Miracle-dz/UniFAR-FTUs huggingface dataset:
Hepatic organic anion transporting polypeptides mediate disposition of milk thistle flavonolignans and pharmacokinetic silymarin‐drug interactions

Silybum marianum (L.) Gaertn. (Asteraceae), commonly known as milk thistle, is a botanical natural product used to self‐treat multiple diseases such as Type 2 diabetes mellitus and nonalcoholic steatohepatitis (NASH). An extract from milk thistle seeds (achenes), termed silymarin, is comprised primarily of several flavonolignans. Systemic concentrations of these flavonolignans can influence the potential biologic effects of silymarin and the risk for pharmacokinetic silymarin‐drug interactions. The aims of this research were to determine the roles of organic anion transporting polypeptides (OATPs/Oatps) in silymarin flavonolignan disposition and in pharmacokinetic silymarin‐drug interactions. The seven major flavonolignans from silymarin were determined to be substrates for OATP1B1, OATP1B3, and OATP2B1. Sprague Dawley rats were fed either a control diet or a NASH‐inducing diet and administered pitavastatin (OATP/Oatp probe substrate), followed by silymarin via oral gavage. Decreased protein expression of Oatp1b2 and Oatp1a4 in NASH animals increased flavonolignan area under the plasma concentration‐time curve (AUC) and maximum plasma concentration. The combination of silymarin inhibition of Oatps and NASH‐associated decrease in Oatp expression caused an additive increase in plasma pitavastatin AUC in the animals. These data indicate that OATPs/Oatps contribute to flavonolignan cellular uptake and mediate the interaction between silymarin and NASH on pitavastatin systemic exposure.
Efficacy of Vortioxetine Monotherapy for Posttraumatic Stress Disorder

Supplemental digital content is available in the text. Abstract Purpose/Background There are few efficacious pharmacological treatments for posttraumatic stress disorder (PTSD) and many patients fail to benefit from existing treatments. Vortioxetine, a recently developed antidepressant, acts as a serotonin modulator through inhibition of the serotonin transporter and actions at multiple types of serotonin receptors. Its unique pharmacodynamic profile suggests it may have efficacy for the treatment of PTSD. Methods/Procedures We conducted a 12-week placebo-controlled, randomized clinical trial of vortioxetine (flexibly dosed from 10 to 20 mg/d) versus placebo in adults with PTSD. The primary outcome was change from baseline in the past-month version of the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), analyzed using a mixed-model repeated-measures analysis of variance. Findings/Results Forty-one patients were randomized, and 32 (78%) completed the 12 weeks of treatment. The mean reduction in CAPS-5 scores at week 12 did not significantly differ between the 2 arms; the effect size for the difference in changes between vortioxetine and placebo on CAPS-5 total scores at week 12 was Cohen d = 0.29. However, at week 8, the drug-placebo difference was d = 0.78, which met the multivariate criteria for statistical significance, P = 0.014. Implications/Conclusions In this study of 41 patients, vortioxetine did not demonstrate superiority over placebo for adults with PTSD. Future PTSD trials may benefit from stratifying the randomization based on number of years since the index traumatic event and a history of failure to respond to treatment.
Identification of tumors with NRG1 rearrangement, including a novel putative pathogenic UNC5D‐NRG1 gene fusion in prostate cancer by data‐drilling a de‐identified tumor database

