Digital Commons Network^™

Rational Combinations Of Targeted Agents In Aml, Prithviraj Bose, Steven Grant

Internal Medicine Publications

Despite modest improvements in survival over the last several decades, the treatment of AML continues to present a formidable challenge. Most patients are elderly, and these individuals, as well as those with secondary, therapy-related, or relapsed/refractory AML, are particularly difficult to treat, owing to both aggressive disease biology and the high toxicity of current chemotherapeutic regimens. It has become increasingly apparent in recent years that coordinated interruption of cooperative survival signaling pathways in malignant cells is necessary for optimal therapeutic results. The modest efficacy of monotherapy with both cytotoxic and targeted agents in AML testifies to this. As the complex …

Determinants Of An Elevated Pulmonary Arterial Pressure In Patients With Pulmonary Arterial Hypertension, Seiichiro Sakao, Norbert F. Voelkel, Nobuhiro Tanabe, Koichiro Tatsumi

Internal Medicine Publications

Given the difficulty of diagnosing early-stage pulmonary arterial hypertension (PAH) due to the lack of signs and symptoms, and the risk of an open lung biopsy, the precise pathological features of presymptomatic stage lung tissue remain unknown. It has been suggested that the maximum elevation of the mean pulmonary arterial pressure (P_pa) is achieved during the early symptomatic stage, indicating that the elevation of the mean P_pa is primarily driven by the pulmonary vascular tone and/or some degree of pulmonary vascular remodeling completed during this stage. Recently, the examination of a rat model of severe PAH …

A Comprehensive Assessment Of Environmental Exposures Among 1000 North American Patients With Primary Sclerosing Cholangitis, With And Without Inflammatory Bowel Disease, J. E. Eaton, B. D. Juran, E. J. Atkinson, E. M. Schlicht, X. Xie, M. De Andrade, C. S. Lammert, V. A. Luketic, J. A. Odin, A. A. Koteish, K. V. Kowdley, K. B. Chopra, G. M. Hirschfield, N. P. Chalasani, K. N. Lazaridis

Internal Medicine Publications

Background

The relationships between primary sclerosing cholangitis (PSC) and the environment are largely unknown.

Aims

To validate associations reported in previous studies and to identify novel environmental exposures among PSC patients.

Methods

We performed a multicenter, case–control analysis utilising self-administered questionnaires. Responses between cases (n = 1000) and controls (n = 663) were compared using multivariable logistic regression adjusted for age and gender. The model was further stratified based on inflammatory bowel disease (IBD) status (with IBD n = 741 without IBD n = 259).

Results

Smoking was associated with PSC only when IBD was present (OR, 0.5; …

State Of The Art On The Evidence Base In Cardiac Regenerative Therapy: Overview Of 41 Systematic Reviews, Mariangela Peruzzi, Elena De Falco, Antonio Abbate, Giuseppe Biondi-Zoccai, Isotta Chimenti, Marzia Lotrionte, Umberto Benedetto, Ronak Delewi, Antonino G. M. Marullo, Giacomo Frati

Internal Medicine Publications

Objectives. To provide a comprehensive appraisal of the evidence from secondary research on cardiac regenerative therapy. Study Design and Setting. Overview of systematic reviews of controlled clinical trials concerning stem cell administration or mobilization in patients with cardiovascular disease. Results. After a systematic database search, we short-listed 41 reviews (660 patients). Twenty-two (54%) reviews focused on acute myocardial infarction (AMI), 19 (46%) on chronic ischemic heart disease (IHD) or heart failure (HF), 29 (71%) on bone marrow-derived stem-cells (BMSC), and 36 (88%) to randomized trials only. Substantial variability among reviews was found for validity (AMSTAR score: median …

Inhibition Of Bcl-2 Sensitizes Mitochondrial Permeability Transition Pore (Mptp) Opening In Ischemia-Damaged Mitochondria, Qun Chen, Haishan Xu, Aijun Xu, Thomas Ross, Elizabeth Bowler, Ying Hu, Edward J. Lesnefsky

Internal Medicine Publications

Background

Mitochondria are critical to cardiac injury during reperfusion as a result of damage sustained during ischemia, including the loss of bcl-2. We asked if bcl-2 depletion not only leads to selective permeation of the outer mitochondrial membrane (MOMP) favoring cytochrome crelease and programmed cell death, but also favors opening of the mitochondrial permeability transition pore (MPTP). An increase in MPTP susceptibility would support a role for bcl-2 depletion mediated cell death in the calcium overload setting of early reperfusion via MPTP as well as later in reperfusion via MOMP as myocardial calcium content normalizes.

