COMP promotes pancreatic fibrosis by activating pancreatic stellate cells through CD36-ERK/AKT signaling pathways.

BACKGROUND: Pancreatic fibrosis is one of the most important pathological features of chronic pancreatitis (CP) and pancreatic stellate cells (PSCs) are the key cells of fibrosis. As an extracellular matrix (ECM) glycoprotein, cartilage oligomeric matrix protein (COMP) is critical for collagen assembly and ECM stability and recent studies showed that COMP exert promoting fibrosis effect in the skin, lungs and liver. However, the role of COMP in activation of PSCs and pancreatic fibrosis remain unclear. We aimed to investigate the role and specific mechanisms of COMP in regulating the profibrotic phenotype of PSCs and pancreatic fibrosis. METHODS: ELISA method was used to determine serum COMP in patients with CP. Mice model of CP was established by repeated intraperitoneal injection of cerulein and pancreatic fibrosis was evaluated by Hematoxylin-Eosin staining (H&E) and Sirius red staining. Immunohistochemical staining was used to detect the expression changes of COMP and fibrosis marker such as α-SMA and Fibronectin in pancreatic tissue of mice. Cell Counting Kit-8, Wound Healing and Transwell assessed the proliferation and migration of human pancreatic stellate cells (HPSCs). Western blotting, qRT-PCR and immunofluorescence staining were performed to detect the expression of fibrosis marker, AKT and MAPK family proteins in HPSCs. RNA-seq omics analysis as well as small interfering RNA of COMP, recombinant human COMP (rCOMP), MEK inhibitors and PI3K inhibitors were used to study the effect and mechanism of COMP on activation of HPSCs. RESULTS: ELISA showed that the expression of COMP significantly increased in the serum of CP patients. H&E and Sirius red staining analysis showed that there was a large amount of collagen deposition in the mice in the CP model group and high expression of COMP, α-SMA, Fibronectin and Vimentin were observed in fibrotic tissues. TGF-ß1 stimulates the activation of HPSCs and increases the expression of COMP. Knockdown of COMP inhibited proliferation and migration of HPSCs. Further, RNA-seq omics analysis and validation experiments in vitro showed that rCOMP could significantly promote the proliferation and activation of HPSCs, which may be due to promoting the phosphorylation of ERK and AKT through membrane protein receptor CD36. rCOMP simultaneously increased the expression of α-SMA, Fibronectin and Collagen I in HPSCs. CONCLUSION: In conclusion, this study showed that COMP was up-regulated in CP fibrotic tissues and COMP induced the activation, proliferation and migration of PSCs through the CD36-ERK/AKT signaling pathway. COMP may be a potential therapeutic candidate for the treatment of CP. Interfering with the expression of COMP or the communication between COMP and CD36 on PSCs may be the next direction for therapeutic research.

Impacts of nature reserve policy on regional ecological environment quality: A case study of Sanjiangyuan region.

Uncovering the ecological effectiveness of nature reserve policies will help protect and manage nature reserves in the future. Taking Sanjiangyuan region as an example, we examined the impacts of the spatial layout characteristics of natural reserves on the ecological environment quality by constructing the dynamic degree of land use and land cover change index, and depicted the spatial differences of the ecological effectiveness of natural reserve policies both inside and outside the natural reserves. Combined with ordinary least squares and field survey results, we explored the influencing mechanism of nature reserve policies on ecological environment quality. The results showed that the ecological quality of the whole region of Sanjiangyuan had been improved significantly since the implementation of the nature reserve policies, and that the transformation of unused land into ecological land was the most important type of land use change for the ecological environment quality improvement. The ecological effectiveness of large-scale nature reserves with concentrated and contiguous distribution was obvious, while the ecological effectiveness of small-scale nature reserves with scattered distribution and close to the administrative boundaries was relatively small. Although the ecological effectiveness of nature reserves was better than that of non-reserved areas, the ecological improvement of nature reserves and the surrounding areas was synchronous. The nature reserve policy had significantly improved ecological environment quality by implementing ecological protection and restoration projects in nature reserves. Meanwhile, it had alleviated the pressure of farmers and herdsmen's activities on the ecological environment by taking measures such as grazing restriction and guiding conversion of industry and production. In the future, we should promote the construction of ecosystem integrity protection network system with National Park as the core, strengthen the integrated protection and linkage management of National Park and surrounding areas, and help farmers and herdsmen further broaden their livelihoods.

