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Variants in the glucocerebrosidase (GBA) gene are recognized as a common and important genetic risk factor for Parkinson disease (PD). However, the impact of variant severity on the clinical phenotype of PD in the Chinese population remains unclear. Thus, the present study aimed to determine the frequency of GBA-related PD (GBA-PD) and the relationship of GBA variant severity with clinical characteristics in a large Chinese cohort.Long-range polymerase chain reaction and next generation sequencing were performed for the entire GBA gene. GBA variant severity was classified into five classes: mild, severe, risk, complex, and unknown.Among the total 737 PD patients, 47 GBA variants were detected in 79 (10.72%) patients, and the most common GBA variants were R163Q, L444P, and R120W. Complete demographic and clinical data were obtained for 673 patients, which revealed that 18.50% of early onset PD patients had GBA variants. Compared with patients without GBA variants, GBA-PD patients experienced PD onset an average of 4 years earlier and had more severe motor and nonmotor symptoms. Patients carrying severe and complex variants had a higher burden of nonmotor symptoms, especially depression, and more mood/cognitive and gastrointestinal symptoms than patients carrying mild variants.GBA-PD is highly prevalent in the Chinese population. The severity of GBA variants underlies distinct phenotypic spectrums, with PD patients carrying severe and complex variants seeming to have similar phenotypes. PD patient stratification by GBA variant severity should become a prerequisite for selecting specific treatments.

To analyze the expression levels, prognostic value and immune infiltration association of Holliday junction protein (HJURP) as well as its feasibility as a pan-cancer biomarker for different cancers. The Protter online tool was utilized to obtain the localization of HJURP, then the methylation of HJURP in tumors were further explored. Thereafter, the mRNA data and clinical characteristics of 33 tumor types from TCGA database were obtained to investigate the expression and prognostic relationship of HJURP in different tumor types. Finally, the composition pattern and immune infiltration of HJURP in different tumors were detected in Tumor Immune Estimation Resource. HJURP was abnormally expressed in most of the cancer types and subtypes in TCGA database. Also, it was associated with poor prognosis of different cohorts. At the same time, the results also showed that HJURP was related to tumor immune evasion through different mechanisms, including T cell rejection and methylation in different cancer types. Besides, the methylation of HJURP was inversely proportional to mRNA expression levels, which mediated the dysfunctional phenotypes of T cells and poor prognosis of different cancer types. Alternatively, our results indicated that HJURP expression was associated with immune cell infiltration in a variety of cancers. HJURP may serve as an oncogenic molecule, and its expression and immune infiltration characteristics can be used as a biomarker for cancer detection, prognosis, treatment design and follow-up.

Purpose Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma. P4HA3 is a key enzyme in collagen biosynthesis and has emerged as important molecules in regulation of proliferation, invasion, and metastasis in various tumor types. The role of P4HA3 in the development of ccRCC has remained to be elucidated. Methods Genes expression, prognostic, and enrichment analyses were carried out with bioinformatics analysis. The efficiency of P4HA3 knockdown was confirmed by real-time quantitative PCR and western blotting. The cellular functions were analyzed by CCK-8, EdU, wound healing, and transwell assays. The levels of related proteins expression were analyzed by western blotting. Results P4HA3 was highly expressed in ccRCC compared with normal tissue samples from the TCGA database. Kaplan-Meier curves results showed that the expression level of P4HA3 was significantly negatively correlated with overall survival of patients. P4HA3 expression knockdown inhibited the proliferation, migration, and invasion of ccRCC cells, as demonstrated by in vitro experiments. In addition, GSEA results revealed that P4HA3 may be related to EMT and involved in the PI3K-AKT-GSK3β pathway in ccRCC; this was tentatively confirmed through western blotting. Conclusion P4HA3 may induce ccRCC progression via the PI3K-AKT-GSK3β signaling pathway and could represent a potential therapeutic target.

