Diseases Commons^™

Presence Of Circulating Tumor Cells Predates Imaging Detection Of Relapse In Patients With Stage Iii Melanoma, Anthony Lucci, Sridevi Addanki, Yi-Ju Chiang, Salyna Meas, Vanessa N Sarli, Joshua R Upshaw, Mayank Manchem, Sapna P Patel, Jennifer A Wargo, Jeffrey E Gershenwald, Merrick I Ross

Faculty, Staff and Student Publications

Stage III melanoma includes nodal metastasis or in-transit disease. Five-year survival rates vary between 32% and 93%. The identification of high-risk patients is important for clinical decision making. We demonstrated previously that ≥1 circulating tumor cells (CTCs) at baseline was associated with recurrence. In this study, we investigated how frequently CTCs were identified prior to radiologically detected recurrence. Stage III patients (n = 325) had imaging at baseline and q 3 months. Baseline and q 6-12 months blood draws (7.5 mL) were performed to identify CTCs up to 3.5 years from diagnosis. CTC assessment was performed using the immunomagnetic …

Adenosine Metabolized From Extracellular Atp Ameliorates Organ Injury By Triggering A2br Signaling, Taha Kelestemur, Zoltán H Németh, Pal Pacher, Jennet Beesley, Simon C Robson, Holger K Eltzschig, György Haskó

Faculty, Staff and Student Publications

BACKGROUND: Trauma and a subsequent hemorrhagic shock (T/HS) result in insufficient oxygen delivery to tissues and multiple organ failure. Extracellular adenosine, which is a product of the extracellular degradation of adenosine 5' triphosphate (ATP) by the membrane-embedded enzymes CD39 and CD73, is organ protective, as it participates in signaling pathways, which promote cell survival and suppress inflammation through adenosine receptors including the A

METHODS: T/HS shock was induced by blood withdrawal from the femoral artery in wild-type, global knockout (CD39, CD73, A

RESULTS: T/HS upregulated the expression of CD39, CD73, and the A

CONCLUSION: In conclusion, the CD39-CD73-A

Microbe Hunters, Paul De Kruif

Zea E-Books Collection

Microbe Hunters by Paul de Kruif was first published in 1926 by Harcourt, Brace and Company, New York. It dramatically recounts the breakthrough discoveries of the fundamental elements of bacteriology. It features exciting profiles of Antony Leeuwenhoek, Lazzaro Spallanzani, Louis Pasteur, Robert Koch, Émile Roux, Emil Behring, Élie Metchnikoff, Theobald Smith, David Bruce, Ronald Ross, Battista Grassi, Walter Reed, and Paul Ehrlich. Their development of germ theory and its scientific proofs led to the first effective treatments for human diseases like anthrax, rabies, diptheria, malaria, sleeping sickness, syphilis, and yellow fever. They also made discoveries that saved the dairy, wine, …

Emt Activates Exocytotic Rabs To Coordinate Invasion And Immunosuppression In Lung Cancer, Guan-Yu Xiao, Xiaochao Tan, Bertha L Rodriguez, Don L Gibbons, Shike Wang, Chao Wu, Xin Liu, Jiang Yu, Mayra E Vasquez, Hai T Tran, Jun Xu, William K Russell, Cara Haymaker, Younghee Lee, Jianjun Zhang, Luisa Solis, Ignacio I Wistuba, Jonathan M Kurie

Faculty, Staff and Student Publications

Epithelial-to-mesenchymal transition (EMT) underlies immunosuppression, drug resistance, and metastasis in epithelial malignancies. However, the way in which EMT orchestrates disparate biological processes remains unclear. Here, we identify an EMT-activated vesicular trafficking network that coordinates promigratory focal adhesion dynamics with an immunosuppressive secretory program in lung adenocarcinoma (LUAD). The EMT-activating transcription factor ZEB1 drives exocytotic vesicular trafficking by relieving Rab6A, Rab8A, and guanine nucleotide exchange factors from miR-148a-dependent silencing, thereby facilitating MMP14-dependent focal adhesion turnover in LUAD cells and autotaxin-mediated CD8

Undetectable Measurable Residual Disease Is Associated With Improved Outcomes In Aml Irrespective Of Treatment Intensity, Alexandre Bazinet, Tapan Kadia, Nicholas J Short, Gautam Borthakur, Sa A Wang, Wei Wang, Sanam Loghavi, Jeffrey Jorgensen, Keyur Patel, Courtney Dinardo, Naval Daver, Yesid Alvarado, Fadi G Haddad, Sherry Pierce, Graciela Nogueras Gonzalez, Abhishek Maiti, Koji Sasaki, Musa Yilmaz, Philip Thompson, William Wierda, Guillermo Garcia-Manero, Michael Andreeff, Elias Jabbour, Marina Konopleva, Xuelin Huang, Hagop Kantarjian, Farhad Ravandi

