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Quantifying the supply and demand relationship between human social consumption and natural ecosystem resources is an effective way to assess the sustainability of ecosystem services. This paper introduces the concepts of footprint size (EFsize) and depth (EFdepth) to emergy analysis to establish a three-dimensional emergy ecological footprint (3D EEF) model and evaluates the environmental sustainability development of Gansu Province from 2001 to 2020. The results show that the minimum value of the 3D emergy ecological footprint (EEF3D) of Gansu Province was 5.98 × 107 hm2 and that the maximum value was 1.41 × 108 hm2. The EEFdepth was slightly more than one in 2015 and 2016, and the ecological resources were in deficit. However, the ecological service system from 2001 to 2020 was almost in a sustainable state. The region’s emergy carrying capacity (ECC) and emergy ecological footprint (EEF) from 2021 to 2030 are predicted using the ARIMA and GM (1, 1) models. The projections show that the ECC and EEF will increase year by year from 2021 to 2030. In the short term, the flow of natural capital can satisfy the development requirements. Finally, policy recommendations are provided for the ecological sustainability of the region.

This paper analyzed the differences between the two harvesting periods (Taiju and Duoju) on the ingredients and pharmacological activity in Chrysanthemum morifolium Ramat.

Supplementary Figure S1-S10, supplementary table S1-S8, supplementary methods. Figure S1. The construction of sunitinib-resistant model and validation of sunitinib resistance. Figure S2. Screening and identification of lncRNA IGFL2-AS1 related to sunitinib resistance. Figure S3. IGFL2-AS1 promotes sunitinib resistance of RCC cells in vitro and in vivo. Figure S4. IGFL2-AS1 overexpression enhances autophagy in RCC cells by regulating alternative splicing of TP53INP2. Figure S5. IGFL2-AS1 functions by binding to hnRNPC protein. Figure S6. IGFL2-AS1 regulates alternative splicing of TP53INP2 through competitively binding to hnRNPC. Figure S7. hnRNPC mediates IGFL2-AS1 packaging into EVs and transmission of sunitinib resistance. Figure S8. m6A epigenetic modification is critical to IGFL2-AS1 interaction with hnRNPC. Figure S9. Characteristics of C-SLN nanoparticles and in vivo application of C-SLN/ASO-IGFL2-AS1 complexes. Figure S10. Extended applicability of IGFL2-AS1 to resistance of cabozantinib and axitinib. Supplementary Table S1. Correlations between IGFL2-AS1 tissue expressions and clinical characteristics of 72 ccRCC patients in the SYSU Cohort. Supplementary Table S2. Univariate and multivariate cox regression analysis of variables associated with PFS in the SYSU cohort. Supplementary Table S3. Correlations between IGFL2-AS1 expressions in serum-derived EVs and clinical characteristics of 60 ccRCC patients in the SYSU Cohort. Supplementary Table S4. Uivariate and multivariate cox regression analysis of variables associated with PFS in the SYSU cohort. Supplementary Table S5. Clinical characteristics of RCC patients in the PDX models. Supplementary Table S6. Targeting sequence of siRNA and ASO. Supplementary Table S7. Primers used in this study for qRT-PCR analysis. Supplementary Table S8. Primary antibodies applied in this study.

Sunitinib resistance remains a serious challenge to the treatment of advanced and metastatic renal cell carcinoma (RCC), yet the mechanisms underlying this resistance are not fully understood. Here, we report that the long noncoding RNA IGFL2-AS1 is a driver of therapy resistance in RCC. IGFL2-AS1 was highly upregulated in sunitinib-resistant RCC cells and was associated with poor prognosis in patients with clear cell RCC (ccRCC) who received sunitinib therapy. IGFL2-AS1 enhanced TP53INP2 expression by competitively binding to hnRNPC, a multifunctional RNA-binding protein that posttranscriptionally suppresses TP53INP2 expression through alternative splicing. Upregulated TP53INP2 enhanced autophagy and ultimately led to sunitinib resistance. Meanwhile, IGFL2-AS1 was packaged into extracellular vesicles through hnRNPC, thus transmitting sunitinib resistance to other cells. N6-methyladenosine modification of IGFL2-AS1 was critical for its interaction with hnRNPC. In a patient-derived xenograft model of sunitinib-resistant ccRCC, injection of chitosan-solid lipid nanoparticles containing antisense oligonucleotide-IGFL2-AS1 successfully reversed sunitinib resistance. These findings indicate a novel molecular mechanism of sunitinib resistance in RCC and suggest that IGFL2-AS1 may serve as a prognostic indicator and potential therapeutic target to overcome resistance.Significance:Extracellular vesicle-packaged IGFL2-AS1 promotes sunitinib resistance by regulating TP53INP2-triggered autophagy, implicating this lncRNA as a potential therapeutic target in renal cell carcinoma.

