Background: Disease progression within < 2 years of initial chemoimmunotherapy and patient age > 60 years have been associated with poor overall survival (OS) in follicular lymphoma (FL). No standard treatment exists for these high-risk patients, and the effectiveness of sequential therapies remains unclear.
Patients and Methods: We studied the course of FL with first-, second-, and third-line treatment. Using large population-based data, we identified 5234 patients with FL diagnosed in 2000 to 2009. Of these patients, 71% had received second-line therapy < 2 years, and 29% had received no therapy after first-line therapy, with a median OS of < 3 years. Treatment included rituximab, R-CVP (rituximab, cyclophosphamide, vincristine), R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine), R-Other (other rituximab-containing), and other regimens. The Aalen-Johansen estimator and Cox proportional hazards models were used to quantify the outcomes and assess the effects of the clinical and sociodemographic factors. Results: R-CHOP demonstrated the most favorable 5-year OS among first- (71%), second- (55%), and third-line (61%) therapies. First-line R-CHOP improved OS (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.50-0.64) and reduced the mortality risks after first-line (HR, 0.60; 95% CI, 0.47-0.77), second-line (HR, 0.40; 95% CI, 0.29-0.53), and third-line (HR, 0.63; 95% CI, 0.53-0.76) treatments. B-symptoms, being married, and histologic grade 1/2 were associated with the use of earlier second-line therapy. Early progression from second- to third-line therapy was associated with poor OS. The repeated use of R-CHOP or R-CVP as first- and second-line treatment yielded high 2-year mortality rates (R-CHOP + R-CHOP, 17.3%; R-CVP + R-CVP, 21.1%).
Conclusion: Our multistate approach assessed the effect of sequential therapy on the immediate and subsequent treatment-line outcomes. We found that R-CHOP in any line improved OS for patients with high-risk FL.
SAMHD1 hydrolyzes 2′-deoxynucleoside-5′-triphosphates (dNTPs) into 2′-deoxynucleosides and inorganic triphosphate products. In this paper, we evaluated the impact of 2′ sugar moiety substitution for different nucleotides on being substrates for SAMHD1 and mechanisms of actions for the results. We found that dNTPs ((2′R)-2′-H) are only permissive in the catalytic site of SAMHD1 due to L150 exclusion of (2′R)-2′-F and (2′R)-2′-OH nucleotides. However, arabinose ((2′S)-2′-OH) nucleoside-5′-triphosphates analogs are permissive to bind in the catalytic site and be hydrolyzed by SAMHD1. Moreover, when the (2′S)-2′ sugar moiety is increased to a (2′S)-2′-methyl as with the SMDU-TP analog, we detect inhibition of SAMHD1's dNTPase activity. Our computational modeling suggests that (2′S)-2′-methyl sugar moiety clashing with the Y374 of SAMHD1. We speculate that SMDU-TP mechanism of action requires that the analog first docks in the catalytic pocket of SAMHD1 but prevents the A351-V378 helix conformational change from being completed, which is needed before hydrolysis can occur. Collectively we have identified stereoselective 2′ substitutions that reveal nucleotide substrate specificity for SAMHD1, and a novel inhibitory mechanism for the dNTPase activity of SAMHD1. Importantly, our data is beneficial for understanding if FDA-approved antiviral and anticancer nucleosides are hydrolyzed by SAMHD1 in vivo.
Objective: HIV-positive individuals are at higher risk than healthy persons for agingrelated diseases, including myocardial infarction and non-AIDS defining cancers. Recent evidence suggests that HIV infection may modulate changes in the host cell epigenome, and these changes represent a potential mechanism through which HIV infection accelerates aging. We assessed the difference in DNA methylation (DNAm) age, an aging marker involving multiple age-related cytosine-guanine dinucleotide (CpG) sites, among antiretroviral treatment (ART)-naive HIV-positive and HIV-negative individuals in a cohort of veterans from the Veterans Aging Cohort Study. Design: Peripheral blood samples were collected from 19 ART-naive, HIV-positive, and 19 HIV-negative male participants, matched by age and race. Blood samples were collected from HIV-positive participants 7-11 years after ART initiation. Methods: We compared DNAm age between HIV-positive and HIV-negative groups at baseline and between HIV-positive patients at baseline and follow-up. We also performed an epigenome-wide analysis to identify CpG methylation sites associated with HIV infection. Results: DNAm age in HIV-positive individuals is, on average, 11.2 years higher than HIV study participants at baseline, and two of 10 HIV-positive individuals showed an increase in DNAm age after ART initiation. Epigenome-wide association studies showed an association of HIV infection with one site, in gene VPS37B, which approached statistical significance in our cohort (P=3.30×10 -6 , Bonferroni-corrected threshold=1.22×10 -7 ) and was replicated in a second, larger cohort. Conclusion: ART treatment-naive HIV-positive individuals have significantly older DNAm age compared to HIV-negative individuals in the Veterans Aging Cohort Study cohort. Longitudinal changes in DNAm age are highly variable across individuals after initiation of antiretroviral therapy.
