Baltimore, MD, United States
Baltimore, MD, United States

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Murray P.G.,University of Birmingham | Fan Y.,Chinese University of Hong Kong | Davies G.,University of Birmingham | Ying J.,Chinese University of Hong Kong | And 17 more authors.
American Journal of Pathology | Year: 2010

The malignant Hodgkin/Reed-Sternberg (HRS) cells of Hodgkin lymphoma (HL) are believed to derive from germinal center (GC) B cells, but lack expression of a functional B cell receptor. As apoptosis is the normal fate of B-cell receptor - negative GC B cells, mechanisms that abrogate apoptosis are thus critical in HL development, such as epigenetic disruption of certain pro-apoptotic cancer genes including tumor suppressor genes. Identifying methylated genes elucidates oncogenic mechanisms and provides valuable biomarkers; therefore, we performed a chemical epigenetic screening for methylated genes in HL through pharmacological demethylation and expression profiling. IGSF4/CADM1/TSLC1, a pro-apoptotic cell adhesion molecule of the immunoglobulin superfamily, was identified together with other methylated targets. In contrast to its expression in normal GC B cells, IGSF4 was down-regulated and methylated in HL cell lines, most primary HL, and microdissected HRS cells of 3/5 cases, but not in normal peripheral blood mononuclear cells and seldom in normal lymph nodes. We also detected IGSF4 methylation in sera of 14/18 (78%) HL patients but seldom in normal sera. Ectopic IGSF4 expression decreased HL cells survival and increased their sensitivity to apoptosis. IGSF4 induction that normally follows heat shock stress treatment was also abrogated in methylated lymphoma cells. Thus, our data demonstrate that IGSF4 silencing by CpG methylation provides an anti-apoptotic signal to HRS cells important in HL pathogenesis. Copyright © American Society for Investigative Pathology.


Messing B.P.,Jr Head And Neck Center | Kim M.,Jr Head And Neck Center | Hirata R.,Jr Head And Neck Center | Gebhart S.,Sydney Kimmel Comprehensive Cancer Center | And 4 more authors.
Laryngoscope | Year: 2015

Objectives/Hypothesis The objective of this study was to evaluate the effectiveness of nystatin and Biotène® mouthwash Oral Rinse for controlling Candida in total laryngectomy (TL) patients with a tracheosophageal voice prosthesis (TEP) because Biotène® mouthwash Oral Rinse is a less costly alternative to nystatin and requires less adherence time. Study Design Randomized, unblinded, crossover trial. Methods Twenty-one TL patients were randomized to receive nystatin followed by Biotène® mouthwash Oral Rinse, or the reverse order, after a basic oral-care phase (i.e., brushing teeth, cleaning dentures). A Provox® 2, 22.5 French TEP, which is an indwelling silicone voice prosthesis, was placed at the beginning of each phase. Patients were provided with oral care instructions at randomization and medication-specific instructions with each treatment's initiation. TEPs were processed and evaluated for Candida growth as colony-forming units (CFUs). Wilcoxon signed-rank tests were used for comparisons between treatments. Results Fifteen patients were available for comparisons of Candida counts (6 received nystatin; 9 received Biotène® mouthwash first). Overall, the median log10 (CFUs) remained high regardless of treatment (no medication: 8.9; nystatin: 8.7; Biotène® mouthwash: 8.4). However, the median counts for both nystatin and Biotène® mouthwash Oral Rinse were lower than those for no medication (difference [Δ]:-0.9 and -0.3, respectively), although only nystatin was significantly lower (P=0.02). There was no significant difference between the two treatments (P=0.22). Overall, median medication-adherence was high (97%), and Biotène® mouthwash adherence was significantly higher than that of nystatin (Δ: 7.6%; P=0.03). Conclusion Nystatin and Biotène® mouthwash Oral Rinse had similar CFU levels, with nystatin showing a significant improvement over usual oral care. Biotène® mouthwash is a less costly alternative to nystatin, with a less complex treatment protocol that might make it preferable to patients and clinicians. © 2014 The American Laryngological, Rhinological and Otological Society, Inc.


