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Cervical cancer is one of the most aggressive female cancers. RNA methylation is a necessary epigenetic modification in biological process. This study aimed to construct an RNA methylation regulator-based risk model for predicting the prognosis of cervical cancer patients.The transcriptome profiles of cervical cancer data were obtained from The Cancer Genome Atlas (TCGA) and GSE44001. An RNA methylation-related risk model was constructed and assessed by the Least absolute shrinkage and selection operator (Lasso)-penalized Cox regression model and receiver operating characteristic (ROC). Kaplan-Meier and Cox regression analyses were used to evaluate the prognostic effect of the risk model and calculated scores. The immune infiltration difference was further analyzed between the subgroups with a single-sample gene set enrichment analysis (ssGSEA).A total of 63 methylation modulators were included in this study, and 618 cervical cancer patients were identified from TCGA and GSE44001. Differential expression genes profiling RNA methylation regulators between normal and tumor samples were distinct. A four-gene signature panel was constructed to predict the prognostic risk. The predictive ability was satisfactory. Cervical cancer patients were classified into high- or low-risk subgroups according to the median risk score. Moreover, the immune infiltration patterns between them differed.A risk model including four RNA methylation regulators was constructed, which will provide new perspectives for further investigation of the relationship between RNA methylation and cervical cancer.

Platelet-derived growth factors (PDGFs) and PDGF receptors (PDGFRs) are expressed in a variety of tumors. Activation of the PDGF/PDGFR signaling pathway is associated with cancer proliferation, metastasis, invasion, and angiogenesis through modulating multiple downstream pathways, including phosphatidylinositol 3 kinase/protein kinase B pathway and mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. Therefore, targeting PDGF/PDGFR signaling pathway has been demonstrated to be an effective strategy for cancer therapy, and accordingly, some great progress has been made in this field in the past few decades. This review will focus on the PDGF isoforms and their binding with the related PDGFRs, the PDGF/PDGFR signaling and regulation, and especially present strategies and inhibitors developed for cancer therapy, and the related clinical benefits and side effects.

Long non-coding RNAs (lncRNAs) act as important regulators of tumorigenesis and development in bladder cancer. However, the underlying molecular mechanisms remain elusive. We previously identified a novel lncRNA signature related to immunity and progression in bladder cancer. Here we further explored the function of RP11-89, a lncRNA discovered in the previous signature. Loss- and gain-of function experiments were performed using CCK-8 assay, flow cytometry, Transwell assays, scratch tests and subcutaneous nude mouse models. High-throughput RNA sequencing was conducted to identify dysregulated genes in bladder cancer cells with RP11-89 knockdown or overexpression. Regulation of RP11-89 on miR-129-5p and PROM2 was explored through luciferase reporter assay, RIP assay and RNA pull-down assay. RP11-89 promoted cell proliferation, migration and tumorigenesis and inhibited cell cycle arrest via the miR-129-5p/PROM2 axis. We found that RP11-89 “sponges” miR-129-5p and upregulates PROM2. Elevated PROM2 in cells was associated with attenuated ferroptosis through iron export, formation of multivesicular bodies and less mitochondrial abnormalities. We demonstrated that RP11-89 is a novel tumorigenic regulator that inhibits ferroptosis via PROM2-activated iron export. RP11-89 may serve as a potential biomarker for targeted therapy in bladder cancer.

To explore the relationship between social isolation and health behaviors and ulcer severity in patients with diabetic foot.A cross-sectional study was conducted with 160 patients suffering from type 2 diabetes mellitus combined with diabetic foot. The patients received treatment at the Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University between September 2020 and December 2021. Patient information was collected, including the scores for Lubben Social Network Scale and the Wagner classification of foot ulcers. Analysis was conducted to study the characteristics of the patients' health behaviors, including whether they received information and education on diabetic foot, whether there were delays in their attempt to access medical service, the frequency of foot examinations, etc. In addition, patient demographic data were collected, including sex, age, education, and employment status. According to their scores for Lubben Social Network Scale, the patients were divided into a social isolation group (The findings suggest that, compared with the non-social-isolation group, the social isolation group had a higher proportion of diabetic foot patients with Wagner grade 3-5 diabetic foot ulcers (Social isolation is correlated to health behaviors and ulcer severity in patients with diabetic foot. Giving more attention to the problem of social isolation of diabetic foot patients and increasing their ties with the social environment and the members of their social network may have a positive effect on improving the delays in diabetic foot patients' attempt to access medical service, which is particularly important for follow-up treatment.

PurposeThis study aims to investigate the prognostic value of composition and spatial architecture of tumor-infiltrating lymphocytes (TILs) as well as PDL1 expression on TILs subpopulations in nasopharyngeal carcinoma (NPC).MethodsA total of 121 patients with NPC were included and divided into two groups: favorable (n = 68) and unfavorable (n = 53). The archived tumor tissues of the included patients were retrieved, and a tissue microarray was constructed. The density and spatial distribution of TILs infiltration were analyzed using the multiplex fluorescent immunohistochemistry staining for CD3, CD4, CD8, Foxp3, cytokeratin (CK), PDL1, and 4′,6-diamidino-2-phenylindole (DAPI). The infiltration density of TILs subpopulations and PDL1 expression were compared between the two groups. The Gcross function was calculated to quantify the relative proximity of any two types of cells. The Cox proportional hazards regression model was used to identify factors associated with overall survival (OS) and disease-free survival (DFS).ResultsThe densities of regulatory T-cells (Tregs), effector T-cells (Teffs), PDL1+ Tregs, and PDL1+ Teffs were significantly higher in patients with unfavorable outcomes. PDL1 expression on tumor cells (TCs) or overall TILs was not associated with survival. Multivariate analysis revealed that higher PDL1+ Tregs infiltration density was independently associated with inferior OS and DFS, whereas Tregs infiltration density was only a prognostic marker for DFS. Spatial analysis revealed that unfavorable group had significantly stronger Tregs and PDL1+ Tregs engagement in the proximity of TCs and cytotoxic T lymphocyte (CTLs). Gcross analysis further revealed that Tregs and PDL1+ Tregs were more likely to colocalize with CTLs. Moreover, increased GTC : Treg (Tregs engagement surrounding TCs) and GCTL : PDL1+ Treg were identified as independent factors correlated with poor outcomes.ConclusionTILs have a diverse infiltrating pattern and spatial distribution in NPC. Increased infiltration of Tregs, particularly PDL1+ Tregs, as well as their proximity to TCs and CTLs, correlates with unfavorable outcomes, implying the significance of intercellular immune regulation in mediating disease progression.

Deep learning has been used extensively in histopathological image classification, but people in this field are still exploring new neural network architectures for more effective and efficient cancer diagnosis. Here, we propose multi-scale, multi-view progressive feature encoding network (MSMV-PFENet) for effective classification. With respect to the density of cell nuclei, we selected the regions potentially related to carcinogenesis at multiple scales from each view. The progressive feature encoding network then extracted the global and local features from these regions. A bidirectional long short-term memory analyzed the encoding vectors to get a category score, and finally the majority voting method integrated different views to classify the histopathological images. We tested our method on the breast cancer histology dataset from the ICIAR 2018 grand challenge. The proposed MSMV-PFENet achieved 93.0$$\%$$ % and 94.8$$\%$$ % accuracies at the patch and image levels, respectively. This method can potentially benefit the clinical cancer diagnosis.

Purpose To predict the incidence of radiation-induced hypothyroidism (RHT) in nasopharyngeal carcinoma (NPC) patients, dosiomics features based prediction models were established. Materials and methods A total of 145 NPC patients treated with radiotherapy from January 2012 to January 2015 were included. Dosiomics features of the dose distribution within thyroid gland were extracted. The minimal-redundancy-maximal-relevance (mRMR) criterion was used to rank the extracted features and selected the most relevant features. Machine learning (ML) algorithms including logistic regression (LR), support vector machine (SVM), random forest (RF), and k-nearest neighbor (KNN) were utilized to establish prediction models, respectively. Nested sampling and hyper-tuning methods were adopted to train and validate the prediction models. The dosiomics-based (DO) prediction models were evaluated through comparing with the dose-volume factor-based (DV) models in terms of the area under the receiver operating characteristic (ROC) curve (AUC). The demographics factors (age and gender) were included in both DO model and DV model. Results Age, V45 and 37 dosiomics features exhibited significant correlations with RHT in univariate analysis. For prediction performance, DO prediction models exhibited better results with the best AUC value 0.7 while DV prediction models 0.61. In DO prediction models, the AUC values displayed a trend from ascending to descending with the increasing of selected features. The highest AUC value was achieved when the number of selected features was 3. In DV prediction model, similar trend was not observed. Conclusion This study established a prediction model based on the dosiomics features with better performance than conventional dose-volume factors, leading to early predict the possible RHT among NPC patients who had received radiotherapy and take precaution measures for NPC patients.

