Effect of CHST11, a novel biomarker, on the biological functionalities of clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a common malignant tumor, and the role of carbohydrate sulfotransferase 11 (CHST11) in this cancer remains unclear. Here, by using bioinformatics methods, we comprehensively analyzed the relationship between CHST11 and clinical significance, immune infiltration, functional enrichment, m6A methylation, and protein-protein interaction networks. We found that CHST11 expression was significantly higher in ccRCC samples than in normal tissues. Additionally, CHST11 levels correlated with the clinicopathological features of ccRCC patients and functioned as a prognostic factor for patient survival. Functional analysis revealed the involvement of CHST11 in metabolic pathways. Immune infiltration and m6A methylation analysis suggested the association of CHST11 with immune cell abundance in the tumor microenvironment and specific methylation patterns in ccRCC. The in vitro analysis of the clinical samples and ccRCC cell lines demonstrated that the overexpression of CHST11 promotes ccRCC cell proliferation, migration, and invasion, while its suppression has the opposite effect. Thus, CHST11 may play a remarkable role in the occurrence and progression of ccRCC. Functionally, CHST11 promotes the aggressiveness of ccRCC cells. These findings provide insights into the role of CHST11 in ccRCC progression.Registry and the Registration No. of the study/trial: No. 2021K034.

Circulating exosomal miR-16-5p and let-7e-5p are associated with bladder fibrosis of diabetic cystopathy.

Diabetic cystopathy (DCP) is a prevalent etiology of bladder dysfunction in individuals with longstanding diabetes, frequently leading to bladder interstitial fibrosis. Research investigating the initial pathological alterations of DCP is notably scarce. To comprehend the development of fibrosis and find effective biomarkers for its diagnosis, we prepared streptozotocin-induced long-term diabetic SD rats exhibiting a type 1 diabetes phenotype and bladder fibrosis in histology detection. After observing myofibroblast differentiation from rats' primary bladder fibroblasts with immunofluorescence, we isolated fibroblasts derived exosomes and performed exosomal miRNA sequencing. The co-differentially expressed miRNAs (DEMis) (miR-16-5p and let-7e-5p) were screened through a joint analysis of diabetic rats and long-term patients' plasma data (GES97123) downloaded from the GEO database. Then two co-DEMis were validated by quantitative PCR on exosomes derived from diabetic rats' plasma. Following with a series of analysis, including target mRNAs and transcription factors (TFs) prediction, hubgenes identification, protein-protein interaction (PPI) network construction and gene enrichment analysis, a miRNA-mediated genetic regulatory network consisting of two miRNAs, nine TFs, and thirty target mRNAs were identified in relation to fibrotic processes. Thus, circulating exosomal miR-16-5p and let-7e-5p are associated with bladder fibrosis of DCP, and the crucial genes in regulatory network might hold immense significance in studying the pathogenesis and molecular mechanisms of fibrosis, which deserves further exploration.

Evaluation of a Patient Decision Aid for Refractive Eye Surgery.

BACKGROUND: We developed a prototype patient decision aid, EyeChoose, to assist college-aged students in selecting a refractive surgery. EyeChoose can educate patients on refractive errors and surgeries, generate evidence-based recommendations based on a user's medical history and personal preferences, and refer patients to local refractive surgeons. OBJECTIVES: We conducted an evaluative study on EyeChoose to assess the alignment of surgical modality recommendations with a user's medical history and personal preferences, and to examine the tool's usefulness and usability. METHODS: We designed a mixed methods study on EyeChoose through simulations of test cases to provide a quantitative measure of the customized recommendations, an online survey to evaluate the usefulness and usability, and a focus group interview to obtain an in-depth understanding of user experience and feedback. RESULTS: We used stratified random sampling to generate 245 test cases. Simulated execution indicated EyeChoose's recommendations aligned with the reference standard in 243 (99%). A survey of 55 participants with 16 questions on usefulness, usability, and general impression showed that 14 questions recorded more than 80% positive responses. A follow-up focus group with 10 participants confirmed EyeChoose's useful features of patient education, decision assistance, surgeon referral, as well as good usability with multimedia resources, visual comparison among the surgical modalities, and the overall aesthetically pleasing design. Potential areas for improvement included offering nuances in soliciting user preferences, providing additional details on pricing, effectiveness, and reversibility of surgeries, expanding the function of surgeon referral, and fixing specific usability issues. CONCLUSION: The initial evaluation of EyeChoose suggests that it could provide effective patient education, generate appropriate recommendations, connect to local refractive surgeons, and demonstrate good system usability in a test environment. Future research is required to enhance the system functions, fully implement and evaluate the tool in naturalistic settings, and examine the findings' generalizability to other populations.

