Medicine and Health Sciences Commons^™

Year In Review, Scott A. Waldman, Andre Terzic

Department of Pharmacology and Experimental Therapeutics Faculty Papers

If examination of journal performance is a surrogate for the vitality of a discipline, the continued ascension of Clinical Pharmacology and Therapeutics (CPT) bodes well for the evolution and practice of human therapeutics in this decade. CPT has excelled as the authoritative, cross-disciplinary journal in experimental and clinical medicine devoted to publishing advances in the nature, action, efficacy and evaluation of therapeutics in humans. Building on a foundation that established the core tenets, and a framework providing the structural integrity for the field, CPT was conceived by visionary precedent editors and editorial teams who were themselves leaders of …

Revised Dose Schema Of Sublingual Buprenorphine In The Treatment Of The Neonatal Opioid Abstinence Syndrome., Walter K Kraft, Kevin Dysart, Jay S Greenspan, Eric Gibson, Karol Kaltenbach, Michelle E Ehrlich

Department of Pharmacology and Experimental Therapeutics Faculty Papers

AIMS: More than half of infants exposed to opioids in utero develop neonatal abstinence syndrome (NAS) of severity to require pharmacological therapy. Current treatments are associated with prolonged hospitalization. We sought to optimize the dose of sublingual buprenorphine in the treatment of NAS.

DESIGN: Randomized, Phase 1, open-label, active-control clinical trial comparing sublingual buprenorphine to oral morphine.

SETTING: Large, urban, tertiary care hospital.

PARTICIPANTS: Twenty-four term infants requiring pharmacological treatment for NAS.

MEASUREMENTS: Outcomes were neonatal safety, length of treatment and length of hospitalization.

FINDINGS: Sublingual buprenorphine was safe and effective. Infants treated with buprenorphine had a 23-day length of …

Differential Subcellular Distribution Of Rat Brain Dopamine Receptors And Subtype-Specific Redistribution Induced By Cocaine., Pamela J Voulalas, John Schetz, Ashiwel S Undieh

College of Pharmacy Faculty Papers

We investigated the subcellular distribution of dopamine D(1), D(2) and D(5) receptor subtypes in rat frontal cortex, and examined whether psychostimulant-induced elevation of synaptic dopamine could alter the receptor distribution. Differential detergent solubilization and density gradient centrifugation were used to separate various subcellular fractions, followed by semi-quantitative determination of the relative abundance of specific receptor proteins in each fraction. D(1) receptors were predominantly localized to detergent-resistant membranes, and a portion of these receptors also floated on sucrose gradients. These properties are characteristic of proteins found in lipid rafts and caveolae. D(2) receptors exhibited variable distribution between cytoplasmic, detergent-soluble and detergent-resistant …

Epidermal Growth Factor Receptor Overexpression In Resected Pancreatic Cancer, Amit Mahipal, Mary J. Mcdonald, Agnieszka Witkiewicz, Brian I. Carr

Department of Medical Oncology Faculty Papers

Conclusions:

Membrane EGFR overexpression is associated with poorer clinical outcomes in patients with pancreatic cancer receiving adjuvant therapy post resection.

Cytoplasmic EGFR overexpression is not associated with clinical outcomes.

Kidney Injury Molecule-1 (Kim-1) As An Early Detection Tool For Acute Kidney Injury And Other Renal Diseases, John Fontanilla, Md, Won K. Han, M.D

Department of Medicine Faculty Papers

Introduction: Although serum creatinine is the standard metric tool for the detection of renal injury, its lack of sensitivity has made the early diagnosis of acute kidney injury (AKI) very difficult. In fact, the absence of sensitive AKI biomarkers has impaired progress in the nephrology field and had a detrimental effect on the design and outcome of AKI clinical trials. Recently, several proteins have shown potential in the early detection of acute and chronic kidney injuries.

