CPEB1 Controls NRF2 Proteostasis and Ferroptosis Susceptibility in Pancreatic Cancer.

Pancreatic cancer is the deadliest malignancy with a poor response to chemotherapy but is potentially indicated for ferroptosis therapy. Here we identified that cytoplasmic polyadenylation element binding protein 1 (CPEB1) regulates NRF2 proteostasis and susceptibility to ferroptosis in pancreatic ductal adenocarcinoma (PDAC). We found that CPEB1 deficiency in cancer cells promotes the translation of p62/SQSTM1 by facilitating mRNA polyadenylation. Consequently, upregulated p62 enhances NRF2 stability by sequestering KEAP1, an E3 ligase for proteasomal degradation of NRF2, leading to the transcriptional activation of anti-ferroptosis genes. In support of the critical role of this signaling cascade in cancer therapy, CPEB1-deficient pancreatic cancer cells display higher resistance to ferroptosis-inducing agents than their CPEB1-normal counterparts in vitro and in vivo. Furthermore, based on the pathological evaluation of tissue specimens from 90 PDAC patients, we established that CPEB1 is an independent prognosticator whose expression level is closely associated with clinical therapeutic outcomes in PDAC. These findings identify the role of CPEB1 as a key ferroptosis regulator and a potential prognosticator in pancreatic cancer.

Prediction Value of Initial Serum Levels of SERPINA3 in Intracranial Pressure and Long-Term Neurological Outcomes in Traumatic Brain Injury.

Traumatic brain injury (TBI) is a severe neurological condition characterized by inflammation in the central nervous system. SERPINA3 has garnered attention as a potential biomarker for assessing this inflammation. Our study aimed to explore the predictive value of postoperative serum SERPINA3 levels in identifying the risk of cerebral edema and its prognostic implications in TBI. This study is a prospective observational study, including 37 patients with TBI who finally met our criteria. The Glasgow Outcome Scale (GOS), Levels of Cognitive Functioning (LCF), Disability Rating Scale (DRS), and Early Rehabilitation Barthel Index (ERBI) scores at six months after trauma were defined as the main study endpoint. We further calculated the ventricle-to-intracranial-volume ratio (VBR) at 6 months from CT scans. The study included patients with Glasgow Coma Scale (GCS) scores ranging from 3 to 8, who were subsequently categorized into two groups: the critical TBI group (GCS 3-5 points) and the severe TBI group (GCS 6-8 points). Within the critical TBI group, SERPINA3 levels were notably lower. However, among patients with elevated SERPINA3 levels, both the peak intracranial pressure (ICP) and average mannitol consumption were significantly reduced compared with those of patients with lower SERPINA3 levels. In terms of the 6-month outcomes measured via the GOS, LCF, DRS, and ERBI, lower levels of SERPINA3 were indicative of poorer prognosis. Furthermore, we found a negative correlation between serum SERPINA3 levels and the VBR. The receiver operating characteristic (ROC) curve and decision curve analysis (DCA) demonstrated the predictive performance of SERPINA3. In conclusion, incorporating the novel biomarker SERPINA3 alongside traditional assessment tools offers neurosurgeons an effective and easily accessible means, which is readily accessible early on, to predict the risk of intracranial pressure elevation and long-term prognosis in TBI patients.

Halide Superionic Conductors with Non-Close-Packed Anion Frameworks.

Halide superionic conductors (SICs) are drawing significant research attention for their potential applications in all-solid-state batteries. A key challenge in developing such SICs is to explore and design halide structural frameworks that enable rapid ion movement. In this work, we show that the close-packed anion frameworks shared by traditional halide ionic conductors face intrinsic limitations in fast ion conduction, regardless of structural regulation. Beyond the close-packed anion frameworks, we identify that the non-close-packed anion frameworks have great potential to achieve superionic conductivity. Notably, we unravel that the non-close-packed UCl3-type framework exhibit superionic conductivity for a diverse range of carrier ions, including Li+, Na+, K+, and Ag+, which are validated through both ab initio molecular dynamics simulations and experimental measurements. We elucidate that the remarkable ionic conductivity observed in the UCl3-type framework structure stems from its significantly more distorted site and larger diffusion channel than its close-packed counterparts. By employing the non-close-packed anion framework as the key feature for high-throughput computational screening, we also identify LiGaCl3 as a promising candidate for halide SICs. These discoveries provide crucial insights for the exploration and design of novel halide SICs.

