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Androgen deprivation therapy (ADT) has long been the only treatment for metastatic hormone-sensitive prostate cancer (mHSPC). In recent years, with the use of docetaxel chemotherapy and the emergence of various novel hormone therapy drugs, such as Abiraterone, Enzalutamide, Apalutamide, Darolutamide, and Rezvilutamide, the treatment strategies for mHSPC have been greatly changed. Furthermore, local treatment has been added to the treatment of low tumor burden mHSPC and triple therapy has been regarded as an important treatment choice for high tumor burden mHSPC. The survival rate of mHSPC patients has increased significantly and the quality of life also improved with these new treatment strategies. This article reviews the latest advances and controversies in the current treatment of mHSPC. Ongoing clinical trials are introduced and further directions are also discussed in this mini-review.

It is known that sialyllactose (SL) in mammalians is a major source of sialic acid (Sia), which can further form cytidine monophosphate sialic acid (CMP-Sia), and the final product is polysialic acid (polySia) using polysialyltransferases (polySTs) on the neural cell adhesion molecule (NCAM). This process is called NCAM polysialylation. The overexpression of polysialylation is strongly related to cancer cell migration, invasion, and metastasis. In order to inhibit the overexpression of polysialylation, in this study, SL was selected as an inhibitor to test whether polysialylation could be inhibited. Our results suggest that the interactions between the polysialyltransferase domain (PSTD) in polyST and CMP-Siaand the PSTD and polySia could be inhibited when the 3′-sialyllactose (3′-SL) or 6′-sialyllactose (6′-SL) concentration is about 0.5 mM or 6′-SL and 3 mM, respectively. The results also show that SLs (particularly for 3′-SL) are the ideal inhibitors compared with another two inhibitors, low-molecular-weight heparin (LMWH) and cytidine monophosphate (CMP), because 3’-SL can not only be used to inhibit NCAM polysialylation, but is also one of the best supplements for infant formula and the gut health system.

Abstract A generation method of new metric in the case of static spherically symmetric space-time is derived. Using this approach, we construct a metric which describes Euler–Heisenberg black hole surrounded by perfect fluid dark matter and investigate its optical and thermodynamic properties. We found that radius of shadow will increase with the increase of dark matter effect, and more strong dark matter will diminish the light intensity of accretion disk generally. Moreover, in thermodynamics, when quantum electrodynamic parameter is positive, there will be a critical value of dark matter parameter, which determine the number of black hole’s critical points.

With the rapid development of Artificial Intelligence, automatic writing evaluation (AWE) has received much attention from English Foreign Language (EFL) writing teachers. However, the obstacles and potential problems of integrating AWE in EFL writing instruction have yet to be explored. Scholars have indicated that the effectiveness of AWE in EFL writing instruction depends on the learners' depth of reflection. Hence, this study proposes a learning approach that integrates AWE and peer assessment (PA) based on the knowledge-building theory, with the expectation that learners will be able to strengthen their reflections on AWE feedback through PA, and thereby improve their EFL writing performance. To examine the effectiveness of the proposed approach, a quasi-experiment was conducted in a university EFL writing class. One of the classes (33 students) was the experimental group using the PA-AWE approach, and the other class (31 students) was a control group that studied using the conventional AWE approach (C-AWE approach). Findings revealed that the PA-AWE group outperformed the C-AWE group regarding EFL writing performance, learning motivation, critical thinking, and reduced EFL writing anxiety. In addition, a thematic inductive qualitative analysis of the interview data indicated each approach's benefits and learning conceptions.

In future regenerative medicine, far-infrared radiation (FIR) may be an essential component of optical therapy. Many studies have confirmed or validated the efficacy and safety of FIR in various diseases, benefiting from new insights into FIR mechanisms and the excellent performance of many applications. However, the lack of consensus on the biological effects and therapeutic parameters of FIR limits its practical applications in the clinic. In this review, the definition, characteristics, and underlying principles of the FIR are systematically illustrated. We outline the therapeutic parameters of FIR, including the wavelength range, power density, irradiation time, and distance. In addition, the biological effects, potential molecular mechanisms, and preclinical and clinical applications of FIR are discussed. Furthermore, the future development and applications of FIR are described in this review. By applying optimal therapeutic parameters, FIR can influence various cells, animal models, and patients, eliciting diverse underlying mechanisms and offering therapeutic potential for many diseases. FIR could represent a superior alternative with broad prospects for application in future regenerative medicine.

