Digital Commons Network^™

Pathogenesis Of Tuberculosis: The 1930 Lübeck Disaster Revisited, Peter Donald, Stefan Kaufmann, Stephanie Thee, Anna Maria Mandalakas, Christoph Lange

Faculty, Staff and Students Publications

During the 1930 Lübeck Mycobacterium bovis bacille Calmette–Guérin (BCG) disaster, 251 neonates received three oral BCG doses accidentally contaminated by virulent Mycobacterium tuberculosis; 67 (26.7%) infants died of tuberculosis. BCG reversion to pathogenicity did not occur. Detailed post mortem examinations clarified contested aspects of tuberculosis pathogenesis. Gastrointestinal infection was seldom “silent” and did not cause typical primary pulmonary lesions. In 15 infants, primary pulmonary foci were found but these resulted from vaccine ingestion and aspiration and were not caused by gastrointestinal infection spreading to the lungs without trace of its journey, as claimed by prominent researchers such as Calmette …

Dual-Mode Tumor Imaging Using Probes That Are Responsive To Hypoxia-Induced Pathological Conditions, S A Amali S Subasinghe, Robia G Pautler, Md Abul Hassan Samee, Jason T Yustein, Matthew J Allen

Faculty, Staff and Students Publications

Hypoxia in solid tumors is associated with poor prognosis, increased aggressiveness, and strong resistance to therapeutics, making accurate monitoring of hypoxia important. Several imaging modalities have been used to study hypoxia, but each modality has inherent limitations. The use of a second modality can compensate for the limitations and validate the results of any single imaging modality. In this review, we describe dual-mode imaging systems for the detection of hypoxia that have been reported since the start of the 21st century. First, we provide a brief overview of the hallmarks of hypoxia used for imaging and the imaging modalities used …

Worsening Glycemia Increases The Odds Of Intermittent But Not Persistent Staphylococcus Aureus Nasal Carriage In Two Cohorts Of Mexican American Adults, Heather T Essigmann, Craig L Hanis, Stacia M Desantis, William B Perkison, David A Aguilar, Goo Jun, D Ashley Robinson, Eric L Brown

Faculty, Staff and Student Publications

Numerous host and environmental factors contribute to persistent and intermittent nasal Staphylococcus aureus carriage in humans. The effects of worsening glycemia on the odds of S. aureus intermittent and persistent nasal carriage was established in two cohorts from an adult Mexican American population living in Starr County, Texas. The anterior nares were sampled at two time points and the presence of S. aureus determined by laboratory culture and

Regulation Of Age-Associated Insulin Resistance By Mt1-Mmp-Mediated Cleavage Of Insulin Receptor, Xuanming Guo, Pallavi Asthana, Susma Gurung, Shuo Zhang, Sheung Kin Ken Wong, Samane Fallah, Chi Fung Willis Chow, Sijia Che, Lixiang Zhai, Zening Wang, Xin Ge, Zhixin Jiang, Jiayan Wu, Yijing Zhang, Xiaoyu Wu, Keyang Xu, Cheng Yuan Lin, Hiu Yee Kwan, Aiping Lyu, Zhongjun Zhou, Zhao-Xiang Bian, Hoi Leong Xavier Wong

Faculty, Staff and Student Publications

Insulin sensitivity progressively declines with age. Currently, the mechanism underlying age-associated insulin resistance remains unknown. Here, we identify membrane-bound matrix metalloproteinase 14 (MT1-MMP/MMP14) as a central regulator of insulin sensitivity during ageing. Ageing promotes MMP14 activation in insulin-sensitive tissues, which cleaves Insulin Receptor to suppress insulin signaling. MT1-MMP inhibition restores Insulin Receptor expression, improving insulin sensitivity in aged mice. The cleavage of Insulin Receptor by MT1-MMP also contributes to obesity-induced insulin resistance and inhibition of MT1-MMP activities normalizes metabolic dysfunctions in diabetic mouse models. Conversely, overexpression of MT1-MMP in the liver reduces the level of Insulin Receptor, impairing hepatic insulin …

