Radical Hysterectomy With Preoperative Conization in Early-Stage Cervical Cancer: A Systematic Review and Pairwise and Network Meta-Analysis.

OBJECTIVE: The investigation of the role of preoperative conization in cervical cancer aiming to explore its potential clinical significance. DATA SOURCES: Cochrane Library, Embase, PubMed, and Web of Science, up to April 28, 2023. METHODS OF STUDY SELECTION: (1) Observational cohort studies, (2) studies comparing radical hysterectomy with preoperative conization (CO) vs radical hysterectomy without preoperative conization (NCO) in patients with early-stage cervical cancer, and (3) studies comparing disease-free survival outcomes. TABULATION, INTEGRATION, AND RESULTS: Two reviewers independently extracted the data and assessed the quality of the studies. The meta-analysis used combined hazard ratios along with their corresponding 95% confidence intervals to compare CO and NCO. We conducted a Bayesian network meta-analysis using Markov chain Monte Carlo methods to compare minimally invasive CO, open CO, minimally invasive NCO, and open NCO. Our study included 15 retrospective trials, 10 of which were used to traditional pairwise meta-analysis and 8 for network meta-analysis. The NCO group exhibited a notably higher probability of cancer recurrence than the CO group (hazard ratio, 0.52; 95% confidence interval, 0.41-0.65). In the network meta-analysis, minimally invasive NCO showed the worst survival outcome. CONCLUSION: Preoperative conization seems to be a protective factor in decreasing recurrence risk, assisting clinicians in predicting survival outcomes for patients with early-stage cervical cancer. It may potentially aid in selecting suitable candidates for minimally invasive surgery in clinical practice.

USP51 promotes non-small cell lung carcinoma cell stemness by deubiquitinating TWIST1.

BACKGROUND: USP51 is a deubiquitinase (DUB), that is involved in diverse cellular processes. Accumulating evidence has demonstrated that USP51 contributes to cancer development. However, its impact on non-small cell lung carcinoma (NSCLC) cell malignancy is largely unknown. METHODS: In this study, we performed bioinformatics analysis on a dataset from The Cancer Genome Atlas to determine the association between USP51 and cell stemness marker expression in NSCLC patients. RT‒qPCR, Western blotting, and flow cytometry were performed to examine the effects of USP51 depletion on stemness marker expression. Colony formation and tumor sphere formation assays were used to assess the stemness of NSCLC cells. A cycloheximide chase time-course assay and a polyubiquitination assay were carried out to analyze the effects of USP51 on the TWIST1 protein level. TWIST1 was overexpressed in USP51 knockdown NSCLC cells to determine whether TWIST1 is required. The effect of USP51 on the in vivo growth of NSCLC cells was tested through subcutaneous injections in mice. RESULTS: We found that USP51 deubiquitinates TWIST1, which is significantly upregulated in the tissues of patients with NSCLC and is closely associated with poor prognosis. USP51 expression was positively correlated with the expression of stemness marker CD44, SOX2, NANOG, and OCT4 in NSCLC patients. USP51 depletion attenuated mRNA, protein, and cell surface expression of stemness markers and the stemness of NSCLC cells. Ectopic USP51 expression potentiated the stability of the TWIST1 protein by attenuating its polyubiquitination. In addition, TWIST1 re-expression in NSCLC cells reversed the inhibitory effect of USP51 knockdown on cell stemness. Furthermore, the in vivo results confirmed the suppressive effect of USP51 depletion on NSCLC cell growth. CONCLUSIONS: Our results show that USP51 maintains the stemness of NSCLC cells by deubiquitinating TWIST1. Knocking it down reduces both cell stemness and growth of NSCLC cells.

Risk stratification for cervical precancer and cancer by DH3-HPV partial genotyping and cytology in women attending cervical screening: A retrospective cohort study.

