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Genetic Evaluation For Hereditary Cancer Syndromes Among African Americans: A Critical Review, Ambreen Khan, Charles R Rogers, Carson D Kennedy, Ana Maria Lopez, Joanne Jeter

Department of Medical Oncology Faculty Papers

While hereditary cancer syndromes have been described and studied for centuries, the completion of the human genome project fueled accelerated progress in precision medicine due to the introduction of genetic testing in the 1990s, creating avenues for tailored treatments and medical management options. However, genetic testing has not benefited everyone equitably, with nearly all of the published work based on individuals of non-Hispanic White/European ancestry. There remains a gap in knowledge regarding the prevalence, penetrance, and manifestations of common hereditary cancer syndromes in the African-American population due to significant disparities in access and uptake of genetic testing. This review summarizes …

Overcrowded Housing Increases Risk For Covid-19 Mortality: An Ecological Study, Karan Varshney, Talia Glodjo, Jenna R Adalbert

College of Population Health Faculty Papers

Objectives: Overcrowded housing is a sociodemographic variable associated with increased infection and mortality rates from communicable diseases. It is not well understood if this association exists for COVID-19. Our objective was hence to determine the association between household overcrowding and risk of mortality from COVID-19, and this was done by performing bivariable and multivariable analyses using COVID-19 data from cities in Los Angeles County.

Results: Bivariate regression revealed that overcrowded households were positively associated with COVID-19 deaths (standardized β = 0.863, p < 0.001). COVID-19 case totals, people aged 60+, and the number of overcrowded households met conditions for inclusion in the backwards stepwise linear regression model. Analysis revealed all independent variables were positively associated with mortality rates, primarily for individuals 60 + (standardized β1 = 0.375, p = 0.001), followed by overcrowded households (standardized β2 = 0.346, p = 0.014), and total COVID-19 cases (standardized β3 = 0.311, p < 0.001). Our findings highlight that residing in overcrowded households may be an important risk factor for COVID-19 mortality. Public health entities should consider this population when allocating resources for prevention and control of COVID-19 mortality and future disease outbreaks.

Overcrowded Housing Increases Risk For Covid-19 Mortality: An Ecological Study., Karan Varshney, Talia Glodjo, Jenna Adalbert

College of Population Health Faculty Papers

OBJECTIVES: Overcrowded housing is a sociodemographic variable associated with increased infection and mortality rates from communicable diseases. It is not well understood if this association exists for COVID-19. Our objective was hence to determine the association between household overcrowding and risk of mortality from COVID-19, and this was done by performing bivariable and multivariable analyses using COVID-19 data from cities in Los Angeles County.

RESULTS: Bivariate regression revealed that overcrowded households were positively associated with COVID-19 deaths (standardized β = 0.863, p < 0.001). COVID-19 case totals, people aged 60+, and the number of overcrowded households met conditions for inclusion in the backwards stepwise linear regression model. Analysis revealed all independent variables were positively associated with mortality rates, primarily for individuals 60 + (standardized β

Auriculocondylar Syndrome 2 Results From The Dominant-Negative Action Of Plcb4 Variants., Stanley M Kanai, Caleb Heffner, Timothy C Cox, Michael L Cunningham, Francisco A Perez, Aaron M Bauer, Philip Reigan, Cristan Carter, Stephen A Murray, David E Clouthier

Faculty Research 2022

Auriculocondylar syndrome 2 (ARCND2) is a rare autosomal dominant craniofacial malformation syndrome linked to multiple genetic variants in the coding sequence of phospholipase C β4 (PLCB4). PLCB4 is a direct signaling effector of the endothelin receptor type A (EDNRA)-Gq/11 pathway, which establishes the identity of neural crest cells (NCCs) that form lower jaw and middle ear structures. However, the functional consequences of PLCB4 variants on EDNRA signaling is not known. Here, we show, using multiple signaling reporter assays, that known PLCB4 variants resulting from missense mutations exert a dominant-negative interference over EDNRA signaling. In addition, using CRISPR/Cas9, we find that …

