Uromodulin and progression of IgA nephropathy.

Background: This study investigates the link between genetic variants associated with kidney function and immunoglobulin A (IgA) nephropathy (IgAN) progression. Methods: We recruited 961 biopsy-proven IgAN patients and 651 non-IgAN end-stage renal disease (ESRD) patients from Ruijin Hospital. Clinical and renal pathological data were collected. The primary outcome was the time to ESRD. A healthy population was defined as estimated glomerular filtration rate >60 mL/min/1.73 m2 without albuminuria or hematuria. Fifteen single-nucleotide polymorphisms (SNPs) were selected from a genome-wide association study of kidney function and genotyped by the SNaPshot. Immunohistochemistry in renal tissue and ELISA in urine samples were performed to explore the potential functions of genetic variations. Results: The rs77924615-G was independently associated with an increased risk for ESRD in IgAN patients after adjustments for clinical and pathologic indices, and treatment (adjusted hazard ratio 2.10; 95% confidence interval 1.14-3.88). No significant differences in ESRD-free survival time were found among different genotypes in non-IgAN ESRD patients (log-rank, P = .480). Moreover, rs77924615 exhibited allele-specific enhancer activity by dual-luciferase reporter assay. Accordingly, the urinary uromodulin-creatinine ratio (uUCR) was significantly higher in healthy individuals with rs77924615 AG or GG than in individuals with AA. Furthermore, uromodulin expression in tubular epithelial cells was higher in patients with rs77924615 AG or GG. Finally, we confirmed that an increased uUCR (P = .009) was associated with faster IgAN progression. Conclusion: The SNP rs77924615, which modulates the enhancer activity of the UMOD gene, is associated with renal function deterioration in IgAN patients by increasing uromodulin levels in both the renal tubular epithelium and urine.

Dual-Responsive Epigenetic Inhibitor Nanoprodrug Combined with Oncolytic Virus Synergistically Boost Cancer Immunotherapy by Igniting Gasdermin E-Mediated Pyroptosis.

Cancer immunotherapy has emerged as a promising approach for the treatment of various cancers. However, the immunosuppressive tumor microenvironment (TME) limits the efficacy of current immunotherapies. In this study, we designed a dual-responsive DNA methyltransferase inhibitor nanoprodrug ACNPs for combination therapy with oncolytic herpes simplex virus (oHSV). We found that the epigenetic inhibitor 5-Azacytidine (5-Aza) upregulated gasdermin E (GSDME) expression at the gene level, whereas the oHSV decreased the ubiquitination and degradation of GSDME to elevate its levels. Based on these observations, we further discovered that ACNPs and oHSV synergistically enhanced GSDME-mediated pyroptosis. Additionally, the combination therapy of ACNPs and oHSV effectively inhibited tumor growth, remodeled the immunosuppressive TME, and improved the efficacy of immune checkpoint blockade (ICB) therapy. These results demonstrate the potential to overcome immunosuppression through synergistic combinations, offering a promising approach for cancer immunotherapy.

Edible herbal source-derived polysaccharides as potential prebiotics: Composition, structure, gut microbiota regulation, and its related health effects.

Recently, with changes in dietary patterns, there has been increased interest in the concept of food and medicine homology, which can help prevent disease development. This has led to a growing focus on the development of functional health foods derived from edible herbal sources. Polysaccharides, found in many edible herbal sources, are gaining popularity as natural ingredients in the production of functional food products. The gut microbiota can effectively utilize most edible herbal polysaccharides (EHPs) and produce beneficial metabolites; therefore, the prebiotic potential of EHPs is gradually being recognized. In this review, we comprehensively discuss the structural features and characterization of EHPs to promote gut microbiota regulation as well as the structure-activity relationship between EHPs and gut microbiota. As prebiotics, intestinal microbiota can use EHPs to indirectly produce metabolites such as short-chain fatty acids to promote overall health; on the other hand, different EHP structures possess some degree of selectivity on gut microbiota regulation. Moreover, we evaluate the functionality and mechanism underlying EHPs in terms of anticancer activity, antimetabolic diseases, anti-inflammatory activity, and anti-neuropsychiatric diseases.

Tuning cellular metabolism for cancer virotherapy.

