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Discovery And Effects Of Pharmacological Inhibition Of The E3 Ligase Skp2 By Small Molecule Protein-Protein Interaction Disruptors, John K. Morrow 2018 The University of Texas M D Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences

Discovery And Effects Of Pharmacological Inhibition Of The E3 Ligase Skp2 By Small Molecule Protein-Protein Interaction Disruptors, John K. Morrow

UT GSBS Dissertations and Theses (Open Access)

Skp2 (S-phase kinase-associated protein 2), one component of the SCF E3 ubiquitin ligase complex, directly interacts with Skp1 and indirectly associates with Cullin1 and Rbx1 to bridge the E2 conjugating enzyme with its protein substrate to execute its E3 ligase activity. Skp2 is an Fbox protein (due to it containing an Fbox domain) and it is the rate-limiting component of the SCF complex. Skp2 targets several cell-cycle regulatory proteins for ubiquitination and degradation; most notable and significant for cancer are the cyclin-dependent kinase inhibitor, p27. Skp2 is an oncogene and studies have shown that over-expression of Skp2 leads to increased ...


Oncology Section Edge Task Force On Cancer: Measures Of Cancer-Related Fatigue—A Systematic Review, Mary Insana Fisher, Claire Davies, Hannah Lacy, Deborah Doherty 2018 University of Dayton

Oncology Section Edge Task Force On Cancer: Measures Of Cancer-Related Fatigue—A Systematic Review, Mary Insana Fisher, Claire Davies, Hannah Lacy, Deborah Doherty

Physical Therapy Faculty Publications

Background: Cancer-related fatigue (CRF) is one of the most common side effects of cancer and cancer treatment. Being able to accurately screen for and assess CRF will improve access to and prescriptions for interventions. Valid and reliable measures to screen for and assess CRF need to be identified.

Purpose: To identify and recommend reliable, valid, and clinically useful tools to screen for and assess CRF among those treated for cancer.

Methods: A systematic review of the literature was conducted to assess the published psychometric properties and clinical feasibility of each method identified. Task force members independently reviewed each measure using ...


Transitioning To The Role Of A Professional Physical Therapist Through Community Engagement, Brittany L. Wentzel 2018 Virginia Wesleyan College

Transitioning To The Role Of A Professional Physical Therapist Through Community Engagement, Brittany L. Wentzel

VA Engage Journal

This article recounts the author's experiences observing and interning with physical therapists in a variety of settings.The hands-on experiences the author describes allowed the author to learn the specific procedures and requirements in a typical day as a Physical Therapist, and to gain knowledge on the protocol for different injuries, the muscles that each exercise strengthens, and how to properly perform exercises to prevent further injuries. The author also explores how these experiences fostered observational and interpersonal skills and solidified the decision to pursue Physical Therapy as a career.


Ajulemic Acid: Potential Treatment For Chronic Inflammation, Sumner Burstein 2018 University of Massachusetts Medical School

Ajulemic Acid: Potential Treatment For Chronic Inflammation, Sumner Burstein

Open Access Articles

Ajulemic acid (AJA, CT-3, IP-751, JBT-101, anabasum) is a first-in-class, synthetic, orally active, cannabinoid-derived drug that preferentially binds to the CB2 receptor and is nonpsychoactive. In preclinical studies, and in Phase 1 and 2 clinical trials, AJA showed a favorable safety, tolerability, and pharmacokinetic profile. It also demonstrated significant efficacy in preclinical models of inflammation and fibrosis. It suppresses tissue scarring and stimulates endogenous eicosanoids that resolve chronic inflammation and fibrosis without causing immunosuppression. AJA is currently being developed for use in 4 separate but related indications including systemic sclerosis (SSc), cystic fibrosis, dermatomyositis (DM), and systemic lupus erythematosus. Phase ...


