Jeffrey A Golden

Brigham and Women's Hospital, Boston, Massachusetts, United States

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Publications (275)1818.1 Total impact

  • Melissa A Stouffer · Jeffrey A Golden · Fiona Francis ·
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    ABSTRACT: A wide spectrum of focal, regional, or diffuse structural brain abnormalities, collectively known as malformations of cortical development (MCDs), frequently manifest with intellectual disability (ID), epilepsy, and/or autistic spectrum disorder (ASD). As the acronym suggests, MCDs are perturbations of the normal architecture of the cerebral cortex and hippocampus. The pathogenesis of these disorders remains incompletely understood; however, one area that has provided important insights has been the study of neuronal migration. The amalgamation of human genetics and experimental studies in animal models has led to the recognition that common genetic causes of neurodevelopmental disorders, including many severe epilepsy syndromes, are due to mutations in genes regulating the migration of newly born post-mitotic neurons. Neuronal migration genes often, though not exclusively, code for proteins involved in the function of the cytoskeleton. Other cellular processes, such as cell division and axon/dendrite formation, which similarly depend on cytoskeletal functions, may also be affected. We focus here on how the susceptibility of the highly organized neocortex and hippocampus may be due to their laminar organization, which involves the tight regulation, both temporally and spatially, of gene expression, specialized progenitor cells, the migration of neurons over large distances and a birthdate-specific layering of neurons. Perturbations in neuronal migration result in abnormal lamination, neuronal differentiation defects, abnormal cellular morphology and circuit formation. Ultimately this results in disorganized excitatory and inhibitory activity leading to the symptoms observed in individuals with these disorders.
    Neurobiology of Disease 08/2015; DOI:10.1016/j.nbd.2015.08.003 · 5.08 Impact Factor
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    ABSTRACT: Some patients with chronic fibrosing interstitial pneumonia (IP) have clinical, serological, and morphological features suggestive of, but not diagnostic for, a connective tissue disease. Several names and diagnostic criteria for this entity have been proposed. The objective of this study was to compare the clinical characteristics and behavior of each of the proposed diagnostic criteria. Patients with chronic fibrosing IP were identified from an ongoing, longitudinal cohort. Four published diagnostic criteria for what we generically label as "IP with features of autoimmunity" were applied to all patients to identify four unique cohorts (Kinder, Vij, Corte, and Fischer). Kaplan-Meier survival functions compared differences in survival in each cohort between patients meeting and not meeting criteria. Unadjusted and adjusted Cox proportional hazard regression models identified predictors of survival. The study cohort included 119 patients, 40% of whom were female. The mean age was 65.5 years. There was overlap between the four different criteria, identifying patients with similar clinical characteristics. Interstitial pneumonia patients with features of autoimmunity tended to have improved survival compared to those without these features (p-value range 0.03-0.10) on univariate analysis. After adjusting for disease severity using the gender-age-physiology score, only the Corte criteria was an independent predictor of survival (p-value 0.04). Interstitial pneumonia with features of autoimmunity may be associated with improved survival compared to those patients without these features depending on which criteria is used to define the population. These data support the efforts being made to standardize the definition. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Respiratory medicine 08/2015; 109(10). DOI:10.1016/j.rmed.2015.08.010 · 3.09 Impact Factor
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    ABSTRACT: Frailty is associated with morbidity and mortality in abdominal organ transplantation but has not been examined in lung transplantation. To examine the construct and predictive validity of frailty phenotypes in lung transplant candidates. In a multicenter prospective cohort we measured frailty with the Fried Frailty Phenotype (FFP) and Short Physical Performance Battery (SPPB). We evaluated construct validity through comparisons to conceptually related factors. In a nested case-control study of frail and non-frail subjects, we measured serum IL-6, tumor necrosis factor-receptor 1 (TNFR1), insulin-like growth factor I (IGF-1), and leptin. We estimated the association between frailty and disability and risk of delisting/death before transplant using multivariate logistic and cox models, respectively. In 395 subjects, 28% were frail by FFP (95%CI 24-33%) and 10% by SPPB (95%CI 7-14%). By either measure, frailty correlated more strongly with exercise capacity and grip strength than with lung function. Frail subjects tended to have higher plasma IL-6 and TNFR1 and lower IGF-1 and leptin. Frailty by either measure was associated with greater disability. After adjusting for age, gender, diagnosis and transplant center, both FFP and SPPB were associated with increased risk of delisting/death before lung transplantation (FFP, HR 1.30, 95%CI 1.01-1.67; SPPB, HR 1.53, 95%CI 1.19-1.59 per one point worsening in score). Frailty is prevalent among lung transplant candidates and is independently associated with greater disability and an increased risk of delisting or death.
    American Journal of Respiratory and Critical Care Medicine 08/2015; DOI:10.1164/rccm.201506-1150OC · 13.00 Impact Factor
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    ABSTRACT: Voriconazole is a triazole antifungal used to prevent and treat invasive fungal infections after lung transplantation, but it has been associated with an increased risk of developing cutaneous squamous cell carcinoma (SCC). Despite widespread use, there are no clear guidelines for optimal prophylactic regimens that balance the competing risks and benefits. We conducted a retrospective cohort study of all lung transplant recipients at the University of California, San Francisco, who were transplanted between October 1991 and December 2012 (n = 455) to investigate whether voriconazole exposure affected development of SCC, Aspergillus colonization, invasive aspergillosis and all-cause mortality. Voriconazole exposure was associated with a 73% increased risk of developing SCC (hazard ratio [HR] 1.73; 95% confidence interval [CI]: 1.04–2.88; p = 0.03), with each additional 30-day exposure at the standard dose increasing the risk by 3.0% (HR 1.03; 95% CI: 1.02–1.04; p < 0.001). Voriconazole exposure reduced risk of Aspergillus colonization by 50% (HR 0.50; 95% CI: 0.34–0.72; p < 0.001), but we were underpowered to detect risk reduction for invasive aspergillosis. Voriconazole exposure significantly reduced all-cause mortality among subjects who developed Aspergillus colonization (HR 0.34; 95% CI: 0.13–0.91; p = 0.03) but had no significant impact on those without colonization. Physicians should consider patient-specific factors that modify the potential risks and benefits of voriconazole for the care of lung transplant recipients.
    American Journal of Transplantation 08/2015; DOI:10.1111/ajt.13431 · 5.68 Impact Factor
  • Youngshin Lim · Il-Taeg Cho · Leah J Schoel · Ginam Cho · Jeffrey A Golden ·
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    ABSTRACT: Mutations in receptor expression enhancing protein 1 (REEP1) are associated with hereditary spastic paraplegias (HSPs). Although axonal degeneration is thought to be a predominant feature in HSP, the role of REEP1 mutations in degeneration is largely unknown. Previous studies have implicated a role for REEP1 in the ER, whereas others localized REEP1 with mitochondria. We sought to resolve the cellular localization of REEP1 and to further elucidate the pathobiology underlying REEP1 mutations in patients. A combination of cellular imaging and biochemical approaches was used to refine the cellular localization of REEP1. Next, Reep1 mutations associated with HSP were functionally tested in neuritic growth and degeneration assays using mouse cortical culture. Finally, a novel assay was developed and used with wild type and mutant Reep1s to measure the interactions between the ER and mitochondria. We found that REEP1 is present at the ER-mitochondria interface, and it contains subdomains for mitochondrial as well as ER localization. Knockdown of Reep1 and the expression of pathological Reep1 mutations resulted in neuritic growth defects and degeneration. Finally, using our novel split-RLuc8 assay, we show REEP1 facilitates ER-mitochondria interactions, a function diminished by disease-associated mutations. Our data potentially reconcile the current conflicting reports regarding REEP1 being either an ER or a mitochondrial protein. Furthermore, our results connect, for the first time, the disrupted ER-mitochondria interactions to a failure in maintaining health of long axons in HSPs. Finally, the split-RLuc8 assay offers a new tool to identify potential drugs for multiple neurodegenerative diseases with ER-mitochondria interaction defects. This article is protected by copyright. All rights reserved. © 2015 American Neurological Association.
    Annals of Neurology 07/2015; 78(5). DOI:10.1002/ana.24488 · 9.98 Impact Factor
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    ABSTRACT: Forced vital capacity (FVC) is a key measure of disease severity in patients with idiopathic pulmonary fibrosis (IPF) and is an important clinical trial endpoint. We hypothesize that reversible airflow limitation co-exists in a subgroup of patients with IPF, and that bronchodilator use will improve the performance characteristics of FVC. IPF patients with pre and post-bronchodilator spirometry testing performed were identified from two tertiary referral cohorts. The difference between pre and post-bronchodilator FVC (intra-test difference) was calculated. The test characteristics of pre and post-bronchodilator FVC change over time (inter-test difference) were assessed in patients with sequential spirometry, and were used to generate sample size estimates for hypothetical clinical trials using change in FVC as the primary endpoint. There were 551 patients, contributing 967 unique spirometry tests. The mean intra-test increase in FVC with bronchodilator use was 0.04 L (2.71 vs. 2.75 L, p < 0.001). Reversible airflow limitation (increase in FEV1 or FVC of ≥12% and ≥200 mL) occurred in 9.1% of patients. The inter-test difference in change in FVC over time were equivalent for pre and post-bronchodilator (p = 0.65), leading to similar sample size estimates in a hypothetical clinical trial using change in FVC as the primary endpoint. Approximately one in ten patients with IPF has physiological evidence of reversible airflow limitation, and bronchodilator use in these patients may improve the assessment of disease progression based on FVC change over time. Bronchodilator use does not appear to meaningfully impact the precision of FVC as an endpoint in clinical trials. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Respiratory medicine 06/2015; 109(8). DOI:10.1016/j.rmed.2015.06.012 · 3.09 Impact Factor
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    ABSTRACT: Context .- We define the scope and needs within the new discipline of computational pathology, a discipline critical to the future of both the practice of pathology and, more broadly, medical practice in general. Objective .- To define the scope and needs of computational pathology. Data Sources .- A meeting was convened in Boston, Massachusetts, in July 2014 prior to the annual Association of Pathology Chairs meeting, and it was attended by a variety of pathologists, including individuals highly invested in pathology informatics as well as chairs of pathology departments. Conclusions .- The meeting made recommendations to promote computational pathology, including clearly defining the field and articulating its value propositions; asserting that the value propositions for health care systems must include means to incorporate robust computational approaches to implement data-driven methods that aid in guiding individual and population health care; leveraging computational pathology as a center for data interpretation in modern health care systems; stating that realizing the value proposition will require working with institutional administrations, other departments, and pathology colleagues; declaring that a robust pipeline should be fostered that trains and develops future computational pathologists, for those with both pathology and nonpathology backgrounds; and deciding that computational pathology should serve as a hub for data-related research in health care systems. The dissemination of these recommendations to pathology and bioinformatics departments should help facilitate the development of computational pathology.
    Archives of pathology & laboratory medicine 06/2015; DOI:10.5858/arpa.2015-0093-SA · 2.84 Impact Factor
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    ABSTRACT: Successful lung transplantation for patients with pulmonary fibrosis from telomerase mutations may be limited by systemic complications of telomerase dysfunction, including myelosuppression, cirrhosis, and malignancy. We describe clinical outcomes in 14 lung transplant recipients with telomerase mutations. Subjects underwent lung transplantation between February 2005 and April 2014 at 5 transplant centers. Data were abstracted from medical records, focusing on outcomes reflecting post-transplant treatment effects likely to be complicated by telomerase mutations. The median age of subjects was 60.5 years (interquartile range = 52.0-62.0), 64.3% were male, and the mean post-transplant observation time was 3.2 years (SD ± 2.9). A mutation in telomerase reverse transcriptase was present in 11 subjects, a telomerase RNA component mutation was present in 2 subjects, and an uncharacterized mutation was present in 1 subject. After lung transplantation, 10 subjects were leukopenic and 5 did not tolerate lymphocyte anti-proliferative agents. Six subjects developed recurrent lower respiratory tract infections, 7 developed acute cellular rejection (A1), and 4 developed chronic lung allograft dysfunction. Eight subjects developed at least 1 episode of acute renal failure and 10 developed chronic renal insufficiency. In addition, 3 subjects developed cancer. No subjects had cirrhosis. At data censorship, 13 subjects were alive. The clinical course for lung transplant recipients with telomerase mutations is complicated by renal disease, leukopenia with intolerance of lymphocyte anti-proliferative agents, and recurrent lower respiratory tract infections. In contrast, cirrhosis was absent, acute cellular rejection was mild, and development of chronic lung allograft dysfunction was comparable to other lung transplant recipients. Although it poses challenges, lung transplantation may be feasible for patients with pulmonary fibrosis from telomerase mutations. Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
    The Journal of Heart and Lung Transplantation 05/2015; 34(4). DOI:10.1016/j.healun.2015.05.002 · 6.65 Impact Factor