Low-Dose 5-Aza and DZnep Alleviate Acute Graft-Versus-Host Disease With Less Side Effects Through Altering T-Cell Differentiation.

Objective: Previous studies showed that hypomethylating agents (HMAs) could alleviate acute graft-versus-host disease (aGvHD), but affect engraftment after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The combination of two different HMAs in lower doses might overcome this problem. This study aimed to evaluate the treatment effect of the combination of two HMAs-azacitidine (5-Aza) and histone H3K27 methyltransferase inhibitor 3-deazaneplanocin (DZNep)-for the prophylaxis of aGvHD after allo-HSCT and to explore the possible mechanisms. Methods: We first optimized the concentrations of individual and combinational 5-Aza and DZNep treatments to ensure no obvious toxicities on activated T cells by evaluating T-cell proliferation, viability, and differentiation. A mouse model of aGvHD was then established to assess the prophylactic efficacy of 5-Aza, DZNep, and their combination on aGvHD. The immunomodulatory effect on T cells and the hematopoietic reconstruction were assessed. Additionally, RNA sequencing (RNA-seq) was performed to identify the underlying molecular mechanisms. Results: Compared with single treatments, the in vitro application of 5-Aza with DZNep could more powerfully reduce the production of T helper type 1 (Th1)/T cytotoxic type 1 (Tc1) cells and increase the production of regulatory T cells (Tregs). In an allo-HSCT mouse model, in vivo administration of 5-Aza with DZNep could enhance the prophylactic effect for aGvHD compared with single agents. The mechanism study demonstrated that the combination of 5-Aza and DZNep in vivo had an enhanced effect to inhibit the production of Th1/Tc1, increase the proportions of Th2/Tc2, and induce the differentiation of Tregs as in vitro. RNA-seq analysis revealed the cytokine and chemokine pathways as one mechanism for the alleviation of aGvHD with the combination of 5-Aza and DZNep. Conclusion: The combination of 5-Aza and DZNep could enhance the prophylactic effect for aGvHD by influencing donor T-cell differentiation through affecting cytokine and chemokine pathways. This study shed light on the effectively prophylactic measure for aGvHD using different epigenetic agent combinations.

The combination of body composition conditions and systemic inflammatory markers has prognostic value for patients with gastric cancer treated with adjuvant chemoradiotherapy.

OBJECTIVE: The aim of this study was to explore the prognostic value of the association between systemic inflammation response markers (red blood cell distribution width, neutrophil platelet score, prognostic nutritional index, neutrophil-to-lymphocyte ratio, neutrophil-to-platelet ratio, lymphocyte-to-monocyte ratio, and systemic immune-inflammation index) and poorer body composition conditions (sarcopenia, myosteatosis, and sarcopenic obesity) among patients with gastric cancer who underwent adjuvant chemoradiotherapy after radical gastrectomy. METHODS: A computed tomography scan was performed within 2 wk of prechemoradiotherapy to identify sarcopenia, myosteatosis and sarcopenic obesity. Tumor and systemic inflammatory response information was recorded. Logistic analysis was used to explore the potential risk factors associated with body composition. Univariate and multivariate Cox analyses were performed for survival analysis. A nomogram was constructed to serve as a prognostic prediction tool for the 3- and 5-y overall survival rates. RESULTS: The study included 223 patients (74 women and 149 men) with gastric cancer treated with adjuvant chemoradiotherapy after radical gastrectomy. The incidences of sarcopenia, myosteatosis, and sarcopenic obesity were 30%, 39%, and 16%, respectively. Logistic analysis demonstrated that a low prognostic nutritional index is a risk factor for sarcopenia, myosteatosis, and sarcopenic obesity. Based on survival analysis, stage (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.23-0.84; P = 0.01), the neutrophil platelet score (HR, 0.50; 95% CI, 0.31-0.82; P = 0.01), the prognostic nutritional index (HR, 0.40; 95% CI, 0.24-0.68; P = 0.00) and sarcopenic obesity (HR, 0.54; 95% CI, 0.31-0.93; P = 0.03) remained independent prognostic factors for overall survival. Accuracy was improved when systemic inflammation markers were incorporated into the nomogram compared with when they were excluded, and the predicted C indexes of the nomogram with and without systemic inflammatory markers were 0.71 (95% CI, 0.67-0.73) and 0.63 (95% CI, 0.57-0.68), respectively. CONCLUSION: The systemic inflammatory response associated with progressive nutritional conditions and body composition conditions with systemic inflammation markers incorporated presented better prognostic value.

