Jeffrey A Golden

Harvard Medical School, Boston, Massachusetts, United States

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Publications (246)1659.82 Total impact

  • [Show abstract] [Hide abstract]
    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; 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-S257. DOI:10.1016/j.healun.2015.01.713 · 6.65 Impact Factor
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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
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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
  • Archives of pathology & laboratory medicine 09/2014; 138(9):1133-8. DOI:10.5858/arpa.2014-0034-ED · 2.84 Impact Factor
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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
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    ABSTRACT: Late Breaking AbstractsSESSION TYPE: Slide PresentationPRESENTED ON: Saturday, March 22, 2014 at 09:00 AM - 10:00 AMPURPOSE: Human immunodeficiency virus seropositivity (HIV+) has been considered a contraindication to lung transplantation (LT) primarily due to potential risks of iatrogenic immunosuppression. With the recent passage of the HIV Organ Policy Equity (HOPE) Act on November 21, 2013, the donation of HIV+ organs for transplant in HIV+ recipients is now legal in the USA. As a result there may be an increase in donors for HIV+ recipients. However, there remains only one fully published case report of LT in an HIV+ patient, limiting the evidence base with which to guide medical decision making. We report 3 HIV+ patients at two different medical centers who underwent LT. Based on the experience of two centers, we compiled data for a case series of three HIV+ patients who underwent LT. Data was abtracted from medical records from the lung transplant programs at the University of California, San Francisco and Houston Methodist Hospital. We reviewed charts to investigate: 1.) Does LT affect the course of HIV infection? 2.) Do LT recipients demonstrate an increased risk for HIV-related opportunistic infections or malignancies? 3.) Can drug-drug interactions between immunosuppressive and antiretroviral medications be easily managed? 4.) Are HIV+ LT recipients at higher risk for acute rejection, similar to HIV+ liver and kidney transplant recipients? Patient 1, transplanted for HIV-associated pulmonary arterial hypertension, experienced recalcitrant acute rejection and the rapid development of bronchiolitis obliterans syndrome. Patients 2 and 3, transplanted for idiopathic pulmonary fibrosis, experienced mild acute rejection but remain free from chronic rejection at 3.5 and 1.5 years after transplant, respectively. We observed no instances of HIV-associated opportunistic infections or malignancies in any of the three cases. Drug-drug interactions, although challenging, were manageable. Unexpectedly, all 3 patients showed signs of pulmonary arterial vasculopathy on explant; all three also had at least one episode of acute cellular rejection in the first year after LT. In Patients 2 and 3, rejection was easily managed and did not recur, whereas Patient 1 required a lymphocyte-depleting agent. Based on this limited experience, LT appears feasible in the setting of HIV, although acute rejection appears to be common. As seen in other solid organ transplant populations, LT in the setting of HIV may be associated with good outcomes, but there may be increased rates of acute rejection. The following authors have nothing to disclose: Ryan Kern, Harish Seethamraju, Paul Blanc, Neeraj Sinha, Matthias Loebe, Jeffrey Golden, Jasleen Kukreja, Scott Scheinin, Steve Hays, Kleinhenz Mary Ellen, Leard Lorri, Charles Hoopes, Jonathan SingerNo Product/Research Disclosure Information.
    Chest 03/2014; 145(3 Suppl):642A. DOI:10.1378/chest.1923375 · 7.48 Impact Factor
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    ABSTRACT: Mutations in the aristaless-related homeobox (ARX) gene result in a spectrum of structural and functional nervous system disorders including lissencephaly, movement disorders, intellectual disabilities, and epilepsy. Some patients also have symptoms indicating hypothalamic dysfunction, but little is known about the role of ARX in diencephalic development. To begin evaluating diencephalic defects, we examined the expression of a panel of known genes and gene products that label specific diencephalic nuclei in 2 different Arx mutant mouse lines at E18.5. Male mice engineered to have a polyalanine expansion mutation (Arx) revealed no expression differences in any diencephalic nucleus when compared with wild-type littermates. In contrast, mice null for Arx (Arx) lost expression of specific markers of the thalamic reticular nucleus and zona incerta (ZI) while retaining expression in other thalamic nuclei and in the hypothalamus. Tyrosine hydroxylase, a marker of the dopaminergic A13 subnucleus of ZI, was among those lost, suggesting a requirement for Arx in normal thalamic reticular nucleus and ZI development and, specifically, for A13 dopaminergic fate. Because the ZI and A13 regions make connections to several hypothalamic nuclei, such misspecification may contribute to the "hypothalamic dysfunction" observed in some patients.
    01/2014; 73(3). DOI:10.1097/NEN.0000000000000048
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    ABSTRACT: Lung transplant (LT) aims to extend survival and improve patient-centred outcomes (PCOs) by reducing disability and improving health-related quality of life (HRQL). Few PCO instruments have been validated in LT populations. We aimed to develop and validate a shortened version of the valued life activities (VLA) disability scale specific to LT. We used data from 140 subjects participating in an ongoing cohort study of LT. Subjects completed a survey battery, including VLA items, and physical assessments before LT. To develop a shortened LT-specific VLA (LT-VLA), we iteratively deleted items from a longer 32-item VLA battery, retaining the instrument's conceptual framework, scoring and performance characteristics. We evaluated LT-VLA validity by testing correlations with a HRQL measure (Short Form-12 Physical Function (SF-12 PF) subscale), forced vital capacity % (FVC%) predicted and 6 minute walk distance (6MWD). Responsiveness was evaluated in 84 subjects who completed assessments before and after LT. The 15-item LT-VLA scoring closely matched the longer VLA (correlations ≥0.96) and had excellent internal consistency (Cronbach's α 0.92). The LT-VLA required only 3 min or less to administer. The LT-VLA, measured as mean difficulty in performing each of the 15 activities queried, correlated with FVC% predicted (r=-0.30), 6MWD (r=-0.38) and SF-12 PF (r=-0.47) (all p<0.01). The LT-VLA mean difficulty was responsive to change from before to after LT (63% improvement; effect size=1.60). The LT-VLA is a short, easy to administer, valid and responsive disease-specific PCO instrument that may be useful in clinical and research applications for lung transplantation.
    Thorax 12/2013; 33(4). DOI:10.1136/thoraxjnl-2013-204557 · 8.29 Impact Factor
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    ABSTRACT: Interstitial Lung Disease Cases ISESSION TYPE: Affiliate Case Report SlidePRESENTED ON: Sunday, October 27, 2013 at 07:30 AM - 08:30 AMINTRODUCTION: Lung transplantation (LT) can be a lifesaving therapy for patients suffering from advanced lung disease due to hypersensitivity pneumonitis (HP). Published data are limited addressing recipient outcomes post-lung transplantation (LT) in HP. In particular, although recurrence of primary disease in the recipient allograft has been described for a number of conditions1 this phenomenon is not well documented in HP. We present a case of recurrent HP in a LT recipient.CASE PRESENTATION: Bilateral LT was performed in 2009 on a 49-year-old woman with advanced fibrotic HP. She initially presented in 1991 complaining of cough and dyspnea, with imaging suggestive of HP and confirmation by surgical biopsy. She had no clear indoor exposure history; the possibility of ambient environmental exposures was considered. Serologic testing demonstrated precipitating antibodies to both bird proteins and fungi. Despite immunosuppressive therapy and potential ambient antigen avoidance by relocating, she had a slow decline in respiratory function and underwent bilateral LT in 2009. She did well for the first 2 years post-LT. By 3 years, however, she developed worsening cough and exertional dyspnea. She had an immune suppressive regimen of prednisone 10 mg daily, mycophenolate mofetil 500 mg bid, and tacrolimus (trough 8-10 ng/mL). CT scanning revealed air trapping; lung function testing showed a declining FEV1. Transbronchial lung biopsies (TBBX) showed non-necrotizing granulomas (culture negative). Repeat TBBXs at 1 month were unchanged. Bronchial alveolar lavage (BAL) showed 29% lymphocytes. The patient noted that pigeons were roosting outside her windows at her new home. Prednisone was increased, the patient again changed residence and her FEV1 stabilized. Subsequent TBBXs show no granulomas; the BAL lymphocytosis has resolved. She now has grade 3/3 bronchiolitis obliterans syndrome. It is unclear whether the recurrent HP contributed to this outcome.DISCUSSION: HP represents an immune reaction to inhaled organic antigens. Despite standard post-LT immunosuppressive regimens, intercurrent or ongoing exposure to an offending antigen may lead to recurrent disease in the allograft. Suggestive findings can include BAL lymphocytosis and non-necrotizing granulomas in the absence of infection.CONCLUSIONS: Our case highlights the importance of antigen recognition and aggressive avoidance or abatement post-LT for HP. This can be particularly problem-ridden if the exposure is poorly characterized. A detailed exposure history not only pre-LT but also at post-LT visits is imperative for this patient population.Reference #1: Collins, J. et al. Frequency and CT findings of recurrent disease after lung transplantation. Radiology 219, 503-509 (2001).DISCLOSURE: The following authors have nothing to disclose: Ryan Kern, Jonathan Singer, Kirk Jones, Kukreja Jasleen, Jeffrey Golden, Steven Hays, Leard Lorriana, Paul BlancNo Product/Research Disclosure Information.
    Chest 10/2013; 144(4_MeetingAbstracts):432A. DOI:10.1378/chest.1701931 · 7.48 Impact Factor
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    ABSTRACT: Mutations in the Aristaless-related homeobox (ARX) gene are found in a spectrum of epilepsy and X-linked intellectual disability disorders. During development Arx is expressed in pallial ventricular zone (VZ) progenitor cells where the excitatory projection neurons of the cortex are born. Arx(-/Y) mice were shown to have decreased proliferation in the cortical VZ resulting in smaller brains; however, the basis for this reduced proliferation was not established. To determine the role of ARX on cell cycle dynamics in cortical progenitor cells, we generated cerebral cortex-specific Arx mouse mutants (cKO). The loss of pallial Arx resulted in the reduction of cortical progenitor cells, particularly the proliferation of intermediate progenitor cells (IPCs) was affected. Later in development and postnatally cKO brains showed a reduction of upper layer but not deeper layer neurons consistent with the IPC defect. Transcriptional profile analysis of E14.5 Arx-ablated cortices compared with control revealed that CDKN1C, an inhibitor of cell cycle progression, is overexpressed in the cortical VZ and SVZ of Arx KOs throughout corticogenesis. We also identified ARX as a direct regulator of Cdkn1c transcription. Together these data support a model where ARX regulates the expansion of cortical progenitor cells through repression of Cdkn1c.
    Cerebral Cortex 08/2013; 25(2). DOI:10.1093/cercor/bht222 · 8.67 Impact Factor
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    ABSTRACT: Background: Lung disease is the leading cause of death in systemic sclerosis (SSc). The diagnosis of SSc-related lung disease (SSc-LD) is often a contraindication to lung transplantation (LT) due to concerns that extrapulmonary involvement will yield worse outcomes. We sought to evaluate posttransplantation outcomes in persons with SSc-LD with esophageal involvement compared with persons with nonconnective tissue disease-related interstitial lung disease (nCTD-ILD). Methods: From 1998 to 2012, persons undergoing LT for SSc-LD were age and gender matched in a 2:1 fashion to controls undergoing LT for nCTD-ILD. Esophageal function was assessed by pH testing and manometry. We defined esophageal dysfunction as the presence of a DeMeester score >14 or dysmotility more severe than "mild nonspecific disorder". The primary outcome was posttransplantation survival. Secondary outcomes included freedom from bronchiolitis obliterans syndrome (fBOS) and rates of acute rejection. Survival and fBOS were estimated with Kaplan-Meier methods. Acute rejection was compared with Student's t test. Results: Survival was similar in 23 persons with SSc-LD and 46 controls who underwent LT (P = 0.47). For the SSc-LD group, 1- and 5-year survival was 83% and 76% compared with 91% and 64% in the nCTD-ILD group, respectively. There were no differences in fBOS (P = 0.83). Rates of acute rejection were less in SSc-ILD (P = 0.05). Esophageal dysfunction was not associated with worse outcomes (P>0.55). Conclusions: Persons with SSc-LD appear to have similar survival and fBOS as persons transplanted for nCTD-ILD. The risk of acute rejection after transplantation may be reduced in persons with SSc-LD. Esophageal involvement does not appear to impact outcomes.
