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关键词： melanoma   anti-PD-1 antibody   anti-CTLA-4 antibody   immunotherapy   IL-2   IFN  

摘要： It has been more than a decade since anti-PD-1 and anti-CTLA-4 antibodies were first introduced for the treatment of unresectable melanoma. The advent of these immunotherapies has dramatically transformed the treatment landscape. In recent years, anti-PD-1 antibodies have become the cornerstone of melanoma therapy, and the development of new treatment regimens has advanced rapidly in both Eastern and Western countries. However, clinical practice has revealed lower response rates in East Asian melanoma patients compared to Caucasian populations. This discrepancy may be partially attributed to T cell immune exhaustion within the tumor microenvironment, although the detailed mechanisms remain unclear. Moreover, there is currently no established treatment for BRAF wild-type melanoma that is resistant to anti-PD-1 antibodies. This review discusses the currently available therapeutic strategies for advanced melanoma and addresses the aforementioned challenges, highlighting recent efforts in both Eastern and Western regions.

关键词： interleukin-18 (IL-18)   chimeric antigen receptor (CAR)   cancer therapy   CAR-T dysfunction   superior antitumor efficacy  

摘要： IL-18-armored chimeric antigen receptor (CAR)-engineered T (***-T) cells have demonstrated enhanced antitumor efficacy in lymphoma patients refractory to conventional CAR-T therapy. Unraveling the mechanisms behind this potent enhancement and mitigating associated toxicities could unlock a new era of next-generation CAR-T therapies with superior effectiveness and broader clinical impact.

关键词： Acute respiratory distress syndrome   COVID-19   cytokines   hematological parameters   polymorphism  

摘要： Background: Acute respiratory distress syndrome (ARDS), which is often observed in severe cases of coronavirus disease 2019 (COVID-19), is known to be a major contributor to higher mortality rates. This study assesses how hematological parameters, inflammatory biomarkers, cytokines, and the-1,082 A/G polymorphism are associated with ARDS severity in COVID-19 patients. Methods: Following exclusions, a 6-month prospective case-control study included 82 healthy controls (HCs) and 158 COVID-19 patients with varying severities of ARDS (mild: 73, moderate: 53, and severe: 32). Blood samples were collected at admission, and laboratory biomarkers were assessed using various methods. Statistical analyses included one-way analysis of variance with Tukey's test for group comparisons, Pearson correlation, and receiver operating characteristic curve for analyzing independent associations with COVID-19 severity. Multiple linear regression and chi-square tests were used to evaluate quantitative outcomes and categorical associations, respectively. Results: Severe ARDS patients exhibited higher C-reactive protein (CRP) levels compared to HCs. Compared to HCs, patients with moderate and severe ARDS had higher neutrophil to lymphocyte ratio (NLR), neutrophil counts, tumor necrosis factor-alpha, and interleukin-10 (IL-10), as well as lower lymphocyte counts and reduced partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio. IL-10, body mass index, CRP, and NLR were associated with reduced PaO2/FiO2 ratio. IL-10 and CRP had the highest area under curve values toward ARDS severity. COVID-19 patients possessing the-1,082 A/G single nucleotide IL-10 GG and GA genotypes and the G allele presented with less severe ARDS. Conclusion: Hematological indices (neutrophil count and NLR), CRP, and serum IL-10 hold promise in monitoring ARDS severity in COVID-19 patients. In addition, COVID-19 patients with GG and AG genotypes and the G allele of the IL-10 gene's-1,082 A/G polymorph

关键词： C-X-C chemokine ligand-1 (CXCL1)   fibroblast   interleukin-6 (IL-6)   interleukin-8 (IL-8)   kallikrein (KLK)   protease-activated receptor-1 (PAR-1)   wound healing  

