BACKGROUND: Current guidelines discourage prophylactic plasma use in non-bleeding patients. This study assesses global plasma transfusion practices in the intensive care unit (ICU) and their alignment with current guidelines. STUDY DESIGN AND METHODS: This was a sub-study of an international, prospective, observational cohort. Primary outcomes were in-ICU occurrence rate of plasma transfusion, proportion of plasma events of total blood products events, and number of plasma units per event. Secondary outcomes included transfusion indications, INR/PT, and proportion of events for non-bleeding indications. RESULTS: Of 3643 patients included, 356 patients (10%) experienced 547 plasma transfusion events, accounting for 18% of total transfusion events. A median of 2 (IQR 1, 2) units was given per event excluding massive transfusion protocol (MTP) and 3 (IQR 2, 6) when MTP was activated. MTP accounted for 39 (7%) of events. Indications of non-MTP events included active bleeding (54%), prophylactic (25%), and pre-procedure (12%). Target INR/PT was stated for 43% of transfusion events; pre-transfusion INR/PT or visco-elastic hemostatic assays (VHA) were reported for 73%. Thirty-seven percent of events were administered for non-bleeding indications, 54% with a pre-transfusion INR < 3.0 and 30% with an INR < 1.5. DISCUSSION: Plasma transfusions occurred in 10% of ICU patients. Over a third were given for non-bleeding indications and might have been avoidable. Target INR/PT was not stated in more than half of transfusions, and pre-transfusion INR/PT or VHA was not reported for 27%. Further research and education is needed to optimize guideline implementation and to identify appropriate indications for plasma transfusion.

• MeSH
• Intensive Care Units * MeSH
• Plasma * MeSH
• Hemorrhage therapy   etiology   prevention & control   MeSH
• Middle Aged MeSH
• Humans MeSH
• Blood Component Transfusion * MeSH
• Prospective Studies MeSH
• Aged MeSH
• Practice Guidelines as Topic MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Observational Study MeSH

INTRODUCTION: The E3 ubiquitin ligase Cbl-b is a novel target in immune-oncology, with critical roles in regulating T-cell activation and signaling pathways. By facilitating the ubiquitination and degradation of key signaling proteins, Cbl-b modulates immune responses, maintaining immune homeostasis and preventing unwarranted T-cell proliferation. The therapeutic potential of Cbl-b as a cancer immunotherapy target is underscored by its contribution to an immunosuppressive tumor microenvironment, with efforts currently underway to develop small-molecule inhibitors. AREAS COVERED: We reviewed the small molecules, and antibody-drug conjugates targeting Cbl-b from 2018 to 2024. The patents were gathered through publicly available databases and analyzed with in-house developed cheminformatic workflow, described within the manuscript. EXPERT OPINION: Targeting Cbl-b presents a promising approach in immuno-oncology, offering a novel pathway to potentiate the immune system's ability to combat cancer beyond PDL1/PD1 inhibition. The development and clinical advancement of Cbl-b inhibitors, as evidenced by the ongoing trials, mark a significant step toward harnessing this target for therapeutic benefits. Overall, the strategic inhibition of Cbl-b holds substantial promise for improving cancer immunotherapy outcomes, heralding a new era in the fight against cancer.

• MeSH
• Adaptor Proteins, Signal Transducing MeSH
• Molecular Targeted Therapy * MeSH
• Immunoconjugates pharmacology   MeSH
• Immunotherapy * methods   MeSH
• Humans MeSH
• Tumor Microenvironment * immunology   MeSH
• Neoplasms * immunology   drug therapy   MeSH
• Patents as Topic * MeSH
• Antineoplastic Agents pharmacology   MeSH
• Proto-Oncogene Proteins c-cbl * immunology   antagonists & inhibitors   MeSH
• Signal Transduction drug effects   MeSH
• T-Lymphocytes immunology   drug effects   MeSH
• Drug Development * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Prognostic value of T-cells between primary colorectal cancer (pCRC) and its paired synchronous and metachronous liver metastasis (LM) is underinvestigated and is the subject of the present study. We enrolled into this retrospective cohort study patients, who underwent resection of both pCRC and synchronous LM (N = 55) or metachronous LM (N = 44). After immunohistochemical staining for CD3+, CD8+, and CD45R0+ whole slides were scanned and T-cell densities were quantified using QuPath software in tumor center (TC), inner margin (IM), outer margin (OM), and peritumor zone (PT) of pCRC and LM. High densities of CD8+ T-cells in TC, OM and PT of synchronous LM were associated with longer disease-free survival (DFS). Greater densities of CD3+ T-cells in IM and PT and CD8+ T-cells in IM, OM and PT in synchronous LM over pCRC were associated with longer DFS. Greater densities of CD8+ T-cells in the TC and IM and CD3+ T-cells in the IM of pCRC were found in the metachronous over synchronous group. The first novel finding demonstrated that high density of CD8+ T cells in synchronous LM were associated with favorable outcome. The second finding of high CD8+ cell density in pCRC in metachronous over synchronous CRC may provide a mechanistic basis for the delay of metastatic spread. Both findings could be applied clinically with own reference values.

