ACSL5, a prognostic factor in acute myeloid leukemia, modulates the activity of Wnt/β-catenin signaling by palmitoylation modification / 医学前沿

Acyl-CoA synthetase long chain family member 5 (ACSL5), is a member of the acyl-CoA synthetases (ACSs) family that activates long chain fatty acids by catalyzing the synthesis of fatty acyl-CoAs. The dysregulation of ACSL5 has been reported in some cancers, such as glioma and colon cancers. However, little is known about the role of ACSL5 in acute myeloid leukemia (AML). We found that the expression of ACSL5 was higher in bone marrow cells from AML patients compared with that from healthy donors. ACSL5 level could serve as an independent prognostic predictor of the overall survival of AML patients. In AML cells, the ACSL5 knockdown inhibited cell growth both in vitro and in vivo. Mechanistically, the knockdown of ACSL5 suppressed the activation of the Wnt/β-catenin pathway by suppressing the palmitoylation modification of Wnt3a. Additionally, triacsin c, a pan-ACS family inhibitor, inhibited cell growth and robustly induced cell apoptosis when combined with ABT-199, the FDA approved BCL-2 inhibitor for AML therapy. Our results indicate that ACSL5 is a potential prognosis marker for AML and a promising pharmacological target for the treatment of molecularly stratified AML.

Abivertinib inhibits megakaryocyte differentiation and platelet biogenesis / 医学前沿

Abivertinib, a third-generation tyrosine kinase inhibitor, is originally designed to target epidermal growth factor receptor (EGFR)-activating mutations. Previous studies have shown that abivertinib has promising antitumor activity and a well-tolerated safety profile in patients with non-small-cell lung cancer. However, abivertinib also exhibited high inhibitory activity against Bruton's tyrosine kinase and Janus kinase 3. Given that these kinases play some roles in the progression of megakaryopoiesis, we speculate that abivertinib can affect megakaryocyte (MK) differentiation and platelet biogenesis. We treated cord blood CD34+ hematopoietic stem cells, Meg-01 cells, and C57BL/6 mice with abivertinib and observed megakaryopoiesis to determine the biological effect of abivertinib on MK differentiation and platelet biogenesis. Our in vitro results showed that abivertinib impaired the CFU-MK formation, proliferation of CD34+ HSC-derived MK progenitor cells, and differentiation and functions of MKs and inhibited Meg-01-derived MK differentiation. These results suggested that megakaryopoiesis was inhibited by abivertinib. We also demonstrated in vivo that abivertinib decreased the number of MKs in bone marrow and platelet counts in mice, which suggested that thrombopoiesis was also inhibited. Thus, these preclinical data collectively suggested that abivertinib could inhibit MK differentiation and platelet biogenesis and might be an agent for thrombocythemia.

Prognostic analysis and predictive model construction of textbook outcome after gallbladder carcinoma surgery / 中华肝胆外科杂志