Dietary Fatty Acid Intake And The Colonic Gut Microbiota In Humans, Anthony A Xu, Luke K Kennedy, Kristi Hoffman, Donna L White, Fasiha Kanwal, Hashem B El-Serag, Joseph F Petrosino, Li Jiao

Faculty, Staff and Students Publications

A high-fat diet has been associated with systemic diseases in humans and alterations in gut microbiota in animal studies. However, the influence of dietary fatty acid intake on gut microbiota in humans has not been well studied. In this cross-sectional study, we examined the association between intake of total fatty acids (TFAs), saturated fatty acids (SFAs), trans fatty acids (TrFAs), monounsaturated fatty acids (MUFAs), polyunsaturated fatty acids (PUFAs), n3-FAs, and n6-FAs, and the community composition and structure of the adherent colonic gut microbiota. We obtained 97 colonic biopsies from 34 participants with endoscopically normal colons. Microbial DNA was used to …

An Epidemic Model With Time-Distributed Recovery And Death Rates, Samiran Ghosh, Vitaly Volpert, Malay Banerjee

Faculty, Staff and Student Publications

A compartmental epidemiological model with distributed recovery and death rates is proposed. In some particular cases, the model can be reduced to the conventional SIR model. However, in general, the dynamics of epidemic progression in this model is different. Distributed recovery and death rates are evaluated from COVID-19 data. The model is validated by the epidemiological data for different countries, and it shows better agreement with the data than the SIR model. The time-dependent disease transmission rate is estimated.

Expanding Anti-Cd38 Immunotherapy For Lymphoid Malignancies, Xu Wang, Xinfang Yu, Wei Li, Praveen Neeli, Ming Liu, Ling Li, Mingzhi Zhang, Xiaosheng Fang, Ken H Young, Yong Li

Faculty, Staff and Students Publications

BACKGROUND: Lymphoid neoplasms, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and NK/T cell neoplasms, are a major cause of blood cancer morbidity and mortality. CD38 (cyclic ADP ribose hydrolase) is a transmembrane glycoprotein expressed on the surface of plasma cells and MM cells. The high expression of CD38 across MM and other lymphoid malignancies and its restricted expression in normal tissues make CD38 an attractive target for immunotherapy. CD38-targeting antibodies, like daratumumab, have been approved for the treatment of MM and tested against lymphoma and leukemia in multiple clinical trials.

METHODS: We generated chimeric antigen receptor (CAR) T cells targeting …

Effectiveness Of Recruitment Strategies Of Latino Smokers: Secondary Analysis Of A Mobile Health Smoking Cessation Randomized Clinical Trial., Evelyn Arana-Chicas, Francisco Cartujano-Barrera, Katherine K. Rieth, Kimber K. Richter, Edward F. Ellerbeck, Lisa Sanderson Cox, Kristi D. Graves, Francisco J. Diaz, Delwyn Catley, Ana Paula Cupertino

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Latinos remain disproportionately underrepresented in clinical trials, comprising only 2%-3% of research participants. In order to address health disparities, it is critically important to increase enrollment of Latino smokers in smoking cessation trials. There is limited research examining effective recruitment strategies for this population.

OBJECTIVE: The purpose of this study was to compare the effectiveness of direct versus mass and high- versus low-effort recruitment strategies on recruitment and retention of Latino smokers to a randomized smoking cessation trial. We also examine how the type of recruitment might have influenced the characteristics of enrolled participants.

