Pyroptosis is an identified programmed cell death that has been highly linked to endoplasmic reticulum (ER) dynamics. However, the crucial proteins for modulating dynamic ER membrane curvature change that trigger pyroptosis are currently not well understood. In this study, a biotin-labeled chemical probe of potent pyroptosis inducer α-mangostin (α-MG) was synthesized. Through protein microarray analysis, reticulon-4 (RTN4/Nogo), a crucial regulator of ER membrane curvature, was identified as a target of α-MG. We observed that chemically induced proteasome degradation of RTN4 by α-MG through recruiting E3 ligase UBR5 significantly enhances the pyroptosis phenotype in cancer cells. Interestingly, the downregulation of RTN4 expression significantly facilitated a dynamic remodeling of ER membrane curvature through a transition from tubules to sheets, consequently leading to rapid fusion of the ER with the cell plasma membrane. In particular, the ER-to-plasma membrane fusion process is supported by the observed translocation of several crucial ER markers to the "bubble" structures of pyroptotic cells. Furthermore, α-MG-induced RTN4 knockdown leads to pyruvate kinase M2 (PKM2)-dependent conventional caspase-3/gasdermin E (GSDME) cleavages for pyroptosis progression. In vivo, we observed that chemical or genetic RTN4 knockdown significantly inhibited cancer cells growth, which further exhibited an antitumor immune response with anti-programmed death-1 (anti-PD-1). In translational research, RTN4 high expression was closely correlated with the tumor metastasis and death of patients. Taken together, RTN4 plays a fundamental role in inducing pyroptosis through the modulation of ER membrane curvature remodeling, thus representing a prospective druggable target for anticancer immunotherapy.
Pyroptosis/immunology* ; Humans ; Endoplasmic Reticulum/immunology* ; Animals ; Nogo Proteins/antagonists & inhibitors* ; Mice ; Cell Line, Tumor ; Xanthones/pharmacology* ; Neoplasms/pathology* ; Mice, Nude

Objective:To explore the application value of PAX1/JAM3 methylation detection by cervical self-collected specimen in cervical cancer screening and the management of premenopausal and postmenopausal women.Method:This study is a single center cross-sectional study. From January 2023 to November 2023, cervical self-collected and physician-collected specimens at the colposcopy clinic were detected the PAX1/JAM3 methylation (PAX1 m/JAM3 m) testing. The consistency between self-collected and physician-collected specimens for PAX1 m/JAM3 m detection were compared based on histopathology. In addition, the clinical efficacy of methylation detection with high-risk human papillomavirus (hrHPV), liquid-based cytology (LBC), and their combination for cervical cancer screening were compared in the study. Results:A total of 301 women were recruited to undergo referral colposcopy examination, and statistical analysis was conducted on 272 women with pathological and diagnostic information. Among them, 102 cases (37.5%) were diagnosed as normal cervical tissue or chronic cervicitis, 72 cases (26.4%) were cervical intraepithelial neoplasia grade 1 (CIN1), 43 cases (15.8%) were CIN2, 29 cases (10.7%) were CIN3, and 26 cases (9.6%) were cervical cancer. According to the minimum quantity formula, they were divided into a consistency cohort of 81 participants and a validation cohort of 191 participants. The consistency between cervical self-collected and physician-collected specimens for detecting PAX1 m/JAM3 m. Results from spearman correlation analysis showed a positive correlation between the self-collected and physician-collected results of PAX1 m/JAM3 m detection, and the correlation coefficient R values are 0.858 ( P<0.001) and 0.828 ( P<0.001). The sensitivity and specificity of PAX1 m/JAM3 m detection for diagnosing CIN2 or more severe lesions (CIN2+) were 77.6% [95% confidence interval ( CI) 65.3%-86.4%] and 87.2% (95% CI 80.5%-91.9%), respectively. In clinical performance comparison, the sensitivity of PAX1 m/JAM3 m combined with HPV16/18 detection, 89.7% (95% CI 79.2%-95.2%), was the same as that of hrHPV detection in CIN2+and 96.0% (95% CI 80.4%-99.3%) in CIN3+, which is higher than 92.0% (95% CI 75.0%-97.8%) of hrHPV and 82.6% (95% CI 62.9%-93.0%) of LBC or the combination of sPAX1 m/JAM3 m and LBC low-grade and higher squamous intraepithelial lesion testing [87.0% (95% CI 67.9%-95.5%)]. Conclusions:Self-collected specimens by women for detection of PAX1 and JAM3 methylation as a promising screening tool for cervical cancer has operational and clinical feasibility. The methylation test can optimize the current cervical cancer screening plan, reduce the number of referral women with false positive diagnosis to colposcopy, and is of great significance for reducing fertility protection and preventing missed diagnosis in women of childbearing age.