Objective:To analyze independent influencing factors of surgical textbook outcome (TO) in patients with gallbladder carcinoma, and to establish a nomogram for predicting TO and evaluated the predictive ability.Methods:Patients with gallbladder carcinoma who underwent surgery in Department of Hepatobiliary and Pancreatic Surgery at Dongfang Hospital Affiliated to Shanghai Tongji University and Department of Biliary Tract Surgery Ⅰ, Third Affiliated Hospital of Naval Medical University (Shanghai Eastern Hepatobiliary Surgery Hospital) from January 2013 to December 2018 were included and the clinical features were retrospectively analyzed. A total of 232 patients were included, including 114 males and 118 females, aged (61.0±9.8) years. According to whether TO reached or not, they were divided into TO group ( n=86) and non-TO group ( n=146). Univariate and multivariate logistic regression were used to analyze the independent influencing factors of TO. The predictive nomogram model of TO was constructed. The receiver operating characteristic (ROC) curve was drawn to evaluate the predictive ability of the model, and the consistency of the predictive model was evaluated by the consistency curve graph and the Hosmer-Lemeshow test. Results:The 1-year and 3-years cumulative survival rates of patients with gallbladder carcinoma in the TO group (86.0% and 62.8%) were better than those in the non-TO group (46.6% and 27.3%), and the difference was statistically significant (χ 2=60.74, P<0.001). In multivariate analysis, higher T stage ( OR=0.16, 95% CI: 0.03-0.79, P<0.001) and cervical gallbladder cancer ( OR=0.14, 95% CI: 0.02-0.94, P=0.004) had the greatest negative association with a TO, and the higher the degree of tumor differentiation ( OR=7.08, 95% CI: 1.34-37.56, P=0.001), the easier it is to achieve TO. The ROC curve showed that the area under the curve of the predictive model was 0.84 (95% CI: 0.79-0.90), suggesting that the model had good predictive performance. A nomogram to assess the probability of TO was developed and had good accuracy in both the consistency curve and Hosmer-Lemeshow test (χ 2=5.77, P=0.673). Conclusion:Tumor T stage, tumor differentiation degree and tumor location are independent influencing factors for achieving TO in patients with gallbladder carcinoma after surgery. The nomogram model constructed according to the above conclusions could accurately predict the probability of reaching TO.

Whole disease cycle management of hilar cholangiocarcinoma / 中华肝胆外科杂志

Hilar cholangiocarcinoma is the most common malignant tumor of the biliary tract, the survival rate is poor due to the difficulty of early diagnosis and surgery. Progress have been made on hilar cholangiocarcinoma treatment during recent years, but it is still challenging to make a breakthrough. The whole disease cycle management is of great significance to improve the prognosis of patients with hilar cholangiocarcinoma. The whole disease cycle management refers to the whole-process scientific management including disease diagnosis, preoperative evaluation and preparation, surgical plan formulation and implementation, preoperative and postoperative adjuvant treatment and follow-up. This article summarized the domestic and foreign progress on the management of hilar cholangiocarcinoma in all stages of the whole disease cycle and shared the author's team's experience in the diagnosis and treatment of hilar cholangiocarcinoma.

Characteristics of immune microenvironment and progress of immune checkpoint inhibitors to cholangiocarcinoma treatment / 中华肝胆外科杂志

Cholangiocarcinoma is a highly malignant disease with low surgical resection rate. It’s resistant to chemoradiotherapy and the prognosis of cholangiocarcinoma is poor. Although immune checkpoint inhibitors (ICIs) have achieved great success in tumor therapy in recent years, patients with cholangiocarcinoma have a poor response to immunotherapy, because of the complexity and diversity of immune microenvironment. Therefore, understanding the composition and characteristics of the immune microenvironment of cholangiocarcinoma, regulating targets in immune microenvironment, and adopting ICIs combined therapy, is important for immunotherapy for cholangiocarcinoma.

Progress of immunotherapy of cholangiocarcinoma / 中华肝胆外科杂志

Cholangiocarcinoma (CCA) is a group of solid tumors with high malignant degree and poor prognosis. Surgical resection has still been the main therapy options. Targeting therapy and immunotherapy are the main anti-tumor methods that have been paid more and more attention in recent years, especially immunotherapy. The tumor microenvironment of CCA is complex, which encompasses not only interstitial and endothelial cells, but also a large number of immune cells. In addition, the innate and adaptive immune systems also play a role. This article summarizes the immune-related studies of cholangiocarcinoma and the latest clinical trials of immunotherapy.

Controversies and Considerations on Surgical Treatment of Gallbladder Cancer / 肿瘤防治研究

Gallbladder cancer is a high malignancy which is predisposed to invade adjacent organs and have lymph node metastasis. Gallbladder cancer is not sensitive to radiotherapy or chemotherapy with the worst prognosis among biliary tract cancers. At present, radical resection is the only possible method to cure gallbladder cancer. However, there are still many controversies about the surgical strategies, the extent of liver resection and lymph node dissection, and the treatment of incidental gallbladder cancer. In addition, under the background of the great success of immunotherapy and targeted therapy in a variety of solid tumors, it is also a question worthy of further considerations that whether the status of surgery in the treatment of advanced gallbladder cancer will be changed in the near future.

