Medical Specialties Commons^™

Greater Male Variability In Daily Energy Expenditure Develops Through Puberty, Lewis G Halsey, Vincent Careau, Philip N Ainslie, Heliodoro Alemán-Mateo, Lene F Andersen, Liam J Anderson, Leonore Arab, Issad Baddou, Linda Bandini, Kweku Bedu-Addo, Ellen E Blaak, Stephane Blanc, Alberto G Bonomi, Carlijn V C Bouten, Pascal Bovet, Soren Brage, Maciej S Buchowski, Nancy Butte, Stephan G Camps, Regian Casper, Graeme L Close, Lisa H Colbert, Jamie A Cooper, Richard Cooper, Prasangi Dabare, Sai Krupa Das, Peter S W Davies, Sanjoy Deb, Christine Delisle Nyström, William Dietz, Lara R Dugas, Simon Eaton, Ulf Ekelund, Asmaa El Hamdouchi, Sonja Entringer, Terrence Forrester, Barry W Fudge, Melanie Gillingham, Annelies H Goris, Michael Gurven, Hinke Haisma, Catherine Hambly, Daniel Hoffman, Marije B Hoos, Sumei Hu, Noorjehan Joonas, Annemiek Joosen, Peter Katzmarzyk, Kitty P Kempen, Misaka Kimura, William E Kraus, Wantanee Kriengsinyos, Rebecca Kuriyan, Robert F Kushner, Estelle V Lambert, Pulani Lanerolle, Christel L Larsson, Nader Lessan, Marie Löf, Corby Martin, Eric Matsiko, Gerwin A Meijer, James C Morehen, James P Morton, Aviva Must, Marian Neuhouser, Theresa A Nicklas, Robert M Ojiambo, Kirsi H Pietilainen, Yannis P Pitsiladis, Jacob Plange-Rhule, Guy Plasqui, Ross L Prentice, Roberto Rabinovich, Susan B Racette, David A Raichen, Eric Ravussin, Leanne Redman, John J Reilly, Rebecca Reynolds, Susan Roberts, Jennifer C Rood, Dulani Samaranayake, Luís B Sardinha, Albertine J Scuitt, Analiza M Silva, Srishti Sinha, Anders M Sjödin, Eric Stice, Albert Stunkard, Samuel S Urlacher, Mauro Eduardo Valencia, Giulio Valenti, Ludo M Van Etten, Edgar A Van Mil, Jeanine A Verbunt, Jonathan C K Wells, George Wilson, Brian Wood, Tsukasa Yoshida, Xueying Zhang, Alexia Murphy-Alford, Cornelia Loechl, Amy Luke, Herman Pontzer, Jennifer Rood, Hiroyuki Sagayama, Klaas R Westerterp, William W Wong, Yosuke Yamada, John R Speakman

Faculty, Staff and Student Publications

There is considerably greater variation in metabolic rates between men than between women, in terms of basal, activity and total (daily) energy expenditure (EE). One possible explanation is that EE is associated with male sexual characteristics (which are known to vary more than other traits) such as musculature and athletic capacity. Such traits might be predicted to be most prominent during periods of adolescence and young adulthood, when sexual behaviour develops and peaks. We tested this hypothesis on a large dataset by comparing the amount of male variation and female variation in total EE, activity EE and basal EE, at …

A Novel Grk3-Hdac2 Regulatory Pathway Is A Key Direct Link Between Neuroendocrine Differentiation And Angiogenesis In Prostate Cancer Progression, Samira Naderinezhad, Guoliang Zhang, Zheng Wang, Dayong Zheng, Mohit Hulsurkar, Michael Bakhoum, Ning Su, Han Yang, Tao Shen, Wenliang Li

Faculty, Staff and Students Publications

The mechanisms underlying the progression of prostate cancer (PCa) to neuroendocrine prostate cancer (NEPC), an aggressive PCa variant, are largely unclear. Two prominent NEPC phenotypes are elevated NE marker expression and heightened angiogenesis. Identifying the still elusive direct molecular links connecting angiogenesis and neuroendocrine differentiation (NED) is crucial for our understanding and targeting of NEPC. Here we found that histone deacetylase 2 (HDAC2), whose role in NEPC has not been reported, is one of the most upregulated epigenetic regulators in NEPC. HDAC2 promotes both NED and angiogenesis. G protein-coupled receptor kinase 3 (GRK3), also upregulated in NEPC, is a critical …