Facilitators And Barriers To Pediatric Clinical Trial Recruitment And Retention In Rural And Community Settings: A Scoping Review Of The Literature, Sara E. Watson, Paul Smith, Jessica Snowden, Vida Vaughn, Lesley Cottrell, Christi A. Madden, Alberta S. Kong, Russell Mcculloh, Crystal Stack Lim, Megan Bledsoe, Karen Kowal, Mary Mcnally, Lisa Knight, Kelly Cowan, Elizabeth Yakes Jimenez

Pediatrics Research and Scholarship

Children in rural settings are under-represented in clinical trials, potentially contributing to rural health disparities. We performed a scoping review describing available literature on barriers and facilitators impacting participation in pediatric clinical trials in rural and community-based (nonclinical) settings. Articles identified via PubMed, CINAHL, Embase, and Web of Science were independently double-screened at title/abstract and full-text levels to identify articles meeting eligibility criteria. Included articles reported on recruitment or retention activities for US-based pediatric clinical studies conducted in rural or community-based settings and were published in English through January 2021. Twenty-seven articles describing 31 studies met inclusion criteria. Most articles …

Examining 24-Hour Activity And Sleep Behaviors And Related Determinants In Latino Adolescents And Young Adults With Obesity, Erica G Soltero, Neeku Navabi, Kiley B Vander Wyst, Edith Hernandez, Felipe G Castro, Stephanie L Ayers, Jenny Mendez, Gabriel Q Shaibi

Children’s Nutrition Research Center Staff Publications

Background.

Few studies have examined 24-hour activity and sleep behaviors and their contribution to type 2 diabetes (T2D) in Latino adolescents and young adults with obesity.

Aim.

This study included quantitative data on T2D risk and 24-hour activity and sleep behaviors and qualitative data on individual, social, and environmental behavioral determinants.

Method.

A 7 day, 24-hour, wrist-worn accelerometer protocol assessed moderate-to-vigorous physical activity (PA), sedentary behaviors (SB), sleep, and sleep regularity, in adolescents (N = 38; 12–16 years) and young adults (N = 22; 18–22 years). T2D-related outcomes included adiposity (BMI, BF%, waist circumference), fasting, and 2-hour glucose. …

Notch-Induced Mdsc Recruitment After Ohsv Virotherapy In Cns Cancer Models Modulates Antitumor Immunotherapy, Yoshihiro Otani, Ji Young Yoo, Cole T Lewis, Samantha Chao, Jessica Swanner, Toshihiko Shimizu, Jin Muk Kang, Sara A Murphy, Kimberly Rivera-Caraballo, Bangxing Hong, Joseph C Glorioso, Hiroshi Nakashima, Sean E Lawler, Yeshavanth Banasavadi-Siddegowda, John D Heiss, Yuanqing Yan, Guangsheng Pei, Michael A Caligiuri, Zhongming Zhao, E Antonio Chiocca, Jianhua Yu, Balveen Kaur

Faculty, Staff and Student Publications

PURPOSE: Oncolytic herpes simplex virus-1 (oHSV) infection of brain tumors activates NOTCH, however the consequences of NOTCH on oHSV-induced immunotherapy is largely unknown. Here we evaluated the impact of NOTCH blockade on virus-induced immunotherapy.

EXPERIMENTAL DESIGN: RNA sequencing (RNA-seq), TCGA data analysis, flow cytometry, Luminex- and ELISA-based assays, brain tumor animal models, and serum analysis of patients with recurrent glioblastoma (GBM) treated with oHSV was used to evaluate the effect of NOTCH signaling on virus-induced immunotherapy.

