Medicine and Health Sciences Commons^™

Clonal Hematopoiesis In Survivors Of Childhood Cancer, Danielle Novetsky Friedman, Irenaeus C C Chan, Kimberly Turner, Jie Liu, Megan A Cooper, Iskra Pusic, Geoffrey Uy, Daniel Link, Kelly L Bolton, Et Al.

2020-Current year OA Pubs

No abstract provided.

Location Of Pathogenic Variants In Psen1 Impacts Progression Of Cognitive, Clinical, And Neurodegenerative Measures In Autosomal-Dominant Alzheimer's Disease, Stephanie A Schultz, Eric Mcdade, Nicolas R Barthelemy, Nelly Joseph-Mathurin, Carlos Cruchaga, Charles D Chen, Tammie L S Benzinger, Anne M Fagan, Brian A Gordon, Jason J Hassenstab, Celeste M Karch, John C Morris, Richard J Perrin, Chengjie Xiong, Randall J Bateman, Et Al.

2020-Current year OA Pubs

Although pathogenic variants in PSEN1 leading to autosomal-dominant Alzheimer disease (ADAD) are highly penetrant, substantial interindividual variability in the rates of cognitive decline and biomarker change are observed in ADAD. We hypothesized that this interindividual variability may be associated with the location of the pathogenic variant within PSEN1. PSEN1 pathogenic variant carriers participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study were grouped based on whether the underlying variant affects a transmembrane (TM) or cytoplasmic (CY) protein domain within PSEN1. CY and TM carriers and variant non-carriers (NC) who completed clinical evaluation, multimodal neuroimaging, and lumbar puncture for collection …

Cation Leak Through The Atp1a3 Pump Causes Spasticity And Intellectual Disability, Daniel G Calame, Marwan Shinawi, Et Al.

2020-Current year OA Pubs

ATP1A3 encodes the α3 subunit of the sodium-potassium ATPase, one of two isoforms responsible for powering electrochemical gradients in neurons. Heterozygous pathogenic ATP1A3 variants produce several distinct neurological syndromes, yet the molecular basis for phenotypic variability is unclear. We report a novel recurrent variant, ATP1A3(NM_152296.5):c.2324C>T; p.(Pro775Leu), in nine individuals associated with the primary clinical features of progressive or non-progressive spasticity and developmental delay/intellectual disability. No patients fulfil diagnostic criteria for ATP1A3-associated syndromes, including alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism or cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss (CAPOS), and none were suspected of having an ATP1A3-related disorder. Uniquely among known …

Pact: A Pipeline For Analysis Of Circulating Tumor Dna, Jace Webster, Ha X Dang, Pradeep S Chauhan, Wenjia Feng, Alex Shiang, Peter K Harris, Russell K Pachynski, Aadel A Chaudhuri, Christopher A Maher

2020-Current year OA Pubs

MOTIVATION: Detection of genomic alterations in circulating tumor DNA (ctDNA) is currently used for active clinical monitoring of cancer progression and treatment response. While methods for analysis of small mutations are more developed, strategies for detecting structural variants (SVs) in ctDNA are limited. Additionally, reproducibly calling small-scale mutations, copy number alterations, and SVs in ctDNA is challenging due to the lack to unified tools for these different classes of variants.

RESULTS: We developed a unified pipeline for the analysis of ctDNA [Pipeline for the Analysis of ctDNA (PACT)] that accurately detects SVs and consistently outperformed similar tools when applied to …

Positron Emission Tomography And Magnetic Resonance Imaging Methods And Datasets Within The Dominantly Inherited Alzheimer Network (Dian), Nicole S Mckay, Brian A Gordon, Russ C Hornbeck, Aylin Dincer, Shaney Flores, Sarah J Keefe, Nelly Joseph-Mathurin, Peter R Millar, Beau M Ances, Charles D Chen, Alisha Daniels, Diana A Hobbs, Kelley Jackson, Deborah Koudelis, Parinaz Massoumzadeh, Austin Mccullough, Michael L Nickels, Farzaneh Rahmani, Laura Swisher, Qing Wang, Carlos Cruchaga, Jason Hassenstab, Celeste Karch, Eric Mcdade, Richard J Perrin, Chengjie Xiong, John C Morris, Randall J Bateman, Tammie L S Benzinger, Et Al.