A mouse model to distinguish NLRP6-mediated inflammasome-dependent and -independent functions.

The NOD-like receptor (NLR) family pyrin domain containing 6 (NLRP6) serves as a sensor for microbial dsRNA or lipoteichoic acid (LTA) in intestinal epithelial cells (IECs), and initiating multiple pathways including inflammasome pathway and type I interferon (IFN) pathway, or regulating nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. NLRP6 can exert its function in both inflammasome-dependent and inflammasome-independent manners. However, there is no tool to distinguish the contribution of individual NLRP6-mediated pathway to the physiology and pathology in vivo. Here, we validated that Arg39 and Trp50 residues in the pyrin domain (PYD) of murine NLRP6 are required for ASC recruitment and inflammasome activation, but are not important for the RNA binding and PYD-independent NLRP6 oligomerization. We further generated the Nlrp6R39E&W50E mutant mice, which showed reduced inflammasome activation in either steady state intestine or during viral infection. However, the type I IFN production in cells or intestine tissue from Nlrp6R39E&W50E mutant mice remain normal. Interestingly, NLRP6-mediated inflammasome activation or the IFN-I production seems to play distinct roles in the defense responses against different types of RNA viruses. Our work generated a useful tool to study the inflammasome-dependent role of NLRP6 in vivo, which might help to understand the complexity of multiple pathways mediated by NLRP6 in response to the complicated and dynamic environmental cues in the intestine.

Role of METTL3 in Aerobic Glycolysis of Glioma by Regulating m6A/miR-27b-3p/PDK1.

Methyltransferase like 3 (METTL3) has been reported to be dysregulated in glioma. However, its role in aerobic glycolysis of glioma remains unknown. This study was conducted to explore the molecular mechanism by which METTL3 regulates aerobic glycolysis of glioma and provide novel targets for the treatment of glioma. The expression levels of METTL3, microRNA (miR)-27b-3p, and pyruvate dehydrogenase kinase 1 (PDK1) were determined in glioma cell lines and normal human astrocytes. Cell proliferation and aerobic glycolysis were evaluated by cell counting kit-8 and colony formation assays and measurements of glucose uptake, lactate production, adenosine triphosphate, Hexokinase activity, oxygen consumption rate, and extracellular acidification rate. After m6A quantification analysis, methylated RNA immunoprecipitation, and the dual-luciferase assay, the rescue experiments were performed using miR-27b-3p inhibitor or pcDNA3.1-PDK1 with pcDNA3.1-METTL3. METTL3 was lower in glioma cells and METTL3 overexpression reduced aerobic glycolysis. METTL3 increased m6A modification to promote the processing of pri-miR-27b by DGCR8 and the expression of mature miR-27b-3p, and miR-27b-3p targeted and inhibited PDK1 expression. miR-27b-3p inhibition or PDK1 overexpression both neutralized the inhibitory role of METTL3 overexpression in aerobic glycolysis. Overall, METTL3 overexpression increased the expression of mature miR-27b-3p via m6A modification and inhibited PDK1 expression, thus suppressing aerobic glycolysis of glioma.

Netrin-1 upregulates GPX4 and prevents ferroptosis after traumatic brain injury via the UNC5B/Nrf2 signaling pathway.