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) can be treated with either high- or low-intensity regimens. Highly sensitive assays for measurable residual disease (MRD) now allow for a more precise assessment of response quality. We hypothesized that treatment (Rx) intensity may not be a key predictor of outcomes, assuming that an optimal response to therapy is achieved. We performed a single-center retrospective study including 635 patients with newly diagnosed AML responding to either intensive cytarabine/anthracycline-based chemotherapy (IA; n = 385) or low-intensity venetoclax-based regimens (LOW + VEN; n = 250) and who had adequate flow cytometry-based MRD testing performed at the time of …

Myc Regulates Csf1 Expression Via Microrna 17/20a To Modulate Tumor-Associated Macrophages In Osteosarcoma, Bikesh K Nirala, Tajhal D Patel, Lyazat Kurenbekova, Ryan Shuck, Atreyi Dasgupta, Nino Rainusso, Cristian Coarfa, Jason T Yustein

Faculty, Staff and Students Publications

Osteosarcoma (OS) is the most common primary bone tumor of childhood. Approximately 20%-30% of OSs carry amplification of chromosome 8q24, which harbors the oncogene c-MYC and correlates with a poor prognosis. To understand the mechanisms that underlie the ability of MYC to alter both the tumor and its surrounding tumor microenvironment (TME), we generated and molecularly characterized an osteoblast-specific Cre-Lox-Stop-Lox-c-MycT58A p53fl/+ knockin genetically engineered mouse model (GEMM). Phenotypically, the Myc-knockin GEMM had rapid tumor development with a high incidence of metastasis. MYC-dependent gene signatures in our murine model demonstrated significant homology to the human hyperactivated MYC OS. We established that …

A Phase 1/2 Study Of Azacitidine, Venetoclax And Pevonedistat In Newly Diagnosed Secondary Aml And In Mds Or Cmmlafter Failure Of Hypomethylating Agents, Nicholas J Short, Muharrem Muftuoglu, Faustine Ong, Lewis Nasr, Walid Macaron, Guillermo Montalban-Bravo, Yesid Alvarado, Mahesh Basyal, Naval Daver, Courtney D Dinardo, Gautam Borthakur, Nitin Jain, Maro Ohanian, Elias Jabbour, Ghayas C Issa, Wei Qiao, Xuelin Huang, Rashmi Kanagal-Shamanna, Keyur P Patel, Prithviraj Bose, Farhad Ravandi, Ricardo Delumpa, Regina Abramova, Guillermo Garcia-Manero, Michael Andreeff, Jorge Cortes, Hagop Kantarjian

Faculty, Staff and Student Publications

BACKGROUND: Pevonedistat is a first-in-class, small molecular inhibitor of NEDD8-activating enzyme that has clinical activity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Preclinical data suggest synergy of pevonedistat with azacitidine and venetoclax.

METHODS: This single-center, phase 1/2 study evaluated the combination of azacitidine, venetoclax and pevonedistat in older adults with newly diagnosed secondary AML or with MDS or chronic myelomonocytic leukemia (CMML) after failure of hypomethylating agents. Patients received azacitidine 75 mg/m

FINDINGS: Forty patients were enrolled (32 with AML and 8 with MDS/CMML). In the AML cohort, the median age was 74 years (range 61-86 years), and …

Mitophagy Promotes Resistance To Bh3 Mimetics In Acute Myeloid Leukemia, Christina Glytsou, Xufeng Chen, Emmanouil Zacharioudakis, Wafa Al-Santli, Hua Zhou, Bettina Nadorp, Soobeom Lee, Audrey Lasry, Zhengxi Sun, Dimitrios Papaioannou, Michael Cammer, Kun Wang, Tomasz Zal, Malgorzata Anna Zal, Bing Z Carter, Jo Ishizawa, Raoul Tibes, Aristotelis Tsirigos, Michael Andreeff, Evripidis Gavathiotis, Iannis Aifantis

