attention. This study aimed to investigate the accuracy, complexity and fluency of written productions of intermediate-level English as a foreign language (EFL) learners once they were exposed to two task repetition types: content repetition (repeating the same task with the same procedures) and procedural repetition (repeating the same procedures with different content). Eighty-six participants were randomly assigned to either content repetition or procedural repetition groups and were engaged in dictogloss tasks three times over a two-week period, with the content of the text differing for the procedural group each time. The results of mixed ANOVAs revealed no difference between the two groups in general accuracy, but the procedural group was superior in terms of task-induced accuracy (error-free use of passive voice). Concerning complexity, the procedural group outperformed in lexical complexity and some sub-dimensions of syntactic complexity. Both groups were also found to perform equally well in terms of fluency. The findings suggest implications for second language (L2) contexts.
Traumatic Distress of COVID-19 and Depression in the General Population: Exploring the Role of Resilience, Anxiety, and Hope

International evidence published so far shows that the COVID-19 pandemic has negatively impacted on global mental health. Specifically, there is some research suggesting that the psychological distress related to depression, anxiety and posttraumatic stress has impacted on the psychological well-being of the general population. Yet, there is limited evidence on the relational paths between COVID-19 traumatic distress and depression. Participants of this cross-sectional study were 456 adults 18 years old or older from the general population (Mean age = 41.2 years, SD = 11.7) who completed an online questionnaire including measures assessing depression, anxiety, resilience, hope and traumatic distress related to COVID-19. Structural equation modelling was applied to examine the proposed mediation model. The results confirmed the proposed model, with traumatic distress of COVID-19, resilience, anxiety and hope explaining a considerable amount of variance (59%) in depression scores. Traumatic distress of COVID-19 was a strong positive predictor of depression, while anxiety, hope and resilience were both joint and unique mediators of this relationship. Exposure to the COVID-19 pandemic is strongly associated with depression in adults of the general population. The co-occurrence of anxiety may negatively contribute to experiencing higher levels of depression, while resilience and hope may act as buffers against depression associated with the impact of this pandemic. Our findings suggest that wide community-based interventions designed to promote resilience, build hope and reduce anxiety may help mitigate depression associated with exposure to the COVID-19 pandemic.
Effects of Sodium-Glucose Co-Transporter 2 Inhibitors on Vascular Cell Function and Arterial Remodeling

Cardiovascular disease is the leading cause of morbidity and mortality in diabetes. Recent clinical studies indicate that sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in patients with diabetes. The mechanism underlying the beneficial effect of SGLT2 inhibitors is not completely clear but may involve direct actions on vascular cells. SGLT2 inhibitors increase the bioavailability of endothelium-derived nitric oxide and thereby restore endothelium-dependent vasodilation in diabetes. In addition, SGLT2 inhibitors favorably regulate the proliferation, migration, differentiation, survival, and senescence of endothelial cells (ECs). Moreover, they exert potent antioxidant and anti-inflammatory effects in ECs. SGLT2 inhibitors also inhibit the contraction of vascular smooth muscle cells and block the proliferation and migration of these cells. Furthermore, studies demonstrate that SGLT2 inhibitors prevent postangioplasty restenosis, maladaptive remodeling of the vasculature in pulmonary arterial hypertension, the formation of abdominal aortic aneurysms, and the acceleration of arterial stiffness in diabetes. However, the role of SGLT2 in mediating the vascular actions of these drugs remains to be established as important off-target effects of SGLT2 inhibitors have been identified. Future studies distinguishing drug- versus class-specific effects may optimize the selection of specific SGLT2 inhibitors in patients with distinct cardiovascular pathologies.
Epigenetic Alterations Upstream and Downstream of p53 Signaling in Colorectal Carcinoma