AIM: We aimed to investigate the regulatory role of Netrin-1 (NTN1) in ferroptosis after traumatic brain injury (TBI) in mice. METHODS: We assessed the expression pattern of NTN1 by RT-PCR, western blot, and immunofluorescence after establishing the TBI model in mice. After treatment with NTN1 shRNA or recombinant NTN1, we determined the biochemical and morphological changes associated with ferroptosis and netrin-1-related pathways. We used Nissl staining to assess lesion volume and Morris water maze and beam-walking test to evaluate ethological manifestation. RESULTS: The mRNA and protein levels of NTN1 were upregulated after TBI. The application of NTN1 shRNA increased the number of FJB positive cells, malondialdehyde (MDA), and reactive oxygen species (ROSs) levels. However, the application of NTN1 recombinant had the opposite effect. Furthermore, knockdown or inhibition of GPX4, Nrf2, and UNC5B counteracted the effects of NTN1 recombinant. Intravenous injection of NTN1 recombinant reduced neuronal loss after CCI and improved motor and cognitive function. CONCLUSION: NTN1 had a neuroprotective effect after TBI and inhibited ferroptosis via activating the UNC5B/Nrf2 pathway. These findings may provide potential therapeutic strategies for TBI.

Effect of voluntary wheel running on gut microbiota composition in developing mice.

Introduction: Background: exercise can increase the species and quantity of beneficial gut microbiota, enrich the diversity of microflora, and promote the development of symbiotic bacteria, especially in the stage of ontogeny. However, there is little evidence of the short-term voluntary exercise effect on the gut microbiota in developing mice. Material and method: therefore, we used short-term voluntary wheel running model to study the gut microbiota of developing mice (1 month old), and detected the fecal samples by 16S rRNA gene sequencing. Results: the results showed that after 4 weeks of voluntary wheel running, the body weight of the running group was significantly lower than that of the control group. Conclusion: there was a significant separation between the running group and the control group in beta diversity measures. At the family level, the clostridiales flora of the running group was higher than that of the control group. Compared with the control group, the abundance of parabacteroides flora and anaerovorax flora increased significantly, and the abundance of anaerotruncus flora and odoribacter flora decreased significantly in the running group. These results showed that gut microbiota be affected after short-term voluntary wheel running in developing mice.

Introducción: Introducción: el ejercicio puede aumentar las especies y la cantidad de microbiota intestinal beneficiosa, enriquecer la diversidad de la microflora y promover el desarrollo de bacterias simbióticas, especialmente en la etapa de ontogenia. Sin embargo, hay poca evidencia del efecto del ejercicio voluntario a corto plazo sobre la microbiota intestinal en ratones en desarrollo. Material y método: por lo tanto, utilizamos un modelo de carrera de ruedas voluntario a corto plazo para estudiar la microbiota intestinal de ratones en desarrollo (1 mes de edad) y detectamos las muestras fecales mediante la secuenciación del gen 16S rRNA. Resultados: los resultados mostraron que después de 4 semanas de carrera voluntaria con ruedas, el peso corporal del grupo de carrera fue significativamente más bajo que el del grupo de control. Conclusión: hubo una diferencia significativa entre el grupo de corredores y el grupo de control en las medidas de diversidad beta. A nivel familiar, la flora de clostridiales del grupo de corredores fue mayor que la del grupo de control. En comparación con el grupo de control, la abundancia de flora parabacteroides y flora anaerovorax aumentó significativamente, y la abundancia de flora anaerotruncus y flora odoribacter disminuyó significativamente en el grupo de carrera. Estos resultados mostraron que la microbiota intestinal se ve afectada después de la carrera voluntaria a corto plazo en ratones en desarrollo.

The Prognostic Value of Deleted in Colorectal Cancer (DCC) Receptor and Serum Netrin-1 in Severe Traumatic Brain Injury.