Faculty, Staff and Student Publications

BH3 mimetics are used as an efficient strategy to induce cell death in several blood malignancies, including acute myeloid leukemia (AML). Venetoclax, a potent BCL-2 antagonist, is used clinically in combination with hypomethylating agents for the treatment of AML. Moreover, MCL1 or dual BCL-2/BCL-xL antagonists are under investigation. Yet, resistance to single or combinatorial BH3-mimetic therapies eventually ensues. Integration of multiple genome-wide CRISPR/Cas9 screens revealed that loss of mitophagy modulators sensitizes AML cells to various BH3 mimetics targeting different BCL-2 family members. One such regulator is MFN2, whose protein levels positively correlate with drug resistance in patients with AML. MFN2 …

A Phase Ib/Ii Study Of Ivosidenib With Venetoclax ± Azacitidine In Idh1-Mutated Myeloid Malignancies, Curtis A Lachowiez, Sanam Loghavi, Zhihong Zeng, Tomoyuki Tanaka, Yi June Kim, Hidetaka Uryu, Sven Turkalj, Niels Asger Jakobsen, Marlise R Luskin, Dzifa Y Duose, Rebecca S S Tidwell, Nicholas J Short, Gautam Borthakur, Tapan M Kadia, Lucia Masarova, George D Tippett, Prithviraj Bose, Elias J Jabbour, Farhad Ravandi, Naval G Daver, Guillermo Garcia-Manero, Hagop Kantarjian, Jacqueline S Garcia, Paresh Vyas, Koichi Takahashi, Marina Konopleva, Courtney D Dinardo

Faculty, Staff and Student Publications

UNLABELLED: The safety and efficacy of combining the isocitrate dehydrogenase-1 (IDH1) inhibitor ivosidenib (IVO) with the BCL2 inhibitor venetoclax (VEN; IVO + VEN) ± azacitidine (AZA; IVO + VEN + AZA) were evaluated in four cohorts of patients with IDH1-mutated myeloid malignancies (n = 31). Most (91%) adverse events were grade 1 or 2. The maximal tolerated dose was not reached. Composite complete remission with IVO + VEN + AZA versus IVO + VEN was 90% versus 83%. Among measurable residual disease (MRD)-evaluable patients (N = 16), 63% attained MRD--negative remissions; IDH1 mutation clearance occurred in 64% of patients receiving …

Effects Of Sex And Estrous Cycle On Intravenous Oxycodone Self-Administration And The Reinstatement Of Oxycodone-Seeking Behavior In Rats, Nicole M. Hinds, Ireneusz D. Wojtas, Corinne A. Gallagher, Claire M. Corbett, Daniel F. Manvich

Rowan-Virtua School of Osteopathic Medicine Departmental Research

The increasing misuse of both prescription and illicit opioids has culminated in a national healthcare crisis in the United States. Oxycodone is among the most widely prescribed and misused opioid pain relievers and has been associated with a high risk for transition to compulsive opioid use. Here, we sought to examine potential sex differences and estrous cycle-dependent effects on the reinforcing efficacy of oxycodone, as well as on stress-induced or cue-induced oxycodone-seeking behavior, using intravenous (IV) oxycodone self-administration and reinstatement procedures. In experiment 1, adult male and female Long-Evans rats were trained to self-administer 0.03 mg/kg/inf oxycodone according to a …

The Swi/Snf Chromatin-Remodeling Subunit Dpf2 Facilitates Nrf2-Dependent Antiinflammatory And Antioxidant Gene Expression, Gloria Mas, Na Man, Yuichiro Nakata, Concepcion Martinez-Caja, Daniel Karl, Felipe Beckedorff, Francesco Tamiro, Chuan Chen, Stephanie Duffort, Hidehiro Itonaga, Adnan K Mookhtiar, Kranthi Kunkalla, Alfredo M Valencia, Clayton K Collings, Cigall Kadoch, Francisco Vega, Scott C Kogan, Ramin Shiekhattar, Lluis Morey, Daniel Bilbao, Stephen D Nimer

Faculty, Staff and Student Publications

During emergency hematopoiesis, hematopoietic stem cells (HSCs) rapidly proliferate to produce myeloid and lymphoid effector cells, a response that is critical against infection or tissue injury. If unresolved, this process leads to sustained inflammation, which can cause life-threatening diseases and cancer. Here, we identify a role of double PHD fingers 2 (DPF2) in modulating inflammation. DPF2 is a defining subunit of the hematopoiesis-specific BAF (SWI/SNF) chromatin-remodeling complex, and it is mutated in multiple cancers and neurological disorders. We uncovered that hematopoiesis-specific Dpf2-KO mice developed leukopenia, severe anemia, and lethal systemic inflammation characterized by histiocytic and fibrotic tissue infiltration resembling a …

