Tumor lineage plasticity (LP) is an emerging hallmark of cancer progression. Through pharmacologically probing the function of epigenetic regulators in prostate cancer cells and organoids, we identified bromodomain protein BRD4 as a crucial player. Integrated ChIP-seq and RNA-seq analysis of tumors revealed, for the first time, that BRD4 directly activates hundreds of genes in the LP programs which include neurogenesis, axonogenesis, EMT and stem cells and key drivers such as POU3F2 (BRN2), ASCL1/2, NeuroD1, SOX2/9, RUNX1/2 and DLL3. Interestingly, BRD4 genome occupancy is reprogrammed by anti-AR drugs from facilitating AR function in CRPC cells to activating the LP programs and is facilitated by pioneer factor FOXA1. Significantly, we demonstrated that BRD4 inhibitor AZD5153, currently at clinical development, possesses potent activities in complete blockade of tumor growth of both de novo neuroendocrine prostate cancer (NEPC) and treatment-induced NEPC PDXs and that suppression of tumor expression of LP programs through reduction of local chromatin accessibility is the primary mechanism of action (MOA) by AZD5153. Together, our study revealed that BRD4 plays a fundamental role in direct activation of tumor LP programs and that its inhibitor AZD5153 is highly promising in effective treatment of the lethal forms of the diseases.

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) cause a severe neurodevelopmental disorder, yet the impact of truncating mutations remains unclear. Here, we introduce the Cdkl5^492stop mouse model, mimicking C-terminal truncating mutations in patients. 492stop/Y mice exhibit altered dendritic spine morphology and spontaneous seizure-like behaviors, alongside other behavioral deficits. After creating cell lines with various Cdkl5 truncating mutations, we found that these mutations are regulated by the nonsense-mediated RNA decay pathway. Most truncating mutations result in CDKL5 protein loss, leading to multiple disease phenotypes, and offering new insights into the pathogenesis of CDKL5 disorder.
Animals ; Disease Models, Animal ; Mice ; Protein Serine-Threonine Kinases/deficiency* ; Mutation/genetics* ; Epileptic Syndromes/genetics* ; Humans ; Dendritic Spines/pathology* ; Spasms, Infantile/genetics* ; Male ; Seizures/genetics* ; Mice, Inbred C57BL

OBJECTIVE: To investigate the spatiotemporal patterns and socioeconomic factors influencing the incidence of tuberculosis (TB) in the Guangdong Province between 2010 and 2019. METHOD: Spatial and temporal variations in TB incidence were mapped using heat maps and hierarchical clustering. Socioenvironmental influencing factors were evaluated using a Bayesian spatiotemporal conditional autoregressive (ST-CAR) model. RESULTS: Annual incidence of TB in Guangdong decreased from 91.85/100,000 in 2010 to 53.06/100,000 in 2019. Spatial hotspots were found in northeastern Guangdong, particularly in Heyuan, Shanwei, and Shantou, while Shenzhen, Dongguan, and Foshan had the lowest rates in the Pearl River Delta. The ST-CAR model showed that the TB risk was lower with higher per capita Gross Domestic Product (GDP) [Relative Risk ( RR), 0.91; 95% Confidence Interval ( CI): 0.86-0.98], more the ratio of licensed physicians and physician ( RR, 0.94; 95% CI: 0.90-0.98), and higher per capita public expenditure ( RR, 0.94; 95% CI: 0.90-0.97), with a marginal effect of population density ( RR, 0.86; 95% CI: 0.86-1.00). CONCLUSION The incidence of TB in Guangdong varies spatially and temporally. Areas with poor economic conditions and insufficient healthcare resources are at an increased risk of TB infection. Strategies focusing on equitable health resource distribution and economic development are the key to TB control.
Humans ; China/epidemiology* ; Incidence ; Bayes Theorem ; Spatio-Temporal Analysis ; Tuberculosis/epidemiology* ; Socioeconomic Factors