Objective Two large randomized trials of patients with differentiated thyroid cancer (DTC) reported recently (HiLo and ESTIMABL1) found that the recurrence rate among patients who underwent 1.1 GBq radioactive iodine (RAI) ablation was not higher than that of patients who underwent 3.7 GBq radioactive iodine (RAI) ablation. However, no similar studies have been conducted in China. We aimed to report clinical outcomes in Chinese patients with low/intermediate risk of recurrence DTC after long-term follow-up, and evaluate the risk factors that influence the presence or absence of incomplete response at the final follow-up. Design A long-term follow-up of a Chinese randomized clinical trial (October 2014 and February 2021) was conducted. Patients A total of 506 DTC patients at low/intermediate risk of recurrence who were randomized into two groups to receive 1.1 (n = 251) or 3.7 GBq (n = 255) RAI ablation following thyroid hormone withdrawal were followed on levothyroxine treatment for a median of 4.5 years (range: 1.6-6.3). Measurements Suppressed serum thyroglobulin (Tg) and anti-thyroglobulin antibody (TgAb) levels were determined, and neck ultrasonography was performed. Results At the final follow-up, 499 (98.6%) patients showed an excellent response. The other seven patients (two patients underwent 1.1 GBq and five patients underwent 3.7 GBq RAI ablation, respectively) showed either structural incomplete response (lymph node metastasis, n = 1), biochemical incomplete response (increased serum Tg ≥ 1 ng/ml, or increased positive TgAb levels, n = 5), or indeterminate response (stable positive TgAb levels, n = 1). The risk of incomplete response at the final follow-up was significantly increased in patients with stimulated serum Tg ≥ 10 ng/ml at ablation (p = .003) and in patients with unsuccessful ablation (p = .008). Conclusion Our findings indicated that there was no difference in the long-term outcomes with RAI ablation using either 1.1 or 3.7 GBq in patients with low/intermediate risk of recurrence DTC, and 1.1 GBq RAI might be suitable for patients who are recommended for ablation.

Background Reliable predictors are urgently needed to identify stage II nasopharyngeal carcinoma (NPC) patients who could benefit from concurrent chemoradiotherapy (CCRT). We aimed to develop a nomogram integrating MRI-identified multidimensional features of lymph nodes to predict survival and assist the decision-making of CCRT for stage II NPC. Patients and methods This retrospective study enrolled 242 stage II NPC patients treated from January 2007 to December 2017. Overall survival (OS) was the primary endpoint. Performance of nomogram was evaluated using calibration curves, Harrell Concordance Index (C-index), area under the curve (AUC) and decision curves analysis (DCA) and was compared with TNM staging. According to the individualized nomogram score, patients were classified into two risk cohorts and therapeutic efficacy of CCRT were evaluated in each cohort. Results Three independent prognostic factors for OS: age, number and location of positive lymph nodes were included into the final nomogram. T stage was also incorporated due to its importance in clinical decision-making. Calibration plots demonstrated a good match between the predicted and our observed OS rates. C-index for nomogram was 0.726 compared with 0.537 for TNM staging (p < 0.001). DCAs confirmed the superior clinical utility of nomograms compared with TNM staging. CCRT compared to intensity-modulated radiotherapy (IMRT) delivered OS benefit to patients in the high-risk group (5-year: 89.9% vs. 72.1%; 10-year: 72.5% vs. 34.2%, p = 0.011), but not in the low-risk group. Conclusions This lymph node features-based nomogram demonstrated excellent discrimination and predictive accuracy for stage II patients and could identify patients who can benefit from CCRT.

Background Systemic lupus erythematosus is a chronic inflammatory autoimmune disease that has various manifestations. Lupus nephritis is a common and severe presentation, which results in increased morbidity and mortality. Belimumab added on standard therapy has been proved to induce disease remission and improve renal parameters. However, the use of belimumab has not been explored in patients requiring dialysis treatment. Methods Seven patients diagnosed as SLE with renal involvement requiring dialysis, who received belimumab in addition to steroids or immunosuppressants were identified. Clinical and biological data were extracted from medical records and laboratory databases. Ten mg/kg belimumab was applied on day 1, 15, 29, and every 28 days thereafter for a total of 8 dose. Renal parameters including urine output and serum creatinine level, immunologic index including anti-ds-DNA antibody titer and complement level, and disease activity were documented to reveal the response to belimumab. Results After belimumab therapy, all the 7 patients receiving dialysis therapy showed immunologic improvement. Disease activity significantly declined from 16.5 to 5.33 using SLEDAI-2K score. Apart from patient 7 on maintenance dialysis, 5 of 6 patients had increased urine output and were out of dialysis treatment. Patient 5 and 6 showed significant decrease in serum creatinine level. Only one pulmonary infection was documented. Conclusions Belimumab added to steroids or immunosuppressive agents was able to improve renal and immunologic parameters and decrease disease activity of SLE patients receiving dialysis treatment. The safety issue is promising with no severe adverse effect recorded. Further large, controlled, randomized clinical trials are required to confirm the results.

Intestinal flora dysbiosis may play an important role in the occurrence and development of chronic fatigue syndrome (CFS), which may induce the inflammatory response and metabolic disturbance of patients with CFS. Acupuncture and moxibustion may achieve anti-fatigue effect by affecting the diversity and quantity of intestinal flora, improving intestinal barrier function, and regulating brain-gut peptides.肠道菌群失调可能在慢性疲劳综合征（CFS）发生发展中起重要作用，可能与其引发的炎性反应和代谢紊乱有关。针灸可能通过影响肠道菌群多样性与数量，改善肠道屏障功能，调控脑肠肽实现抗疲劳作用。.

Background Osteoarthritis, a common degenerative disease of articular cartilage, is characterized by degeneration of articular cartilage, changes in subchondral bone structure, and formation of osteophytes, with main clinical manifestations including increasingly serious swelling, pain, stiffness, deformity, and mobility deficits of the knee joints. With the advent of the big data era, the processing of mass data has evolved into a hot topic and gained a solid foundation from the steadily developed and improved machine learning algorithms. Aiming to provide a reference for the diagnosis and treatment of osteoarthritis, this paper using machine learning identifies the key feature genes of osteoarthritis and explores its relationship with immune infiltration, thereby revealing its pathogenesis at the molecular level. Methods From the GEO database, GSE55235 and GSE55457 data were derived as training sets and GSE98918 data as a validation set. Differential gene expressions of the training sets were analyzed, and the LASSO regression model and support vector machine model were established by applying machine learning algorithms. Moreover, their intersection genes were regarded as feature genes, the receiver operator characteristic (ROC) curve was drawn, and the results were verified using the validation set. In addition, the expression spectrum of osteoarthritis was analyzed by immunocyte infiltration and the co-expression correlation between feature genes and immunocytes was construed. Conclusion EPYC and KLF9 can be viewed as feature genes for osteoarthritis. The silencing of EPYC and the overexpression of KLF9 are associated with the occurrence of osteoarthritis and immunocyte infiltration.

Purpose Concurrent chemoradiotherapy (CCRT) is a standard treatment choice for locally advanced hypopharyngeal carcinoma. The aim of this study was to investigate whether induction chemotherapy (IC) followed by CCRT is superior to CCRT alone to treat locally advanced hypopharyngeal carcinoma. Methods and materials Patients (n = 142) were randomized to receive two cycles of paclitaxel/cisplatin/5-fluorouracil (TPF) IC followed by CCRT or CCRT alone. The primary end point was overall survival (OS). The secondary end points included the larynx-preservation rate, progression-free survival (PFS), distant metastasis-free survival (DMFS), and toxicities. Results Ultimately, 113 of the 142 patients were analyzed. With a median follow-up of 45.6 months (interquartile range 26.8–57.8 months), the 3-year OS was 53.1% in the IC + CCRT group compared with 54.8% in the CCRT group (hazard ratio, 1.004; 95% confidence interval, 0.573–1.761; P = 0.988). There were no statistically significant differences in PFS, DMFS, and the larynx-preservation rate between the two groups. The incidence of grade 3–4 hematological toxicity was much higher in the IC+ CCRT group than in the CCRT group (54.7% vs. 10%, P Conclusions Adding induction TPF to CCRT did not improve survival and the larynx-preservation rate in locally advanced hypopharyngeal cancer, but caused a higher incidence of acute hematological toxicities. Trial registration ClinicalTrials.gov, number NCT03558035. Date of first registration, 15/06/2018.