Circular Rna As Therapeutic Targets In Atherosclerosis: Are We Running In Circles?, Jeffrey Triska, Christo Mathew, Yang Zhao, Yuqing E Chen, Yochai Birnbaum

Faculty, Staff and Students Publications

Much attention has been paid lately to harnessing the diagnostic and therapeutic potential of non-coding circular ribonucleic acids (circRNAs) and micro-RNAs (miRNAs) for the prevention and treatment of cardiovascular diseases. The genetic environment that contributes to atherosclerosis pathophysiology is immensely complex. Any potential therapeutic application of circRNAs must be assessed for risks, benefits, and off-target effects in both the short and long term. A search of the online PubMed database for publications related to circRNA and atherosclerosis from 2016 to 2022 was conducted. These studies were reviewed for their design, including methods for developing atherosclerosis and the effects of the …

Invited Review: Adrenocortical Function In Avian And Non-Avian Reptiles: Insights From Dispersed Adrenocortical Cells., Rocco V. Carsia, Patrick J. Mcilroy, Henry B John-Alder

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Herein we review our work involving dispersed adrenocortical cells from several lizard species: the Eastern Fence Lizard (Sceloporus undulatus), Yarrow's Spiny Lizard (Sceloporus jarrovii), Striped Plateau Lizard (Sceloporus virgatus) and the Yucatán Banded Gecko (Coleonyx elegans). Early work demonstrated changes in steroidogenic function of adrenocortical cells derived from adult S. undulatus associated with seasonal interactions with sex. However, new information suggests that both sexes operate within the same steroidogenic budget over season. The observed sex effect was further explored in orchiectomized and ovariectomized lizards, some supported with exogenous testosterone. Overall, a suppressive effect of testosterone was evident, especially in cells …

Dna Methylation-Based Classifier Differentiates Intrahepatic Pancreato-Biliary Tumours, Mihnea P Dragomir, Teodor G Calina, Eilís Perez, Simon Schallenberg, Meng Chen, Thomas Albrecht, Ines Koch, Peggy Wolkenstein, Benjamin Goeppert, Stephanie Roessler, George A Calin, Christine Sers, David Horst, Florian Roßner, David Capper

Faculty, Staff and Student Publications

BACKGROUND: Differentiating intrahepatic cholangiocarcinomas (iCCA) from hepatic metastases of pancreatic ductal adenocarcinoma (PAAD) is challenging. Both tumours have similar morphological and immunohistochemical pattern and share multiple driver mutations. We hypothesised that DNA methylation-based machine-learning algorithms may help perform this task.

METHODS: We assembled genome-wide DNA methylation data for iCCA (n = 259), PAAD (n = 431), and normal bile duct (n = 70) from publicly available sources. We split this cohort into a reference (n = 399) and a validation set (n = 361). Using the reference cohort, we trained three machine learning models to differentiate between these entities. Furthermore, …

Evidence Of Novel Susceptibility Variants For Prostate Cancer And A Multiancestry Polygenic Risk Score Associated With Aggressive Disease In Men Of African Ancestry, Fei Chen, Ravi K Madduri, Alex A Rodriguez, Burcu F Darst, Alisha Chou, Xin Sheng, Anqi Wang, Jiayi Shen, Edward J Saunders, Suhn K Rhie, Jeannette T Bensen, Sue A Ingles, Rick A Kittles, Sara S Strom, Benjamin A Rybicki, Barbara Nemesure, William B Isaacs, Janet L Stanford, Wei Zheng, Maureen Sanderson, Esther M John, Jong Y Park, Jianfeng Xu, Ying Wang, Sonja I Berndt, Chad D Huff, Edward D Yeboah, Yao Tettey, Joseph Lachance, Wei Tang, Christopher T Rentsch, Kelly Cho, Benjamin H Mcmahon, Richard B Biritwum, Andrew A Adjei, Evelyn Tay, Ann Truelove, Shelley Niwa, Thomas A Sellers, Kosj Yamoah, Adam B Murphy, Dana C Crawford, Alpa V Patel, William S Bush, Melinda C Aldrich, Olivier Cussenot, Gyorgy Petrovics, Jennifer Cullen, Christine M Neslund-Dudas, Mariana C Stern, Zsofia Kote-Jarai, Koveela Govindasami, Michael B Cook, Anand P Chokkalingam, Ann W Hsing, Phyllis J Goodman, Thomas J Hoffmann, Bettina F Drake, Jennifer J Hu, Jacob M Keaton, Jacklyn N Hellwege, Peter E Clark, Mohamed Jalloh, Serigne M Gueye, Lamine Niang, Olufemi Ogunbiyi, Michael O Idowu, Olufemi Popoola, Akindele O Adebiyi, Oseremen I Aisuodionoe-Shadrach, Hafees O Ajibola, Mustapha A Jamda, Olabode P Oluwole, Maxwell Nwegbu, Ben Adusei, Sunny Mante, Afua Darkwa-Abrahams, James E Mensah, Halimatou Diop, Stephen K Van Den Eeden, Pascal Blanchet, Jay H Fowke, Graham Casey, Anselm J Hennis, Alexander Lubwama, Ian M Thompson, Robin Leach, Douglas F Easton, Michael H Preuss, Ruth J Loos, Susan M Gundell, Peggy Wan, James L Mohler, Elizabeth T Fontham, Gary J Smith, Jack A Taylor, Shiv Srivastava, Rosaline A Eeles, John D Carpten, Adam S Kibel, Luc Multigner, Marie-Élise Parent, Florence Menegaux, Geraldine Cancel-Tassin, Eric A Klein, Caroline Andrews, Timothy R Rebbeck, Laurent Brureau, Stefan Ambs, Todd L Edwards, Stephen Watya, Stephen J Chanock, John S Witte, William J Blot, J Michael Gaziano, Amy C Justice, David V Conti, Christopher A Haiman