Traumatic brain injury (TBI) is a common neurological disease. Netrin-1 and deleted in colorectal cancer (DCC) receptor are potential biomarkers associated with nerve regeneration and immune regulation. We aimed to investigate the ability of the DCC receptor and Netrin-1 to predict a high ICP level after operation in severe traumatic brain injury and their prognostic significance. This study is a prospective observational study. We selected 23 patients with traumatic brain injury who had undergone surgical operations as subjects. Immunohistochemical staining was performed on the contusion tissue that was removed by the operation to determine the expression of DCC receptor. At the same time, enzyme-linked immunosorbent assay (ELISA) kits were used to detect the serum Netrin-1 content. Determination of intracranial pressure (ICP) value was measured by intraventricular catheter. The Glasgow Outcome Scale (GOS) score at six months after trauma was defined as the main study endpoint. The results showed that serum Netrin-1 concentrations of patients in the critical TBI group (GCS 3-5 points) was significantly lower than that in the severe TBI group (GCS 6-8 points). The ICP peak and average mannitol consumption in the high Netrin-1 group were significantly lower than those in the low Netrin-1 group. DCC receptor-positive patients had a significantly lower ICP peak. There was no significant difference in six month-GOS scores between patients in the high and low Netrin-1 groups, while DCC receptor concentrations below 3.82 ng/mL predicted poor prognosis (GOS 1-3 points). In conclusion, the expression level of the DCC receptor can better evaluate the postoperative high ICP level and prognosis than the level of serum Netrin-1 in severe traumatic brain injury.

Cordycepin suppresses glutamatergic and GABAergic synaptic transmission through activation of A1 adenosine receptor in rat hippocampal CA1 pyramidal neurons.

Cordycepin (known as 3-deoxyadenosine, CRD), a natural product from the valuable traditional Chinese medicine Cordyceps militaris, has been reported to improve cognitive function and modulate neuroprotective effects on the central nervous system (CNS). However, the modulating mechanisms of cordycepin on information processing in hippocampal CA1 pyramidal neurons are not fully understood. To clarify how cordycepin modulates synaptic responses of pyramidal neurons in rat hippocampal CA1 region, we conducted an electrophysiological experiment using whole-cell patch-clamp technique. The spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs, respectively) and the spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs, respectively) recorded by this technique evaluated pure single or multi-synapse responses and enabled us to accurately quantify how cordycepin influenced the pre and postsynaptic aspects of synaptic transmission. The present results showed that cordycepin significantly decreased the frequency of both glutamatergic and GABAergic postsynaptic currents without affecting the amplitude, while these inhibitory effects were antagonized by the A1 adenosine receptor antagonist (DPCPX), but not the A2A (ZM 241385), A2B (MRS1754) and A3 (MRS1191) adenosine receptor antagonists. Taken together, our results suggested that cordycepin had a clear presynaptic effect on glutamatergic and GABAergic transmission, and provided novel evidence that cordycepin suppresses the synaptic transmission through the activation of A1AR.

Preparation of nano sustained-release fertilizer using natural degradable polymer polylactic acid by coaxial electrospinning.

Polylactic acid (PLA) is a novel biodegradable material that is widely used in fields like medicine, petrochemicals, disposable products, and has played significant role in the fast-growing agriculture sector in recent years. In this study, nanoscale sustained-release urea fiber materials were successfully fabricated by coaxial electrospinning by encapsulating urea inside polylactic acid fibers. The effects of different concentrations of PLA and urea on the preparation of fibrous membranes as well as the effects of different concentrations of PH and variations in temperature on the sustained release were investigated. The experimental results showed that the proposed method was feasible and the urea fiber membranes acidic and basic conditions as well as elevated temperatures. The sustained release time for the urea was as long as 84 d. Scanning electron microscopy and Fourier transform infrared spectrophotometry were employed to characterize the morphology of the electrospun nanofibers. Thermogravimetric analysis and differential scanning calorimetry showed that the release system was thermally stable up to a temperature of 126 °C, and urea concentration was determined by UV-Vis spectrophotometry. This method has broad application prospects in agricultural production and provides a more rational fertilizer choice for soil-free cultivation.

Effects of Family Intervention on Physical Activity and Sedentary Behavior in Children Aged 2.5-12 Years: A Meta-Analysis.

