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mRNA‐based molecular subtypes have implications for bladder cancer prognosis and clinical benefit from certain therapies. Whether small extracellular vesicles (sEVs) can reflect bladder cancer molecular subtypes is unknown. We performed whole transcriptome RNA sequencing for formalin fixed paraffin embedded (FFPE) tumour tissues and sEVs separated from matched tissue explants, urine and plasma in patients with bladder cancer. sEVs were separated using size‐exclusion chromatography, and characterized by transmission electron microscopy, nano flow cytometry and western blots, respectively. High yield of sEVs were obtained using approximately 1 g of tissue, incubated with media for 30 min. FFPE tumour tissue and tumour tissue‐derived sEVs demonstrated good concordance in molecular subtype classification. All urinary sEVs were classified as luminal subtype, while all plasma sEVs were classified as Ba/Sq subtype, regardless of the molecular subtypes indicated by their matched FFPE tumour tissue. The comparison within urine sEVs, which may exclude the sample type specific background, could pick up the different biology between NMIBC and MIBC, as well as the signature genes related to molecular subtypes. Four candidate sEV‐related bladder cancer‐specific mRNA biomarkers, FAM71E2, OR4K5, FAM138F and KRTAP26‐1, were identified by analysing matched urine sEVs, tumour tissue derived sEVs, and adjacent normal tissue derived sEVs. Compared to sEVs separated from biofluids, tissue‐derived sEVs may reflect more tissue‐ or disease‐specific biological features. Urine sEVs are promising biomarkers to be used for liquid biopsy‐based molecular subtype classification, but the current algorithm needs to be modified/adjusted. Future work is needed to validate the four new bladder cancer‐specific biomarkers in large cohorts. [ABSTRACT FROM AUTHOR]

With the development of technology, the application of intelligent coal gangue sorting is more and more favored by coal mining enterprises. The coal gangue intelligent sorting system has higher requirements on the coal conveyor belt. The traditional transmission system has the problems of slow speed response, unstable operation, high energy consumption and jitter in the process of speed change. Using PLC, touch screen, frequency converter, RS-485, sensors and so on, the speed control and speed monitoring system of belt transport mechanism is constructed. By analyzing the error law of the system speed control and using Numpy system analysis and calculation, speed pre-compensation can be made. Then by controling speed precision through the PID and monitoring display through the time-speed curve, the real-time automation gives an alarm for abnormal speed situation. According to the speed requirement of the intelligent sorting system of coal gangue, the system can quickly reach the predetermined speed value, and effectively eliminate the shaking phenomenon in the process of changing speed. The system has strong universality, easy maintenance, and stable speed control, which is conducive to improving the reliability and efficiency of the intelligent sorting system for coal gangue and reduceing transmission mechanism wear caused by dithering. [ABSTRACT FROM AUTHOR]

As an efficient watermark attack method, geometric distortions destroy the synchronization between the watermark encoder and decoder. Local geometric distortion is a considerable challenge in the watermarking field. Although many geometric distortion resilient watermarking schemes have been proposed, few perform well against local geometric distortions, such as random bending attacks (RBAs). To address this problem, this paper proposes a novel watermark synchronization process and a corresponding watermarking scheme. In our scheme, the watermark bits are represented by random patterns. The message is encoded to obtain a watermark unit, and the watermark unit is flipped to generate a symmetrical watermark. Then, the symmetrical watermark is additively embedded into the spatial domain of the host image. In watermark extraction, we first obtain the theoretical mean-square error minimized estimation of the watermark. Then, an autoconvolution function is applied to this estimation to detect the symmetry and obtain a watermark unit map. According to this map, the watermark can be accurately synchronized, and then extraction can be performed. Experimental results demonstrate the excellent robustness of the proposed watermarking scheme to local geometric distortions, global geometric distortions, common image processing operations, and some kinds of combined attacks. [ABSTRACT FROM AUTHOR]

• Behavior of Cr-coated clad under integral LOCA test is simulated in FEA. • Current burst criteria for Zircaloy is ineffective to capture Cr-coated concept. • New overstress and plasticity instability criteria for the Cr coating are proposed. • Coating thickness is found to be numerically insensitive to burst temperature. Chromium (Cr) coated cladding is one of the most promising accident-tolerant fuels for pressurized water reactors. The behavior of Cr-coated cladding under the accident conditions is crucial to quantify its implication on safety, licensing and economics. This work focuses on the modeling of the burst behavior of Cr-coated cladding under Loss of Coolant Accidents (LOCAs). For this purpose, the material properties and behavior models of Zircaloy and chromium have been studied and implemented into the ABAQUS. Then the ABAQUS models are compared against several burst tests done by Korea Atomic Energy Research Institute (KAERI) and Électricité de France (EDF). During the comparison process, different high temperature creep models, zircaloy cladding burst criteria and coating thicknesses are adopted to investigate the thermo-mechanical performance and burst behavior of Cr-coated claddings under LOCA. Based on the comparative computational analysis, 100% and 85% Cr fracture strength and the strain rate of 0.23 /s and 0.07 /s are proposed as a new overstress burst criterion for coated cladding under a heating rate from 5 K/s and 10 K/s. The effect of coating thickness on the proposed criteria and the ballooning behavior of the coated cladding was predicted to be insignificant. The proposed criteria are beneficial for better understanding of the coated clad burst phenomena and the best estimation of coated clad performance under LOCA scenarios. [ABSTRACT FROM AUTHOR]

