Glycosylation Targeting: A Paradigm Shift in Cancer Immunotherapy.

Immunotherapy has shown great potential in cancer treatment. However, even with the intervention of techniques such as immune checkpoint inhibitor therapy, tumors can still achieve immune escape, leading to a low response rate. Abnormal glycosylation is a widely recognized hallmark of cancer. The development of a complex "glyco-code" on the surface of tumor cells can potentially influence the immune system's ability to monitor tumors and can impact the anti-tumor immune response. Therefore, abnormal glycosylation has emerged as a promising target for immunotherapy. Many recent studies have shown that targeted glycosylation can reshape the tumor microenvironment (TME) and promote the immune response, thereby improving the response to immunotherapy. This review summarizes how glycosylation affects anti-tumor immune function in the TME and synthesizes the latest research progress on targeted glycosylation in immunotherapy. It is hoped that by elucidating the basic laws and biological connotations of glycosylation, this review will enable researcher to thoroughly analyze the mechanism of its influence on the immune metabolic regulation network, which will provide a theoretical tool for promoting the clinical application of glycosylation codes.

The histone methyltransferase ASH1L protects against bone loss by inhibiting osteoclastogenesis.

Absent, small, or homeotic1-like (ASH1L) is a histone lysine methyltransferase that generally functions as a transcriptional activator in controlling cell fate. So far, its physiological relevance in bone homeostasis and osteoclast differentiation remains elusive. Here, by conditional deleting Ash1l in osteoclast progenitors of mice, we found ASH1L deficiency resulted in osteoporosis and potentiation of osteoclastogenesis in vivo and in vitro. Mechanistically, ASH1L binds the promoter of the Src homology 3 and cysteine-rich domain 2 (Stac2) and increases the gene's transcription via histone 3 lysine 4 (H3K4) trimethylation modification, thus augmenting the STAC2's protection against receptor activator of nuclear factor kB ligand (RANKL)-initiated inflammation during osteoclast formation. Collectively, we demonstrate the first piece of evidence to prove ASH1L as a critical checkpoint during osteoclastogenesis. The work sheds new light on our understanding about the biological function of ASH1L in bone homeostasis, therefore providing a valuable therapeutic target for the treatment of osteoporosis or inflammatory bone diseases.

A multifunctional CaCO3 bioreactor coated with coordination polymers enhances cancer immunotherapy.

Designing effective nanomedicines to induce durable anti-tumor immunity represents a promising strategy for improving moderate immune stimulation. In this study, we engineered a multifunctional nanoreactor (named SCGFP NPs) for remodeling the tumor microenvironment (TME) to improve the therapeutic efficacy of immunotherapy. The core of SCGFP NPs consists of CaCO3 loaded with SN38, prepared by the gas diffusion method, and coated with a significant amount of gallic acid-Fe3+-PEG coordination polymer on the surface. In the acidic TME, SCGFP NPs explosively release exogenous Ca2+ and SN38. The SN38-induced intracellular Ca2+ accumulation and exogenous Ca2+ synergistically trigger immunogenic cell death (ICD) through sustained Ca2+ overload. The ablation of tumors with high-intensity photothermal therapy (PTT) by near-infrared (NIR) irradiation of GA-Fe3+ induces tumor cell necrosis, further enhancing ICD activation. Additionally, SN38 upregulates PD-L1, amplifying tumor responsiveness to immune checkpoint inhibitors (ICIs). This study indicates that SCGFP NPs, through the integration of a trimodal therapeutic strategy, hold enormous potential for various types of tumor immunotherapy through distinct mechanisms or synergistic effects.

Construction and Validation of a Nomogram Predicting the Overall Survival Benefit of Unilateral Breast Cancer Patients Undergoing Contralateral Prophylactic Mastectomy.