Introduction: To use a quantitative approach to examine the effects of family interventions on physical activity (PA) and sedentary behavior (SB) in children aged 2. 5-12 years. Methods: PubMed, OVID, Web of Science, and others were searched from their inception to May 2020. Intervention studies that examined the effects of family interventions on PA among children aged 2.5-12 years were included in this meta-analysis. Lastly, subgroup analyses were conducted to examine the potential modifying effects of family intervention's characteristics and study quality. Results: Eleven articles met the inclusion criteria for this review. Studies investigated a range of PA outcomes, including moderate-to-vigorous PA (MVPA), total PA (TPA), daily steps, and SB levels. Meta-analysis showed that family intervention had a significant effect on PA [standardized mean difference (SMD) = 0.10; 95% CI = 0.01-0.19], especially for daily steps [weight means difference (WMD) = 1,006; 95% CI = 209-1,803], but not for SB (WMD = -0.38; 95% CI = -7.21-6.46). Subgroup analyses indicated the improvements in PA occurred when children were 6-12 years old, intervention focused on PA only, intervention duration ≤ 10 weeks, and "low risk of bias" study performed. Conclusions: Family intervention may be a promising way to promote children's PA levels, especially for daily steps. Trial Registration: Meta-analysis protocol was registered on PROSPERO: CRD42020193667.

The clinical value of three-dimensional measurement in the diagnosis of thoracic myelopathy caused by ossification of the ligamentum flavum.

BACKGROUND: Thoracic ossification of the ligamentum flavum (OLF) is a major cause of thoracic myelopathy, which is often accompanied by multiple segmental stenosis or other degenerative spinal diseases. However, in the above situations, it is difficult to determine the exact segment responsible. The objective of this study was to analyze three-dimensional (3D) radiological parameters in order to establish a novel diagnostic method for discriminating the responsible segment in OLF-induced thoracic myelopathy, and to evaluate its superiority compared to the conventional diagnostic methods. METHODS: Eighty-one patients who underwent surgery for thoracic myelopathy caused by OLF from 2016 to 2020 were enrolled in this study as the myelopathy group, and 79 patients who had thoracic OLF but displayed no definite neurological signs from 2018 to 2020 were enrolled as the non-myelopathy group. We measured the one-dimensional (1D), two-dimensional (2D), and 3D radiological parameters, calculated their optimal cutoff values, and compared their diagnostic values. RESULTS: Significant differences were observed in the 1D, 2D, and 3D radiological parameters between the myelopathy and non-myelopathy groups (P<0.01). As a 3D radiological parameter, the OLF volume (OLFV) ratio (OLFV ratio = OLFV/normal canal volume × 100%) was the most accurate parameter for diagnosing OLF-induced thoracic myelopathy, with a diagnostic coincidence rate of 88.1%. We also found that an OLFV ratio of 26.3% could be used as the optimal cutoff value, with a sensitivity of 87.7% and a specificity of 88.6%. Moreover, the OLFV ratio [area under the curve (AUC): 0.92, 95% confidence interval (CI): 0.86-0.95] showed a statistically higher diagnostic value than the 1D and 2D parameters (AUC: 0.75, 95% CI: 0.67-0.81; AUC: 0.84, 95% CI: 0.77-0.89, respectively) (P<0.05). Pearson correlation analysis illustrated that the OLFV ratio was significantly negatively correlated with preoperative modified Japanese Orthopedic Association (mJOA) score (r=-0.73, 95% CI: -0.81 to -0.60, P<0.01). CONCLUSIONS: Our results demonstrate the superiority of the OLFV ratio over the conventional 1D and 2D computed tomography (CT)-based radiological parameters for the diagnosis of OLF-induced thoracic myelopathy. The novel diagnostic method based on the OLFV ratio will help to determine the responsible segment in multi-segmental thoracic OLF or when thoracic OLF coexists with other degenerative spinal diseases. The OLFV ratio also accurately reflects the clinical state of symptomatic patients with thoracic OLF.

How much space of the spinal canal should be restored by hoisting the vertebrae-OPLL complex for sufficient decompression in anterior controllable antedisplacement and fusion? A multicenter clinical radiological study.