Faculty, Staff and Student Publications

BACKGROUND: Genetic factors play an important role in prostate cancer (PCa) susceptibility.

OBJECTIVE: To discover common genetic variants contributing to the risk of PCa in men of African ancestry.

DESIGN, SETTING, AND PARTICIPANTS: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness.

RESULTS AND LIMITATIONS: Nine …

Bladder-Sparing Treatment In Patients With Bacillus Calmette-Guerin-Unresponsive Non-Muscle-Invasive Bladder Cancer: An Analysis Of Long-Term Survival Outcomes, Wei Shen Tan, Valentina Grajales, Roberto Contieri, Patrick Hensley, Kelly Bree, Pavlos Msaouel, Charles C Guo, Graciela M Nogueras-Gonzalez, Neema Navai, Colin P Dinney, Ashish M Kamat

Faculty, Staff and Student Publications

BACKGROUND: Data for bladder-sparing treatment (BST) in bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) patients report short-term outcomes limited to 1-2 yr.

OBJECTIVE: To assess long-term survival outcomes of BCG-unresponsive NMIBC patients treated with BST.

DESIGN SETTING AND PARTICIPANTS: BCG-unresponsive NMIBC patients diagnosed between January 2000 and September 2021 from an institutional NMIBC registry were evaluated.

INTERVENTION: Long-term survival outcomes for patients receiving BST, early radical cystectomy (RC), and delayed RC were compared.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoints were overall survival (OS) and cancer-specific survival (CSS).

RESULTS AND LIMITATIONS: In total, 114 patients with a median follow-up …

Estrogen-Related Receptor Signaling In Skeletal Muscle Fitness, Danesh Sopariwala, Hao Nguyen, Vihang Narkar

Faculty, Staff and Student Publications

Skeletal muscle is a highly plastic tissue that can alter its metabolic and contractile features, as well as regenerative potential in response to exercise and other conditions. Multiple signaling factors including metabolites, kinases, receptors, and transcriptional factors have been studied in the regulation of skeletal muscle plasticity. Recently, estrogen-related receptors (ERRs) have emerged as a critical transcriptional hub in control of skeletal muscle homeostasis. ERRα and ERRγ - the two highly expressed ERR sub-types in the muscle respond to various extracellular cues such as exercise, hypoxia, fasting and dietary factors, in turn regulating gene expression in the skeletal muscle. On …

Amyloid-Beta Protein Concentration Dependence Of Reversible Aggregation Using Gold Colloid Particles, Renee Spencer, Lila Kocieniewski, Bryan Martinez, Kazushige Yokoyama

McNair Scholars Program

Although Alzheimer’s and COVID-19 are different diseases, the commonality between them is during the process of them developing in a person by fibrillogenesis. The product of fibrillogenesis results in the development of these diseases. We study the first stage of fibrillogenesis where the amyloid-beta peptide monomers are assembled into an oligomer. We want to isolate this oligomer using gold colloids because this step can be reversed. Utilizing gold colloids allows us to freeze fibrillogenesis in the first step by folding and unfolding the protein repeatedly through a series of pH changes from 4 or below to 10 or higher. At …