Clinical characteristics and prognostic values of 1p32.3 deletion detected through fluorescence in situ hybridization in patients with newly diagnosed multiple myeloma: a single-center study in China / 医学前沿

This study aimed to investigate the prevalence, clinical characteristics, and prognostic impact of 1p32.3 deletion in patients with newly diagnosed multiple myeloma (MM). A retrospective analysis was conducted on 411 patients with newly diagnosed MM; among which, 270 received bortezomib-based therapies, and 141 received thalidomide-based therapies. Fluorescence in situ hybridization (FISH) was performed to detect six cytogenetic abnormalities, namely, del(1p32.3), gain(1q21), del(17p13), del(13q14), t(4;14), and t(11;14). Results showed that 8.3% of patients with MM were detected with del(1p32.3) and had significantly more bone marrow plasma cells (P = 0.025), higher β2-microglobulin levels (P = 0.036), and higher lactate dehydrogenase levels (P = 0.042) than those without del(1p32.3). Univariate analysis showed that patients with del(1p32.3) under thalidomide-based therapies (median PFS 11.6 vs. 31.2 months, P = 0.002; median OS 16.8 vs. 45.9 months, P < 0.001) were strongly associated with short progression-free survival (PFS) (P = 0.002) and overall survival (OS) (P < 0.001). Multivariate analysis revealed that del(1p32.3) remained a powerful independent factor with worse PFS (P = 0.006) and OS (P = 0.016) for patients under thalidomide-based treatments. Patients with del(1p32.3) under bortezomib-based treatments tended to have short PFS and OS. In conclusion, del(1p32.3) is associated with short PFS and OS in patients with MM who received thalidomide- or bortezomib-based treatments.

Research and development of primary bilateral lipedema / 中华整形外科杂志

Lipedema is secondary to local fat deposition, a disease characterized by the symmetric thickening of lower limbs, mostly occurs in women, especially in adolescence and pregnancy. In its early stage, it could be easily confused with lymphedema. Extensive literature review on primary fat edema in recent years, as well as a summary of the clinical symptoms and signs and diagnosis and treatment of lipedema were conducted, so as to provide a useful reference for clinicians.