Background::Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized immune-mediated disorder that can affect almost any organ in the human body. IgG4-RD can be categorized into proliferative and fibrotic subtypes based on patients’ clinicopathological characteristics. This study aimed to compare the clinical manifestations, laboratory findings, and treatment outcomes of IgG4-RD among different subtypes.Methods::We prospectively enrolled 622 patients with newly diagnosed IgG4-RD at Peking Union Medical College Hospital from March 2011 to August 2021. The patients were divided into three groups according to their clinicopathological characteristics: proliferative, fibrotic, and mixed subtypes. We compared demographic features, clinical manifestations, organ involvement, laboratory tests, and treatment agents across three subtypes. We then assessed the differences in treatment outcomes among 448 patients receiving glucocorticoids alone or in combination with immunosuppressants. Moreover, risk factors of relapse were revealed by applying the univariate and multivariate Cox regression analysis.Results::We classified the 622 patients into three groups consisting of 470 proliferative patients, 55 fibrotic patients, and 97 mixed patients, respectively. We found that gender distribution, age, disease duration, and frequency of allergy history were significantly different among subgroups. In terms of organ involvement, submandibular and lacrimal glands were frequently involved in the proliferative subtype, while retroperitoneum was the most commonly involved site in both fibrotic subtype and mixed subtype. The comparison of laboratory tests revealed that eosinophils ( P = 0.010), total IgE ( P = 0.006), high-sensitivity C-reactive protein ( P <0.001), erythrocyte sedimentation rate ( P <0.001), complement C4 ( P <0.001), IgG ( P = 0.001), IgG1 (P <0.001), IgG4 (P <0.001), and IgA ( P <0.001), at baseline were significantly different among three subtypes. Compared with proliferative and mixed subtypes, the fibrotic subtype showed the lowest rate of relapse (log-rank P = 0.014). Conclusions::Our study revealed the differences in demographic characteristics, clinical manifestations, organ involvement, laboratory tests, treatment agents, and outcomes across proliferative, fibrotic, and mixed subtypes in the retrospective cohort study. Given significant differences in relapse-free survival among the three subtypes, treatment regimens, and follow-up frequency should be considered separately according to different subtypes.Trial Registration::ClinicalTrials. gov, NCT01670695.

Inflammasome is a kind of intracellular polyprotein complex,which is an important component of the complex system of local inflammatory microenvironment after human tissue damage.When the inflammasome is activated,it induces the activation of cysteine aspartate proteinase 1(caspase-1),mediates the maturation and secretion of proinflammatory cytokines,such as interleukin(IL)-1 β and IL-18,and induces cell death,which plays an important role in regulating the host immune response to pathogen infection and tissue repair of cell damage.Nod-like receptor protein 3(NLRP3)inflammatory body,which is composed of NLRP3,pro-cysteine aspartic acid specific protease-1(pro-caspase-1)and apoptosis-related spot-like protein(ASC),is the most deeply and widely studied type of inflammatory body,which plays an important role in the regulation of inflammation.When NLRP3 inflammatory bodies are activated,inflammatory mediators are produced and released,which participate in the occurrence and development of a variety of inflammatory diseases.Some studies have shown that traditional Chinese medicine can improve the pathological state of a variety of diseases by inhibiting NLRP3 inflammatory bodies,and play a role in the prevention and treatment of a variety of inflammatory diseases,including cardiovascular diseases,joint inflammation,diabetes and so on.This paper systematically combs the mechanism of NLRP3 inflammatory bodies,and summarizes the latest research reports on the effects of traditional Chinese medicine compound prescription,traditional Chinese medicine monomers and traditional Chinese medicine extracts on NLRP3 inflammatory bodies in the treatment of inflammatory diseases,in order to provide new ideas for the further study of the pathogenesis and drug treatment of many inflammatory diseases.

