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Proteomic Profiling Of High Risk Medulloblastoma Reveals Functional Biology, Jerome A. Staal, Ling San Lau, Huizhen Zhang, Wendy J. Ingram, Andrew R. Hallahan, Roger J. Packer, Brian R. Rood, Kristy J. Brown, +6 Additional Authors Jan 2015

Proteomic Profiling Of High Risk Medulloblastoma Reveals Functional Biology, Jerome A. Staal, Ling San Lau, Huizhen Zhang, Wendy J. Ingram, Andrew R. Hallahan, Roger J. Packer, Brian R. Rood, Kristy J. Brown, +6 Additional Authors

Neurology Faculty Publications

Genomic characterization of medulloblastoma has improved molecular risk classification but struggles to define functional biological processes, particularly for the most aggressive subgroups. We present here a novel proteomic approach to this problem using a reference library of stable isotope labeled medulloblastoma-specific proteins as a spike-in standard for accurate quantification of the tumor proteome. Utilizing high-resolution mass spectrometry, we quantified the tumor proteome of group 3 medulloblastoma cells and demonstrate that high-risk MYC amplified tumors can be segregated based on protein expression patterns. We cross-validated the differentially expressed protein candidates using an independent transcriptomic data set and further confirmed them in …

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Effect Of Single Embryo Transfer On The Risk Of Preterm Birth Associated With In Vitro Fertilization, A. J. Fechner, K. R. Brown, N. Onwubalili, S. K. Jindal, G. Weiss, L. T. Goldsmith, P. G. Mcgovern Jan 2015

Effect Of Single Embryo Transfer On The Risk Of Preterm Birth Associated With In Vitro Fertilization, A. J. Fechner, K. R. Brown, N. Onwubalili, S. K. Jindal, G. Weiss, L. T. Goldsmith, P. G. Mcgovern

Journal Articles

To determine whether elective single embryo transfer (eSET) reduces the risk of preterm delivery associated with in vitro fertilization (IVF). This is an observational study of 3125 eSET cycles performed from 2008 to 2009 and reported to the Society for Assisted Reproductive Technology (SART) database. Preterm delivery rates were compared to the overall preterm delivery rate among all patients undergoing IVF over the same time period. The 3125 eSET cycles resulted in 1507 live births (live birth rate 48.2 %) Among these deliveries were 27 twins (1.8 %) and one set of triplets (0.07 %). The overall preterm delivery rate …

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A Critical Role For The Host Mediator Macrophage Migration Inhibitory Factor In The Pathogenesis Of Malarial Anemia, M. A. Mcdevitt, J. Xie, S. Ganapathy-Kanniappan, J. Griffith, A. Liu, C. Mcdonald, P. Thuma, V. R. Gordeuk, C. N. Metz, R. Mitchell, J. Keefer, J. David, L. Leng, R. Bucala Jan 2015

A Critical Role For The Host Mediator Macrophage Migration Inhibitory Factor In The Pathogenesis Of Malarial Anemia, M. A. Mcdevitt, J. Xie, S. Ganapathy-Kanniappan, J. Griffith, A. Liu, C. Mcdonald, P. Thuma, V. R. Gordeuk, C. N. Metz, R. Mitchell, J. Keefer, J. David, L. Leng, R. Bucala

Journal Articles

No abstract provided.

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Metabolic Resting-State Brain Networks In Health And Disease, P. G. Spetsieris, J. H. Ko, C. C. Tang, A. Nazem, W. Sako, S. Peng, Y. Ma, V. Dhawan, D. Eidelberg Jan 2015

Metabolic Resting-State Brain Networks In Health And Disease, P. G. Spetsieris, J. H. Ko, C. C. Tang, A. Nazem, W. Sako, S. Peng, Y. Ma, V. Dhawan, D. Eidelberg

Journal Articles

The delineation of resting state networks (RSNs) in the human brain relies on the analysis of temporal fluctuations in functional MRI signal, representing a small fraction of total neuronal activity. Here, we used metabolic PET, which maps nonfluctuating signals related to total activity, to identify and validate reproducible RSN topographies in healthy and disease populations. In healthy subjects, the dominant (first component) metabolic RSN was topographically similar to the default mode network (DMN). In contrast, in Parkinson's disease (PD), this RSN was subordinated to an independent disease-related pattern. Network functionality was assessed by quantifying metabolic RSN expression in cerebral blood …