Revolutionizing cancer treatment: nanotechnology-enabled photodynamic therapy and immunotherapy with advanced photosensitizers.

Nanotechnology-enhanced photodynamic therapy (PDT) and immunotherapy are emerging as exciting cancer therapeutic methods with significant potential for improving patient outcomes. By combining these approaches, synergistic effects have been observed in preclinical studies, resulting in enhanced immune responses to cancer and the capacity to conquer the immunosuppressive tumor microenvironment (TME). Despite challenges such as addressing treatment limitations and developing personalized cancer treatment strategies, the integration of nanotechnology-enabled PDT and immunotherapy, along with advanced photosensitizers (PSs), represents an exciting new avenue in cancer treatment. Continued research, development, and collaboration among researchers, clinicians, and regulatory agencies are crucial for further advancements and the successful implementation of these promising therapies, ultimately benefiting cancer patients worldwide.

Novel gene signature for predicting biochemical recurrence-free survival of prostate cancer and PRAME modulates prostate cancer progression.

Biochemical recurrence (BCR) is considered as an early sign of prostate cancer (PCa) progression after initial treatment, such as radical prostatectomy and radiotherapy; hence, it is important to stratify patients at risk of BCR. In this study, we established a robust 8-gene signature (APOF, Clorf64, RPE65, SEMG1, ARHGDIG, COMP, MKI67 and PRAME) based on the PCa transcriptome profiles in the Cancer Genome Atlas (TCGA) for predicting BCR-free survival of PCa, which was further validated in the MSK-IMPACT Clinical Sequencing Cohort (MSKCC) PCa cohort. Moreover, we found that one risk-related gene (PRAME) was upregulated in tumor samples, particularly in high-risk group was well as in patients metastatic tumor and was correlated with chemotherapeutic drug response. In vitro experiments showed that knocking down PRAME reduced the proliferation, migration, and invasion of PCa cells. Therefore, our study established a new 8-gene signature that could accurately predict the BCR risk of PCa. Inhibition of PRAME attenuated the proliferation, invasion, and migration of PCa cells. These findings provide a novel tool for stratifying high-risk PCa patient and shed light on the mechanism of PCa progression.

A novel necroptosis-related long noncoding RNA model for predicting clinical features, immune characteristics, and therapeutic response in clear cell renal cell carcinoma.

Background: Necroptosis is an immune-related cell death pathway involved in the regulation of the tumor microenvironment (TME). Here, we aimed to explore the role of necroptosis in clear cell renal cell carcinoma (ccRCC) and construct a necroptosis-related lncRNA (NRL) model to assess its potential association with clinical characteristics and immune status. Methods: Gene expression profiles and clinical data for ccRCC patients were obtained from the Cancer Genome Atlas (TCGA). Pearson's correlation, univariate Cox, and least absolute shrinkage and selection operator analyses were used to develop an NRL model. Kaplan-Meier (K-M) and receiver operating characteristic (ROC) curve analyses were used to determine the prognostic value of the NRL model. The clinical information was used to assess the diagnostic value of the NRL model. The TME, immune function, immune cell infiltration, and immune checkpoints associated with the NRL model risk score were studied using the ESTIMATE, GSEA, ssGSEA, and CIBERSORT algorithms. The immunophenoscore (IPS) and half-maximal inhibitory concentration (IC50) were used to compare the efficacies of immunotherapy and chemotherapy based on the NRL model. Finally, in vitro assays were performed to confirm the biological roles of NRLs. Results: A total of 18 necroptosis-related genes and 285 NRLs in ccRCC were identified. A four-NRL model was constructed and showed good performance in the diagnosis and prognosis of ccRCC patients. The ESTIMATE scores, tumor mutation burden, and tumor stemness indices were significantly correlated with NRL model risk score. Immune functions such as chemokine receptors and immune receptor activity showed differences between different risk groups. The infiltration of immunosuppressive cells such as Tregs was higher in high-risk patients than in low-risk patients. High-risk patients were more sensitive to immunotherapy and some chemotherapy drugs, such as sunitinib and temsirolimus. Finally, the expression of NRLs included in the model was verified, and knocking down these NRLs in tumor cells affected cell proliferation, migration, and invasion. Conclusion: Necroptosis plays an important role in the progression of ccRCC. The NRL model we constructed can be used to predict the clinical characteristics and immune features of ccRCC patients.

