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Objective: Numerous studies emphasize the pivotal role of inflammation in metabolic dysfunction-associated steatotic liver disease (MASLD) development. Some link specific systemic immune biomarkers (e.g., systemic immuno-inflammatory index [SII], neutrophil-to-albumin ratio [NPAR] and neutrophil-to-lymphocyte ratio [NLR]) to hepatic steatosis risk. However, the relevance of other markers like systemic immune-inflammation index [SIRI], platelet-to-lymphocyte ratio [PLR] and lymphocyte/monocyte ratio [LMR] in MASLD remains unclear. Limited literature covers all six markers together. This study aims to investigate the association between SII, SIRI, LMR, NLR, PLR, and NPAR and MASLD, assessing their predictive value. Methods: In this cross-sectional analysis of adults from NHANES (2007-2018), we investigated the relationship between six systemic immune biomarkers, stratified by quartiles: quartile1 (Q1), quartile2 (Q2), quartile3 (Q3) and quartile4 (Q4), and the outcome of MASLD assessed by Fatty Liver Index (FLI) and United States Fatty Liver Index (USFLI). Logistic regression and restricted cubic splines (RCS) were employed to assess the association between systemic immune biomarkers and MASLD risks. Propensity score matching controlled for potential confounders, and receiver operating characteristic (ROC) curve analysis evaluated the biomarkers' predictive performances for MASLD. Subgroup and interaction analysis were conducted to explore the effects of systemic immune biomarkers on MASLD risks. Multicollinearity was quantified using the variance inflation factor. Results: In total, 14,413 participants were included and 6,518 had MASLD. Compared with non-MASLD, participants with MASLD had higher SII, SIRI, NLR, PLR, and NPAR (p < 0.001). SII, SIRI, NLR, and NPAR were further validated in the restricted cubic splines (RCS) regression model and identified as positive linear relationships (p for nonlinear >0.05). The prevalence of MASLD increased with the Q4 of SII [OR = 1.47, 95%CI (1.24, 1.74)], SIRI [OR = 1.30, 95%CI (1.09, 1.54)], NLR [OR = 1.25, 95%CI (1.04, 1.49)], PLR [OR = 1.29, 95%CI (1.09, 1.53)] and NPAR [OR = 1.29, 95%CI (1.09, 1.54)] compared to the Q1 after adjusting for the bias caused by potential confounders. However, the propensity score matching analysis only supported an association between the highest SII, SIRI, NLR NPAR and the risk of MASLD. The results of the subgroup analysis showed considerable robustness in the relationship. Conclusion: Higher SII, SIRI, NLR and NPAR were positively associated with a heightened risk of MASLD. NPAR showed the superior predictive value, followed by SII, SIRI and NLR. This needs to be validated in additional longitudinal studies and clinical trials.

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PROBLEM: Female sex workers (FSW) experience a disproportionately high burden of HIV infection, yet characterization of the vaginal immune microenvironment that may impact biological risk is not well studied among FSW in the United States. Additionally, feasible methodology for collecting biological materials has not been evaluated in this population. METHODS: We enrolled 10 FSW (5 premenopausal, 5 postmenopausal) who participated in a survey and provided vaginal swabs. Biomarkers were assessed by ELISA, and included cytokines, chemokines, and antimicrobial/wound-healing mediators. RESULTS: One hundred percent of FSW were African American, with a median age of 43.5. The median age when participants started sex work was 17.5, with 60% working 7 days per week and seeing up to 10 clients per night. Eighty percent reported recent unprotected sex and only 30% used some form of contraception. One self-reported sexually transmitted infection at the time of visit and two reported living with HIV. Vaginal secretions showed detectable levels of all biomarkers tested, except MIP3α and MIP1α, which were undetectable in all samples. When stratified by age/menopause status, no significant changes were observed except for Serpin A1 with higher median levels in premenopausal compared to postmenopausal FSW (median 5.79 vs. 5.205 log pg/mL, p = 0.016). Comparison with samples from an existing repository of non-FSW women showed significantly reduced chemokines IL8 (p = 0.045), MIP3α (p ≤ 0.001), and MIP1ß (p = 0.015) in the FSW group. CONCLUSIONS: We report characterization of the vaginal secretome in a cohort of FSW in the United States. Understanding of the genital immune microenvironment can inform future research in HIV prevention and therapeutic options in this population.

