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A resurging interest in targeted covalent inhibitors (TCIs) focus on compounds capable of irreversibly reacting with nucleophilic amino acids in a druggable target. p97 is an emerging protein target for cancer therapy, viral infections and neurodegenerative diseases. Extensive efforts were devoted to the development of p97 inhibitors. The most promising inhibitor of p97 was in phase 1 clinical trials, but failed due to the off-target-induced toxicity, suggesting the selective inhibitors of p97 are highly needed. We report herein a new type of TCIs (i.e., FL-18) that showed proteome-wide selectivity towards p97. Equipped with a Michael acceptor and a basic imidazole, FL-18 showed potent inhibition towards U87MG tumor cells, and in proteome-wide profiling, selectively modified endogenous p97 as confirmed by in situ fluorescence scanning, label-free quantitative proteomics and functional validations. FL-18 selectively modified cysteine residues located within the D2 ATP site of p97. This covalent labeling of cysteine residue in p97 was verified by LC‒MS/MS-based site-mapping and site-directed mutagenesis. Further structure-activity relationship (SAR) studies with FL-18 analogs were established. Collectively, FL-18 is the first known small-molecule TCI capable of covalent engagement of p97 with proteome-wide selectivity, thus providing a promising scaffold for cancer therapy.
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Objective:To investigate the clinical application of cervix-uterine internal target volume (ITV) in volume-modulated arc therapy (VMAT) for cervical cancer under different bladder filling conditions, aiming to obtain more accurate planning target volume (PTV).Methods:Sixty-two patients with cervical cancer receiving radiotherapy rather than surgery were selected and randomly divided into the study ( n=31) and control groups ( n=31). In the study group, individualized ITV, PTV and PTV margin were obtained under three bladder filling status by localization CT scan to compare the VMAT. The target area and organs at risk (OARs) within the target area were statistically compared between two groups. The target missing rate in CBCT, adverse events and short-term efficacy of radiotherapy were analyzed in two groups. Results:There was no significant difference in the volume of target area and OARs in the target area between two groups (both P>0.05). In the study group, the target missing rate and target missing volume were significantly lower compared with those in the control group (both P<0.05). There was no significant difference in the incidence of acute radiation-induced adverse events between two groups ( P>0.05). The 1-, 2-year overall survival and progress-free survival did not significantly differ between two groups (all P>0.05). One patient in the study group had uterine recurrence and 2 cases in the control group. Conclusion:Application of individualized cervix-uterine ITV and PTV in definitive VMAT under different bladder filling conditions can improve the accuracy of target area contouring and improve the local control rate in cervical cancer patients.
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Objective To determine the dose-response relationship of ropivacaine for paravertebral nerve block in treating acute severe herpetic neuralgia.Methods One hundred patients with herpetic neuralgia,with the course of disease ≤ 1 month,of numeric rating scale score ≥ 7 points,scheduled for elective paravertebral nerve block with ropivacaine under ultrasound guidance,were divided into 5 groups n=20 each) using a random number table method:5 different concentrations of ropivacaine groups R1.5 groups).The herpes zoster-affected thoracic spinal nerves were identified,and the mixture 5 ml was injected into the paravertebral space corresponding to the spinal nerves.The mixture solution contained ropivacaine with the concentrations of 0.075 0％ (group R1),0.112 5％ (group R2),0.150 0％ (group R3),0.187 5％ (group R4) and 0.225 0％ (group R5),compound betamethasone 1 ml,and mecobalamin injection 1 ml diluted to 20 ml with normal saline.Effective block was defined as numeric rating scale score≤ 1 point at 10 min after paravertebral nerve block with ropivacaine.The median effective concentration (EC50),95％ effective concentration (EC9s) and 95％ confidence interval of ropivacaine for paravertebral nerve block in treating acute severe shingles neuralgia were calculated by Probit analysis.Results The EC50 and EC95 (95％ confidence interval) of ropivacaine for paravertebral nerve block in treating acute severe shingles neuralgia were 0.150 0％ (0.097 0％-0.216 0％) and 0.216 0％ (0.175 0％-0.541 0％),respectively.Conclusion The EC50and EC95 of ropivacaine for paravertebral nerve block in treating acute severe herpetic neuralgia are 0.150 0％ and 0.216 0％,respectively.