RESULTS: TCGA data analysis of patients with grade IV glioma and oHSV treatment of experimental brain tumors in mice showed that NOTCH signaling significantly …

Disrupting The Myc-Tfeb Circuit Impairs Amino Acid Homeostasis And Provokes Metabolic Anergy, Mario R Fernandez, Franz X Schaub, Chunying Yang, Weimin Li, Seongseok Yun, Stephanie K Schaub, Frank C Dorsey, Min Liu, Meredith A Steeves, Andrea Ballabio, Alexandar Tzankov, Zhihua Chen, John M Koomen, Anders E Berglund, John L Cleveland

Duncan NRI Faculty and Staff Publications

MYC family oncoproteins are regulators of metabolic reprogramming that sustains cancer cell anabolism. Normal cells adapt to nutrient-limiting conditions by activating autophagy, which is required for amino acid (AA) homeostasis. Here we report that the autophagy pathway is suppressed by Myc in normal B cells, in premalignant and neoplastic B cells of Eμ-Myc transgenic mice, and in human MYC-driven Burkitt lymphoma. Myc suppresses autophagy by antagonizing the expression and function of transcription factor EB (TFEB), a master regulator of autophagy. Mechanisms that sustained AA pools in MYC-expressing B cells include coordinated induction of the proteasome and increases in AA …

Antimicrobial Susceptibility Testing For Helicobacter Pylori Is Now Widely Available: When, How, Why, David Y Graham, Steven F Moss

Faculty, Staff and Students Publications

No abstract provided.

Retinal Organoids Derived From Rhesus Macaque Ipscs Undergo Accelerated Differentiation Compared To Human Stem Cells, Antonio Jacobo Lopez, Sangbae Kim, Xinye Qian, Jeffrey Rogers, J Timothy Stout, Sara M Thomasy, Anna La Torre, Rui Chen, Ala Moshiri

Faculty, Staff and Students Publications

PURPOSE: To compare the timing and efficiency of the development of Macaca mulatta, a nonhuman primate (NHP), induced pluripotent stem cell (rhiPSC) derived retinal organoids to those derived from human embryonic stem cells (hESCs).

RESULTS: Generation of retinal organoids was achieved from both human and several NHP pluripotent stem cell lines. All rhiPSC lines resulted in retinal differentiation with the formation of optic vesicle-like structures similar to what has been observed in hESC retinal organoids. NHP retinal organoids had laminated structure and were composed of mature retinal cell types including cone and rod photoreceptors. Single-cell RNA sequencing was conducted at …

Changes In Physical Activity Associated With The Covid-19 Pandemic In Individuals With Overweight And Obesity: An Interrupted Time Series Analysis With Historical Controls, Michael C Robertson, Che Young Lee, Ivan Haw-Chong Wu, Yue Liao, Margaret Raber, Nathan Parker, Thuan Le, Leticia Gatus, Karen M Basen-Engquist

Faculty, Staff and Students Publications

The objective of this study was to investigate changes in physical activity patterns associated with the COVID-19 pandemic in individuals with overweight and obesity who were participating in a school district worksite weight loss program. We conducted comparative design interrupted time series analyses on physical activity device (Fitbit) data from the 2018-2019 and 2019-2020 school years (N = 211). We administered a questionnaire in 2020 to supplement device data. After the stay-at-home orders in 2020, participants tended to decrease their weekly step count (B = -1315.7, SE = 627.7, p = .045), decrease their weekly "Lightly active minutes" (B = …

Target To Treatment: A Charge To Develop Biomarkers Of Response And Tolerability In Child And Adolescent Psychiatry., Stephani L. Stancil, John Tumberger, Jeffrey R. Strawn

Manuscripts, Articles, Book Chapters and Other Papers

The current pediatric mental health crisis is characterized by staggering rates of depression, anxiety, and suicide. Beyond this, first-line pharmacologic interventions for depressive and anxiety disorders in children and adolescents produce variable responses with two in five youths failing to respond. Given the heterogeneity of treatment response in pediatric depressive and anxiety disorders, pharmacodynamic biomarkers are necessary to develop precision therapeutics by identifying clear targets to guide treatment. This mini-review summarizes candidate biomarkers and their development in pediatric mental health conditions. A framework for how these biomarkers may relate to safety, efficacy (e.g., surrogates for clinical endpoints), tolerability or target …

