Local focal adhesion kinase (FAK) is a non-receptor intracellular tyrosine kinase that plays an important role in tumor initiation, development, metastasis and invasion, and is considered to be an important target for the development of antineoplastic drugs. It has both kinase-dependent and non-kinase-dependent scaffolding functions. However, traditional small molecular inhibitors can only inhibit its kinase-dependent activity, so it is difficult to target the kinase-independent scaffolding function. Therefore, there is an urgent need for novel strategies to enhance FAK targeting to lay the foundation for determining the druggability and discovery of FAK inhibitors. Proteolysis targeting chimera (PROTAC) is a new drug development strategy that can recruit E3 ligase to specifically ubiquitinylate target proteins for degradation through the proteasome system. The unique mechanism of action of the PROTAC system could be used to target and degrade the FAK protein, thus eliminating the scaffolding function of FAK. In this review, FAK protein, the signaling pathway, and small molecule inhibitors are briefly described, and the latest research progress in targeting the degradation of FAK using PROTAC technology is summarized.

BACKGROUNDHepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide. In order to investigate the molecular biologic mechanism of HCC's development, we studied the expressions of SE-1, CD105 and CD31 in tumor endothelial cells (TECs) of HCC and in the serum of rats.

METHODSWe analyzed the expressions of SE-1, CD31 and CD105 in rat HCC tumor tissues using immunohistochemistry (IHC). Twenty HCC bearing rats and eighteen normal rats were examined for the expressions of SE-1, CD31 and CD105 antigens in serum by enzyme-linked immunosorbent assay (ELISA).

RESULTSSE-1, CD31 and CD105 antigens were detected both in HCC tissue and in normal liver tissue with higher expressions of CD31 and CD105 in HCC while the SE-1 antigen expression was higher in normal liver. Similarly, serum CD31 and CD105 in rats with HCC were significantly increased compared with normal rats (t = 2.8628, P = 0.0086; t = 4.4922, P < 0.0001, respectively). In contrast, SE-1 antigen in HCC rat serum was significantly decreased compared with normal rats (t = 3.4983, P = 0.0011).

CONCLUSIONSE-1, CD31 and CD105 are closely related with liver tumor angiogenesis, which is similar to their performances in terms of their expressions in the serum.

Animals ; Antigens, CD ; blood ; Carcinoma, Hepatocellular ; blood supply ; chemistry ; Endothelial Cells ; chemistry ; immunology ; Enzyme-Linked Immunosorbent Assay ; Immunohistochemistry ; Liver Neoplasms, Experimental ; blood supply ; chemistry ; Male ; Neovascularization, Pathologic ; blood ; Platelet Endothelial Cell Adhesion Molecule-1 ; blood ; Rats ; Rats, Inbred BUF

OBJECTIVETo introduce the postero- lateral surgical approach to the posterior malleolar fracture and report its clinical outcomes in 32 cases.

METHODSThis study consisted of 32 cases, 22 males and 10 females with the mean age of 48 years (range, 21-63 years), suffering from posterior malleolar fracture. All cases were treated with the posterolateral surgical approach to the ankle. The average follow-up period was 28 months (range, 24-35 months). The clinical outcomes of these cases were evaluated on the basis of the Olerud-Molander Ankle (OMA) score and plain radiographs.

RESULTSAll cases showed radiological evidence of bony union at follow-up. The average OMA score was 82 points; 21 cases had excellent scores (90-100 points), 9 good (61-90 points), and 2 fair (31-60 points). The excellent-to-good rate was 93.8%. Although most cases did not show any wound dehiscence or necrosis, one patient had a superficial infection which healed after using antibiotic dressing and one had sural cutaneous nerve injury that underwent spontaneous remission without any treatment after three months. In addition, one presented with mild symptoms of peroneal tendonitis that disappeared after plate removal.

CONCLUSIONThe posterolateral approach offers an effective technique for fracture reduction and fixation of large posterior malleolar fragments.

