Late Effects in Hematopoietic Cell Transplant Recipients with Acquired Severe Aplastic Anemia: A Report from the Late Effects Working Committee of the Center for International Blood and Marrow Transplant Research

With improvements in hematopoietic cell transplant (HCT) outcomes for severe aplastic anemia (SAA), there is a growing population of SAA survivors after HCT. However, there is a paucity of information regarding late effects that occur after HCT in SAA survivors. This study describes the malignant and nonmalignant late effects in survivors with SAA after HCT. A descriptive analysis was conducted of 1718 patients post-HCT for acquired SAA between 1995 and 2006 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). the prevalence and cumulative incidence estimates of late effects are reported for 1-year HCT survivors with SAA. of the HCT recipients, 1176 (68.5%) and 542 (31.5%) patients underwent a matched sibling donor (MSD) or unrelated donor (URD) HCT, respectively. the median age at the time of HCT was 20 years. the median interval from diagnosis to transplantation was 3 months for MSD HCT and 14 months for URD HCT. the median follow-up was 70 months and 67 months for MSD and URD HCT survivors, respectively. Overall survival at I year, 2 years, and 5 years for the entire cohort was 76% (95% confidence interval [CI]: 74-78), 73% (95% CI: 71-75), and 70% (95% CI: 68-72). Among 1-year survivors of MSD HCT, 6% had 1 late effect and 1% had multiple late effects. for 1-year survivors of URD HCT, 13% had 1 late effect and 2% had multiple late effects. Among survivors of MSD HCT, the cumulative incidence estimates of developing late effects were all <3% and did not increase over time. in contrast, for recipients of URD HCT, the cumulative incidence of developing several late effects exceeded 3% by 5 years: gonadal dysfunction 10.5% (95% CI: 7.3-14.3), growth disturbance 7.2% (95% CI: 4.4-10.7), avascular necrosis 6.3% (95% CI: 3.6-9.7), hypothyroidism 5.5% (95% CI: 2.8-9.0), and cataracts 5.1% (95% CI: 2.9-8.0). Our results indicated that all patients undergoing HCT for SAA remain at risk for late effects, must be counseled about, and should be monitored for late effects for the remainder of their lives.Public Health Service Grant from the National Cancer InstituteNational Heart, Lung, and Blood InstituteNational Institute of Allergy and Infectious DiseasesNational Cancer InstituteHealth Resources and Services Administration/Department of Health and Human ServicesOffice of Naval ResearchAllosAmgenAngioblastChildrens Hosp Orange Cty, Dept Hematol, Orange, CA 92668 USACIBMTR Med Coll Wisconsin, Dept Biostat, Milwaukee, WI USAMed Coll Wisconsin, CIBMTR Stat Ctr, Milwaukee, WI 53226 USAKing Faisal Specialist Hosp & Res Ctr, Dept Oncol, Riyadh 11211, Saudi ArabiaNew York Med Coll, Dept Pediat Hematol Oncol & Stem Cell Transplanta, Valhalla, NY 10595 USAStemcyte, Covina, CA USADana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USAUniv Florida, Dept Hematol Oncol, Gainesville, FL USAPrincess Margaret Hosp, Dept Med, Toronto, ON M4X 1K9, CanadaUniv S Florida, All Childrens Hosp, Dept Pediat Hematol & Oncol, St Petersburg, FL 33701 USAUniv Basel Hosp, Dept Hematol, CH-4031 Basel, SwitzerlandOregon Hlth & Sci Univ, Dept Hematol & Oncol, Portland, OR 97201 USAChildrens Natl Med Ctr, Dept Blood & Marrow Transplantat, Washington, DC 20010 USABaylor Coll Med, Ctr Cell Therapy, Dept Hematol & Oncol, Houston, TX 77030 USAUniv N Carolina Hosp, Dept Pediat, Chapel Hill, NC USAUniv Hosp Case, Med Ctr, Dept Med, Cleveland, OH USAUniv Arkansas Med Sci, Dept Hematol & Oncol, Little Rock, AR 72205 USACincinnati Childrens Hosp Med Ctr, Dept Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH USATufts Med Ctr, Dept Med & Pediat, Boston, MA USAUniv S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Hematol & Oncol, Tampa, FL 33612 USAFlorida Ctr Cellular Therapy, Dept Med, Orlando, FL USAUniv Fed Parana, Dept Bone Marrow Transplantat, BR-80060000 Curitiba, Parana, BrazilVanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USAInst Oncol Pediat, Dept Pediat, São Paulo, BrazilFred Hutchinson Canc Res Ctr, Dept Clin Res & Transplantat, Seattle, WA 98104 USAMt Sinai Med Ctr, Dept Bone Marrow & Stem Cell Transplantat, New York, NY 10029 USAUniv N Carolina Hosp, Dept Hematol & Oncol, Chapel Hill, NC USAUniv Manitoba, CancerCare Manitoba, Dept Manitoba Blood & Marrow Transplant Program, Winnipeg, MB, CanadaKarolinska Univ Hosp, Ctr Allogene Stem Cell Transplantat, Dept Pediat, Stockholm, SwedenLouisiana State Univ, Hlth Sci Ctr, Childrens Hosp, Dept Pediat, New Orleans, LA USADept Natl Marrow Donor Program, Minneapolis, MN USAPublic Health Service Grant from the National Cancer Institute: U24-CA76518National Heart, Lung, and Blood Institute: 5U01HL069294Office of Naval Research: N00014-06-1-0704Office of Naval Research: N00014-08-1-0058HHSH234200637015CWeb of Scienc

