Disruption of the ERLIN-TM6SF2-APOB complex destabilizes APOB and contributes to non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by excess lipid accumulation in the liver without significant consumption of alcohol. The transmembrane 6 superfamily member 2 (TM6SF2) E167K missense variant strongly associates with NAFLD in humans. The E167K mutation destabilizes TM6SF2, resulting in hepatic lipid accumulation and low serum lipid levels. However, the molecular mechanism by which TM6SF2 regulates lipid metabolism remains unclear. By using tandem affinity purification in combination with mass spectrometry, we found that apolipoprotein B (APOB), ER lipid raft protein (ERLIN) 1 and 2 were TM6SF2-interacting proteins. ERLINs and TM6SF2 mutually bound and stabilized each other. TM6SF2 bound and stabilized APOB via two luminal loops. ERLINs did not interact with APOB directly but still increased APOB stability through stabilizing TM6SF2. This APOB stabilization was hampered by the E167K mutation that reduced the protein expression of TM6SF2. In mice, knockout of Tm6sf2 and knockdown of Tm6sf2 or Erlins decreased hepatic APOB protein level, causing lipid accumulation in the liver and lowering lipid levels in the serum. We conclude that defective APOB stabilization, as a result of ERLINs or TM6SF2 deficiency or E167K mutation, is a key factor contributing to NAFLD.

First line nucleos(t)ide analog monotherapy is more cost-effective than combination strategies in hepatitis B e antigen-positive chronic hepatitis B patients in China / 中华医学杂志(英文版)

BACKGROUND@#Nucleos(t)ide analog (NA) in combination with peginterferon (PegIFN) therapy in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) shows better effectiveness than NA monotherapy in hepatitis B surface antigen loss, termed "functional cure," based on previous published studies. However, it is not known which strategy is more cost-effective on functional cure. The aim of this study was to analyze the cost-effectiveness of first-line monotherapies and combination strategies in HBeAg-positive CHB patients in China from a social perspective.@*METHODS@#A Markov model was developed with functional cure and other five states including CHB, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, and death to assess the cost-effectiveness of seven representative treatment strategies. Entecavir (ETV) monotherapy and tenofovir disoproxil fumarate (TDF) monotherapy served as comparators, respectively.@*RESULTS@#In the two base-case analysis, compared with ETV, ETV generated the highest costs with $44,210 and the highest quality-adjusted life-years (QALYs) with 16.78 years. Compared with TDF, treating CHB patients with ETV and NA - PegIFN strategies increased costs by $7639 and $6129, respectively, gaining incremental QALYs by 2.20 years and 1.66 years, respectively. The incremental cost-effectiveness ratios were $3472/QALY and $3692/QALY, respectively, which were less than one-time gross domestic product per capita. One-way sensitivity analysis and probabilistic sensitivity analyses showed the robustness of the results.@*CONCLUSION@#Among seven treatment strategies, first-line NA monotherapy may be more cost-effective than combination strategies in HBeAg-positive CHB patients in China.

First line nucleos(t)ide analog monotherapy is more cost-effective than combination strategies in hepatitis B e antigen-positive chronic hepatitis B patients in China / 中华医学杂志(英文版)

Background@#Nucleos(t)ide analog (NA) in combination with peginterferon (PegIFN) therapy in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) shows better effectiveness than NA monotherapy in hepatitis B surface antigen loss, termed "functional cure," based on previous published studies. However, it is not known which strategy is more cost-effective on functional cure. The aim of this study was to analyze the cost-effectiveness of first-line monotherapies and combination strategies in HBeAg-positive CHB patients in China from a social perspective.@*Methods@#A Markov model was developed with functional cure and other five states including CHB, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, and death to assess the cost-effectiveness of seven representative treatment strategies. Entecavir (ETV) monotherapy and tenofovir disoproxil fumarate (TDF) monotherapy served as comparators, respectively.@*Results@#In the two base-case analysis, compared with ETV, ETV generated the highest costs with $44,210 and the highest quality-adjusted life-years (QALYs) with 16.78 years. Compared with TDF, treating CHB patients with ETV and NA - PegIFN strategies increased costs by $7639 and $6129, respectively, gaining incremental QALYs by 2.20 years and 1.66 years, respectively. The incremental cost-effectiveness ratios were $3472/QALY and $3692/QALY, respectively, which were less than one-time gross domestic product per capita. One-way sensitivity analysis and probabilistic sensitivity analyses showed the robustness of the results.@*Conclusion@#Among seven treatment strategies, first-line NA monotherapy may be more cost-effective than combination strategies in HBeAg-positive CHB patients in China.