Genetic Variants In Hsd17b3, Smad3, And Ipo11 Impact Circulating Lipids In Response To Fenofibrate In Individuals With Type 2 Diabetes, Daniel M. Rotroff, Sonja S. Pijut, Skylar W. Marvel, John R. Jack, Tammy M. Havener, Aurora Pujol, Agatha Schluter, Gregory A. Graf, Henry N. Ginsberg, Hetal S. Shah, He Gao, Mario-Luca Morieri, Alessandro Doria, Josyf C. Mychaleckyi, Howard L. McLeod, John B. Buse, Michael J. Wagner, Alison A. Motsinger-Reif, ACCORD/ACCORDion Investigators 2018 North Carolina State University

Genetic Variants In Hsd17b3, Smad3, And Ipo11 Impact Circulating Lipids In Response To Fenofibrate In Individuals With Type 2 Diabetes, Daniel M. Rotroff, Sonja S. Pijut, Skylar W. Marvel, John R. Jack, Tammy M. Havener, Aurora Pujol, Agatha Schluter, Gregory A. Graf, Henry N. Ginsberg, Hetal S. Shah, He Gao, Mario-Luca Morieri, Alessandro Doria, Josyf C. Mychaleckyi, Howard L. Mcleod, John B. Buse, Michael J. Wagner, Alison A. Motsinger-Reif, Accord/Accordion Investigators

Pharmaceutical Sciences Faculty Publications

Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin‐treated patients with T2D, we examined lipid changes in response to fenofibrate therapy using a genomewide association study (GWAS). Associations were followed‐up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects (P < 5 × 10‐6). Rare variant and gene expression changes ...


Heavily And Fully Modified Rnas Guide Efficient Spycas9-Mediated Genome Editing, Aamir Mir, Julia F. Alterman, Matthew R. Hassler, Alexandre J. Debacker, Edward Hudgens, Dimas Echeverria, Michael H. Brodsky, Anastasia Khvorova, Jonathan K. Watts, Erik J. Sontheimer 2018 University of Massachusetts Medical School

Heavily And Fully Modified Rnas Guide Efficient Spycas9-Mediated Genome Editing, Aamir Mir, Julia F. Alterman, Matthew R. Hassler, Alexandre J. Debacker, Edward Hudgens, Dimas Echeverria, Michael H. Brodsky, Anastasia Khvorova, Jonathan K. Watts, Erik J. Sontheimer

University of Massachusetts Medical School Faculty Publications

RNA-based drugs depend on chemical modifications to increase potency and nuclease stability, and to decrease immunogenicity in vivo. Chemical modification will likely improve the guide RNAs involved in CRISPR-Cas9-based therapeutics as well. Cas9 orthologs are RNA-guided microbial effectors that cleave DNA. No studies have yet explored chemical modification at all positions of the crRNA guide and tracrRNA cofactor. Here, we have identified several heavily-modified versions of crRNA and tracrRNA that are more potent than their unmodified counterparts. In addition, we describe fully chemically modified crRNAs and tracrRNAs (containing no 2'-OH groups) that are functional in human cells. These designs ...


Down-Regulation Of Microrna-203-3p Initiates Type 2 Pathology During Schistosome Infection Via Elevation Of Interleukin-33, Xing He, Jun Xie, Yange Wang, Xiaobin Fan, Qin Su, Yue Sun, Nanhang Lei, Dongmei Zhang, Guangping Gao, Weiqing Pan 2018 Second Military Medical University

Down-Regulation Of Microrna-203-3p Initiates Type 2 Pathology During Schistosome Infection Via Elevation Of Interleukin-33, Xing He, Jun Xie, Yange Wang, Xiaobin Fan, Qin Su, Yue Sun, Nanhang Lei, Dongmei Zhang, Guangping Gao, Weiqing Pan

Open Access Articles

The type 2 immune response is the central mechanism of disease progression in schistosomiasis, but the signals that induce it after infection remain elusive. Aberrant microRNA (miRNA) expression is a hallmark of human diseases including schistosomiasis, and targeting the deregulated miRNA can mitigate disease outcomes. Here, we demonstrate that efficient and sustained elevation of miR-203-3p in liver tissues, using the highly hepatotropic recombinant adeno-associated virus serotype 8 (rAAV8), protects mice against lethal schistosome infection by alleviating hepatic fibrosis. We show that miR-203-3p targets interleukin-33 (IL-33), an inducer of type 2 immunity, in hepatic stellate cells to regulate the expansion and ...


