LDHA-mediated M2-type macrophage polarization via tumor-derived exosomal EPHA2 promotes renal cell carcinoma progression.

Lactate dehydrogenase A (LDHA) is known to promote the growth and invasion of various types of tumors, affects tumor resistance, and is associated with tumor immune escape. But how LDHA reshapes the tumor microenvironment and promotes the progression of renal cell carcinoma (RCC) remains unclear. In this study, we found that LDHA was highly expressed in clear cell RCC (ccRCC), and this high expression was associated with macrophage infiltration, while macrophages were highly infiltrated in ccRCC, affecting patient prognosis via M2-type polarization. Our in vivo and in vitro experiments demonstrated that LDHA and M2-type macrophages could enhance the proliferation, invasion, and migration abilities of ccRCC cells. Mechanistically, high expression of LDHA in ccRCC cells upregulated the expression of EPHA2 in exosomes derived from renal cancer. Exosomal EPHA2 promoted M2-type polarization of macrophages by promoting activation of the PI3K/AKT/mTOR pathway in macrophages, thereby promoting the progression of ccRCC. All these findings suggest that EPHA2 may prove to be a potential therapeutic target for advanced RCC.

A Mendelian randomization study on causal effects of leisure sedentary behavior on the risk of erectile dysfunction.

BACKGROUND: Erectile dysfunction has been associated with leisure sedentary behavior in several epidemiological and observational studies. However, the interpretation of these findings is difficult due to residual confounding or reverse causality. OBJECTIVES: To explore the causal association between leisure sedentary behavior and erectile dysfunction, and to explore the underlying mechanism using Mendelian randomization. MATERIALS AND METHODS: In the present study, publicly available large-scale genome-wide association studies of leisure sedentary behaviors (television watching, computer use, and driving), erectile dysfunction, sex hormones (total testosterone, bioactive testosterone, estradiol, follicle-stimulating hormone, luteinizing hormone, prolactin, and sex hormone binding globulin), biomarkers of endothelial function (C reactive protein, E-selectin, and matrix metalloproteinase 7), and psychiatric symptoms (depression and anxiety) were used to perform two-sample Mendelian randomization analyses. The inverse variance weighting method was the main method used to estimate the association, and sensitivity analyses were also performed. RESULTS: A greater risk of erectile dysfunction was significantly associated with a higher genetic susceptibility to leisure computer usage (odds ratio = 3.57; 95% confidence interval = 1.78-7.16; p < 0.001). No evidence was obtained to suggest that watching television or driving for leisure increased the risk of erectile dysfunction. No association was found between computer use and depression, anxiety, C reactive protein, E-selectin, matrix metalloproteinase 7, or other sex hormones, with the exception of follicle-stimulating hormone levels (odds ratio = 0.29; 95% confidence interval = 0.12-0.69; p = 0.01). No indication of heterogeneity or pleiotropy was identified by sensitivity analysis. DISCUSSION: Extended computer usage for leisure raised the likelihood of developing erectile dysfunction, which may be associated to lower follicle-stimulating hormone levels; however, the role of endothelial dysfunction and psychological disorders in the development of erectile dysfunction should not be underestimated. Moderate physical activity may help to correct the dysfunction. CONCLUSION: The present study offered substantial evidence for a positive causal association between computer use and the risk of erectile dysfunction. However, a definitive causal association needs to be established by further research.

Trans-retro-peritoneal laparoscopic partial nephrectomy for posterior hilar tumor: technical feasibility and preliminary results.

Background: Urologists still encounter challenges when it comes to the surgical management of tumors located on the posterior lip and posterior renal hilar region. We propose a trans-retro-peritoneal (TRP) technique to address the difficulties associated with posterior hilar tumors during retroperitoneal laparoscopic partial nephrectomy (LPN). Its efficacy was evaluated in a retrospective case-control study. Methods: The patients with posterior hilar tumors (≤7 cm) that underwent retroperitoneal LPN were included. The TRP technique allowed the posterior hilar tumor completely visible by incising the ventral peritoneum and rotating kidney ventrally during retroperitoneal LPN, which was applied in 36 cases, while the conventional retroperitoneal LPN was performed in 22 cases. Perioperative data were analyzed to evaluate the efficacy of TRP-LPN. Results: In TRP-LPN group, the TRP technique was successfully performed in all the patients without converting to open surgery or radical nephrectomy. The warm ischemia time was significantly shorter in TRP-LPN group than conventional LPN group (20.3 vs. 28.5 min, P<0.001). Furthermore, the mean estimated blood loss in TRR-LPN group was significantly less than that in conventional LPN group (86.5 vs. 90.9 mL, P<0.05). The mean operation time and recovery time of gastrointestinal function were similar between two groups. No severe complications occurred, and no positive surgical margin was found. The rate of Trifecta achievement was 50.0% (18/36) and 31.8% (7/22) respectively for TRP-LPN and conventional LPN (P=0.175). After mean follow-up of 21 months, no recurrence or metastasis occurred in all cases. Conclusions: Our findings, as demonstrated by the Trifecta outcomes, support the feasibility and efficacy of TRP-LPN in managing posterior renal hilar tumors. This approach may be considered as an efficient option for surgical management of such tumors.

Integrative transcriptome and proteome analyses of clear cell renal cell carcinoma develop a prognostic classifier associated with thrombus.

Clear cell renal cell carcinoma (ccRCC) with venous tumor thrombus (VTT) is associated with poor prognosis. Our integrative analyses of transcriptome and proteome reveal distinctive molecular features of ccRCC with VTT, and yield the development of a prognostic classifier to facilitate ccRCC molecular subtyping and treatment. The RNA sequencing and mass spectrometry were performed in normal-tumor-thrombus tissue triples of five ccRCC patients. Statistical analysis, GO and KEGG enrichment analysis, and protein-protein interaction network construction were used to interpret the transcriptomic and proteomic data. A six-gene-based classifier was developed to predict patients' survival using Cox regression, which was validated in an independent cohort. Transcriptomic analysis identified 1131 tumorigenesis-associated differentially expressed genes (DEGs) and 856 invasion-associated DEGs. Overexpression of transcription factor EGR2 in VTT indicated its important role in tumor invasion. Furthermore, proteomic analysis showed 597 tumorigenesis-associated differentially expressed proteins (DEPs) and 452 invasion-associated DEPs. The invasion-associated DEPs showed unique enrichment in DNA replication, lysine degradation, and PPAR signaling pathway. Integration of transcriptome and proteome reveals 142 tumorigenesis-associated proteins and 84 invasion-associated proteins displaying changes consistent with corresponding genes in transcriptomic profiling. Based on their different expression patterns among normal-tumor-thrombus triples, RAB25 and GGT5 were supposed to play a consistent role in both tumorigenesis and invasion processes, while SHMT2 and CADM4 might play the opposite roles in tumorigenesis and thrombus invasion. A prognostic classifier consisting of six DEGs (DEPTOR, DPEP1, NAT8, PLOD2, SLC7A5, SUSD2) performed satisfactorily in predicting survival of ccRCC patients (HR = 4.41, P < 0.001), which was further validated in an independent cohort of 40 cases (HR = 5.52, P = 0.026). Our study revealed the transcriptomic and proteomic profiles of ccRCC patients with VTT, and identified the distinctive molecular features associated with VTT. The six-gene-based prognostic classifier developed by integrative analyses may facilitate ccRCC molecular subtyping and treatment.

Excavation of diagnostic biomarkers and construction of prognostic model for clear cell renal cell carcinoma based on urine proteomics.

Purpose: Clear cell renal cell carcinoma (ccRCC) is the most common pathology type in kidney cancer. However, the prognosis of advanced ccRCC is unsatisfactory. Thus, early diagnosis becomes one of the most important research priorities of ccRCC. However, currently available studies about ccRCC lack urine-related further studies. In this study, we applied proteomics to search urinary biomarkers to assist early diagnosis of ccRCC. In addition, we constructed a prognostic model to assist judge patients' prognosis. Materials and methods: Urine which was used to perform 4D label-free quantitative proteomics was collected from 12 ccRCC patients and 11 non-tumor patients with no urinary system diseases. The urine of 12 patients with ccRCC confirmed by pathological examination after surgery was collected before operatoin. Bioinformatics analysis was used to describe the urinary proteomics landscape of these patients with ccRCC. The top ten proteins with the highest expression content were selected as the basis for subsequent validation. Urine from 46 ccRCC patients and 45 control patients were collected to use for verification by enzyme linked immunosorbent assay (ELISA). In order to assess the prognostic value of urine proteomics, a prognostic model was constructed by COX regression analysis on the intersection of RNA-sequencing data in The Cancer Genome Atlas (TCGA) database and our urine proteomic data. Results: 133 proteins differentially expressed in the urinary samples were found and 85 proteins (Fold Change, FC>1.5) were identified up-regulated while 48 down-regulated (FC<0.5). Top 10 proteins including S100A14, PKHD1L1, FABP4, ITIH2, C3, C8G, C2, ATF6, ANGPTL6, F13B were performed ELISA to verify. The results showed that PKHD1L1, ANGPTL6, FABP4 and C3 were statistically significant (P<0.05). We performed multivariate logistic regression analysis and plotted a nomogram. Receiver operating characteristic (ROC) curve indicted that the diagnostic efficiency of combined indicators is satisfactory (Aare under curve, AUC=0.835). Furthermore, the prognostic value of the urine proteomics was explored through the intersection between urine proteomics and TCGA RNA-seq data. Thus, COX regression analysis showed that VSIG4, HLA-DRA, SERPINF1, and IGLV2-23 were statistically significant (P<0.05). Conclusion: Our study indicated that the application of urine proteomics to explore diagnostic biomarkers and to construct prognostic models of renal clear cell carcinoma is of certain clinical value. PKHD1L1, ANGPTL6, FABP4 and C3 can assist to diagnose ccRCC. The prognostic model constituted of VSIG4, HLA-DRA, SERPINF1, and IGLV2-23 can significantly predict the prognosis of ccRCC patients, but this still needs more clinical trials to verify.

Integrative analysis of transcriptomic landscape and urinary signature reveals prognostic biomarkers for clear cell renal cell carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) patients with venous tumor thrombus (VTT) have poor prognosis. We aimed to reveal features of ccRCC with VTT and develop a urine-based prognostic classifier to predict ccRCC prognosis through integrative analyses of transcriptomic landscape and urinary signature. Methods: RNA sequencing was performed in five patients with ccRCC thrombus-tumor-normal tissue triples, while mass spectrometry was performed for urine samples from 12 ccRCC and 11 healthy controls. A urine-based classifier consisting of three proteins was developed to predict patients' survival and validated in an independent cohort. Results: Transcriptomic analysis identified 856 invasion-associated differentially expressed genes (DEGs). Furthermore, proteomic analysis showed 133 differentially expressed proteins (DEPs). Integration of transcriptomic landscape and urinary signature reveals 6 urinary detectable proteins (VSIG4, C3, GAL3ST1, TGFBI, AKR1C3, P4HB) displaying abundance changes consistent with corresponding genes in transcriptomic profiling. According to TCGA database, VSIG4, TGFBI, and P4HB were significantly overexpressed in patients with shorter survival and might be independent prognostic factors for ccRCC (all p<0.05). A prognostic classifier consisting of the three DEPs highly associated with survival performed satisfactorily in predicting overall survival (HR=2.0, p<0.01) and disease-free survival (HR=1.6, p<0.001) of ccRCC patients. The ELISA analysis of urine samples from an independent cohort confirmed the satisfied predictive power of the classifier for pathological grade (AUC=0.795, p<0.001) and stage (AUC=0.894, p<0.001). Conclusion: Based on integrative analyses of transcriptomic landscape and urinary signature, the urine-based prognostic classifier consisting of VSIG4, TGFBI, and P4HB has satisfied predictive power of ccRCC prognosis and may facilitate ccRCC molecular subtyping and treatment.

Deciphering the Role of Melatonin-Related Signatures in Tumor Immunity and the Prognosis of Clear Cell Renal Cell Carcinoma.

Methods: Adopting multiomics data from TCGA and other public datasets, we analysed the expression, mutation, and prognostic evaluation in multiple cancers. ccRCC patients were categorized into two subgroups by an unsupervised cluster algorithm: melatonin-pattern cancer subtype 1 (MPCS1) and subtype 2 (MPCS2). We then explored the immune microenvironment, immune therapy response, and tumor metabolic pathways between the two subtypes. The clinical characteristics, genomic mutation landscape, and molecular inhibitor response were further investigated. Finally, a melatonin regulator-related prognostic model was constructed to predict patient prognosis in ccRCC. Results: We found that melatonin regulators were dysregulated depending on distinct cancer types, which were associated with genomic variation. The two subtypes indicated different clinical characteristics and biological processes in ccRCC. MPCS2, an aggressive subtype, led an advanced clinical stage and poorer survival of ccRCC patients. The activated oncogenic signaling pathway and metabolic signatures were responsible for cancer progression in the MPCS2 subtype. The MPCS2 subgroup suggested a higher tumor mutational burden and immune dysfunction state, resulting in a lower response to immunotherapy. The copy number variations of MPCS2 were significantly more frequent than those of MPCS1. In addition, the two subgroups exhibited distinct drug responsiveness, with MPCS2 being less responsive to multiple drugs. Finally, we established a subtype biomarker-based prognostic risk model that exhibited satisfactory performance in ccRCC patients. Conclusion: Melatonin regulator-related features could remodel functional pathways and the tumor immune microenvironment through genomic mutations and pathway regulation. Melatonin regulator-associated molecular subtypes enhance the understanding of the molecular characteristics of renal cancer and can guide clinical treatment. Activating the melatonergic system axis may improve the effect of immunotherapy for ccRCC.

Cervical Anatomical Landmarks Indicate the Amount of Vertebra Resection during ACAF Surgery: A Semi-Quantitative Anatomical Parameter Study on Imaging Data.

OBJECTIVE: With the innovation and development of cervical spine surgical procedures, there is currently a lack of new and reliable data on cervical anatomical landmarks. The purpose of this study is to measure the CT data of the cervical vertebrae of healthy volunteers, so as to make up for the missing part of the measured value of cervical vertebra bone markers, and provide data support for the safety and accuracy of anterior controllable antedisplacement and fusion (ACAF) surgery. METHODS: From January 2019 to January 2020, the cervical computed tomography (CT) scan image data of volunteers in Changhai Hospital and Zhabei Hospital were randomly selected. The radiological parameters included three parameters were measured in the upper lamina plane. a: the distance from the anterior edge of the vertebral body to the anterior edge of the bilateral uncinate joint; c1: the sagittal diameter of the vertebral body; and d: the distance between the anterior edge of the uncinate joint. Three parameters were measured in the pedicle plane. b: the vertical distance from the anterior edge of the vertebral body to the junction line between the two lateral processes; c2: the sagittal diameter of the vertebral body; e: the transverse diameter of the vertebral body; and f: the sagittal diameter of the vertebral canal. The correlation ratios were calculated: a/c1, b/c2, a/f, b/f, d/e. The data between the two groups were compared by independent sample t-test. RESULTS: Finally, 51 patients were included in this study, 18 males and 33 females, with an average age of 47.9 years (21-72 years). The maximum values of seven parameters measured were all at C7. The minimum b value was at C5, and the minimum f value was at C4. The minimum values of the other five parameters were all at C3, and there was an increasing relationship from C3 to C7 (P < 0.05). There was significant difference between male and female with regard to c1, c2, e and d values (P < 0.05). No significant differences were observed between men and women regard to the ratio of related parameters (a/c1, b/c2, a/f, b/f, d/e). CONCLUSIONS: Anatomical consideration of this area is useful to estimate amount of vertebral body resection when performing the bony cut made in ACAF surgery; however, pre-operative examinations with appropriate radiographic analysis are also recommended.

Definition and verification of novel metastasis and recurrence related signatures of ccRCC: A multicohort study.

Background: Cancer metastasis and recurrence remain major challenges in renal carcinoma patient management. There are limited biomarkers to predict the metastatic probability of renal cancer, especially in the early-stage subgroup. Here, our study applied robust machine-learning algorithms to identify metastatic and recurrence-related signatures across multiple renal cancer cohorts, which reached high accuracy in both training and testing cohorts. Methods: Clear cell renal cell carcinoma (ccRCC) patients with primary or metastatic site sequencing information from eight cohorts, including one out-house cohort, were enrolled in this study. Three robust machine-learning algorithms were applied to identify metastatic signatures. Then, two distinct metastatic-related subtypes were identified and verified; matrix remodeling associated 5 (MXRA5), as a promising diagnostic and therapeutic target, was investigated in vivo and in vitro. Results: We identified five stable metastasis-related signatures (renin, integrin subunit beta-like 1, MXRA5, mesenchyme homeobox 2, and anoctamin 3) from multicenter cohorts. Additionally, we verified the specificity and sensibility of these signatures in external and out-house cohorts, which displayed a satisfactory consistency. According to these metastatic signatures, patients were grouped into two distinct and heterogeneous ccRCC subtypes named metastatic cancer subtype 1 (MTCS1) and type 2 (MTCS2). MTCS2 exhibited poorer clinical outcomes and metastatic tendencies than MTCS1. In addition, MTCS2 showed higher immune cell infiltration and immune signature expression but a lower response rate to immune blockade therapy than MTCS1. The MTCS2 subgroup was more sensitive to saracatinib, sunitinib, and several molecular targeted drugs. In addition, MTCS2 displayed a higher genome mutation burden and instability. Furthermore, we constructed a prognosis model based on subtype biomarkers, which performed well in training and validation cohorts. Finally, MXRA5, as a promising biomarker, significantly suppressed malignant ability, including the cell migration and proliferation of ccRCC cell lines in vitro and in vivo. Conclusions: This study identified five robust metastatic signatures and proposed two metastatic probability clusters with stratified prognoses, multiomics landscapes, and treatment options. The current work not only provided new insight into the heterogeneity of renal cancer but also shed light on optimizing decision-making in immunotherapy and chemotherapy.

A morphology-based nephrometry score to predict pathological upstaging to T3 renal cell carcinoma.

Background: Patients with clinical T1-2 renal cell carcinoma (RCC) upstaging to pathological T3 showed worse survival prognosis than those without upstaging. We aimed to develop and validate a morphology-based nephrometry scoring system for predicting pathological upstaging to T3 of RCC. Methods: We retrospectively reviewed 200 patients with clinical T1-2 RCC who underwent surgical treatment. The nephrometry scores were measured through preoperative computed tomography images. The risk factors of pathological upstaging were identified by logistic regression models. The predictive accuracy of a novel morphology-based nephrometry scoring system (M-Index), was compared with R.E.N.A.L (radius, exophytic/endophytic, nearness, anterior/posterior, location), PADUA (preoperative aspects and dimensions used for an anatomic classification), DAP (diameter, axial, polar) and C-Index scores. Results: The upstaging rate of the population was 17% (34 out of 200 patients). The upstaging and non-upstaging groups were comparable in terms of age, gender ratio, body mass index, tumor laterality, and pathological type, while the upstaging group tended to have large tumor diameter, irregular tumor morphology, inner tumor location, and short polar and axial distance. Large tumor diameter refers to larger than 5 cm, while irregular tumor morphology refers to not regular shapes such as round, oval, or lobular. Univariate and multivariate logistic regression analyses showed that tumor morphology [odds ratio (OR) 3.26, 95% confidence interval (CI): 1.79-5.97] and tumor rim location (OR 2.95, 95% CI: 1.16-7.46) were independent risk factors for pathological upstaging. The receiver operating characteristic curve and decision curve analysis (DCA) demonstrated the novel M-Index based on tumor morphology and rim location outperformed R.E.N.A.L, PADUA, DAP, and C-Index in the prediction of pathological upstaging (area under curve 0.756 vs. 0.728 vs. 0.641 vs. 0.661 vs. 0.743). Conclusions: Consisting of fewer non-complex parameters, the M-Index is an intuitive and practical tool with satisfactory predictive power for pathological upstaging to T3 in RCC patients undergoing surgery.

Clinical Correlation of Prostatic Calculi With Semen Parameters in Adult Men With Fertility Intention.

To investigate the correlation of prostatic calculi (PC) with semen parameters in men with fertility intention, this retrospective case-control study enrolled 1,303 participants ranging from 20 to 59 years old; 725 were diagnosed with PC using abdominal ultrasonography. Patients with PC were classified into the type A calculi group (discrete and small echoes) and type B calculi group (coarse and large masses of multiple echoes). Five hundred and seventy-eight men without PC were recruited for the control group. The clinical data of each group were collected and analyzed. The total motility was significantly lower for subjects with type B calculi (41.84% ± 17.50%) than for subjects in the type A calculi (51.78% ± 20.84%; p < .001) and control (54.47% ± 20.74%; p < .001) groups. The percentage of progressively motile was significantly lower for the type B calculi (31.66% ± 14.68%) group than the type A calculi (40.17% ± 17.09%; p < .001) and control (41.83% ± 17.05%; p < .001) groups. The results of the hypo-osmotic swelling test yielded significantly lower percentages in the type B calculi group (59.88% ± 17.13%) than the type A calculi (65.28 ± 14.43%; p = .005) and control (66.92 ± 16.12%; p < .001) groups. The type B calculi group had a significantly higher percentage of round cell concentration than control (4.5% vs. 1.0%; p = .007) did. Small and discrete PC may not influence semen quality among adult men with fertility intention, but larger and coarser PC are associated with decreased sperm motility.

Predictive significance of serum inhibin B on testicular haploid gamete retrieval outcomes in nonobstructive azoospermic men.

The purpose of this study was to determine the diagnostic accuracy of serum inhibin B (INHB) as a predictor of the retrieval outcome of testicular haploid gametes (spermatids and testicular spermatozoa) in nonobstructive azoospermic men. Serum hormone levels, testicular volume, and histological evaluation were performed in 403 Chinese nonobstructive azoospermic men. Testicular haploid gamete was successfully retrieved in 213 of 403 patients (52.85%). The haploid gamete group always had higher INHB levels than the non-haploid gamete group. According to the receiver operating characteristic (ROC) curve analysis, INHB was a good predictor of testicular haploid gamete retrieval outcome in all patients (sensitivity: 77.93% and specificity: 91.58%) and patients with normal follicle-stimulating hormone (FSH; sensitivity: 88.52% and specificity: 70.83%). The area under the ROC curve (AUC) of INHB was similar to that of FSH in all patients or patients with normal FSH. In patients with elevated FSH, INHB was superior to FSH in predicting the presence of haploid gamete (AUC: 0.73 vs 0.55, P < 0.05), with a sensitivity of 60.00% and a specificity of 80.28%. It concluded that serum INHB as an effective marker for spermatogenesis was a significant predictor of testicular haploid gamete retrieval outcomes in nonobstructive azoospermic men. Especially, INHB is superior to FSH in predicting the presence of haploid gamete in the patients with elevated FSH.

Clinical effect of Jiutengzhuyu tablets on promoting blood circulation in women with oviducal obstruction.

OBJECTIVE: To test the clinical curative effect of Jiutengzhuyu tablets, a patented Chinese vine-derived drug used for promoting blood circulation, on women with oviducal obstruction. METHODS: Patients with tubal infertility were divided randomly into two groups: 58 patients in the treatment group and 57 in a control group. The treated patients took Jiutengzhuyu tablets orally for 25 days. The control group received an intrauterine infusion of 5 mg dexamethasone sodium phosphate, 4000 units of chymotrypsin, 80 000 units of gentamicin sulfate dissolved in 20 mL of normal saline at 1 mL/min. After 3 months of treatment, the curative effect on tubal patency was assessed and a 1-year follow-up visit was used to document any pregnancies. RESULTS: The total effective rate was 78% in the treatment group and 32% in the control group with a statistically significant difference (chi2 = 24.57, P < 0.01). CONCLUSION: Jiutengzhuyu was effective in treating infertility caused by tubal infertility with a Traditional Chinese Medicine diagnosis of blood stasis.