Incidence trends and survival of metastatic prostate cancer with bone and visceral involvement: 2010-2019 surveillance, epidemiology, and end results.

Background: The incidence of prostate cancer (PCa) has continued to increase since the US Preventive Services Task Force (USPSTF) recommendations against prostate-specific antigen (PSA)-based screening for all men in 2012, approximately half of additional diagnosed cases are advanced-stage, including regional PCa and metastatic PCa (mPCa). It is very important to investigate the shift in mPCa incidence and mPCa-related mortality risk, as the survival of mPCa remains poor. Objective: To investigate the incidence temporal trend of mPCa stratified by metastatic site, including bone and visceral metastatic involvement, and potential survival improvements. Materials: Based on the recently released Surveillance, Epidemiology, and End Results (SEER) data (2010-2019), the age-adjusted incidence rates of mPCa with bone and visceral involvement with annual percentage changes (APCs) were assessed by a joinpoint regression model in men aged 45 years and older by age and race groups, and potential recent improvements in overall survival (OS) and cancer-specific survival (CSS) were estimated by the Kaplan-Meier method and Cox regression model. Results: From 2010 to 2019, a total of 19081 (84.8%) and 3413 (15.2%) mPCa patients with bone and visceral involvement, respectively, were recorded in the SEER database. Considering all races and age groups, the incidence rate of mPCa with bone metastasis remained stable during 2017-2019 (APC, 0.9%; p=0.421) after increasing during 2010-2017 (APC, 5.8%; p<0.001). For visceral metastasis, the incidence rate increased by 12.3% (p<0.001) per year from 2010-2019. Non-Hispanic Black men have higher incidence rates than other populations, and the Non-Hispanic Black to Non-Hispanic White incidence rates ratios of mPCa declined with the greater increasing pace of incidence of Non-Hispanic White men. There was a slight improvement in both OS and CSS among men with bone and visceral metastasis involvement when comparing the 2013-2016 period to the pre-2013 period. Conclusion: Our findings show that the incidence of mPCa with bone and visceral involvement has increased in recent years and that there has been a potential improvement in survival. Future efforts are still needed to watch closely if the rising incidence trends continue.

The role of cytoreductive radical prostatectomy and lymph node dissection in bone-metastatic prostate cancer: A population-based study.

BACKGROUNDS: The role of cytoreductive radical prostatectomy (cRP) for bone-metastatic prostate cancer (bmPCa) remains controversial. We aimed to figure out whether cRP and lymph node dissection (LND) can benefit bmPCa. METHODS: 11,271 PCa patients with bone metastatic burden from 2010 to 2019 were identified using SEER-Medicare. Overall survival (OS) and cancer-specific survival (CSS) rates were visualized using Kaplan-Meier plots. Multivariable Cox regression analyses were constructed to examine the effects of cRP and LND on survival, after stratifying to age, prostate specific antigen (PSA), clinical stages, Gleason score, metastatic burden, radiotherapy, and chemotherapy status. RESULTS: 317 PCa patients underwent cRP and cRP was increasingly performed for bmPCa from 2010 (2.2%) to 2019 (3.0%) (p < 0.05). In multi analyses, cRP was predisposed to a better OS or CSS in patients with age < 75, PSA < 98 ng/mL, bone-only metastatic sites or patients not receiving chemotherapy (all p < 0.05). For the patients undergoing cRP, LND especially extended LND was associated with a better OS or CSS (all p < 0.05). CONCLUSIONS: cRP might benefit OS or CSS in young patients with low PSA and bone-only metastatic sites not receiving chemotherapy. And a clear OS or CSS benefit of LND especially extended LND was observed in patients undergoing cRP.

Development and validation of a novel 5 cuproptosis-related long noncoding RNA signature to predict diagnosis, prognosis, and drug therapy in clear cell renal cell carcinoma.