The catalytic activity of PtnCum (n = 1-3, m = 0-2) clusters for methanol dehydrogenation to CO.

A large number of experiments show that PtCu catalyst has a good catalytic effect on methanol decomposition. Therefore, density functional theory (DFT) was used to further study the dehydrogenation of methanol catalyzed by PtnCum (n = 1-3, m = 0-2). The energy diagrams of O-adsorption path and H-adsorption path were drawn. By calculation, the Pt is the active site of the whole reaction process, and the barrier energy of the rate-determining step is 11.09 kcal mol-1 by Pt2Cu, which is lower than that of Pt3 and PtCu2. However, the complete dehydrogenation product of methanol, CO, is easier to dissociate from PtCu2 clusters than from Pt3 and Pt2Cu clusters. Therefore, Cu doping can improve the catalytic activity and anti-CO toxicity of Pt to a certain extent.

[Clinical Efficacy of the MDS Patients Treated by Allo-HSCT].

OBJECTIVE: To analyze clinical effectiveness of myelodysplastic syndrome (MDS) patients treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT), and to investigate new therapy strategy for the treatment of relapse after allo-HSCT. METHODS: 72 MDS patients treated by HSCT in our hospital from April 2013 to November 2019 were enrolled and analyzed retrospectively. The effect of allo-HSCT was summarized. The risk factors affecting the survival and relapse of the patients were investigated. RESULTS: Among 72 patients, the median follow up was 37(12-111) months. 57 patients survived（79.2%），while 15 patients died（20.8%）. The 5-year overall survival (OS) rate and 5-year disease-free survival (DFS) rate were 76.6% and 62.3%, respectively. IPSS-R, TP53 mutation and chronic graft versus-host-disease (cGVHD) were the risk factors affecting the OS of the MDS patients after treated by allo-HSCT. IPSS-R, TP53 mutation and Ⅲ-Ⅳ° acute graft versus-host-disease (aGVHD) were the risk factors affecting the DFS of the MDS patients after treated by allo-HSCT. After transplanted, 19 patients (26.4%) emerged aGVHD, and 5 patients (6.9%) emerged Ⅲ-Ⅳ° aGVHD, 25 patients (34.7%) emerged cGVHD, while 4 patients (5.6%) emerged extensive cGVHD. 17 patients (23.3%) relapsed, and the 5-year cumulative incidence of relapse (CIR) rate was 27.5%. IPSS-R, TP53 mutation and cGVHD were the risk factors affecting the relapse of the patients. The median survival time after relapse was 9 months. There were 7 out of 17 relapsed patients survived without disease, while 10 patients died. The OS rate of patients treated with maintained hypomethylation agents(HMA) combined with G-CSF mobilized donor lymphocyte infusion (DLI) was significantly higher than the patients without HMA (80.0% vs 10.0%, P=0.002). CONCLUSION: Allo-HSCT is an effective therapy for intermediate and high risk MDS patients. But relapse after HSCT is still a major problem that affecting the survival of the patients. Maintenance treatment of HMA combined with DLI may improve the long-time survival of MDS patients with relapsed after treated by allo-HSCT.