This study aimed to decipher the pharmacodynamic material basis and mechanism of herbal pair Bupleurum scorzonerifolium-Paeonia lactiflora(BS-PL) against liver cancer based on UPLC-Q-TOF-MS and network pharmacology. MTT assay and human hepatocellular carcinoma HepG2 cells were used to screen the effective part of BS-PL, the active components of which were further analyzed and identified by UPLC-Q-TOF-MS. Next, we applied Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) to screen the active ingredients with OB≥30%. Then TCMSP and SwissTargetPrediction were used to collect and predict component targets, followed by the search of liver cancer-related targets with GeneCards and DisGeNET. The intersection targets were obtained using Venny 2.1.0. Protein-protein interaction(PPI) network was constructed using STRING to uncover the core targets, which were subjected to Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis based on DAVID. Finally, the effects of active ingredients on the expression of main proteins enriched in the key pathways of HepG2 cells were verified by Western blot. The results indicated that compared with 30%, 50%, and 70% ethanol extracts of BS-PL, the n-butanol extraction part(CSYZ) from 95% ethanol extract of BS-PL exhibited the best anti-tumor effect. UPLC-Q-TOF-MS revealed 31 ingredients, 14 of which showed OB≥30%. A total of 220 intersection targets were obtained, from which 35 were selected as the key targets under the condition of two times the median of degree. Among the 215 items with Plt;0.05 obtained through GO enrichment analysis, 154 were classified into biological processes, 22 into cell components and 39 into molecular functions. KEGG enrichment analysis revealed 95 significantly affected signaling pathways, and the ones(sorted in a descending order by P value) closely related to the anti-liver cancer effect of herbal pair were PI3 K-AKT signaling pathway, TNF signaling pathway, MAPK signaling pathway, HIF-1 signaling pathway, and ErbB signaling pathway. Finally, the PI3 K/AKT signaling pathway involving the largest number of targets was extrapolated, and it was found that this pathway contained 15 core targets and 8 active components. Experimental verification showed that the effective components of BS-PL significantly inhibited the expression of p-PI3 K and p-AKT, consistent with the prediction results of network pharmacology. In conclusion, the main pharmacodynamic substances of BS-PL against liver cancer are 14 components like saikosaponin a, saikosaponin d, and paeoniflorin, which exert the anti-liver cancer effect by regulating PI3 K/AKT pathway.

Purpose Conditional survival (CS) and failure hazard estimations can provide important dynamic prognostic information for clinical decision‐making and surveillance counseling. The current study aimed to investigate the CS and dynamic failure hazard in non‐metastatic nasopharyngeal carcinoma (NPC) treated with intensity‐modulated radiotherapy (IMRT). Methods Conditional overall survival (COS) and progression‐free survival (CPFS) estimates adjusted for age and gender against each AJCC 8th stage were calculated. Multivariable Cox regression (MCR) models were fitted in the entire population at baseline and subsequently separate MCR models were fitted in patients who have maintained event‐free time of 1 to 10 years to generate respective hazard ratio (HR). Annual hazard rates of death and progression over 10 years for each stage were also estimated. Results A total of 1993 patients were eligible for analysis. The estimated 5‐year OS and PFS for entire cohort were 79.0% and 70.7% at initial diagnosis. After 5 years of event‐free follow‐up, additional 5‐year COS and CPFS increased to 85.9% and 85.5%, respectively. Stage I/II maintained dramatically favorable CS and low hazard (< 5%) of death and progression over time. Relative to stage I/II, stage III manifested non‐significantly higher failure hazard for the first 3 years of survivorship and approached to similar level of stage I/II afterwards. Stage IVA presented most impressive improvement in terms of both COS (∆=9.8%) and CPFS (∆ = 16.8%) whereas still drastically inferior to that of stage I‐III across all conditional time points. After 4 years of follow‐up, progression hazard of stage IVA became relatively steady of approximate 6%. Conclusions Survival prospect of non‐metastatic NPC improves over years with distinct dynamic patterns across stages, providing important implications for personalized decision‐making in terms of both clinical management and surveillance counseling. Stage‐dependent and hazard‐adapted clinical management and surveillance are warranted., This study aimed to investigate the conditional survival (CS) and dynamic failure hazard in non‐metastatic nasopharyngeal carcinoma (NPC) treated with intensity‐modulated radiotherapy (IMRT). Survival prospect of non‐metastatic NPC improved over years with distinct dynamic patterns across stage, providing important implications for personalized decision‐making in terms of both clinical management and surveillance counseling. Stage‐dependent and hazard‐adapted clinical management and surveillance are warranted.

This study aims to construct a robust prognostic model for adult adrenocortical carcinoma (ACC) by large‐scale multiomics analysis and real‐world data. The RPPA data, gene expression profiles and clinical information of adult ACC patients were obtained from The Cancer Proteome Atlas (TCPA), Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Integrated prognosis‐related proteins (IPRPs) model was constructed. Immunohistochemistry was used to validate the prognostic value of the IPRPs model in Fudan University Shanghai Cancer Center (FUSCC) cohort. 76 ACC cases from TCGA and 22 ACC cases from GSE10927 in NCBI’s GEO database with full data for clinical information and gene expression were utilized to validate the effectiveness of the IPRPs model. Higher FASN (P = .039), FIBRONECTIN (P

Purpose This study aims to identify potential prognostic biomarkers of bladder cancer (BCa) based on large-scale multi-omics data and investigate the role of SRC in improving predictive outcomes for BCa patients and those receiving immune checkpoint therapies (ICTs). Methods Large-scale multi-comic data were enrolled from the Cancer Proteome Atlas, the Cancer Genome Atlas and gene expression omnibus based on machining-learning methods. Immune infiltration, survival and other statistical analyses were implemented using R software in cancers (n = 12,452). The predictive value of SRC was performed in 81 BCa patients receiving ICT from aa validation cohort (n = 81). Results Landscape of novel candidate prognostic protein signatures of BCa patients was identified. Differential BECLIN, EGFR, PKCALPHA, ANNEXIN1, AXL and SRC expression significantly correlated with the outcomes for BCa patients from multiply cohorts (n = 906). Notably, risk score of the integrated prognosis-related proteins (IPRPs) model exhibited high diagnostic accuracy and consistent predictive ability (AUC = 0.714). Besides, we tested the clinical relevance of baseline SRC protein and mRNA expression in two independent confirmatory cohorts (n = 566) and the prognostic value in pan-cancers. Then, we found that elevated SRC expression contributed to immunosuppressive microenvironment mediated by immune checkpoint molecules of BCa and other cancers. Next, we validated SRC expression as a potential biomarker in predicting response to ICT in 81 BCa patient from FUSCC cohort, and found that expression of SRC in the baseline tumour tissues correlated with improved survival benefits, but predicts worse ICT response. Conclusion This study first performed the large-scale multi-omics analysis, distinguished the IPRPs (BECLIN, EGFR, PKCALPHA, SRC, ANNEXIN1 and AXL) and revealed novel prediction model, outperforming the currently traditional prognostic indicators for anticipating BCa progression and better clinical strategies. Additionally, this study provided insight into the importance of biomarker SRC for better prognosis, which may inversely improve predictive outcomes for patients receiving ICT and enable patient selection for future clinical treatment.