  • The Journal of Heart and Lung Transplantation 04/2015; 34(4):S256. DOI:10.1016/j.healun.2015.01.712 · 6.65 Impact Factor

  • The Journal of Heart and Lung Transplantation 04/2015; 34(4):S256-S257. DOI:10.1016/j.healun.2015.01.713 · 6.65 Impact Factor
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    The Journal of Heart and Lung Transplantation 04/2015; 34(4):S15. DOI:10.1016/j.healun.2015.01.028 · 6.65 Impact Factor

  • The Journal of Heart and Lung Transplantation 04/2015; 34(4):S148. DOI:10.1016/j.healun.2015.01.398 · 6.65 Impact Factor
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    ABSTRACT: Belatacept is a novel immunosuppressant that blocks a T-cell costimulation pathway and is approved for use in adult kidney transplant recipients. Its safety and efficacy have not been established after lung transplantation. We present a case of a lung transplant recipient treated with belatacept. A 56-year-old man underwent bilateral lung retransplantation for bronchiolitis obliterans syndrome (BOS). In the third year posttransplant, he developed hemolytic uremic syndrome (HUS) attributed to tacrolimus. Tacrolimus was changed to sirolimus. One month later, he presented with worsening renal function and HUS attributed to sirolimus. Plasmapheresis and steroid pulse were initiated with clinical improvement, and sirolimus was switched to belatacept. He experienced no episodes of cellular rejection but developed recurrent BOS. Complications during treatment included anemia and recurrent pneumonias. The safety and efficacy of belatacept in lung transplantation remains unclear; further studies are needed.
    09/2014; 2(3). DOI:10.1177/2324709614546866
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    ABSTRACT: Rationale: Obesity and underweight are contraindications to lung transplantation based on their associations with mortality in studies performed before implementation of the lung allocation score (LAS)-based organ allocation system in the United States Objectives: To determine the associations of body mass index (BMI) and plasma leptin levels with survival after lung transplantation. Methods: We used multivariable-adjusted regression models to examine associations between BMI and 1-year mortality in 9,073 adults who underwent lung transplantation in the United States between May 2005 and June 2011, and plasma leptin and mortality in 599 Lung Transplant Outcomes Group study participants. We measured body fat and skeletal muscle mass using whole-body dual X-ray absorptiometry in 142 adult lung transplant candidates. Measurements and main results: Adjusted mortality rates were similar among normal weight (BMI 18.5-24.9 kg/m(2)), overweight (BMI 25.0-29.9), and class I obese (BMI 30-34.9) transplant recipients. Underweight (BMI < 18.5) was associated with a 35% increased rate of death (95% confidence interval, 10-66%). Class II-III obesity (BMI ≥ 35 kg/m(2)) was associated with a nearly twofold increase in mortality (hazard ratio, 1.9; 95% confidence interval, 1.3-2.8). Higher leptin levels were associated with increased mortality after transplant surgery performed without cardiopulmonary bypass (P for interaction = 0.03). A BMI greater than or equal to 30 kg/m(2) was 26% sensitive and 97% specific for total body fat-defined obesity. Conclusions: A BMI of 30.0-34.9 kg/m(2) is not associated with 1-year mortality after lung transplantation in the LAS era, perhaps because of its low sensitivity for obesity. The association between leptin and mortality suggests the need to validate alternative methods to measure obesity in candidates for lung transplantation. A BMI greater than or equal to 30 kg/m(2) may no longer contraindicate lung transplantation.