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Implications Of Epigenetic Variability Within A Cell Population For "Cell Type" Classification, I. Tabansky, J. N.H. Stern, D. W. Pfaff Jan 2015

Implications Of Epigenetic Variability Within A Cell Population For "Cell Type" Classification, I. Tabansky, J. N.H. Stern, D. W. Pfaff

Journal Articles

Here, we propose a new approach to defining nerve "cell types" in reaction to recent advances in single cell analysis. Among cells previously thought to be equivalent, considerable differences in global gene expression and biased tendencies among differing developmental fates have been demonstrated within multiple lineages. The model of classifying cells into distinct types thus has to be revised to account for this intrinsic variability. A "cell type" could be a group of cells that possess similar, but not necessarily identical properties, variable within a spectrum of epigenetic adjustments that permit its developmental path toward a specific function to be …

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Parkinson's Disease-Related Spatial Covariance Pattern Identified With Resting-State Functional Mri, T. Wu, Y. Ma, Z. Zheng, S. Peng, X. Wu, D. Eidelberg, P. Chan Jan 2015

Parkinson's Disease-Related Spatial Covariance Pattern Identified With Resting-State Functional Mri, T. Wu, Y. Ma, Z. Zheng, S. Peng, X. Wu, D. Eidelberg, P. Chan

Journal Articles

In this study, we sought to identify a disease-related spatial covariance pattern of spontaneous neural activity in Parkinson's disease using resting-state functional magnetic resonance imaging (MRI). Time-series data were acquired in 58 patients with early to moderate stage Parkinson's disease and 54 healthy controls, and analyzed by Scaled Subprofile Model Principal Component Analysis toolbox. A split-sample analysis was also performed in a derivation sample of 28 patients and 28 control subjects and validated in a prospective testing sample of 30 patients and 26 control subjects. The topographic pattern of neural activity in Parkinson's disease was characterized by decreased activity in …

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First-In-Human, Phase 1, Randomized, Dose-Escalation Trial With Recombinant Anti-Il-20 Monoclonal Antibody In Patients With Psoriasis, A. B. Gottlieb, J. G. Krueger, M. Sandberg Lundblad, M. Gothberg, B. E. Skolnick Jan 2015

First-In-Human, Phase 1, Randomized, Dose-Escalation Trial With Recombinant Anti-Il-20 Monoclonal Antibody In Patients With Psoriasis, A. B. Gottlieb, J. G. Krueger, M. Sandberg Lundblad, M. Gothberg, B. E. Skolnick

Journal Articles

BACKGROUND: The current trial was a first-in-human clinical trial evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the recombinant monoclonal anti-interleukin-20 (IL-20) antibody, NNC0109-0012, which targets the inflammatory cytokine IL-20. METHODS: In total, 48 patients aged 18 to 75 years with moderate to severe stable chronic plaque psoriasis with affected body surface area >/=15% and physician global assessment score >/=3 were enrolled in this randomized, double-blind, multicenter, placebo-controlled, phase 1 dose-escalation trial. Patients were randomized within each single dose cohort (0.01, 0.05, 0.2, 0.6, 1.5, or 3.0 mg/kg) or multiple dose cohort (0.05, 0.2, 0.5, 1.0, or 2.0 …

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New Best1 Mutations In Autosomal Recessive Bestrophinopathy, A. T. Fung, S. Yzer, N. Goldberg, H. Wang, M. Nissen, A. Giovannini, J. E. Merriam, E. N. Bukanova, L. A. Yannuzzi, R. Allikmets, +2 Additional Authors Jan 2015

New Best1 Mutations In Autosomal Recessive Bestrophinopathy, A. T. Fung, S. Yzer, N. Goldberg, H. Wang, M. Nissen, A. Giovannini, J. E. Merriam, E. N. Bukanova, L. A. Yannuzzi, R. Allikmets, +2 Additional Authors

Journal Articles

PURPOSE: To report the ocular phenotype in patients with autosomal recessive bestrophinopathy and carriers, and to describe novel BEST1 mutations. METHODS: Patients with clinically suspected and subsequently genetically proven autosomal recessive bestrophinopathy underwent full ophthalmic examination and investigation with fundus autofluorescence imaging, spectral domain optical coherence tomography, electroretinography, and electrooculography. Mutation analysis of the BEST1 gene was performed through direct Sanger sequencing. RESULTS: Five affected patients from four families were identified. Mean age was 16 years (range, 6-42 years). All affected patients presented with reduced visual acuity and bilateral, hyperautofluorescent subretinal yellowish deposits within the posterior pole. Spectral domain optical …

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Lifitegrast Ophthalmic Solution 5.0% Versus Placebo For Treatment Of Dry Eye Disease: Results Of The Randomized Phase Iii Opus-2 Study, J. Tauber, P. Karpecki, R. Latkany, J. Luchs, J. Martel, K. Sall, A. Raychaudhuri, V. Smith, C. P. Semba Jan 2015

Lifitegrast Ophthalmic Solution 5.0% Versus Placebo For Treatment Of Dry Eye Disease: Results Of The Randomized Phase Iii Opus-2 Study, J. Tauber, P. Karpecki, R. Latkany, J. Luchs, J. Martel, K. Sall, A. Raychaudhuri, V. Smith, C. P. Semba

Journal Articles

PURPOSE: Lifitegrast is an integrin antagonist that decreases T-cell-mediated inflammation associated with dry eye disease (DED). We report the results of OPUS-2, a phase III study evaluating the efficacy and safety of lifitegrast compared with placebo for the treatment of DED. DESIGN: A 12-week, multicenter, randomized, prospective, double-masked, placebo-controlled clinical trial. PARTICIPANTS: Adults aged >/=18 years with use of artificial tears within 30 days, inferior corneal staining score >/=0.5 (0-4 scale), Schirmer tear test (without anesthesia) >/=1 and/=40 (0-100 visual analogue scale [VAS]). METHODS: Subjects were randomized 1:1 after 14-day placebo run-in to lifitegrast ophthalmic solution 5.0% or placebo twice …

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Ld Score Regression Distinguishes Confounding From Polygenicity In Genome-Wide Association Studies, B. K. Bulik-Sullivan, P. R. Loh, H. K. Finucane, S. Ripke, J. Yang, N. Patterson, M. J. Daly, A. L. Price, B. M. Neale, A. Malhotra Jan 2015

Ld Score Regression Distinguishes Confounding From Polygenicity In Genome-Wide Association Studies, B. K. Bulik-Sullivan, P. R. Loh, H. K. Finucane, S. Ripke, J. Yang, N. Patterson, M. J. Daly, A. L. Price, B. M. Neale, A. Malhotra

Journal Articles

Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the …

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A Common Polymorphism In Scn2a Predicts General Cognitive Ability Through Effects On Pfc Physiology, M. A. Scult, J. W. Trampush, F. Zheng, E. D. Conley, T. Lencz, A. K. Malhotra, D. Dickinson, D. R. Weinberger, A. R. Hariri Jan 2015

A Common Polymorphism In Scn2a Predicts General Cognitive Ability Through Effects On Pfc Physiology, M. A. Scult, J. W. Trampush, F. Zheng, E. D. Conley, T. Lencz, A. K. Malhotra, D. Dickinson, D. R. Weinberger, A. R. Hariri

Journal Articles

Here we provide novel convergent evidence across three independent cohorts of healthy adults (n = 531), demonstrating that a common polymorphism in the gene encoding the alpha2 subunit of neuronal voltage-gated type II sodium channels (SCN2A) predicts human general cognitive ability or "g." Using meta-analysis, we demonstrate that the minor T allele of a common polymorphism (rs10174400) in SCN2A is associated with significantly higher "g" independent of gender and age. We further demonstrate using resting-state fMRI data from our discovery cohort (n = 236) that this genetic advantage may be mediated by increased capacity for information processing between the dorsolateral …

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Association Of A Schizophrenia Risk Variant At The Drd2 Locus With Antipsychotic Treatment Response In First-Episode Psychosis, J. P. Zhang, D. G. Robinson, Juan Gallego, M. John, J. Yu, J. Addington, M. Tohen, John Kane, Anil Malhotra, T. Lencz Jan 2015

Association Of A Schizophrenia Risk Variant At The Drd2 Locus With Antipsychotic Treatment Response In First-Episode Psychosis, J. P. Zhang, D. G. Robinson, Juan Gallego, M. John, J. Yu, J. Addington, M. Tohen, John Kane, Anil Malhotra, T. Lencz

Journal Articles

Findings from the Psychiatric Genomics Consortium genome-wide association study (GWAS) showed that variation at the DRD2 locus is associated with schizophrenia risk. However, the functional significance of rs2514218, the top DRD2 single nucleotide polymorphism in the GWAS, is unknown. Dopamine D2 receptor binding is a common mechanism of action for all antipsychotic drugs, and DRD2 variants were related to antipsychotic response in previous studies. The present study examined whether rs2514218 genotype could predict antipsychotic response, including efficacy and adverse events, in a cohort of patients with first episode of psychosis treated with either risperidone or aripiprazole for 12 weeks. Subjects …

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Clinical And Functional Outcomes After 2 Years In The Early Detection And Intervention For The Prevention Of Psychosis Multisite Effectiveness Trial, W. R. Mcfarlane, B. Levin, L. Travis, F. L. Lucas, S. Lynch, M. Verdi, Barbara Cornblatt, S. F. Taylor, A. M. Auther, E. Spring, +11 Additional Authors Jan 2015

Clinical And Functional Outcomes After 2 Years In The Early Detection And Intervention For The Prevention Of Psychosis Multisite Effectiveness Trial, W. R. Mcfarlane, B. Levin, L. Travis, F. L. Lucas, S. Lynch, M. Verdi, Barbara Cornblatt, S. F. Taylor, A. M. Auther, E. Spring, +11 Additional Authors

Journal Articles

OBJECTIVE: To test effectiveness of the Early Detection, Intervention, and Prevention of Psychosis Program in preventing the onset of severe psychosis and improving functioning in a national sample of at-risk youth. METHODS: In a risk-based allocation study design, 337 youth (age 12-25) at risk of psychosis were assigned to treatment groups based on severity of positive symptoms. Those at clinically higher risk (CHR) or having an early first episode of psychosis (EFEP) were assigned to receive Family-aided Assertive Community Treatment (FACT); those at clinically lower risk (CLR) were assigned to receive community care. Between-groups differences on outcome variables were adjusted …

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Multirater Agreement Of The Causes Of Anterior Cruciate Ligament Reconstruction Failure: A Radiographic And Video Analysis Of The Mars Cohort, M. J. Matava, R. A. Arciero, K. M. Baumgarten, J. A. Hannafin, B. S. Miller, C. W. Nissen, T. N. Taft, B. R. Wolf, E. B. Hershman, R. W. Wright, +3 Additional Authors Jan 2015

Multirater Agreement Of The Causes Of Anterior Cruciate Ligament Reconstruction Failure: A Radiographic And Video Analysis Of The Mars Cohort, M. J. Matava, R. A. Arciero, K. M. Baumgarten, J. A. Hannafin, B. S. Miller, C. W. Nissen, T. N. Taft, B. R. Wolf, E. B. Hershman, R. W. Wright, +3 Additional Authors

Journal Articles

BACKGROUND: Anterior cruciate ligament (ACL) reconstruction failure occurs in up to 10% of cases. Technical errors are considered the most common cause of graft failure despite the absence of validated studies. Limited data are available regarding the agreement among orthopaedic surgeons regarding the causes of primary ACL reconstruction failure and accuracy of graft tunnel placement. HYPOTHESIS: Experienced knee surgeons have a high level of interobserver reliability in the agreement about the causes of primary ACL reconstruction failure, anatomic graft characteristics, and tunnel placement. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 3. METHODS: Twenty cases of revision ACL reconstruction were …

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Romidepsin In Peripheral And Cutaneous T-Cell Lymphoma: Mechanistic Implications From Clinical And Correlative Data, S. E. Bates, R. Eisch, A. Ling, D. Rosing, M. Turner, S. Pittaluga, H. M. Prince, M. H. Kirschbaum, S. L. Allen, R. L. Piekarz, +15 Additional Authors Jan 2015

Romidepsin In Peripheral And Cutaneous T-Cell Lymphoma: Mechanistic Implications From Clinical And Correlative Data, S. E. Bates, R. Eisch, A. Ling, D. Rosing, M. Turner, S. Pittaluga, H. M. Prince, M. H. Kirschbaum, S. L. Allen, R. L. Piekarz, +15 Additional Authors