Oncolytic viruses (OVs) represent an emerging immunotherapeutic strategy owing to their capacity for direct tumor lysis and induction of antitumor immunity. However, hurdles like transient persistence and moderate efficacy necessitate innovative approaches. Metabolic remodeling has recently gained prominence as a strategic intervention, wherein OVs or combination regimens could reprogram tumor and immune cell metabolism to enhance viral replication and oncolysis. In this review, we summarize recent advances in strategic reprogramming of tumor and immune cell metabolism to enhance OV-based immunotherapies. Specific tactics include engineering viruses to target glycolytic, glutaminolytic, and nucleotide synthesis pathways in cancer cells, boosting viral replication and tumor cell death. Additionally, rewiring T cell and NK cell metabolism of lipids, amino acids, and carbohydrates shows promise to enhance antitumor effects. Further insights are discussed to pave the way for the clinical implementation of metabolically enhanced oncolytic platforms, including balancing metabolic modulation to limit antiviral responses while promoting viral persistence and tumor clearance.

Prognostic and predictive value of tumor deposits in advanced signet ring cell colorectal cancer: SEER database analysis and multicenter validation.

BACKGROUND: Colorectal signet-ring cell carcinoma (SRCC) is a rare cancer with a bleak prognosis. The relationship between its clinicopathological features and survival remains incompletely elucidated. Tumor deposits (TD) have been utilized to guide the N staging in the 8th edition of American Joint Committee on Cancer (AJCC) staging manual, but their prognostic significance remains to be established in colorectal SRCC. PATIENTS AND METHODS: The subjects of this study were patients with stage III/IV colorectal SRCC who underwent surgical treatment. The research comprised two cohorts: a training cohort and a validation cohort. The training cohort consisted of 631 qualified patients from the SEER database, while the validation cohort included 135 eligible patients from four independent hospitals in China. The study assessed the impact of TD on Cancer-Specific Survival (CSS) and Overall Survival (OS) using Kaplan-Meier survival curves and Cox regression models. Additionally, a prognostic nomogram model was constructed for further evaluation. RESULTS: In both cohorts, TD-positive patients were typically in the stage IV and exhibited the presence of perineural invasion (PNI) (P < 0.05). Compared to the TD-negative group, the TD-positive group showed significantly poorer CSS (the training cohort: HR, 1.87; 95% CI, 1.52-2.31; the validation cohort: HR, 2.43; 95% CI, 1.55-3.81; all P values < 0.001). This association was significant in stage III but not in stage IV. In the multivariate model, after adjusting for covariates, TD maintained an independent prognostic value (P < 0.05). A nomogram model including TD, N stage, T stage, TNM stage, CEA, and chemotherapy was constructed. Through internal and external validation, the model demonstrated good calibration and accuracy. Further survival curve analysis based on individual scores from the model showed good discrimination. CONCLUSION: TD positivity is an independent factor of poor prognosis in colorectal SRCC patients, and it is more effective to predict the prognosis of colorectal SRCC by building a model with TD and other clinically related variables.

BUB1 Promotes Gemcitabine Resistance in Pancreatic Cancer Cells by Inhibiting Ferroptosis.

The development of chemotherapy resistance severely limits the therapeutic efficacy of gemcitabine (GEM) in pancreatic cancer (PC), and the dysregulation of ferroptosis is a crucial factor in the development of chemotherapy resistance. BUB1 Mitotic Checkpoint Serine/Threonine Kinase (BUB1) is highly overexpressed in PC patients and is closely associated with patient prognosis. However, none of the literature reports the connection between BUB1 and ferroptosis. The molecular mechanisms underlying GEM resistance are also not well understood. Therefore, this study first established the high expression levels of BUB1 in PC patients, then explored the role of BUB1 in the process of ferroptosis, and finally investigated the mechanisms by which BUB1 regulates ferroptosis and contributes to GEM resistance in PC cells. In this study, downregulation of BUB1 enhanced the sensitivity of PC cells to Erastin, and inhibited cell proliferation and migration. Mechanistically, BUB1 could inhibit the expression levels of Neurofibromin 2 (NF2) and MOB kinase activator 1 (MOB1), and promote Yes-associated protein (YAP) expression, thereby inhibiting ferroptosis and promoting GEM resistance in PC cells. Furthermore, the combination of BUB1 inhibition with GEM exhibited a synergistic therapeutic effect. These findings reveal the mechanisms underlying the development of GEM chemotherapy resistance based on ferroptosis and suggest that the combined use of BUB1 inhibitors may be an effective approach to enhance GEM efficacy.

