Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BIDrs9604789 variant with an increased risk of developing the disease (ORMeta = 1.31, p = 9.67 × 10-6). We also confirmed the association of TP63rs1515496 and TP63rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 × 10-8 and OR = 1.16, p = 2.74 × 10-5). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also found that carriers of the TP63rs1515496G allele had increased numbers of FOXP3+ Helios+ T regulatory cells and CD45RA+ T regulatory cells (p = 7.67 × 10-4 and p = 1.56 × 10-3), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10-4). These results were in agreement with research suggesting that the TP63rs1515496 variant alters binding sites for FOXA1 and CTCF, which are transcription factors involved in modulating specific subsets of regulatory T cells. In conclusion, this study identifies BID as new susceptibility locus for PDAC and confirms previous studies suggesting that the TP63 gene is involved in the development of PDAC. This study also suggests new pathogenic mechanisms of the TP63 locus in PDAC.

• MeSH
• Autophagy * genetics   MeSH
• White People genetics   MeSH
• Carcinoma, Pancreatic Ductal * genetics   pathology   MeSH
• Forkhead Transcription Factors MeSH
• Genetic Predisposition to Disease * MeSH
• Hepatocyte Nuclear Factor 3-alpha genetics   metabolism   MeSH
• Polymorphism, Single Nucleotide * MeSH
• Cohort Studies MeSH
• Humans MeSH
• Biomarkers, Tumor * genetics   MeSH
• Tumor Suppressor Proteins * genetics   MeSH
• Pancreatic Neoplasms * genetics   pathology   MeSH
• Case-Control Studies MeSH
• Transcription Factors genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH

OBJECTIVE: The aim of the study was the assessment of adherence to antiretroviral (ARV) treatment in a population of people living with HIV (PWH), improving the awareness of PWH, drawing attention to the risk of developing HIV drug resistance and subsequent treatment failure. METHODS: The basic cohort consisted of PWH followed up long-term at the HIV centre of the University Hospital Pilsen. Adherence to treatment was assessed by ARV levels. Nucleoside analogs were determined in urine by high pressure liquid chromatography (HPLC), in relation to clinical data, viral load (HIV RNA), and absolute CD4 and CD8 T cell counts. To assess mental and physical state of the patients, a modified SF-36 questionnaire was used to measure social relationships, education and ability to relax. RESULTS: From a group of 131 PWH, 18 (13.7%) with zero levels and 113 (86.3%) with any detectable ARV levels were followed for 6-12 months. A statistically significant lower viral load was demonstrated in patients who adhered to the treatment at the time of the test as indicated by ARV levels in the urine. CD4 T lymphocyte values in adherent patients were, as expected, statistically significantly higher. A significant difference for CD8 T lymphocyte was not demonstrated. A survey assessed subjective factors influencing the degree of adherence. PWH consider important: quality care enabling trust, low risk of developing opportunistic infections, self-sufficiency, quality of sleep, managing leisure activities, and good family relationships. Quality of life evaluation and satisfaction in the monitored areas were similar in both groups of PWH. CONCLUSIONS: Non-adherence leads to deterioration of CD4 and viral load levels and may be the cause of the development of HIV drug resistance and treatment failure on the part of the patient. PWH with zero or low urinary nucleoside levels were repeatedly instructed about the need for regular and sustained medication use. Regular checks with a laboratory examination service are needed to detect early emergence of resistance and side effects of the treatment, which are initially only detectable in the laboratory.