Facilitators And Barriers To Pediatric Clinical Trial Recruitment And Retention In Rural And Community Settings: A Scoping Review Of The Literature., Sara E. Watson, Paul Smith, Jessica Snowden, Vida Vaughn, Lesley Cottrell, Christi A. Madden, Alberta S. Kong, Russell Mcculloh, Crystal Stack Lim, Megan Bledsoe, Karen Kowal, Mary Mcnally, Lisa Knight, Kelly Cowan, Elizabeth Yakes Jimenez

Manuscripts, Articles, Book Chapters and Other Papers

Children in rural settings are under-represented in clinical trials, potentially contributing to rural health disparities. We performed a scoping review describing available literature on barriers and facilitators impacting participation in pediatric clinical trials in rural and community-based (nonclinical) settings. Articles identified via PubMed, CINAHL, Embase, and Web of Science were independently double-screened at title/abstract and full-text levels to identify articles meeting eligibility criteria. Included articles reported on recruitment or retention activities for US-based pediatric clinical studies conducted in rural or community-based settings and were published in English through January 2021. Twenty-seven articles describing 31 studies met inclusion criteria. Most articles …

Predictive Radiation Oncology - A New Nci-Doe Scientific Space And Community, Jeffrey C Buchsbaum, David A Jaffray, Demba Ba, Lynn L Borkon, Christine Chalk, Caroline Chung, Matthew A Coleman, C Norman Coleman, Maximilian Diehn, Kelvin K Droegemeier, Heiko Enderling, Michael G Espey, Emily J Greenspan, Christopher M Hartshorn, Thuc Hoang, H Timothy Hsiao, Cynthia Keppel, Nathan W Moore, Fred Prior, Eric A Stahlberg, Georgia Tourassi, Karen E Willcox

Faculty, Staff and Student Publications

With a widely attended virtual kickoff event on January 29, 2021, the National Cancer Institute (NCI) and the Department of Energy (DOE) launched a series of 4 interactive, interdisciplinary workshops-and a final concluding "World Café" on March 29, 2021-focused on advancing computational approaches for predictive oncology in the clinical and research domains of radiation oncology. These events reflect 3,870 human hours of virtual engagement with representation from 8 DOE national laboratories and the Frederick National Laboratory for Cancer Research (FNL), 4 research institutes, 5 cancer centers, 17 medical schools and teaching hospitals, 5 companies, 5 federal agencies, 3 research centers, …

Loss Of Rnf43 Accelerates Kras-Mediated Neoplasia And Remodels The Tumor Immune Microenvironment In Pancreatic Adenocarcinoma, Abdel Nasser Hosein, Gita Dangol, Takashi Okumura, Jason Roszik, Kimal Rajapakshe, Megan Siemann, Mohamed Zaid, Bidyut Ghosh, Maria Monberg, Paola A Guerrero, Aatur Singhi, Cara L Haymaker, Hans Clevers, Lotfi Abou-Elkacem, Sonja M Woermann, Anirban Maitra

Faculty, Staff and Student Publications

Background & aims: RNF43 is an E3 ubiquitin ligase that is recurrently mutated in pancreatic ductal adenocarcinoma (PDAC) and precursor cystic neoplasms of the pancreas. The impact of RNF43 mutations on PDAC is poorly understood and autochthonous models have not been characterized sufficiently. In this study, we describe a genetically engineered mouse model (GEMM) of PDAC with conditional expression of oncogenic Kras and deletion of the catalytic domain of Rnf43 in exocrine cells.

Methods: We generated Ptf1a-Cre;LSL-KrasG12D;Rnf43flox/flox (KRC) and Ptf1a-Cre; LSL-KrasG12D (KC) mice and animal survival was assessed. KRC mice were sacrificed at 2 months, 4 months, and at moribund …

Fluvoxamine For Outpatient Management Of Covid-19 To Prevent Hospitalization: A Systematic Review And Meta-Analysis, Todd C Lee, Simone Vigod, Émilie Bortolussi-Courval, Ryan Hanula, David R Boulware, Eric J Lenze, Angela M Reiersen, Emily G Mcdonald

2020-Current year OA Pubs

Importance: Widely available and affordable options for the outpatient management of COVID-19 are needed, particularly for therapies that prevent hospitalization.