Bulk anda single-cell transcriptome profiling reveals the molecular characteristics of T cell-mediated tumor killing in pancreatic cancer.

Background: Despite the potential of immune checkpoint blockade (ICB) as a promising treatment for Pancreatic adenocarcinoma (PAAD), there is still a need to identify specific subgroups of PAAD patients who may benefit more from ICB. T cell-mediated tumor killing (TTK) is the primary concept behind ICB. We explored subtypes according to genes correlated with the sensitivity to TKK and unraveled their underlying associations for PAAD immunotherapies. Methods: Genes that control the responsiveness of T cell-induced tumor destruction (GSTTK) were examined in PAAD, focusing on their varying expression levels and association with survival results. Moreover, samples with PAAD were separated into two subsets using unsupervised clustering based on GSTTK. Variability was evident in the tumor immune microenvironment, genetic mutation, and response to immunotherapy among different groups. In the end, we developed TRGscore, an innovative scoring system, and investigated its clinical and predictive significance in determining sensitivity to immunotherapy. Results: Patients with PAAD were categorized into 2 clusters based on the expression of 52 GSTTKs, which showed varying levels and prognostic relevance, revealing unique TTK patterns. Survival outcome, immune cell infiltration, immunotherapy responses, and functional enrichment are also distinguished among the two clusters. Moreover, we found the CATSPER1 gene promotes the progression of PAAD through experiments. In addition, the TRGscore effectively predicted the responses to chemotherapeutics or immunotherapy in patients with PAAD and overall survival. Conclusions: TTK exerted a vital influence on the tumor immune environment in PAAD. A greater understanding of TIME characteristics was gained through the evaluation of the variations in TTK modes across different tumor types. It highlights variations in the performance of T cells in PAAD and provides direction for improved treatment approaches.

Globotriaosylsphingosine improves risk stratification of kidney progression in Fabry disease patients.

BACKGROUND: Kidney damage is common in patients with Fabry disease (FD), but more accurate information about the risk of progression to kidney failure is needed for clinical decision-making. In particular, FD patients with mild renal involvement often lack timely intervention and treatment. We aimed to utilize a model to predict the risk of renal progression in FD patients. METHODS: Between November 2011 and November 2019, ERT-naive patients with FD were recruited from three medical centers in China. To assess the risk of a 50% decline in the estimated glomerular filtration rate (eGFR) or end-stage kidney disease (ESKD), Cox proportional hazards models were utilized. The performance of these models was assessed using discrimination, calibration, and reclassification. RESULTS: A total of 117 individuals were enrolled. The mean follow-up time was 4.8 years, during which 35 patients (29.9 %) progressed to the composite renal outcomes. Male sex, baseline proteinuria, eGFR and globotriaosylsphingosine (Lyso-Gb3) were found to be independent risk factors for kidney progression by the Cox model, based on which a combined model containing those clinical variables and Lyso-Gb3 and clinical models including only clinical indicators were constructed. The two prediction models had relatively good performance, with similar model fit measured by R2 (59.8 % vs. 61.1 %) and AIC (51.54 vs. 50.08) and a slight increase in the C statistic (0.949 vs. 0.951). Calibration curves indicated closer alignment between predicted and actual renal outcomes in the combined model. Furthermore, subgroup analysis revealed that Lyso-Gb3 significantly improved the predictive performance of the combined model for kidney prognosis in low-risk patients with a baseline eGFR over 60 ml/min/1.73 m2 or proteinuria levels less than 1 g/d when compared to the clinical model. CONCLUSIONS: Lyso-Gb3 improves the prediction of kidney outcomes in FD patients with a low risk of progression, suggesting that these patients may benefit from early intervention to assist in clinical management. These findings need to be externally validated.

C/EBPα aggravates renal fibrosis in CKD through the NOX4-ROS-apoptosis pathway in tubular epithelial cells.