    American Journal of Respiratory and Critical Care Medicine 09/2014; 190(9). DOI:10.1164/rccm.201405-0973OC · 13.00 Impact Factor
  • Ginam Cho · Youngshin Lim · Il-Taeg Cho · Jacqueline C. Simonet · Jeffrey A. Golden ·
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    ABSTRACT: Mutations in the Aristaless related homeodomain transcription factor (ARX) are associated with a diverse set of X-linked mental retardation and epilepsy syndromes in humans. Although most studies have been focused on its function in the forebrain, ARX is also expressed in other regions of the developing nervous system including the floor plate (FP) of the spinal cord where its function is incompletely understood. To investigate the role of Arx in the FP, we performed gain-of-function studies in the chick using in ovo electroporation, and loss-of-function studies in Arx-deficient mice. We have found that Arx, in conjunction with FoxA2, directly induces Sonic hedgehog (Shh) expression through binding to a Shh floor plate enhancer (SFPE2). We also observed that FoxA2 induces Arx through its transcriptional activation domain whereas Nkx2.2, induced by Shh, abolishes this induction. Our data support a feedback loop model for Arx function; through interactions with FoxA2, Arx positively regulates Shh expression in the FP, and Shh signaling in turn activates Nkx2.2, which suppresses Arx expression. Furthermore, our data are evidence that Arx plays a role as a context dependent transcriptional activator, rather than a primary inducer of Shh expression, potentially explaining how mutations in ARX are associated with diverse, and often subtle, defects.
    Developmental Biology 09/2014; 393(1). DOI:10.1016/j.ydbio.2014.06.012 · 3.55 Impact Factor
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    Archives of pathology & laboratory medicine 09/2014; 138(9):1133-8. DOI:10.5858/arpa.2014-0034-ED · 2.84 Impact Factor
  • Jacqueline C Simonet · C Nicole Sunnen · Jue Wu · Jeffrey A Golden · Eric D Marsh ·
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    ABSTRACT: Mutations in the Aristaless-Related Homeobox (ARX) gene cause structural anomalies of the brain, epilepsy, and neurocognitive deficits in children. During forebrain development, Arx is expressed in both pallial and subpallial progenitor cells. We previously demonstrated that elimination of Arx from subpallial-derived cortical interneurons generates an epilepsy phenotype with features overlapping those seen in patients with ARX mutations. In this report, we have selectively removed Arx from pallial progenitor cells that give rise to the cerebral cortical projection neurons. While no discernable seizure activity was recorded, these mice exhibited a peculiar constellation of behaviors. They are less anxious, less social, and more active when compared with their wild-type littermates. The overall cortical thickness was reduced, and the corpus callosum and anterior commissure were hypoplastic, consistent with a perturbation in cortical connectivity. Taken together, these data suggest that some of the structural and behavioral anomalies, common in patients with ARX mutations, are specifically due to alterations in pallial progenitor function. Furthermore, our data demonstrate that some of the neurobehavioral features found in patients with ARX mutations may not be due to on-going seizures, as is often postulated, given that epilepsy was eliminated as a confounding variable in these behavior analyses.
    Cerebral Cortex 05/2014; 25(9). DOI:10.1093/cercor/bhu090 · 8.67 Impact Factor

