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关键词： Leiomyoma   PCNA   IL-8   Myometrium   Immunohistochemistry   ELISA  

摘要： Background: The most prevalent neoplasms of the female genital tract are uterine leiomyomas, a uterine fibroid which rarely turn into cancer. We examined the levels of proliferating cell nuclear antigen (PCNA) and interleukin-8 (IL-8) in female patients with Leiomyomas. Methods: The presence of PCNA and IL-8 were measured in 28 females with Leiomyoma and 20 healthy controls. Tissue PCNA levels were measured by immunohistochemistry (IHC) method and serum IL-8 levels were measured by an ELISA technique. Age and menopausal stage on Leiomyoma development were also examined. Results: Forty-eight Iraqi women were divided into 28 uterine Leiomyoma patients of whom leiomyoma tissues, adjacent myometrium and serum samples were collected during hysterectomy. Serum samples were collected from 28 patients and 20 female controls. PCNA was positively expressed in 11 out of 28 (39.2 %) leiomyoma tissues;all 20 normal myometrium were negative. The presence of PCNA was unrelated to age and menopausal stage. The mean level of serum IL-8 was elevated significantly in patients (140 pg/ml) compared to that of control (60 pg/ml;P < 0.05). The IL -8 levels were increased in postmenopausal stage. Conclusions: Each PCNA;IL-8 showed significantly elevated levels in patients with Leiomyoma.

关键词： Regulatory T cells   Treg cells plasticity   Interleukin-35   Therapeutic role   Lung   Breast   And colorectal cancer  

摘要： T lymphocytes are among the immunological cells that make up the tumor microenvironment (TME), and they are essential in the growth of tumors and anti-tumor reactions. Regulatory T cells (Treg cells) are a subset of CD4+ T cells in the immune system that suppress the immune system. They are distinguished by their expression of the master transcription factor forkhead box protein P3 (FOXP3). Furthermore, Treg cells are essential for maintaining immunological homeostasis, inhibiting inflammation, and maintaining self-tolerance. In a variety of malignancies within the TME, Treg cells demonstrate notable flexibility and functional diversity. Highly plastic Treg cells can change into Th-like Treg cells in specific circumstances, which allow them to secrete particular pro- inflammatory cytokines. Interleukin 35 (IL-35) is a part of the immunosuppressive cytokines that belong to the IL-12 family. Treg cells release IL-35, which was elevated in the peripheral blood and TME of numerous cancer patients, implying that IL-35 in the TME may be an intriguing target for cancer therapy. In cancer, IL-35 is a twoedged sword;it promotes tumorigenicity in cancer cells while shielding them from apoptosis. Nonetheless, other investigations have mentioned its conflicting effects on cancer prevention. Herein, we provide an updated understanding of the critical mechanisms behind the anticancer immunity mediated by Treg cells plasticity, the role of IL-35, and tactics to strengthen the immune response against malignancies, outlining major clinical trials that used Treg cells/IL-35 therapies in the three main cancer types (lung, breast, and colorectal cancers).

关键词： autophagy   CTSL   IL6-JAK-STAT3 signalling pathway   laryngeal cancer  

摘要： Cathepsin L (CTSL) is an important oncogene. However, its mechanism of action in laryngeal cancer is still unclear. This study aims to explore the role of CTSL in laryngeal cancer and its clinical significance. Conducting bioinformatics analysis utilising the Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database. Performing CCK8 analysis, Western blotting, qRT-PCR, wound healing assay and transwell invasion assay. Additionally, conducting immunoprecipitation experiments and immunohistochemical staining to investigate the impact of CTSL on cell proliferation, autophagy and related signalling pathways. We observed a significant upregulation of CTSL in laryngeal cancer tissues, and its elevated levels are indicative of poor prognosis in laryngeal cancer patients. The proliferation of laryngeal cancer cells relies on the expression of CTSL, with overexpression of this gene enhancing the proliferative capacity of these cells. Concurrently, CTSL is closely associated with the autophagic levels in laryngeal cancer cells. During the autophagic process mediated by CTSL, the IL6-JAK-STAT3 signalling pathway is activated, suggesting that CTSL promotes autophagy through the IL6-JAK-STAT3 pathway. Considering the correlation between CTSL and autophagy, we developed and validated a multi-gene signature. The risk score derived from this signature demonstrates significant potential in predicting various aspects. We found that CTSL upregulates autophagy in laryngeal cancer cells by activating the IL6-JAK-STAT3 signalling pathway. By taking into account the autophagy-regulating role of CTSL, the clinical predictive ability of CTSL in HNSC can be enhanced.