METHODS: Latino smokers were enrolled …

A Human Single-Neuron Dataset For Face Perception, Runnan Cao, Chujun Lin, Nicholas J Brandmeir, Shuo Wang

2020-Current year OA Pubs

The human amygdala and hippocampus have long been associated with face perception. Here, we present a dataset of single-neuron activity in the human amygdala and hippocampus during face perception. We recorded 2082 neurons from the human amygdala and hippocampus when neurosurgical patients with intractable epilepsy performed a one-back task using natural face stimuli, which mimics natural face perception. Specifically, our data include (1) single-neuron activity from the amygdala (996 neurons) and hippocampus (1086 neurons), (2) eye movements (gaze position and pupil), (3) psychological assessment of the patients, and (4) social trait judgment ratings from a subset of patients and a …

Transmission, Strain Diversity, And Zoonotic Potential Of Chronic Wasting Disease, Sandra Pritzkow

Faculty, Staff and Student Publications

Chronic wasting disease (CWD) is a prion disease affecting several species of captive and free-ranging cervids. In the past few decades, CWD has been spreading uncontrollably, mostly in North America, resulting in a high increase of CWD incidence but also a substantially higher number of geographical regions affected. The massive increase in CWD poses risks at several levels, including contamination of the environment, transmission to animals cohabiting with cervids, and more importantly, a putative transmission to humans. In this review, I will describe the mechanisms and routes responsible for the efficient transmission of CWD, the strain diversity of natural CWD, …

Criminal, Legal, And Ethical Kidney Donation And Transplantation: A Conceptual Framework To Enable Innovation, Alvin E Roth, Ignazio R Marino, Kimberly D Krawiec, Michael A Rees

Department of Surgery Faculty Papers

No abstract provided.

Efficacy And Outcomes Of Faecal Microbiota Transplantation For Recurrent Clostridioides Difficile Infection In Children With Inflammatory Bowel Disease, Maribeth R Nicholson, Erin Alexander, Sonia Ballal, Zev Davidovics, Michael Docktor, Michael Dole, Jonathan M Gisser, Alka Goyal, Suchitra K Hourigan, M Kyle Jensen, Jess L Kaplan, Richard Kellermayer, Judith R Kelsen, Melissa A Kennedy, Sahil Khanna, Elizabeth D Knackstedt, Jennifer Lentine, Jeffery D Lewis, Sonia Michail, Paul D Mitchell, Maria Oliva-Hemker, Tiffany Patton, Karen Queliza, Sarah Sidhu, Aliza B Solomon, David L Suskind, Madison Weatherly, Steven Werlin, Edwin F De Zoeten, Stacy A Kahn, North American Society Of Pediatric Gastroenterology And Nutrition Faecal Microbiota Transplantation Special Interest Group

Faculty, Staff and Students Publications

BACKGROUND: Children with inflammatory bowel disease [IBD] are disproportionally affected by recurrent Clostridioides difficile infection [rCDI]. Although faecal microbiota transplantation [FMT] has been used with good efficacy in adults with IBD, little is known about outcomes associated with FMT in paediatric IBD.

METHODS: We performed a retrospective review of FMT at 20 paediatric centres in the USA from March 2012 to March 2020. Children with and without IBD were compared with determined differences in the efficacy of FMT for rCDI. In addition, children with IBD with and without a successful outcome were compared with determined predictors of success. Safety data …

Bilateral Upper Extremity Motor Priming (Bump) Plus Task-Specific Training For Severe, Chronic Upper Limb Hemiparesis: Study Protocol For A Randomized Clinical Trial, Mary Ellen Stoykov, Olivia M Biller, Alexandra Wax, Erin King, Jacob M Schauer, Louis F Fogg, Daniel M Corcos

Department of Occupational Therapy Faculty Papers

BACKGROUND: Various priming techniques to enhance neuroplasticity have been examined in stroke rehabilitation research. Most priming techniques are costly and approved only for research. Here, we describe a priming technique that is cost-effective and has potential to significantly change clinical practice. Bilateral motor priming uses the Exsurgo priming device (Exsurgo Rehabilitation, Auckland, NZ) so that the less affected limb drives the more affected limb in bilateral symmetrical wrist flexion and extension. The aim of this study is to determine the effects of a 5-week protocol of bilateral motor priming in combination with task-specific training on motor impairment of the affected …

