Miracle-dz/UniFAR-FTUs huggingface dataset:
CD3+CD4+gp130+ T Cells Are Associated With Worse Disease Activity in Systemic Lupus Erythematosus Patients

The receptors for IL-35, IL-12Rβ2 and gp130, have been implicated in the inflammatory pathophysiology of autoimmune diseases. In this study, we set out to investigate the serum IL-35 levels and the surface levels of IL-12Rβ2 and gp130 in CD3+CD4+, CD3+CD4─ and CD3─CD4─ lymphocyte subpopulations in systemic lupus erythematosus (SLE) patients (n=50) versus healthy controls (n=50). The potential T cell subsets associated with gp130 transcript (i.e. IL6ST) expression in CD4+ T cells of SLE patients was also examined in publicly-available gene expression profiling (GEP) datasets. Here, we report that serum IL-35 levels were significantly higher in SLE patients than healthy controls (p=0.038) but it was not associated with SLEDAI-2K scores. The proportions of IL-12Rβ2+ and gp130+ cells in SLE patients did not differ significantly with those of healthy controls in all lymphocyte subpopulations investigated. Essentially, higher SLEDAI-2K scores were positively correlated with increased proportion of gp130+ cells, but not IL-12Rβ2+ cells, on CD3+CD4+ T cells (r=0.425, p=0.002, q=0.016). Gene Set Enrichment Analysis (GSEA) of a GEP dataset of CD4+ T cells isolated from SLE patients (n=8; GSE4588) showed that IL6ST expression was positively associated with genes upregulated in CD4+ T cells vs myeloid or B cells (q<0.001). In an independent GEP dataset of CD4+ T cells isolated from SLE patients (n=9; GSE1057), IL6ST expression was induced upon anti-CD3 stimulation, and that Treg, TCM and CCR7+ T cells gene sets were significantly enriched (q<0.05) by genes highly correlated with IL6ST expression (n=92 genes; r>0.75 with IL6ST expression) upon anti-CD3 stimulation in these SLE patients. In conclusion, gp130 signaling in CD3+CD4+ T cell subsets may contribute to increased disease activity in SLE patients, and it represents a promising therapeutic target for inhibition in the disease.
Left Ventricular Remodeling Following Balloon Mitral Valvuloplasty in Rheumatic Mitral Stenosis: Magnetic Resonance Imaging Study

Background: Rheumatic heart disease affects primarily cardiac valves, it could involve the myocardium either primarily or secondary to heart valve affection. The influence of balloon mitral valvuloplasty (BMV) on left ventricular function has not been sufficiently studied. Aim: To determine the influence of balloon mitral valvuloplasty (BMV) on both global and regional left ventricular (LV) function. Methods: Thirty patients with isolated rheumatic mitral stenosis (MS) were studied. All patients had cardiac magnetic resonance imaging (CMR) before, 6 months and 1 year after successful BMV. LV volumes, ejection fraction (EF), regional and global LV deformation, and LV late gadolinium enhancement were evaluated. Results: At baseline, patients had median EF of 57 (range: 45–69) %, LVEDVI of 74 (44–111) ml/m2 and LVESVI of 31 (14–57) ml/m2 with absence of late gadolinium enhancement in all myocardial segments. Six months following BMV, there was a significant increase in LV peak systolic global longitudinal strain (GLS) (−16.4 vs. −13.8, p < 0.001) and global circumferential strain (GCS) (−17.8 vs. −15.6, p = 0.002). At 1 year, there was a trend towards decrease in LVESVI (29 ml/m2, p = 0.079) with a significant increase in LV EF (62%, p < 0.001). A further significant increase, compared to 6 months follow up studies, was noticed in GLS (−17.9 vs. −16.4, p = 0.008) and GCS (−19.4 vs. −17.8 p = 0.03). Conclusions: Successful BMV is associated with improvement in global and regional LV systolic strain which continues for up to 1 year after the procedure.
Precision Medicine in Graves’ Disease: CD40 Gene Variants Predict Clinical Response to an Anti-CD40 Monoclonal Antibody