• MeSH
• CD8-Positive T-Lymphocytes immunology   MeSH
• Adult MeSH
• Colorectal Neoplasms * pathology   immunology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasms, Multiple Primary pathology   immunology   MeSH
• Liver Neoplasms * secondary   immunology   pathology   MeSH
• Disease-Free Survival MeSH
• Prognosis MeSH
• Retrospective Studies MeSH
• Neoplasms, Second Primary pathology   MeSH
• Aged MeSH
• T-Lymphocytes immunology   pathology   MeSH
• Lymphocytes, Tumor-Infiltrating immunology   pathology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Prostate cancer (PCa) is a malignancy with significant immunosuppressive properties and limited immune activation. This immunosuppression is linked to reduced cytotoxic T cell activity, impaired antigen presentation, and elevated levels of immunosuppressive cytokines and immune checkpoint molecules. Studies demonstrate that cytotoxic CD8+ T cell infiltration correlates with improved survival, while increased regulatory T cells (Tregs) and tumor-associated macrophages (TAMs) are associated with worse outcomes and therapeutic resistance. Th1 cells are beneficial, whereas Th17 cells, producing interleukin-17 (IL-17), contribute to tumor progression. Tumor-associated neutrophils (TANs) and immune checkpoint molecules, such as PD-1/PD-L1 and T cell immunoglobulin-3 (TIM-3) are also linked to advanced stages of PCa. Chemotherapy holds promise in converting the "cold" tumor microenvironment (TME) to a "hot" one by depleting immunosuppressive cells and enhancing tumor immunogenicity. SUMMARY: This comprehensive review examines the immune microenvironment in PCa, focusing on the intricate interactions between immune and tumor cells in the TME. It highlights how TAMs, Tregs, cytotoxic T cells, and other immune cell types contribute to tumor progression or suppression and how PCa's low immunogenicity complicates immunotherapy. KEY MESSAGES: The infiltration of cytotoxic CD8+ T cells and Th1 cells correlates with better outcomes, while elevated T regs and TAMs promote tumor growth, metastasis, and resistance. TANs and natural killer (NK) cells exhibit dual roles, with higher NK cell levels linked to better prognoses. Immune checkpoint molecules like PD-1, PD-L1, and TIM-3 are associated with advanced disease. Chemotherapy can improve tumor immunogenicity by depleting T regs and myeloid-derived suppressor cells, offering therapeutic promise.

• MeSH
• Immunotherapy methods   MeSH
• Humans MeSH
• Tumor-Associated Macrophages immunology   MeSH
• Tumor Microenvironment * immunology   MeSH
• Prostatic Neoplasms * immunology   pathology   therapy   MeSH
• T-Lymphocytes, Regulatory immunology   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Immunotherapy represents a revolutionary advancement in cancer treatment, which has traditionally focused on T cells; however, the role of B cells in cancer immunotherapy has gained interest because of their role in antigen presentation, antibody production, and cytokine release. In this study, we examined the role of B cells in previously developed intratumoral MBTA therapy (mannan-BAM, TLR ligands, and anti-CD40 antibody) in murine models of MTT pheochromocytoma. The results indicated that B cells significantly enhance the success of MBTA therapy, with wild-type mice exhibiting a lower tumor incidence and smaller tumors compared with B cell-deficient mice. Increased IL-6 and TNF-alpha levels indicated severe inflammation and a potential cytokine storm in B cell-deficient mice. Neutralization of TNF-alpha ameliorated these complications but resulted in increased tumor recurrence. The results highlight the important role of B cells in enhancing the immune response and maintaining immune homeostasis during MBTA therapy. Our findings offer new insights into improving therapeutic outcomes.

