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Abstract Conventional androgen deprivation therapy (ADT) targets the androgen receptor (AR) inhibiting prostate cancer (PCa) progression; however, it can eventually lead to recurrence as castration‐resistant PCa (CRPC), which has high mortality rates and lacks effective treatment modalities. The study confirms the presence of high glutathione peroxidase 4 (GPX4) expression, a key regulator of ferroptosis (i.e., iron‐dependent program cell death) in CRPC cells. Therefore, inducing ferroptosis in CRPC cells might be an effective therapeutic modality for CRPC. However, nonspecific uptake of ferroptosis inducers can result in undesirable cytotoxicity in major organs. Thus, to precisely induce ferroptosis in CRPC cells, a genetic engineering strategy is proposed to embed a prostate‐specific membrane antigen (PSMA)‐targeting antibody fragment (gy1) in the macrophage membrane, which is then coated onto mesoporous polydopamine (MPDA) nanoparticles to produce a biomimetic nanoplatform. The results indicate that the membrane‐coated nanoparticles (MNPs) exhibit high specificity and affinity toward CRPC cells. On further encapsulation with the ferroptosis inducers RSL3 and iron ions, MPDA/Fe/RSL3@M‐gy1 demonstrates superior synergistic effects in highly targeted ferroptosis therapy eliciting significant therapeutic efficacy against CRPC tumor growth and bone metastasis without increased cytotoxicity. In conclusion, a new therapeutic strategy is reported for the PSMA‐specific, CRPC‐targeting platform for ferroptosis induction with increased efficacy and safety.

This study was aimed at optimization of the fermentation conditions for agarase production by Sphingomonas sp.Q2 which was isolated from Gracilaria and characterization of its enzymatic properties and degradation products. The optimum fermentation conditions were determined by response surface analysis. The agarase was purified by (NH4)2SO4 precipitation and column separation and its enzymatic properties was investigated. The results indicated that the optimal culture medium components for agarase production were agar 4.42 g/L, K2HPO4 1.30 g/L, NaCl 10.51 g/L. The highest enzyme activity of 1085.71 U/mL was obtained ,which was 1.58 times compared with the initial activity. The crude enzyme was purified 7 times with 112048.82 U/mg of enzyme activity. The recovery rate of agarase was 48.04%. The enzyme had optimal temperature and pH of 40 ℃ and 6.5, respectively. The enzyme activity remained above 90% when stored at the optimum temperature for 8 h. The capital hydrolysates were identified as neoagarotetraose by MS and 13C-NMR. The agarase showed a good thermal stability and high stability, which laid the foundation for the development and application of functional oligosaccharides agar.

Background. MRI is an important tool for accurate detection and targeted biopsy of prostate lesions. However, the imaging appearances of some prostate cancers are similar to those of the surrounding normal tissue on MRI, which are referred to as MRI-invisible prostate cancers (MIPCas). The detection of MIPCas remains challenging and requires extensive systematic biopsy for identification. In this study, we developed a weakly supervised UNet (WSUNet) to detect MIPCas. Methods. The study included 777 patients (training set: 600; testing set: 177), all of them underwent comprehensive prostate biopsies using an MRI-ultrasound fusion system. MIPCas were identified in MRI based on the Gleason grade (≥7) from known systematic biopsy results. Results. The WSUNet model underwent validation through systematic biopsy in the testing set with an AUC of 0.764 (95% CI: 0.728-0.798). Furthermore, WSUNet exhibited a statistically significant precision improvement of 91.3% (p

Abstract Background Few studies have compared the use of transabdominal ultrasound (TAUS) and magnetic resonance imaging (MRI) to measure prostate volume (PV). In this study, we evaluate the accuracy and reliability of PV measured by TAUS and MRI. Methods A total of 106 patients who underwent TAUS and MRI prior to radical prostatectomy were retrospectively analyzed. The TAUS-based and MRI-based PV were calculated using the ellipsoid formula. The specimen volume measured by the water-displacement method was used as a reference standard. Correlation analysis and intraclass correlation coefficients (ICC) were performed to compare different measurement methods and Bland Altman plots were drawn to assess the agreement. Results There was a high degree of correlation and agreement between the specimen volume and PV measured with TAUS (r = 0.838, p