The Development Of Benzimidazole-Based Clickable Probes For The Efficient Labeling Of Cellular Protein Arginine Deiminases (Pads), Venkatesh V. Nemmara, Venkataraman Subramanian, Aaron Muth, Santanu Mondal, Ari J. Salinger, Aaron J. Maurais, Ronak Tilvawala, Eranthie Weerapana, Paul R. Thompson 2018 University of Massachusetts Medical School

The Development Of Benzimidazole-Based Clickable Probes For The Efficient Labeling Of Cellular Protein Arginine Deiminases (Pads), Venkatesh V. Nemmara, Venkataraman Subramanian, Aaron Muth, Santanu Mondal, Ari J. Salinger, Aaron J. Maurais, Ronak Tilvawala, Eranthie Weerapana, Paul R. Thompson

Thompson Lab Publications

Citrullination is the post-translational hydrolysis of peptidyl-arginines to form peptidyl-citrulline, a reaction that is catalyzed by the protein arginine deiminases (PADs), a family of calcium-regulated enzymes. Aberrantly increased protein citrullination is associated with a slew of autoimmune diseases (e.g., rheumatoid arthritis (RA), multiple sclerosis, lupus, and ulcerative colitis) and certain cancers. Given the clear link between increased PAD activity and human disease, the PADs are therapeutically relevant targets. Herein, we report the development of next generation cell permeable and "clickable" probes (BB-Cl-Yne and BB-F-Yne) for covalent labeling of the PADs both in vitro and in cell-based systems. Using advanced ...


Oligonucleotides Targeting Tcf4 Triplet Repeat Expansion Inhibit Rna Foci And Mis-Splicing In Fuchs' Dystrophy, Jiaxin Hu, Ziye Rong, Xin Gong, Zhengyang Zhou, Vivek K. Sharma, Chao Xing, Jonathan K. Watts, David R. Corey, V. Vinod Mootha 2018 UT Southwestern Medical Center

Oligonucleotides Targeting Tcf4 Triplet Repeat Expansion Inhibit Rna Foci And Mis-Splicing In Fuchs' Dystrophy, Jiaxin Hu, Ziye Rong, Xin Gong, Zhengyang Zhou, Vivek K. Sharma, Chao Xing, Jonathan K. Watts, David R. Corey, V. Vinod Mootha

RNA Therapeutics Institute Publications

Fuchs' endothelial corneal dystrophy (FECD) is the most common repeat expansion disorder. FECD impacts 4% of U.S. population and is the leading indication for corneal transplantation. Most cases are caused by an expanded intronic CUG tract in the TCF4 gene that forms nuclear foci, sequesters splicing factors and impairs splicing. We investigated the sense and antisense RNA landscape at the FECD gene and find that the sense-expanded repeat transcript is the predominant species in patient corneas. In patient tissue, sense foci number were negatively correlated with age and showed no correlation with sex. Each endothelial cell has approximately 2 ...


A Delayed Diagnosis Of Tarsometatarsal Ligament (Lisfranc) Sprain In A Female College Soccer Athlete And Foot Rehabilitation, Boyoung Park 2018 University of Nebraska at Omaha

A Delayed Diagnosis Of Tarsometatarsal Ligament (Lisfranc) Sprain In A Female College Soccer Athlete And Foot Rehabilitation, Boyoung Park

Student Research and Creative Activity Fair

A Delayed Diagnosis of Tarsometatarsal Ligament (Lisfranc) Sprain in a Female College Soccer Athlete and Foot Rehabilitation

Park B*, Nicola M*, Wilkins S*: *University of Nebraska at Omaha, Omaha, NE

Objective: To emphasize the importance of the correct treatment protocol and the proper rehabilitation exercises based on the patient’s injury condition and healing process. Background: A 22-year-old female division I soccer athlete underwent tarsometatarsal ligament repair to stabilize midfoot. The patient started feeling pain in the dorsal aspect of her left 1st and 2nd metatarsals at the beginning of the season, however, she reported no specific mechanism of injury ...