Sunitinib resistance remains a serious challenge to the treatment of advanced and metastatic renal cell carcinoma (RCC), yet the mechanisms underlying this resistance are not fully understood. Here, we report that the long noncoding RNA IGFL2-AS1 is a driver of therapy resistance in RCC. IGFL2-AS1 was highly upregulated in sunitinib-resistant RCC cells and was associated with poor prognosis in patients with clear cell RCC (ccRCC) who received sunitinib therapy. IGFL2-AS1 enhanced TP53INP2 expression by competitively binding to hnRNPC, a multifunctional RNA-binding protein that posttranscriptionally suppresses TP53INP2 expression through alternative splicing. Upregulated TP53INP2 enhanced autophagy and ultimately led to sunitinib resistance. Meanwhile, IGFL2-AS1 was packaged into extracellular vesicles through hnRNPC, thus transmitting sunitinib resistance to other cells. N6-methyladenosine modification of IGFL2-AS1 was critical for its interaction with hnRNPC. In a patient-derived xenograft model of sunitinib-resistant ccRCC, injection of chitosan-solid lipid nanoparticles containing antisense oligonucleotide-IGFL2-AS1 successfully reversed sunitinib resistance. These findings indicate a novel molecular mechanism of sunitinib resistance in RCC and suggest that IGFL2-AS1 may serve as a prognostic indicator and potential therapeutic target to overcome resistance. Significance: Extracellular vesicle-packaged IGFL2-AS1 promotes sunitinib resistance by regulating TP53INP2-triggered autophagy, implicating this lncRNA as a potential therapeutic target in renal cell carcinoma.

Long noncoding RNAs (lncRNAs) have been reported to exert important roles in tumors, including clear cell renal cell carcinoma (ccRCC). PVT1 is an important oncogenic lncRNA which has critical effects on onset and development of various cancers, however, the underlying mechanism of PVT1 functioning in ccRCC remains largely unknown. VHL deficiency-induced HIF2α accumulation is one of the major factors for ccRCC. Here, we identified the potential molecular mechanism of PVT1 in promoting ccRCC development by stabilizing HIF2α. PVT1 was significantly upregulated in ccRCC tissues and high PVT1 expression was associated with poor prognosis of ccRCC patients. Both gain-of-function and loss-of function experiments revealed that PVT1 enhanced ccRCC cells proliferation, migration, and invasion and induced tumor angiogenesis in vitro and in vivo. Mechanistically, PVT1 interacted with HIF2α protein and enhanced its stability by protecting it from ubiquitination-dependent degradation, thereby exerting its biological significance. Meanwhile, HIF2α bound to the enhancer of PVT1 to transactivate its expression. Furthermore, HIF2α specific inhibitor could repress PVT1 expression and its oncogenic functions. Therefore, our study demonstrates that the PVT1/ HIF2α positive feedback loop involves in tumorigenesis and progression of ccRCC, which may be exploited for anticancer therapy.

A three-dimensional (3D) energy footprint combines a 3D ecological footprint with energy theory. In this paper, based on 3D energy footprint theory, we calculated the 3D energy footprint of Gansu Province from 2001 to 2020, and quantitatively evaluated the value of the province’s ecosystem services. Moreover, we also analyzed the sustainability of its ecosystem. The results show that the energy footprint of Gansu Province has been on the rise since 2001. From 2001 to 2020, only the 2015 and 2016 energy footprints in Gansu were greater than the energy carrying capacity, and the footprint depth was greater than 1, indicating that the flow of natural resources cannot meet the development needs of the province, resulting in an ecological deficit. The 3D energy footprint of Gansu Province doubled from 2001 to 2020, indicating that human use of natural resources is increasing. From the perspective of sustainable development, the development of the ecological economic system in Gansu Province only in 2015 and 2016 was not sustainable, and the development of the ecological economic system in the other years studied was sustainable.

Background Sudden cardiac death (SCD) accounts for a large proportion of the total deaths across different age groups. Although numerous candidate genes related to SCD have been identified by genetic association studies and genome wide association studies (GWAS), the molecular mechanisms underlying SCD are still unclear, and the biological functions and interactions of these genes remain obscure. To clarify this issue, we performed a comprehensive and systematic analysis of SCD-related genes by a network and pathway-based approach. Methods By screening the publications deposited in the PubMed and Gene-Cloud Biotechnology Information (GCBI) databases, we collected the genes genetically associated with SCD, which were referred to as the SCD-related gene set (SCDgset). To analyze the biological processes and biochemical pathways of the SCD-related genes, functional analysis was performed. To explore interlinks and interactions of the enriched pathways, pathway crosstalk analysis was implemented. To construct SCD-specific molecular networks, Markov cluster algorithm and Steiner minimal tree algorithm were employed. Results We collected 257 genes that were reported to be associated with SCD and summarized them in the SCDgset. Most of the biological processes and biochemical pathways were related to heart diseases, while some of the biological functions may be noncardiac causes of SCD. The enriched pathways could be roughly grouped into two modules. One module was related to calcium signaling pathway and the other was related to MAPK pathway. Moreover, two different SCD-specific molecular networks were inferred, and 23 novel genes potentially associated with SCD were also identified. Conclusions In summary, by means of a network and pathway-based methodology, we explored the pathogenetic mechanism underlying SCD. Our results provide valuable information in understanding the pathogenesis of SCD and include novel biomarkers for diagnosing potential patients with heart diseases; these may help in reducing the corresponding risks and even aid in preventing SCD.