New species of Crossodonthina from Mangshan National Nature Reserve (Nanling National Forest Park), China (Collembola: Neanuridae).

Two new species of the genus Crossodonthina (Collembola: Neanuridae: Neanurinae: Lobellini) are recorded from Mangshan National Nature Reserve, Chenzhou City, Hunan Province and Ruyuan Yao Autonomous County, Guangdong Province, Central-South China. Crossodonthina clavata sp. nov. is characterized by 3+3 uncolored eyes on head; labral chaetotaxy as 0/2, 2; cephalic chaeta O present; cephalic tubercles Dl, L and So fused each other; mandible with 4 basal teeth and five fringed rami; maxilla with two lamellae and each lamella with two apical teeth. Crossodonthina acuminata sp. nov. can be recognized by 3 black eyes per side on head; mandible with 3 basal teeth and 8 rami; all cephalic tubercles independent, chaeta O on tubercle Fr present; cephalic tubercle Di, De on posterior area of head with 2 chaetae each, intermediate between cross and non-cross type chaetotaxy; tubercle De of Th. I with 3(2) chaetae; furcular remnant without chaeta. It is the first record of Neanuridae species from Mangshan National Nature Reserve.

[Clinical Analysis for Patients with AML Treated after Allo-HSCT].

OBJECTIVE: To analyze risk factors that affect survival and relapse of AML patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and to investigate the therapy choices after AML relapse. METHODS: Clinical data of 180 AML patients achieved complete remission (CR) before HSCT from January 2009 to December 2018 treated in our center were analyzed retrospectively. Risk factors for survival and relapse after allo-HSCT were analyzed by COX regression. RESULTS: Among 180 AML patients, 134 survived (74.4%), 46 patients died (25.6%), and 40 patients relapsed (22.2%). The rate of overall survival (OS), event-free survival (EFS) and cumulative rate of relapse in 5-years was 74.3%、42.5% and 25.0%, respectively. High-risk, adverse cytogenetics, CR2 at HSCT and no cGvHD were independent risk factors that affect OS. CR2 at HSCT, high-risk were independent risk factors that affect EFS. High-risk, MRD+ after one course of induction therapy, adverse cytogenetics and no cGVHD were independent risk factors that affect relapse. The OS rate of relapse patients could be improved by the usage of hypomethylation agents combined with G-CSF mobilized donor lymphocyte infusion (DLI), and 2-year OS rate was 62.5%. CONCLUSION: The survival rate of AML is greatly improved by allo-HSCT, but relapse is still one of the most important factors that influence survival of the AML patients. The maintenance therapy of hypomethylation agents combined with DLI may be a new effective treatment option for patients who relapse after HSCT.

[Analysis of Decitabine Therapeutic Effeicacy for Patients with Relapsed MDS/AML and High-Risk AML Patients after HSCT].

OBJECTIVE: To investigate the therapeutic efficacy of using decitabine as maintenance therapy for patients with relapsed MDS/AML and as prophylactic therapy for patients with high-risk AML after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: Clinical data of 10 patients with MDS/AML from November 2016 to May 2018 were analyzed retrospectively. Among 10 patients there were 4 cases of AML, 2 cases of MDS, and 4 cases of AML transformed from MDS (t-AML). The 10 patients were devided into 2 groups: the relapsed group (n=8) and the prophylactic group (n=2). In relapsed group the decitabine was used as maintenance therapy after achieved complete remission (CR) with decitabine chemotherapy. In prophylactic group the decitabine was used as prophylactic therapy if the patients didn't appear the symptom of graft-versus- host-disease (GVHD) during 30 to 45 d after allo-HSCT. Eight patients received G-CSF-mobilized donor lymphocyte infusion (DLI). The dosage of decitabine for maintenance therapy and prophylactic therapy was 5 mg/m2 for 7 to 10 days every 4 to 6 weeks, as 1 cycle, amount to 3 to 7 cycles. The dosage was adjusted by the endurance of patients. RESULTS: Until Nov 30, 2018, 7 out of 10 patients survived. The average survival time was 15.5±1.9 months. 1-year OS rate was 64.0%. Six patients appeared aGVHD, and four patients appeared cGVHD. CONCLUSION: The usage of decitabine combined with DLI in patients with relapsed MDS/AML and high-risk AML after allo-HSCT can prolong lives of patients, reduce relapsed rate, and provide the probability for long time survival.

