Multidrug resistance (MDR) is the main cause of clinical treatment failure and poor prognosis in cancer. Targeting P-glycoprotein (P-gp) has been regarded as an effective strategy to overcome MDR. In this work, we reported our preclinical studies of the triazolo[1,5-a]pyrimidine-based compound WS-716 as a highly potent, specific, and orally active P-gp inhibitor. Through direct binding to P-gp, WS-716 inhibited efflux function of P-gp and specifically reversed P-gp-mediated MDR to paclitaxel (PTX) in multiple resistant cell lines, without changing its expression or subcellular localization. WS-716 and PTX synergistically inhibited formation of colony and 3D spheroid, induced apoptosis and cell cycle arrest at G2/M phase in resistant SW620/Ad300 cells. In addition, WS-716 displayed minimal effect on the drug-metabolizing enzyme cytochrome P4503A4 (CYP3A4). Importantly, WS-716 increased sensitivity of both pre-clinically and clinically derived MDR tumors to PTX in vivo with the T/C value of 29.7% in patient-derived xenograft (PDX) models. Relative to PTX treatment alone, combination of WS-716 and PTX caused no obvious adverse reactions. Taken together, our preclinical studies revealed therapeutic promise of WS-716 against MDR cancer, the promising data warrant its further development for cancer therapy.

OBJECTIVES: To investigate the clinical treatment outcomes and the changes of the outcomes over time in extremely preterm twins in Guangdong Province, China. METHODS: A retrospective analysis was performed for 269 pairs of extremely preterm twins with a gestational age of <28 weeks who were admitted to the department of neonatology in 26 grade A tertiary hospitals in Guangdong Province from January 2008 to December 2017. According to the admission time, they were divided into two groups: 2008-2012 and 2013-2017. Besides, each pair of twins was divided into the heavier infant and the lighter infant subgroups according to birth weight. The perinatal data of mothers and hospitalization data of neonates were collected. The survival rate of twins and the incidence rate of complications were compared between the 2008-2012 and 2013-2017 groups. RESULTS: Compared with the 2008-2012 group, the 2013-2017 group (both the heavier infant and lighter infant subgroups) had lower incidence rates of severe asphyxia and smaller head circumference at birth (P<0.05). The mortality rates of both of the twins, the heavier infant of the twins, and the lighter infant of the twins were lower in the 2013-2017 group compared with the 2008-2012 group (P<0.05). Compared with the 2008-2012 group, the 2013-2017 group (both the heavier infant and lighter infant subgroups) had lower incidence rates of pulmonary hemorrhage, patent ductus arteriosus (PDA), periventricular-intraventricular hemorrhage (P-IVH), and neonatal respiratory distress syndrome (NRDS) and a higher incidence rate of bronchopulmonary dysplasia (P<0.05). CONCLUSIONS There is a significant increase in the survival rate over time in extremely preterm twins with a gestational age of <28 weeks in the 26 grade A tertiary hospitals in Guangdong Province. The incidences of severe asphyxia, pulmonary hemorrhage, PDA, P-IVH, and NRDS decrease in both the heavier and lighter infants of the twins, but the incidence of bronchopulmonary dysplasia increases. With the improvement of diagnosis and treatment, the multidisciplinary collaboration between different fields of fetal medicine including prenatal diagnosis, obstetrics, and neonatology is needed in the future to jointly develop management strategies for twin pregnancy.
Bronchopulmonary Dysplasia/epidemiology* ; Female ; Gestational Age ; Humans ; Infant ; Infant, Extremely Premature ; Infant, Newborn ; Pregnancy ; Respiratory Distress Syndrome, Newborn/epidemiology* ; Retrospective Studies ; Treatment Outcome

