Objective To investigate the relationship of compression area, time and weight as risky factors with local injury and systemic pathophysiological responses in rats so as to establish repeatable experimental model of crush syndrome. Methods A total of 144 male SD rats were divided into two groups, ie, mortality investigation group and biochemical indicator investigation group. Every group included the same 18 subgroups based on 18 kinds of combination with different levels of compression area (the right or both hind limbs), time (4, 6, 8 hours) and weight (2, 3, 4 kg). The circumference of the compressed hind limbs of all rats were measured and serum potassium (K+), serum creatine phosphokinase (CK), creatinine and carbamide were measured too before compression and three hours after decompression. Incidence of myoglobinuria of all rats was recorded. Muscles and kidneys were evaluated morphologically. Results The compressed hind limbs of all rats swelled significantly after three hours of reperfusion (P ＜ 0. 05). All serum K + , CK, CR and BUN were increased significantly with the increase and prolongation of the compression area, time and weight (P ＜ 0.05). Signs of direct cellular damage and ischemia-reperfusion injury were found in histology specimens of local compressed muscle.Hyperemia of glomeruli and renal tubule was found in the kidneys. Renal tubular necrosis and renal tubular cast were observed in group with compression weight ≥3 kg and compression duration ≥6 hours.Conclusions Increase and prolongation of the compression area, time and weight can aggravate the severity of crush injury. Compression area is more risky factor of severe crush injury. Both hind limbs ascompression area, compression weight ≥ 3 kg and compression duration ≥ 6 hours can be the effective experimental conditions for establishment of crush syndrome model in rats.

Objective To investigate the relationship of STAT3 signal transduction pathway with proliferation,apoptosis and COX-2 expression of human esophageal carcinoma Eca-109 cell lines.Methods Eca-109 cells were treated with selective JAK2 inhibitor,AG490.MTT assay was used to detect the proliferation of Eca-109 cells,apoptosis was detected by flow cytometry,agarose gel electrophoresis of DNA and transmission electron micrograph(TEM).The expression of JAK2、p-JAK2、p-Stat3 and COX-2 was examined by Western blot.RT-PCR was performed to detect the levels of COX-2 mRNA expression.Results AG490 significantly inhibited the growth of human Eca-109 cells in a dose and time-dependent manner and induced apoptosis.AG490 inhibited the expressions of JAK2/STAT3 signal transduction pathway protein and down-regulated the expressions of p-JAK2 and p-Stat3(P

Objective To study the association of serum L-kynurenine changes with nutritional status and vascular stiffness in maintenance hemodialysis (MHD) patients. Methods Twenty gender- and age-matched healthy volunteers (healthy group) and 40 MHD patients,including 20 cases with α-keto aicd(α-keto acid group)and 20 cases without α-keto aicd(non-α-keto acid group)were enrolled in the study.Serum L-kynurenine was measured by high performance liquid chromatography.C-reactive protein (CRP)and interleukin 6 (IL-6)were detected.Subjective global assessment(SGA)and malnutrition inflammation score(MIS)were applied to evaluate the nutritional status.Pulse wave velocity(PWV)was used to evaluate arterial stiffness for both groups of MHD patients. Results Serum L-kynurenine was significantly higher in MHD patients than that in healthy subjects[(3.20±1.12)μmol/L vs (1.74±0.27)μmol/L,P<0.01],while such difference was not found between α-keto aicd group and non-α-keto-aicd group [(3.20±0.88)μmol/L vs (3.29±1.34)μmol/L,P>0.05].IL-6 was significantly higher in MHD patients as compared to healthy subjects[(6.45±3.78)ng/L vs(1.38±1.59)ng/L,P<0.01],while such difference was found between α-keto aicd group and non-α-keto aicd group[(3.37±0.82)ng/L vs (9.62±2.48)ng/L,P<0.051.There was no difference of CRP concentration between two MHD groups.As compared to non-α-keto acid group,higher SGA score(26.00±1.75 vs 22.67±2.61,P=0.001),lower MIS score(5.82±2.27 vs 10.00±2.62,P=0.002),lower left side PWV[(21.11±8.21)m/s vs(24.57±5.45)m/s,P=0.244]and lower right side PWV[(19.27±3.22)m/s vs (24.19±5.41)m/s,P=0.015]were observed in α-keto aicd group.Pearson analysis showed positive correlation between serum L-kynurenine and IL-6(r=0.352,P=0.011)and negative correlation between L-kynurenine and pre-dialysis Scr(r=-0.412,P=0.019). Conclusions Inflammation is common in MHD patients.Tryptophan degeneration product L-kynurenine may indicate inflammation status.α-keto acid improves nutritional status,anemia and arterial stiffness maybe through the alleviation of inflammation in MHD patients.