关键词： Brazilian population   HLA-B   new allele   NGS  

摘要： Identification of the novel HLA-B*58:01:51 allele in a Brazilian bone marrow donor.

关键词： p21-activated kinase 4   pancreatic cancer   MHC I   autophagy   chloroquine  

摘要： Background/Objectives: Pancreatic ductal adenocarcinoma (PDA) is one of the most malignant solid cancers. KRAS mutation accounts for over 90% of cases. p21-activated kinases (PAKs) act downstream of KRAS and are involved in tumorigenesis. The inhibition of PAK4 suppresses PDA by stimulating the tumor infiltration of cytotoxic T cells. The major histocompatibility complex class I (MHC I) is a key in presenting antigens to cytotoxic T cells. MHC I degradation via autophagy promotes the immune evasion of pancreatic cancer. We investigated the effect of PAK4 inhibition on MHC I expression and autophagy. Methods: In this study, using proteomic analysis, fluorescence-activated cell sorting (FACS), and immunoblotting, we examined the effect of PAK4 knockout (KO) in human PDA cells on the expression of MHC I and autophagy to identify the mechanism involved in the stimulation of cytotoxic T cells by PAK4 inhibition. Results: We found that PAK4 KO increased MHC I expression in two human PDA cell lines: MiaPaCa-2 and PANC-1. PAK4 KO also increased cancer cell autophagy. However, the inhibition of autophagy by chloroquine (CQ) did not affect the effect of PAK4 KO on apoptosis and cell death. More importantly, the inhibition of autophagy by CQ did not alter the expression of MHC I stimulated by PAK4 KO, indicating that PAK4 KO stimulated MHC I expression via an autophagy-independent pathway. Conclusions: We identified a role of PAK4 in MHC I expression by PDA cells, which is independent of autophagy.

关键词： NRP1   Group 3 innate lymphoid cells (ILC3s)   Inflammatory bowel disease (IBD)   Mucosal Immunity  

摘要： Group 3 innate lymphoid cells (ILC3s) control tissue homeostasis and orchestrate mucosal inflammation;however, the precise mechanisms governing ILC3 activity are fully understood. Here, we identified the transmembrane protein neuropilin-1 (NRP1) as a positive regulator of interleukin (IL)-17-producing ILC3s in the intestine. NRP1 was markedly upregulated in intestinal mucosal biopsies from patients with inflammatory bowel disease (IBD) compared with healthy controls. Genetic deficiency of NRP1 reduces the frequency of ILC3s in the gut and impairs their production of IL-17A in an NF-kappa B signaling-dependent and cell-intrinsic manner. The diminished IL-17A production in ILC3s altered the composition of the microbiota and improved the outcome of dextran sodium sulfate (DSS)-induced colitis. Furthermore, pharmacological inhibition of NRP1 with EG00229 alleviated the severity of colitis. These observations demonstrated the critical role of NRP1 in the control of intestinal ILC3s, suggesting that NRP1 is a potential therapeutic target for IBD.

关键词： Danggui Beimu Kushen pill   ulcerative colitis   interleukin-6   interleukin-17   Th17  

摘要： Background/Objectives: Danggui Beimu Kushen pill (DBK) is a traditional Chinese medicine renowned for its efficacy in the treatment of inflammatory conditions. It has been used in the modern clinical treatment of ulcerative colitis (UC). Further research is required to clarify its underlying mechanisms. Methods: DBK compounds were analyzed using UPLC-ESI-MS/MS. A mouse model of Dextran sulfate sodium (DSS)-induced UC was used to assess the efficacy of DBK. Network pharmacology identified DBK targets in UC, which were validated by molecular docking simulations. Cytokine levels were quantified using ELISA. Western blotting, immunofluorescence (IF), and immunohistochemistry (IHC) were employed to explore its underlying molecular mechanisms. Results: DBK treatment enhanced body weight and colon length in mice with DSS-induced colitis. Inflammatory cytokine levels (TNF-alpha, IL-1 beta, IL-6, IL-23, and IL-17A) were notably decreased in both serum and colon tissues. Network pharmacology and molecular docking analyses identified the IL-6/IL-6R and IL-17A/IL-17RA signaling pathways as crucial for the DBK treatment of UC. Additional validation using WB, IHC, and IF analyses demonstrated that DBK alleviated UC by suppressing the IL-6/STAT3 and IL-17/TRAF6/NF-kappa B pathways. Conclusions: DBK mitigates intestinal injury in mice with DSS-induced colitis and exerts therapeutic effects on UC by inhibiting the IL-6/IL-6R and IL-17A/IL-17RA signaling pathways to reduce inflammation. These findings provide significant insights into the mechanism of DBK treatment for UC.

