Design of a highly potent GLP-1R and GCGR dual-agonist for recovering hepatic fibrosis

Currently, there is still no effective curative treatment for the development of late-stage liver fibrosis. Here, we have illustrated that TB001, a dual glucagon-like peptide-1 receptor/glucagon receptor (GLP-1R/GCGR) agonist with higher affinity towards GCGR, could retard the progression of liver fibrosis in various rodent models, with remarkable potency, selectivity, extended half-life and low toxicity. Four types of liver fibrosis animal models which were induced by CCl4, α-naphthyl-isothiocyanate (ANIT), bile duct ligation (BDL) and Schistosoma japonicum were used in our study. We found that TB001 treatment dose-dependently significantly attenuated liver injury and collagen accumulation in these animal models. In addition to decreased levels of extracellular matrix (ECM) accumulation during hepatic injury, activation of hepatic stellate cells was also inhibited via suppression of TGF-β expression as well as downstream Smad signaling pathways particularly in CCl4-and S. japonicum-induced liver fibrosis. Moreover, TB001 attenuated liver fibrosis through blocking downstream activation of pro-inflammatory nuclear factor kappa B/NF-kappa-B inhibitor alpha (NFκB/IKBα) pathways as well as c-Jun N-terminal kinase (JNK)-dependent induction of hepatocyte apoptosis. Furthermore, GLP-1R and/or GCGR knock-down results represented GCGR played an important role in ameliorating CCl4-induced hepatic fibrosis. Therefore, TB001 can be used as a promising therapeutic candidate for the treatment of multiple causes of hepatic fibrosis demonstrated by our extensive pre-clinical evaluation of TB001.

Progress of cellular growth factors in neurorehabilitation and neuroplasticity / 中国康复理论与实践

@#With potent biological activities, cellular growth factors are polypeptide factors that primarily stimulate cell growth and proliferation. They participate in the regulation of not only normal physiological functions such as human embryonic development and cell growth, but also neurorehabilitation and neuroplasticity in pathological processes such as nerve injury and recovery. Specifically, cellular growth factors have been shown to promote neuron survival, facilitate nerve regeneration and regulate synaptic plasticity, promote cell differentiation/vascular regeneration and modulate the microenvironment, promote nerve fiber myelination and improve nerve conduction. This review summarized current knowledge on the roles and various growth factors in neurorehabilitation and neuroplasticity, providing an update on potential clinical application of cellular growth factors in the field of neural rehabilitation.

Enhanced postoperative recovery for laparoscopic resection of gastirc gastrointestinal stromal tumors / 中华普通外科杂志

Objective To investigate the efficacy and safety of the enhanced recovery after surgery (ERAS) protocol in patients with gastric gastrointestinal stromal tumors (GISTs) in favorable sites.Methods Between March 2015 and January 2017,86 gastric GISTs patients undergoing laparoscopic resection in favorable sites were retrospectively analyzed.The patients were divided into ERAS protocol group (n =44) and conventional protocol group (n =42).Perioperative data and postoperative recovery parameters were compared.Results Compared with conventional group,postoperative recovery parameters in ERAS group such as time to first flatus,the first defecation,return to normal diet,physical activity outof-bed,and the hospital stay were obviously shortened.The postoperative pain score [(3.1 ± 3.0) vs.(5.2±3.2),P ＜0.05] and insulin resistance [(4.0±7.5) vs.(9.5 ±2.2),P ＜0.05] were significantly reduced in the ERAS protocol group than in the conventional protocol group.However,no statistically significant differences were observed in terps of operation time and intraoperative blood loss (P ＞ 0.05).There were no martality in both groups.The postoperative complications were 4.5％ and 4.7％ respectively.Conclusion Laparoscopic technique in favorable sites combined with the ERAS protocol enhance postoperative recovery and shorten hospital stay in gastric GIST patients.

Bcl-2 Gene Amplification and Protein Expression and Their Relationship with Clinicopathological Characteristics and Immunophenotype of Primary Gastrointestinal Diffuse Large B-cell Lymphoma / 胃肠病学