BACKGROUND: Currently, research on the prognostic factors of unilateral breast cancer (UBC) patients receiving contralateral prophylactic mastectomy (CPM) is limited. This study aimed to construct a new nomogram to predict these patients' overall survival (OS). METHODS: In this retrospective study, 88,477 patients who underwent CPM or unilateral mastectomy (UM) were selected from the Surveillance, Epidemiology, and End Results database. Kaplan-Meier curves and Cox regression analyses were used to determine the difference in the impact of the 2 surgical methods on the prognosis. Multivariate Cox analysis was used to determine the best prognostic variable and construct a nomogram. The concordance index (C-index), receiver operating characteristic (ROC) curve, calibration curve, decision curve analysis (DCA), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used to evaluate the discrimination capability and clinical effectiveness of the nomogram. RESULTS: The prognosis of patients receiving CPM and UM was significantly different. The DCA curves indicated that the nomogram could provide more excellent clinical net benefits for these patients. The NRI and IDI of the nomogram demonstrated that its performance was better than that of the classical tumor-node-metastasis (TNM) staging system. CONCLUSION: This study developed and validated a practical nomogram to predict the OS of UBC patients undergoing CPM, which provided a beneficial tool for clinical decision-making management.

Perioperative outcomes of bilateral axillo-breast approach robotic thyroidectomy (BABART) versus minimally invasive thyroidectomy (MIT): a systematic review and meta-analysis.

Minimally invasive thyroidectomy (MIT) is increasingly being used for the thyroid tumors. The comparison of bilateral axillo-breast approach robotic thyroidectomy (BABART) with other MIT has not yet led to a unified conclusion with regard to surgical outcomes. To conduct a systematic review and meta-analysis of the literature on the surgical outcomes of BABART compared with MIT. We performed a systematic search in PubMed, Web of Science, Embase and Cochrane Library database for randomized control trials (RCTs) and non-RCTs that compare BABART to MIT. The primary outcomes included perioperative, postoperative complications. The odds ratio (OR) and mean difference (MD) were applied for the comparison of dichotomous and continuous variables with 95% confidence intervals (CIs). Nine studies, comprising 3645 patients, were included in the meta-analysis. Our findings indicated that there were no significant differences in hospital stay, number of retrieved lymph nodes, recurrent laryngeal nerve (RLN) injury, and vocal cord dysfunction between BABRT and MIT. However, BABART was associated with a shorter operation time (MD = - 21.45 min, 95% CI [- 47.27, 4.38], p = 0.1) and lower rate of permanent hypoparathyroidism (OR = 0.42, 95% CI [0.20, 0.88], p = 0.02). Additionally, the MIT group had reduced postoperative pain score (MD = 0.45, 95% CI [0.02, 0.88], p = 0.04) and lower rate of hypocalcemia (OR = 2.31, 95% CI [1.04, 5.13], p = 0.04) than the BABART group. In comparison with MIT, BABART exhibits better results in terms of operative time and the rate of permanent hypoparathyroidism, with no significant difference in hospital stay, number of retrieved lymph nodes, RLN injury, and vocal cord dysfunction. However, the postoperative pain score and the rate of hypocalcemia of MIT are slightly better that of BABART.

Genome-wide DNA methylation analysis identifies potent CpG signature for temzolomide response in non-G-CIMP glioblastomas with unmethylated MGMT promoter: MGMT-dependent roles of GPR81.

PURPOSES: To identify potent DNA methylation candidates that could predict response to temozolomide (TMZ) in glioblastomas (GBMs) that do not have glioma-CpGs island methylator phenotype (G-CIMP) but have an unmethylated promoter of O-6-methylguanine-DNA methyltransferase (unMGMT). METHODS: The discovery-validation approach was planned incorporating a series of G-CIMP-/unMGMT GBM cohorts with DNA methylation microarray data and clinical information, to construct multi-CpG prediction models. Different bioinformatic and experimental analyses were performed for biological exploration. RESULTS: By analyzing discovery sets with radiotherapy (RT) plus TMZ versus RT alone, we identified a panel of 64 TMZ efficacy-related CpGs, from which a 10-CpG risk signature was further constructed. Both the 64-CpG panel and the 10-CpG risk signature were validated showing significant correlations with overall survival of G-CIMP-/unMGMT GBMs when treated with RT/TMZ, rather than RT alone. The 10-CpG risk signature was further observed for aiding TMZ choice by distinguishing differential outcomes to RT/TMZ versus RT within each risk subgroup. Functional studies on GPR81, the gene harboring one of the 10 CpGs, indicated its distinct impacts on TMZ resistance in GBM cells, which may be dependent on the status of MGMT expression. CONCLUSIONS: The 64 TMZ efficacy-related CpGs and in particular the 10-CpG risk signature may serve as promising predictive biomarker candidates for guiding optimal usage of TMZ in G-CIMP-/unMGMT GBMs.