BACKGROUND: Chronic kidney disease (CKD) is a prevalent renal disorder with various risk factors. Emerging evidence indicates that the transcriptional factor CCAAT/enhancer binding protein alpha (C/EBPα) may be associated with renal fibrosis. However, the precise role of C/EBPα in CKD progression remains unexplored. METHODS: We investigated the involvement of C/EBPα in CKD using two distinct mouse models induced by folic acid (FA) and unilateral ureteral obstruction (UUO). Additionally, we used RNA sequencing and KEGG analysis to identify potential downstream pathways governed by C/EBPα. FINDINGS: Cebpa knockout significantly shielded mice from renal fibrosis and reduced reactive oxygen species (ROS) levels in both the FA and UUO models. Primary tubular epithelial cells (PTECs) lacking Cebpa exhibited reduced apoptosis and ROS accumulation following treatment with TGF-ß. RNA sequencing analysis suggested that apoptosis is among the primary pathways regulated by C/EBPα, and identified NADPH oxidoreductase 4 (NOX4) as a key protein upregulated upon C/EBPα induction (ICCB280). Treatment with l-Theanine, a potential NOX4 inhibitor, mitigated renal fibrosis and inflammation in both the FA and UUO mouse models. INTERPRETATION: Our study unveils a role for C/EBPα in suppressing renal fibrosis, mitigating ROS accumulation, and reducing cell apoptosis. Furthermore, we investigate whether these protective effects are mediated by C/EBPα's regulation of NOX4 expression. These findings present a promising therapeutic target for modulating ROS and apoptosis in renal tubular cells, potentially offering an approach to treating CKD and other fibrotic diseases.

Near-infrared-II Ag2S quantum dot probes targeting podoplanin enhance immunotherapy in oral squamous cell carcinoma.

Partial epithelial-mesenchymal transition (pEMT) plays a vital role in oral squamous cell carcinoma (OSCC) cervical lymph node metastasis and tumor immune escape as an immune barrier. However, targeted interventions for pEMT have yet to be established. In this study, we generated an αPDPN-Ag2S probe by modifying a Podoplanin(PDPN) monoclonal antibody on the surface of near infrared (NIR)-II Ag2S quantum dots (QDs) with carboxyl groups through an amide reaction. Then, we evaluated its in vivo targeting ability, therapeutic efficacy of eliminating pEMT using αPDPN-Ag2S-mediated NIR-II photoimmunotherapy (PIT) and biological safety. Here, we found that pEMT is related to CD8 + T-cell infiltration in our human OSCC tissue microarray. Compared with PdpnWT SCC7, the slower growth rate of subcutaneous graft tumors implanted with PdpnKD SCC7 was associated with a change in the tumor immune microenvironment (TIM) in an immunocompetent C3H/HeJ mouse model. In vitro, αPDPN-Ag2S plus NIR 808 nm laser irradiation induced SCC7 cell death. In vivo, NIR-II imaging results show that the αPDPN-Ag2S probe has a good active-targeting ability in a 4-nitroquinoline 1-oxide (4NQO)-induced C57 mouse OSCC model and C3H/HeJ SCC7 subcutaneous graft tumor model. Elimination of pEMT cells by NIR-II αPDPN-Ag2S probe-mediated PIT significantly reversed the local immunosuppressive tumor microenvironment and enhanced PD-1 immunotherapy efficacy. The safety profiles of αPDPN-Ag2S in BALB/c mice were also acceptable. Thus, αPDPN-Ag2S has important clinical translational value in predicting the risk of cervical lymph node metastasis. Importantly, our study proposed a new way to improve the efficacy of tumor immunotherapy.

Oral glucocorticoids with intravenous cyclophosphamide or oral glucocorticoids alone in the treatment of IgA nephropathy present with nephrotic syndrome and mesangioproliferative glomerulonephritis.