The fusion genes containing neuregulin‐1 (NRG1) are newly described potentially actionable oncogenic drivers. Initial clinical trials have shown a positive response to targeted treatment in some cases of NRG1 rearranged lung adenocarcinoma, cholangiocarcinoma, and pancreatic carcinoma. The cost‐effective large scale identification of NRG1 rearranged tumors is an open question. We have tested a data‐drilling approach by performing a retrospective assessment of a de‐identified molecular profiling database of 3263 tumors submitted for fusion testing. Gene fusion detection was performed by RNA‐based targeted next‐generation sequencing using the Archer Fusion Plex kits for Illumina (ArcherDX Inc., Boulder, CO). Novel fusion transcripts were confirmed by a custom‐designed RT‐PCR. Also, the aberrant expression of CK20 was studied immunohistochemically. The frequency of NRG1 rearranged tumors was 0.2% (7/3263). The most common histologic type was lung adenocarcinoma (n = 5). Also, renal carcinoma (n = 1) and prostatic adenocarcinoma (n = 1) were found. Identified fusion partners were of a wide range (CD74, SDC4, TNC, VAMP2, UNC5D), with CD74, SDC4 being found twice. The UNC5D is a novel fusion partner identified in prostate adenocarcinoma. There was no co‐occurrence with the other tested fusions nor KRAS, BRAF, and the other gene mutations specified in the applied gene panels. Immunohistochemically, the focal expression of CK20 was present in 2 lung adenocarcinomas. We believe it should be considered as an incidental finding. In conclusion, the overall frequency of tumors with NRG1 fusion was 0.2%. All tumors were carcinomas. We confirm (invasive mucinous) lung adenocarcinoma as being the most frequent tumor presenting NRG1 fusion. Herein novel putative pathogenic gene fusion UNC5D‐NRG1 is described. The potential role of immunohistochemistry in tumor identification should be further addressed.
Tuning the Properties of MOF‐808 via Defect Engineering and Metal Nanoparticle Encapsulation

Abstract Defect engineering and metal encapsulation are considered as valuable approaches to fine‐tune the reactivity of metal–organic frameworks. In this work, various MOF‐808 (Zr) samples are synthesized and characterized with the final aim to understand how defects and/or platinum nanoparticle encapsulation act on the intrinsic and reactive properties of these MOFs. The reactivity of the pristine, defective and Pt encapsulated MOF‐808 is quantified with water adsorption and CO2 adsorption calorimetry. The results reveal strong competitive effects between crystal morphology and missing linker defects which in turn affect the crystal morphology, porosity, stability, and reactivity. In spite of leading to a loss in porosity, the introduction of defects (missing linkers or Pt nanoparticles) is beneficial to the stability of the MOF‐808 towards water and could also be advantageously used to tune adsorption properties of this MOF family.
Complex Relationship Between Cardiac Fibroblasts and Cardiomyocytes in Health and Disease

Abstract Cardiac fibroblasts are the primary cell type responsible for deposition of extracellular matrix in the heart, providing support to the contracting myocardium and contributing to a myriad of physiological signaling processes. Despite the importance of fibrosis in processes of wound healing, excessive fibroblast proliferation and activation can lead to pathological remodeling, driving heart failure and the onset of arrhythmias. Our understanding of the mechanisms driving the cardiac fibroblast activation and proliferation is expanding, and evidence for their direct and indirect effects on cardiac myocyte function is accumulating. In this review, we focus on the importance of the fibroblast‐to‐myofibroblast transition and the cross talk of cardiac fibroblasts with cardiac myocytes. We also consider the current use of models used to explore these questions.
2‐O‐Octadecylascorbic acid represses RhoGDIβ expression and ameliorates DNA damage‐induced abnormal spindle orientations