Retrospective analysis on the efficacy of sunitinib/sorafenib in combination with dendritic cells-cytokine-induced killer in metastasis renal cell carcinoma after radical nephrectomy.

OBJECTIVE: Sunitinib/sorafenib (SU/SO), dendritic cells (DCs), or DC-cytokine-induced killer (CIK) could significantly prolong progression-free survival (PFS), 3-year overall survival (OS), or 5-year OS for patients with metastatic renal cell carcinoma (mRCC). We retrospectively analyzed the clinical efficacy between SU/SO combined with DC-CIK and SU/SO monotherapy in treating renal cell carcinoma (RCC) patients with metastasis after radical nephrectomy. MATERIALS AND METHODS: All patients (n = 34) with postoperative mRCC in our hospital from January 2009 to January 2014 were received either SU/SO monotherapy (Group 1, n = 15) or in combination with DC-CIK (Group 2, n = 19). A retrospective study was based on the primary endpoint (PFS) and secondary endpoint (OS). RESULTS: At a median follow-up of 19.5 months, in Group 2, as compared with in Group 1, the median PFS was significantly longer (28.0 vs. 11.0 months, P = 0.03). Moreover, the 3-year OS was higher (57.1% vs. 28.6%). The cases of progressive diseases (PDs) and deaths were less in Group 2 than that in Group 1 (PD: 8 vs. 9, deaths: 3 vs. 5); however, the cases of stable diseases were more (11 vs. 6). In addition, the 3-year OS was higher in SU + DC-CIK group than that in SO + DC-CIK group (63.36% vs. 50%). There was no significant difference for PFS between SO + DC-CIK group and SU single agent group. CONCLUSIONS: SU/SO with DC-CIK could significantly prolong the median PFS, improve the 3-year OS rate, prolong the 3-year OS. It is likely to be a new approach for mRCC after radical nephrectomy.

Recombinant canine adenovirus type 2 expressing rabbit hemorrhagic disease virus VP60 protein provided protection against RHD in rabbits.

Rabbit hemorrhagic disease virus (RHDV) is responsible for rabbit hemorrhagic disease (RHD), which is an acute, lethal and highly contagious disease in both wild and domestic rabbits. Although current vaccines are highly effective for controlling RHD, they are derived from infected rabbit livers and their use is thus associated with safety and animal-welfare concerns. In this study, we generated a recombinant lentogenic canine adenovirus type 2 (CAV2) vector expressing the RHDV vp60 gene, named rCAV2-VP60. rCAV2-VP60 expressed VP60 protein in Madin-Darby canine kidney cells as demonstrated by western blot and immunofluorescence assay. Polymerase chain reaction confirmed that the vp60 gene was successfully inserted into rCAV2-VP60 and was still detectable after 20 passages, indicating its stable genetic character. We evaluated the feasibility of rCAV2-VP60 as a live-virus-vectored RHD vaccine in rabbits. rCAV2-VP60 significantly induced specific antibodies to RHDV and provided effective protection against RHDV lethal challenge. These results suggest that rCAV2 expressing RHDV VP60 could be a safe and efficient candidate vaccine against RHDV in rabbits.

Fundamental contradiction and coordination mechanism of health economic evaluation between social perspective and hospital perspective / 中国卫生政策研究

This study analyzed the inconsistences between health economic evaluation of social perspective and hospital perspective,and based on the relevant theories of health economic evaluation demonstrated that for health technology,especially innovative ones, there was contradiction between study results of the social perspective and hospitals,leading to pricing decision-making problems. This article believes that involving multiple stakeholders in hospital decision making process and non-bundled pricing method for innovative health technology could be optional mechanisms for resolving this contradiction.