Clear-cell renal cell carcinoma (ccRCC) carries a variable prognosis. Prognostic biomarkers can stratify patients according to risk, and can provide crucial information for clinical decision-making. We screened for an autophagy-related long non-coding lncRNA (lncRNA) signature to improve postoperative risk stratification in The Cancer Genome Atlas (TCGA) database. We confirmed this model in ICGC and SYSU cohorts as a significant and independent prognostic signature. Western blotting, autophagic-flux assay and transmission electron microscopy were used to verify that regulation of expression of 8 lncRNAs related to autophagy affected changes in autophagic flow in vitro. Our data suggest that 8-lncRNA signature related to autophagy is a promising prognostic tool in predicting the survival of patients with ccRCC. Combination of this signature with clinical and pathologic parameters could aid accurate risk assessment to guide clinical management, and this 8-lncRNAs signature related to autophagy may serve as a therapeutic target.

Peimine, one of the major quality markers in Fritillaria Cirrhosae Bulbus, was expected to become a new anti-asthma drug. However, its metabolic profiles and anti-asthma mechanism have not been clarified previously. In this study, a method was developed for the detection of peimine metabolites in vitro by ultra-high-performance liquid chromatography coupled with hybrid triple quadrupole time-of-flight mass spectrometry. The potential anti-asthma mechanism was predicted by an integrated analysis of network pharmacology and molecular docking. A total of 19 metabolites were identified with the aid of software and molecular networking. The metabolic profiles of peimine elucidated that the metabolism was a multi-pathway process with characteristics of species difference. The network pharmacology results showed that peimine and its metabolites could regulate multiple asthma-related targets. The above targets were involved in various regulatory pathways linked to asthma. Moreover, the results of molecular docking showed that both peimine and its metabolites had a certain affinity with the β

An ileal conduit for urinary diversion after radical cystectomy is a common surgical procedure for muscle-invasive bladder cancer. Mucocutaneous separation, one of several potential complications following surgery, can cause life-threatening sepsis and may have long-term consequences such as stomal stenosis or retraction. However, there are few reports describing the treatment of mucocutaneous separation. Purpose The purpose of this case study was to report the outcome of a team-based, integrated conservative treatment of a 46-year-old patient with a complex mucocutaneous separation. Case study Abdominal distension, fever, and progressive oliguria developed in the patient 6 days after radical cystectomy and ileal conduit surgery. Gastrointestinal decompression, parenteral nutrition, urinary diversion, and antibiotic therapy were initiated. Fifteen (15) days postoperatively, peristomal ulcers and mucocutaneous separation were observed. After 16 days of treatment with hydrocolloid powder, a silver-containing hydrofiber dressing, and meticulous pouching techniques, the wounds were healed. No additional peristomal lesions developed or surgical procedures were required for repairing the stoma, and no adverse reactions were seen. Conclusion Comprehensive treatment provided by an ostomy care team facilitated the recovery and healing of a patient who had a complicated mucocutaneous separation of his urostomy.

Enhancer can transcribe RNAs, however, most of them were neglected in traditional RNA-seq analysis workflow. Here, we developed a Pipeline for Enhancer Transcription (PET, http://fun-science.club/PET) for quantifying enhancer RNAs (eRNAs) from RNA-seq. By applying this pipeline on lung cancer samples and cell lines, we showed that the transcribed enhancers are enriched with histone marks and transcription factor motifs (JUNB, Hand1-Tcf3 and GATA4). By training a machine learning model, we demonstrate that enhancers can predict prognosis better than their nearby genes. Integrating the Hi-C, ChIP-seq and RNA-seq data, we observe that transcribed enhancers associate with cancer hallmarks or oncogenes, among which LcsMYC-1 (Lung cancer-specific MYC eRNA-1) potentially supports MYC expression. Surprisingly, a significant proportion of transcribed enhancers contain small protein-coding open reading frames (sORFs) and can be translated into microproteins. Our study provides a computational method for eRNA quantification and deepens our understandings of the DNA, RNA and protein nature of enhancers.

Mesenchymal stem cells (MSCs) have shown some efficacy in the COVID-19 treatment. We proposed that exogenous supplementation of ACE2 via MSCs (ACE2-MSCs) might have better therapeutic effects. We constructed SARS-CoV-2 spike glycoprotein stably transfected AT-II and Beas-2B cells and used SARS-CoV-2 spike pseudovirus to infect hACE2 transgenic mice. The results showed that spike glycoprotein transfection triggers the release of apoptotic bodies and formation of membrane pores in pyroptosis. Inflammatory factors and pyroptosis factors were highly upregulated by spike glycoprotein transfection. SARS-CoV-2 spike pseudovirus worsened lung injury and increased the main factors of cytokine storm and pyroptosis. Compared to using MSCs or rh-ACE2 alone, the administration of ACE2-MSCs could significantly reduce these factors better and alleviate lung injury