To evaluate the effect of DH3-human papillomavirus (HPV) partial genotyping for risk stratification in cervical cancer screening, we conducted a post hoc analysis within a retrospective cohort of 7263 Chinese women aged 21-71 years who participated in population-based screening. The residual cytological samples at baseline were retested with DH3-HPV and Hybrid Capture 2 (HC2) assay after 3-year follow-up. Risk values with 95% confidence intervals (CIs) of cervical intraepithelial neoplasia (CIN) grade 3/2 or worse (CIN3+/CIN2+) were estimated based on HPV and cytology results. The report complies with the STROBE statement. Across every cytological result, risk estimates obtained from DH3-HPV and HC2 were similar or almost identical. By DH3-HPV partial genotyping, risks of CIN3+/CIN2+ were invariably higher for HPV16/18 than other high-risk HPV (hrHPV). Among women with normal cytology, immediate CIN3+ risks were 8.16% (95% CI = 4.19%-15.28%) for HPV16/18 positive and 0.48% (95% CI = 0.13%-1.73%) for other hrHPV positive. Among women with any abnormal cytology, immediate CIN3+ risks were 33.33% (95% CI = 22.24%-46.64%) for HPV16/18, and 13.33% (95% CI = 8.37%-20.56%) for other hrHPV. Among 5840 women completed 3-year follow-up, the cumulative CIN3+ risk was 25.56% (95% CI = 18.91%-33.59%) for HPV16/18 and 8.22% (95% CI = 6.02%-11.13%) for other hrHPV. Women with an HPV-negative result with DH3-HPV or HC2 test had very low cumulative 3-year CIN3+ risk (0.06%, 95% CI = 0.02%-0.17%), which was about one-tenth of women with normal cytology at baseline (0.62%, 95% CI = 0.45%-0.86%). Similar patterns were observed for the endpoint of CIN2+. These findings suggest that partial genotyping of DH3-HPV performs well in risk stratification, which can better balance the benefits and harms of cervical cancer screening.

The severity and infection of acute pancreatitis may increase the risk of bleeding in patients undergoing EUS-guided drainage and endoscopic necrosectomy: a large retrospective cohort.

BACKGROUND: There has been great progress in the use of endoscopic ultrasound (EUS)-guided drainage in acute pancreatitis patients using a novel lumen-apposing metal stent (LAMS) in the last decade, but some patients experience bleeding. Our research analyzed the preprocedural risk factors for bleeding. METHODS: From July 13, 2016 to June 23, 2021, we retrospectively analyzed all patients who received endoscopic drainage by the LAMS in our hospital. Univariate and multivariate statistical analyses were used to identify the independent risk factors. We plotted ROC curves based on the independent risk factors. RESULTS: A total of 205 patients were analyzed and 5 patients were excluded. A total of 200 patients were included in our research. Thirty (15%) patients presented with bleeding. In the multivariate analysis, computed tomography severity index score (CTSI) score [odds ratio (OR), 2.66; 95% CI: 1.31-5.38; P = 0.007], positive blood cultures [odds ratio (OR), 5.35; 95% CI: 1.31-21.9; P = 0.02], and Acute Physiology and Chronic Health Evaluation II (APACHE II) score [odds ratio (OR), 1.14; 95% CI: 1. 01-1.29; P = 0.045] were associated with bleeding. The area under the ROC curve of the combined predictive indicator was 0.79. CONCLUSION: Bleeding in endoscopic drainage by the LAMS is significantly associated with the CTSI score, positive blood cultures, and APACHE II score. This result could help clinicians make more appropriate choices.

Global research trends of immunotherapy and biotherapy for inflammatory bowel disease: a bibliometric analysis from 2002 to 2021.

BACKGROUND: It is known that inflammatory bowel disease is the result of a defective immune system, and immunotherapy and biological therapy have gradually become important means to treat it. This paper focused on the bibliometric statistical analysis of the current research progress to summarize the research status of this field and analyze the research trends in recent years. METHODS: Two visualization tools, CiteSpace and VOSviewer, were used to explore the data of journals, institutions, countries/regions, authors, references, and keywords for the literature included in the Web of Science Core Collection from January 1, 2002, to December 31, 2021. RESULTS: A total of 312 papers were published in 120 journals by 603 institutions from 40 countries/regions, with 9463 co-cited references. The United States has the most publications with the highest total citations in the world. Inflammatory Bowel Diseases published the maximum number of papers, and Gastroenterology devoted the most co-citations to immunotherapy and biological therapy for IBD. In addition, we found that the studies before 2009 mostly focused on clinical trials while researchers have paid more attention to clinical management in therapy for IBD since 2009. Combination therapy and management of the treatment for the disease have become research hotspots. CONCLUSION: The focus of immunotherapy and biotherapy for IBD has shifted from clinical trials to the management of the risks and benefits of immunotherapy.

tRNA-derived fragments as novel potential biomarkers for relapsed/refractory multiple myeloma.