A Defect In Mitochondrial Fatty Acid Synthesis Impairs Iron Metabolism And Causes Elevated Ceramide Levels, Debdeep Dutta, Oguz Kanca, Seul Kee Byeon, Paul C Marcogliese, Zhongyuan Zuo, Rishi V Shridharan, Jun Hyoung Park, Undiagnosed Diseases Networ, Guang Lin, Ming Ge, Gali Heimer, Jennefer N Kohler, Matthew T Wheeler, Benny A Kaipparettu, Akhilesh Pandey, Hugo J Bellen

Faculty, Staff and Students Publications

In most eukaryotic cells, fatty acid synthesis (FAS) occurs in the cytoplasm and in mitochondria. However, the relative contribution of mitochondrial FAS (mtFAS) to the cellular lipidome is not well defined. Here we show that loss of function of Drosophila mitochondrial enoyl coenzyme A reductase (Mecr), which is the enzyme required for the last step of mtFAS, causes lethality, while neuronal loss of Mecr leads to progressive neurodegeneration. We observe a defect in Fe-S cluster biogenesis and increased iron levels in flies lacking mecr, leading to elevated ceramide levels. Reducing the levels of either iron or ceramide suppresses the neurodegenerative …

Phenoscore Quantifies Phenotypic Variation For Rare Genetic Diseases By Combining Facial Analysis With Other Clinical Features Using A Machine-Learning Framework, Alexander J M Dingemans, Max Hinne, Kim M G Truijen, Lia Goltstein, Jeroen Van Reeuwijk, Nicole De Leeuw, Janneke Schuurs-Hoeijmakers, Rolph Pfundt, Illja J Diets, Joery Den Hoed, Elke De Boer, Jet Coenen-Van Der Spek, Sandra Jansen, Bregje W Van Bon, Noraly Jonis, Charlotte W Ockeloen, Anneke T Vulto-Van Silfhout, Tjitske Kleefstra, David A Koolen, Philippe M Campeau, Elizabeth E Palmer, Hilde Van Esch, Gholson J Lyon, Fowzan S Alkuraya, Anita Rauch, Ronit Marom, Diana Baralle, Pleuntje J Van Der Sluijs, Gijs W E Santen, R Frank Kooy, Marcel A J Van Gerven, Lisenka E L M Vissers, Bert B A De Vries

Faculty, Staff and Students Publications

Several molecular and phenotypic algorithms exist that establish genotype-phenotype correlations, including facial recognition tools. However, no unified framework that investigates both facial data and other phenotypic data directly from individuals exists. We developed PhenoScore: an open-source, artificial intelligence-based phenomics framework, combining facial recognition technology with Human Phenotype Ontology data analysis to quantify phenotypic similarity. Here we show PhenoScore's ability to recognize distinct phenotypic entities by establishing recognizable phenotypes for 37 of 40 investigated syndromes against clinical features observed in individuals with other neurodevelopmental disorders and show it is an improvement on existing approaches. PhenoScore provides predictions for individuals with variants …

Polygenic Genetic Variation Affecting Antibody Formation Underlies Hypertensive Renal Injury In The Stroke-Prone Spontaneously Hypertensive Rat, Isha S Dhande, Yaming Zhu, Aniket S Joshi, M John Hicks, Michael C Braun, Peter A Doris

Faculty, Staff and Students Publications

During development of the spontaneously hypertensive rat (SHR), several distinct but closely related lines were generated. Most lines are resistant to hypertensive renal disease. However, the SHR-A3 line (stroke-prone SHR) experiences end-organ injury (EOI) and provides a model of injury susceptibility that can be used to uncover genetic causation. In the present study, we generated a congenic line in which three distinct disease loci in SHR-A3 are concurrently replaced with homologous loci from an injury-resistant SHR line (SHR-B2). Verification that all three loci were homozygously replaced in this triple congenic line [SHR-A3(Trip B2)] while the genetic background of SHR-A3 was …

Factors Influencing Prescribing The First Add-On Disease-Modifying Antirheumatic Drugs In Patients Initiating Methotrexate For Rheumatoid Arthritis, Yinan Huang, Satabdi Chatterjee, Sandeep K Agarwal, Hua Chen, Michael L Johnson, Rajender R Aparasu

Faculty, Staff and Students Publications

BACKGROUND: Advances in Disease-Modifying Antirheumatic Drugs (DMARDs) have expanded the treatment landscape for Rheumatoid Arthritis (RA). Guidelines recommend adding either conventional synthetic (cs), biologic (b), or targeted synthetic (ts) DMARDs to methotrexate (MTX) for managing RA. Limited evidence exists regarding the factors that contribute to adding a DMARD agent to the MTX regimen. This study examined the factors associated with adding the first DMARD in RA patients initiating MTX.

