International journal of clinical and experimental pathology最新文献

Objectives: Gastric cancer (GC) ranks as the fourth most prevalent malignancy globally and is a leading cause of cancer-related mortality. This study aims to comprehensively investigate the pathogenesis of gastric cancer and propose innovative strategies for early diagnosis.

Methods: Leveraging data from The Cancer Genome Atlas (TCGA), we identified that hsa-miR-100-5p exhibits significantly reduced expression in gastric cancer tissues compared to normal tissues. Subsequently, the low expression levels and clinical significance of hsa-miR-100-5p were further validated through quantitative analysis in a cohort of 58 GC patients.

Results: Treatment with an hsa-miR-100-5p mimic markedly inhibited the proliferation of BGC823 cells, whereas the introduction of an hsa-miR-100-5p inhibitor promoted cell proliferation. A dual-luciferase reporter assay confirmed that atypical chemokine receptor 3 (ACKR3) is a direct target gene of hsa-miR-100-5p. Furthermore, our findings revealed a significant negative correlation between ACKR3 expression and hsa-miR-100-5p levels. Immunological correlation analysis suggested that ACKR3 may play a critical role in modulating the tumor microenvironment within cancer-associated fibroblasts.

Conclusion: Collectively, these results indicate that hsa-miR-100-5p may regulate ACKR3 to enhance the migration and proliferation of GC cells, thereby contributing to the onset and progression of gastric cancer.

Osteosarcoma (OS) is a primary malignant bone tumor. Ferroptosis is closely related to the progression of osteosarcoma. The aim of this study is to explore the mechanism of ferroptosis-related genes in the progression of osteosarcoma.

Methods: Utilizing the scRNA-seq dataset of osteosarcoma, differentially expressed genes (scRNA-DEGs) were identified between the osteosarcoma group and the control group, and ferroptosis-related genes in the TARGET-OS dataset were identified through WGCNA. By intersecting these two sets of ferroptosis-related genes, key candidate genes related to ferroptosis were obtained. The prognostic genes were selected from key candidate genes through univariate Cox and LASSO regression analysis. A prognostic model based on these genes was then constructed to investigate the relationship between ferroptosis and the prognosis of osteosarcoma patients. The correlation between the prognostic genes and immune cells, as well as immune checkpoint genes, was investigated through immune infiltration analysis. The drugs binding to prognostic genes were predicted.

Results: We identified 48 ferroptosis-related genes in the scRNA-seq dataset, and 3859 ferroptosis-related genes were identified in the TARGET-OS dataset. After intersecting the two sets, 12 key ferroptosis-related genes were obtained, among which four genes (IFNG, HMOX1, CDKN1A, LGMN) were related to the prognosis of osteosarcoma patients. The prognostic model could accurately predict patient survival with good stability. Immune infiltration analysis revealed that the prognostic genes were significantly correlated with multiple immune cell types, and the expression of some immune checkpoint genes showed significant differences between control and osteosarcoma groups. Furthermore, we found that the prognostic genes were highly expressed in osteoblasts and macrophages.

Conclusions: Four genes (IFNG, HMOX1, CDKN1A, LGMN) were closely related to the prognosis of osteosarcoma patients. These genes may serve as potential therapeutic targets for the treatment of osteosarcoma.

This study aimed to unravel the regulatory mechanism of the microRNA (miR)-183-5p/STC1 axis in regulating mitoxantrone (MIT)-induced immunogenic cell death (ICD) within hepatocellular carcinoma (HCC) cells and assess its therapeutic potential. Dual-luciferase reporter assays were employed to validate that miR-183-5p directly interacts with the 3'-untranslated region (3'-UTR) of STC1 mRNA. HepG2 cells were subjected to treatment with MIT, either in the presence of miR-183-5p inhibitors or STC1 knockout. The expression levels of ICD markers, namely adenosine triphosphate (ATP), high mobility group box 1 (HMGB1), calreticulin (CALR), along with cellular proliferation and apoptosis, were subsequently evaluated. The dual-luciferase assays confirmed that miR-183-5p specifically binds to a defined sequence (5'-GUGCCAU-3') within the 3'-UTR of STC1 mRNA. In MIT-treated HepG2 cells, inhibition of miR-183-5p resulted in a significant upregulation of both STC1 mRNA (+0.78-fold) and protein levels (+0.21-fold). This was accompanied by an enhanced the expression of ICD markers, including a 0.26-fold increase in CALR membrane exposure, a 0.27-fold rise in ATP secretion, and a 0.44-fold elevation in HMGB1 release. Notably, the effects induced by miR-183-5p inhibition were partially mitigated by STC1 gene knockout. Further investigations demonstrated that combination of miR-183-5p inhibitors with MIT synergistically boosted STC1 expression by 5.08-fold. Conversely, STC1 knockout triggered a 184.1% surge in miR-183-5p expression, indicating a negative feedback loop between them. Functional cellular assays revealed that miR-183-5p inhibition significantly augmented MIT's anti-proliferative efficacy, increasing the inhibition rate from 41.9% to 68.0%, and enhanced its pro-apoptotic effects, elevating the apoptosis rate from 30.57% to 36.08%. However, STC1 knockout attenuated these effects. Collectively, our finding indicate that the miR-183-5p/STC1 axis modulates MIT's cytotoxicity through targeted regulation and a negative feedback mechanisms, thereby influencing HCC cell proliferation, apoptosis, and ICD. These insights offer noval strategies for synergistic therapy that integrate epigenetics and the immune microenvironment in HCC treatment.