Background: Cuproptosis has been reported as a new form of cell death. However, its potential mechanism of action in clear cell renal cell carcinoma (ccRCC) remains unclear. Therefore, we systematically clarified the role of cuproptosis in ccRCC and aimed to develop a novel signature of cuproptosis-related long noncoding RNAs (lncRNA) (CRLs) to assess the clinical characteristics of ccRCC patients. Methods: Gene expression, copy number variation, gene mutation, and clinical data for ccRCC were obtained from The Cancer Genome Atlas (TCGA). CRL signature was constructed with least absolute shrinkage and selection operator (LASSO) regression analysis. The clinical diagnostic value of the signature was verified by clinical data. The prognostic value of the signature was detected by Kaplan-Meier analysis and receiver operating characteristic (ROC) curve. The prognostic value of the nomogram was evaluated by calibration curves, ROC curves, and decision curve analysis (DCA). Gene set enrichment analysis (GSEA), single sample GSEA (ssGSEA) and cell type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm were used to analyze the differences of immune function and immune cell infiltration among different risk groups. Prediction of clinical treatment differences in populations with different risks and susceptibilities was completed with R package (The R Foundation of Statistical Computing). Verification of key lncRNA expression was performed by quantitative real-time polymerase chain reaction (qRT-PCR). Results: The cuproptosis-related genes were extensively dysregulated in ccRCC. A total of 153 differentially expressed prognostic CRLs were identified in ccRCC. Furthermore, a 5-lncRNA signature (AC015912.3, AC026401.3, AC103706.1, AC134312.5, and EMX2OS) were obtained that showed good performance in the diagnosis and prognosis of ccRCC. The nomogram could more accurately predict overall survival (OS). Immune functions such as T-cell and B-cell receptor signaling pathways showed differences between different risk groups. Clinical treatment value analysis showed that the signature may be able to effectively guide immunotherapy and target therapy. In addition, qRT-PCR results showed significant differences in the expression of key lncRNAs in ccRCC. Conclusions: Cuproptosis plays an important role in the progression of ccRCC. The 5-CRL signature can guide the prediction of clinical characteristics and tumor immune microenvironment of ccRCC patients.

The mechanism of long-chain acyl-CoA synthetase 3 in inhibiting cell proliferation, migration, and invasion in clear cell renal cell carcinoma.

Long-chain acyl-CoA synthases 3 (ACSL3) can activate long-chain fatty acids, which are often deregulated in tumors. However, the biological function of ACSL3 in clear cell renal cell carcinoma (ccRCC) is still unclear. In this research, the expression level, prognostic value, GO and KEGG functional enrichment analyses, genomic changes, clinical significance, immune infiltration of ACSL3 in ccRCC were comprehensively analysed. The expression levels of ACSL3 in ccRCC tissues were detected by quantitative reverse transcription-polymerase chain reaction (RT-qPCR), immunohistochemical staining (IHC), and Western blotting analysis. The proliferation, invasion, migration, apoptotic and lipid synthesis abilities of ccRCC cells were assessed using the cell counting kit (CCK-8), clone formation, scratch assay, Transwell assay, flow cytometry and Oil Red O assay, respectively. The results showed that ACSL3 was obviously downregulated in ccRCC and significantly associated with poor prognosis and clinicopathological factors of ccRCC patients. Additionally, the functional enrichment analysis indicated that ACSL3 was mainly involved in lipid synthesis and metabolism. The result of immune infiltration analysis proved that ACSL3 might regulate the tumor microenvironment of ccRCC. In addition, we demonstrated that overexpression of the ACSL3 could inhibit the proliferation, migration, and invasion of ccRCC cells, and promote apoptosis, reduce abnormal lipid accumulation. In conclusion, ACSL3 might be a novel ccRCC biomarker and the target for ccRCC tumor therapy.

Comparisons of the diagnostic accuracy across prostate health index, prostate health index density, and percentage free prostate-specific antigen for clinically significant prostate cancer: a prospective diagnostic study.