Ankle Fractures ; Ankle Joint ; surgery ; Bone Plates ; Fracture Fixation, Internal ; Humans

Objective To investigate the effects of Sacubitril/Valsartan on amino terminal probrain natriuretic peptide (NT-proBNP),high sensitivity C-reactive protein (hs-CRP),soluble suppression of tumorigenicity 2(sST2)levels and on left ventricular(LV)structure in NYHA Ⅳ heart failure with reduced ejection fraction(HFrEF) patients.Methods A total of 67 HFrEF patients with NYHA Ⅳ were randomly divided into the control group (n =30)receiving conventional medical treatment,and the observation group(n=32)receiving Sacubitril/Valsartan instead of ACEI(or ARB if ACEI induced cough) in conventional medical treatment.NT-proBNP levels were determined by fluorescer-enhanced chemiluminescence.hs CRP levels were detected by latecx enhanced immunoturbidimetric assay.sST2 levels were determined by enzyme-linked immunosorbent assay (ELISA).The modified Simpson method was used to detect left ventricular end-diastolic diameter (LVEDD),LV posterior wall(LVPW)and LV ejection fraction(LVEF).Two groups of patients were treated and followed-up for 6 months.Results Clinical efficacy was better in the observation group than in the control group(effective rate,20 cases or 61.3％ vs.8 cases or 26.7％,P＜0.05).As compared with the control group,the observation group of patients had an increased LVEF[(46.7±9.2) ％ vs.(41.8±8.0)％,P＜0.05]and a decreased LVEDD[(52.6±6.7)mm vs.(58.8±7.5)mm,P＜0.05].After vs.before treatment,NT-proBNP,hs-CRP and sST2 levels were decreased in both control and observation groups [(1 427 ± 219) μg/L vs.(2 615 ± 273)μg/L,(1.14 ± 1.02) mg/L vs.(1.55±1.38)mg/L,(0.30±0.12)μg/L vs.(0.41±0.10)μg/L,all P＜0.05],and the decrements were much more in the observation group than in the control group (P＜0.05).The annual accumulated frequence and duration of hospitalization were less in the observation group than in the control group[(0.8±0.6)times vs.(1.8±1.0) times,(10.2±5.8)d vs.(16.5±7.2)d,P＜0.05].The maintenance dose of tolasemide was lower in the observation group than in the control group [(15.2±8.4)mg vs.(20.6±10.8)mg,P＜0.05].Conclusions Sacubitril/valsartan therapy is safe and effective and it can reduce hs-CRP and sST2 levels and improve the ventricular remodeling in HFrEF patients of HYHA Ⅳ.

OBJECTIVELandmark trials have demonstrated that statins can reduce the risk of coronary events. Despite the widespread use of statins in the settings of primary and secondary prevention of CHD, withdrawal of statins is a frequent problem in clinical practice. Several recent clinical studies have suggested that withdrawal of statin therapy might be associated with an increase in thrombotic vascular events and the onset of acute coronary syndromes. However, the effects of discontinuing of statins treatment on endothelial function and underlying mechanism are unknown. Objectives We investigated the effects after withdrawal of simvastatin on brachial artery endothelial function in patients unreached cholesterol target with coronary heart disease (CHD) or CHD risk factors.

METHODSWe included 33 patients with established CHD or CHD risk factors, whose serum cholesterol did not achieve NCEP target level. They were administered simvastatin (20 mg) for 4 weeks. Endothelial dependent flow-mediated vasodilation (FMD) was assessed in the brachial artery using high-resolution ultrasound at baseline, after 4 weeks of simvastatin and after termination of therapy 1 week. We evaluated fasting serum lipid profiles and vasoactive substances simultaneously, included nitric oxide (NO), endothelin (ET), 6-keto-PGF1(alpha) and thromboxane B(2) (TXB(2)), which were measured as plasma prostacyclin and TXA(2) respectively.

RESULTSSimvastatin treatment reduced low density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels and improved endothelial-dependent vasodilation in patients after 4 weeks. Withdrawal of simvastatin, however, FMD showed a significant reduction [(4.82 +/- 0.71)% vs (11.51 +/- 0.87)%, P < 0.01], that remained in low level after 1 week, and the FMD were even lower than the baseline values [(4.82 +/- 0.71)% vs (5.89 +/- 0.65)%, P < 0.01]. After terminating simvastatin treatment, serum NO and plasma 6-keto-PGF1(alpha) levels decreased, as well as plasma ET and serum LDL-C levels increased. But there was no significant difference between plasma TXB(2) levels before and after withdrawal of simvastatin (P > 0.05). Overall, there were significant positive correlations between withdrawal-induced changes in FMD and serum NO level (r = 0.674, P = 0.004), whereas no correlations were shown between the changes in FMD and serum LDL-C level (r = -0.414, P = 0.083).