[Relationship between NK Cell Reconstitution and aGVHD after Allo-HSCT].

OBJECTIVE: To investigate the relationship between NK cell count/activity and acute graft-versus-host disease (aGVHD) in patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: A total of 26 patients who had undergone allo-HSCT from January to July 2015 were enrolled in this study. The NK cell count/activity in the peripheral blood of recipients on day 30 after allo-HSCT were monitored by using 4-color flow cytometry. The incidence of aGVHD in patients was evaluated by clinical manifestation combinating with related pathologic indicators, and the relationship between NK cell count/activity and aGVHD were analyzed. RESULTS: In the aGVHD group and the no-aGVHD group, the NK cell count and activity on days 30 after allo-HSCT were 655±216 cells/µl vs 1169±372 cells/µl(P=0.002) and 7.3±3.6% vs 9.0±3.6% (P=0.008). In the II-IV grade aGVHD group and the 0-I grade aGVHD group, the NK cell count/activity were 617±220 cells/µl vs 1081±399 cells/µl (P=0.001) and 4.2±1.7% vs 8.3±3.5%(P=0.001). As compared with the 0-I grade aGVHD group, patients in the II-IV grade aGVHD group had higher relapse rate (57% vs 5%)(P=0.010) , lower 1-year progression-free survival(PFS) rate (43% vs 84%)(P=0.010). CONCLUSION: NK cell count/activity on day 30 after allo-HSCT were closely relates with aGVHD, which may be a potential marker for aGVHD and can provide a new target for aGVHD therapy.

Acquired amegakaryocytic thrombocytopenic purpura induced by percutaneous ethanol injection during treatment of hepatocellular carcinoma: A case report.

Percutaneous ethanol injection is an important localized treatment method for patients presenting with hepatocellular carcinoma (HCC). Among the advantages of percutaneous ethanol injection are its minimal invasiveness, simplicity, low cost and low risk of complications. However, the increasing popularity of percutaneous ethanol injection has resulted in serious adverse effects attributed to individual variations. The present study describes the case of a patient who exhibited acquired amegakaryocytic thrombocytopenic purpura, caused by percutaneous ethanol injection treatment for HCC. This complication was promptly identified, and platelet transfusion and injection of recombinant human interleukin-11 resulted in a rapid recovery of the patient's platelet count. Attention should be given to this rare complication in patients administered percutaneous ethanol injection treatment for HCC.

Outcome of myeloablative allogeneic peripheral blood hematopoietic stem cell transplantation for refractory/relapsed AML patients in NR status.

To further find effective method to improve the long term survival of refractory or relapsed acute myeloid leukemia (AML) patients, we retrospectively analyzed the outcomes of myeloablative hematopoietic stem cell transplantation (HSCT) for 133 consecutive patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) therapy related AML(t-AML) in not remission status. The overall 3-year OS and DFS were 40.9% and 35.6% respectively. The variables associated with improved long term DFS were a bone marrow blast cell count less than 20% and an intensified conditioning regimen. In addition, the t-AML group had higher rates of relapse and III-IV acute GVHD than the primary AML group. The unrelated donor group had similar OS and DFS with sibling groups. Our study suggested that decreasing bone marrow blast cell counts before HSCT and strengthening the conditioning regimen may improve long-term DFS for refractory/relapsed AML patients, and unrelated donor group can get similar effect when compared to the sibling group.

[Cytogenetic abnormalities of 50 MDS patients by FISH detection and conventional karyotype analysis].

