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Castration-resistant prostate cancer (CRPC) that occurs after the failure of androgen deprivation therapy is the leading cause of deaths in prostate cancer patients. Thus, there is an obvious and urgent need to fully understand the mechanism of CRPC and discover novel therapeutic targets. Long noncoding RNAs (lncRNAs) are crucial regulators in many human cancers, yet their potential roles and molecular mechanisms in CRPC are poorly understood. In this study, we discovered that an lncRNA HOXD-AS1 is highly expressed in CRPC cells and correlated closely with Gleason score, T stage, lymph nodes metastasis, and progression-free survival. Knockdown of HOXD-AS1 inhibited the proliferation and chemo-resistance of CRPC cells in vitro and in vivo. Furthermore, we identified several cell cycle, chemo-resistance, and castration-resistance-related genes, including PLK1, AURKA, CDC25C, FOXM1, and UBE2C, that were activated transcriptionally by HOXD-AS1. Further investigation revealed that HOXD-AS1 recruited WDR5 to directly regulate the expression of target genes by mediating histone H3 lysine 4 tri-methylation (H3K4me3). In conclusion, our findings indicate that HOXD-AS1 promotes proliferation, castration resistance, and chemo-resistance in prostate cancer by recruiting WDR5. This sheds a new insight into the regulation of CRPC by lncRNA and provides a potential approach for the treatment of CRPC. [Display omitted] Huang, Lin, and colleagues show that long noncoding RNA HOXD-AS1 is upregulated in castration-resistant prostate cancer (CRPC) and correlated with disease progression. HOXD-AS1 promotes proliferation, castration resistance, and chemo-resistance of prostate cancer cells via interacting with WDR5, which in turn activates the transcription of downstream genes.

Background Progression to a castration resistance state is the main cause of deaths in prostate cancer (PCa) patients. Androgen Receptor (AR) signaling plays the central role in progression of Castration Resistant Prostate Cancer (CRPC), therefore understanding the mechanisms of AR activation in the milieu of low androgen is critical to discover novel approach to treat CRPC. Methods Firstly, we explore the CRPC associated lncRNAs by transcriptome microarray. The expression and clinical features of lnc-LBCS are analyzed in three independent large-scale cohorts. The functional role and mechanism of lnc-LBCS are further investigated by gain and loss of function assays in vitro. Results The expression of Lnc-LBCS was lower in CRPC cells lines and tissues. LBCS downregulation was correlated with higher Gleason Score, T stage and poor prognosis of PCa patients. LBCS overexpression decreases, whereas LBCS knockdown increases, the traits of castration resistance in prostate cancer cells under androgen ablated or AR blocked condition. Moreover, knockdown of LBCS was sufficient to activate AR signaling in the absence of androgen by elevating the translation of AR protein. Mechanistically, LBCS interacted directly with hnRNPK to suppress AR translation efficiency by forming complex with hnRNPK and AR mRNA. Conclusions Lnc-LBCS functions as a novel AR translational regulator that suppresses castration resistance of prostate cancer by interacting with hnRNPK. This sheds a new insight into the regulation of CRPC by lncRNA mediated AR activation and LBCS-hnRNPK-AR axis provides a promising approach to the treatment of CRPC.