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Objective@#To investigate the etiology, clinical and pathological characteristics of laryngeal leukoplakia and the predictive risk factors of recurrence and malignant transformation.@*Methods@#Clinical data of 263 patients with laryngeal leukoplakia between January 2000 and December 2015 were analyzed retrospectively.@*Results@#The pathological diagnoses included squamous epithelial hyperplasia (54.4%), mild dysplasia (17.9%), moderate dysplasia (12.2%), severe dysplasia and carcinoma in situ (12.5%), and invasive carcinoma (3.0%). Age and the extent of lesion were statistically different among different pathological groups (P<0.05). Gender, smoking and alcohol consumption did not show statistical differences among different pathological groups (P>0.05). Follow-up of 215 patients, excluding 6 cases of invasive carcinoma. The recurrence rate was 20.6%(43/209), and the malignant transformation rate was 5.3%(11/209). Multivariate analysis showed that pathological classification of moderate to severe dysplasia was the independent risk factor for recurrence and malignant transformation of laryngeal leukoplakia (P<0.05). In patients with severe dysplasia and carcinoma in situ, the recurrence proportion of conservative treatment, vocal cords (partial) resection and radiotherapy were 8/10, 0/10 and 2/11 respectively.@*Conclusions@#Laryngeal leukoplakia occurs frequently in elderly men with long-term smoking history. Pathological diagnoses are different. The grade of dysplasia is the predictive risk factor for the recurrence and malignant transformation of laryngeal leukoplakia. More aggressive treatment and closer follow-up should be warranted for patients with moderate dysplasia, severe dysplasia and carcinoma in situ.
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Objective To investigate the effect of azelastin nasal spray combined with desloratadine in the treatment of allergic rhinitis .Methods Two hundred patients with allergic rhinitis were selected .According to the digital meter method ,the patients were randomly divided into observation group and control group ,with 100 cases in each group .The control group was treated by azelastin nasal spray , the observation group was given azelastin nasal spray combined with desloratadine .The clinical effects of the two groups were compared .Results The effective rate of the observation group(96.00%) was higher than that of the control group (80.00%),the difference was statistically significant(χ2 =6.235,P<0.05).After treatment,the scores of runny nose,nasal itching,nasal congestion,sneezing and the inferior turbinate swelling in the observation group were (1.1 ±0.2) points,(1.2 ±0.7) points,(1.1 ± 0.3)points,(0.8 ±0.3) points,(0.9 ±0.2) points,respectively,which were significantly lower than those in the control group [(1.4 ±0.9)points,(1.9 ±0.6)points,(1.8 ±0.8)points,(1.7 ±0.7)points,(1.9 ±0.9)points] (t=5.154,5.226,5.154,5.226,5.011,all P<0.05).Conclusion Azelastin nasal spray combined with deslorata-dine tablets in the treatment of allergic rhinitis can quickly relieve the patients 'clinical symptoms,improve the effec-tive rate,and it is safe and worthy of clinical popularization and application .
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Objective@#To explore the safety and validity of endoscopic cricopharyngeal myotomy in patients with cricopharyngeal achalasia.@*Methods@#A total of 19 patients with cricopharyngeal achalasia suffered from sustained dysphagia were enrolled in this study. The patients were divided into transcervical cricopharyngeal myotomy(CPM) group and endoscopic CPM (ECPM) group. Swallowing function and complications were evaluated.SPSS7.0 software was used to analyze the data.@*Results@#The swallowing function improved significantly in seven patients in ECPM group, and 9 patients improved in CPM group.The video fluoroscopic swallowing study(VFSS)-swallowing score, VFSS-aspiration score and drinking test score were (3.1±1.1), (3.4±0.8) and (2.0±0.6)in post-ECPM, (3.4±1.4), (3.0±0.9) and (2.2±0.6)in post-CPM. No statistical difference was found in validity between CPM group and ECPM group(t=-0.435, t=1.086, t=-0.607, P>0.05). No statistical difference was observed on the occurrence of complication between two groups. Only one patient had subcutaneous emphysema after operation in ECPM.@*Conclusions@#New surgical instruments and endoscopic surgical technique were safe and effective for cricopharyngeal achalasia. Because these instruments are cheaper, laryngeal endoscopic cricopharyngeal myotomy is easier to be popularized more easily than microscopic laser assistted CPM.
