Medical Specialties Commons^™

Generation And Validation Of An Anti-Human Pank3 Mouse Monoclonal Antibody, Sunada Khadka, Long Vien, Paul Leonard, Laura Bover, Florian Muller

Faculty, Staff and Student Publications

Coenzyme A (CoA) is an essential co-factor at the intersection of diverse metabolic pathways. Cellular CoA biosynthesis is regulated at the first committed step-phosphorylation of pantothenic acid-catalyzed by pantothenate kinases (PANK1,2,3 in humans, PANK3 being the most highly expressed). Despite the critical importance of CoA in metabolism, the differential roles of PANK isoforms remain poorly understood. Our investigations of PANK proteins as potential precision oncology collateral lethality targets (PANK1 is co-deleted as part of the PTEN locus in some highly aggressive cancers) were severely hindered by a dearth of commercial antibodies that can reliably detect endogenous PANK3 protein. While …

Oral Nanomedicines For Sirna Delivery To Treat Inflammatory Bowel Disease, Jongyoon Shinn, Juyeon Lee, Seon Ah Lee, Seon Ju Lee, Ah Hyun Choi, Jung Seo Kim, Su Jin Kim, Hyo Jin Kim, Cherin Lee, Yejin Kim, Joohyeon Kim, Jonghee Choi, Byungchae Jung, Taeho Kim, Hyeontaek Nam, Hyungjun Kim, Yonghyun Lee

Faculty, Staff and Student Publications

RNA interference (RNAi) therapies have significant potential for the treatment of inflammatory bowel diseases (IBD). Although administering small interfering RNA (siRNA) via an oral route is desirable, various hurdles including physicochemical, mucus, and cellular uptake barriers of the gastrointestinal tract (GIT) impede both the delivery of siRNA to the target site and the action of siRNA drugs at the target site. In this review, we first discuss various physicochemical and biological barriers in the GI tract. Furthermore, we present recent strategies and the progress of oral siRNA delivery strategies to treat IBD. Finally, we consider the challenges faced in the …

Mucopolysaccharidoses And The Blood-Brain Barrier, Onur Sahin, Hannah P Thompson, Grant W Goodman, Jun Li, Akihiko Urayama

Faculty, Staff and Student Publications

Mucopolysaccharidoses comprise a set of genetic diseases marked by an enzymatic dysfunction in the degradation of glycosaminoglycans in lysosomes. There are eight clinically distinct types of mucopolysaccharidosis, some with various subtypes, based on which lysosomal enzyme is deficient and symptom severity. Patients with mucopolysaccharidosis can present with a variety of symptoms, including cognitive dysfunction, hepatosplenomegaly, skeletal abnormalities, and cardiopulmonary issues. Additionally, the onset and severity of symptoms can vary depending on the specific disorder, with symptoms typically arising during early childhood. While there is currently no cure for mucopolysaccharidosis, there are clinically approved therapies for the management of clinical symptoms, …

Pathogenesis Of Tobacco-Associated Lung Adenocarcinoma Is Closely Coupled With Changes In The Gut And Lung Microbiomes, Casey T Finnicum, Zahraa Rahal, Maya Hassane, Warapen Treekitkarnmongkol, Ansam Sinjab, Rhiannon Morris, Yuejiang Liu, Elizabeth L Tang, Sarah Viet, Jason L Petersen, Philip L Lorenzi, Lin Tan, Joseph Petrosino, Kristi L Hoffman, Junya Fujimoto, Seyed Javad Moghaddam, Humam Kadara

Faculty, Staff and Students Publications

Microbial dysbiosis has emerged as a modulator of oncogenesis and response to therapy, particularly in lung cancer. Here, we investigate the evolution of the gut and lung microbiomes following exposure to a tobacco carcinogen. We performed 16S rRNA-Seq of fecal and lung samples collected prior to and at several timepoints following (nicotine-specific nitrosamine ketone/NNK) exposure in Gprc5a^−/− mice that were previously shown to exhibit accelerated lung adenocarcinoma (LUAD) development following NNK exposure. We found significant progressive changes in human-relevant gut and lung microbiome members (e.g., Odoribacter, Alistipes, Akkermansia, and Ruminococus) that are closely associated with …