Tribbles homolog 3 (TRIB3), a pseudokinase that regulates multiple intracellular signaling pathways, has been reported to promote the growth of multiple tumors. However, its role in clear cell renal cell carcinoma (ccRCC) remains unelucidated. We evaluated the role of TRIB3 in ccRCC using publicly available data from The Cancer Genome Atlas and analyzed its relationship with the tumor microenvironment; moreover, we used gene knockout and overexpression techniques to detect the effects of TRIB3 on the biological behavior of ccRCC cells. RT-qPCR and western blotting were used to detect transfection efficiency, and the invasiveness of ccRCC cells was determined by Transwell migration assays. We found that TRIB3 overexpression was significantly associated with increased grade, stage, and distant metastasis, positively correlated with ccRCC invasiveness, and also an independent risk factor for overall survival (OS). In addition, 361 differentially expressed genes (DEGs) related to TRIB3 were identified. Functional enrichment analysis showed that DEGs were mainly enriched in humoral immune responses, collagen-containing extracellular matrix, and serine hydrolase activity. Immune landscape characterization revealed that TRIB3 expression was significantly and negatively associated with CD8

Background To identify the malignant potential and prognostic indicators of renal epithelioid angiomyolipoma (eAML), clinicopathological and molecular features as well as the drug efficacy of 67 eAML cases were analyzed. Materials and methods Sixty-seven renal eAML patients were enrolled and the immunohistochemical features of these patients were examined. FFPE slides of all patients were re-examined. 21 patients with metastasis received Everolimus 10 mg orally once daily. Responses were evaluated with RECIST criteria by three authors. A risk stratification model was constructed using the following factors: pT3 and pT4, presence of necrosis, mitotic count ≥ 2; the presence of atypical mitoses; severe nuclear atypia, SMA negative, Ki-67 ≥ 10%. Results The average percentage of the epithelioid component was 85.6% (range 80–95%). Immunohistochemically, Ki-67 ≥ 10% and negative SMA staining were significantly correlated with malignant characteristics (Ki-67: p p = 0.001). Survival analysis suggested that pT3-pT4 stage, presence of necrosis, severe nuclear atypia, presence of atypical mitoses, mitotic count ≥ 2, Ki-67 ≥ 10% and negative SMA expression were significantly associated with poorer PFS and OS (p Conclusion The risk stratification model could well distinguish eAML patients at high risk of recurrence/metastasis. Everolimus targeted treatment showed good efficacy in patients with recurrence/metastasis.

BackgroundDual blockade of immune checkpoint and angiogenesis is an effective strategy for multiple cancers. Camrelizumab is a monoclonal antibody against PD-1, and famitinib is a multitargeted receptor tyrosine kinase inhibitor with antiangiogenesis and antiproliferation activities against tumor cells. We conducted an open-label, multicenter phase 2 basket study of camrelizumab and famitinib in eight cohorts of genitourinary or gynecological cancers. Here, findings in cohort of advanced or metastatic urothelial carcinoma with platinum-progressive disease (cohort 2) are presented.MethodsPatients who had progressed after platinum-based chemotherapy for advanced or metastatic disease or had progressed within 12 months after completion of platinum-based (neo)adjuvant therapy were given camrelizumab (200 mg intravenously every 3 weeks) plus famitinib (20 mg orally once daily). Primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1.ResultsTotally, 36 patients were recruited. With a median duration from enrollment to data cut-off of 11.9 months (range 6.1–28.5), ORR was 30.6% (95% CI 16.3% to 48.1%). Median duration of response (DoR) was 6.3 months (95% CI 2.1 to not reached). Median progression-free survival (PFS) was 4.1 months (95% CI 2.2 to 8.2), and median overall survival (OS) was 12.9 months (95% CI 8.8 to not reached). Patients with bladder cancer (n=18) had numerically better outcomes, with an ORR of 38.9% (95% CI 17.3% to 64.3%) and a median PFS of 8.3 months (95% CI 4.1 to not reached). Median DoR and OS in this subpopulation had not been reached with lower limit of 95% CI of 4.2 months for DoR and 11.3 months for OS, respectively. Of 36 patients, 22 (61.1%) had grade 3 or 4 treatment-related adverse events, mainly decreased platelet count and hypertension.ConclusionsCamrelizumab plus famitinib showed potent antitumor activity in advanced or metastatic urothelial carcinoma patients after platinum-based chemotherapy. Patients with bladder cancer seemed to have better response to this combination.Trial registration numberNCT03827837.

Clear cell renal cell carcinoma (ccRCC) is the most common and highly malignant pathological type of kidney cancer. We sought to establish a metabolic signature to improve post‐operative risk stratification and identify novel targets in the prediction models for ccRCC patients. A total of 58 metabolic differential expressed genes (MDEGs) were identified with significant prognostic value. LASSO regression analysis constructed 20‐mRNA signatures models, metabolic prediction models (MPMs), in ccRCC patients from two cohorts. Risk score of MPMs significantly predicts prognosis for ccRCC patients in TCGA (P

Increasing evidence has shown that Rad50, a protein involved in the DNA damage repair process, significantly correlated with tumor prognosis. This study focused on Rad50 expression in tumor samples and its prognostic value for patients with prostate cancer (PCa). In this study, significantly elevated Rad50 expression in PCa tissues compared to normal tissues (P < .01). Five independent Oncomine databases validated significant differential expression of Rad50 (P < .001). Hence, 80 patients with PCa from Fudan University Shanghai Cancer Center (FUSCC) and 351 patients with PCa with available protein expression data from The Cancer Genome Atlas (TCGA) were included to investigate the survival benefit. Univariate and multivariate Cox regression analyses were performed to investigate the significance of clinicopathological factors on disease-free survival (DFS) and overall survival (OS). Kaplan-Meier analysis indicated that elevated Rad50 protein expression levels significantly correlated with unfavorable DFS (P = .005) in the FUSCC cohort and poorer OS (P = .04) in TCGA cohort. Furthermore, coregulation analysis of proteins indicated that 76 coregulated proteins were associated with Rad50, while 11 most highly involved hub proteins, including Rad50, MRE11A, DUT, POLR3A, MCM3AP, RECQL, PNPT1, RANBP3, DDX1, SNRPB, and UGN, were significantly coregulated in the protein-protein interaction network. Functional enrichment analysis consecutively indicated significant functions and signaling pathways including DNA replication, spliceosome, DNA geometric change, homologous recombination, and G2M checkpoint. This study first reveals that elevated Rad50 expression is significantly associated with aggressive progression and poor survival for patients with PCa. Together, these data suggest that Rad50 may act as an oncoprotein, guide the molecular diagnosis, and may shed light on novel individual therapeutic strategies for progressive PCa patients.

The tumorigenic role and underlying mechanisms of lipid accumulation, commonly observed in many cancers, remain insufficiently understood. In this study, we identified an AMP-activated protein kinase (AMPK)–GATA-binding protein 3 (GATA3)–enoyl-CoA hydratase short-chain 1 (ECHS1) pathway that induces lipid accumulation and promotes cell proliferation in clear cell renal cell carcinoma (ccRCC). Decreased expression of ECHS1, which is responsible for inactivation of fatty acid (FA) oxidation and activation of de novo FA synthesis, positively associated with ccRCC progression and predicted poor patient survival. Mechanistically, ECHS1 downregulation induced FA and branched-chain amino acid (BCAA) accumulation, which inhibited AMPK-promoted expression of GATA3, a transcriptional activator of ECHS1. BCAA accumulation induced activation of mTORC1 and de novo FA synthesis, and promoted cell proliferation. Furthermore, GATA3 expression phenocopied ECHS1 in predicting ccRCC progression and patient survival. The AMPK–GATA3–ECHS1 pathway may offer new therapeutic approaches and prognostic assessment for ccRCC in the clinic. Significance: These findings uncover molecular mechanisms underlying lipid accumulation in ccRCC, suggesting the AMPK–GATA3–ECHS1 pathway as a potential therapeutic target and prognostic biomarker.

Epithelial-to-mesenchymal transition (EMT) is important in tumor invasiveness and metastasis. We aimed to determine prognostic value of six key EMT markers (CDH1, CDH2, SNAI1, SNAI2, VIM, TWIST1) in clear cell renal cell carcinoma (ccRCC). A total of 533 ccRCC patients with RNASeq data from The Cancer Genome Atlas (TCGA) cohort were included for analysis. Gene expression of these EMT markers was compared between tumor and normal tissues based on Oncomine database and TCGA cohort. Their correlations with progression-free survival (PFS) and overall survival (OS) were also examined in both TCGA cohort and FUSCC (Fudan University Shanghai Cancer Center) cohort. Cox proportional hazards regression model and Kaplan-Meier plot were used to assess the relative factors. Functional enrichment analyses were utilized to describe biologic function annotations and significantly involved hallmarks pathways of each gene. We found that Epithelial marker, CDH1 expression was lower, while mesenchymal markers (CDH2, SNAI1, VIM, TWIST1) expression was higher in ccRCC primary tumors. In the TCGA cohort, we found that patients with higher expression of VIM, TWIST1 or lower expression of CDH1 had worse prognosis. Further, in the FUSCC cohort, we confirmed the predictive ability of mesenchymal markers and epithelial marker expression in PFS and OS of ccRCC patients. After generating Cox regression models, EMT markers (CDH1, SNAI1, VIM, and TWIST1) were independent prognostic factors of both PFS and OS in ccRCC patients. Our preliminary EMT prediction model can facilitate further screening of EMT biomarkers and cast a better understanding of EMT gene function in ccRCC.