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Neoadjuvant chemotherapy (NAC) is now the standard of care for patients with locally advanced breast cancer (BC). TIL scoring is prognostic and adds predictive value to the residual cancer burden evaluation after NAC. However, NAC induces changes in the tumor, and the reliability of TIL scoring in post-NAC samples has not yet been studied. H&E- and dual CD3/CD20 chromogenic IHC-stained tissues were scored for stromal and intra-tumoral TIL by two experienced pathologists on pre- and post-treatment BC tissues. Digital TIL scoring was performed using the HALO® image analysis software (version 2.2). In patients with residual disease, we show a good inter-pathologist correlation for stromal TIL on H&E-stained tissues (CCC value 0.73). A good correlation for scoring with both staining methods (CCC 0.81) and the digital TIL scoring (CCC 0.77) was also observed. Overall concordance for TIL scoring in patients with a complete response was however poor. This study reveals there is good reliability for TIL scoring in patients with detectable residual tumors after NAC treatment, which is comparable to the scoring of untreated breast cancer patients. Based on the good consistency observed with digital TIL scoring, the development of a validated algorithm in the future might be advantageous.

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A raise in the incidence of NENs is expected. Therefore, the identification of new therapeutic strategies, such as immunotherapy, remains crucial. To date, immune checkpoint inhibitors as monotherapy have shown modest activity in unselected NENs. Although immunotherapy combos (plus another immune agents or chemotherapy, among others) are potentially more active than single agents, this has not been uniformly confirmed, even in high-grade NENs. Other immunotherapeutic strategies under development include bispecific antibodies, targeting specific tumor antigens like DLL3, and cell therapy. Currently, no predictive immune biomarkers are available to guide clinical decisions. A comprehensive tumor molecular profiling approach needs to be developed for the selection of patients with NEN who could potentially benefit from immunotherapy. Ideally, clinical trials should incorporate this tumor molecular profiling to identify predictive biomarkers and improve efficacy. Achieving this goal requires an international collaborative effort.

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Ischemic stroke is the leading cause of long-term disability in adults, accounting for 80% of stroke cases. Diffusion weighted imaging (DWI) examination is the main test for acute ischemic stroke, but in recent years, several studies have shown that some patients show negative DWI examination after the onset of ischemic stroke with symptoms of significant neurological deficits. In this study, we investigated potential biomarkers related to immune metabolism in the peripheral blood of DWI-negative versus DWI-positive patients after ischemic stroke and explored their possible regulatory processes in ischemic stroke. The datasets related to ischemic stroke were downloaded from the GEO database, immune-related genes and metabolism-related genes were obtained from the ImmPort database and MSigDB database, respectively, and immune-related differential genes were obtained based on immune scores using the algorithm of the R software package "GSVA." Candidate genes were selected based on intersections, hub genes were screened using the algorithm in Cytoscape software, and finally, GeneMANIA analysis, GSEA enrichment analysis, subcellular localization, gene transcription factor and gene-drug interaction networks, and disease correlation analyses were performed for the hub genes. Five hub genes (GART, TYMS, PPAT, CTPS1, and PAICS) were obtained by PPI network analysis and software analysis. Among them, PPAT and PAICS may be the real hub genes with consistent and significantly differentiated results from the discovery and validation sets. The functions of these hub genes may be related to pathways such as nucleotide biosynthetic processes. The constructed hub gene ceRNA network showed that hsa-10a-5p is the key miRNA connecting PAICS and multiple lncRNAs in this study. Differential genes related to immunity and metabolism in DWI-negative and DWI-positive patients after IS were identified using bioinformatics analysis, and their pathways and related TF-RNAs, miRNAs, and lncRNAs were identified. These genes may be considered effective targets for the diagnosis and treatment of ischemic stroke.