Background: Few studies have evaluated the treatment of immunoglobulin A nephropathy (IgAN) patients with nephrotic syndrome (NS) and mesangioproliferative glomerulonephritis (MPGN). The aim of this study was to compare the therapeutic effects of oral glucocorticoids (GCS) combined with intravenous cyclophosphamide (CTX) and oral GCS alone in the treatment of the MPGN-IgAN patients with NS. Methods: Biopsy-proven primary IgAN patients who were aged ≥14 years at diagnosis, had coexistent NS and MPGN and estimated glomerular filtration rate (eGFR) ≥15 mL/min/1.73 m2, and were treated by oral GCS combined with intravenous CTX or oral GCS alone for 6-12 months were retrospectively included. The patients in the GCS + CTX (prednisone 0.6-0.8 mg/kg/day and intravenous CTX 0.6-1.0 g monthly) or GCS (prednisone 0.8-1 mg/kg/day) group were rather matched at a 1:1 ratio on key characteristics by propensity score matching. The primary outcome was defined as either complete remission or partial remission at Month 24. The secondary outcome was a composite renal endpoint defined as a 50% decline in eGFR, doubling of serum creatinine or progression to end-stage kidney disease. Results: Among the 146 IgAN patients who met the inclusion criteria, 42 patients were enrolled in the GCS + CTX group, and 42 patients were enrolled in the GCS group after propensity score matching. The clinical and histological parameters were similar between the two groups. Remission occurred more frequently in the GCS + CTX group at Month 6 (88.1% vs 52.4%, P < 0.001), Month 12 (88.1% vs 56.1%, P = 0.001) and Month 24 (85.0% vs 47.5%, P < 0.001) than in the GCS group. Moreover, subgroup analysis revealed that the higher response rate at Month 24 in the GCS + CTX group than in the GCS group was also present in different subgroups defined by sex, age, eGFR or Oxford MEST-C. Notably, we found that eGFR decreased at a lower rate in patients from the GCS + CTX group than in patients from the GCS group [eGFR slope: 0.05(-3.09, 3.67) vs -2.56 (-11.30, 0.86) mL/min/1.73 m2/year, P = 0.03]. Based on multivariate Cox regression analysis, GCS + CTX treatment was found to be independently associated with a decrease in risk for the composite endpoint after adjusted by the International Risk Prediction Score with race (hazard ratio = 0.17, 95% confidence interval 0.04-0.83, P = .03). There was no significant difference in adverse events (50.0% vs 42.9%, P = 0.51) or serious adverse events (7.1% vs 11.9%, P = .71) between the two groups. Conclusions: Oral GCS combined with intravenous CTX is superior to GCS alone in treating MPGN-IgAN patients combined with NS. As the retrospective design and small sample size, our findings need to be validated by a prospective study.

Effects of electroacupuncture on refractory interstitial cystitis/bladder pain syndrome: A one-year follow-up case report.

BACKGROUND: Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) commonly face a decline in their quality of life and social functioning upon discontinuation of conventional therapy, which is known for its limited efficacy and the risk of relapse. While the existing evidence is somewhat restricted, acupuncture is being explored as a potential and effective treatment option for IC/BPS. CASE PRESENTATION: A 67-year-old woman, diagnosed with refractory IC/BPS, underwent treatment at the Medical Acupuncture Department of Sanming Integrated Traditional Chinese and Western Medicine Hospital. She reported symptoms of lower urinary system dysfunction, including urgency, frequency, and nocturia, along with chronic pelvic pain, and a persistent feeling of pressure and discomfort lasting over 8 years. The patient's visual analog scale (VAS) score for pelvic pain was 7 points prior to receiving acupuncture treatment. Throughout the day, she had more than 10 urinations, and at night, she urinated about once per hour. The O'Leary-Sant interstitial cystitis symptom index/interstitial cystitis problem index (ICSI/ICPI) score was 34 points, and the pelvic pain and urgency frequency (PUF) score was 19 points. RESULTS: The patient's complaints were significantly alleviated after 12 sessions of electroacupuncture treatment at BL32, BL33, BL35, and SP6 over 4 weeks. The patient claimed total relief from pelvic pain, with a VAS score of 0. The patient achieved a PUF score of 4 points and an ICSI/ICPI score of 7 points. In addition, there was a significant reduction in the frequency and urgency of urination. The patient experienced a frequency of 4-5 urinations during the day and 1-2 times at night. Subsequently, the patient's mental state and sleep quality were improved. The patient's symptoms did not change at one-year follow-up. CONCLUSION: Electroacupuncture has proven to be an effective management method for IC/BPS, as evidenced by the patient's alleviated lower urinary system symptoms and reduced pelvic pain.

Development of a CD8+ T cell-based molecular classification for predicting prognosis and heterogeneity in triple-negative breast cancer by integrated analysis of single-cell and bulk RNA-sequencing.