Simple Summary Colorectal cancer (CRC) belongs to the most common cancer types. It is well known that half of all CRC possess missense mutations in the TP53 tumor suppressor gene. However, the entire signaling cascade upstream and downstream of the p53 protein may also contribute to CRC development, if relevant players in this signaling cascade lost their function. Besides p53 loss-of-function by mutations, epigenetic changes (DNA methylation, post translational modifications of histones, micro-RNAs) play a vital role in CRC development. In the present review, we concentrated on the epigenetic modifications related to the entire p53 signal transduction cascade upstream and downstream of p53. Indeed, numerous epigenetic aberrations influence the tumor suppressor function of p53 independent of missense mutations. Thus, the role of p53 for CRC development, therapy response and survival prognosis of patients may be much more complex than predicted earlier. Hence, we are in need to use novel diagnostic methods that are capable of evaluating the genetic and epigenetic changes in the “p53 signalome”, so that diagnosis and management of CRC will improve. Abstract Colorectal cancer (CRC) belongs to the most common tumor types, and half of all CRC harbor missense mutations in the TP53 tumor suppressor gene. In addition to genetically caused loss of function of p53, epigenetic alterations (DNA methylation, histone modifications, micro-RNAs) contribute to CRC development. In this review, we focused on epigenetic alterations related to the entire p53 signaling pathway upstream and downstream of p53. Methylation of genes which activate p53 function has been reported, and methylation of APC and MGMT was associated with increased mutation rates of TP53. The micro-RNA 34a activates TP53 and was methylated in CRC. Proteins that regulate TP53 DNA methylation, mutations, and acetylation of TP53-related histones were methylated in CRC. P53 regulates the activity of numerous downstream proteins. Even if TP53 is not mutated, the function of wildtype p53 may be compromised if corresponding downstream genes are epigenetically inactivated. Thus, the role of p53 for CRC development, therapy response, and survival prognosis of patients may be much more eminent than previously estimated. Therefore, we propose that novel diagnostic devices measuring the entirety of genetic and epigenetic changes in the “p53 signalome” have the potential to improve the predictive and prognostic power in CRC diagnostics and management.
In Vitro Anti-Candida Activity and Action Mode of Benzoxazole Derivatives

A newly synthetized series of N-phenacyl derivatives of 2-mercaptobenzoxazole, including analogues of 5-bromo- and 5,7-dibromobenzoxazole, were screened against Candida strains and the action mechanism was evaluated. 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(4-bromophenyl)ethanone (5d), 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(2,3,4-trichloro-phenyl)ethanone (5i), 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(2,4,6-trichlorophenyl)ethanone (5k) and 2-[(5-bromo-1,3-benzoxazol-2-yl)sulfanyl]-1-phenylethanone (6a) showed anti-C. albicans SC5314 activity, where 5d displayed MICT = 16 µg/mL (%R = 100) and a weak anti-proliferative activity against the clinical strains: C. albicans resistant to azoles (Itr and Flu) and C. glabrata. Derivatives 5k and 6a displayed MICP = 16 µg/mL and %R = 64.2 ± 10.6, %R = 88.0 ± 9.7, respectively, against the C. albicans isolate. Derivative 5i was the most active against C. glabrata (%R = 53.0 ± 3.5 at 16 µg/mL). Benzoxazoles displayed no MIC against C. glabrata. Benzoxazoles showed a pleiotropic action mode: (1) the total sterols content was perturbed; (2) 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(3,4-dichlorophenyl)ethanol and 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(2,3,4-trichlorophenyl)ethanol (8h–i) at the lowest fungistatic conc. inhibited the efflux of the Rho123 tracker during the membrane transport process; (3) mitochondrial respiration was affected/inhibited by the benzoxazoles: 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(4-chlorophenyl)ethanol and 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(4-bromophenyl)ethanol 8c–d and 8i. Benzoxazoles showed comparable activity to commercially available azoles due to (1) the interaction with exogenous ergosterol, (2) endogenous ergosterol synthesis blocking as well as (3) membrane permeabilizing properties typical of AmB. Benzoxazoles display a broad spectrum of anti-Candida activity and action mode towards the membrane without cross-resistance with AmB; furthermore, they are safe to mammals.
Metalloproteinases 1 and 3 as Potential Biomarkers in Breast Cancer Development

Breast cancer continues to be one of the main causes of morbidity and mortality globally and was the leading cause of cancer death in women in Spain in 2020. Early diagnosis is one of the most effective methods to lower the incidence and mortality rates of breast cancer. The human metalloproteinases (MMP) mainly function as proteolytic enzymes degrading the extracellular matrix and plays important roles in most steps of breast tumorigenesis. This retrospective cohort study shows the immunohistochemical expression levels of MMP-1, MMP-2, MMP-3, and MMP-9 in 154 women with breast cancer and 42 women without tumor disease. The samples of breast tissue are assessed using several tissue matrices (TMA). The percentages of staining (≤50%–>50%) and intensity levels of staining (weak, moderate, or intense) are considered. The immunohistochemical expression of the MMP-1-intensity (p = 0.043) and MMP-3 percentage (p = 0.018) and intensity, (p = 0.025) present statistically significant associations with the variable group (control–case); therefore, expression in the tumor tissue samples of these MMPs may be related to the development of breast cancer. The relationships between these MMPs and some clinicopathological factors in breast cancer are also evaluated but no correlation is found. These results suggest the use of MMP-1 and MMP-3 as potential biomarkers of breast cancer diagnosis.
Assessing the Risk of Respiratory-Related Healthcare Visits Associated with Wildfire Smoke Exposure in Children 0–18 Years Old: A Systematic Review