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First-line systemic therapy for patients with advanced or metastatic non-small cell lung cancer (NSCLC) has rapidly evolved over the past two decades. First, molecularly targeted therapy for a growing number of gain-of-function molecular targets has been shown to improve progression-free survival (PFS) and overall survival (OS) with favorable toxicity profiles compared to platinum-containing chemotherapy and can be given as first-line systemic therapy in ~25% of patients with NSCLC. Actionable genetic alterations include EGFR, BRAF V600E, and MET exon 14 splicing site-sensitizing mutations, as well as ALK-, ROS1-, RET-, and NTRK-gene fusions. Secondly, inhibitors of programmed cell death protein 1 or its ligand 1 (PD-1/L1) such as pembrolizumab, atezolizumab, or cemiplimab monotherapy have become a standard of care for ~25% of patients with NSCLC whose tumors have high PD-L1 expression (total proportion score (TPS) ≥50%) and no sensitizing EGFR/ALK alterations. Lastly, for the remaining ~50% of patients who are fit and whose tumors have no or low PD-L1 expression (TPS of 0-49%) and no sensitizing EGFR/ALK aberrations, platinum-containing chemotherapy with the addition of a PD-1/L1 inhibitor alone or in combination of a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor improves PFS and OS compared to chemotherapy alone. The objectives of this review are to summarize the current data and perspectives on first-line systemic treatment in patients with unresectable NSCLC and propose a practical algorithm for implementing precision biomarker testing at diagnosis.

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BACKGROUND: Mutation or amplification of the mesenchymal-epithelial transition (MET) tyrosine kinase receptor causes dysregulation of receptor function and stimulates tumor growth in non-small cell lung cancer (NSCLC) with the most common mutation being MET exon 14 (METex14). We sought to compare the genomic and immune landscape of MET-altered NSCLC with MET wild-type NSCLC. METHODS: 18,047 NSCLC tumors were sequenced with Tempus xT assay. Tumors were categorized based on MET exon 14 (METex14) mutations; low MET amplification defined as a copy number gain (CNG) 6-9, high MET amplification defined as CNG ≥ 10, and MET other type mutations. Immuno-oncology (IO) biomarkers and the frequency of other somatic gene alterations were compared across MET-altered and MET wild-type groups. RESULTS: 276 (1.53%) METex14, 138 (0.76%) high METamp, 63 (0.35%) low METamp, 27 (0.15%) MET other, and 17,543 (97%) MET wild-type were identified. Patients with any MET mutation including METex14 were older, while patients with METex14 were more frequently female and nonsmokers. MET gene expression was highest in METamp tumors. PD-L1 positivity rates were higher in MET-altered groups than MET wild-type. METex14 exhibited the lowest tumor mutational burden (TMB) and lowest neoantigen tumor burden (NTB). METamp exhibited the lowest proportion of CD4 T cells and the highest proportion of NK cells. There were significant differences in co-alterations between METamp and METex14. CONCLUSIONS: METex14 tumors exhibited differences in IO biomarkers and the somatic landscape compared to non-METex14 NSCLC tumors. Variations in immune profiles can affect immunotherapy selection in MET-altered NSCLC and require further exploration.

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Optical tissue clearing and three-dimensional (3D) immunofluorescence (IF) microscopy is transforming imaging of the complex tumor microenvironment (TME). However, current 3D IF microscopy has restricted multiplexity; only 3 or 4 cellular and noncellular TME components can be localized in cleared tumor tissue. Here we report a light-emitting diode (LED) photobleaching method and its application for 3D multiplexed optical mapping of the TME. We built a high-power LED light irradiation device and temperature-controlled chamber for completely bleaching fluorescent signals throughout optically cleared tumor tissues without compromise of tissue and protein antigen integrity. With newly developed tissue mounting and selected region-tracking methods, we established a cyclic workflow involving IF staining, tissue clearing, 3D confocal microscopy, and LED photobleaching. By registering microscope channel images generated through 3 work cycles, we produced 8-plex image data from individual 400 µm-thick tumor macrosections that visualize various vascular, immune, and cancer cells in the same TME at tissue-wide and cellular levels in 3D. Our method was also validated for quantitative 3D spatial analysis of cellular remodeling in the TME after immunotherapy. These results demonstrate that our LED photobleaching system and its workflow offer a novel approach to increase the multiplexing power of 3D IF microscopy for studying tumor heterogeneity and response to therapy.