2020-Current year OA Pubs

The Dominantly Inherited Alzheimer Network (DIAN) is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). ADAD arises from mutations occurring in three genes. Offspring from ADAD families have a 50% chance of inheriting their familial mutation, so non-carrier siblings can be recruited for comparisons in case-control studies. The age of onset in ADAD is highly predictable within families, allowing researchers to estimate an individual's point in the disease trajectory. These characteristics allow candidate AD biomarker measurements to be reliably mapped during the preclinical phase. Although ADAD represents a small proportion of AD cases, understanding neuroimaging-based changes that occur during …

Phase Ii, Open-Label Study Of Encorafenib Plus Binimetinib In Patients With Brafv600-Mutant Metastatic Non-Small-Cell Lung Cancer, Gregory J Riely, Daniel Morgensztern, Et Al.

2020-Current year OA Pubs

PURPOSE: The combination of encorafenib (BRAF inhibitor) plus binimetinib (MEK inhibitor) has demonstrated clinical efficacy with an acceptable safety profile in patients with

METHODS: In this ongoing, open-label, single-arm, phase II study, patients with

RESULTS: At data cutoff, 98 patients (59 treatment-naïve and 39 previously treated) with

CONCLUSION: For patients with treatment-naïve and previously treated

Deletion Of Taf1 And Taf5 In Zebrafish Capitulate Cardiac And Craniofacial Abnormalities Associated With Tafopathies Through Perturbations In Metabolism, Jamison Leid, Ryan Gray, Peter Rakita, Andrew L Koenig, Rohan Tripathy, James A J Fitzpatrick, Charles Kaufman, Lilianna Solnica-Krezel, Kory J Lavine

2020-Current year OA Pubs

Intellectual disability is a neurodevelopmental disorder that affects 2-3% of the general population. Syndromic forms of intellectual disability frequently have a genetic basis and are often accompanied by additional developmental anomalies. Pathogenic variants in components of TATA-binding protein associated factors (TAFs) have recently been identified in a subset of patients with intellectual disability, craniofacial hypoplasia, and congenital heart disease. This syndrome has been termed as a TAFopathy and includes mutations in TATA binding protein (TBP), TAF1, TAF2, and TAF6. The underlying mechanism by which TAFopathies give rise to neurodevelopmental, craniofacial, and cardiac abnormalities remains to be defined. Through a forward …

A Single F153sβ3 Mutation Causes Constitutive Integrin Αiibβ3 Activation In A Variant Form Of Glanzmann Thrombasthenia, Sevasti B Koukouritaki, Aye Myat M Thinn, Katrina J Ashworth, Juan Fang, Haley S Slater, Lily M Du, Huong Thi Thu Nguyen, Xavier Pillois, Alan T Nurden, Christopher J Ng, Jorge Di Paola, Jieqing Zhu, David A Wilcox

2020-Current year OA Pubs

This report identifies a novel variant form of the inherited bleeding disorder Glanzmann thrombasthenia, exhibiting only mild bleeding in a physically active individual. The platelets cannot aggregate ex vivo with physiologic agonists of activation, although microfluidic analysis with whole blood displays moderate ex vivo platelet adhesion and aggregation consistent with mild bleeding. Immunocytometry shows reduced expression of αIIbβ3 on quiescent platelets that spontaneously bind/store fibrinogen, and activation-dependent antibodies (ligand-induced binding site-319.4 and PAC-1) report β3 extension suggesting an intrinsic activation phenotype. Genetic analysis reveals a single F153Sβ3 substitution within the βI-domain from a heterozygous T556C nucleotide substitution of ITGB3 exon …