[Pathological Features, Treatment Options and Prognosis Assessment of Patients with Bone Lymphoma in Real-World].

OBJECTIVE: To investigate the clinical manifestations pathologic features, treatment options and prognosis of patients with bone lymphoma. METHODS: The clinical characteristics, pathologic features, treatment and prognosis of 34 BL patients diagnosed by histopathologic method or/and PET-CT and treated in first hospital of peking university from January 2004 to April 2018 were analyzed retrospectively. RESULTS: The median age of 34 BL patients was 56 years old, the male and female ratio was 1.43∶1 (24 /10). Among 34 patients, the patients with primary bone lymphoma(PBL) were 8 cases, the patients with secondary bone lymphoma(SBL) was 26 cases, the PBL and SBL ratio was 0.31∶1. Bone lymphoma lacks typical systemic symptoms, and its onset began mostly from bone pain and pathologic bone fracture. The most frequent pathological type of bone lymphoma in our study was diffuse large B-cell lymphoma (DLBCL), accounting for 55.88%. At present, the conventional treatment for bone lymphoma includes chemotherapy, or chemotherapy combined with radiotherapy and surgery, as well as hematopoietic stem cell transplantation. The average and median OS time of BL patients were 349 years and 3 years respectively, meanwhile the OS rate for three years and two years were 56.25% and 78.16%, respectively. Factors that affect survival of BL patients were PBL and SBL classification, pathological type, blood LDH level, and treatment methods. CONCLUSION: Bone lymphoma is usually concealed onset，an adequate and adequate combination therapy can improve the survival rate and transplantation therapy plays an important role. Primary bone lymphoma is rare, the prognosis of patients with primary bone lymphoma is good, whereas the prognosis of patients with secondary bone lymphoma is poor.

Thrombophilia Caused by Beta2-Glycoprotein I Deficiency: In Vitro Study of a Rare Mutation in APOH Gene.

This study aimed to explore the mechanism of a novel mutation (p.Lys38Glu) in apolipoprotein H (APOH) gene causing hereditary beta2-glycoprotein I (ß2GPI) deficiency and thrombosis in a proband with thrombophilia. The plasma level of ß2GPI was measured by ELISA and Western blotting, and anti-ß2GPI antibody by ELISA. Lupus anticoagulant (LA) was assayed using the dilute Russell viper venom time. Deficiency of the major natural anticoagulants including protein C (PC), protein S (PS), antithrombin (AT) and thrombomodulin (TM) was excluded from the proband. A mutation analysis was performed by amplification and sequencing of the APOH gene. Wild type and mutant (c.112A>G) APOH expression plasmids were constructed and transfected into HEK293T cells. The results showed that the thrombin generation capacity of the proband was higher than that of the other family members. Missense mutation p.Lys38Glu in APOH gene and LA coexisted in the proband. The mutation led to ß2GPI deficiency and thrombosis by impairing the protein production and inhibiting the platelet aggregation. It was concluded that the recurrent thrombosis of the proband is associated with the coexistence of p.Lys38Glu mutation in APOH gene and LA in plasma.

[Detecting HB-1 Expression Level in Bone Marrow of Acute Leukemia Patients by Real-Time Fluorescence Quantitative RT-PCR].