IntroductionUlcerative colitis, a subtype of chronic inflammatory bowel disease (IBD), is characterized by relapsing colonic inflammation and ulcers. The traditional Chinese herbal formulation Huang Lian Jie Du (HLJD) decoction is used clinically to treat diarrhea and colitis. However, the mechanisms associated with the effects of treatment remain unclear. This study aims to elucidate the molecular mechanistic effects of HLJD formulation on colitis.MethodsChronic colitis in mice was induced by adding 1% dextran sulfate sodium (DSS) to their drinking water continuously for 8 weeks, and HLJD decoction at the doses of 2 and 4 g/kg was administered orally to mice daily from the second week until experimental endpoint. Stool consistency scores, blood stool scores, and body weights were recorded weekly. Disease activity index (DAI) was determined before necropsy, where colon tissues were collected for biochemical analyses. In addition, the fecal microbiome of treated mice was characterized using 16S rRNA amplicon sequencing.ResultsHLJD decoction at doses of 2 and 4 g/kg relieved DSS-induced chronic colitis in mice by suppressing inflammation through compromised macrophage activity in colonic tissues associated with the colony-stimulating factor 1 receptor (Csf1r)/Src pathway. Furthermore, the HLJD formula could modify the gut microbiota profile by decreasing the abundance of Bacteroides, Odoribacter, Clostridium_sensu_stricto_1, and Parasutterella. In addition, close correlations between DAI, colon length, spleen weight, and gut microbiota were identified.DiscussionOur findings revealed that the HLJD formula attenuated DSS-induced chronic colitis by reducing inflammation via Csf1r/Src-mediated macrophage infiltration, as well as modulating the gut microbiota profile.

Abstract Background Older critically ill patients experience rapid muscle loss during stay in an intensive care unit (ICU) due to physiological stress and increased catabolism. This may lead to increased ICU length of stay, delayed weaning from ventilation and persistent functional limitations. We hypothesized that with optimal nutrition and early physical therapy acting in synergism, we can reduce muscle mass loss and improve functional outcomes. Methods This was a prospective, single blinded randomized, controlled single-center pilot study to compare the lean muscle mass (measured at bilateral quadriceps femoris using ultrasound) of older ICU patients at 4 time points over 14 days between the control and intervention groups. The control group received standard weight-based empiric feeding and standard ICU physiotherapy. The intervention group received indirect calorimetry directed feeding adjusted daily and 60 min per day of cycle ergometry. 21 patients were recruited and randomized with 11 patients in the control arm and 10 patients in the intervention arm. Secondary outcome measures included ICU and hospital mortality, length of stay, functional assessments of mobility and assessment of strength. Results Median age was 64 in the control group and 66 in the intervention group. Median calories achieved was 24.5 kcal/kg per day in the control group and 23.3 kcal/kg per day in the intervention group. Cycle ergometry was applied to patients in the intervention group for a median of 60 min a day and a patient had a median of 8.5 sessions in 14 days. Muscle mass decreased by a median of 4.7cm2 in the right quadriceps femoris in the control group and 1.8cm2 in the intervention group (p = 0.19), while the left quadriceps femoris decreased by 1.9cm2 in the control group and 0.1cm2 in the intervention group (p = 0.51). Conclusion In this pilot study, we found a trend towards decrease muscle loss in bilateral quadriceps femoris with our combined interventions. However, it did not reach statistical significance likely due to small number of patients recruited in the study. However, we conclude that the intervention is feasible and potentially beneficial and may warrant a larger scale study to achieve statistical significance. Trial Registration This study was registered on Clinicaltrials.gov on 30th May 2018 with identifier NCT03540732.

Abstract The translocation of YAP from the cytoplasm to the nucleus is critical for its activation and plays a key role in tumor progression. However, the precise molecular mechanisms governing the nuclear import of YAP are not fully understood. In this study, we have uncovered a crucial role of SOX9 in the activation of YAP. SOX9 promotes the nuclear translocation of YAP by direct interaction. Importantly, we have identified that the binding between Asp-125 of SOX9 and Arg-124 of YAP is essential for SOX9-YAP interaction and subsequent nuclear entry of YAP. Additionally, we have discovered a novel asymmetrical dimethylation of YAP at Arg-124 (YAP-R124me2a) catalyzed by PRMT1. YAP-R124me2a enhances the interaction between YAP and SOX9 and is associated with poor prognosis in multiple cancers. Furthermore, we disrupted the interaction between SOX9 and YAP using a competitive peptide, S-A1, which mimics an α-helix of SOX9 containing Asp-125. S-A1 significantly inhibits YAP nuclear translocation and effectively suppresses tumor growth. This study provides the first evidence of SOX9 as a pivotal regulator driving YAP nuclear translocation and presents a potential therapeutic strategy for YAP-driven human cancers by targeting SOX9-YAP interaction.

Abstract Hypomyelinating leukodystrophy (HLD) is a rare genetic heterogeneous disease that can affect myelin development in the central nervous system. This study aims to analyze the clinical phenotype and genetic function of a family with HLD-7 caused by POLR3A mutation. The proband (IV6) in this family mainly showed progressive cognitive decline, dentin dysplasia, and hypogonadotropic hypogonadism. Her three old brothers (IV1, IV2, and IV4) also had different degrees of ataxia, dystonia, or dysarthria besides the aforementioned manifestations. Their brain magnetic resonance imaging showed bilateral periventricular white matter atrophy, brain atrophy, and corpus callosum atrophy and thinning. The proband and her two living brothers (IV2 and IV4) were detected to carry a homozygous mutation of the POLR3A (NM_007055.4) gene c. 2300G > T (p.Cys767Phe), and her consanguineous married parents (III1 and III2) were p.Cys767Phe heterozygous carriers. In the constructed POLR3A wild-type and p.Cys767Phe mutant cells, it was seen that overexpression of wild-type POLR3A protein significantly enhanced Pol III transcription of 5S rRNA and tRNA Leu-CAA. However, although the mutant POLR3A protein overexpression was increased compared to the wild-type protein overexpression, it did not show the expected further enhancement of Pol III function. On the contrary, Pol III transcription function was frustrated (POLR3A, BC200, and tRNA Leu-CAA expression decreased), and MBP and 18S rRNA expressions were decreased. This study indicates that the POLR3A p.Cys767Phe variant caused increased expression of mutated POLR3A protein and abnormal expression of Pol III transcripts, and the mutant POLR3A protein function was abnormal.

Hyaluronan and proteoglycan link protein 1 (Hapln1) supports active cardiomyogenesis in zebrafish hearts, but its regulation in mammal cardiomyocytes is unclear. This study aimed to explore the potential regulation of Hapln1 in the dedifferentiation and proliferation of cardiomyocytes and its therapeutic value in myocardial infarction with human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) and an adult mouse model of myocardial infarction. HiPSC-CMs and adult mice with myocardial infarction were used as in vitro and in vivo models, respectively. Previous single-cell RNA sequencing data were retrieved for bioinformatic exploration. The results showed that recombinant human Hapln1 (rhHapln1) promotes the proliferation of hiPSC-CMs in a dose-dependent manner. As a physical binding protein of Hapln1, versican interacted with Nodal growth differentiation factor (NODAL) and growth differentiation factor 11 (GDF11). GDF11, but not NODAL, was expressed by hiPSC-CMs. GDF11 expression was unaffected by rhHapln1 treatment. However, this molecule was required for rhHapln1-mediated activation of the transforming growth factor (TGF)-β/Drosophila mothers against decapentaplegic protein (SMAD)2/3 signaling in hiPSC-CMs, which stimulates cell dedifferentiation and proliferation. Recombinant mouse Hapln1 (rmHapln1) could induce cardiac regeneration in the adult mouse model of myocardial infarction. In addition, rmHapln1 induced hiPSC-CM proliferation. In conclusion, Hapln1 can stimulate the dedifferentiation and proliferation of iPSC-derived cardiomyocytes by promoting versican-based GDF11 trapping and subsequent activation of the TGF-β/SMAD2/3 signaling pathway. Hapln1 might be an effective hiPSC-CM dedifferentiation and proliferation agent and a potential reagent for repairing damaged hearts.

Statins therapy is efficacious in diminishing the risk of major cardiovascular events in diabetic patients. However, our research has uncovered a correlation between the prolonged administration of statins and an elevated risk of myocardial dysfunction in patients with type II diabetes mellitus (TIIDM). Here, we report the induction of sterol regulatory element-binding protein 1 (SREBP1) activation, associated lipid peroxidation, and the consequent diabetic myocardial dysfunction after statin treatment and explored the underlying mechanisms. In db/db mice, we observed that 40 weeks atorvastatin (5 and 10 mg/kg) and rosuvastatin (20 mg/kg) administration exacerbated diabetic myocardial dysfunction by echocardiography and cardiomyocyte contractility assay, increased myocardial inflammation and fibrosis as shown by CD68, IL-1β, Masson's staining and Collagen1A1 immunohistochemistry (IHC) staining, increased respiratory exchange ratio (RER) by metabolic cage system assessment, exacerbated mitochondrial structural pathological changes by transmission electron microscopy (TEM) examination, increased deposition of lipid and glycogen by TEM, Oil-red and periodic acid-schiff stain (PAS) staining, which were corresponded with augmented levels of myocardial SREBP1 protein and lipid peroxidation marked by 4-hydroxynonenal (4-HNE) staining. Comparable myocardial fibrosis was also observed in KK-ay and low-dose streptozotocin (STZ)-induced TIIDM mice. Elevated SREBP1 levels were observed in the heart tissues from diabetic patients, which was positively correlated with their myocardial dysfunction. To elucidate the role of statin induced SREBP1 in lipid peroxidation and lipid deposition and related mechanism, we cultured neonatal mouse primary cardiomyocytes (NMPCs) and treated them with atorvastatin (10 μM, 24 h), tracing with [U–13C]-glucose and evaluating for SREBP1 expression and localization. We found that statin treatment elevated de novo lipogenesis (DNL) and the levels of SREBP1 cleavage-activating protein (SCAP), reduced the interaction of SCAP with insulin-induced gene 1 (Insig1), and enhance SCAP/SREBP1 translocation to the Golgi, which facilitate SREBP1 cleavage leading to its nuclear trans-localization and activation in NMPCs. Ultimately, SREBP1 knockdown or l-carnitine mitigated long-term statins therapy induced lipid peroxidation and myocardial fibrosis in low-dose STZ treated SREBP1+/− mice and l-carnitine treated db/db mice. In conclusion, we demonstrated that statin therapy may augment DNL by activating SREBP1, resulting in myocardial lipid peroxidation and lipid deposition.

Objective This study explored the molecular mechanisms by which dexmedetomidine (Dex) alleviates cisplatin (CP)-induced acute kidney injury (AKI) in rats.Methods CP-induced AKI models were established, and Dex was intraperitoneally injected at different concentrations into rats in the model groups. Subsequently, rats were assigned to the control, CP, CP + Dex 10 μg/kg, and CP + Dex 25 μg/kg groups. After weighing the kidneys of the rats, the kidney arterial resistive index was calculated, and CP-induced AKI was evaluated. In addition, four serum biochemical indices were measured: histopathological damage in rat kidneys was detected; levels of inflammatory factors, interleukin (IL)-1β, IL-18, IL-6, and tumor necrosis factor alpha, in kidney tissue homogenate of rats were assessed through enzyme-linked immunosorbent assay (ELISA); and levels of NLRP-3, caspase-1, cleaved caspase-1, gasdermin D (GSDMD), and GSDMD-N in kidney tissues of rats were determined via western blotting.Results Dex treatment reduced nephromegaly and serum clinical marker upregulation caused by CP-induced AKI. In addition, hematoxylin and eosin staining revealed that Dex treatment relieved CP-induced kidney tissue injury in AKI rats. ELISA analyses demonstrated that Dex treatment reduced the upregulated levels of proinflammatory cytokines in the kidney tissue of AKI rats induced by CP, thereby alleviating kidney tissue injury. Western blotting indicated that Dex alleviated CP-induced AKI by inhibiting pyroptosis mediated by NLRP-3 and caspase-1.Conclusion Dex protected rats from CP-induced AKI, and the mechanism may be related to NLRP-3/Caspase-1-mediated pyroptosis.