The epidermal growth factor receptor (EGFR) family members EGFR and HER2 play pivotal roles in oncogenesis and tumor progression. Anticancer drugs targeting EGFR and HER2 have been developed. Long noncoding RNAs (lncRNAs) have been reported to regulate cancer development and progression through signaling pathways. However, lncRNAs that regulate EGFR and HER2 expression remain unknown. Here, we show that lncRNA myosin light chain kinase-antisense RNA 1 (MYLK-AS1) promotes EGFR and HER2 expression and activates their downstream signaling pathway. MYLK-AS1 increases hepatocellular carcinoma (HCC) cell proliferation, migration, and invasion in vitro. Consistently, MYLK-AS1 knockdown hinders tumor growth in vivo. Mechanistically, MYLK-AS1 enhances HCC cell proliferation, migration, and invasion through stimulating the EGFR/HER2-extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. In addition, MYLK-AS1 is overexpressed in HCC patients and negatively correlated with HCC prognosis. Thus, MYLK-AS1 is an upstream regulator of EGFR/HER2, and acts as an oncogene, suggesting an additional target for cancer therapeutics.

Psoriatic arthritis (PsA) is a unique immune-mediated disease with cutaneous and osteoarticular involvement. However, only a few studies have explored the susceptibility of osteoarticular involvement in psoriasis (Ps) at the genetic level. This study investigated the biomarkers associated with osteoarticular participation and potential shared molecular mechanisms for PsA and ankylosing spondylitis (AS).MethodsThe RNA-seq data of Ps, PsA, and AS in the Gene Expression Omnibus (GEO) database were obtained. First, we used the limma package and the weighted gene co-expression network analysis (WGCNA) to identify the potential genes related to PsA and AS. Then, the shared genes in PsA and AS were performed using the GO, KEGG, and GSEA analyses. We also used machine learning to screen hub genes. The results were validated using external datasets and native cohorts. Finally, we used the CIBERSORT algorithm to estimate the correlation between hub genes and the abundance of immune cells in tissues.ResultsAn overlap was observed between the PsA and AS-related modules as 9 genes. For differentially expressed genes in AS and PsA, only one overlapping gene was found (COX7B). Gene enrichment analysis showed that the above 9 genes might be related to the mRNA surveillance pathway. The GSEA analyses showed that COX7B was involved in adaptive immune response, cell activation, etc. The PUM1 and ZFP91, identified from the support vector machine, had preferable values as diagnostic markers for osteoarticular involvement in Ps and AS (AUC > 0.7). Finally, CIBERSORT results showed PUM1 and ZFP91 involvement in changes of the immune microenvironment.ConclusionFor the first time, this study showed that the osteoarticular involvement in psoriasis and AS could be mediated by the mRNA surveillance pathway-mediated abnormal immunologic process. The biological processes may represent the cross talk between PsA and AS. Therefore, PUM1 and ZFP91 could be used as potential biomarkers or therapeutic targets for AS and Ps patients.

Objective This study aims to identify potential prognostic and therapeutic biomarkers in papillary renal cell carcinoma (pRCC). Methods Two microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database and differentially expressed genes (DEGs) were identified. The protein-protein interaction (PPI) networks and functional annotations of DEGs were established. Survival analysis was utilized to evaluate the prognostic significance of the DEGs and the association between the expression level of candidate biomarkers and various tumour-infiltrating immune cells was explored. The role of PTTG1 in tumour microenvironments (TME) was further explored using Single-cell RNA-seq and its prognostic and therapeutic significance was validated in Fudan University Shanghai Cancer Centre (FUSCC) cohort. Results Eight genes, including BUB1B, CCNB1, CCNB2, MAD2L1, TTK, CDC20, PTTG1, and MCM were found to be negatively associated with patients’ prognosis. The expression level of PTTG1 was found to be significantly associated with lymphocytes, immunomodulators, and chemokine in the TCGA cohort. Single-cell RNA-seq information indicated that PTTG1 was strongly associated with the proliferation of T cells. In the FUSCC cohort, the expression level of PTTG1 was also statistically significant for both progression-free survival (PFS) and overall survival (OS) prediction (HR = 2.683, p

Background Labor represents a period of significant physical activity. Inefficient energy supply may delay labor process and even lead to cesarean delivery. Herein we investigated whether ingestion of a carbohydrate-rich beverage could reduce cesarean delivery in laboring women with epidural analgesia. Methods This multicenter randomized trial was conducted in obstetrician-led maternity units of nine tertiary hospitals in China. Primigravidae with single term cephalic pregnancy who were preparing for vaginal birth under epidural analgesia were randomized to intake a carbohydrate-rich beverage or commercially available low-carbohydrate beverages during labor. The primary outcome was the rate of cesarean delivery. Secondary outcomes included maternal feeling of hunger, assessed with an 11-point scale where 0 indicated no hunger and 10 the most severe hunger, and maternal and neonatal blood glucose after childbirth. Results Between 17 January 2018 and 20 July 2018, 2008 women were enrolled and randomized, 1953 were included in the intention-to-treat analysis. The rate of cesarean delivery did not differ between the two groups (11.3% [111/982] with carbohydrate-rich beverage vs. 10.9% [106/971] with low-carbohydrate beverages; relative risk 1.04, 95% CI 0.81 to 1.33; p = 0.79). Women in the carbohydrate-rich beverage group had lower subjective hunger score (median 3 [interquartile range 2 to 5] vs. 4 [2 to 6]; median difference − 1; 95% CI − 1 to 0; p < 0.01); their neonates had less hypoglycemia (1.0% [10/968] vs. 2.3% [22/956]; relative risk 0.45; 95% CI 0.21 to 0.94; p = 0.03) when compared with those in the low-carbohydrate beverage group. They also had higher rates of maternal hyperglycemia (6.9% [67/965] vs. 1.9% [18/953]; p < 0.01) and neonatal hyperglycemia (9.2% [89/968] vs. 5.8% [55/956]; p < 0.01), but none required special treatment. Conclusions For laboring primigravidae with epidural analgesia, ingestion of a carbohydrate-rich beverage compared with low-carbohydrate beverages did not reduce cesarean delivery, but relieved maternal hunger and reduced neonatal hypoglycemia at the expense of increased hyperglycemia of both mothers and neonates. Optimal rate of carbohydrate supplementation remains to be determined. Trial registration www.chictr.org.cn; identifier: ChiCTR-IOR-17011994; registered on 14 July 2017.

There is sparse research reporting effective interventions for preventing nausea and emesis caused by concurrent chemoradiotherapy (CCRT) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC).Treatment-naïve LA-HNSCC patients received intensity-modulated radiotherapy with concomitant cisplatin 100 mg/mA total of 43 patients with LA-HNSCC were enrolled. The median age was 53 years, and 86.0% were male. All patients received radiotherapy and 86.0% of patients completed both cycles as planned. The overall CR rate was 86.0% (95% confidence interval [CI]: 72.1-94.7). The CR rates for cycles 1 and 2 were 88.4% (95% CI: 74.9-96.1) and 89.2% (95% CI: 74.6-97.0). The complete protection rate in the overall phase was 72.1% (95% CI: 56.3-84.7). The emesis-free and nausea-free responses in the overall phase were 88.4% (95% CI: 74.9-96.1) and 60.5% (95% CI: 44.4-75.0), respectively. The adverse events related to antiemetics were constipation (65.1%) and hiccups (16.3%), but both were grade 1-2. There was no grade 4 or 5 treatment-related toxicity with antiemetic usage.The addition of aprepitant into ondansetron and dexamethasone provided effective protection from nausea and emesis in patients with LA-HNSCC receiving radiotherapy and concomitant high-dose cisplatin chemotherapy.

