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  • 1
    In: JAMA, American Medical Association (AMA), Vol. 329, No. 5 ( 2023-02-07), p. 376-
    Abstract: Anti–vascular endothelial growth factor (VEGF) injections in eyes with nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) reduce development of vision-threatening complications from diabetes over at least 2 years, but whether this treatment has a longer-term benefit on visual acuity is unknown. Objective To compare the primary 4-year outcomes of visual acuity and rates of vision-threatening complications in eyes with moderate to severe NPDR treated with intravitreal aflibercept compared with sham. The primary 2-year analysis of this study has been reported. Design, Setting, and Participants Randomized clinical trial conducted at 64 clinical sites in the US and Canada from January 2016 to March 2018, enrolling 328 adults (399 eyes) with moderate to severe NPDR (Early Treatment Diabetic Retinopathy Study [ETDRS] severity level 43-53) without CI-DME. Interventions Eyes were randomly assigned to 2.0 mg aflibercept (n = 200) or sham (n = 199). Eight injections were administered at defined intervals through 2 years, continuing quarterly through 4 years unless the eye improved to mild NPDR or better. Aflibercept was given in both groups to treat development of high-risk proliferative diabetic retinopathy (PDR) or CI-DME with vision loss. Main Outcomes and Measures Development of PDR or CI-DME with vision loss (≥10 letters at 1 visit or ≥5 letters at 2 consecutive visits) and change in visual acuity (best corrected ETDRS letter score) from baseline to 4 years. Results Among participants (mean age 56 years; 42.4% female; 5% Asian, 15% Black, 32% Hispanic, 45% White), the 4-year cumulative probability of developing PDR or CI-DME with vision loss was 33.9% with aflibercept vs 56.9% with sham (adjusted hazard ratio, 0.40 [97.5% CI, 0.28 to 0.57] ; P   & amp;lt; .001). The mean (SD) change in visual acuity from baseline to 4 years was −2.7 (6.5) letters with aflibercept and −2.4 (5.8) letters with sham (adjusted mean difference, −0.5 letters [97.5% CI, −2.3 to 1.3]; P  = .52). Antiplatelet Trialists’ Collaboration cardiovascular/cerebrovascular event rates were 9.9% (7 of 71) in bilateral participants, 10.9% (14 of 129) in unilateral aflibercept participants, and 7.8% (10 of 128) in unilateral sham participants. Conclusions and Relevance Among patients with NPDR but without CI-DME, at 4 years treatment with aflibercept vs sham, initiating aflibercept treatment only if vision-threatening complications developed, resulted in statistically significant anatomic improvement but no improvement in visual acuity. Aflibercept as a preventive strategy, as used in this trial, may not be generally warranted for patients with NPDR without CI-DME. Trial Registration ClinicalTrials.gov Identifier: NCT02634333
    Type of Medium: Online Resource
    ISSN: 0098-7484
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    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
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  • 2
    In: GeroScience, Springer Science and Business Media LLC, Vol. 44, No. 3 ( 2022-06), p. 1641-1655
    Abstract: Prolonging survival in good health is a fundamental societal goal. However, the leading determinants of disability-free survival in healthy older people have not been well established. Data from ASPREE, a bi-national placebo-controlled trial of aspirin with 4.7 years median follow-up, was analysed. At enrolment, participants were healthy and without prior cardiovascular events, dementia or persistent physical disability. Disability-free survival outcome was defined as absence of dementia, persistent disability or death. Selection of potential predictors from amongst 25 biomedical, psychosocial and lifestyle variables including recognized geriatric risk factors, utilizing a machine-learning approach. Separate models were developed for men and women. The selected predictors were evaluated in a multivariable Cox proportional hazards model and validated internally by bootstrapping. We included 19,114 Australian and US participants aged ≥65 years (median 74 years, IQR 71.6–77.7). Common predictors of a worse prognosis in both sexes included higher age, lower Modified Mini-Mental State Examination score, lower gait speed, lower grip strength and abnormal (low or elevated) body mass index. Additional risk factors for men included current smoking, and abnormal eGFR. In women, diabetes and depression were additional predictors. The biased-corrected areas under the receiver operating characteristic curves for the final prognostic models at 5 years were 0.72 for men and 0.75 for women. Final models showed good calibration between the observed and predicted risks. We developed a prediction model in which age, cognitive function and gait speed were the strongest predictors of disability-free survival in healthy older people. Trial registration Clinicaltrials.gov (NCT01038583)
    Type of Medium: Online Resource
    ISSN: 2509-2715 , 2509-2723
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 3