BACKGROUND: tRNA-derived fragments have been reported to be key regulatory factors in human tumors. However, their roles in the progression of multiple myeloma remain unknown. RESULTS: This study employed RNA-sequencing to explore the expression profiles of tRFs/tiRNAs in new diagnosed MM and relapsed/refractory MM samples. The expression of selected tRFs/tiRNAs were further validated in clinical specimens and myeloma cell lines by qPCR. Bioinformatic analysis was performed to predict their roles in multiple myeloma progression.We identified 10 upregulated tRFs/tiRNAs and 16 downregulated tRFs/tiRNAs. GO enrichment and KEGG pathway analysis were performed to analyse the functions of 1 significantly up-regulated and 1 significantly down-regulated tRNA-derived fragments. tRFs/tiRNAs may be involved in MM progression and drug-resistance. CONCLUSION: tRFs/tiRNAs were dysregulated and could be potential biomarkers for relapsed/refractory MM.

Clinical characteristics of single human papillomavirus 53 infection: a retrospective study of 419 cases.

BACKGROUND: Human papillomavirus (HPV) infection is the main cause of cervical cancer. Characteristics of HPV infections, including the HPV genotype and duration of infection, determine a patient's risk of high-grade lesions. Risk quantification of cervical lesions caused by different HPV genotypes is an important component of evaluation of cervical lesion. Data and evidence are necessary to gain a deeper understanding of the pathogenicity of different HPV genotypes. The present study investigated the clinical characteristics of patients infected with single human papillomavirus (HPV) 53. METHODS: This retrospective study analyzed the clinical data of patients who underwent cervical colposcopy guided biopsy between October 2015 and January 2021. The clinical outcomes and the follow-up results of the patients with single HPV53 infection were described. RESULTS: 82.3% of the initial histological results of all 419 patients with single HPV53 infection showed negative (Neg). The number of patients with cervical intraepithelial neoplasia (CIN)1, CIN2, CIN3, vaginal intraepithelial neoplasia (VaIN)1, CIN1 + VaIN1, CIN1 + VaIN2, and CIN2 + VaIN2 was 45, 10, 2, 9, 6, 1, and 1, respectively. Cancer was not detected in any patient. When the cytology was negative for intraepithelial lesion or malignancy (NILM), atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesion (LSIL), we observed a significant difference in the distribution of histological results (P < 0.05). 95 patients underwent follow-up with cytology according to the exclusion criteria. No progression of high-grade lesions was observed during the follow-up period of 3-34 months. CONCLUSIONS: The lesion caused by HPV53 infection progressed slowly. The pathogenicity of a single HPV53 infection was low.

The Effect of Autophagic Activity on the Function of Apheresis Platelets and on the Efficacy of Clinical Platelet Transfusion.

Platelet activation and survival jointly determine the efficacy of clinical platelet transfusion. This study aimed to discuss the effect of autophagic activity on activation and aggregation of apheresis platelets and on the efficacy of clinical platelet transfusion. In this study, we investigated the effects of autophagic activity of apheresis platelets for different blood types and after different storage durations on platelet activation and aggregation functions. By Western blot, immunofluorescence, and RT-qPCR detection, we found that with the prolongation of the storage duration, the expressions of both autophagy-related proteins and genes were upregulated in apheresis platelets and their expressions were insignificantly higher in the apheresis platelets of type A and O blood than in those of type B and type AB blood. After RAPA/IGF-1 pretreatment, there was a significant increase/reduction in autophagic activity. After RAPA and IGF-1 pretreatment, an opposite variation trend was observed with platelet activation and aggregation. Autophagic activity of platelets correlated negatively with the efficacy of clinical platelet transfusion. These research findings provide a theoretical basis for effective clinical platelet transfusion.

ROS Promote Ox-LDL-Induced Platelet Activation by Up-Regulating Autophagy Through the Inhibition of the PI3K/AKT/mTOR Pathway.