OBJECTIVE: To investigate the expression level of HB-1 gene in patients with acute lymphoblastic leukemia (ALL) and the significance of HB-1 gene in monitoring of minimal residual disease (MRD). METHODS: The method of real-time fluorescence quantitative RT-PCR (Taqman probe) was established to detect the expression levels of HB-1 gene; then the sensitivity, specificity and repeatability of this assay were evaluated and verified. The HB-1 gene expression levels in bone marrow of 183 cases of ALL, 70 cases of acute myeloid leukemias (AML), 52 cases of non-malignant hematologic diseases and 24 healthy hematopoietic stem cell donors were detected. The correlation of HB-1 level with diagnosis and relapse was analyzed by detecting bone marrow samples of 33 B-ALL. RESULTS: The sensitivity of this assay reached the 10-4 level. The coefficient of variation for inter-batch and inter-tube of HB-1 were 6.79% and 4.80%, respectively. It was found that HB-1 gene specifically expressed in acute B lymphoblastic leukemia. The median expression levels of HB-1 gene in newly diagnosed and relapsed B-ALL patients were statistically significantly higher than those in ALL in complete remission(CR), newly diagnosed T-ALL, newly diagnosed AML, non-malignant hematologic diseases, and healthy hematopoietic stem cell donors(33.0% vs 0.68%, 0.07%, 0.02%, 0.58% and 0, respectively) (P<0.01). No statistical differences were found between newly diagnosed T-ALL, newly diagnosed AML, non-malignant hematologic diseases and healthy donors (P>0.05). The expression level of HB-1 gene declined sharply when B-ALL patients reached complete remission (0-7.99%, with median level 0.68%), but increased when relapsed (7.69%, 8.08% and 484.0% in 3 relapsed samples), which was in accordance with results of flow cytometry. CONCLUSION: HB-1 gene specifically expressed in acute B lymphoblastic leukemia cells. The established real-time fluorescence quantitative RT-PCR assay shows good sensitivity, specificity and repeatability, thus, can be used as a biological marker in the clinical detection, monitoring MRD and predicting of early relapse for B-ALL patients.

Association of thrombomodulin c.1418C>T polymorphism and venous thromboembolism.

OBJECTIVES: To investigate the association between thrombomodulin c.1418C>T polymorphism and venous thrombosis. METHODS: Systematic searches of Pubmed, EMBASE, Chinese Biomedical Database, Chinese National Knowledge Infrastructure, the VIP Database and WANFANG Database were performed. Pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to assess the strength of the association. Subgroup analysis was conducted to seek for potential sources of heterogeneity. RESULTS: A total of 8 studies were collected in our analysis, including 2519 cases and 3196 controls. No significant association between thrombomodulin c.1418C>T polymorphism and venous thrombosis was shown under the five genetic models (T vs C: OR=1.02, 95% CI=0.82-1.26; TT vs CC: OR=0.90, 95% CI=0.52-1.56; CT vs CC: OR=1.07, 95% CI=0.84-1.37; CT+TT vs CC: OR=1.05, 95% CI=0.82-1.34; TT vs CT+CC: OR=0.81, 95% CI=0.59-1.11). Similar results were observed in the following subgroup analysis based on ethnicity and source of control. However, an increased risk of venous thrombosis was found in Asian populations under three genetic models (T vs C: OR=1.31, 95% CI=1.01-1.70; CT vs CC: OR=1.41, 95% CI=1.00-2.98; TT+CT vs CC vs CC: OR=1.41, 95% CI=1.02-1.95). CONCLUSION: Current studies on the thrombomodulin c.1418C>T polymorphism are of great heterogeneity. It might not be a risk factor for venous thromboembolism.

A new approach combining venoarterial extracorporeal membrane oxygenation and CRRT for adults: a retrospective study.