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 21, No. 2 ( 2015-02), p. 266-274
    Type of Medium: Online Resource
    ISSN: 1083-8791
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2015
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  • 4
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 25-25
    Abstract: Introduction: There is strong experimental and clinical data to indicate the critical involvement of immune evasion in relapsed leukemia in children. A well-defined characteristic of refractory leukemia is the accumulation of genetic aberrations and mutations that may act as drivers or passengers in the process of tumor recurrence. Many of these mutations get translated into proteins that contain tumor-specific immune-stimulatory epitopes (neoantigens) that can elicit host antitumor immune responses. Although, in general, the mutation rate is lower in pediatric tumors, recent studies have shown that almost 90% of pediatric leukemias carry potentially actionable neoepitopes. In this study, we describe the results from a comprehensive experimental approach of neoantigen prediction coupled with antigen processing and HLA-binding prediction algorithms with in vitro validation assays for the generation of neoantigen vaccines against high-risk leukemias in children. Methods: DNA and RNA from leukemia cells and matched fibroblasts were obtained. Raw reads were aligned to human reference genome and somatic variants (SNVs) were called using Strelka v1.0.1441. RNA-seq data from leukemic cells were used to predict neoantigen expression levels resulting from SNVs using STAR (2.4.1)12 and Cufflinks v2.2.1. Normalized expression data were then cross-referenced with the list of SNVs to identify leukemia-specific mutant proteins. HLA typing for each sample was carried out from RNA-seq data using seq2HLA v2.2. Using the patient's HLA phenotype, we then used NetMHCons v1.1 to predict short peptides derived from leukemia-specific mutant proteins that will bind to autologous HLA Class I molecules. These 8/9-mers were filtered to predict a high likelihood of proteasomal or immune-proteasomal processing and transporter associated with antigen processing (TAP) using NetChop v3.1 and the immune epitope database (IEDB), respectively. The peptides identified were rank-ordered based on the composite immunogenicity score derived from MHC class I binding affinities, proteasomal processing and TCR binding predictions and synthesized accordingly. Peripheral blood derived dendritic cells (DCs) and CD8+ T-cells were isolated and expanded in culture with relevant cytokines. The DCs were pulsed with peptides and then co-cultured with CD8+ T-cells. After five days, the primed CD8+ T-Cells were separated, washed and exposed to the patient's leukemic cells at varying ratios and the leukemia specific CD8+ T-cell activation was quantified by IFN gamma secretion using ELISpot assays. Results: In the leukemia specimen studied, approximately 5% of all on-target germline mutations were found only in leukemic cells. Tumor mutational burden was, on average, 0.34 mut/Mb. Analysis of the highest ranking synthetic peptides (approximately 10 per leukemia sample) showed leukemia-specific activation of patient's T-cells as measured by the mean number of spots observed in ELISpot assays. For example, in patient one (15 year old male, high-risk ALL, one year off therapy), 14 individual short sequences were identified and corresponding peptides were synthesized. Among these, three peptides were not soluble and three peptides showed significant activity above controls. Maximum leukemia specific T-cell activation was noted with peptide #7 QQSALVLL (mean 135 ELISpots compared to 72 in controls, p & lt;0.05, triplicate) indicating a strong nonantigenic potential in this region. Furthermore, this activity was significantly diminished when an extra amino acid was added to this peptide (LQQSALVLL, mean 79 spots) showing the specificity of the approach. A number of other peptides and combinations in non-overlapping regions gave intermediate activities. Discussion: Completed data, including the vaccine peptide sequences and corresponding activities showed the feasibility of identifying pediatric leukemia neoantigen sequences in personalized mutational landscapes of these patients. In addition, we have provided an in vitro experimental approach to validate the potential of such vaccines in future clinical studies and this methodology can also be used to identify agents for effective combinations such as immune checkpoint inhibitors. A clinical trial using these strategies is in development for the treatment of high-risk leukemia in children. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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  • 5
    In: Genetics in Medicine, Elsevier BV, Vol. 13, No. 3 ( 2011-03), p. 230-254
    Type of Medium: Online Resource
    ISSN: 1098-3600
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2011
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  • 6
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3074-3074