BACKGROUND/AIMS: Oxidized low-density lipoprotein (oxLDL) promotes unregulated platelet activation in patients with dyslipidemic disorders. Although oxLDL stimulates activating signaling, researchers have not clearly determined how these events drive accelerated thrombosis. Here, we describe the mechanism by which ROS regulate autophagy during ox-LDL-induced platelet activation by modulating the PI3K/AKT/mTOR signaling pathway. METHODS: For in vitro experiments, ox-LDL, the ROS scavenger N-acetylcysteine (NAC), the mTOR inhibitor rapamycin and the autophagy inhibitor 3-MA were used alone or in combination with other compounds to treat platelets. Then, platelet aggregation was evaluated on an aggregometer and platelet adhesion was measured under shear stress. The levels of a platelet activation marker (CD62p) were measured by flow cytometry, reactive oxygen species (ROS) levels were then quantified by measuring DCFH-DA fluorescence intensity via flow cytometry. Nitric oxide (NO) and superoxide (O2·-) levels were determined by the nitric acid deoxidize enzyme method and lucigenin-enhanced chemiluminescence (CL), respectively. Transmission electron microscopy was used to observe the autophagosome formation, immunofluorescence staining was employed to detect LC3 expression and western blotting was used to measure the levels of PI3K/AKT/mTOR pathway- and autophagy-related proteins. RESULTS: Ox-LDL-induced platelets showed a significant increase in platelet aggregation and adhesion, CD62p expression, ROS level and O2·- content, with an elevated LC3II/LC3I ratio and Beclin1 expression, but a dramatic reduction in the levels of p62 and pathway-related proteins (all P < 0.05). However, platelet activation and autophagy were aggravated by the Rapamycin treatment, and decreased following treatment with NAC, 3-MA, or NAC and 3-MA, together with increased activity of the PI3K/AKT/mTOR pathway. Additionally, decreased platelet activation and autophagy were observed in platelets treated with NAC and Rapamycin or Rapamycin and 3-MA compared with platelets treated with Rapamycin alone, suggesting that both NAC and 3-MA reversed the effects of Rapamycin. CONCLUSION: Inhibition of ROS production may reduce autophagy to suppress ox-LDL-induced platelet activation by activating PI3K/AKT/mTOR pathway.

Mesenchymal stem cells drive paclitaxel resistance in ErbB2/ErbB3-coexpressing breast cancer cells via paracrine of neuregulin 1.

We had previously demonstrated that increased expression of ErbB3 is required for ErbB2-mediated paclitaxel resistance in breast cancer cells. In the present study, we have explored the possible role of mesenchymal stem cells (MSCs) in regulating the paclitaxel-sensitivity of ErbB2/ErbB3-coexpressing breast cancer cells. We show that human umbilical cord-derived MSCs express significantly higher level of neuregulin-1 as compared with ErbB2/ErbB3-coexpressing breast cancer cells themselves. Coculture or treatment with conditioned medium of MSCs not only decreases the anti-proliferation effect of paclitaxel on ErbB2/ErbB3-coexpressing breast cancer cells, but also significantly inhibits paclitaxel-induced apoptosis. We further demonstrate that this MSCs-drived paclitaxel resistance in ErbB2/ErbB3-coexpressing breast cancer cells could be attributed to upregulation of Survivin via paracrine effect of NRG-1/ErbB3/PI-3K/Akt signaling, as either specific knockdown expression of ErbB3, or blocking of downstream PI-3K/Akt signaling, or specific inhibition of Survivin can completely reverse this effect. Moreover, targeted knockdown of NRG-1 expression in MSCs abrogates theirs effect on paclitaxel sensitivity of ErbB2/ErbB3-coexpressing breast cancer cells. Taken together, our study indicate that paracrine of NRG-1 by MSCs induces paclitaxel resistance in ErbB2/ErbB3-coexpressing breast cancer cells through PI-3K/Akt signaling-dependent upregulation of Survivin. Our findings suggest that simultaneously targeting mesenchymal stem cells in tumor microenvironment may be a novel strategy to overcome paclitaxel resistance in patients with ErbB2/ErbB3-coexpressing breast cancer.

RhPDCD5 combined with dexamethasone increases antitumor activity in multiple myeloma partially via inhibiting the Wnt signalling pathway.