CONCLUSIONSAbrupt withdrawal of simvastatin therapy resulted in the significant adverse impact on brachial artery endothelial function in patients unreached cholesterol target with CHD or CHD risk factors. Termination of therapy may suppress endothelial NO production and impair endothelial function that is independent of lipid-lowering effect.

Aged ; Brachial Artery ; drug effects ; Cholesterol, LDL ; blood ; Coronary Disease ; drug therapy ; physiopathology ; Endothelium, Vascular ; physiopathology ; Female ; Humans ; Hypolipidemic Agents ; administration & dosage ; Male ; Middle Aged ; Nitric Oxide ; blood ; Risk Factors ; Simvastatin ; administration & dosage ; Vasodilation

A detection method for furazolidone and florfenicol in soil with various environmental matrices was established using ultra performance liquid chromatography-tandem spectrometry (UPLC / MS / MS) technique. Extracting solution of a mixture of phosphate buffer (pH = 3) and acetonitrile (3 : 7, V/ V) was used in this experiment. The extracted water samples were enriched by SAX-HLB solid phase extraction column before the process of nitrogen blowing ( high purity nitrogen). The enriched antibiotics were desalted with 8 mL of methanol. Waters BEH C18(2. 1 × 100 mm) column was used for the sample separation. UPLC / MS / MS was carried out for qualitative and quantitative analysis under multi-reaction monitoring mode. The detection limit of the method was determined by 3 times of signal-to-noise ratio, and the limit of determination of the method was determined by 10 times of signal-to-noise ratio. The results showed that the detection limits of furazolidone and florfenicol were 1. 19 and 0. 41 μg / kg, respectively, and the limits of quantitation of furazolidone and florfenicol were 3. 40 and 1. 37 μg / kg, respectively. Besides, recovery experiment showed that, for the soil samples spiked with 50 μg / L furazolidone and florfenicol, the recoveries were 79% for florfenicol and 92% for furazolidone. Similarly, for the soil samples spiked with 200 μg / L furazolidone and florfenicol, the recoveries were 96% for furazolidone and 86% for florfenicol.

OBJECTIVETo investigate the clinical effects of the minimal invasive osteotomy treatment for hallux valgus combined with tailor's bunion deformity.

METHODSFrom May 2007 to May 2009, Forty-nine feet of 32 patients (a mean age of 57 years old) of hallux valgus combined with tailor's bunion deformity were reviewed retrospectively, including 2 males(2 feet) and 30 females (47 feet). All patients were treated by the minimal invasive osteotomy. The axial and lateral films of all feet with loading were taken before and after operation. The hallux abducto valgus angle(HAV),intermetatarsal angle(IM), fourth-fifth intermetatarsal angle (IM 4 to 5), modified fourth-fifth intermetatarsal angle (MIM 4 to 5), Metatarsophalangeal-fifth angle (MPA) and lateral deviation of the fifth matatarsal angle (LDA) were compared before and after operation. Therapeutic effects of all the patients were observed after operation, the item including AFAS score and WEN Jian-min's therapeutic effects standard.

RESULTSThe average operating time was 40 minutes. All the patients were followed up,and the duration ranged from 6 to 24 months. The HAV angle, IM angle, IM 4 to 5 angle, MIM 4 to 5 angle,MPA angle and LDA angle significantly decreased after operation. The AFAS score significantly raised after operation. According to the criteria, 33 feet got an excellent result, 15 good and 1 fair.

CONCLUSIONThe minimal invasive osteotomy treatment for hallux valgus combined with tailor's bunion is effective and safe. This method is mini-trauma,less pain and it can make a very soon rehabilitation. This method has widely clinical value.