  • The Lancet Respiratory Medicine 05/2014; 2(5):e5. DOI:10.1016/S2213-2600(14)70075-X · 9.63 Impact Factor
  • Daniel E Lysko · Mary Putt · Jeffrey A Golden ·
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    ABSTRACT: Normal cerebral cortical function requires a highly ordered balance between projection neurons and interneurons. During development these two neuronal populations migrate from distinct progenitor zones to form the cerebral cortex, with interneurons originating in the more distant ganglionic eminences. Moreover, deficits in interneurons have been linked to a variety of neurodevelopmental disorders underscoring the importance of understanding interneuron development and function. We, and others, have identified SDF1 signaling as one important modulator of interneuron migration speed and leading process branching behavior in mice, although how SDF1 signaling impacts these behaviors remains unknown. We previously found SDF1 inhibited leading process branching while increasing the rate of migration. We have now mechanistically linked SDF1 modulation of leading process branching behavior to a dual regulation of both actin and microtubule organization. We find SDF1 consolidates actin at the leading process tip by de-repressing calpain protease and increasing proteolysis of branched-actin-supporting cortactin. Additionally, SDF1 stabilizes the microtubule array in the leading process through activation of the microtubule-associated protein doublecortin (DCX). DCX stabilizes the microtubule array by bundling microtubules within the leading process, reducing branching. These data provide mechanistic insight into the regulation of interneuron leading process dynamics during neuronal migration in mice and provides insight into how cortactin and DCX, a known human neuronal migration disorder gene, participate in this process.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2014; 34(14):4941-62. DOI:10.1523/JNEUROSCI.4351-12.2014 · 6.34 Impact Factor

  • The Journal of Heart and Lung Transplantation 04/2014; 33(4):S300. DOI:10.1016/j.healun.2014.01.805 · 6.65 Impact Factor

Publication Stats

9k Citations
1,818.10 Total Impact Points


  • 1997-2015
    • Brigham and Women's Hospital
      • Department of Pathology
      Boston, Massachusetts, United States
  • 1996-2015
    • Harvard Medical School
      • Department of Genetics
      Boston, Massachusetts, United States
  • 1982-2015
    • University of California, San Francisco
      • • Department of Medicine
      • • Division of Hospital Medicine
      • • Department of Surgery
      San Francisco, California, United States
  • 2014
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1998-2014
    • The Children's Hospital of Philadelphia
      • • Department of Pathology and Laboratory Medicine
      • • Department of Pediatrics
      Filadelfia, Pennsylvania, United States
  • 1983-2014
    • San Francisco VA Medical Center
      San Francisco, California, United States
  • 2001-2011
    • University of Pennsylvania
      • • Department of Pathology and Laboratory Medicine
      • • Department of Pathology
      • • Department of Medicine
      Philadelphia, Pennsylvania, United States
  • 2009-2010
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 2008
    • Hospital of the University of Pennsylvania
      Philadelphia, Pennsylvania, United States
    • Treatment Research Institute, Philadelphia PA
      Filadelfia, Pennsylvania, United States
  • 2006
    • University of California, Los Angeles
      Los Angeles, California, United States
  • 2000
    • Max Planck Institute of Molecular Cell Biology and Genetics
      Dresden, Saxony, Germany
  • 1991-1995
    • Howard Hughes Medical Institute
      Ашбърн, Virginia, United States