Multiple myeloma (MM) is one of the most common hematological malignancies and characterized by the clonal accumulation of malignant plasma cells. Significant progress has been made in MM treatment recently, while MM still remains incurable. Our previous studies showed that the recombined human programmed cell death 5 (rhPDCD5) can promote MM apoptosis induced by dexamethasone (Dex). Here, we expanded the findings by showing that the rhPDCD5 alone could not induce an obvious growth inhibition of U266 cells (a MM cell line). Of note, with the combination of dexamethasone (Dex), the growth of MM cells was significantly inhibited and accompanied with the cell cycle arrest in G0/G1. For mechanism study, we found that the combination treatment of rhPDCD5 plus Dex downregulated the mRNA and protein expressions of Wnt effectors including ß-catenin, ß-catenin (Ser675), TCF4, survivin and c-Myc when compared to Dex only. Moreover, the activation of WNT pathway induced by LiCl can also be inhibited by this combination treatment. Taken together, our study demonstrated that the combination of rhPDCD5 and Dex can suppress the proliferation of multiple myeloma cells partially via inhibiting the WNT signalling pathway.

Activation of the Nuclear Erythroid 2-Related Factor 2 Antioxidant Responsive Element (Nrf2-ARE) Signaling Pathway Alleviates Acute Graft-Versus-Host Disease by Reducing Oxidative Stress and Inhibiting Infiltration of Inflammatory Cells in an Allogeneic Stem Cell Transplantation Mouse Model.

BACKGROUND Acute graft-versus-host disease (aGVHD) limits the wider application of hematopoietic stem cell transplantation (HSCT). We explored the relationship between the Nrf2-ARE signaling pathway and aGVHD and identified effective and efficient therapeutic targets for the prevention and management of aGVHD following HSCT. MATERIAL AND METHODS C57BL/6 and BALB/c mice were used to establish the aGVHD model. The bone marrow and spleen mononuclear cells were separated from the donor mice and injected into the caudal vein of recipient mice that had undergone total body irradiation (TBI, 8 Gy). Sulforaphane (SFN) was used to activate the Nrf2-ARE signaling pathway. RESULTS The long-term survival rate of the SFN group was higher than that of the control group (40% vs. 0%, p<0.05, n=10). There were worse pathological changes and a greater infiltration of inflammatory cells in the liver, small intestine, and lung tissues of the control group. Furthermore, the Nrf2, NQO1, and HO-1 mRNA and protein levels were higher in the small intestines of the SFN group than in the control group (p<0.05, n=4). CONCLUSIONS The Nrf2-ARE signaling pathway plays a vital role in preventing aGVHD in an HSCT mouse model by regulating the expression of the downstream antioxidant genes NQO1 and HO-1 and by inhibiting the local inflammatory reaction.

Impact of perioperative blood transfusion on survival of patients undergoing laparoscopic gastrectomy for gastric cancer.

PURPOSE: Previous studies have suggested that perioperative blood transfusion is associated with poor prognosis in patients undergoing radical gastrectomy for gastric cancer. The purpose of this study was to evaluate the impact of blood transfusion on the long-term survival of such patients. METHODS: Short- and long-term outcomes were retrieved from a prospectively collected database of patients who underwent laparoscopic gastrectomy with radical intent for gastric cancer. RESULTS: A total of 309 patients who underwent laparoscopic radical gastrectomy were evaluated. Sixty-one (19.7%) received blood transfusions during or within 30 days after gastrectomy. These patients were typically older, had lower preoperative hemoglobin levels, had a more advanced cancer stage, had more than two comorbidities, had a higher rate of postoperative 30-day complications, and had a higher conversion rate. The overall survival (OS) (p=0.040) and disease-free survival (DFS) (p=0.004) were significantly decreased in patients who received blood transfusions. Multivariate analysis revealed that perioperative blood transfusion was not independently associated with decreased OS and DFS but that cancer stage and having more than two comorbidities were independent risk factors. CONCLUSION: Perioperative blood transfusion was associated with decreased OS and DFS in this patient series, but this apparently reflected the relatively poor medical condition of these patients requiring gastrectomy and was not a causative relationship.

Concurrent targeting Akt and sphingosine kinase 1 by A-674563 in acute myeloid leukemia cells.