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James P Wirth;
Bradley A Woodruff;
Reina Engle-Stone;
Sorrel ML Namaste;
Victor J Temple;
Nicolai Petry;
Barbara Macdonald;
Parminder Suchdev;
Fabian Rohner;
Grant J Aaron
Background: Anemia in women of reproductive age (WRA) (age range: 15-49 y) remains a public health problem globally, and reducing anemia in women by 50% by 2025 is a goal of the World Health Assembly.Objective: We assessed the associations between anemia and multiple proximal risk factors (e.g., iron and vitamin A deficiencies, inflammation, malaria, and body mass index) and distal risk factors (e.g., education status, household sanitation and hygiene, and urban or rural residence) in nonpregnant WRA.Design: Cross-sectional, nationally representative data from 10 surveys (n = 27,018) from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project were analyzed individually and pooled by the infection burden and risk in the country. We examined the severity of anemia and measured the bivariate associations between anemia and factors at the country level and by infection burden, which we classified with the use of the national prevalences of malaria, HIV, schistosomiasis, sanitation, and water-quality indicators. Pooled multivariate logistic regression models were constructed for each infection-burden category to identify independent determinants of anemia (hemoglobin concertation < 120 g/L).Results: Anemia prevalence was ∼40% in countries with a high infection burden and 12% and 7% in countries with moderate and low infection burdens, respectively. Iron deficiency was consistently associated with anemia in multivariate models, but the proportion of anemic women who were iron deficient was considerably lower in the high-infection group (35%) than in the moderate- and low-infection groups (65% and 71%, respectively). In the multivariate analysis, inflammation, vitamin A insufficiency, socioeconomic status, and age were also significantly associated with anemia, but malaria and vitamin B-12 and folate deficiencies were not.Conclusions: The contribution of iron deficiency to anemia varies according to a country's infection burden. Anemia-reduction programs for WRA can be improved by considering the underlying infection burden of the population and by assessing the overlap of micronutrient deficiencies and anemia.
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Sandeep J. Joseph;
Daniel Cox;
Bernard Wolff;
Shatavia S. Morrison;
Natalia A. Kozak-Muiznieks;
Michael Frace;
Xavier Didelot;
Santiago Castillo-Ramirez;
Jonas Winchell;
Timothy Read;
Deborah Dean
Legionella species inhabit freshwater and soil ecosystems where they parasitize protozoa. L. pneumonphila (LP) serogroup-1 (Lp1) is the major cause of Legionnaires' Disease (LD), a life-threatening pulmonary infection that can spread systemically. The increased global frequency of LD caused by Lp and non-Lp species underscores the need to expand our knowledge of evolutionary forces underlying disease pathogenesis. Whole genome analyses of 43 strains, including all known Lp serogroups 1-17 and 17 emergent LD-causing Legionella species (of which 33 were sequenced in this study) in addition to 10 publicly available genomes, resolved the strains into four phylogenetic clades along host virulence demarcations. Clade-specific genes were distinct for genetic exchange and signal-transduction, indicating adaptation to specific cellular and/or environmental niches. CRISPR spacer comparisons hinted at larger pools of accessory DNA sequences in Lp than predicted by the pan-genome analyses. While recombination within Lp was frequent and has been reported previously, population structure analysis identified surprisingly few DNA admixture events between species. In summary, diverse Legionella LD-causing species share a conserved core-genome, are genetically isolated from each other, and selectively acquire genes with potential for enhanced virulence.