The appropriate regulation of spindle orientation maintains proper tissue homeostasis and avoids aberrant tissue repair or regeneration. Spindle misorientation due to imbalance or improper functioning leads to a loss of tissue integrity and aberrant growth, such as tissue loss or overgrowth. Pharmacological manipulation to prevent spindle misorientation will enable a better understanding of how spindle orientation is involved in physiological and pathological conditions and will provide therapeutic possibilities to treat patients associated with abnormal tissue function caused by spindle misorientation. N‐terminal‐deleted Rho guanine nucleotide dissociation inhibitor β (RhoGDIβ/RhoGDI2/LyGDI) produced by caspase‐3 activation perturbs spindle orientation in surviving cells following exposure to either ionizing radiation or UVC. Thus, presumably, RhoGDIβ cleaved by caspase‐3 activation acts as a determinant of radiation‐induced spindle misorientation that promote aberrant tissue repair due to deregulation of directional organization of cell population and therefore becomes a potential target of drugs to prevent such response. The objective of this study was to screen and identify chemicals that suppress RhoGDIβ expression. We focused our attention on ascorbic acid (AA) derivatives because of their impact on the maintenance of skin tissue homeostasis. Here, we screened for AA derivatives that suppress RhoGDIβ expression in HeLa cells and identified a lipophilic derivative, 2‐O‐octadecylascorbic acid (2‐OctadecylAA), as a novel RhoGDIβ inhibitor that ameliorated ionizing radiation‐induced abnormal spindle orientations. Among all examined AA derivatives, which were also antioxidative, the inhibition activity was specific to 2‐OctadecylAA. Therefore, this activity was not due to simple antioxidant properties. 2‐OctadecylAA was previously shown to prevent hepatocellular carcinoma development. Our findings suggest that the anticarcinogenic effects of 2‐OctadecylAA are partly due to RhoGDIβ inhibition mechanisms by which spindle orientation perturbations are attenuated. Thus, the molecular targeting features of RhoGDIβ warrant its further development for the treatment or control of spindle orientation abnormalities that affect epithelial homeostasis.
Metabolomic Analysis of Skin Biopsies from Patients with Atopic Dermatitis Reveals Hallmarks of Inflammation, Disrupted Barrier Function and Oxidative Stress

The main objectives of this study were to characterize the metabolomic profile of lesional skin of patients with atopic dermatitis, and to compare it with non-lesional skin of patients with atopic dermatitis and skin of controls with no dermatological disease. Skinpunch biopsies were collected from 15 patients and 17 controls. Targeted analysis of 188 metabolites was conducted. A total of 77 metabolites and their ratios were found, which differed significantly between lesional skin of atopic dermatitis, non-lesional skin of atopic dermatitis and skin of controls. The metabolites were members of the following classes: amino acids, biogenic amines, acylcarnitines, sphingomyelins or phosphatidylcholines, and the most significant differences between the groups compared were in the concentrations of putrescine, SM.C26. 0 and SM.C26. 1. The alterations in metabolite levels indicate inflammation, impaired barrier function, and susceptibility to oxidative stress in atopic skin.
Vibration-induced nystagmus and head impulse test screening for vestibular schwannoma

Abstract Level of evidence II-2 Background Vestibular schwannomas are benign tumors of the eight cranial nerve that may cause asymmetric sensorineural hearing loss (ASHL) and vestibular dysfunction. Objective The aim of this study was to assess the role of the video head impulse test (vHIT) and vibration-induced nystagmus (VIN) test in diagnosing vestibular schwannoma in a population of patients with Asymmetric sensorineural hearing loss. Material and methods For this prospective case-control study, 23 consecutive patients with ASHL and normal magnetic resonance were enrolled in the control group, and 33 consecutive patients with ASHL and vestibular schwannoma were enrolled in the case group. Gold standard was magnetic resonance imaging. Audiometry, vHIT, and VIN tests were performed for each patient. Significance of VIN and vHIT testing was determined by evaluation of their sensitivity, specificity, and correlation with vestibular function tests. Results Regarding the vHIT, sensitivity and specificity were 45.5% and 82.6%, respectively, for horizontal canal gain, 60.6% and 87.6%, respectively, for posterior canal gain, and 45.5% and 78.3%, respectively, when analyzing superior canal gains. Regarding the VIN test, the sensitivity and specificity were 81.8% and 73.9%, respectively, when based on the presence of a VIN with any mastoid stimulation. Conclusions Our results suggest that using the VIN test may be an efficient approach to screen for vestibular schwannoma in patients with asymmetric sensorineural hearing loss. Significance Our results suggest that using the VIN test may be an efficient approach to screen for vestibular schwannoma in patients with ASHL.
Does aerobic performance define match running performance among professional soccer players? A position-specific analysis