Alcapa – A Rare Cause Of Effort Angina In An Adult: A Case Report, Henita Joshna Menezes, Raghav R. Nagpal, Sonia R B D'Souza, Ramachandran Padmakumar

Manipal Journal of Nursing and Health Sciences

Introduction: ALCAPA – ‘Anomalous Left Coronary Artery from the Pulmonary Artery’, it is an infrequent congenital cardiovascular abnormality distinguished by the ‘left coronary artery’ originating from the ‘pulmonary artery’ in place of its normal origin, the aorta. Failing to treat this critical condition, might result in myocardial ischemia, left ventricular dysfunction, and a risk of sudden heart-related death.

Clinical manifestations: Exertional chest pain and fatigue since 6 months.

Diagnosis, therapeutic intervention, and outcomes: The diagnosis was established with the help of transoesophageal echocardiography and coronary angiogram. Surgical repair by Left Coronary Artery reimplantation was done with a successful outcome.

Conclusion: …

The Time-Course Of Cancer Cachexia Onset Reveals Biphasic Transcriptional Disruptions In Female Skeletal Muscle Distinct From Males, Francielly Morena, Seongkyun Lim, Ana Regina Cabrera, Eleanor R. Schrems, Ronald G. Jones, Megan E. Rosa-Caldwell, Tyrone A. Washington, Kevin A. Murach, Nicholas P. Greene

Health, Human Performance and Recreation Faculty Publications and Presentations

Background

Cancer-cachexia (CC) is a debilitating condition affecting up to 80% of cancer patients and contributing to 40% of cancer-related deaths. While evidence suggests biological sex differences in the development of CC, assessments of the female transcriptome in CC are lacking, and direct comparisons between sexes are scarce. This study aimed to define the time course of Lewis lung carcinoma (LLC)-induced CC in females using transcriptomics, while directly comparing biological sex differences.

Results

We found the global gene expression of the gastrocnemius muscle of female mice revealed biphasic transcriptomic alterations, with one at 1 week following tumor allograft and another …

Genome-Wide Association Study Of Thoracic Aortic Aneurysm And Dissection In The Million Veteran Program, Derek Klarin, Poornima Devineni, Anoop K Sendamarai, Anthony R Angueira, Sarah E Graham, Ying H Shen, Michael G Levin, James P Pirruccello, Ida Surakka, Purushotham R Karnam, Tanmoy Roychowdhury, Yanming Li, Minxian Wang, Krishna G Aragam, Kaavya Paruchuri, Verena Zuber, Gabrielle E Shakt, Noah L Tsao, Renae L Judy, Ha My T Vy, Shefali S Verma, Daniel J Rader, Ron Do, Joseph E Bavaria, Girish N Nadkarni, Marylyn D Ritchie, Stephen Burgess, Dong-Chuan Guo, Patrick T Ellinor, Scott A Lemaire, Dianna M Milewicz, Cristen J Willer, Pradeep Natarajan, Philip S Tsao, Saiju Pyarajan, Scott M Damrauer

Faculty, Staff and Student Publications

The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and …

Interferon Signaling Promotes Tolerance To Chromosomal Instability During Metastatic Evolution In Renal Cancer, Luigi Perelli, Federica Carbone, Li Zhang, Justin K Huang, Courtney Le, Hania Khan, Francesca Citron, Edoardo Del Poggetto, Tony Gutschner, Hideo Tomihara, Melinda Soeung, Rosalba Minelli, Sanjana Srinivasan, Michael Peoples, Truong Nguyen Anh Lam, Sebastian Lundgren, Ruohan Xia, Cihui Zhu, Alaa M T Mohamed, Jianhua Zhang, Kanishka Sircar, Alessandro Sgambato, Jianjun Gao, Eric Jonasch, Giulio F Draetta, Andrew Futreal, Ziad Bakouny, Eliezer M Van Allen, Toni Choueiri, Sabina Signoretti, Pavlos Msaouel, Kevin Litchfield, Samra Turajlic, Linghua Wang, Ying Bei Chen, Renzo G Di Natale, A Ari Hakimi, Virginia Giuliani, Timothy P Heffernan, Andrea Viale, Christopher A Bristow, Nizar M Tannir, Alessandro Carugo, Giannicola Genovese