摘要： Human tissue kallikrein 14 (KLK14) is protease with trypsin/chymotrypsin specificity that is abundant in the skin. It is involved in skin desquamation and wound healing by cleaving cell-cell adhesion molecules and extracellular matrix components. In the process of wound healing, a paracrine communication between the epithelium, human skin fibroblasts (HSFs), and immune cells is essential for proper regulation. Previous reports highlighted stimulation of interleukin-6 (IL-6), interleukin-8 (IL-8), and growth-regulated alpha protein (CXCL1) production by keratinocyte-conditioned medium in fibroblast cells and implicated these cytokines in cancer. Here, we hypothesize that KLK14 may be a paracrine mediator released by keratinocytes that activates fibroblasts via proteinase-activated receptor (PAR) pathway, affecting the HSF secretome. Semiquantitative real-time PCR and ELISA demonstrated that proteolytically active KLK14 induced the expression of IL-6, IL-8, and CXCL1 by 15-, 847-, and 50-fold, respectively, and resulted in the release of the proteins in ng/ml quantities from stimulated HSFs to the culture medium. Through the implementation of the PAR-1 antagonist RWJ 56110, we demonstrated that the KLK14-mediated release of IL-6 and IL-8 is dependent on PAR-1 activation. Contrarily, PAR-1 activation was shown to function as a limiting factor in the KLK14-mediated CXCL1-releasing pathway. Furthermore, human recombinant IL-6, IL-8, and CXCL1 enhanced closure of a cell-free gap in an HaCaT cell monolayer, mimicking wound healing of keratinocytes in the skin. KLK14-stimulated HSF conditioned media also induced wound healing in the HaCaT model in an IL-6-dependent manner, as a cytokine-neutralizing antibody significantly decreased this activity. Thus, KLK14 in the skin may participate in paracrine signaling between fibroblasts and keratinocytes, in that keratinocyte-secreted KLK14 initiates the release of IL-6, IL-8, and CXCL1 from fibroblasts, which in turn act on proxima

关键词： rheumatoid arthritis   immunoglobulin G   disease activity   cytokine   joint erosions  

摘要： Background Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic joint inflammation driven by a complex interplay of autoantibodies, cytokines, and chemokines. While the role of proinflammatory cytokines, such as interleukin-1(IL-1), interleukin-6(IL-6), and tumor necrosis factor-alpha (TNF-alpha), in the pathogenesis of RA has been well-established, the contribution of the immunoglobulin G subclass IgG4 remains a topic of ongoing investigation. This cross sectional study aim was to compare the levels of IgG4 and these key inflammatory cytokines in Malaysian patients with *** The study enrolled a total of 194 RA patients. All subjects were tested for their serum IgG4, IL-1, IL-6 and TNF-alpha levels. Besides, subjects were assessed for their disease activity based on DAS28, functional disability based on HAQ-DI (Health Assessment Questionnaire-Disability Index) and the severity of the radiographic joint erosions by using the Modified Sharp Score (MSS).Results Correlation analysis revealed a moderate positive association between IgG4 and IL-6 levels (r=0.348, p=0.001), but there were no significant correlations with IL-1 and TNF alpha levels. IgG4 levels showed a significant positive correlation with DAS28, MSS, and HAQ-DI. All 3 cytokine levels had significant relationships with the DAS28 scores, but for the MSS, only TNF-alpha (p=0.024) and IL-6 (p=0.016) demonstrated significant associations. None of the cytokines correlated significantly with the HAQ-DI *** The positive correlation between IgG4 and IL-6 levels underscores the possibility for IL-6-driven pathways to influence IgG4 production. Serum IgG4 was associated with more clinical aspects of RA compared to the classical inflammatory cytokines.

摘要： BACKGROUND AND OBJECTIVES:many specialized immunonutrient formulas are available, with an emphasis on combining arginine, omega 3 fatty acids, and nucleotides. These nutrients can reduce the inflammatory pattern, with an increased contribution to resolving infections. Considering the inflammatory catharsis resulting from COVID-19, this study aimed to evaluate the effect of immunonutrition on serum albumin, IL-6, and TNF-α levels in patients with COVID-19. MATERIALS AND METHODS:a randomized double-blind clinical trial conducted in 2020 in Salvador, Bahia, Brazil. Adult patients diagnosed with COVID-19 were randomized to receive a standard hyperproteic normocaloric supplement (control) or a supplement enriched with immunonutrients (experiment) for a period of 07 days. The participants were monitored for a period of 08 days, including the assessment of risk and nutritional status, and collection of blood samples to evaluate albumin, IL-6, and TNF-α. RESULTS:70 patients were included in the study. 64 were randomly allocated to receive an immunonutrient diet or a standard control diet. The nutritional diagnosis was 27.6 (± 0.8) kg/m² and the nutritional risk was 41.9 %. In the experiment group, there was an average increase in albumin to 0.84 (± 0.65) mg/dL, while in the control group this increase was of 0.21 (± 0.52) mg/dL. Regarding the IL-6 doses, there was a reduction both in the experiment group (-257.27 ± 448.89 pg/ml) and in the control group (-142.75 ± 253.29 pg/ml). When comparing the difference in TNF-α levels, a reduction was observed in the experiment group (-3.72 ± 5.98 pg/ml), while an increase in the control group (5.33 ± 10.48 pg/ml) was observed. CONCLUSIONS:the use of an oral supplement enriched with immunonutrients seems to be able to reduce the IL-6 and TNF-α serum levels and increase serum albumin levels.

关键词： 口咽念珠病   β-防御素   多聚免疫球蛋白受体   分泌型免疫球蛋白   IL-17信号通路  

摘要： 口咽念珠病在免疫力低下的人群中呈现高发趋势，基于宿主黏膜免疫调控层面预防该疾病的发生是一种新型防治策略。防御素和分泌型免疫球蛋白作为黏膜的第一道防线，是口腔抗致病菌感染的关键效应分子。该研究旨在筛选具有调控宿主抗菌物质分泌能力的口腔共生菌，并阐明其宿主-微生物互作调控黏膜免疫的作用机制。通过HOK-16B口腔角质细胞模型从15株唾液联合乳杆菌中筛选获得CCFM1417，进一步利用白色念珠菌感染的小鼠口咽念珠病模型评估其菌体裂解物的预防效果，并解析宿主体内IL-17信号通路及抗菌效应分子的变化。分子机制研究表明，该菌株通过激活IL-17/IKBζ信号通路，驱动防御素mBD3表达上调至（30.69±6.35）pg/mg（较模型组提高2.25倍），同时诱导多聚免疫球蛋白受体PIgR和分泌型免疫球蛋白SIgA水平的协同升高（较模型组分别提高1.57和1.94倍），能够有效地预防小鼠口咽念珠病的发生。该研究揭示了唾液联合乳杆菌CCFM1417通过IL-17/IKBζ信号通路调控宿主黏膜抗菌物质分子的分泌，为研发精准化抗口咽念珠菌感染疗法提供了理论依据。

关键词： basophil   common beta chain   IL-3   IL-4   IL-5   phosphorylation   Shc   survival  

摘要： Granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5 signals are transmitted via the shared receptor subunit common beta (beta c). Earlier studies showed that distinct subdomains and tyrosine residues of beta c are connected to specific downstream signaling pathways. However, as most of those pathways are for survival/proliferation, much remains to be learned about how beta c transmits signals for effector functions. Here, by reconstituting primary beta c-deficient basophils with beta c mutants, we found that the tyrosine 573 of beta c was required for recruiting and phosphorylating the adaptor ShcA and IL-4 production. Furthermore, dominant-negative ShcA and the ShcA inhibitor idebenone inhibited IL-4 production but not cell survival. These results provided further insight into how the functional pleiotropy of cytokines is supported by the structure of their receptors.

关键词： Dry eye disease   Interferon-inducible transmembrane protein 1   Interferon-alpha   Extracellular signal-regulated kinase   Apoptosis  

摘要： BackgroundDry eye disease (DED) is a ubiquitous and intricate ocular condition featured by the disruption of tear film homeostasis and inflammation of the ocular surface. This study aimed to examine the mechanism of interferon-inducible transmembrane protein 1 (IFITM1) in dry eye disease (DED).MethodsHCE-T cells were damaged through exposure to hypertonic (NaCl) conditions. Cells with interferon-alpha (IFN alpha) knockdown and/or IFITM1 overexpression were established, and transfection efficiency was measured by reverse transcription-quantitative PCR (RT-qPCR). Flow cytometry was used to detect apoptosis. Western blot was exploited to measure apoptosis-related protein and IFITM1/extracellular signal-regulated kinase (ERK) pathway-related proteins to clarify the mechanism of IFITM1 inducing *** levels of IFN alpha in HCE-T cells were elevated under hypertonic conditions. Knockdown of IFN alpha suppressed the apoptosis, down-regulated the apoptosis proteins BCL2-Associated X (Bax), up-regulated B-cell lymphoma-2 (Bcl-2), diminished IFITM1 expression, and activated the ERK pathway. The overexpression of IFITM1 reversed the regulatory effects of IFN alpha knockdown on HCE-T *** research demonstrated that IFN alpha enhances IFITM1 to obstruct the ERK pathway and thus results in corneal epithelial cell injury. Knockdown of IFN alpha activates the ERK pathway via inhibiting IFITM1 to alleviate corneal epithelial cell damage. This study discovered the important role of the IFN alpha-IFITM1-ERK axis in DED and revealed the potential therapeutic targets for DED.