Journal Articles

Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients …

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Phase Ii, Multicenter, Randomized Trial Of Cpx-351 (Cytarabine: Daunorubicin) Liposome Injection Versus Intensive Salvage Therapy In Adults With First Relapse Aml, J. E. Cortes, S. L. Goldberg, E. J. Feldman, D. A. Rizzeri, D. E. Hogge, M. Larson, A. Pigneux, C. Recher, G. Schiller, J. E. Kolitz, +3 Additional Authors Jan 2015

Phase Ii, Multicenter, Randomized Trial Of Cpx-351 (Cytarabine: Daunorubicin) Liposome Injection Versus Intensive Salvage Therapy In Adults With First Relapse Aml, J. E. Cortes, S. L. Goldberg, E. J. Feldman, D. A. Rizzeri, D. E. Hogge, M. Larson, A. Pigneux, C. Recher, G. Schiller, J. E. Kolitz, +3 Additional Authors

Journal Articles

BACKGROUNDCPX-351 is a liposome-encapsulated fixed-molar-ratio formulation of cytarabine and daunorubicin that exploits molar ratio-dependent drug-drug synergy to enhance antileukemic efficacy. METHODSThis phase II study randomized 125 patients 2:1 to CPX-351 or investigators' choice of first salvage chemotherapy. Patients with acute myeloid leukemia (AML) in first relapse after initial Complete Remission (CR) lasting 1 month were stratified per the European Prognostic Index (EPI) into favorable, intermediate, and poor-risk groups based on duration of first CR, cytogenetics, age, and transplant history. Control salvage treatment was usually based on cytarabine and anthracycline, often with 1 or more additional agents. Survival at 1 year …

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Full-Length Soluble Urokinase Plasminogen Activator Receptor Down-Modulates Nephrin Expression In Podocytes, M. Alfano, P. Cinque, G. Giusti, S. Proietti, M. Nebuloni, S. Danese, S. D'Alessio, M. Genua, P. C. Singhal, J. Mikulak, +5 Additional Authors Jan 2015

Full-Length Soluble Urokinase Plasminogen Activator Receptor Down-Modulates Nephrin Expression In Podocytes, M. Alfano, P. Cinque, G. Giusti, S. Proietti, M. Nebuloni, S. Danese, S. D'Alessio, M. Genua, P. C. Singhal, J. Mikulak, +5 Additional Authors

Journal Articles

Increased plasma level of soluble urokinase-type plasminogen activator receptor (suPAR) was associated recently with focal segmental glomerulosclerosis (FSGS). In addition, different clinical studies observed increased concentration of suPAR in various glomerular diseases and in other human pathologies with nephrotic syndromes such as HIV and Hantavirus infection, diabetes and cardiovascular disorders. Here, we show that suPAR induces nephrin down-modulation in human podocytes. This phenomenon is mediated only by full-length suPAR, is time-and dose-dependent and is associated with the suppression of Wilms' tumor 1 (WT-1) transcription factor expression. Moreover, an antagonist of alpha v beta 3 integrin RGDfv blocked suPAR-induced suppression of …

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Hypersensitivity To Intravenous Iron: Classification, Terminology, Mechanisms And Management, J. Szebeni, S. Fishbane, M. Hedenus, S. Howaldt, F. Locatelli, S. Patni, D. Rampton, G. Weiss, J. Folkersen Jan 2015

Hypersensitivity To Intravenous Iron: Classification, Terminology, Mechanisms And Management, J. Szebeni, S. Fishbane, M. Hedenus, S. Howaldt, F. Locatelli, S. Patni, D. Rampton, G. Weiss, J. Folkersen

Journal Articles

Intravenous (IV) iron therapy is widely used in iron deficiency anemias when oral iron is not tolerated or ineffective. Administration of IV iron is considered a safe procedure, but severe hypersensitivity reactions (HSRs) can occur at a very low frequency. Recently, new guidelines have been published by the European Medicines Agency (EMA) with the intention of making IV-iron therapy safer; however, the current protocols are still non-specific, non-evidence-based empiric measures which neglect the fact that the majority of IV-iron reactions are not Ig-E-mediated anaphylactic reactions. The field would benefit from new specific and effective methods for the prevention and treatment …