Objective: To perform a meta-analysis of the available randomized clinical trial evidence for fluvoxamine in the outpatient management of COVID-19.

Data Sources: World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov.

Study Selection: Studies with completed outpatient trials with available results that compared fluvoxamine with placebo were included.

Data Extraction and Synthesis: The PRISMA 2020 guidelines were followed and study details in terms of inclusion criteria, trial demographics, and the prespecified outcome of all-cause hospitalization were extracted. Risk of …

Inhibiting Type I Arginine Methyltransferase Activity Promotes T Cell-Mediated Antitumor Immune Responses, Andrew Fedoriw, Leilei Shi, Shane O'Brien, Kimberly N Smitheman, Yunfei Wang, Jiakai Hou, Christian Sherk, Satyajit Rajapurkar, Jenny Laraio, Leila J Williams, Chunyu Xu, Guangchun Han, Qin Feng, Mark T Bedford, Linghua Wang, Olena Barbash, Ryan G Kruger, Patrick Hwu, Helai P Mohammad, Weiyi Peng

Faculty, Staff and Student Publications

Protein arginine methyltransferases (PRMT) are a widely expressed class of enzymes responsible for catalyzing arginine methylation on numerous protein substrates. Among them, type I PRMTs are responsible for generating asymmetric dimethylarginine. By controlling multiple basic cellular processes, such as DNA damage responses, transcriptional regulation, and mRNA splicing, type I PRMTs contribute to cancer initiation and progression. A type I PRMT inhibitor, GSK3368715, has been developed and has entered clinical trials for solid and hematologic malignancies. Although type I PRMTs have been reported to play roles in modulating immune cell function, the immunologic role of tumor-intrinsic pathways controlled by type I …

Effect Of Perfluorocarbon Composition On Activation Of Phase-Changing Ultrasound Contrast Agents, Trevor M Mitcham, Dmitry Nevozhay, Yunyun Chen, Linh D Nguyen, Gianmarco F Pinton, Stephen Y Lai, Konstantin V Sokolov, Richard R Bouchard

Faculty, Staff and Student Publications

BACKGROUND: While microbubble contrast agents (MCAs) are commonly used in ultrasound (US), they are inherently limited to vascular targets due to their size. Alternatively, phase-changing nanodroplet contrast agents (PNCAs) can be delivered as nanoscale agents (i.e., small enough to extravasate), but when exposed to a US field of sufficient mechanical index (MI), they convert to MCAs, which can be visualized with high contrast using nonlinear US.

PURPOSE: To investigate the effect of perfluorocarbon (PFC) core composition and presence of cholesterol in particle coatings on stability and image contrast generated from acoustic activation of PNCAs using high-frequency US suitable for clinical …

Development And Characterization Of Anti-Galectin-9 Antibodies That Protect T Cells From Galectin-9-Induced Cell Death, Riyao Yang, Linlin Sun, Ching-Fei Li, Yu-Han Wang, Weiya Xia, Boning Liu, Yu-Yi Chu, Laura Bover, Long Vien, Mien-Chie Hung

Faculty, Staff and Student Publications

Antibodies that target immune checkpoint proteins such as programmed cell death protein 1, programmed death ligand 1, and cytotoxic T-lymphocyte-associated antigen 4 in human cancers have achieved impressive clinical success; however, a significant proportion of patients fail to respond to these treatments. Galectin-9 (Gal-9), a β-galactoside-binding protein, has been shown to induce T-cell death and facilitate immunosuppression in the tumor microenvironment by binding to immunomodulatory receptors such as T-cell immunoglobulin and mucin domain-containing molecule 3 and the innate immune receptor dectin-1, suggesting that it may have potential as a target for cancer immunotherapy. Here, we report the development of two …