Background CD40, a key co-stimulatory molecule expressed on antigen-presenting cells, is genetically associated with a number of autoimmune diseases including Graves’ disease (GD). Therefore, recent therapies targeting CD40 have been developed, including the anti-CD40 monoclonal antibody Iscalimab. In a recent pilot study, Iscalimab was shown to induce clinical remission in ~ 50% of GD patients, but the reason why only 50% of GD patients responded is not known. The aim of our study was to test the hypothesis that specific CD40 single nucleotide polymorphism (SNP) genotypes and haplotypes are associated with clinical response of GD patients to Iscalimab. Methods We extracted genomic DNA from the whole blood of 13 GD patients treated with Iscalimab, and genotyped seven CD40 single nucleotide polymorphisms (SNPs) associated with autoimmunity. Additionally, we analyzed CD40 mRNA expression levels in whole blood. The patients’ CD40 SNP genotypes and mRNA levels were tested for association with clinical response to Iscalimab. Results Three common haplotypes, designated haplotypes A, B, and C, were identified. Haplotypes B and C were associated with higher CD40 mRNA levels and clinical response to Iscalimab (i.e., patients achieving euthyroidism without need for additional medications), while haplotype A was associated with decreased CD40 mRNA levels and no response to Iscalimab. Conclusion Our data suggest that genetic polymorphisms in the CD40 gene drive its expression levels and response to Iscalimab. Polymorphisms associated with higher CD40 levels are also associated with clinical response to CD40-targeted therapies. These results set the stage to implementing precision medicine in the therapeutic approach to GD.
Anti-Tumor Effects of BDH1 in Acute Myeloid Leukemia

Dysregulation of ketone metabolism has been reported in various types of cancer. In order to find out its role in acute myeloid leukemia (AML) pathogenesis, we first analyzed the expression levels of 10 key genes involved in ketone metabolism in AML blasts and CD34+ hematopoietic stem cells (HSCs) from healthy donors. We found that the expression level of BDH1 was significantly lower in AML than in normal HSCs. The downregulation of BDH1 gene expression in AML cell lines as compared with normal HSCs was further confirmed with real-time RT-PCR. Analysis of TCGA and other database revealed that the downregulation of BDH1 was associated with worse prognosis in AML patients. In addition, we showed that overexpression of BDH1 inhibited the viability and proliferation of AML cells. In contrast, BDH1 knock-down promoted AML cell growth. Collectively, our results suggest the previously unappreciated anti-tumor role of BDH1 in AML, and low BDH1 expression predicts poor survival.
Diagnostic Accuracy of the Drug Use Disorder Identification Test and Its Short Form, the DUDIT-C, in German Adolescent Psychiatric Patients

Background A common screening instrument for substance use disorders (SUDs) is the Drug Use Disorders Identification Test (DUDIT) which includes a short form regarding only drug consumption (DUDIT-C). We aim to assess if a German version of the DUDIT, adapted for adolescents, is a suitable screening instrument in a sample of adolescent psychiatric patients. Methods N = 124 (54 female) German adolescent (M = 15.6 + 1.5 years) psychiatric patients completed the DUDIT and received a diagnostic interview (MINI-KID) assessing DSM-5 SUD criteria. A confirmatory factor analysis (CFA), receiver operating characteristic (ROC) curves, the area under the curve (AUC), and Youden’s Index were calculated. Results A two-factor model of the DUDIT shows the best model fit (CFI = 0.995, SRMR = 0.055, RMSEA = 0.059, WRMR = 0.603). The DUDIT as well as the DUDIT-C show high diagnostic accuracy, with AUC = 0.95 and AUC = 0.88, respectively. For the DUDIT a cut-off value of 8.5 was optimal (sensitivity = 0.93, specificity = 0.91, J = 0.84), while for the DUDIT-C the optimal cut-off value was at 1.5 (sensitivity = 0.86, specificity = 0.84, J = 0.70). Conclusion This is the first psychometric evaluation of the DUDIT in German, adolescent psychiatric outpatients, using the DSM-5 diagnostic criteria. The DUDIT as well as the DUDIT-C are well suited for use in this population. Since in our sample only few patients presented with a mild or moderate SUD, our results need to be replicated in a sample of adolescents with mild SUD.
Environmental Tobacco Smoke in Occupational Settings: Effect and Susceptibility Biomarkers in Workers From Lisbon Restaurants and Bars

