Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been reapproved for heart failure (HF) therapy in patients with and without diabetes. However, the initial glucose-lowering indication of SGLT2i has impeded their uses in cardiovascular clinical practice. A challenge of SGLT2i then becomes how to separate their anti-HF activity from glucose-lowering side-effect. To address this issue, we conducted structural repurposing of EMPA, a representative SGLT2 inhibitor, to strengthen anti-HF activity and reduce the SGLT2-inhibitory activity according to structural basis of inhibition of SGLT2. Compared to EMPA, the optimal derivative JX01, which was produced by methylation of C2-OH of the glucose ring, exhibited weaker SGLT2-inhibitory activity (IC₅₀ > 100 nmol/L), and lower glycosuria and glucose-lowering side-effect, better NHE1-inhibitory activity and cardioprotective effect in HF mice. Furthermore, JX01 showed good safety profiles in respect of single-dose/repeat-dose toxicity and hERG activity, and good pharmacokinetic properties in both mouse and rat species. Collectively, the present study provided a paradigm of drug repurposing to discover novel anti-HF drugs, and indirectly demonstrated that SGLT2-independent molecular mechanisms play an important role in cardioprotective effects of SGLT2 inhibitors.

Objective:To explore the clinical application and curative effect of brachytherapy of denture applicators with 125I seeds in the treatment of palatal malignant tumor. Methods:Thirty patients with palatal malignant tumor who underwent surgical resection in Shandong Provincial Hospital from February 2012 to January 2020, and brachytherapy was performed with applicator additional 125I seeds 2 weeks after surgery. All patients were followed up for treatment effect and adverse reactions. Results:All patients wore 125I seeds denture base denture applicator well, no 125I seeds displacement and loss. 30 patients had 10-60 months of follow-up, among which 1 patient received palliative treatment with 125I seeds denture applicator alone died after 10 months of follow-up; 1 patient with adenoid cystic carcinoma recurred after 2 years of follow-up and underwent surgical treatment again; the rest patients did not see tumor recurrence or metastasis. The side effects, pronunciation and chewing function were improved in patients ( P<0.05). Conclusions:For patients with palatal malignant tumor, postoperative 125I seeds denture applicator can effectively prevent tumor recurrence and metastasis, reduce complications, and improve the quality of life.

This article aims to study the factors affecting the flexibility of the tip of an epidural anesthesia catheter. The flexibility of the tip of the epidural anesthesia catheter was tested with a softness tester from four aspects:raw materials, tip structure, tip processing technology, and the outer diameter of the catheter. Highly flexible and malleable polymer material with a smooth tip, the tip softening process and the proper outer diameter can effectively improve the tip flexibility of the epidural anesthesia catheter.
Anesthesia, Epidural ; Catheterization ; Catheters ; Epidural Space

In order to unveil ubiquitin pathway genes (UPGs) that are essential for non-small cell lung cancer (NSCLC) cell proliferation, we recently conducted a siRNA screening experiment to knockdown the expression of 696 UPGs found in the human genome in A549 and H1975 NSCLC cells. We found that silencing of one of the candidates, RFWD3 that encodes an E3 ubiquitin ligase essential for the repair of DNA interstrand cross-links in response to DNA damage, led to dramatic inhibition of NSCLC cell proliferation with significant Z-scores. Knockdown of RFWD3 suppressed colony forming activity of NSCLC cells.We further evaluated the significance of RFWD3 in NSCLCs and found that this gene was more elevated in tumor samples than in paired normal lung tissues and was inversely associated with the clinical outcome of patients with NSCLC. Moreover, RFWD3 expression was significantly higher in smokers than in non-smokers. These results show for the first time that RFWD3 is required for NSCLC cell proliferation and may have an important role in lung carcinogenesis.

Objective:To evaluate the imaging features of CT scan in patients with COVID-19.Methods:Clinical data of 56 patients with COVID-19 from January 17 to 19, 2020 admitted to Wenzhou Central Hospital and the Second Affiliated Hospital of Wenzhou Medical University were retrospectively reviewed. The clinical manifestations, lung imaging characteristics and treatment outcomes of patients with different severity were analyzed with SAS software.Results:Fever (92.8%, 52/56), dry cough (75.0%, 42/56) and asthenia (58.9%, 33/56) were the first symptoms in most of the patients; some patients also had shortness of breath (25.0%, 14/56) and pharyngeal pain (10.7%, 6/56). Chest high-resolution CT scan showed that in 42 moderate patients, ground glass-like high-density shadows in the lung were observed in 30 cases (71.4%) ; localized plaque consolidation shadows and bronchial inflation signs were observed in 10 cases (23.8%). In 12 severe patients, 11 had high-density patches involving multiple lung lobes (≥3). In 2 critically ill patients the patches and stripes involving the entire lung were observed; and cord-like high-density shadow, local consolidation and fibrosis were also shown.Conclusion:The multiple ground-glass changes outside the lungs are early imaging manifestations of COVID-19 patients. The increase in pulmonary lobe consolidation and fibrosis may indicate the disease progression, and the degree of lung consolidation and fibrosis is closely related to the disease severity.

Objective: To investigate the prognostic value of N-terminal B-type natriuretic peptide (NT-proBNP) on all-cause mortality in heart failure patients with preserved ejection fraction (HFpEF) at real world scenarios. Methods: Patients who met the diagnostic criteria of HFpEF in the China National Heart Failure Registration Study (CN-HF) were divided into death and survival groups. The demographic data, physical examination, results of the first echocardiography, laboratory results at admission, complications, drug use and clinical outcomes were obtained from CN-HF. The univariate Cox proportional hazard model was used to screen the variates that might predict prognosis, and then the covariates with statistical significance were included in the multivariate Cox regression model to analyze the predictive value of baseline NT-proBNP on all-cause death. Spearman correlation analysis was used to evaluate the relationship between NT-proBNP and estimated glomerular filtration rate (eGFR), so as to further explore the predictive value of the interaction between renal dysfunction and NT-proBNP on death. Since NT-proBNP did not obey the binary normal distribution, it was expressed by the natural logarithm of NT-proBNP (LnNT-proBNP). Results: A total of 1 846 HFpEF patients were enrolled in this study, with an average age of 71.5 years, 1 017 males(55.1%), median NT-proBNP 860 ng/L, and median eGFR 73.9 ml·min^-1·1.73m^-2. After a median follow-up of 34 months, 213 (11.5%) patients died. Patients in the death group were older, with higher NYHA classification Ⅲ-Ⅳ ratio, longer hospital stay, higher serum potassium and NT-proBNP level, prevalence of complications of diabetes mellitus, arrhythmia and atrial fibrillation, use of angiotensin receptor antagonist(ARB), mineralocorticoid receptor antagonists (MRA), diuretic and digoxin was significantly higher in death group than in survival group. Body mass index (BMI), diastolic blood pressure, left ventricular ejection fraction (LVEF), hemoglobin, serum cholesterol(TC), serum triglycerides (TG) and eGFR, and use of angiotensin converting enzyme inhibitors (ACEI), statins and aspirin were lower in death group than in survival group. Univariate Cox regression analysis showed that NT-proBNP was a predictor of all-cause death in HFpEF patients (HR=2.522, 95%CI 2.040-3.119, P<0.001). Multivariate Cox regression analysis showed that the elevated NT-proBNP remains as the independent predictor of all-cause death in patients with HFpEF (HR=1.230, 95%CI 1.049-1.442, P=0.011) after adjusting for age, BMI, diastolic blood pressure, LVEF, hemoglobin, serum potassium, serum sodium, TC, serum high-density lipoprotein cholesterol (HDL-C), TG, eGFR, atrial fibrillation, as well as the treatment of ACEI/ARB, MRA, diuretics and digoxin. Spearman correlation analysis showed that LnNT-proBNP was negatively correlated with eGFR (r=-0.361, P<0.001), but there was no interaction between NT-proBNP and renal dysfunction in predicting death in HFpEF patients (P>0.05). Conclusion The elevated level of NT-proBNP at admission is an independent predictor of all-cause mortality in HFpEF patients.

Recently, Ng et al. reported that the A:T > T:A substitutions, proposed to be a signature of aristolochic acid (AA) exposure, were detected in 76/98 (78%) of patients with hepatocellular carcinoma (HCC) from the Taiwan Province of China, and 47% to 1.7% of HCCs from the Chinese mainland and other countries harbored the nucleotide changes. However, other carcinogens, e.g., tobacco carcinogens 4-aminobiphenyl and 1,3-butadiene, air toxic vinyl chloride and its reactive metabolites chloroethylene oxide, melphalan and chlorambucil, also cause this signature in the genome. Since tobacco smoke is a worldwide public health threat and vinyl chloride distributes globally and is an air pollutant in Taiwan Province, the estimation of the patients' exposure history is the key to determine the "culprit" of the A:T > T:A mutations. Apparently, without estimation of the patients' exposure history, the conclusion of Ng et al. is unpersuasive and misleading.
Aristolochic Acids ; toxicity ; Carcinogens ; toxicity ; Carcinoma, Hepatocellular ; chemically induced ; genetics ; China ; Environment ; Humans ; Liver Neoplasms ; chemically induced ; genetics ; Mutation ; Taiwan ; Tobacco ; toxicity ; Vinyl Chloride ; toxicity

Objective To evaluate the clinical repair effects of the reconstruction of different vermilion tubercle after primary cleft lip repair.Methods According to the tight lip deformity and dif ferent degrees of defect of the vermilion tubercle and exposing the gums and the crown of the anterior incisors,178 patients after primary repair of the cleft lip from Department of Oral and Maxillofacial Surgery of Xiangya Hospital,Central South University were classified into the tight lip deformity and four grades of whistling deformities.According to different deformities and defects,the different operative techniques were used as follows:classic Abbé flap and modified Abbé flap were used for tight lip deformity;the bilateral advanced myomucosal flaps of lip were used for the grade Ⅰ;modified Abbé flap was used for repairing the grade Ⅱ and the grade Ⅲ whistling deformities;for grade Ⅳ whistling deformity,we mainly used classic Abbé flap.The follow-up after operation was performed,all patient's Cupid's bow,Cupid's bow peak,the vermilion tubercle and the height and width of the upper lip were observed.The scarring of the upper lip was also observed.Results The follow-up after operation was performed from six months to ninteen years,all the 187 patient's anatomical structures of the upper lip were nearly normal after recovery.The all patients showed an obvious Cupid's bow,Cupid's bow peak,the vermilion tubercle and the height and width of the upper lip.The relation of the upper lip and lower lip was harmonious.The scarring of the upper lip was not obvious 2 years after operation.Conclusions The different repair methods are chosen to repair different deformity and defect that has an important clinical value.

Objective The expression of chemokine C-X-C motif ligand 13 (CXCL13) within liver in primary biliary cholangitis (PBC) patients is significantly increased, but its origin and mechanism is not clear yet.The study aimed to investigate the expression of CXCL13 in the liver of mice through establishing a mouse model of PBC.Methods C57BL/6 mice were randomly divided into experiment group (n=20) control group(n=10).The mice in the experimental group were intraperitoneally injected with polyriboinosinic polyribocytidylic acid (Poly I:C) while the mice in control group were injected with PBS of the same volume.The level of serum AMA was quantified by ELISA and intrahepatic inflammatory cells were assessed by HE staining.Kupffer cells, liver sinusoidal endothelial cells, and infiltrating lymphocytes in the liver of mice were collected by in situ perfusion enzyme digestion and magnetic bead separation methods.The transcriptional level of intrahepatic CXCL13 in liver tissues and cell subpopulations were detected by qPCR.Results The serum AMA titers of the mice in experiment group increased gradually with the prolonging of modeling time and the positive rates at the 4th, 8th, and 12th week after the first injection of Poly I:C were 5.9%, 52.9% and 76.5% respectively.While the serum AMA titers of the mice in control group were at a lower level through the modeling process, with only 2 mice presenting a little higher level above positive cutoff value at the 12th week.The results of HE staining in liver tissues of both groups showed that there were a great amount of intensely infiltrating inflammatory cells in the mice of experimental group while no inflammatory cell infiltration were found in the mice of control group.The separation purity of Kupffer cells and liver sinusoidal endothelial cells in the mice of experiment group tested by flow cytometry were 76%-80%, 68%-72% respectively.Compared with the CXCL13 mRNA level in Kupffer cells [2.34(0.22-8.64)], the expression levels in liver sinusoidal endothelial cells and infiltrating lymphocytes declined[0.27(0.03-1.64), 0.05(0-0.22), P<0.05].Conclusion The chemokine CXCL13 is predominantly produced by Kupffer cells in the liver of PBC mice established by Poly I:C injection.

Objective: To evaluate the clinical effectiveness of salvianolic acid B (SA-B) and triamcinolone acetonide (TA) by means of combined intralesional injection in the treatment of oral submucous fibrosis (OSF). Methods: According to clinical findings and symptoms, TA combined with SA-B were consecutively applied intralesionally 1 time weekly for 30 times. Mouth opening degree, color change of the buccal mucosae and numeral increase of the capillary vessels were determined by degree Ⅰ-Ⅳ visual analog scale were evaluated at 12, 24, and 36 months, respectively. Results: One hundred and fourteen subjects fulfilled the study without obvious adverse reactions. After treatment for 1 year, the net gain in mouth opening of the early stage group was (5.5 ± 1.5) mm at 12 months, (8.8 ± 1.6) mm at 24 months and (12.0±1.2) mm at 36 months. The net gain in mouth opening of the middle stage group were (5.3±1.7) mm at 12 months, (10.5±1.5) mm at 24 months and (14.5±2.4) mm at 36 months. The net gain in mouth opening of the advanced stage group were (5.7±1.3) mm at 12 months, (13.7±1.3) mm at 24 months and (15.5±1.5) mm at 36 months. The effective rates of color change of the buccal mucosae and numeral increase of the capillary vessels after treatment for 36 months were 100% in early stage group, 93% (51/55) in middle stage group and 90% (36/40) in advanced stage group. Conclusions TA and SA-B combined intralesional injection in the treatment of oral submucous fibrosis is effective.