Abstract Background Prostate cancer (PCa), one of the common malignant tumors, is the second leading cause of cancer-related deaths in men. The circadian rhythm plays a critical role in disease. Circadian disturbances are often found in patients with tumors and enable to promote tumor development and accelerate its progression. Accumulating evidence suggests that the core clock gene NPAS2 (neuronal PAS domain-containing protein 2) has been implicated in tumors initiation and progression. However, there are few studies on the association between NPAS2 and prostate cancer. The purpose of this paper is to investigate the impact of NPAS2 on cell growth and glucose metabolism in prostate cancer. Methods Quantitative real-time PCR (qRT-PCR), immunohistochemical (IHC) staining, western blot, GEO (Gene Expression Omnibus) and CCLE (Cancer Cell Line Encyclopedia) databases were used to analyze the expression of NPAS2 in human PCa tissues and various PCa cell lines. Cell proliferation was assessed using MTS, clonogenic assays, apoptotic analyses, and subcutaneous tumor formation experiments in nude mice. Glucose uptake, lactate production, cellular oxygen consumption rate and medium pH were measured to examine the effect of NPAS2 on glucose metabolism. The relation of NPAS2 and glycolytic genes was analyzed based on TCGA (The Cancer Genome Atlas) database. Results Our data showed that NPAS2 expression in prostate cancer patient tissue was elevated compared with that in normal prostate tissue. NPAS2 knockdown inhibited cell proliferation and promoted cell apoptosis in vitro and suppressed tumor growth in a nude mouse model in vivo. NPAS2 knockdown led to glucose uptake and lactate production diminished, oxygen consumption rate and pH elevated. NPAS2 increased HIF-1A (hypoxia-inducible factor-1A) expression, leading to enhanced glycolytic metabolism. There was a positive correlation with the expression of NPAS2 and glycolytic genes, these genes were upregulated with overexpression of NPAS2 while knockdown of NPAS2 led to a lower level. Conclusion NPAS2 is upregulated in prostate cancer and promotes cell survival by promoting glycolysis and inhibiting oxidative phosphorylation in PCa cells.

IntroductionThe platelet-lymphocyte ratio (PLR), neutrophil-lymphocyte ratio (NLR), and systemic immune-inflammation index (SII) are markers for systemic inflammatory responses and have been shown by numerous studies to correlate with the prognosis of gastric cancer (GC). However, the diagnostic value of these three markers in GC is unclear, and no research has examined them in combination. In this study, we investigated the value of the PLR, NLR, and SII individually or in combination for GC diagnosis and elucidated the connection of these three markers with GC patients’ clinicopathological features.MethodsThis retrospective study was conducted on 125 patients diagnosed with GC and 125 healthy individuals, whose peripheral blood samples were obtained for analysis. The preoperative PLR, NLR, and SII values were subsequently calculated.ResultsThe results suggest that the PLR, NLR, and SII values of the GC group were considerably higher than those of the healthy group (all P ≤ 0.001); moreover, all three parameters were notably higher in early GC patients (stage I/II) than in the healthy population. The diagnostic value of each index for GC was analyzed using receiver operating characteristic (ROC) curve analysis and area under the curve (AUC) calculation. The diagnostic efficacy of the SII alone (AUC: 0.831; 95% confidence interval [CI], 0.777–0.885) was expressively better than those of the NLR (AUC: 0.821; 95% CI: 0.769–0.873, P = 0.017) and PLR (AUC: 0.783; 95% CI: 0.726–0.840; P = 0.020). The AUC value of the combination of the PLR, NLR, and SII (AUC: 0.843; 95% CI: 0.791–0.885) was significantly higher than that of the combination of the SII and NLR (0.837, 95% CI: 0.785–0.880, P≤0.05), PLR (P = 0.020), NLR (P = 0.017), or SII alone (P ≤ 0.001). The optimal cut-off values were determined for the PLR, NLR, and SII using ROC analysis (SII: 438.7; NLR: 2.1; PLR: 139.5). Additionally, the PLR, NLR, and SII values were all meaningfully connected with the tumor size, TNM stage, lymph node metastasis, and serosa invasion (all P ≤ 0.05). Elevated levels of the NLR and SII were linked to distant metastasis (all P ≤ 0.001).DiscussionThese data suggest that the preoperative PLR, NLR, and SII could thus be utilized as diagnostic markers for GC or even early GC. Among these three indicators, the SII had the best diagnostic efficacy for GC, and the combination of the three could further improve diagnostic efficiency.