ABSTRACT Aerobic performance is considered an important determinant of match running performance in soccer, but studies have rarely investigated this issue in top-level players. This study examined the possible associations between direct measures of aerobic performance and match running performance in elite soccer players. Aerobic performance was tested at the beginning of the season in laboratory settings. The match-running performance was measured by a global positioning system over a competitive half-season for a total of 82 match performances in professional players from Croatia (age: 23.76 ± 2.64; body height: 181.62 ± 7.09 cm; body mass: 77.01 ± 6.34 kg) and clustered as central player (n = 57) and side player (n = 25) performance. No significant differences in aerobic performance were noted between central and side players. The anaerobic threshold was correlated with high-speed running (19.8–25.1 km/h), sprint running (>25.1 km/h), and high-intensity running (>19.8 km/h) among side players (r = 0.52, 0.53, and 0.59, respectively; p < 0.01). For central players, the aerobic threshold was correlated with the total distance covered, low-intensity running (<14.3 km/h), and distance covered in the zone of running (14.4–19.7 km/h) (r = 0.47, 0.49, and 0.39; p < 0.01, 0.01, and 0.03, respectively). Conditioning for central players should include activities with intensities corresponding to aerobic thresholds, while conditioning of side players should be focused on the development of anaerobic thresholds.
COVID‐19: immunopathology, pathophysiological mechanisms, and treatment options

Coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), continues to spread globally despite the worldwide implementation of preventive measures to combat the disease. Although most COVID‐19 cases are characterised by a mild, self‐limiting disease course, a considerable subset of patients develop a more severe condition, varying from pneumonia and acute respiratory distress syndrome (ARDS) to multi‐organ failure (MOF). Progression of COVID‐19 is thought to occur as a result of a complex interplay between multiple pathophysiological mechanisms, all of which may orchestrate SARS‐CoV‐2 infection and contribute to organ‐specific tissue damage. In this respect, dissecting currently available knowledge of COVID‐19 immunopathogenesis is crucially important, not only to improve our understanding of its pathophysiology but also to fuel the rationale of both novel and repurposed treatment modalities. Various immune‐mediated pathways during SARS‐CoV‐2 infection are relevant in this context, which relate to innate immunity, adaptive immunity, and autoimmunity. Pathological findings in tissue specimens of patients with COVID‐19 provide valuable information with regard to our understanding of pathophysiology as well as the development of evidence‐based treatment regimens. This review provides an updated overview of the main pathological changes observed in COVID‐19 within the most commonly affected organ systems, with special emphasis on immunopathology. Current management strategies for COVID‐19 include supportive care and the use of repurposed or symptomatic drugs, such as dexamethasone, remdesivir, and anticoagulants. Ultimately, prevention is key to combat COVID‐19, and this requires appropriate measures to attenuate its spread and, above all, the development and implementation of effective vaccines. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
Epicardial Surface Area of Infarction

Supplemental Digital Content is available in the text. Background: Microvascular obstruction (MO) is a pathophysiologic complication of acute myocardial infarction that portends poor prognosis; however, it is transient and disappears with infarct healing. Much remains unknown regarding its pathophysiology and whether there are predictors of MO that could function as stable surrogates. We tested for clinical and cardiovascular magnetic resonance predictors of MO to gain insight into its pathophysiology and to find a stable surrogate. Methods: Three hundred two consecutive patients from 2 centers underwent cardiovascular magnetic resonance within 2 weeks of first acute myocardial infarction. Three measures of infarct morphology: infarct size, transmurality, and a new index—the epicardial surface area (EpiSA) of full-thickness infarction—were quantified on delayed-enhancement cardiovascular magnetic resonance. Results: Considering all clinical characteristics, only measures of infarct morphology were independent predictors of MO. EpiSA was the strongest predictor of MO and provided incremental predictive value beyond that of infarct size and transmurality (P<0.0001). In patients with 3-month follow-up cardiovascular magnetic resonance (n=81), EpiSA extent remained stable while MO disappeared, and EpiSA was a predictor of adverse ventricular remodeling. After 20 months of follow-up, 11 died and 1 had heart transplantation. Patients with an EpiSA larger than the median value (≥6%) had worse outcome than those with less than the median value (adverse events: 6.4% versus 1.9%, P=0.045). Conclusions: The EpiSA of infarction is a novel index of infarct morphology which accurately predicts MO during the first 2 weeks of MI, but unlike MO, does not disappear with infarct healing. This index has potential as a stable surrogate of the presence of acute MO and may be useful as a predictor of adverse remodeling and outcome which is less dependent on the time window of patient assessment.
Different clinical features between patients with ROS1-positive and ALK-positive advanced non-small cell lung cancer

