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关键词： histocompatibility antigen classes   coronavirus   polymorphism   genetic   HLA-DR beta-chains   in silico model  

摘要： The high variability of human leukocyte antigen (HLA) genes results in each molecule having distinct antigenic peptide binding capacities, potentially influencing the immune response to SARS-CoV-2. This study aimed to investigate associations between HLA class I (A, B) and class II (DRB1) polymorphisms and COVID-19 severity in a South Brazilian population, and to evaluate the binding affinity of alleles to viral peptides. A cross-sectional study included 503 unvaccinated patients with RT-qPCR-confirmed COVID-19: 145 non-severe, 129 severe, and 229 critical. HLA typing was performed using PCR-SSO and Luminex (TM) technology. The DRB1*11 allelic group was significantly associated with protection against severe and critical cases, while DRB1*15 was associated with increased risk;both remained significant after Bonferroni correction. Other allelic groups were associated with disease outcomes but lost significance after correction: B*49 and B*08 (risk);and B*37, B*50, and A*03 (protection). In silico analysis revealed that the DRB1*15 allele group showed a higher proportion of strong binders, mostly from non-structural proteins, while DRB1*11:01 binders, though fewer in number, were concentrated in the M protein. These results suggest functional differences in antigen presentation and reinforce the relevance of class II HLA, particularly DRB1, in modulating COVID-19 severity.

关键词： NLR   PHR   PLR   Psoriasis vulgaris   SII  

摘要： Background and objective IL-17 and IL-23 inhibitors are widely used as biological agents in patients with psoriasis vulgaris to suppress inflammation and reduce disease severity. This study aimed to examine changes in inflammatory parameters, including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), systemic inflammation index (SII), platelet/hemoglobin ratio (PHR), and red cell distribution width/platelet ratio (RPR), as well as the Psoriasis Area and Severity Index (PASI), in psoriasis patients receiving biological therapy (IL-17 and IL-23 inhibitors). Materials and methods This retrospective study included 110 patients with psoriasis vulgaris treated with IL-23 (risankizumab, guselkumab or IL-17 inhibitors ( secukinumab, and ixekizumab). Disease severity was assessed using the PASI score. Hematological parameters (NLR, PLR, SII, PHR, and RPR) and PASI values of the patients were recorded and analyzed at baseline (month 0) and during treatment (month 6). Results A significant decrease was observed in NLR, SII, and PHR values during treatment. NLR decreased significantly from 2.43 +/- 1.25 at baseline to 2.12 +/- 0.81 at month 6 (p = 0.002). Both IL-17 and IL-23 groups significantly reduced NLR (p = 0.044, p = 0.029, respectively). SII decreased significantly from 695 +/- 390 at baseline to 588 +/- 288 at month 6 (p = 0.002). Both groups significantly reduced SII levels (p = 0.044, p = 0.018, respectively).PHR decreased significantly from 19.8 +/- 6.60 at baseline to 19.2 +/- 6.58 at month 6 (p = 0.033).PASI score significantly decreased during treatment (p < 0.001). Conclusion The significant reduction in NLR and SII levels in both the IL-17 and IL-23 groups suggests that these markers may be used together rather than separately in treatment follow-up. The significant decrease in PHR levels may indicate that IL-17 and IL-23 inhibitors contribute to reducing cardiovascular disease risk in patients with psoriasis vulgaris and promote a favorable