Background: As the novel serum biomarkers, it has not been clearly clarified that the diagnostic accuracy of prostate health index (PHI) and prostate health index density (PHID) are superior to that of percentage free prostate-specific antigen (%fPSA) in detection of clinically significant prostate cancer (csPCa), especially in the gray zone. Therefore, this study aimed to compare the diagnostic value of PHI, PHID, and %fPSA for csPCa in the patients with prostate-specific antigen (PSA) >4 ng/mL and those with PSA within 4-10 ng/mL. Methods: In this study, the serum samples and clinicopathological features were prospectively obtained from the patients who underwent prostate biopsy between September 2019 and December 2020. According to the inclusion criteria, the patients with total PSA (tPSA) >4 ng/mL, prostate magnetic resonance imaging or ultrasound clearly suggesting an occupying lesion were enrolled in this study. The patients with Gleason score ≥7 indicated csPCa. The receiver operating characteristic curves and the area under the curve (AUC) values were used to assess the diagnostic performance. Results: Among the 296 patients (mean age 67.5 years, median tPSA 7.94 ng/mL) included in this study, there were 54 in the csPCa group (mean age 70.4 years, median tPSA 11.0 ng/mL) and 242 in the non-csPCa group (mean age 66.8 years, median tPSA 7.67 ng/mL). Based on the PSA level, there were 198 patients with PSA within the gray zone, which included 40 patients in the csPCa group and 158 in the non-csPCa group. In all patients, the sensitivity of PHID for detecting csPCa was 96.30%, and the specificity was 33.06% with the cut-off value of 0.51. Moreover, both PHID and PHI did better in the diagnosis of csPCa (AUC: 0.880 and 0.867, respectively) compared with other PSA derivative markers. Similarly, in the patients with PSA level in the gray zone, the diagnostic accuracy of PHID and PHI in predicting csPCa (AUC: 0.788 and 0.777, respectively) were better than other PSA derivative markers. Conclusions: PHID presented the better diagnostic accuracy in predicting csPCa in patients with PSA in the gray zone than other PSA derivative markers, which could be a promising biomarker for making the biopsy strategy.

Partial and radical cystectomy provides equivalent oncologic outcomes in bladder cancer when combined with adequate lymph node dissection: A population-based study.

PURPOSE: To compare the oncologic outcomes of bladder cancer (BCa) patients after partial cystectomy (PC) or radical cystectomy (RC) combined with lymph node dissection (LND). METHODS: Relevant data from BCa patients who had >3 lymph nodes (LNs) removed were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Different thresholds of LN count in LND were tested to eliminate potential selection bias, and the optimal threshold was applied to screen patients who underwent adequate LND. After propensity score matching, the oncologic outcomes after PC or RC were compared in patients who underwent adequate LND. RESULTS: After preliminary screening, 6,785 BCa cases diagnosed between 2004 and 2015 with removal of > 3 LNs were enrolled in the analysis, including 633 (9.3%) PC cases and 6,152 (90.7%) RC cases. The PC and RC groups presented entirely different profiles in clinical parameters such as sex, T stage, number of lymph nodes (LNs) removed, and adjuvant therapy. In particular, the LN-positive rate and count were higher in the RC group, even after adjusting for other confounding factors. After comparison using different thresholds, the LN positive rate and count were similar when the LN count in LND was restricted to > 12. In patients who had > 12 LNs removed, after propensity score matching, PC and RC presented similar oncologic outcomes. Further exploration found that the prognosis of patients was associated with age, T stage, and the number of positive LNs. CONCLUSION: PC and RC could provide equivalent oncologic outcomes in BCa when combined with adequate LND. The conclusion needs further validation in future studies.

Proxalutamide in metastatic castration-resistant prostate cancer: Primary analysis of a multicenter, randomized, open-label, phase 2 trial.

We aim to assess the safety and efficacy of proxalutamide, a novel androgen receptor antagonist, for men with metastatic castration-resistant prostate cancer (mCRPC) in a multicenter, randomized, open-label, phase 2 trial. In our study, the enrolled mCRPC patients were randomized to 100, 200 and 300 mg dose groups at 1:1:1. The primary efficacy endpoint was prostate-specific antigen (PSA) response rate. The secondary endpoints included objective response rate (ORR), disease control rate (DCR) and time to PSA and radiographic progression. Safety and pharmacokinetics were also assessed. Finally, there were 108 patients from 17 centers being enrolled. By week 16, there were 13 (35.1%), 12 (36.4%) and 15 (42.9%) patients with confirmed 50% or greater PSA decline in 100 mg (n = 37), 200 mg (n = 33) and 300 mg (n = 35) groups, respectively. Among the 19 patients with target lesions at study entry, three (15.8%) had a partial response and 12 (63.2%) had stable disease. The ORRs of 20.0%, 22.2%, 0% and DCRs of 80.0%, 88.9%, 60.0% were, respectively, achieved in 100, 200 and 300 mg groups. By the maximum follow-up time of 24 weeks, there were 42.6% and 10.2% of cases experiencing PSA progression and radiographic progression, respectively. Overall, adverse events (AEs) were experienced by 94.4% of patients, most of which were mild or moderate. There were 28 patients experiencing ≥grade 3 AEs. The most common AEs were fatigue (17.6%), anemia (14.8%), elevated AST (14.8%) and ALT (13.0%), decreased appetite (13.0%). These findings preliminarily showed the promising antitumor activity of proxalutamide in patients with mCRPC with a manageable safety profile. The proxalutamide dose of 200 mg daily is recommended for future phase 3 trial (Clinical trial registration no. CTR20170177).