• MeSH
• Medication Adherence * psychology   MeSH
• Adult MeSH
• HIV Infections * drug therapy   psychology   MeSH
• Cohort Studies MeSH
• Quality of Life * MeSH
• Anti-HIV Agents * therapeutic use   urine   MeSH
• Middle Aged MeSH
• Humans MeSH
• CD4 Lymphocyte Count MeSH
• Viral Load MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Numerous studies have reported that increased interleukin 6 (IL-6) and soluble IL-6 receptor (sIL-6) levels induce inflammatory conditions. However, the exact mechanisms by which IL-6 drives inflammatory conditions remain unclear. Therefore, we investigated the potential role of IL-6/sIL-6R in inducing energy metabolism, including glycolysis, oxidative phosphorylation, lactate secretion and Akt/mTOR phosphorylation, in Jurkat cells, and whether IL-6 would increase the risk of developing inflammatory conditions due to the high metabolic profile of the T cells. Jurkat CD4 T-cell lines were stimulated with IL-6/sIL-6R for 24 h prior to 48-h stimulation with anti-CD3/CD28. Lactate secretion, glycolysis and oxidative phosphorylation levels were characterized using the Seahorse XF analyser. The Akt and mTOR phosphorylation status was detected using Western blotting. IL-6/sIL-6R significantly induced glycolysis and oxidative phosphorylation and their related parameters, including glycolytic capacity and maximal respiration, followed by significantly increased lactate secretion. Akt and mTOR phosphorylation were increased, which could have resulted from energy metabolism. Here we show that IL-6 enhanced the metabolic profile of Jurkat cells. This effect could have consequences for the metabolism-related signalling pathways, including Akt and mTOR, suggesting that IL-6 might promote T-cell energy metabolism, where T-cell hyperactivity might increase the inflammatory disease risk. The findings should be validated using studies on primary cells isolated from humans.

• MeSH
• Energy Metabolism * drug effects   MeSH
• Phosphorylation drug effects   MeSH
• Glycolysis drug effects   MeSH
• Interleukin-6 * metabolism   MeSH
• Jurkat Cells MeSH
• Lactic Acid metabolism   MeSH
• Humans MeSH
• Oxidative Phosphorylation drug effects   MeSH
• Proto-Oncogene Proteins c-akt * metabolism   MeSH
• Signal Transduction * drug effects   MeSH
• TOR Serine-Threonine Kinases * metabolism   MeSH
• Inflammation * metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

INTRODUCTION: The efficacy of anti-CD20 antibodies has significantly contributed to advancing our understanding of disease pathogenesis and improved treatment outcomes in relapsing-remitting multiple sclerosis (RRMS). A comprehensive analysis of the peripheral immune cell profile, combined with prospective clinical characterization, of RRMS patients treated with ocrelizumab (OCR) or ofatumumab (OFA) was performed to further understand immune reconstitution following B-cell depletion. METHODS: REBELLION-MS is a longitudinal analysis of RRMS patients treated with either OCR (n = 34) or OFA (n = 25). Analysis of B, T, natural killer (NK) and natural killer T (NKT) cells at baseline, month 1, and 12 was performed by multidimensional flow cytometry. Data were analyzed by conventional gating and unsupervised computational approaches. In parallel, different clinical parameters were longitudinally assessed. Twenty treatment-naïve age/sex-matched RRMS patients were included as the control cohort. RESULTS: B-cell depletion by OCR and OFA resulted in significant reductions in CD20+ T and B cells as well as B-cell subsets, alongside an expansion of CD5+CD19+CD20- B cells, while also elevating exhaustion markers (CTLA-4, PD-1, TIGIT, TIM-3) across T, B, NK, and NKT cells. Additionally, regulatory T-cell (TREG) numbers increased, especially in OCR-treated patients, and reductions in double-negative (CD3+CD4-CD8-) T cells (DN T cells) were observed, with these DN T cells having higher CD20 expression compared to CD4 or CD8 positive T cells. These immune profile changes correlated with clinical parameters, suggesting pathophysiological relevance in RRMS. CONCLUSIONS: Our interim data add weight to the argumentation that the exhaustion/activation markers, notably TIGIT, may be relevant to the pathogenesis of MS. In addition, we identify a potentially interesting increase in the expression of CD5+ on B cells. Finally, we identified a population of double-negative T cells (KLRG1+HLADR+, in particular) that is associated with MS activity and decreased with CD20 depletion.