An International Working Group Consensus Report For The Prioritization Of Molecular Biomarkers For Ewing Sarcoma, David S Shulman, Sarah B Whittle, Didier Surdez, Kelly M Bailey, Enrique De Álava, Jason T Yustein, Adam Shlien, Masanori Hayashi, Alexander J R Bishop, Brian D Crompton, Steven G Dubois, Neerav Shukla, Patrick J Leavey, Stephen L Lessnick, Heinrich Kovar, Olivier Delattre, Thomas G P Grünewald, Cristina R Antonescu, Ryan D Roberts, Jeffrey A Toretsky, Franck Tirode, Richard Gorlick, Katherine A Janeway, Damon Reed, Elizabeth R Lawlor, Patrick J Grohar

Faculty, Staff and Students Publications

The advent of dose intensified interval compressed therapy has improved event-free survival for patients with localized Ewing sarcoma (EwS) to 78% at 5 years. However, nearly a quarter of patients with localized tumors and 60-80% of patients with metastatic tumors suffer relapse and die of disease. In addition, those who survive are often left with debilitating late effects. Clinical features aside from stage have proven inadequate to meaningfully classify patients for risk-stratified therapy. Therefore, there is a critical need to develop approaches to risk stratify patients with EwS based on molecular features. Over the past decade, new technology has enabled …

Pulmonary Hypertension With “Normal” Pulmonary Vascular Resistance, Marwan F. Jumean, Sriram Nathan, Maria Patarroyo Aponte

Journal of Shock and Hemodynamics

Abstracts not available for Perspectives.

Role Of Veno-Arterial Extracorporeal Membrane Oxygenation In Left Ventricular Conditioning After Lung Transplantation, Emily A. Ingebretson

Journal of Shock and Hemodynamics

End-stage pulmonary hypertension alters intracardiac pressures, leading to distention and failure of the right ventricle, leftward shifting of the intraventricular septum, and, thus, underfilling of the left ventricle (LV). Following the resolution of severely elevated pulmonary vascular resistance with bilateral lung transplantation, the LV is exposed to relatively high filling pressures from a potentially hypertrophic right ventricle pushing blood through normalized pulmonary vascular resistance. Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) may be a valuable tool to provide a more gradual exposure of the LV to the newly available preload in the immediate postoperative phase of transplantation, thereby reducing the likelihood …

Scai Shock Stage Classification: What Is Missing From The Latest Update?, Biykem Bozkurt

Journal of Shock and Hemodynamics

The revised Society for Cardiovascular Angiography and Interventions classifications reflect graduation of severity within each stage and pathway by which patients progress or recover. However, they are limited regarding the following: their predictive role to guide therapy; escalation of therapy or referral; variability in diagnostic criteria and interpretation; presence of other disease modifiers and confounders; variability of etiology and reversibility of cause; response to therapy and trajectory to be taken into risk stratification; magnitude and phenotypes of end-organ damage. Thus, we need a modified risk score to predict the necessity to escalate therapy and consider advanced therapies, such as mechanical …

Should All Shock Centers Offer Ecpr? Balancing Futility, Cost Effectiveness, And Hope, Michael Mooney

Journal of Shock and Hemodynamics

There are over 400,000 out-of-hospital cardiac arrests (OHCA) in the United States annually. Of those, 50% are refractory cardiac arrest, defined as the lack of return of spontaneous circulation (ROSC) after 30 minutes of appropriate cardiopulmonary resuscitation (CPR) in the absence of hypothermia. Extracorporeal cardiopulmonary resuscitation (ECPR) has been increasingly used given its potential to improve survival and offer improved neurological outcomes.

Systemic Inflammatory Response Syndrome And Mechanical Circulatory Support Devices, Mircea R. Mihu, Aly El-Banayosy

Journal of Shock and Hemodynamics

Systemic inflammatory response syndrome is an increased inflammatory state affecting the whole body. Mechanical circulatory support (MCS) is a temporary or permanent form of extracorporeal support that may have an associated complication of an exacerbated inflammatory response to the extracorporeal circuit. This brief review will focus on understanding the complex pathophysiology of inflammatory response to MCS, factors that influence the extent of the inflammatory response, the inflammatory response and outcomes as well as potential therapeutic strategies.

Role Of Hypothermia In Cardiogenic Shock, Filio Billia

Journal of Shock and Hemodynamics

While patient management in the intensive care unit has undoubtedly improved over the last 20 years, many questions remain. Neurological prognostication has become very important and aided in improving survival outcomes over time. The limited number of randomized control trials and limitations from currently completed studies leave the field with little certainty regarding targeted temperature management. In addition, implementing hypothermia can use multiple methods and protocols that impact the interpretation and comparison of results.

Management Of Severe Aortic Stenosis In Cardiogenic Shock: Early Percutaneous Mechanical Circulatory Support Or Emergent Transcatheter Aortic Valve Replacement?, Sandeep Nathan

Journal of Shock and Hemodynamics

Aortic stenosis (AS) affects an estimated 1.5 million patients in the United States, with 250,000 patients or more suffering severe, symptomatic aortic stenosis. A subset of these patients also have unrevascularized coronary artery disease and left ventricular dysfunction, representing an extreme risk population of AS patients. Cardiogenic shock (CS) complicates a small minority of AS presentations and/or patients referred for transcatheter aortic valve replacement (TAVR) but is responsible in these cases for a disproportionately high rate of morbidity and mortality. Indeed, CS results in a 4-fold increase in TAVR mortality, proportional to shock severity and largely independent of procedural complications. …

A Case Of Inferior Myocardial Infarction Complicated By Ventricular Septal Rupture Leading To Cardiogenic Shock: Tandem Heart To The Rescue!, Shehab Al-Ansari, Sachin Kumar, Angelo Nascimbene, Manish K. Patel, Igor D. Gregoric

Journal of Shock and Hemodynamics

Ventricular septal rupture (VSR) is a rare but life-threatening complication of acute myocardial infarction. We present a case of VSR-related refractory cardiogenic shock that was successfully managed with TandemHeart® followed by surgical repair.

Early Unloading In Venoarterial Extracorporeal Membrane Oxygenation Shock: When, How, Where, And Why?, Benedikt Schrage

Journal of Shock and Hemodynamics

As extracorporeal membrane oxygenation increases the left ventricular afterload, a successful treatment plan should include strategies to address this issue. One promising approach to do so is the addition of a second device for active left ventricular unloading. However, this relatively new approach is currently only based on retrospective data. This article summarizes the current perspectives on this approach, provides recommendations for its application, and highlights the need for randomized data on this topic.

Microcirculation Versus Macrocirculation In Cardiogenic Shock, Christian Jung

Journal of Shock and Hemodynamics

Macro- and microcirculation are important parameters in cardiogenic shock. Microcirculation is relevant for monitoring organ function and prognosis. Serum lactate might be the best daily life parameter to assess microcirculation, and the crude 8-hour value can be used for outcome prediction. Any treatment should consider the consequences of microcirculation and macrocirculation.

Hemodynamics Of Prolonged Percutaneous Mechanical Circulatory Support – When Vasodilatation Sets, Holger Thiele

Journal of Shock and Hemodynamics

Hemodynamics play an important role in cardiogenic shock assessment for prognosis estimation and for phenotyping cardiogenic shock. This is best done by pulmonary artery catheters. In general, at the beginning of cardiogenic shock, patients have vasoconstriction, which over time may lead to vasodilation. This is often triggered by percutaneous mechanical circulatory support. This review will elucidate the hemodynamics and the factors that possibly lead to vasodilation in patients with mechanical circulatory support.

Society For Improving Medical Professional Learning Collaborative: What’S It All About?, Joseph B. Zwischenberger, Katherine Breetz, Daniel Cooper

Journal of Shock and Hemodynamics

The Society for Improving Medical Professional Learning (SIMPL) Collaborative is a non-profit, educational, quality improvement consortium focused on developing tools, curricula, and policies to improve physician training. The goal is to provide educators and learners with convenient, reliable, and valid evaluation tools for frequent, real-time workplace assessment and feedback. The SIMPL Operating Room application provides this platform. It was developed to provide high-quality, time-sensitive, procedural feedback. Its objective is to facilitate intra-rotation corrections.