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Older patients with cancer, particularly those over 75 years of age, often experience poorer clinical outcomes compared to younger patients. This can be attributed to age-related comorbidities, weakened immune function, and reduced tolerance to treatment-related adverse effects. In the immune checkpoint inhibitors (ICI) era, age has emerged as an influential factor impacting the discovery of predictive biomarkers for ICI treatment. These age-linked changes in the immune system can influence the composition and functionality of tumor-infiltrating immune cells (TIICs) that play a crucial role in the cancer response. Older patients may have lower levels of TIICs infiltration due to age-related immune senescence particularly T cell function, which can limit the effectivity of cancer immunotherapies. Furthermore, age-related immune dysregulation increases the exhaustion of immune cells, characterized by the dysregulation of ICI-related biomarkers and a dampened response to ICI. Our review aims to provide a comprehensive understanding of the mechanisms that contribute to the impact of age on ICI-related biomarkers and ICI response. Understanding these mechanisms will facilitate the development of treatment approaches tailored to elderly individuals with cancer.

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Introduction: In the era of personalized medicine and treatment optimization, use of immune biomarkers holds promise for estimating the prognosis of patients with head and neck squamous cell carcinoma (HNSCC) undergoing definitive treatment. Methods: To evaluate the prognostic potential of immune biomarkers, we conducted a prospective monocentric cohort study with loco-regionally advanced HNSCC patients indicated for definitive radiotherapy/radiochemotherapy at the Department of Oncology, Ostrava University Hospital, Czech Republic, between June 2020 and August 2023. We focused on the expression of programmed death ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs) relative to overall survival (OS) and specific survival rates. Associations between biomarkers and survival rates were assessed by crude and adjusted hazard ratios (cHR, aHR, respectively) obtained from Cox proportional hazards regression. Results: Among a total of 55 patients within a median follow-up of 19.7 months, there were 21 (38.2%) all-cause deaths and 15 (27.3%) cancer-related deaths. An overall survival (OS) rate of 61.8% and a disease-specific survival (DSS) rate of 72.7% were recorded. A significant association between survival rates and a ≥10% difference in PD-L1 expression on immune versus tumor cells (high PD-L1IC expression) was documented regardless of the type of analysis (univariate or multivariate). In addition, a stronger association was confirmed for OS and the composite biomarker high PD-L1IC expression along with either median-higher CD8+ TIL count or increased TIL density ≥30%, as indicated by an aHR of 0.08 (95% CI, 0.01 to 0.52) and 0.07 (95% CI, 0.01 to 0.46), respectively. Similar results were demonstrated for other specific survival rates. Discussion: The early outcomes of the present study suggest the utility of a strong prognostic factor involving a composite biomarker high PD-L1IC expression along with increased TIL density in HNSCC patients undergoing definitive radiotherapy and radiochemotherapy. Trial registration: The study is registered with Clinicaltrials.gov. - NCT05941676.

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Background: Cervical cancer (CC) is a highly malignant gynecological cancer with a direct causal link to inflammation, primarily resulting from persistent high-risk human papillomavirus (HPV) infection. Given the challenges in early detection and mid to late-stage treatment, our research aims to identify inflammation-associated immune biomarkers in CC. Methods: Using a bioinformatics approach combined with experimental validation, we integrated two CC datasets (GSE39001 and GSE63514) in the Gene Expression Omnibus (GEO) to eliminate batch effects. Immune-related inflammation differentially expressed genes (DGEs) were obtained by R language identification. Results: This analysis identified 37 inflammation-related DEGs. Subsequently, we discussed the different levels of immune infiltration between CC cases and controls. Weighted gene co-expression network analysis (WGCNA) identified seven immune infiltration-related modules in CC. We identified 15 immune DEGs associated with inflammation at the intersection of these findings. In addition, we constructed a protein interaction network using the String database and screened five hub genes using "CytoHubba": CXC chemokine ligand 8 (CXCL8), CXC chemokine ligand 10 (CXCL10), CX3C chemokine receptor 1 (CX3CR1), Fc gamma receptors 3B (FCGR3B), and SELL. The expression of these five genes in CC was determined by PCR experiments. In addition, we assessed their diagnostic value and further analyzed the association of immune cells with them. Conclusions: Five inflammation- and immune-related genes were identified, aiming to provide new directions for early diagnosis and mid to late-stage treatment of CC from multiple perspectives.