PURPOSE: This study aimed to assess a new approach combining venoarterial (VA) extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) in adults, while monitoring CRRT circuit pressures. METHODS: The inlet and outlet of the CRRT circuit were connected to preoxygenator port and postoxygenator port, respectively. Then, complications and CRRT circuit pressures were evaluated. RESULTS: 7 patients underwent combined VA-ECMO and CRRT; 16 filters were used. CRRT blood flow ranged from 150 to 200 mL/min; the CRRT to ECMO blood flow ratio was <0.1. The CRRT pressures at treatment initiation were normal. No complications were reported. CONCLUSIONS: This approach combining VA-ECMO and CRRT in adults did not compromise the accuracy of pressure monitoring systems for CRRT circuit function, and caused no complications. Hence, it may be a feasible method for performing combined VA-ECMO and CRRT in adults.

Air pollution and venous thrombosis: a meta-analysis.

Exposure to air pollution has been linked to cardiovascular and respiratory disorders. However, the effect of air pollution on venous thrombotic disorders is uncertain. We performed a meta-analysis to assess the association between air pollution and venous thrombosis. PubMed, Embase, EBM Reviews, Healthstar, Global Health, Nursing Database, and Web of Science were searched for citations on air pollutants (carbon monoxide, sulfur dioxide, nitrogen dioxide, ozone, and particulate matters) and venous thrombosis. Using a random-effects model, overall risk estimates were derived for each increment of 10 µg/m(3) of pollutant concentration. Of the 485 in-depth reviewed studies, 8 citations, involving approximately 700,000 events, fulfilled the inclusion criteria. All the main air pollutants analyzed were not associated with an increased risk of venous thrombosis (OR = 1.005, 95% CI = 0.998-1.012 for PM2.5; OR = 0.995, 95% CI = 0.984-1.007 for PM10; OR = 1.006, 95% CI = 0.994-1.019 for NO2). Based on exposure period and thrombosis location, additional subgroup analyses provided results comparable with those of the overall analyses. There was no evidence of publication bias. Therefore, this meta analysis does not suggest the possible role of air pollution as risk factor for venous thrombosis in general population.

Efficacy and Safety of Panobinostat in Relapsed or/and Refractory Multiple Myeloma: Meta Analyses of Clinical Trials and Systematic Review.

During the past decades, many novel agents have improved response and survival of patients with multiple myeloma. Nevertheless, it remains challenging when they suffer relapsing. Thus, novel therapeutic agents are needed. We aimed to assess the efficacy and safety of a novel agent panobinostat for patients with relapsed or/and refractory MM. A systematic literature review identified studies for clinical trials about panobinostat in patients with relapsed or/and refractory MM. We searched studies published between January 2000 and December 2015 in Pubmed, Ovid, EBSCO and the Cochrane library. Random-effect pooled estimates were calculated for overall response rate and rates of common adverse effects. The results showed 11 clinical trials including 700 patients with relapsed or/and refractory MM treated with panobinostat were identified. The ORR varied between 0.08 and 0.67. Pooled analyses showed the results that the ORR was 0.45 (95% CI: 0.31-0.59, I(2) = 90.5%, P = 0.000) for panobinostat combined with any other kind of drugs. The most common Grade3/4 adverse effects were thrombocytopenia, neutropenia, lymphopenia, anemia, diarrhea, fatigue, nausea and so on. In conclusion, based on our analyses, the regimen of panobinostat combining with other agents seems to be well tolerated and efficacious in patients with relapsed or/and refractory MM.

A genetic analysis of 23 Chinese patients with hemophilia B.