Areas covered: This review discusses the current status of kidney injury molecule-1 (KIM-1) as a potential diagnostic tool in patients with various acute …

Expression Of Aldehyde Dehydrogenase In Dysplastic Lesions Arising From Inflammatory Bowel Disease, Adam D. Toll, Bruce M. Boman, Juan P. Palazzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Conclusion: Our study demonstrates ALDH1 is significantly expressed in dysplatic lesions arising from IBD. ALDH1-expression in cancer stem cells suggest an important causative role in the progression to cancer in IBD. Although we found high sensitivity for dysplasia, the specificity was poor. In addition to neoplasia, ALDH1-expressing stem cells proliferate in response to chronic inflammation, accounting for the cases of inflammatory atypia with positive ALDHI1 expression.

Fus Transgenic Rats Develop The Phenotypes Of Amyotrophic Lateral Sclerosis And Frontotemporal Lobar Degeneration., Cao Huang, Hongxia Zhou, Jianbin Tong, Han Chen, Yong-Jian Liu, Dian Wang, Xiaotao Wei, Xu-Gang Xia

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Fused in Sarcoma (FUS) proteinopathy is a feature of frontotemporal lobar dementia (FTLD), and mutation of the fus gene segregates with FTLD and amyotrophic lateral sclerosis (ALS). To study the consequences of mutation in the fus gene, we created transgenic rats expressing the human fus gene with or without mutation. Overexpression of a mutant (R521C substitution), but not normal, human FUS induced progressive paralysis resembling ALS. Mutant FUS transgenic rats developed progressive paralysis secondary to degeneration of motor axons and displayed a substantial loss of neurons in the cortex and hippocampus. This neuronal loss was accompanied by ubiquitin aggregation and …

Clinical Translational Science 2020: Disruptive Innovation Redefines The Discovery-Application Enterprise, Scott A. Waldman, Andre Terzic

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Vaccines, analgesia, and antibiotics embody some of the most

enduring therapeutic breakthroughs that have transformed

medicine. Building on such fine paradigms of biomedical

innovation, the evolution of technologies has increasingly

sparked spectacular advances across the continuum of wellness

and disease-spanning medical and surgical specialties. Discovery

science—fueled by government and private sector resources—has

systematically instituted the principles of modern healthcare

delivery ensuring that medical practice is based on up-to-date

scientifi c evidence. Th e harmony between science, technology,

and resources has culminated in a golden age of discovery and

translation, eradicating infections, curing cancers, and palliating

endocrine and metabolic diseases. Indeed, …

Comparative Gender Analysis Of The Efficacy And Safety Of Atazanavir/Ritonavir And Lopinavir/Ritonavir At 96 Weeks In The Castle Study., Kathleen E Squires, Margaret Johnson, Rong Yang, Jonathan Uy, Louise Sheppard, Judith Absalon, Donnie Mcgrath

Department of Medicine Faculty Papers

OBJECTIVES: To examine whether the overall results of the CASTLE study pertain to both genders, we analysed the efficacy and safety of atazanavir/ritonavir and lopinavir/ritonavir in 277 female and 606 male patients in the open-label, multinational trial over 96 weeks. The trial is registered with ClinicalTrials.gov, number NCT00272779.

METHODS: Treatment-naive patients aged ≥ 18 years with HIV-1 RNA ≥ 5000 copies/mL were randomized to receive either atazanavir/ritonavir 300/100 mg once daily or lopinavir/ritonavir 400/100 mg twice daily, with fixed-dose tenofovir/emtricitabine 300/200 mg once daily.