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Objective@#To introduce the method of transoral coblation-assisted endoscopic minimally invasive surgery for superficial tongue base tumour.@*Methods@#A total of 15 patients treated with transoral coblation-assisted endoscopic minimally invasive surgery from Mar. 2006 to Aug. 2016 were retrospectively reviewed. There were 9 patients with malignant tumors, 6 patients with benign neoplasms. Adjuvant postoperative radiation therapy was applied in three cases of squamous cell carcinoma, neck was performed in four cases of cancer. One case of non-Hodgkin lymphoma received postoperative chemotherapy.@*Results@#One case with ectopic thyroid gland was treated by subtotal resection and one case with squamous cell carcinoma changed into open surgery because of major lingual artery bleeding. The En bloc resection under edoscope was achieved in 92.86%(13/14)of patients. Fifteen cases of neoplasms were followed-up for 8-50 months(median 20 months), one patient with Cowden syndrome was lost to follow-up because of appendical carcinoid combined pulmonary metastasis, one patient with non-Hodgkin lymphoma died of recurrence in other head neck areas 2 years after chemotherapy.@*Conclusion@#Transoral coblation-assisted endoscopic surgery can successfully treat for the patients with superficial tongue base tumours.
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<p><b>OBJECTIVE</b>To investigate the impact of gender on early outcomes of patients with acute ST-segment elevation myocardial infarction (STEMI) who were treated with primary percutaneous coronary intervention (PCI) as their reperfusion strategy.</p><p><b>METHODS</b>The present study included consecutive patients with STEMI treated with primary PCI in our hospital from November 2003 to December 2012. Gender difference and predictors of 30 day all-cause death were examined among 957 patients, 197 of whom were women (20.6%). The impact of gender on 30 all-cause death was further evaluated by a propensity-matched analysis to adjust the differences in baseline characteristics between men and women.</p><p><b>RESULTS</b>Compared with men, women were older ((69.4±10.2) years old vs. (60.6±12.6) years old, P<0.001), more likely to have hypertension (72.1% (142/197) vs. 54.6% (415/760), P<0.001) and diabetes (45.2% (89/197) vs. 32.4% (246/760), P = 0.001), but less likely to be treated with β-blockers (85.3% (168/197) vs. 92.0% (699/760), P = 0.006) and angiotensin converting-enzyme inhibitors/angiotensin-receptor blockers (82.2% (162/197) vs. 88.4% (672/760), P = 0.024). Symptom-to-balloon time was longer in women than in men (330 (240, 600) minutes vs. 270 (180, 450) minutes, P < 0.001). Multivariate linear regression analysis of log-transformed symptom-to-balloon time revealed that female gender was an independent predictor of longer symptom-to-balloon time (β = 0.141, 95% confidence interval (CI) 0.053-0.228, P = 0.002). Women with STEMI had higher unadjusted 30 day all-cause death (12.6% vs. 4.2%, P < 0.001) than men. Female gender independently predicted 30 day all-cause mortality both with (hazard ratio (HR) = 3.497, 95% CI 1.485-8.234, P = 0.004) and without (HR = 2.495, 95% CI 1.170-5.323, P = 0.018) the adjustment for baseline characteristics by propensity-matched analysis.</p><p><b>CONCLUSIONS</b>Even with primary PCI as their reperfusion strategy, women with STEMI had higher 30 day all-cause death than men. Aggressive control of cardiovascular risk factors, adequate medical treatment and shortening of delay in reperfusion therapy might further improve the outcomes of female STEMI patients undergoing primary PCI.</p>
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Aged , Aged, 80 and over , Female , Humans , Male , Acute Disease , Cause of Death , Hypertension , Multivariate Analysis , Myocardial Infarction , Therapeutics , Percutaneous Coronary Intervention , Proportional Hazards Models , Risk Factors , Sex Factors , Time FactorsABSTRACT