METHODS: This retrospective cohort study utilized the MarketScan data (2012-2014) involving adults (aged ≥18) with RA initiating an MTX (index date) between Jul 1, 2012 and Dec 30, 2013, and with …

Myths And Methodologies: Cardiopulmonary Exercise Testing For Surgical Risk Stratification In Patients With An Abdominal Aortic Aneurysm; Balancing Risk Over Benefit, Damian M Bailey, Richard G Davies, George A Rose, Michael H Lewis, Ahmed Abd Aldayem, Chistopher P Twine, Wael Awad, Matti Jubouri, Idhrees Mohammed, Carlos A Mestres, Edward P Chen, Joseph S Coselli, Ian M Williams, Mohamad Bashir, International Academic Surgical Consortium (Thalamus)

Faculty, Staff and Students Publications

The extent to which patients with an abdominal aortic aneurysm (AAA) should exercise remains unclear, given theoretical concerns over the perceived risk of blood pressure-induced rupture, which is often catastrophic. This is especially pertinent during cardiopulmonary exercise testing, when patients are required to perform incremental exercise to symptom-limited exhaustion for the determination of cardiorespiratory fitness. This multimodal metric is being used increasingly as a complementary diagnostic tool to inform risk stratification and subsequent management of patients undergoing AAA surgery. In this review, we bring together a multidisciplinary group of physiologists, exercise scientists, anaesthetists, radiologists and surgeons to challenge the enduring …

Il17a Blockade With Ixekizumab Suppresses Muvb Signaling In Clinical Psoriasis, Scott A Ochsner, Mesias Pedroza, Rudolf T Pillich, Venkatesh Krishnan, Bruce W Konicek, Ernst R Dow, So Young Park, Sandeep K Agarwal, Neil J Mckenna

Faculty, Staff and Students Publications

Unbiased informatics approaches have the potential to generate insights into uncharacterized signaling pathways in human disease. In this study, we generated longitudinal transcriptomic profiles of plaque psoriasis lesions from patients enrolled in a clinical trial of the anti-IL17A antibody ixekizumab (IXE). This dataset was then computed against a curated matrix of over 700 million data points derived from published psoriasis and signaling node perturbation transcriptomic and chromatin immunoprecipitation-sequencing datasets. We observed substantive enrichment within both psoriasis-induced and IXE-repressed gene sets of transcriptional targets of members of the MuvB complex, a master regulator of the mitotic cell cycle. These gene sets …

The Transcription Factor Chrebp Links Mitochondrial Lipidomes To Mitochondrial Morphology And Progression Of Diabetic Kidney Disease, Li Li, Jianyin Long, Koki Mise, Naravat Poungavrin, Philip L Lorenzi, Iqbal Mahmud, Lin Tan, Pradip K Saha, Yashpal S Kanwar, Benny H Chang, Farhad R Danesh

Faculty, Staff and Students Publications

A substantial body of evidence has established the contributions of both mitochondrial dynamics and lipid metabolism to the pathogenesis of diabetic kidney disease (DKD). However, the precise interplay between these two key metabolic regulators of DKD is not fully understood. Here, we uncover a link between mitochondrial dynamics and lipid metabolism by investigating the role of carbohydrate-response element-binding protein (ChREBP), a glucose-responsive transcription factor and a master regulator of lipogenesis, in kidney podocytes. We find that inducible podocyte-specific knockdown of ChREBP in diabetic db/db mice improves key biochemical and histological features of DKD in addition to significantly reducing mitochondrial fragmentation. …

Nurse Leader Perceptions Of Data In The Veterans Health Administration: A Qualitative Evaluation, Janine J Wong, Richard P Sorelle, Christine Yang, Melissa K Knox, Sylvia J Hysong, Lynette E Dorsey, Patrick N O'Mahen, Laura A Petersen

Faculty, Staff and Students Publications

Healthcare systems and nursing leaders aim to make evidence-based nurse staffing decisions. Understanding how nurses use and perceive available data to support safe staffing can strengthen learning healthcare systems and support evidence-based practice, particularly given emerging data availability and specific nursing challenges in data usability. However, current literature offers sparse insight into the nature of data use and challenges in the inpatient nurse staffing management context. We aimed to investigate how nurse leaders experience using data to guide their inpatient staffing management decisions in the Veterans Health Administration, the largest integrated healthcare system in the United States. We conducted semistructured …

A Single Dominant Locus Restricts Retrovirus Replication In Ybr/Ei Mice, Helen A Beilinson, Amanda Sevilleja, Jessica Spring, Fernando Benavides, Vera Beilinson, Nickolas Neokosmidis, Tatyana Golovkina

Faculty, Staff and Student Publications

Differential responses to viral infections are influenced by the genetic makeup of the host. Studies of resistance to retroviruses in human populations are complicated due to the inability to conduct proof-of-principle studies. Inbred mouse lines, which have a range of susceptible phenotypes to retroviruses, are an ideal tool to identify and characterize mechanisms of resistance and define their genetic underpinnings. YBR/Ei mice become infected with Mouse Mammary Tumor Virus, a mucosally transmitted murine retrovirus, but eliminate the virus from their pedigrees. Virus elimination correlates with a lack of virus-specific neonatal oral tolerance, which is a major mechanism for blocking the …

Barriers To Human Papillomavirus Vaccine Uptake: Role Of State Religiosity And Healthcare Professionals' Participation In A State Vaccine Program, Monalisa Chandra, Ikponmwosa Osaghae, Rajesh Talluri, Sanjay Shete

Faculty, Staff and Student Publications

BACKGROUND: Despite the known benefits of preventing human papillomavirus (HPV)-related cancers, HPV vaccine coverage is low in the United States. Grounded in Social Ecological theory, we assessed the macro-level (state) and meso-level (organization) factors associated with HPV vaccine initiation and up-to-date.

METHODS: Data from 2020 National Immunization Survey-Teen were used to study a sample of 20 163 US adolescents (aged 13-17 years). The data were collected from each teen's parents or guardians and health-care professionals. Weighted prevalence estimates were calculated, and multivariable regression analyses were conducted.

RESULTS: The prevalence of HPV vaccine initiation was 75.1% and of remaining up-to-date was …

Archival Single-Cell Genomics Reveals Persistent Subclones During Dcis Progression, Kaile Wang, Tapsi Kumar, Junke Wang, Darlan Conterno Minussi, Emi Sei, Jianzhuo Li, Tuan M Tran, Aatish Thennavan, Min Hu, Anna K Casasent, Zhenna Xiao, Shanshan Bai, Lei Yang, Lorraine M King, Vandna Shah, Petra Kristel, Carolien L Van Der Borden, Jeffrey R Marks, Yuehui Zhao, Amado J Zurita, Ana Aparicio, Brian Chapin, Jie Ye, Jianjun Zhang, Don L Gibbons, Ellinor Sawyer, Alastair M Thompson, Andrew Futreal, E Shelley Hwang, Jelle Wesseling, Esther H Lips, Nicholas E Navin

Faculty, Staff and Student Publications

Ductal carcinoma in situ (DCIS) is a common precursor of invasive breast cancer. Our understanding of its genomic progression to recurrent disease remains poor, partly due to challenges associated with the genomic profiling of formalin-fixed paraffin-embedded (FFPE) materials. Here, we developed Arc-well, a high-throughput single-cell DNA-sequencing method that is compatible with FFPE materials. We validated our method by profiling 40,330 single cells from cell lines, a frozen tissue, and 27 FFPE samples from breast, lung, and prostate tumors stored for 3-31 years. Analysis of 10 patients with matched DCIS and cancers that recurred 2-16 years later show that many primary …

Relationship Between Plasma Fluoride Levels, Glutathione Peroxidase Activity, Hemoglobin, And Abortion In Rural And Urban Pregnant Women From Settat (Morocco), Lalla Asmaa Katir Masnaoui, Abdellatif Rahim, Habiba Bouchab, Bouchra El Amiri, Boubker Nasser, Essamadi Abdel Khalid

Makara Journal of Health Research

Background: This study aimed to investigate the relationship between plasma fluoride and hemoglobin levels, glutathione peroxidase (GPx) activity, and abortion among rural and urban pregnant women from Settat province (Morocco).

Methods: Blood samples were collected from rural pregnant women who had not undergone abortion (N = 224), rural pregnant women who had an abortion (N = 38), urban pregnant women who had not undergone abortion (N = 163), and urban pregnant women who had an abortion (N = 14).