Serine hydroxymethyltransferase 2 (SHMT2) is a key enzyme that regulates serine/glycine transition; however, its specific function and molecular mechanisms in tumors remain controversial. In this study, we aimed to enhance the understanding in this regard. Through in vitro and in vivo experiments, as well as data analyses using public databases, we investigated the effect of SHMT2 in prostate cancer. Our results indicated that SHMT2 acts as a prostate cancer tumor proliferation suppressor and negatively regulates the aggressive behavior of prostate cancer through activation of epithelial–mesenchymal transition. Additionally, downregulated SHMT2 expression was observed in more advanced prostate cancer phenotypes, and further analysis showed that its depletion promoted proliferation and migration in prostate cancer cell lines. Taken together, our results revealed the function of SHMT2 in prostate cancer and may potentially play a role in the exploration of new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Purpose: Benefits of docetaxel-based neoadjuvant chemohormonal therapy (NCHT) before radical prostatectomy (RP) remain largely unknown. We explored whether docetaxel-based NCHT would bring pathological benefits and improve biochemical progression-free survival (bPFS) over neoadjuvant hormonal therapy (NHT) in locally advanced prostate cancer., Materials and Methods: A randomized trial was designed recruiting 141 locally advanced, high-risk prostate cancer patients who were randomly assigned at the ratio of 2:1 to the NCHT group (75 mg/m 2 body surface area every 3 weeks plus androgen deprivation therapy for 6 cycles) and the NHT group (androgen deprivation therapy for 24 weeks). The primary end point was 3-year bPFS. Secondary end points were pathological response including pathological downstaging and minimal residual disease rates., Results: The NCHT group showed significant benefits in 3-year bPFS compared to the NHT group (29% vs 9.5%, P = .002). At a median follow-up of 53 months, the NCHT group achieved a significantly longer median bPFS time than the NHT group (17 months vs 14 months). No significant differences were found between the 2 groups in pathological downstaging and minimal residual disease rates., Conclusions: NCHT plus RP achieved significant bPFS benefits when compared with NHT plus RP in high-risk, locally advanced prostate cancer. A larger cohort with longer follow-up duration is essential in further investigation.

Objective: To systematically evaluate the effect of levosimendan on cardiac function and outcomes in patients with sepsis., Method: We searched multiple databases including CNKI, VIP, WanFang Data, WOS, PubMed, EMbase, and The Cochrane Library up to February 2023. We targeted RCTs comparing levosimendan with dobutamine as a control for treating sepsis. After a rigorous screening and quality evaluation, 18 studies were selected for meta-analysis using Review Manager 5.4., Results: Out of 18 studies involving 980 sepsis patients, the meta-analysis revealed the following for the levosimendan group compared to dobutamine: (1) A significant reduction in mortality rate (OR = 0.63, 95% CI (0.42,0.95), P = .03). (2) Shortened ICU stay (MD = -2.55, 95% CI (-3.12, -1.98), P < .00001). (3) Increased left ventricular ejection fraction (LVEF) (MD = 6.05, 95%CI (5.28, 6.81), P < .00001) and cardiac index (CI) (MD = 0.47, 95%CI (0.35, 0.59), P < .00001). (4) Decreased blood lactate (Lac) (MD = -1.31, 95%CI (-1.73, -0.90), P < .00001) and troponin I (TnI) levels (MD = -0.43, 95%CI (-0.66, -0.21), P = .0002). (5) Reduced incidence of adverse events (OR = 0.43, 95% CI (0.23,0.81), P = .008)., Conclusions: Compared to dobutamine, levosimendan substantially enhances cardiac function in sepsis patients, leading to improved outcomes and fewer adverse events.