Exosomal lncCRLA is predictive for the evolvement and development of lung adenocarcinoma.

Lung adenocarcinoma, the most common histological subtype of non-small cell lung cancer, exhibits heterogeneity that enables adaptability, limits therapeutic success, and remains incompletely understood. Our team uncovers that lncRNA related to chemotherapy resistance in lung adenocarcinoma (lncCRLA) is preferentially expressed in lung adenocarcinoma cells with the mesenchymal phenotype. lncCRLA can not enhance chemotherapy resistance in lung adenocarcinoma due to its binding to RIPK1 in exosomes, which is released into intercellular media and transferred by exosomes from mesenchymal-like to epithelial-like cells. However, plasmatic lncCRLA corresponding to tissue lncCRLA functions as a preferred biomarker to reflect the response to chemotherapy and disease progression of lung adenocarcinoma. Through single-cell sequencing, RNA-Mutect technique and spatial transcriptomics, a handful of hybrid EMT cells with elevated lncCRLA are characterized as the origin of lung adenocarcinoma, which are indiscriminated from hybrid EMT cells by the in-depth sequencing. Plasmatic lncCRLA is properly predictive for the preinvasive lesion of lung adenocarcinoma that would evolve to invasive lesion. That notion is confirmed by a brand-new transgenic mouse model in which EMT is tracked by Cre and Dre system. Dasatinib is potential to hinder the spontaneous progression from preinvasive to invasive lesion of lung adenocarcinoma. Together, plasmatic lncCRLA is defined as a brand-new circulating biomarker to predict the occurrence and evolvement of lung adenocarcinoma, a light for early detection of lung adenocarcinoma.

Neoadjuvant immunotherapy combined with chemotherapy in the treatment of stage III lung squamous cell carcinoma: a retrospective cohort study.

Background: Neoadjuvant immunochemotherapy has been proven to be a successful therapeutic strategy for patients with locally advanced non-small cell lung cancer (NSCLC). Nevertheless, there is a paucity of information regarding surgical feasibility and safety as well as tumor response. The present study aimed to investigate the therapeutic and surgical outcomes for patients with stage III lung squamous cell carcinoma (LSCC). Methods: Patients with stage III potentially resectable LSCC treated with neoadjuvant immunochemotherapy at The First Affiliated Hospital of Ningbo University between March 2020 and June 2022 were retrospectively included. Oncologic outcomes and intraoperative and postoperative variables were assessed. Results: A total of 17 locally advanced LSCC patients were included in the study. Patients in stages IIIA and IIIB were represented by 10 (58.8%) and 7 (41.2%) cases, respectively. A minimally invasive procedure was successfully completed in 12 out of 17 cases (70.6%). A total of 10 patients (58.8%) had standard lobectomies performed, 1 (5.9%) had a bilobectomy, 3 (17.6%) had pneumonectomies, and 1 (5.9%) had a wedge resection. A total of 7 patients (41.2%) experienced postoperative complications, and there were no 30- or 90-day mortalities. The 2-year disease-free survival (DFS) and overall survival (OS) rates were 76.6% and 82.5%, respectively. The rate of major pathological response (MPR) was 70.6%. Conclusions: Lung resection after immunochemotherapy for potentially resectable stage III LSCC is feasible and safe. This treatment strategy results in a significant pathologic response and promising rates of OS at 2 years.

Paternal lipopolysaccharide exposure induced intrauterine growth restriction via the inactivation of placental MEST/PI3K/AKT pathway in mice.