Transcriptome Profiling Of Neovascularized Corneas Reveals Mir-204 As A Multi-Target Biotherapy Deliverable By Raavs, Yi Lu, Phillip W. L. Tai, Jianzhong Ai, Dominic J. Gessler, Qin Su, Xieyi Yao, Qiang Zheng, Phillip D. Zamore, Xun Xu, Guangping Gao 2018 University of Massachusetts Medical School

Transcriptome Profiling Of Neovascularized Corneas Reveals Mir-204 As A Multi-Target Biotherapy Deliverable By Raavs, Yi Lu, Phillip W. L. Tai, Jianzhong Ai, Dominic J. Gessler, Qin Su, Xieyi Yao, Qiang Zheng, Phillip D. Zamore, Xun Xu, Guangping Gao

Open Access Articles

Corneal neovascularization (NV) is the major sight-threatening pathology caused by angiogenic stimuli. Current drugs that directly target pro-angiogenic factors to inhibit or reverse the disease require multiple rounds of administration and have limited efficacies. Here, we identify potential anti-angiogenic corneal microRNAs (miRNAs) and demonstrate a framework that employs discovered miRNAs as biotherapies deliverable by recombinant adeno-associated viruses (rAAVs). By querying differentially expressed miRNAs in neovascularized mouse corneas induced by alkali burn, we have revealed 39 miRNAs that are predicted to target more than 5,500 differentially expressed corneal mRNAs. Among these, we selected miR-204 and assessed its efficacy and therapeutic ...


Editorial: Nucleic Acids Research And Nucleic Acid Therapeutics, Barry L. Stoddard, Anastasia Khvorova, David R. Corey, William S. Dynan, Keith R. Fox 2018 Fred Hutchinson Cancer Research Center, WA

Editorial: Nucleic Acids Research And Nucleic Acid Therapeutics, Barry L. Stoddard, Anastasia Khvorova, David R. Corey, William S. Dynan, Keith R. Fox

RNA Therapeutics Institute Publications

Nucleic Acids Research has recently commissioned the publication of a series of Survey and Summary articles that encapsulate the current ‘state of the art’ surrounding the creation, function, behavior and optimization of nucleic acid molecules that may be adopted for clinical applications.


The Coding Regions Of Germline Mrnas Confer Sensitivity To Argonaute Regulation In C. Elegans, Meetu Seth, Masaki Shirayama, Wen Tang, En-Zhi Shen, Shikui Tu, Heng-Chi Lee, Zhiping Weng, Craig C. Mello 2018 University of Massachusetts Medical School

The Coding Regions Of Germline Mrnas Confer Sensitivity To Argonaute Regulation In C. Elegans, Meetu Seth, Masaki Shirayama, Wen Tang, En-Zhi Shen, Shikui Tu, Heng-Chi Lee, Zhiping Weng, Craig C. Mello

RNA Therapeutics Institute Publications

Protein-coding genes undergo a wide array of regulatory interactions with factors that engage non-coding regions. Open reading frames (ORFs), in contrast, are thought to be constrained by coding function, precluding a major role in gene regulation. Here, we explore Piwi-interacting (pi)RNA-mediated transgene silencing in C. elegans and show that marked differences in the sensitivity to piRNA silencing map to the endogenous sequences within transgene ORFs. Artificially increasing piRNA targeting within the ORF of a resistant transgene can lead to a partial yet stable reduction in expression, revealing that piRNAs not only silence but can also "tune" gene expression. Our ...


Impact Of A Pilot Outreach Program Upon Provider Awareness And Prescribing Of A Concerning Opioid Combination Regimen, Briana Santaniello, Thomas C. Pomfret, Mark A. Tesell, Nicole M. Trask, Caroline J. Alper, Karen M. Clements, Vincent Palumbo, Kimberly Lenz, Paul L. Jeffrey 2018 Magellan Rx Management

Impact Of A Pilot Outreach Program Upon Provider Awareness And Prescribing Of A Concerning Opioid Combination Regimen, Briana Santaniello, Thomas C. Pomfret, Mark A. Tesell, Nicole M. Trask, Caroline J. Alper, Karen M. Clements, Vincent Palumbo, Kimberly Lenz, Paul L. Jeffrey

Commonwealth Medicine Publications

This pilot program was developed in response to a drug utilization review within a large Medicaid population that revealed some hazardous practices. Co-prescribing of opioids with benzodiazepines, gabapentin, and other stimulants occurred in more than 500 members, putting them at risk for additive central nervous system depression, misuse, abuse, and death from overdose.