<p><b>OBJECTIVE</b>To investigate the activated clotting time (ACT) level after administration of guideline-recommended dose of unfractionated heparin (UFH) and to confirm the importance of ACT monitoring in percutaneous coronary intervention (PCI).</p><p><b>METHODS</b>We performed a retrospective study on 1 062 patients undergoing elective PCI in Peking Union Medical College Hospital from May 1, 2011 to December 31, 2012. All patients were administrated weight-adjusted UFH (70-100 U/kg) based on PCI guideline of ACCF/AHA/SCAI. Patients were divided into 3 groups: ACT < 300 s (598 cases), ACT 300-350 s (183 cases) and ACT > 350 s (281 cases). ACT level and factors that may affect UFH anticoagulation were analyzed.</p><p><b>RESULTS</b>(1) The mean age was (63.0 ± 10.6) years and 751 (70.7%) patients were men. The mean weight was (70.5 ± 11.7) kg, and the mean UFH dose used was (100.7 ± 9.1) U/kg. (2) The median ACT was 285 (240-352) s after the UFH use. Pre-defined ACT target (300-350 s) was achieved only in 17.2% (183/1 062) patients. (3) Age, gender, height, weight, UFH/weight and the risk factors of coronary heart disease were similar among 3 groups (all P > 0.05). Multifactor linear correlation analysis showed that UFH/weight was related to ACT level (r = 0.07, P < 0.01), but other factors were not related to ACT level (all P > 0.05). (4) Among 598 patients with ACT < 300 s, 444 (74.2%) patients received additional UFH. No major bleeding events were observed in 1 062 patients. The incidence of minor bleeding and ischemic complications within 48 h after procedure were similar among 4 groups of ACT < 300 s with additional UFH, ACT < 300 s without additional UFH, ACT 300-350 s and ACT > 350 s (all P > 0.05).</p><p><b>CONCLUSIONS</b>In this single-center study, only a small proportion of patients reached the ACT target after administration of weight-adjusted UFH. Our results supported the recommendation of ACT monitoring in current PCI guideline to improve efficacy and safety of UFH anticoagulation therapy.</p>
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Aged , Female , Humans , Male , Middle Aged , Anticoagulants , Therapeutic Uses , Coronary Disease , Hemorrhage , Epidemiology , Heparin , Therapeutic Uses , Percutaneous Coronary Intervention , Retrospective Studies , Risk Factors , Treatment Outcome , Whole Blood Coagulation TimeABSTRACT
Objectives We sought to determine the factors that predicted in-hospital heart failure(HF)in patients undergoing successful primary percutaneous coronary intervention(PCI)for ST-segment elevation myocardial infarction(STEMI). Methods The clinical and angiographic data were retrospectively reviewed in patients undergoing successful primary PCI for their ifrst STEMI. According to the occurrence of in-hospital HF, patients were divided into HF group and non-HF group. The incidence and predictors of in-hospital HF and its impact on prognosis were determined. Results A total of 834 patients were included, among them 94 patients (11.3%) were in the HF group and 740 patients(88.7%) were in the non-HF group. The mean age was (62.9±12.9) years and 662 patients (79.4%) were male. All-cause mortality at 30 days was signiifcantly higher in the HF group than in the non-HF group (24.5%vs. 1.5%, P<0.001). In Cox regression analysis, left anterior descending artery (LAD) as the culprit vessel (HR 2.173, 95% CI 1.12~4.212, P=0.022), ln 24 h NT-proBNP (HR 1.904, 95%CI 1.479~2.452, P<0.001), 24 h hsCRP≥11.0 mg/L (median) (HR 2.901, 95%CI 1.309~6.430, P=0.009) and baseline serum glucose (HR 1.022, 95%CI 1.000 ~ 1.044, P=0.046) were independent predictors of in-hospital HF. Receiver operator characteristic analysis identiifed 24 h NT-proBNP ≥ 1171 pg/ml (c=0.883, P < 0.001) and 24 h hsCRP ≥ 13.5 mg/L (c=0.829, P < 0.001) were the best cut-off values in discriminating in-hospital HF with a sensitivity and speciifcity of 92.5%and 76.8%for 24 h NT-proBNP, 86.0%and 77.0%for 24 h hsCRP, respectively. Even among patients with LAD as the culprit vessel, the incidence of in-hospital HF was only 0.4%in patients whose 24 h NT-proBNP was<1171 pg/ml and 24 h hsCRP was<13.5 mg/L;while the incidence of in-hospital HF was up to 60.9%in patients whose 24 h NT-proBNP≥1171 pg/ml and 24 h hsCRP≥13.5 mg/L (P<0.001). Conclusions The incidence of in-hospital HF was still high in STEMI patients even after successful primary PCI. Patients with in-hospital HF had poor prognosis. LAD as the culprit vessel, hsCRP, NT-proBNP and baseline serum glucose were independent predictors of in-hospital HF. Assessment and combined use of different serum biomarkers were effective methods to estimate the risk of in-hospital HF in STEMI patients undergoing primary PCI.