Maternal lipopolysaccharide (LPS) exposure during pregnancy has been related to IUGR. Here, we explored whether paternal LPS exposure before mating impaired fetal development. All male mice except controls were intraperitoneally injected with LPS every other day for a total of five injections. The next day after the last LPS, male mice were mated with untreated female mice. Interestingly, fetal weight and crown-rump length were reduced, while the incidence of IUGR was increased in paternal LPS exposure group. Additionally, paternal LPS exposure leaded to poor placental development through causing cell proliferation inhibition and apoptosis. Additional experiment demonstrated that the inactivation of placental PI3K/AKT pathway might be involved in paternal LPS-induced cell proliferation inhibition and apoptosis of trophoblast cells. Furthermore, the mRNA and protein levels of mesoderm specific transcript (MEST), a maternally imprinted gene with paternal expression, were significantly decreased in mouse placentas from paternal LPS exposure. Further analysis showed that paternal LPS exposure caused the inactivation of placental PI3K/AKT pathway and then cell proliferation inhibition and apoptosis might be via down-regulating placental MEST. Overall, our results provide evidence that paternal LPS exposure causes poor placental development and subsequently IUGR may be via down-regulating MEST/PI3K/AKT pathway, and then inducing cell proliferation inhibition and apoptosis in placentas.

Characteristics of fibrotic-foci-like lung adenocarcinoma on 18 F-FDG PET/computed tomography and HRCT.

PURPOSE: To assess the characteristics of fibrotic-foci-like lung adenocarcinoma on 18 F-fluorodeoxyglucose PET/computed tomography ( 18 F-FDG PET/CT) and high-resolution computed tomography (HRCT). MATERIAL AND METHODS: This was a retrospective study with 20 cases in the fibrotic-foci-like lung adenocarcinoma group; the control group was old fibrotic-foci of the lung with 20 cases. The following 18 F-FDG PET/CT and HRCT features were evaluated: the maximum standardized uptake value (SUVmax); the tumor-to-background ratios of SUVmax (TBRmax); the long-to-short diameter ratio (L/S); anatomic location; location type; internal characteristics; marginal characteristics and surrounding structures. In the fibrotic-foci-like lung adenocarcinoma group, a comparison of 18 F-FDG uptake between the metastatic group ( n  = 10) and the non-metastatic group ( n  = 10) was performed. Finally, the comparison of diagnostic accuracy for fibrotic-foci-like lung adenocarcinoma between 18 F-FDG PET/CT and HRCT was performed. RESULTS: The SUVmax [2.6 (1.7-7.9) vs. 1.0 (0.7-1.4)], TBRmax [2.9 (2.1-9.9) vs. 1.3 (1.2- 1.7)], L/S [2.4 (1.7-3.8) vs. 4.0 (3.2-6.3)], ground-glass opacity (GGO) [13/20 (65.0%) vs. 4/20 (20.0%)], and vessel convergence [7/20 (35.0%) vs. 1/20 (5.0%)] were found to be statistically significant differences between the fibrotic-foci-like lung adenocarcinoma group and the old fibrotic-foci group ( P  < 0.05). SUVmax [7.9 (4.7-8.8) vs. 1.7 (1.2-2.2)] and TBRmax [9.9 (6.5-11.0) vs. 2.1 (1.6-2.9)] were found to be statistically significant differences between the metastatic group and the non-metastatic group ( P  < 0.05). 18 F-FDG PET/CT showed the higher diagnostic accuracy for fibrotic-foci-like lung adenocarcinoma than HRCT [95.0% (19/20) vs. 65.0% (13/20), P  < 0.05]. CONCLUSION: The specific characteristics of fibrotic-foci-like lung adenocarcinoma on 18 F-FDG PET/CT and HRCT were high 18 F-FDG uptake, GGO, and vessel convergence, which could be distinguished from old fibrotic-foci of the lung.

Annexin A3 accelerates osteoclast differentiation by promoting the level of RANK and TRAF6.

Annexin A3 (ANXA3), a member of Annexin family, is reported to mediate membrane transport and cancer development. However, the effect of ANXA3 on osteoclast formation and bone metabolism is still unclear. In this study, we found that knockdown of ANXA3 can significantly inhibit receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation through NF-κB signaling. ANXA3 downregulation abrogated the expression of osteoclast-specific genes, including Acp5, Mmp9 and Ctsk in osteoclast precursors. Moreover, lentiviral of shRNA against ANXA3 reversed the bone loss in osteoporosis using ovariectomized mice model. Mechanistically, we found that ANXA3 directly bound to RANK and TRAF6 to accelerate osteoclast differentiation by promoting their transcription and limiting degradation. In conclusion, we propose a fundamentally novel RANK-ANXA3-TRAF6 complex to effectively modulate the formation and differentiation of osteoclast to manipulate bone metabolism. The ANXA3-targeted therapeutic strategy may provide new insight for bone degrading-related diseases prevention and treatment.