Expression and significance of L-FABP in hilar cholangiocarcinoma / 中华消化外科杂志

Objective To explore the expression of liver fatty acid binding protein (L-FABP) in tissues of hilar cholangiocarcinoma and the relationship between expression of L-FABP and clinicopathological factors and prognosis of the patients.Methods The retrospective case-control study was conducted.The clinicopathological data of 132 patients with hilar cholangiocarcinoma who were admitted to the Navy General Hospital between January 2003 and January 2013 were collected.The expression of L-FABP in tumor tissues and adjacent tissues of hilar cholangiocarcinoma and normal bile duct tissues were respectively detected by immunohistochemistry.Observation indicators:(1) expression of L-FABP by immunohistochemistry;(2) relationship between clinicopathological factors of patients and expression of L-FABP in tumor tissues;(3) follow-up and survival situations;(4) prognostic analysis of patients after radical resection of hilar cholangiocarcinoma.Follow-up using outpatient examination and telephone interview was performed to detect postoperative overall survival time up to June 2017.Count data were described as percentage and compared using the chi-square test.The survival time was calculated by the Kaplan-Meier method.Measurement data with skewed distribution were described as M (range).The univariate analysis and multivariate analysis were respectively done using the nonparametric test and COX regression model.Results (1) Expression of L-FABP by immunohistochemistry:the positive expressions of L-FABP were located in the cytoplasm.The low,moderate and high expression rates of L-FABP in tumor tissues were respectively 11.36％ (15/132),71.97％ (95/132) and 16.67％ (22/132),and positive-staining cells showed platy and / or diffuse distribution;the low,moderate and high expression rates of L-FABP in adjacent tissues of hilar cholangiocarcinoma were respectively 77.27％ (102/132),7.58％ (10/132) and 15.15％ (20/132),and positive-staining cells showed scattered or platy distribution,with a weaker staining intensity compared with tumor tissues;there was no positive expression in normal bile duct tissues.There was a statistically significant difference in expressions of L-FABP among tumor tissues and adjacent tissues of hilar cholangiocarcinoma and normal bile duct tissues (x2=5.423,P ＜ 0.05).(2) Relationship between clinicopathological factors of patients and expression of L-FABP in tumor tissues:cases with low,moderate and high expressions of L-FABP in tumor tissues were respectively 10,30,5 in 45 patients with tumor diameter ＜ 3 cm and 4,29,9 in 42 patients with 3 cm ≤ tumor diameter ≤ 5 cm and 1,36,8 in 45 patients with tumor diameter ＞ 5 cm,with a statistically significant difference (x2 =10.171,P＜ 0.05).(3) Follow-up and survival situations:132 patients were followed up for 5-90 months,with a median time of 33 months.During the followup,postoperative overall median survival time of 132 patients was 31 months.(4) Prognostic analysis of patients after radical resection of hilar cholangiocarcinoma:results of univariate analysis showed that tumor differentiation,lymph node metastasis and expressions of L-FABP in tumor tissues were related factors affecting prognosis of patients after radical resection of hilar cholangiocarcinoma (Z =1.845,3.156,1.243,P＜0.05).Results of multivariate analysis showed that tumor differentiation,lymph node metastasis and expressions of L-FABP in tumor tissues were independent factors affecting prognosis of patients after radical resection of hilar cholangiocarcinoma (odds ratio =0.431,1.806,3.692,95％ confidence interval:0.292-0.693,0.974-2.973,1.875-11.364,P＜0.05).Conclusions The high expression of L-FABP in tumor tissues is significantly correlated with the tumor diameter.Tumor differentiation,lymph node metastasis and expressions of L-FABP in tumor tissues are independent factors affecting prognosis of patients after radical resection of hilar cholangiocarcinoma.

Prognostic significance of proteins expression by immunohistochemical method in diffuse large B cell lymphoma / 中华血液学杂志

Objective@#To analyze the prognostic significance of TP53, Bcl-2, Bcl-6, Myc proteins expression by immunohistochemical method (IHC) in diffuse large B cell Lymphoma (DLBCL) .@*Methods@#Clinical and pathologic data of 223 patients with DLBCL hospitalized in Zhejiang First Hospital from March 2009 to June 2015 were retrospectively analyzed.@*Results@#The 223 cases, a median age of 56 years old with a male predominance, had shown a 39.0% of TP53 positive expression, 38.6% of Myc, 69.1% of Bcl-2, 56.5% of Bcl-6, and 22.7% of Myc/Bcl-2 double expression. According to Hans’ classification, 27.4% were GCB and 72.6% were non-GCB. With a median follow-up of 38 (2-97) months, the 3 and 5 years survival rates were 70% and 66% , respectively. By multivariate analysis, TP53 over-expression and Myc/Bcl-2 double expression were independently associated with poor outcomes. 3-year and 5-year overall survival were 59% and 57% for patients with TP53 positive, 77% and 71% for patients with TP53 negative expression. Patients with non-GCB subtype receiving chemotherapy combined with rituximab had a higher OS than those without rituximab. But rituximab did not improve the prognosis of patients with TP53 positive.@*Conclusion@#Myc/Bcl-2 double expression and TP53 over-expression are poor prognosis for DLBCL patients. Patients with Myc/Bcl-2 double expression have shorter OS. Patients with non-GCB subtype who received chemotherapy combined with rituximab have a better OS than those without rituximab. But rituximab does not improve the prognosis of patients with TP53 positive.