Background: Triple-negative breast cancer (TNBC), although the most intractable subtype, is characterized by abundant immunogenicity, which enhances responsiveness to immunotherapeutic measures. Methods: First, we identified CD8+ T cell core genes (TRCG) based on single-cell sequence and traditional transcriptome sequencing and then used this data to develop a first-of-its-kind classification system based on CD8+ T cells in patients with TNBC. Next, TRCG-related patterns were systematically analyzed, and their correlation with genomic features, immune activity (microenvironment associated with immune infiltration), and clinicopathological characteristics were assessed in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), the Cancer Genome Atlas (TCGA), GSE103091, GSE96058 databases. Additionally, a CD8+ T cell-related prognostic signature (TRPS) was developed to quantify a patient-specific TRCG pattern. What's more, the genes-related TRPS was validated by polymerase chain reaction (PCR) experiment. Results: This study, for the first time, distinguished two subsets in patients with TNBC based on the TRCG. The immune microenvironment and prognostic stratification between these have distinct heterogeneity. Furthermore, this study constructed a novel scoring system named TRPS, which we show to be a robust prognostic marker for TNBC that is related to the intensity of immune infiltration and immunotherapy. Moreover, the levels of genes related the TRPS were validated by quantitative Real-Time PCR. Conclusions: Consequently, this study unraveled an association between the TRCG and the tumor microenvironment in TNBC. TRPS model represents an effective tool for survival prediction and treatment guidance in TNBC that can also help identify individual variations in TME and stratify patients who are sensitive to anticancer immunotherapy.

Sublytic C5b-9 induces TIMP3 expression by glomerular mesangial cells via TRAF6-dependent KLF5 K63-linked ubiquitination in rat Thy-1 nephritis.

Rat Thy-1 nephritis (Thy-1N) is an experimental model for studying human mesangioproliferative glomerulonephritis (MsPGN), and its pathological features are glomerular mesangial cell (GMC) proliferation and extracellular matrix (ECM) accumulation. Although we have confirmed that renal lesions of Thy-1N rats are sublytic C5b-9-dependent, and ECM accumulation is related to tissue inhibitor of matrix metalloproteinase (TIMP) inhibiting matrix metalloproteinase (MMP) activity, whether sublytic C5b-9 can induce TIMP production by GMC in Thy-1N rat and the underlying mechanism remains unclear. In the study, we proved that the expressions of TIMP3, krϋppel-like transcription factor 5 (KLF5) and tumor necrosis factor receptor-associated factor 6 (TRAF6) were simultaneously up-regulated both in the renal tissues of Thy-1N rats (in vivo) and in the GMC exposed to sublytic C5b-9 (in vitro). Further mechanism exploration discovered that KLF5 and TRAF6 as two upstream molecules could induce TIMP3 gene transcription through binding to the same region i.e., -1801nt to -1554nt (GGGGAGGGGC) and -228nt to -46nt (GCCCCGCCCC) of TIMP3 promoter. In the process, TRAF6 mediated KLF5 K63-linked ubiquitination at K99 and K100 enhancing KLF5 nuclear localization and binding to TIMP3 promoter, augmenting its gene activation. Furthermore, the experiments in vivo exhibited that silencing KLF5, TRAF6 or TIMP3 gene could markedly lessen renal KLF5 K63-linked ubiquitination or TIMP3 induction, ECM accumulation and other pathological changes of Thy-1N rats. Besides, the positive expressions of above-mentioned these proteins and ECM accumulation and their correlation in the renal tissues of MsPGN patients were also demonstrated. Overall, our findings implicate that KLF5 and TRAF6 play a promoting role in sublytic C5b-9-triggered TIMP3 gene transcription and expression, which might provide a novel mechanistic insight into rat Thy-1N and human MsPGN.

Hormone replacement therapy did not increase risk of melanoma in Chinese female with menopausal and postmenopausal disorders: A population-based retrospective cohort study in Taiwan.