Results: The highest (p < 0.01) plasma fluoride levels and the lowest (p < 0.01) GPx activity were observed in rural pregnant women. In all participants, plasma fluoride levels were significantly higher (p < 0.001), and the GPx activity was significantly (p < 0.001) lower in pregnant women who had an abortion compared with those who did not undergo such process. No significant difference was observed between the hemoglobin levels of all participants. Furthermore, abortion was positively correlated with plasma fluoride levels (p < 0.001) and negatively correlated with GPx activity (p < 0.001) in rural participants.

Conclusions: Rural pregnant women had higher plasma …

Pan-Cancer Analysis Of Post-Translational Modifications Reveals Shared Patterns Of Protein Regulation, Yifat Geffen, Shankara Anand, Yo Akiyama, Tomer M Yaron, Yizhe Song, Jared L Johnson, Akshay Govindan, Özgün Babur, Yize Li, Emily Huntsman, Liang-Bo Wang, Chet Birger, David I Heiman, Qing Zhang, Mendy Miller, Yosef E Maruvka, Nicholas J Haradhvala, Anna Calinawan, Saveliy Belkin, Alexander Kerelsky, Karl R Clauser, Karsten Krug, Shankha Satpathy, Samuel H Payne, D R Mani, Michael A Gillette, Saravana M Dhanasekaran, Mathangi Thiagarajan, Mehdi Mesri, Henry Rodriguez, Ana I Robles, Steven A Carr, Alexander J Lazar, François Aguet, Lewis C Cantley, Li Ding, Gad Getz, Clinical Proteomic Tumor Analysis Consortium

Faculty, Staff and Student Publications

Post-translational modifications (PTMs) play key roles in regulating cell signaling and physiology in both normal and cancer cells. Advances in mass spectrometry enable high-throughput, accurate, and sensitive measurement of PTM levels to better understand their role, prevalence, and crosstalk. Here, we analyze the largest collection of proteogenomics data from 1,110 patients with PTM profiles across 11 cancer types (10 from the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium [CPTAC]). Our study reveals pan-cancer patterns of changes in protein acetylation and phosphorylation involved in hallmark cancer processes. These patterns revealed subsets of tumors, from different cancer types, including those with …

Pan-Cancer Proteogenomics Connects Oncogenic Drivers To Functional States, Yize Li, Eduard Porta-Pardo, Collin Tokheim, Matthew H Bailey, Tomer M Yaron, Vasileios Stathias, Yifat Geffen, Kathleen J Imbach, Song Cao, Shankara Anand, Yo Akiyama, Wenke Liu, Matthew A Wyczalkowski, Yizhe Song, Erik P Storrs, Michael C Wendl, Wubing Zhang, Mustafa Sibai, Victoria Ruiz-Serra, Wen-Wei Liang, Nadezhda V Terekhanova, Fernanda Martins Rodrigues, Karl R Clauser, David I Heiman, Qing Zhang, Francois Aguet, Anna P Calinawan, Saravana M Dhanasekaran, Chet Birger, Shankha Satpathy, Daniel Cui Zhou, Liang-Bo Wang, Jessika Baral, Jared L Johnson, Emily M Huntsman, Pietro Pugliese, Antonio Colaprico, Antonio Iavarone, Milan G Chheda, Christopher J Ricketts, David Fenyö, Samuel H Payne, Henry Rodriguez, Ana I Robles, Michael A Gillette, Chandan Kumar-Sinha, Alexander J Lazar, Lewis C Cantley, Gad Getz, Li Ding

Faculty, Staff and Student Publications

Cancer driver events refer to key genetic aberrations that drive oncogenesis; however, their exact molecular mechanisms remain insufficiently understood. Here, our multi-omics pan-cancer analysis uncovers insights into the impacts of cancer drivers by identifying their significant cis-effects and distal trans-effects quantified at the RNA, protein, and phosphoprotein levels. Salient observations include the association of point mutations and copy-number alterations with the rewiring of protein interaction networks, and notably, most cancer genes converge toward similar molecular states denoted by sequence-based kinase activity profiles. A correlation between predicted neoantigen burden and measured T cell infiltration suggests potential vulnerabilities for immunotherapies. Patterns of …