Differential Function And Maturation Of Human Stem Cell-Derived Islets After Transplantation, Kristina G Maxwell, Michelle H Kim, Sarah E Gale, Jeffrey R Millman

2020-Current year OA Pubs

Insulin-producing stem cell-derived islets (SC-islets) provide a virtually unlimited cell source for diabetes cell replacement therapy. While SC-islets are less functional when first differentiated in vitro compared to isolated cadaveric islets, transplantation into mice has been shown to increase their maturation. To understand the effects of transplantation on maturation and function of SC-islets, we examined the effects of cell dose, transplantation strategy, and diabetic state in immunocompromised mice. Transplantation of 2 and 5, but not 0.75 million SC-islet cells underneath the kidney capsule successfully reversed diabetes in mice with pre-existing diabetes. SQ and intramuscular injections failed to reverse diabetes at …

Cistrome And Transcriptome Analysis Identifies Unique Androgen Receptor (Ar) And Ar-V7 Splice Variant Chromatin Binding And Transcriptional Activities, Paul Basil, Matthew J Robertson, William E Bingman, Amit K Dash, William C Krause, Ayesha A Shafi, Badrajee Piyarathna, Cristian Coarfa, Nancy L Weigel

Faculty, Staff and Students Publications

The constitutively active androgen receptor (AR) splice variant, AR-V7, plays an important role in resistance to androgen deprivation therapy in castration resistant prostate cancer (CRPC). Studies seeking to determine whether AR-V7 is a partial mimic of the AR, or also has unique activities, and whether the AR-V7 cistrome contains unique binding sites have yielded conflicting results. One limitation in many studies has been the low level of AR variant compared to AR. Here, LNCaP and VCaP cell lines in which AR-V7 expression can be induced to match the level of AR, were used to compare the activities of AR and …

Mutations Of The Dna Repair Gene Pnkp In A Patient With Microcephaly, Seizures, And Developmental Delay (Mcsz) Presenting With A High-Grade Brain Tumor, Bingcheng Jiang, Cameron Murray, Bonnie L Cole, J N Mark Glover, Gordon K Chan, Jean Deschenes, Rajam S Mani, Sudip Subedi, John D Nerva, Anthony C Wang, Christina M Lockwood, Heather C Mefford, Sarah E S Leary, Jeffery G Ojemann, Michael Weinfeld, Chibawanye I Ene

Faculty, Staff and Student Publications

Polynucleotide Kinase-Phosphatase (PNKP) is a bifunctional enzyme that possesses both DNA 3'-phosphatase and DNA 5'-kinase activities, which are required for processing termini of single- and double-strand breaks generated by reactive oxygen species (ROS), ionizing radiation and topoisomerase I poisons. Even though PNKP is central to DNA repair, there have been no reports linking PNKP mutations in a Microcephaly, Seizures, and Developmental Delay (MSCZ) patient to cancer. Here, we characterized the biochemical significance of 2 germ-line point mutations in the PNKP gene of a 3-year old male with MSCZ who presented with a high-grade brain tumor (glioblastoma multiforme) within the cerebellum. …

Anti-Tumor Activity Of Cetuximab Plus Avelumab In Non-Small Cell Lung Cancer Patients Involves Innate Immunity Activation: Findings From The Cave-Lung Trial, Carminia Maria Della Corte, Morena Fasano, Vincenza Ciaramella, Flora Cimmino, Robert Cardnell, Carl M Gay, Kavya Ramkumar, Lixia Diao, Raimondo Di Liello, Giuseppe Viscardi, Vincenzo Famiglietti, Davide Ciardiello, Giulia Martini, Stefania Napolitano, Concetta Tuccillo, Teresa Troiani, Erika Martinelli, Jing Wang, Lauren Byers, Floriana Morgillo, Fortunato Ciardiello

Faculty, Staff and Student Publications

BACKGROUND: We recently conducted Cetuximab-AVElumab-Lung (CAVE-Lung), a proof-of-concept, translational and clinical trial, to evaluate the combination of two IgG1 monoclonal antibodies (mAb): avelumab, an anti-PD-L1 drug, and cetuximab, an anti-epidermal growth factor receptor (EGFR) drug, as second- or third-line treatment in non-small cell lung cancer (NSCLC) patients. We have reported clinically relevant anti-tumor activity in 6/16 patients. Clinical benefit was accompanied by Natural Killer (NK) cell-mediated antibody-dependent cell cytotoxicity (ADCC). Among the 6 responding patients, 3 had progressed after initial response to a previous treatment with single agent anti-PD-1, nivolumab or pembrolizumab.