Methods

Calcium retention capacity …

Structural Mechanisms Of Dream Complex Assembly And Regulation, Keelan Z. Guiley, Tyler J. Liban, Jessica G. Felthousen, Parameshwaran Ramanan, Larisa Litovchick, Seth M. Rubin

Internal Medicine Publications

The DREAM complex represses cell cycle genes during quiescence through scaffolding MuvB proteins with E2F4/5 and the Rb tumor suppressor paralog p107 or p130. Upon cell cycle entry, MuvB dissociates from p107/p130 and recruits B-Myb and FoxM1 for up-regulating mitotic gene expression. To understand the biochemical mechanisms underpinning DREAM function and regulation, we investigated the structural basis for DREAM assembly. We identified a sequence in the MuvB component LIN52 that binds directly to the pocket domains of p107 and p130 when phosphorylated on the DYRK1A kinase site S28. A crystal structure of the LIN52–p107 complex reveals that LIN52 uses a …

Co-Administration Of The Mtorc1/Torc2 Inhibitor Ink128 And The Bcl-2/Bcl-Xl Antagonist Abt-737 Kills Human Myeloid Leukemia Cells Through Mcl-1 Down-Regulation And Akt Inactivation, Mohamed Rahmani, Mandy Mayo Aust, Elisa Hawkins, Rebecca E. Parker, Masey Ross, Maciej Kmieciak, Leonid Borisovich Reshko, Kathryn A. Rizzo, Catherine I. Dumur, Andrea Ferreira-Gonzalez, Steven Grant

Internal Medicine Publications

Effects of concurrent inhibition of mTORC1/2 and Bcl-2/Bcl-xL in human acute myeloid leukemia cells were examined. Tetracycline-inducible Bcl-2/Bcl-xL dual knockdown markedly sensitized acute myeloid leukemia cells to the dual TORC1/2 inhibitor INK128 in vitro as well as in vivo. Moreover, INK128 co-administered with the Bcl-2/xL antagonist ABT-737 sharply induced cell death in multiple acute myeloid leukemia cell lines, including TKI-resistant FLT3-ITD mutants and primary acute myeloid leukemia blasts carrying various genetic aberrations e.g., FLT3, IDH2, NPM1, and Kras, while exerting minimal toxicity toward normal hematopoietic CD34+ cells. Combined treatment was particularly active against CD34+/CD38−/CD123+ primitive leukemic progenitor …

Infrared Imaging Enhances Retinal Crystals In Bietti’S Crystalline Dystrophy, Vikram S. Brar, William H. Benson

Internal Medicine Publications

Infrared imaging dramatically increased the number of crystalline deposits visualized compared with clinical examination, standard color fundus photography, and red free imaging in patients with Bietti’s crystalline dystrophy. We believe that this imaging modality significantly improves the sensitivity with which these lesions are detected, facilitating earlier diagnosis and may potentially serve as a prognostic indicator when examined over time.

An International Survey On Taking Up A Career In Cardiovascular Research: Opportunities And Biases Toward Would-Be Physician-Scientists, Giuseppe Biondi-Zoccai, Enrico Cerrato, Mariangela Peruzzi, Fabrizio D'Ascenzo, Elena De Falco, Isotta Chimenti, Sebastiano Sciarretta, Antonino G. M. Marullo, Elena Cavarretta, Ernesto Greco, Umberto Benedetto, Giulio Pompilio, Javier Escaned, Antonio Abbate, Alain Carpentier, Juan Carlos Chachques, Giacomo Frati

Internal Medicine Publications

Background

Cardiovascular research is the main shaper of clinical evidence underpinning decision making, with its cyclic progression of junior researchers to mature faculty members. Despite efforts at improving cardiovascular research training, several unmet needs persist. We aimed to appraise current perceptions on cardiovascular research training with an international survey.