Individualized prognosis stratification in muscle invasive bladder cancer: A pairwise TP53-derived transcriptome signature.

TP53 is the most frequently mutated gene in muscle invasive bladder cancer (MIBC) and there are two gene signatures regarding TP53 developed for MIBC prognosis. However, they are limited to immune genes only and unable to be used individually across platforms due to their quantitative manners. We used 827 gene expression profiles from seven MIBC cohorts with varied platforms to build a pairwise TP53-derived transcriptome signature, 13 gene pairs (13-GPs). Since the 13-GPs model is a single sample prognostic predictor, it can be applied individually in practice and is applicable to any gene-expression platforms without specific normalization requirements. Survival difference between high-risk and low-risk patients stratified by the 13-GPs test was statistically significant (HR range: 2.26-2.76, all P < .0001). Discovery and validation sets showed that the 13-GPs was an independent prognostic factor after adjusting other clinical features (HR range: 2.21-2.82, all P < .05). Moreover, it was a potential supplement to the consensus molecular classification of MIBC to further stratify the LumP subtype (patients with better prognoses). High- and low-risk patients by the 13-GPs model presented distinct immune microenvironment and DDR mutation rates, suggesting that it might have the potential for immunotherapy. Being a general approach to other cancer types, this study demonstrated how we integrated gene variants with pairwise gene panels to build a single sample prognostic test in translational oncology.

A systematic review verified by bioinformatic analysis based on TCGA reveals week prognosis power of CAIX in renal cancer.

BACKGROUND: Carbonic anhydrase IX (CAIX) protein has been correlated with progression and survival in patients with some tumors such as head and neck carcinoma. But renal cell carcinoma is an exception. The prognostic value of CAIX in RCC used to be associated with patients' survival according to published works. This study aimed to rectify the former conclusion. METHODS: This study was registered in PROSPERO (CRD42020160181). A literature search of the PubMed, Embase, Cochrane library and Web of Science databases was performed to retrieve original studies until April of 2022. Twenty-seven studies, including a total of 5462 patients with renal cell carcinoma, were reviewed. Standard meta-analysis methods were used to evaluate the prognostic impact of CAIX expression on patient prognosis. The hazard ratio and its 95% confidence interval were recorded for the relationship between CAIX expression and survival, and the data were analyzed using Stata 11.0. Then we verify the meta-analysis resort to bioinformatics (TCGA). RESULTS: Our initial search resulted in 908 articles in total. From PubMed, Embase, Web of Science electronic and Cochrane library databases, 493, 318 and 97 potentially relevant articles were discovered, respectively. We took the analysis between CA9 and disease-specific survival (HR = 1.18, 95% CI: 0.82-1.70, I2 = 79.3%, P<0.05), a subgroup then was performed to enhance the result (HR = 1.63, 95%CI: 1.30-2.03, I2 = 26.3%, P = 0.228); overall survival was also parallel with the former (HR = 1.13, 95%CI: 0.82-1.56, I2 = 79.8%, P<0.05), then a subgroup also be performed (HR = 0.90, 95%CI:0.75-1.07, I2 = 23.1%, P = 0.246) to verify the result; the analysis between CAIX and progression-free survival got the similar result (HR = 1.73, 95%CI:0.97-3.09, I2 = 82.4%, P<0.05), we also verify the result by subgroup analysis (HR = 1.04, 95%CI:0.79-1.36, I2 = 0.0%, P = 0.465); at last the relationship between CAIX and recurrence-free survival got the same result, too (HR = 0.99, 95%CI: 0.95-1.02, I2 = 57.8%, P = 0.050), the subgroup's result was also parallel with the former (HR = 1.01, 95%CI: 0.91-1.03, I2 = 0.00%, P = 0.704). To validate our meta-analysis, we took a bioinformatic analysis based on TCGA database, survival curve between low and high CAIX expression in four endpoints (DSS, OS, PFI, DFI) have corresponding P value (DSS:P = 0.23, OS:P = 0.77, PFI:P = 0.25, DFI:P = 0.78). CONCLUSIONS: CAIX expression in patients with RCC is an exception to predict tumor survival. Both low CAIX expression and high expression are not associated with survivals in RCC patients.

