ALBERT

Description: Describes the involvement of churches and other faith-based organizations (FBOs) in addressing the HIV/AIDS epidemic in Belize, Guatemala, and Honduras. The authors describe the range of FBO activities and discuss the advantages and challenges to such involvement and possible ways that FBOs can enhance their efforts, both independently and in collaboration with other organizations, such as government ministries of health.

Description: Describes the involvement of churches and other faith-based organizations (FBOs) in addressing the HIV/AIDS epidemic in Belize, Guatemala, and Honduras. The authors describe the range of FBO activities and discuss the advantages and challenges to such involvement and possible ways that FBOs can enhance their efforts, both independently and in collaboration with other organizations, such as government ministries of health.

Description: Natural killer (NK)-cell lymphomas/leukemias are a group of aggressive malignancies distinct from the indolent large granular lymphocyte (LGL) proliferations. In the World Health Organization (WHO) classification, NK-cell malignancies are divided into two groups (1) extranodal NK-cell lymphoma, nasal type (ENKL), and (2) aggressive NK-cell leukemia (ANKL). Only three studies of genome wide alteration have been published in these malignancies. We studied eight NK lymphoma cell lines (NK-92, KHYG1, YT, HANK-1, NK-YS, SNK-6, SNK-3 and KAI3) and seven NK lymphomas/leukemias specimens to: determine DNA gains and losses in comparative genomic hybridizations (CGH) and compare these alterations with those reported literature to define recurring chromosomal abnormalities, obtain transcription profiles of NK malignancies and compare them with normal NK cells(resting or IL-2 stimulated), and correlate the genomic profiles with transcriptional profiles to identify possible candidate genes involved in lymphoma development. Whole genome tiling arrays, containing 26,819 bacterial artificial chromosomes (BAC) were employed for CGH study. Our CGH study identified frequent recurrent abnormalities that have been reported in all previous studies. These include gains in 17q11.2–q21 (frequency: 40%); 1q22–q23.1 (frequency: 50 %); and 7q21.13–q22.1(frequency: 50%) and all these regions showed at least a frequency of 17% in other reports. A number of regions were also described in at least one other published reports (e.g. 1q32.2–q41, 6p25.5 and 17q 21.2). Regions of loss with a frequency ≥ 20% including 11q23.1–23.2(20%); 7p22.1–p22.2 (40%); 6q21(50%); 6q25.1–25.3(50%); and 17p13–13.1(50%) showed consistent results with previous reports. 6q21 loss was detected in two ANKL cell lines (NK92 and KHYG1) but not in ENKL cell lines . Gains of 8p12–q21.12, 8q22.1–q24.13, and 8q24.21 were also unique to ANKL cell lines. Transcriptional profiling using affymetrix gene chips on these cell lines and tumor specimen were compared with normal resting and IL-2 activated NK cells. We observed significant down-regulation (6–9 folds) of killer cell Ig-like receptor (KIR) (KIR2DL3, KIR2DS1, KIR3DL1, KIR3DL2) in NK-cell lymphoma as compared to normal NK cells. This may be related to the restricted clonal expression of the KIRs in neoplasms. High expression of pro-proliferative genes (e.g. Cyclin B1, A2, BUB1, CDC2, CDC20, CDCA1, CDCA3, and CDC7) was observed in NK lymphoma. On examining gene signatures/pathways (using BRB-array Tools), we observed significant increased expression of genes (p

Description: Introduction: The final events of the activated clotting cascade include the conversion of fibrinogen to fibrin and stabilization of the growing fibrin clot by factor XIII (FXIII). A missense variant in the alpha chain of fibrinogen, α-fibrinogen (FGA) Thr312Ala (rs6050, NM_000508.3:c.991A〉G, NP_000499.1:p.[Thr331Ala]), has been previously shown to interfere with FXIII-dependent cross-linking, leading to stiffer blood clots. It is believed this pathophysiology underlies the increased risk of venous thromboembolism (VTE) associated with the variant. The Thr312Ala variant has been shown to be significantly associated with VTE among White, Non-Hispanic populations. The only investigation of the variant in a Black population (Rasmussen-Torvik et al 2007) found no significant relationship between Thr312Ala and VTE, but the authors cite the relatively small number of participants included in the analysis as a possible reason for a null finding. We investigated the association between FGA Thr312Ala and VTE in a case-control study enrolling a relatively large racially diverse study population. Methods: Conditional logistic regression was used to assess the association between FGA Thr312Ala and VTE among enrollees in the Genetic Attributes and Thrombosis Epidemiology (GATE) study, a case-control study enrolling 1,042 VTE cases and 1,213 controls with no history of VTE, frequency-matched on age, sex, and race. Crude models conditioned on the matching factors, and adjusted models conditioned on the matching factors and controlled for patient characteristics found to be associated with both case/control status and FGA Thr312Ala genotype. Among all patient characteristics evaluated, the β-fibrinogen (FGB) promoter region variant -455 G〉A (rs1800790, NM_001184741.1:c.-463G〉A) was the only patient characteristic associated with both case/control status and FGA Thr312Ala genotype. Potential effect modification was assessed using likelihood ratio tests. Results: Among 660 White controls and 528 White cases in the GATE study, carrying at least one FGA rs6050 G (Ala) allele was associated with increased odds of VTE compared to not carrying a G allele (odds ratio (OR) and 95% confidence interval (CI) 1.2 [1.0-1.5]) in a crude model. This association was strongest when restricting to n=205 idiopathic (unprovoked) cases, n=125 recurrent cases, or n=112 cases exhibiting both deep vein thrombosis (DVT) and pulmonary embolism (PE) (Table 1). This association was modified by obesity status, with the effect among obese enrollees being multiplicative (Table 2). In contrast, there was no association between carrying at least one FGA rs6050 G (Ala) allele and VTE among 553 Black controls and 514 Black cases in the GATE study (OR and 95% CI 1.0 [0.8-1.2]) when assessing the association among all cases (Table 1). However, the odds of VTE was higher among Black participants carrying the G allele compared to those not carrying the allele when restricting to n=103 PE only cases (OR and 95% CI 1.5 [1.0-2.4]). The association between FGA Thr312Ala and VTE did not appear to be modified by obesity status among Black participants (Table 2). Conclusions: These results indicate that the FGA Thr312Ala (rs6050, NM_000508.3:c.991A〉G, NP_000499.1:p.[Thr331Ala]) polymorphism is associated with VTE among White participants in the GATE study, with the strongest effect seen in participants exhibiting both DVT and PE. However, the association among Black participants appears limited to PE, indicating further exploration of genetic risk factors for VTE in Black populations is warranted in order to better understand genetic risk factors for all types of VTE in this population. Disclosures Payne: Bayer: Other: treatment product donation; Bioverativ: Other: treatment product donation; Novo Nordisk: Other: treatment product donation; Shire: Other: treatment product donation; Genentech: Membership on an entity's Board of Directors or advisory committees. Patel:Daiichi Sankyo: Other: DSMB member.