The Effect Of Dnaaf5 Gene Dosage On Primary Ciliary Dyskinesia Phenotypes, Amjad Horani, Deepesh Kumar Gupta, Jian Xu, Huihui Xu, Lis Del Carmen Puga-Molina, Celia M. Santi, Sruthi Ramagiri, Steven K. Brennan, Jiehong Pan, Jeffrey R. Koenitzer, Tao Huang, Rachael M. Hyland, Sean P. Gunsten, Shin-Cheng Tzeng, Jennifer M. Strahle, Pleasantine Mill, Moe R. Mahjoub, Susan K Dutcher, Steven L Brody

2020-Current year OA Pubs

DNAAF5 is a dynein motor assembly factor associated with the autosomal heterogenic recessive condition of motile cilia, primary ciliary dyskinesia (PCD). The effects of allele heterozygosity on motile cilia function are unknown. We used CRISPR-Cas9 genome editing in mice to recreate a human missense variant identified in patients with mild PCD and a second, frameshift-null deletion in Dnaaf5. Litters with Dnaaf5 heteroallelic variants showed distinct missense and null gene dosage effects. Homozygosity for the null Dnaaf5 alleles was embryonic lethal. Compound heterozygous animals with the missense and null alleles showed severe disease manifesting as hydrocephalus and early lethality. However, animals …

Defects In Lysosomal Function And Lipid Metabolism In Human Microglia Harboring A Trem2 Loss Of Function Mutation, Fabia Filipello, Shih-Feng You, Farzaneh S Mirfakhar, Sidhartha Mahali, Bryan Bollman, Mariana Acquarone, Jacob A Marsh, Anirudh Sivaraman, Rita Martinez, Claudia Cantoni, Luca De Feo, Laura Ghezzi, Miguel A Minaya, Arun Renganathan, Anil G Cashikar, Wandy Beatty, Abhirami K Iyer, Marina Cella, Laura Piccio, Celeste M Karch, Et Al.

2020-Current year OA Pubs

TREM2 is an innate immune receptor expressed by microglia in the adult brain. Genetic variation in the TREM2 gene has been implicated in risk for Alzheimer's disease and frontotemporal dementia, while homozygous TREM2 mutations cause a rare leukodystrophy, Nasu-Hakola disease (NHD). Despite extensive investigation, the role of TREM2 in NHD pathogenesis remains poorly understood. Here, we investigate the mechanisms by which a homozygous stop-gain TREM2 mutation (p.Q33X) contributes to NHD. Induced pluripotent stem cell (iPSC)-derived microglia (iMGLs) were generated from two NHD families: three homozygous TREM2 p.Q33X mutation carriers (termed NHD), two heterozygous mutation carriers, one related non-carrier, and two …

Safety And Efficacy Of Vanzacaftor-Tezacaftor-Deutivacaftor In Adults With Cystic Fibrosis: Randomised, Double-Blind, Controlled, Phase 2 Trials, Ahmet Z Uluer, Ronald C Rubenstein, Et Al.

2020-Current year OA Pubs

BACKGROUND: Elexacaftor-tezacaftor-ivacaftor has been shown to be safe and efficacious in people with cystic fibrosis and at least one F508del allele. Our aim was to identify a novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination capable of further increasing CFTR-mediated chloride transport, with the potential for once-daily dosing.

METHODS: We conducted two phase 2 clinical trials to assess the safety and efficacy of a once-daily combination of vanzacaftor-tezacaftor-deutivacaftor in participants with cystic fibrosis who were aged 18 years or older. A phase 2 randomised, double-blind, active-controlled study (VX18-561-101; April 17, 2019, to Aug 20, 2020) was carried out to …

Cat Lca-Crx Model, Homozygous For An Antimorphic Mutation Has A Unique Phenotype, Laurence M Occelli, Nicholas M Tran, Shiming Chen, Simon M Petersen-Jones

2020-Current year OA Pubs

PURPOSE: Mutations in the CRX transcription factor are associated with dominant retinopathies often with more severe macular changes. The CRX-mutant cat (Rdy-A182d2) is the only animal model with the equivalent of the critical retinal region for high-acuity vision, the macula. Heterozygous cats (CRXRdy/+) have a severe phenotype modeling Leber congenital amaurosis. This study reports the distinct ocular phenotype of homozygous cats (CRXRdy/Rdy).