Background: Afatinib, Dacomitinib, Osimertinib, Aumolertinib, Furmonertinib, Gefitinib, Erlotinib, and Icotinib have all been shown to work and be safe for people with epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) in recent years, but differences in efficacy, safety, and lack of comparative trials cause clinical confusion in treatment selection. This study analyzes their efficacy and safety via network meta-analysis to inform clinical decisions.

Method: We searched PubMed, Embase, Cochrane Library, and Web of Science for pertinent studies. The objective response rate (ORR), median progression-free survival (mPFS), time to treatment failure (TTF), median overall survival (mOS), and adverse events (AEs) were then extracted.

Result: In the efficacy analysis, Afatinib had the greatest ORR at SUCRA=95.9%, outperforming Gefitinib (SUCRA=22.7%) and Icotinib (SUCRA=30.7%). Furmonertinib had the longest mPFS of SUCRA=92.6%, outperforming Gefitinib (SUCRA=10.1%) and Afatinib (SUCRA=11.8%). Dacomitinib had the best TTF (SUCRA=84.1%), followed by Afatinib and Icotinib, which had a longer TTF than Gefitinib (SUCRA=7.0%). In safety evaluations, Aumolertinib performed best in overall grade 1-5 AEs (SUCRA=30.0%) and high-grade (≥3) AEs safety (SUCRA=9.5%), while Afatinib had the worst overall safety rating (SUCRA=68.3%), and Osimertinib had the worst high-grade (≥3) AEs profile. Afatinib and Osimertinib showed significantly greater grade ≥3 AEs compared to Furmonertinib, Icotinib, and Gefitinib. Aumolertinib had reduced frequencies of rash and diarrhea, while Afatinib/Dacomitinib had increased risks of vomiting.

Conclusion: This network meta-analysis reveals that in first-line treatment, the third-generation EGFR-TKI Furmonertinib has exceptional advantages in mPFS and safety and is suited for patients with long-term disease control needs. Although second-generation Afatinib has the highest objective remission rate, it also increases the possibility of grade ≥3 AEs. Clinically, personalized programs should be devised based on the patient's mutation type, tolerance, and other factors. More head-to-head trials will be required in the future to validate the findings and optimize treatment techniques.

Immune checkpoint inhibitors are increasingly used in neoadjuvant non-small cell lung carcinoma (NSCLC). Data regarding histologic features of the tumor microenvironment in this group of patients are limited. This study aimed to analyze the histologic features and the immune cell infiltrates within the tumor microenvironment of NSCLC after neoadjuvant immunotherapy. We evaluated surgical specimens of four NSCLC patients with different pathologic responses, who underwent chemo-immune neoadjuvant therapy. The following markers were analyzed by IHC: CD3, CD4, CD8 (T cells), CD21, CD20, CD138 (DCs, B and plasma cells), CD56 (NK), CD68 (Macrophages), Perforin, Granzyme, CD137 (active-T-cells), FOXP3 (regulatory-T-cells), IgM, and PD-L1. Multiple areas of equal size were counted. These counts were correlated with tumor regression grade (TRG) and response to therapy. The prevalence of tertiary lymphoid structures, low cytotoxic (CD8+) T lymphocyte count, high expression of CD137 and CD137/FOXP3 ratio, and low expression of PD-L1 from immune cells within the tumor microenvironment were associated with high TRG and therapy responsiveness. The expression of other markers was not significantly different according to outcome. Our results highlight the importance of CD137 expression and CD137/FOXP3 ratio on immune cells as activation markers. Further studies will be needed to investigate its value as a possible predictive marker of responsiveness to immunotherapy. The unexpected findings of this study (namely, low count of cytotoxic cells in cases with high TRG) may be explained by considering the period between immunotherapy and histological evaluation.