Objective To observe the clinical efficacy of joint needling method combined with ultrasound in the treatment of qi stagnation and blood stasis type of patellofemoral pain syndrome(PFPS).Methods Eighty-six patients with qi stagnation and blood stasis type of PFPS were randomly divided into observation group and control group,with 43 cases in each group.The control group was given western medicine conventional treatment combined with functional exercise,and the observation group was given joint needling method combined with ultrasound treatment on the basis of the control group.Both groups were treated for 2 consecutive weeks.After 2 weeks of treatment,the clinical efficacy of the two groups was evaluated,and the changes in the Visual Analogue Scale(VAS)scores of knee pain and the Kujala scale scores of the two groups were observed before and after treatment.The changes in active range of motion(AROM)of the affected knee joint were compared before and after treatment between the two groups.Results(1)After treatment,the VAS scores of the two groups of patients were significantly improved(P＜0.05),and the observation group was significantly superior to the control group in improving the level of VAS scores,and the difference was statistically significant(P＜0.05).(2)After treatment,the Kujala scores of patients in the two groups were significantly improved(P＜0.05),and the observation group was significantly superior to the control group in improving the level of Kujala scores,and the difference was statistically significant(P＜0.05).(3)After treatment,the AROM of patients in the two groups were significantly improved(P＜0.05),and the observation group was significantly superior to the control group in improving the level of AROM,and the difference was statistically significant(P＜0.05).(4)The total effective rate was 95.35%(41/43)in the observation group and 81.40%(35/43)in the control group.The efficacy of the observation group was superior to that of the control group,and the difference was statistically significant(P＜0.05).Conclusion The joint needling method combined with ultrasound can significantly relieve the pain symptoms of patients with PFPS and promote the recovery of knee joint function,and the clinical efficacy is remarkable.

Aldehyde oxidase (AOX) is a molybdoenzyme that is primarily expressed in the liver and is involved in the metabolism of drugs and other xenobiotics. AOX-mediated metabolism can result in unexpected outcomes, such as the production of toxic metabolites and high metabolic clearance, which can lead to the clinical failure of novel therapeutic agents. Computational models can assist medicinal chemists in rapidly evaluating the AOX metabolic risk of compounds during the early phases of drug discovery and provide valuable clues for manipulating AOX-mediated metabolism liability. In this study, we developed a novel graph neural network called AOMP for predicting AOX-mediated metabolism. AOMP integrated the tasks of metabolic substrate/non-substrate classification and metabolic site prediction, while utilizing transfer learning from ¹³C nuclear magnetic resonance data to enhance its performance on both tasks. AOMP significantly outperformed the benchmark methods in both cross-validation and external testing. Using AOMP, we systematically assessed the AOX-mediated metabolism of common fragments in kinase inhibitors and successfully identified four new scaffolds with AOX metabolism liability, which were validated through in vitro experiments. Furthermore, for the convenience of the community, we established the first online service for AOX metabolism prediction based on AOMP, which is freely available at https://aomp.alphama.com.cn.

Bone and soft tissue tumors are diverse and with complicated histologic components and significantly divergent biological behaviors.Conventional imaging examinations,such as CT,magnetic resonance imaging(MRI)and positron emission tomography(PET),are limited to the identification of anatomical structures and abnormal signals,which are difficult to meet the qualitative requirements of imaging.With the improvement of digitalization in hospitals and medical institutions,the introduction of electronic medical records and the improvement of computational power,modern intelligent medical treatment gradually evolves to the combination of human brain,big data and artificial intelligence.Researchers are committed to mining deeper image data information,and radiomics came into being.Radiomics is a method of extracting and analyzing subvisual quantitative features from medical images and quantifying tumor heterogeneity through modeling,which is of great significance in the accurate diagnosis and treatment of bone and soft tissue tumors.

The high selectivity and affinity of antibody binding make antibodies widely used in therapeutics, diagnostics, and basic sciences. However, the toxicity of some antibodies has limited their utility. In the past decade, by increasing tissue specificity, conditionally active antibodies have further improved the safety and efficacy of antibodies, widened or even created a therapeutic window. Conditionally active antibodies are antibodies activatable under particular stimuli but have little or no antigen-binding activity in circulation and normal tissues. Conditionally active antibodies are designed to respond to endogenous or exogenous stimuli, such as light, temperature, enzymatic activity, pH, adenosine triphosphate (ATP), ions, effector molecules, and antigen combinations. Currently, two pH-activated antibodies have been approved for clinical use, and multiple conditionally active antibodies have entered clinical trials. This article describes the current status of the field of conditionally active antibodies, focusing on the three major types of conditionally active antibodies activated by pH, ATP and protease, including their design principles, implementation methods, relevant examples and the latest research progress. In addition, this review summarizes tumor-associated proteases and discusses the role of several key proteases in the development and progression of cancer, which can provide reference for the research and development of conditionally active antibodies. Many opportunities remain untapped in this field, waiting for more efficient and generally applicable activation strategies to be developed at the interface between chemistry and biotechnology.

Misuse of pyrrolizidine alkaloid (PA)-containing herbs is the major cause of hepatic sinusoidal obstruction syndrome (HSOS) in China. And diuretics are among the most commonly used medications for the treatment of PA-induced HSOS in clinical practice. As a traditional diuretic in traditional Chinese medicine, the diuretic mechanism of Alismatis Rhizoma (AR) has not been fully clarified, and there is no report on AR ameliorating PA-induced HSOS from a diuretic point of view. Therefore, this study aims to investigate the therapeutic potential of alisol B 23-acetate (AB23A) against acute liver injury induced by senecionine (a representative toxic PA) in mice, and to further elucidate its effect on impaired water-liquid balance in mice exposed to PA. All experiments were approved by the Animal Research Committee of Shanghai University of Traditional Chinese Medicine (Registration number: PZSHUTCM220808017). Animal welfare and the animal experimental protocols were strictly consistent with related ethics regulations of Shanghai University of Traditional Chinese Medicine. Model of mice was induced by a single oral exposure of senecioine (50 mg·kg^-1) (SEN group), and AB23A (40 mg·kg^-1) intervention group (AB23A+SEN group), solvent control group (Ctrl group) and AB23A control group (AB23A group) were set up. The results showed that AB23A could significantly attenuate the levels of serum biochemical indices of liver functions in senecioine-induced acute liver injury mice, as evident by alleviated hepatocyte necrosis and hepatic sinusoidal stasis. AB23A also improved kidney function of mice exposed to senecionine, fascinated urinary excretion and repaired electrolyte disorders, as well as decreased content of senecioine metabolites. Further, the protein and mRNA expression of genes related to the water balance pathway were measured. AB23A could significantly down-regulate the elevated protein and mRNA expression levels of aquaporin 2 (AQP2) and angiotensin II type 1 receptor, and inhibit the transport of AQP2 to the apical plasma membrane induced by senecionine exposure. AB23A also significantly decreased serum levels of angiotensin II. In vitro studies further confirmed that AB23A regulates AQP2 expression in renal inner medullary collecting duct cells 3 (IMCD3). These data indicate that AB23A regulates the expression of AQP2 in renal medulla, thereby affecting its water reabsorption in mice with senecionine-induced acute liver injury. This work achieves a better understanding of the diuretic effect of AR, and provides experimental foundation and theoretical basis for the treatment of PA-induced acute liver injury by AR in clinics.

Objective:To investigate the application value of ultrasound technology in transurethral enucleation and resection of the prostate(TUERP).Methods:This study included 78 BPH patients admitted in our hospital from June 2021 to June 2023,aged 70.68±8.63 years and with the indication of surgery.We randomly divided them into two groups to receive TUERP(the control group,n=39)and ultrasound-assisted TUERP(the US-TUERP group,n=39).We statistically analyzed and compared the rele-vant parameters obtained before and after operation between the two groups.Results:No statistically significant differences were ob-served in the operation time and bladder irrigation time between the two groups(P>0.05).More glandular tissues were removed but less intraoperative bleeding and fewer perioperative complications occurred in the US-TUERP group than in the control.Compared with the baseline,IPSS,postvoid residual urine volume(PVR),quality of life score(QOL)and maximum urinary flow rate(Qmax)were significantly improved in both groups at 1 and 3 months after surgery,even more significantly in the US-TUERP than in the control group(P<0.05).Conclusion:US-TUERP helps achieve complete resection of the hyperplastic prostatic tissue along the surgical capsule at the anatomical level,with a higher safety,fewer perioperative complications,and better therapeutic effects.

Objective:To evaluate the safety and efficiency of China-made Toumai Robot-assisted laparoscopic radical prosta-tectomy(LRP).Methods:This study included 40 cases of PCa treated from January 2023 to May 2023 by robot-assisted LRP with preservation of the bladder neck and maximal functional urethral length,15 cases with the assistance of Toumai Robot(the TMR group)and the other 25 with the assistance of da Vinci Robot as controls(the DVR group).We recorded the docking time,laparo-scopic surgery time,vesico-urethral anastomosis time,intraoperative blood loss and postoperative urinary continence,and compared them between the two groups.Results:Operations were successfully completed in all the cases.No statistically significant differ-ences were observed between the TMR and DVR groups in the docking time(6 min vs 5 min,P＞0.05)or intraoperative blood loss(200 ml vs 150 ml,P＞0.05).The TMR group,compared with the DVR group,showed a significantly longer median laparoscopic surgery time(146 min vs 130 min,P＜0.05)and median vesico-urethral anastomosis time(19 min vs 16 min,P＜0.05).There were no statistically significant differences between the TMR and DVR groups in the rates of urinary continence recovery immediately af-ter surgery(60.0％[9/15]vs 64.0％[16/25],P＞0.05)or at 1 month(80.0％[12/15])vs(76.0％[19/25],P＞0.05),3 months(93.3％[14/15])vs(92.0％[23/25],P＞0.05)and 6 months postoperatively(100％[15/15])vs(96％[24/25],P＞0.05).Conclusion:China-made Toumai? Robot surgical system is safe and reliable for laparoscopic radical prosta-tectomy,with satisfactory postoperative recovery of urinary continence.