Biochemical, Biophysical, And Immunological Characterization Of Respiratory Secretions In Severe Sars-Cov-2 Infections, Michael J Kratochvil, Gernot Kaber, Sally Demirdjian, Pamela C Cai, Elizabeth B Burgener, Nadine Nagy, Graham L Barlow, Medeea Popescu, Mark R Nicolls, Michael G Ozawa, Donald P Regula, Ana E Pacheco-Navarro, Samuel Yang, Vinicio A De Jesus Perez, Harry Karmouty-Quintana, Andrew M Peters, Bihong Zhao, Maximilian L Buja, Pamela Y Johnson, Robert B Vernon, Thomas N Wight, Carlos E Milla, Angela J Rogers, Andrew J Spakowitz, Sarah C Heilshorn, Paul L Bollyky

Faculty, Staff and Student Publications

Thick, viscous respiratory secretions are a major pathogenic feature of COVID-19, but the composition and physical properties of these secretions are poorly understood. We characterized the composition and rheological properties (i.e., resistance to flow) of respiratory secretions collected from intubated COVID-19 patients. We found the percentages of solids and protein content were greatly elevated in COVID-19 compared with heathy control samples and closely resembled levels seen in cystic fibrosis, a genetic disease known for thick, tenacious respiratory secretions. DNA and hyaluronan (HA) were major components of respiratory secretions in COVID-19 and were likewise abundant in cadaveric lung tissues from these …

Effect Of Musculature On Mortality, A Retrospective Cohort Study, Amy L Shaver, Mary E Platek, Anurag K Singh, Sung Jun Ma, Mark Farrugia, Gregory Wilding, Andrew D Ray, Heather M Ochs-Balcom, Katia Noyes

Department of Medical Oncology Faculty Papers

Background: While often life-saving, treatment for head and neck cancer (HNC) can be debilitating resulting in unplanned hospitalization. Hospitalizations in cancer patients may disrupt treatment and result in poor outcomes. Pre-treatment muscle quality and quantity ascertained through diagnostic imaging may help identify patients at high risk of poor outcomes early. The primary objective of this study was to determine if pre-treatment musculature was associated with all-cause mortality.

Methods: Patient demographic and clinical characteristics were abstracted from the cancer center electronic database (n = 403). Musculature was ascertained from pre-treatment CT scans. Propensity score matching was utilized to adjust for confounding …

A Multi-Ethnic Polygenic Risk Score Is Associated With Hypertension Prevalence And Progression Throughout Adulthood, Nuzulul Kurniansyah, Matthew O Goodman, Tanika N Kelly, Tali Elfassy, Kerri L Wiggins, Joshua C Bis, Xiuqing Guo, Walter Palmas, Kent D Taylor, Henry J Lin, Jeffrey Haessler, Yan Gao, Daichi Shimbo, Jennifer A Smith, Bing Yu, Elena V Feofanova, Roelof A J Smit, Zhe Wang, Shih-Jen Hwang, Simin Liu, Sylvia Wassertheil-Smoller, Joann E Manson, Donald M Lloyd-Jones, Stephen S Rich, Ruth J F Loos, Susan Redline, Adolfo Correa, Charles Kooperberg, Myriam Fornage, Robert C Kaplan, Bruce M Psaty, Jerome I Rotter, Donna K Arnett, Alanna C Morrison, Nora Franceschini, Daniel Levy, Tamar Sofer, Nhlbi Trans-Omics In Precision Medicine (Topmed) Consortium

