Pd-Catalyzed Enantioselective Desymmetrizing 1,7-Enyne Cycloisomerization of Alkyne-Tethered Cyclopentenes.

An enantioselective Pd-catalyzed intramolecular desymmetrizing cycloisomerization of N-(cyclopent-3-en-1-yl)propiolamides has been developed by employing a new chiral phosphoramidite ligand. A series of structurally unique bridged azabicycles are achieved in moderate to excellent yields with good E/Z selectivity and high enantioselectivity. Synthetic transformations are conducted to demonstrate the practical utility of this reaction.

Pd-Catalyzed Asymmetric Intramolecular Dearomatizing Reductive Heck Reaction of Indoles.

An enantioselective Pd-catalyzed intramolecular dearomative reductive Heck reaction of N-(o-bromoaryl) indole-3-carboxamide is developed. By employing Pd(dba)2/SPINOL-based phosphoramidite as the chiral catalyst and HCO2Na as the hydride source, a series of enantioenriched spiro indolines bearing vicinal stereocenters were afforded in moderate to good yields with excellent enantioselectivities. The reductive Heck reaction of formal tetrasubstituted alkene bearing ß-hydrogens is therefore realized by inhibiting ß-H elimination.

Copper-catalyzed intramolecular dearomative aza-Wacker reaction of indole.

Herein, we describe a copper-catalyzed intramolecular dearomative amination of indoles via a formal aza-Wacker reaction. This protocol provides an efficient method to access aza-polycyclic indoline molecules bearing exocyclic CC bonds in moderate to excellent yields in the presence of molecular oxygen as an oxidant. It is worth noting that indolin-3-ones are achieved when employing C3-non-substituted indoles as substrates.

Nomogram predicting the efficacy of transurethral surgery in benign prostatic hyperplasia patients.

PURPOSE: This study aimed to develop and validate a nomogram for predicting the efficacy of transurethral surgery in benign prostatic hyperplasia (BPH) patients. METHODS: Patients with BPH who underwent transurethral surgery in the West China Hospital and West China Shang Jin Hospital were enrolled. Patients were retrospectively involved as the training group and were prospectively recruited as the validation group for the nomogram. Logistic regression analysis was utilized to generate nomogram for predicting the efficacy of transurethral surgery. The discrimination of the nomogram was assessed using the area under the receiver operating characteristic curve (AUC) and calibration plots were applied to evaluate the calibration of the nomogram. RESULTS: A total of 426 patients with BPH who underwent transurethral surgery were included in the study, and they were further divided into a training group (n = 245) and a validation group (n = 181). Age (OR 1.07, 95% CI 1.02-1.15, P < 0.01), the compliance of the bladder (OR 2.37, 95% CI 1.20-4.67, P < 0.01), the function of the detrusor (OR 5.92, 95% CI 2.10-16.6, P < 0.01), and the bladder outlet obstruction (OR 2.21, 95% CI 1.07-4.54, P < 0.01) were incorporated in the nomogram. The AUC of the nomogram was 0.825 in the training group, and 0.785 in the validation group, respectively. CONCLUSION: The nomogram we developed included age, the compliance of the bladder, the function of the detrusor, and the severity of bladder outlet obstruction. The discrimination and calibration of the nomogram were confirmed by internal and external validation.

Palladium-Catalyzed Dearomative Heck/Suzuki Coupling of C2-Deuterated or C2-Nonsubstituted Indoles.

A palladium-catalyzed dearomative diarylation of C2-deuterated or C2-nonsubstituted indoles through domino Heck/Suzuki coupling is established. Relying on electron-deficient phosphite ligand, side reactions including intermolecular Suzuki coupling and intramolecular C-D/H arylation are inhibited and a wide range of 2,3-diarylated indolines bearing vicinal tertiary stereocenters including deuterated ones are afforded in moderate to excellent yields (up to 94%) and excellent diastereoselectivities (>20:1). The catalyst loading can be lowered to 0.02 mol % at elevated temperature.