关键词： Inflammatory bowel disease   Crohn's disease   Ulcerative colitis   Infliximab   Tuberculosis  

摘要： Background and study aims: Tuberculosis (TB) is a well-recognized adverse effect associated with using biological therapy to manage various autoimmune conditions. There is a dearth of information about the development of TB after using anti-TNF agents in patients with inflammatory bowel disease (IBD) from TB-endemic countries like India. This study aimed to estimate the risk of TB and its predictors after treatment with anti-TNF agents in patients with IBD. Patients and Methods: The present study is a retrospective analysis of data of patients with IBD from two tertiary care centers in India receiving anti-TNF therapy. Patients who had undergone chest X-ray, high-resolution computed tomography of the chest, and tuberculin skin test, with a follow-up duration of at least 6 months, were included in the analysis. Results: In this multi-center study, 95 patients on anti-TNF agents for IBD (Median age of onset: 27 years, 62.1 % males) were followed up for a median duration of 9 (6-142) months. Among patients with IBD, 79 (83.2 %) had Crohn's disease, and 16 (16.8 %) had ulcerative colitis. Infliximab was the commonest biological, used in 82.1 % of cases, followed by adalimumab (17.9 %). On follow-up, 8.4 % (8/95) of the patients developed TB, among which the majority had extrapulmonary tuberculosis (5/8). On multivariate analysis, the duration of biological (Odds ratio: 1.047, 95 % confidence interval 1.020-1.075;p = 0.001) use was the only independent predictor of the development of TB with biologicals. Conclusion: Among Indian patients with IBD, there is a high risk of TB with anti-TNF agents, which increases with the duration of therapy. The current methods for latent TB screening in Indians are ineffective, and predicting TB after initiating biological therapy is difficult.

关键词： HLA   HLA-C*01:282   new allele   next-generation sequencing  

摘要： The novel allele HLA-C*01:282 has a single non-synonymous mutation compared to HLA- C*01:02:01:01 in codon 100 in Exon 3.

关键词： Inflammatory bowel disease   Osteoporosis   Osteoclast   Myeloid progenitor cells   TNF-a  

摘要： Inflammatory bowel disease (IBD) is characterized by very severe intestinal inflammation associated with extraintestinal manifestations. One of the most critical ones is bone destruction, which remains a major cause of morbidity and a risk factor for osteopenia and osteoporosis in IBD patients. In various mouse models of IBD, we and other have demonstrated concomitant bone loss due to a significant increase in osteoclast activity. Besides bone resorption, osteoclasts are known to control hematopoietic niches in vivo and modulate inflammatory responses in vitro, suggesting they may participate in chronic inflammation in vivo. Here, using different models of colitis, we showed that osteoclast inhibition significantly reduced disease severity and that induction of osteoclast differentiation by RANKL contributed to disease worsening. Our results demonstrate a direct link between osteoclast activity and myeloid cell accumulation in the intestine during colitis. RNAseq analysis of osteoclasts from colitic mice revealed overexpression of genes involved in the remodeling of hematopoietic stem cell niches. We also demonstrated that osteoclasts induced hematopoietic progenitor proliferation accompanied by a myeloid skewing in the early phases of colitis, which was confirmed in a model of RANKL-induced osteoclastogenesis. Mechanistically, inhibition of TNF-alpha reduced the induction of myeloid skewing by OCL both in vitro and in vivo. Lastly, we observed that osteoclastic activity and the proportion of myeloid cells in the blood are positively correlated in patients with Crohn's disease. Collectively, our results shed light on a new role of osteoclasts in colitis in vivo, demonstrating they exert their colitogenic activity through an early action on hematopoiesis, leading to an increase in myelopoiesis sustaining gut inflammation.