    Abstract: Abstract 3074 Children with high-risk NB often receive using multiple treatment modalities including autoHCT. Disease remains the most common cause of treatment failure and the most recent cooperative group studies report survival rates approaching 45%. Prior reports showed comparable outcomes of patients with NB receiving auto- and allo-transplants, despite differences in relapse risk and treatment-related mortality (TRM). To update these data the CIBMTR conducted a retrospective review of 143 transplants reported 1990–2007 at 61centers, the largest group reported to date. For this analysis, patients were categorized into 2 groups for comparison: those without (Group 1; n=97) and those with a prior auto HCT (Group 2; n=46). Of the patients in Group 1, 31% were in first remission, 25% in partial response (PR) or very good PR (VGPR), and 24% with no response or with persistent/progressive disease. Of the patients Group 2, 17% were in first remission, 26% in PR or VGPR, and 28% with no response or with persistent/progressive disease. Median ages at alloHCT were similar for Group 1 (5y, range 〈 1 to 55) and Group 2 (7y, range 2–32), while the median time from diagnosis to alloHCT was shorter (9 mo) for Group 1 than Group 2 (27 mo). In Group 1, 57% received grafts from HLA-matched related donors, 27% from mismatched related donors and 16% from unrelated donors. In Group 2, 39% received grafts from matched related donors, 9% from mismatched related donors and 52% from unrelated donors. In Group 1, stem cell sources were marrow (71%), peripheral blood (10%) and cord blood (16%). In Group 2, stem cell sources were marrow (35%), peripheral blood (28%) and cord blood (37%). There was no difference in the prevalence of acute (p=.15) or chronic GVHD (p=.24) between the two groups. Median follow-up was 84 months (range, 〈 1 to 191) and 45 months (range 1 to 58) for those without and with prior autologous HCT. 1 year and 5 year OS were 59% and 29% for Group 1 and 50% and 7% for Group 2. Table 1 outlines the univariate analysis of some outcomes for the groups:Group 1: No prior AutoGroup 2: prior Autop-ValueTRM 100 days 1-year3% (1–9)2% (0–11)0.905825% (16–35)24% (12–37)0.8916Relapse 1-year 5-year27% (17–38)57% (41–70)0.001246% (34–58)70% (53–82)0.0123EFS 1-year 5-year48% (36–59)19% (9–32)0.000627% (17–38)6%A (1–17)0.0018OS 1-year 5-year59% (48–68)50% (35–64)0.343929% (20–39)7% (1–18)0.0005 Univariate analysis by donor-type also indicated higher relapse rates after unrelated donor transplants and lower relapse rates after HLA-mismatched related transplants compared with HLA-identical related donor transplants (p 〈 0.0001). EFS and survival were significantly lower for unrelated donor transplants 1 and 3 years but not 5 years post-HCT. Patients in 1st CR at transplant had lower relapse rates and better EFS and survival compared to those not in 1st CR. The presence of acute and/or chronic GVHD did not correlate with outcome in univariate analyses. The most common causes of death in Groups 1 vs. 2 were relapse (64%/75%), GVHD (5%/0%), infections (11%/5%), and organ toxicity (11%/13%). Our analysis indicates that alloHCT can cure some NB patients, with lower relapse rates and improved survival in patients without a history of autoHCT compared with those patients who had undergone auto HCT first. AlloHCT for patients after autoHCT does not seem to offer benefit. However, the reasons for Group 1 patients not receiving autoHCT as part of their upfront therapy are unclear, and this group could include patients who were curable without alloHCT. Disease recurrence remains the most common cause of treatment failure while TRM is low. Future studies comparing OS after autoHCT and alloHCT for patients in CR1 should be considered. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 7
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 291, No. 5507 ( 2001-02-16), p. 1304-1351
    Abstract: A 2.91-billion base pair (bp) consensus sequence of the euchromatic portion of the human genome was generated by the whole-genome shotgun sequencing method. The 14.8-billion bp DNA sequence was generated over 9 months from 27,271,853 high-quality sequence reads (5.11-fold coverage of the genome) from both ends of plasmid clones made from the DNA of five individuals. Two assembly strategies—a whole-genome assembly and a regional chromosome assembly—were used, each combining sequence data from Celera and the publicly funded genome effort. The public data were shredded into 550-bp segments to create a 2.9-fold coverage of those genome regions that had been sequenced, without including biases inherent in the cloning and assembly procedure used by the publicly funded group. This brought the effective coverage in the assemblies to eightfold, reducing the number and size of gaps in the final assembly over what would be obtained with 5.11-fold coverage. The two assembly strategies yielded very similar results that largely agree with independent mapping data. The assemblies effectively cover the euchromatic regions of the human chromosomes. More than 90% of the genome is in scaffold assemblies of 100,000 bp or more, and 25% of the genome is in scaffolds of 10 million bp or larger. Analysis of the genome sequence revealed 26,588 protein-encoding transcripts for which there was strong corroborating evidence and an additional ∼12,000 computationally derived genes with mouse matches or other weak supporting evidence. Although gene-dense clusters are obvious, almost half the genes are dispersed in low G+C sequence separated by large tracts of apparently noncoding sequence. Only 1.1% of the genome is spanned by exons, whereas 24% is in introns, with 75% of the genome being intergenic DNA. Duplications of segmental blocks, ranging in size up to chromosomal lengths, are abundant throughout the genome and reveal a complex evolutionary history. Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems. DNA sequence comparisons between the consensus sequence and publicly funded genome data provided locations of 2.1 million single-nucleotide polymorphisms (SNPs). A random pair of human haploid genomes differed at a rate of 1 bp per 1250 on average, but there was marked heterogeneity in the level of polymorphism across the genome. Less than 1% of all SNPs resulted in variation in proteins, but the task of determining which SNPs have functional consequences remains an open challenge.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2001
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  • 8
    In: Blood, American Society of Hematology, Vol. 116, No. 19 ( 2010-11-11), p. 4007-4015
    Abstract: Although some trials have allowed matched or single human leukocyte antigen (HLA)–mismatched related donors (mmRDs) along with HLA-matched sibling donors (MSDs) for pediatric bone marrow transplantation in early-stage hematologic malignancies, whether mmRD grafts lead to similar outcomes is not known. We compared patients 〈 18 years old reported to the Center for International Blood and Marrow Transplant Research with acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and myelodysplastic syndrome undergoing allogeneic T-replete, myeloablative bone marrow transplantation between 1993 and 2006. In total, patients receiving bone marrow from 1208 MSDs, 266 8/8 allelic-matched unrelated donors (URDs), and 151 0-1 HLA-antigen mmRDs were studied. Multivariate analysis showed that recipients of MSD transplants had less transplantation-related mortality, acute graft-versus-host disease (GVHD), and chronic GVHD, along with better disease-free and overall survival than the URD and mmRD groups. No differences were observed in transplant-related mortality, acute and chronic GVHD, relapse, disease-free survival, or overall survival between the mmRD and URD groups. These data show that mmRD and 8/8 URD outcomes are similar, whereas MSD outcomes are superior to the other 2 sources. Whether allele level typing could identify mmRD recipients with better outcomes will not be known unless centers alter practice and type mmRD at the allele level.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 9
    In: Blood Advances, American Society of Hematology, Vol. 7, No. 14 ( 2023-07-25), p. 3612-3623
    Abstract: The National Institutes of Health Consensus criteria for chronic graft-versus-host disease (cGVHD) diagnosis can be challenging to apply in children, making pediatric cGVHD diagnosis difficult. We aimed to identify diagnostic pediatric cGVHD biomarkers that would complement the current clinical criteria and help differentiate cGVHD from non-cGVHD. The Applied Biomarkers of Late Effects of Childhood Cancer (ABLE) study, open at 27 transplant centers, prospectively evaluated 302 pediatric patients after hematopoietic cell transplant (234 evaluable). Forty-four patients developed cGVHD. Mixed and fixed effect regression analyses were performed on diagnostic cGVHD onset blood samples for cellular and plasma biomarkers, with individual markers declared relevant if they met 3 criteria: an effect ratio ≥1.3 or ≤0.75; an area under the curve (AUC) of ≥0.60; and a P value & lt;5.814 × 10−4 (Bonferroni correction) (mixed effect) or & lt;.05 (fixed effect). To address the complexity of cGVHD diagnosis in children, we built a machine learning–based classifier that combined multiple cellular and plasma biomarkers with clinical factors. Decreases in regulatory natural killer cells, naïve CD4 T helper cells, and naïve regulatory T cells, and elevated levels of CXCL9, CXCL10, CXCL11, ST2, ICAM-1, and soluble CD13 (sCD13) characterize the onset of cGVHD. Evaluation of the time dependence revealed that sCD13, ST2, and ICAM-1 levels varied with the timing of cGVHD onset. The cGVHD diagnostic classifier achieved an AUC of 0.89, with a positive predictive value of 82% and a negative predictive value of 80% for diagnosing cGVHD. Our polyomic approach to building a diagnostic classifier could help improve the diagnosis of cGVHD in children but requires validation in future prospective studies. This trial was registered at www.clinicaltrials.gov as #NCT02067832.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2023
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  • 10
    In: Nature, Springer Science and Business Media LLC, Vol. 443, No. 7108 ( 2006-9), p. 218-221
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2006
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