Faculty, Staff and Student Publications

Molecular routes to metastatic dissemination are critical determinants of aggressive cancers. Through in vivo CRISPR-Cas9 genome editing, we generated somatic mosaic genetically engineered models that faithfully recapitulate metastatic renal tumors. Disruption of 9p21 locus is an evolutionary driver to systemic disease through the rapid acquisition of complex karyotypes in cancer cells. Cross-species analysis revealed that recurrent patterns of copy number variations, including 21q loss and dysregulation of the interferon pathway, are major drivers of metastatic potential. In vitro and in vivo genomic engineering, leveraging loss-of-function studies, along with a model of partial trisomy of chromosome 21q, demonstrated a dosage-dependent effect …

Effects Of A Pragmatic Home-Based Exercise Program Concurrent With Neoadjuvant Therapy On Physical Function Of Patients With Pancreatic Cancer: The Pancfit Randomized Clinical Trial, An T Ngo-Huang, Nathan H Parker, Lianchun Xiao, Keri L Schadler, Maria Q B Petzel, Laura R Prakash, Michael P Kim, Ching-Wei D Tzeng, Jeffrey E Lee, Naruhiko Ikoma, Robert A Wolff, Milind M Javle, Eugene J Koay, Shubham D Pant, Justin P Folloder, Xuemei Wang, Alicia M Cotto, Ye Rang Ju, Naveen Garg, Huamin Wang, Eduardo D Bruera, Karen M Basen-Engquist, Matthew H G Katz

Faculty, Staff and Student Publications

OBJECTIVE: To determine the effects of a preoperative, home-based exercise program on fitness and physical function in patients with pancreatic cancer.

BACKGROUND: We previously established a well-tolerated preoperative exercise program after finding a high frequency of sarcopenia and frailty in patients with pancreatic cancer.

METHODS: In this randomized, controlled trial (NCT03187951), patients with pancreatic cancer were randomized to Arm A: enhanced usual care or Arm B: prescribed aerobic and resistance exercise during neoadjuvant therapy. Patients received nutrition counseling and activity trackers. The primary endpoint was 6-minute walk distance (6MWD; ≥14 meters improvement was clinically meaningful). Secondary endpoints included …

Emerging Signaling Regulation Of Sinoatrial Node Dysfunction, Mingjie Zheng, Shannon Erhardt, Yuhan Cao, Jun Wang

Faculty, Staff and Student Publications

PURPOSE OF REVIEW: The sinoatrial node (SAN), the natural pacemaker of the heart, is responsible for generating electrical impulses and initiating each heartbeat. Sinoatrial node dysfunction (SND) causes various arrhythmias such as sinus arrest, SAN block, and tachycardia/bradycardia syndrome. Unraveling the underlying mechanisms of SND is of paramount importance in the pursuit of developing effective therapeutic strategies for patients with SND. This review provides a concise summary of the most recent progress in the signaling regulation of SND.

RECENT FINDINGS: Recent studies indicate that SND can be caused by abnormal intercellular and intracellular signaling, various forms of heart failure (HF), …

Factors Affecting Treatment Adherence Among Leprosy Patients: Perceptions Of Healthcare Providers, Veincent Christian F Pepito, Arianna Maever Loreche, Rae Erica D Samontina, Sarah Jane A Abdon, David Norman L Fuentes, Ofelia P Saniel

Faculty, Staff and Student Publications

BACKGROUND: Treatment adherence is a vital aspect in the management of chronic diseases like leprosy; however, most studies on treatment adherence focus on patients. This study aims to examine the perceptions of healthcare providers on factors that can promote or prevent patients from adhering to treatment.

METHODS: We conducted three focus group discussions (FGDs) with healthcare providers who have at least one year experience in managing leprosy in three large leprosy case-holding hospitals in Metro Manila, Philippines. We audio-recorded, transcribed, translated the FGD proceedings, and analyzed the transcripts thematically to identify patient-intrinsic and patient-extrinsic enablers and barriers to treatment adherence …

Transcriptional Profiling And Consensus Molecular Subtype Assignment To Understand Response And Resistance To Anti-Epidermal Growth Factor Receptor Therapy In Colorectal Cancer, Saikat Chowdhury, Ria Gupta, Joshua Millstein, Kangyu Lin, Valsala Haridas, Mohammad A Zeineddine, Christine Parseghian, Heinz-Josef Lenz, Scott Kopetz, John Paul Shen

Faculty, Staff and Student Publications

PURPOSE: Activating mutations in KRAS, NRAS, and BRAF are known to cause resistance to anti–epidermal growth factor receptor (EGFR) therapy; however, only approximately 40% of patients with colorectal cancer (CRC) with RASWT tumors respond to anti-EGFR treatment. We sought to discover novel biomarkers to predict response to anti-EGFR antibody treatment in CRC and to understand mechanisms of resistance to anti-EGFR therapy.