Objectives: To investigate the relationship between the Triglyceride-Glucose Index (TGI), a surrogate marker of insulin resistance (IR), and serum vitamin D levels in postmenopausal Saudi women, a population at high risk of both metabolic dysfunction and vitamin D deficiency.

Methods: This cross-sectional study included 1,020 postmenopausal Saudi women who were categorized into two groups based on TGI values (< 8.7 and ≥ 8.7). Anthropometric, biochemical, and clinical parameters were assessed. Statistical analyses, including multivariate regression, were performed to evaluate the association between TGI and vitamin D levels, adjusting for confounding variables such as body mass index (BMI).

Results: Women with TGI ≥ 8.7 had significantly higher BMI, systolic and diastolic blood pressure, fasting glucose, and triglyceride levels, along with lower high-density lipoprotein cholesterol (HDL) cholesterol and serum vitamin D concentrations compared to those with TGI < 8.7. A significant inverse association between TGI and vitamin D levels was found, which remained robust after adjusting for BMI and other confounders. Multivariate regression revealed systolic blood pressure and HDL cholesterol as positive and negative predictors of TGI, respectively, while vitamin D levels showed an independent inverse association. Contributing factors to vitamin D deficiency included limited sun exposure, poor dietary intake, and cultural practices.

Conclusions: The study identifies a significant inverse association between TGI and vitamin D levels, underscoring the metabolic interrelationship between insulin resistance and vitamin D deficiency in postmenopausal Saudi women. Public health strategies targeting both conditions may mitigate metabolic and cardiovascular risks in this vulnerable population. Further longitudinal and interventional research is warranted to confirm causality and evaluate the benefits of vitamin D supplementation.

Objective: Liver hepatocellular carcinoma (LIHC) is the most prevalent liver malignancy, often diagnosed at advanced stages, and resulting in a poor prognosis for patients. Ubiquitin-specific peptidase 22 (USP22) belongs to the ubiquitin-specific processing proteases (USPs) subfamily and has been identified as a gene signature associated with various cancer types in previous studies. However, the exact role of USP22 in LIHC remains to be fully elucidated.

Methods: Multiple online bioinformatics databases were usedto investigate gene expression patterns, prognosis, mutations, and immune infiltration in LIHC patients. The UALCAN database was employed to analyze the gene expression of USP22 and its correlation with clinicopathologic data. The cBioPortal database was used to analyze the mutation status, and the Human Protein Atlas (HPA) database was utilized to illustrate the protein's localization. The STRING and GeneMANIA databases were employed to establish the protein-protein interaction (PPI) network. The GEPIA2 database was used to identify the top 100 genes correlated with USP22 in LIHC, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the 'clusterProfiler' R package. The TISIDB database was used to analyze the correlation between the USP22 gene and immune infiltration in LIHC.

Results: USP22 was upregulated in LIHC, with high levels of USP22 correlating with poor overall survival (OS) (P=0.019) and showing associations with tumor stage, histologic subtype, and TP53 mutant status. Immunohistochemistry data showed that USP22 localized in the nucleus of hepatocytes. Nine proteins, including ATXN7, ENY2, TRRAP, TAF5L, TADA3, TADA1, SUPT3H, SUPT20H, and ATXN7L3, were identified as the hub binding proteins in PPI networks. GO and KEGG enrichment analyses indicated that the genes correlated with USP22 in HCC were involved in histone modification, RNA splicing, and regulation of mRNA metabolic processes and were associated with the Notch signaling pathway, ubiquitin-mediated proteolysis, and the Wnt signaling pathway. Moreover, USP22 expression exhibited a significant negative correlation with immune infiltration by CD8+ T cells, macrophages, monocytes, and NK cells.

Conclusions: The prognostic relevance of USP22 in LIHC was found by leveraging data from multiple databases, providing fresh insight that targeting USP22 may help develop new therapeutic approaches for LIHC.

Objective: To investigate the correlation between refractory gastroesophageal reflux disease (RGERD) and the esophagogastric junction (EGJ), as well as to assess their effect on the efficacy of acid suppression therapy.