RESULTS: At week 96, confirmed virological response rates (HIV RNA <50 copies>/mL; intent-to-treat analysis) were higher in …

Prolactin-Induced Mouse Mammary Carcinomas Model Estrogen Resistant Luminal Breast Cancer., Lisa M Arendt, Debra E Rugowski, Tara A Grafwallner-Huseth, Maria Jose Garcia-Barchino, Hallgeir Rui, Linda A Schuler

Kimmel Cancer Center Faculty Papers

INTRODUCTION: Tumors that express estrogen receptor alpha (ERα+) comprise 75% of breast cancers in women. While treatments directed against this receptor have successfully lowered mortality rates, many primary tumors initially or later exhibit resistance. The paucity of murine models of this "luminal" tumor subtype has hindered studies of factors that promote their pathogenesis and modulate responsiveness to estrogen-directed therapeutics. Since epidemiologic studies closely link prolactin and the development of ERα+ tumors in women, we examined characteristics of the aggressive ERα+ and ERα- carcinomas which develop in response to mammary prolactin in a murine transgenic model (neu-related lipocalin- prolactin (NRL-PRL)). To …

Analysis Of The Proteome Of Human Airway Epithelial Secretions., Mehboob Ali, Erik P Lillehoj, Yongsung Park, Yoshiyuki Kyo, K Chul Kim

Department of Pharmacology and Experimental Therapeutics Faculty Papers

BACKGROUND: Airway surface liquid, often referred to as mucus, is a thin layer of fluid covering the luminal surface that plays an important defensive role against foreign particles and chemicals entering the lungs. Airway mucus contains various macromolecules, the most abundant being mucin glycoproteins, which contribute to its defensive function. Airway epithelial cells cultured in vitro secrete mucins and nonmucin proteins from their apical surface that mimics mucus production in vivo. The current study was undertaken to identify the polypeptide constituents of human airway epithelial cell secretions to gain a better understanding of the protein composition of respiratory mucus.

RESULTS: …

Evidence-Based Genomic Diagnosis Characterized Chromosomal And Cryptic Imbalances In 30 Elderly Patients With Myelodysplastic Syndrome And Acute Myeloid Leukemia., Renu Bajaj, Fang Xu, Bixia Xiang, Katherine Wilcox, Autumn J Diadamo, Rachana Kumar, Alexandra Pietraszkiewicz, Stephanie Halene, Peining Li

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: To evaluate the clinical validity of genome-wide oligonucleotide array comparative genomic hybridization (aCGH) for detecting somatic abnormalities, we have applied this genomic analysis to 30 cases (13 MDS and 17 AML) with clonal chromosomal abnormalities detected in more than 50% of analyzed metaphase cells.

RESULTS: The aCGH detected all numerical chromosomal gains and losses from the mainline clones and 113 copy number alterations (CNAs) ranging from 0.257 to 102.519 megabases (Mb). Clinically significant recurrent deletions of 5q (involving the RPS14 gene), 12p12.3 (ETV6 gene), 17p13 (TP53 gene), 17q11.2 (NF1 gene) and 20q, double minutes containing the MYC gene and …

Tdp-43 Potentiates Alpha-Synuclein Toxicity To Dopaminergic Neurons In Transgenic Mice., Tian Tian, Cao Huang, Jianbin Tong, Ming Yang, Hongxia Zhou, Xugang Xia

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

TDP-43 and α-synuclein are two disease proteins involved in a wide range of neurodegenerative diseases. While TDP-43 proteinopathy is considered a pathologic hallmark of sporadic amyotrophic lateral sclerosis and frontotemporal lobe degeneration, α-synuclein is a major component of Lewy body characteristic of Parkinson's disease. Intriguingly, TDP-43 proteinopathy also coexists with Lewy body and with synucleinopathy in certain disease conditions. Here we reported the effects of TDP-43 on α-synuclein neurotoxicity in transgenic mice. Overexpression of mutant TDP-43 (M337V substitution) in mice caused early death in transgenic founders, but overexpression of normal TDP-43 only induced a moderate loss of cortical neurons in …

The Pulmonologist's Role In Caring For Pregnant Women With Regard To The Reproductive Risks Of Diagnostic Radiological Studies Or Radiation Therapy, Robert L. Brent Dr.

The Selected Works of Robert Brent

None

The Pulmonologist's Role In Caring For Pregnant Women With Regard To The Reproductive Risks Of Diagnostic Radiological Studies Or Radiation Therapy, Robert L. Brent Dr.