Objective This work focused on investigating the relation of centromeric protein A (CENPA) gene expression with prognosis of papillary renal cell carcinoma (PRCC). Methods We obtained data from PRCC cases in TCGA. Thereafter, CENPA levels between the paired PRCC and matched non-carcinoma samples were analyzed by Wilcoxon rank-sum test, while the relations of clinicopathological characteristics with CENPA level were examined by logistic regression and Wilcoxon rank-sum test. The prognostic value of CENPA was assessed by plotting the receiver operating feature curve (ROC) and calculating the value of area under curve (AUC). In addition, relations between clinicopathological characteristics and PRCC survival were analyzed through Kaplan–Meier (KM) and Cox regression analyses. After dividing the total number of patients into the trial cohort and the validation cohort in a ratio of 7:3, we constructed a nomogram in trial cohort according to multivariate Cox regression results for predicting how CENPA affected patient survival and used the calibration curve to verify its accuracy in both cohorts. We also determined CENPA levels within cancer and matched non-carcinoma samples through immunohistochemistry (IHC). Finally, we utilized functional enrichment for identifying key pathways related to differentially expressed genes (DEGs) between PRCC cases with CENPA up-regulation and down-regulation. Results CENPA expression enhanced in PRCC tissues compared with healthy counterparts (P P P = 0.001). In the meantime, univariate as well as multivariate analysis showed an independent association of CENPA with overall survival (OS, P Conclusion CENPA expression increases within PRCC samples, which predicts dismal PRCC survival. CENPA may become a molecular prognostic marker and therapeutic target for PRCC patients.

Qinke Li, Maoqing Lu, Zhechuan Zhang, Ronggui Zhang Department of Urology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Ronggui ZhangDepartment of Urology, The Second Affiliated Hospital, Linjiang Road, Chongqing Medical University, Chongqing, 400010, People’s Republic of ChinaTel +86-23-13983790901Fax +23-63832133Email zrgcqmu@126.comBackground: Heat shock proteins (HSPs) are widely involved in tumor occurrence and development and are prognostic markers for multiple tumors. However, the role of HSPs in clear cell renal cell carcinoma (ccRCC) remains unclear.Methods: We used Cytoscape to identify hub genes in the ccRCC single-cell sequencing data set from the Gene Expression Omnibus (GEO) data repository. We identified subtypes, C1 and C2, of The Cancer Genome Atlas (TCGA) patients based on the expression of hub genes using unsupervised consensus clustering. Principal component analysis (PCA) was used to verify the clustering differences, and Kaplan–Meier (K-M) estimate was used to verify the survival differences between C1 and C2 patients. We used TIMER 2.0 and CIBERSORT to evaluate the immune cell infiltration of HSP genes and C1 and C2 patients. The R package “pRRophetic” was used to evaluate the sensitivity in C1 and C2 patients to the four first-line treatment drugs.Results: We identified six hub genes (HSP90AA1, HSPH1, HSPA1B, HSPA8, and HSPA1A) encoding HSP, five of which were significantly downregulated in TCGA group, and four had a protective effect on prognosis (p < 0.05). Survival analysis showed that C1 patients had a better overall survival (p < 0.001). TIMER 2.0 analysis showed that three HSP genes were significantly correlated with the infiltration of CD4+ T cells and CD4+ Th1 cells (|cor|> 0.5, p< 0.001). CIBERSORT showed significant differences in multiple infiltrating immune cells between C1 and C2 patients. Meanwhile, the expression of PD1 was significantly lower in C1 patients than in C2 patients, and the expression of PDL1 is the another way around. Drug sensitivity analysis showed that C1 patients were more sensitive to sorafenib, pazopanib, and axitinib (p < 0.001).Conclusion: Our research revealed two molecular subtypes of ccRCC based on 6 HSP genes, and revealed significant differences between the two subtypes in terms of clinical prognosis, immune infiltration, and drug sensitivity.Keywords: ccRCC, bioinformatics, immune, molecular subtypes, prognosis

