Digital Commons Network^™

Are The Post-Covid-19 Posttraumatic Stress Disorder (Ptsd) Symptoms Justified By The Effects Of Covid-19 On Brain Structure? A Systematic Review, Georgios D Kotzalidis, Ottavia Marianna Ferrara, Stella Margoni, Valentina Ieritano, Antonio Restaino, Evelina Bernardi, Alessia Fischetti, Antonello Catinari, Laura Monti, Daniela Pia Rosaria Chieffo, Alessio Simonetti, Gabriele Sani

Faculty, Staff and Students Publications

COVID-19 affects brain function, as deduced by the "brain fog" that is often encountered in COVID-19 patients and some cognitive impairment that is observed in many a patient in the post-COVID-19 period. Approximately one-third of patients, even when they have recovered from the acute somatic disease, continue to show posttraumatic stress disorder (PTSD) symptoms. We hypothesized that the persistent changes induced by COVID-19 on brain structure would overlap with those associated with PTSD. We performed a thorough PubMed search on 25 April 2023 using the following strategy: ((posttraumatic OR PTSD) AND COVID-19 AND (neuroimaging OR voxel OR VBM OR freesurfer …

Phase 1b Study Of Combined Selinexor And Eribulin For The Treatment Of Advanced Solid Tumors And Triple-Negative Breast Cancer, Blessie Elizabeth Nelson, Sadia Saleem, Senthil Damodaran, Neeta Somaiah, Sarina Piha-Paul, Julia Ann Moore, Bulent Yilmaz, Deby Ogbonna, Daniel D Karp, Ecaterina Dumbrava, Apostolia M Tsimberidou, David S Hong, Jordi Rodon Ahnert, Denái R Milton, Xiaofeng Zheng, Daniel J Booser, Nuhad K Ibrahim, Anthony P Conley, Priya Bhosale, Cristhiam M Rojas Hernandez, Debasish Tripathy, Aung Naing, Funda Meric-Bernstam

Faculty, Staff and Student Publications

BACKGROUND: Selinexor (KPT-330) is a potent inhibitor of exportin 1 (XPO1), in turn inhibiting tumor growth. Selinexor enhances the antitumor efficacy of eribulin in triple-negative breast cancer (TNBC) in vitro and in vivo. Given the unmet medical need in TNBC and sarcoma, the authors explored the safety and efficacy of this combination.

METHODS: The authors conducted a phase 1b trial of combined selinexor and eribulin using a 3 + 3 dose-escalation design in patients who had advanced solid tumors and in those who had TNBC in a dose-expansion cohort.

RESULTS: Patients with TNBC (N = 19), sarcoma (N = 9), …

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

Faculty, Staff and Student Publications

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

Five-Year Patient-Reported Outcomes In Nrg Oncology Rtog 0938, Evaluating Two Ultrahypofractionated Regimens For Prostate Cancer, Himanshu R Lukka, Snehal Deshmukh, Deborah W Bruner, Jean-Paul Bahary, Colleen A F Lawton, Jason A Efstathiou, Rajat J Kudchadker, Lee E Ponsky, Samantha A Seaward, Ian S Dayes, Darindra D Gopaul, Jeff M Michalski, Guila Delouya, Irving D Kaplan, Eric M Horwitz, Mack Roach, Felix Y Feng, Stephanie L Pugh, Howard M Sandler, Lisa A Kachnic

Faculty, Staff and Student Publications

PURPOSE: There is considerable interest in very short (ultrahypofractionated) radiation therapy regimens to treat prostate cancer based on potential radiobiological advantages, patient convenience, and resource allocation benefits. Our objective is to demonstrate that detectable changes in health-related quality of life measured by the bowel and urinary domains of the Expanded Prostate Cancer Index Composite (EPIC-50) were not substantially worse than baseline scores.

METHODS AND MATERIALS: NRG Oncology's RTOG 0938 is a nonblinded randomized phase 2 study of National Comprehensive Cancer Network low-risk prostate cancer in which each arm is compared with a historical control. Patients were randomized to 5 fractions …

Actionability Classification Of Variants Of Unknown Significance Correlates With Functional Effect, Amber Johnson, Patrick Kwok-Shing Ng, Michael Kahle, Julia Castillo, Bianca Amador, Yujia Wang, Jia Zeng, Vijaykumar Holla, Thuy Vu, Fei Su, Sun-Hee Kim, Tara Conway, Xianli Jiang, Ken Chen, Kenna R Mills Shaw, Timothy A Yap, Jordi Rodon, Gordon B Mills, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Genomically-informed therapy requires consideration of the functional impact of genomic alterations on protein expression and/or function. However, a substantial number of variants are of unknown significance (VUS). The MD Anderson Precision Oncology Decision Support (PODS) team developed an actionability classification scheme that categorizes VUS as either "Unknown" or "Potentially" actionable based on their location within functional domains and/or proximity to known oncogenic variants. We then compared PODS VUS actionability classification with results from a functional genomics platform consisting of mutant generation and cell viability assays. 106 (24%) of 438 VUS in 20 actionable genes were classified as oncogenic in functional …

The Cerebellum Contributes To Generalized Seizures By Altering Activity In The Ventral Posteromedial Nucleus, Jaclyn Beckinghausen, Joshua Ortiz-Guzman, Tao Lin, Benjamin Bachman, Luis E Salazar Leon, Yu Liu, Detlef H Heck, Benjamin R Arenkiel, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Thalamo-cortical networks are central to seizures, yet it is unclear how these circuits initiate seizures. We test whether a facial region of the thalamus, the ventral posteromedial nucleus (VPM), is a source of generalized, convulsive motor seizures and if convergent VPM input drives the behavior. To address this question, we devise an in vivo optogenetic mouse model to elicit convulsive motor seizures by driving these inputs and perform single-unit recordings during awake, convulsive seizures to define the local activity of thalamic neurons before, during, and after seizure onset. We find dynamic activity with biphasic properties, raising the possibility that heterogenous …

An Observational Study To Develop A Predictive Model For Bacterial Pneumonia Diagnosis In Severe Covid-19 Patients-C19-Pneumoscore, Eloisa Sofia Tanzarella, Joel Vargas, Marco Menghini, Stefania Postorino, Francesca Pozzana, Maria Sole Vallecoccia, Francesco Lorenzo De Matteis, Federico Franchi, Amato Infante, Luigi Larosa, Maria Antonietta Mazzei, Salvatore Lucio Cutuli, Domenico Luca Grieco, Alessandra Bisanti, Simone Carelli, Gianmarco Lombardi, Edoardo Piervincenzi, Gabriele Pintaudi, Tommaso Pirronti, Mario Tumbarello, Massimo Antonelli, Gennaro De Pascale

Faculty, Staff and Student Publications

In COVID-19 patients, antibiotics overuse is still an issue. A predictive scoring model for the diagnosis of bacterial pneumonia at intensive care unit (ICU) admission would be a useful stewardship tool. We performed a multicenter observational study including 331 COVID-19 patients requiring invasive mechanical ventilation at ICU admission; 179 patients with bacterial pneumonia; and 152 displaying negative lower-respiratory samplings. A multivariable logistic regression model was built to identify predictors of pulmonary co-infections, and a composite risk score was developed using β-coefficients. We identified seven variables as predictors of bacterial pneumonia: vaccination status (OR 7.01; 95% CI, 1.73-28.39); chronic kidney disease …

Molecular Dissection And Testing Of Prss37 Function Through Lc-Ms/Ms And The Generation Of A Prss37 Humanized Mouse Model, Courtney Sutton, Kaori Nozawa, Katarzyna Kent, Alexander Saltzman, Mei Leng, Sureshbabu Nagarajan, Anna Malovannaya, Masahito Ikawa, Thomas X Garcia, Martin M Matzuk

Faculty, Staff and Students Publications

The quest for a non-hormonal male contraceptive pill for men still exists. Serine protease 37 (PRSS37) is a sperm-specific protein that when ablated in mice renders them sterile. In this study we sought to examine the molecular sequelae of PRSS37 loss to better understand its molecular function, and to determine whether human PRSS37 could rescue the sterility phenotype of knockout (KO) mice, allowing for a more appropriate model for drug molecule testing. To this end, we used CRISPR-EZ to create mice lacking the entire coding region of Prss37, used pronuclear injection to create transgenic mice expressing human PRSS37, intercrossed these …

Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven By Different P53 Mutants, Dhruv Chachad, Lalit R Patel, Carlos Vera Recio, Rasoul Pourebrahim, Elizabeth M Whitley, Wenyi Wang, Xiaoping Su, An Xu, Dung-Fang Lee, Guillermina Lozano

Faculty, Staff and Student Publications

Missense mutations in the DNA binding domain of p53 are characterized as structural or contact mutations based on their effect on the conformation of the protein. These mutations show gain-of-function (GOF) activities, such as promoting increased metastatic incidence compared with p53 loss, often mediated by the interaction of mutant p53 with a set of transcription factors. These interactions are largely context specific. To understand the mechanisms by which p53 DNA binding domain mutations drive osteosarcoma progression, we created mouse models, in which either the p53 structural mutant p53R172H or the contact mutant p53R245W are expressed specifically in osteoblasts, yielding osteosarcoma …

Bicc1 Drives Pancreatic Cancer Progression By Inducing Vegf-Independent Angiogenesis, Chongbiao Huang, Hui Li, Yang Xu, Chao Xu, Huizhi Sun, Zengxun Li, Yi Ge, Hongwei Wang, Tiansuo Zhao, Song Gao, Xiuchao Wang, Shengyu Yang, Peiqing Sun, Zhe Liu, Jing Liu, Antao Chang, Jihui Hao

Faculty, Staff and Student Publications

VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors. Nevertheless, pancreatic adenocarcinoma (PAAD) cells can reinstate tumor angiogenesis via activation of VEGF-independent pathways, thereby conferring resistance to VEGF inhibitors. Bioinformatic analysis showed that BICC1 was one of the top genes involved in the specific angiogenesis process of PAAD. The analysis of our own cohort confirmed that BICC1 was overexpressed in human PAAD tissues and was correlated to increased microvessel density and tumor growth, and worse prognosis. In cells and mice with xenograft tumors, BICC1 facilitated angiogenesis in pancreatic cancer in a VEGF-independent …

Resistance To Human Immunodeficiency Virus 1 Infection Conferred By A Compound Ccr5Δ32 And Ccr5 C20s Heterozygote, Bashar Alkhatib, Mary Jabari, Shymaa Bilasy, Husni Abdul-Rahman, Kamal Sandhu, Stephen Lai, Ghalib Alkhatib

Faculty, Staff and Student Publications

We analyzed findings in a same-gender couple discordant in their human immunodeficiency virus (HIV) status. The HIV+ partner was homozygous for CCR5 while his receptive HIV- partner was a CCR5Δ32 heterozygote with a C20S missense mutation in his CCR5 allele. The cells from the HIV- partner showed significant resistance to R5 fusion/infection and had no chemotactic response to CCL4 (macrophage inflammatory protein 1β). We demonstrated abundant CCR5-specific RNA in the HIV- partner's cells but no detectable CCR5 protein. CCR5 promoter region cloned from each partner's DNA indicated no significant impact on RNA transcription. The compound effect of CCR5Δ32 and C20S …

Analysis Of Performance And Failure Modes Of The Iroc Proton Liver Phantom, Hunter Mehrens, Paige Taylor, Paola Alvarez, Stephen Kry

Faculty, Staff and Student Publications

Purpose: To analyze trends in institutional performance and failure modes for the Imaging and Radiation Oncology Core’s (IROC’s) proton liver phantom.

Materials and Methods: Results of 66 phantom irradiations from 28 institutions between 2015 and 2020 were retrospectively analyzed. Univariate analysis and random forest models were used to associate irradiation conditions with phantom results. Phantom results included pass/fail classification, average thermoluminescent dosimeter (TLD) ratio of both targets, and percentage of pixels passing gamma of both targets. The following categories were evaluated in terms of how they predicted these outcomes: irradiation year, treatment planning system (TPS), TPS algorithm, treatment machine, number …

Genomic Landscape Of Down Syndrome-Associated Acute Lymphoblastic Leukemia, Zhenhua Li, Ti-Cheng Chang, Jacob J Junco, Meenakshi Devidas, Yizhen Li, Wenjian Yang, Xin Huang, Dale J Hedges, Zhongshan Cheng, Mary Shago, Andrew J Carroll, Nyla A Heerema, Julie Gastier-Foster, Brent L Wood, Michael J Borowitz, Lauren Sanclemente, Elizabeth A Raetz, Stephen P Hunger, Eleanor Feingold, Tracie C Rosser, Stephanie L Sherman, Mignon L Loh, Charles G Mullighan, Jiyang Yu, Gang Wu, Philip J Lupo, Karen R Rabin, Jun J Yang

Faculty, Staff and Students Publications

Trisomy 21, the genetic cause of Down syndrome (DS), is the most common congenital chromosomal anomaly. It is associated with a 20-fold increased risk of acute lymphoblastic leukemia (ALL) during childhood and results in distinctive leukemia biology. To comprehensively define the genomic landscape of DS-ALL, we performed whole-genome sequencing and whole-transcriptome sequencing (RNA-Seq) on 295 cases. Our integrated genomic analyses identified 15 molecular subtypes of DS-ALL, with marked enrichment of CRLF2-r, IGH::IGF2BP1, and C/EBP altered (C/EBPalt) subtypes compared with 2257 non-DS-ALL cases. We observed abnormal activation of the CEBPD, CEBPA, and CEBPE genes in 10.5% of DS-ALL cases via a …

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

Faculty, Staff and Student Publications

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

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

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

CONCLUSION: In conclusion, the CD39-CD73-A

Relative Burden Of Cancer And Noncancer Mortality Among Long-Term Survivors Of Breast, Prostate, And Colorectal Cancer In The Us, Madhav Kc, Jane Fan, Terry Hyslop, Sirad Hassan, Michael Cecchini, Shi-Yi Wang, Andrea Silber, Michael S. Leapman, Ira Leeds, Stephanie B. Wheeler, Lisa P. Spees, Cary P. Gross, Maryam Lustberg, Rachel A. Greenup, Amy C. Justice, Kevin C. Oeffinger, Michaela A. Dinan

Kimmel Cancer Center Faculty Papers

IMPORTANCE: Improvements in cancer outcomes have led to a need to better understand long-term oncologic and nononcologic outcomes and quantify cancer-specific vs noncancer-specific mortality risks among long-term survivors.

OBJECTIVE: To assess absolute and relative cancer-specific vs noncancer-specific mortality rates among long-term survivors of cancer, as well as associated risk factors.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study included 627 702 patients in the Surveillance, Epidemiology, and End Results cancer registry with breast, prostate, or colorectal cancer who received a diagnosis between January 1, 2003, and December 31, 2014, who received definitive treatment for localized disease and who were alive 5 …

Microbe Hunters, Paul De Kruif

Zea E-Books Collection

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

Mettl3-Mediated M6a Modification Of Linc00839 Maintains Glioma Stem Cells And Radiation Resistance By Activating Wnt/Β-Catenin Signaling, Jianxing Yin, Fangshu Ding, Zhangchun Cheng, Xin Ge, Yanhui Li, Ailiang Zeng, Junxia Zhang, Wei Yan, Zhumei Shi, Xu Qian, Yongping You, Zhiliang Ding, Jing Ji, Xiefeng Wang

Faculty, Staff and Student Publications

Long noncoding RNAs (lncRNAs) are involved in glioma initiation and progression. Glioma stem cells (GSCs) are essential for tumor initiation, maintenance, and therapeutic resistance. However, the biological functions and underlying mechanisms of lncRNAs in GSCs remain poorly understood. Here, we identified that LINC00839 was overexpressed in GSCs. A high level of LINC00839 was associated with GBM progression and radiation resistance. METTL3-mediated m6A modification on LINC00839 enhanced its expression in a YTHDF2-dependent manner. Mechanistically, LINC00839 functioned as a scaffold promoting c-Src-mediated phosphorylation of β-catenin, thereby inducing Wnt/β-catenin activation. Combinational use of celecoxib, an inhibitor of Wnt/β-catenin signaling, greatly sensitized GSCs to …

High Glucose-Upregulated Pd-L1 Expression Through Ras Signaling-Driven Downregulation Of Ptrh1 Leads To Suppression Of T Cell Cytotoxic Function In Tumor Environment, Chenggang Gao, Jiaoshun Chen, Jianwei Bai, Haoxiang Zhang, Yanyi Tao, Shihong Wu, Hehe Li, Heshui Wu, Qiang Shen, Tao Yin

School of Graduate Studies Faculty Publications

Background: Nearly 80% of patients with pancreatic cancer suffer from glucose intolerance or diabetes. Pancreatic cancer complicated by diabetes has a more immunosuppressive tumor microenvironment (TME) and is associated with a worse prognosis. The relationship between glucose metabolism and programmed cell death-Ligand 1 (PD-L1) is close and complex. It is important to explore the regulation of high glucose on PD-L1 expression in pancreatic cancer and its effect on infiltrating immune effectors in the tumor microenvironment. Methods: Diabetic murine models (C57BL/6) were used to reveal different immune landscape in euglycemic and hyperglycemic pancreatic tumor microenvironment. Bioinformatics, WB, iRIP [Improved RNA Binding …

Tissue Resident Regulatory T Cells And Immunopathology During Influenza Infections, Michael Mcgee

LSU Doctoral Dissertations

Influenza (flu) virus infections are a leading cause of respiratory illness. Globally there are approximately 290,000-650,000 deaths and 3-5 million cases of severe illness during the average flu season. Severe flu infection is associated with the combination of a strong pro-inflammatory and weak anti-inflammatory response. Regulatory T cell subsets suppress pro-inflammatory responses during flu infection, with production of the immunomodulatory cytokine IL-10 playing a critical role in this process. