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关键词： biomarker   CD8 T cells   computational pathology   melanoma   MHC-I  

摘要： The success of immune checkpoint inhibitors (ICI) in melanoma therapy has catalyzed the introduction of ICI in increasingly early stages of the disease. This exposes many patients with a lower risk of relapse to the risk of protracted adverse events, highlighting the need for biomarkers guiding the use of ICI. Already many years ago, brisk infiltration of primary melanomas by lymphocytes has been linked to improved patient outcome, but controversial findings due to a high variability in classification systems have been described CD8+ T cells have been identified as a primary mediator of antitumor immunity in patients treated with ICI. As CD8+ T cells require the presentation of antigens via MHC-I on target cells, downregulation and loss of MHC-I have been observed as resistance mechanisms to ICI. In this study, we revisit the role of MHC-I expression and CD8+ T-cell infiltration in melanoma evolution using a cohort of advanced primary and matched metastatic melanomas by using an automated immunohistochemistry and digital pathology workflow. Our results show that downregulation of MHC-I expression is a frequent event in advanced primary melanomas that is associated with decreased CD8+ T-cell infiltration and an early metastatic spread to sentinel lymph nodes. Furthermore, MHC-I downregulation and decreased infiltration with CD8+ T cells are also associated with resistance to ICI. Our results suggest that analyses of MHC-I expression and CD8+ T-cell infiltration patterns could serve as future biomarkers to guide the decision to treat patients in early stages of melanoma with ICI. (c) 2024 THE AUTHORS. Published by Elsevier Inc. on behalf of the United States & Canadian Academy of Pathology. This is an open access article under the CC BY license (http:// ***/licenses/by/4.0/).

关键词： compatibility platelets   HLA antibody positivity   intravenous immunoglobulin   nursing   platelet transfusion refractoriness  

摘要： Hepatic arterial infusion chemotherapy in conjunction with the combination therapy of atezolizumab (T) and bevacizumab (A) is widely used in hepatocellular carcinoma. Some adverse events such as hypertension, weakness and elevated transaminase levels occurred during treatment, while there is currently no reported case about thrombocytopenia with concomitant HLA antibody-positive PTR. We summarize the critical care nursing experience of a patient with PTR because of HLA antibody positivity during hepatic arterial infusion chemotherapy in conjunction with atezolizumab plus bevacizumab (T + A) regimen. This paper explains the nursing measures for patients with severe thrombocytopenia and proposes nursing measures for situations where conventional treatments are ineffective. Key nursing points include the administration of intravenous immunoglobulin (IVIG) and HLA-compatible platelets, prevention of complications, psychological care, oral care, and skin management. Through systematic treatment and targeted nursing care, the patient's platelet count rebounded after 9 days, leading to a successful recovery and discharge. Subsequent follow-up assessments revealed the patient's sustained well-being. Thrombocytopenia is a potential adverse reaction during the treatment of liver cancer. When platelet transfusion is ineffective, vigilance is necessary for the possibility of HLA positivity, and prompt symptomatic management is warranted.

关键词： thymic stromal lymphopoietin (TSLP)   interleukin-4   chronic rhinosinusitis (CRS)   chronic rhinosinusitis with nasal polyps (CRSwNP)   patient reported outcome measures (PROMs)   fractional exhaled nitric oxide   SNOT-22   UPSIT   endotype   functional endoscopic sinus surgery  

摘要： Background Thymic stromal lymphopoietin (TSLP) plays an important role in mediating the type-2-inflammatory response. This study examined how TSLP and interleukin (IL)-4 levels in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) correlated with clinical and postoperative outcomes. Methods Solid-phase sandwich ELISA was used to analyze TSLP and IL-4 levels in mucus (n = 47), plasma (n = 17), polyp (n = 30), inferior (n = 25), and middle (n = 26) turbinate tissue collected during functional endoscopic sinus surgery (FESS) in CRSwNP patients (n = 76) and controls (n = 11). Inclusion criteria includes patients with medical treatment refractory CRSwNP confirmed by endoscopy or maxillofacial CT. Exclusion criteria include history of immunodeficiency, coagulation disorders, fungal sinusitis, or cystic fibrosis. Levels of TSLP and IL-4 were correlated with SNOT-22, UPSIT, and fractional exhaled nitric oxide (FeNO) using MannWhitney U two-tailed test and linear regression with Spearman correlation coefficient test. Results TSLP is elevated in the inferior turbinates (effect size = 2.695, p = 0.0007) of CRSwNP patients compared to controls. IL-4 is expressed at elevated levels in the inferior (effect size = 3.092, p < 0.0001) and middle turbinates (effect size = 2.041, p = 0.019) compared to controls. Mucus TSLP (r = 0.4013, p = 0.0153) and IL-4 (r = 0.6138, p < 0.0001) positively correlate with preoperative FeNO levels. Lower TSLP in the inferior (r = -0.5179, p = 0.0231) and middle turbinates (r = -0.5075, p = 0.0224) and lower IL-4 in the inferior turbinates (r = -0.5205, p = 0.0223) correlate with a greater improvement in SNOT-22 post-FESS. Conclusion TSLP and IL-4 are elevated in patients with CRSwNP and correlated with increased preoperative FeNO levels and decreased sinonasal quality of life benefit after FESS. Expression of TSLP and IL-4 may play a role in guiding postoperative expectations in patients with treatment refractory CRSwNP.

关键词： HLA   HLA-C   new allele   sequencing-based typing  

摘要： The new allele HLA-C*15:275 differs from HLA-C*15:02:01:01 by one non-synonymous nucleotide substitution in exon 3.

关键词： HLA-B*27:282   HLA-B*40:593   NGS   novel HLA allele  

摘要： Two novel HLA alleles, HLA-B*27:282 and HLA-B*40:593, were detected using next generation sequencing technology.

关键词： Inflammatory biomarkers   Type 2 diabetes mellitus   Coronary artery disease   Cardiovascular prognosis   TNF receptor 1  

摘要： Objectives: To examine the relationship between inflammatory biomarkers and the occurrence of cardiovascular events in patients with type 2 diabetes mellitus (DM2) and stable coronary artery disease. Methods: A total of 964 patients with stable coronary artery disease were included. Plasma levels of inflammatory markers, including tumour necrosis factor receptors 1 and 2 (TNF-R1 and TNF-R2), growth differentiation factor-15 (GDF-15), soluble suppression of tumorigenicity 2 (sST2), and high-sensitivity C-reactive protein (hsCRP) were measured. The primary endpoint was the development of acute ischaemic events (any type of acute coronary syndrome, stroke, or transient ischaemic attack). Results: There were 232 diabetic patients and 732 non-diabetic patients. Patients with coronary artery disease and DM2 (232, 24%) had higher levels of TNF-R1, TNF-R2, GDF-15, sST2 (P<.001), and hsCRP compared to patients without DM2, indicating a higher inflammatory state. After a median follow-up of 5.39 (2.81-6.92) years, patients with DM2 more frequently developed the primary endpoint (15.9% vs 10.8%;P=.035). Plasma levels of TNF-R1 were independent predictors of the primary endpoint in patients with DM2, along with male gender, triglyceride levels, and the absence of treatment with angiotensin-converting enzyme inhibitors. None of these inflammatory markers predicted the development of this event in non-diabetic patients. Conclusions: Patients with stable coronary artery disease and DM2 exhibit elevated levels of the proinflammatory markers TNF-R1, TNF-R2, GDF-15, and sST2. Moreover, TNF-R1 is an independent predictor of acute ischaemic events only in diabetic patients. (c) 2024 Sociedad Espanola de Arteriosclerosis. Published by Elsevier Espana, S.L.U. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： HLA   MHC   next-generation sequencing   structural variation  

摘要： The Major Histocompatibility Complex (MHC) of human chromosome 6 contains multiple genes critical for immunity. The exceptional polymorphism of this genomic region that establishes and maintains immune diversity can be technically challenging to characterise and analyse. In this study, we present a family where the mother and one of her children have no HLA-B allele in common, implying the absence of HLA-B from the maternal haplotype. Homozygosity of the mother and child was confirmed using three independent PCR-based methods and high throughput DNA sequencing. Through probe-based MHC region enrichment, sequencing, and read mapping, we located the breakpoints of a large (36.5 kbp) deletion encompassing the entire HLA-B gene. Accordingly, the deletion was present on the maternal haplotype and transmitted to the child. This study demonstrates strategies for locating large deletions in complex genomic regions and highlights the dynamic nature of MHC structure and variation.