Late effects in hematopoietic cell transplant recipients with acquired severe aplastic anemia: a report from the late effects working committee of the center for international blood and marrow transplant research (CIBMTR)

CHOC Children’s Hospital - UC Irvine, Orange, CAMedical College of Wisconsin, Milwaukee, WIMedical College of Wisconsin, Milwaukee, WIKing Faisal Specialist Hospital and Research Center, Riyadh, TX, Saudi ArabiaNew York Medical College, Valhalla, NYStemcyte, Covina, CADana Farber Cancer Institute, Boston, MAUniversity of Florida, Gainesville, FLPrincess Margaret Hospital, Toronto, ON, CanadaAll Children’s Hospital, St. Petersburg, FLUniversity Hospital Basel, Basel, SwitzerlandOregon Health and Science University, Portland, ORChildren’s National Medical Center, Washington, DCBaylor College of Medicine Center for Cell Therapy, Houston, TXUniversity of North Carolina Hospitals, Chapel Hill, NCUniversity Hospitals Case Medical Center, Cleveland, OHUniversity of Arkansas for Medical Sciences, Little Rock, ARCincinnati Children’s Hospital Medical Center, Cincinnati, OHTufts Medical Center, Boston, MAH Lee Moffitt Cancer Center and Research Institute, Tampa, FLFlorida Center for Cellular Therapy, Orlando, FLUniversidade Federal de Parana, Curitiba, BrazilVanderbilt University Medical Center, Nashville, TNInstituto de Oncologia Pediatrica, Sao Paulo, BrazilFred Hutchinson Cancer Research Center, Seattle, WAMount Sinai Medical Center, New York, NYUniversity of North Carolina, Chapel Hill, NCCancerCare Manitoba, University of Manitoba, Winnipeg, CanadaKarolinska University Hospital, Center for Allogeneic Stem Cell Transplantation, Stockholm, SwedenChildrens Hospital LSU Health Sciences Center, New Orleans, LANational Marrow Donor Program, Minneapolis, MNWeb of Scienc

Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders

Background: De novo missense variants in CDK13 have been described as the cause of syndromic congenital heart defects in seven individuals ascertained from a large congenital cardiovascular malformations cohort. We aimed to further define the phenotypic and molecular spectrum of this newly described disorder. Methods: To minimise ascertainment bias, we recruited nine additional individuals with CDK13 pathogenic variants from clinical and research exome laboratory sequencing cohorts. Each individual underwent dysmorphology exam and comprehensive medical history review. Results: We demonstrate greater than expected phenotypic heterogeneity, including 33% (3/9) of individuals without structural heart disease on echocardiogram. There was a high penetrance for a unique constellation of facial dysmorphism and global developmental delay, as well as less frequently seen renal and sacral anomalies. Two individuals had novel CDK13 variants (p.Asn842Asp, p.Lys734Glu), while the remaining seven unrelated individuals had a recurrent, previously published p.Asn842Ser variant. Summary of all variants published to date demonstrates apparent restriction of pathogenic variants to the protein kinase domain with clustering in the ATP and magnesium binding sites. Conclusions: Here we provide detailed phenotypic and molecular characterisation of individuals with pathogenic variants in CDK13 and propose management guidelines based upon the estimated prevalence of anomalies identified. Keywords: CDK13, CHDFIDD, De novo variant, Neurodevelopmental disorders, Agenesis of the corpus callosum, Hypertelorism, Developmental delay, Cyclin-dependent kinase, Undiagnosed Diseases Networ