Environmental tobacco smoke (ETS) has been recognized as a major health hazard by environmental and public health authorities worldwide. In Portugal, smoke-free laws are in force for some years, banning smoking in most indoor public spaces. However, in hospitality venues such as restaurants and bars, owners can still choose between a total smoke-free policy or a partial smoking restriction with designated smoking areas, if adequate reinforced ventilation systems are implemented. Despite that, a previous study showed that workers remained continuously exposed to higher ETS pollution in Lisbon restaurants and bars where smoking was still allowed, comparatively to total smoke-free venues. This was assessed by measurements of indoor PM2.5 and urinary cotinine, a biomarkers of tobacco smoke exposure, demonstrating that partial smoking restrictions do not effectively protect workers from ETS. The aim of the present work was to characterize effect and susceptibility biomarkers in non-smokers from those hospitality venues occupationally exposed to ETS comparatively to non-exposed ones. A group of smokers was also included for comparison. The sister chromatid exchange (SCE), micronucleus (MN) and comet assays in whole peripheral blood lymphocytes (PBLs) and the micronucleus assay in exfoliated buccal cells, were used as biomarkers of genotoxicity. Furthermore, a comet assay after ex vivo challenge of leukocytes with an alkylating agent, ethyl methanesulfonate (EMS), was used to analyze the repair capacity of those cells. Genetic polymorphisms in genes associated with metabolism and DNA repair were also included. The results showed no clear association between occupational exposure to ETS and the induction of genotoxicity. Interestingly, the leukocytes from non-smoking ETS-exposed individuals displayed lower DNA damage levels in response to the ex vivo EMS challenge, in comparison to those from non-exposed workers, suggesting a possible adaptive response. The contribution of individual susceptibility to the effect biomarkers studied was unclear, deserving further investigation.
Real-World Clinical Outcomes of Biosimilar Trastuzumab (CT-P6) in HER2-Positive Early-Stage and Metastatic Breast Cancer

Background The trastuzumab biosimilar CT-P6 has demonstrated equivalent efficacy and comparable safety to reference trastuzumab (RTZ) in clinical trials of human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC). Here, we present the first real-world comparison of CT-P6 versus RTZ with dual HER2-targeted therapy for the neoadjuvant and palliative first-line treatment with HER2-positive EBC and metastatic breast cancer (MBC) patients in two tertiary hospitals in Korea. Methods We retrospectively investigated medical records in the Severance Breast Cancer Registry in Korea. We identified patients with HER2-positive EBC (n=254) who had received neoadjuvant chemotherapy with RTZ or CT-P6, plus pertuzumab, carboplatin and docetaxel (TCHP) and untreated stage IV MBC (n=103) who had received palliative first-line treatment with RTZ or CT-P6, plus pertuzumab and docetaxel (THP) between May 2014 and December 2019. The primary endpoints were pathologic complete response (pCR) in the EBC and progression-free survival (PFS) in the MBC cohort. Overall survival (OS), overall response rate (ORR), disease control rate (DCR), and cardiac safety were secondary endpoints. Results A similar percentage of EBC patients achieved a pCR with CT-P6 versus RTZ (74.4% [93/125]) vs 69.8% [90/129], p=0.411). For patients with MBC, median follow-up duration was 23.0 and 41.0 months for CT-P6 and RTZ groups, respectively; median PFS did not differ significantly between two groups (13.0 vs 18.0 months, 95% confidence intervals (CIs) 0.0-26.6 vs 11.3-24.7, p=0.976). The ORR, DCR, and cardiac safety profiles did not also show significant difference efficacy outcomes between two groups. Conclusions These real-world data suggest that biosimilar trastuzumab CT-P6 has similar effectiveness and cardiac safety to RTZ in HER2-positive EBC and MBC patients, when administered as part of dual HER2-targeted therapy with pertuzumab plus chemotherapy in the neoadjuvant or palliative setting.
Psychometric Properties of the Spanish Version of the Cognitive Emotional Regulation Difficulties Questionnaire (CERQ) in Higher Education Students in Times of Covid-19