Background: During the COVID-19 pandemic, elective surgery has to undergo longer wait times, including nephrectomy for T1 renal cell carcinoma (RCC). This study aimed to investigate the time-to-surgery (TTS) of Chinese T1 RCC patients and its influencing factors, and to illustrate the impact of TTS on the prognosis of T1 RCC. Methods: We retrospectively enrolled 762 Chinese patients with pathological T1 RCC that underwent nephrectomy. To discover the impact of TTS on survival outcomes, we explored the possible delay intervals by week using the Kaplan-Meier method and Log-rank test. Cox proportional hazard models with inverse probability-treatment weighting (IPTW) were used to assess the association between TTS and disease-free survival (DFS) and overall survival (OS). Results: The median TTS of T1 RCC patients was 15 days. The Charlson comorbidity index, the Preoperative Aspects and Dimensions Used for an Anatomical (PADUA) score, and the maximal tumor diameter on presentation were independent influencing factors for TTS. The cut-off point of TTS was selected as 5 weeks according to the Log-rank analysis. For T1a RCC, patients with TTS > 5 weeks had similar DFS (HR = 2.39; 95% CI, 0.82–6.94; p = 0.109) and OS (HR = 1.28; 95% CI, 0.23–7.16; p = 0.779) compared to patients with TTS ≤ 5 weeks. For T1b RCC, patients with TTS > 5 weeks had shorter DFS (HR = 2.90; 95% CI = 1.46–5.75; p = 0.002) and OS (HR = 2.49, 95% CI = 1.09–5.70; p = 0.030) than patients with TTS ≤ 5 weeks. Conclusions: Prolonged TTS had no impact on the prognosis of T1a RCC while surgery delayed for over 5 weeks may lead to worse survival in T1b RCC.

Background Congenital scrotal agenesis (CSA) is very rare. There are 11 cases of congenital scrotal agenesis or absence reported in the literature, most of which are bilateral and accompanied by cryptorchidism. Only two cases of which are unilateral scrotal agenesis and not accompanied by cryptorchidism. This is the first reported case of unilateral scrotal agenesis with cryptorchidism and scrotoplasty. Case summary A 2-year-old boy was admitted to our hospital with left cryptorchidism and ipsilateral CSA. An innovative method was used in the patient where a scrotal skin pedicle from the right part of scrotal skin was transplanted to the left side. At the same time, descent orchiopexy was performed. At the 4-mo follow-up, the left testicle was located in the scrotum and the size and shape were normal. Conclusion For unilateral CSA with ipsilateral cryptorchidism, contralateral scrotal pedicle transplantation and descent orchiopexy appear to be a successful surgical option.

Background Amplified in breast cancer 1 (AIB1) is a candidate oncogene in human breast cancer, which has been identified to be amplified and overexpressed in several types of other human cancers. Abnormalities of AIB1 and its clinical/prognostic significance, however, in upper tract urothelial carcinoma (UTUC) remain unclear. Objective To explore what role AIB1 plays in upper tract urothelial carcinoma. Methods The expression of AIB1 was analyzed using immunohistochemical staining in 133 UTUC patients. Overall, cancer specific and recurrence-free survival rates (OS, CSS, and RFS) were estimated using the Kaplan-Meier method. Multivariable COX regression models containing relevant clinicopathological variables addressed the prediction of postoperative outcome. Results High AIB1 expression was observed to be associated with increased hazard ratios for 5-year CSS (80.6% vs. 55.8%, p= 0.008) and OS (78.1% vs. 54.8%, p= 0.006). Multivariable analysis revealed that elevated AIB1 expression was an independent prognostic predictor of OS, CSS and RFS. Additionally, pT, pN and hydronephrosis were independently associated with oncologic outcome of UTUC. Three proposed nomograms were proposed to provide an individualized risk estimate of postoperative outcome in patients with UTUC. Conclusions AIB1 can be used as an independent molecular marker for the prognosis of clinical outcomes of UTUC.

Background: Hypoxia is a hallmark of solid cancers, including hepatocellular carcinoma (HCC). There is scarce information about how hypoxia avoids immunologic stress and maintains a cancer-promoting microenvironment. Methods: The Cancer Genome Atlas, RNA-seq data, and Oncomine database were used to discover the correlation of RNASEH2A with tumor progression; then expression of RNASEH2A mRNA and protein were detected in HCC tissues and cells subjected to hypoxia or with the treatment of CoCl2 via real-time quantitative polymerase chain reaction and immunochemistry assays. Finally, the effect of RNASEH2A on cell proliferation and the involved signaling pathway was explored further. Results: RNASEH2A was positively correlated with tumor grade, size, vascular invasion, and poor prognosis. The expression of RNASEH2A mRNA and protein were increased and dependent on hypoxia-inducible factor 2α in HCC tissues and cell lines. Knockout of RNASEH2A in HCC cells greatly reduced cell proliferation and induced the transcription of multiple cGAS-STING (cyclic GMP–AMP synthase–stimulator of interferon genes) targeted type 1 interferon-related genes, including IFIT1, USP18, and CXCL10, which suggests knockout of RNASEH2A may produce immunologic stress and tumor suppressive effects. Conclusions: RNASEH2A plays a critical role and potentially predicts patient outcomes in HCC, which uncovers a new mechanism that RNASEH2A contributes to limit immunologic stress of cancer cells in the context of hypoxia.