Faculty, Staff and Student Publications

In a multi-stage analysis of 52,436 individuals aged 17-90 across diverse cohorts and biobanks, we train, test, and evaluate a polygenic risk score (PRS) for hypertension risk and progression. The PRS is trained using genome-wide association studies (GWAS) for systolic, diastolic blood pressure, and hypertension, respectively. For each trait, PRS is selected by optimizing the coefficient of variation (CV) across estimated effect sizes from multiple potential PRS using the same GWAS, after which the 3 trait-specific PRSs are combined via an unweighted sum called "PRSsum", forming the HTN-PRS. The HTN-PRS is associated with both prevalent and incident hypertension at 4-6 …

Hoxa9 Overexpression Contributes To Stem Cell Overpopulation That Drives Development And Growth Of Colorectal Cancer, Brian Osmond, Caroline O.B. Facey, Chi Zhang, Bruce M. Boman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

HOX proteins are transcription factors that regulate stem cell (SC) function, but their role in the SC origin of cancer is under-studied. Aberrant expression of HOX genes occurs in many cancer types. Our goal is to ascertain how retinoic acid (RA) signaling and the regulation of HOXA9 expression might play a role in the SC origin of human colorectal cancer (CRC). Previously, we reported that aldehyde dehydrogenase (ALDH) and other RA pathway components are co-expressed in colonic cancer SCs (CSCs) and that overpopulation of ALDH-positive CSCs occurs during colon tumorigenesis. Our hypothesis is RA signaling regulates HOXA9 expression, and dysregulated …

Lilrb2-Mediated Trem2 Signaling Inhibition Suppresses Microglia Functions, Peng Zhao, Yuanzhong Xu, Lu-Lin Jiang, Xuejun Fan, Zhiqiang Ku, Leike Li, Xiaoye Liu, Mi Deng, Hisashi Arase, Jay-Jiguang Zhu, Timothy Y Huang, Yingjun Zhao, Chengcheng Zhang, Huaxi Xu, Qingchun Tong, Ningyan Zhang, Zhiqiang An

Faculty, Staff and Student Publications

Background: Microglia plays crucial roles in Alzheimer's disease (AD) development. Triggering receptor expressed on myeloid cells 2 (TREM2) in association with DAP12 mediates signaling affecting microglia function. Here we study the negative regulation of TREM2 functions by leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2), an inhibitory receptor bearing ITIM motifs.

Methods: To specifically interrogate LILRB2-ligand (oAβ and PS) interactions and microglia functions, we generated potent antagonistic LILRB2 antibodies with sub-nanomolar level activities. The biological effects of LILRB2 antagonist antibody (Ab29) were studied in human induced pluripotent stem cell (iPSC)-derived microglia (hMGLs) for migration, oAβ phagocytosis, and upregulation of inflammatory …

Ros And Mirna Dysregulation In Ovarian Cancer Development, Angiogenesis And Therapeutic Resistance, David C Stieg, Yifang Wang, Ling-Zhi Liu, Bing-Hua Jiang

Kimmel Cancer Center Faculty Papers

The diverse repertoires of cellular mechanisms that progress certain cancer types are being uncovered by recent research and leading to more effective treatment options. Ovarian cancer (OC) is among the most difficult cancers to treat. OC has limited treatment options, especially for patients diagnosed with late-stage OC. The dysregulation of miRNAs in OC plays a significant role in tumorigenesis through the alteration of a multitude of molecular processes. The development of OC can also be due to the utilization of endogenously derived reactive oxygen species (ROS) by activating signaling pathways such as PI3K/AKT and MAPK. Both miRNAs and ROS are …

Genomic Features Underlie The Co-Option Of Sva Transposons As Cis-Regulatory Elements In Human Pluripotent Stem Cells, Samantha M Barnada, Andrew Isopi, Daniela Tejada-Martinez, Clément Goubert, Sruti Patoori, Luca Pagliaroli, Mason Tracewell, Marco Trizzino