CDH13 is a prognostic biomarker and a potential therapeutic target for patients with clear cell renal cell carcinoma.

CDH13 is an atypical member of the cadherin family and is closely related to the clinicopathological factors and prognosis of many types of cancer. However, the role of CDH13 in clear cell renal cell carcinoma (ccRCC) remains unknown. Therefore, we comprehensively analyzed the expression level, diagnostic efficacy, clinical significance, prognostic value, immune infiltration, methylation status, genetic alteration, and biological functions of CDH13 in ccRCC patients. The results showed that CDH13 was significantly upregulated in ccRCC and strongly correlated with better survival, lower cancer stages, and lower tumor grades of ccRCC patients. Additionally, the immune infiltration analysis indicated that CDH13 might play a crucial role in regulating the tumor microenvironment of ccRCC. The results of methylation analysis showed that the epigenetic status of CDH13 was altered, and the prognosis of ccRCC patients was related not only to DNA methylation but also to m6A modification of CDH13. Finally, the results based on clinical samples further elucidated the expression pattern of CDH13 in ccRCC. In conclusion, CDH13 might be a novel prognostic biomarker and therapeutic target for patients with ccRCC. And our study provides new insights into the potential molecular changes and strategies for the treatment of ccRCC.

The predictive accuracy of preoperative erythrocyte count and maximum tumor diameter to maximum kidney diameter ratio in renal cell carcinoma.

Background: The purpose of this study was to investigate the predictive accuracy of erythrocyte count and maximum tumor diameter to maximum kidney diameter ratio (TKR) in patients with renal cell carcinoma (RCC). Methods: We retrospectively analyzed the clinicopathological epidemiological characteristics of patients with RCC in the First Hospital of Shanxi Medical University from 2010 to 2014. Among them, 295 cases with complete follow-up data at the time of visit were selected. We collected data including erythrocyte counts and length of each diameter line of the tumor and kidney. To predict the prognosis of RCC, receiver operating characteristic (ROC) curve analysis was used to calculate the cutoff value of each parameter. Results: Of the 295 included patients, 199 (67.5%) were male, 96 (32.5%) were female, and the mean (± SD) age was 56.45±11.03 years. The area under the curve (AUC) of the erythrocyte count and the TKR for predicting the prognosis of RCC were 0.672 (SD 0.031; P<0.001) and 0.800 (SD 0.030; P<0.001), respectively. When the cutoff value of the erythrocyte count and TKR count were 3.975 and 0.452, the highest Youden index values were 0.309 and 0.685, and the corresponding sensitivity and specificity were 0.826 and 0.685, and 0.483 and 1.000, respectively. Conclusions: An erythrocyte count <3.975×1012/L and a TKR >0.452 were found to be risk factors for poor prognosis in patients with RCC.

Systematic Construction and Validation of a Novel Macrophage Differentiation-Associated Prognostic Model for Clear Cell Renal Cell Carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) is a malignant tumor of the human urinary system. Macrophage differentiation is associated with tumorigenesis. Therefore, exploring the prognostic value of macrophage differentiation-associated genes (MDGs) may contribute to better clinical management of ccRCC patients. Methods: The RNA sequence data of ccRCC were obtained from The Cancer Genome Atlas (TCGA) database. Differentially expressed MDGs were unveiled in ccRCC and normal samples. The prognostic model was established according to the univariate and multivariate Cox regression analyses. By combining clinico-pathological features and prognostic genes, a nomogram was established to predict individual survival probability. The Tumor Immune Estimation Resource (TIMER) database was utilized to analyze the correlation between prognostic genes and immune infiltrating cells. Eventually, the mRNA and protein expression levels of prognostic genes were verified. Results: A total of 52 differentially expressed prognosis-related MDGs were identified in ccRCC. Afterward, a six-gene prognostic model (ABCG1, KDF1, KITLG, TGFA, HAVCR2, and CD14) was constructed through the Cox analysis. The overall survival in the high-risk group was relatively poor. Moreover, the risk score was identified as an independent prognostic factor. We constructed a prognostic nomogram with a well-fitted calibration curve based on risk score and clinical data. Furthermore, the prognostic genes were significantly related to the level of immune cell infiltration including B cells, CD8+T cells, CD4+T cells, macrophages, neutrophils, and dendritic cells. Finally, the mRNA expression of prognostic genes in clinical ccRCC tissues showed that the ABCG1, HAVCR2, CD14, and TGFA mRNA in tumor samples were increased compared with the adjacent control tissue samples, while KDF1 and KITLG were decreased, which was consistent with the verification results in the GSE53757. Conclusion: In conclusion, this study identified and validated a macrophage differentiation-associated prognostic model for ccRCC that could be used to predict the outcomes of the ccRCC patients.