Wildfires are increasing in frequency, size, and intensity, and increasingly affect highly populated areas. Wildfire smoke impacts cardiorespiratory health; children are at increased risk due to smaller airways, a higher metabolic rate and ongoing development. The objective of this systematic review was to describe the risk of pediatric respiratory symptoms and healthcare visits following exposure to wildfire smoke. Medical and scientific databases and the grey literature were searched from inception until December 2020. Included studies evaluated pediatric respiratory-related healthcare visits or symptoms associated with wildfire smoke exposure. Prescribed burns, non-respiratory symptoms and non-pediatric studies were excluded. Risk of bias was evaluated using the National Toxicology Program’s Office of Health Assessment and Translation Risk of Bias Rating Tool. Data are presented narratively due to study heterogeneity. Of 2138 results, 1167 titles and abstracts were screened after duplicate removal; 65 full text screens identified 5 pre-post and 11 cross-sectional studies of rural, urban and mixed sites from the USA, Australia, Canada and Spain. There is a significant increase in respiratory emergency department visits and asthma hospitalizations within the first 3 days of exposure to wildfire smoke, particularly in children < 5 years old.
Within-Day Energy Balance and Metabolic Suppression in Male Collegiate Soccer Players

Metabolic suppression due to relative energy deficiency can cause various physiological impairments in athletes. The purpose of this study was to evaluate within-day energy balance (WDEB) and the ratio between measured and predicted resting energy expenditure (REEratio) and to investigate the relationships between the markers of metabolic suppression. Ten male collegiate soccer players completed a 7-day food diary, physical activity, and heart rate records during the training and rest days. Energy intake (EI) and energy expenditure (EE) were analyzed to evaluate WDEB components. Body composition was measured using dual-energy X-ray absorptiometry (DXA), and blood sampling was conducted for hormonal analysis. The REE was measured using the Douglas bag method and predicted using the DXA-predicted method to calculate the REEratio. Participants were categorized into the normal (REEratio ≥ 0.94, n = 5) and suppressed (REEratio < 0.94, n = 5) groups. There were no group differences in the components of WDEB, except diet-induced thermogenesis (DIT), but EI was significantly higher in the normal group than in the suppressed group (7-day total: 3660 ± 347 vs. 3024 ± 491 kcal/day, p = 0.046 and rest days: 3772 ± 463 vs. 2796 ± 800 kcal/day, p = 0.046). Analysis of hormonal markers of metabolic suppression only showed a significant positive association between insulin-like growth factor-1 (IGF-1) and REEratio (r = 0.771, p = 0.009). The relationships between metabolic suppression and the markers of energy deficiency were inconclusive. There are possible associations of insufficient EI and IGF-1 levels with metabolic suppression, and further study is required to understand energy deficiency in male soccer players.
Methodological Characteristics, Physiological and Physical Effects, and Future Directions for Combined Training in Soccer: A Systematic Review

Combined training (CT) may combine strength and endurance training within a given time period, but it can also encompass additional protocols consisting of velocity, balance, or mobility as part of the same intervention. These combined approaches have become more common in soccer. This systematic review was conducted to (1) characterize the training protocols used in CT studies in soccer, (2) summarize the main physiological and physical effects of CT on soccer players, and (3) provide future directions for research. Methods: A systematic review of Cochrane Library, PubMed, Scopus, SPORTDiscus, and Web of Science databases was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The PICOS were defined as follows: P (soccer players of any age or sex); I (CT combining strength and endurance or sprinting or balance or mobility training); C (the control group (whenever applicable), with or without comparative interventions in addition to usual soccer training); O (acute and/or chronic responses: biochemical, physiological and physical); S (must have at least two groups, either randomized or non-randomized). The database search initially identified 79 titles. From those, eight articles were deemed eligible for the systematic review. Three studies analyzed acute responses to concurrent training, while the remaining five analyzed adaptations to CT. In those tested for acute responses, physiological (hormonal) and physical (strength and power external load, internal load) parameters were observed. Adaptations were mainly focused on physical parameters (strength and power, sprints, jumps, repeated sprint ability, aerobic, change-of-direction), with relatively little focus on physiological parameters (muscle architecture). Short-term responses to CT can affect hormonal responses of testosterone after resistance training with internal and external load. In turn, these responses’ effects on strength and power have produced mixed results, as have adaptations. Specifically, strength and hypertrophy are affected to a lesser extent than speed/power movements. Nevertheless, it is preferable to perform CT before endurance exercises since it is a limiting factor for interference. Volume, intensity, rest between sessions, and athletes’ fitness levels and nutrition dictate the degree of interference.