Methods and Results

We administered a 20-closed-question survey to mentors and mentees belonging to different international institutions. A total of 247 (12%) surveys were available (out of 2,000 invitations). Overall, mentees and mentors were reasonably satisfied with the educational and research resources. Significant differences were found analyzing results according to gender, …

Dysregulated Hepatic Methionine Metabolism Drives Homocysteine Elevation In Diet-Induced Nonalcoholic Fatty Liver Disease, Tommy Pacana, Sophie Cazanave, Aurora Verdianelli, Vaishali Patel, Hae-Ki Min, Faridoddin Mirshahi, Eoin Quinlivan, Arun J. Sanyal

Internal Medicine Publications

Methionine metabolism plays a central role in methylation reactions, production of glutathione and methylarginines, and modulating homocysteine levels. The mechanisms by which these are affected in NAFLD are not fully understood. The aim is to perform a metabolomic, molecular and epigenetic analyses of hepatic methionine metabolism in diet-induced NAFLD. Female 129S1/SvlmJ;C57Bl/6J mice were fed a chow (n = 6) or high-fat high-cholesterol (HFHC) diet (n = 8) for 52 weeks. Metabolomic study, enzymatic expression and DNA methylation analyses were performed. HFHC diet led to weight gain, marked steatosis and extensive fibrosis. In the methionine cycle, hepatic methionine was depleted (30%, …

Inhibition Of Bcl-2 Sensitizes Mitochondrial Permeability Transition Pore (Mptp) Opening In Ischemia-Damaged Mitochondria, Qun Chen, Haishan Xu, Aijun Xu, Thomas Ross, Elizabeth Bowler, Ying Hu, Edward J. Lesnefsky

Internal Medicine Publications

Background

Mitochondria are critical to cardiac injury during reperfusion as a result of damage sustained during ischemia, including the loss of bcl-2. We asked if bcl-2 depletion not only leads to selective permeation of the outer mitochondrial membrane (MOMP) favoring cytochrome c release and programmed cell death, but also favors opening of the mitochondrial permeability transition pore (MPTP). An increase in MPTP susceptibility would support a role for bcl-2 depletion mediated cell death in the calcium overload setting of early reperfusion via MPTP as well as later in reperfusion via MOMP as myocardial calcium content normalizes.

Methods

Calcium retention capacity …

Epigenetic Modifications Of The Pgc-1Α Promoter During Exercise Induced Expression In Mice, Timothy L. Lochmann, Ravindar R. Thomas, James P. Bennett, Shirley M. Taylor

Massey Comprehensive Cancer Center Publications

The transcriptional coactivator, PGC-1α, is known for its role in mitochondrial biogenesis. Although originally thought to exist as a single protein isoform, recent studies have identified additional promoters which produce multiple mRNA transcripts. One of these promoters (promoter B), approximately 13.7kb upstream of the canonical PGC-1α promoter (promoter A), yields alternative transcripts present at levels much lower than the canonical PGC-1α mRNA transcript. In skeletal muscle, exercise resulted in a substantial, rapid increase of mRNA of these alternative PGC-1α transcripts. Although the β2-adrenergic receptor was identified as a signaling pathway that activates transcription from PGC-1α promoter B, it is not …

Role Of Interleukin-1 In Radiation-Induced Cardiomyopathy, Eleonora Mezzaroma, Ross B. Mikkelsen, Stefano Toldo, Adolfo G. Mauro, Khushboo Sharma, Carlo Marchetti, Asim Alam, Benjamin W. Van Tassell, David A. Gewirtz, Antonio Abbate

Pharmacotherapy and Outcomes Science Publications

Thoracic X-ray therapy (XRT), used in cancer treatment, is associated with increased risk of heart failure. XRT-mediated injury to the heart induces an inflammatory response leading to cardiomyopathy. The aim of this study was to determine the role of interleukin (IL)-1 in response to XRT injury to the heart and on the cardiomyopathy development in the mouse. Female mice with genetic deletion of the IL-1 receptor type I (IL-1R1 knockout mice [IL-1R1 KO]) and treatment with recombinant human IL-1 receptor antagonist anakinra, 10 mg/kg twice daily for 7 d, were used as independent approaches to determine the role of IL-1. …

Quality Control Material For The Detection Of Somatic Mutations In Fixed Clinical Specimens By Next-Generation Sequencing, Catherine I. Dumur, Jorge A. Almenara, Celeste N. Powers, Andrea Ferreira-Gonzalez

Pathology Publications

Background: Targeted next generation sequencing (NGS) technology to assess the mutational status of multiple genes on formalin-fixed, paraffin embedded (FFPE) tumors is rapidly being adopted in clinical settings, where quality control (QC) practices are required. Establishing reliable FFPE QC materials for NGS can be challenging and/or expensive. Here, we established a reliable and cost-effective FFPE QC material for routine utilization in the Ion AmpliSeq™ Cancer Hotspot Panel v2 (CHP2) assay.

Methods: The performance characteristics of the CHP2 assay were determined by sequencing various cell line mixtures and 55 different FFPE tumors on the Ion Torrent PGM platform. A FFPE QC …

Nosocomial Keratitis Caused By Methicillin-Resistant Staphylococcus Aureus: Case Report And Preventative Measures, Puneet S. Braich, Shruti Aggarwal, Sabrina Mukhtar, David Rp Almeida

Ophthalmology Publications

A 47-year-old African-American woman was admitted to the intensive care unit of our community hospital for respiratory failure secondary to severe decompensated heart failure, requiring intubation. In the ensuing days, she developed a methicillin-resistant Staphylococcus aureus (MRSA) infection of the cornea, despite no growth of MRSA in multiple blood, sputum, and urine cultures. This unexpected corneal infection complicated her hospital stay, and increased morbidity and disease-related cost. Risk factors, warning signs, and preventative measures for MRSA keratitis secondary to lagophthalmos (inability to completely close one's eyelids) are outlined in this case report. Implementing simple precautions such as taping eyelids shut …

Relocation Consequences On An Ophthalmology Consultation Service From An Inpatient To Outpatient Facility, Jorawer S. Singh, Vincent M. Imbrogno, Mary K. Howard, Amandip S. Cheema, Ausra D. Selvadurai, Surbhi Bansal

Ophthalmology Publications

Importance

This study shows that relocation of an academic ophthalmology residency program from an inpatient to an outpatient setting in western New York does not affect the consult volume but affects management patterns and follow-up rates.

Objective

To investigate the effects on the ophthalmology consultation service of an academic program with relocation from a Regional Level-1 Trauma center to an outpatient facility.

Design

Consultation notes from 3 years before and 3 years after the University at Buffalo’s (UB) Department of Ophthalmology relocation from a Regional Level-1 Trauma center (Erie County Medical Center) to an outpatient facility (Ross Eye Institute) were …

Prevalence And Factors Predictive Of Intraocular Fungal Infection In Patients With Fungemia At An Academic Urban Tertiary Care Center, Elena Geraymovych, Joseph H. Conduff, Puneet S. Braich, Christopher T. Leffler, Vikram S. Brar

Ophthalmology Publications

Objective

To report the prevalence and to identify factors predictive of intraocular infection in patients with fungemia receiving prophylactic antifungal therapy.

Methods

A retrospective review of patients who received prophylactic antifungal therapy and a dilated fundus examination at an academic urban tertiary care center from 2000 to 2007. Basic demographic information, fungal species grown, antifungal agent(s) used, number of positive blood culture specimens, visual acuity, visual symptoms, and known risks of disseminated candidiasis were noted. Logistic regression analysis was used to determine the factors significantly associated with intraocular fungal infection.

Results

A total of 132 patients with positive fungemia culture …

Infrared Imaging Enhances Retinal Crystals In Bietti’S Crystalline Dystrophy, Vikram S. Brar, William H. Benson

Ophthalmology Publications

Infrared imaging dramatically increased the number of crystalline deposits visualized compared with clinical examination, standard color fundus photography, and red free imaging in patients with Bietti’s crystalline dystrophy. We believe that this imaging modality significantly improves the sensitivity with which these lesions are detected, facilitating earlier diagnosis and may potentially serve as a prognostic indicator when examined over time.

Self-Organizing Feature Maps Identify Proteins Critical To Learning In A Mouse Model Of Down Syndrome, Clara Higuera, Katheleen J. Gardiner, Krzysztof J. Cios

Computer Science Publications

Down syndrome (DS) is a chromosomal abnormality (trisomy of human chromosome 21) associated with intellectual disability and affecting approximately one in 1000 live births worldwide. The overexpression of genes encoded by the extra copy of a normal chromosome in DS is believed to be sufficient to perturb normal pathways and normal responses to stimulation, causing learning and memory deficits. In this work, we have designed a strategy based on the unsupervised clustering method, Self Organizing Maps (SOM), to identify biologically important differences in protein levels in mice exposed to context fear conditioning (CFC). We analyzed expression levels of 77 proteins …

Self-Organizing Feature Maps Identify Proteins Critical To Learning In A Mouse Model Of Down Syndrome, Clara Higuera, Katheleen J. Gardiner, Kryzysztof Cios

Computer Science Publications

Down syndrome (DS) is a chromosomal abnormality (trisomy of human chromosome 21) associated with intellectual disability and affecting approximately one in 1000 live births worldwide. The overexpression of genes encoded by the extra copy of a normal chromosome in DS is believed to be sufficient to perturb normal pathways and normal responses to stimulation, causing learning and memory deficits. In this work, we have designed a strategy based on the unsupervised clustering method, Self Organizing Maps (SOM), to identify biologically important differences in protein levels in mice exposed to context fear conditioning (CFC). We analyzed expression levels of 77 proteins …

Self-Organizing Feature Maps Identify Proteins Critical To Learning In A Mouse Model Of Down Syndrome, Clara Higuera, Kathleen J. Gardiner, Kryzysztof Cios

Computer Science Publications

Down syndrome (DS) is a chromosomal abnormality (trisomy of human chromosome 21) associated with intellectual disability and affecting approximately one in 1000 live births worldwide. The overexpression of genes encoded by the extra copy of a normal chromosome in DS is believed to be sufficient to perturb normal pathways and normal responses to stimulation, causing learning and memory deficits. In this work, we have designed a strategy based on the unsupervised clustering method, Self Organizing Maps (SOM), to identify biologically important differences in protein levels in mice exposed to context fear conditioning (CFC). We analyzed expression levels of 77 proteins …

Vedolizumab: An Α4Β7 Integrin Antagonist For Ulcerative Colitis And Crohn’S Disease, Lauren N. Cherry, Nancy S. Yunker, Erika R. Lambert, Dalemarie Vaughan, Denise K. Lowe

VCU Health Publications

Ulcerative colitis (UC) and Crohn’s disease (CD) are chronic, relapsing inflammatory bowel diseases associated with significant morbidity. Conventional therapies for these diseases include corticosteroids, aminosalicylates, immunomodulators, and monoclonal antibodies. Over the years tumor necrosis factor (TNF)-α antagonists alone or in combination with other therapies have emerged as the cornerstone of treatment for induction and maintenance of remission of moderate to severe UC and CD. Unfortunately, some patients with moderate to severe UC and CD are unable to attain or maintain remission with TNF-α antagonist treatment. Vedolizumab, a humanized monoclonal antibody, is the first integrin receptor antagonist approved that selectively antagonizes …

Perceived Stress Levels, Chemotherapy, Radiation Treatment And Tumor Characteristics Are Associated With A Persistent Increased Frequency Of Somatic Chromosomal Instability In Women Diagnosed With Breast Cancer: A One Year Longitudinal Study, Noran Aboalela, Debra E. Lyon, R. K. Elswick Jr., Debra Lynch Kelly, Jenni Brumelle, Harry D. Bear, Colleen Jackson-Cook

VCU Health Publications

While advances in therapeutic approaches have resulted in improved survival rates for women diagnosed with breast cancer, subsets of these survivors develop persistent psychoneurological symptoms (fatigue, depression/anxiety, cognitive dysfunction) that compromise their quality of life. The biological basis for these persistent symptoms is unclear, but could reflect the acquisition of soma-wide chromosomal instability following the multiple biological/psychological exposures associated with the diagnosis/treatment of breast cancer. An essential first step toward testing this hypothesis is to determine if these cancer-related exposures are indeed associated with somatic chromosomal instability frequencies. Towards this end, we longitudinally studied 71 women (ages 23-71) with early-stage …