Endothelial Cell Capture of Heparin-Binding Growth Factors under Flow

Circulation is an important delivery method for both natural and synthetic molecules, but microenvironment interactions, regulated by endothelial cells and critical to the molecule's fate, are difficult to interpret using traditional approaches. In this work, we analyzed and predicted growth factor capture under flow using computer modeling and a three-dimensional experimental approach that includes pertinent circulation characteristics such as pulsatile flow, competing binding interactions, and limited bioavailability. An understanding of the controlling features of this process was desired. The experimental module consisted of a bioreactor with synthetic endothelial-lined hollow fibers under flow. The physical design of the system was incorporated into the model parameters. The heparin-binding growth factor fibroblast growth factor-2 (FGF-2) was used for both the experiments and simulations. Our computational model was composed of three parts: (1) media flow equations, (2) mass transport equations and (3) cell surface reaction equations. The model is based on the flow and reactions within a single hollow fiber and was scaled linearly by the total number of fibers for comparison with experimental results. Our model predicted, and experiments confirmed, that removal of heparan sulfate (HS) from the system would result in a dramatic loss of binding by heparin-binding proteins, but not by proteins that do not bind heparin. The model further predicted a significant loss of bound protein at flow rates only slightly higher than average capillary flow rates, corroborated experimentally, suggesting that the probability of capture in a single pass at high flow rates is extremely low. Several other key parameters were investigated with the coupling between receptors and proteoglycans shown to have a critical impact on successful capture. The combined system offers opportunities to examine circulation capture in a straightforward quantitative manner that should prove advantageous for biologicals or drug delivery investigations

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities for ultra-rare inherited bleeding disorders.

BACKGROUND: Ultra-rare inherited bleeding disorders (BDs) present important challenges for generating a strong evidence foundation for optimal diagnosis and management. Without disorder-appropriate treatment, affected individuals potentially face life-threatening bleeding, delayed diagnosis, suboptimal management of invasive procedures, psychosocial distress, pain, and decreased quality-of-life. RESEARCH DESIGN AND METHODS: The National Hemophilia Foundation (NHF) and the American Thrombosis and Hemostasis Network identified the priorities of people with inherited BDs and their caregivers, through extensive inclusive community consultations, to inform a blueprint for future decades of research. Multidisciplinary expert Working Group (WG) 3 distilled highly feasible transformative ultra-rare inherited BD research opportunities from the community-identified priorities. RESULTS: WG3 identified three focus areas with the potential to advance the needs of all people with ultra-rare inherited BDs and scored the feasibility, impact, and risk of priority initiatives, including 13 in systems biology and mechanistic science; 2 in clinical research, data collection, and research infrastructure; and 5 in the regulatory process for novel therapeutics and required data collection. CONCLUSIONS: Centralization and expansion of expertise and resources, flexible innovative research and regulatory approaches, and inclusion of all people with ultra-rare inherited BDs and their health care professionals will be essential to capitalize on the opportunities outlined herein

Identification of novel candidate disease genes from de novo exonic copy number variants

Background: Exon-targeted microarrays can detect small ( Methods: We retrospectively analyzed data from 63,127 patients referred for clinical chromosomal microarray analysis (CMA) at Baylor Genetics laboratories, including 46,755 individuals tested using exon-targeted arrays, from 2007 to 2017. Small CNVs harboring a single gene or two to five non-disease-associated genes were identified; the genes involved were evaluated for a potential disease association. Results: In this clinical population, among rare CNVs involving any single gene reported in 7200 patients (11%), we identified 145 de novo autosomal CNVs (117 losses and 28 intragenic gains), 257 X-linked deletion CNVs in males, and 1049 inherited autosomal CNVs (878 losses and 171 intragenic gains); 111 known disease genes were potentially disrupted by de novo autosomal or X-linked (in males) single-gene CNVs. Ninety-one genes, either recently proposed as candidate disease genes or not yet associated with diseases, were disrupted by 147 singlegene CNVs, including 37 de novo deletions and ten de novo intragenic duplications on autosomes and 100 X-linked CNVs in males. Clinical features in individuals with de novo or X-linked CNVs encompassing at most five genes (224 bp to 1.6 Mb in size) were compared to those in individuals with larger-sized deletions (up to 5 Mb in size) in the internal CMA database or loss-of-function single nucleotide variants (SNVs) detected by clinical or research whole-exome sequencing (WES). This enabled the identification of recently published genes (BPTF, NONO, PSMD12, TANGO2, and TRIP12), novel candidate disease genes (ARGLU1 and STK3), and further confirmation of disease association for two recently proposed disease genes (MEIS2 and PTCHD1). Notably, exon-targeted CMA detected several pathogenic single-exon CNVs missed by clinical WES analyses. Conclusions: Together, these data document the efficacy of exon-targeted CMA for detection of genic and exonic CNVs, complementing and extending WES in clinical diagnostics, and the potential for discovery of novel disease genes by genome-wide assay.Peer reviewe