Ischemic brain stroke is pathologically characterized by tissue acidosis, sustained calcium entry and progressive cell death. Previous studies focusing on antagonizing N-methyl-d-aspartate (NMDA) receptors have failed to translate any clinical benefits, suggesting a non-NMDA mechanism involved in the sustained injury after stroke. Here, we report that inhibition of intracellular proton-sensitive Ca2+-permeable transient receptor potential vanilloid 3 (TRPV3) channel protects against cerebral ischemia/reperfusion (I/R) injury. TRPV3 expression is upregulated in mice subjected to cerebral I/R injury. Silencing of TRPV3 reduces intrinsic neuronal excitability, excitatory synaptic transmissions, and also attenuates cerebral I/R injury in mouse model of transient middle cerebral artery occlusion (tMCAO). Conversely, overexpressing or re-expressing TRPV3 increases neuronal excitability, excitatory synaptic transmissions and aggravates cerebral I/R injury. Furthermore, specific inhibition of TRPV3 by natural forsythoside B decreases neural excitability and attenuates cerebral I/R injury. Taken together, our findings for the first time reveal a causative role of neuronal TRPV3 channel in progressive cell death after stroke, and blocking overactive TRPV3 channel may provide therapeutic potential for ischemic brain injury.

To investigate the transdermal absorption activity of hyaluronic acid oligosaccharides, hyaluronic acid oligosaccharides were prepared by enzymatic degradation of hyaluronic acid using hyaluronic acid lyase, and the hyaluronic acid oligosaccharides were analyzed by infrared spectroscopy and mass spectrometry, and their hygroscopic properties, body surface moisturizing properties and transdermal absorption properties were evaluated. The results showed that the optimum substrate concentration for the enzymatic preparation of hyaluronan oligosaccharides by hyaluronan lysis enzyme was 1%, and the optimum enzyme addition was 3.0 U/mg. The enzymatic preparation of hyaluronan oligosaccharides was free of moieties, and the enzymatic products were mainly unsaturated hyaluronan disaccharides. The enzymatically prepared hyaluronan oligosaccharide had excellent surface moisturizing and transdermal absorption properties, and would have a broad application prospect in the field of biochemicals.

Abstract Bladder cancer (BLCA) is the most common malignancy whose early diagnosis can ensure a better prognosis. However, the predictive accuracy of commonly used predictors, including patients’ general condition, histological grade, and pathological stage, is insufficient to identify the patients who need invasive treatment. Autophagy is regarded as a vital factor in maintaining mitochondrial function and energy homeostasis in cancer cells. Whether autophagy-related genes (ARGs) can predict the prognosis of BLCA patients deserves to be investigated. Based on BLCA data retrieved from the Cancer Genome Atlas and ARGs list obtained from the Human Autophagy Database website, we identified prognosis-related differentially expressed ARGs (PDEARGs) through Wilcox text and constructed a PDEARGs-based prognostic model through multivariate Cox regression analysis. The predictive accuracy, independent forecasting capability, and the correlation between present model and clinical variables or tumor microenvironment were evaluated through R software. Enrichment analysis of PDEARGs was performed to explore the underlying mechanism, and a systematic prognostic signature with nomogram was constructed by integrating clinical variables and the aforementioned PDEARGs-based model. We found that the risk score generated by PDEARGs-based model could effectively reflect deteriorated clinical variables and tumor-promoting microenvironment. Additionally, several immune-related gene ontology terms were significantly enriched by PDEARGs, which might provide insights for present model and propose potential therapeutic targets for BLCA patients. Finally, a systematic prognostic signature with promoted clinical utility and predictive accuracy was constructed to assist clinician decision. PDEARGs are valuable prognostic predictors and potential therapeutic targets for BLCA patients.

Over the past two decades, there has been a tendency toward early diagnosis of prostate cancer due to raised awareness among the general public and professionals, as well as the promotion of prostate-specific antigen (PSA) screening. As a result, patients with prostate cancer are detected at an earlier stage. Due to the risks of urine incontinence, erectile dysfunction, etc., surgery is not advised because the tumor is so small at this early stage. Doctors typically only advise active surveillance. However, it will bring negative psychological effects on patients, such as anxiety. And there is a higher chance of cancer progression. Focal therapy has received increasing attention as an alternative option between active monitoring and radical therapy. Due to its minimally invasive, oncological safety, low toxicity, minimal effects on functional outcomes and support by level 1 evidence from the only RCT within the focal therapy literature, photodynamic treatment (PDT) holds significant promise as the focal therapy of choice over other modalities for men with localized prostate cancer. However, there are still numerous obstacles that prevent further advancement. The review that follows provides an overview of the preclinical and clinical published research on PDT for prostate cancer from 1999 to the present. It focuses on clinical applications of PDT and innovative techniques and technologies that address current problems, especially the use of nanoparticle photosensitizers in PDT of prostate cancer.