Objective: Adrenocortical carcinoma (ACC) is a rare malignant tumor. Chromatin regulators (CRs) can drive epigenetic changes, which have been considered as one of the most vital hallmarks of tumors. This study aimed to explore the CR signature for ACC in order to clarify the molecular basis of ACC’s pathogenic mechanism and provide novel methods to diagnose and treat ACC clinically.Methods: This study obtained transcriptome sequencing datasets of ACC patients and sequencing data on normal adrenal tissues in TCGA and GTEx databases, respectively. Meanwhile, prognostic genes were selected through Lasso and Cox regression analyses. Using the transcriptome sequencing datasets of ACC patients downloaded from the GEO database to finish validation, we performed Kaplan–Meier (KM) analysis for evaluating the differential survival between low- and high-risk groups. Then, this work constructed the risk model for predicting ACC prognosis. TIMER 2.0 was employed to assess the differences in immune infiltration between the two groups. Furthermore, this work adopted the R package “pRRophetic” for exploring and estimating the sensitivity of patients to different chemotherapeutic agents.Results: A 5-CR model was established to predict ACC survival, and the CR signature was confirmed as a factor in order to independently predict ACC patient prognosis. In addition, a nomogram composed of the risk score and clinical T stage performed well in the prediction of patients’ prognosis. Differentially expressed CRs (DECRs) were mostly associated with the cell cycle, base excision repair, colon cancer, gene duplication, homologous recombination, and other signaling pathways for the high-risk group. As for the low-risk group, DECRs were mainly enriched in allograft rejection, drug metabolism of cytochrome P450, metabolism of xenogeneic organisms by cytochrome P450, retinol metabolism, and other signaling pathways. According to TIMER analysis, the immune infiltration degrees of endothelial cells, M2 macrophages, myeloid dendritic cells, CD4+ Th1 cells, NKT cells, and M0 macrophages showed significant statistical differences between the high- and low-risk groups, and high infiltration levels of M0 and M2 macrophages were more pronounced in higher T stage (T3 and T4), N stage (N1), and clinical stages (III and IV). In addition, high-risk cases exhibited higher sensitivity to etoposide and doxorubicin. Additionally, low-risk patients had significantly decreased expression of RRM1 compared with high-risk cases, suggesting the better effect of mitotane treatment.Conclusion: This study identified the DECRs, which might be related to ACC genesis and progression. The pathways enriched by these DECRs were screened, and these DECRs were verified with excellent significance for estimating ACC survival. Drug sensitivity analysis also supported the current clinical treatment plan. Moreover, this study will provide reliable ideas and evidence for diagnosing and treating ACC in the clinic.

This study explores the core genes involved in the pathogenesis of ACTH-independent macronodular adrenal hyperplasia (AIMAH), so as to provide robust biomarkers for the clinical diagnosis and treatment of this disease. Gene Expression Omnibus (GEO) database was used to obtain GSE25031 microarray dataset. R package “limma” was applied to identify differentially expressed genes (DEGs) between AIMAH and normal samples. The Database for Annotation, Visualization and Integrated Discovery (DAVID) was employed to perform Gene Ontology (GO) annotation for the DEGs, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was conducted. A protein-protein interaction network (PPI) was constructed using the STRING online website and visualized using the Cytoscape software. The key modules and hub genes were then identified. Finally, Gene Set Enrichment Analysis (GSEA) enrichment analysis was carried out to find the signaling pathways of significant clinical value in AIMAH. A total of 295 DEGs between AIMAH and healthy samples were screened out, including 164 upregulated genes and 131 downregulated genes. Combining enrichment analysis and PPI network construction, there were 5 signifiant pathways and 10 hub genes, among which 3 genes (FOS, FOSB, and DUSP1) were identified as potential core genes of clinical significance in AIMAH. In conclusion, the 3 core genes, FOS, FOSB, and DUSP1, identified here might be potential biomarkers for AIMAH, and the current study is of guiding significance for clinical diagnosis and treatment of this disease.