Methods: This prospective cohort study (ChiCTR2500101077) enrolled 81 patients with reflux esophagitis (RE) at Pingxiang People's Hospital from April 2023 to September 2024. Participants underwent high-resolution manometry (HRM) to classify EGJ subtypes (I-III) and received an 8-week course of vonorasen fumarate therapy. Refractory reflux esophagitis (RRE) was defined as the persistence of GERD-Q symptoms following treatment. Patients diagnosed with RRE underwent 24-hour pH-impedance monitoring to evaluate the efficacy of acid suppression.

Results: The EGJ subtypes were classified as Type I (n=44), Type II (n=21), and Type III (n=16). After treatment, 37 patients were diagnosed with RRE, including 13 cases of Type I, 12 cases of Type II, and 12 cases of Type III, with significant differences observed among the three groups (P<0.004). The EGJ subtype negatively correlated with LES pressure (r=-0.626, P<0.001). 24 h-pH impedance monitoring demonstrated significant differences in reflux metrics, including total reflux episodes (P<0.001), acid exposure percentage (P<0.001), prolonged reflux episodes (P<0.003), and DeMeester score (P<0.001) among the EGJ subtypes, with correlation coefficients of 0.800, 0.787, 0.489, and 0.800, respectively.

Conclusion: EGJ type significantly influences the development of RRE, with Type III EGJ exhibiting the strongest association. An abnormal EGJ structure reduces LES pressure and increases acid exposure, thereby diminishing the efficacy of acid suppression.

Background: Durvalumab may improve survival in patients with advanced non-small cell lung cancer (NSCLC) when given as maintenance therapy; nevertheless, further research is required. Durvalumab and other drugs have enhanced survival rates in advanced NSCLC. The optimal therapy combination is uncertain. This trial will evaluate the effectiveness and tolerability of Durvalumab-based combination therapy for advanced NSCLC.

Methods: We searched PubMed, Embase, the Cochrane Library, and Web of Science for relevant papers, obtaining information on overall response rate (ORR), median progression-free survival (mPFS), median overall survival (mOS), and adverse events (AEs).

Results: 13 studies were included that involved a total of 2,277 participants. The ORR of Durvalumab combination therapy in NSCLC was 41.6%, rising to 47.1% within the radiation or chemotherapy cohort. The mPFS was 5.1 months, while the mOS was 13.5 months. The 1-year progression-free survival (PFS) rate was 49.0%, while the 2-year overall survival (OS) rate was 42.9%. In the radiation and chemotherapy subgroups, these rates rose to 53.4% and 61.1%, respectively. The prevalent adverse responses were anemia (31.3%), nausea (18.9%), and fatigue (18.6%).

Conclusions: Our meta-analysis demonstrated that Durvalumab combination treatment is both effective and safe for advanced NSCLC, particularly in patients undergoing combined chemoradiotherapy. These results encourage more Phase III studies. The review agreement is recorded on PROSPERO (CRD42024622471) and is on the NIHR HTA program website.

Background: This study investigated the clinical and pathological characteristics of gastric-type endocervical adenocarcinoma (G-EAC) to advance the early diagnosis and treatment of this disease.

Methods: The diagnosis, treatment, follow-up, pathological morphology, immunohistochemical characteristics and other data of 15 patients of G-EAC visiting our hospital from December 2016 to March 2024 were retrospectively analyzed, and the relevant literature was discussed.

Results: The mean age of participants was 45.13 years. There were four cases with vaginal discharge, eight cases with spontaneous vaginal contact bleeding, one case where hysterosalpingography (HSG) demonstrated uterine cavity fluid accumulation, and two cases of abdominal pain and swelling with pelvic mass (one with fever) as the initial symptom. There were two participants with Peutz-Jeghers syndrome (PJS). Histologically speaking, G-EAC exhibited various morphologic characteristics, including well-differentiated glands and unusual glands dispersed randomly within the cervical stroma and lacking lobular structures. Neutrophil infiltration and glandular abscess formation were commonly observed. Immunohistochemical analysis showed no expression of ER, PR, or NapsinA, but varying degrees of CK7, MUC6, MUC5AC, CEA, HNF1β, and PAX-8 expression. During the follow-up, which lasted from 1 to 88 months, 2 participants died after 6 months and 10 months respectively. Moreover, 5 participants exhibited distant metastasis, and the remaining 8 participants were healthy and disease free.

Conclusion: G-EAC is an uncommon subtype of cervical adenocarcinoma that frequently manifests as an advanced-stage cancer with vague clinical symptoms, making biopsy-based diagnosis challenging. Since conventional treatments demonstrated limited efficacy, clinicians and pathologists should pay particular attention to this entity.