Can we infer tumor presence of single cell transcriptomes and their tumor of origin from bulk transcriptomes by machine learning?

There is a growing need to build a model that uses single cell RNA-seq (scRNA-seq) to separate malignant cells from nonmalignant cells and to identify tumor of origin of single cells and/or circulating tumor cells (CTCs). Currently, it is infeasible to build a tumor of origin model learnt from scRNA-seq by machine learning (ML). We then wondered if an ML model learnt from bulk transcriptomes is applicable to scRNA-seq to infer single cells' tumor presence and further indicate their tumor of origin. We used k-nearest neighbors, one-versus-all support vector machine, one-versus-one support vector machine, random forest and introduced scTumorTrace to conduct a pioneering experiment containing leukocytes and seven major cancer types where bulk RNA-seq and scRNA-seq data were available. 13 ML models learnt from bulk RNA-seq were all reliable to use (F-score > 96%) shown by a validation set of bulk transcriptomes, but none of them was applicable to scRNA-seq except scTumorTrace. Making inferences from bulk RNA-seq to scRNA-seq was impaired by feature selection and improved by log2-transformed TPM units. scTumorTrace with transcriptome-wide 2-tuples showed F-score beyond 98.74 and 94.29% in inferring tumor presence and tumor of origin at single-cell resolution and correctly identified 45 single candidate prostate CTCs but lineage-confirmed non-CTCs as leukocytes. We concluded that modern ML techniques are quantitative and could hardly address the raised questions. scTumorTrace with transcriptome-wide 2-tuples is qualitative, standardization-free and not subject to log2-transformed quantities, enabling us to infer tumor presence of single cell transcriptomes and their tumor of origin from bulk transcriptomes.

Extended endocrine therapy in breast cancer: A basket of length-constraint feature selection metaheuristics to balance Type I against Type II errors.

Extended endocrine therapy beyond 5 years is of major concern to ER + breast cancer survivors. However, it might be unsuitable to apply routinely used genomic tests designed for early recurrence risks to distant recurrence within 10 years in extended treatment context. These tests initially aim at high sensitivities with Type I errors much higher than Type II. Having lower positive predictive values (PPVs), these tests can bring many false positives who might not need further treatment options to avoid adversely affecting quality of life. Alternatively, we proposed a top-down approach to the raised issues. We built 149 targeted genes from four genomic tests upon 381 ER-positive node-negative patients with either metastasis free beyond 10 years (n = 202) or metastasis within 10 years (n = 179). By a basket of SVM-wrapped length-constraint feature selection (LCFS), we discovered four genomic SVMs that traded off Type I against Type II errors. Two independent cohorts were used to validate disease outcome predictions. A 36-gene SVM balanced sensitivities with PPVs at good levels: 74% vs 76% on 10-fold cross validation (n = 347) and 75% vs 71% on a test set (n = 34). Neither Oncotype DX RS (cutoff = 18, 31, 60.97) nor PAM50 ROR-S (cutoff = 29, 53, 61.18) could. Independent cohorts showed the 36-gene SVM predicted disease free survival (n = 136, HR = 2.59; 95% CI, 1.4-4.8) and disease specific survival (n = 127, HR = 4.06; 95% CI, 1.63-10.11) better than RS (DFS, HR = 2.15; DSS, HR = 3.86) and ROR-S (DFS, HR = 2.29; DSS, HR = 2.76). The case study demonstrated how we identified a genomic test to balance Type I against Type II errors for risk stratification. The top-down approach centered around the LCFS-metaheuristics basket is a generic methodology for clinical decision-making and quality of life using targeted profiling data where the number of dimensions (p) is smaller than the number of samples (n).