Frequency and Etiologies of Visual Disturbance After Cataract Surgery Identified in Neuro-Ophthalmology Clinics.

BACKGROUND: To identify the frequency and etiologies of visual disturbances after cataract surgery in patients referred to Neuro-ophthalmology. METHODS: This study is a retrospective chart review. Records of patients 18 years and older referred to neuro-ophthalmology clinics for new-onset visual disturbances within 6 months of cataract surgery were reviewed. Those with pre-existing neuro-ophthalmic disorders, combined intraocular procedures with cataract surgery, or inadequate follow-up were excluded. The main outcome measures were frequency and etiologies of visual disturbances after cataract surgery. Secondary analyses of a cohort of patients who had cataract surgery at our institution were performed to determine the frequency and etiology of visual disturbances after uneventful cataract surgery. RESULTS: One hundred seventy-three patients met the inclusion criteria (internal referral: 36/173, from outside surgeons: 137/173). Sixty-one percent (106/173) were newly diagnosed with neuro-ophthalmic etiologies, including 21% (36/173) with afferent and 40% (70/173) with efferent disorders. Thirty-six percent (62/173) of patients had non neuro-ophthalmic causes and 3% (5/173) had systemic conditions responsible for visual disturbances postoperatively. Decompensated strabismus causing diplopia was the most common neuro-ophthalmic diagnosis after cataract surgery (50%, 53/106). Of the 13,715 patients who had cataract surgery performed at our institution over a 9-year period, 20 of 36 patients referred for visual disturbances were identified with neuro-ophthalmic etiologies of which 85% (17/20) had postoperative diplopia. CONCLUSIONS: In our study, decompensated strabismus causing diplopia was the most common neuro-ophthalmic visual disturbance after cataract surgery. Detailed history and ocular alignment should be assessed before cataract surgery to identify patients with the risk.

The relationship between immediate postmastectomy reconstruction modalities and survival benefits in patients with triple negative breast cancer.

INTRODUCTION: Immediate postmastectomy reconstruction for breast cancer has been widely used due to its unique esthetic and psychological effects. However, no other population-based study has investigated the effects of different reconstruction types on the survival in patients with triple negative breast cancer (TNBC). METHODS: We selected patients who met the eligibility criteria from the Surveillance, Epidemiology, and End Results cancer registry (N = 9760). We then assessed the effect of different reconstructive surgical approaches (implant, autologous, implant and autologous combined reconstruction) on the overall survival (OS) and breast cancer-specific survival (BCSS) by using the Kaplan-Meier survival curve and Cox proportional hazard regression analyses. The nomograms were used to predict OS and BCSS. And the competitive risk model was used to assess breast cancer-specific death (BCSD) and non-breast cancer-specific death (NBCSD). RESULTS: Statistical analysis suggested that the three reconstruction methods had better OS and BCSS with lower hazard than mastectomy alone (log-rank test, p < 0.05). Multivariate stratified analysis showed that patients aged 40-60 years had the greatest improvement in OS (Adjusted hazard ratio [AHR], 0.646; 95% Confidence Interval [CI], 0.439-0.950; p = 0.026) with combined reconstruction. BCSS could be improved only by implant reconstruction (AHR, 0.672; 95% CI, 0.514-0.878; p = 0.004). In addition, autologous reconstruction (AHR, 0.570; 95% CI, 0.350-0.929; p = 0.024) and implant reconstruction (AHR, 0.538; 95% CI, 0.339-0.853; p = 0.008) improved OS in patients >60 years of age. The survival prediction model quantified the survival benefits of TNBC patients undergoing different surgeries. Moreover, the C-indexes showed the good predictive ability of the nomograms. CONCLUSIONS: Our results suggest that for TNBC patients, there is a survival benefit of immediate postmastectomy reconstruction compared with mastectomy alone. Among them, implant reconstruction has the most obvious advantage.

A ROS/Akt/NF-κB Signaling Cascade Mediates Epidermal Growth Factor-Induced Epithelial-Mesenchymal Transition and Invasion in Human Breast Cancer Cells.

