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Germline SAMD9 and SAMD9L mutations (SAMD9/9L.sup.mut) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a clinically annotated pediatric MDS cohort (n = 669) to define the prevalence, genetic landscape, phenotype, therapy outcome and clonal architecture of SAMD9/9L syndromes. In consecutively diagnosed MDS, germline SAMD9/9L.sup.mut accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9L.sup.mut cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%; constitutional abnormalities were noted in 57%; and immune dysfunction was present in 28%. The clinical outcome was independent of germline mutations. In total, 67 patients had 58 distinct germline SAMD9/9L.sup.mut clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9L.sup.mut suppressed HEK293 cell growth, and mutations expressed in CD34.sup.+ cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9L.sup.mut patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7 [plus or minus] cancer mutations), and 51% had adaptive nature (revertant UPD7q, somatic SAMD9/9L.sup.mut). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9L.sup.mut MDS and exemplify the exceptional plasticity of hematopoiesis in children. This analysis of a large, clinically annotated cohort of individuals with predisposition to myelodysplastic syndromes reveals insights into the genetic determinants of disease progression and their relationship with clinical manifestations and therapy outcome., Author(s): Sushree S. Sahoo [sup.1] [sup.2] , Victor B. Pastor [sup.2] , Charnise Goodings [sup.1] , Rebecca K. Voss [sup.2] , Emilia J. Kozyra [sup.2] [sup.3] , Amina Szvetnik [sup.2] [...]

In this article, the static and the free vibration behavior of laminated woven glass/epoxy composite plate have been investigated numerically and validated through subsequent experimentation. The laminated composite shear deformable plate has been modelled mathematically using two different higher-order kinematic theories and the commercial finite element package (ANSYS). The domain has been discretized using the finite element steps and the desired responses (deflections and frequencies) are computed numerically using homemade computer code developed in MATLAB environment. The validity and the convergence behavior of developed models have been established by comparing the responses with those available published literature, simulation and the corresponding experiment. Finally, the effects of geometrical and material parameters (thickness ratio, modular ratio and support conditions) and the necessity of higher-order model for the analysis of laminated structure have been highlighted by solving wide variety of static and vibration examples. [ABSTRACT FROM AUTHOR]

Induced pluripotent stem cells (iPSCs) have emerged as powerful tools for in vitro modeling of bone marrow failure (BMF) syndromes and hereditary conditions predisposing to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). This review synthesizes recent advances in iPSC-based disease modeling for various inherited BMF/MDS disorders, including Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia syndrome, Shwachman-Diamond syndrome, and severe congenital neutropenia as well as GATA2, RUNX1, ETV6, ANKRD26, SAMD9, SAMD9L, and ADH5/ALDH2 syndromes. Although the majority of these iPSC lines are derived from patient cells, some are generated by introducing patient-specific mutations into healthy iPSC backgrounds, offering complementary approaches to disease modeling. The review highlights the ability of iPSCs to recapitulate key disease phenotypes, such as impaired hematopoietic differentiation, telomere dysfunction, and defects in DNA repair or ribosome biogenesis. We discuss how these models have enhanced our understanding of disease pathomechanisms, hematopoietic defects, and potential therapeutic approaches. Challenges in generating and maintaining disease-specific iPSCs are examined, particularly for disorders involving DNA repair. We emphasize the necessity of creating isogenic controls to elucidate genotype-phenotype relationships. Furthermore, we address limitations of current iPSC models, including genetic variability among iPSC clones derived from the same patient, and difficulties in achieving robust engraftment of iPSC-derived hematopoietic progenitor cells in mouse transplantation models. The review also explores future directions, including the potential of iPSC models for drug discovery and personalized medicine approaches. This review underscores the significance of iPSC technology in advancing our understanding of inherited hematopoietic disorders and its potential to inform novel therapeutic strategies., Competing Interests: Conflicts of Interest Disclosure SS received financial support from Aplastic Anemia & MDS International Foundation (grant no. NIH 1K99DK135910-01A1) and Edward P. Evans MDS Foundation. MWW received financial support from Edward P. Evans MDS Foundation, The Vera and Joseph Dresner Foundation, and German Federal Ministry of Education and Research (BMBF) 01GM1911A/01GM2207A “MyPred - Network for young individuals with syndromes predisposing to myeloid malignancies.” All other authors declare no conflict of interest pertaining to this work., (Copyright © 2024 International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)

Familial myelodysplastic syndromes arise from haploinsufficiency of genes involved in hematopoiesis and are primarily associated with early-onset disease. Here we describe a familial syndrome in seven patients from four unrelated pedigrees presenting with myelodysplastic syndrome and loss of chromosome 7/7q. Their median age at diagnosis was 2.1 years (range, 1-42). All patients presented with thrombocytopenia with or without additional cytopenias and a hypocellular marrow without an increase of blasts. Genomic studies identified constitutional mutations (p.H880Q, p.R986H, p.R986C and p.V1512M) in the SAMD9L gene on 7q21, with decreased allele frequency in hematopoiesis. The non-random loss of mutated SAMD9L alleles was attained via monosomy 7, deletion 7q, UPD7q, or acquired truncating SAMD9L variants p.R1188X and p.S1317RfsX21. Incomplete penetrance was noted in 30% (3/10) of mutation carriers. Long-term observation revealed divergent outcomes with either progression to leukemia and/or accumulation of driver mutations (n=2), persistent monosomy 7 (n=4), and transient monosomy 7 followed by spontaneous recovery with SAMD9L -wildtype UPD7q (n=2). Dysmorphic features or neurological symptoms were absent in our patients, pointing to the notion that myelodysplasia with monosomy 7 can be a sole manifestation of SAMD9L disease. Collectively, our results define a new subtype of familial myelodysplastic syndrome and provide an explanation for the phenomenon of transient monosomy 7. Registered at: www.clinicaltrials.gov; #NCT00047268 ., (Copyright© 2018 Ferrata Storti Foundation.)