Objective To compare the baseline clinical characteristics between patients with ROS1-positive and ALK-positive advanced non-small cell lung cancer (NSCLC), and the correlations of these subtypes with the distribution of metastases. Methods We compared the clinical characteristics and imaging features of patients with ROS1-positive and ALK-positive NSCLC using statistical methods. Results Data for 232 patients were analyzed. Compared with ALK-positive NSCLC, ROS1-positive NSCLC was more likely to occur in women (71% vs 53%), and primary lesions ≤3 cm were more common in patients with ROS1-positive compared with ALK-positive NSCLC (58% vs 37%). There was no significant difference in the distribution of metastases between the two groups. Subgroup analysis within the ROS1-positive group showed that, compared with primary lesions >3 cm, primary lesions ≤3 cm were more likely to present as peripheral tumors (72% vs 43%) and more likely to exhibit non-solid density (44% vs 4%). Conclusions Although ROS1-positive and ALK-positive NSCLCs show similar clinical features, the differences may help clinicians to identify patients requiring further genotyping at initial diagnosis.
Who should we ask about mental health symptoms in adolescents with CFS/ME? Parent-child agreement on the revised children’s anxiety and depression scale

Background: One in three adolescents with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) have mental health problems. Multi-informant perspectives are key to psychological assessment. Understanding parent-child agreement is crucial to accurate diagnosis, particularly where severe fatigue limits self-report. Methods: Agreement on the revised children’s anxiety and depression scale (RCADs) was assessed between parents and children with CFS/ME (n = 93) using Bland-Altman plots, cross tabulations and regression analyses. Results: Diagnostic thresholds were met more frequently based on child-report. Parent- and child-report had similar sensitivity and specificity on RCADS compared to gold-standard diagnostic interviews. Regression analysis found similar accuracy between both reports. For anxiety diagnoses, odds ratio (OR) for child-report was 1.10 (CI = 1.06–1.14), and 1.10 (CI = 1.05–1.14) for parent-report. For depression, OR for child report was 1.26 (CI = 1.11–1.43), while for parent-report is was 1.25 (CI = 1.10–1.41). For total score, OR for child-report was 1.10 (CI = 1.05–1.13) while OR for parent-report was 1.09 (CI = 1.05–1.13). Conclusions: Reasonable agreement was observed between parent- and child-report of mental health symptoms in paediatric CFS/ME. While parent-report can facilitate psychological evaluation in CFS/ME, this is not a substitute for a child’s own report.
Measuring butyrylcholinesterase activity and hematological parameters in farmers exposed to pesticides: a case and control study from Morocco

Abstract The Farmers are exposed to a wide range of pesticides. The application of these pesticides has been documented to lead to several adverse health effects. This aim of this case-control study was to estimate risks linked to pesticide exposure among farmers in the Souss region of Morocco through the analysis of serum butyrylcholinesterase (BChE) activity and hematological parameters. This prospective study included 98 participants (49 farmers and 49 controls). A questionnaire was used to collect socio-demographic data, technical information regarding the application of pesticides, previous poisonings by pesticides, and training on the use of pesticides. The blood samples were collected for hematological parameters and BChE analysis, and the activity of BChE was measured spectrophotometrically by the butyrlthiocholine method. The results showed no significant differences in hemoglobin (HB), hematocrit, mean corpuscular volume, platelets, red blood cell, and leukocyte cell counts between both the exposed farmer and the control group. In contrast, a significant decreased in mean corpuscular HB, mean corpuscular HB concentration, eosinophils, and basophils counts were observed. In addition, the exposed group showed a significant decrease in the BChE activity (p < .001) compared to the control group. Farmers exposed to pesticides in the Souss Massa region may be at risk of hematological alterations as well as neurotoxicity, characterized by inhibition of BChE enzyme activity.