The CD-TK double suicide gene has become an effective therapy for bladder cancer. A novel molecular-targeted ultrasound (US) method has been developed to precisely guide nanobubbles loaded with this gene to regions within bladder tumor cells and is widely used due to its efficiency in delivering drugs to the target tumor. Uniform nanoscaled nanobubbles loaded with CD-TK double suicide gene were developed using a thin-film hydration sonication, carbodiimide chemistry approaches, and electrostatic adsorption methods. In the present study, we synthesized CD-TK double suicide gene-loaded cationic nanobubbles conjugated with anti-VEGFR2 that can bind with VEGFR2-positive cells. Fluorescence and flow cytometry evidence show that CD-TK double suicide gene-loaded nanobubbles were successfully developed. CD-TK-CNBs delivered via US-mediated nanobubble destruction (UMND) enhanced transfection efficiency, overexpression of CD-TK double suicide gene, and tumor cell apoptosis, and inhibited tumor cell growth in vitro. These CD-TK-CNBs may become a novel treatment for bladder cancer.

Objective: This work focused on investigating the relation of centromeric protein A (CENPA) gene expression with prognosis of papillary renal cell carcinoma (PRCC). Methods: We obtained data from PRCC cases in TCGA. Thereafter, CENPA levels between the paired PRCC and matched non-carcinoma samples were analyzed by Wilcoxon rank-and-sum test, while the relations of clinicopathological characteristics with CENPA level were examined by logistic regression and Wilcoxon rank-sum test. The prognostic value of CENPA was assessed by plotting the receiver operating feature curve (ROC) and calculating the value of area under curve (AUC). In addition, relations between clinicopathological features and PRCC survival were analyzed through Kaplan-Meier (KM) and Cox regression analyses. Additionally, we constructed a nomogram according to multivariate Cox regression results for predicting how CENPA affected patient survival. We also determined CENPA levels within cancer and matched non-carcinoma samples through immunohistochemistry (IHC). Finally, we utilized functional enrichment for identifying key pathways related to differentially expressed genes (DEGs) between PRCC cases with CENPA up-regulation and down-regulation. Results: CENPA expression enhanced in PRCC tissues compared with healthy counterparts (P Conclusion: CENPA expression increases within PRCC samples, which predicts dismal PRCC survival. CENPA may become a molecular prognostic marker and therapeutic target for PRCC patients.

Objective: To analyze expression levels, prognostic value and immune infiltration association of Holliday junction protein (HJURP) as well as its feasibility as a pan-cancer biomarker for different cancers. Methods: The Protter online tool was utilized to obtain the protein structure and localization of HJURP in diverse tumors, then the mutation and methylation of HJURP in tumors were further explored. Thereafter, the mRNA data and clinical characteristics of 33 tumor types from TCGA database were obtained for investigating HJURP levels within different tumor types and different tumor stages and its prognostic relation. Finally, the composition pattern and immune infiltration of HJURP in different tumors were detected in Tumor Immune Estimation Resource. Results: HJURP was abnormally expressed in most of the cancer types and subtypes in TCGA database. Also, it was related to metastasis, tumor stage, and poor prognosis of different cohorts. Moreover, HJURP was related to tumor immune escape through diverse mechanisms, including T cell rejection and methylation within diverse cancers. Besides, the methylation of HJURP was inversely proportional to mRNA expression levels, which mediated the dysfunctional phenotypes of T cells and poor prognosis of different cancer types. Patients with HJURP mutations had a higher tumor mutation load than those with no HJURP mutations. Alternatively, based on this work, HJURP level was related to immune cell infiltration within diverse cancers. Conclusions: HJURP may serve as an oncogenic molecule, and its expression and immune infiltration characteristics can be used as the diagnostic, prognostic marker and therapeutic target.