Description: Introduction: Black Americans have been reported to have a higher incidence of venous thromboembolism (VTE) compared to white Americans. The underlying cause of this disparity is not well characterized. Protein S, protein C, and antithrombin deficiency are known risk factors for VTE. There is inconsistent data regarding racial variation on the effect of protein S, protein C, and antithrombin levels and/or deficiency and risk of VTE. Most prior studies have not included a large black study population. The aim of this investigation is to compare levels of protein C, protein S, and antithrombin between VTE cases and controls by race among enrollees in the Genetic Attributes and Thrombosis Epidemiology (GATE) study, accounting for genetic differences such as hemoglobin genotype that may contribute to differences in protein levels by race. Methods: Testing for protein S, protein C, and antithrombin deficiency was performed on a subset of participants enrolled in the GATE study, a case-control study comprised of VTE cases and controls frequency-matched on age, sex, and race (self-identified). Controls had no history of VTE and did not receive anticoagulant therapy. Antigen and activity levels in cases were measured at least one month after completion of anticoagulation therapy. A priori cutoff levels for determining deficiency status were standardized per Centers for Disease Control Hemostasis Laboratory reference ranges. Beta hemoglobin genotype was determined by either a multiplex genotyping assay or sequencing of the beta hemoglobin gene. Differences in protein levels between cases and controls were compared using the Wilcoxon rank sum test. Conditional logistic regression analysis was performed to evaluate the association between protein S, protein C, or antithrombin deficiency and VTE. Crude models were conditioned on the matching factors, and adjusted models were conditioned on the matching factors and controlled for patient characteristics found to be associated with VTE and protein S, protein C, or antithrombin deficiency. Potential effect modification was assessed using likelihood ratio tests. Results: Among 2,454 subjects enrolled in the GATE study, 1,436 subjects (63.6%) had samples available for analysis. Protein S activity and total protein S antigen levels were significantly lower among VTE cases compared to controls in both white and black participants; however, antithrombin levels were higher among VTE cases compared to controls in white participants only. (Table 1) The prevalence of protein S and protein C deficiency was higher among VTE cases compared to controls in both white and black participants in the GATE study (Table 2). The prevalence of antithrombin deficiency was similar between VTE cases compared to controls. Adjusting for the effect of family history of VTE, history of cancer, and hemoglobin genotype, the effect of protein S and protein C deficiency on odds of VTE was stronger among black participants compared to white participants (Table 2). Conclusions: The effects of protein S and protein C deficiency on the odds of being a VTE case were higher among black participants in the GATE study, controlling for confounding variables including hemoglobin genotype. While these results indicate protein S and protein C deficiency may be important contributors to disparities in VTE occurrence, additional investigations using a larger study populations and different study designs are warranted. Disclosures Patel: Daiichi Sankyo: Other: DSMB member. Payne:Bioverativ: Other: treatment product donation; Novo Nordisk: Other: treatment product donation; Shire: Other: treatment product donation; Genentech: Membership on an entity's Board of Directors or advisory committees; Bayer: Other: treatment product donation.

Description: Factor H is a plasma protein that regulates activation of the alternative complement system. Mutations in the factor H gene are associated with a rare form of thrombotic microangiopathy, known as atypical hemolytic uremic syndrome. Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are characterized by systemic (TTP) or renal (HUS) microvascular thrombosis. The clinical presentations of TTP and HUS have some common clinical features, including the presence of thrombocytopenia, intravascular hemolysis, and mechanical injury to red cells. We investigated whether factor H has any interaction with proteins involved in the pathogenesis of thrombotic thrombocytopenic purpura, namely von Willebrand Factor (VWF) and ADAMTS-13. We found that factor H binds to the A1 and A2 domains of VWF, and inhibits cleavage of VWF by ADAMTS-13 under static and flowing conditions. Factor H deficient mice had a delayed thrombous formation after vessel wall injury, and showed a lower mortality rate and a higher platelet count after Shiga toxin/lipopolysaccharide challenge compared to their wild-type littermates. We concluded that factor H, in addition to its complement regulatory activity, might regulates cleavage of VWF by ADAMTS-13. Presence of an abnormal factor H that is unable to control complement activity on cell surfaces but still capable of inhibiting cleavage of VWF might contribute to the pathogenesis of thrombotic microangiopathies.