Adult ; Aged ; Aged, 80 and over ; Bunion, Tailor's ; surgery ; Female ; Hallux Valgus ; surgery ; Humans ; Male ; Middle Aged ; Minimally Invasive Surgical Procedures ; methods ; Osteotomy ; methods

Objective To learn the epidemiological characteristics of severe hand,foot,mouth disease (HFMD)in Fengtai District,and to provide the theoretical basis for the prevention and intervention of severe hand,foot,mouth disease cases. Methods Descriptive epidemiological analysis was conducted on the incidence data of severe cases of HFMD in Fengtai District,2010 -2015.Results The reported number of severe cases of HFMD was highest in 2010.The cases decreased year by year,and the annual incidence peak was present during June -August.The most cases were young children aged 1 -5 years. EV71 was the major pathogen,but other intestinal virus presented a rising trend.Cases were mainly floating population and presented regional distribution of small commodity wholesale market.Clinical features were mainly fever,rash,accompanied by more nervous system symptoms.The clinical symptoms include fever and rash usually accompanied by symptoms of the nervous system.Conclusion Severe cases presented a decline trend,and the proportion of other intestinal virus pathogen was increasing.More attention should be paid to other enterovirus infection of hand,foot and mouth disease among children.

OBJECTIVETo study neck and shoulder work-related muscle fatigue of female sewing machine operators.

METHODS18 health female sewing machine operators without musculoskeletal disorders work in Beijing garment industry factory as volunteers in participate of this study. The maximal voluntary contraction (MVC) and 20% MVC of bilateral upper trapezium and cervical erectors spinae was tested before sewing operations, then the whole 20 time windows (1 time window = 10 min) sewing machine operations was monitored and the surface electromyography (sEMG) signals simultaneously was recorded after monitoring the 20%MVC was tested. Use amplitude analysis method to reduction recorded EMG signals.

RESULTSDuring work, the median load for the left cervical erector spinae (LCES), right cervical erector spinae (RCES), left upper trapezium (LUT) and right upper trapezium (RUT) respectively was 6.78 ± 1.05, 6.94 ± 1.12, 5.68 ± 2.56 and 6.47 ± 3.22, work load of right is higher than the left; static load analysis indicated the value of RMS(20%MVC) before work was higher than that value after work, the increase of right CES and UT RMS(20%MVC) was more; the largest 20%MVE of bilateral CES occurred at 20th time window, and that of bilateral UT happened at 16th.

CONCLUSIONSThe work load of female sewing machine operators is sustained "static" load, and work load of right neck-shoulder is higher than left, right neck-shoulder muscle is more fatigable and much serious once fatigued.

Adult ; Electromyography ; Female ; Humans ; Muscle Fatigue ; physiology ; Posture ; Shoulder ; physiology ; Textile Industry ; Work ; Young Adult

OBJECTIVETo explore early diagnosis, treatment and prevention of gastrointestinal (GI) bleeding after cardiac surgery.

METHODSIn the last 13 years, cases complicated with GI bleeding after cardiac surgeries were analyzed retrospectively.

RESULTSFourty-four GI bleeding occurred post-operatively in (6 +/- 3) d. The mortality was 23% (10/44). Thirty-eight were located in upper GI tract, of them 26 underwent conservative therapy while 4 died of other than GI bleeding cause; six underwent laparotomy while 1 and 3 died of septicemia and multi-organ failure respectively; six underwent gastric endoscopic hemostasis by electrocautery or clipping the bleeding vessel while all survived. Six were located in lower GI tract, and 2 of them underwent laparotomy without finding bleeding section and died of multi-organ failure. By multivariable logistic regression analysis, deaths were highly related to the post-operative ventilator-dependence, acute renal insufficiency, intra-aortic balloon pump (IABP) assisting and laparotomy.

CONCLUSIONThe mortality of GI bleeding after cardiac surgeries is very high, early gastrointestinal endoscopic examination and minimally invasive intervention can treat this complication more effectively. GI bleeding must be prevented whenever complicating post-operative ventilator-dependence, acute renal insufficiency, and IABP assisting after cardiac surgery.

Adult ; Aged ; Cardiac Surgical Procedures ; adverse effects ; Early Diagnosis ; Female ; Gastrointestinal Hemorrhage ; diagnosis ; etiology ; mortality ; therapy ; Humans ; Male ; Middle Aged ; Postoperative Complications ; Retrospective Studies ; Risk Factors