Akt signaling plays a pivotal role in acute myeloid leukemia (AML) development and progression. In the present study, we evaluated the potential anti-AML activity by a novel Akt kinase inhibitor A-674563. Our results showed that A-674563 dose-dependently inhibited survival and proliferation of U937 AML cells and six lines of human AML progenitor cells, yet sparing human peripheral blood mononuclear leukocytes (PBMCs). A-674563 activated caspase-3/9 and apoptosis in the AML cells. Reversely, the pan-caspase inhibitor z-VAD-CHO dramatically alleviated A-674563-induced AML cell apoptosis and cytotoxicity. For the molecular study, we showed that A-674563 blocked Akt activation in U937 cells and human AML progenitor cells. Further, A-674563 decreased sphingosine kinase 1 (SphK1) activity in above AML cells to deplete pro-survival sphingosine-1-phosphate (S1P) and boost pro-apoptotic ceramide production. Such an effect on SphK1 signaling by A-674563 appeared independent of Akt blockage. Significantly, K6PC-5, a novel SphK1 activator, or supplement with S1P attenuated A-674563-induced ceramide production, and subsequent U937 cell death and apoptosis. Importantly, intraperitoneal injection of A-674563 at well-tolerated doses suppressed U937 leukemic xenograft tumor growth in nude mice, whiling significantly improving the animal survival. The results of the current study demonstrate that A-674563 exerts potent anti-leukemic activity in vitro and in vivo, possibly via concurrent targeting Akt and SphK1 signalings.

Activated platelet-derived exosomal LRG1 promotes multiple myeloma cell growth.

The hypercoagulable state is a hallmark for patients with multiple myeloma (MM) and is associated with disease progression. Activated platelets secrete exosomes and promote solid tumor growth. However, the role of platelet-derived exosomes in MM is not fully clear. We aim to study the underlying mechanism of how platelet-derived exosomes promote MM cell growth. Flow cytometry, Western blot, proteome analysis, co-immunoprecipitation, immunofluorescence staining, and NOD/SCID mouse subcutaneous transplantation model were performed to investigate the role of exosomal LRG1 on multiple myeloma cell growth. Peripheral blood platelets in MM patients were in a highly activated state, and platelet-rich plasma from MM patients significantly promoted cell proliferation and decreased apoptotic cells in U266 and RPMI8226 cells. Leucine-rich-alpha-2-glycoprotein 1 (LRG1) was significantly enriched in MM platelet-derived exosomes. Blocking LRG1 in recipient cells using LRG1 antibody could significantly eliminate the proliferation-promoting effect of platelet-derived exosomes on MM cells. And high exosomal LRG1 was associated with poor prognosis of patients with MM. Mechanistic studies revealed that LRG1 interacted with Olfactomedin 4 (OLFM4) to accelerate MM progression by activating the epithelial-to-mesenchymal transition (EMT) signaling pathway and promoting angiogenesis. Our results revealed that blocking LRG1 is a promising therapeutic strategy for the treatment of MM.

scRNA-Seq and Bulk-Seq Analysis Identifies S100A9 Plasma Cells as a Potentially Effective Immunotherapeutic Agent for Multiple Myeloma.

Purpose: Immunological regimens are an important area of research for treating multiple myeloma (MM). Plasma cells play a crucial role in immunotherapy. Patients and Methods: In our study, we used both single-cell RNA sequencing (scRNA-seq) and bulk sequencing techniques to analyze MM patients. We analyzed each sample using gene set variation analysis (GSVA) based on immune-related gene sets. We also conducted further analyses to compare immune infiltration, clinical characteristics, and expression of immune checkpoint molecules between the H-S100A9 and L-S100A9 groups of MM patients. Results: We identified eight subpopulations of plasma cells, with S100A9 plasma cells being more abundant in patients with 1q21 gain and 1q21 diploid. CellChat analysis revealed that GAS and HGF signaling pathways were prominent in intercellular communication of S100A9 plasma cells. We identified 14 immune-related genes in the S100A9 plasma cell population, which allowed us to classify patients into the H-S100A9 group or the L-S100A9 group. The H-S100A9 group showed higher ESTIMATE, immune and stroma scores, lower tumor purity, and greater immune checkpoint expression. Patients with 1q21 gain and four or more copies had the lowest ESTIMATE score, immune score, stroma score, and highest tumor purity. Drug sensitivity analysis indicated that the H-S100A9 group had lower IC50 values and greater drug sensitivity compared to the L-S100A9 group. Quantitative reverse transcription (RT-q) PCR showed significantly elevated expression of RNASE6, LYZ, S100A8, S100A9, and S100A12 in MM patients compared to the healthy control group. Conclusion: Our study has identified a correlation between molecular subtypes of S100A9 plasma cells and the response to immunotherapy in MM patients. These findings improve our understanding of tumor immunology and provide guidance for developing effective immunotherapy strategies for this patient population.