Background: As one of the most widely used anti-diabetic drugs for type II diabetes, metformin has been shown to exhibit anti-cancer activity in recent years. Epidermal growth factor (EGF) and its receptor, EGFR, play important roles in cancer metastasis in various tumors, including breast cancer. Epithelial-mesenchymal transition (EMT) is a critical process for cancer invasion and metastasis. In this study, we use EGF as a metastatic inducer to investigate the effect of metformin on cancer cell migration, invasion and EMT. Methods: Human breast cancer MCF-7 cells were exposed to EGF with or without metformin or N-acetyl cysteine (NAC). The effects of metformin on breast cancer cell proliferation were analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The production of reactive oxygen species (ROS) was tested using 2,7-dichlorodihydrofluorecein diacetate (DCFH-DA). The migratory and invasive abilities of tumor cells were analyzed using wound healing assay and transwell invasion assay, respectively. The expressions of E-cadherin, N-cadherin and Snail were tested using real-time quantitative polymerase chain reaction (qRT-PCR) and western blotting at mRNA and protein levels. The activation of protein kinase B (Akt) and nuclear factor kappa B (NF-κB) were measured by western blotting. Results: Our results showed that metformin inhibited breast cancer cell proliferation in a dose-dependent manner with or without EGF. EGF-induced alterations in cell morphology that are characteristic of EMT were reversed by metformin. Metformin also inhibited the EGF-modulated expression of E-cadherin, N-cadherin and Snail and further suppressed cell invasion and migration. In addition, metformin suppressed EGF-induced phosphorylation of Akt and NF-κB. ROS is involved in EGF-induced cancer invasion and activation of phosphatidylinositol 3-kinase (PI3K)/Akt/NF-κB pathway. Conclusion: Taken together, these data indicate that metformin suppresses EGF-induced breast cancer cell migration, invasion and EMT through the inhibition of the PI3K/Akt/NF-κB pathway. These results provide a novel mechanism to explain the role of metformin as a potent anti-metastatic agent in breast cancer cells.

Prognostic effect of radiotherapy in breast cancer patients underwent immediate reconstruction after mastectomy.

Introduction: It is still unclear whether radiotherapy affects the long-term survival of breast cancer (BC) patients after immediate breast reconstruction (IBR). This study aims to evaluate the actual prognostic impact of radiotherapy on BC patients undergoing IBR, and to construct survival prediction models to predict the survival benefit of radiotherapy. Methods: Data on eligible BC patients were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Competing risk models were used to assess breast cause-specific death (BCSD) and non-breast cancer cause-specific death (NBCSD). Kaplan-Meier curve, Cox risk regression model and forest map were used to evaluate and demonstrate overall survival (OS) and breast cancer-specific survival (BCSS). Survival prediction nomograms were used to predict OS and BCSS probabilities. Results: A total of 22,218 patients were selected, 24.9% received radiotherapy and 75.1% were without radiotherapy. Competing risk models showed that whether BCSD or NBCSD, the cumulative long-term risk of death in the radiotherapy group was higher than that in the non-radiotherapy group. The Kaplan-Meier curve showed that patients with different lymph node metastasis had different radiotherapy benefits. Multivariate stratified analysis showed that radiotherapy after autologous reconstruction was associated with poor BCSS in patients with stage N0, and radiotherapy after autologous reconstruction and combined reconstruction improved OS and BCSS in patients with stage N3. The C-indexes of nomogram (between 0.778 and 0.847) and calibration curves showed the good prediction ability of survival prediction model. Conclusions: Radiotherapy can improve OS and BCSS in N3 stage BC patients undergoing immediate autologous reconstruction after mastectomy. The practical nomograms can be used to predict OS and BCSS of patients with or without radiotherapy, which is helpful for individualized treatment.

The efficacy of parecoxib in improving pain after total knee or total hip arthroplasty: Systematic review and meta-analysis.