MATERIALS AND METHODS: Transcriptomic profiles from three clinical and two preclinical cohorts treated with cetuximab were used to assign consensus molecular subtypes (CMS) to each sample and correlated with outcomes.

RESULTS: Restricting to RASWT patients, …

Genomic Analysis Of Clostridioides Difficile Recovered From Horses In Western Australia, Natasza M. R. Hain-Saunders, Daniel R. Knight, Mieghan Bruce, David Byrne, Thomas V. Riley

Research outputs 2022 to 2026

Clostridioides difficile poses an ongoing threat as a cause of gastrointestinal disease in humans and animals. Traditionally considered a human healthcare-related disease, increases in community-associated C. difficile infection (CDI) and growing evidence of inter-species transmission suggest a wider perspective is required for CDI control. In horses, C. difficile is a major cause of diarrhoea and life-threatening colitis. This study aimed to better understand the epidemiology of CDI in Australian horses and provide insights into the relationships between horse, human and environmental strains. A total of 752 faecal samples from 387 Western Australian horses were collected. C. difficile was isolated from …

A Review On Antibiotic Resistance And The Use Of Medicinal Plants In The Management Of Uropathogenic Bacteria, Hubza Ruatt Khan, Mehvish Javeed, Iqra Batool, Rabeea Anwar, Asma Ashraf, Sara Janiad

Journal of Bioresource Management

UTIs are the most prevalent infections and are caused by uropathogenic microbes such as Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus spp. Antibiotic resistance has hampered the management of UTIs over the years, with direct repercussions on the treatment cost, the infection severity, and the duration of hospitalization. This review discussed the route of infections, risk factors connected to UTIs, antibiotic resistance issues as well as an alternative therapy to overcome the problem of antibiotic resistance. The medicinal plants, which have been utilized for thousands of years to cure a variety of ailments, represent a …

Twenty-Year Survival Following Lung Transplantation, John James Miggins, Ross M Reul, Spencer Barrett, Abbas Rana, Ahmed Alnajar, Jordan Dunson, Alexis Shafii, Puneet Garcha, John Goss, Gabriel Loor

Faculty, Staff and Students Publications

BACKGROUND: Lung transplantation median survival has seen improvements due to recognition of short-term survival factors but continues to trail behind other solid organs due to limited understanding of long-term survivorship. Given the creation of the United Network for Organ Sharing (UNOS) database in 1986, it was difficult to accrue data on long-term survivors until recently. This study characterizes factors impacting lung transplant survival beyond 20 years, conditional to 1-year survival.

METHODS: Lung transplant recipients listed in UNOS from 1987 to 2002 who survived to 1 post-transplant year were reviewed. Kaplan-Meier and adjusted Cox regression analyses were performed at 20 and …

A Phase I Study Of Milademetan (Ds3032b) In Combination With Low Dose Cytarabine With Or Without Venetoclax In Acute Myeloid Leukemia: Clinical Safety, Efficacy, And Correlative Analysis, Jayastu Senapati, Muharrem Muftuoglu, Jo Ishizawa, Hussein A Abbas, Sanam Loghavi, Gautam Borthakur, Musa Yilmaz, Ghayas C Issa, Samuel I Dara, Mahesh Basyal, Li Li, Kiran Naqvi, Rasoul Pourebrahim, Elias J Jabbour, Steven M Kornblau, Nicholas J Short, Naveen Pemmaraju, Guillermo Garcia-Manero, Farhad Ravandi, Joseph Khoury, Naval Daver, Hagop M Kantarjian, Michael Andreeff, Courtney D Dinardo

Faculty, Staff and Student Publications

In TP53 wild-type acute myeloid leukemia (AML), inhibition of MDM2 can enhance p53 protein expression and potentiate leukemic cell apoptosis. MDM2 inhibitor (MDM2i) monotherapy in AML has shown modest responses in clinical trials but combining options of MDM2i with other potent AML-directed agents like cytarabine and venetoclax could improve its efficacy. We conducted a phase I clinical trial (NCT03634228) to study the safety and efficacy of milademetan (an MDM2i) with low-dose cytarabine (LDAC)±venetoclax in adult patients with relapsed refractory (R/R) or newly diagnosed (ND; unfit) TP53 wild-type AML and performed comprehensive CyTOF analyses to interrogate multiple signaling pathways, the p53-MDM2 …