关键词： Systemic sclerosis   Interleukin 40   Biomarkers  

摘要： BackgroundInterleukin 40 (IL-40) is a cytokine implicated in malignancies and rheumatic disorders. Its association with fibrotic mediators has been previously described. Since inflammation and fibrosis are hallmarks of systemic sclerosis (SSc), we aimed to analyze the role of IL-40 in SSc. MethodsIL-40 levels were analyzed in the serum of 90 SSc patients and 75 healthy controls (HCs). IL-40 expression in dermal biopsies from 5 SSc patients and 5 HCs was assessed via immunohistochemistry. IL-40 was analyzed in 39 SSc patients with interstitial lung disease treated with cyclophosphamide (CPA) and in 24 SSc patients with active progressive disease treated with rituximab (RTX). SSc activity was assessed by the European Scleroderma Study Group (ESSG) index. The effect of recombinant IL-40 on peripheral blood mononuclear cells (PBMCs) from 10 SSc patients was determined in vitro. IL-40 was analyzed in 24 individuals at risk of developing SSc (VEDOSS), who were categorized as progressors (n = 11) and nonprogressors (n = 13). ResultsIL-40 expression was elevated in the skin of SSc patients compared to HCs, particularly in fibroblasts and immune infiltrates. Serum IL-40 was increased in SSc compared to HCs (p < 0.0001) and was associated with ESSG (r = 0.372, p = 0.0005) and gastrointestinal involvement (p < 0.05). IL-40 correlated with serum IL-8 (r = 0.270, p = 0.019) and TGF-beta 1 (r = 0.301, p = 0.024) levels. In the CPA and RTX cohort, no significant changes in the serum IL-40 were observed upon treatment. Baseline and changes in IL-40 levels were associated with changes in several clinical parameters. IL-40 was elevated in patients at risk of SSc compared to HCs (p = 0.0003). No significant changes were observed in progressors vs. nonprogressors;however, IL-40 was associated with capillaroscopy findings (p < 0.05). IL-40 induced the upregulation of IL-6 (p = 0.002), MCP-1 (p = 0.002) and IL-10 (p = 0.002) in PBMCs from SSc patients in vitro. ConclusionsIL-40 was upreg

关键词： Artificial tears   dry eye disease   lifestyle advice   management   therapy   treatment   medication   pharmacological   CMC   Carboxymethylcellulose   CsA   Cyclosporine   DED   Dry eye disease   DEWS   Dry eye workshops   FDA   Food and Drug Administration   HP-guar   Hydroxypropyl guar   HA   Hyaluronic acid   IL   Interleukin   IPL   Intense pulsed light   LASIK   Laser-assisted in situ keratomileusis   LLT   Lipid layer thickness   LLLT   Low-level light therapy   MGD   Meibomian gland dysfunction   MMP   Matrix metalloproteinase   NGF   Nerve growth factor   NIBUT   Non-invasive breakup time   NF-kB   Nuclear factor kappa-light-chain-enhancer of activated B cells   OSDI   Ocular Surface Disease Index   PEG   Polyethylene glycol   PRGF   Plasma rich in growth factors   PRP   Platelet-rich plasma   PUFA   Polyunsaturated fatty acids   RCT   Randomized controlled trial   rhPRG4   Recombinant human proteoglycan 4   ROS   Reactive oxygen species   SANDE   Symptom Assessment iN Dry Eye (questionnaire)   SDP-4   Silk-derived protein   SPEED   Standard Patient Evaluation of Eye Dryness (questionnaire)   TBUT   Tear breakup time   TFOS   Tear Film & Ocular Surface Society   TMH   Tear meniscus height   TRPM8   Transient Receptor Potential cation channel subfamily M member 8   TTO   Tea tree oil   UCS   Umbilical cord serum  

摘要： This report provides an evidence-based review of current strategies to manage dry eye disease (DED). First-line management focuses on methods to replenish, conserve and stimulate the tear film, with an emphasis on ocular supplements, which remain the cornerstone of DED treatment. Meibomian gland dysfunction, a primary contributor to DED, is typically treated with warm compresses and a wide variety of in-office treatments, including device-driven technologies to warm the eyelids, intense pulsed light therapy, low-level light therapy and other new and emerging technologies. Lid hygiene treatments include lid wipes, anti- Demodex therapies, blepharoexfoliation and topical antibiotics. DED caused by certain etiological drivers can benefit from anti-inflammatory therapies, including corticosteroids, T-cell immunomodulatory topical drugs and a wide variety of pharmacological agents, in addition to biologic tear substitutes such as autologous serum and platelet-rich plasma. Emerging therapies, such as neuromodulation via nasal neurostimulation and novel pharmacological treatments offer potential future options. Advanced options, including amniotic membrane grafts and complex surgical methods, provide options for severe or refractory cases. Lifestyle modifications, including optimized blinking, dietary supplementation and environmental adjustments, play a crucial role in long-term management. Patient education and adherence to treatment regimens remain essential for sustained symptom relief. The TFOS DEWS III prescribing algorithm provides an evidence-based framework to offer guidance to clinicians in selecting relevant interventions based on disease etiology that aim to provide targeted management of the subtype of DED that an individual is experiencing.