• MeSH
• Antigens, CD20 * immunology   MeSH
• B-Lymphocytes immunology   drug effects   MeSH
• Killer Cells, Natural immunology   MeSH
• Adult MeSH
• Antibodies, Monoclonal, Humanized * therapeutic use   pharmacology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Longitudinal Studies MeSH
• Multiple Sclerosis, Relapsing-Remitting * immunology   drug therapy   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: Accumulating evidence suggests that spontaneous preterm labor is a syndrome caused by multiple pathological processes. The breakdown of maternal-fetal tolerance has been proposed as a key mechanism of idiopathic spontaneous preterm labor, often viewed as a chronic inflammatory process resulting from the maternal immune system's impaired tolerance of the fetus from early pregnancy. Regulatory T cells are crucial for maintaining maternal-fetal tolerance. Even a partial reduction in their levels can disrupt this tolerance, leading to adverse pregnancy outcomes such as preterm labor. Given the complexity of the T lymphocyte-mediated immune response, identifying candidate signaling pathways involved in maternal-fetal tolerance is challenging. However, current literature highlights the importance of the functional and developmental markers FoxP3, CD45RA, Helios, and CD39 due to their immunosuppressive abilities essential for maintaining pregnancy. OBJECTIVE: This study aimed to determine whether changes in numbers of selected regulatory T cell subpopulations in the first trimester are associated with subsequent spontaneous preterm labor. STUDY DESIGN: This prospective study enrolled 43 women with early singleton pregnancies, excluding those with autoimmune diseases, diabetes mellitus (type 1, type 2), primary hypertension, or who had been treated with vaginal progesterone prior to sample collection. We analyzed regulatory T cell subpopulations in maternal circulation using the DURAClone IM T cell kit, focusing on the following subsets: CD4+CD25+FoxP3+, CD4+CD25+FoxP3+CD45RA, CD4+CD25+FoxP3+Helios+, and CD4+CD25+FoxP3+CD39-. RESULTS: Among the participants, 7 experienced spontaneous preterm labor between the 23rd and 33rd weeks of gestation, while 36 delivered at term. The preterm group showed a significant reduction in numbers of all analyzed regulatory T cell subpopulations: CD4+CD25+FoxP3+ (median 0.0410×10ˆ9/L vs median 0.0550×10ˆ9/L, P=.0217), CD4+CD25+FoxP3+CD45RA- (median 0.0310×10ˆ9/L vs median 0.0420×10ˆ9/L, P=.0216), CD4+CD25+FoxP3+Helios+ (median 0.0270×10ˆ9/L vs median 0.0370×10ˆ9/L, P=.0260), CD4+CD25+FoxP3+CD39- (median 0.0300×10ˆ9/L vs median 0.0420×10ˆ9/L, P=.0427). CONCLUSION: Early first trimester alterations in specific regulatory T cell subpopulations, including diminished levels of CD4+CD25+FoxP3+, CD4+CD25+FoxP3+CD45RA-, CD4+CD25+FoxP3+Helios+, and CD4+CD25+FoxP3+CD39-, are associated with idiopathic spontaneous preterm labor. These findings suggest that early changes in these lymphocyte subpopulations may be linked to spontaneous preterm birth. This highlights the need for further research to understand the mechanisms underlying regulatory T-cell dynamics and their impact on pregnancy outcomes.