Sunitinib resistance is a major challenge in systemic therapy for renal cell carcinoma (RCC). The role of circular RNAs (circRNAs) in regulating sunitinib resistance of RCC is largely unknown. We established sunitinib-resistant RCC cell lines in vivo. Through RNA-sequencing, we identified circSNX6, whose expression is upregulated in sunitinib-resistant cells compared with their parental cells. High circSNX6 expression was correlated with sunitinib resistance and worse oncologic outcomes in a cohort of 81 RCC patients. In vitro and in vivo experiments confirmed that circSNX6 could promote sunitinib resistance in RCC. circSNX6 acts as a molecular "sponge" to relieve the suppressive effect of microRNA (miR)-1184 on its target gene, glycerophosphocholine phosphodiesterase 1 (GPCPD1), which increases intracellular lysophosphatidic acid (LPA) levels and, ultimately, promotes sunitinib resistance in RCC cells. Our findings demonstrated that the circSNX6/miR-1184/GPCPD1 axis had a critical role in regulation of intracellular LPA levels and sunitinib resistance in RCC; they also provide a novel prognostic indicator and promising therapeutic targets.

Most localized human renal clear cell carcinoma (ccRCC)-related deaths result from cancer recurrence and metastasis. However, the precise molecular mechanisms largely remain unknown. In recent years, an increasing number of long noncoding RNAs (lncRNAs) have been shown to be vital regulators of tumorigenesis. In this study, we characterized a lncRNA DUXAP9 and the upregulation of DUXAP9 was analyzed by quantitative real-time PCR in 112 pairs of localized ccRCC tumor tissues compared with adjacent normal tissues. Kaplan–Meier curves showed that patients of localized ccRCC with high DUXAP9 expression had poorer overall survival (Pin vitro and reversed epithelial–mesenchymal transition (EMT), whereas overexpression of DUXAP9 promoted renal cancer cells proliferation and motility capacities in vitro and induced EMT. Pull-down, RNA immunoprecipitation and RNA stability assays (involving actinomycin D) showed that DUXAP9 was methylated at N6-adenosine and binds to IGF2BP2, which increases its stability. DUXAP9 activate PI3K/AKT pathway and Snail expression in renal cancer cells. DUXAP9 may be useful as a prognostic marker and/or therapeutic target in localized ccRCC.

Background: Immune checkpoint inhibitors (ICI) have been shown to improve overall survival (OS) in clear cell renal cell carcinoma (ccRCC) patients. However, less than half of the ccRCC patients have objective response to ICI. Objective: We aim to assess the role of DDX39B in predicting ccRCC patients'OS and ICI therapy response. Methods: DDX39B was detected by immunohistochemistry in a tissue microarray of 305 ccRCC patients. DDX39B and its relationship with the prognosis of ccRCC were also evaluated in TCGA set and a RECA-EU set. The expression of DDX39B and patients survival was also analysed in two datasets of ccRCC patients treated with ICI. Results: Overexpression of DDX39B predicted poor OS of ccRCC patients in SYSU set, TCGA set, and a RECA-EU set. DDX39B expression was significantly positive with the expression of PD-L1 and other immunomodulators., DDX39B negatively correlated with cytotoxic T-lymphocyte and HDAC10 exon 3 inclusion in ccRCC. DDX39B knockdown decreased the expression of PD-L1 and increased the expression of HDAC10 exon 3 in renal cancer ACHN cells. Patients of ccRCC with lower levels of HDAC10 exon 3 inclusion have higher TNM stage, higher Fuhrman grade and poor OS. There was a tendency that patients with DDX39B high expression had longer OS and PFS than patients with DDX39B low expression in ccRCC patients treated with ICI. Conclusion: DDX39B gene is highly expressed in ccRCC and is closely related to patients' OS. DDX39B might increase PD-L1 expression via the enhancement of HDAC10 exon 3 skipping, thereby promoting the ICI therapy response.