Objective:To verify the predictive value of the Second Revision of the International Staging System (R2-ISS) in newly diagnosed patients with multiple myeloma (MM) who underwent first-line autologous hematopoietic stem cell transplantation (ASCT) in a new drug era in China.Methods:This multicenter retrospective cohort study enrolled patients with newly diagnosed MM from three centers in China (Beijing Chao-Yang Hospital, Capital Medical University; the First Affiliated Hospital, Sun Yat-Sen University, and the Second Affiliated Hospital of Naval Medical University) from June 2008 to June 2018. A total of 401 newly diagnosed patients with MM who were candidates for ASCT were enrolled in this cohort, all received proteasome inhibitor and/or immunomodulator-based induction chemotherapy followed by ASCT. Baseline and follow-up data were collected. The patients were regrouped using R2-ISS. Progression-free survival (PFS) and overall survival (OS) were analyzed. The Kaplan-Meier method was used to analyze the survival curve and two survival curves were compared using the log-rank test. Cox regression analysis were performed to analyze the relationship between risk factors and survival.Results:The median age of the patients was 53 years (range 25-69 years) and 59.5% (240 cases) were men. Newly diagnosed patients with renal impairment accounted for 11.5% (46 cases). According to Revised-International Staging System (R-ISS), 74 patients (18.5 %) were diagnosed with stage Ⅰ, 259 patients (64.6%) with stage Ⅱ, and 68 patients (17.0%) with stage Ⅲ. According to the R2-ISS, the distribution of patients in each group was as follows: 50 patients (12.5%) in stage Ⅰ, 95 patients (23.7%) in stage Ⅱ, 206 patients (51.4%) in stage Ⅲ, and 50 patients (12.5%) in stage Ⅳ. The median follow-up time was 35.9 months (range, 6-119 months). According to the R2-ISS stage, the median PFS in each group was: 75.3 months for stage Ⅰ; 62.0 months for stage Ⅱ, 39.2 months for stage Ⅲ, and 30.3 months for stage Ⅳ; and the median OS was not reached, 86.6 months, 71.6 months, and 38.5 months, respectively. There were statistically significant differences in PFS and OS between different groups (both P<0.001). Multivariate Cox regression analysis showed that stages Ⅲ and Ⅳ of the R2-ISS were independent prognostic factors for PFS ( HR=2.37, 95% CI 1.30-4.30; HR=4.50, 95% CI 2.35-9.01) and OS ( HR=4.20, 95% CI 1.50-11.80; HR=9.53, 95% CI 3.21-28.29). Conclusions:The R2-ISS has significant predictive value for PFS and OS for transplant-eligible patients with MM in the new drug era. However, the universality of the R2-ISS still needs to be further verified in different populations.

Objective To analyze the rebleeding rate in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) after endoscopic treatment of esophagogastric variceal bleeding and then assessed the risk factors of the rebleeding in the patients. Methods This study retrospectively recruited 169 hepatitis B-associated HCC patients complicated with PVTT and esophagogastric variceal bleeding treated by endoscopy in Department of Gastroenterology, Beijing Ditan Hospital from September 2008 to December 2016. Among them, 47 patients had PVTT Ⅱ, 67 patients had PVTT Ⅲ, and 55 patients had PVTT Ⅳ. Their clinicopathological and follow-up data were retrieved from the medical records and statistically analyzed. Continuous data were compared among groups using ANOVA or Kruskal-Wallis H test. Categorial data were compared among groups using Chi-square test or corrected Fisher test. The Kaplan-Meier curves and Log-rank test were performed to analyze the rebleeding rate and cumulative survival rates after treatment. The univariate multivariate Cox regression analyses were used to identify the risk factors affecting the rebleeding of patients. Results Compared with PVTT Ⅱ and Ⅲ, PVTT Ⅳ patients had a higher serum level of the direct bilirubin ( Z =6.153, P =0.046). The endoscopy treatment successfully blocked esophagogastric variceal bleeding in all patients. There was no significant difference in the rebleeding rates within six months and a year after the treatment (all P > 0.05). It was also no statistically significant difference in cumulative survival rates in six months and l-, 2-, and 3-year after the treatment in PVTT Ⅱ, Ⅲ, and Ⅳ patients (all P > 0.05). Cox multivariate regression analysis showed that hepatic encephalopathy ( HR =3.643, 95% CI : 2.099-6.325, P < 0.001), γ-glutamyltransferase ( HR =1.002, 95% CI : 1.000-1.005, P =0.029), AFP ( HR =1.000, 95% CI : 1.000-1.000, P =0.002) and numbers of tumor lesions ( HR =1.647, 95% CI : 1.011-2.684, P =0.045) were all independent risk factors for 1-year rebleeding in these PVTT patients with esophagogastric variceal bleeding after endoscopic treatment. Conclusion Endoscopic hemostasis is a feasible treatment option for HCC patients with PVTT and esophagogastric variceal bleeding. However, there was no significant difference in the rebleeding and cumulative survival rates in these patients. Furthermore, hepatic encephalopathy, γ-glutamyltransferase, AFP and numbers of tumor lesions were all independent risk factors for 1-year rebleeding in these patients.

Metformin is currently a strong candidate anti-tumor agent in multiple cancers. However, its anti-tumor effectiveness varies among different cancers or subpopulations, potentially due to tumor heterogeneity. It thus remains unclear which hepatocellular carcinoma (HCC) patient subpopulation(s) can benefit from metformin treatment. Here, through a genome-wide CRISPR-Cas9-based knockout screen, we find that DOCK1 levels determine the anti-tumor effects of metformin and that DOCK1 is a synthetic lethal target of metformin in HCC. Mechanistically, metformin promotes DOCK1 phosphorylation, which activates RAC1 to facilitate cell survival, leading to metformin resistance. The DOCK1-selective inhibitor, TBOPP, potentiates anti-tumor activity by metformin in vitro in liver cancer cell lines and patient-derived HCC organoids, and in vivo in xenografted liver cancer cells and immunocompetent mouse liver cancer models. Notably, metformin improves overall survival of HCC patients with low DOCK1 levels but not among patients with high DOCK1 expression. This study shows that metformin effectiveness depends on DOCK1 levels and that combining metformin with DOCK1 inhibition may provide a promising personalized therapeutic strategy for metformin-resistant HCC patients.
Animals ; Antineoplastic Agents/therapeutic use* ; Carcinoma, Hepatocellular/metabolism* ; Cell Line, Tumor ; Clustered Regularly Interspaced Short Palindromic Repeats ; Genome ; Humans ; Liver Neoplasms/metabolism* ; Metformin/therapeutic use* ; Mice ; Phosphorylation ; Synthetic Lethal Mutations ; Transcription Factors/metabolism* ; rac GTP-Binding Proteins/metabolism*