METHODS: We report long-term clinical follow-up and additional …

Mitochondrial Phenotypes In Genetically Diverse Neurodegenerative Diseases And Their Response To Mitofusin Activation, Xiawei Dang, Emily K Walton, Barbara Zablocka, Robert H Baloh, Michael E Shy, Gerald W Dorn Ii

Open Access Publications

Mitochondrial fusion is essential to mitochondrial fitness and cellular health. Neurons of patients with genetic neurodegenerative diseases often exhibit mitochondrial fragmentation, reflecting an imbalance in mitochondrial fusion and fission (mitochondrial dysdynamism). Charcot-Marie-Tooth (CMT) disease type 2A is the prototypical disorder of impaired mitochondrial fusion caused by mutations in the fusion protein mitofusin (MFN)2. Yet, cultured CMT2A patient fibroblast mitochondria are often reported as morphologically normal. Metabolic stress might evoke pathological mitochondrial phenotypes in cultured patient fibroblasts, providing a platform for the pre-clinical individualized evaluation of investigational therapeutics. Here, substitution of galactose for glucose in culture media was used to redirect …

Skp2 Stabilizes Mcl-1 And Confers Radioresistance In Colorectal Cancer, Xinfang Yu, Li Zhou, Wenbin Liu, Lijun Liu, Feng Gao, Wei Li, Haidan Liu

Faculty, Staff and Students Publications

Overexpression of Skp2 plays a critical role in tumorigenesis and correlates with poor prognosis in human malignancies. Thus, Skp2 has been proposed as an attractive target for anti-tumor interventions. The expression of Skp2 in human colorectal cancer (CRC) and the role of Skp2 in tumorigenic properties and irradiation sensitivities of CRC cells were examined by anchorage-dependent and -independent growth assays, immunoblot, flow cytometry, immunohistochemical staining, ubiquitination analysis, co-immunoprecipitation assay, CRISPR-Cas9-based gene knockout, and xenograft experiments. Skp2 is highly expressed in CRC patient tissues. Blocking Skp2 expression reduces the tumorigenic properties of CRC cells in vitro and in vivo. Depletion of …

Adherence Enables Neisseria Gonorrhoeae To Overcome Zinc Limitation Imposed By Nutritional Immunity Proteins, Jocelyn C Ray, Asya Smirnov, Stavros A Maurakis, Simone A Harrison, Eugene Ke, Walter J Chazin, Cynthia Nau Cornelissen, Alison K Criss

Open Access Publications

Neisseria gonorrhoeae (Gc) must overcome the limitation of metals such as zinc to colonize mucosal surfaces in its obligate human host. While the zinc-binding nutritional immunity proteins calprotectin (S100A8/A9) and psoriasin (S100A7) are abundant in human cervicovaginal lavage fluid, Gc possesses TonB-dependent transporters TdfH and TdfJ that bind and extract zinc from the human version of these proteins, respectively. Here we investigated the contribution of zinc acquisition to Gc infection of epithelial cells of the female genital tract. We found that TdfH and TdfJ were dispensable for survival of strain FA1090 Gc that was associated with Ect1 human immortalized epithelial …

Metronidazole Treatment Rapidly Reduces Genital Inflammation Through Effects On Bacterial Vaginosis-Associated Bacteria Rather Than Lactobacilli, Eric Armstrong, Hilary Reno, Et Al.