Wearable Biosensor With Molecularly Imprinted Conductive Polymer Structure To Detect Lentivirus In Aerosol, Jaskirat Singh Batra, Ting-Yen Chi, Mo-Fan Huang, Dandan Zhu, Zheyuan Chen, Dung-Fang Lee, Jun Kameoka

Faculty, Staff and Student Publications

The coronavirus disease (COVID-19) pandemic has increased pressure to develop low-cost, compact, user-friendly, and ubiquitous virus sensors for monitoring infection outbreaks in communities and preventing economic damage resulting from city lockdowns. As proof of concept, we developed a wearable paper-based virus sensor based on a molecular imprinting technique, using a conductive polyaniline (PANI) polymer to detect the lentivirus as a test sample. This sensor detected the lentivirus with a 4181 TU/mL detection limit in liquid and 0.33% to 2.90% detection efficiency in aerosols at distances ranging from 30 cm to 60 cm. For fabrication, a mixture of a PANI monomer …

One Cluster Per Condition Is Not A Valid Design In Cluster-Randomized Trials Comment On Wang Et Al The Effect Of Different Physical Exercise Programs On Physical Fitness Among Preschool Children: A Cluster-Randomized Controlled Trial Int J Environ Res Public Health 2023, 20, 4254, Yasaman Jamshidi-Naeini, Armando Pena, Abu Bakkar Siddique, Andrew W Brown, David B Allison

Children’s Nutrition Research Center Staff Publications

Wang et al. [...].

Hypothyroidism Following Radiotherapy For Head And Neck Cancer: A Systematic Review Of The Literature And Opportunities To Improve The Therapeutic Ratio, Michael K Rooney, Lauren M Andring, Kelsey L Corrigan, Vincent Bernard, Tyler D Williamson, Clifton D Fuller, Adam S Garden, Brandon Gunn, Anna Lee, Amy C Moreno, William H Morrison, Jack Phan, David I Rosenthal, Michael Spiotto, Steven J Frank

Faculty, Staff and Student Publications

(1) Background: Radiotherapy (RT) is a central component for the treatment of many head and neck cancers. In this systematic review of the literature, we aimed to characterize and quantify the published evidence on RT-related hypothyroidism, including estimated incidence, clinical risk factors, and dosimetric parameters that may be used to guide clinical decision making. Furthermore, we aimed to identify potential areas of improvement in the prevention and clinical management of RT-induced hypothyroidism, including the role of modern advanced therapeutic techniques. (2) Methods: We conducted a systemic review of the literature in accordance with Preferred Reporting Items for Systematic Reviews and …

An Evolutionarily Nascent Architecture Underlying The Formation And Emergence Of Biomolecular Condensates, Nima Jaberi-Lashkari, Byron Lee, Fardin Aryan, Eliezer Calo

Faculty, Staff and Student Publications

Biomolecular condensates are implicated in core cellular processes such as gene regulation and ribosome biogenesis. Although the architecture of biomolecular condensates is thought to rely on collective interactions between many components, it is unclear how the collective interactions required for their formation emerge during evolution. Here, we show that the structure and evolution of a recently emerged biomolecular condensate, the nucleolar fibrillar center (FC), is explained by a single self-assembling scaffold, TCOF1. TCOF1 is necessary to form the FC, and it structurally defines the FC through self-assembly mediated by homotypic interactions of serine/glutamate-rich low-complexity regions (LCRs). Finally, introduction of TCOF1 …

Mapping The Evolution Of T Cell States During Response And Resistance To Adoptive Cellular Therapy, Pavan Bachireddy, Elham Azizi, Cassandra Burdziak, Vinhkhang N Nguyen, Christina S Ennis, Katie Maurer, Cameron Y Park, Zi-Ning Choo, Shuqiang Li, Satyen H Gohil, Neil G Ruthen, Zhongqi Ge, Derin B Keskin, Nicoletta Cieri, Kenneth J Livak, Haesook T Kim, Donna S Neuberg, Robert J Soiffer, Jerome Ritz, Edwin P Alyea, Dana Pe'er, Catherine J Wu

Faculty, Staff and Student Publications

No abstract provided.

