Metabolic reprogramming based on RNA sequencing of gemcitabine-resistant cells reveals the FASN gene as a therapeutic for bladder cancer.

Bladder cancer (BLCA) is the most frequent malignant tumor of the genitourinary system. Postoperative chemotherapy drug perfusion and chemotherapy are important means for the treatment of BLCA. However, once drug resistance occurs, BLCA develops rapidly after recurrence. BLCA cells rely on unique metabolic rewriting to maintain their growth and proliferation. However, the relationship between the metabolic pattern changes and drug resistance in BLCA is unclear. At present, this problem lacks systematic research. In our research, we identified and analyzed resistance- and metabolism-related differentially expressed genes (RM-DEGs) based on RNA sequencing of a gemcitabine-resistant BLCA cell line and metabolic-related genes (MRGs). Then, we established a drug resistance- and metabolism-related model (RM-RM) through regression analysis to predict the overall survival of BLCA. We also confirmed that RM-RM had a significant correlation with tumor metabolism, gene mutations, tumor microenvironment, and adverse drug reactions. Patients with a high drug resistance- and metabolism-related risk score (RM-RS) showed more active lipid synthesis than those with a low RM-RS. Further in vitro and in vivo studies were implemented using Fatty Acid Synthase (FASN), a representative gene, which promotes gemcitabine resistance, and its inhibitor (TVB-3166) that can reverse this resistance effect.

Cellular senescence and metabolic reprogramming model based on bulk/single-cell RNA sequencing reveals PTGER4 as a therapeutic target for ccRCC.

Clear cell renal cell carcinoma (ccRCC) is the prevailing histological subtype of renal cell carcinoma and has unique metabolic reprogramming during its occurrence and development. Cell senescence is one of the newly identified tumor characteristics. However, there is a dearth of methodical and all-encompassing investigations regarding the correlation between the broad-ranging alterations in metabolic processes associated with aging and ccRCC. We utilized a range of analytical methodologies, such as protein‒protein interaction network analysis and least absolute shrinkage and selection operator (LASSO) regression analysis, to form and validate a risk score model known as the senescence-metabolism-related risk model (SeMRM). Our study demonstrated that SeMRM could more precisely predict the OS of ccRCC patients than the clinical prognostic markers in use. By utilizing two distinct datasets of ccRCC, ICGC-KIRC (the International Cancer Genome Consortium) and GSE29609, as well as a single-cell dataset (GSE156632) and real patient clinical information, and further confirmed the relationship between the senescence-metabolism-related risk score (SeMRS) and ccRCC patient progression. It is worth noting that patients who were classified into different subgroups based on the SeMRS exhibited notable variations in metabolic activity, immune microenvironment, immune cell type transformation, mutant landscape, and drug responsiveness. We also demonstrated that PTGER4, a key gene in SeMRM, regulated ccRCC cell proliferation, lipid levels and the cell cycle in vivo and in vitro. Together, the utilization of SeMRM has the potential to function as a dependable clinical characteristic to increase the accuracy of prognostic assessment for patients diagnosed with ccRCC, thereby facilitating the selection of suitable treatment strategies.

Modified Y-V plasty based on MRU evaluation for iatrogenic bladder outlet obliteration: a multicentre experience in China.

PURPOSE: To compare the diagnostic ability of traditional radiographic urethrography and magnetic resonance urethrography (MRU) for iatrogenic bladder outlet obliteration (BOO), and explore the efficacy and complications of laparoscopic modified Y-V plasty for patients selected based on MRU evaluation. METHODS: 31 patients with obliteration segments ≤ 2 cm and no false passages or diverticula based on MRU evaluation from eight centers in China were included. Obliteration segments were measured preoperatively by MRU and conventional RUG/VCUG and compared with intra-operative measurements. Surgical effects were evaluated by uroflow rates, urethrography, or cystoscopy at 1, 3, 6, and 12 months post-operation and then every 12 months. Postoperative urinary continence was assessed by 24-h urine leakage (g/day). RESULTS: The results showed that MRU measured the length of obliteration more accurately than RUG/VCUG (MRU 0.91 ± 0.23 cm, RUG/VCUG 1.72 ± 1.08 cm, Actual length 0.96 ± 0.36 cm, p < 0.001), and clearly detected false passages and diverticula. Laparoscopic Y-V plasty was modified by incisions at 5 and 7 o'clock positions and double-layer suture with barbed sutures. All operations were successfully completed within a median time of 75 (62-192) minutes and without any complications. Urethral patency and urinary continence rates were 90.3% (28/31) and 87.1% (27/31), respectively. Three recurrences were cured by direct visual internal urethrotomy. Four patients had stress urinary incontinence after catheter removal 14 days post-operation, with urine leakage of 80-120 g/day, not relieved during follow-up. CONCLUSIONS: Laparoscopic modified Y-V plasty based on MRU evaluation is a promising approach for iatrogenic BOO, with a high patency rate and a low incontinence rate.