Background: Aberrant Bcl-2 transcription is closely related with nodal diffuse large B-cell lymphoma (DLBCL), however, the relationship between Bcl-2 and primary gastrointestinal DLBCL (PGI-DLBCL) was not fully studied.Aims: To investigate the relationship between Bcl-2 gene amplification and protein expression and clinicopathological characteristics, immunophenotype and prognosis of PGI-DLBCL.Methods: Clinical data was collected from 136 PGI-DLBCL patients receiving surgical treatment, and a telephone interview was conducted for survival information.Bcl-2 gene amplification and protein expression in tumor tissue were determined by fluorescence in situ hybridization and immuno-histochemistry, respectively, and relationships between Bcl-2 and clinicopathological characteristics, immunophenotype and prognosis of PGI-DLBCL were analyzed.Results: Among 136 PGI-DLBCL patients, 33 (24.3%) showing gene amplification and 90 (66.2%) showing protein expression of Bcl-2;gene amplification was correlated with primary tumor location, Ann Arbor stage, serum lactate dehydrogenase level, B symptom and International Prognostic Index (IPI) score (P<0.05), while protein expression was correlated with primary tumor location and immunophenotype (P<0.05).5-year overall survival (OS) in patients positive for Bcl-2 gene amplification and patients with non-GCB immunophenotype and positive for Bcl-2 protein expression were inferior to those negative ones (41.5%vs.71.5%, P<0.05;54.6% vs.84.6%, P<0.05).In Bcl-2 gene amplification or protein expression positive patients, 5-year OS of CHOP chemotherapy was inferior to that of rituximab combined with CHOP chemotherapy (48.6%vs.80.3%, P<0.05;66.4%vs.83.4%, P<0.05).Conclusions: Detection of Bcl-2 gene amplification is useful for prediction of prognosis in PGI-DLBCL.Both patients with Bcl-2 gene amplification and non-GCB patients with Bcl-2 protein expression have a poorer prognosis.Rituximab may improve the prognosis in patients with Bcl-2 gene amplification or protein expression.

Postoperative early enteral nutrition by Freka trelumina or feeding jejunostomy in old patients with gastric cancer / 中华普通外科杂志

Objective To compare the clinical efficacy of Freka trelumina (FT) vs.feeding jejunostomy (FJ) in carrying out postoperative early enteral nutrition (EEN) in old patients with gastric cancer.Method 168 old gastric cancer cases were derided into FT group (n =54) with EEN, FJ group (n =50) with gastric tube and EEN, and total parenteral nutrition (TPN) group (n =64).Results Compared with TPN group, postoperative body weight, serum albumin and prealbumin level in FT and FJ groups were significantly higher, intestinal function recovery time, days of postoperative hospitalization and costs were significantly lower.The incidence of cough, sputum and sore throat of patients in FT group were significantly higher than those in FJ and TPN groups (P ＜ 0.05).Conclusions Postoperative EEN through FT and FJ was effective to improve nutritional parameter, accelerate intestinal function recovery, reduce the number of days of postoperative hospitalization, total costs, anastomotic stomal leak and gastroparesis rate.

Bacterial drug resistance situation and clinical features of urinary tract infection in children / 国际检验医学杂志

Objective To analyze the basic clinical characteristics,auxiliary diagnostic indexes,bacterial infection spectrum and drug resistance of child urinary tract infection to provide the basis for the prevention,diagnosis and treatment of child UTI.Methods The clinical data in the inpatients with UTI or complicating UTI in our hospital from January 2012 to March 2014 were collected. The repeated strains were excluded.The differences in the pathogens between the patients with complicated UTI and the patients with non-complicated UTI were comprehensively analyzed.Results The onset peak of child UTI for the first time was 0 -0.5 years old.Escherichia coli ,Klebsiella and Pseudomonas aeruginosa are the major pathogens of child UTI,in which 110 strains were Escherichia coli,accounting for 52.9%.The enterobacteriaceae pathogens of UTI had higher sensitivity to carbapenems antibacterial drugs,with the resistance rate of less than 10%;the resistance rate of others detected antibacterial drugs was more than 20%.Con-clusion UTI in the children inpatients of this area has higher drug resistance rate,in the treatment of child UTI,the antibacterial drugs should be rationally used by combining the bacterial drug resistance situation in the local place and the disease severity in or-der to avoid the aggravation of bacterial drug resistance.

Clinico-pathological characteristics and prognosis of 40 patients with gastric neuroendocrine carcinoma / 中华普通外科杂志

Objective To analyze the clinico-pathological characteristics and prognostic factors of patients with gastric neuroendocrine carcinoma(G-NEC).Methods Clinical data of 40 cases of G-NEC form January 2003 to August 2013 at Ren Ji Hospital of Shanghai Jiaotong University were analyzed.Tumors were classified into different grades and stages according to the 2010 WHO classification and the 2006 European neuroendocrine tumor society (ENETS).Follow-up was conducted by telephone.The survival curves were drawn using Kaplan-Meier method.Univariate analysis was performed by the Log-rank test and multivariate analysis was performed by the COX proportional hazards model.Results Among the 40 G-NECs patients,29 were male(72％) and 11 were female(28％),with an median age of 61 years.Tumors located in the gastric cardia in 20 cases,in the gastric antrum in 11 cases and in the gastric body in 9 cases.Tumor ranged from 1 cm-20 cm.All patients were G-NEC (G3).Follow-up rate was 100％ (40/40).The median overall survival rate was 12 months,and one-year survival rate was 82％.Immunohistochemically G-NEC cells were positive for CgA and Syn in 11 cases.Gender (x2 =5.673,P ＜ 0.05),Ki-67 index (x2 =8.612,P ＜ 0.05),and lymphnode involvement (x2 =0.559,P ＜ 0.05) were prognostic factors of G-NEC patients.Conclusions The symptoms of G-NEC are nonspecific.Its diagnosis relies on pathological examination and immunohistochemistry.Syn and CgA are the most important markers.Female gender,lower Ki-67 index and lower lymph node metastasis predict a survival advantage.