Department of Biochemistry and Molecular Biology Faculty Papers

Domestication of transposable elements (TEs) into functional cis-regulatory elements is a widespread phenomenon. However, the mechanisms behind why some TEs are co-opted as functional enhancers while others are not are underappreciated. SINE-VNTR-Alus (SVAs) are the youngest group of transposons in the human genome, where ~3,700 copies are annotated, nearly half of which are human-specific. Many studies indicate that SVAs are among the most frequently co-opted TEs in human gene regulation, but the mechanisms underlying such processes have not yet been thoroughly investigated. Here, we leveraged CRISPR-interference (CRISPRi), computational and functional genomics to elucidate the genomic features that underlie SVA domestication …

Anxiety Symptoms And Suicidal Thoughts And Behaviors Among Patients With Mood Disorders, Marsal Sanches, Linh K Nguyen, Tong Han Chung, Paul Nestadt, Holly C Wilcox, William H Coryell, Jair C Soares, Sudhakar Selvaraj

Faculty, Staff and Student Publications

Background: Though the association between anxiety disorders and suicidal behavior is well-described, the impact of anxiety symptoms on suicidal thoughts and behaviors (STB) across different mood disorders is still unclear.

Methods: We performed a registry-based retrospective study utilizing outcome measure data collected by the National Network of Depression Centers (NNDC), a nationwide nonprofit consortium of 26 leading clinical and academic member centers in the United States. The sample consisted of 2607 outpatients with mood disorders (major depressive disorder or bipolar disorders). Demographic and clinical variables were compared based on the presence or absence of STB and severity of anxiety symptoms …

B- And T-Cell Subset Abnormalities In Monogenic Common Variable Immunodeficiency, Saba Fekrvand, Shaghayegh Khanmohammadi, Hassan Abolhassani, Reza Yazdani

Department of Neurology Faculty Papers

Common variable immunodeficiency (CVID) is a heterogeneous group of inborn errors of immunity characterized by reduced serum concentrations of different immunoglobulin isotypes. CVID is the most prevalent symptomatic antibody deficiency with a broad range of infectious and non-infectious clinical manifestations. Various genetic and immunological defects are known to be involved in the pathogenesis of CVID. Monogenic defects account for the pathogenesis of about 20-50% of CVID patients, while a variety of cases do not have a defined genetic background. Deficiencies in molecules of B cell receptor signaling or other pathways involving B-cell development, activation, and proliferation could be associated with …

Chemotherapy Coupled To Macrophage Inhibition Induces T-Cell And B-Cell Infiltration And Durable Regression In Triple-Negative Breast Cancer, Swarnima Singh, Nigel Lee, Diego A Pedroza, Igor L Bado, Clark Hamor, Licheng Zhang, Sergio Aguirre, Jingyuan Hu, Yichao Shen, Yitian Xu, Yang Gao, Na Zhao, Shu-Hsia Chen, Ying-Wooi Wan, Zhandong Liu, Jeffrey T Chang, Daniel Hollern, Charles M Perou, Xiang H F Zhang, Jeffrey M Rosen

Duncan NRI Faculty and Staff Publications

Immunosuppressive elements within the tumor microenvironment, such as tumor-associated macrophages (TAM), can present a barrier to successful anti-tumor responses by cytolytic T cells. Here we employed preclinical syngeneic p53 null mouse models of triple-negative breast cancer (TNBC) to develop a treatment regimen that harnessed the immunostimulatory effects of low-dose cyclophosphamide coupled with the pharmacologic inhibition of TAMs using either a small molecule CSF1R inhibitor or an anti-CSF1R antibody. This therapeutic combination was effective in treating several highly aggressive TNBC murine mammary tumor and lung metastasis models. Single cell RNA sequencing characterized tumor-infiltrating lymphocytes (TIL) including helper T cells and antigen-presenting …

Navigation Programs Relevant For African American Men With Prostate Cancer: A Scoping Review Protocol, Nynikka R. Palmer, Ashley Nicole Smith, Brittany A. Campbell, Ghilamichael Andemeskel, Peggy Tahir, Tisha M. Felder Phd, Msw, Barbara Cicerelli