Objective:To study the mechanism of icariin inhibiting the proliferation of human PCa PC-3 cells based on cell metabolomics technology.Methods:We determined the proliferation activity of human PC-3 cells by methyl thiazolyl tetrazolium(MTT)assay,and compared the proliferation of the PC-3 cells among the control,5-fluorouracil and icariin intervention groups.Using the Bligh Dyer method,we extracted endogenous metabolites from the cells,analyzed the metabolic profile by ultra-high pressure liquid chromatography tandem quadrupole time-of-flight mass spectrometry,identified the differential metabolites by principal component anal-ysis and orthogonal partial least-squares discrimination analysis,and enriched the metabolic pathways based on the MetaboAnalyst data-base.Results:Icariin significantly inhibited the proliferation of human PCa PC-3 cells.A total of 89 differential metabolites were i-dentified,mainly including amino acids,phosphatidylcholine,phosphatidylethanolamine,lysophosphatidylcholine,and lysophosphati-dylethanolamine,all with the tendency to return to the normal level after icariin intervention.Icariin significantly downregulated the metabolic levels of the glycerophospholipid metabolites phosphatidylcholine,phosphatidylethanolamine,lysophosphatidylcholine and ly-sophosphatidylethanolamine,and upregulated those of amino acid metabolites tryptophan,leucine,and proline in the PC-3 cells.Conclusion:Icariin inhibits the proliferation of human PCa PC-3 cells,which may be closely related to its regulatory effect on lipid metabolism(glycerophospholipid metabolism)and amino acid metabolism.

BACKGROUND: Controversy exists as to the optimal treatment approach for ostial left anterior descending (LAD) or ostial left circumflex artery (LCx) lesions. Drug-coated balloons (DCB) may overcome some of the limitations of drug-eluting stents (DES). Therefore, we investigated the security and feasibility of the DCB policy in patients with ostial LAD or ostial LCx lesions, and compared it with the conventional DES-only strategy. METHODS: We retrospectively enrolled patients with de novo ostial lesions in the LAD or LCx who underwent interventional treatment. They were categorized into two groups based on their treatment approach: the DCB group and the DES group. The treatment strategies in the DCB group involved the use of either DCB-only or hybrid strategies, whereas the DES group utilized crossover or precise stenting techniques. Two-year target lesion revascularization was the primary endpoint, while the rates of major adverse cardiovascular events, cardiac death, target vessel myocardial infarction, and vessel thrombosis were the secondary endpoints. Using propensity score matching, we assembled a cohort with comparable baseline characteristics. To ensure result analysis reliability, we conducted sensitivity analyses, including interaction, and stratified analyses. RESULTS: Among the 397 eligible patients, 6.25% of patients who were planned to undergo DCB underwent DES. A total of 108 patients in each group had comparable propensity scores and were included in the analysis. Two-year target lesion revascularization occurred in 5 patients (4.90%) and 16 patients (16.33%) in the DCB group and the DES group, respectively (odds ratio = 0.264, 95% CI: 0.093-0.752, P = 0.008). Compared with the DES group, the DCB group demonstrated a lower major adverse cardiovascular events rate (7.84% vs. 19.39%, P = 0.017). However, differences with regard to cardiac death, non-periprocedural target vessel myocardial infarction, and definite or probable vessel thrombosis between the groups were non-significant. CONCLUSIONS The utilization of the DCB approach signifies an innovative and discretionary strategy for managing isolated ostial lesions in the LAD or LCx. Nevertheless, a future randomized trial investigating the feasibility and safety of DCB compared to the DES-only strategy specifically for de novo ostial lesions in the LAD or LCx is highly warranted.