OBJECTIVE: To explore whether opening the external urethral orifice in the coronal sulcus can reduce the incidence of epididymitis after operating on hypospadias with a prostatic cyst connected to the vas deferens.MATERIALS AND METHODS: Three patients (group A) (average age = 3.3 years old) with severe hypospadias and prostatic cyst underwent cystostomy, hypospadias correction and urethroplasty, along with relocation of the external orifice of urethra. Group B consisted of 4 patients (average age = 6.9 years old) presenting with epididymitis after hypospadias surgery and Unsuccessful conservative treatment. Patients underwent urethral dilatation along with urethral catheterization, cutting of the original corpus cavernosum that encapsulated the urethra, and extension of the position of the external urethral orifice to the coronal sulcus. RESULTS: In group A, 3 children underwent bladder fistula removal 2 weeks after operation. All patients were followed up for 5-7 years. The vulva developed normally without any complications. Four children in group B underwent stent removal 12 weeks after operation, and one patient was still stenosed and dilated again. All patients were followed up for 2-12 years without epididymitis recurrence. Penile erection and ejaculation were normal in adulthood. CONCLUSION: For hypospadias patients experiencing complications due to the presence of a prostatic sac, especially those with prostatic sac connected to the vas deferens, the positioning of the external urethral orifice in the coronary sulcus would be helpful to reduce the occurrence of epididymitis.

Background To explore whether opening the external urethral orifice in the coronal sulcus can reduce the incidence of epididymitis after operating on hypospadias with prostatic utricle cyst (PUC) connecting to the vas deferens. Group A consisted of 3 patients with severe hypospadias and PUC undergoing cystostomy, hypospadias correction and urethroplasty, along with the relocation of the external orifice of the urethra to the coronal sulcus. Group B consisted of 4 patients having initial hypospadias repaired with meatus in the orthotopic position in the glans, presenting with multiple epididymitis after hypospadias surgery and unsuccessful conservative treatment. MR confirmed that all the Group B patients had PUC connecting to the vas deferens. Group B patients underwent urethral dilatation along with urethral catheterization, cutting of the original corpus cavernosum that encapsulated the urethra, and extension of the position of the external urethral orifice to the coronal sulcus. Results In group A, 3 children underwent bladder fistula removal 2 weeks after the operation. The penis developed normally without any complications. Four children in group B underwent stent removal 12 weeks after operation, and one patient was still stenosed and dilated again. All patients in group B were followed without epididymitis recurrence. Conclusions For patients with hypospadias complicating with a PUC, connecting to one side of the vas deferens, the positioning of the external urethral orifice in the coronary sulcus would be helpful to reduce the occurrence of epididymitis.

Background To investigate the value of using contrast-enhanced transrectal ultrasound (CETRUS) to reduce unnecessary collection of biopsies during prostate cancer diagnosis and its utility in predicting biochemical recurrence in patients with localized prostate cancer. Methods This was a prospective study of suspected prostate cancer patients who were evaluated with CETRUS followed by a prostate biopsy. Prostate blood flow via CETRUS was graded using a 5-point scale. The relationship between CETRUS score and biopsy outcome was then analyzed for all patients; univariate and multi-variate analyses were used to determine the probable prognostic factors for biochemical recurrence in patients with localized prostate cancer that underwent a radical prostatectomy. Results A total of 347 patients were enrolled in the study. Prostate cancer was found in 164 patients. A significant positive correlation (r = 0.69, p 3; p = 0.015). Multivariate Cox regression analysis indicated that CETRUS score was an independent predictor of biochemical recurrence (HR: 7.02; 95% CI: 2.00–24.69; p = 0.002). Conclusions CETRUS scores may be a useful tool for reducing the collection unnecessary biopsy samples during prostate cancer diagnosis and are predictive of biochemical recurrence in patients with localized prostate cancer following a radical prostatectomy.

RNA methylation is involved in multiple physiological and pathological processes. However, the role of RNA methylation in spinal cord regeneration has not been reported. In this study, we find an altered m6A (N6-methyladenosine) RNA methylation profiling following zebrafish spinal cord injury (SCI), in line with an altered transcription level of the m6A methylase Mettl3. Interestingly, many of the differential m6A-tagged genes associated with neural regeneration are hypomethylated, but their transcription levels are upregulated in SCI. Moreover, we find that METTL3 may be important for spinal cord regeneration. We also show a conserved feature of METTL3 changes in mouse SCI model, in which the expression of METTL3 is increased in both astrocytes and neural stem cells. Together, our results indicate that m6A RNA methylation is dynamic and conserved following SCI and may contribute to spinal cord regeneration.

As one of the 10 most common cancers in men, the incidence of renal cell carcinoma (RCC) has been increasing in recent years. Clear cell renal cell carcinoma (ccRCC) is the most common pathological type of RCC, counting for 80%-90% of cases. Immunotherapy is becoming increasingly important in the treatment of advanced RCC. Tumor mutation burden (TMB) is a potent marker for predicting the response to immune checkpoint blockade (ICB) treatment. Here, we analyzed somatic mutation data for ccRCC from The Cancer Genome Atlas datasets. We found that the frequently mutated gene SYNE1 is associated with higher TMBs and with a poor clinical prognosis. To further investigate the relationship between SYNE1 mutation and the immune system, we used Gene Set Enrichment Analysis and the CIBERSORT algorithm. They showed that SYNE1 mutations correlate with immune system pathways and immune cell tumor infiltration. We also found that SYNE1 mutation correlated with a better response to ICB therapy. Thus, mutation of SYNE1 correlates with a higher TMB and a poorer outcome in ccRCC, but may mediate better responses to ICB therapy.