关键词： Lung carcinoma   Molecular pathogenesis   HLA-A   HLA-B   HLA-DR  

摘要： According to GLOBOCAN 2022 estimates, lung cancer is the leading cause of cancer morbidity and mortality in 2022. 5 year survival rate is dismal for the disease, despite advances in therapeutic modalities. Current research into lung cancer therapy is largely focused on molecular advancements. Our study was focused on finding association between the HLA expression in lung carcinoma patients, in northern region of India. It contributes data for basic molecular understanding of pathogenesis in lung cancer patients. This study was conducted in the Department of Pathology and Department of Pulmonary critical care and sleep medicine, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi. A total of 35 lung cancer cases and 35 healthy controls were taken over a period of 18 months and results were compared. In our study the mean age of presentation for lung carcinoma patients was 52.29 years HLA-A11 (p value = 0.028) and HLA-B51 (p value = 0.035), were under expressed in the patients as compared to control group, and HLA-DRB1*15 (p value = 0.037) was over expressed in the patients as compared to control group. However, no statistically significant result was seen in co-relation to the clinical staging. The results of this small sample study provide data for a completely new population and might help to guide in understanding the role of HLA in lung carcinoma patients for future studies.

关键词： syphilis   serofast state   IFN-gamma   polymorphism   SNP   874 T/A   2109 A/G  

摘要： Background: In approximately 20% of patients with early syphilis, the classical serological response pattern is absent following treatment. They experience a serofast state, which manifests as less than a 4-fold decline in non-treponemal titres, without any clinical signs of treatment failure or reinfection. The effectiveness of the immune defense against T. pallidum, as well as its potential failure and the occurrence of the serofast state, depends on the Th1 cellular response, including cytokines such as IFN-gamma. The aim of this prospective observational study was to investigate the impact of IFN-gamma gene polymorphisms on the occurrence of the serofast state. Materials and methods: A cohort of 97 patients with early syphilis (73.2% secondary syphilis, 26.8% early latent syphilis) and 50 healthy volunteers were enrolled. Two single nucleotide polymorphisms (SNPs) in the IFN-gamma gene promoter region, +874 T>A (rs2430561) and +2109 A>G (rs1861494), were analyzed. Serum IFN-gamma levels were measured at baseline, prior to treatment. Patients were stratified into serofast (n=18) and serologically cured (n=79) groups. Results: Serofast patients exhibited significantly lower baseline serum IFN-gamma levels compared to the serologically cured group (p=0.01). All healthy subjects had IFN-gamma levels below the detection limit. Analysis of IFN-gamma gene polymorphisms revealed a significant association with treatment outcomes. The +874 AA and +2109 GG genotypes, associated with low IFN-gamma production, were significantly more frequent in serofast patients (p=0.0004 and p=0.002, respectively), with odds ratios (OR) of 7.1 (95% CI: 2.2-23.2) and 5.5 (95% CI: 1.8-17.3), respectively. Additionally, carriers of the +874A/+2109G haplotype were significantly more likely to remain serofast (OR 4.4, p=0.01). Conversely, the +874 TT and +2109 AA genotypes, associated with high IFN-gamma production, were significantly linked to serological cure (OR 4.4, p=0.03;OR 4.4, p=0.01).

关键词： Hypobaric hypoxia   HAPE   NKT cells   IL-10   curcumin  

摘要： Background: There are environment-dependent pro-inflammatory and anti-inflammatory pathways during exposure to high altitudes. Although inhibiting the inflammatory pathway can alleviate high altitude pulmonary edema (HAPE), it is currently unclear whether inflammation is the cause of edema or the result of edema in HAPE-afflicted patients. Natural killer T (NKT) cells are a subset of T cells that play an important role in a variety of lung diseases. However, its specific role in HAPE remains unclear. Methods: HAPE rat model was established under hypobaric hypoxia condition. To investigate the role of NKT cells in HAPE, phenotypic and functional changes of NKT cells and their subpopulations were analyzed by flow cytometry. To further investigate the effect of TNF-alpha on NKT cells, rats were given intraperitoneal injection of TNF-alpha, and then, NKT cells were characterized by flow cytometry. Subsequently, the levels of TNF-alpha in the lungs and spleens of rats were detected by ELISA, and HAPE rats were treated with curcumin. Results: Compared with normal control, the ratio of TNF-alpha and IL-10 secreted by lung NKT cells was decreased in HAPE rats induced by hypoxia. Further analysis showed that the mean fluorescence intensity (MFI) of TNF-alpha in NKT cells did not change significantly, but the MFI of IL-10 increased significantly. Moreover, the MFI of IL-10 produced by TNF-alpha-treated rat lung NKT cells was higher, which was completely different from spleen NKT cells. ELISA experiments indicated that TNF-alpha was enriched in the lung tissue of rats regardless of hypoxia, and the level of TNF-alpha in lung tissue was upregulated after hypoxia. Furthermore, when HAPE rats were treated with curcumin, the MFI of IL-10 in the NKT cell subsets decreased. Conclusions: NKT cells produce high levels of IL-10, which inhibits the production of lung inflammation in HAPE rats. With the increase of TNF-alpha level, the inhibitory effect of lung NKT cells on inflammation