Pd-Catalyzed Intramolecular Dearomative [4 + 2] Cycloaddition of Naphthalenes with Arylalkynes.

A Pd-catalyzed intramolecular dearomative [4 + 2] cycloaddition reaction of naphthalenes with arylalkynes is developed. The protocol provides a straightforward method to access a range of polycyclic dihydronaphthalenes containing two vicinal all-carbon stereocenters in moderate yields under mild conditions in an air atmosphere. The deuterium labeling experiment suggests a pathway involving electrophilic dearomatization followed by Friedel-Crafts cyclization. Several synthetic transformations of the product were conducted to demonstrate the utility of this reaction.

The effect of bladder function on the efficacy of transurethral prostatectomy in patients with benign prostatic hyperplasia: a retrospective, single-center study.

We investigated the impact and predictive value of bladder function in patients with benign prostatic hyperplasia (BPH) on the efficacy of transurethral prostatectomy. Symptomatic, imaging, and urodynamic data of patients who underwent transurethral prostatectomy at West China Hospital of Sichuan University (Chengdu, China) from July 2019 to December 2021 were collected. Follow-up data included the quality of life (QoL), International Prostate Symptom Score (IPSS), and IPSS storage and voiding (IPSS-s and IPSS-v). Moreover, urinary creatinine (Cr), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and prostaglandin estradiol (PGE2) were measured in 30 patients with BPH and 30 healthy participants. Perioperative indicators were determined by subgroup analyses and receiver operating characteristic (ROC) curve analysis. Among the 313 patients with BPH included, patients with severe micturition problems had more improvements but higher micturition grades postoperatively than those with moderate symptoms. Similarly, good bladder sensation, compliance, and detrusor contractility (DC) were predictors of low postoperative IPSS and QoL. The urinary concentrations of BDNF/Cr, NGF/Cr, and PGE2/Cr in patients were significantly higher than those in healthy participants (all P < 0.001). After evaluation, only DC was significantly related to both urinary indicators and postoperative recovery of patients. Patients with good DC, as predicted by urinary indicators, had lower IPSS and IPSS-v than those with reduced DC at the 1st month postoperatively (both P < 0.05). In summary, patients with impaired bladder function had poor recovery. The combined levels of urinary BDNF/Cr, NGF/Cr, and PGE2/Cr in patients with BPH may be valid predictors of preoperative bladder function and postoperative recovery.

Nickel-Catalyzed Enantioselective Dearomative Heck-Reductive Allylic Defluorination Reaction of Indoles.

Herein, we describe a nickel-catalyzed asymmetric dearomative aryl-difluoroallylation reaction of indoles with α-trifluoromethyl alkenes as an electrophilic coupling partner. The reaction proceeds via a cascade sequence involving dearomative Heck cyclization and reductive allylic defluorination. A series of gem-difluoroallyl substituted indolines are obtained in moderate to good yields (36-77% yield) with excellent enantioselectivity (up to 99% ee). The reaction features broad functional group tolerance, scaled-up synthesis, and late-stage diversification.

Cobalt-catalyzed enantioselective desymmetrizing reductive cyclization of alkynyl cyclodiketones.

A highly enantioselective cobalt-catalyzed desymmetrizing reductive cyclization of alkynyl cyclodiketones has been developed. Under mild reaction conditions by employing HBpin as a reducing agent and ferrocene-based PHOX as a chiral ligand, a series of polycyclic tertiary allylic alcohols bearing contiguous quaternary stereocenters are achieved in moderate to excellent yields with excellent enantioselectivities (up to 99%). Broad substrate scope and high functional group compatibility are observed in this reaction. A CoH-catalyzed pathway involving alkyne hydrocobaltation followed by nucleophilic addition to the C[double bond, length as m-dash]O bond is proposed. Synthetic transformations of the product are conducted to demonstrate the practical utilities of this reaction.

Role of the heat shock protein family in chlorpromazine-induced cardiotoxicity.