关键词： Sickle cell anemia   capillary density   capillary diameter   muscle hypotrophy   energy metabolism   AOPP   Advanced oxidation protein products   ANGPT2   Angiopoietin 2   CA   Carbonic anhydrase   CAF   Number of capillaries in contact with a fiber   CAFA   CAF/muscle fiber surface area   CapTor   Capillary tortuosity   CAT   Chloramphenicol acetyltransferase   CD   Capillary density   CK   Creatine kinase   COD   Capillary outer diameter   CON   Control   COP   Capillary outer perimeter   COx   Cytochrome c oxidase   CS   Citrate synthase   ET   endurance-trained group   GPX   Glutathione peroxidase   HbF   Fetal hemoglobin   HbS   Sickle hemoglobin   HIF-1α   Hypoxia-inducible factor-1α   HK   Hexokinase   ICAM   Intercellular adhesion molecule   IL   Interleukin   LC/PF   Capillary length of contact/fiber perimeter   LDH   Lactate dehydrogenase   MMP   Matrix metalloprotease   MCH   Mean corpuscular hemoglobin content   MCHC   Mean corpuscular hemoglobin concentration   MCSD   Mean capillary to sarcolemma distance   MCT   Monocarboxylate transporter   MCV   Mean corpuscular volume   NAD   Nicotinamide adenine dinucleotide   NAD   Nicotinamide adenine dinucleotide oxidized   NADH   Reduced nicotinamide adenine dinucleotide   NBC   Sodium/bicarbonate cotransporter   NF-κB   Nuclear factor-kappa B   NHE1   Sodium/proton exchanger   NO   Nitric oxide   PFK   Phosphofructokinase   PMN   Polymorphonuclear neutrophils   REDD1   Regulated in Development DNA damages responses 1   SCD   Sickle cell disease   SCT   Sickle cell trait   SOD   Superoxide dismutase   UT   Untrained group   VEGF   Vascular endothelial growth factor   VOCs   Vaso-occlusive crises   VOEs   Vaso-occlusive events   β-HAD   β-hydroxyacyl-coA dehydrogenase  

摘要： Sickle cell disease (SCD) is associated with microvascular and muscle remodeling as well as reduced exercise tolerance. However, SCD-repercussions on microvasculature and muscle remain unknown in women. The present study aimed to compare i) muscle microvascular and energetic characteristics of female and male healthy subjects (CON), carriers of sickle cell trait (SCT) and patients with SCD, and ii) adaptations to endurance training (ET) compared to habitual life (UT) in patients. In SCD, correlations between capillary density and plasma L-selectin (p<0.001) and ICAM (p<0.01) and between capillary diameter and mean corpuscular hemoglobin S concentration (p<0.01) were noticed. The capillary network rarefaction observed in SCD was more pronounced in women than in men (interaction: p<0.01). Muscle hypoxia markers were not different between groups. Compared to CON, the surface area for 100 myocytes was lower in men with SCD (both p<0.001) but not in women. Advanced oxidation protein products were increased in SCD patients and to a greater extent in men (interaction: p<0.02). Components of muscle pH regulation were specifically higher in SCT. Compared to UT, ET saw its microvascular network and oxidative capacities increase, without differences between men and women. O ur results suggest that SCD-associated capillary rarefaction and enlargement could be related to disturbed hemodynamics and reduced erythrocytes deformability, respectively. The specific remodeling in female SCD patients included aggravated microvascular remodeling but preserved myocytes. Muscle pH regulation mechanisms appeared specifically up-regulated in SCT carriers. Men and women with SCD improved similarly their microvasculature and muscle energetic characteristics in response to endurance training. NCT02571088