METHODS: Gene expression changes were assessed at both mRNA and protein levels. Changes in globe morphology and retinal structure were analyzed.

RESULTS: CRXRdy/Rdy cats had high levels of mutant CRX mRNA and protein. The expression of photoreceptor target …

Distinct Effects Of Two Hearing Loss-Associated Mutations In The Sarcomeric Myosin Myh7b, Lindsey A Lee, Samantha K Barrick, Ada E Buvoli, Jonathan Walklate, W Tom Stump, Michael Geeves, Michael J Greenberg, Leslie A Leinwand

2020-Current year OA Pubs

For decades, sarcomeric myosin heavy chain proteins were assumed to be restricted to striated muscle where they function as molecular motors that contract muscle. However, MYH7b, an evolutionarily ancient member of this myosin family, has been detected in mammalian nonmuscle tissues, and mutations in MYH7b are linked to hereditary hearing loss in compound heterozygous patients. These mutations are the first associated with hearing loss rather than a muscle pathology, and because there are no homologous mutations in other myosin isoforms, their functional effects were unknown. We generated recombinant human MYH7b harboring the D515N or R1651Q hearing loss-associated mutation and studied …

Influence Of Genomic Landscape On Cancer Immunotherapy For Newly Diagnosed Ovarian Cancer: Biomarker Analyses From The Imagyn050 Randomized Clinical Trial, Charles N Landen, Premal H Thaker, Et Al.

2020-Current year OA Pubs

PURPOSE: To explore whether patients with BRCA1/2-mutated or homologous recombination deficient (HRD) ovarian cancers benefitted from atezolizumab in the phase III IMagyn050 (NCT03038100) trial.

PATIENTS AND METHODS: Patients with newly diagnosed ovarian cancer were randomized to either atezolizumab or placebo with standard chemotherapy and bevacizumab. Programmed death-ligand 1 (PD-L1) status of tumor-infiltrating immune cells (IC) was determined centrally (VENTANA SP142 assay). Genomic alterations, including deleterious BRCA1/2 alterations, genomic loss of heterozygosity (gLOH), tumor mutation burden (TMB), and microsatellite instability (MSI), were evaluated using the FoundationOne assay. HRD was defined as gLOH ≥ 16%, regardless of BRCA1/2 mutation status. Potential associations …

Bk Channels Of Five Different Subunit Combinations Underlie The De Novo Kcnma1 G375r Channelopathy, Yanyan Geng, Ping Li, Alice Butler, Bill Wang, Lawrence Salkoff, Karl L Magleby

2020-Current year OA Pubs

The molecular basis of a severe developmental and neurological disorder associated with a de novo G375R variant of the tetrameric BK channel is unknown. Here, we address this question by recording from single BK channels expressed to mimic a G375R mutation heterozygous with a WT allele. Five different types of functional BK channels were expressed: 3% were consistent with WT, 12% with homotetrameric mutant, and 85% with three different types of hybrid (heterotetrameric) channels assembled from both mutant and WT subunits. All channel types except WT showed a marked gain-of-function in voltage activation and a smaller decrease-of-function in single-channel conductance, …

The Genetic Determinants Of Recurrent Somatic Mutations In 43,693 Blood Genomes, Joshua S Weinstock, C Charles Gu, Et Al.

2020-Current year OA Pubs

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid …

Increased Clonal Hematopoiesis Involving Dna Damage Response Genes In Patients Undergoing Lung Transplantation, Laneshia K Tague, Karolyn A. Oetjen, Anirudh Mahadev, Matthew J. Walter, Hephzibah Anthony, Daniel Kreisel, Daniel C. Link, Andrew E Gelman