The Cognitive Emotion Regulation Questionnaire (CERQ) is an instrument developed to assess the cognitive strategies of emotional regulation used by people after experiencing a negative event. The present study aimed to validate the Spanish version of the CERQ in students of the University of Granada (Spain) during the Covid-19 homebound. An online scale was developed and applied based on the Spanish version of the CERQ-S36, consisting of 36 items structured around nine cognitive strategies. Using a mixed sampling, the scale was applied to 450 students from different degree programmes. Regarding the psychometric results of the scale, firstly, in relation to reliability as internal consistency, we found that the scale applied to University students in a Covid-19 setting is highly stable. Secondly, in reference to concurrent criterion validity, we can conclude that the items individually measure the same as the total scale (taken as internal criterion), and thirdly and finally, in relation to construct validation, the two factor analyses implemented, one exploratory and the other confirmatory in nature, conform a factor structure of latent dimensions identical to the original one. In conclusion, the results obtained as a whole suggest that the CERQ-S36 scale could be useful for assessing cognitive coping in University populations in times of crisis. In situations such as the current global emergency due to the presence of Covid-19, the scale is useful for understanding emotional regulation strategies. More studies should be carried out with this scale to find out how emotions influence and what consequences they have on the health and psychological functioning of University students in times of social crisis.
Irisin, Fibroplast Growth Factor-21, and Follistatin Responses to Endurance Rowing Training Session in Female Rowers

Purpose: This study examined selected myokine responses to an endurance rowing training session, and whether metabolic demands of the acute aerobic rowing exercise together with training volume, aerobic capacity, and body composition variables affect potential exercise-induced changes in the myokine levels in female rowers. Methods: Fifteen national level female rowers [18.3 ± 1.6 years; 172.0 ± 5.0 cm, 67.5 ± 8.8 kg; maximal oxygen consumption (VO2max): 47.2 ± 7.9 ml.min.−1 kg−1] performed a 1-h rowing ergometer exercise at the intensity of 70% of VO2max [distance: 12.1 ± 1.1 km; energy expenditure (EE): 639 ± 69 kcal; heart rate (HR): 151 ± 7 beats.min−1] followed by a 30-min recovery period. Venous blood samples were collected before and after exercise, and analyzed for irisin, fibroplast growth factor-21 (FGF-21), and follistatin conentrations. Results: Plasma irisin and FGF-21 concentrations were increased (by 8%; p = 0.013 and by 13%; p < 0.0001, respectively) immediately after the aerobic rowing exercise. Follistatin was significantly increased (by 11%; p = 0.001) only after the first 30 min of recovery. Exercise metabolic demand variables such as distance covered and total EE were correlated with the pre-to-post-exercise increases in FGF-21 concentrations (r = 0.52; p = 0.047 and r = 0.68; p = 0.005, respectively). Exercise-induced increases in irisin levels were related to aerobic capacity as measured by VO2max (r = 0.53; p = 0.041) and training stress as measured by weekly training volume (r = 0.54; p = 0.039) in female rowers. Conclusion: Acute negative energy balance induced by a single endurance rowing training session elicited significant increases in irisin, FGF-21, and follistatin levels in national level female rowers. While exercise-induced increases in FGF-21 levels were associated with exercise metabolic demand measures, exercise-induced increases in irisin concentrations were related to aerobic capacity and training stress measures in female rowers.
Macrophage Activation Syndrome in Pediatric Systemic Lupus Erythematosus: A Systematic Review of the Diagnostic Aspects

Macrophage Activation Syndrome (MAS) is a very severe complication of different rheumatic diseases, including pediatric Systemic Lupus Erythematosus (pSLE). MAS is not considered as a frequent complication of pSLE; however, its occurrence could be under-estimated and the diagnosis can be challenging. In order to address this issue, we performed a systematic review of the available medical literature, aiming to retrieve all those papers providing diagnostic (clinical/laboratory) data on patients with pSLE-related MAS, in individual or aggregated form. The selected case reports and series provided a pool of 46 patients, accounting for 48 episodes of MAS in total. We re-analyzed these patients in light of the diagnostic criteria for MAS validated in systemic Juvenile Idiopathic Arthritis (sJIA) patients and the preliminary diagnostic criteria for MAS in pSLE, respectively. Five clinical studies were also selected and used to support this analysis. This systematic review confirms that MAS diagnosis in pSLE patients is characterized by several diagnostic challenges, which could lead to delayed diagnosis and/or under-estimation of this complication. Specific criteria should be considered to diagnose MAS in different rheumatic diseases; as regards pSLE, the aforementioned preliminary criteria for MAS in pSLE seem to perform better than the sJIA-related MAS criteria, because of a lower ferritin cut-off.
Neurodegenerative Disease Risk in Carriers of Autosomal Recessive Disease