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Identification And Characterization Of Distinct Il-17f Expression Patterns And Signaling Pathways In Chronic Lymphocytic Leukemia And Normal B Lymphocytes, B. Sherry, P. Jain, P. Y. Chiu, L. Leung, S. L. Allen, J. E. Kolitz, K. R. Rai, J. Barrientos, S. Liang, R. Hawtin, N. Chiorazzi Jan 2015

Identification And Characterization Of Distinct Il-17f Expression Patterns And Signaling Pathways In Chronic Lymphocytic Leukemia And Normal B Lymphocytes, B. Sherry, P. Jain, P. Y. Chiu, L. Leung, S. L. Allen, J. E. Kolitz, K. R. Rai, J. Barrientos, S. Liang, R. Hawtin, N. Chiorazzi

Journal Articles

Chronic lymphocytic leukemia (CLL) is characterized by a progressive accumulation of B lymphocytes. T cell abnormalities are a common feature of CLL and contribute to impaired immune function in these patients. T cells are ineffective in eliminating the leukemic clone and may actually promote tumor growth and survival. Previous work from our laboratory documented elevated circulating levels of IL-17A-producing Th17 cells in CLL patients as compared to healthy age-matched control subjects. These high circulating Th17 levels associated with better prognostic markers and significantly longer overall survival, even among patients whose clones used unmutated IGHVs (U-CLL). Recent studies suggest that Th17 …

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Apolipoprotein L1 (Apol1) Variants (Vs) A Possible Link Between Heroin-Associated Nephropathy (Han) And Hiv-Associated Nephropathy (Hivan), X. Lan, T. K. Rao, P. N. Chander, K. Skorecki, P. C. Singhal Jan 2015

Apolipoprotein L1 (Apol1) Variants (Vs) A Possible Link Between Heroin-Associated Nephropathy (Han) And Hiv-Associated Nephropathy (Hivan), X. Lan, T. K. Rao, P. N. Chander, K. Skorecki, P. C. Singhal

Journal Articles

In 1970s, Heroin-associated Nephropathy (HAN), one form of focal and segmental glomerulosclerosis (FSGS), was a predominant cause of End-stage Kidney Disease (ESKD) in African-Americans (AAs). In 1980s, with the surge of Acquired Immune Deficiency Syndrome (AIDS) in AAs, HAN more or less disappeared, and the incidence of Human Immunodeficiency Virus associated Nephropathy (HIVAN) markedly increased. Recent studies in AAs have identified APOL1 variants (Vs) as a major risk factor for the development and progression of non-diabetic kidney diseases including idiopathic FSGS and hypertension-attributed nephrosclerosis. These observations have also offered partial insights into the mechanisms of development, and higher rate of …

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Introduction: Moving Beyond Chemotherapy, F. Muggia, E. Teplinsky Jan 2015

Introduction: Moving Beyond Chemotherapy, F. Muggia, E. Teplinsky

Journal Articles

Epithelial ovarian cancer and related cancers arising in extrauterine Mullerian epithelium are generally chemosensitive—particularly to the platinum drugs, cisplatin and carboplatin, that form the backbone of first-line treatments upon diagnosis even at early stages. Doublets of platinums with paclitaxel have represented the standard-of-care since the late 1990s, with further notable advances taking place by intraperitoneal administration (in Gynecologic Oncology Group studies) after optimal surgical cytoreduction is achieved, and by divided doses of paclitaxel (in a Japanese GOG study). Adding another agent to improve on these results has otherwise proven to be quite challenging. Nevertheless, continued forays into introducing ‘targeted therapies’ …

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Acute Myeloid Leukemia Ontogeny Is Defined By Distinct Somatic Mutations, R. C. Lindsley, B. G. Mar, E. Mazzola, P. V. Grauman, S. Shareef, S. L. Allen, A. Pigneux, M. Wetzler, R. K. Stuart, B. L. Ebert, +9 Additional Authors Jan 2015

Acute Myeloid Leukemia Ontogeny Is Defined By Distinct Somatic Mutations, R. C. Lindsley, B. G. Mar, E. Mazzola, P. V. Grauman, S. Shareef, S. L. Allen, A. Pigneux, M. Wetzler, R. K. Stuart, B. L. Ebert, +9 Additional Authors