2020-Current year OA Pubs

BACKGROUNDCellular stressors influence the development of clonal hematopoiesis (CH). We hypothesized that environmental, inflammatory, and genotoxic stresses drive the emergence of CH in lung transplant recipients. METHODSWe performed a cross-sectional cohort study of 85 lung transplant recipients to characterize CH prevalence. We evaluated somatic variants using duplex error-corrected sequencing and germline variants using whole exome sequencing. We evaluated CH frequency and burden using χ2 and Poisson regression, and we evaluated associations with clinical and demographic variables and clinical outcomes using χ2, logistic regression, and Cox regression. RESULTSCH in DNA damage response (DDR) genes TP53, PPM1D, and ATM was increased in …

Expanding The Muscle Imaging Spectrum In Dysferlinopathy: Description Of An Outlier Population From The Classical Mri Pattern, Laura Llansó, Alan Pestronk, Et Al.

2020-Current year OA Pubs

Dysferlinopathy is a muscle disease characterized by a variable clinical presentation and is caused by mutations in the DYSF gene. The Jain Clinical Outcome Study for Dysferlinopathy (COS) followed the largest cohort of patients (n=187) with genetically confirmed dysferlinopathy throughout a three-year natural history study, in which the patients underwent muscle function tests and muscle magnetic resonance imaging (MRI). We previously described the pattern of muscle pathology in this population and established a series of imaging criteria for diagnosis. In this paper, we describe the muscle imaging and clinical features of a subgroup of COS participants whose muscle imaging results …

Outcome Prediction By The 2022 European Leukemianet Genetic-Risk Classification For Adults With Acute Myeloid Leukemia: An Alliance Study, Krzysztof Mrózek, Geoffrey L Uy, Et Al.

2020-Current year OA Pubs

Recently, the European LeukemiaNet (ELN) revised its genetic-risk classification of acute myeloid leukemia (AML). We categorized 1637 adults with AML treated with cytarabine/anthracycline regimens according to the 2022 and 2017 ELN classifications. Compared with the 2017 ELN classification, 2022 favorable group decreased from 40% to 35% and adverse group increased from 37% to 41% of patients. The 2022 genetic-risk groups seemed to accurately reflect treatment outcomes in all patients and patients aged <60 years, but in patients aged ≥60 years, relapse rates, disease-free (DFS) and overall (OS) survival were not significantly different between intermediate and adverse groups. In younger African-American patients, DFS and OS did not differ between intermediate-risk and adverse-risk patients nor did DFS between favorable and intermediate groups. In Hispanic patients, DFS and OS did not differ between favorable and intermediate groups. Outcome prediction abilities of 2022 and 2017 ELN classifications were similar. Among favorable-risk patients, myelodysplasia-related mutations did not affect patients with CEBPA

Surgical Results Of The Lung Cancer Mutation Consortium 3 Trial: A Phase Ii Multicenter Single-Arm Study To Investigate The Efficacy And Safety Of Atezolizumab As Neoadjuvant Therapy In Patients With Stages Ib-Select Iiib Resectable Non-Small Cell Lung Cancer, Valerie W Rusch, G Alexander Patterson, Salama N Waqar, Et Al.

2020-Current year OA Pubs

OBJECTIVE: Multimodality treatment for resectable non-small cell lung cancer has long remained at a therapeutic plateau. Immune checkpoint inhibitors are highly effective in advanced non-small cell lung cancer and promising preoperatively in small clinical trials for resectable non-small cell lung cancer. This large multicenter trial tested the safety and efficacy of neoadjuvant atezolizumab and surgery.

METHODS: Patients with stage IB to select IIIB resectable non-small cell lung cancer and Eastern Cooperative Oncology Group performance status 0/1 were eligible. Patients received atezolizumab 1200 mg intravenously every 3 weeks for 2 cycles or less followed by resection. The primary end point was …

Genetic Subgroups Inform On Pathobiology In Adult And Pediatric Burkitt Lymphoma, Nicole Thomas, Nancy L. Bartlett, Lee Ratner, Et Al.