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A series of 2-(3-butynoicamidophenyl)benzothiazole derivatives were synthesized starting from 4-fluoro-3-nitrobenzoic acid. Structures of all the synthesized compounds were confirmed by 1H NMR and HR-MS. Their antitumor activities against human tumor cells lines (HCT116, Mia-PaCa2, U87-MG, A549, NCI-H1975) were evaluated by MTT assay. The results revealed that most of the synthesized compounds showed potent activities against HCT116, Mia-PaCa2, U87-MG tumor cells lines. Particularly, compounds 14c and 14h exhibited better activity with IC50 values of 1 x 10(-8) mol x L(-1) against U87-MG and HCT116 respectively. The structure-activity relationship of compounds was also discussed preliminarily.
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A novel series of sorafenib analogs containing 2-picolinyl hydrazide moiety were designed and synthesized. In vitro, most of synthesized compounds have antiproliferation activity on MDA-MB-231, ACHN, HepG2, Mia-PaCa-2 and SW1990 cell lines tested by MTT assay. It is worth noting that the antitumor activities of compounds 2c, 2d and 2f are more potent than that of sorafenib on pancreatic cancer cells Mia-PaCa-2 and SW1990, and the activities of compounds 3f and 3g are 2-3 times than that of sorafenib on human hepatocellular carcinoma HepG2 cell line.
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Objective To evaluate the effects of drug-eluting stents (DES) versus bare-metal stents (BMS) on clinical outcomes in patients with acute ST-segment elevation myocardial infarction (ASTEMI) receiving primary percutaneous coronary intervention (PPCI). Methods The 217patients with ASTEMI receiving PPCI from Jan. 2005 to Dec. 2007 were enrolled in this study. And they were divided into two groups: DES group (n=92) and BMS group (n=125). The baseline characteristics including age, gender, angiographic characteristics, stents characteristics, Killip classification, cardiac troponin I(CTnI)levels, left ventricular ejection fraction(LVEF), hemoglobin levels, hypertension, diabetes, hyperlipidemia, obesity and smoking of the two groups were collected.Clinical follow-up end point were major adverse cardiac event(MACE)including death, acute myocardial infarction, stent thrombosis and stent restenosis. Clinical follow-up duration was(16.8±11.3) months (6-38 months). Results The average age (years), rate of Killip classification (class 2, 3, 4), average diameter (mm) of stent were significantly higher in BMS group than in DES group(64.6±11.9 vs. 61.2±11.8, t=2.09, P=0.037;25.9% vs. 12.2%, χ2=5.53, P=0.019;3.07±0.38 vs. 2.91±0. 40, t=2.78, P=0.006). And the average LVEF (%) was significantly lower in BMS group than in DES group (55.4±11.9 vs. 60.3±12.8, t= -2.57, P=0.011). The average length (mm) of stent, rate of stent post dilatation and diabetes were significantly higher in DES group than inBMSgroup (32.8±16.2 vs. 26.2±11.2, t=-3.54, P=0.001;45.7% vs. 21.6%, χ2=13.85, P=0. 000;28.2% vs. 16.0%, χ2=4.77, P=0.030). MACE occurred in 36 patients during clinical follow-up, 6 in DES group and 30 in BMS group. Incidence of MACE was significantly lower in DES group than in BMS group(6.5% vs. 24.0%, χ2=11.70, P＜0.01). Conclusions Using DES in ASTEMI patients is safe and may improve clinical outcomes by reducing incidence of MACE compared with BMS.