SIMPL is available to all residency programs and has matured to include over 175 residency programs, involving 19 different specialties, 4000 trainees, 5000 attendings, and 354,800 evaluations …

Houston Shock: A Practical Scoring System Incorporating Cardiogenic Shock Dynamic Changes, Marwan F. Jumean, Sriram Nathan, Igor D. Gregoric, Biswajit Kar

Journal of Shock and Hemodynamics

Cardiogenic shock has an unacceptably high mortality rate and additional tools are needed to improve outcomes. The Society of Cardiovascular Angiography and Interventions (SCAI) shock severity classification has provided a unified definition of shock severity that has proven to be reproducible and predictive of survival. However, cardiogenic shock assessment goes beyond standardizing its severity, and a uniform and practical approach to comprehensive assessment that may guide therapy in a dynamic state is currently lacking.

Since cardiogenic shock is a rapidly evolving pathophysiological catastrophe, we propose a new assessment tool – the Houston SHOCK Score – which incorporates dynamic changes. The …

A Small Molecule Antagonist Of Smn Disrupts The Interaction Between Smn And Rnap Ii, Yanli Liu, Aman Iqbal, Weiguo Li, Zuyao Ni, Yalong Wang, Jurupula Ramprasad, Karan Joshua Abraham, Mengmeng Zhang, Dorothy Yanling Zhao, Su Qin, Peter Loppnau, Honglv Jiang, Xinghua Guo, Peter J Brown, Xuechu Zhen, Guoqiang Xu, Karim Mekhail, Xingyue Ji, Mark T Bedford, Jack F Greenblatt, Jinrong Min

Faculty, Staff and Student Publications

Survival of motor neuron (SMN) functions in diverse biological pathways via recognition of symmetric dimethylarginine (Rme2s) on proteins by its Tudor domain, and deficiency of SMN leads to spinal muscular atrophy. Here we report a potent and selective antagonist with a 4-iminopyridine scaffold targeting the Tudor domain of SMN. Our structural and mutagenesis studies indicate that both the aromatic ring and imino groups of compound 1 contribute to its selective binding to SMN. Various on-target engagement assays support that compound 1 specifically recognizes SMN in a cellular context and prevents the interaction of SMN with the R1810me2s of RNA polymerase …

Association Between Abnormal Lipid Profile And Inflammation And Progression Of Myelodysplastic Syndrome To Acute Leukemia, Wei Qiao, Elliana Young, Chun Feng, Suyu Liu, Jeff Jin, Laila Noor, Cristhiam M Rojas Hernandez, Gautam Borthakur, Olga Gorlova, Vahid Afshar-Kharghan

Faculty, Staff and Student Publications

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with a small risk of developing hematologic malignancies and a higher risk of cardiovascular diseases (CVD). We asked whether the reverse correlation exists and cardiometabolic risk factors have an impact on the progression of myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). We investigated the association between abnormal lipid profiles and inflammation in MDS, which shares many genetic mutations with CHIP, and the risk of developing acute leukemia. We examined the medical records of 11071 MDS patients. Among them, 5422 had at least one lipid profile or C-reactive protein (CRP) measurement. In …

Targeting Ras Mutant Colorectal Cancer With Dual Inhibition Of Mek And Cdk4/6, Alexey V Sorokin, Preeti Kanikarla Marie, Lea Bitner, Muddassir Syed, Melanie Woods, Ganiraju Manyam, Lawrence N Kwong, Benny Johnson, Van K Morris, Philip Jones, David G Menter, Michael S Lee, Scott Kopetz

Faculty, Staff and Student Publications

UNLABELLED: KRAS and NRAS mutations occur in 45% of colorectal cancers, with combined MAPK pathway and CDK4/6 inhibition identified as a potential therapeutic strategy. In the current study, this combinatorial treatment approach was evaluated in a co-clinical trial in patient-derived xenografts (PDX), and safety was established in a clinical trial of binimetinib and palbociclib in patients with metastatic colorectal cancer with RAS mutations. Across 18 PDX models undergoing dual inhibition of MEK and CDK4/6, 60% of tumors regressed, meeting the co-clinical trial primary endpoint. Prolonged duration of response occurred predominantly in TP53 wild-type models. Clinical evaluation of binimetinib and palbociclib …

Mri-Based Digital Models Forecast Patient-Specific Treatment Responses To Neoadjuvant Chemotherapy In Triple-Negative Breast Cancer, Chengyue Wu, Angela M Jarrett, Zijian Zhou, Nabil Elshafeey, Beatriz E Adrada, Rosalind P Candelaria, Rania M M Mohamed, Medine Boge, Lei Huo, Jason B White, Debu Tripathy, Vicente Valero, Jennifer K Litton, Clinton Yam, Jong Bum Son, Jingfei Ma, Gaiane M Rauch, Thomas E Yankeelov

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) is persistently refractory to therapy, and methods to improve targeting and evaluation of responses to therapy in this disease are needed. Here, we integrate quantitative MRI data with biologically based mathematical modeling to accurately predict the response of TNBC to neoadjuvant systemic therapy (NAST) on an individual basis. Specifically, 56 patients with TNBC enrolled in the ARTEMIS trial (NCT02276443) underwent standard-of-care doxorubicin/cyclophosphamide (A/C) and then paclitaxel for NAST, where dynamic contrast-enhanced MRI and diffusion-weighted MRI were acquired before treatment and after two and four cycles of A/C. A biologically based model was established to …

Protocol For Establishing A Protein-Protein Interaction Network Using Tandem Affinity Purification Followed By Mass Spectrometry In Mammalian Cells, Weixiang Bian, Hua Jiang, Shan Feng, Junjie Chen, Wenqi Wang, Xu Li

Faculty, Staff and Student Publications

Identification of protein interactors is fundamental to understanding their functions. Here, we describe a modified protocol for tandem affinity purification coupled with mass spectrometry (TAP/MS), which includes two-step purification. We detail the S-, 2×FLAG-, and Streptavidin-Binding Peptide (SBP)- tandem tags (SFB-tag) system for protein purification. This protocol can be used to identify protein interactors and establish a high-confidence protein-protein interaction network based on computational models. This is particularly useful for identifying

Serologic Versus Molecular Testing For Screening For Hepatitis C Virus Infection In Patients With Hematologic Malignancies, Harrys A Torres, Georgios Angelidakis, Ying Jiang, Minas Economides, Khalis Mustafayev, Marcel Yibirin, Robert Orlowski, Richard Champlin, Srdan Verstovsek, Issam Raad

Faculty, Staff and Student Publications

Testing for antibody against hepatitis C virus (anti-HCV) is a low-cost diagnostic method worldwide; however, an optimal screening test for HCV in patients with cancer has not been established. We sought to identify an appropriate screening test for HCV infection in patients with hematologic malignancies and/or hematopoietic cell transplants (HCT). Patients in our center were simultaneously screened using serological (anti-HCV) and molecular (HCV RNA) assays (February 2019-November 2019). In total, 214 patients were enrolled in this study. Three patients (1.4%) were positive for anti-HCV, and 2 (0.9%) were positive for HCV RNA. The overall percentage agreement was 99.5% (95% CI: …

Multicenter Collaborative Study Of The Interaction Of Antifungal Combinations Against Browzine Journal Cover Candida Spp By Loewe Additivity And Bliss Independence-Based Response Surface Analysis, Joseph Meletiadis, David R Andes, Shawn R Lockhart, Mahmoud A Ghannoum, Cindy C Knapp, Luis Ostrosky-Zeichner, Michael A Pfaller, Vishnu Chaturvedi, Thomas J Walsh

Faculty, Staff and Student Publications

Combination antifungal therapy is widely used but not well understood. We analyzed the spectrophotometric readings from a multicenter study conducted by the New York State Department of Health to further characterize the in vitro interactions of the major classes of antifungal agents against Candida spp. Loewe additivity-based fractional inhibitory concentration index (FICi) analysis and Bliss independence-based response surface (BIRS) analysis were used to analyze two-drug inter- and intraclass combinations of triazoles (AZO) (voriconazole, posaconazole), echinocandins (ECH) (caspofungin, micafungin, anidulafungin), and a polyene (amphotericin B) against Candida albicans, C. parapsilosis, and C. glabrata. Although mean FIC indices did not differ statistically …