2020-Current year OA Pubs

BackgroundBacterial vaginosis (BV) causes genital inflammation and increases HIV risk, whereas a vaginal microbiota dominated by Lactobacillus species is associated with immune quiescence and relative HIV protection. BV treatment reduces genital inflammation, but it is unclear whether this reduction is driven by a decrease in BV-associated bacteria or an increase in Lactobacillus species.METHODSTo evaluate the short-term effect of standard BV treatment on genital immunology and the vaginal microbiota, vaginal swabs were collected immediately before and after metronidazole treatment for BV and analyzed with multiplex ELISA, metagenomic sequencing, and quantitative PCR.RESULTSTopical metronidazole treatment rapidly reduced vaginal levels of proinflammatory cytokines, chemokines, …

Considerations For The Use Of Phage Therapy In Clinical Practice, Gina A Suh, Thomas P Lodise, Pranita D Tamma, Jane M Knisely, Jose Alexander, Saima Aslam, Karen D Barton, Erica Bizzell, Katherine M C Totten, Joseph L Campbell, Benjamin K Chan, Scott A Cunningham, Katherine E Goodman, Kerryl E Greenwood-Quaintance, Anthony D Harris, Shayla Hesse, Anthony Maresso, Veronique Nussenblatt, David Pride, Michael J Rybak, Zoe Sund, David Van Duin, Daria Van Tyne, Robin Patel

Faculty, Staff and Students Publications

Increasing antimicrobial resistance and medical device-related infections have led to a renewed interest in phage therapy as an alternative or adjunct to conventional antimicrobials. Expanded access and compassionate use cases have risen exponentially but have varied widely in approach, methodology, and clinical situations in which phage therapy might be considered. Large gaps in knowledge contribute to heterogeneity in approach and lack of consensus in many important clinical areas. The Antibacterial Resistance Leadership Group (ARLG) has convened a panel of experts in phage therapy, clinical microbiology, infectious diseases, and pharmacology, who worked with regulatory experts and a funding agency to identify …

T-Cell Responses To Immunodominant Listeria Epitopes Limit Vaccine-Directed Responses To The Colorectal Cancer Antigen, Guanylyl Cyclase C, John C. Flickinger, Jagmohan Singh, Yanki Yarman, Robert D Carlson, Joshua Barton, Scott A Waldman, Adam E. Snook

Department of Pharmacology and Experimental Therapeutics Faculty Papers

The Gram-positive bacterium Listeria monocytogenes (Lm) is an emerging platform for cancer immunotherapy. To date, over 30 clinical trials have been initiated testing Lm cancer vaccines across a wide variety of cancers, including lung, cervical, colorectal, and pancreatic. Here, we assessed the immunogenicity of an Lm vaccine against the colorectal tumor antigen GUCY2C (Lm-GUCY2C). Surprisingly, Lm-GUCY2C vaccination did not prime naïve GUCY2C-specific CD8+ T-cell responses towards the dominant H-2Kd-restricted epitope, GUCY2C254-262. However, Lm-GUCY2C produced robust CD8+ T-cell responses towards Lm-derived peptides suggesting that GUCY2C254-262 peptide may be subdominant to Lm-derived peptides. Indeed, incorporating immunogenic Lm peptides into an adenovirus-based GUCY2C …

Elucidating Mechanisms Of Genetic Cross-Disease Associations At The Procr Vascular Disease Locus, David Stacey, Lingyan Chen, Paulina J Stanczyk, Joanna M M Howson, Amy M Mason, Stephen Burgess, Stephen Macdonald, Jonathan Langdown, Harriett Mckinney, Kate Downes, Neda Farahi, James E Peters, Saonli Basu, James S Pankow, Weihong Tang, Nathan Pankratz, Maria Sabater-Lleal, Paul S De Vries, Nicholas L Smith, Amy D Gelinas, Daniel J Schneider, Nebojsa Janjic, Nilesh J Samani, Shu Ye, Charlotte Summers, Edwin R Chilvers, John Danesh, Dirk S Paul

Faculty, Staff and Student Publications

Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, …