Effects of antisense oligonucleotides targeting microRNA-17 on human leukemic K562 cells / 白血病·淋巴瘤

Objective To explore the inhibitory effect of anti-miRNA-17 oligonucleotide on leukemic K562 cells.Methods K562 cells were transfected with anti-miRNA-17 oligonucleotide,cell viability was analyzed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetra-zoliunbromide (MTT) assay.Apoptosis was detected by flow cytometry,expression of miRNA-17 in K562 cells was measured by real-time PCR.Results MTT results showed transfection of antisense nucleic acid significantly decreased cell proliferation activity,after 24,48,72 h they were respectively 0.8719±0.001,0.7102±0.002,0.5507±0.001,the difference being statistically significant (P ＜ 0.05) when compared to the random control (t =182.575,269.77,660.4) or control group (t =537.98,571.20,1230.51).FCM test results showed that after 48 h of transfecting antisense nucleic acid apoptosis rate was (20.14 ± 0.01) ％,and was statistically significant compared to the randomized control or blank control group (t =2347.6,2568.2,P ＜ 0.01).Fluorescence real-time quantitative PCR confirmed antisense nucleic acid significantly decreased the relative expression level of miR-17 in K562 cells (0.07).The difference was statistically significant compared to the random group or blank group (1,1.01) (t =148.63,147.04,P ＜ 0.05).Conclusion Targeted inhibition of miR-17 with oligonucleotide can suppress K562 cell growth and induce apoptosis.

Effect of autophagy on paclitaxel-induced CaSki cell death / 中南大学学报(医学版)

Objective To observe the effect of autophagy on paclitaxel-induced CaSki cell death through the regulation of the expression of autophagy gene Beclin1, and to explore the interaction and relationship between autophagy and apoptosis. Methods Eukaryotic expression vector pcDNA3.1-Beclin1 and RNA interference vector pSUPER-Beclin1 were transfected into human cervical cancer CaSki cells in vitro and screened for stable expression cell lines. The formation of autophagic vacuoles was observed with an electronic microscope. The expression of Beclin1 and LC3 was measured by Western blot. After being treated with paclitaxel, the change of cell proliferation was assessed by MTT assay, the percentage of apoptotic cells and autophagic cells were analyzed by flow cytometry. Results A lot of autophagic vacuoles were observed in pcDNA3.1-Beclin1 cells by electronic microscopy. Beclin1 and LC3 protein expression was up-regulated in CaSki cells transfected with pcDNA3.1-Beclin1, and was inhibited in cells transfected with pSUPER-Beclin1. MTT assay revealed the survival rate of CaSki cells was significantly decreased after being transfected with pcDNA3.1-Beclin1. After being treated with paclitaxel, the percentages of apoptotic cells and autophagic cells were both increased in pcDNA3.1-Beclin1 group compared with that of the blank control group especially the increase of apoptosis was particularly evident. Conclusion Autophagy and apoptosis have different roles in the process of paclitaxel-induced cervical cancer CaSki cell line death. Overexpression of Beclin1 in CaSki cells may enhance the apoptosis induced by paclitaxel.

Bone marrow biopsy combined bone marrow smear for diagnosis of 86 MDS / 白血病·淋巴瘤

Objective To explore the clinical significance of the union between marrow smear and marrow biopsy in the myelodysplastic syndrome(MDS) diagnosis. Methods Bone marrow aspirate and smear were initially abtained, then bone tissues encircled drill and section at the same point which is called as. easy one-step technology to 86 MDS patients were analysed. Results In 86 cases of MDS patients, there were 30 cases of hyperplasia extreme degree of reduction by 34.88 %, 56 eases of active, obvious and extremely active active (65.12 %), 43 cases for red RCMD (50.00 %), 32 cases for the granulocyte dysplasia (37.21%), 22 cases for megakaryocyte RCMD (25.58 %) in bone marrow aspiration smears; compared with 15 cases of hyperplasia extreme degree of reduction and the reduction (17.44 %), 71 eases of active, obviously active and extremely active (82.56 %); 16 cases for red RCMD (18.61%), 52 cases for the granulocyte dysplasia (60.47 %), 56 cases for megakaryocyte RCMD (65.12 %) in bone marrow biopsy sections. 66 cases in 86 cases of bone marrow biopsy and bone marrow smear of WHO classification were in line with the rate of 76.74 %.Conclusion The biopsy slide and the puncture smear synchronization observation is more advantageous than the conventional puncture smear morphology observation and combining two method may increase the accuracy in the MDS diagnosis.