BACKGROUND Tyrosine kinase inhibitors (TKIs) are used to treat metastatic disease associated with clear cell renal cell carcinoma (ccRCC); however, most patients develop resistance after 6 to 15 months. As such, identifying biomarkers of TKI resistance may be useful for prognosis. MATERIAL AND METHODS We analyzed ChIP-seq data related to TKI resistance from the Gene Expression Omnibus and RNA-Seq and clinical data from The Cancer Genome Atlas database. We used univariate Cox analysis and Cox regression/Lasso analysis to determine a risk score. The Kaplan-Meier estimate and receiver operating characteristic curve verified the risk score's sensitivity and specificity. The stratified analysis and the univariate and multivariate analyses revealed its predictive power. We predicted survival time by constructing a nomogram. RESULTS Of the 32 differentially expressed genes (DEGs) related to TKI resistance, 6 (ACE2, MMP24, SLC44A4, C1R, C1ORF194, ADAMTS15) were used to establish a risk score. Kaplan-Meier analysis showed that high-risk patients had shorter median survival times than low-risk patients, notably among those with metastatic disease (1.51 vs. 4.55 years). The stratified analysis revealed that patients with advanced disease had relatively higher risk scores than patients at early stages (P

In this communication, a gold-coated polydimethylsiloxane (PDMS) chip with cell-sized microwells was prepared through a stamping and spraying process that was applied directly for high-throughput electrochemiluminescence (ECL) analysis of intracellular glucose at single cells. As compared with the previous multiple-step fabrication of photoresist-based microwells on the electrode, the preparation process is simple and offers fresh electrode surface for higher luminescence intensity. More luminescence intensity was recorded from cell-retained microwells than that at the planar region among the microwells that was correlated with the content of intracellular glucose. The successful monitoring of intracellular glucose at single cells using this PDMS chip will provide an alternative strategy for high-throughput single-cell analysis. Graphical abstract ᅟ.

Varicocele, a cause of male infertility, occurs in nearly 40% of infertile males. It has been postulated that varicoceles may cause sperm DNA damage. Sperm DNA integrity has been recognized as one of the important determinants of normal fertilization and embryo growth in natural and assisted conception. Eighty-three human studies were identified after an extensive literature search involving the role of varicoceles in sperm DNA damage. Of the 83 studies, 12 were selected that measured similar types of reactive sperm DNA damage. Seven studies determined the damage of sperm DNA in varicocele-associated patients and six studies evaluated the efficacy of varicocelectomy. One study was a duplicate because both outcomes were included. Data were analysed using RevMan software. The overall estimate showed that patients with varicoceles have significantly higher sperm DNA damage than controls, with a mean difference of 9.84% (95% CI 9.19 to 10.49; P

p53 is one of the most widely investigated molecular markers in bladder cancer and its polymorphisms have been related to individual cancer risks. The objective of this study was to explore the association of p53 codon 72 polymorphism with susceptibility and clinicopathologic characteristics of bladder cancer in a Chinese population.We investigated the impact of p53 codon 72 polymorphism in a hospital-based case-control study of bladder cancer. We tested peripheral blood samples from 120 patients with bladder cancer and 120 healthy individuals of similar age and from the same geographical region. The polymorphisms were analyzed using polymerase chain reaction-restriction fragment length polymorphism assay.There was an association between smoking status and bladder cancer (odds ratio [OR] = 2.25; 95% confidence interval [95% CI] = 1.31, 3.87; p = 0.003). Patients with bladder cancer had a significantly lower frequency of Arg/Arg (OR = 0.53; 95% CI = 0.31, 0.89; p = 0.02) and Arg allele (OR = 0.66; 95% CI = 0.45, 0.95; p = 0.03) than controls. Patients with invasive bladder cancer had a significantly lower frequency of Arg/Arg (OR = 0.29; 95% CI = 0.10, 0.88; p = 0.03) than those with superficial bladder cancer. When stratifying by the grade and histological type of bladder cancer, we found no statistical association.These data suggest that the p53 codon 72 Arg/Arg genotype and Arg allele are associated with a lower risk of bladder cancer in Chinese population.