Extracellular cancer­associated fibroblasts: A novel subgroup in the cervical cancer microenvironment that exhibits tumor­promoting roles and prognosis biomarker functions.

Tumor invasion and metastasis are the processes that primarily cause adverse outcomes in patients with cervical cancer. Cancer-associated fibroblasts (CAFs), which participate in cancer progression and metastasis, are novel targets for the treatment of tumors. The present study aimed to assess the heterogeneity of CAFs in the cervical cancer microenvironment through single-cell RNA sequencing. After collecting five cervical cancer samples and obtaining the CAF-associated gene sets, the CAFs in the cervical cancer microenvironment were divided into myofibroblastic CAFs and extracellular (ec)CAFs. The ecCAFs appeared with more robust pro-tumorigenic effects than myCAFs according to enrichment analysis. Subsequently, through combining the ecCAF hub genes and bulk gene expression data for cervical cancer obtained from The Cancer Genome Atlas and Gene Ontology databases, univariate Cox regression and least absolute shrinkage and selection operator analyses were performed to establish a CAF-associated risk signature for patients with cancer. The established risk signature demonstrated a stable and strong prognostic capability in both the training and validation cohorts. Subsequently, the association between the risk signature and clinical data was evaluated, and a nomogram to facilitate clinical application was established. The risk score was demonstrated to be associated with both the tumor immune microenvironment and the therapeutic responses. Moreover, the signature also has predictive value for the prognosis of head and neck squamous cell carcinoma, and bladder urothelial carcinoma, which were also associated with human papillomavirus infection. In conclusion, the present study assessed the heterogeneity of CAFs in the cervical cancer microenvironment, and a subgroup of CAFs that may be closely associated with tumor progression was defined. Moreover, a signature based on the hub genes of ecCAFs was shown to have biomarker functionality in terms of predicting survival rates, and therefore this CAF subgroup may become a therapeutic target for cervical cancer in the future.

Causal relationship between primary biliary cholangitis and inflammatory bowel disease: a Mendelian randomization study.

Background: Several studies indicated that inflammatory bowel disease (IBD) may contribute to increased susceptibility to primary biliary cholangitis (PBC). However, the causal relationship between IBD and PBC remains unclear. Methods: The genetic variant data of patients with IBD and PBC were obtained from published genome-wide association studies (GWASs). The IBD data were further divided into a discovery dataset and a validation dataset depending on the data source. We conducted a two-sample Mendelian randomization (MR) analysis using the inverse variance weighting (IVW), MR-Egger, weighted median (WM), MR robust adjusted profile score (MR-RAPS), and maximum likelihood (ML) methods, with IVW being the main focus, to verify the causal relationship between IBD and PBC. Additionally, a series of sensitivity analyses were performed to ensure the reliability of the results. Results: In the discovery cohort, the IVW analysis results (OR = 1.114, P = 0.011) indicated a significant association between IBD and PBC. The MR-RAPS (OR = 1.130, P = 0.007) and ML (OR = 1.115, P = 0.011) analyses yielded results consistent with those of IVW in confirming IBD as a risk factor for PBC. In the validation cohort, consistent findings were observed regarding the causal relationship between IBD and PBC using IVW, MR-RAPS, and ML analyses; all three methods identified IBD as a risk factor for developing PBC. By the IVW analysis, Crohn's disease (CD) emerged as the most prominent subtype of IBD associated with an increased risk of developing PBC in both the discovery cohort (OR = 1.068, P = 0.049) and the validation cohort (OR = 1.082, P = 0.019). Conclusion: The results of the MR analysis suggest a causal relationship between IBD and PBC, highlighting the necessity for proactive PBC prevention in patients with IBD, particularly those with CD.