BACKGROUND: The cyclooxygenase-2 (COX-2) selective inhibitor parecoxib is widely used in the treatment of pain and inflammation. Parecoxib has been adopted for use for postoperative analgesia following a range of surgical procedures (orthopedic, general, gynecological, and dental surgery). Total knee or total hip arthroplasty (THA) surgery is mostly done in older patients, so postoperative analgesics need to be used more carefully, and the safety and efficacy of parecoxib in this type of surgery need to be further verified. The aim of this study was to investigate the effects of parecoxib on patient safety, cumulative morphine consumption and was at 24 and 48 hours in the analgesic treatment of total knee or THA for meta-analysis and systematic review, with few studies in this area so far. METHODS: We searched the Online Database Cochrane Library, PubMed, Web of Science, EMBASE, and CBM (SinoMed), CNKI, VIP, WANFANG up to January 2021. According to the value of I2, the random-effect model or fixed-effect model was supposed to combine data from studies, respectively. Publication bias was assessed through funneling plot and Beggs test. Review Manager 5.3 and Stata 16.0 software were applied to perform the statistical analyses. RESULTS: Eleven RCTs which involved 1690 participants were included in this study. The meta-analysis indicated parecoxib sodium could not significantly reduce the incidence of adverse events after total knee or THA compared with placebo. There was no statistical significance in incidence of nausea and vomiting. 24 hours resting VAS score was statistically significant between the group. The 48-hour resting VAS scores did not indicate a significant difference between the groups. CONCLUSION: Parecoxib can reduce the incidence of adverse events after total knee or total hip surgery to some extent but cannot reduce the incidence of nausea and vomiting. Twenty-four hour postoperative analgesia is better than placebo, but 48 hours after operation analgesia is the same as placebo.

Identification of glycogene signature as a tool to predict the clinical outcome and immunotherapy response in breast cancer.

Background: Breast cancer is one of the most important diseases in women around the world. Glycosylation modification correlates with carcinogenesis and roles of glycogenes in the clinical outcome and immune microenvironment of breast cancer are unclear. Methods: A total of 1297 breast cancer and normal cases in the TCGA and GTEx databases were enrolled and the transcriptional and survival information were extracted to identify prognostic glycogenes using Univariate Cox, LASSO regression, Multivariate Cox analyses and Kaplan-Meier method. The immune infiltration pattern was explored by the single sample gene set enrichment method. The HLA and immune checkpoint genes expression were also compared in different risk groups. The expressions of a glycogene MGAT5 as well as its products were validated by immunohistochemistry and western blotting in breast cancer tissues and cells. Results: A 19-glycogene signature was identified to separate breast cancer patients into high- and low-risk groups with distinct overall survival rates (P < 0.001). Compared with the high-risk group, proportion of naive B cells, plasma cells and CD8+ T cells increased in the low-risk group (P < 0.001). Besides, expressions of HLA and checkpoint genes, such as CD274, CTLA4, LAG3 and TIGIT3, were upregulated in low-risk group. Additionally, highly expressed MGAT5 was validated in breast cancer tissues and cells. Downstream glycosylation products of MGAT5 were all increased in breast cancer. Conclusions: We identified a 19-glycogene signature for risk prediction of breast cancer patients. Patients in the low-risk group demonstrated a higher immune infiltration and better immunotherapy response. The validation of MGAT5 protein suggests a probable pathway and target for the development and treatment of breast cancer.

Melatonin ameliorates diabetic hyperglycaemia-induced impairment of Leydig cell steroidogenic function through activation of SIRT1 pathway.