    Transplantation 04/2013; 95(7):975-980. DOI:10.1097/TP.0b013e3182845f23 · 3.83 Impact Factor
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    ABSTRACT: Background: Community acquired respiratory virus (CARV) infections in lung transplant recipients (LTR) have been associated with adverse outcomes, including acute rejection (AR) and decline in allograft function, in some but not in all studies. Methods: Spirometry and transbronchial biopsy results of LTR diagnosed with CARV infection over a two-yr period were extracted from clinical records. Primary outcomes, studied at 1-2.5 months postinfection, were as follows: (i) incidence of biopsy-proven AR (grade >A0) and (ii) allograft function, defined by forced expiratory volume in one s (FEV(1)). A reference group of biopsies (n = 526) collected during the study period established the baseline incidence of AR. Rhinovirus (RV) and non-rhinovirus (non-RV) infections were analyzed as subgroups. Results: Eighty-seven cases of CARV infection were identified in 59 subjects. Incidences of AR were similar in the post-CARV and reference groups and did not differ significantly after RV vs. non-RV infection. Allograft function declined significantly after non-RV infection, but not after RV infection. Conclusions: In LTR, CARV infections other than RV are associated with allograft dysfunction at 1-2.5 months after infection. However, CARVs do not appear associated with AR at this time point. The impact of specific CARVs on lung allografts, including the development of chronic allograft rejection, merits further study.
    Clinical Transplantation 12/2012; 27(1). DOI:10.1111/ctr.12054 · 1.52 Impact Factor
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    ABSTRACT: RATIONALE: Lung transplantation offers great promise for otherwise terminal lung diseases, but the development of bronchiolitis obliterans syndrome (BOS) continues to limit survival. While acute rejection and lymphocytic bronchiolitis have been identified as risk factors for the development of BOS, it is unclear whether large-airway lymphocytic inflammation conveys the same risk. OBJECTIVES: We evaluated lymphocytic bronchitis on endobronchial biopsies as a risk factor for BOS and mortality. METHODS: Endobronchial biopsies were collected and graded during surveillance following lung transplantation. We assessed samples with negative cultures collected in the first 90 days from 298 subjects and compared large-airway lymphocytic bronchitis assessed by a 0 to 2 "E-score" and with standard A and BR pathology scores for acute rejection and small-airway lymphocytic bronchiolitis, respectively. RESULTS: We found surprisingly little association between large- and small-airway lymphocytic inflammation scores from a given bronchoscopy. Endobronchial lymphocytic bronchitis was more prevalent in subjects in BOS stage 0p and BOS stages 1-3 at the time of biopsy. Within 90 days after transplantation, increasing maximum E-score was associated with greater risk of BOS (adjusted hazards ratio 1.76, 95% CI 1.11-2.78, P = 0.02) and in this analysis 90-day maximum E-scores were the only score type predictive of BOS (P < 0.01). CONCLUSIONS: These results would support a multicenter study to evaluate endoscopic biopsies for the identification of patients at increased risk for BOS. The association of endobronchial lymphocytic inflammation and BOS may have mechanistic implications.
    American Journal of Respiratory and Critical Care Medicine 12/2012; 187(4). DOI:10.1164/rccm.201206-1025OC · 13.00 Impact Factor

Publication Stats

8k Citations
1,659.82 Total Impact Points


  • 1996–2015
    • Harvard Medical School
      • Department of Genetics
      Boston, Massachusetts, United States
  • 1983–2015
    • 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
  • 1997–2013
    • Brigham and Women's Hospital
      • Department of Pathology
      Boston, Massachusetts, United States
  • 2004–2011
    • 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
  • 1983–1985
    • San Francisco VA Medical Center
      San Francisco, California, United States