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Spermatogonial stem cells (SSCs) play crucial roles in the preservation of male fertility. However, successful ex vivo expansion of authentic human SSCs remains elusive due to the inadequate understanding of SSC homeostasis regulation. Using rhesus monkeys (Macaca mulatta) as a representative model, we characterized SSCs and progenitor subsets through single-cell RNA sequencing using a cell-specific network approach. We also profiled chromatin status and major histone modifications (H3K4me1, H3K4me3, H3K27ac, H3K27me3 and H3K9me3), and subsequently mapped promoters and active enhancers in TSPAN33+ putative SSCs. Comparing the epigenetic changes between fresh TSPAN33+ cells and cultured TSPAN33+ cells (resembling progenitors), we identified the regulatory elements with higher activity in SSCs, and the potential transcription factors and signaling pathways implicated in SSC regulation. Specifically, TGF-β signaling is activated in monkey putative SSCs. We provided evidence supporting its role in promoting self-renewal of monkey SSCs in culture. Overall, this study outlines the epigenetic landscapes of monkey SSCs and provides clues for optimization of the culture condition for primate SSCs expansion., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Aim: To evaluate the efficacy and safety of triptorelin after radical prostatectomy (RP) in patients with negative lymph nodes., Methods: PRIORITI (NCT01753297) was a prospective, open-label, randomized, controlled, phase 4 study conducted in China and Russia. Patients with high-risk (Gleason score ≥ 8 and/or pre-RP prostate-specific antigen [PSA] ≥ 20 ng/mL and/or primary tumor stage 3a) prostate adenocarcinoma without evidence of lymph node or distant metastases were randomized to receive triptorelin 11.25 mg at baseline (≤ 8 weeks after RP) and at 3 and 6 months, or active surveillance. The primary endpoint was biochemical relapse-free survival (BRFS), defined as the time from randomization to biochemical relapse (BR; increased PSA > 0.2 ng/mL). Patients were monitored every 3 months for at least 36 months; the study ended when 61 BRs were observed., Results: The intention-to-treat population comprised 226 patients (mean [standard deviation] age, 65.3 [6.4] years), of whom 109 and 117 were randomized to triptorelin or surveillance, respectively. The median BRFS was not reached. The 25th percentile time to BRFS (95% confidence interval) was 39.1 (29.9-not estimated) months with triptorelin and 30.0 (18.6-42.1) months with surveillance (p = 0.16). There was evidence of a lower risk of BR with triptorelin versus surveillance but this was not statistically significant at the 5% level (p = 0.10). Chemical castration was maintained at month 9 in 93.9% of patients who had received triptorelin. Overall, triptorelin was well tolerated and had an acceptable safety profile., Conclusion: BRFS was observed to be longer with triptorelin than surveillance, but the difference was not statistically significant., Plain Language Summary: After a diagnosis of prostate cancer, one of the current treatments is surgical removal of the prostate and its cancer from the body. This is called radical prostatectomy. This may cure the person. Unfortunately, sometimes the tumor may have already spread into neighboring cells (lymph nodes). If this has happened, we know that giving people a chemical castration therapy to lower their levels of male sex hormones may reduce the risk of the cancer spreading further. This is achieved by giving people an androgen deprivation therapy (ADT), such as triptorelin (which is used in this study). What we do not yet know, and what we investigated in this study, is whether ADT can also benefit people who do not have signs that their cancer has already spread to the lymph nodes. Our study involved 226 men from China and Russia and investigated whether giving triptorelin for 9 months would lead to better outcomes compared with giving no additional treatment (active surveillance). All people in the study had radical prostatectomy but only half of them were given triptorelin in the following 8 weeks. The time frame of 8 weeks was used because this is the time needed to make sure that the surgery had gone well, and that no biological markers of cancer were still present in the person's blood (the marker is called prostate-specific antigen [PSA]). High levels of PSA are a sign that the prostate cancer has returned. People were monitored for 3 years with regular checks of their castration status and levels of the cancer marker (PSA). At the end of the study, we saw that it took longer for PSA levels to increase for people who had taken triptorelin than it did for those who had not had additional treatment, but the difference was not statistically significant. There were no unexpected safety concerns seen among the people taking triptorelin. Our findings are promising but more studies are needed to confirm if starting triptorelin shortly after surgery can benefit this group of people who have had their prostate cancer treated by radical prostatectomy and have no signs that their cancer has spread to the lymph nodes. [Correction added on 31th July 2024, after first online publication: Plain language summary is added in this version.]., (© 2024 The Author(s). Asia‐Pacific Journal of Clinical Oncology published by John Wiley & Sons Australia, Ltd.)

The potential of circular RNAs (circRNAs) as biomarkers and therapeutic targets is becoming increasingly evident, yet their roles in cardiac regeneration and myocardial renewal remain largely unexplored. Here, we investigated the function of circIGF1R and related mechanisms in cardiac regeneration. Through analysis of circRNA sequencing data from neonatal and adult cardiomyocytes, circRNAs associated with regeneration were identified. Our data showed that circIGF1R expression was high in neonatal hearts, decreased with postnatal maturation, and up-regulated after cardiac injury. The elevation was validated in patients diagnosed with acute myocardial infarction (MI) within 1 week. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and myocardial tissue from mice after apical resection and MI, we observed that circIGF1R overexpression enhanced cardiomyocyte proliferation, reduced apoptosis, and mitigated cardiac dysfunction and fibrosis, while circIGF1R knockdown impeded endogenous cardiac renewal. Mechanistically, we identified circIGF1R binding proteins through circRNA precipitation followed by mass spectrometry. RNA pull-down Western blot and RNA immunoprecipitation demonstrated that circIGF1R directly interacted with DDX5 and augmented its protein level by suppressing ubiquitin-dependent degradation. This subsequently triggered the β-catenin signaling pathway, leading to the transcriptional activation of cyclin D1 and c-Myc. The roles of circIGF1R and DDX5 in cardiac regeneration were further substantiated through site-directed mutagenesis and rescue experiments. In conclusion, our study highlights the pivotal role of circIGF1R in facilitating heart regeneration and repair after ischemic insults. The circIGF1R/DDX5/β-catenin axis emerges as a novel therapeutic target for enhancing myocardial repair after MI, offering promising avenues for the development of regenerative therapies., Competing Interests: Competing interests: The authors declare that they have no competing interests., (Copyright © 2024 Tian-Kai Shan et al.)

Background: Hepatic arterial infusion chemotherapy and camrelizumab plus apatinib (TRIPLET protocol) is promising for advanced hepatocellular carcinoma (Ad-HCC). However, the usefulness of microwave ablation (MWA) after TRIPLET is still controversial., Aim: To compare the efficacy and safety of TRIPLET alone (T-A) vs TRIPLET-MWA (T-M) for Ad-HCC., Methods: From January 2018 to March 2022, 217 Ad-HCC patients were retrospectively enrolled. Among them, 122 were included in the T-A group, and 95 were included in the T-M group. A propensity score matching (PSM) was applied to balance bias. Overall survival (OS) was compared using the Kaplan-Meier curve with the log-rank test. The overall objective response rate (ORR) and major complications were also assessed., Results: After PSM, 82 patients were included both the T-A group and the T-M group. The ORR (85.4%) in the T-M group was significantly higher than that (65.9%) in the T-A group ( P < 0.001). The cumulative 1-, 2-, and 3-year OS rates were 98.7%, 93.4%, and 82.0% in the T-M group and 85.1%, 63.1%, and 55.0% in the T-A group (hazard ratio = 0.22; 95% confidence interval: 0.10-0.49; P < 0.001). The incidence of major complications was 4.9% (6/122) in the T-A group and 5.3% (5/95) in the T-M group, which were not significantly different ( P = 1.000)., Conclusion: T-M can provide better survival outcomes and comparable safety for Ad-HCC than T-A., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Ethnopharmacological Relevance: Ferroptosis, a recently identified non-apoptotic form of cell death reliant on iron, is distinguished by an escalation in lipid reactive oxygen species (ROS) that are iron-dependent. This phenomenon has a strong correlation with irregularities in iron metabolism and lipid peroxidation. Salvia miltiorrhiza Bunge (DS), a medicinal herb frequently utilized in China, is highly esteemed for its therapeutic effectiveness in enhancing blood circulation and ameliorating blood stasis, particularly during the treatment of cardiovascular diseases (CVDs). Numerous pharmacological studies have identified that DS manifests antioxidative stress effects as well as inhibits lipid peroxidation. However, ambiguity persists regarding the potential of DS to impede ferroptosis in cardiomyocytes and subsequently improve myocardial damage post-myocardial infarction (MI)., Aim of the Study: The present work focused on investigating whether DS could be used to prevent the ferroptosis of cardiomyocytes and improve post-MI myocardial damage., Materials and Methods: In vivo experiments: Through ligation of the left anterior descending coronary artery, we constructed both a wild-type (WT) and NF-E2 p45-related factor 2 knockout (Nrf2-/-) mouse model of MI. Effects of DS and ferrostatin-1 (Fer-1) on post-MI cardiomyocyte ferroptosis were examined through detecting ferroptosis and myocardial damage-related indicators as well as Nrf2 signaling-associated protein levels. In vitro experiments: Erastin was used for stimulating H9C2 cardiomyocytes to construct an in vitro ferroptosis cardiomyocyte model. Effects of DS and Fer-1 on cardiomyocyte ferroptosis were determined based on ferroptosis-related indicators and Nrf2 signaling-associated protein levels. Additionally, inhibitor and activator of Nrf2 were used for confirming the impact of Nrf2 signaling on DS's effect on cardiomyocyte ferroptosis., Results: In vivo: In comparison to the model group, DS suppressed ferroptosis in cardiomyocytes post-MI and ameliorated myocardial damage by inducing Nrf2 signaling-related proteins (Nrf2, xCT, GPX4), diminishing tissue ferrous iron and malondialdehyde (MDA) content. Additionally, it enhanced glutathione (GSH) levels and total superoxide dismutase (SOD) activity, effects that are aligned with those of Fer-1. Moreover, the effect of DS on alleviating cardiomyocyte ferroptosis after MI could be partly inhibited through Nrf2 knockdown. In vitro: Compared with the erastin group, DS inhibited cardiomyocyte ferroptosis by promoting the expression of Nrf2 signaling-related proteins, reducing ferrous iron, ROS, and MDA levels, but increasing GSH content and SOD activity, consistent with the effect of Fer-1. Additionally, Nrf2 inhibition increased erastin-mediated ferroptosis of cardiomyocytes through decreasing Nrf2 signaling-related protein expressions. Co-treatment with DS and Nrf2 activator failed to further enhance the anti-ferroptosis effect of DS., Conclusion: MI is accompanied by cardiomyocyte ferroptosis, whose underlying mechanism is probably associated with Nrf2 signaling inhibition. DS possibly suppresses ferroptosis of cardiomyocytes and improves myocardial damage after MI through activating Nrf2 signaling., Competing Interests: Declaration of competing interest The authors indicated no potential conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The regenerative capacity of the adult mammalian hearts is limited. Numerous studies have explored mechanisms of adult cardiomyocyte cell-cycle withdrawal. This translational study evaluated the effects and underlying mechanism of rhCHK1 (recombinant human checkpoint kinase 1) on the survival and proliferation of cardiomyocyte and myocardial repair after ischemia/reperfusion injury in swine., Methods and Results: Intramyocardial injection of rhCHK1 protein (1 mg/kg) encapsulated in hydrogel stimulated cardiomyocyte proliferation and reduced cardiac inflammation response at 3 days after ischemia/reperfusion injury, improved cardiac function and attenuated ventricular remodeling, and reduced the infarct area at 28 days after ischemia/reperfusion injury. Mechanistically, multiomics sequencing analysis demonstrated enrichment of glycolysis and mTOR (mammalian target of rapamycin) pathways after rhCHK1 treatment. Co-Immunoprecipitation (Co-IP) experiments and protein docking prediction showed that CHK1 (checkpoint kinase 1) directly bound to and activated the Serine 37 (S37) and Tyrosine 105 (Y105) sites of PKM2 (pyruvate kinase isoform M2) to promote metabolic reprogramming. We further constructed plasmids that knocked out different CHK1 and PKM2 amino acid domains and transfected them into Human Embryonic Kidney 293T (HEK293T) cells for CO-IP experiments. Results showed that the 1-265 domain of CHK1 directly binds to the 157-400 amino acids of PKM2. Furthermore, hiPSC-CM (human iPS cell-derived cardiomyocyte) in vitro and in vivo experiments both demonstrated that CHK1 stimulated cardiomyocytes renewal and cardiac repair by activating PKM2 C-domain-mediated cardiac metabolic reprogramming., Conclusions: This study demonstrates that the 1-265 amino acid domain of CHK1 binds to the 157-400 domain of PKM2 and activates PKM2-mediated metabolic reprogramming to promote cardiomyocyte proliferation and myocardial repair after ischemia/reperfusion injury in adult pigs.

The peroxisome is a versatile organelle that performs diverse metabolic functions. PEX3, a critical regulator of the peroxisome, participates in various biological processes associated with the peroxisome. Whether PEX3 is involved in peroxisome-related redox homeostasis and myocardial regenerative repair remains elusive. We investigate that cardiomyocyte-specific PEX3 knockout (Pex3-KO) results in an imbalance of redox homeostasis and disrupts the endogenous proliferation/development at different times and spatial locations. Using Pex3-KO mice and myocardium-targeted intervention approaches, the effects of PEX3 on myocardial regenerative repair during both physiological and pathological stages are explored. Mechanistically, lipid metabolomics reveals that PEX3 promotes myocardial regenerative repair by affecting plasmalogen metabolism. Further, we find that PEX3-regulated plasmalogen activates the AKT/GSK3β signaling pathway via the plasma membrane localization of ITGB3. Our study indicates that PEX3 may represent a novel therapeutic target for myocardial regenerative repair following injury., (© 2024. The Author(s).)

Prostate cancer causes numerous male deaths annually. Although great progress has been made in the diagnosis and treatment of prostate cancer during the past several decades, much about this disease remains unknown, especially its pathobiology. The kinesin superfamily is a pivotal group of motor proteins, that contains a microtubule-based motor domain and features an adenosine triphosphatase activity and motility characteristics. Large-scale sequencing analyses based on clinical samples and animal models have shown that several members of the kinesin family are dysregulated in prostate cancer. Abnormal expression of kinesins could be linked to uncontrolled cell growth, inhibited apoptosis and increased metastasis ability. Additionally, kinesins may be implicated in chemotherapy resistance and escape immunologic cytotoxicity, which creates a barrier to cancer treatment. Here we cover the recent advances in understanding how kinesins may drive prostate cancer progression and how targeting their function may be a therapeutic strategy. A better understanding of kinesins in prostate cancer tumorigenesis may be pivotal for improving disease outcomes in prostate cancer patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of interests NDJ reports advisory board and personal fees from AstraZeneca, Bayer, Clovis, Janssen, Merck, Merck Sharp & Dohme, Novartis, Sanofi, Astellas, and AAA Accelerator Solutions. FF reports personal fees from Janssen, Astellas, Serimmune, Foundation Medicine, Exact Sciences, Bristol-Myers Squibb, Varian Medical Systems, Novartis, Roivant, Myovant, Bayer, BlueStar Genomics, Artera, Tempus, Genentech, PFS Genomics, and Amgen, and holds stock options in Serimmune, BlueStar Genomics, and Artera. SG reports fees from Tolremo, Ipsen, Silvio Grasso Consulting, WebMD–Medscape, the American Society of Clinical Oncology, European Society for Medical Oncology, Peer Voice, SAKK, the German-speaking European School of Oncology, Radiotelevisione Svizzera Italiana, the Swiss Academy of Multidisciplinary Oncology, Meister ConCept, AdMeTech Foundation, EPG Health, Intellisphere, and Schweizerische Gessellschaft für Medizineische Onkologie. SG also reports travel support from AstraZeneca, Bayer, Intellisphere, and Gilead, paid advisory board participation for Merck Sharp & Dohme, Telixpharma, Bristol-Myers Squibb, AAA International, Orion, Bayer, Novartis, Modra Pharmaceuticals, AstraZeneca, Myriad Genetic, Daiichi Sankyo, Boehringer Ingelheim, Innomedica, Macrogenics, and Pfizer, and holds a patent (WO2009138392). BA-L reports fees from the Cancer Prevention and Research Institute of Texas, the Commonwealth Foundation, the Lyda Hill Foundation, Cancer Research UK, the Wellcome Trust, the Bob Champion Trust, AstraZeneca, Astex Pharmaceuticals, the New York Genome Center, and Existentia, travel support from Cancer Research UK, Astex, the STAT summit, the American Society of Hematology, and the American Association for Cancer Research, and participation in a Cancer Research UK data strategy board. GA reports fees from Janssen, Novartis, Astellas, the Institute of Cancer Research, Veracyte, Artera, Pfizer, AstraZeneca, Astellas, Novartis, Arvinas, Bayer, Sanofi, Propella, and Orion, holds a patent related to blood-based methylation markers (GB1915469.9), and has received equipment from Agilent. EC reports fees from Janssen. RE reports book royalties plus support and fees from the UK National Institute for Health and Care Research, AstraZeneca, Bayer, Ipsen, the Active Surveillance Movember Committee, the American Society of Clinical Oncology, University of Chicago, Dana Farber Cancer Institute, the Spanish National Cancer Research Center, Our Future Health, Jnetics UK, the Institute of Cancer Research, and Convergence Science Centre. RE also reports a pending Cancer Research UK patent, a stock ISA, receipt of gifts from patients (within limits allowed), and other financial interests in private medical practice. SH reports participation on data safety monitoring boards and advisory boards. DH reports fees from Techtrials, Astellas, Adium, Ipsen, Janssen, Bayer, Merck Sharp & Dohme, and Pfizer. MSH reports fees or grant funding from the Prostate Cancer Foundation, the Prostate Cancer Theranostics and Imaging Centre of Excellence, the Australian National Health and Medical Research Council, Movember, the US Department of Defense, Medical Research Future Fund, Bayer, the Peter MacCallum Foundation, Isotopia, the Australian Nuclear Science and Technology Organisation, Merck Sharpe & Dohme, Novartis, AstraZeneca, and Astellas. MSH also reports unrenumerated leadership or fiduciary role in Australian Friends of Sheba. MMog reports fees from NHS England, the UK National Institute for Health and Care Research, and Bayer. CM reports fees from UK National Institute for Health and Care Research, the UK Medical Research Council, Prostate Cancer UK, Cancer Rsearch UK, Sonacare, Ipsen, Bayer, and Astellas. AMo reports fees from Bayer, Myovant, Pfizer, Astellas, AstraZeneca, AAA, Bayer, Exelixis, Janssen, Lantheus, Myovant, Merck, Novartis, Sanofi, and Telix, participation in data Safety monitoring boards and advisory boards for Gilead, and a leadership or fiduciary role in ZERO Prostate Cancer. MMor reports fees from the National Cancer Institute Comprehensive Cancer Center, Lantheus, AstraZeneca, Amgen, Daiichi, Convergent, Pfizer, Clarity, Blue Earth Diagnostics, POINT Diagnostics, Z-Alpha, Ambrx, Flare, Fusion, Curium, Transtherabio, Doximity, BMS, and Celgene, reports a US patent application (18/448 609) for a method of treating prostate cancer, and holds stock options in Doximity. DM reports fees from Novartis, Janssen, Bayer, Astellas, Ipsen, and AstraZeneca. PLN reports fees from Bayer, Astellas, Boston Scientific, AIQ, Astellas, Novartis, Janssen, Blue Earth, Nanocan, and Theranano, and holds stock options in Stratagen Bio, Nanocan, and Reversal Therapeutics. CP reports fees from Artera, which has a financial relationship with University College London (his employer) as part of a data licensing agreement. All other authors declare no competing interests.

Hyperoside is a natural flavonol glycoside widely found in plants and has been reported to have a variety of pharmacological effects, including anticancer abilities. In this study, we demonstrated for the first time that hyperoside inhibited the proliferation of bladder cancer cells in vitro and in vivo. Moreover, hyperoside could not only induce cell cycle arrest, but also induce apoptosis of a few bladder cancer cells. Quantitative proteomics, bioinformatics analysis and Western blotting confirmed that hyperoside induced the overexpression of EGFR, Ras and Fas proteins, which affects a variety of synergistic and antagonistic downstream signaling pathways, including MAPKs and Akt, ultimately contributing to its anticancer effects in bladder cancer cells. This study reveals that hyperoside could be a promising therapeutic strategy for the prevention of bladder cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Administration of CHK1-targeted anticancer therapies is associated with an increased cumulative risk of cardiac complications, which is further amplified when combined with gemcitabine. However, the underlying mechanisms remain elusive. In this study, we generated hiPSC-CMs and murine models to elucidate the mechanisms underlying CHK1 inhibition combined with gemcitabine-induced cardiotoxicity and identify potential targets for cardioprotection. Mice were intraperitoneally injected with 25 mg/kg CHK1 inhibitor AZD7762 and 20 mg/kg gemcitabine for 3 weeks. hiPSC-CMs and NMCMs were incubated with 0.5 uM AZD7762 and 0.1 uM gemcitabine for 24 h. Both pharmacological inhibition or genetic deletion of CHK1 and administration of gemcitabine induced mtROS overproduction and pyroptosis in cardiomyocytes by disrupting mitochondrial respiration, ultimately causing heart atrophy and cardiac dysfunction in mice. These toxic effects were further exacerbated with combination administration. Using mitochondria-targeting sequence-directed vectors to overexpress CHK1 in cardiomyocyte (CM) mitochondria, we identified the localization of CHK1 in CM mitochondria and its crucial role in maintaining mitochondrial redox homeostasis for the first time. Mitochondrial CHK1 function loss mediated the cardiotoxicity induced by AZD7762 and CHK1-knockout. Mechanistically, mitochondrial CHK1 directly phosphorylates SIRT3 and promotes its expression within mitochondria. On the contrary, both AZD7762 or CHK1-knockout and gemcitabine decreased mitochondrial SIRT3 abundance, thus resulting in respiration dysfunction. Further hiPSC-CMs and mice experiments demonstrated that SIRT3 overexpression maintained mitochondrial function while alleviating CM pyroptosis, and thereby improving mice cardiac function. In summary, our results suggest that targeting SIRT3 could represent a novel therapeutic approach for clinical prevention and treatment of cardiotoxicity induced by CHK1 inhibition and gemcitabine., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Ferroptosis, a new regulated cell death pathway, plays a crucial part in the development of cardiovascular disease. However, the precise underlying mechanism remains unclear. Therefore, this study aimed to elucidate this., Methods: Herein, an erastin-induced H9C2 cell ferroptosis in vitro model and a myocardial infarction murine model, which was created by ligating the left anterior descending coronary artery, were established. Ferroptosis-related indicators, myocardial injury-related indicators, and Nrf2 signaling-related proteins expression were analyzed to explore the potential mechanism underlying cardiomyocyte ferroptosis-mediated cardiovascular disease development., Results: We demonstrated that Nrf2 downregulation in myocardial tissue, accompanied by ferroptotic events and changes in xCT and GPX4 expressions, induced cardiomyocyte ferroptosis and myocardial injury after myocardial infarction. These events, including ferroptosis and changes in Nrf2, xCT, and GPX4 expressions, were improved by ferrostatin-1 in vivo and in vitro. Besides, Nrf2 deficiency or inhibition aggravated myocardial infarction-induced cardiomyocyte ferroptosis by decreasing xCT and GPX4 expressions in vivo and in vitro. Moreover, ferrostatin-1 directly targeted Nrf2, as evidenced by surface plasmon resonance analysis., Conclusions: These results indicated that myocardial infarction is accompanied by cardiomyocyte ferroptosis and that Nrf2 signaling plays a crucial part in regulating cardiomyocyte ferroptosis after myocardial infarction., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Insensible Urinary Incontinence (IUI) is a situation when you complain of urinary incontinence but are unaware of how it occurred. Therefore, it is necessary to apply highly specific diagnostic methods to promote accuracy in the diagnosis of IUI, including pelvic floor ultrasound (PFU) and urodynamic studies (UDS)., Methods: A total of 41 women with IUI were retrospectively included. Patients were categorized into two groups: the urodynamic urinary incontinence group (UUI group, n=20) and the non-urodynamic urinary incontinence group (NUUI group, n=21), according to the urine leakage during UDS. The baseline clinical characteristics, UDS results, and PFU parameters were collected., Results: Compared with the NUUI group, the UUI group had a smaller maximum cystometric capacity (P=0.008), lower maximum urethral closure pressure (P=0.005), shorter functional urethral length (FUL) (P=0.01), more bladder neck funneling (BNF) (P=0.02), greater BNF depth (P=0.04), and larger BNF area (P=0.01). The area and depth of BNF were negatively correlated with maximum urethral closure pressure (r=-0.42, P=0.01), FUL (r=-0.36, P=0.02 versus r=-0.39, P=0.01), and maximum cystometric capacity (r=-0.35, P=0.03), but positively correlated with maximum urinary flow rate (r=0.33, P=0.04 versus r=0.36, P=0.02). The canonical correlation analysis of the ultrasound parameters and UDS parameters shows that the first pair of canonical variables was statistically significant (r1=0.9, P<0.001)., Conclusions: The PFU is associated with UDS in evaluating IUI. It has the advantages of low cost and high comfort, thus should be used as an auxiliary examination for IUI., (Copyright © 2023. Published by Elsevier Masson SAS.)

Cardiac hypertrophy, as one of the major predisposing factors for chronic heart failure, lacks effective interventions. Exploring the pathogenesis of cardiac hypertrophy will reveal potential therapeutic targets. S-nitrosylation is a kind of posttranslational modification that occurs at active cysteines of proteins to mediate various cellular processes. We here identified heat shock protein 90 (Hsp90) as a highly S-nitrosylated target in the hearts of rodents with hypertrophy, and the role of Hsp90 in cardiac hypertrophy remains undefined. The S-nitrosylation of Hsp90 (SNO-Hsp90) levels were elevated in angiotensin II (Ang II)- or phenylephrine (PE)-treated neonatal rat cardiomyocytes (NRCMs) in vitro as well as in cardiomyocytes isolated from mice subjected to transverse aortic constriction (TAC) in vivo. We demonstrated that the elevated SNO-Hsp90 levels were mediated by decreased S-nitrosoglutathione reductase (GSNOR) expression during cardiac hypertrophy, and delivery of GSNOR adeno-associated virus expression vectors (AAV9-GSNOR) decreased the SNO-Hsp90 levels to attenuate cardiac hypertrophy. Mass spectrometry analysis revealed that cysteine 589 (Cys589) might be the S-nitrosylation site of Hsp90. Delivery of the mutated AAV9-Hsp90-C589A inhibited SNO-Hsp90 levels and attenuated cardiac hypertrophy. We further revealed that SNO-Hsp90 led to increased interaction of glycogen synthase kinase 3β (GSK3β) and Hsp90, leading to elevated GSK3β phosphorylation and decreased eIF2Bε phosphorylation, thereby aggravating cardiac hypertrophy. Application of GSK3β inhibitor TWS119 abolished the protective effect of Hsp90-C589A mutation in Ang II-treated NRCMs. In conclusion, this study demonstrates a critical role of SNO-Hsp90 in cardiac hypertrophy, which may be of a therapeutic target for cardiac hypertrophy treatment., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

We retrospectively studied the diagnosis and treatment of a case of AAD misdiagnosed as stroke since atypical symptoms as the first manifestation, and discussed the clinical features and manifestations, diagnosis, and differential diagnosis of the case in the context of relevant domestic and international literature. The patient, a 49‑year-old male with herpes zoster for more than 1 month, presented with sudden onset of right-sided chest and back pain, accompanied by numbness and weakness of the left limb, and was tentatively diagnosed with post-herpetic neuralgia combined with stroke due to the history of herpes zoster. Non-specific ST-T alterations, D-dimer 20ug / ml, and non-traumatic angiographic findings in the transthoracic and abdominal aorta demonstrated slight thickening of the patient's ascending aorta, and the lumen of the root sinus region showed intimal flap formation with a larger pseudocoel and smaller true lumen, which ultimately confirmed the diagnosis of acute aortic coarctation with atypical presentation. So clinicians need to improve their basic theoretical knowledge, strengthen the understanding of AAD, focus on physical examination, improve relevant auxiliary examinations expeditiously, and pay attention to the significance of specific auxiliary examinations in order to decrease misdiagnosis and missed diagnosis of atypical manifestations of AAD patients.

Introduction: Enzalutamide significantly improved clinical outcomes compared with placebo in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) with disease progression despite androgen deprivation therapy (ADT) in the PREVAIL study. However, few patients from Asia were enrolled. Our study (NCT02294461) aimed to evaluate the safety and efficacy of enzalutamide in this disease setting in patients in mainland China, Korea, Taiwan, and Hong Kong., Methods: In this double-blind, phase III study, patients with asymptomatic/mildly symptomatic metastatic prostate cancer and disease progression despite ADT were randomized to enzalutamide (160 mg/day) or placebo. The primary endpoint was time to prostate-specific antigen (PSA) progression. Secondary endpoints included overall survival, radiographic progression-free survival, time to first skeletal-related event (SRE), time to initiation of cytotoxic chemotherapy, PSA response ≥ 50%, best overall soft-tissue response, and safety. Pre-planned interim analysis was scheduled following approximately 175 PSA-progression events (67% of targeted total of 261 events). An additional 5-year landmark analysis of overall survival, time to antineoplastic therapy, and safety was performed., Results: The double-blind study period was stopped after interim analysis owing to the benefit of enzalutamide over placebo. Overall, 388 patients were randomized (enzalutamide, n = 198; placebo, n = 190). Baseline characteristics were balanced between treatment groups. Enzalutamide significantly reduced risk of PSA progression vs placebo (hazard ratio 0.38; 95% CI 0.27-0.52; P < 0.0001). Median time to PSA progression was 8.31 months with enzalutamide and 2.86 months with placebo. Secondary endpoints, including 5-year overall survival, were significantly improved with enzalutamide, except time to first SRE. Adverse-event incidence was similar between enzalutamide and placebo. Fatigue was the most common drug-related adverse event in both treatment groups., Conclusion: Enzalutamide significantly reduced risk of PSA progression, improved secondary efficacy endpoints, and was well tolerated in chemotherapy-naïve Asian patients with mCRPC with disease progression despite ADT., Trial Registration: www., Clinicaltrials: gov NCT02294461., (© 2022. The Author(s).)

Cardiac fibrosis (CF) is an irreversible pathological process that occurs in almost all kinds of cardiovascular diseases. Phosphorylation-dependent activation of c-Jun N-terminal kinase (JNK) induces cardiac fibrosis. However, whether S-nitrosylation of JNK mediates cardiac fibrosis remains an open question. A biotin-switch assay confirmed that S-nitrosylation of JNK (SNO-JNK) increased significantly in the heart tissues of hypertrophic patients, transverse aortic constriction (TAC) mice, spontaneously hypertensive rats (SHRs), and neonatal rat cardiac fibroblasts (NRCFs) stimulated with angiotensin II (Ang II). Site to site substitution of alanine for cysteine in JNK was applied to determine the S-nitrosylated site. S-Nitrosylation occurred at both Cys116 and Cys163 and substitution of alanine for cysteine 116 and cysteine 163 (C116/163A) inhibited Ang II-induced myofibroblast transformation. We further confirmed that the source of S-nitrosylation was inducible nitric oxide synthase (iNOS). 1400 W, an inhibitor of iNOS, abrogated the profibrotic effects of Ang II in NRCFs. Mechanistically, SNO-JNK facilitated the nuclear translocation of JNK, increased the phosphorylation of c-Jun, and induced the transcriptional activity of AP-1 as determined by chromatin immunoprecipitation and EMSA. Finally, WT and iNOS -/- mice were subjected to TAC and iNOS knockout reduced SNO-JNK and alleviated cardiac fibrosis. Our findings demonstrate an alternative mechanism by which iNOS-induced SNO-JNK increases JNK pathway activity and accelerates cardiac fibrosis. Targeting SNO-JNK might be a novel therapeutic strategy against cardiac fibrosis., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Objective: To investigate the efficacy and safety of infliximab (IFX) therapy for children with Kawasaki disease. Methods: Sixty-eight children with Kawasaki disease who received IFX therapy in Children's Hospital of Fudan University from January 2014 to April 2021 were enrolled. The indications for IFX administration, changes in laboratory parameters before and after IFX administration, response rate, drug adverse events and complications and outcomes of coronary artery aneurysms (CAA) were retrospectively analyzed. Comparisons between groups were performed with unpaired Student t test or Mann-Whitney U test or chi-square test. Results: Among 68 children with Kawasaki disease, 52 (76%) were males and 16 (24%) were females. The age of onset was 2.1 (0.5, 3.8) years. IFX was administered to: (1) 35 children (51%) with persistent fever who did not respond to intravenous immunoglobulin (IVIG) or steroids, 28 of the 35 children (80%) developed CAA before IFX therapy; (2) 32 children (47%) with continuous progression of CAA; (3) 1 child with persistent arthritis. In all cases, IFX was administered as an additional treatment (the time from the onset of illness to IFX therapy was 21 (15, 30) days) which consisted of second line therapy in 20 (29%), third line therapy in 20 (29%), and fourth (or more) line therapy in 28 (41%). C-reactive protein (8 (4, 15) vs. 16 (8, 43) mg/L, Z =-3.38, P =0.001), serum amyloid protein A (17 (10, 42) vs. 88 (11, 327) mg/L, Z=-2.36, P =0.018) and the percentage of neutrophils (0.39±0.20 vs. 0.49±0.21, t =2.63, P =0.010) decreased significantly after IFX administration. Fourteen children (21%) did not respond to IFX and received additional therapies mainly including steroids and cyclophosphamide. There was no significant difference in gender, age at IFX administration, time from the onset of illness to IFX administration, the maximum coronary Z value before IFX administration, and the incidence of systemic aneurysms between IFX-sensitive group and IFX-resistant group (all P >0.05). Infections occurred in 11 cases (16%) after IFX administration, including respiratory tract, digestive tract, urinary tract, skin and oral infections. One case had Calmette-Guérin bacillus-related adverse reactions 2 months after IFX administration. All of these adverse events were cured successfully. One child died of CAA rupture, 6 children were lost to follow up, the remaining 61 children were followed up for 6 (4, 15) months. No CAA occurred in 7 children before and after IFX treatment, while CAA occurred in 54 children before IFX treatment. CAA regressed in 23 (43%) children at the last follow-up, and the diameter of coronary artery recovered to normal in 10 children. Conclusion: IFX is an effective and safe therapeutic choice for children with Kawasaki disease who are refractory to IVIG or steroids therapy or with continuous progression of CAA.

Background: Panax ginseng Meyer ( P. ginseng ), a herb distributed in Korea, China and Japan, exerts benefits on diverse inflammatory conditions. However, the underlying mechanism and active ingredients remains largely unclear. Herein, we aimed to explore the active ingredients of P. ginseng against inflammation and elucidate underlying mechanisms., Methods: Inflammation model was constructed by lipopolysaccharide (LPS) in C57BL/6 mice and RAW264.7 macrophages. Molecular docking, molecular dynamics, surface plasmon resonance imaging (SPRi) and immunofluorescence were utilized to predict active component., Results: P. ginseng significantly inhibited LPS-induced lung injury and the expression of pro-inflammatory factors, including TNF-α, IL-6 and IL-1β. Additionally, P. ginseng blocked fluorescence-labeled LPS (LPS488) binding to the membranes of RAW264.7 macrophages, the phosphorylation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs). Furthermore, molecular docking demonstrated that ginsenoside Ro (GRo) docked into the LPS binding site of toll like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD2) complex. Molecular dynamic simulations showed that the MD2-GRo binding conformation was stable. SPRi demonstrated an excellent interaction between TLR4/MD2 complex and GRo (K D value of 1.16 × 10 -9 M). GRo significantly inhibited LPS488 binding to cell membranes. Further studies showed that GRo markedly suppressed LPS-triggered lung injury, the transcription and secretion levels of TNF-α, IL-6 and IL-1β. Moreover, the phosphorylation of NF-κB and MAPKs as well as the p65 subunit nuclear translocation were inhibited by GRo dose-dependently., Conclusion: Our results suggest that GRo exerts anti-inflammation actions by direct inhibition of TLR4 signaling pathway., (© 2021 The Korean Society of Ginseng. Publishing services by Elsevier B.V.)

Background: Kawasaki disease (KD) is an acute systemic vasculitis of unclear etiology that mainly affects infants and young children. Strategies to reduce the incidence and severity of coronary artery lesions (CALs), the determinant factor in the long-term prognosis of KD, are currently a focus of studies on KD. Corticosteroids, preferred in the treatment of the majority of vasculitides, are controversial in the treatment of acute KD. In this trial, we will evaluate whether the addition of prednisolone to standard intravenous immunoglobulin (IVIG) plus aspirin therapy can reduce the occurrence of CAL in Chinese patients with KD., Methods: This is a multicenter, prospective, open-label, randomized controlled trial, which is expected to be conducted in more than 20 hospitals in China and aims to assess the efficacy and safety of IVIG + prednisolone treatment versus standard treatment. Patients with KD who fulfill the inclusion and exclusion criteria will be recruited and randomized (1:1) to receive either a large dose of IVIG (2 g/kg over 12-24 h with a maximum dose of 60 g) + aspirin 30 mg/kg/d or IVIG (2 g/kg over 12-24 h) + aspirin 30 mg/kg/d + prednisolone (2 mg/kg/d with a maximum dose of 60 mg tapered over 15 days after normalization of C-reactive protein concentration). The primary outcome will be the occurrence of CAL at 1 month of illness. The follow-up duration for each participant will be set as 1 year. Patients and treating physicians will be unmasked to group allocation., Discussion: This will be the first multicenter randomized controlled trial to evaluate the efficacy of IVIG + aspirin + prednisolone in Chinese pediatric patients with KD, which may provide high-level evidence for improving the initial treatment for acute KD., Trial Registration: ClinicalTrials.gov NCT04078568 . Registered on 16 August 2018., (© 2021. The Author(s).)

Background: Kawasaki disease (KD) is a systemic vasculitis that predominantly affects medium-sized arteries. In addition to well-known coronary artery aneurysms (CAAs), peripheral systemic artery aneurysms (SAAs) have also been sporadically reported. In the literatures, SAAs occurred mainly in untreated, intravenous immunoglobin (IVIG)-resistant, or severe refractory KD, and thrombotic events in SAAs were rarely reported., Case Presentation: A 10-month-old boy with a history of KD was referred to our hospital for suspected pseudoaneurysm of the axillary arteries. Four months prior to presentation, he had persistent fever, conjunctival congestion, and rash. On the 10th day of fever echocardiogram showed biliteral CAAs. He was then diagnosed with KD and given IVIG 2 g/kg and aspirin at a local hospital. His fever and symptoms soon subsided and he was discharged with low dose aspirin and dipyridamole. One month prior to presentation, his parents incidentally palpated swellings in his bilateral axillae. On admission, physical examination revealed a pulsatile swelling in his right axilla and a non-pulsatile swelling in the left with impalpable left brachial and radial pulses, cooler and less active left upper limb than the right one. While the pulses of other three limbs were normal. Ultrasound examination revealed giant bilateral axillary artery aneurysms (AAAs) with massive thrombus in the left. Angiography confirmed giant bilateral AAAs with left AAAs completely occluded and fine collateral vessels connecting to the distal brachial artery, in addition to giant bilateral multiple CAAs without stenoses. The patient was given intravenous prostaglandin for 10 days to allow for formation of collateral circulation, as well as aspirin, low molecular weight heparin (which was switched to warfarin before discharge) and metoprolol. At discharge, the temperature and movement of his left upper limb improved significantly. On follow-up at 7 months, his left upper limb further improved and was similar to the right with no occurrence of cardiovascular events. The images of CAAs and AAAs on echocardiogram and computerized tomography remained the same., Conclusions: This case highlights the importance of evaluating peripheral SAAs in KD patients with CAAs, even if their course of treatment appears smooth. For both large non-aortic SAAs and CAAs in KD patients, antithrombotic therapy is of utmost importance., (© 2021. The Author(s).)

Objective: To investigate the mechanism of honokiol (HNK) on bladder cancer cells and its synergistic anticancer effect with hydroxycamptothecin (HCPT)., Methods: Control, HNK, HCPT, and HNK plus HCPT groups were established. The morphological characteristics of T24 cells were examined microscopically. The maximal experimental concentration of HNK and HCPT were determined according to IC10 detected by MTT. T24 cell viability and the percentage of apoptotic cells were assessed on the basis of MTT and flow cytometric analysis. The expression of caspase-3, caspase-9, phosphorylated nuclear factor-kappa B (NF-κB)-p65, Akt, and extracellular signal-regulated kinase (ERK) proteins were analyzed by Western blot., Results: Apoptosis in T24 cells was observed microscopically in both the HNK and HCPT groups and even more obvious in the HNK plus HCPT groups. The percentage of T24 cell viability decreased down to 19.41% , and the percentage of apoptotic cells rose to 54.08% when treated with HNK plus HCPT in an HNK dose-dependent manner. The induction of caspase-3 and caspase-9 proteins and the inhibition of phosphorylation of NF-κB-p65, Akt, and ERK proteins in T24 cells were demonstrated in the HNK groups, and more significantly in the HNK plus HCPT groups, but not in the HCPT group., Conclusion: The anticancer effect of HNK may be due to the activation of the caspase pathway and inhibition of phosphorylation of NF-κB, Akt, and ERK. HNK in combination with HCPT produces a synergistic cell-killing effect on bladder cancer cells.

Inhibiting myocardial fibrosis can help prevent cardiovascular diseases, including heart failure. Magnolol (Mag), a natural component of Magnoliae officinalis, has been reported to inhibit fibrosis. However, the mechanism of Mag activity and its effects on myocardial fibrosis remain unclear. Here, we investigated the involvement of ALDH2, an endogenous protective agent against myocardial fibrosis, in the Mag-mediated inhibition of cardiac fibroblast proliferation and collagen synthesis. We found that Mag significantly inhibited cardiac fibroblast proliferation and collagen synthesis, based on the results of MTT, EdU and western blot assays. Moreover, molecular docking, molecular dynamics simulation and surface plasmon resonance (SPR) assays showed that Mag could bind directly and stably to ALDH2. Further analysis of the mechanism of these effects indicated that treatment with Mag dose-dependently enhanced ALDH2 activity without altering protein expression. Mag could enhance the activity of recombinant human ALDH2 proteins with a half-maximal effective concentration of 5.79 × 10 -5 M. In addition, ALDH2 activation via Alda-1 inhibited cardiac fibroblast proliferation and collagen synthesis, while ALDH2 inhibition via daidzin partially blocked the suppressive effects of Mag. In summary, Mag may act as a natural ALDH2 agonist and inhibit cardiac fibroblast proliferation and collagen synthesis., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Small double-stranded RNAs (dsRNAs) have been proved to effectively up-regulate the expression of particular genes by targeting their promoters. These small dsRNAs were also termed small activating RNAs (saRNAs). We previously reported that several small double-stranded RNAs (dsRNAs) targeting the PRKC apoptosis WT1 regulator (PAWR) promoter can up-regulate PAWR gene expression effectively in human cancer cells. The present study was conducted to evaluate the antitumor potential of PAWR gene induction by these saRNAs in bladder cancer. Promisingly, we found that up-regulation of PAWR by saRNA inhibited the growth of bladder cancer cells by inducing cell apoptosis and cell cycle arrest which was related to inhibition of anti‑apoptotic protein Bcl-2 and inactivation of the NF-κB and Akt pathways. The activation of the caspase cascade and the regulation of cell cycle related proteins also supported the efficacy of the treatment. Moreover, our study also showed that these saRNAs cooperated with cisplatin in the inhibition of bladder cancer cells. Overall, these data suggest that activation of PAWR by saRNA may have a therapeutic benefit for bladder cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Podophyllotoxin (POD) is one of the most characterized lignans that is commonly found in podophyllum, and its preparations and derivatives are widely used in clinical treatment due to strong antitumor and antivirus activities. POD has been reported for its neurotoxicity, liver toxicity, and potential reproductive toxicity. In the present study, we investigated the effects of POD on the organelles of mouse oocytes during meiosis. Our results showed that exposure to POD significantly reduced the developmental competence of mouse oocytes. Further analysis revealed that the endoplasmic reticulum (ER) failed to accumulate to the spindle periphery, suggesting that POD exposure might affect protein synthesis during oocyte meiotic maturation. Similarly, abnormal Golgi apparatus distribution was found after POD exposure, which could be confirmed by the aberrant localization of Rab11a-related vesicles, indicating that POD induced vesicle-based protein transport disorder. We also found the aberrant accumulation of lysosomes in the cytoplasm of POD-exposed oocytes, which implied that POD might lead to aberrant protein degradation. Moreover, the perinuclear distribution of mitochondria was also significantly disturbed, indicating the mitochondrial dysfunction after POD exposure. In all, our study illustrated that exposure to POD might disrupt protein synthesis, transport, degradation, and ATP production by its effects on the distribution and functions of organelles during mouse oocyte meiotic maturation., 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 © 2021 Lu, Xie, Kong, Xu and Sun.)

Cardiovascular disease, a disease caused by many pathogenic factors, is one of the most common causes of death worldwide, and oxidative stress plays a major role in its pathophysiology. Tanshinone I (Tan I), a natural compound with cardiovascular protective effects, is one of the main active compounds extracted from Salvia miltiorrhiza . Here, we investigated whether Tan I could attenuate oxidative stress and oxidative stress-induced cardiomyocyte apoptosis through Nrf2/MAPK signaling in vivo and in vitro . We found that Tan I treatment protected cardiomyocytes against oxidative stress and oxidative stress-induced apoptosis, based on the detection of relevant oxidation indexes such as reactive oxygen species, superoxide dismutase, malondialdehyde, and apoptosis, including cell viability and apoptosis-related protein expression. We further examined the mechanisms underlying these effects, determining that Tan I activated nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) transcription into the nucleus and dose-dependently promoted the expression of Nrf2, while inhibiting MAPK signaling activation, including P38 MAPK, SAPK/JNK, and ERK1/2. Nrf2 inhibitors in H9C2 cells and Nrf2 knockout mice demonstrated aggravated oxidative stress and oxidative stress-induced cardiomyocyte injury; Tan I treatment suppressed these effects in H9C2 cells; however, its protective effect was inhibited in Nrf2 knockout mice. Additionally, the analysis of surface plasmon resonance demonstrated that Tan I could directly target Nrf2 and act as a potential Nrf2 agonist. Collectively, these data strongly indicated that Tan I might inhibit oxidative stress and oxidative stress-induced cardiomyocyte injury through modulation of Nrf2 signaling, thus supporting the potential therapeutic application of Tan I for oxidative stress-induced CVDs., 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 © 2021 Wu, Xie, Hua, Xu, Chen, Han, Tan, Fan, Chen, Li, Liu and Zhou.)

Background and Objectives: Little is known about nutritional status in patients with hepatocellular carcinoma (HCC) after multiple rounds of transarterial chemoembolization (TACE). We established a comprehensive nutritional index (CNI) and evaluated its prognostic value for overall survival (OS) and time to progression (TTP)., Methods and Study Design: HCC patients (N=282) who underwent multiple TACE treatments were enrolled. CNI was established by principal component analysis based on body mass index, usual body weight percentage, hemoglobin, total lymphocyte count, and albumin; the cutoff value was determined by receiver operating characteristic curve and Youden index analysis. The correlation between CNI and treatment-related complications was analyzed with Spearman's method. The Kaplan-Meier method with log-rank test and Cox proportional hazards model were used to compare the prognostic values of CNI, prognostic nutritional index (PNI), and nutrition risk index (NRI) for OS and TTP., Results: Nutritional status declined after repeated TACE (p<0.001). CNI (cutoff= 0.251) varied according to albumin-bilirubin grade, tumor size, and number of TACE treatments (p<0.001 or 0.025) and was negatively correlated with rate of serious complications (r=-0.185, p=0.002). Patients with low CNI had shorter OS (p=0.014) and TTP (p=0.007); high CNI predicted longer OS (hazard ratio [HR], 0.72; 95% confidence interval [CI]: 0.52-1.00, p=0.048) and TTP (HR, 0.69; 95% CI: 0.50-0.94, p=0.019). Post-treatment PNI and NRI were unrelated to prognosis (p>0.05)., Conclusions: HCC patients have poor nutritional status after multiple TACE treatments, which predicts shorter OS and TTP. The prognostic performance of CNI is superior to those of PNI and NRI.

Background: We sought to investigate epidemiologic features of Kawasaki disease (KD) in Shanghai from 2013 through 2017 and identify risk factors for coronary artery lesions (CAL)., Methods: As in our previous three surveys, a set of questionnaires and diagnostic guidelines for KD were sent to 50 hospitals providing pediatric medical care in Shanghai. Medical records of KD patients diagnosed from January 2013 through December 2017 were retrospectively analyzed. Multivariate logistic regression analysis was performed to identify risk factors for CAL., Results: A total of 4,452 cases were enrolled. Male-to-female ratio was 1.7:1. The incidence of KD was 68.8 to 107.3 per 100,000 children aged <5 years from 2013 to 2017. Age at onset ranged from 15 days to 14.0 years (median: 1.8 years). KD occurred more frequently in spring and summer. Of 4,325 patients (97.0%) receiving intravenous immunoglobulin (IVIG), 362 (8.4%) were resistant to initial IVIG. CAL occurred in 406 (9.1%) patients, including 118 (2.7%) with medium aneurysms and 31 (0.7%) with giant aneurysms. Recurrent cases were 60 (1.3%). No death was found in this survey. Higher platelet levels, lower albumin levels, male sex, incomplete KD, IVIG resistance, and receiving initial IVIG ≤4 days or >10 days, were independently associated with CAL., Conclusions: The incidence of KD in Shanghai had substantially increased while the proportion of CAL had substantially decreased as compared with our previous surveys. Higher platelet levels, lower albumin levels, male sex, incomplete KD, IVIG resistance, and receiving initial IVIG ≤4 days or >10 days, were risk factors for CAL.

Background: Determining whether members follow guidelines, including guidelines prepared to help direct practice management during the coronavirus disease 2019 (COVID-19) pandemic, is an important goal for medical associations., Objective: To determine whether practice of urologists is in line with guidelines for the management of common urological conditions during the COVID-19 pandemic produced by leading (inter)national urological associations., Design, Setting, and Participants: Self-selected urologists completed a voluntary survey available online from March 27 to April 11, 2020 and distributed globally by the Société Internationale d'Urologie., Outcome Measurements and Statistical Analysis: Responses to two survey questions on the (1) management of 14 common urological procedures and (2) priority scoring of 10 common urological procedures were evaluated by practice setting and geographical region using chi-square and one-way analysis of variance analyses, respectively., Results and Limitations: There were 2494 respondents from 76 countries. Oncological conditions were prioritised over benign conditions, and benign conditions were deferred when feasible and safe. Oncological conditions with the greatest malignant potential were prioritised over less aggressive cancers. Respondents from Europe were least likely to postpone and most likely to prioritise conditions identified by guidelines as being of the highest priority. Respondents' priority scoring of urological procedures closely matched the priorities assigned by guidelines. The main limitation of this study is that respondents were self-selected, and access to the survey was limited by language and technology barriers., Conclusions: Prioritisation and management of urological procedures during the COVID-19 pandemic are in line with current guidelines. The greatest agreement was reported in Europe. Observed differences may be related to limited resources in some settings., Patient Summary: When deciding how best to treat patients during the coronavirus disease 2019 (COVID-19) pandemic, urologists are taking into account both expert recommendations and the availability of important local resources., (Copyright © 2020 European Association of Urology. All rights reserved.)

Objective: To explore the value of artificial intelligence combined with multi-parametric MRI (AI-mpMRI) in the early diagnosis of prostate cancer., Methods: This retrospective study included 64 cases of prostate cancer confirmed by biopsy and treated by radical prostatectomy from May 2017 to February 2018. The mpMRI images of T2 weighted imaging (T2WI), diffusion weighted imaging (DWI) and dynamic-contrast enhanced (DCE) MRI and the pathological sections corresponding to the three sequential MRI images were collected. The benign and malignant regions were labeled on the pathological slice level, the three sequential MRI axial images at the same level were virtually covered with the pathological slice using computer-aided transparent mapping technology, and selected the fixed-sized benign and malignant regions of interest (ROI). The MATLAB software was used to display the features of the images and screen out the characteristic parameters with P < 0.05, so as to derive high-accuracy analytical methods for the diagnosis of prostate cancer., Results: A total of 31 image characteristics were extracted with the MATLAB software, and 3 high-accuracy analytical methods screened out for the diagnosis of prostate cancer, including the linear discrimination, logistic regression analysis, and support vector machine classification, with the accuracy rates of 75.9%, 75.4% and 74.9% and the areas under the curve (AUC) of 0.83, 0.82 and 0.82, respectively., Conclusions: AI-mpMRI can achieve a high detection rate in the early diagnosis of prostate cancer and therefore has a high clinical application value.

The coronavirus disease 2019 (COVID-19) pandemic is unlike anything seen before by modern science-based medicine. Health systems across the world are struggling to manage it. Added to this struggle are the effects of social confinement and isolation. This brings into question whether the latest guidelines are relevant in this crisis. We aim to support urologists in this difficult situation by providing tools that can facilitate decision making, and to minimise the impact and risks for both patients and health professionals delivering urological care, whenever possible. We hope that the revised recommendations will assist urologist surgeons across the globe to guide the management of urological conditions during the current COVID-19 pandemic., (Copyright © 2020. Published by Elsevier B.V.)

Background: Subgroup analysis of clinical trials of PD-1/PD-L1 inhibitors have reported ethnic differences in outcomes. We systematically collected published data and performed a meta-analysis to compare therapeutic efficacy in Asian and non-Asian patients receiving PD-1/PD-L1 inhibitors., Methods: Eligible studies included phase II and III prospective clinical trials with available subgroup data on Asian versus non-Asian populations. Overall survival (OS) and progression-free survival (PFS) were used to evaluate differences in outcome between Asian versus non-Asian cancer patients., Results: A total of 11,020 cancer patients from 19 prospective randomized controlled clinical trials were included. The overall estimated HR for OS was 0.69 with 95% CI of 0.61-0.77 in Asian versus 0.82 with 95% CI of 0.77-0.88 in non-Asian patients. The estimated hazard ratio (HR) for PFS measured 0.54 (95% CI, 0.32-0.76) and 0.69 (95% CI, 0.54-0.85) in Asian and non-Asian patients, respectively. Pooled ratios of OS HRs and PFS HRs reported in Asian versus non-Asian cancer patients were 0.84 (95% CI, 0.75-0.94) and 0.78 (95% CI, 0.59-0.97), respectively., Conclusions: This meta-analysis shows for the first time that Asian cancer patients have a significantly improved survival benefit than non-Asian patients receiving PD-1/PD-L1 inhibitor-based therapy., Competing Interests: JS’ conflicts can be found at: https://www.nature.com/onc/editors. None are relevant here. No other author declares a conflict., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Introduction: Laparoscopic radical prostatectomy (LRP) has become a common option for the treatment of prostate cancer. The aim of our study was to examine whether LRP performed within 12 weeks of transurethral resection of the prostate (TURP) is associated with surgical difficulty or outcomes., Material and Methods: A single-institutional retrospective analysis was performed on patients who underwent LRP for incidental prostate cancer after TURP between July 2009 and December 2017. The interval between TURP and LRP was determined and patients with intervals of ≤ 12 weeks were compared to those with intervals of > 12 weeks. Patient characteristics, perioperative, pathological, and postoperative functional outcomes were analyzed to determine statistically significant differences between the 2 groups. Multivariable analyses were performed to determine whether the interval between TURP and LRP was a significant independent predictor of these outcomes., Results: A total of 56 incidental prostate cancer patients detected by TURP were included in this study. No significant differences were detected in estimated blood loss, operative duration, postoperative length of stay, and rate of positive margin, Gleason score upgrading, major complications, incontinence and prostate-specific antigen (PSA) recurrence in patients with a TURP to LRP interval above and below 12 weeks. The TURP to LRP interval was not an independent predictor of outcomes during or after LRP., Conclusions: Our results showed that performing LRP within 12 weeks after TURP does not adversely influence surgical difficulty or outcomes., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2020 Termedia & Banach.)

Objective: To investigate the protective effect of miR-129-5p on ischemia-reperfusion (I/R) injury via targeting high mobility group box-1 (HMGB1)., Materials and Methods: Rat models of myocardial I/R and hypoxia/reoxygenation (H/R) cardiomyocytes were established, and the miR-129-5p and HMGB1 expression levels in myocardium of I/R rats and in cardiomyocytes of H/R rats were quantified by RT-PCR. The over-expression of miR-129-5p was performed on I/R rats, and the over-expression of miR-129-5p and down-regulation of HMGB1 were performed on cardiomyocytes of H/R rats. Triphenyltetrazolium chloride (TTC) staining was used to measure myocardial infarct size (IS). TUNEL (TdT-mediated dUTP end nick labeling) staining was employed to observe cardiomyocyte apoptosis in the myocardium of rats, and flow cytometry to observe cardiomyocyte apoptosis of I/R and H/R rats respectively. Dual-Luciferase reporter assay was used to verify the target relation between miR-129-5p and HMGB1., Results: MiR-129-5p was lowly expressed and HMGB1 was highly expressed in myocardial I/R injury rats and cardiomyocytes of H/R rats. Over-expression of miR-129-5p effectively reduced myocardial IS and cardiomyocyte apoptosis in rats with myocardial I/R injury, and significantly down-regulated the pro-apoptotic protein Bax, as well as significantly up-regulated the anti-apoptotic protein Bcl-2. Either over-expression of miR-129-5p or low-expression of HMGB1 in cardiomyocytes of H/R rats also achieved the same effects as described above. Dual-Luciferase reporter assay determined that miR-129-5p was a target for HMGB1., Conclusions: MiR-129-5p plays a protective role on myocardial I/R injury by regulating HMGB1 expression. Besides, it inhibits cardiomyocyte apoptosis and is expected to become a novel molecular marker or therapeutic target for myocardial I/R injury.

To study the migration and transformation of methylmercury during advanced anaerobic digestion of sludge and the role of sulfate, this study investigated the migration and transformation of methylmercury during different stages of sludge anaerobic digestion (AD) with thermal hydrolysis pretreatment and under different dosages of sulfate addition. The results showed that mercury methylation occurred in the initial stage of AD (Day 1-3), the ratio of methylmercury to total mercury increased from 0.024% (range of 0.019%-0.033%) to 0.038% (range of 0.030%-0.048%), and the net increment of methylmercury increased by 3.97, 6.09, 0.17, 3.71, and 1.66 times, respectively. In the following Day 3-5, the demethylation process occurred with the net yield of methylmercury decreased by 71.25% (ranging from 67.42% to 75.10%). Sulfate inhibited the methylation of mercury in the initial stage of AD, but had little effect on it in the late stage. This was related to the reduction of the bioavailability of neutral mercury complexes by charged groups of HgHS 2 2- and HgS 2 2- , as well as the immobilization of iron sulfide and mercury sulfide on S 2- and bioavailable mercury. Redundancy analysis (RDA) showed that mercury methylation was affected by several factors:organic substances such as propionic acid, isobutyric acid, isovaleric acid, and Fe may promote mercury methylation, whereas protein and higher pH may be inhibitors of mercury methylation in AD of sludge.

Background: Oxidative stress-induced cardiomyocytes apoptosis is a key pathological process in ischemic heart disease. Glutathione reductase (GR) reduces glutathione disulfide to glutathione (GSH) to alleviate oxidative stress. Ginsenoside Rb1 (GRb1) prevents the apoptosis of cardiomyocytes; however, the role of GR in this process is unclear. Therefore, the effects of GRb1 on GR were investigated in this study., Methods: The antiapoptotic effects of GRb1 were evaluated in H9C2 cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, annexin V/propidium iodide staining, and Western blotting. The antioxidative effects were measured by a reactive oxygen species assay, and GSH levels and GR activity were examined in the presence and absence of the GR inhibitor 1,3-bis-(2-chloroethyl)-1-nitrosourea. Molecular docking and molecular dynamics simulations were used to investigate the binding of GRb1 to GR. The direct influence of GRb1 on GR was confirmed by recombinant human GR protein., Results: GRb1 pretreatment caused dose-dependent inhibition of tert-butyl hydroperoxide-induced cell apoptosis, at a level comparable to that of the positive control N-acetyl-L-cysteine. The binding energy between GRb1 and GR was positive (-6.426 kcal/mol), and the binding was stable. GRb1 significantly reduced reactive oxygen species production and increased GSH level and GR activity without altering GR protein expression in H9C2 cells. Moreover, GRb1 enhanced the recombinant human GR protein activity in vitro , with a half-maximal effective concentration of ≈2.317 μM. Conversely, 1,3-bis-(2-chloroethyl)-1-nitrosourea co-treatment significantly abolished the GRb1's apoptotic and antioxidative effects of GRb1 in H9C2 cells., Conclusion: GRb1 is a potential natural GR agonist that protects against oxidative stress-induced apoptosis of H9C2 cells., (© 2019 The Korean Society of Ginseng, Published by Elsevier Korea LLC.)

A facile method was developed for synthesis of boronic acid-functionalized silica nanocomposites (SiO 2 -BA) by 'thiol-ene' click reaction, where silica nanoparticles were synthesized by using tetraethoxysilane (TEOS) and γ-mercaptopropyl trimethoxysilane (γ-MPTS) as precursors. The morphology and structure properties of the resultant SiO 2 -BA were characterized by transmission electronic microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), and Brunner-Emmet-Teller measurements (BET). The adsorption behavior of the SiO 2 -BA for glycoproteins was evaluated. Under the optimized conditions, the SiO 2 -BA exhibited higher adsorption capacity towards glycoproteins (ovalbumin, OVA, 7.64 μmol/g) than non-glycoproteins (bovine serum albumin, BSA, 0.83 μmol/g). In addition, the practicality of the SiO 2 -BA was further assessed by selective enrichment of glycoproteins from egg white samples., (© 2019 Wiley-VHCA AG, Zurich, Switzerland.)

Previous studies have reported that miR-107 could be utilized as a potential peripheral biomarker in prostate cancer (PCa). However, the specific functions of miR-107 in prostate cancer and its relevant mechanisms are still unknown. The aim of this research was to investigate the cellular functions of miR-107 in PCa and reveal the relevant mechanisms. MicroRNA tailing quantitative real-time PCR (qRT-PCR) was adopted to measure the expression of miR-107 in PCa cell line DU145 and PC3, as well as in normal prostate cell line RWPE-1. The miR-107 expression pattern in PCa tissues and paired peritumoral tissues were determined by Chromogenic In Situ Hybridization (CISH). Cell viability, colony formation, flow cytometry cell cycle and apoptosis, wound healing and Transwell migration assays were performed to study the miR-107 functions in PCa cells. Further, qRT-PCR, western blot analysis and dual-luciferase reporter assays were conducted to verify the target of miR-107 in PCa. Results demonstrated that miR-107 was downregulated in PCa cells and tissues in comparison with normal prostate cells and peritumoral tissues, and the over-expression of miR-107 suppressed proliferation and induced G1/S arrest of PCa cells but had no effects on apoptosis or cell motility of PCa cells. MiR-107 was found to target cyclin E1 (CCNE1) in PCa cells by directly binding to its 3'-UTR. In conclusion, miR-107 could be a potential tumor suppressor in PCa, and the restoration of miR-107 might provide a new therapeutic option for PCa.

Ethnopharmacological Relevance: Atopic dermatitis (AD), a disorder prevalent during childhood and adulthood, seriously affects the patient's quality of life. Although Huang-Lian-Jie-Du-Tang (HLJDT) has shown anti-inflammatory effects in previous studies, its effects and mechanism of action underlying AD disorder are still largely unknown., Objective: This study explored the anti-inflammatory and immunomodulatory effects of HLJDT on the AD-like dermal disorder, induced in vitro by lipopolysaccharide (LPS)-triggered inflammation, and in vivo by 2,4-dinitrochlorobenzene (DNCB)., Materials and Methods: In vivo HLJDT effects were investigated by determining the severity of dermatitis, which consisted of observing signs of skin lesions, visually and through haematoxylin and eosin (HE) staining, in mouse ears and dorsal skin, measuring serum levels of interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, interferon (IFN)-γ, the tumour necrosis factor (TNF)-α, and determining the splenic index, number of splenic CD4 + /CD8 + T-lymphocytes, as well as the phosphorylation levels of mitogen-activated protein kinases (including MAPKs-p38, ERK, and JNK), IκB-α, and nuclear factor kappa B (NF-κB) (p65) within dermal lesions. Morphological changes in LPS-induced inflammation were observed under a microscope, and ELISA and qPCR assays were used to measure IL-1α, IL-1β, IL-6, and TNF-α expression levels. The protein expression levels of P-ERK/ERK, P-p38/p38, P-JNK/JNK, P-IKβ-α, and P-p65 were measured through western blotting. Additionally, p65 expression was assessed by immunofluorescence, and LPS binding to RAW264.7 cell membrane was studied with laser confocal microscopy., Results: HLJDT could remarkably mitigate DNCB-induced AD-like lesion symptoms, alleviating inflammatory mediator infiltration in mouse ears and dorsal skin tissue, down-regulating serum expression levels of IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IFN-γ, and TNF-α, normalising the splenic CD4 + /CD8 + T-lymphocyte ratio, and inactivating MAPKs (including p38, ERK, and JNK), IκB-α, and NF-κB (p65) in dorsal skin. Furthermore, HLJDT inhibited LPS-induced differentiation of RAW264.7 cells, as evidenced by the decreased protein and mRNA expression of IL-1α, IL-1β, IL-6, and TNF-α. Additionally, it decreased ERK, p38, JNK, IKβ-α, and p65 phosphorylation levels in the MAPKs/NF-κB pathway, inhibited p65 nuclear translocation, and reduced LPS binding to the RAW264.7 cell membrane., Conclusions: HLJDT significantly improved AD-like symptoms via inhibition of the MAPKs/NF-κB pathway. Therefore, administration of HLJDT might be a potential treatment for AD in the clinical setting., (Copyright © 2019. Published by Elsevier B.V.)

Vascular smooth muscle cell (VSMC) proliferation plays a critical role in arterial remodeling during various vascular diseases including atherosclerosis and hypertension. Tanshinone I, a major component of Salvia miltiorrhiza, exerts protective effects against cardiovascular diseases. In this study, we investigated the effects of tanshinone I on VSMC proliferation, as well as the underlying mechanisms. We found that this compound inhibited the proliferation of VSMCs in a dose-dependent manner, based on 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) and 5-ethynyl-2'-deoxyuridine (EdU) assays. Western blotting demonstrated that tanshinone I inhibited the expression of proliferation-related proteins, including cyclin-dependent kinase 4 (CDK4), cyclin D3, and cyclin D1, in a dose-dependent manner. Molecular docking showed that this compound docked to the inhibitor-binding site of the insulin-like growth factor 1 (IGF-1) receptor (IGF-1R), and the binding energy between tanshinone I and IGF-1R was -9.021 kcal/mol. Molecular dynamic simulations showed that the IGF-1R-tanshinone I binding was stable. We also found that tanshinone I dose-dependently inhibited IGF-1R activation and its downstream molecules, insulin receptor substrate (IRS)-1, phosphatidylinositol-3-Kinase (PI3K), Akt, glycogen synthase kinase-3 beta (GSK3β), mammalian target of rapamycin (mTOR), 70S6K, and ribosomal protein S6 (RPS6). Notably, activation of IGF-1R by recombinant IGF-1 rescued the activity of IGF-1R and its downstream molecules, and the proliferation of tanshinone I-treated VSMC. In addition, blocking PI3K signaling with LY294002 showed the important role of this pathway in tanshinone I-mediated suppression of VSMC proliferation. Collectively, these data demonstrated that tanshinone I might inhibit VSMC proliferation by inhibiting IGF-1R/PI3K signaling., (Copyright © 2019. Published by Elsevier B.V.)