Hemophilia B (HB) is an X-linked recessive bleeding disorder caused by mutations in the coagulation factor IX (FIX) gene. Genotyping patients with HB is essential for genetic counseling and provides useful information for patient management. In this study, the F9 gene from 23 patients with HB was analyzed by direct sequencing. Nineteen point mutations were identified, including a novel missense variant (c.520G > C, p.Val174Leu) in a patient with severe HB and a previously unreported homozygous missense mutation (c.571C > T, p.Arg191Cys) in a female patient with mild HB. Two large F9 gene deletions with defined breakpoints (g.10413_11363del, g.12163_23369del) were identified in two patients with severe HB using a primer walking strategy followed by sequencing. The flanking regions of the two breakpoints revealed recombination-associated elements (repetitive elements, non-B conformation forming motifs) with a 5-bp microhomology in the breakpoint junction of g.12163_23369del. These findings imply that non-homologous end joining and microhomology-mediated break-induced replication are the putative mechanisms for the deletions of the F9 gene. Because the g.12163_23369del deletion caused exons to be absent without a frameshift mutation occurring, a smaller FIX protein was observed in western blot analyses.

Compound heterozygous protein C deficiency in a family with venous thrombosis: Identification and in vitro study of p.Asp297His and p.Val420Leu mutations.

Hereditary protein C deficiency (PCD) is an autosomal inherited disorder associated with high risk for venous thromboembolism (VTE). This study aimed to explore the functional consequences of two missense mutations, p.Asp297His and p.Val420Ile, responsible for type I/II PCD and recurrent deep vein thrombosis (DVT) in a Chinese family. The plasma protein C activities (PC:A) of the proband and his sister were reduced to 4% and 5% of normal activity. However, protein C antigen (PC:Ag) concentrations were not equally decreased, with levels of 90.5% and 88.7%, respectively. Two missense mutations p.Asp297His and p.Val420Leu were identified in the protein C gene (PROC). The PC:A and PC:Ag levels in heterozygous state for p.Asp297His were 66% and 64.8%, whereas in heterozygous state for p.Val420Leu, these levels were 67% and 145%, respectively. Wild type (WT) and two mutant PROC cDNA expression plasmids were constructed and transfected into HEK 293T cells. Western blot analysis revealed that both p.Asp297His and p.Val420Leu showed a normal intracellular protein level. The extracellular protein level and specific activity of p.Asp297His were equally reduced to 37.7 ± 4.3% and 22.1 ± 2.5%, respectively. Mutant p.Val420Leu showed a relatively higher PC:Ag level and undetectable PC:A. Immunofluorescence staining revealed that WT and p.Val420Leu proteins were largely co-localized with both the protein disulfide isomerase (PDI) and cis-Golgi Marker (GM130), while the PC p.Asp297His mutant protein was mainly co-localized with PDI and much less co-localized with GM130. The thrombosis symptom in this family was associated with the two missense mutations in the PROC gene.

Phenotypic and genotypic characterization of four factor VII deficiency patients from central China.

Hereditary coagulation factor VII deficiency (FVIID) is a rare autosomal, recessive inherited hemorrhagic disorder related to a variety of mutations or polymorphisms throughout the factor VII (FVII) gene (F7). The aims of this study were to characterize the molecular defect of the F7 gene in four unrelated patients with FVIID and to find the genotype-phenotype correlation. All nine exons, exon-intron boundaries, and 5' and 3'-untranslated regions of the F7 gene were amplified by PCR and the purified PCR products were sequenced directly. Suspected mutations were confirmed by another PCR and sequencing of the opposite strand. Family studies were also performed. A total of five unique lesions were identified, including three missense mutations (c.384A>G, c.839A>C, c.1163T>G, predicting p.Tyr128Cys, p.Glu280Ala and p.Phe388Cys substitution, respectively) and two splice junction mutations (c.572-1G>A, c.681+1G>T), among which two (p.Glu280Ala, p.Phe388Cys) were novel. A previously reported mutation p.Tyr128Cys was seen in the homozygous state in two unrelated patients. The other two cases were both compound heterozygotes of a missense mutation and a splicing site mutation. Multiple sequence alignment using DNAMAN analysis showed that all the missense mutations were found in residues that highly conserved across species and vitamin K-dependent serine proteases. Online software Polyphen and SIFT were used to confirm the pathogenic of the missense mutation. p.Tyr128Cys seems to be a hotspot of the F7 gene in ethnic Han Chinese population.