Since the utilization of anthracyclines in cancer therapy, severe cardiotoxicity has become a major obstacle. The major challenge in treating cancer patients with anthracyclines is minimizing cardiotoxicity without compromising antitumor efficacy. Herein, histone deacetylase SIRT6 expression was reduced in plasma of patients treated with anthracyclines-based chemotherapy regimens. Furthermore, overexpression of SIRT6 alleviated doxorubicin-induced cytotoxicity in cardiomyocytes, and potentiated cytotoxicity of doxorubicin in multiple cancer cell lines. Moreover, SIRT6 overexpression ameliorated doxorubicin-induced cardiotoxicity and potentiated antitumor efficacy of doxorubicin in mice, suggesting that SIRT6 overexpression could be an adjunctive therapeutic strategy during doxorubicin treatment. Mechanistically, doxorubicin-impaired mitochondria led to decreased mitochondrial respiration and ATP production. And SIRT6 enhanced mitochondrial biogenesis and mitophagy by deacetylating and inhibiting Sgk1. Thus, SIRT6 overexpression coordinated metabolic remodeling from glycolysis to mitochondrial respiration during doxorubicin treatment, which was more conducive to cardiomyocyte metabolism, thus protecting cardiomyocytes but not cancer cells against doxorubicin-induced energy deficiency. In addition, ellagic acid, a natural compound that activates SIRT6, alleviated doxorubicin-induced cardiotoxicity and enhanced doxorubicin-mediated tumor regression in tumor-bearing mice. These findings provide a preclinical rationale for preventing cardiotoxicity by activating SIRT6 in cancer patients undergoing chemotherapy, but also advancing the understanding of the crucial role of SIRT6 in mitochondrial homeostasis.

Objective: To understand the current status of diagnosis and treatment of chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL) among hematologists, oncologists, and lymphoma physicians from hospitals of different levels in China. Methods: This multicenter questionnaire survey was conducted from March 2021 to July 2021 and included 1,000 eligible physicians. A combination of face-to-face interviews and online questionnaire surveys was used. A standardized questionnaire regarding the composition of patients treated for CLL/SLL, disease diagnosis and prognosis evaluation, concomitant diseases, organ function evaluation, treatment selection, and Bruton tyrosine kinase (BTK) inhibitor was used. Results: ①The interviewed physicians stated that the proportion of male patients treated for CLL/SLL is higher than that of females, and the age is mainly concentrated in 61-70 years old. ②Most of the interviewed physicians conducted tests, such as bone marrow biopsies and immunohistochemistry, for patient diagnosis, in addition to the blood test. ③Only 13.7% of the interviewed physicians fully grasped the initial treatment indications recommended by the existing guidelines. ④In terms of cognition of high-risk prognostic factors, physicians' knowledge of unmutated immunoglobulin heavy-chain variable and 11q- is far inferior to that of TP53 mutation and complex karyotype, which are two high-risk prognostic factors, and only 17.1% of the interviewed physicians fully mastered CLL International Prognostic Index scoring system. ⑤Among the first-line treatment strategy, BTK inhibitors are used for different types of patients, and physicians have formed a certain understanding that BTK inhibitors should be preferentially used in patients with high-risk factors and elderly patients, but the actual use of BTK inhibitors in different types of patients is not high (31.6%-46.0%). ⑥BTK inhibitors at a reduced dose in actual clinical treatment were used by 69.0% of the physicians, and 66.8% of the physicians had interrupted the BTK inhibitor for >12 days in actual clinical treatment. The use of BTK inhibitors is reduced or interrupted mainly because of adverse reactions, such as atrial fibrillation, severe bone marrow suppression, hemorrhage, and pulmonary infection, as well as patients' payment capacity and effective disease progression control. ⑦Some differences were found in the perceptions and behaviors of hematologists and oncologists regarding the prognostic assessment of CLL/SLL, the choice of treatment options, the clinical use of BTK inhibitors, etc. Conclusion: At present, a gap remains between the diagnosis and treatment of CLL/SLL among Chinese physicians compared with the recommendations in the guidelines regarding the diagnostic criteria, treatment indications, prognosis assessment, accompanying disease assessment, treatment strategy selection, and rational BTK inhibitor use, especially the proportion of dose reduction or BTK inhibitor discontinuation due to high adverse events.
Female ; Humans ; Male ; Aged ; Middle Aged ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy* ; Prognosis ; Lymphoma, B-Cell ; Immunohistochemistry ; Immunoglobulin Heavy Chains/therapeutic use*