Bcl-2 Inhibition Combined With Pparα Activation Synergistically Targets Leukemic Stem Cell-Like Cells In Acute Myeloid Leukemia, Chendi Xie, Hui Zhou, Dongmei Qin, Huijian Zheng, Yuanfang Tang, Wenjuan Li, Jie Zhou, Long Liu, Xinxin Yu, Hongpeng Duan, Yong Zhou, Zhifeng Li, Zhihong Fang, Yiming Luo, Bing Z Carter, Bing Xu, Jie Zha

Faculty, Staff and Student Publications

Persistence of leukemic stem cells (LSCs) is one of the determining factors to acute myeloid leukemia (AML) treatment failure and responsible for the poor prognosis of the disease. Hence, novel therapeutic strategies that target LSCs are crucial for treatment success. We investigated if targeting Bcl-2 and peroxisome proliferator activated receptor α (PPARα), two distinct cell survival regulating mechanisms could eliminate LSCs. This study demonstrate that the Bcl-2 inhibitor venetoclax combined with the PPARα agonist chiglitazar resulted in synergistic killing of LSC-like cell lines and CD34+ primary AML cells while sparing their normal counterparts. Furthermore, the combination regimen significantly suppressed AML …

Hypothyroidism Following Radiotherapy For Head And Neck Cancer: A Systematic Review Of The Literature And Opportunities To Improve The Therapeutic Ratio, Michael K Rooney, Lauren M Andring, Kelsey L Corrigan, Vincent Bernard, Tyler D Williamson, Clifton D Fuller, Adam S Garden, Brandon Gunn, Anna Lee, Amy C Moreno, William H Morrison, Jack Phan, David I Rosenthal, Michael Spiotto, Steven J Frank

Faculty, Staff and Student Publications

(1) Background: Radiotherapy (RT) is a central component for the treatment of many head and neck cancers. In this systematic review of the literature, we aimed to characterize and quantify the published evidence on RT-related hypothyroidism, including estimated incidence, clinical risk factors, and dosimetric parameters that may be used to guide clinical decision making. Furthermore, we aimed to identify potential areas of improvement in the prevention and clinical management of RT-induced hypothyroidism, including the role of modern advanced therapeutic techniques. (2) Methods: We conducted a systemic review of the literature in accordance with Preferred Reporting Items for Systematic Reviews and …

A Comprehensive Drosophila Resource To Identify Key Functional Interactions Between Sars-Cov-2 Factors And Host Proteins, Annabel Guichard, Shenzhao Lu, Oguz Kanca, Daniel Bressan, Yan Huang, Mengqi Ma, Sara Sanz Juste, Jonathan C Andrews, Kristy L Jay, Marketta Sneider, Ruth Schwartz, Mei-Chu Huang, Danqing Bei, Hongling Pan, Liwen Ma, Wen-Wen Lin, Ankush Auradkar, Pranjali Bhagwat, Soo Park, Kenneth H Wan, Takashi Ohsako, Toshiyuki Takano-Shimizu, Susan E Celniker, Michael F Wangler, Shinya Yamamoto, Hugo J Bellen, Ethan Bier

Faculty, Staff and Students Publications

Development of effective therapies against SARS-CoV-2 infections relies on mechanistic knowledge of virus-host interface. Abundant physical interactions between viral and host proteins have been identified, but few have been functionally characterized. Harnessing the power of fly genetics, we develop a comprehensive Drosophila COVID-19 resource (DCR) consisting of publicly available strains for conditional tissue-specific expression of all SARS-CoV-2 encoded proteins, UAS-human cDNA transgenic lines encoding established host-viral interacting factors, and GAL4 insertion lines disrupting fly homologs of SARS-CoV-2 human interacting proteins. We demonstrate the utility of the DCR to functionally assess SARS-CoV-2 genes and candidate human binding partners. We show that …

Non-Coding Rnas: Foes Or Friends For Targeting Tumor Microenvironment, Anna Szymanowska, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Paola Amero

Faculty, Staff and Student Publications

Non-coding RNAs (ncRNAs) are a group of molecules critical for cell development and growth regulation. They are key regulators of important cellular pathways in the tumor microenvironment. To analyze ncRNAs in the tumor microenvironment, the use of RNA sequencing technology has revolutionized the field. The advancement of this technique has broadened our understanding of the molecular biology of cancer, presenting abundant possibilities for the exploration of novel biomarkers for cancer treatment. In this review, we will summarize recent achievements in understanding the complex role of ncRNA in the tumor microenvironment, we will report the latest studies on the tumor microenvironment …

Flavonoids Quercetin And Kaempferol Are Nr4a1 Antagonists And Suppress Endometriosis In Female Mice, Lei Zhang, Kumaravel Mohankumar, Gregory Martin, Fuada Mariyam, Yuri Park, Sang Jun Han, Stephen Safe