Effect of decitabine on serum platelet derived growth factor levels in patients with leukemia / 中国生化药物杂志

Objective To investigate the effect of decitabine on serum platelet derived growth factor levels in patients with leukemia. Methods 120 cases of acute myeloid leukemia patients admitted to our hospital from January 2012 to December 2014 were selected as the study subjects.The control group was given CAG regimen: 1-14 d Seventh days of intravenous infusion of 20 mg/d aclarubicin, first to fourteen days subcutaneous injection of 10 mg/m2 , 1 times per 12 h, 1-13 d cytosine arabinosine days under the subcutaneous injection of granulocyte colony stimulating factor 300μg/d.The observation group was given to the west of the lake 25 mg/d, intravenous infusion, used for 5 days.The levels of platelet derived growth factor PDGF in the two groups were compared and the therapeutic effect.Results Before treatment, differences of PDGF in control group and observation group was no statistical significance.After treatment, PDGF in observation group was lower than control group ( P <0.05).The proportion of primary cells of bone marrow of two groups after treatment was lower than before treatment, and the observation group was more lower.Total effective rate of observation group was 55.0%,which was higher than that in control group(35.0%)(P<0.05).Conclusion Decitabine could reduce the level of of PDGF in patients with leukemia, and improve the total effective rate.

Analysis of the karyotype abnormalities and its prognostic in 298 patients with myelodysplastic syndrome / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the relationship between cytogenetic markers with World Health Organization (WHO) classification, disease progress and prognosis in cases with primary myelodysplastic syndromes (MDS).</p><p><b>METHODS</b>298 patients with de novo MDS from the first affiliated hospital of medical school, Zhejiang University were enrolled in the retrospective analysis of WHO classification, karyotype, and prognosis. Follow-up study was also conducted.</p><p><b>RESULTS</b>The WHO classifications at first diagnosis were as follows: refractory cytopenia with unilineage dysplasia (RCUD), 18 cases; refractory anemia with ring sideroblasts (RARS), 8 cases; refractory cytopenia with multiline dysplasia (RCMD), 104 cases; refractory anemia with excess blasts-1, 76 cases; refractory anemia with excess blasts-2, 85 cases; MDS unclassified (MDS-U), 5 cases involved; and single del (5q), 2 cases. 39.6% of MDS patients carried karyotypic abnormalities. Among them, the frequency of numerical abnormalities, structural abnormalities and the existence of composite abnormalities were 45, 31, and 42, respectively. The composite abnormalities were unbalanced translocations and complex chromosomal abnormalities. The incidence of both karyotypic abnormalities and complex chromosomal abnormalities in RAEB group was higher than that in non-RAEB group (P<0. 05). An analysis based on IPSS-R Scoring System showed that advanced risk stratification (except the low-risk group) gradually enhanced the incidence of karyotypic abnormalities (P<0.05). In addition, the probability of evolution to leukemia increased with the higher IPSS-R score (P<0.05). In RAEB group, the cases with +8 chromosome, accounting for 19.5% of karyotypic abnormalities, had worse prognosis than those with normal chromosomes.</p><p><b>CONCLUSION</b>Karyotype was identified with an independent risk factor in MDS patients. Therefore, the information on cytogenetic analysis was critical for diagnosis, prognosis and individual treatment. MDS patients presenting+8 chromosome, an intermediate risk factor, were associated with a poorer outcome compared to cases with normal chromosomes in RAEB group.</p>

Progress in the study of clinical characteristics and pathogenesis of IDH1/2 gene mutations in acute myeloid leukemia patients / 白血病·淋巴瘤

Acute myeloid leukemia is a group of malignant tumor characterized by chromosome abnormality and/or gene mutations.Its pathogenesis is very complex.Gene mutations in IDH1/2 which encode metabolic enzyme were found by sequencing recently.This discovery aroused interest in the domestic and foreign research group.A series of clinical and basic research was also conducted.This review is based on these studies.