BACKGROUND CONTEXT: Anterior controllable antedisplacement and fusion (ACAF) is a novel surgical technique for the treatment of ossification of the posterior longitudinal ligament (OPLL). Its prognostic factors for decompression have not been well studied. Additionally, no detailed radiological standard has been set for hoisting the vertebrae-OPLL complex (VOC) in ACAF. PURPOSE: To identify the possible prognostic factors for decompression outcomes after ACAF for cervical OPLL, to determine the critical value of radiological parameters for predicting good outcomes, and to establish a radiological standard for hoisting the VOC in ACAF. STUDY DESIGN: This was a retrospective multicenter study. PATIENT SAMPLE: A total of 121 consecutive patients with OPLL who underwent ACAF at a point between January 2017 and June 2018 at any one of seven facilities and were monitored for at least 1 year afterward were enrolled in a multicenter study. OUTCOME MEASURES: Japanese Orthopedic Association (JOA) scores, recovery rate (RR) of neurologic function, and surgical complications were used to determine the effectiveness of ACAF. METHODS: Patients were divided into two groups according to their RR for neurologic function. Patients with an RR of ≥50% and an RR of <50% were designated as having good and poor decompression outcomes, respectively. The relationship between various possible prognostic factors and decompression outcomes was assessed by univariate and multivariate analysis. The receiver operating characteristic curve was used to determine the optimal cutoff value of the radiological parameters for prediction of good decompression outcomes. Next, the patients were redivided into three groups according to the cutoff value of the selected radiological parameter (postoperative anteroposterior canal diameter [APD] ratio). Patients with postoperative APD ratios of ≤80.7%, 80.7%-100%, and ≥100% were defined as members of the incomplete, optimal, and excessive antedisplacement groups, respectively. Differences in decompression outcomes among the three groups were compared to verify the reliability of the postoperative APD ratio and assess the necessity of excessive antedisplacement. RESULTS: Multivariate logistic regression analysis showed that patients' age at surgery (odds ratio [OR]=1.18; 95% confidence interval [CI]=1.08-1.29; p<.01) and postoperative APD ratio (OR=0.83; 95% CI=0.77-0.90; p<.01) were independently associated with decompression outcomes. The optimal cutoff point of the postoperative APD ratio was calculated at 80.7%, with 86.2% sensitivity and 73.5% specificity. There were no significant differences in the postoperative JOA scores and RRs between the excessive antedisplacement group and optimal antedisplacement group (p>.05). However, a lower incidence of cerebrospinal fluid leakage and screw slippage was observed in the optimal antedisplacement group (p<.05). CONCLUSIONS: Patients' age at surgery and their postoperative APD ratio are the two prognostic factors of decompression outcomes after ACAF. The postoperative APD ratio is also the most accurate radiological parameter for predicting good outcomes. Our findings suggest that it is essential for neurologic recovery to restore the spinal canal to more than 80.7% of its original size (postoperative APD ratio >80.7%), and restoration to less than its original size (postoperative APD ratio <100%) will help reduce the incidence of surgical complications. This may serve as a valuable reference for establishment of a radiological standard for hoisting the VOC in ACAF.

Cuprous oxide nanoparticles trigger reactive oxygen species-induced apoptosis through activation of erk-dependent autophagy in bladder cancer.

Cisplatin-based chemotherapy is the first-line treatment for patients with advanced bladder cancer. However, as more than 50% of patients are ineligible for cisplatin-based chemotherapy, there is an urgent need to develop new drugs. Cuprous oxide nanoparticles (CONPs), as a new nano-therapeutic agent, have been proved to be effective in many kinds of tumors. In the present study, CONPs showed dose-dependent and time-dependent inhibitory effects on various bladder cancer cell lines (T24, J82, 5637, and UMUC3) and weak inhibitory effects on non-cancerous epithelial cells (SVHUCs). We found that CONPs induced cell cycle arrest and apoptosis in bladder cancer cells. We further demonstrated that the potential mechanisms of CONP-induced cytotoxicity were apoptosis, which was triggered by reactive oxygen species through activation of ERK signaling pathway, and autophagy. Moreover, the cytotoxic effect of CONPs on bladder cancer was confirmed both in orthotopic xenografts and subcutaneous nude mouse models, indicating that CONPs could significantly suppress the growth of bladder cancer in vivo. In further drug combination experiments, we showed that CONPs had a synergistic drug-drug interaction with cisplatin and gemcitabine in vitro, both of which are commonly used chemotherapy agents for bladder cancer. We further proved that CONPs potentiated the antitumor activity of gemcitabine in vivo without exacerbating the adverse effects, suggesting that CONPs and gemcitabine can be used for combination intravesical chemotherapy. In conclusion, our preclinical data demonstrate that CONPs are a promising nanomedicine against bladder cancer and provide good insights into the application of CONPs and gemcitabine in combination for intravesical bladder cancer treatment.

