Bromuconazole exposure induces cardiac dysfunction by upregulating the expression LEF1.

With the wide application of bromuconazole (BRO), a kind of triazole fungicide, the environmental problems caused by BRO have been paid more and more attention. In this study, adult male zebrafish were exposed to environmental related concentration and the maximum non-lethal concentration for zebrafish larvae (0,50 ng/L and 7.5 mg/L) for 7 days, respectively. Zebrafish exposed to BRO exhibited a significant reduction in body length and an increase in fatness index, indicating adverse physiological changes. Notably, the exposed zebrafish showed enlarged heart ventricular volumes and thinner heart walls. Transcriptome analysis of heart samples showed that BRO exposure mainly affected pathways related to cardiac energy metabolism. In addition, the amount of ATP in the heart tissue was correspondingly reduced, and the expression levels of genes related to controlling ion balance and myosin synthesis in the heart were also altered. The study extended its findings to the rat cardiomyocytes (H9C2), where similar cardiotoxic effects including changes in transcription of genes related to energy metabolism and heart function were also observed, suggesting a potential universal mechanism of BRO-induced cardiotoxicity. In a doxorubicin (DOX) induced larval zebrafish heart failure model, the expression of lymphoid enhancer-binding factor 1(LEF1), a key gene in the Wnt/ß-catenin signaling pathway, was significantly increased in larval zebrafish and adult fish heart tissues and cardiomyocytes, suggesting that LEF1 might play an important role in BRO-induced cardiotoxicity. Taken together, BRO exposure could interfere with cardiac function and metabolic capacity by abnormal activation the expression of LEF1. The study emphasized the urgent need for monitoring and regulating BRO due to its harmful effects on the hearts of aquatic organisms.

Epoxiconazole altered hepatic metabolism in adult zebrafish based on transcriptomic analysis.

Epoxiconazole (EPX) is a triazole fungicide, which has been widely used in pest control of cereal crops. However, its extensive use has led to concerning levels of residue in water bodies, posing substantial risks to aquatic life. In this study, we characterized the toxicological effects of EPX on 6-month-old male and female zebrafish at 70 and 700 µg/L, respectively. The results revealed that EPX exposure markedly increased both body length and weight in zebrafish of both sexes, consequently elevating their condition factor. Besides, EPX exposure resulted in notable alterations in hepatic histopathology. These changes included loosened hepatocyte structure, ballooning degeneration, nucleolysis, and disappearance of cell line, with male zebrafish exhibiting more severe damage. High concentration of EPX also significantly increased hepatic lipid accumulation in male zebrafish, as well as increased hepatic triglyceride (TG) levels. Correspondingly, there was a notable alteration in the transcription of genes including cyp51, hmgcr, and PPAR-γ, which associated with cholesterol and lipid metabolism. Interestingly, with the hepatic transcriptomic analysis, high concentration of EPX produced 195 upregulated and 107 downregulated differential expression genes. Both KEGG and GO analyses identified significant enrichment of these genes in lipid and amino acid metabolism pathways. Notably, some key genes involved in the steroid synthesis pathway were marked upregulated. In addition, molecular docking study confirmed that EPX could bind CYP51 protein well (△G = -7.7 kcal/mol). Taken together, these findings demonstrated the multiple toxic effects of EPX on adult zebrafish.

Molecular basis of the inositol deacylase PGAP1 involved in quality control of GPI-AP biogenesis.

The secretion and quality control of glycosylphosphatidylinositol-anchored proteins (GPI-APs) necessitates post-attachment remodeling initiated by the evolutionarily conserved PGAP1, which deacylates the inositol in nascent GPI-APs. Impairment of PGAP1 activity leads to developmental diseases in humans and fatality and infertility in animals. Here, we present three PGAP1 structures (2.66-2.84 Å), revealing its 10-transmembrane architecture and product-enzyme interaction details. PGAP1 holds GPI-AP acyl chains in an optimally organized, guitar-shaped cavity with apparent energetic penalties from hydrophobic-hydrophilic mismatches. However, abundant glycan-mediated interactions in the lumen counterbalance these repulsions, likely conferring substrate fidelity and preventing off-target hydrolysis of bulk membrane lipids. Structural and biochemical analyses uncover a serine hydrolase-type catalysis with atypical features and imply mechanisms for substrate entrance and product release involving a drawing compass movement of GPI-APs. Our findings advance the mechanistic understanding of GPI-AP remodeling.