The poster presentation outlines the objectives, methods, and results of a telephonic outreach program that addressed these safety concerns. It captures prescriber awareness of the presence and risks of potentially deadly medication combinations among members in their care, with some intriguing results.

Our experts provide health plans ...


A Budget Impact Model For Two Investigational Agents For The Treatment Of Nonalcoholic Steatohepatitis, Nicole M. Trask, Pavel Lavitas, Vincent Palumbo 2018 University of Massachusetts Medical School

A Budget Impact Model For Two Investigational Agents For The Treatment Of Nonalcoholic Steatohepatitis, Nicole M. Trask, Pavel Lavitas, Vincent Palumbo

Commonwealth Medicine Publications

Statistics show approximately 15 million Americans suffer from NASH, a nonalcoholic fatty liver disease that is projected to become the most common reason for liver transplantation. There are no FDA approved therapies for NASH, so doctors are forced to treat patients with off-label medications while keeping an eye out for breakthroughs in medication development.

Two novel therapies, obeticholic acid and elafibranor, are currently in Phase III trials. If they receive FDA approval, interest will be high as they will be the first treatments specifically labeled for NASH. We detail a budget impact model for a sample state Medicaid plan in ...


Novel Candidate Genes Important For Asthma And Hypertension Comorbidity Revealed From Associative Gene Networks, Olga V. Saik, Pavel S. Demenkov, Timofey V. Ivanisenko, Elena Yu. Bragina, Maxim B. Freidin, Irina A. Goncharova, Victor E. Dosenko, Olga I. Zolotareva, Ralf Hofestaedt, Inna N. Lavrik, Evgeny I. Rogaev, Vladimir A. Ivanisenko 2018 Institute of Cytology and Genetics

Novel Candidate Genes Important For Asthma And Hypertension Comorbidity Revealed From Associative Gene Networks, Olga V. Saik, Pavel S. Demenkov, Timofey V. Ivanisenko, Elena Yu. Bragina, Maxim B. Freidin, Irina A. Goncharova, Victor E. Dosenko, Olga I. Zolotareva, Ralf Hofestaedt, Inna N. Lavrik, Evgeny I. Rogaev, Vladimir A. Ivanisenko

Open Access Articles

BACKGROUND: Hypertension and bronchial asthma are a major issue for people's health. As of 2014, approximately one billion adults, or ~ 22% of the world population, have had hypertension. As of 2011, 235-330 million people globally have been affected by asthma and approximately 250,000-345,000 people have died each year from the disease. The development of the effective treatment therapies against these diseases is complicated by their comorbidity features. This is often a major problem in diagnosis and their treatment. Hence, in this study the bioinformatical methodology for the analysis of the comorbidity of these two diseases have been ...


Antiplatelet Therapy Changes For Patients With Myocardial Infarction With Recurrent Ischemic Events: Insights Into Contemporary Practice From The Translate-Acs (Treatment With Adp Receptor Inhibitors: Longitudinal Assessment Of Treatment Patterns And Events After Acute Coronary Syndrome) Study, Alexander C. Fanaroff, Lisa A. Kaltenbach, Eric D. Peterson, Mohammed W. Akhter, Mark B. Effron, Timothy D. Henry, Tracy Y. Wang 2018 Duke University

Antiplatelet Therapy Changes For Patients With Myocardial Infarction With Recurrent Ischemic Events: Insights Into Contemporary Practice From The Translate-Acs (Treatment With Adp Receptor Inhibitors: Longitudinal Assessment Of Treatment Patterns And Events After Acute Coronary Syndrome) Study, Alexander C. Fanaroff, Lisa A. Kaltenbach, Eric D. Peterson, Mohammed W. Akhter, Mark B. Effron, Timothy D. Henry, Tracy Y. Wang

Cardiovascular Medicine Publications and Presentations

BACKGROUND: Guidelines recommend P2Y12 inhibitor therapy for 1 year after myocardial infarction (MI), yet little guidance is provided on antiplatelet management for patients with recurrent ischemic events during that year. We describe changes in P2Y12 inhibitor type among patients with recurrent ischemic events in the first year after MI.