Prognostic value of the combined expression of tumor-associated trypsin inhibitor (TATI) and p53 in patients with bladder cancer undergoing radical cystectomy.

BACKGROUND: Urothelial carcinoma of the bladder is a heterogeneous disease for which reliable prognostic molecular biomarkers have not been established. OBJECTIVE: To investigate the prognostic value of tumor-associated trypsin inhibitor (TATI) expression combined with p53 expression in bladder cancer patients who have undergone radical cystectomy. METHODS: Tissue microarrays from 110 patients were analyzed immunohistochemically for TATI and p53 protein expression. Complete clinical-pathological information and follow-up data were collected. Univariable Kaplan-Meier analysis and log-rank test were performed to assess the association between TATI and p53 expression patterns with clinical outcomes. Cox's proportional hazard analysis was performed to identify potential independent risk factors for predicting disease progression and evaluate the prognostic value of combining the expression of TATI and p53 on progression-free survival (PFS) and overall survival (OS). RESULTS: TATI expression was positively correlated with favorable differentiation of bladder cancer, and lower tumor stage. p53 expression was positively related to tumor stage, tumor grade, and lymph-node invasion. Univariate Kaplan-Meier analysis revealed significant differences between TATI-positive vs. TATI-negative and p53-positive vs. p53-negative patients, regarding PFS. Multivariate analysis showed that both TATI and p53 expression were independent factors for predicting disease progression. CONCLUSION: TATI expression patterns could enhance the prognostic value of p53 overexpression on progression.

Dysbiosis signatures of the microbial profile in tissue from bladder cancer.

BACKGROUND: To examine the microbial profiles in parenchyma tissues in bladder cancer. METHODS: Tissue samples of cancerous bladder mucosa were collected from patients diagnosed with bladder cancer (22 carcinoma tissues and 12 adjacent normal tissues). The V3-V4 region of the bacterial 16S rRNA gene was PCR amplified, followed by sequencing on an Illumina MiSeq platform. Bioinformatics analysis for microbial classification and functional assessment was performed to assess bladder microbiome diversity and variations. RESULTS: The predominant phylum in both tissues was Proteobacteria. The cancerous tissues exhibited lower species richness and diversity. Beta diversity significantly differed between the cancerous and normal tissues. Lower relative abundances of the microbial genera Lactobacillus, Prevotella_9, as well as Ruminococcaceae were observed, whereas those of Cupriavidus spp., an unknown genus of family Brucellaceae, and Acinetobacter, Anoxybacillus, Escherichia-Shigella, Geobacillus, Pelomonas, Ralstonia, and Sphingomonas were higher in the cancerous tissues. These findings indicate that these genera may be potentially utilized as biomarkers for bladder cancer. PICRUSt analysis revealed that several pathways involved in the metabolism of harmful chemical compounds were enriched in the cancer tissues, thereby providing evidence that environmental factors are strongly associated with bladder cancer etiology. CONCLUSION: This is the first study that has described and analyzed the dysbiotic motifs of urinary microbiota in the parenchymatous tissues of bladder cancer via 16S rRNA gene sequencing. Our results suggest that changes in the bladder microbiome may serve as biomarkers for bladder cancer, possibly assisting in disease screening and monitoring.