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Heavy training has been reported to be immunosuppressive in athletes and lead to blunted cortisol responses to exercise. Cortisol elevates the number of dendritic cells (DCs), key antigen-presenting cells that interact with T cells to initiate an immune response. Reproducible cortisol responses to a 30-min cycle test have been identified but were based on percentage of work rate maximum. To ensure physiological consistency, submaximal anchors, that is, ventilatory threshold (VT1 ) should prescribe intensity. This study aims to assess the reproducibility of the DC and T cell responses to an adapted stress test to assess its usefulness in assessing DC dysfunction with intensified training. Twelve males cycled for 1 min at 20% below VT1 and 4 min at 50% between VT1 and V ̇ O 2 max ${\dot{V}}_{{{\mathrm{O}}}_{\mathrm{2}}\max }$ , for 30 min (20/50), with blood samples pre-, post- and 30 min post-exercise. This was repeated twice, 2-7 days apart. Flow cytometry assessed total DCs, plasmacytoid DCs, myeloid DCs, total T cells, T helper cells and T cytotoxic cells. No significant trial or interaction effects were found for any variable. A significant main effect of time for all variables was found; immune cells increased from pre- to post-exercise and decreased to baseline 30 min post-exercise, apart from plasmacytoid DCs, which remained elevated 30 min post-exercise. Intraclass correlation coefficients showed overall good-to-excellent reliability for all immune cells, with smallest real difference and Bland-Altman analysis verifying high reproducibility between trials. These results suggest that the 20/50 exercise test induces reproducible DC and T cell count changes, which, implemented before and after a period of intensified training, may highlight the negative states of overtraining.

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Multiplexed quantification of low-abundance protein biomarkers in complex biofluids is important for biomedical research and clinical diagnostics. However, in situ sampling without perturbing biological systems remains challenging. In this work, we report a buoyant biosensor that enables in situ monitoring of protein analytes at attomolar concentrations with a 15 min temporal resolution. The buoyant biosensor implemented with fluorescent nanolabels enabled the ultrasensitive and multiplexed detection and quantification of cytokines. Implementing the biosensor in a digital manner (i.e., counting the individual nanolabels) further improves the low detection limit. We demonstrate that the biosensor enables the detection and quantification of the time-varying concentrations of cytokines (e.g., IL-6 and TNF-α) in macrophage culture media without perturbing the live cells. The easy-to-apply biosensor with attomolar sensitivity and multiplexing capability can enable an in situ analysis of protein biomarkers in various biofluids and tissues to aid in understanding biological processes and diagnosing and treating diverse diseases.

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BACKGROUND: Triple-negative breast cancer (TNBC) is a subtype of breast cancer with limited treatment options and poor prognosis. This study aimed to identify potential therapeutic targets based on the expression profiles of differentially expressed genes (DEGs) in TNBC. METHODS: The Limma package was used to identify DEGs in TCGA and GEO datasets. Immunohistochemical (IHC) analysis and western blotting were used to determine the expression of ZDHHC9 in TNBC tissues. Flow cytometry assay and tissue immunofluorescence analysis were used to detect infiltration of multiple immune cells in tumor tissue at different levels of ZDHHC9 expression. RESULTS: ZDHHC9 was identified as a key factor associated with resistance to ICB therapy through weighted gene co-expression network analysis (WGCNA) and single-cell RNA sequencing (scRNA-seq). Subsequently, immunohistochemical (IHC) analysis and western blotting verified that ZDHHC9 expression was elevated in TNBC cancer tissues and that elevated expression of ZDHHC9 was associated with the poor survival of patients with TNBC. Analysis of data from several public datasets revealed that patients with high ZDHHC9 expression had an increased proportion of Ki-67 + breast cancer cells and tended to be basal-like breast cancer. In addition, in vitro and in vivo experiments demonstrated that high expression of ZDHHC9 significantly predicted the efficacy and responsiveness of immunotherapy in TNBC. CONCLUSION: These findings suggest that ZDHHC9 is a valuable marker for guiding the classification, diagnosis and prognosis of TNBC and developing specific targeted therapies.