Journal Articles

Acute myeloid leukemia (AML) can develop after an antecedent myeloid malignancy (secondary AML [s-AML]), after leukemogenic therapy (therapy-related AML [t-AML]), or without an identifiable prodrome or known exposure (de novo AML). The genetic basis of these distinct pathways of AML development has not been determined. We performed targeted mutational analysis of 194 patients with rigorously defined s-AML or t-AML and 105 unselected AML patients. The presence of a mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 was >95% specific for the diagnosis of s-AML. Analysis of serial samples from individual patients revealed that these mutations occur early …

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Clinical Features, And Gene- And Microrna-Expression Patterns In Adult Acute Leukemia Patients With T(11;19)(Q23;P13.1) And T(11;19)(Q23;P13.3), B. Bhatnagar, J. S. Blachly, J. Kohlschmidt, A. K. Eisfeld, S. Volinia, D. Nicolet, A. J. Carroll, A. M. Block, J. E. Kolitz, C. D. Bloomfield, +3 Additional Authors Jan 2015

Clinical Features, And Gene- And Microrna-Expression Patterns In Adult Acute Leukemia Patients With T(11;19)(Q23;P13.1) And T(11;19)(Q23;P13.3), B. Bhatnagar, J. S. Blachly, J. Kohlschmidt, A. K. Eisfeld, S. Volinia, D. Nicolet, A. J. Carroll, A. M. Block, J. E. Kolitz, C. D. Bloomfield, +3 Additional Authors

Journal Articles

No abstract provided.

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First Human Treatment With Investigational Rhgus Enzyme Replacement Therapy In An Advanced Stage Mps Vii Patient, J. E. Fox, L. Volpe, J. Bullaro, E. D. Kakkis, W. S. Sly Jan 2015

First Human Treatment With Investigational Rhgus Enzyme Replacement Therapy In An Advanced Stage Mps Vii Patient, J. E. Fox, L. Volpe, J. Bullaro, E. D. Kakkis, W. S. Sly

Journal Articles

Mucopolysaccharidosis type VII (MPS VII, Sly syndrome) is a very rare lysosomal storage disease caused by a deficiency of the enzyme beta-glucuronidase (GUS), which is required for the degradation of three glycosaminoglycans (GAGs): dermatan sulfate, heparan sulfate, and chondroitin sulfate. Progressive accumulation of these GAGs in lysosomes leads to increasing dysfunction in numerous tissues and organs. Enzyme replacement therapy (ERT) has been used successfully for other MPS disorders, but there is no approved treatment for MPS VII. Here we describe the first human treatment with recombinant human GUS (rhGUS), an investigational therapy for MPS VII, in a 12-year old boy …

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Abnormal Erythroid Maturation Leads To Microcytic Anemia In The Tsap6/Steap3 Null Mouse Model, L. Blanc, J. Papoin, G. Debnath, M. Vidal, R. Amson, A. Telerman, X. L. An, N. Mohandas Jan 2015

Abnormal Erythroid Maturation Leads To Microcytic Anemia In The Tsap6/Steap3 Null Mouse Model, L. Blanc, J. Papoin, G. Debnath, M. Vidal, R. Amson, A. Telerman, X. L. An, N. Mohandas

Journal Articles

Genetic ablation of the ferrireductase STEAP3, also known as TSAP6, leads to severe microcytic and hypochromic red cells with moderate anemia in the mouse. However, the mechanism leading to anemia is poorly understood. Previous results indicate that TSAP6/Steap3 is a regulator of exosome secretion. Using TSAP6/Steap3 knockout mice, we first undertook a comprehensive hematologic characterization of the red cell compartment, and confirmed a dramatic decrease in the volume and hemoglobin content of these erythrocytes. We observed marked anisocytosis as well as the presence of fragmenting erythrocytes. Consistent with these observations, we found by ektacytometry decreased membrane mechanical stability of knockout …

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Association Of Prenatal Perchlorate, Thiocyanate, And Nitrate Exposure With Neonatal Size And Gestational Age, K. A. Evans, D. Q. Rich, B. Weinberger, A. M. Vetrano, L. Valentin-Blasini, P. O. Strickland, B. C. Blount Jan 2015

Association Of Prenatal Perchlorate, Thiocyanate, And Nitrate Exposure With Neonatal Size And Gestational Age, K. A. Evans, D. Q. Rich, B. Weinberger, A. M. Vetrano, L. Valentin-Blasini, P. O. Strickland, B. C. Blount