Genetics has driven significant discoveries in the field of neurodegenerative diseases (NDDs). An emerging theme in neurodegeneration warrants an urgent and comprehensive update: that carrier status of early-onset autosomal recessive (AR) disease, typically considered benign, is associated with an increased risk of a spectrum of late-onset NDDs. Glucosylceramidase beta (GBA1) gene mutations, responsible for the AR lysosomal storage disorder Gaucher disease, are a prominent example of this principle, having been identified as an important genetic risk factor for Parkinson disease. Genetic analyses have revealed further examples, notably GRN, TREM2, EIF2AK3, and several other LSD and mitochondria function genes. In this Review, we discuss the evidence supporting the strikingly distinct allele-dependent clinical phenotypes observed in carriers of such gene mutations and its impact on the wider field of neurodegeneration.
Chemical Analysis and Anthelmintic Activity Against Teladorsagia Circumcincta of Nordic Bark Extracts In vitro

Helminth parasitic infections are common in small ruminants in Norway; infection is usually treated with anthelmintic drugs, but anthelmintic resistance is an increasing problem. It is necessary to identify strategies to reduce the use of anthelmintic drugs and mitigate the impact of anthelmintic resistance. Condensed tannin (CT)-rich forages have been shown to reduce the helminth burden in small ruminants, but these forages have limited cultivation potential in Scandinavia. A good source for CT in cold climatic regions may be the bark of several commercially utilized tree species. In the present study, we determined the content and characterized the type of CT in bark extracts of pine (Pinus sylvestris L.), spruce (Picea abies L.), and birch (Betula pubescens). Extracts of selected bark samples were tested for their anthelmintic efficacy against the ovine infectious nematode Teladorsagia circumcincta. Total CT content was higher in the bark from younger (10–40 years old) pine and spruce trees; it decreased with tree age in pine, whereas it remained relatively stable in the bark of spruce and birch. Pine trees consisted of 100% procyanidins, whereas prodelphinins were present in most spruce (4–17%) and all birch samples (5–34%). Our studies clearly showed that there is variation in the anthelmintic activity of water and acetone extracts of bark samples collected from various sites around Norway, as this was measured with two independent in vitro assays, the egg hatch and larvae motility assays. The anthelmintic activity of some extracts was consistent between the two assays; for example, extracts from the three samples with the highest CT content showed very high activity in both assays, whereas the extract from the sample with the lowest CT content showed the lowest activity in both assays. For other extracts, activity was not consistent across the assays, which could be attributed to the susceptibility of the different stages of the parasitic life cycle. We demonstrated that bark extracts from commercially used trees in Scandinavia have the potential to be used as alternatives to anthelmintics. Further work should focus on refining the associations between bark extracts and anthelmintic activity to identify the best strategies to reduce the input of anthelmintic drugs in livestock production systems.
Amino Acid Trp: The Far Out Impacts of Host and Commensal Tryptophan Metabolism

Tryptophan (Trp) is an essential amino acid primarily derived from the diet for use by the host for protein synthesis. The intestinal tract is lined with cells, both host and microbial, that uptake and metabolize Trp to also generate important signaling molecules. Serotonin (5-HT), kynurenine and its downstream metabolites, and to a lesser extent other neurotransmitters are generated by the host to signal onto host receptors and elicit physiological effects. 5-HT production by neurons in the CNS regulates sleep, mood, and appetite; 5-HT production in the intestinal tract by enterochromaffin cells regulates gastric motility and inflammation in the periphery. Kynurenine can signal onto the aryl hydrocarbon receptor (AHR) to elicit pleiotropic responses from several cell types including epithelial and immune cells, or can be further metabolized into bioactive molecules to influence neurodegenerative disease. There is a remarkable amount of cross-talk with the microbiome with regard to tryptophan metabolites as well. The gut microbiome can regulate the production of host tryptophan metabolites and can use dietary or recycled trp to generate bioactive metabolites themselves. Trp derivatives like indole are able to signal onto xenobiotic receptors, including AHR, to elicit tolerogenic effects. Here, we review studies that demonstrate that tryptophan represents a key intra-kingdom signaling molecule.