The Selected Works of Robert Brent

No abstract

Evaluation Of Reproductive And Developmental Risks Of Caffeine, Robert L. Brent Dr.

The Selected Works of Robert Brent

No abstract provided.

An Evidence-Based Review Of Fat Modifying Supplemental Weight Loss Products., Amy M Egras, William R Hamilton, Thomas L Lenz, Michael S Monaghan

College of Pharmacy Faculty Papers

Objective. To review the literature on fat modifying dietary supplements commonly used for weight loss. Methods. Recently published randomized, placebo-controlled trials were identified in PubMed, MEDLINE, International Pharmaceutical Abstracts, Cochrane Database, and Google Scholar using the search terms dietary supplement, herbal, weight loss, obesity, and individual supplement names. Discussion. Data for conjugated linoleic acid (CLA), Garcinia cambogia, chitosan, pyruvate, Irvingia gabonensis, and chia seed for weight loss were identified. CLA, chitosan, pyruvate, and Irvingia gabonensis appeared to be effective in weight loss via fat modifying mechanisms. However, the data on the use of these products is limited. Conclusion. Many obese …

The Effects Of Laropiprant, A Selective Prostaglandin D₂ Receptor 1 Antagonist, On The Antiplatelet Activity Of Clopidogrel Or Aspirin., Aimee Dallob, Wen-Lin Luo, Julie Mabalot Luk, Lisa Ratcliffe, Amy O Johnson-Levonas, Jules I Schwartz, Victor Dishy, Walter K. Kraft, Jan N De Hoon, Anne Van Hecken, Inge De Lepeleire, Waldemar Radziszewski, John A Wagner, Eseng Lai

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Laropiprant (LRPT) is being developed in combination with Merck's extended-release niacin (ERN) formulation for the treatment of dyslipidemia. LRPT, an antagonist of the prostaglandin PGD₂ receptor DP1, reduces flushing symptoms associated with ERN. LRPT also has affinity for the thromboxane A₂ receptor TP (approximately 190-fold less potent at TP compared with DP1). Aspirin and clopidogrel are two frequently used anti-clotting agents with different mechanisms of action. Since LRPT may potentially be co-administered with either one of these agents, these studies were conducted to assess the effects of steady-state LRPT on the antiplatelet activity of steady-state clopidogrel or aspirin. Bleeding time …

Does Treatment Of Premature Labor With Terbutaline Increase The Risk Of Autism Spectrum Disorders?, Robert L. Brent Dr.

The Selected Works of Robert Brent

none

The Role Of The Pediatrican In The Effort To Prevent Congenital Malformations, Robert L. Brent Dr.

The Selected Works of Robert Brent

No

The Professonal Responsibility Model Of Obstetrical Ethics: Avoiding The Perils Of Clashing Rights, Robert L. Brent, Frank A. Chervenak, Md, Laurence B. Mccullough, Phd

The Selected Works of Robert Brent

Obstetric ethics is sometimes represented by polarized views. One extreme asserts the rights of the fetus as the overwhelming ethical consideration. Both assertions are overly simplistic. Such oversimplification is called reductionism. This article explains the fallacy of rights-based reductionism and 2 models of obstetric ethics based on it and explains why the fetal rights reductionism model and the pregnant woman's rights reductionism model result in conceptual and clinical failure and therefore should be abandoned. The article argues for the professional responsibility model of obstetric ethics, which emphasizes the importance of medical science and compassionate clinical care of both the pregnant …

Protein Modification By Arginylation, Hideko Kaji, Akira Kaji

Department of Biochemistry and Molecular Biology Faculty Papers

The modification of protein by arginine catalyzed by arginyltransferases (ATE1) described by the Kashina group in this issue shows that arginylation of protein occurs widely in biology and is being recognized as a key regulatory reaction such as phosphorylation of proteins (Wang et al., 2011).