• MeSH
• Leukocyte Common Antigens metabolism   MeSH
• Apyrase immunology   MeSH
• Antigens, CD immunology   MeSH
• Adult MeSH
• Forkhead Transcription Factors * metabolism   MeSH
• Humans MeSH
• Young Adult MeSH
• Obstetric Labor, Premature * immunology   MeSH
• Prospective Studies MeSH
• Pregnancy Trimester, First immunology   MeSH
• T-Lymphocytes, Regulatory * immunology   MeSH
• Pregnancy MeSH
• Ikaros Transcription Factor MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Immune checkpoint inhibitors (ICIs), including those targeting PD-1, are currently used in a wide range of tumors, but only 20-40% of patients achieve clinical benefit. The objective of our study was to find predictive peripheral blood-based biomarkers for ICI treatment. METHODS: In 41 patients with advanced malignant melanoma (MM) and NSCLC treated with PD-1 inhibitors, we analyzed peripheral blood-based immune subsets by flow cytometry before treatment initialization and the second therapy dose. Specifically, we assessed basic blood differential count, overall T cells and their subgroups, B cells, and myeloid-derived suppressor cells (MDSC). In detail, CD4 + and CD8 + T cells were assessed according to their subtypes, such as central memory T cells (TCM), effector memory T cells (TEM), and naïve T cells (TN). Furthermore, we also evaluated the predictive value of CD28 and ICOS/CD278 co-expression on T cells. RESULTS: Patients who achieved disease control on ICIs had a significantly lower baseline proportion of CD4 + TEM (p = 0.013) and tended to have a higher baseline proportion of CD4 + TCM (p = 0.059). ICI therapy-induced increase in Treg count (p = 0.012) and the proportion of CD4 + TN (p = 0.008) and CD28 + ICOS- T cells (p = 0.012) was associated with disease control. Patients with a high baseline proportion of CD4 + TCM and a low baseline proportion of CD4 + TEM showed significantly longer PFS (p = 0.011, HR 2.6 and p ˂ 0.001, HR 0.23, respectively) and longer OS (p = 0.002, HR 3.75 and p ˂ 0.001, HR 0.15, respectively). Before the second dose, the high proportion of CD28 + ICOS- T cells after ICI therapy initiation was significantly associated with prolonged PFS (p = 0.017, HR 2.51) and OS (p = 0.030, HR 2.69). Also, a high Treg count after 2 weeks of ICI treatment was associated with significantly prolonged PFS (p = 0.016, HR 2.33). CONCLUSION: In summary, our findings suggest that CD4 + TEM and TCM baselines and an early increase in the Treg count induced by PD-1 inhibitors and the proportion of CD28 + ICOS- T cells may be useful in predicting the response in NSCLC and MM patients.

• MeSH
• Inducible T-Cell Co-Stimulator Protein metabolism   MeSH
• Programmed Cell Death 1 Receptor antagonists & inhibitors   MeSH
• CD28 Antigens MeSH
• CD8-Positive T-Lymphocytes immunology   drug effects   metabolism   MeSH
• Adult MeSH
• Immune Checkpoint Inhibitors * therapeutic use   pharmacology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Melanoma * drug therapy   immunology   blood   pathology   MeSH
• Lung Neoplasms * drug therapy   immunology   blood   pathology   MeSH
• Carcinoma, Non-Small-Cell Lung * drug therapy   immunology   blood   pathology   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigms for hematological malignancies. However, more than half of these patients cannot achieve sustainable tumor control, partially due to the inadequate potency of CAR-T cells in eradicating tumor cells. T cells are crucial components of the anti-tumor immune response, and multiple intrinsic T-cell features significantly influence the outcomes of CAR-T cell therapy. Herein, we review progressing research on T-cell characteristics that impact the effectiveness of CAR-T cells, including T-cell exhaustion, memory subsets, senescence, regulatory T-cells, the CD4+ to CD8+ T-cell ratio, metabolism, and the T-cell receptor repertoire. With comprehensive insight into the biological processes underlying successful CAR-T cell therapy, we will further refine the applications of these novel therapeutic modalities, and enhance their efficacy and safety for patients.