• MeSH
• B-Lymphocytes * immunology   MeSH
• Pheochromocytoma * immunology   therapy   MeSH
• Immunotherapy * methods   MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Adrenal Gland Neoplasms * immunology   therapy   MeSH
• Tumor Necrosis Factor-alpha MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Intramural MeSH

Our aim is to determine the number of leukocytes, T lymphocytes and B lymphocytes and the expression of activation markers CD200 and CD23 on B lymphocytes in atopic dermatitis (AD) patients (treated and not treated with dupilumab) during the pollen season. We examined 29 patients not treated with dupilumab, 24 patients treated with dupilumab and 40 healthy subjects as a control group. The count of T and B lymphocytes and their subsets were assessed by flow cytometry. The non-parametric Kruskal-Wallis one-factor analysis of variance with post hoc by Dunn's test with Bonferroni's modification was used for statistical processing. Although there was a significant improvement in skin findings in patients treated with dupilumab, the changes in immunological profile show a persistent altered immune response characterized by dysregulation and overactivation of B lymphocytes. Dupilumab therapy leads to normalization of relative T regulatory lymphocytes and total memory B lymphocytes and to decreased count of absolute CD8+ T lymphocytes. Why carry out this study?Studies investigating the immunological profile of atopic dermatitis (AD) patients during the pollen season are rare. There are no studies investigating the count of B lymphocytes (CD5+, CD22+ and CD73+ B lymphocytes) and the expression of activation markers CD23 and CD200 on B lymphocytes and on their subsets during pollen season in AD patients treated and non-treated with dupilumab therapy.What was learned from the study?In atopic dermatitis (AD) patients with and without dupilumab therapy, we confirmed the significantly higher count of absolute neutrophils, absolute monocytes, absolute eosinophils, absolute basophils, non-switched B lymphocytes, transitional B lymphocytes, CD23 memory, naive, non-switched, switched and total CD23 B lymphocytes, the relative count of CD200 memory and CD200 switched B lymphocytes.In dupilumab treated patients, we confirmed the significantly higher count of relative eosinophils, relative CD16+ eosinophils, relative CD200 non-switched B lymphocytes and lower count of absolute CD8+ T lymphocytes. Further studies should focus on investigating the effect of dupilumab on CD8+ T lymphocytes and their subpopulations.In patients without dupilumab therapy, we confirmed the significantly higher count of relative neutrophils, relative T regulatory lymphocytes and total memory B lymphocytes.The changes in the count of CD5+, CD22+ and CD73+ B lymphocytes were not observed during pollen season in both groups of AD patients.

• MeSH
• Dermatitis, Atopic * drug therapy   immunology   MeSH
• B-Lymphocytes immunology   MeSH
• Antigens, CD MeSH
• Adult MeSH
• Antibodies, Monoclonal, Humanized * therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Pollen immunology   MeSH
• Receptors, IgE MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Most kidney transplant patients who undergo biopsies are classified as having no rejection based on consensus thresholds. However, we hypothesized that because these patients have normal adaptive immune systems, T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) may exist as subthreshold activity in some transplants currently classified as no rejection. To examine this question, we studied genome-wide microarray results from 5086 kidney transplant biopsies (from 4170 patients). An updated molecular archetypal analysis designated 56% of biopsies as no rejection. Subthreshold molecular TCMR and/or ABMR activity molecular activity was detectable as elevated classifier scores in many biopsies classified as no rejection, with ABMR activity in many TCMR biopsies and TCMR activity in many ABMR biopsies. In biopsies classified as no rejection histologically and molecularly, molecular TCMR classifier scores correlated with increases in histologic TCMR features and molecular injury, lower estimated glomerular filtration rate, and higher risk of graft loss, and molecular ABMR activity correlated with increased glomerulitis and donor-specific antibody. No rejection biopsies with high subthreshold TCMR or ABMR activity had a higher probability of having TCMR or ABMR, respectively, diagnosed in a future biopsy. We conclude that many kidney transplant recipients have unrecognized subthreshold TCMR or ABMR activity, with significant implications for future problems.

• MeSH
• Biopsy MeSH
• Adult MeSH
• Glomerular Filtration Rate MeSH
• Isoantibodies immunology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Follow-Up Studies MeSH
• Graft Survival immunology   MeSH
• Prognosis MeSH
• Graft Rejection * pathology   immunology   etiology   MeSH
• Risk Factors MeSH
• T-Lymphocytes immunology   MeSH
• Kidney Transplantation * adverse effects   MeSH
• Kidney Function Tests MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Although chronic inflammation is implicated in the pathogenesis of diffuse large B-cell lymphoma (DLBCL), the mechanisms responsible are unknown. We demonstrate that the overexpression of the collagen receptor, DDR1, correlates with reduced expression of spindle checkpoint genes, with three transcriptional signatures of aneuploidy and with a higher frequency of copy number alterations, pointing to a potential role for DDR1 in the acquisition of aneuploidy in DLBCL. In support of this, we found that collagen treatment of primary germinal centre B cells transduced with DDR1, not only partially recapitulated the aberrant transcriptional programme of DLBCL but also downregulated the expression of CENPE, a mitotic spindle that has a crucial role in preventing chromosome mis-segregation. CENPE expression was also downregulated following DDR1 activation in two B-cell lymphoma lines and was lost in most DDR1-expressing primary tumours. Crucially, the inhibition of CENPE and the overexpression of a constitutively activated DDR1 were able to induce aneuploidy in vitro. Our findings identify a novel mechanistic link between DDR1 signalling and chromosome instability in B cells and provide novel insights into factors driving aneuploidy in DLBCL.