Lasers versus bipolar technology in the transurethral treatment of benign prostatic enlargement: a systematic review and meta-analysis of comparative studies.

PURPOSE: To systematically review studies comparing the overall efficacy and safety of lasers and bipolar technology for the transurethral treatment of benign prostatic enlargement (BPE). METHODS: A systematic review of the literature was completed in February 2018. Studies with comparative data between different lasers and bipolar technologies (enucleation or resection) were included in this review. A meta-analysis was performed using STATA 14.0, and subgroup analyses were also performed regarding the type of laser (holmium, thulium, green light and diode). RESULTS: 27 studies with 31 published articles (4382 patients) were selected for the meta-analysis. Compared with bipolar technology, lasers demonstrated shorter catheterization duration (standardized mean difference (SMD): 1.44; 95% CI 1.07-1.81; p < 0.001) and shorter hospital stay (SMD: 1.16; 95% CI 0.83-1.49; p < 0.001), and a smaller drop in hemoglobin (Hb) level (SMD: 0.86; 95% CI 0.47-1.26; p < 0.001). However, significant heterogeneity was detected in the studies and statistical significance was lost on sub-analyses. Furthermore, there were no significant differences between lasers and bipolar technology in the maximum flow rate (Qmax) and international prostate symptom score (IPSS) at a minimum of 3 months after treatment. Complications, including urethral stricture, urinary incontinence, urinary tract infection, re-catheterization and blood transfusion, did not significantly differ between lasers and bipolar technology. CONCLUSION: Early efficacy and safety profiles were comparable between bipolar and laser treatments. Differences were observed in terms of smaller reduction in Hb, shorter catheterization duration and shorter hospital stay in favor of lasers. However, the smaller reduction in Hb, with lasers, did not translate into reduced transfusion requirements. Furthermore, there was significant heterogeneity in the studies and, in subgroup analyses, the differences were not statistically significant.

Mettl14 inhibits bladder TIC self-renewal and bladder tumorigenesis through N6-methyladenosine of Notch1.

BACKGROUND: N6-methyladenosine (m6A) emerges as one of the most important modification of RNA. Bladder cancer is a common cancer type in developed countries, and hundreds of thousands of bladder cancer patients die every year. MATERIALS AND METHODS: There are various cells in bladder tumor bulk, and a small population cells defined as tumor initiating cells (TIC) have self-renewal and differentiation capacities. Bladder TICs drive bladder tumorigenesis and metastasis, and their activities are fine regulated. However, the role of N6-methyladenosine in bladder TIC self-renewal is unknown. RESULTS: Here, we found a decrease of N6-methyladenosine in bladder tumors and bladder TICs. N6-methyladenosine levels are related to clinical severity and outcome. Mettl14 is lowly expressed in bladder cancer and bladder TICs. Mettl14 knockout promotes the proliferation, self-renewal, metastasis and tumor initiating capacity of bladder TICs, and Mettl14 overexpression exerts an opposite role. Mettl14 and m6A modification participate in the RNA stability of Notch1 mRNA. Notch1 m6A modification inhibits its RNA stability. Notch1 plays an essential role in bladder tumorigenesis and bladder TIC self-renewal. CONCLUSION: This work reveals a novel role of Mettl14 and N6-methyladenosine in bladder tumorigenesis and bladder TICs, adding new layers for bladder TIC regulation and N6-methyladenosine function.

[Clinical characterization of testicular yolk sac tumor in children and adults].

OBJECTIVE: To compare the clinical characteristics of simple testicular yolk sac tumor (YST) in children with those in adults so as to improve the diagnosis and treatment of the malignance. METHODS: This study included 75 cases of simple testicular YST pathologically confirmed between May 2008 and July 2018, which were divided into groups A (aged <18 years, n = 64) and B (aged ≥18 years, n = 11). We analyzed the clinical data on all the cases and compared the clinical manifestations, laboratory results, pathological findings, clinical stages, treatment methods and prognostic outcomes between the two groups of patients. RESULTS: The patients of group A ranged in age from 6 months to 5 years (ï¼»1.38 ± 0.89ï¼½ yr), with the tumor diameter of 0.9－6.0 (2.48 ± 1.12) cm, while those of group B from 25 to 49 years (median 34 years), with the tumor diameter of 3.5－6.3 (5.16 ± 1.32) cm, most presenting with a painless scrotal mass, 4 (6.2%) in group A and 5 (45.5%) in group B with testis pain. There were statistically significant differences between the two groups in the tumor diameter and initial manifestations (P < 0.05). All the patients were treated by radical high-level spermatectomy and orchiectomy and, in addition, 1 in group A and 3 in group B by retroperitoneal lymph node dissection (RPLND), 24 in the former and 5 in the latter group followed by chemotherapy. Elevated levels of serum alpha-fetoprotein (AFP) were observed in all the cases. Sixty-five of the patients were followed up for 10－78 (52.00 ± 23.78) months, during which 2 cases of simple metastasis, 3 cases of simple relapse, 3 cases of relapse with metastasis and 5 cases of death were found in group A, and 5 cases of simple metastasis, 1 case of simple relapse, 1 case of relapse with metastasis and 4 cases of death in group B. CONCLUSIONS: There are significant differences in the clinical manifestation, biological behavior, treatment and prognosis of testicular YST between children and adults. In children, most of the testicular YST cases are at clinical stage I and preferably treated by radical high-level spermatectomy and orchiectomy with favorable prognosis. In adults, however, the tumor is highly malignant, with high incidences of recurrence and metastasis and poor prognosis, for the treatment of which the first choice is radical high-level spermatectomy and orchiectomy combined with RPLND and chemotherapy.

MKP2 inhibits TGF-ß1-induced epithelial-to-mesenchymal transition in renal tubular epithelial cells through a JNK-dependent pathway.

Epithelial-to-mesenchymal transition (EMT) is a phenotypic conversion that plays a crucial role in renal fibrosis leading to chronic renal failure. Mitogen-activated protein kinase phosphatase 2 (MKP2) is a member of the dual-specificity MKPs that regulate the MAP kinase pathway involved in transforming growth factor-ß1 (TGF-ß1)-induced EMT. However, the function of MKP2 in the regulation of EMT and the underlying mechanisms are still largely unknown. In the present study, we detected the expression of MKP2 in an animal model of renal fibrosis and evaluated the potential role of MKP2 in tubular EMT induced by TGF-ß1. We found that the expression of MKP2 was up-regulated in the tubular epithelial of unilateral ureter obstruction rats. Meanwhile, we also demonstrated that TGF-ß1 up-regulated MKP2 expression in NRK-52E cells during their EMT phenotype acquisition. Importantly, overexpression of MKP2 inhibited c-Jun amino terminal kinase (JNK) signaling and partially reversed EMT induced by TGF-ß1. Moreover, reducing MKP2 expression enhanced JNK phosphorylation, promoted the E-cadherin suppression and induced α-SMA expression and fibronectin secretion in response to TGF-ß1, which could be rescued by a JNK inhibitor. These results provide the first evidence that MKP2 is a negative feedback molecule induced by TGF-ß1, and MKP2 overexpression inhibits TGF-ß1-induced EMT through the JNK signaling pathway. MKP2 could be a promising target to be used in gene therapy for renal fibrosis.

NDRG2 knockdown promotes fibrosis in renal tubular epithelial cells through TGF-ß1/Smad3 pathway.