Using An In-Vitro Biofilm Model To Assess The Virulence Potential Of Bacterial Vaginosis Or Non-Bacterial Vaginosis Gardnerella Vaginalis Isolates, Joana Castro, Patricia Alves, Cármen Sousa, Tatiana Cereija, Ângela França, Kimberly K. Jefferson, Nuno Cerca

VCU Health Publications

Gardnerella vaginalis is the most common species found in bacterial vaginosis (BV). However, it is also present in a significant proportion of healthy women and G. vaginalis vaginal colonization does not always lead to BV. In an effort to better understand the differences between G. vaginalis isolated from women with a positive (BV) versus a negative (non-BV) diagnosis of BV, we compared the virulence potential of 7 BV and 7 non-BV G. vaginalis isolates and assessed the virulence factors related to biofilm formation, namely: initial adhesion and cytotoxic effect, biofilm accumulation, susceptibility to antibiotics, and transcript levels of the known …

Novel Zno Hollow-Nanocarriers Containing Paclitaxel Targeting Folate-Receptors In A Malignant Ph-Microenvironment For Effective Monitoring And Promoting Breast Tumor Regression, Nagaprasad Puvvada, Shashi Rajput, B. N. Prashanth Kumar, Siddik Sarkar, Suraj Konar, Keith R. Brunt, Raj R. Rao, Abhijit Mazumdar, Swadesh K. Das, Ranadhir Basu, Paul B. Fisher, Mahitosh Mandal, Amita Pathak

VCU Health Publications

Low pH in the tumor micromilieu is a recognized pathological feature of cancer. This attribute of cancerous cells has been targeted herein for the controlled release of chemotherapeutics at the tumour site, while sparing healthy tissues. To this end, pH-sensitive, hollow ZnO-nanocarriers loaded with paclitaxel were synthesized and their efficacy studied in breast cancer in vitro and in vivo. The nanocarriers were surface functionalized with folate using click-chemistry to improve targeted uptake by the malignant cells that over-express folate-receptors. The nanocarriers released ~75% of the paclitaxel payload within six hours in acidic pH, which was accompanied by switching of …

“I Am Not Free While [Anyone] Is Unfree”: A Proposal And Framework For Enmarginalized Feminist Policy Analysis, Avina Ross

Social Work Student Works

This paper introduces a new feminist approach and framework to policy analysis. As an integration of intersectionality, Black feminist thought and endarkened feminist epistemology, enmarginalized feminist policy analysis (EFPA) offers an intersectional and flexible scope in a framework to assess policy for a diversity of populations, focusing on groups who are forced to live marginal and oppressed lives. Discussion is provided on existing approaches and frameworks in addition to an overview of the theoretical underpinnings of EFPA. A nine-component framework, which includes a section for analyst reflexivity, is provided to guide users in conducting EFPA. The author concludes with implications …

Medical Literary Messenger (Vol. 3, No. 1, Fall 2015)

Medical Literary Messenger

Gone / Carl Zettelmeyer -- A Faded Scar with Palpable Edges / Melissa Cronin -- Broken / Mary Sesso -- Going Viral / Nancy Brewka-Clark -- Epitaph / Sherre Vernon -- Ringing the Bell / Michelle M. Tokarczyk -- Shiva Dream / Jennifer Kemnitz -- Anorexia Nervosa / Mohamed Osman -- Hospice Nurse Retires / Laura Rodley -- Fernand / Sharon Israel -- Morgenbesser’s Lament / Ronald W. Pies -- Dietary Rounds / Virginia Aronson -- Blindness / Mohamed Osman -- The Proper Ways / William Palmer -- Overnight / Richard Hubbard -- Needle to Neck / Megan Lemay -- …

Disappearing Before My Eyes, Edward F. Ansello

Director's Editorials from Age in Action

Dr. Edward Ansello details the last memories he made and recalled with his mother, who struggled with memory loss in later life.

Preventing Financial Exploitation, Edward F. Ansello

Director's Editorials from Age in Action

Financial exploitation of older adults isn’t going away. We each need to be aware and proactive.

Remembering Our Friends, Edward F. Ansello

Director's Editorials from Age in Action

We remember three men whose caring for others was, indeed, exceptional: Bill Egelhoff, Benny Lambert, and Frank Hall.