Hormone replacement therapy (HRT) is widely used to relieve symptoms of menopause with proven efficacy. However, there has been significant controversy surrounding the use of HRT because of its potential link with an increased risk of cancer, particularly female reproductive organ cancers. That HRT increases the risk of melanoma is also disputed, and several cohort studies have produced variable results. To delineate the association between HRT and melanoma in Taiwan, we conducted a population-based retrospective cohort study on 14 291 patients who had received HRT and 57 164 population controls in Taiwan between 2000 and 2013. Multivariate odds ratios (ORs) were calculated utilizing conditional logistic regression. Overall, the use of HRT was not significantly correlated with a higher risk of developing melanoma in Taiwan (95% confidence interval 0.386-1.099; p = 0.341). The hazard ratio analysis of melanoma and different HRTs showed there was no significant association between melanoma and the use of oral or external estrogens alone, including conjugated estrogens, estradiol, and estriol. Estrogen plus progesterone combined therapy was associated with a lower risk of melanoma. Only one case of melanoma was observed among the 2880 patients in this subgroup.

ALIX promotes cell migration and invasion of head and neck squamous cell carcinoma by regulating the expression of MMP9, MMP14, VEGF-C.

OBJECTIVE: The poor survival rate of head and neck squamous cell carcinoma (HNSCC), one of the most prevalent human cancer, is attributed to frequent locoregional recurrence and lymph node metastases. Though it is reported that the expression of ALG-2 interacting protein X (ALIX) closely correlates with the progression of various tumors, its role in HNSCC remains unclear. The present study aims to investigate the role of ALIX in the development of HNSCC. DESIGN: With immunohistochemical staining, the expression levels of ALIX and series of related functional proteins were compared in normal mucosal (n = 18), HNSCC tissues (n = 54), and metastatic lymph nodes (n = 11). Further, the correlation analysis was performed among the proteins detected. By knocking down ALIX in HNSCC cell lines, the correlation of ALIX with the proteins was verified in vitro. The role of ALIX in proliferation, migration, and invasion of HNSCC cells was further studied by flow cytometry, wounding healing, and transwell assays, respectively. RESULTS: Higher expression level of ALIX was revealed in HNSCC samples, especially in metastatic lymph nodes, than in normal mucosal tissues. Accordingly, increasing levels of MMP9, MMP14, and VEGF-C were also discovered in metastatic lymph nodes and significantly correlated with the expression of ALIX. In vitro assays demonstrated that the knockdown of ALIX reduced both the transcriptional and protein levels of MMP9, MMP14, and VEGF-C, together with suppressed migration and weakened invasion of HNSCC cell lines. CONCLUSIONS: ALIX up-regulated the expression of MMP9, MMP14 and VEGF-C, and promoted migration and invasion of HNSCC cells.

Chinese Experts Consensus and Practice Guideline on Discoid Lateral Meniscus.

Discoid lateral meniscus (DLM) is the most common congenital variant of the lateral meniscus, which is prone to degeneration and lesions, and often leads to knee osteoarthritis. At present, there is no consensus on the clinical practice of DLM, and this expert consensus and practice guidelines on DLM was developed and approved by Chinese Society of Sports Medicine according to the Delphi method. Among 32 statements drafted, 14 statements were excluded for redundant information, and 18 statements achieved consensus. This expert consensus focused on the definition, epidemiology, etiology, classification, clinical manifestations, diagnosis, treatment, prognosis, and rehabilitation of DLM. Restoring the normal shape, retaining appropriate width and thickness, and ensuring the stability of the remnant meniscus is critical to sustaining the physiological function of the meniscus and preserving the knee. The partial meniscectomy with or without repair should be the first-line treatment when possible, given that the clinical and radiological long-term outcomes of total or subtotal meniscectomy are worse.

Effects of Electroacupuncture for Opioid-Induced Constipation in Patients With Cancer in China: A Randomized Clinical Trial.