Introduction: Cancer-associated fibroblasts (CAFs) are one of the most abundant cell types in tumor microenvironment. However, the phenotypic and functional heterogeneities among CAFs have not been sufficiently investigated in prostate cancer., Methods: We obtained and analyzed the single-cell RNA-sequencing data from 26 hormone-sensitive prostate cancer samples and 8 castration-resistant prostate cancer samples, along with the analysis of bulk-sequencing datasets. Furthermore, we performed multicolor immunofluorescence staining to verify the findings from the data analysis., Results: We identified two major CAFs subtypes with distinct molecular characteristics and biological functions in prostate cancer microenvironment, namely αSMA+ CAV1+ CAFs-C0 and FN1+ FAP+ CAFs-C1. Another single-cell RNA-sequencing dataset containing 7 bone metastatic prostate cancer samples demonstrated that osteoblasts in the bone metastatic lesions comprised two subtypes with molecular characteristics and biological functions similar to CAFs-C0 and CAFs-C1 in the primary tumor sites. In addition, we discovered a transcriptional factor regulatory network depending on CAFs-C1. CAFs-C1, but not CAFs-C0, was associated with castration resistance and poor prognosis. We also found that CAFs-C1 signature was involved in treatment resistance to immune checkpoint inhibitors., Discussion: In summary, our results identified the presence of heterogeneous CAFs subtypes in prostate cancer microenvironment and the potential of specific CAFs subtype as therapeutic target for castration-resistant prostate cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pan, Ma, Liu, Qian, Shao, Liu, Wang and Xue.)

Introduction: Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer with poor prognosis and resistance to hormone therapy, which has limited therapeutic approaches. Therefore, this study aimed to identify a novel treatment for NEPC and provide evidence of its inhibitory effects., Methods: We performed a high-throughput drug screening and identified fluoxetine, originally an FDA-approved antidepressant, as candidate therapeutic agent for NEPC. We carried out both in vitro and in vivo experiments to demonstrate the inhibitory effects of fluoxetine on NEPC models and its mechanism in detail., Results: Our results demonstrated that fluoxetine effectively curbed the neuroendocrine differentiation and inhibited cell viability by targeting the AKT pathway. Preclinical test in NEPC mice model (PBCre4: Ptenf/f; Trp53f/f; Rb1f/f) showed that fluoxetine effectively prolonged the overall survival and reduced the risk of tumor distant metastases., Discussion: This work repurposed fluoxetine for antitumor application, and supported its clinical development for NEPC therapy, which may provide a promising therapeutic strategy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Ji, Li, Liu, Shen, Su, Ma, Zhang, Wang, Zhu and Xue.)

Considering the dismal prognosis of castration-resistant prostate cancer (CRPC), it is critical to identify novel therapeutic targets in this disease. Malignant cells have metabolic dependencies distinct from their healthy counterparts, resulting in therapeutic vulnerabilities. Although PTEN and TP53 are the most frequently comutated or codeleted driver genes in lethal CRPC, the metabolic dependencies underlying PTEN/p53 deficiency-driven CRPC for therapeutic intervention remain largely elusive. In this study, PTEN/p53 deficient tumors were determined to be reliant on cholesterol metabolism. Moreover, PTEN/p53 deficiency transcriptionally upregulated squalene epoxidase (SQLE) via activation of sterol regulatory element-binding protein 2 (SREBP2). In addition, PTEN deficiency enhanced the protein stability of SQLE by inhibiting the PI3K/Akt/GSK3β-mediated proteasomal pathway. Consequently, SQLE increased cholesterol biosynthesis to facilitate tumor cell growth and survival. Pharmacologic blockade of SQLE with FR194738 profoundly suppressed the invasive program of CRPC. Collectively, these results demonstrate a synergistic relationship between SQLE and PTEN/p53 deficiency in CRPC development and progression. Therefore, pharmacologic interventions targeting SQLE may hold promise for the treatment of patients with CRPC., Significance: This study reveals PTEN and p53 deficiency confers a dependence on SQLE-mediated cholesterol metabolism, providing insights for new therapeutic strategies for treating castration-resistant prostate cancer., (©2022 American Association for Cancer Research.)

The androgen receptor (AR) signaling is a key contributor to tumorigenesis and the progression of prostate cancer. A subset of patients may develop neuroendocrine (NE) features, resulting in resistance to androgen deprivation therapy and poor prognosis. In this study, we combined immunostaining and bulk and single-cell transcriptome analyses to better characterize the status of AR in prostate cancer with neuroendocrine differentiation. The exploration of online datasets indicated the existence of AR HIGH /NE HIGH prostate cancer and revealed that these double-high cases are majorly present in castration-resistant prostate cancer with a less neuroendocrine-transdifferentiated state. We then reviewed 8,194 prostate cancer cases with available immunohistochemistry reports and found 2.3% cases ( n = 189) that showed at least one of the NE markers (chromogranin A, synaptophysin, and neural cell adhesion molecule 1) being positive in at least 5% of epithelial cells. Within these 189 cases, we observed that 81.0% cases ( n = 153) showed AR positive and 19.0% ( n = 36) showed AR negative. Patients with AR loss tumors demonstrated a correlation with adverse clinical stages, indicating a trade-off between AR and advanced disease in neuroendocrine differentiation. Using multiplex immunofluorescence staining, we observed the co-localization of AR and NE markers in prostate cancer cells. In addition, data mining of single-cell transcriptome further confirmed the existence of AR HIGH /NE HIGH prostate cancer cells in castration-resistant samples and suggested that AR still exerts its androgen response and anti-apoptotic effect in these double-high cells. Thus, our study provides a better understanding of AR signaling in the cellular plasticity of prostate cancer with neuroendocrine differentiation and allows new insights into the therapeutic development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Su, Chen, Jiang, Yu, Zhang, Ma, Ji, Shen, Xin, Qi, Xue and Wang.)