This study was purposed to compare detectable rate of cytogenetic abnormalities including -5/5q-, -7/7q-, 20q-,+8, and -Y in MDS by FISH and metaphase cytogenetics, and to investigate the relationship between cytogenetic abnormalities and progression from MDS to acute leukemia. Metaphase cytogenetics and FISH testing for -5/5q-, -7/7q-, 20q-,+8, and -Y were performed in 50 bone marrow samples obtained from patients with MDS diagnosed according to the WHO criteria (2008). Evolution from MDS to AML was followed up for each patient. The results showed that the cytogenetic abnormalities including -5/5q-, -7/7q-, 20q-,+8, and -Y were identified in 25 (50%) of 50 by metaphase cytogenetics, and in 20 (40%) of 50 by FISH. -5/5q-, 7/7q-, 20q- , +8, or -Y was identified by metaphase cytogenetics in 3 (6%) of 50, 13 (26%) of 50, 6 (12%) of 50, 12 (24%) of 50, and 1 (2%) of 50, respectively, and by FISH in 3 (6%) of 50, 10 (20%) 0f 50, 3 (6%) of 50, 10 (20%) of 50, and 1 of 50 (2%), respectively. The detectable rate ranking was -7/7q- >+8>20q->-5/5q->-Y. 47 patients received allogeneic hematopoietic stem cell transplantation. In the IPSS poor prognosis group, 6 (46.2%)of 13 received transplantation before progression to acute leukemia. In the IPSS good prognosis group, 10 (45.5% ) of 22 received transplantation before progression to acute leukemia. In the IPSS intermediate prognosis group, 2 (16.7%) of 12 received trans- plantation before progression to acute leukemia. The rate of progression to acute leukemia was 7.7% (1/13) in the IPSS poor prognosis group, 4.5% (1/22) in the IPSS good prognosis group, and 58.3% (7/12) in the IPSS intermediate prognosis group. The low rate of progression to acute leukemia in the IPSS poor prognosis group might be associated with the high rate of allogeneic hematopoietic stem transplantation. It is concluded that there is higher detectable rate for detecting a certain chromosome by FISH probe than that by metaphase cytogenetics, especially for detecting low clone chromosomal abnormalities and mitotic figures less than 20. There is no difference between IPSS good prognosis group and IPSS poor prognosis group in our study probably because of allogeneic hematopoietic stem cell transplantation.

[A multicenter retrospective analysis of diagnosis and treatment of 72 hemophagocytic syndrome patients.].

OBJECTIVE: To explore early diagnosis of hemophagocytic syndrome (HPS) and effective treatment. METHODS: A multicenter retrospective study was carried out to analyze the causes, clinical features, laboratory findings, treatment and clinical outcomes of 72 patients with HPS. RESULTS: Among the 72 patients, EBV infection and T lymphoma were the most common initiating diseases. The most common clinical features were persistent fever (100%) and splenomegaly (83.3%). The diagnostic sensitivity was persistent fever (100%), peripheral cytopenia in two or more lineages (97.2%), high concentration of serum soluble CD25 (93.1%) and low NK cell activity (94.4%). The median percentage of serum glycosylated ferritin was significantly lower in patients in HPS group \[(17.4 +/- 16.0)%\] than in control group \[(53.6 +/- 13.3)%\] (P < 0.01). And the median level of serum TNF-alpha was significantly higher in patients group \[(143.2 +/- 64.8) microg/L\] than in controls \[(66.9 +/- 19.4) microg/L\] (P < 0.01). Hepatic dysfunction was seen in most patients (83.6%) mainly manifested as elevated liver enzymes and hypoalbuminemia. The 15-week total survival rate was 46.8% in 47 treated patients, and was 63% in 27 treated with fludarabine in combination with high dose methylprednisolone. The platelet count and fibrinogen level were significantly lower in death group than in survival group. CONCLUSIONS: The diagnostic sensitivities of presistent fever, peripheral cytopenia in two or more lineages, high concentration of serum soluble CD25 and low NK cell activity are relatively high and lacking hemophagocytosis does not exclude the diagnosis. Low percentage of glycosylated ferritin and high concentration of TNF-alpha would be helpful to the diagnosis. High dose methylprednisolone combined with fludarabine is an effective therapy. Platelet count and fibrinogen level are poor prognostic factors for HPS.

