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Abstract Background Bladder cancer (BLCA) is a common malignancy characterized by dysregulated transcription and a lack of effective therapeutic targets. In this study, we aimed to identify and evaluate novel targets with clinical potential essential for tumor growth in BLCA. Methods CRISPR-Cas9 screening was used to identify transcription factors essential for bladder cancer cell viability. The biological functions of KLF16 in bladder cancer were investigated both in vitro and in vivo. The regulatory mechanism between KLF16 and MYC was elucidated through a series of analyses, including RNA sequencing, quantitative polymerase chain reaction (qPCR), RNA immunoprecipitation, Western blotting, Mass spectrometry, Dual-luciferase reporter assays, Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing, OptoDroplets assays, and RNA stability assay. The clinical relevance of KLF16 and MYC in bladder cancer was evaluated through analyses of public databases and immunohistochemistry. Results Krüppel-like factor 16 (KLF16) was essential for BLCA cell viability. Elevated expression of KLF16 was observed in bladder cancer tissues, and higher expression levels of KLF16 were correlated with poor progression-free survival (PFS) and cancer-specific survival (CSS) probabilities in BLCA patients. Mechanistically, KLF16 mRNA competed with the mRNA of dual-specificity phosphatase 16 (DUSP16) for binding to the RNA-binding protein, WW domain binding protein 11 (WBP11), resulting in destabilization of the DUSP16 mRNA. This, in turn, led to activation of ERK1/2, which stabilized the MYC protein. Furthermore, KLF16 interacted with MYC to form nuclear condensates, thereby enhancing MYC’s transcriptional activity. Additionally, MYC transcriptionally upregulated KLF16, creating a positive feedback loop between KLF16 and MYC that amplified their oncogenic functions. Targeting this loop with bromodomain inhibitors, such as OTX015 and ABBV-744, suppressed the transcription of both KLF16 and MYC, resulting in reduced BLCA cell viability and tumor growth, as well as increased sensitivity to chemotherapy. Conclusions Our study revealed the crucial role of the KLF16/MYC regulatory axis in modulating tumor growth and chemotherapy sensitivity in BLCA, suggesting that combining bromodomain inhibitors, such as OTX015 or ABBV-744, with DDP or gemcitabine could be a promising therapeutic intervention for BLCA patients.

Abstract The induction of type-I interferons (IFN-Is) is important for the efficacy of chemotherapy. By investigating the role of amino acids in regulation of IFN-I production under chemo-drug treatment in bladder cancer (BC) cells, we find an inherent AhR-dependent negative feedback to restrain STING signaling and IFN-I production. Mechanistically, in a ligand dependent manner, AhR bridges STING and CUL4B/RBX1 E3 ligase complex, facilitating STING degradation through ubiquitin-proteasome pathway. Inhibition of AhR increases STING levels and reduces tumor growth under cisplatin or STING agonist treatment. Endogenous AhR ligands are mainly consisted of tryptophan (Trp) metabolites; dietary Trp restriction, blocking the key Trp metabolism rate-limiting enzyme IDO1 or inhibition of cellular Trp importation also show similar effect as AhR inhibition. Clinically, BC patients with higher intratumoral expression of AhR or stronger intratumoral Trp metabolism (higher IDO1 or Kyn levels) that lead to higher AhR activation show worse response rate to neoadjuvant chemotherapy (NAC).

Background: The survival benefit of partial nephrectomy (PN) in pT3a RCC patients is controversial. Here we aimed to explore the potential benefit of PN for pT3aN0M0 renal cell carcinoma (RCC). Material and methods: Data of patients with pT3aN0M0 RCC who were diagnosed between 2010 and 2012 in the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database were retrospectively collected. Overall survival (OS) and cancer specific survival (CSS) were compared using a Cox proportional hazards model between PN and radical nephrectomy (RN) in pT3aN0M0 RCC. Propensity score (–adjusted, –stratified, –weighted, and –matched) analyses were performed to control for imbalances in individual risk factors. Results: A total of 1277 patients with pT3aN0M0 RCC were identified, of whom 200 patients were treated with PN and 1077 patients were RN. PN showed favorable OS and CSS in 0–4 cm pT3aN0M0 RCC (P

Summary: Dysregulation of transcription is a hallmark of cancer, including bladder cancer (BLCA). CRISPR-Cas9 screening using a lentivirus library with single guide RNAs (sgRNAs) targeting human transcription factors and chromatin modifiers is used to reveal genes critical for the proliferation and survival of BLCA cells. As a result, the nuclear transcription factor Y subunit gamma (NFYC)-37, but not NFYC-50, is observed to promote cell proliferation and tumor growth in BLCA. Mechanistically, NFYC-37 interacts with CBP and SREBP2 to activate mevalonate pathway transcription, promoting cholesterol biosynthesis. However, NFYC-50 recruits more of the arginine methyltransferase CARM1 than NFYC-37 to methylate CBP, which prevents the CBP-SREBP2 interaction and subsequently inhibits the mevalonate pathway. Importantly, statins targeting the mevalonate pathway can suppress NFYC-37-induced cell proliferation and tumor growth, indicating the need for conducting a clinical trial with statins for treating patients with BLCA and high NFYC-37 levels, as most patients with BLCA have high NFYC-37 levels.

Abstract Multidrug resistance gene 1 (MDR1), a key factor contributing to drug insensitivity, has been associated with treatment failure and poor prognoses in various cancers, including bladder urothelial carcinoma (UC). Here we show that positive Nkx2.8 expression was associated with better prognosis of UC patients received chemotherapy. Patients with positive Nkx2.8 expression had promising prognosis from adjuvant chemotherapy. Enforced expression of Nkx2.8 promotes drug sensitivity of UC cells. Mechanistic investigations showed that Nkx2.8 negatively regulated expression of MDR1 by binds directly to the MDR1 promoter and transcriptionally represses MDR1 expression. P-gp inhibitor reversed chemosensitivity inhibition by Nkx2.8 scilencing. In clinical UC specimens, expression of Nkx2.8 inversely correlated with P-gp expression, and UC patients with Nkx2.8 positivity and low P-gp expression displayed the best prognosis. Our findings uncovered a new mechanism of chemosensitivity in UC cells and proposing Nkx2.8-MDR1 axis as a novel candidate target for therapeutic intervention of UC.

Abstract Background Whether MTHFR C677T genotype affects pregnancy outcomes following assisted reproductive technology is conflicting. And the role of MTHFR C677T genotype on cumulative live birth has not been reported. This study aims to investigate the effect of MTHFR C677T genotype on cumulative live birth following in-vitro fertilization and embryo transfer (IVF-ET). Methods This is a retrospective cohort study that includes 1173 women undergoing their first IVF-ET. We retrospectively compared the reproductive outcomes among the groups stratified by MTHFR C677T genotypes (677CC, 677CT, 677TT). We performed interaction analysis to detect the factor that interacts with the MTHFR C677T genotype. Poisson regression analyses were used to evaluate the associations between MTHFR C677T genotypes with the number of transferable embryos and the number of good-quality embryos. Cox regression analysis was used to evaluate the association between MTHFR C677T genotypes with cumulative live birth. All regression analyses were adjusted with the confounding factors which may independently impact reproductive outcomes. Results There is a significant interactive effect of MTHFR 677TT genotype with GnRHa protocol on reproductive outcomes (P for interaction0.05). Conclusions MTHFR 677TT genotype is associated with decreased number of transferable embryos, decreased number of good-quality embryos, and decreased cumulative live birth rate in the first complete cycle in patients undergoing GnRHa short protocol.

Abstract Introduction Unlike the established evidence to use chemotherapy for urothelial carcinoma of the bladder, presently there are insufficient data to inform a recommendation on upper urinary tract urothelial carcinoma treatment. The prognosis for patients with stage T4 and positive lymph nodes is poor; however, primary tumors in the renal pelvis are associated with favorable prognoses compared to those located in the ureter. Our study aimed at investigating the effectiveness of chemotherapy in patients with pT3N0M0 renal pelvic urothelial carcinomas (RPUC) who have relative favorable prognosis. Methods Patients with pT3N0M0 tumors who underwent radical nephroureterectomy combined with bladder cuff excision between 2005 and 2014 and registered in the Surveillance, Epidemiology, and End Results database were eligible for inclusion (n = 939). Baseline characteristics between the chemotherapy and observation groups were controlled for with inverse probability of treatment weighting (IPTW)‐adjusted analysis. Results After the IPTW‐adjusted analysis, the 5‐year IPTW‐adjusted rates of overall survival (OS) for the chemotherapy and observation groups were 53.1% and 44.9%, respectively. The IPTW‐adjusted Kaplan‐Meier curves suggested that chemotherapy was associated with increased OS compared with observation (P = .028). In the IPTW‐adjusted Cox proportional hazards regression model, chemotherapy was associated with favorable survival benefits compared with observation (hazard ratio [HR] 0.71, 95% CI 0.52‐0.92, P = .031), and this was maintained after bootstrapping (HR 0.72, 95% CI 0.49‐0.93). Chemotherapy had a protective effect on OS benefits, which were found in a majority of the results of the subgroup analysis and were consistent with the main results (all P‐interactions > 0.05). Conclusion Chemotherapy may provide significant OS benefits for patients with pT3N0M0 RPUC. The results of our study could strengthen the evidence for using adjuvant chemotherapy in this rare group of patients.

Background and aims: Lung cancer patients suffer from deterioration in their physical and psychological function, which exerts a negative influence on their quality of life (QOL). Telemedicine has been proven to be an effective intervention for patients with several chronic diseases. The aim of this systematic review and meta-analysis was to investigate the efficacy of telemedicine in improving QOL in lung cancer patients. Methods: PubMed, Cochrane Library, EMBASE, Web of Science and Scopus databases were searched for randomized controlled trials that investigated the effectiveness of telemedicine in lung cancer patients. Review Manager 5.3 and Stata 15.1 were used to perform data analysis. Results: Our meta-analysis included eight clinical trials with a total of 635 lung cancer patients. The results showed that the telemedicine group had significantly higher QOL than the usual care group [standard mean difference (SMD) 0.96, 95% confidence interval (CI) 0.29–1.63, I 2 = 91%]. In addition, the telemedicine group had lower anxiety (SMD −0.44, 95% CI −0.66 to −0.23, I 2 = 3%) and depression scores (SMD −0.48, 95% CI −0.91 to −0.05, I 2 = 66%) than the usual care group. However, no significant differences were found in fatigue and pain outcomes between the two groups. Conclusion: Telemedicine may be an effective method of improving QOL in lung cancer patients and the further development and use of telemedicine care is recommended.

Heat treatment can induce muscle protein denaturation and aggregation and eventually the sol-gel tradition of proteins. The aggregation rate, degree, morphology and pattern can affect the quality of protein gels. Traditional Chinese soy sauce and pot-roast meat products are processed at temperatures above 100 ℃, and secondary heating treatment is commonly used to extend the shelf life of canned foods, both of which can lead to excessive protein aggregation, in turn reducing the fluidity of water as well as protein digestibility, destroying the quality of meat products and reducing the nutritional value. In this paper, the mechanisms of protein aggregation are analyzed by using the Lumry-Eyring nucleated polymerization (LENP) model. Three protein aggregation modes are described including fibril aggregation, hydrogel aggregation and amorphous aggregation. Four strategies for inhibiting excessive thermal aggregation are reviewed from the perspective of the spatial conformation of proteins. pH, amino acids and polyphenol compounds along with hydrophobic and reducing small molecules can effectively inhibit excessive aggregation of myofibrillar proteins and improve the gel properties of heat-induced proteins. As a molecular chaperone, casein can obviously enhance the thermal stability and reduce the degree of aggregation of proteins. Therefore, these strategies for inhibiting excessive aggregation can enhance the gel and texture quality of meat products.