Background Chemotherapy and/or immunotherapy are first-line treatments for advanced muscle-invasive bladder cancer (BCa), but the unsatisfactory objective response rate to these treatments yields poor 5-year patient survival. Discovery of therapeutic targets essential for BCa maintenance is critical to improve therapy response in clinic. This study evaluated the role of targeting WD repeat domain 5 (WDR5) with the small molecule compound OICR-9429 and whether it could be used to treat bladder cancer. Methods We analysed the expression and clinical prognosis of WDR5 in a TCGA cohort. The pharmacological role of OICR-9429 was further investigated in vitro and in vivo. RNA sequencing, western blot, and chromatin immunoprecipitation (ChIP) were utilized to explored the mechanism underlying OICR-9429-induced WDR5 inhibition. Results First, we found that WDR5 expression was upregulated in BCa and was associated with histologic grade, metastasis status, histologic subtype, and molecular subtype. High WDR5 expression level was also correlated with shorter overall survival (OS) in BCa. The WDR5 inhibitor OICR-9429 reduced cell viability by decreasing H3K4me3 levels but not WDR5 levels in T24, UM-UC-3, and TCCSUP BCa cells. OICR-9429 suppressed the proliferation of BCa cells by blocking the G1/S phase transition. Next, OICR-9429 enhanced apoptosis and chemosensitivity to cisplatin in BCa cells. In addition, OICR-9429 independently inhibited the motility and metastatic behaviour of BCa cells. In vivo experiments further revealed that OICR-9429 suppressed tumour growth, enhanced chemosensitivity, and reduced the toxicity of cisplatin in BCa. Notably, WDR5 was positively correlated with programmed death-ligand 1 (PD-L1) expression, and OICR-9429 suppressed immune evasion by blocking PD-L1 induced by IFN-γ. Mechanistically, some cell cycle-, antiapoptosis-, DNA repair-, metastasis-, and immune evasion-related genes, including BIRC5, XRCC2, CCNB1, CCNE2, PLK1, AURKA, FOXM1, and PD-L1 were identified to be directly regulated by OICR-9429 in a H3K4me3-dependent manner. Conclusions Our novel finding is that the WDR5 inhibitor, OICR-9429, suppressed proliferation, metastasis and PD-L1-based immune evasion while enhancing apoptosis and chemosensitivity to cisplatin in BCa by blocking the WDR5-MLL complex mediating H3K4me3 in target genes. Hence, our findings offer insight into a multipotential anticancer compound, OICR-9429, which enhances the antitumour effect of cisplatin or immunotherapy in BCa.

Abstract Background/Aims: Long non-coding RNAs (lncRNAs) have emerged as new regulators and biomarkers in several cancers. However, few lncRNAs have been well characterized in clear cell renal cell carcinoma (ccRCC). Methods: We investigated the lncRNA expression profile by microarray analysis in 5 corresponding ccRCC tissues and adjacent normal tissues. Lung cancer–associated transcript 1 (LUCAT1) expression was examined in 90 paired ccRCC tissues by real-time PCR and validated by The Cancer Genome Atlas (TCGA) database. Kaplan-Meier analysis was used to examine the prognostic value of LUCAT1 and CXCL2 in ccRCC patients. Loss and gain of function were performed to explore the effect of LUCAT1 on proliferation and invasion in ccRCC cells. Western blotting was performed to evaluate the underlying mechanisms of LUCAT1 in ccRCC progression. Chemokine stimulation assay was performed to investigate possible mechanisms controlling LUCAT1 expression in ccRCC cells. Enzyme-linked immunosorbent assays were performed to determine serum CXCL2 in ccRCC patients and healthy volunteers. Receiver operating characteristic curve analysis was performed to examine the clinical diagnostic value of serum CXCL2 in ccRCC. Results: We found that LUCAT1 was significantly upregulated in both clinical ccRCC tissues (n = 90) and TCGA ccRCC tissues (n = 448) compared with normal tissues. Statistical analysis revealed that the LUCAT1 expression level positively correlated with tumor T stage (P < 0.01), M stage (P < 0.01), and TNM stage (P < 0.01). Overall survival and disease-free survival time were significantly shorter in the high-LUCAT1-expression group than in the low-LUCAT1-expression group (log-rank P < 0.01). LUCAT1 knockdown inhibited ccRCC cell proliferation and colony formation, induced cell cycle arrest at G1 phase, and inhibited cell migration and invasion. Overexpression of LUCAT1 promoted proliferation, migration, and invasion of ccRCC cells. Mechanistic investigations showed that LUCAT1 induced cell cycle G1 arrest by regulating the expression of cyclin D1, cyclin-dependent kinase 4, and phosphorylated retinoblastoma transcriptional corepressor 1. Moreover, LUCAT1 promoted proliferation and invasion in ccRCC cells partly through inducing the phosphorylation of AKT and suppressing the phosphorylation of GSK-3β. We also revealed that chemokine CXCL2, upregulated in ccRCC, induced LUCAT1 expression and might be a diagnostic and prognostic biomarker in ccRCC. Conclusions: LUCAT1 was upregulated in ccRCC tissues and renal cancer cell lines, and significantly correlated with malignant stage and poor prognosis in ccRCC. LUCAT1 promoted proliferation and invasion in ccRCC cells through the AKT/GSK-3β signaling pathway. We also revealed that LUCAT1 overexpression was induced by chemokine CXCL2. These findings indicate that the CXCL2/LUCAT1/AKT/GSK-3β axis is a potential therapeutic target and molecular biomarker for ccRCC.