Faculty, Staff and Students Publications

Nuclear receptor 4A1 (NR4A1) plays an important role in endometriosis progression; levels of NR4A1 in endometriotic lesions are higher than in normal endometrium, and substituted bis-indole analogs (NR4A1) antagonists suppress endometriosis progression in mice with endometriosis. In addition, the flavonoids kaempferol and quercetin are natural products that directly bind NR4A1 and significantly repress the intrinsic NR4A1-dependent transcriptional activity in human endometriotic epithelial and stromal cells and Ishikawa endometrial cancer cells. NR4A1 knockdown and inhibition of NR4A1 by kaempferol and quercetin suppressed proliferation of human endometriotic epithelial cells and Ishikawa cells by inhibiting epidermal growth factor receptor/c-Myc/survivin-mediated growth-promoting and survival pathways, …

The Histone Chaperone Function Of Daxx Is Dispensable For Embryonic Development, Chang Sun, Yuan Qi, Natalie Fowlkes, Nina Lazic, Xiaoping Su, Guillermina Lozano, Amanda R Wasylishen

Faculty, Staff and Student Publications

Daxx functions as a histone chaperone for the histone H3 variant, H3.3, and is essential for embryonic development. Daxx interacts with Atrx to form a protein complex that deposits H3.3 into heterochromatic regions of the genome, including centromeres, telomeres, and repeat loci. To advance our understanding of histone chaperone activity in vivo, we developed two Daxx mutant alleles in the mouse germline, which abolish the interactions between Daxx and Atrx (DaxxY130A), and Daxx and H3.3 (DaxxS226A). We found that the interaction between Daxx and Atrx is dispensable for viability; mice are born at the …

A Non-Coding Insertional Mutation Of Grhl2 Causes Gene Over-Expression And Multiple Structural Anomalies Including Cleft Palate, Spina Bifida And Encephalocele, Zoe Crane-Smith, Sandra C P De Castro, Evanthia Nikolopoulou, Paul Wolujewicz, Damian Smedley, Yunping Lei, Emma Mather, Chloe Santos, Mark Hopkinson, Andrew A Pitsillides, Richard H Finnell, M Elisabeth Ross, Andrew J Copp, Nicholas D E Greene

Faculty, Staff and Students Publications

Orofacial clefts, including cleft lip and palate (CL/P) and neural tube defects (NTDs) are among the most common congenital anomalies, but knowledge of the genetic basis of these conditions remains incomplete. The extent to which genetic risk factors are shared between CL/P, NTDs and related anomalies is also unclear. While identification of causative genes has largely focused on coding and loss of function mutations, it is hypothesized that regulatory mutations account for a portion of the unidentified heritability. We found that excess expression of Grainyhead-like 2 (Grhl2) causes not only spinal NTDs in Axial defects (Axd) mice but also multiple …

Targeting Breast Cancer: The Familiar, The Emerging, And The Uncharted Territories, Hamidreza Montazeri Aliabadi, Arthur Manda, Riya Sidgal, Co Chung

Pharmacy Faculty Articles and Research

Breast cancer became the most diagnosed cancer in the world in 2020. Chemotherapy is still the leading clinical strategy in breast cancer treatment, followed by hormone therapy (mostly used in hormone receptor-positive types). However, with our ever-expanding knowledge of signaling pathways in cancer biology, new molecular targets are identified for potential novel molecularly targeted drugs in breast cancer treatment. While this has resulted in the approval of a few molecularly targeted drugs by the FDA (including drugs targeting immune checkpoints), a wide array of signaling pathways seem to be still underexplored. Also, while combinatorial treatments have become common practice in …

Structures Of The Insecticidal Toxin Complex Subunit Xpta2 Highlight Roles For Flexible Domains, Cole L Martin, David W Chester, Christopher D Radka, Lurong Pan, Zhengrong Yang, Rachel C Hart, Elad M Binshtein, Zhao Wang, Lisa Nagy, Lawrence J Delucas, Stephen G Aller

Faculty, Staff and Students Publications

The Toxin Complex (Tc) superfamily consists of toxin translocases that contribute to the targeting, delivery, and cytotoxicity of certain pathogenic Gram-negative bacteria. Membrane receptor targeting is driven by the A-subunit (TcA), which comprises IgG-like receptor binding domains (RBDs) at the surface. To better understand XptA2, an insect specific TcA secreted by the symbiont