关键词： cartilage degeneration   interleukin-6 receptor   JAK2 signaling   osteoarthritis   senescent cells  

摘要： Osteoarthritis (OA) is an age-related degenerative joint disease, prominently influenced by the pro-inflammatory cytokine interleukin-6 (IL-6). Although elevated IL-6 levels in joint fluid are well-documented, the uneven cartilage degeneration observed in knee OA patients suggests additional underlying mechanisms. This study investigates the role of interleukin-6 receptor (IL-6R) in mediating IL-6 signaling and its contribution to OA progression. Here, significantly elevated IL-6R expression is identified in degenerated cartilage of OA patients. Further, in vivo experiments reveal that intra-articular injection of recombinant IL-6R protein or activation of gp130 (Y757F mutation) accelerates OA progression. Conversely, knockout of IL-6R or JAK2, as well as treatment with a JAK inhibitor, alleviates OA symptoms. Mechanistically, chondrocytes derived from degenerative cartilage exhibit impaired nuclear localization of SOX9, a key regulator of cartilage homeostasis. JAK inhibition stabilizes SIRT1, reduces SOX9 acetylation, and thereby facilitates SOX9 nuclear localization, promoting cartilage repair. Additionally, the JAK inhibitor-induced apoptosis in p21-positive senescent cells, and their targeted clearance successfully alleviates OA in p21-3MR mice. In conclusion, these findings reveal a novel mechanism by which inhibiting the IL-6R/JAK2 pathway can alleviate OA. Furthermore, this study proposes targeting p21-positive senescent cells as a new therapeutic strategy for OA.

关键词： CC chemokine receptor 4   interleukin-4   T follicular helper cells   IgG4-related disease   IgG4  

摘要： Objective Human T follicular helper (Tfh) cells are classified into three subsets: Tfh1, Tfh2, and Tfh17 cells. Among them, Tfh2 cells are defined as CXCR3-negative and CCR6-negative, and may contain diverse cell populations. We examined whether CCR4 serves as a marker for identifying Tfh2 cells that produce interleukin (IL)-4 and its involvement in IgG4-related disease (IgG4-RD). Methods Single cell analysis of IL-4-producing Tfh subset was performed using multi-colour flow cytometry and t-SNE method. Blood samples were obtained from 23 treatment-na & iuml;ve patients with active IgG4-RD. CCR4+Tfh2 cells were also assessed in affected tissues of IgG4-RD by flow cytometry and immunohistochemical staining. Results Tfh2 cells expressing CCR4 were identified as Tfh cells that specifically produce IL-4. CCR4+Tfh2 cells showed higher expression of GATA-3 and ICOS than CCR4-Tfh2 cells, while there was no difference in the expression of BCL-6 and FOXP3. The proportion of CCR4+Tfh2 cells in peripheral blood was increased in IgG4-RD compared to healthy controls, and even more CCR4+Tfh2 cells infiltrated into the affected lesions. CCR4+GATA-3+Tfh2 cells diffusely infiltrated tertiary lymphoid tissues and storiform fibrosis lesions. The proportion of CCR4+Tfh2 cells showed a significant correlation specifically with serum IgG4 levels among clinical indicators. Glucocorticoid therapy did not correct the increased proportion of CCR4+Tfh2 cells. Conclusion CCR4 serves as a marker for identifying Tfh2 cells that specifically produce IL-4. CCR4+Tfh2 cells are a widely present T cell population that infiltrates tertiary lymphoid tissues and storiform fibrosis of IgG4-RD. Glucocorticoid fails to effectively target CCR4+Tfh2 cells that may contribute to a high relapse rate during glucocorticoid tapering in this disease.