Background Osteoarthritis (OA) is the most common joint disease, and is most frequently seen in the knees. However, there is no effective therapy to relieve the progression of knee OA. Metformin is a safe, well-tolerated oral medication that is extensively used as first-line therapy for type 2 diabetes. Previous observational studies and basic researches suggested that metformin may have protective effects on knee OA, which needs to be verified by clinical trials. This study, therefore, aims to examine the effects of metformin versus placebo on knee cartilage volume loss and knee symptoms in overweight knee OA patients by a randomized controlled trial over 24 months. Methods This protocol describes a multicenter, randomized, double-blind, and placebo-controlled clinical trial aiming to recruit 262 overweight knee OA patients. Participants will be randomly allocated to the two arms of the study, receiving metformin hydrochloride sustained-release tablets or identical inert placebo for 24 months (start from 0.5 g/day for the first 2 weeks, and increase to 1 g/day for the second 2 weeks, and further increase to 2 g/day for the remaining period if tolerated). Primary outcomes will be changes in tibiofemoral cartilage volume and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score over 24 months. Secondary outcomes will be changes in visual analogue scale (VAS) knee pain, tibiofemoral cartilage defects, effusion-synovitis volume, and tibiofemoral bone marrow lesions maximum size over 24 months. The primary analyses will be intention-to-treat analyses of primary and secondary outcomes. Per-protocol analyses will be performed as the secondary analyses. Discussion If metformin is proved to slow knee cartilage volume loss and to relieve knee symptoms among overweight knee OA patients, it will have the potential to become a disease modifying drug for knee OA. Metformin is a convenient intervention with low cost, and its potential effects on slowing down the structural progression and relieving the symptoms of knee OA would effectively reduce the disease burden worldwide. Trial registration ClinicalTrials. gov NCT05034029. Registered on 30 Sept 2021.

Background To investigate the clinical characteristics of metachronous second primary malignancies (Met‐SPMs) and its impact on prognosis in hypopharyngeal carcinoma (HPC). Methods We reviewed 593 newly diagnosed HPC patients without invasive synchronous SPMs (Syn‐SPMs) who were treated in our cancer center between 2009 and 2019. According to the status during follow‐up, patients were classified into three groups: (a) without SPMs (No‐SPMs, n = 440), (b) with tumors in situ in the esophagus or stomach (Tis, n = 80), or (c) with Met‐SPMs (n = 73). Results The median follow‐up time for entire cohort (n = 593) was 66.7 months. Met‐SPMs were present in 12.3% of the cohort (73/593). The predominant site of SPMs was esophagus, followed by lung, oral cavity, thyroid, stomach, and oropharynx. In Met‐SPMs group, both index tumor and SPMs were the main causes of death. Tis group exhibited comparable 5‐year overall survival (OS) and disease‐specific survival (DSS) with that of No‐SPMs group. The Met‐SPMs group had similar 5‐year OS rate and better 5‐year DSS rate of 47.3% versus 43.6% (odds ratio [OR], 0.931; 95% confidence interval [CI], 0.681–1.274, p = 0.657) and 66.3% vs. 46.2% (OR, 0.600; 95% CI, 0.402–0.896, p = 0.012), respectively, compared with the No‐SPMs group. Conclusion The overall incidence of Met‐SPMs in HPC was 12.3%. The occurrence of Met‐SPMs does not jeopardize the survival outcome of HPC. Routine surveillance of Met‐SPMs was requisite for patients with HPC.

Purpose To define the clinical characteristics of irradiation-induced nasopharyngeal necrosis (INN) after intensity-modulated radiotherapy (IMRT) and identify the influence of treatment strategies on INN in primary nasopharyngeal carcinoma (NPC) patients. Patients and methods From 2008 to 2019, NPC patients pathologically diagnosed with INN after primary IMRT were reviewed. Those patients were matched with propensity scores for patients without INN in our center. The impact of treatment strategies on INN occurrence was assessed using univariate and multivariate logistic regression analysis. Results The incidence rate of INN was 1.9% among the primary NPC population, and 53 patients with INN were enrolled. Headache and foul odor were the main symptoms, and 71.7% of cases had pseudomembrane during or at the end of radiotherapy. All patients were in early or middle stage INN, and no one presented with skull-based osteoradionecrosis. Then 212 non-INN patients were included based on propensity scores match. Overall survival (p = 0.248) and progression-free survival (p = 0.266) curves were similar between the INN and non-INN groups. Treatment strategies including combining chemotherapy or molecular targeted therapy with radiotherapy were not associated with INN occurrence, while boost dose (OR 7.360; 95% CI 2.301–23.547; p = 0.001) was a predictor factor for it. However, the optimal threshold for an accumulated dose to predict INN's occurrence was failed to determine. Conclusion In the IMRT era, the severity of INN in primary NPC patients is lessened. This study showed that treatment strategies contributed little to develop INN, while the accumulated dose of radiation may relate to its occurrence.

Traditionally, clear cell papillary renal cell carcinoma (ccpRCC) was considered to share similar molecular and histological characteristics with clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC). Here we aimed to identify somatic and germline variants of ccpRCC. For this purpose, we conducted whole-exome sequencing to detect somatic variants in the tissues of 18 patients with pathologically confirmed ccpRCC, who underwent surgical treatment at Fudan University Shanghai Cancer Center. Targeted sequencing was conducted to detect germline variants in paired tumor or normal tissues or blood. Somatic and germline variants of ccRCC and Renal cell carcinoma included in The Cancer Genome Atlas data and other published data were analyzed as well. The molecular profiles of ccpRCC, ccRCC and pRCC were compared. Among the 387 somatic variants identified, TCEB1 (3/18) and VHL (3/18) variants occurred at the highest frequencies. Germline mutation detection showed that nine variants associated with Fanconi anemia (VAFAs) pathway (FANCA, 6/18; FANCI, 3/18) were identified in 18 ccpRCC patients. Among ccpRCC patients with VAFAs, five out of eight patients had second primary malignancy or family history of cancer. Somatic variants characteristics may distinguish ccpRCC from ccRCC or pRCC and germline VAFAs may be a molecular characterization of ccpRCC. Compared with ccRCC or pRCC, ccpRCC patients may be significantly correlated with higher risk of developing second primary malignancy.

Clear cell renal cell carcinoma (ccRCC) is one of the most common cancers worldwide. Despite intense efforts to elucidate its pathogenesis, the molecular mechanisms and genetic characteristics of this cancer remain unknown. In this study, three expression profile data sets (GSE15641, GSE16441 and GSE66270) were integrated to identify candidate genes that could elucidate functional pathways in ccRCC. Expression data from 63 ccRCC tumors and 54 normal samples were pooled and analyzed. The GSE profiles shared 379 differentially expressed genes (DEGs), including 249 upregulated genes, and 130 downregulated genes. A protein-protein interaction network (PPI) was constructed and analyzed using STRING and Cytoscape. Functional and signaling pathways of the shared DEGs with significant p values were identified. Kaplan-Meier plots of integrated expression scores were used to analyze survival outcomes. These suggested that FN1, ICAM1, CXCR4, TYROBP, EGF, CAV1, CCND1 and PECAM1/CD31 were independent prognostic factors in ccRCC. Finally, to investigate early events in renal cancer, we screened for the hub genes CCND1 and PECAM1/CD31. In summary, integrated bioinformatics analysis identified candidate DEGs and pathways in ccRCC that could improve our understanding of the causes and underlying molecular events of ccRCC. These candidate genes and pathways could be therapeutic targets for ccRCC.