Chlorpromazine (CPZ), a first-generation antipsychotic, is widely used in treating schizophrenia and other psychiatric disorders. However, CPZ is also associated with an increased likelihood of sudden cardiac death, and the underlying mechanisms remain unclear. In our study, we aimed to determine the CPZ-induced changes in some members of the heat shock protein family in rat hearts and further explore the possible mechanisms of CPZ-induced cardiotoxicity. Twenty-four Sprague Dawley rats were randomly divided into three groups (n = 8 per group): control, low dose (33.216 mg/kg) and high dose (94.211 mg/kg). CPZ administration induced hypothermia in rats. Pathological changes, including ischaemia and hypoxia, were observed in rat hearts. Furthermore, the serum levels of cardiac Troponin T (c-TN-T) and brain natriuretic peptide (BNP) were elevated in the CPZ-exposed groups. Meanwhile, the protein and gene expression of HSP70, HSP60, HSP27 and HSP10 significantly differed between the CPZ-exposed and control groups. We conclude that acute CPZ exposure could lead to myocardial injury in rats, in which HSPs might play a crucial role. Further investigations are required to elucidate the underlying mechanisms.

Dearomatizing [2+2+1] Spiroannulation of Indoles with Alkynes.

A palladium-catalyzed dearomatizing [2+2+1] spiroannulation of indoles with two molecular internal alkynes is developed in the presence of Cu(OAc)2/O2 as the oxidant, in which a domino sequence including C-H activation of indole followed by consecutive Heck reactions is involved. A range of 3,3'-spiroindolines bearing tetrasubstituted cyclopentadiene moieties and exocyclic C═C bonds at C2 are obtained in moderate to excellent yields.

Enhanced recovery after surgery in transurethral surgery for benign prostatic hyperplasia.

Enhanced recovery after surgery (ERAS) measures have not been systematically applied in transurethral surgery for benign prostatic hyperplasia (BPH). This study was performed on patients with BPH who required surgical intervention. From July 2019 to June 2020, the ERAS program was applied to 248 patients, and the conventional program was applied to 238 patients. After 1 year of follow-up, the differences between the ERAS group and the conventional group were evaluated. The ERAS group had a shorter time of urinary catheterization compared with the conventional group (mean ± standard deviation [s.d.]: 1.0 ± 0.4 days vs 2.7 ± 0.8 days, P < 0.01), and the pain (mean ± s.d.) was significantly reduced through postoperative hospitalization days (PODs) 0-2 (POD 0: 1.7 ± 0.8 vs 2.4 ± 1.0, P < 0.01; POD 1: 1.6 ± 0.9 vs 3.5 ± 1.3, P < 0.01; POD 2: 1.2 ± 0.7 vs 3.0 ± 1.3, P < 0.01). No statistically significant difference was found in the rate of postoperative complications, such as postoperative bleeding (P = 0.79), urinary retention (P = 0.40), fever (P = 0.55), and readmission (P = 0.71). The hospitalization cost of the ERAS group was similar to that of the conventional group (mean ± s.d.: 16 927.8 ± 5808.1 Chinese Yuan [CNY] vs 17 044.1 ± 5830.7 CNY, P =0.85). The International Prostate Symptom Scores (IPSS) and quality of life (QoL) scores in the two groups were also similar when compared at 1 month, 3 months, 6 months, and 12 months after discharge. The ERAS program we conducted was safe, repeatable, and efficient. In conclusion, patients undergoing the ERAS program experienced less postoperative stress than those undergoing the conventional program.

Enhanced recovery after surgery in transurethral surgery for benign prostatic hyperplasia / 亚洲男科学杂志(英文版)

Enhanced recovery after surgery (ERAS) measures have not been systematically applied in transurethral surgery for benign prostatic hyperplasia (BPH). This study was performed on patients with BPH who required surgical intervention. From July 2019 to June 2020, the ERAS program was applied to 248 patients, and the conventional program was applied to 238 patients. After 1 year of follow-up, the differences between the ERAS group and the conventional group were evaluated. The ERAS group had a shorter time of urinary catheterization compared with the conventional group (mean ± standard deviation [s.d.]: 1.0 ± 0.4 days vs 2.7 ± 0.8 days, P < 0.01), and the pain (mean ± s.d.) was significantly reduced through postoperative hospitalization days (PODs) 0-2 (POD 0: 1.7 ± 0.8 vs 2.4 ± 1.0, P < 0.01; POD 1: 1.6 ± 0.9 vs 3.5 ± 1.3, P < 0.01; POD 2: 1.2 ± 0.7 vs 3.0 ± 1.3, P < 0.01). No statistically significant difference was found in the rate of postoperative complications, such as postoperative bleeding (P = 0.79), urinary retention (P = 0.40), fever (P = 0.55), and readmission (P = 0.71). The hospitalization cost of the ERAS group was similar to that of the conventional group (mean ± s.d.: 16 927.8 ± 5808.1 Chinese Yuan [CNY] vs 17 044.1 ± 5830.7 CNY, P =0.85). The International Prostate Symptom Scores (IPSS) and quality of life (QoL) scores in the two groups were also similar when compared at 1 month, 3 months, 6 months, and 12 months after discharge. The ERAS program we conducted was safe, repeatable, and efficient. In conclusion, patients undergoing the ERAS program experienced less postoperative stress than those undergoing the conventional program.

Abnormal spinal curvature and associated factors among primary and secondary school students in Sichuan Province / 中国学校卫生

Objective@#To investigate abnormal spinal curvature among primary and secondary school students in Sichuan Province, so as to provide evidence for scientific prevention.@*Methods@#Using a stratified cluster random sampling method, a total of 210 713 students of grade 4 to grade 12 from 21 cities (prefectures) in Sichuan Province were selected for spinal curvature screening and questionnaire survey from September to November 2022. Chi-square test and multivariate Logistic regression model were used to analyze the influencing factors of abnormal spinal curvature.@*Results@#The detection rate of abnormal spinal curvature was 3.42%, with urban areas (4.54%) higher than that in suburban areas(2.57%), girls (3.86%) higher than that in boys(2.98%), high school students (4.70%) higher than that in middle school students (3.80%) and elementary school students(2.21%), the differences were statistically significant ( χ 2=606.96, 123.81, 645.24, P <0.01). Multivariate Logistic regression analysis showed that urban area, junior and senior high school, girl, carrying backpack on one shoulder, desks and chairs adjusted for student height less than ≤1 time every school year, moderate-to-vigorous physical activity less than 1 h per week, and indoors sedentary time more than 10 h/d were positively associated with abnormal spinal curvature ( OR=1.72, 1.75, 1.87, 1.26, 1.09, 1.07, 1.10, 1.25 , P <0.05).@*Conclusion@#The detection rate of abnormal spinal curvature of primary and secondary school students may be affected by the urbanicity, educational stage as well as gender in Sichuan Province. More attention should be paid to urban high school girls, and targeted strategies should be explored to reduce the incidence of abnormal spinal curvature.

The effect of bladder function on the efficacy of transurethral prostatectomy in patients with benign prostatic hyperplasia: a retrospective, single-center study / 亚洲男科学杂志(英文版)

We investigated the impact and predictive value of bladder function in patients with benign prostatic hyperplasia (BPH) on the efficacy of transurethral prostatectomy. Symptomatic, imaging, and urodynamic data of patients who underwent transurethral prostatectomy at West China Hospital of Sichuan University (Chengdu, China) from July 2019 to December 2021 were collected. Follow-up data included the quality of life (QoL), International Prostate Symptom Score (IPSS), and IPSS storage and voiding (IPSS-s and IPSS-v). Moreover, urinary creatinine (Cr), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and prostaglandin estradiol (PGE2) were measured in 30 patients with BPH and 30 healthy participants. Perioperative indicators were determined by subgroup analyses and receiver operating characteristic (ROC) curve analysis. Among the 313 patients with BPH included, patients with severe micturition problems had more improvements but higher micturition grades postoperatively than those with moderate symptoms. Similarly, good bladder sensation, compliance, and detrusor contractility (DC) were predictors of low postoperative IPSS and QoL. The urinary concentrations of BDNF/Cr, NGF/Cr, and PGE2/Cr in patients were significantly higher than those in healthy participants (all P < 0.001). After evaluation, only DC was significantly related to both urinary indicators and postoperative recovery of patients. Patients with good DC, as predicted by urinary indicators, had lower IPSS and IPSS-v than those with reduced DC at the 1st month postoperatively (both P < 0.05). In summary, patients with impaired bladder function had poor recovery. The combined levels of urinary BDNF/Cr, NGF/Cr, and PGE2/Cr in patients with BPH may be valid predictors of preoperative bladder function and postoperative recovery.

Hydnocarpin inhibits malignant progression of triple negative breast cancer via CNOT4-mediated ubiquitination and degradation of YAP / 中国中药杂志

This study aims to investigate the effect and mechanism of hydnocarpin(HC) in treating triple negative breast cancer(TNBC). Cell counting kit-8(CCK-8), xCELLigence real-time cellular analysis(RTCA), and colony formation assay were employed to determine the effects of HC on the proliferation of two TNBC cell lines: MDA-MB-231 and MDA-MB-436. The effects of HC on the migration and invasion of TNBC cells were detected by high-content analysis, wound-healing assay, and Transwell assay. The changes in the epithelial-mesenchymal transition(EMT) and the expression of invasion-and migration-associated proteins [E-cadherin, vimentin, Snail, matrix metalloproteinase-2(MMP-2), and MMP-9] were detected by Western blot. Western blot and RT-qPCR were employed to determine the protein and mRNA levels of Yes-associated protein(YAP) and downstream targets(CTGF and Cyr61). TNBC cells were transfected with Flag-YAP for the overexpression of YAP, and the role of YAP as a key target for HC to inhibit TNBC malignant progression was examined by CCK-8 assay, Transwell assay, and wound-healing assay. The pathway of HC-induced YAP degradation was detected by the co-treatment of proteasome inhibitor with HC and ubiquitination assay. The binding of HC to YAP and the E3 ubiquitin ligase Ccr4-not transcription complex subunit 4(CNOT4) was detected by microscale thermophoresis(MST) assay and drug affinity responsive target stability(DARTS) assay. The results showed that HC significantly inhibited the proliferation, colony formation, invasion, and EMT of TNBC cells. HC down-regulated the protein and mRNA levels of CTGF and Cyr61. HC down-regulated the total protein level of YAP, while it had no effect on the mRNA level of YAP. The overexpression of YAP antagonized the inhibitory effects of HC on the proliferation, migration, and invasion of TNBC cells. HC promoted the degradation of YAP through the proteasome pathway and up-regulated the ubiquitination level of YAP. The results of MST and DARTS demonstrated direct binding between HC, YAP, and CNOT4. The above results indicated that HC inhibited the malignant progression of TNBC via CNOT4-mediated degradation and ubiquitination of YAP.

A novel technique of pure transperitoneal laparoscopic nephroureterectomy at a single position for native upper tract urothelial carcinoma in ipsilateral renal transplant recipients / 中华器官移植杂志

Objective:To explore the techniques and outcomes of pure laparoscopic native nephroureterectomy (LNUT) with ipsilateral allograft at a single position for upper tract urothelial carcinoma (UTUC) in renal transplant (RT) recipients.Methods:Clinical data were retrospectively reviewed for 12 renal transplant children undergoing native UTUC with ipsilateral allograft from January 2016 to December 2021.There were 4 boys and 8 girls.Complete LNUT was performed with bladder cuff resection at a single position via a transperitoneal approach.The interval between UTUC and RT was 12-146 months.There were 6 pelvic UCs and 6 ureter UCs.Results:All laparoscopic procedures were successfully completed without any serious perioperative complication.Postoperative pathological examination confirmed the diagnosis of urothelial carcinoma.And all surgical margins were negative.One patient experienced an elevation of creatinine after one cycle chemotherapy and normalized after withdrawing chemotherapy.The median follow-up period was (4-65) month.Two cases of contralateral native transitional cell carcinoma had radical nephroureterectomy two years later and another two cases underwent transurethral resection of bladder tumor one year later.One case died from tumor metastasis.The remainders had no tumor recurrence or metastasis during follow-ups.Conclusions:Complete single-position LNUT for UTUC with ipsilateral allograft is a safe and effective mini-invasive technique.Effectively avoiding the injury of allograft, it also offers the advantages of standard operation, minimal trauma, simple handling and enhanced recovery after surgery (ERAS).

Enantioselective Pd-catalyzed dearomative reductive Heck and domino Heck-Suzuki reactions of 2-CF3-indoles.

Highly enantioselective palladium-catalyzed dearomative reductive Heck reaction and domino Heck-Suzuki reaction of 2-CF3-indoles have been developed. Using Pd(OAc)2/(R)-Synphos as the catalyst and Et3SiH as a hydride source, a variety of indolines bearing a 2-trifluoromethyl quaternary stereocenter were obtained via a dearomative reductive Heck reaction. Alternatively, using Pd(dba)2/phosphoramidite as the catalyst and Ar4BNa as a coupling partner, structurally diverse indolines containing two vicinal carbon stereocenters were afforded through the domino dearomative Heck-Suzuki reaction.

A new approach to generating virtual samples to enhance classification accuracy with small data-a case of bladder cancer.

In the medical field, researchers are often unable to obtain the sufficient samples in a short period of time necessary to build a stable data-driven forecasting model used to classify a new disease. To address the problem of small data learning, many studies have demonstrated that generating virtual samples intended to augment the amount of training data is an effective approach, as it helps to improve forecasting models with small datasets. One of the most popular methods used in these studies is the mega-trend-diffusion (MTD) technique, which is widely used in various fields. The effectiveness of the MTD technique depends on the degree of data diffusion. However, data diffusion is seriously affected by extreme values. In addition, the MTD method only considers data fitted using a unimodal triangular membership function. However, in fact, data may come from multiple distributions in the real world. Therefore, considering the fact that data comes from multi-distributions, in this paper, a distance-based mega-trend-diffusion (DB-MTD) technique is proposed to appropriately estimate the degree of data diffusion with less impacts from extreme values. In the proposed method, it is assumed that the data is fitted by the triangular and trapezoidal membership functions to generate virtual samples. In addition, a possibility evaluation mechanism is proposed to measure the applicability of the virtual samples. In our experiment, two bladder cancer datasets are used to verify the effectiveness of the proposed DB-MTD method. The experimental results demonstrated that the proposed method outperforms other VSG techniques in classification and regression items for small bladder cancer datasets.

Abnormal global alternative RNA splicing in COVID-19 patients.

Viral infections can alter host transcriptomes by manipulating host splicing machinery. Despite intensive transcriptomic studies on SARS-CoV-2, a systematic analysis of alternative splicing (AS) in severe COVID-19 patients remains largely elusive. Here we integrated proteomic and transcriptomic sequencing data to study AS changes in COVID-19 patients. We discovered that RNA splicing is among the major down-regulated proteomic signatures in COVID-19 patients. The transcriptome analysis showed that SARS-CoV-2 infection induces widespread dysregulation of transcript usage and expression, affecting blood coagulation, neutrophil activation, and cytokine production. Notably, CD74 and LRRFIP1 had increased skipping of an exon in COVID-19 patients that disrupts a functional domain, which correlated with reduced antiviral immunity. Furthermore, the dysregulation of transcripts was strongly correlated with clinical severity of COVID-19, and splice-variants may contribute to unexpected therapeutic activity. In summary, our data highlight that a better understanding of the AS landscape may aid in COVID-19 diagnosis and therapy.