Publications

BACKGROUND:

The excess incidence and mortality due to prostate cancer that impacts African American men constitutes the largest of all cancer disparities. Patient navigation is a patient-centered healthcare system intervention to eliminate barriers to timely, high-quality care across the cancer continuum and improves health outcomes among vulnerable patients. However, little is known regarding the extent to which navigation programs include cultural humility to address prostate cancer disparities among African American men. We present a scoping review protocol of an in-depth examination of navigation programs in prostate cancer care-including navigation activities/procedures, training, and management-with a special focus on cultural context and …

Challenges And Opportunities For Advancing Patient-Centered Clinical Decision Support: Findings From A Horizon Scan, Prashila Dullabh, Shana F Sandberg, Krysta Heaney-Huls, Lauren S Hovey, David F Lobach, Aziz Boxwala, Priyanka J Desai, Elise Berliner, Chris Dymek, Michael I Harrison, James Swiger, Dean F Sittig

Faculty, Staff and Student Publications

OBJECTIVE: We conducted a horizon scan to (1) identify challenges in patient-centered clinical decision support (PC CDS) and (2) identify future directions for PC CDS.

MATERIALS AND METHODS: We engaged a technical expert panel, conducted a scoping literature review, and interviewed key informants. We qualitatively analyzed literature and interview transcripts, mapping findings to the 4 phases for translating evidence into PC CDS interventions (Prioritizing, Authoring, Implementing, and Measuring) and to external factors.

RESULTS: We identified 12 challenges for PC CDS development. Lack of patient input was identified as a critical challenge. The key informants noted that patient input is critical …

Estimating Circadian Phase In Elementary School Children: Leveraging Advances In Physiologically Informed Models Of Circadian Entrainment And Wearable Devices, Jennette P Moreno, Kevin M Hannay, Olivia Walch, Hafza Dadabhoy, Jessica Christian, Maurice Puyau, Abeer El-Mubasher, Fida Bacha, Sarah R Grant, Rebekah Julie Park, Philip Cheng

Faculty, Staff and Students Publications

STUDY OBJECTIVES: Examine the ability of a physiologically based mathematical model of human circadian rhythms to predict circadian phase, as measured by salivary dim light melatonin onset (DLMO), in children compared to other proxy measurements of circadian phase (bedtime, sleep midpoint, and wake time).

METHODS: As part of an ongoing clinical trial, a sample of 29 elementary school children (mean age: 7.4 ± .97 years) completed 7 days of wrist actigraphy before a lab visit to assess DLMO. Hourly salivary melatonin samples were collected under dim light conditions (<5 >lx). Data from actigraphy were used to generate predictions of circadian …

Variants In Asph Cause Exertional Heat Illness And Are Associated With Malignant Hyperthermia Susceptibility, Yukari Endo, Linda Groom, Alper Celik, Natalia Kraeva, Chang Seok Lee, Sung Yun Jung, Lois Gardner, Marie-Anne Shaw, Susan L Hamilton, Philip M Hopkins, Robert T Dirksen, Sheila Riazi, James J Dowling

Faculty, Staff and Students Publications

Exertional heat illness (EHI) and malignant hyperthermia (MH) are life threatening conditions associated with muscle breakdown in the setting of triggering factors including volatile anesthetics, exercise, and high environmental temperature. To identify new genetic variants that predispose to EHI and/or MH, we performed genomic sequencing on a cohort with EHI/MH and/or abnormal caffeine-halothane contracture test. In five individuals, we identified rare, pathogenic heterozygous variants in ASPH, a gene encoding junctin, a regulator of excitation-contraction coupling. We validated the pathogenicity of these variants using orthogonal pre-clinical models, CRISPR-edited C2C12 myotubes and transgenic zebrafish. In total, we demonstrate that ASPH variants represent …