Background and objective: Morphologic variations of disease are often linked to underlying molecular events and patient outcome, suggesting that quantitative morphometric analysis may provide further insight into disease mechanisms. In this paper a methodology for the subclassification of disease is developed using image analysis techniques. Morphologic signatures that represent patient-specific tumor morphology are derived from the analysis of hundreds of millions of cells in digitized whole slide images. Clustering these signatures aggregates tumors into groups with cohesive morphologic characteristics. This methodology is demonstrated with an analysis of glioblastoma, using data from The Cancer Genome Atlas to identify a prognostically significant morphology-driven subclassification, in which clusters are correlated with transcriptional, genetic, and epigenetic events.
Materials and methods: Methodology was applied to 162 glioblastomas from The Cancer Genome Atlas to identify morphology-driven clusters and their clinical and molecular correlates. Signatures of patient-specific tumor morphology were generated from analysis of 200 million cells in 462 whole slide images. Morphology-driven clusters were interrogated for associations with patient outcome, response to therapy, molecular classifications, and genetic alterations. An additional layer of deep, genome-wide analysis identified characteristic transcriptional, epigenetic, and copy number variation events.
Results and discussion: Analysis of glioblastoma identified three prognostically significant patient clusters (median survival 15.3, 10.7, and 13.0 months, log rank p=1.4e-3). Clustering results were validated in a separate dataset. Clusters were characterized by molecular events in nuclear compartment signaling including developmental and cell cycle checkpoint pathways. This analysis demonstrates the potential of high-throughput morphometrics for the subclassification of disease, establishing an approach that complements genomics.
Neighborhood conditions and sexual network turnover have been associated with the acquisition of HIV and other sexually transmitted infections (STIs). However, few studies investigate the influence of neighborhood conditions on sexual network turnover. This longitudinal study used data collected across 7 visits from a predominantly substance-misusing cohort of 172 African American adults relocated from public housing in Atlanta, Georgia, to determine whether post-relocation changes in exposure to neighborhood conditions influence sexual network stability, the number of new partners joining sexual networks, and the number of partners leaving sexual networks over time. At each visit, participant and sexual network characteristics were captured via survey, and administrative data were analyzed to describe the census tracts where participants lived. Multilevel models were used to longitudinally assess the relationships of tract-level characteristics to sexual network dynamics over time. On average, participants relocated to neighborhoods that were less economically deprived and violent, and had lower alcohol outlet densities. Post-relocation reductions in exposure to alcohol outlet density were associated with fewer new partners joining sexual networks. Reduced perceived community violence was associated with more sexual partners leaving sexual networks. These associations were marginally significant. No post-relocation changes in place characteristics were significantly associated with overall sexual network stability. Neighborhood social context may influence sexual network turnover. To increase understanding of the social–ecological determinants of HIV/STIs, a new line of research should investigate the combined influence of neighborhood conditions and sexual network dynamics on HIV/STI transmission over time.
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Mauricio A. Martins;
Young C. Shin;
Lucas Gonzalez-Nieto;
Aline Domingues;
Martin J. Gutman;
Helen S. Maxwell;
Iris Castro;
Diogo M. Magnani;
Michael Ricciardi;
Nuria Pedreño-Lopez;
Varian Bailey;
Dillon Betancourt;
John Altman;
Matthias Pauthner;
Dennis R. Burton;
Benjamin von Bredow;
David T. Evans;
Maoli Yuan;
Christopher L. Parks;
Keisuke Ejima;
David B. Allison;
Eva Rakasz;
Glen N. Barber;
Saverio Capuano;
Jeffrey D. Lifson;
Ronald C. Desrosiers;
David I. Watkins
The ability to control lentivirus replication may be determined, in part, by the extent to which individual viral proteins are targeted by the immune system. Consequently, defining the antigens that elicit the most protective immune responses may facilitate the design of effective HIV-1 vaccines. Here we vaccinated four groups of rhesus macaques with a heterologous vector prime/boost/boost/boost (PBBB) regimen expressing the following simian immunodeficiency virus (SIV) genes: env, gag, vif, rev, tat, and nef (Group 1); env, vif, rev, tat, and nef (Group 2); gag, vif, rev, tat, and nef (Group 3); or vif, rev, tat, and nef (Group 4). Following repeated intrarectal challenges with a marginal dose of the neutralization-resistant SIVmac239 clone, vaccinees in Groups 1–3 became infected at similar rates compared to control animals. Unexpectedly, vaccinees in Group 4 became infected at a slower pace than the other animals, although this difference was not statistically significant. Group 1 exhibited the best post-acquisition virologic control of SIV infection, with significant reductions in both peak and chronic phase viremia. Indeed, 5/8 Group 1 vaccinees had viral loads of less than 2,000 vRNA copies/mL of plasma in the chronic phase. Vaccine regimens that did not contain gag (Group 2), env (Group 3), or both of these inserts (Group 4) were largely ineffective at decreasing viremia. Thus, vaccine-induced immune responses against both Gag and Env appeared to maximize control of immunodeficiency virus replication. Collectively, these findings are relevant for HIV-1 vaccine design as they provide additional insights into which of the lentiviral proteins might serve as the best vaccine immunogens.