BACKGROUND The serine peptidase inhibitor Kazal type 13 (SPINK13) gene has tumor suppressor activity, but its role in renal cell carcinoma (RCC) remains unknown. This study aimed to investigate mRNA expression of SPINK13 in clear cell renal cell carcinoma (CCRCC) in human tissue and to use bioinformatics data to investigate the role of SPINK13 expression as a clinicopathological and prognostic biomarker for patients with CCRCC. MATERIAL AND METHODS Patients with CCRCC (N=533) with available RNA sequence data from The Cancer Genome Atlas (TCGA)-CCRCC database were analyzed with patients who had a tissue diagnosis of CCRCC (N=305) at the Fudan University Shanghai Cancer Center (FUSCC). Differential transcriptional and proteome expression profiles were obtained from the ONCOMINE cancer microarray database, TCGA, and the Human Protein Atlas (HPA) database. Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) measured SPINK13 mRNA expression in 305 samples of CCRCC tissue from the FUSCC. The effects of clinicopathological parameters on progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier and log-rank test. RESULTS Transcriptional and proteome expression of SPINK13 were significantly increased CCRCC tissue samples. Increased SPINK13 mRNA expression was significantly associated with reduced PFS and OS in 838 patients with CCRCC patients from the two independent cohorts, the FUSCC and the TCGA-CCRCC cohorts (p

Background Growing evidence has demonstrated immune reactivity as a confirmed important carcinogenesis and therapy efficacy for clear cell renal cell carcinoma (ccRCC). Aquaporin 9 (AQP9) is involved in many immune-related signals; however, its role in ccRCC remains to be elucidated. This study investigated AQP9 expression in tumor tissues and defined the prognostic value in ccRCC patients. Methods A total of 913 ccRCC patients with available RNA-sequence data from the Cancer Genome Atlas (TCGA) database and Fudan University Shanghai Cancer Center (FUSCC) were consecutively recruited in analyses. Differential transcriptional and proteome expression profiles were obtained and validated using multiple datasets. A partial likelihood test from Cox regression analysis was developed to address the influence of independent factors on progression-free survival (PFS) and overall survival (OS). The Kaplan–Meier method and log-rank test were performed to assess survival. Receiver operating characteristic (ROC) curves were used to describe binary classifier value of AQP9 using area under the curve (AUC) score. Functional enrichment analyses and immune infiltration analysis were used to describe significantly involved hallmark pathways of hub genes. Results Significantly elevated transcriptional and proteomic AQP9 expressions were found in ccRCC samples. Increased AQP9 mRNA expression was significantly associated with advanced clinicopathological parameters and correlated with shorter PFS and OS in TCGA and FUSCC cohorts (p AQP9 (PFS, AUC = 0.823; OS, AUC = 0.828). Functional annotations indicated that AQP9 is involved in the most significant hallmarks including complement, coagulation, IL6/JAK–STAT3, inflammatory response and TNF-alpha signaling pathways. Conclusion Our study revealed that elevated AQP9 expression was significantly correlated with aggressive progression, poor survival and immune infiltrations in ccRCC patients, and we validated its prognostic value in a real-world cohort. These data suggest that AQP9 may act as an oncogene and a promising prognostic marker in ccRCC.

To explore the feasibility and superiority of iodine delivery rate (IDR) and tube voltage determined by patients' body mass index (BMI) in coronary CT angiography (CCTA), a total of 1567 patients undertaking CCTA during Feb. and Dec. 2016 were enrolled and divided into two groups. In the control group, the IDR and tube voltage were fixed, while in the experimental group, the IDR and tube voltage were determined by patients' BMI. The volume of iodinated contrast media (ICM), extravasation rate, extravasation volume, extravasation recovery interval, incidence rate of adverse reactions, effective dose (ED) and image quality of the two groups were compared. The experiments demonstrated that the ICM volume, extravasation rate, extravasation volume, extravasation recovery interval, incidence of adverse reactions and ED were lower or shorter in the experimental group than in the control group, and the differences were statistically significant (all P

Intratumoral fibrosis is a frequent histologic finding in highly vascularized clear cell renal cell carcinoma (ccRCC). Here, we investigated the expression of a family of collagen-modifying enzymes, procollagen-lysine, 2-oxoglutarate 5-dioxygenases 1, 2, and 3 (PLOD1/2/3), in ccRCC tissues and assessed the prognostic value of wild-type and genetically mutated PLOD1/2/3 for ccRCC patients. Normal kidney and ccRCC mRNA and protein expression datasets were obtained from Oncomine, The Cancer Genome Atlas, and Human Protein Atlas databases. Associations between PLOD1/2/3 expression, clinicopathological variables, and patient survival were evaluated using Cox regression and Kaplan–Meier analyses. PLOD1/2/3 mRNA and protein expression levels were significantly elevated in ccRCC tissues compared with normal kidney. Increased PLOD1/2/3 mRNA expression was significantly associated with advanced tumor stage, high pathological grade, and shorter progression-free and overall survival (all p

Circular RNAs (circRNAs) are a novel class of noncoding RNAs that have regulatory functions in varieties of diseases. The purpose of this study was to investigate the potential role of circRNAs in anorectal malformations (ARM). With sequencing analysis, 78 circRNAs were identified to be differentially expressed on gestational day (GD) 19 in ARM and normal anorectal tissues, including 41 upregulated and 37 downregulated circRNAs. Among the downregulated circRNAs, rno_circ_0004002 was selected as the candidate circRNA. Functionally, silencing of rno_circ_0004002 was correlated with suppression of proliferation, and promotion of apoptosis and epithelial-mesenchymal transition (EMT) in anorectal development. For the mechanism investigation, bioinformatic prediction and luciferase reporter assay revealed that rno_circ_0004002 was proved to be a sponge of miR-342-5p, and miR-342-5p could target 3'-UTR of Wnt3a to negatively regulate its expression. The quantitative reverse transcription polymerase chain reaction (qRT-PCR) results showed that the expression of miR-342-5p was significantly increased in ARM anorectal tissues compared with normal tissues on GD19 and GD21, and the expression of Wnt3a demonstrated the opposite on GD21. In addition, rescue assays disclosed that miR-342-5p inhibitor could reverse the role of rno_circ_0004002 knockdown on the repression of anorectal development. In summary, our study shed light on the regulatory mechanism of rno_circ_0004002 in cell proliferation, apoptosis, and EMT via sponging miR-342-5p, which downregulated the Wnt3a expression in anorectal development. We also suggested that GD19 and GD21 was the crucial time in the progression of ARM, and rno_circ_0004002/miR-342-5p/Wnt3a might serve as potential therapeutic targets for ARM.

Osteonecrosis of the femoral head (ONFH) usually occurs in young people and is closely associated with autoimmune reactions. Follistatin-like 1 (FSTL1) was recently proven to participate in several inflammation-related diseases. The role of FSTL1 in ONFH is still unclear. Serum levels of FSTL1 were not significantly different in ONFH patients and healthy individuals. In contrast, elevated expression levels of FSTL1 were observed in degraded cartilage and synovial fluid in ONFH patients and in a cultured human primary chondrocyte model treated with interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α). Suppression of FSTL1 by FSTL1-siRNA downregulated the inflammatory response mediated by IL-1β or TNF-α in cultured human chondrocytes. In a human cartilage culture model, FSTL1 promoted the production of inflammatory cytokines and cartilage degradation enzymes. The activation of NFκB signaling pathway was detected in degenerated cartilage from ONFH patients and in FSTL1-treated chondrocytes. Additionally, administration of an NFκB inhibitor (JSH-23) significantly reduced the overexpression of inflammatory cytokines and protein degradation enzymes induced by FSTL1 and maintained the level of major cartilage matrix components (aggrecan and collagen II). In summary, FSTL1 was involved in the degeneration progression of the ONFH and might provide a novel direction for treating and curing ONFH.

Summary Elevation in homocysteine (Hcy) level is associated with insulin resistance; however, the causality between them and the underlying mechanism remain elusive. Here, we show that Hcy induces insulin resistance and causes diabetic phenotypes by protein cysteine-homocysteinylation (C-Hcy) of the pro-insulin receptor (pro-IR). Mechanistically, Hcy reacts and modifies cysteine-825 of pro-IR in the endoplasmic reticulum (ER) and abrogates the formation of the original disulfide bond. C-Hcy impairs the interaction between pro-IR and the Furin protease in the Golgi apparatus, thereby hindering the cleavage of pro-IR. In mice, an increase in Hcy level decreases the mature IR level in various tissues, thereby inducing insulin resistance and the type 2 diabetes phenotype. Furthermore, inhibition of C-Hcy in vivo and in vitro by overexpressing protein disulfide isomerase rescues the Hcy-induced phenotypes. In conclusion, C-Hcy in the ER can serve as a potential pharmacological target for developing drugs to prevent insulin resistance and increase insulin sensitivity.