Understanding the maturation stress and wood properties of poplar tension wood is critical for improving lumber yields and utilization ratio. In this study, the released longitudinal maturation strains (RLMS), anatomical features, physical and mechanical properties, and nano-mechanical properties of the cell wall were analyzed at different peripheral positions and heights in nine artificially inclined, 12-year-old poplar (Populus × euramericana cv. ‘Zhonglin46’) trees. The correlations between the RLMS and the wood properties were determined. The results showed that there were mixed effects of inclination on wood quality and properties. The upper sides of inclined stems had higher RLMS, proportion of G-layer, bending modulus of elasticity, and indentation modulus of the cell wall but a lower microfibril angle than the lower sides. At heights between 0.7 m and 2.2 m, only the double-wall thickness increased with height; the RLMS and other wood properties such as fiber length and basic density fluctuated or changed little with height. The RLMS were good indicators of wood properties in the tension wood area and at heights between 0.7 m and 1.5 m. The results of this study present opportunities to better understand the interactions and effects of these two phenomena, which both occur quite frequently in poplar stands and can influence the wood quality of valuable assortments.

Autism spectrum disorder (ASD) affects ~2% of the population in the US, and monogenic forms of ASD often result in the most severe manifestation of the disorder. Recently, SCN2A has emerged as a leading gene associated with ASD, of which abnormal sleep pattern is a common comorbidity. SCN2A encodes the voltage-gated sodium channel NaV1.2. Predominantly expressed in the brain, NaV1.2 mediates the action potential firing of neurons. Clinical studies found that a large portion of children with SCN2A deficiency have sleep disorders, which severely impact the quality of life of affected individuals and their caregivers. The underlying mechanism of sleep disturbances related to NaV1.2 deficiency, however, is not known. Using a gene-trap Scn2a-deficient mouse model (Scn2atrap), we found that Scn2a deficiency results in increased wakefulness and reduced non-rapid-eye-movement (NREM) sleep. Brain region-specific Scn2a deficiency in the suprachiasmatic nucleus (SCN) containing region, which is involved in circadian rhythms, partially recapitulates the sleep disturbance phenotypes. At the cellular level, we found that Scn2a deficiency disrupted the firing pattern of spontaneously firing neurons in the SCN region. At the molecular level, RNA-sequencing analysis revealed differentially expressed genes in the circadian entrainment pathway including core clock genes Per1 and Per2. Performing a transcriptome-based compound discovery, we identified dexanabinol (HU-211), a putative glutamate receptor modulator, that can partially reverse the sleep disturbance in mice. Overall, our study reveals possible molecular and cellular mechanisms underlying Scn2a deficiency-related sleep disturbances, which may inform the development of potential pharmacogenetic interventions for the affected individuals.

Jingliang Zhang et al. examine how dysfunctional PKA signaling impacts neuronal activity and seizure susceptibility in a mouse model of temporal lobe epilepsy. Their data suggest that autophosphorylation of the RIIβ subunit regulates neuronal excitability, and may act as a future therapeutic target.

Systematic administration of anti-inflammatory cytokine interleukin 4 (IL-4) has been shown to improve recovery after cerebral ischemic stroke. However, whether IL-4 affects neuronal excitability and how IL-4 improves ischemic injury remain largely unknown. Here we report the neuroprotective role of endogenous IL-4 in focal cerebral ischemia–reperfusion (I/R) injury. In multi-electrode array (MEA) recordings, IL-4 reduces spontaneous firings and network activities of mouse primary cortical neurons. IL-4 mRNA and protein expressions are upregulated after I/R injury. Genetic deletion of Il-4 gene aggravates I/R injury in vivo and exacerbates oxygen-glucose deprivation (OGD) injury in cortical neurons. Conversely, supplemental IL-4 protects Il-4−/− cortical neurons against OGD injury. Mechanistically, cortical pyramidal and stellate neurons common for ischemic penumbra after I/R injury exhibit intrinsic hyperexcitability and enhanced excitatory synaptic transmissions in Il-4−/− mice. Furthermore, upregulation of Nav1.1 channel, and downregulations of KCa3.1 channel and α6 subunit of GABAA receptors are detected in the cortical tissues and primary cortical neurons from Il-4−/− mice. Taken together, our findings demonstrate that IL-4 deficiency results in neural hyperexcitability and aggravates I/R injury, thus activation of IL-4 signaling may protect the brain against the development of permanent damage and help recover from ischemic injury after stroke.

