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MED12 Regulates HSC-Specific Enhancers Independently of Mediator Kinase Activity to Control Hematopoiesis

Aranda-Orgilles, Beatriz; Saldana-Meyer, Ricardo; Wang, Eric; Trompouki, Eirini; Fassl, Anne; Lau, Stephanie; Mullenders, Jasper; Rocha, Pedro P; Raviram, Ramya; Guillamot, Maria; Sanchez-Diaz, Maria; Wang, Kun; Kayembe, Clarisse; Zhang, Nan; Amoasii, Leonela; Choudhuri, Avik; Skok, Jane A; Schober, Markus; Reinberg, Danny; Sicinski, Piotr; Schrewe, Heinrich; Tsirigos, Aristotelis; Zon, Leonard I; Aifantis, Iannis
Hematopoietic-specific transcription factors require coactivators to communicate with the general transcription machinery and establish transcriptional programs that maintain hematopoietic stem cell (HSC) self-renewal, promote differentiation, and prevent malignant transformation. Mediator is a large coactivator complex that bridges enhancer-localized transcription factors with promoters, but little is known about Mediator function in adult stem cell self-renewal and differentiation. We show that MED12, a member of the Mediator kinase module, is an essential regulator of HSC homeostasis, as in vivo deletion of Med12 causes rapid bone marrow aplasia leading to acute lethality. Deleting other members of the Mediator kinase module does not affect HSC function, suggesting kinase-independent roles of MED12. MED12 deletion destabilizes P300 binding at lineage-specific enhancers, resulting in H3K27Ac depletion, enhancer de-activation, and consequent loss of HSC stemness signatures. As MED12 mutations have been described recently in blood malignancies, alterations in MED12-dependent enhancer regulation may control both physiological and malignant hematopoiesis.
PMCID:5268820
PMID: 27570068
ISSN: 1875-9777
CID: 2232392

Case Report of a Patient With Treatment-Refractory Nontuberculous Mycobacteria (NTM) Lung Infection Treated With Once Daily (QD) Liposomal Amikacin for Inhalation (LAI) [Meeting Abstract]

Daglian, Dena; Lau, Stephanie; Eagle, Gina; McGinnis, John; Micioni, Liza; Addrizzo-Harris, Doreen
ISI:000366134400158
ISSN: 0012-3692
CID: 1909272

Delivery and Safety of Inhaled Interferon-gamma in Idiopathic Pulmonary Fibrosis

Diaz, KT; Skaria, S; Harris, K; Solomita, M; Lau, S; Bauer, K; Smaldone, GC; Condos, R
Abstract Background: Inhaled interferon-gamma aerosol (aINF-gamma) may be effective treatment for idiopathic pulmonary fibrosis (IPF). We evaluated safety and delivery of aIFN-gamma (100 mug 3 times/week) in 10 IPF patients using the I-neb (Philips Respironics, Parsippany, NJ). Methods: IFN-gamma activity in the aerosol was confirmed by viral inhibition. Ten patients with an average age of 68 diagnosed with IPF (American Thoracic Society/European Respiratory Society consensus guidelines) were enrolled. In vivo deposition was measured via a gamma camera. The nebulizer recorded patient adherence to therapy. Pulmonary function tests [PFTs, forced vital capacity (FVC), total lung capacity (TLC), diffusing capacity for carbon monoxide (DLCO)] and the 6-min walk test were measured at baseline, and every 12-14 weeks for 80 weeks. Bronchoalveolar lavage (BAL) of the middle lobe was performed at baseline and 28 weeks. BAL and plasma samples were analyzed for chemokines and cytokines, including INF-gamma. Results: All 10 patients tolerated 80 weeks of inhaled IFN-gamma well, with no systemic side effects. True adherence with aerosol treatment averaged 96.7+/-4.81% (+/-SEM). In vivo lung deposition averaged 65.4+/-4.8mug and oropharyngeal deposition 12.6+/-3.0 mug. BAL IFN-gamma increased 60-fold and profibrotic cytokines (FGP-2, Flt-3 ligand, IL-5) were significantly decreased; IFN-gamma plasma levels were unchanged. PFTs showed minimal change in FVC. Post hoc analysis indicated that the slope of decline in TLC and DLCO reversed after beginning therapy. The 6-min walk was unchanged. Conclusions: IFN-gamma is safe in IPF and can be effectively delivered to lung parenchyma. PFTs remained stable throughout the trial. Reversal of pretherapy PFT decline may define an end-point for future clinical trials.
PMID: 22360317
ISSN: 1941-2711
CID: 160160

Characteristics of a residential and working community with diverse exposure to World Trade Center dust, gas, and fumes

Reibman, Joan; Liu, Mengling; Cheng, Qinyi; Liautaud, Sybille; Rogers, Linda; Lau, Stephanie; Berger, Kenneth I; Goldring, Roberta M; Marmor, Michael; Fernandez-Beros, Maria Elena; Tonorezos, Emily S; Caplan-Shaw, Caralee E; Gonzalez, Jaime; Filner, Joshua; Walter, Dawn; Kyng, Kymara; Rom, William N
OBJECTIVE: To describe physical symptoms in those local residents, local workers, and cleanup workers who were enrolled in a treatment program and had reported symptoms and exposure to the dust, gas, and fumes released with the destruction of the World Trade Center (WTC) on September 11, 2001. METHODS: Symptomatic individuals underwent standardized evaluation and subsequent treatment. RESULTS: One thousand eight hundred ninety-eight individuals participated in the WTC Environmental Health Center between September 2005 and May 2008. Upper and lower respiratory symptoms that began after September 11, 2001 and persisted at the time of examination were common in each exposure population. Many (31%) had spirometry measurements below the lower limit of normal. CONCLUSIONS: Residents and local workers as well as those with work-associated exposure to WTC dust have new and persistent respiratory symptoms with lung function abnormalities 5 or more years after the WTC destruction
PMCID:2756680
PMID: 19365288
ISSN: 1536-5948
CID: 98897