Construction of adenovirus carrying dual-target shRNA for Oct-4 and Survivin and its inhibitory effect on human hepatocellular carcinoma cells / 生物工程学报

The transcriptional factor Oct-4 and Survivin are the key regulatory factors in cancer cell proliferation and mitosis. A dual cancer-specific shRNA adenovirus vector, Ad5-Dual-shRNA, targeting Oct-4 and Survivin genes was constructed by molecular cloning and recombination. After cells were infected with virus, hepatocellular carcinoma cell line EHBH-H1 was used for detecting the expression of Oct-4 and Survivin proteins by Western blotting. The viral cytotoxic effect on cancer cells was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) reduction assay in vitro, and the inhibition effect on tumor xenografts was observed in nude mice. The results showed that the expression of Oct-4 and Survivin in cancer cell line EHBH-H1 could be silenced markedly by Ad5-Dual-shRNA. In MTT and animal experiments, Ad5-Dual-shRNA also represented much stronger anti-tumor effect on tumor growth than Ad5-Surv-shRNA and Ad5-Oct4-shRNA. From this research we can draw a conclusion that the cancer-specific adenovirus vector expressing dual-shRNA targeting Oct-4 and Survivin genes may provide us a more effective, specific and convenient gene therapy method.

Obesity,Hypertension and Aging are Three Most Important Components of Metabolic Syndrome / 中华高血压杂志

Objective To explore the most important risk factors in metabolic syndrome(MS) components.Methods Ninety-four individuals were classified into MS and non-MS group according to the diagnostic criteria for MS proposed by Chinese Diabetes Society(CDS) revised in 2006 or International Diabetes Federal(IDF) in 2005.Age,waist circumference(WC),body mass index(BMI),fasting plasma glucose,lipid profile,blood pressure and blood cell counts in two groups were compared.Partial least squares discriminant analysis(PLSDA) was carried out to determine the most important components of MS.Results Patients with MS diagnosed by CDS or IDF criteria have significantly older age,higher BMI,WC,blood pressure,fasting plasma glucose,triglycerides,insulin levels,insulin resistance index,high sensitivity CRP and fibrinogen levels compared with non-MS group.PLSDA analysis shows WC,BMI,blood pressure and aging are most important components of MS.Conclusion Obesity,hypertension and aging are three most important components of MS with obesity is the utmost among them.

Waist Circumference is The Most Important Components of Metabolic Syndrome / 中华高血压杂志

Objective Among the various components of metabolic syndrome(MS),this investigation attempt to find the most important one.Furthermore,to verify the feasibility of using waist circumference(WC)for assessing the diagnostic criteria for MS proposed by the CDS in 2004.Methods Among 163 cases recruited,80 patients met the criteria of MS and 83 cases were diagnosed as non-metabolic syndrome group(non-MS).Age,WC,body mass index(BMI),fasting plasma glucose,lipid profile,blood pressure were compared between patients of MS and non-MS.Logistic regression analysis and area under curve(AUC)of receiver-operating characteristic(ROC)were used to study the predictive value of WC.Results Patients with CDS-defined MS showed a significantly higher age,WC,SBP,DBP,fasting plasma glucose,triglycerides(TG),1/HDL-C when compared with non-MS group.After adjusting for age,the family history of diabetes and hypertension,smoke,multiple logistic regression analysis revealed WC was the most important predictive factor for MS group.ROC analysis showed that the AUC of WC was 0.92 in the males,the cut-off value is 89.5 cm,the sensitivity was 0.84,the specificity was 0.93;the AUC of WC was 0.93 in the females,the sensitivity was 0.97,the specificity was 0.81 when cut-off value is 80.8 cm.This investigation has shown that smoking was also a component of MS.The relative risk of MS in current smokers and sustained smoker was higher than that of abstinence(6.88 vs 1.00 and 3.96 vs 1.00).Conclusion Central obesity is the riskest indicator for the diagnostic criteria for MS proposed by the CDS,WC is verified to be the accuracy and satisfactory predictive indicators for MS.Smoking may be a novel component of MS.