2020-Current year OA Pubs

Burkitt lymphoma (BL) accounts for most pediatric non-Hodgkin lymphomas, being less common but significantly more lethal when diagnosed in adults. Much of the knowledge of the genetics of BL thus far has originated from the study of pediatric BL (pBL), leaving its relationship to adult BL (aBL) and other adult lymphomas not fully explored. We sought to more thoroughly identify the somatic changes that underlie lymphomagenesis in aBL and any molecular features that associate with clinical disparities within and between pBL and aBL. Through comprehensive whole-genome sequencing of 230 BL and 295 diffuse large B-cell lymphoma (DLBCL) tumors, we identified …

Skeletal Dysplasia-Causing Trpv4 Mutations Suppress The Hypertrophic Differentiation Of Human Ipsc-Derived Chondrocytes, Amanda R Dicks, Grigory I Maksaev, Zainab Harissa, Alireza Savadipour, Ruhang Tang, Nancy Steward, Wolfgang Liedtke, Colin G Nichols, Chia-Lung Wu, Farshid Guilak

2020-Current year OA Pubs

Mutations in the TRPV4 ion channel can lead to a range of skeletal dysplasias. However, the mechanisms by which TRPV4 mutations lead to distinct disease severity remain unknown. Here, we use CRISPR-Cas9-edited human-induced pluripotent stem cells (hiPSCs) harboring either the mild V620I or lethal T89I mutations to elucidate the differential effects on channel function and chondrogenic differentiation. We found that hiPSC-derived chondrocytes with the V620I mutation exhibited increased basal currents through TRPV4. However, both mutations showed more rapid calcium signaling with a reduced overall magnitude in response to TRPV4 agonist GSK1016790A compared to wildtype (WT). There were no differences in …

Fmr1 Mutation Alters The Early Development Of Sensory Coding And Hunting And Social Behaviors In Larval Zebrafish, Shuyu I Zhu, Michael H Mccullough, Zac Pujic, Jordan Sibberas, Biao Sun, Thomas Darveniza, Bianca Bucknall, Lilach Avitan, Geoffrey J Goodhill

2020-Current year OA Pubs

Autism spectrum disorders (ASDs) are developmental in origin; however, little is known about how they affect the early development of behavior and sensory coding. The most common inherited form of autism is Fragile X syndrome (FXS), caused by a mutation in

Phase Ib Study Of Telisotuzumab Vedotin In Combination With Erlotinib In Patients With C-Met Protein-Expressing Non-Small-Cell Lung Cancer, D Ross Camidge, Daniel Morgensztern, Et Al.

2020-Current year OA Pubs

PURPOSE: Overexpression of c-Met protein and epidermal growth factor receptor (

PATIENTS AND METHODS: This study evaluated Teliso-V (2.7 mg/kg once every 21 days) plus erlotinib (150 mg once daily) in adult patients (age ≥ 18 years) with c-Met+ NSCLC. Later enrollment required presence of an

RESULTS: As of January 2020, 42 patients were enrolled (N = 36 efficacy-evaluable). Neuropathies were the most common any-grade adverse events reported, with 24 of 42 patients (57%) experiencing at least one event. The pharmacokinetic profile of Teliso-V plus erlotinib was similar to Teliso-V monotherapy. Median PFS for all efficacy-evaluable patients was 5.9 months …

Body Mass Index And Molecular Subtypes Of Colorectal Cancer, Neil Murphy, Yin Cao, Et Al.

2020-Current year OA Pubs

BACKGROUND: Obesity is an established risk factor for colorectal cancer (CRC), but the evidence for the association is inconsistent across molecular subtypes of the disease.

METHODS: We pooled data on body mass index (BMI), tumor microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, and Jass classification types for 11 872 CRC cases and 11 013 controls from 11 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for covariables.

RESULTS: Higher BMI was associated with increased CRC risk (OR per 5 kg/m2 = 1.18, 95% CI = …

Distinct Clonal Identities Of B-Alls Arising After Lenolidomide Therapy For Multiple Myeloma, Erica K Barnell, Zachary L Skidmore, Kenneth F Newcomer, Monique Chavez, Katie M Campbell, Kelsy C Cotto, Nicholas C Spies, Marianna B Ruzinova, Tianjiao Wang, Brooj Abro, Bijal A Parikh, Eric J Duncavage, John L Frater, Yi-Shan Lee, Anjum Hassan, Justin A King, Daniel R Kohnen, Mark A Fiala, John S Welch, Geoffrey L Uy, Kiran Vij, Ravi Vij, Malachi Griffith, Obi L Griffith, Lukas D Wartman, Et Al.