Aifuwa I.,Johns Hopkins University | Giri A.,Johns Hopkins University | Longe N.,Johns Hopkins University | Lee S.H.,Johns Hopkins University | And 3 more authors.
Oncotarget | Year: 2015

Cells induced into senescence exhibit a marked increase in the secretion of pro-inflammatory cytokines termed senescence-associated secretory phenotype (SASP). Here we report that SASP from senescent stromal fibroblasts promote spontaneous morphological changes accompanied by an aggressive migratory behavior in originally non-motile human breast cancer cells. This phenotypic switch is coordinated, in space and time, by a dramatic reorganization of the actin and microtubule filament networks, a discrete polarization of EB1 comets, and an unconventional front-to-back inversion of nucleus-MTOC polarity. SASP-induced morphological/migratory changes are critically dependent on microtubule integrity and dynamics, and are coordinated by the inhibition of RhoA and cell contractility. RhoA/ROCK inhibition reduces focal adhesions and traction forces, while promoting a novel gliding mode of migration.


Li D.,Sloan Kettering Cancer Center | Pant S.,Peggy and Charles Stephenson Oklahoma Cancer Center | Ryan D.P.,Massachussetts General Hospital | Laheru D.,Sydney Kimmel Comprehensive Cancer Center | And 10 more authors.
Pancreatology | Year: 2014

Background Nucleotide transporters such as human equilibrative nucleoside transporter-1 (hENT1) play a major role in transporting gemcitabine into cells. CO-1.01 (gemcitabine-5′-elaidate) is a novel cytotoxic agent consisting of a fatty acid derivative of gemcitabine, which is transported intracellularly independent of hENT1. CO-1.01 was postulated to have efficacy as a second-line treatment in gemcitabine-refractory pancreatic adenocarcinoma in patients with negative tumor hENT1 expression.Methods Eligibility criteria included patients with either a newly procured or archival biopsy tumor confirming the absence of hENT1 and either gemcitabine-refractory metastatic pancreas adenocarcinoma or with progression of disease following resection during or within 3 months of adjuvant gemcitabine therapy. Patients were treated with intravenous infusion of CO-1.01 dosed at 1250 mg/m2 on Days 1, 8, and 15 of a 4-week cycle. The primary end point was disease control rate (DCR).Results Nineteen patients were enrolled of which 18 patients were evaluable for efficacy assessment. Thirteen patients (68%) had liver metastases, 6 (32%) had lymph node metastases, and 10 (53%) had lung metastases. Two of 18 patients (11%) achieved disease control. The median survival time was 4.3 (95% CI 2.1-8.1) months. All patients experienced at least one treatment-related adverse event with the majority of events being mild or moderate.Conclusion This study did not meet its primary endpoint and no efficacy signal was identified for CO-1.01 in treating progressive metastatic pancreas adenocarcinoma. © 2014, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.


Kim D.-H.,Johns Hopkins University | Wirtz D.,Johns Hopkins University | Wirtz D.,Sydney Kimmel Comprehensive Cancer Center
Biomaterials | Year: 2015

The nuclear lamina is a thin filamentous meshwork that provides mechanical support to the nucleus and regulates essential cellular processes such as DNA replication, chromatin organization, cell division, and differentiation. Isolated horizontal imaging using fluorescence and electron microscopy has long suggested that the nuclear lamina is composed of structurally different A-type and B-type lamin proteins and nuclear lamin-associated membrane proteins that together form a thin layer that is spatially isotropic with no apparent difference in molecular content or density between the top and bottom of the nucleus. Chromosomes are condensed differently along the radial direction from the periphery of the nucleus to the nuclear center; therefore, chromatin accessibility for gene expression is different along the nuclear radius. However, 3D confocal reconstruction reveals instead that major lamin protein lamin A/C forms an apically polarized Frisbee-like dome structure in the nucleus of adherent cells. Here we show that both A-type lamins and transcriptionally active chromatins are vertically polarized by the tension exercised by the perinuclear actin cap (or actin cap) that is composed of highly contractile actomyosin fibers organized at the apical surface of the nucleus. Mechanical coupling between actin cap and lamina through LINC (linkers of nucleoskeleton and cytoskeleton) protein complexes induces an apical distribution of transcription-active subnucleolar compartments and epigenetic markers of transcription-active genes. This study reveals that intranuclear structures, such as nuclear lamina and chromosomal architecture, are apically polarized through the extranuclear perinuclear actin cap in a wide range of somatic adherent cells. © 2015 Elsevier Ltd.