Bone defects caused by different causes such as trauma, severe bone infection and other factors are common in clinic and difficult to treat. Usually, bone substitutes are required for repair. Current bone grafting materials used clinically include autologous bones, allogeneic bones, xenografts, and synthetic materials, etc. Other than autologous bones, the major hurdles of rest bone grafts have various degrees of poor biological activity and lack of active ingredients to provide osteogenic impetus. Bone marrow contains various components such as stem cells and bioactive factors, which are contributive to osteogenesis. In response, the technique of bone marrow enrichment, based on the efficient utilization of components within bone marrow, has been risen, aiming to extract osteogenic cells and factors from bone marrow of patients and incorporate them into 3D scaffolds for fabricating bone grafts with high osteoinductivity. However, the scientific guidance and application specification are lacked with regard to the clinical scope, approach, safety and effectiveness. In this context, under the organization of Chinese Orthopedic Association, the Expert consensus for the clinical application of autologous bone marrow enrichment technique for bone repair ( version 2023) is formulated based on the evidence-based medicine. The consensus covers the topics of the characteristics, range of application, safety and application notes of the technique of autologous bone marrow enrichment and proposes corresponding recommendations, hoping to provide better guidance for clinical practice of the technique.

The Prostate Imaging Reporting and Data System (PI-RADS) has good ability to identify the nature of lesions on prostate magnetic resonance imaging (MRI). However, some lesions are still reported as PI-RADS 4 and 5 but are biopsy-proven benign. Herein, we aimed to summarize the reasons for the negative prostate biopsy of patients who were assessed as PI-RADS 4 and 5 by biparameter MRI. We retrospectively sorted out the prostate MRI, treatment, and follow-up results of patients who underwent a biparameter MRI examination of the prostate in The First Affiliated Hospital of Nanjing Medical University (Nanjing, China) from August 2019 to June 2021 with PI-RADS 4 and 5 but a negative biopsy. We focused on reviewing the MRI characteristics. A total of 467 patients underwent transperineal prostate biopsy. Among them, biopsy pathology of 93 cases were negative. After follow-up, 90 patients were ruled out of prostate cancer. Among the 90 cases, 40 were considered to be overestimated PI-RADS after review. A total of 22 cases were transition zone (TZ) lesions with regular appearance and clear boundaries, and 3 cases were symmetrical lesions. Among 15 cases, the TZ nodules penetrated the peripheral zone (PZ) and were mistaken for the origin of PZ. A total of 17 cases of lesions were difficult to distinguish from prostate cancer. Among them, 5 cases were granulomatous inflammation (1 case of prostate tuberculosis). A total of 33 cases were ambiguous lesions, whose performance was between PI-RADS 3 and 4. In summary, the reasons for "false-positive MRI diagnosis" included PI-RADS overestimation, ambiguous images giving higher PI-RADS, diseases that were really difficult to distinguish, and missed lesion in the initial biopsy; and the first two accounted for the most.
Male ; Humans ; Prostatic Neoplasms/pathology* ; Magnetic Resonance Imaging/methods* ; Retrospective Studies ; Image-Guided Biopsy/methods* ; Prostate/pathology*