Mitochondrial Genome Sequence Analysis: A Custom Bioinformatics Pipeline Substantially Improves Affymetrix Mitochip V2.0 Call Rate And Accuracy., Hongbo M Xie, Juan C Perin, Theodore G Schurr, Matthew C Dulik, Sergey I Zhadanov, Joseph A Baur, Michael P King, Emily Place, Colleen Clarke, Michael Grauer, Jonathan Schug, Avni Santani, Anthony Albano, Cecilia Kim, Vincent Procaccio, Hakon Hakonarson, Xiaowu Gai, Marni J Falk

Department of Biochemistry and Molecular Biology Faculty Papers

BACKGROUND: Mitochondrial genome sequence analysis is critical to the diagnostic evaluation of mitochondrial disease. Existing methodologies differ widely in throughput, complexity, cost efficiency, and sensitivity of heteroplasmy detection. Affymetrix MitoChip v2.0, which uses a sequencing-by-genotyping technology, allows potentially accurate and high-throughput sequencing of the entire human mitochondrial genome to be completed in a cost-effective fashion. However, the relatively low call rate achieved using existing software tools has limited the wide adoption of this platform for either clinical or research applications. Here, we report the design and development of a custom bioinformatics software pipeline that achieves a much improved call rate …

Serum Monocyte Chemoattractant Protein-1 In Pancreatic Cancer., Jennifer Sullivan, Qiaoke Gong, Terry Hyslop, Harish Lavu, Galina Chipitsyna, Charles Yeo, Hwyda A Arafat

Department of Surgery Faculty Papers

Background/Aims. Pancreatic ductal adenocarcinoma (PDA) has etiological association with chronic inflammation. Elevated circulating levels of inflammatory mediators, such as monocyte chemoattractant protein-1 (MCP-1), are found in obese individuals. We hypothesized that serum MCP-1 levels are elevated in obese PDA patients. Methods. ELISA was used to analyze MCP-1 serum levels in PDA (n = 62) and intraductal papillary mucinous neoplasms (IPMN) (n = 27). Recursive partitioning statistical analysis investigated the relationship between log MCP-1 and clinicopathological parameters. Results. Log MCP-1 values were significantly (P < 0.05) elevated in patients with BMI ≥ 37.5. In patients with BMI < 37.5, average log MCP-1 values were significantly elevated in PDA patients when compared to IPMN patients. Within the IPMN group, higher log MCP-1 levels correlated with increased age. Recursive partitioning analysis of IPMN versus PDA revealed a strategy of predicting characteristics of patients who are more likely to have cancer. This strategy utilizes log MCP-1 as the primary factor and also utilizes smoking status, gender, and age. Conclusion. MCP-1 is a promising biomarker in pancreatic cancer. The potential of using MCP-1 to distinguish PDA from IPMN patients must be studied in larger populations to validate and demonstrate its eventual clinical utility.

Update On Pain Management In Sickle Cell Disease., Samir K Ballas

Department of Medicine Faculty Papers

Acute pain is the hallmark of sickle cell disease and is the most common cause of hospital admissions. Tissue damage due to vaso-occlusion releases numerous inflammatory mediators that initiate the transmission of painful stimuli that culminate in the perception of pain. The acute sickle cell painful crisis evolves along four phases. Each phase is coupled with changes in certain markers of the disease. Hospital readmission occurs within 1 week in about 16% of discharged patients and within 1 month in about 50% of discharged patients. Failure to treat acute pain aggressively may lead to chronic pain syndrome which, in turn, …

Defining The Phenotypes Of Sickle Cell Disease., Samir K. Ballas

Department of Medicine Faculty Papers

The sickle cell gene is pleiotropic in nature. Although it is a single gene mutation, it has multiple phenotypic expressions that constitute the complications of sickle cell disease. The frequency and severity of these complications vary considerably both latitudinally in patients and longitudinally in the same patient over time. Thus, complications that occur in childhood may disappear, persist or get worse with age. Dactylitis and stroke, for example, occur mostly in childhood, whereas leg ulcers and renal failure typically occur in adults. It is essential that the phenotypic manifestations of sickle cell disease be defined accurately so that communication among …