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.

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.

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.

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.

Case Report: Two different acromelic dysplasia phenotypes in a Chinese family caused by a missense mutation in FBN1 and a literature review.

Background: Acromelic dysplasia caused by FBN1 mutation includes acromicric dysplasia (AD), geleophysic dysplasia 2 (GD2), and Weill-Marchesani syndrome 2 (WMS2). All three diseases share severe short stature and brachydactyly. Besides phenotypic similarity, there is a molecular genetic overlap among them, as identical FBN1 gene mutations have been identified in patients with AD, GD2, and WMS2. However, no family with different acromelic dysplasia phenotypes due to the same variant has been described in English reports. Case report: The proband presented with typical facial features, severe short stature, short limbs, stubby hands and feet and radiological abnormalities. Her elder sister and mother had similar physical features. In addition, her elder sister was found to have aortic valve stenosis by echocardiography. Mutation analysis demonstrated a heterozygous missense mutation, c.5179C>T (p.Arg1727Trp) in exon 42 of the FBN1. The proband and her mother were diagnosed with AD, and her elder sister with GD2. The proband was treated with recombinant human growth hormone (rhGH) and had a body length gain of 0.72 SDS in half a year. Conclusion: These findings expand the phenotypic spectrum of FBN1 gene mutations and highlight that identical FBN1 genotypes can result in different phenotypes of acromelic dysplasia in a family. The efficacy of rhGH therapy in patients with acromelic dysplasia is controversial. More follow-up is needed on the long-term efficacy of rhGH therapy.

m6A-Mediated Induction of 7-Dehydrocholesterol Reductase Stimulates Cholesterol Synthesis and cAMP Signaling to Promote Bladder Cancer Metastasis.

Dysregulation of cholesterol homeostasis occurs in multiple types of tumors and promotes cancer progression. Investigating the specific processes that induce abnormal cholesterol metabolism could identify therapeutic targets to improve cancer treatment. In this investigation, we observed upregulation of 7-dehydrocholesterol reductase (DHCR7), a vital enzyme involved in the synthesis of cholesterol, within bladder cancer (BC) tissues in comparison to normal tissues, which was correlated with increased BC metastasis. Increased expression of DHCR7 in BC was attributed to decreased mRNA degradation mediated by YTHDF2. Loss or inhibition of DHCR7 reduced BC cell invasion in vitro and metastasis in vivo. Mechanistically, DHCR7 promoted BC metastasis by activating the cAMP/PKA/FAK pathway. Specifically, DHCR7 increased cAMP levels by elevating cholesterol content in lipid rafts, thereby facilitating the transduction of signaling pathways mediated by cAMP receptors. DHCR7 additionally enhanced the cAMP signaling pathway by reducing the concentration of 7-DHC and promoting the transcription of the G protein-coupled receptor GIPR. Overall, these findings demonstrate that DHCR7 plays an important role in BC invasion and metastasis by modulating cholesterol synthesis and cAMP signaling. Furthermore, inhibition of DHCR7 shows promise as a viable therapeutic strategy for suppressing BC invasion and metastasis.

A case report of anti-GAD65 antibody-positive autoimmune encephalitis in children associated with autoimmune polyendocrine syndrome type-II and literature review.

Background: Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme for the synthesis of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Antibodies against glutamic acid decarboxylase (GAD) are associated with various neurologic conditions described in patients, including stiff person syndrome, cerebellar ataxia, refractory epilepsy, and limbic and extra limbic encephalitis. While there are few case reports and research on anti-GAD65 antibody-associated encephalitis in adults, such cases are extremely rare in pediatric cases. Methods: For the first time, we report a case of anti-GAD65-positive autoimmune encephalitis associated with autoimmune polyendocrine syndrome (APS) type II. We reviewed previously published pediatric cases of anti-GAD65 autoimmune encephalitis to discuss their clinical features, laboratory tests, imaging findings, EEG patterns, and prognosis. Case presentation: An 8-year-old, male child presented to the outpatient department after experiencing generalized convulsions for twenty days. The child was admitted for epilepsy and had received oral sodium valproate (500 mg/day) in another center, where investigations such as USG abdomen and MRI brain revealed no abnormalities, however, had abnormal EEG with diffuse mixed activity in the left anterior middle prefrontal temporal region. On the follow-up day, a repeat blood test showed a very low serum drug concentration of sodium valproate hence the dose was increased to 750 mg/day. Then, the child experienced adverse effects including increased sleep, thirst, and poor appetite, prompting the parents to discontinue the medication. A repeat MRI showed increased signals on FLAIR sequences in the right hippocampus hence admitted for further management. The child's past history included a diagnosis of hypothyroidism at the age of 4, and receiving levothyroxine 75 mcg once daily. His parents are healthy with no history of any similar neurological, autoimmune, or genetic diseases, but his uncle had a history of epilepsy. At presentation, he had uncontrolled blood glucose levels with elevated HbA1c levels. Additionally, the serum and CSF autoantibodies were positive against the anti-GAD65 antibody with the titer of 1:100 and 1:32 respectively. The patient was managed with a mixed type of insulin regimen and received first-line immunotherapy (intravenous immunoglobulin, IVIG) for five consecutive days, followed by oral prednisone and sodium valproate as an antiepileptic drug. Upon achieving a favorable clinical outcome, the patient was discharged with oral medications. Results: Among the 15 pediatric patients reported in this literature, nine presented with limbic encephalitis (LE), three with extralimbic encephalitis (ELE), and three with a combination of limbic and extralimbic encephalitis. Most of these cases exhibited T2-W FLAIR hyperintensities primarily localized to the temporal lobes in the early phase, progressing to hippocampal sclerosis/atrophy in the later phase on MRI. EEG commonly showed slow or spike waves on frontotemporal lobes with epileptic discharges. Prognostic factors varied among patients, with some experiencing persistent refractory seizures, type-1 diabetes mellitus (T1DM), persistent memory impairment, persistent disability requiring full assistance, and, in severe cases, death. Conclusion: Our findings suggest that anti-GAD65 antibody-positive autoimmune encephalitis patients may concurrently present with other APS. Our unique case presented with multiple endocrine syndromes and represents the first reported occurrence in children. Early diagnosis and timely initiation of immunotherapy are crucial for improving clinical symptoms and reducing the likelihood of relapses or permanent disabilities. Therefore, emphasis should be placed on prompt diagnosis and appropriate treatment implementation to achieve better patient outcomes.