2020-Current year OA Pubs

Patients with multiple myeloma (MM) who are treated with lenalidomide rarely develop a secondary B-cell acute lymphoblastic leukemia (B-ALL). The clonal and biological relationship between these sequential malignancies is not yet clear. We identified 17 patients with MM treated with lenalidomide, who subsequently developed B-ALL. Patient samples were evaluated through sequencing, cytogenetics/fluorescence in situ hybridization (FISH), immunohistochemical (IHC) staining, and immunoglobulin heavy chain (IgH) clonality assessment. Samples were assessed for shared mutations and recurrently mutated genes. Through whole exome sequencing and cytogenetics/FISH analysis of 7 paired samples (MM vs matched B-ALL), no mutational overlap between samples was observed. Unique dominant …

Preclinical Studies In Krabbe Disease: A Model For The Investigation Of Novel Combination Therapies For Lysosomal Storage Diseases, Gregory Heller, Allison M Bradbury, Mark S Sands, Ernesto R Bongarzone

2020-Current year OA Pubs

Krabbe disease (KD) is a lysosomal storage disease (LSD) caused by mutations in the galc gene. There are over 50 monogenetic LSDs, which largely impede the normal development of children and often lead to premature death. At present, there are no cures for LSDs and the available treatments are generally insufficient, short acting, and not without co-morbidities or long-term side effects. The last 30 years have seen significant advances in our understanding of LSD pathology as well as treatment options. Two gene therapy-based clinical trials, NCT04693598 and NCT04771416, for KD were recently started based on those advances. This review will …

The Mutational Landscape In Chronic Myelomonocytic Leukemia And Its Impact On Allogeneic Hematopoietic Cell Transplantation Outcomes: A Center For Blood And Marrow Transplantation Research (Cibmtr) Analysis, Matthew Mei, Ravi Vij, Et Al.

2020-Current year OA Pubs

Somatic mutations are recognized as an important prognostic factor in chronic myelomonocytic leukemia (CMML). However, limited data are available regarding their impact on outcomes after allogeneic hematopoietic cell transplantation (HCT). In this registry analysis conducted in collaboration with the Center for International Blood and Marrow Transplantation Registry database/sample repository, we identified 313 adult patients with CMML (median age: 64 years, range, 28- 77) who underwent allogeneic HCT during 2001-2017 and had an available biospecimen in the form of a peripheral blood sample obtained prior to the start of conditioning. In multivariate analysis, a CMML-specific prognostic scoring system (CPSS) score of …

Expanded Analysis Of High-Grade Astrocytoma With Piloid Features Identifies An Epigenetically And Clinically Distinct Subtype Associated With Neurofibromatosis Type 1, Patrick J Cimino, Sonika Dahiya, Et Al.

2020-Current year OA Pubs

High-grade astrocytoma with piloid features (HGAP) is a recently recognized glioma type whose classification is dependent on its global epigenetic signature. HGAP is characterized by alterations in the mitogen-activated protein kinase (MAPK) pathway, often co-occurring with CDKN2A/B homozygous deletion and/or ATRX mutation. Experience with HGAP is limited and to better understand this tumor type, we evaluated an expanded cohort of patients (n = 144) with these tumors, as defined by DNA methylation array testing, with a subset additionally evaluated by next-generation sequencing (NGS). Among evaluable cases, we confirmed the high prevalence CDKN2A/B homozygous deletion, and/or ATRX mutations/loss in this tumor …

Self-Hybridization In Leishmania Major, Tiago R Ferreira, Ehud Inbar, Jahangheer Shaik, Brendan M Jeffrey, Kashinath Ghosh, Deborah E. Dobson, Stephen M. Beverley, David Sacks

2020-Current year OA Pubs

Genetic exchange between different