PurposePLND (pelvic lymph node dissection)-validated nomograms are widely accepted clinical tools to determine the necessity of PLND by predicting the metastasis of lymph nodes (LNMs) in pelvic region. However, these nomograms are in lacking of a threshold to predict the metastasis of extrareolar lymph nodes beyond pelvic region, which is not suitable for PLND. The aim of this study is to evaluate a threshold can be set for current clinical PLND-validated nomograms to predict extrareolar LN metastases beyond pelvic region in high-risk prostate cancer patients, by using 68Ga-PSMA PET/CT as a reference to determine LN metastases (LNMs).Experimental DesignWe performed a retrospective analysis of 57 high-risk treatment-naïve PC patients in a large tertiary care hospital in China who underwent 68Ga-PSMA-617 PET/CT imaging. LNMs was detected by 68Ga-PSMA-617 PET/CT and further determined by imaging follow-up after anti-androgen therapy. The pattern of LN metastatic spread of PC patients were evaluated and analyzed. The impact of 68Ga-PSMA PET/CT on clinical decisions based on three clinical PLND-validated nomograms (Briganti, Memorial Sloan Kettering Cancer Center, Winter) were evaluated by a multidisciplinary prostate cancer therapy team. The diagnostic performance and the threshold of these nomograms in predicting extrareolar LNMs metastasis were evaluated via receiver operating characteristic (ROC) curve analysis.ResultsLNMs were observed in 49.1% of the patients by 68Ga-PSMA PET/CT, among which 65.5% of LNMs were pelvic-regional and 34.5% of LNMs were observed in extrareolar sites (52.1% of these were located above the diaphragm). The Briganti, MSKCC and Winter nomograms showed that 70.2%-71.9% of the patients in this study need to receive ePLND according to the EAU and NCCN guidelines. The LN staging information obtained from 68Ga-PSMA PET/CT would have led to changes of planned management in 70.2% of these patients, including therapy modality changes in 21.1% of the patients, which were mainly due to newly detected non-regional LNMs. The thresholds of nomograms to predict non-regional LNMs were between 64% and 75%. The PC patients with a score >64% in Briganti nomogram, a score >75% in MSKCC nomogram and a score >67% in Winter nomogram were more likely to have non-regional LNMs. The AUCs (Area under curves) of the clinical nomograms (Briganti, MSKCC and Winter) in predicting non-regional LNMs were 0.816, 0.830 and 0.793, respectively.ConclusionsBy using 68Ga-PSMA PET/CT as reference of LNM, the PLND-validated clinical nomograms can not only predict regional LNMs, but also predict non-regional LNMs. The additional information from 68Ga-PSMA PET/CT may provide added benefit to nomograms-based clinical decision-making in more than two-thirds of patients for reducing unnecessary PLND. We focused on that a threshold can be set for current clinical PLND-validated nomograms to predict extrareolar LN metastases with an AUC accuracy of about 80% after optimizing the simple nomograms which may help to improve the efficiency for PC therapy significantly in clinical practice.

Inflammatory bowel disease (IBD) has been gradually considered a public health challenge worldwide. Sulfated polysaccharides, extracted from seaweed, have been shown to have an anti-inflammatory effect on the disease. In this study, LMW-ulvan, a unique sulfate Ulva polysaccharide with low molecular weight, was prepared using the enzymatic method. The structural characterization of LMW-ulvan and its protective effect on colitis induced by dextran sulfate sodium (DSS) were studied. The results showed that LMW-ulvan with molecular weight of 2.56 kDa consists of 57.23% rhamnose (Rha), 28.76% xylose (Xyl), 7.42% glucuronic acid (GlcA), and 1.77% glucose (Glc). Its backbone contains (1→3,4)-linked Rha, (1→4)-linked Xyl, and (1→4)-linked GlcA with small amounts of (1→4)-linked Rha residues; sulfate substitution was at C-3 of Rha. LMW-ulvan was found to reduce DSS-induced disease activity index, colon shortening, and colonic tissue damage, which were associated with decreased oxidative stresses and inflammation, thus improving the expression of tight junction proteins. These results indicate that LMW-ulvan is able to improve colitis and may be a promising application for IBD.