Kim D.-H.,Johns Hopkins University | Cho S.,Johns Hopkins University | Wirtz D.,Johns Hopkins University | Wirtz D.,Sydney Kimmel Comprehensive Cancer Center
Journal of Cell Science | Year: 2014

Although eukaryotic cells are known to alternate between 'advancing' episodes of fast and persistent movement and 'hesitation' episodes of low speed and low persistence, the molecular mechanism that controls the dynamic changes in morphology, speed and persistence of eukaryotic migratory cells remains unclear. Here, we show that the movement of the interphase nucleus during random cell migration switches intermittently between two distinct modes-rotation and translocation-that follow with high fidelity the sequential rounded and elongated morphologies of the nucleus and cell body, respectively. Nuclear rotation and translocation mediate the stopand-go motion of the cell through the dynamic formation and dissolution, respectively, of the contractile perinuclear actin cap, which is dynamically coupled to the nuclear lamina and the nuclear envelope through LINC complexes. A persistent cell movement and nuclear translocation driven by the actin cap are halted following the disruption of the actin cap, which in turn allows the cell to repolarize for its next persistent move owing to nuclear rotation mediated by cytoplasmic dynein light intermediate chain 2. © 2014. Published by The Company of Biologists Ltd.


Kim D.-H.,Johns Hopkins University | Chambliss A.B.,Johns Hopkins University | Wirtz D.,Johns Hopkins University | Wirtz D.,Sydney Kimmel Comprehensive Cancer Center
Soft Matter | Year: 2013

The perinuclear actin cap (or actin cap) is a recently characterized cytoskeletal organelle composed of thick, parallel, and highly contractile acto-myosin filaments that are specifically anchored to the apical surface of the interphase nucleus. The actin cap is present in a wide range of adherent eukaryotic cells, but is disrupted in several human diseases, including laminopathies and cancer. Through its large terminating focal adhesions and anchorage to the nuclear lamina and nuclear envelope through LINC complexes, the perinuclear actin cap plays a critical role both in mechanosensation and mechanotransduction, the ability of cells to sense changes in matrix compliance and to respond to mechanical forces, respectively. © 2013 The Royal Society of Chemistry.


Belinsky S.A.,Lovelace Respiratory Research Institute | Grimes M.J.,Lovelace Respiratory Research Institute | Picchi M.A.,Lovelace Respiratory Research Institute | Mitchell H.D.,Lovelace Respiratory Research Institute | And 9 more authors.
Cancer Research | Year: 2011

Epigenetic therapy for solid tumors could benefit from an in vivo model that defines tumor characteristics of responsiveness and resistance to facilitate patient selection. Here we report that combining the histone deacetylase inhibitor entinostat with the demethylating agent vidaza profoundly affected growth of K-ras/ p53 mutant lung adenocarcinomas engrafted orthotopically in immunocompromised nude rats by targeting and ablating pleomorphic cells that occupied up to 75% of the tumor masses. A similar reduction in tumor burden was seen with epigenetic therapy in K-ras or EGFR mutant tumors growing orthotopically. Increased expression of proapoptotic genes and the cyclin-dependent kinase inhibitor p21 was seen. Hundreds of genes were demethylated highlighted by the reexpression of polycomb-regulated genes coding for transcription factor binding proteins and the p16 gene, a key regulator of the cell cycle. Highly significant gene expression changes were seen in key regulatory pathways involved in cell cycle, DNA damage, apoptosis, and tissue remodeling. These findings show the promise for epigenetic therapy in cancer management and provide an orthotopic lung cancer model that can assess therapeutic efficacy and reprogramming of the epigenome in tumors harboring different genetic and epigenetic profiles to guide use of these drugs. © 2011 American Association for Cancer Research.


Hecht V.C.,Massachusetts Institute of Technology | Sullivan L.B.,Massachusetts Institute of Technology | Kimmerling R.J.,Massachusetts Institute of Technology | Kim D.-H.,Johns Hopkins University | And 10 more authors.
Journal of Cell Biology | Year: 2016

Cytokine regulation of lymphocyte growth and proliferation is essential for matching nutrient consumption with cell state. Here, we examine how cellular biophysical changes that occur immediately after growth factor depletion promote adaptation to reduced nutrient uptake. After growth factor withdrawal, nutrient uptake decreases, leading to apoptosis. Bcl-xL expression prevents cell death, with autophagy facilitating long-term cell survival. However, autophagy induction is slow relative to the reduction of nutrient uptake, suggesting that cells must engage additional adaptive mechanisms to respond initially to growth factor depletion. We describe an acute biophysical response to growth factor withdrawal, characterized by a simultaneous decrease in cell volume and increase in cell density, which occurs before autophagy initiation and is observed in both FL5.12 Bcl-xL cells depleted of IL-3 and primary CD8+ T cells depleted of IL-2 that are differentiating toward memory cells. The response reduces cell surface area to minimize energy expenditure while conserving biomass, suggesting that the biophysical properties of cells can be regulated to promote survival under conditions of nutrient stress. © 2016 Newell-Litwa.

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