This study aimed to explore the moderating role of socioeconomic status (SES) in the association between multimorbidity and health-related quality of life (HRQOL) among cancer patients in Anhui China. A total of 560 cancer patients were recruited for the cross-section study. Socio-demographic and clinical characteristics were analyzed using descriptive statistics. Tobit regression analysis was employed to investigate the relationship between multimorbidity and HRQOL as well as to assess the moderating effect of SES. The research findings indicated that 76.61% of cancer patients experienced multimorbidity, with psychological multimorbidity being the most prevalent (45.54%), followed by physical-psychological multimorbidity (20.89%). Moreover, physical-psychological multimorbidity had the most substantial adverse effect on HRQOL ( P < .001). The presence of multimorbidity was correlated with a significant decline in HRQOL, with a 17.5% ( P < .001) decrease in HRQOL for each additional multimorbidity. Additionally, SES played a significant role in moderating the impact of multimorbidity on HRQOL in cancer patients. (Marginal effect = −0.022, P < .01). The high SES group exhibited a higher overall HRQOL than the low SES group (Marginal effect = 0.068, P < .001). And with the increase of multimorbidity, HRQOL in the higher SES showed a more pronounced downward trend, compared with the lower SES ( β = −.270 vs β = −.201, P < .001). Our findings underscore the importance of preventing and managing multimorbidity in cancer patients, particularly those with low SES. Furthermore, it is essential to consider the impact of the rapid decline in HRQOL as the number of multimorbidity increases in individuals with higher SES. It is imperative to explore interdisciplinary and continuous collaborative management models.

The shear behavior of simply supported RC beams strengthened with polyethylene terephthalate (PET) fiber-reinforced polymer (FRP) was studied in this paper. The test variables include strengthening schemes (i.e., U-wrapping and full-wrapping) and FRP reinforcement ratios. A comprehensive and meticulous investigation was conducted on the failure mode of RC beams, shear force-deflection curves, the development process of shear cracks, the evolution of FRP strain, and the interaction between FRP and concrete. The shear capacity and deformation were increased by 42.5–123.2% and −16.34–96.89% using the fully wrapped scheme, respectively. The improvement in shear capacity was 42.5–72.55% when the U-wrapped scheme was adopted. The PET FRP fully wrapped beams exhibited a type of ductile shear failure. The strain of PET FRP in the fully wrapped specimen exceeded 4% without fracture, ensuring the deformation capacity after the peak load. The shear deformation caused the increase in post-peak mid-span deflection. The U-wrapped specimens showed debonding failure, with the debonding strain of PET FRP being more than that of conventional FRP. Finally, six design guidelines for PET FRP shear contribution were evaluated for both U-wrapped and fully wrapped schemes.

RNA molecules play multifaceted functional and regulatory roles within cells and have garnered significant attention in recent years as promising therapeutic targets. With remarkable successes achieved by artificial intelligence (AI) in different fields such as computer vision and natural language processing, there is a growing imperative to harness AI’s potential in computer-aided drug design (CADD) to discover novel drug compounds that target RNA. Although machine-learning (ML) approaches have been widely adopted in the discovery of small molecules targeting proteins, the application of ML approaches to model interactions between RNA and small molecule is still in its infancy. Compared to protein-targeted drug discovery, the major challenges in ML-based RNA-targeted drug discovery stem from the scarcity of available data resources. With the growing interest and the development of curated databases focusing on interactions between RNA and small molecule, the field anticipates a rapid growth and the opening of a new avenue for disease treatment. In this review, we aim to provide an overview of recent advancements in computationally modeling RNA-small molecule interactions within the context of RNA-targeted drug discovery, with a particular emphasis on methodologies employing ML techniques.