Renal fibrosis is a common pathological pathway of various chronic kidney diseases progressing to end-stage renal disease and is characterized by tubular atrophy, fibroblast/myofibroblast activation and excessive deposition of extracellular matrix (ECM). N-Myc downstream-regulated gene-2 (NDRG2) is reported to be associated with liver fibrosis in rats. However, the biological function of NDRG2 in renal fibrosis remains unclear. Therefore, we investigate the effect of NDRG2 on renal fibrosis and the underlying mechanism of NDRG2 in TGF-ß1-induced renal tubular epithelial cells (HK-2). Our results show that TGF-ß1 down-regulates NDRG2 mRNA and protein expression in HK-2 cells. Moreover, NDRG2 knockdown dramatically reduces the TGF-ß1-induced protein and mRNA of E-cadherin and increases the TGF-ß1-induced protein and mRNA expression level of α-SMA, Vimentin, Snail, Col-I, Col-III and FN; this is reversed by NDRG2 overexpression. Furthermore, NDRG2 silencing significantly increases the phosphorylation level of Smad3 (p-Smad3), which is decreased by NDRG2 overexpression, although these have no effect on the protein expression of p-Smad2 and Smad7. In addition, SIS3, a specific inhibitor of Smad3 phosphorylation, partly reverses the effect of NDRG2 knockdown on the protein and mRNA expression of epithelial-mesenchymal transition (EMT) markers and ECM components in TGF-ß1-induced HK-2 cells. Taken together, our results indicate that NDRG2 knockdown promotes renal fibrosis through its effect on the protein and mRNA expression of EMT markers and ECM components by regulating the downstream Smad3 signaling pathway in renal tubular epithelial cells. Modulation of NDRG2 expression might provide a new therapy for renal fibrosis.

Pirfenidone suppresses MAPK signalling pathway to reverse epithelial-mesenchymal transition and renal fibrosis.

AIM: Recent studies indicate that pirfenidone (PFD) may have anti-fibrotic effects in many tissues, but the potential molecular mechanism remains unknown. The purpose of this study is to investigate the potential effects of PFD on epithelial-to-mesenchymal transition (EMT) and renal fibrosis in a unilateral ureteral obstruction (UUO) rat model and the involved molecular mechanism related to cultured human renal proximal tubular epithelial cells (HK-2). METHODS: Sixty rats were randomly divided into three groups: sham-operated, vehicle-treated UUO, and PFD-treated UUO. Kidney specimens were collected at day 7 or 14 after UUO. PFD treatment was also performed for human HK-2. The tubulointerstitial injury, interstitial collagen deposition, and expression of type I and III collagen, α-SMA, S100A4, fibronection and E-cadherin were assessed. In addition, extracellular signal regulated kinase (ERK1/2), p38 MAPK (p38), and c-Jun N-terminal kinase/stress-activated protein kinase (JNK) were also detected. RESULTS: In vitro, PFD significantly attenuated TGF-ß1-induced EMT and extracellular matrix (ECM) synthesis, as determined by reducing expression of α-SMA, type I and III collagen, S100A4, fibronection, and increased expression of E-cadherin. PFD treatment attenuated TGF-ß1-induced up-regulation of phosphorylation of ERK1/2, p38 and JNK. In vivo, PFD reduced the degree of tubulointerstitial injury and renal fibrosis, which was associated with reduced expression of TGF-ß1, type III collagen, α-SMA, S100A4, fibronection, and increased expression of E-cadherin. CONCLUSION: These results suggest that pirfenidone is able to attenuate EMT and fibrosis in vivo and in vitro through antagonizing the MAPK pathway, providing a potential treatment to alleviate renal tubulointerstitial fibrosis.

Primary Ewing's Sarcoma/Primitive Neuroectodermal Tumor of Kidney with Caval Involvement in a Pregnant Woman.

In this article, we report the case of a woman in whom was found an abdominal mass during pregnancy and who underwent nephrectomy and extraction of the emboli after delivery. The kidney had a volume of 15 × 10 × 8 cm and pathological diagnosis was primary Ewing's sarcoma. The patient was treated with conventional chemotherapy for 1 year after surgery, at which time multiple metastases were found. From this case, we surmise that hormonal changes that occur during pregnancy may accelerate the growth of Ewing's sarcoma of the kidney, suggesting that renal tumors in pregnant women demand serious attention and that anti-cancer treatment should begin as soon as possible.

Urinary Emmprin, matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 as potential biomarkers in children with ureteropelvic junction narrowing on conservative treatment.

BACKGROUND: Rapid diagnosis and initiation of the treatment on congenital obstructive nephropathy are important for young children to slow down renal injury. The aim of our study was to investigate the role of urinary extracellular matrix metalloproteinase inducer (Emmprin), matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) in the long-term follow-up of children with ureteropelvic junction (UPJ) narrowing on conservative treatment. METHODS: The study included 40 children with non-obstructed hydronephrosis due to unilateral UPJ narrowing who were treated conservatively and followed up for 24 months. Voided urine samples were collected at diagnosis and at 3, 9, 15 and 24 months of follow-up, respectively. Three enzymes concentrations were measured in urine. RESULTS: During the follow-up, 25 children showed renal function stabilization (non-obstructed group) and 15 children renal function deterioration (obstructed group). In the non-obstructed group, a comparison between urine three enzymes levels at the last follow-up and at baseline showed no significant differences (all P > 0.05). Glomerular filtration rate (GFR) and split renal function (SRF) showed similar trends. In the obstructed group, a comparison between the three enzymes levels at diagnosis and at basal condition showed a significant increase (all P < 0.01). But GFR and SRF showed a marked reduction at diagnosis (all P < 0.001). Receiver operator characteristic (ROC) analyses revealed a better diagnostic profile for uEmmprin, uMMP-9 and uTIMP-1 in identifying children with abnormal SRF (<40%) at 24 months of follow-up [area under the curve (AUC) 0.877, 0.727 and 0.823, respectively]. CONCLUSIONS: Urinary Emmprin, MMP-9 and TIMP-1 may be noninvasive potential biomarkers that could be used for long-term follow-up of children with UPJ narrowing on conservative treatment to determine those who might develop obstruction.

Introducing the Quill™ device for modified sleeve circumcision with subcutaneous suture: a retrospective study of 70 cases.

OBJECTIVE: The purpose of the study was to evaluate the safety and feasibility of treatment for male circumcision using modified sleeve circumcision and subcuticular suture with the Quill™ device. METHODS: From May 2011 to March 2012, 70 consecutive cases of male circumcision were performed using an alternative technique with the Quill™ device by a single surgeon in our institution. The inclusion and exclusion criteria for the selection process of this procedure were the same as for conventional circumcision. We evaluated the indications and perioperative outcomes. The circumcisions were performed as day-case procedures under local anesthesia. RESULTS: All patients were followed up for a minimum of 3-6 months. The ages ranged from 8 to 68 (mean = 27.0 years, SD = 10). The indications for surgery were either cosmetic (n = 16, 22.9%) or medical [redundant prepuce (n = 36, 51.4%), phimosis (n = 5, 7.1%), paraphimosis (n = 2, 2.9%), balanoposthitis (n = 9, 12.9%), melanoma (n = 1, 1.4%), and condyloma acuminata (n = 1, 1.4%)] (n = 54, 77.1%). The mean operation time in this group was 29 min (19-38 min) when the Quill™ device was used. In all, 3 cases developed complications (4.3%). The final cosmetic result was satisfactory for both the patients and their spouses or parents. CONCLUSION: This study showed that modified sleeve circumcision and subcuticular suture were safe and reliable surgical methods of circumcision that provide a better cosmetic result.

Quantitative assessment of the association between miR-196a2 rs11614913 polymorphism and cancer risk: evidence based on 45,816 subjects.

MicroRNAs (miRNAs) are small non-coding RNA molecules, which participate in diverse biological processes and may regulate tumor suppressor genes or oncogenes. Single nucleotide polymorphisms (SNPs) in miRNA may contribute to diverse functional consequences, including cancer development, by altering miRNA expression. Numerous studies have shown the association between miR-196a2 rs11614913 SNPs and cancer risk; however, the results are generally debatable and inconclusive, mainly due to limited statistical power. We carried out a meta-analysis of 46 studies including 20,673 cases and 25,143 controls to assess the association between the miR-196a2 rs11614913 and cancer risk by pooled odds ratios (ORs) and 95 % confidence intervals (CIs). Overall, we found a significant association between the rs11614913 (C > T) polymorphism and cancer susceptibility (recessive model, OR = 0.89, 95 % CI = 0.81-0.98). In the stratified analysis by cancer type, significant association of cancer risk was observed in lung cancer (allelic contrast, OR = 0.89, 95 % CI = 0.82-0.97; homozygote comparison, OR = 0.79, 95 % CI = 0.67-0.94; recessive model, OR = 0.84, 95 % CI = 0.74-0.96) and liver cancer (allelic contrast, OR = 0.88, 95 % CI = 0.79-0.99; homozygote comparison, OR = 0.77, 95 % CI = 0.61-0.98; heterozygote comparison, OR = 0.84, 95 % CI = 0.74-0.95; dominant model, OR = 0.82, 95 % CI = 0.73-0.92). During further stratified analysis by ethnicity, the rs11614913 polymorphism showed statistically significant association with increased risks of cancer in Asians (heterozygote model, OR = 1.15, 95 % CI = 1.01-1.30) but not in Caucasians. This meta-analysis suggests that the miR-196a2 rs11614913 polymorphism may contribute to decreased susceptibility to cancer, especially including liver cancer and lung cancer. However, it may be a risk factor for cancer development in Asians. Larger, better studies of homogeneous cancer patients are needed to further assess the correlation between this polymorphism and cancer risk.