Background: Hypoxia-induced M1 polarization of microglia and resultant inflammation take part in the damage caused by hypoxic-ischemic encephalopathy (HIE). Histone lactylation, a novel epigenetic modification where lactate is added to lysine residues, may play a role in HIE pathogenesis. This study investigates the role of histone lactylation in hypoxia-induced M1 microglial polarization and inflammation, aiming to provide insights for HIE treatment. Methods: In this study, we assessed the effects of hypoxia on microglial polarization using both an HIE animal model and an oxygen–glucose deprivation cell model. Histone lactylation at various lysine residues was detected by Western blotting. Microglial polarization and inflammatory cytokines were analyzed by immunofluorescence, qPCR, and Western blotting. RNA sequencing, ChIP-qPCR, and siRNA were used to elucidate mechanisms of H3K9 lactylation. Results: H3K9 lactylation increased due to cytoplasmic lactate during M1 polarization. Inhibiting P300 or reducing lactate dehydrogenase A expression decreased H3K9 lactylation, suppressing M1 polarization. Transcriptomic analysis indicated that H3K9 lactylation regulated M1 polarization via the TNF signaling pathway. ChIP-qPCR confirmed H3K9 lactylation enrichment at the TNFα locus, promoting OGD-induced M1 polarization and inflammation. Conclusions: H3K9 lactylation promotes M1 polarization and inflammation via the TNF pathway, identifying it as a potential therapeutic target for neonatal HIE.

Neuroendocrine prostate cancer (NEPC) represents a particularly aggressive subtype of prostate cancer with a challenging prognosis. The purpose of this investigation is to craft and confirm the reliability of nomograms that can accurately forecast the 1-, 3-, and 5-year overall survival (OS) and cancer-specific survival (CSS) rates for individuals afflicted with NEPC. Data pertaining to patients diagnosed with NEPC within the timeframe of 2010 to 2020 was meticulously gathered and examined from the Surveillance, Epidemiology, and End Results Program (SEER). To predict OS and CSS, we devised and authenticated two distinct nomograms, utilizing predictive variables pinpointed through both univariate and multivariate Cox regression analyses. The study encompassed 393 of NEPC patients, who were systematically divided into training and validation cohorts at a 2:1 ratio. Key prognostic factors were isolated, verified, and integrated into the respective nomograms for OS and CSS. The performance metrics, denoted by C-indices, stood at 0.730, 0.735 for the training set, and 0.784, 0.756 for the validation set. The precision and clinical relevance of the nomograms were further corroborated by the analysis of receiver operating characteristic curves, calibration plots, and decision curve analyses. The constructed nomograms have demonstrated impressive efficacy in forecasting the 1-, 3-, and 5-year OS and rates for patients with NEPC. Implementing these predictive tools in clinical settings is anticipated to considerably enhance the care and treatment planning for individuals diagnosed with this aggressive form of prostate cancer, thus providing tailored and more precise prognostic assessments.

Fiber Bragg grating has been successfully fabricated in the silica microfiber by the use of femtosecond laser point-by-point inscription. Temporal thermal response of the fabricated silica microfiber Bragg grating has been measured by the use of the CO 2 laser thermal excitation method, and the result shows that the time constant of the microfiber Bragg grating is reduced by an order of magnitude compared with the traditional single-mode fiber Bragg grating and the measured time constant is ~ 21ms.