Background: Immune checkpoint inhibit(ICI) treatment has been used to treat advanced urothelial cancer. Molecular markers might improve risk stratification and prediction of ICI benefit for urothelial cancer patients. Methods: We analyzed 406 cases of bladder urothelial cancer from the cancer genome atlas(TCGA) data set, and identified 161 messenger RNAs(mRNAs) as differentially expressed immunity genes(DEIGs). Using the LASSO Cox regression model, an eight-mRNA-based risk signature was built. We validated the prognostic and predictive accuracy of this immune related risk signature in 348 metastatic urothelial cancer(mUC) samples treated with anti–PD-L1(atezolizumab) from IMvigor210. Findings: We built an immune related risk signature based on the eight mRNAs: ANXA1, IL22, IL9R, KLRK1, LRP1, NRG3, SEMA6D and STAP2.The eight-mRNA-based risk signature successfully categorizes patients into high-risk and low-risk groups. Overall survival was significantly different between these groups no matter in the initial TCGA training set, the internal TCGA testing set, all TCGA set or the ICI treatment set. The hazard ratio(HR) of the high-risk group to the low-risk group was 3.65(p

4-Nitrophenol (PNP) has been extensively used in manufacturing for several decades. Its toxic effects on the male reproductive system have been reported, but the underlying mechanisms remain unclear. In this study, we utilized two testicular somatic cell lines (TM3 and TM4 cells) to explore the possible toxic effects of PNP on the male reproductive system. The activity of the cells after exposure to different doses of PNP (0.01, 0.1, 1, 10 and 100 μM) was evaluated. PNP treatment at 10 μM significantly inhibited cell viability, and 10 μM PNP was thus selected for subsequent experiments. Although PNP (10 μM) inhibited cell proliferation, promoted cell apoptosis, and changed the cell cycle distribution and ultrastructure in both types of cells, these effects were more significant in the TM4 cells. In addition, an Agilent mouse mRNA array was used to identify the gene expression differences between the control and PNP (10 μM) exposed TM3 and TM4 cells. The microarray analysis identified 67 and 1372 differentially expressed genes mainly concentrated in endothelial cell morphogenesis and anatomical structure development in TM3 cells and associated with cardiovascular system development and circulatory system development in TM4 cells. Moreover, a pathway analysis revealed that PNP not only predominately affected meiotic recombination and meiosis in TM3 cells, but also influenced axon guidance and developmental biology in TM4 cells. These results suggest that TM3 and TM4 cells exhibit different responses to PNP, which might mediate different toxic mechanisms.

We previously identified the important role of RIN1 expression in the prognosis of clear cell renal cell carcinoma (ccRCC). The role of RIN1 in ccRCC malignancy and underlying molecular mechanisms remain unclear. Here we report that ccRCC cells and tissues expressed more RIN1 than normal controls. Gain-of-function and loss-of-function studies demonstrated that RIN1 enhanced ccRCC cell growth, migration and invasion abilities in vitro and promoted tumor growth and metastasis in vivo. Mechanistic studies revealed that RIN1 has an activating effect on EGFR signaling in ccRCC. In addition, we unveil Rab25, a critical GTPase in ccRCC malignancy, as a functional RIN1 interacting partner. Knockdown of Rab25 eliminated the augmentation of carcinoma cell proliferation, migration and invasion by ectopic RIN1. We also confirmed that RIN1 and Rab25 expression correlates with the overall-survival of ccRCC patients from TCGA. These findings suggest that RIN1 plays an important oncogenic role in ccRCC malignancy by activation of EGFR signaling through interacting with Rab25, and RIN1 could be employed as an effective therapeutic target for ccRCC.

T-DNA tagging lines are useful for analyzing the functions of genes and regulatory elements. We have previously generated approximately 100,000 insertional mutants in japonica rice (Oryza sativa), using T-DNA vectors carrying the promoter-less GUS reporter gene. In this study, we conducted GUS assays of seedlings from 430 lines in which TDNA was inserted into transcription factor genes. Among the 75 lines that showed GUS signals, nine displayed an endospermpreferential expression pattern; two lines demonstrated GUS signals in both endosperm and roots; 21 lines had GUS expression mainly in leaves; 19 lines showed GUS signal in both leaves and roots; and 24 lines expressed GUS predominantly in the roots. Co-segregation analyses of 49 homozygous lines indicated that the GUS expression patterns observed from 38 lines were due to the T-DNA insertion. We also identified fusion transcripts between tagged genes and the GUS reporter in six lines. Quantitative RT-PCR confirmed that the GUS expression patterns of those tagged lines indeed represent organ- and tissue-preferential expression of the tagged genes. The GUS-tagged transcription factor lines identified here will be useful for functional analysis of these candidates.