Glutathione S-transferase P1 (GSTP1) is an important phase II enzyme involved in the metabolism of xenobiotics and whose polymorphisms have been related to individual cancer risks. The objective of this study was to explore the association of GSTP1 A1578G (Ile105Val) polymorphism with susceptibility and clinicopathologic characteristics of bladder cancer in a Chinese population.We investigated the distribution of GSTP1 A1578G polymorphism in 200 bladder cancer patients and in 200 age- and sex-matched cancer-free controls. The polymorphisms were analyzed using polymerase chain reaction-restriction fragment length polymorphism assay. Genotype and allele frequencies and their associations with demographic factors, smoking status, stage, grade, and histological type of bladder cancer were investigated.The prevalence of GSTP1 GG genotype in cases was 22.5%, compared with 13.5% in the control group (odds ratio = 1.86, 95% confidence interval = 1.10-3.14, p = 0.02). There was an association between smoking status and bladder cancer (odds ratio = 1.77, 95% confidence interval = 1.17-2.67, p = 0.007). When stratifying by the stage, grade, and histological type of bladder cancer, we found no statistical association.These data seem to indicate that the GSTP1 GG genotype is associated with a modest increase in the risk of bladder cancer in a Chinese population.

Studies investigating the association between glutathione S-transferase M1 (GSTM1) polymorphism and bladder cancer risk report conflicting results. The objective of this study was to quantitatively summarize the evidence for such a relationship. We performed a systematic search of the National Library of Medline and Embase databases. This meta-analysis included 26 case-control studies, which included 5029 bladder cancer cases and 6680 controls. The combined results based on all studies showed that the GSTM1 null genotype was associated with an increased risk of bladder cancer (OR = 1.46, 95% confidence interval [CI] = 1.35, 1.57). When stratifying for race, results were similar among Asians (OR = 1.60, 95% CI = 1.27, 2.01) and Caucasians (OR = 1.44, 95% CI = 1.33, 1.57) except Africans (OR = 1.25, 95% CI = 0.76, 2.06). When stratifying by the smoking, stage, grade, and histological type of bladder cancer, we found no statistical association. Our meta-analysis suggests that the GSTM1 null genotype is associated with a modest increase in the risk of bladder cancer.

To investigate the clinical characteristic, diagnosis and treatment of familial adenomatous polyposis (FAP).According to family history of the proband, we surveyed the pedigree and retrospectively analyzed the clinical characteristics of 10 FAP patients in 3 generations of the family.Among all 10 cases, 3 died of colorectal cancer including two of whom had history of intestinal obstruction.Seven people of the third generation were all diagnosed as FAP. Among them, only 2 patients had clinical symptoms. Colonoscopy was done in all 7 patients before 35 years old. However, none of them had polyps or evidence of cancer.Surgical operation was performed on 1 patient and high frequency electric cutting under endoscopy was performed on 6 patients.The early clinical manifestations of FAP are nonspecific. Pedigree investigation and colonoscopy screening for high-risk population are important to find early asymptomatic FAP patients.

Adding Sewage Sludge (SS) in sintering process may provide an alternative for disposal of SS. Therefore, the combustion characteristics of SS and Coal Powder (CP) mixed with the sinter were compared by Thermogravimetric Analysis (TGA) and the effects of adding SS on metallurgical properties of sinter were investigated by sintering pot tests in this paper. TGA results show that the combustion characteristics of SS (5%)-Sinter are better than CP (5%)-Sinter at the same heating rate. Besides, it is beneficial to decrease the ignition temperature by adding more SS into the sinter. The results of sintering pot tests indicate that increasing SS from 0% to 9% in the sintering process can increase the tumbler strength from 62% to 68% and the shatter strength from 63% to 67.4%, and reduce the abrasion index from 4.5% to 3.8%. In addition, the S content in the sinter from sintering pot tests, obtained via X-Ray Fluorescence, decreases from 0.223% to 0.197% and the P content increases from 0.201% to 0.276%; however, these changes are acceptable for the sinter. All these imply that SS is not only a good fuel for sintering, but that adding SS in the sintering process is appropriate as it could improve the metallurgical properties of the sinter to some extent. This will provide a good basis for the practical use of SS in the sintering process of the steel plant.

This paper presents the R&D of GaAs-based heterojunction materials, describes mainly the material properties and the characterization techniques. The microwave device has been fabricated with the as-grown structure material and the testing frequency which has entered into W-band has shown.