• MeSH
• Aneuploidy * MeSH
• B-Lymphocytes metabolism   MeSH
• Chromosomal Instability * genetics   MeSH
• Lymphoma, Large B-Cell, Diffuse * genetics   pathology   metabolism   MeSH
• Collagen pharmacology   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Discoidin Domain Receptor 1 * genetics   metabolism   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Signal Transduction MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Severe combined immunodeficiency (SCID) is a fatal but treatable inborn error of immunity (IEI). Newborn screening (NBS) using T-cell receptor excision circles (TREC) has been adopted globally, with very few countries incorporating kappa recombination excision circles (KREC) to also detect early B-cell development disorders, such as X-linked agammaglobulinemia (XLA). OBJECTIVE: To evaluate the effectiveness of a 2-year pilot SCID NBS program in the Czech Republic, emphasising the utility of combined TREC/KREC screening. METHODS: Between January 2022 and December 2023, a dual TREC/KREC NBS pilot was conducted across the Czech Republic, alongside spinal muscular atrophy (SMA) screening. Approximately 200,000 newborns were screened using quantitative real-time PCR on dried blood spots collected 48-72 h after birth. RESULTS: The pilot referred 58 newborns, identifying 21 cases of IEI, including two SCID cases, with an overall incidence of TREC/KREC screenable IEI of 10.5/100,000 newborns. SCID incidence was 1/100,000. KREC screening proved invaluable, detecting 10 cases of congenital agammaglobulinemia including novel non-XLA forms, which increased the estimated incidence of agammaglobulinemia in the Czech Republic sixfold. Over one-third of low KREC results were linked to maternal immunosuppression. CONCLUSION: The Czech pilot demonstrated the effectiveness of integrated TREC/KREC NBS in detecting both T- and B-cell immunodeficiencies. As of 2024, SCID and SMA screening are included in the nationwide NBS, with KREC screening significantly improving early detection of B-cell disorders.

• MeSH
• Agammaglobulinemia diagnosis   MeSH
• B-Lymphocytes immunology   MeSH
• Genetic Diseases, X-Linked MeSH
• Humans MeSH
• Infant, Newborn MeSH
• Neonatal Screening * methods   MeSH
• Pilot Projects MeSH
• Receptors, Antigen, T-Cell * genetics   MeSH
• Severe Combined Immunodeficiency * diagnosis   genetics   epidemiology   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Infant, Newborn MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH

Nonobese diabetic (NOD) mice are a widely used animal model to study mechanisms leading to autoimmune diabetes. A gluten-free diet reduces and delays the incidence of diabetes in NOD mice, but the underlying mechanisms remain largely unknown. In this study, we performed single-cell transcriptomic and flow cytometry analysis of T cells and innate lymphocytes in the spleen and pancreatic lymph nodes of NOD mice fed a gluten-free or standard diet. We observed that the gluten-free diet did not induce a substantial alteration in the abundance or phenotype of any lymphocyte subset that would directly explain its protective effect against diabetes. However, the gluten-free diet induced subtle changes in the differentiation of subsets with previously proposed protective roles in diabetes development, such as Tregs, activated γδT cells, and NKT cells. Globally, the gluten-free diet paradoxically promoted activation and effector differentiation across multiple subpopulations and induced genes regulated by IL-2, IL-7, and IL-15. In contrast, the standard diet induced type I interferon-responsive genes. Overall, the gluten-free diet might prevent diabetes in NOD mice by inducing small-scale changes in multiple cell types rather than acting on a specific lymphocyte subset.

• MeSH
• Lymphocyte Activation immunology   MeSH
• Diet, Gluten-Free * MeSH
• Cell Differentiation MeSH
• Diabetes Mellitus, Type 1 * immunology   MeSH
• Mice, Inbred NOD MeSH
• Mice MeSH
• T-Lymphocyte Subsets * immunology   MeSH
• Transcriptome MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH