The potential of organoids in renal cell carcinoma research.

Renal cell carcinoma, a leading cause of death in urological malignancies, arises from the nephron. Its characteristics include diversity in disease biology, varied clinical behaviors, different prognoses, and diverse responses to systemic therapies. The term 'organoids' is used to describe structures resembling tissues created through the three-dimensional cultivation of stem cells in vitro. These organoids, when derived from tumor tissues, can retain the diversity of the primary tumor, mirror its spatial tissue structure, and replicate similar organ-like functions. In contrast to conventional two-dimensional cell cultures and the transplantation of tumor tissues into other organisms, organoids derived from tumors maintain the complexity and microenvironment of the original tumor tissue. This fidelity makes them a more reliable model for the development of cancer drugs, potentially accelerating the translation of these drugs to clinical use and facilitating personalized treatment options for patients. This review aims to summarize the recent advancements in the use of organoids for studying renal cell carcinoma, focusing on their cultivation, potential applications, and inherent limitations.

Green supply chain finance strategies with market competition and financial constraints.

In the context of sustainable development, market competition is intensifying, and financial constraints have emerged as a significant hindrance to green project investment. Green Supply Chain Finance (GSCF), characterized by long-term collaboration, has emerged as a crucial financial approach to mitigate corporate financial limitations and channel capital flows into environmentally friendly industries. We propose a two-echelon supply chain with one supplier and two competing retailers over a single period and investigate ordering, sales, and financing decisions simultaneously under competition. Retailers constrained by financial considerations may secure GSCF or traditional bank financing (BF) loans. This study investigates the influence of competition on pricing and sales strategies during the selling season. The results demonstrate that retailers select between clearance and responsive selling strategies based on the level of market competition. During the ordering season, retailers share the product market equally when interest rates are uniform, and the supplier formulates a supply chain contract while considering the financing interest rate. In the presence of differential interest rates, retailers may not always opt for the GSCF, even when they offer an interest rate advantage, due to the comprehensive impacts of operational and financial strategies. Remarkably, competitive retailers do not choose the GSCF when their initial green investment capital surpasses a certain threshold.

Blockchain technology for supply chain traceability: A game-theoretic analysis between e-platforms.

In view of the rapid development and application of blockchain technology, this paper considers a secondary supply chain system consisting of a single upstream supplier and a downstream e-tailer that implements blockchain technology and a traditional e-tailer that does not implement blockchain technology. We establish the demand function of two channels based on consumers' sensitivity to the blockchain and use the Stackelberg game model to compare and analyse the e-tailers' profits from the two channels. For the basic properties, interestingly, we find that there exists a critical threshold on the cost sensitivity to effort that helps each e-tailer decide whether to implement effort. If the cost sensitivity to effort is high, the two-sided e-tailers will reduce their effort as much as possible to obtain greater profits. Conversely, if the cost sensitivity to effort is low, they will increase their effort to obtain more benefits. We also discuss the role of blockchain technology in competition between e-tailers and analyse the impact of the product brand effect brought by the traceability characteristic of blockchain on the competition between e-tailers. To check the robustness of the core results and to investigate different forms of supply chain configurations, this paper further develops the analysis of the supplier entering agency agreements with two-sided e-tailers. Under this scenario, the supplier sells their products directly to consumers through two-sided e-platforms and shares revenue with e-tailers as platform agency fees. These core ideas remain valid in the extended model.

LncRNA SNHG1 Facilitates Tumor Proliferation and Represses Apoptosis by Regulating PPARγ Ubiquitination in Bladder Cancer.

BACKGROUND: Long noncoding RNAs regulate various biological effects in the progression of cancers. We found that the expression of SNHG1 was significantly up-regulated in bladder cancer after analyzing data obtained from TCGA and GEO. However, the potential role of SNHG1 remains to be investigated in bladder cancer. It was validated that SNHG1 was overexpressed in bladder cancer tissues detected by qRT-PCR and FISH, which was also associated with poor clinical outcome. Additionally, SNHG1 was verified to facilitate tumor proliferation and repress apoptosis in vitro and in vivo. RESULTS: SNHG1 could act as a competitive endogenous RNA and decrease the expression of murine double minute 2 (MDM2) by sponging microRNA-9-3p. Furthermore, MDM2 induced ubiquitination and degradation of PPARγ that contributed to the development of bladder cancer. CONCLUSIONS: the study elucidated that SNHG1 played an important role in bladder cancer and provided a potential therapeutic target for bladder cancer.

Comprehensive bioinformatics analysis of the E2F family in human clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) originates from renal tubular epithelial cells and is the most common pathological renal cell carcinoma type with the worst prognosis. The relationship between the expression, prognosis and mechanism of ccRCC and the E2F family remains challenging. In the present study, RNA sequencing and clinical data of ccRCC from The Cancer Genome Atlas and two datasets, GSE36895 and GSE53757, from the Gene Expression Omnibus were used to identify the role of the E2F family in ccRCC. A total of 10 groups of tumor tissues and paired-normal tissues from patients with ccRCC were verified by reverse transcription-quantitative PCR. the expression, tumor grade and stage, prognosis and regulatory mechanism of the E2F family in ccRCC were analyzed. It was found that the expression levels of E2F1 to 4 and 6 to 8 were higher in ccRCC tissues than in normal tissues, whereas the expression level of E2F5 was lower in the former than in the latter. The expression levels of E2F1 to 8 were correlated with tumor stage and grade. Low expression of E2F1 to 5 and 7 to 8 was significantly associated with longer overall survival, disease-specific survival and progression-free survival times. The data revealed that the E2F family rarely has genetic mutations. The expression of E2F1, E2F2, E2F5, E2F7 and E2F8 was significantly correlated with DNA methylation, and E2F1 to E2F7 were significantly correlated with copy number and the data showed that the expression of E2Fs was significantly correlated with the cell cycle. The results of the present study suggested that E2F family genes may be potential targets for ccRCC molecular diagnosis and targeted therapy.

Targeting PDE4B (Phosphodiesterase-4 Subtype B) for Cardioprotection in Acute Myocardial Infarction via Neutrophils and Microcirculation.

BACKGROUND: Timely and complete restoration of blood flow is the most effective intervention for patients with acute myocardial infarction. However, the efficacy is limited by myocardial ischemia-reperfusion (MI/R) injury. PDE4 (phosphodiesterase-4) hydrolyzes intracellular cyclic adenosine monophosphate and it has 4 subtypes A-D. This study aimed to delineate the role of PDE4B (phosphodiesterase-4 subtype B) in MI/R injury. METHODS: Mice were subjected to 30-minute coronary artery ligation, followed by 24-hour reperfusion. Cardiac perfusion was assessed by laser Doppler flow. Vasomotor reactivities were determined in mouse and human coronary (micro-)arteries. RESULTS: Cardiac expression of PDE4B, but not other PDE4 subtypes, was increased in mice following reperfusion. PDE4B was detected primarily in endothelial and myeloid cells of mouse and human hearts. PDE4B deletion strikingly reduced infarct size and improved cardiac function 24-hour or 28-day after MI/R. PDE4B in bone marrow-derived cells promoted MI/R injury and vascular PDE4B further exaggerated this injury. Mechanistically, PDE4B mediated neutrophil-endothelial cell interaction and PKA (protein kinase A)-dependent expression of cell adhesion molecules, neutrophil cardiac infiltration, and release of proinflammatory cytokines. Meanwhile, PDE4B promoted coronary microcirculatory obstruction and vascular permeability in MI/R, without affecting flow restriction-induced thrombosis. PDE4B blockade increased flow-mediated vasodilatation and promoted endothelium-dependent dilatation of coronary arteries in a PKA- and nitric oxide-dependent manner. Furthermore, postischemia administration with piclamilast, a PDE4 pan-inhibitor, improved cardiac microcirculation, suppressed inflammation, and attenuated MI/R injury in mice. Incubation with sera from patients with acute myocardial infarction impaired acetylcholine-induced relaxations in human coronary microarteries, which was abolished by PDE4 inhibition. Similar protection against MI/R-related coronary injury was recapitulated in mice with PDE4B deletion or inhibition, but not with the pure vasodilator, sodium nitroprusside. CONCLUSIONS: PDE4B is critically involved in neutrophil inflammation and microvascular obstruction, leading to MI/R injury. Selective inhibition of PDE4B might protect cardiac function in patients with acute myocardial infarction designated for reperfusion therapy.

Identification of a Hemizygous Novel Splicing Variant in ATRX Gene: A Case Report and Literature Review.

Background: Alpha-thalassemia/intellectual disability syndrome (ATR-X) (OMIM # 301040) was first described by Wilkie et al. (1). Several studies found that children who presented with significantly consistent clinical phenotypes of hemoglobin H (Hb H) disease and profound mental handicap carried ATRX chromatin remodeler (ATRX, OMIM*300032) gene variants. With the recent development of exome sequencing (ES), ATRX gene variants of severe to profound intellectual disability without alpha-thalassemia have been implicated in intellectual disability-hypotonic facies syndrome, X-linked, 1(MRXHF1, OMIM #309580). These two diseases present similar clinical manifestations and the same pattern of inheritance. Case Presentation: We reported a 3-year-old boy with intellectual disability, language impairment, hypotonia, and mild craniofacial abnormalities (flat nasal bridge, small and triangular nose, anteverted nostrils, and widely spaced incisors) and reviewed MRXHF1 cases. At an early stage, the patient developed global developmental delay (GDD). After 6 months of rehabilitation therapy, the patient's motor ability did not make big progress, as well as his speech or nonverbal communication. We performed whole-genome sequencing (WGS), Sanger sequencing, reverse transcription-polymerase chain reaction (RT-PCR), and X-inactivation studies. A novel hemizygous intronic variant in ATRX (c.5786+4A>G; NM_000489.6) was identified, which led to exon 24 skipping. The carrier mother showed extremely skewed X-chromosome inactivation (XCI). These results may contribute to the patient's phenotypes. Conclusions: The novel hemizygous intronic variant in ATRX is the genetic etiology of the boy. Identification of this variant is helpful for parents to take prenatal diagnostic tests. Also, this new case expands the phenotypes of MRXHF1 and the mutational spectrum of the ATRX gene.

Exosomal MicroRNA-9-3p Secreted from BMSCs Downregulates ESM1 to Suppress the Development of Bladder Cancer.

Exosomes, carriers to transfer endogenous molecules, derived from bone marrow-derived mesenchymal stem cells (BMSCs) have been reported to play a role in the progression of bladder cancer. Here we aimed to test the functional mechanism of microRNA-9-3p (miR-9-3p)-containing exosomes derived from BMSCs in bladder cancer. BMSCs were cocultured with bladder cancer cells, and exosomes secreted from BMSCs were identified. Next, the expression of miR-9-3p and endothelial cell-specific molecule 1 (ESM1) in bladder cancer tissues and cells was determined. Then effects of miR-9-3p and ESM1 via BMSC-derived exosomes on bladder cancer cell viability, migration, invasion, and apoptosis were determined by loss- and gain-of-function experiments and on in vivo tumor growth, and metastasis was assessed in nude mice. miR-9-3p expression was decreased and ESM1 was increased in bladder cancer. BMSCs inhibited bladder cancer cell viability, migration, and invasion, and induced apoptosis, whereas the addition of exosome secretion inhibitor GW4869 achieved the opposite effects. Moreover, exosomal miR-9-3p upregulation or ESM1 silencing suppressed bladder cancer cell viability, migration, and invasion; induced cell apoptosis; and inhibited in vivo tumor growth and metastasis. Taken together, BMSC-derived exosomal miR-9-3p suppressed the progression of bladder cancer through ESM1 downregulation, offering a potential novel therapeutic target for bladder cancer therapy.

Serum metabolomic analysis of human upper urinary tract urothelial carcinoma.

To find potential serum biomarkers for upper tract urothelial carcinomas (UTUCs) via (1)H nuclear magnetic resonance ((1)H NMR)-based metabolomic analysis. Serum specimens collected from 34 healthy individuals and 39 patients with UTUCs were subjected to (1)H NMR-based metabolomic analysis. Principal component and orthogonal partial least squares discriminant analyses were used to analyse the data. Compared with serum samples from healthy subjects, samples from UTUC patients showed elevated levels of lactate and creatinine as well as decreased levels of glucose, glutamine and taurine. Serum low-density lipoprotein/very low-density lipoprotein, valine and glycoprotein levels showed decreasing trends whereas serum polyunsaturated fatty acids and 3,7-dimethyluric acid level presented increasing trends in UTUC patients. (1)H NMR-based metabolomic analysis of serum enhances the current understanding of the mechanisms involved in UTUC development. The present analysis may be a valuable tool for UTUC detection.

Effects of TSP-1-696 C/T polymorphism on bladder cancer susceptibility and clinicopathologic features.

Thrombospondin-1 (TSP-1) is a glycoprotein that plays a major role in bladder cancer. We investigated the relationship between the distribution of the TSP-1 -696 C/T polymorphism (rs2664139) and the clinical features of bladder cancer. TaqMan assay was used to determine the genotype among the 609 cases and 670 controls in a Chinese population. Logistic regression was used to assess the association between the polymorphism and bladder cancer risk. Compared with the CT/TT genotypes, the CC genotype was associated with a significantly increased risk of bladder cancer (adjusted odds ratio [OR] 1.43, 95% CI 1.01-2.04), which was more prominent among the male participants (OR 1.82, 95% CI 1.20-2.76). The polymorphism was associated with a higher risk of developing grade 3 (OR 1.84, 95% CI 1.00-3.36), multiple-tumor (OR 1.81, 95% CI 1.08-3.02), and large-tumor (OR 1.94, 95% CI 1.22-3.10) bladder cancers. These observations suggest that the TSP-1 -696 C/T polymorphism may contribute to bladder cancer susceptibility in the Chinese population.

TSP-1-1223 A/G Polymorphism as a Potential Predictor of the Recurrence Risk of Bladder Cancer in a Chinese Population.

Backgrounds. TSP-1 is a glycoprotein that functions in the biology of bladder cancer. We investigated the relationship between the distribution of TSP-1-1223 A/G polymorphism (rs2169830) and the clinical characteristics of bladder cancer. Materials and Methods. TaqMan assay was performed to determine the genotype of 609 cases and 670 control subjects in a Chinese population. Logistic regression was used to assess the association between the polymorphism and the risk of bladder cancer. Quantitative real-time polymerase chain reaction was performed to determine TSP-1 mRNA expression. Survival curves were generated using the Kaplan-Meier method. Results. No significant differences were detected in the genotype frequencies of healthy control subjects and patients with bladder cancer. By contrast, the time until the first recurrence differed significantly between genotypes (P = 0.017). The expression of TSP-1 mRNA in bladder cancer tissues was lower in patients with an AG genotype than in those with an AA genotype. The lowest expression was observed in patients with a GG genotype. Conclusions. In conclusion, TSP-1-1223 A/G polymorphism may contribute to the recurrence of bladder cancer in Chinese population.

Functional promoter -94 ins/del ATTG polymorphism in NFKB1 gene is associated with bladder cancer risk in a Chinese population.

BACKGROUND: A functional -94 insertion/deletion polymorphism (rs28362491) in the promoter of the NFKB1 gene was reported to influence NFKB1 expression and confer susceptibility to different types of cancer. This study aims to determine whether the polymorphism is associated with risk of bladder cancer. MATERIALS AND METHODS: TaqMan assay was used to determine genotype among 609 cases and 640 controls in a Chinese population. Logistic regression was used to assess the association between the polymorphism and bladder cancer risk, and quantitative real-time polymerase chain reaction was used to determine NFKB1 mRNA expression. RESULTS: Compared with the ins/ins/ins/del genotypes, the del/del genotype was associated with a significantly increased risk of bladder cancer [adjusted odd ratio (OR) = 1.92, 95% confidence interval (CI) = 1.42-2.59]. The increased risk was more prominent among subjects over 65 years old (OR = 2.37, 95% CI= 1.52-3.70), male subjects (OR = 1.97, 95% CI = 1.40-2.79) and subjects with self-reported family history of cancer (OR = 3.59, 95% CI = 1.19-10.9). Furthermore, the polymorphism was associated with a higher risk of developing non-muscle invasive bladder cancer (OR= 2.07, 95% CI= 1.51-2.85), grade 1 bladder cancer (OR = 2.40, 95% CI = 1.68-3.43), single tumor bladder cancer (OR = 2.04, 95% CI = 1.48-2.82) and smaller tumor size bladder cancer (OR = 2.10, 95% CI= 1.51-2.92). The expression of NFKB1 mRNA in bladder cancer tissues with homozygous insertion genotype was higher than that with deletion allele. CONCLUSIONS: In conclusion, the -94 ins/del ATTG polymorphism in NFKB1 promoter may contribute to the etiology of bladder cancer in the Chinese population.