// Jun Lu 1, * , Jin-Huan Wei 1, * , Zi-Hao Feng 1, * , Zhen-Hua Chen 1, * , Yong-Qian Wang 2 , Yong Huang 1 , Yong Fang 1 , Yan-Ping Liang 1 , Jun-Jie Cen 1 , Yi-Hui Pan 1 , Bing Liao 3 , Wen-Fang Chen 3 , Wei Chen 1 , Jun-Hang Luo 1 1 Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangdong, China 2 Department of Musculoskeletal Oncology, First Affiliated Hospital, Sun Yat-sen University, Guangdong, China 3 Department of Pathology, First Affiliated Hospital, Sun Yat-sen University, Guangdong, China * These authors contributed equally to this work Correspondence to: Jun-Hang Luo, email: luojunh@mail.sysu.edu.cn Keywords: miR-106b-5p, stemness, Wnt signalling, tumorigenesis, renal cell carcinoma Received: October 29, 2016 Accepted: February 06, 2017 Published: February 21, 2017 ABSTRACT Purpose: To examine the role of miR-106b-5p in regulating the cancer stem-cell-like phenotype in clear cell renal cell carcinomas (ccRCC). Experimental Design: Real-time PCR was performed to evaluate miR-106b-5p levels in ccRCC cell lines and patients specimens. A series of in vivo and in vitro assays were performed to confirm the effect of miR-106b-5p on ccRCC stemness phenotype. Results: ccRCC cells and tissues expressed more miR-106b-5p than normal controls. Gain- and loss-of-function studies demonstrated that overexpression of miR-106b-5p in ccRCC cells increased the spheres formation ability and the proportion of side population cells. Ectopic expression of miR-106b-5p in ccRCC cells increased tumour growth rates and the number of metastatic colonies in the lungs by using an orthotopic kidney cancer model and a tail vein injection model, respectively. Mechanistic studies revealed that, miR-106b-5p has an activating effect on Wnt/β-catenin signalling. miR-106p-5p overexpression simultaneously targets multiple negative regulators of the Wnt/β-catenin pathway, namely, LZTFL1, SFRP1 and DKK2. In addition, we also confirmed that miR-106b-5p and its targets expression correlates with the overall-survival of ccRCC patients from TCGA. Conclusions: These findings suggest that miR-106b-5p mediates the constitutive activation of Wnt/β-catenin signalling, likely serving as a potential therapeutic target for ccRCC.

The transition of meristems is an important developmental process for crop plants. Florigen is considered to be produced in leaves, then moves into the shoot apical meristem (SAM), triggers the transition from the vegetative to the reproductive phase. However, little is known whether Florigen functions in callus development or not. By fused reporter gene β-glucuronidase (GUS) to 1.7 kb promoter of Heading date 3a (Hd3a), GUS signals were detected in the scutellum cells, as well as in green point of the putative transgenic calli. Quantitative RT-PCR results demonstrated that the expression level of Hd3a was increased gradually over time along with the transition from scutellum-deprived callus to shoot. As reported that ectopic expression of FT-like genes caused earlier flowering, we also found that 80% constitutive expression of Hd3a transgenic callus showed formation floral-like organ structures. However, Hd3a RNA interference (RNAi) transgenic calli did not show any obvious phenotype, although AP1 or AP1-like genes—OsMADS14, OsMADS15, and OsMADS18- expression level is decreased during callus development. Both in Hd3a and RFT1 overexpression transgenic calli, Hd3a also modulated AP1 or AP1-like genes, as well AEPALLATA (SEP)-like gene, OsMADS34 during green point formation. Meanwhile, transgenic calli of RFT1and OsMADS50, but not OsEhd1, shared similar results as Hd3a. All of these findings suggested that florigen genes Hd3a and RFT1 have partial conserved functions in the transition of meristems during callus development.

Aim: To study the expression of EIF5A2 in urinary tract urothelial carcinoma and its clinicopathological features and prognosis. Methods: EIF5A2 expression was detected via immunohistochemistry in 101 patients. Results: Kaplan–Meier analysis showed that the EIF5A2 low expression group had significantly longer overall survival (OS; p

Under long day (LD) lengths, flowering can be delayed in rice by modulating several regulatory genes. We found activation tagging lines that showed an early flowering phenotype preferentially under LD conditions. Expression of Rice outermost cell-specific gene 4 (Roc4), encoding a homeodomain Leu-zipper class IV family protein, was significantly increased. Transcript levels of Grain number, plant height, and heading date7 (Ghd7) were significantly reduced while those of Ghd7 downstream genes were increased. However, other flowering regulators were unaffected. Whereas constitutive overexpression of Roc4 in 'Dongjin' japonica rice, which carries active Ghd7, also caused LD-preferential early flowering, its overexpression in 'Longjing27' rice, which is defective in functional Ghd7, did not produce the same result. This confirmed that Roc4 regulates flowering time mainly through Ghd7. Phytochromes and O. sativa GIGANTEA (OsGI) function upstream of Roc4. Transgenic plants showed ubiquitous expression of the β-glucuronidase reporter gene under the Roc4 promoter. Furthermore, Roc4 had transcriptional activation activity in the N-terminal region of the StAR-related lipid-transfer domain. All of these findings are evidence that Roc4 is an LD-preferential flowering enhancer that functions downstream of phytochromes and OsGI, but upstream of Ghd7.