Photonic-integrated circuits based on erbium-doped thin film lithium niobate on insulator has attracted broad interests with insofar various waveguide amplifiers and microlasers demonstrated. Wideband operation facilitated by the broadband absorption and emission of erbium ions necessitates the functional integration of wavelength filter and multiplexer on the same chip. Here, a low-loss wavelength division multiplexer at the resonant pumping and emission wavelengths (∼1480 nm and 1530–1560 nm) of erbium ions based on angled multimode interferometer is realized in the erbium-doped thin film lithium niobate on insulator fabricated by the photolithography assisted chemomechanical etching technique. The minimum on-chip insertion losses of the fabricated device are <0.7 dB for both wavelength ranges, and a 3-dB bandwidth of >20 nm is measured at the telecom C-band. Besides, direct visualization of the multimode interference pattern by the visible upconversion fluorescence of erbium ions compares well with the simulated light propagation in the multimode interferometer. Spectral tuning of the wavelength division multiplexer by structural design is also demonstrated and discussed.

Objective Conventional survival analysis plays a limited role in patients who have survived a period after initial treatment. The present study analyzed how conditional survival (CS) predicted survival rate over time for nonmetastatic muscle‐invasive bladder cancer (MIBC) patients after trimodal treatment. Method This retrospective study from the SEER database included consecutive patients with nonmetastatic MIBC who received trimodal therapy (TMT) between January 2010 and December 2017. Kaplan‐Meier analysis was used to estimate overall survival (OS) and cancer‐specific survival (CSS). CS was defined as the rate of surviving y years after already surviving for x years. Multivariate Cox regression analysis was used to identify prognostic factors. Result A total of 1110 nonmetastatic MIBC patients treated with TMT were included. Given a 1‐, 2‐, 3‐, and 4‐year after TMT, the rate of surviving to 5‐year, respectively, improved by +5.0 (20.0%), +17.0 (32.0%), +30.0 (45.0%), and +52.8 (67.8%) from those calculated at baseline (15.0%). The 2‐year CS rate of patients who had survived 1‐, 2‐, or 3‐year after TMT improved, respectively, compared to 3‐, 4‐, or 5‐year actual survival. Multivariate Cox regression analysis demonstrated that adverse variables (T stage, age) of OS and CSS lost their prognostic significance over time. Discussion and Conclusion Conditional survival rate of surviving to 5‐year after TMT kept a relatively stable level over time. In addition, those adverse variables were not always the prognostic factors over time. Only age was always the significant prognostic factor for conditional OS from baseline to 5‐year survival. Our results provided real‐time survival information and prognosis estimates to adjust follow‐up plans for nonmetastatic MIBC patients after TMT. Some variables were not always the prognostic factor over time. Only age was always the prognostic factor for conditional overall survival from baseline to 5‐year survival. Our results provided real‐time survival information and prognosis estimates to adjust follow‐up plans for non‐metastatic muscle‐invasive bladder cancer patients after trimodal therapy.

Under the background of the continuous progress of Industry 4.0 reform, the market demand for mobile robots in major world economies is gradually increasing. In order to improve the mobile robot's movement path planning quality and obstacle avoidance ability, this research adjusted the node selection method, pheromone update mechanism, transition probability and volatility coefficient calculation method of the ant colony algorithm, and improved the search direction setting and cost estimation calculation method of the A* algorithm. Thus, a robot movement path planning model can be designed with respect to the improved ant colony algorithm and A* algorithm. The simulation experiment results on grid maps show that the planning model constructed in view of the improved algorithm, the traditional ant colony algorithm, the Tianniu whisker search algorithm, and the particle swarm algorithm designed in this study converged after 8, 37, 23, and 26 iterations, respectively. The minimum path lengths after convergence were 13.24m, 17.82m, 16.24m, and 17.05m, respectively. When the edge length of the grid map is 100m, the minimum planning length and total moving time of the planning model constructed in view of the improved algorithm, the traditional ant colony algorithm, the longicorn whisker search algorithm, and the particle swarm algorithm designed in this study are 49m, 104m, 75m, 93m and 49s, 142s, 93s, and 127s, respectively. This indicates that the model designed in this study can effectively shorten the mobile path and training time while completing mobile tasks. The results of this study have a certain reference value for optimizing the robot's movement mode and obstacle avoidance ability.