BACKGROUND: Diabetes mellitus (DM)-related complications are important health problems worldwide. The underlying mechanisms for diabetic male subfertility/infertility are considerably complicated and need to be unveiled for therapeutic intervention. Melatonin treatment was investigated to assess the beneficial effects on injured steroidogenic function in DM due to its regulatory roles in mitochondria and autophagy. METHODS: Diabetic hyperglycaemia was induced in rats injected with streptozotocin (STZ, 55 mg/kg/d) or simulated in TM3 Leydig cell line cultured with medium containing 30 mM D-glucose. Then, diabetic rats or the TM3 cells under high glucose were treated with melatonin. The diabetic rats were randomly divided into diabetes mellitus group (DM group), insulin treatment group (DM + INS group) and melatonin treatment group (DM + MT group). The TM3 Leydig cells were divided into a normal glucose control group (NG group), a high glucose treatment group (HG group), and a melatonin treatment group (HG + MT group). Then, Sirt1 (silent mating type information regulation 2 homologue) 1 expression was knocked down by siRNA. RESULTS: The results showed that hyperglycaemia induced a decline in steroidogenesis, accompanied by autophagy defects, mitochondrial dysfunction and oxidative stress, in rats in the DM group or TM3 Leydig cells in the HG group. Furthermore, reduced SIRT1 expression levels and hyperacetylation were found in Leydig cells of DM group. Melatonin treatment ameliorated hyperglycaemia-induced impairment of Leydig cell function with simultaneous stimulation of 5'-adenosine monophosphate activated protein kinase (AMPK)/SIRT1 activity and the expression of autophagy-related genes. With regards to mitochondrial function, it promoted mitochondrial biogenesis with elevated PGC-1α, NRF1 and mtTFA, improved mitochondrial morphology, increased BNIP3L-related mitophagy and alleviated oxidative stress. Further results revealed that knockdown of Sirt1 in Leydig cells prevented the protective effects provided by melatonin against high glucose treatment, and interestingly, neutralization of reactive oxygen species (ROS) by N-acetyl-L-cysteine pretreatment abolished the stimulatory effect of melatonin on AMPK/SIRT1 activity in Leydig cells and prevented the induction of autophagy and mitochondrial biogenesis in the context of high glucose, indicating that modulation of SIRT1 pathway by melatonin was closely linked to ROS levels and oxidative stress. CONCLUSIONS: These findings suggest that SIRT1 pathway plays essential roles in the pleiotropic actions of melatonin on Leydig cells and in the prevention of hyperglycaemia-induced steroidogenic dysfunction. The stimulatory action of melatonin on SIRT1 pathway is related to oxidative stress and its antioxidant property. Our data provide new evidence for the relationship of melatonin and SIRT1 pathway in the context of hyperglycaemia, and melatonin as a combination therapy may be useful to combat DM-related complications, especially male reproductive system injury.

Dysregulation and prometastatic function of glycosyltransferase C1GALT1 modulated by cHP1BP3/ miR-1-3p axis in bladder cancer.

BACKGROUND: Abnormal glycosylation in a variety of cancer types is involved in tumor progression and chemoresistance. Glycosyltransferase C1GALT1, the key enzyme in conversion of Tn antigen to T antigen, is involved in both physiological and pathological conditions. However, the mechanisms of C1GALT1 in enhancing oncogenic phenotypes and its regulatory effects via non-coding RNA are unclear. METHODS: Abnormal expression of C1GALT1 and its products T antigen in human bladder cancer (BLCA) were evaluated with BLCA tissue, plasma samples and cell lines. Effects of C1GALT1 on migratory ability and proliferation were assessed in YTS-1 cells by transwell, CCK8 and colony formation assay in vitro and by mouse subcutaneous xenograft and trans-splenic metastasis models in vivo. Dysregulated circular RNAs (circRNAs) and microRNAs (miRNAs) were profiled in 3 pairs of bladder cancer tissues by RNA-seq. Effects of miR-1-3p and cHP1BP3 (circRNA derived from HP1BP3) on modulating C1GALT1 expression were investigated by target prediction program, correlation analysis and luciferase reporter assay. Functional roles of miR-1-3p and cHP1BP3 on migratory ability and proliferation in BLCA were also investigated by in vitro and in vivo experiments. Additionally, glycoproteomic analysis was employed to identify the target glycoproteins of C1GALT1. RESULTS: In this study, we demonstrated upregulation of C1GALT1 and its product T antigen in BLCA. C1GALT1 silencing suppressed migratory ability and proliferation of BLCA YTS-1 cells in vitro and in vivo. Subsets of circRNAs and miRNAs were dysregulated in BLCA tissues. miR-1-3p, which is reduced in BLCA tissues, inhibited transcription of C1GALT1 by binding directly to its 3'-untranslated region (3'-UTR). miR-1-3p overexpression resulted in decreased migratory ability and proliferation of YTS-1 cells. cHP1BP3 was upregulated in BLCA tissues, and served as an miR-1-3p "sponge". cHP1BP3 was shown to modulate migratory ability, proliferation, and colony formation of YTS-1 cells, and displayed tumor-suppressing activity in BLCA. Target glycoproteins of C1GALT1, including integrins and MUC16, were identified. CONCLUSIONS: This study reveals the pro-metastatic and proliferative function of upregulated glycosyltransferase C1GLAT1, and provides preliminary data on mechanisms underlying dysregulation of C1GALT1 via miR-1-3p / cHP1BP3 axis in BLCA.