Journal Articles

BACKGROUND: Perchlorate and similar anions compete with iodine for uptake into the thyroid by the sodium iodide symporter (NIS). This may restrict fetal growth via impaired thyroid hormone production. METHODS: We collected urine samples from 107 pregnant women and used linear regression to estimate differences in newborn size and gestational age associated with increases in perchlorate, thiocyanate, nitrate, and perchlorate equivalence concentrations (PEC; measure of total NIS inhibitor exposure). RESULTS: NIS inhibitor concentrations were not associated with newborn weight, length, or gestational age. Each 2.62ng/mug creatinine increase in perchlorate was associated with smaller head circumference (0.32cm; 95% CI: -0.66, 0.01), …

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De Novo Mutations In Congenital Heart Disease With Neurodevelopmental And Other Congenital Anomalies, J. Homsy, S. Zaidi, Y. Shen, J. S. Ware, K. E. Samocha, K. J. Karczewski, S. R. Depalma, D. Mckean, A. Romano-Adesman, W. K. Chung, +31 Additional Authors Jan 2015

De Novo Mutations In Congenital Heart Disease With Neurodevelopmental And Other Congenital Anomalies, J. Homsy, S. Zaidi, Y. Shen, J. S. Ware, K. E. Samocha, K. J. Karczewski, S. R. Depalma, D. Mckean, A. Romano-Adesman, W. K. Chung, +31 Additional Authors

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Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD, and CA but only 2% of patients with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, a regulator of mRNA splicing. Genes mutated in other cohorts examined for NDD were enriched in CHD cases, …

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Differences In Birth Weight Associated With The 2008 Beijing Olympics Air Pollution Reduction: Results From A Natural Experiment, D. Q. Rich, K. Liu, J. Zhang, S. W. Thurston, T. P. Stevens, Y. Pan, C. Kane, B. Weinberger, P. Ohman-Strickland, +3 Additional Authors Jan 2015

Differences In Birth Weight Associated With The 2008 Beijing Olympics Air Pollution Reduction: Results From A Natural Experiment, D. Q. Rich, K. Liu, J. Zhang, S. W. Thurston, T. P. Stevens, Y. Pan, C. Kane, B. Weinberger, P. Ohman-Strickland, +3 Additional Authors

Journal Articles

BACKGROUND: Previous studies have reported decreased birth weight associated with increased air pollutant concentrations during pregnancy. However, it is not clear when during pregnancy increases in air pollution are associated with the largest differences in birth weight. OBJECTIVES: Using the natural experiment of air pollution declines during the 2008 Beijing Olympics, we evaluated whether having specific months of pregnancy (i.e., 1st...8th) during the 2008 Olympics period was associated with larger birth weights, compared with pregnancies during the same dates in 2007 or 2009. METHODS: Using n = 83,672 term births to mothers residing in four urban districts of Beijing, we …

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High Incidence Of Noonan Syndrome Features Including Short Stature And Pulmonic Stenosis In Patients Carrying Nf1 Missense Mutations Affecting P.Arg1809: Genotype-Phenotype Correlation, K. Rojnueangnit, J. Xie, A. Gomes, A. Sharp, T. Callens, Y. Chen, Y. Liu, M. Cochran, M. G. Bialer, L. Messiaen, +63 Additional Authors Jan 2015

High Incidence Of Noonan Syndrome Features Including Short Stature And Pulmonic Stenosis In Patients Carrying Nf1 Missense Mutations Affecting P.Arg1809: Genotype-Phenotype Correlation, K. Rojnueangnit, J. Xie, A. Gomes, A. Sharp, T. Callens, Y. Chen, Y. Liu, M. Cochran, M. G. Bialer, L. Messiaen, +63 Additional Authors

Journal Articles

Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple cafe-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly …

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Proton-Pump Inhibitor Treatment In Eosinophilic Esophagitis Is Associated With Decreased Eosinophil Degranulation, J. Levine, Y. Lu, C. Carreon, M. Edelman Jan 2015

Proton-Pump Inhibitor Treatment In Eosinophilic Esophagitis Is Associated With Decreased Eosinophil Degranulation, J. Levine, Y. Lu, C. Carreon, M. Edelman

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