Purpose: This study aimed to identify the potential prognostic role of HK3 and provide clues about glycolysis and the microenvironmental characteristics of ccRCC. Methods: Based on the Cancer Genome Atlas (TCGA, n = 533) and Gene expression omnibus (GEO) (n = 127) databases, real-world (n = 377) ccRCC cohorts, and approximately 15,000 cancer samples, the prognostic value and immune implications of HK3 were identified. The functional effects of HK3 in ccRCC were analyzed in silico and in vitro. Results: The large-scale findings suggested a significantly higher HK3 expression in ccRCC tissues and the predictive efficacy of HK3 for tumor progression and a poor prognosis. Next, the subgroup survival and Cox regression analyses showed that HK3 serves as a promising and independent predictive marker for the prognosis and survival of patients with ccRCC from bioinformatic databases and real-world cohorts. Subsequently, we found that HK3 could be used to modulate glycolysis and the malignant behaviors of ccRCC cells. The comprehensive results suggested that HK3 is highly correlated with the abundance of immune cells, and specifically stimulates the infiltration of monocytes/macrophages presenting surface markers, regulates the immune checkpoint molecules PD-1 and CTLA-4 of exhaustive T cells, restrains the immune escape of tumor cells, and prompts the immune-rejection microenvironment of ccRCC. Conclusion: In conclusion, the large-scale data first revealed that HK3 could affect glycolysis, promote malignant biologic processes, and predict the aggressive progression of ccRCC. HK3 may stimulate the abundance of infiltrating monocytes/macrophages presenting surface markers and regulate the key molecular subgroups of immune checkpoint molecules of exhaustive T cells, thus inducing the microenvironmental characteristics of active anti-tumor immune responses.

Background To determine whether 1.1 GBq radioiodine therapy is as effective as 3.7 GBq for ablation in Chinese patients with differentiated thyroid cancer (DTC). Methods In this single-center randomized study, we compared the successful radioiodine ablation rates of 1.1 GBq and 3.7 GBq for patients with DTC. Results At 6-8 months after radioiodine ablation, there were 95 (39%) patients in the 1.1 GBq group and 79 (32%) patients in the 3.7 GBq group with thyroid hormone withdrawal (THW), and ablation success rates were 84% versus 80%, respectively; and 149 (61%) patients in the 1.1 GBq group and 169 (68%) patients in the 3.7 GBq group without THW, and ablation success rates were 89% versus 90%, respectively. In total, the ablation was successful in 412 (87%) of the 474 patients, and it was similar between the two groups. Conclusions Low-dose radioiodine ablation was as effective as high dose in Chinese DTC patients.

Thioredoxin reductase (TrxR) enzymes are critical in regulating redox homeostasis in cells. We report the first two-photon fluorescent probe of mammalian TrxR (TP-TRFS). TP-TRFS retains high specificity in recognizing TrxR. More importantly, the two-photon absorbing character of TP-TRFS enables it to be used in vivo. With the aid of TP-TRFS, a remarkable decline of the TrxR function was observed in the brain of a mouse model of stroke for the first time, providing a mechanistic link of TrxR dysfunction with stroke.

To explore clinical and radiographic effects of percutaneous pie-crusting deep medial collateral ligament release in patients with posterior horn tear of medial meniscus combined with tight medial compartment.From January 2012 to December 2016, 35 patients with medial meniscus posterior horn injury were treated with percutaneous pie crusting deep medial collateral ligament release technique, including 21 males and 14 females, aged from 21 to 55 years old with an average of (39.1±6.5) years old. Degree of meniscus extrusion were recorded before and 24 months after operation. The knee valgus stress test was performed to evaluate stability of medial collateral ligament, and compared difference between healthy and affected side. Lysholm and IKDC functional scores were compared before and 24 months after operation.All patients were followed up from 27 to 60 months with an average of (36.7±6.8) months. All patients were underwent operation, the wound healed well without complications. Operative time ranged from 0.5 to 1.2 h with an average of (0.8±0.4) h. Nineteen patients were performed partial meniscectomy, 16 patients were performed repair suture. Convex of meniscus before operation was (1.5±0.7) mm, and (1.7±0.4) mm after operation;had no statistical difference(For patients with medial meniscus tear of posterior horn combined with tight medial compartment, percutaneous pie-crusting deep medial collateralligament release could improve medial compartment space, and Knee valgus instability and meniscus extrusion are not affected.

BACKGROUND Esthesioneuroblastoma (ENB) is a rare malignant neoplasm. Currently, no consistent and universal staging system for ENB exists. The aim of this study is to propose a TNM-based classification. SUBJECTS AND METHODS Hundred and forty-two patients from our institution, with ENB pathologically confirmed between July 1978 and December 2018, were reviewed. All patients were restaged according to the Kadish stage, Morita stage and American Joint Committee on Cancer (AJCC) T classification from clinical and radiological data. Multivariate Cox proportional hazard regression analyses were performed to determine the impact of various factors. The goodness-of-fit and predictive accuracy of the different staging systems were calculated using R software. RESULTS The median follow-up time was 57 months (range: 4-229 months). According to the Kadish system, the 5-year overall survival (OS) for patients with stage A, B and C was 100%, 83.6% and 64.2%, respectively (P = .055). With respect to the Morita classification, 5-year OS for stages A, B, C and D was 100%, 83.6%, 70.7% and 50.0%, respectively (P = .004). Analysis based on the proposed staging model demonstrated 5-year OS for stage I, II, III and IV disease was 100%, 88.9%, 75.9% and 49.0%, respectively (P

Background The aim of this study is to evaluate the efficacy of different treatment strategies and the potential prognostic factors of esthesioneuroblastoma (ENB). Materials and methods Between April 1984 and December 2018, 138 patients with non-metastatic ENB were retrospectively analyzed. The treatment modalities mainly included surgery alone (n = 7), radiotherapy alone (n = 33), concurrent chemoradiotherapy (n = 17), surgery combined with current chemoradiotherapy (n = 32), and surgery plus radiotherapy (n = 49). Results The median follow-up time for the entire cohort was 61 months (range, 4–231 months). The 5-year overall survival (OS), locoregional failure-free survival (LRFFS), and distant metastasis-free survival (DMFS) rate were 69.6, 78.0 and 73.9%, respectively. Surgery combined with radiotherapy elicited superior survival results, and the combination of surgery and current chemoradiotherapy achieved the best prognoses for all patients, patients with advanced Kadish disease, patients receiving intensity modulated radiation therapy and those with positive surgical margin. Univariate analysis identified orbital invasion and treatment modalities were predictors for OS, LRFFS and DMFS. Lymph node metastasis was associated with OS and DMFS, but not LRFFS. Intracranial invasion, advanced Kadish stage and not receiving concurrent chemotherapy were also predictive of lower OS. Multivariate analyses indicated that lymph node metastasis was an independent prognostic factor affecting DMFS, whereas treatment modalities was independent prognostic factors for OS and LRFFS. Conclusion Orbital invasion, intracranial invasion, lymph node metastasis and advanced Kadish disease at initial diagnosis were significantly associated with inferior prognosis. Regarding the treatment modality, the optimal strategy remined surgery with radiotherapy-based multimodality treatment. The concurrent chemoradiotherapy may play a more beneficial role.

The research progress of acupuncture analgesia in recent years is analyzed to summarize the analgesic mechanism of acupuncture on neuropathic pain. The analgesic mechanism of acupuncture on neuropathic pain is discussed from peripheral level and central level, including peripheral sensitization and immune inflammatory response, changes of ion channel, central sensitization, regulation of cell signal pathway, activation of spinal glial cells, etc. It is suggested that the focus of future research should include conducting in-vitro studies with the help of multi-omics technology to detect the changes of metabolic substances and signal pathway molecules in patients with neuropathic pain before and after acupuncture to further clarify the mechanism of acupuncture analgesia.

Background: Guanxin V (GXV), a traditional herbal mixture, has been widely used in clinical practice for the treatment of coronary artery disease (CAD). This retrospective study was designed to assess the safety and effectiveness of GXV for CAD. Methods: In our study, December 2006 to January 2009, 101 patients with CAD from Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine were enrolled, of whom 52 patients received GXV plus guideline-recommended medical therapy (GMT) (GXV group), 49 patients received GMT alone (GMT group). The general clinical information, traditional Chinese medicine syndrome score (TSS), the therapeutic effects, 6-minute walk test (6MWT), adverse events, echocardiography, and laboratory information were collected and analyzed pre-and post-treatment. Results: We did not find differences in the information between the two groups before treatment. Patients in the GXV group had decreased TSS (P < 0.0001) and increased therapeutic effects (P = 0.763) and 6MWT (P < 0.0001) than those in the GMT group and there were no significant differences in safety between the two groups. Moreover, patients in the GXV group improved ejection fraction, cardiac output, and stroke volume (P = 0.2113, 0.0001, 0.0002, respectively), and dropped BNP (P = 0.3856) compared with those in the GMT group. Conclusions: Superiority in the GXV group for patients with CAD was demonstrated over the GMT group for both the safety and effectiveness endpoints. This suggests that GXV is a potentially safe and effective treatment for CAD patients.