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Many studies aim to detect the early phase of dementia. One of the major ways to achieve this is to identify corresponding biomarkers, particularly immune blood biomarkers. The objective of this study was to identify such biomarkers in patients with mild cognitive impairment (MCI) in an experiment that included cognitive training. A group of patients with MCI diagnoses over the age of 65 participated in the study (n = 136). Measurements of cognitive functions (using the Mini-Mental State Examination scale and Montreal Cognitive Assessment) and determination of 27 serum biomarkers were performed twice: on the first visit and on the second visit, one year after the cognitive training. APOE genotypes were also determined. Concentrations of EGF (F = 17; p = 0.00007), Eotaxin (F = 7.17; p = 0.008), GRO (F = 13.42; p = 0.0004), IL-8 (F = 8.16; p = 0.005), MCP-1 (F = 13.46; p = 0.0001) and MDC (F = 5.93; p = 0.016) increased after the cognitive training in MCI patients. All these parameters except IL-8 demonstrated a weak correlation with other immune parameters and were poorly represented in the principal component analysis. Differences in concentrations of IP-10, FGF-2, TGFa and VEGF in patients with MCI were associated with APOE genotype. Therefore, the study identified several immune blood biomarkers that could potentially be associated with changes in cognitive function.

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The immunological genes that may interact with inflammatory postpartum diseases in Italian buffaloes were examined in this study. A total number of 120 female Italian buffaloes (60 normal and 60 with inflammatory reproductive diseases) were employed. Each buffalo's jugular vein was pierced to get five milliliters of blood. To obtain whole blood and extract DNA and RNA, the blood was placed within tubes containing sodium fluoride or EDTA anticoagulants. The immunological (IKBKG, LGALS, IL1B, CCL2, RANTES, MASP2, HMGB1, and S-LZ) genes' nucleotide sequence differences between healthy buffaloes and buffaloes affected by inflammatory reproductive diseases were found by employing PCR-DNA sequencing. According to Fisher's exact test (p ˂ 0.01), there were noticeably different probabilities of all major nucleotide changes spreading among buffalo groups with and without reproductive problems. Buffaloes were significantly more likely to express the examined genes when they had inflammatory reproductive diseases. The outcomes might support the significance of these markers' nucleotide variations and gene expression patterns as indicators of the prevalence of inflammatory reproductive disorders and provide a workable buffalo management policy.

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Although immunotherapy has proved to be a very efficient therapeutic strategy for many types of tumors, the results for pancreatic cancer (PC) have been very poor. Indeed, chemotherapy remains the standard treatment for this tumor in the advanced stage. Clinical data showed that only a small portion of PC patients with high microsatellite instability/mismatch repair deficiency benefit from immunotherapy. However, the low prevalence of these alterations was not sufficient to lead to a practice change in the treatment strategy of this tumor. The main reasons for the poor efficacy of immunotherapy probably lie in the peculiar features of the pancreatic tumor microenvironment in comparison with other malignancies. In addition, the biomarkers usually evaluated to define immunotherapy efficacy in other cancers appear to be useless in PC. This review aims to describe the main features of the pancreatic tumor microenvironment from an immunological point of view and to summarize the current data on immunotherapy efficacy and immune biomarkers in PC.