Objective: To explore the effect of growth arrest-specific5 (GAS5) inhibition on the proliferation, colony formation, invasion, migration andepithelial-mesenchymal transition(EMT), cancer cell stem of HCT-116 and its mechanism. Methods: The colorectal carcinoma (CRC) cell HCT116 was divided into blank control, negative control (NC), si-GAS5 and si-GAS5+ miR-21 inhibitor groups. The quantitative real-time polymerase chain reaction (qRT-PCR) was used to test the expressions of miR-21 and GAS5 at 48 h after transfection. The binding site of GAS5 and miR-21 was determined by luciferase reporter array. Cell proliferation ability was detected by CCK-8 assay. Cell colony ability was detected by colony formation assay. Cell invasion and migration abilities were detected by Transwell assay. Cell cycle and apoptosis were examined by flow cytometer (FCM). The protein levels of EMT associated factors including Snail, N-cadherin, vimentin, E-cadherin, stem cell related factors including CD44, SOX2, Oct2, and PTEN/Akt signal pathway associated factors were examined by western blotting. Results: The expression levels of miR-21 in blank, NC, si-GAS5 group were 1.00±0.10, 1.00±0.10, 1.80±0.20, the absorbance values were 0.51±0.02, 0.50±0.01 and 0.65±0.01, the cell clones were 90±4, 91±5, 200±8, the invaded cells were 118±3, 119±3, 150±4, the migrated cells were 110±2, 108±2, 127±2, the cell ratios in G(1) phase were (49.3±2.1)%, (50.1±2.0)% and (42.2±1.1)%, the cell ratios in S phase were (19.2±1.2)%, (20.2±1.1)% and (28.3±2.2)%, the cell apoptotic ratios were (14.4±2.2)%, (14.5±2.1)% and (7.2±1.3)%. These results indicated that inhibition of GAS5 up regulated the expression level of miR-21, promoted cell proliferation, invasion and migration, decreased G(1)-phase cells and increased S-phase cells, and suppressed cell apoptosis (P<0.05). Moreover, inhibition of GAS5 up regulated the expressions of Snail, N-cadherin, vimentin, Sox2, CD44, Oct2 and p-Akt in HCT-116 cells (P<0.05), while down regulated the expressions of E-cadherin and PTEN (P<0.05). Inhibition of miR-21 reversed the impact of GAS5 knockdown on PTEN/Akt signaling pathway (P<0.05). Conclusion: GAS5 can act as a competing endogenous RNA for miR-21, and down regulation of GAS5 can promote the development of CRC by activating the miR-21/PTEN/Akt signaling pathway and promoting the acquisition of EMT and tumor cell stemness.
Humans ; Cadherins/metabolism* ; Cell Line, Tumor ; Cell Movement/genetics* ; Cell Proliferation/genetics* ; Colorectal Neoplasms/pathology* ; Epithelial-Mesenchymal Transition/genetics* ; Gene Expression Regulation, Neoplastic ; MicroRNAs/metabolism* ; Proto-Oncogene Proteins c-akt/metabolism* ; PTEN Phosphohydrolase/metabolism* ; Vimentin/metabolism*

BACKGROUND: Imprecise interpretation of coronary angiograms was reported and resulted in inappropriate revascularization. Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score is a comprehensive system to evaluate the complexity of the overall lesions. We hypothesized that a real-time SYNTAX score feedback from image analysts may rectify the mis-estimation and improve revascularization appropriateness in patients with stable coronary artery disease (CAD). METHODS: In this single-center, historical control study, patients with stable CAD with coronary lesion stenosis ≥50% were consecutively recruited. During the control period, SYNTAX scores were calculated by treating cardiologists. During the intervention period, SYNTAX scores were calculated by image analysts immediately after coronary angiography and were provided to cardiologists in real-time to aid decision-making. The primary outcome was revascularization deemed inappropriate by Chinese appropriate use criteria for coronary revascularization. RESULTS: A total of 3245 patients were enrolled and assigned to the control group (08/2016-03/2017, n = 1525) or the intervention group (03/2017-09/2017, n = 1720). For SYNTAX score tertiles, 17.9% patients were overestimated and 4.3% were underestimated by cardiologists in the control group. After adjustment, inappropriate revascularization significantly decreased in the intervention group compared with the control group (adjusted odds ratio [OR]: 0.83; 95% confidence interval [CI]: 0.73-0.95; P = 0.007). Both inappropriate percutaneous coronary intervention (adjusted OR: 0.82; 95% CI: 0.74-0.92; P < 0.001) and percutaneous coronary intervention utilization (adjusted OR: 0.88; 95% CI: 0.79-0.98; P = 0.016) decreased significantly in the intervention group. There was no significant difference in 1-year adverse cardiac events between the control group and the intervention group. CONCLUSIONS: Real-time SYNTAX score feedback significantly reduced inappropriate coronary revascularization in stable patients with CAD. CLINICAL TRIAL REGISTRATION Nos. NCT03068858 and NCT02880605; https://www.clinicaltrials.gov.

Background:The Chinese appropriate use criteria (AUC) for coronary revascularization was released in 2016 to improve the use of coronary revascularization.This study aimed to evaluate the association between the appropriateness of coronary revascularization based on the Chinese AUC and 1-year outcomes in stable coronary artery disease (CAD) patients.Methods:We conducted a prospective,multi-center cohort study of stable CAD patients with coronary lesion stenosis ≥50％.After the classification of appropriateness based on Chinese AUC,patients were categorized into the coronary revascularization group or the medical therapy group based on treatment received.The primary outcome was a composite of death,myocardial infarction,stroke,repeated revascularization,and ischemic symptoms with hospital admission.Results:From August 2016 to August 2017,6085 patients were consecutively enrolled.Coronary revascularization was associated with a lower adjusted hazard of 1-year major adverse cardiovascular and cerebrovascular events (MACCEs;hazard ratio [HR]:0.62;95％ confidence interval [CI]:0.45-0.86;P =0.004) than medical therapy in patients with appropriate indications (n =1617).No significant benefit in 1-year MACCEs was found after revascularization compared to after medical therapy in patients with uncertain indications (n =2658,HR:0.81;95％ CI:0.52-1.25;P =0.338) and inappropriate indications (n =1810,HR:0.80;95％ CI:0.51-1.23;P=0.308).Contusions:In patients with appropriate indications according to Chinese AUC,coronary revascularization was associated with significantly lower risk of MACCEs at 1 year.No benefit was found in coronary revascularization in patients with inappropriate indications.Our findings provide evidence for using Chinese AUC to guide clinical decision-making.

BACKGROUND: Increasing evidence has shown that visit-to-visit variability (VVV) of blood pressure (BP) is associated with an increased risk of cardiovascular disease (CVD). The objective of this study was to evaluate the impact of VVV of systolic blood pressure (SBP) and diastolic blood pressure (DBP) on the risk of CVD among patients with type 2 diabetes mellitus (T2DM) in China. METHODS: We conducted a retrospective cohort study of 10,163 T2DM patients who were not previously diagnosed with CVD from January 2008 to December 2012 in Ningbo, China. The VVV of BP was calculated using five metrics, including standard deviation (SD), coefficient of variation (CV), variation independent of mean, average real variability, and successive variability (SV) of measurements, obtained over a 24-month measurement period. Hazard ratios and 95% confidence intervals (CIs) were estimated by Cox proportional hazards regression models for the associations of variability in BP with risk of CVD. RESULTS: A total of 894 CVD events were observed during a median follow-up of 49.5 months. The hazard ratio in the highest quintile of SD of SBP was 1.24 (95% CI, 1.01 to 1.52) compared with patients in the lowest quintile. The association between higher VVV of DBP and risk of CVD was not consistent across different metrics and sensitivity analyses. CONCLUSION: Higher VVV of SBP was associated with an increased risk of CVD, irrespective of the mean SBP level. Future studies are needed to confirm these findings.
Blood Pressure ; Cardiovascular Diseases ; China ; Cohort Studies ; Diabetes Mellitus, Type 2 ; Follow-Up Studies ; Humans ; Retrospective Studies

Humans ; Joint Dislocations ; Lunate Bone ; Wrist Injuries

Objective To investigate the clinical efficacy of electrothermal acupuncture plus joint mobilization in treating knee osteoarthritis.Methods One hundred patients with knee osteoarthritis were randomized to treatment and control groups, 50 cases each. The control group received Maitland's technique and the treatment group, electrothermal acupuncture in addition. The Osteoarthritis Index score was recorded and cytokines (IL-1, IL-6 and TNF-α) contents were measured in the two groups before and after four weeks of treatment. The clinical therapeutic effects were compared between the two groups.Results The total efficacy rate was 91.5％ in the treatment group and 80.0％ in the control group; there was a statistically significant difference between the two groups (P<0.05). There were statistically significant pre-/post-treatment differences in the WOMAC score and cytokines in the two groups (P<0.01,P<0.05). There were statistically significant post-treatment differences in the WOMAC score and cytokines between the treatment and control groups (P<0.05).Conclusion Electrothermal acupuncture plus joint mobilization is an effective way to treat knee osteoarthritis.

Objective: To describe the incidence,clinical characteristics,therapy strategy and outcomes of spontaneous coronary artery dissection based on single-center experience in China.Methods:We performed retrospective case-identification study in 16 526 patients underwent coronary angiography in Zhongshan Hospital of Fudan University between March 2015 to December 2016,and identified 17 patients with spontaneous coronary artery dissection.Risk factors,clinical features,angiographic features,therapy strategy,and clinical outcomes were analyzed.Results:The incidence of SCAD was 17 of 16 526(1.03/1 000).The mean age was(49.06 ± 10.73)years old(range:26-67 years old).In these 17 cases,4 cases were males,and others were females.Females constituted 13 of 17(76.5%).All SCAD patients presented with acute coronary syndrome,including 10 patients with acute ST-elevated myocardial infarction,3 patients with acute non-ST-elevated myocardial infarction and 4 patients with unstable angina.Twenty dissection sites were identified in 17 SCAD patients. Dissection was predominantly located at the left descending artery(50%)and the right coronary artery(35%).All lesions fell into three types:type Ⅰ(n=5),type Ⅱ A(n= 7),type ⅡB(n= 6),and type Ⅲ(n= 2).The TIMI flow in the distal segment of the coronary dissection was classified as follows:class 0(n=4),class 1(n=2),class 3(n=14).Conservative medical treatment was adopted by 7 of 17(41.1%)patients,and percutaneous transluminal coronary angioplasty(PTCA)in 1 of 17(5.9%)patients.No recurrent angina and other cardiovascular events was observed during clinical follow up. Percutaneous coronary intervention(PCI)was performed in 9 of 17(52.9%)patients,and the mean number of deployed stent was(2.44 ± 1.13).Intramural hematoma was extended during PCI in 5 of 9(55.6%)patients,resulting in new-onset nonfatal myocardial infarction in one patient and cardiac death in another patient.Conclusions:SCAD should be considered in young and middle-aged female patients presented with acute coronary syndrome,especially in those with few coronary risk factors. Interventional cardiologist should be familiar with the angiographic characteristics of SCAD,and turn to intravascular ultrasound if necessary.Conservative treatment should be the first choice in most patients with SCAD,while PCI intervention could be considered in high risk patients.Be caution to prevent interventional complications such as dissection expansion in the patients with high-risk.

Cyclic ADP-ribose (cADPR) releases Ca²⁺ from ryanodine receptor (RyR)-sensitive calcium pools in various cell types. In cardiac myocytes, the physiological levels of cADPR transiently increase the amplitude and frequency of Ca²⁺ (that is, a rapid increase and decrease of calcium within one second) during the cardiac action potential. In this study, we demonstrated that cADPR levels higher than physiological levels induce a slow and gradual increase in the resting intracellular Ca²⁺ ([Ca²⁺](i)) level over 10 min by inhibiting the sarcoendoplasmic reticulum Ca²⁺ ATPase (SERCA). Higher cADPR levels mediate the tyrosine-dephosphorylation of α-actin by protein tyrosine phosphatase 1B (PTP1B) present in the endoplasmic reticulum. The tyrosine dephosphorylation of α-actin dissociates phospholamban, the key regulator of SERCA, from α-actin and results in SERCA inhibition. The disruption of the integrity of α-actin by cytochalasin B and the inhibition of α-actin tyrosine dephosphorylation by a PTP1B inhibitor block cADPR-mediated Ca²⁺ increase. Our results suggest that levels of cADPR that are relatively higher than normal physiological levels modify calcium homeostasis through the dephosphorylation of α-actin by PTB1B and the subsequent inhibition of SERCA in cardiac myocytes.
Action Potentials ; Adenosine Diphosphate* ; Adenosine Triphosphatases ; Calcium ; Cyclic ADP-Ribose ; Cytochalasin B ; Endoplasmic Reticulum ; Homeostasis ; Muscle Cells* ; Myocytes, Cardiac ; Protein Tyrosine Phosphatase, Non-Receptor Type 1* ; Protein Tyrosine Phosphatases* ; Reticulum ; Ryanodine Receptor Calcium Release Channel ; Tyrosine