关键词： chronic lymphocytic leukemia   IL-10   MYC   statins   Toll-like receptors  

摘要： The cytokine-signaling inhibitor ruxolitinib causes disease flares of chronic lymphocytic leukemia (CLL). This tumor-promoting activity correlates with its ability to inhibit interleukin (IL)-10 production by CLL B cells that have been activated with IL-2 and the Toll-like receptor 7 (TLR7) agonist resiquimod (called 2S cells) in vitro. In TLR-activated normal human B cells, IL-10 production is regulated by cholesterol biosynthesis and can be inhibited by statins. The goal of this study was to determine if statins affect IL-10 production by 2S cells. Lipophilic statins decreased IL-10 production from 2S CLL cells by inhibiting activation of MYC along with secondary signaling events that amplify and maintain IL10 transcription. IL-10 production was restored when the prenylation defect imposed by statins was corrected by adding geranylgeranyl pyrophosphate. CLL cells activated by ruxolitinib in vivo were enriched with genes associated with prenylation inhibition in TLR-activated human B cells in vitro. These findings suggest IL-10 production by 2S-activated CLL cells is regulated by cholesterol biosynthesis in part through geranylgeranyl pyrophosphate production and substrate prenylation. If IL-10 production in the 2S model constitutes a surrogate test for drug responses in vivo, realization of the potential clinical benefits of statins in CLL may require coadministration of other agents.

关键词： Adult-onset Still's disease   Mass cytometry   Tocilizumab  

摘要： BackgroundEarly administration of IL-6R blockade is effective in adult-onset Still's disease (AOSD), but the underlying immune alterations during combined immunotherapy remain *** employed high-dimensional single-cell mass cytometry and an unbiased bioinformatics pipeline to characterize the immune landscape in treatment-na & iuml;ve AOSD patients, stable AOSD patients after 24 weeks of IL-6R blockade plus methotrexate and prednisone, and matched healthy controls. Cytokine profiling was conducted using a high-throughput cytometric bead array, and potential regulatory networks were identified using the PerformanceAnalytics package. Validation was performed via flow cytometry and mRNA *** identified 22 peripheral immune cell populations and characterized their composition and phenotypic markers. Treatment-na & iuml;ve AOSD patients exhibited significant depletion of CD4+ T cells and B cells, along with excessive activation of CD8+ T cells and a previously unreported CD45+CD3-CD19-CD10-CD66a+ population, findings that were validated in an independent AOSD cohort. mRNA sequencing revealed the proinflammatory role of CD8+ T cells. Notably, these dysregulated immune profiles were markedly restored following immunotherapy. IL-18, IL-21, and IFN-gamma demonstrated strong associations with adaptive immune cells and AOSD clinical *** IL-6R blockade effectively modulates immune dysregulation in refractory AOSD, reversing key pathological immune alterations and highlighting its therapeutic potential.

关键词： alpha-olefins   Fischer-Tropsch synthesis   green separation technology   ionic liquids   microwave-assisted extraction  

摘要： The actual applications of extraction methods for alpha-olefins separation are limited by their long time and high energy consumption. Hence, this study employs microwave technology to intensify the extraction process using Ag-based ionic liquid (Ag-IL), where the influence of microwave irradiation and the mechanism of microwave-assisted ionic liquid extraction (MAILE) are investigated, along with a comprehensive techno-economic analysis of process feasibility. The results of COSMO-RS and DFT simulations demonstrate the dominant role of pi-complexation in identifying Ag-IL with high selectivity, indicating the possible enhancement caused by microwave irradiation. The subsequent kinetic experiments show that compared with conventional routes, the MAILE accelerated the extraction process by approximately 89.72%. As a result, the total annual cost of unit product of the overall process is reduced by 6.43% according to techno-economic analysis by Aspen Plus, indicating that MAILE is a cost-effective, scalable, and sustainable approach to alpha-olefin separation, offering process efficiency and environmental sustainability.