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.

Caspase-3 mediates apoptosis of striatal cells in GA I rat model.

In previous study, glutaric acid (GA) induced apoptosis of primary striatal neuron in vitro. In order to investigate the neurotoxic effects of GA on neonatal rat corpus striatum and the possible mechanism, 34 male pups were randomly assigned to NS group, low dose GA (LGA, 5 µmol GA/g body weight) group and high dose GA (HGA, 10 µmol GA/g body weight) group. These pups were subcutaneously administered with three injections from postnatal day 3 to 22 at 7:30 am, 15:00 pm and 22:30 pm and killed 12 h after the last injection. Microscopic pathology in corpus striatum was evaluated by HE staining. The apoptotic cells were identified by TUNEL staining. The transcript levels of caspase-3, 8, 9, Bax, Bcl-2 were detected by using real-time PCR and the protein levels of procaspase-3 and the active fraction were evaluated by Western blotting. In LGA and HGA groups, ventricle collapse, cortical atrophy by a macroscope and interstitial edema, vacuolations, widened perivascular space of bilateral striatum by a microscope were observed. TUNEL assay revealed that the apoptotic cells were increased in LGA and HGA groups. The transcript of caspase-3 was up-regulated to 2.5 fold, accompanied by the up-regulation of caspase-9, Bax and down-regulation of Bcl-2. The protein levels of procaspase-3 and the active fraction were up-regulated in LGA and HGA groups. The rat model for GA I showed mitochondrial apoptotic pathway may be involved in the GA-induced striatal lesion. Further studies should be taken to investigate the underlying mechanisms.

Co-Effects of Hydrological Conditions and Industrial Activities on the Distribution of Heavy Metal Pollution in Taipu River, China.

In Taipu River, after being transformed from a drainage channel to a drinking water supply river in 1995, heavy metals that have accumulated in sediments have become an environmental issue. Herein, we collected sediments of Taipu River in 2018, 2020, and 2021 and analyzed the distribution of Sb, As, Cd, Cu, Pb, Cr, and Zn to identify their sources. The results revealed that the mean concentrations of heavy metals were above the background values, except for Cr and As. During the non-flood season, the midstream of Taipu River becomes a heavy metal hotspot, with their concentrations 2-5 times higher than those in upstream sediment. There were significant correlations (r = 0.79-0.99) among drainage, precipitation and flow rate, which indicated that drainage caused by both the opening of Taipu Gate and precipitation control the flow rate and, then, possibly influenced the distribution of heavy metals. Moreover, three sources (industrial sources, particle deposition sources, and natural sources) were characterized as the determinants for the accumulation of heavy metal by the Positive Matrix Factorization model, with the contribution rates of 41.7%, 32.9%, and 25.4%, respectively. It is recommended that the influence of hydrological conditions and industrial activities should be a key consideration when developing regulations for the management of heavy metals in rivers.

Incidence of Newly Diagnosed Type 1 Diabetes Mellitus in Children and Adolescents in Henan Province of China from 2017 to 2020: A Retrospective Multicenter Study Based on Hospitalization Data

Objective: The incidence of type 1 diabetes mellitus (T1DM) is rapidly increasing worldwide. However, the incidence in Henan Province of China has been unknown for more than two decades. This study aimed to estimate the incidence of T1DM in the 0.5-14.9 years age group in Henan Province of China from 2017 to 2020. Methods: A retrospective analysis of hospital registration data from 18 cities in Henan Province, China, identified 1726 patients (843 males, 883 females) between 0.5-14.9 years of age with newly diagnosed T1DM in Henan Province from January 1st, 2017, to December 31st, 2020, covering more than 19 million children years at risk. Results: The crude incidence of T1DM per 100 000 person years for the 0.5-14.9 years age group in the Henan Province of China was 2.19 [95% confidence interval (CI): 1.99, 2.40], with a peak in the 10-14.9 years age group. The rate ratio of females to males was 1.32 (95% CI: 1.20, 1.45) in the 0.5-14.9 years age group. The incidence rate was higher in females than males in the 5-9.9 years age group (p<0.01) and the 10-14.9 years age group (p<0.01). The seasonality of the incidence was different from that in previous reports, with the lowest incidence in the spring. Conclusion: The incidence of T1DM in the 0.5-14.9 years age group in Henan Province was still among the lowest reported globally, but was in line with other incidence rates reported from China.

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.