Over-expression of testis-specific expressed gene 1 attenuates the proliferation and induces apoptosis of GC-1spg cells.

The effects of over-expression of testis-specific expressed gene 1 (TSEG-1) on the viability and apoptosis of cultured spermatogonial GC-1spg cells were investigated, and the immortal spermatogonial cell line GC-1spg (CRL-2053™) was obtained as the cell model in order to explore the function of TSEG-1. We transfected the eukaryotic vector of TSEG-1, named as pEGFP-TSEG-1 into cultured spermatogonial GC-1spg cells. Over-expression of TSEG-1 inhibited the proliferation of GC-1spg cells, and arrested cell cycle slightly at G0/G1 phase. Transfection of TSEG-1 attenuated the transcript levels of Ki-67, PCNA and cyclin D1. In addition, over-expression of TSEG-1 induced early and late apoptosis, and reduced the mitochondrial membrane potential of GC-1spg cells. Moreover, transfection of TSEG-1 significantly enhanced the ratio of Bax/Bcl-2 and transcript levels of caspase 9, and decreased the expression of Fas and caspase 8 in GC-1spg cells. These results indicated over-expression of TSEG-1 suppresses the proliferation and induces the apoptosis of GC-1spg cells, which establishes a basis for further study on the function of TSEG-1.

Fatty Acid Oxidation Mediated by Malonyl-CoA Decarboxylase Represses Renal Cell Carcinoma Progression.

Fatty acid metabolism reprogramming is a prominent feature of clear cell renal cell carcinoma (ccRCC). Increased lipid storage supports ccRCC progression, highlighting the importance of understanding the molecular mechanisms driving altered fatty acid synthesis in tumors. Here, we identified that malonyl-CoA decarboxylase (MLYCD), a key regulator of fatty acid anabolism, was downregulated in ccRCC, and low expression correlated with poor prognosis in patients. Restoring MLYCD expression in ccRCC cells decreased the content of malonyl CoA, which blocked de novo fatty acid synthesis and promoted fatty acid translocation into mitochondria for oxidation. Inhibition of lipid droplet accumulation induced by MLYCD-mediated fatty acid oxidation disrupted endoplasmic reticulum and mitochondrial homeostasis, increased reactive oxygen species levels, and induced ferroptosis. Moreover, overexpressing MLYCD reduced tumor growth and reversed resistance to sunitinib in vitro and in vivo. Mechanistically, HIF2α inhibited MLYCD translation by upregulating expression of eIF4G3 microexons. Together, this study demonstrates that fatty acid catabolism mediated by MLYCD disrupts lipid homeostasis to repress ccRCC progression. Activating MLYCD-mediated fatty acid metabolism could be a promising therapeutic strategy for treating ccRCC. SIGNIFICANCE: MLYCD deficiency facilitates fatty acid synthesis and lipid droplet accumulation to drive progression of renal cell carcinoma, indicating inducing MYLCD as a potential approach to reprogram fatty acid metabolism in kidney cancer.

Urinary heme oxygenase-1 in children with congenital hydronephrosis due to ureteropelvic junction obstruction.

CONTEXT: Heme oxygenase-1 (HO-1) is implicated to be correlated with renal function in oxidative stress. OBJECTIVE: To determine whether urinary (u) HO-1 is associated with the progression of congenital obstructive hydronephrosis (HN). METHODS: A total 50 children with HN (study group and control 1) and 30 healthy children were enrolled in this study. RESULTS: The uHO-1/cr levels increased significantly and negatively correlated with split renal function in study group before and during surgery. One month after surgery, it decreased significantly. CONCLUSION: Increased uHO-1 levels could be a potential biomarker for evaluating the progression of obstructive nephropathy.

A Metabolism-Related Gene Landscape Predicts Prostate Cancer Recurrence and Treatment Response.

Background: Prostate cancer (PCa) is the most common malignant tumor in men. Although clinical treatments of PCa have made great progress in recent decades, once tolerance to treatments occurs, the disease progresses rapidly after recurrence. PCa exhibits a unique metabolic rewriting that changes from initial neoplasia to advanced neoplasia. However, systematic and comprehensive studies on the relationship of changes in the metabolic landscape of PCa with tumor recurrence and treatment response are lacking. We aimed to construct a metabolism-related gene landscape that predicts PCa recurrence and treatment response. Methods: In the present study, we used differentially expressed gene analysis, protein-protein interaction (PPI) networks, univariate and multivariate Cox regression, and least absolute shrinkage and selection operator (LASSO) regression to construct and verify a metabolism-related risk model (MRM) to predict the disease-free survival (DFS) and response to treatment for PCa patients. Results: The MRM predicted patient survival more accurately than the current clinical prognostic indicators. By using two independent PCa datasets (International Cancer Genome Consortium (ICGC) PCa and Taylor) and actual patients to test the model, we also confirmed that the metabolism-related risk score (MRS) was strongly related to PCa progression. Notably, patients in different MRS subgroups had significant differences in metabolic activity, mutant landscape, immune microenvironment, and drug sensitivity. Patients in the high-MRS group were more sensitive to immunotherapy and endocrine therapy, while patients in the low-MRS group were more sensitive to chemotherapy. Conclusions: We developed an MRM, which might act as a clinical feature to more accurately assess prognosis and guide the selection of appropriate treatment for PCa patients. It is promising for further application in clinical practice.

TSEG-1, a novel member of histone H2A variants, participates in spermatogenesis via promoting apoptosis of spermatogenic cells.

A novel variant of histone H2A, named as testis specific expressed gene 1 (TSEG-1, approved symbol: H2afb1), was identified from adult mouse testis. The TSEG-1 gene is 610-bp in length and consists of one exon. TSEG-1 transcript was robustly and exclusively expressed in adult mouse testis, mainly in spermatocytes. In developmental testis, the TSEG-1 transcript was robustly expressed since postnatal day (P) 21, peaked at P30, and gradually decreased in the testis of aging mouse. The surgical cryptorchidism mouse model showed an increase in the TSEG-1 expression, accompanied by enhanced apoptosis of spermatogenic cells. The EGFP-tagged TSEG-1 protein is located in the nuclei of cultured spermatocytes (GC-2spd cells). Transfection of TSEG-1 into GC-2spd cells resulted in suppressed cell viabilities, increased apoptosis, and decreased mitochondrial membrane potential. Intratesticular injection of TSEG-1 resulted in increased apoptosis of spermatogenic cells in vivo. These results suggest that TSEG-1 may participate in the spermatogenesis via regulating the apoptosis of spermatogenic cells.

Bioinformatics Analysis of GFAP as a Potential Key Regulator in Different Immune Phenotypes of Prostate Cancer.

Tumor immune escape plays an essential role in both cancer progression and immunotherapy responses. For prostate cancer (PC), however, the molecular mechanisms that drive its different immune phenotypes have yet to be fully elucidated. Patient gene expression data were analyzed from The Cancer Genome Atlas-prostate adenocarcinoma (TCGA-PRAD) and the International Cancer Genome Consortium (ICGC) databases. We used a Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) analysis and an unsupervised clustering analysis to identify patient subgroups with distinct immune phenotypes. These distinct phenotypes were then explored for associations for differentially expressed genes (DEGs) and both epigenetic and genetic landscapes. Finally, we used a protein-protein interaction analysis to identify key hub genes. We identified two patient subgroups with independent immune phenotypes associated with the expression of Programmed death-ligand 1 (PD-L1). Patient samples in Cluster 1 (C1) had higher scores for immune-cell subsets compared to Cluster 2 (C2), and C2 samples had higher specific somatic mutations, MHC mutations, and genomic copy number variations compared to C1. We also found additional cluster phenotype differences for DNA methylation, microRNA (miRNA) expression, and long noncoding RNA (lncRNA) expression. Furthermore, we established a 4-gene model to distinguish between clusters by integrating analyses for DEGs, lncRNAs, miRNAs, and methylation. Notably, we found that glial fibrillary acidic protein (GFAP) might serve as a key hub gene within the genetic and epigenetic regulatory networks. These results improve our understanding of the molecular mechanisms underlying tumor immune phenotypes that are associated with tumor immune escape. In addition, GFAP may be a potential biomarker for both PC diagnosis and prognosis.