METHODS AND RESULTS: The TRANSLATE-ACS (Treatment With ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome) study enrolled 12 365 patients with MI treated with percutaneous coronary intervention. We examined whether P2Y12 inhibitor choice changed among patients with recurrent MI, stent thrombosis, and/or unplanned revascularization ...


Pof8 Is A La-Related Protein And A Constitutive Component Of Telomerase In Fission Yeast, Diego J. Paez-Moscoso, Lili Pan, Rutendo F. Sigauke, Morgan R. Schroeder, Wen Tang, Peter Baumann 2018 Stowers Institute for Medical Research, MO

Pof8 Is A La-Related Protein And A Constitutive Component Of Telomerase In Fission Yeast, Diego J. Paez-Moscoso, Lili Pan, Rutendo F. Sigauke, Morgan R. Schroeder, Wen Tang, Peter Baumann

RNA Therapeutics Institute Publications

Telomerase reverse transcriptase (TERT) and the non-coding telomerase RNA subunit (TR) constitute the core of telomerase. Here we now report that the putative F-box protein Pof8 is also a constitutive component of active telomerase in fission yeast. Pof8 functions in a hierarchical assembly pathway by promoting the binding of the Lsm2-8 complex to telomerase RNA, which in turn promotes binding of the catalytic subunit. Loss of Pof8 reduces TER1 stability, causes a severe assembly defect, and results in critically short telomeres. Structure profile searches identified similarities between Pof8 and telomerase subunits from ciliated protozoa, making Pof8 next to TERT the ...


Inactivation Of Myeloma Cancer Cells By Helium And Argon Plasma Jets: The Effect Comparison And The Key Reactive Species, Zeyu Chen, Qingjie Cui, Chen Chen, Dehui Xu, Dingxin Liu, H. L. Chen, Michael G. Kong 2018 Old Dominion University

Inactivation Of Myeloma Cancer Cells By Helium And Argon Plasma Jets: The Effect Comparison And The Key Reactive Species, Zeyu Chen, Qingjie Cui, Chen Chen, Dehui Xu, Dingxin Liu, H. L. Chen, Michael G. Kong

Bioelectrics Publications

In plasma cancer therapy, the inactivation of cancer cells under plasma treatment is closely related to the reactive oxygen and nitrogen species (RONS) induced by plasmas. Quantitative study on the plasma-induced RONS that related to cancer cells apoptosis is critical for advancing the research of plasma cancer therapy. In this paper, the effects of several reactive species on the inactivation of LP-1 myeloma cancer cells are comparatively studied with variable working gas composition, surrounding gas composition, and discharge power. The results show that helium plasma jet has a higher cell inactivation efficiency than argon plasma jet under the same discharge ...


Relationships Between Clinical Scales And Binge Eating Days In Adults With Moderate To Severe Binge Eating Disorder In Two Phase Iii Studies, Leslie L. Citrome, Judith C. Kando, Caleb Bliss 2018 New York Medical College

Relationships Between Clinical Scales And Binge Eating Days In Adults With Moderate To Severe Binge Eating Disorder In Two Phase Iii Studies, Leslie L. Citrome, Judith C. Kando, Caleb Bliss

NYMC Faculty Publications

OBJECTIVES:

In two Phase III studies, lisdexamfetamine dimesylate (LDX) reduced binge eating (BE) days/week in adults with moderate to severe binge eating disorder (BED) and was associated with improvement based on the Clinical Global Impressions-Improvement (CGI-I) scale. In this study, post hoc analyses examined the relationships between clinical observations and clinical rating scales in individuals with BED.

CLINICAL TRIAL REGISTRATION:

NCT01718483 (ClinicalTrials.gov/ct2/show/NCT01718483); NCT01718509(ClinicalTrials.gov/ct2/show/NCT01718509).

METHODS:

Two 12-week, double-blind, placebo-controlled studies randomized (1:1) adults meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, BED criteria and with protocol-defined ...


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