Background: Prostate cancer is usually considered as immune "cold" tumor with poor immunogenic response and low density of tumor-infiltrating immune cells, highlighting the need to explore clinically actionable strategies to sensitize prostate cancer to immunotherapy. In this study, we investigated whether docetaxel-based chemohormonal therapy induces immunologic changes and potentiates checkpoint blockade immunotherapy in prostate cancer. Methods: We performed transcriptome and histopathology analysis to characterize the changes of prostate cancer immune microenvironment before and after docetaxel-based chemohormonal therapy. Furthermore, we investigated the therapeutic benefits and underlying mechanisms of chemohormonal therapy combined with anti-PD1 blockade using cellular experiments and xenograft prostate cancer models. Finally, we performed a retrospective cohort analysis to evaluate the antitumor efficacy of anti-PD1 blockade alone or in combination with docetaxel-based chemotherapy. Results: Histopathology assessments on patient samples confirmed the enrichment of tumor-infiltrating T cells after chemohormonal therapy. Moreover, we found that docetaxel activated the cGAS/STING pathway in prostate cancer, subsequently induced IFN signaling, resulting in lymphocytes infiltration. In a xenograft mouse model, docetaxel-based chemohormonal therapy prompted the intratumoral infiltration of T cells and upregulated the abundance of PD1 and PD-L1, thereby sensitizing mouse tumors to the anti-PD1 blockade. To determine the clinical significance of these results, we retrospectively analyzed a cohort of 30 metastatic castration-resistant prostate cancer patients and found that docetaxel combined with anti-PD1 blockade resulted in better prostate-specific antigen progression-free survival when compared with anti-PD1 blockade alone. Conclusions: Our study demonstrates that docetaxel activates the antitumoral immune response and facilitates T cell infiltration in a cGAS/STING-dependent manner, providing a combination immunotherapy strategy that would improve the clinical benefits of immunotherapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objective: To explore the value of surface-enhanced Raman spectroscopy analysis of pretreated plasma samples in prediction of bladder cancer (BCa) recurrence after neoadjuvant chemotherapy (NAC) and radical cystectomy (RC)., Patients and Methods: SERS was used to analyze plasma samples collected before biopsy and treatment in BCa patients undergoing NAC and RC. The value of clinicopathological parameters and distinctive SERS peaks in the prediction of disease recurrence were analyzed in Cox regression proportional hazard analysis and Log rank test. Principal component analysis and linear discriminant analysis (PCA-LDA) were employed to process spectral data and construct diagnostic algorithms., Results: A total of 88 patients with 440 plasma SERS spectra were collected. The SRES spectra from recurrent patients were compared with patients who remained recurrence free. The SERS demonstrated higher levels of circulating free nucleic acid components in recurrent population, which is represented by significantly higher intensities at SERS peaks of 725 cm -1 , 1328 cm -1 and 1455 cm -1 . The SERS also detected significantly lower levels of tryptophan shown as lower significantly intensities at the 1558 cm -1 , which is proved to be an independent predictor of BCa recurrence. The addition of SERS peaks of 1558 cm -1 to classic clinicopathological predictors including pathological tumor stage, lymph node metastasis and pathological downstaging can significantly enhance the power of the predictive model from 0.66 to 0.76 in the area under curve (AUC) of receiver operating characteristic (ROC) curves. Meanwhile, the PCA-LDA diagnostic model based on SERS spectra reveals a high accuracy of 85.2% in prediction of disease recurrence and the AUC of 0.92 in the ROC curve. When validated in the leave-one-out cross-validation method, the accuracy of the model remained 84.1%., Conclusion: We show that SERS analysis of plasma before NAC treatment can accurately classify patients with different risks of disease recurrence after surgery and improve the power of clinicopathological predictive models, thus refining clinical decision-making., Competing Interests: The authors have declared that no competing interest exists in this work., (© 2022 Qian et al.)