Pools of mosquitoes collected in Côte d’Ivoire and Mexico were tested for cytopathic effects on the mosquito cell line C6/36. Seven pools induced strong cytopathic effects after one to five days post infection and were further investigated by deep sequencing. The genomes of six virus isolates from Côte d’Ivoire showed pairwise nucleotide identities of ∼99% among each other and of 56%-60% to Dezidougou virus and Wallerfield virus, two insect-specific viruses belonging to the proposed new taxon Negevirus. The novel virus was tentatively named Goutanap virus. The isolate derived from the Mexican mosquitoes showed 95% pairwise identity to Piura virus and was suggested to be a strain of Piura virus, named C6.7-MX-2008. Phylogenetic inferences based on a concatenated alignment of the methyltransferase, helicase, and RNA-dependent RNA polymerase domains showed that the new taxon Negevirus formed two monophyletic clades, named Nelorpivirus and Sandewavirus after the viruses grouping in these clades. Branch lengths separating these clades were equivalent to those of the related genera Cilevirus, Higrevirus and Blunervirus, as well as to those within the family Virgaviridae. Genetic distances and phylogenetic analyses suggest that Nelorpivirus and Sandewavirus might form taxonomic groups on genus level that may define alone or together with Cilevirus, Higrevirus and Blunervirus a viral family.
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Xuanping Zhang;
Giuseppina Imperatore;
William Thomas;
Yiling J. Cheng;
Felipe Lobelo;
Keri Norris;
Heather M. Devlin;
Mohammed Ali;
Stephanie Gruss;
Barbara Bardenheier;
Pyone Cho;
Isabel Garcia de Quevedo;
Uma Mudaliar;
Jinan Saaddine;
Linda S. Geiss;
Edward W. Gregg
This study systematically assessed the effectiveness of lifestyle interventions on glycemic indicators among adults (⩾18 years) without IGT or diabetes. Randomized controlled trials using physical activity (PA), diet (D), or their combined strategies (PA + D) with follow-up ⩾12 months were systematically searched from multiple electronic-databases between inception and May 4, 2016. Outcome measures included fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), fasting insulin (FI), homeostasis model assessment-estimated insulin resistance (HOMA-IR), and bodyweight. Included studies were divided into low-range (FPG <5.5 mmol/L or HbA1c <5.5%) and high-range (FPG ⩾5.5 mmol/L or HbA1c ⩾5.5%) groups according to baseline glycemic levels. Seventy-nine studies met inclusion criteria. Random-effect models demonstrated that compared with usual care, lifestyle interventions achieved significant reductions in FPG (−0.14 mmol/L [95%CI, −0.19, −0.10]), HbA1c (−0.06% [−0.09, −0.03]), FI (%change: −15.18% [−20.01, −10.35]), HOMA-IR (%change: −22.82% [−29.14, −16.51]), and bodyweight (%change: −3.99% [−4.69, −3.29]). The same effect sizes in FPG reduction (0.07) appeared among both low-range and high-range groups. Similar effects were observed among all groups regardless of lengths of follow-up. D and PA + D interventions had larger effects on glucose reduction than PA alone. Lifestyle interventions significantly improved FPG, HbA1c, FI, HOMA-IR, and bodyweight among adults without IGT or diabetes, and might reduce progression of hyperglycemia to type 2 diabetes mellitus.