Association Between Abnormal Lipid Profile And Inflammation And Progression Of Myelodysplastic Syndrome To Acute Leukemia, Wei Qiao, Elliana Young, Chun Feng, Suyu Liu, Jeff Jin, Laila Noor, Cristhiam M Rojas Hernandez, Gautam Borthakur, Olga Gorlova, Vahid Afshar-Kharghan

Faculty, Staff and Student Publications

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with a small risk of developing hematologic malignancies and a higher risk of cardiovascular diseases (CVD). We asked whether the reverse correlation exists and cardiometabolic risk factors have an impact on the progression of myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). We investigated the association between abnormal lipid profiles and inflammation in MDS, which shares many genetic mutations with CHIP, and the risk of developing acute leukemia. We examined the medical records of 11071 MDS patients. Among them, 5422 had at least one lipid profile or C-reactive protein (CRP) measurement. In …

“Stripe” Transcription Factors Provide Accessibility To Co-Binding Partners In Mammalian Genomes, Yongbing Zhao, Supriya V Vartak, Andrea Conte, Xiang Wang, David A Garcia, Evan Stevens, Seol Kyoung Jung, Kyong-Rim Kieffer-Kwon, Laura Vian, Timothy Stodola, Francisco Moris, Laura Chopp, Silvia Preite, Pamela L Schwartzberg, Joseph M Kulinski, Ana Olivera, Christelle Harly, Avinash Bhandoola, Elisabeth F Heuston, David M Bodine, Raul Urrutia, Arpita Upadhyaya, Matthew T Weirauch, Gordon Hager, Rafael Casellas

Faculty, Staff and Student Publications

Regulatory elements activate promoters by recruiting transcription factors (TFs) to specific motifs. Notably, TF-DNA interactions often depend on cooperativity with colocalized partners, suggesting an underlying cis-regulatory syntax. To explore TF cooperativity in mammals, we analyze ∼500 mouse and human primary cells by combining an atlas of TF motifs, footprints, ChIP-seq, transcriptomes, and accessibility. We uncover two TF groups that colocalize with most expressed factors, forming stripes in hierarchical clustering maps. The first group includes lineage-determining factors that occupy DNA elements broadly, consistent with their key role in tissue-specific transcription. The second one, dubbed universal stripe factors (USFs), comprises ∼30 SP, …

Remission Of Liquid Tumors And Sars-Cov-2 Infection: A Literature Review, Dong Ho Shin, Andrew Gillard, Arie Van Wieren, Candelaria Gomez-Manzano, Juan Fueyo

Faculty, Staff and Student Publications

The coronavirus disease 2019 (COVID-19) pandemic has produced a new global challenge for patients with cancer. The disease and the immunosuppression induced by cancer therapies have generated a perfect storm of conditions to increase the severity of the symptoms and worsen the prognosis. However, a few clinical reports showcased the power of viruses to induce remission in some patients suffering from liquid tumors. Here, we reviewed six cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that resulted in cancer remission, simultaneously highlighting the strengths and the unique challenges of oncolytic virotherapy. Virotherapy has become a special case of cancer …

Journal Of Shock And Hemodynamics, Vol 1., Iss. 1 (Print Version)

Journal of Shock and Hemodynamics

The print version of Volume I, Issue I of the Journal of Shock and Hemodynamics was published in September 2022. The PDF of the print version is downloadable here.

Mochi: A Comprehensive Cross-Platform Tool For Amplicon-Based Microbiota Analysis, Jun-Jie Zheng, Po-Wen Wang, Tzu-Wen Huang, Yao-Jong Yang, Hua-Sheng Chiu, Pavel Sumazin, Ting-Wen Chen

Children’s Nutrition Research Center Staff Publications

Motivation: Microbiota analyses have important implications for health and science. These analyses make use of 16S/18S rRNA gene sequencing to identify taxa and predict species diversity. However, most available tools for analyzing microbiota data require adept programming skills and in-depth statistical knowledge for proper implementation. While long-read amplicon sequencing can lead to more accurate taxa predictions and is quickly becoming more common, practitioners have no easily accessible tools with which to perform their analyses.

Results: We present MOCHI, a GUI tool for microbiota amplicon sequencing analysis. MOCHI preprocesses sequences, assigns taxonomy, identifies different abundant species and predicts species diversity and …