Importance: Opioid-induced constipation (OIC) is prevalent among patients treated with opioids for cancer pain. Safe and effective therapies for OIC in patients with cancer remain an unmet need. Objective: To determine the efficacy of electroacupuncture (EA) for OIC in patients with cancer. Design, Setting, and Participants: This randomized clinical trial was conducted at 6 tertiary hospitals in China among 100 adult patients with cancer who were screened for OIC and enrolled between May 1, 2019, and December 11, 2021. Interventions: Patients were randomized to receive 24 sessions of EA or sham electroacupuncture (SA) over 8 weeks and then were followed up for 8 weeks after treatment. Main Outcomes and Measures: The primary outcome was the proportion of overall responders, defined as patients who had at least 3 spontaneous bowel movements (SBMs) per week and an increase of at least 1 SBM from baseline in the same week for at least 6 of the 8 weeks of the treatment period. All statistical analyses were based on the intention-to-treat principle. Results: A total of 100 patients (mean [SD] age, 64.4 [10.5] years; 56 men [56.0%]) underwent randomization; 50 were randomly assigned to each group. Among them, 44 of 50 patients (88.0%) in the EA group and 42 of 50 patients (84.0%) in the SA group received at least 20 (≥83.3%) sessions of treatment. The proportion of overall responders at week 8 was 40.1% (95% CI, 26.1%-54.1%) in the EA group and 9.0% (95% CI, 0.5%-17.4%) in the SA group (difference between groups, 31.1 percentage points [95% CI, 14.8-47.6 percentage points]; P < .001). Compared with SA, EA provided greater relief for most OIC symptoms and improved quality of life among patients with OIC. Electroacupuncture had no effects on cancer pain and its opioid treatment dosage. Electroacupuncture-related adverse events were rare, and, if any, all were mild and transient. Conclusions and Relevance: This randomized clinical trial found that 8-week EA treatment could increase weekly SBMs with a good safety profile and improve quality of life for the treatment of OIC. Electroacupuncture thus provided an alternative option for OIC in adult patients with cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT03797586.

Efficacy and safety of acupuncture for hand osteoarthritis: study protocol for a multi-center, randomized, sham-controlled clinical trial.

BACKGROUND: Hand osteoarthritis (OA) is a prevalent disorder in the general population. Patients with hand OA often report symptoms of pain, stiffness, and functional limitations, which cause clinical burden and impact on quality of daily life. However, the efficacy of current therapies for hand OA is limited. Other therapies with better effects and less adverse events are in urgent need. Acupuncture is well known for analgesia and has been proved effective in treating basal thumb joint arthritis. This study aims to clarify the efficacy and safety of acupuncture treatment for clinical symptomatic improvement of hand OA. METHODS: This will be a sham-controlled, randomized, multi-center clinical trial. A total of 340 participants will be recruited and randomly allocated to either traditional acupuncture group or sham acupuncture group. All participants will receive 12 treatment sessions over 4 weeks and 2 follow-up assessments in the following 3 months at week 8 and week 16. The primary outcome will be the proportion of responders at week 5. Secondary outcomes will include visual analog scale, Australian Canadian Osteoarthritis Hand Index, Functional Index for hand OA, the number of symptomatic joints, hand grip strength and pinch strength, global assessment, the World Health Organization Quality of Life abbreviated version and expectations. Safety will be evaluated during the whole process of the trial. All outcomes will be analyzed following the intention-to-treat principle. DISCUSSION: This prospective trial will provide high-quality evidence on evaluating the efficacy and safety of acupuncture treatment for hand OA. Results of this trial might contribute in offering a new option to clinical recommendations. Trial registration ClinicalTrials.gov Identifier: NCT05267093. Registered 23 February 2022.

Autophagy-Targeted Calcium Phosphate Nanoparticles Enable Transarterial Chemoembolization for Enhanced Cancer Therapy.

Transarterial chemoembolization (TACE) is commonly used for treating advanced hepatocellular carcinoma (HCC). However, the instability of lipiodol-drug emulsion and the altered tumor microenvironment (TME, such as hypoxia-induced autophagy) postembolization are responsible for the unsatisfactory therapeutic outcomes. Herein, pH-responsive poly(acrylic acid)/calcium phosphate nanoparticles (PAA/CaP NPs) were synthesized and used as the carrier of epirubicin (EPI) to enhance the efficacy of TACE therapy through autophagy inhibition. PAA/CaP NPs have a high loading capacity of EPI and a sensitive drug release behavior under acidic conditions. Moreover, PAA/CaP NPs block autophagy through the dramatic increase of intracellular Ca2+ content, which synergistically enhances the toxicity of EPI. TACE with EPI-loaded PAA/CaP NPs dispersed in lipiodol shows an obvious enhanced therapeutic outcome compared to the treatment with EPI-lipiodol emulsion in an orthotopic rabbit liver cancer model. This study not only develops a new delivery system for TACE but also provides a promising strategy targeting autophagy inhibition to improve the therapeutic effect of TACE for the HCC treatment.