Atr-Mediated Cd47 And Pd-L1 Up-Regulation Restricts Radiotherapy-Induced Immune Priming And Abscopal Responses In Colorectal Cancer, Rodney Cheng-En Hsieh, Sunil Krishnan, Ren-Chin Wu, Akash R Boda, Arthur Liu, Michelle Winkler, Wen-Hao Hsu, Steven Hsesheng Lin, Mien-Chie Hung, Li-Chuan Chan, Krithikaa Rajkumar Bhanu, Anupallavi Srinivasamani, Ricardo Alexandre De Azevedo, Yung-Chih Chou, Ronald A Depinho, Matthew Gubin, Eduardo Vilar, Chao Hsien Chen, Ravaen Slay, Priyamvada Jayaprakash, Shweta Mahendra Hegde, Genevieve Hartley, Spencer T Lea, Rishika Prasad, Brittany Morrow, Coline Agnes Couillault, Madeline Steiner, Chun-Chieh Wang, Bhanu Prasad Venkatesulu, Cullen Taniguchi, Yon Son Betty Kim, Junjie Chen, Nils-Petter Rudqvist, Michael A Curran

Faculty, Staff and Student Publications

Radiotherapy (RT) of colorectal cancer (CRC) can prime adaptive immunity against tumor-associated antigen (TAA)-expressing CRC cells systemically. However, abscopal tumor remissions are extremely rare, and the postirradiation immune escape mechanisms in CRC remain elusive. Here, we found that irradiated CRC cells used ATR-mediated DNA repair signaling pathway to up-regulate both CD47 and PD-L1, which through engagement of SIRPα and PD-1, respectively, prevented phagocytosis by antigen-presenting cells and thereby limited TAA cross-presentation and innate immune activation. This postirradiation CD47 and PD-L1 up-regulation was observed across various human solid tumor cells. Concordantly, rectal cancer patients with poor responses to neoadjuvant RT exhibited …

Systemic Ablation Of Camkk2 Impairs Metastatic Colonization And Improves Insulin Sensitivity In Tramp Mice: Evidence For Cancer Cell-Extrinsic Camkk2 Functions In Prostate Cancer, Thomas L Pulliam, Dominik Awad, Jenny J Han, Mollianne M Murray, Jeffrey J Ackroyd, Pavithr Goli, Jonathan S Oakhill, John W Scott, Michael M Ittmann, Daniel E Frigo

Faculty, Staff and Students Publications

Despite early studies linking calcium-calmodulin protein kinase kinase 2 (CAMKK2) to prostate cancer cell migration and invasion, the role of CAMKK2 in metastasis in vivo remains unclear. Moreover, while CAMKK2 is known to regulate systemic metabolism, whether CAMKK2's effects on whole-body metabolism would impact prostate cancer progression and/or related comorbidities is not known. Here, we demonstrate that germline ablation of

Tomatoes, Lycopene, And Prostate Cancer: What Have We Learned From Experimental Models?, Nancy E Moran, Jennifer M Thomas-Ahner, Lei Wan, Krystle E Zuniga, John W Erdman, Steven K Clinton

Children’s Nutrition Research Center Staff Publications

Human epidemiology suggests a protective effect of tomatoes or tomato phytochemicals, such as lycopene, on prostate cancer risk. However, human epidemiology alone cannot reveal causal relations. Laboratory animal models of prostate cancer provide opportunities to investigate hypotheses regarding dietary components in precisely controlled, experimental systems, contributing to our understanding of diet and cancer risk relations. We review the published studies evaluating the impact of tomatoes and/or lycopene in preclinical models of prostate carcinogenesis and tumorigenesis. The feeding of tomatoes or tomato components demonstrates anti-prostate cancer activity in both transplantable xenograft models of tumorigenesis and models of chemically- and genetically-driven carcinogenesis. …