Evaluation of risks perceived by people using HIV voluntary counseling and testing services / 中国艾滋病性病

Objective To investigate and analyze structure of risk perceived by people using HIV voluntary counseling and testing services and related factors.Method Two hundred and sixty eight VCT users were selected from 2 CDCs and 2 hospitals in Beijing and their perceived risks in the process of VCT were assessed by using self-administered question- naires.Factor analysis was performed to understand the relationship between different perceived risks,and risks perceived by different users were evaluated.Results Six factors were obtained from the factor analysis which included:fear of priva- cy disclosure,embarrassment,concern over the reliability of HIV tests,cost & time consumption,the tragic outcomes of HIV positive tests,and potential medical expenditures in the future.And the risks perceived by low and high income users were much higher than those perceived by middle income users.Conclusion There are clear structure of risks perceived by people using HIV voluntary counseling and testing,and people with different incomes have different levels of perceived risks.

[Effectiveness of allogeneic peripheral blood stem cell transplantation in 23 patients with myelodysplastic syndromes].

OBJECTIVE: To analyse the outcome of allogeneic peripheral blood stem cell transplantation (allo-PBSCT) for myelodysplastic syndromes (MDS). METHODS: Twenty-three patients with MDS received G-CSF mobilized HLA-identical sibling allo-PBSCT. The numbers of mononuclear cells (MNC) and CD34+ cells were 8. 25 (4.50 -22.36) x 10(8)/kg and 5.59 (1.57 - 12.22) x 10(6)/kg respectively. CsA and shorten course MTX were used for graft-versus-host disease (GVHD) prophylaxis and MMF was given on + 1 d - +28 d posttransplantation. RESULTS: Among 23 patients, 22 achieved hematopoietic recovery. The median time of ANC > 1.0 x 10(9)/L and BPC > 50 x 10(9)/L were + 13 (+ 11 - +17) days and + 30 (+13 + 102) days respectively. Two patients died of transplant related complications and three died of disease relapse, while 18 patients survived. Kaplan-Meier analysis showed disease free survival and relapse rate were (77.8 +/- 8.7)% and (14.4 +/- 7.5)% respectively. CONCLUSION: Allo-PBSCT is an effective treatment for MDS patients.

[The role of CD25 antibody in unrelated hematopoietic stem cell transplantation].

OBJECTIVE: To explore the role of CD(25) antibody on engraftment and graft-versus-host disease (GVHD) prophylaxis in unrelated hematopoietic stem cell transplantation (UHSCT). METHODS: CD(25) 1 mg/kg was given on day 1, day 4 post-transplantation in 27 patients of UHSCT. RESULTS: Hematopoietic recovery was obtained in 26 patients. One patient died before hematopoietic recovery. Acute GVHD occurred in 17 patients and 6 patients with II or more than degree acute GVHD (23%). Three patients experienced relapse and other 3 patients with serious infection. In these 26 eligible patients, 19 patients got disease free survival. CONCLUSIONS: CD(25) antibody plays an important role on engraftment and GVHD prophylaxis in the treatment of UHSCT and does not increase rate of leukemia relapse. It provides a way of GVHD prophylaxis in unrelated and HLA mismatched hematopoietic stem cell transplantation.

[Clinical study on anti-leukemia effect mediated by dentritic cells].

Immunotherapy of tumor is extensively attentioned as an important part of combined therapy of tumor in recent years. Dendritic cell (DC) is the most powerful antigen presenting cell (APC) by now which not only activates auto-immunity to attack tumor cells, but also does help to enhance antitumor effect for allogenic bodies. To explore the feasibility and safety of clinical therapy application of peripheral blood derived DC cultured ex vivo, and analyze the influence of DC-inducing-immunotherapy upon long-term survival of ANLL patients accepted autologous bone marrow transplantation, peripheral blood mononuclear cells (PBMNC) of 13 ANLL patients after autologous bone marrow transplantation were collected by using CS3000Plus. DC immunotherapy was administered after cultivation of PBMNC ex vivo for 2 weeks, desease-free survival time was observed after therapy for long time follow-up. The results showed that no any severe adverse event associated with DC therapy was observed, the survival analysis of Kaplan-Meier suggested that five year survival rate was 75.52% in DC group while 45.71% in non-DC group. DC group surpassed non-DC group in accumulative survival rate. It is concluded that the ex vivo cultivation and clinical therapy application of DC derived from peripheral blood are feasible and safe, DC immunotherapy in patients with acute non-lymphocytic leukemia after autologous bone marrow transplantation prolongs desease-free survival time and enhances long-term survival rate.