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Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has prevailed globally since November 2021. The extremely high transmissibility and occult manifestations were notable, but the severity and mortality associated with the Omicron variant and subvariants cannot be ignored, especially for immunocompromised populations. However, no prognostic model for specially predicting the severity of the Omicron variant infection is available yet. In this study, we aim to develop and validate a prognostic model based on immune variables to early recognize potentially severe cases of Omicron variant-infected patients. Methods: This was a single-center prognostic study involving patients with SARS-CoV-2 Omicron variant infection. Eligible patients were randomly divided into the training and validation cohorts. Variables were collected immediately after admission. Candidate variables were selected by three variable-selecting methods and were used to construct Cox regression as the prognostic model. Discrimination, calibration, and net benefit of the model were evaluated in both training and validation cohorts. Results: Six hundred eighty-nine of the involved 2,645 patients were eligible, consisting of 630 non-ICU cases and 59 ICU cases. Six predictors were finally selected to establish the prognostic model: age, neutrophils, lymphocytes, procalcitonin, IL-2, and IL-10. For discrimination, concordance indexes in the training and validation cohorts were 0.822 (95% CI: 0.748-0.896) and 0.853 (95% CI: 0.769-0.942). For calibration, predicted probabilities and observed proportions displayed high agreements. In the 21-day decision curve analysis, the threshold probability ranges with positive net benefit were 0~1 and nearly 0~0.75 in the training and validation cohorts, correspondingly. Conclusions: This model had satisfactory high discrimination, calibration, and net benefit. It can be used to early recognize potentially severe cases of Omicron variant-infected patients so that they can be treated timely and rationally to reduce the severity and mortality of Omicron variant infection.

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The effectiveness of breeding for inherent disease resistance in animals could be considerably increased by identifying the genes and mutations that cause diversity in disease resistance. One hundred and twenty adult female Baladi goats (sixty pneumonic and sixty apparently healthy) were used in this study. DNA and RNA were extracted from blood samples collected from the jugular vein of each goat. SLC11A1, CD-14, CCL2, TLR1, TLR7, TLR8, TLR9, ß defensin, SP110, SPP1, BP1, A2M, ADORA3, CARD15, IRF3, and SCART1 SNPs that have been previously found to be associated with pneumonia resistance/susceptibility were identified via PCR-DNA sequencing. The pneumonic and healthy goats differed significantly, according to a Chi-square analysis of the discovered SNPs. The mRNA levels of the studied immune markers were noticeably greater in the pneumonic goats than in the healthy ones. The findings could support the significance of the use of immune gene expression profiles and nucleotide variations as biomarkers for the susceptibility/resistance to pneumonia and provide a practical management technique for Baladi goats. These results also suggest a potential strategy for lowering pneumonia in goats by employing genetic markers linked to an animal's ability to fend off infection in selective breeding.

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Background: Ras guanine nucleotide-releasing protein 2 (RASGRP2), one of the guanine nucleotide exchange factors (GEFs), has attracted much attention in recent years. However, the correlation between RASGRP2 and immune infiltration and malignant features in lung adenocarcinoma (LUAD) has rarely been mentioned. Methods: The Limma package and the LASSO regression model were performed to screen for differentially expressed genes. Data from the TCGA and 5 GEO databases were used to explore the expression level of RASGRP2 in LUAD patients. A weighted co-expression network and LinkFinder module were established to find the related genes of RASGRP2. The ESTIMATE algorithm was used to analyze the correlation between RASGRP2 and immune infiltration in LUAD. Tumor-infiltrating immune cells were sorted and sequenced at the single-cell level to analyze differences in RASGRP2. Real-time PCR and immunohistochemistry were performed in the real-world cohort to verify the expression of RASGRP2 and its correlation with immune-related genes. Clone formation and EdU assays were used to verify the proliferation ability. The proportion of apoptotic cells was analyzed by flow cytometry. Observation of mitochondrial membrane potential (MMP) changes by fluorescence microscopy. Results: Our results suggested that decreased RASGRP2 was associated with worse clinical parameters and prognosis in LUAD patients. And we constructed a FLI1-HSA-miR-1976-RASGRP2 transcriptional network to support the role of RASGRP2. Enrichment analysis revealed that RASGRP2 was involved in lymphocyte activation and leukocyte adhesion. RASGRP2 was found to be positively correlated with the infiltration of most immune cells, immunoregulators, and chemokines in a subsequent study. Meanwhile, the real-world cohort confirmed that the expression levels of PDCD1, CTLA4, CD40LG, CCL14, CXCR5, and CCR7 were higher in the high-RASGRP2 expression group. Cytological experiments proved that RASGRP2 inhibited cell proliferation in LUAD by regulating mitochondrial-dependent apoptosis. Conclusion: RASGRP2 was a potential immune-related biomarker of LUAD. In addition, RASGRP2 was involved in the malignant progression of LUAD through the regulation of mitochondrial-dependent apoptosis.

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