• MeSH
• Receptors, Chimeric Antigen * immunology   MeSH
• Hematologic Neoplasms * therapy   immunology   MeSH
• Immunotherapy, Adoptive * methods   MeSH
• Humans MeSH
• T-Lymphocytes immunology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

BACKGROUND: To date there remains much ambiguity in the literature regarding the immunological interplay between SARS-CoV-2 and HIV and the true risk posed to coinfected individuals. There has been little conclusive data regarding the use of CD4 cell count and HIV viral load stratification as predictors of COVID-19 severity in this cohort. METHODS: We performed a retrospective, observational cohort study on people living with HIV (PLWH) who contracted COVID-19 in central and eastern Europe. We enrolled 536 patients from 16 countries using an online survey. We evaluated patient demographics, HIV characteristics and COVID-19 presentation and outcomes. Statistical analysis was performed using SPSS 20.1. RESULTS: The majority of the study cohort were male (76.4%) and 152 (28.3%) had a significant medical comorbidity. Median CD4 cell count at COVID-19 diagnosis was 605 cells/μL [interquartile range (IQR) 409-824]. The majority of patients on antiretroviral therapy (ART) were virally suppressed (92%). In univariate analysis, CD4 cell count <350 cells/μL was associated with higher rates of hospitalization (p < 0.0001) and respiratory failure (p < 0.0001). Univariate and multivariate analyses found that an undetectable HIV VL was associated with a lower rate of hospitalization (p < 0.0001), respiratory failure (p < 0.0001), ICU admission or death (p < 0.0001), and with a higher chance of full recovery (p < 0.0001). CONCLUSION: We can conclude that detectable HIV viral load was an independent risk factor for severe COVID-19 illness and can be used as a prognostic indicator in this cohort.

• MeSH
• COVID-19 * epidemiology   complications   MeSH
• HIV Infections * complications   drug therapy   epidemiology   MeSH
• Humans MeSH
• CD4 Lymphocyte Count MeSH
• Respiratory Insufficiency * MeSH
• Retrospective Studies MeSH
• SARS-CoV-2 MeSH
• COVID-19 Testing MeSH
• Viral Load MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Observational Study MeSH
• Geographicals
• Europe, Eastern MeSH

Acute cellular rejection (ACR) frequently occurs following lung transplantation (LuTx) and represents a risk factor for the development of chronic lung allograft dysfunction (CLAD) as well as long-term survival. The histopathological diagnosis of ACR carries a burden of interobserver variability. The widespread utilization and cost-effectiveness of immunohistochemistry (IHC) was proven beneficial in diagnosing rejection in human kidney transplantations and LuTx rat models. However, its potential for ACR detection in patients remains unexplored. We analyzed surface markers (CD3, CD4, CD8, CD20, CD68, CD47, PD-1, PD-L1, and CD31/PECAM-1) on lung tissue cryobiopsy samples collected within 6 months post-LuTx from 60 LuTx recipients, 48 of whom were diagnosed with ACR. Additionally, serum samples from 51 patients were analyzed using a multiplex bead-based Luminex assay. The cytokines and markers included PD-L1, IL2, TNFα, IFNγ, and Granzyme B. We observed a significant increase in PD-L1 tissue expression within the rejection group, suggesting a concerted effort to suppress immune responses, especially those mediated by T-cells. Furthermore, we noted significant differences in PECAM-1 levels between ACR/non-ACR. Additionally, peripheral blood C-reactive-protein levels tended to be higher in the ACR group, while Luminex serum analyses did not reveal any significant differences between groups. In conclusion, our findings suggest the potential value of PECAM-1 and PD-L1 markers in diagnosing ACR.

• MeSH
• Acute Disease MeSH
• B7-H1 Antigen * metabolism   blood   MeSH
• Platelet Endothelial Cell Adhesion Molecule-1 * metabolism   MeSH
• Biomarkers * blood   metabolism   MeSH
• Adult MeSH
• Immunohistochemistry MeSH
• Middle Aged MeSH
• Humans MeSH
• Lung pathology   MeSH
• Graft Rejection * diagnosis   blood   MeSH
• Aged MeSH
• Lung Transplantation * adverse effects   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

• MeSH
• Classification MeSH
• Neoplasms diagnosis   MeSH
• Publication type
• Monograph MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• patologie
• onkologie