Identification and validation of CRLF1 and NRG1 as immune-related signatures in hypertrophic scar.

BACKGROUND: Hypertrophic scar (HTS) is a prevalent chronic inflammatory skin disorder characterized by abnormal proliferation and extracellular matrix deposition and the precise mechanisms underlying HTS remain elusive. This study aimed to identify and validate potential immune-related genes associated with hypertrophic scar formation. METHODS: Skin samples from normal (n = 12) and hypertrophic scar tissues (n = 12) were subjected to RNA-seq analysis. Differentially expressed genes (DEGs) and significant modular genes in Weighted gene Co-expression Network Analysis (WGCNA) were identified. Subsequently, functional enrichment analysis was performed on the intersecting genes. Additionally, eight immune-related genes were matched from the ImmPort database. Validation of NRG1 and CRLF1 was carried out using an external cohort (GSE136906). Furthermore, the association between these two genes and immune cells was assessed by Spearman correlation analysis. Finally, RNA was extracted from normal and hypertrophic scar samples, and RT-qPCR, Immunohistochemistry staining and Western Blot were employed to validate the expression of characteristic genes. RESULTS: A total of 940 DEGs were identified between HTS and normal samples, and 288 key module genes were uncovered via WGCNA. Enrichment analysis in key module revealed involvement in many immune-related pathways, such as Th17 cell differentiation, antigen processing and presentation and B cell receptor signaling pathway. The eight immune-related genes (IFI30, NR2F2, NRG1, ESM1, NFATC2, CRLF1, COLEC12 and IL6) were identified by matching from the ImmPort database. Notably, we observed that activated mast cell positively correlated with CRLF1 expression, while CD8 T cells exhibited a positive correlation with NRG1. The expression of NRG1 and CRLF1 was further validated in clinical samples. CONCLUSION: In this study, two key immune-related genes (CRLF1 and NRG1) were identified as characteristic genes associated with HTS. These findings provide valuable insights into the immune-related mechanisms underlying hypertrophic scar formation.

Preharvest application of MeJA enhancing the quality of postharvest grape berries via regulating terpenes biosynthesis and phenylpropanoid metabolisms.

Methyl jasmonate (MeJA) is an important phytohormone that regulates the development of grape, but the effect and underpin mechanism of its preharvest application on secondary metabolites accumulation in postharvest grape berries are still unclear. In this study, the transcriptome profiles combined with metabolic components analysis were used to determine the effect of preharvest MeJA application on the quality formation of postharvest rose-flavor table grape Shine Muscat. The results indicated that preharvest MeJA treatment had no significant effect on TSS content, but had a down-regulation effect on the accumulation of reducing sugar and titratable acid in the berries. The content of chlorophylls and carotenoids in treated berries was significantly higher than that of the control. Many phenolic components, such as trans-ferulic acid, resveratrol, quercetin, and kaempferol, were sensitive to MeJA and their contents were also significantly higher than that of the control under MeJA treatments during the shelf life. Compared with other volatile aroma components, terpenoid components were more sensitive to preharvest MeJA signals, the content of which presented an overall upward trend with increasing MeJA concentration and prolonging storage time. Furthermore, most of the differentially expressed genes in the general phenylpropanoid pathway and terpenoid biosynthesis pathway were up-regulated responding to MeJA signals. The most upregulated regulatory factors, such as VvWRKY72, VvMYB24, and VvWRI1, may be involved in MeJA signal transduction and regulation. Preharvest MeJA may be an effective technique for enhancing the quality of postharvest Shine Muscat grape berries, with its positive effect on enhancing the characteristic aroma and nutritional components.

A deep learning model, NAFNet, predicts adverse pathology and recurrence in prostate cancer using MRIs.

We aimed to apply a potent deep learning network, NAFNet, to predict adverse pathology events and biochemical recurrence-free survival (bRFS) based on pre-treatment MRI imaging. 514 prostate cancer patients from six tertiary hospitals throughout China from 2017 and 2021 were included. A total of 367 patients from Fudan University Shanghai Cancer Center with whole-mount histopathology of radical prostatectomy specimens were assigned to the internal set, and cancer lesions were delineated with whole-mount pathology as the reference. The external test set included 147 patients with BCR data from five other institutes. The prediction model (NAFNet-classifier) and integrated nomogram (DL-nomogram) were constructed based on NAFNet. We then compared DL-nomogram with radiology score (PI-RADS), and clinical score (Cancer of the Prostate Risk Assessment score (CAPRA)). After training and validation in the internal set, ROC curves in the external test set showed that NAFNet-classifier alone outperformed ResNet50 in predicting adverse pathology. The DL-nomogram, including the NAFNet-classifier, clinical T stage and biopsy results, showed the highest AUC (0.915, 95% CI: 0.871-0.959) and accuracy (0.850) compared with the PI-RADS and CAPRA scores. Additionally, the DL-nomogram outperformed the CAPRA score with a higher C-index (0.732, P < 0.001) in predicting bRFS. Based on this newly-developed deep learning network, NAFNet, our DL-nomogram could accurately predict adverse pathology and poor prognosis, providing a potential AI tools in medical imaging risk stratification.

Prospective clinical sequencing of 1016 Chinese prostate cancer patients: uncovering genomic characterization and race disparity.

Although there is a well-known disparity in prostate cancer (PC) incidence and mortality between Chinese and Western patients, the underlying genomic differences have been investigated only sparsely. This clinicogenomic study was conducted to reveal the genomic mutations contributing to the PC disparity across ethnicities and investigate the mutational profile of Chinese PC patients. A total of 1016 Chinese PC patients were prospectively enrolled and subjected to targeted sequencing, resulting in usable sequencing data for 41 genes from 859 patients. Genomic data retrieved from The Cancer Genome Atlas (TCGA; locoregional PC), Memorial Sloan Kettering Cancer Center [MSKCC; metastatic castration-sensitive PC (mCSPC)], and Stand Up To Cancer [SU2C; metastatic castration-resistant PC (mCRPC)] cohorts were used as comparators representing Western men. Genomic mutations were analyzed using an integrated bioinformatic strategy. A comparison of the disease stages revealed that mutations in tumor protein 53 (TP53), androgen receptor (AR), forkhead box A1 (FOXA1), and genes involved in the cell cycle pathway were enriched in mCRPC. Mutations in adenomatous polyposis coli (APC) gene were found to be more prevalent in patients with visceral metastasis. Genomic differences between Western and Chinese men were mainly observed in castration-sensitive PC, with tumors from Chinese men having more FOXA1 (11.4% vs. 4.2%) but fewer TP53 (4.8% vs. 13%) mutations in locoregional PC and harboring fewer TP53 (11% vs. 29.2%), phosphatase and tensin homolog (PTEN; 2.5% vs. 10.3%), and APC (1.7% vs. 7.4%) mutations in the mCSPC stage than those of Western men. Patients of both ethnicities with mCRPC had similar mutational spectra. Furthermore, FOXA1 class-2 was less common than FOXA1 class-1 and showed no enrichment in metastasis, contrary to the findings in the Western cohort. Our study provides a valuable resource for a better understanding of PC in China and reveals the genomic alterations associated with PC disparity across races.

Sufu limits sepsis-induced lung inflammation via regulating phase separation of TRAF6.

Rationale: Sepsis is a potentially life-threatening condition caused by the body's response to a severe infection. Although the identification of multiple pathways involved in inflammation, tissue damage and aberrant healing during sepsis, there remain unmet needs for the development of new therapeutic strategies essential to prevent the reoccurrence of infection and organ injuries. Methods: Expression of Suppressor of Fused (Sufu) was evaluated by qRT-PCR, western blotting, and immunofluorescence in murine lung and peritoneal macrophages. The significance of Sufu expression in prognosis was assessed by Kaplan-Meier survival analysis. The GFP-TRAF6-expressing stable cell line (GFP-TRAF6 Blue cells) were constructed to evaluate phase separation of TRAF6. Phase separation of TRAF6 and the roles of Sufu in repressing TRAF6 droplet aggregation were analyzed by co-immunoprecipitation, immunofluorescence, Native-PAGE, FRAP and in vitro assays using purified proteins. The effects of Sufu on sepsis-induced lung inflammation were evaluated by cell function assays, LPS-induced septic shock model and polymicrobial sepsis-CLP mice model. Results: We found that Sufu expression is reduced in early response to lipopolysaccharide (LPS)-induced acute inflammation in murine lung and peritoneal macrophages. Deletion of Sufu aggravated LPS-induced and CLP (cecal ligation puncture)-induced lung injury and lethality in mice, and augmented LPS-induced proinflammatory gene expression in cultured macrophages. In addition, we identified the role of Sufu as a negative regulator of the Toll-Like Receptor (TLR)-triggered inflammatory response. We further demonstrated that Sufu directly interacts with TRAF6, thereby preventing oligomerization and autoubiquitination of TRAF6. Importantly, TRAF6 underwent phase separation during LPS-induced inflammation, which is essential for subsequent ubiquitination activation and NF-κB activity. Sufu inhibits the phase-separated TRAF6 droplet formation, preventing NF-κB activation upon LPS stimulation. In a septic shock model, TRAF6 depletion rescued the augmented inflammatory phenotype in mice with myeloid cell-specific deletion of Sufu. Conclusions: These findings implicated Sufu as an important inhibitor of TRAF6 in sepsis and suggest that therapeutics targeting Sufu-TRAF6 may greatly benefit the treatment of sepsis.

Simplicillium sinense sp. nov., a novel potential pathogen of tinea faciei.

Simplicillium species are widely distributed with a broad spectrum of hosts and substrates. Generally, these species are entomopathogenic or mycoparasitic. Notably, some isolates of Simplicillium lanosoniveum and Simplicillium obclavatum were obtained from human tissues. In this study, two fungi were isolated from the annular itchy patch of infected skin of a 46-year-old man with diabetes mellitus. Based on a combination of morphological characteristics and phylogenetic analysis, a novel species, Simplicillium sinense, was introduced herein. It morphologically differs from the remaining Simplicillium in the size of phialides and conidia. Additionally, it grows slowly on YPD at 37°C. Antimicrobial susceptibility testing presented that this fungus is resistant to most azole antifungals. Therefore, the diagnosis of tinea faciei was made, and after 2 weeks of being treated with oral terbinafine (250 mg, once a day) and topical terbinafine cream for 1 month, the rash was mainly resolved and no recurrence happened after 6 months of follow-up. Herein, Simplicillium sinense was introduced as a new fungal taxon. Meanwhile, a case of superficial infection caused by S. sinense was reported. So far, it is the third Simplicillium species obtained from human tissue. Meanwhile, terbinafine is recommended as the first-line antifungal treatment against Simplicillium infection.

Relationships of body composition and adipocytokines with outcomes in metastatic castration-resistant prostate cancer patients receiving docetaxel chemotherapy.

We evaluated the relationships of body composition and serum adipocytokine levels with progression-free survival (PFS) and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients receiving docetaxel. The medical records of mCRPC patients who received docetaxel between January 2011 and December 2015 at Fudan University Shanghai Cancer Center (Shanghai, China) were reviewed. The following body composition parameters were calculated using computed tomography: skeletal muscle index (SMI), visceral adipose tissue index (VATI), and subcutaneous adipose tissue index (SATI). Pretreatment serum adipocytokine levels, including interleukin 6, insulin, leptin, monocyte chemoattractant protein-1, adiponectin, and resistin, were measured using the multiplex bead-based immunoassays. Cox regression and Kaplan-Meier methods were used for survival analyses. Of the 453 mCRPC patients initially identified, 105 were included in the analysis. High VATI group patients had longer PFS (median, 10 months vs 7 months, P = 0.008) and OS (median, 24 months vs 15 months, P = 0.017), compared with low VATI group patients. SMI and SATI were not significantly associated with PFS or OS. Of the six detected adipocytokines, only leptin was associated with mCRPC prognosis. High leptin group patients had shorter PFS (median, 7 months vs 12 months, P = 0.0018) and OS (median, 17 months vs 22 months, P = 0.042), compared with low leptin group patients. Multivariate analysis showed that a high VATI was an independent protective factor for PFS and OS, while a high leptin level was an independent risk factor for PFS and OS. Therefore, VATI and serum leptin levels could provide important information concerning mCRPC prognosis.

Radiomics based on biparametric MRI for the detection of significant residual prostate cancer after androgen deprivation therapy: using whole-mount histopathology as reference standard.

We aimed to study radiomics approach based on biparametric magnetic resonance imaging (MRI) for determining significant residual cancer after androgen deprivation therapy (ADT). Ninety-two post-ADT prostate cancer patients underwent MRI before prostatectomy (62 with significant residual disease and 30 with complete response or minimum residual disease [CR/MRD]). Totally, 100 significant residual, 52 CR/MRD lesions, and 70 benign tissues were selected according to pathology. First, 381 radiomics features were extracted from T2-weighted imaging, diffusion-weighted imaging, and apparent diffusion coefficient (ADC) maps. Optimal features were selected using a support vector machine with a recursive feature elimination algorithm (SVM-RFE). Then, ADC values of significant residual, CR/MRD lesions, and benign tissues were compared by one-way analysis of variance. Logistic regression was used to construct models with SVM features to differentiate between each pair of tissues. Third, the efficiencies of ADC value and radiomics models for differentiating the three tissues were assessed by area under receiver operating characteristic curve (AUC). The ADC value (mean ± standard deviation [s.d.]) of significant residual lesions ([1.10 ± 0.02] × 10-3 mm2 s-1) was significantly lower than that of CR/MRD ([1.17 ± 0.02] × 10-3 mm2 s-1), which was significantly lower than that of benign tissues ([1.30 ± 0.02] × 10-3 mm2 s-1; both P < 0.05). The SVM feature models were comparable to ADC value in distinguishing CR/MRD from benign tissue (AUC: 0.766 vs 0.792) and distinguishing residual from benign tissue (AUC: 0.825 vs 0.835) (both P > 0.05), but superior to ADC value in differentiating significant residual from CR/MRD (AUC: 0.748 vs 0.558; P = 0.041). Radiomics approach with biparametric MRI could promote the detection of significant residual prostate cancer after ADT.

Cardiac damage in autoimmune diseases: Target organ involvement that cannot be ignored.

Autoimmune diseases are diseases that cause damage to the body's own tissues as a result of immune dysfunction, often involving multiple organs and systems. The heart is one of the common target organs of autoimmune diseases. The whole structure of the heart can be affected, causing microcirculatory disorders, arrhythmias, pericardial damage, myocarditis, myocardial fibrosis, and impaired valvular function. However, early clinical manifestations of autoimmune heart damage are often overlooked because they are insidious or have no typical features. The damage is often severe and irreversible when symptoms are apparent, even life-threatening. Therefore, early detection and treatment of heart damage in autoimmune diseases is particularly important. Herein, we review the clinical features and mechanisms of cardiac damage in common rheumatic diseases.

Application of Internet-based multidisciplinary management in patients with genitourinary cancers in China: A brief introduction to a new model of healthcare service for cancer survivors during COVID-19 pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has triggered multiple global healthcare system crises. Apart from the pandemic itself, the travel restriction and social distance policy for the purpose of epidemic control has cast a shadow on the management of cancer survivors. Cancer survivors suffered a double blow from both the epidemic and cancer. To deal with the challenge, we explored a new Internet-based patient management model. This model has overcome the limitation of time and space and thus can help oncologists to provide remote multidisciplinary healthcare services for cancer survivors. These patients can get high-quality cancer management from multidisciplinary experts without too much transportation. This model has been applied in patients with genitourinary cancers and proved to be effective and efficient. Our study demonstrated that more patients benefited from this model during the pandemic of COVID-19, especially in those affected heavily by COVID-19. These results suggested that it can also give insight into the management of other cancer survivors in China. Given the long-term impact of the COVID-19 pandemic, we would like to introduce our new model of healthcare service and the application of Internet-based multidisciplinary management to our global peers and medical industries to help their cancer survivors who are delayed in treatment due to the COVID-19 pandemic.

Rezvilutamide versus bicalutamide in combination with androgen-deprivation therapy in patients with high-volume, metastatic, hormone-sensitive prostate cancer (CHART): a randomised, open-label, phase 3 trial.

BACKGROUND: Rezvilutamide, a novel androgen-receptor inhibitor with low blood-brain barrier penetration, has shown potent antitumour activity against metastatic castration-resistant prostate cancer. In this study, we aimed to evaluate the efficacy and safety of rezvilutamide versus bicalutamide in combination with androgen-deprivation therapy (ADT) for high-volume, metastatic, hormone-sensitive prostate cancer. METHODS: CHART is a randomised, open-label, phase 3 study done at 72 hospitals in China, Poland, Czech Republic, and Bulgaria. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and had high-volume metastatic, hormone-sensitive prostate cancer. Previous chemotherapy or other localised treatment for prostate cancer were not allowed. Patients were randomly assigned (1:1) to receive ADT plus either rezvilutamide (240 mg) or bicalutamide (50 mg) orally once daily. Randomisation was done via an interactive response technology system (block size of four) and stratified according to ECOG performance status and presence of visceral metastasis (excluding lymph nodes). Herein, we present the results of the preplanned interim analyses for the two co-primary endpoints of radiographic progression-free survival assessed by a blinded independent review committee and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study medication. This study is ongoing, but is closed to recruitment. This trial is registered with ClinicalTrials.gov, NCT03520478. FINDINGS: Between June 28, 2018, and Aug 6, 2020, 792 patients were screened and 654 patients were randomly assigned to receive rezvilutamide plus ADT (n=326) or bicalutamide plus ADT (n=328). At the preplanned interim analysis for radiographic progression-free survival (data cutoff May 16, 2021), the median follow-up duration was 21·2 months (IQR 16·6-25·8). Rezvilutamide significantly improved radiographic progression-free survival compared with bicalutamide (median radiographic progression-free survival not reached [95% CI not reached-not reached] vs 25·1 months [95% CI 15·7-not reached]; hazard ratio [HR] 0·44 [95% CI 0·33-0·58]; p<0·0001). At the preplanned interim analysis for overall survival (data cutoff Feb 28, 2022), the median follow-up duration was 29·3 months (IQR 21·0-33·3). Rezvilutamide significantly improved overall survival compared with bicalutamide (HR 0·58 [95% CI 0·44-0·77]; p=0·0001; median overall survival was not reached [95% CI not reached-not reached] vs not reached [36·2-not reached]). The most common grade 3 or worse adverse events of any cause in the safety population were hypertension (26 [8%] of 323 patients in the rezvilutamide group vs 24 [7%] of 324 patients in the bicalutamide group), hypertriglyceridaemia (24 [7%] vs seven [2%]), increased weight (20 [6%] vs 12 [4%]), anaemia (12 [4%] vs 16 [5%]), and hypokalaemia (11 [3%] vs four [1%]). Serious adverse events were reported in 90 (28%) of 323 patients in the rezvilutamide group and 69 (21%) of 324 patients in the bicalutamide group. No treatment-related deaths occurred in patients in the rezvilutamide group; one treatment-related death of unknown specific cause (<1%) occurred in the bicalutamide group. INTERPRETATION: In the two interim analyses, rezvilutamide plus ADT significantly improved radiographic progression-free survival and overall survival compared with bicalutamide plus ADT in patients with high-volume, metastatic, hormone-sensitive prostate cancer, with a tolerable safety profile. FUNDING: Jiangsu Hengrui Pharmaceuticals.

Activity and safety of SHR3680, a novel antiandrogen, in patients with metastatic castration-resistant prostate cancer: a phase I/II trial.

BACKGROUND: Antagonizing the androgen-receptor (AR) pathway is an effective treatment strategy for patients with metastatic castration-resistant prostate cancer (CRPC). Here, we report the results of a first-in-human phase 1/2 study which assessed the safety, pharmacokinetics, and activity of SHR3680 (a novel AR antagonist) in patients with metastatic CRPC. METHODS: This phase 1/2 study enrolled patients with progressive metastatic CRPC who had not been previously treated with novel AR-targeted agents. In the phase 1 dose-escalation portion, patients received oral SHR3680 at a starting daily dose of 40 mg, which was subsequently escalated to 80 mg, 160 mg, 240 mg, 360 mg, and 480 mg per day. In phase 2 dose-expansion portion, patients were randomized to receive daily dose of 80 mg, 160 mg, or 240 mg of SHR3680. The primary endpoint in phase 1 was safety and tolerability and in phase 2 was the proportion of patients with a prostate-specific antigen (PSA) response (≥ 50% decrease of PSA level) at week 12. RESULTS: A total of 197 eligible patients were enrolled and received SHR3680 treatment, including 18 patients in phase 1 and 179 patients in phase 2. No dose-limiting toxicities were reported and the maximum tolerated dose was not reached. Treatment-related adverse events (TRAEs) occurred in 116 (58.9%) patients, with the most common one being proteinuria (13.7%). TRAEs of grade ≥ 3 occurred in only 23 (11.7%) patients, and no treatment-related deaths occurred. Antitumor activities were evident at all doses, including PSA response at week 12 in 134 (68.0%; 95% CI, 61.0-74.5) patients, stabilized bone disease at week 12 in 174 (88.3%; 95% CI, 87.2-95.5) patients, and responses in soft tissue lesions in 21 (34.4%, 95% CI, 22.7-47.7) of 61 patients. CONCLUSION: SHR3680 was well tolerated and safe, with promising anti-tumor activity across all doses tested in patients with metastatic CRPC. The dose of 240 mg daily was recommended for further phase 3 study. TRIAL REGISTRATION: Clinical trials.gov NCT02691975; registered February 25, 2016.

Prostate Cancer Screening Using Prostate-Specific Antigen Tests in a High-Risk Population in China: A Cost-Utility Analysis.

BACKGROUND: Both National Comprehensive Cancer Network and Chinese guidelines recommend beginning prostate-specific antigen (PSA) screening for men aged 50 years or 45 years with a family history because they were at a higher risk of developing prostate cancer. Several model-based economic evaluations of PSA screening studies have been conducted, but with little evidence from China. OBJECTIVE: The aim of this study was to conduct an economic evaluation of the cost-utility of PSA-based prostate cancer screening in Chinese men. METHODS: We developed a decision-tree and Markov model in Excel (Microsoft Corp, Redmond, Washington) to compare 2 strategies that can be used to detect prostate cancer: PSA-based screening followed by a biopsy, and non-PSA screening. We assumed that the patients would repeat screening in subsequent years if their first-year PSA value was higher than 4.0 ng/mL. The model adopted health care system perspective and lifetime horizon. Screening efficacy, cost, utility, and long-term survival of prostate cancer were retrieved from published literature and physician surveys. Both quality-adjusted life year and costs were discounted at an annual rate of 3.5%. Uncertainty was assessed by 1-way and probabilistic sensitivity analyses. Our model also calculated the risk-to-benefit ratio as the ratio of overdiagnosis (biopsy without diagnosed) to prostate cancer-related deaths prevented in different age groups. RESULTS: The results suggested that PSA-based screening was cost-effective compared with no PSA screening, with an incremental cost-utility ratio of ¥11,381 ($1821/€1480) per quality-adjusted life year. This value was less than the threshold of 1-time gross domestic product per capita in China (ie, ¥70,892 [$11,343/€9216]). Sensitivity analyses confirmed the robustness of the results. The risk-to-benefit ratios of the 50 to 65 years and the 65 to 80 years age groups were 1.3 and 2.8, respectively. CONCLUSIONS: PSA-based prostate cancer screening appears to be cost-effective in some high-risk Chinese men. PSA screening (PSA testing followed by magnetic resonance imaging and biopsy if positive) can be recommended for Chinese men aged 50 to 65 years because this approach had the lowest risk-to-benefit ratio. The approach should be further adapted based on future updated data. (Curr Ther Res Clin Exp. 2022; 83:XXX-XXX)© 2022 Elsevier HS Journals, Inc.

Sliding of HIV-1 reverse transcriptase over DNA creates a transient P pocket - targeting P-pocket by fragment screening.

HIV-1 reverse transcriptase (RT) slides over an RNA/DNA or dsDNA substrate while copying the viral RNA to a proviral DNA. We report a crystal structure of RT/dsDNA complex in which RT overstepped the primer 3'-end of a dsDNA substrate and created a transient P-pocket at the priming site. We performed a high-throughput screening of 300 drug-like fragments by X-ray crystallography that identifies two leads that bind the P-pocket, which is composed of structural elements from polymerase active site, primer grip, and template-primer that are resilient to drug-resistance mutations. Analogs of a fragment were synthesized, two of which show noticeable RT inhibition. An engineered RT/DNA aptamer complex could trap the transient P-pocket in solution, and structures of the RT/DNA complex were determined in the presence of an inhibitory fragment. A synthesized analog bound at P-pocket is further analyzed by single-particle cryo-EM. Identification of the P-pocket within HIV RT and the developed structure-based platform provide an opportunity for the design new types of polymerase inhibitors.