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Objective To investigate the change of caspase-3 in rabbits after lung ischemia-reperfusion injury(LIRI) and the effect of puerarin(葛根素).Methods Thirty healthy rabbits used for unilateral lung ischemia-reperfusion model were randomly divided into 3 groups(each n=10): control group(C group),lung ischemia-reperfusion group(I/R group) and puerarin group.The activity of serum superoxide dismutase(SOD),the contents of serum malondialdehyde(MDA) and nitric oxide(NO),the wet to dry weight(W/D) ratio of lung tissue and the index of quantitative assessment of histological lung injury(IQA) were measured respectively in different groups;the pneumocyte apoptosis index(AI) was achieved by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling(TUNEL);caspase-3 protein and mRNA expression were studied by using in situ hybridization(ISH) and immunocytochemistry(IHC) techniques in the groups mentioned above.Results The activity of SOD and content of NO were significantly lower in I/R group than those in C group(both P
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BACKGROUND: Human body is an irregular geometrical one, so it is very diffcult to measure its volume.OBJECTIVE: To establish multiple regression equations by taking body height and body mass as the independent variables and body volume as the dependent variable, calculate the body volume of female college students and select optimal regression equations.DESIGN: A single-sample univariate analysis.SETTING: Department of Physical Education of Lishui College, Department of Physical Education of Zhejiang University and Academy of police in Zhejiang. PARTICIPANTS: Eighteen female students aged 18-22 years were selected from Zhejiang Lishui College.METHODS: Both the body height and body mass indexes of the female students were measured with the nation-ratified constitutional test instrument, and the body volume index was measured with a self-made iron container with a diameter of 0.95 m and height of 1.20 m. There was a scale mark for height in the container, water was poured to a fixed height, then the student slowly immersed herself into the water completely and the height difference was recorded. Body volume (m3)=(0.95÷2)2×3.141 59×height difference. The measured data were statistically calculated. Regression equations were established by taking body height and body mass as the independent variables and body volume as the dependent variable,and the optimal regression equation was selected.MAIN OUTCOME MEASURES: The measured data of body height,body mass and body volume of female students and the calculated results of the regression equations were observed.RESULTS: The measured data of body height, body mass and body volume of 18 female students all entered into the in result analysis ① A regression equation in two unknowns for calculating body volume was established: (y)=-0.031 016+0.000 761×body mass+0.000 267×body height. ②A regression equation in one unknown for body volume and its optimal selection: The linear equation was y=0.001×body mass+0.000 8; the logarithm equation was y=0.005 1Ln (body mass)-0.15; the power equation was (y)=0.001×body mass0.9909; the exponent equation was y =0.0192×e0.0188x.and the multiple correlation coefficient R2=0.9497-0.9591, all were close to 1, indicating that the body volume predicted by models was highly correlated with the actual one (r ＞ r0.001(18-2), P ＜ 0.001), the predicted values of the 4 models were not different from the actual one. ③ Analyzing from the simplicity of calculation and the economic way of index measurement, Logarithm equation is the best in the 5 regression equations. ④ The body volume covered body shape, physical function and Physique.CONCLUSION: The index of body volume is one of the important indexes, which cannot be neglected in the study of Physique. Analyzing from the simplicity of calculation and the economic way of index measurement, Logarithm equation is the best.
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0.05) was observed. The protein expressions of TLR-4, NF-?B p65, HSP70 and ICAM-1mRNA in IR group were significantly increased as compared to C group and PD group, while those expressions in PD group were evidently higher than those in C group (all P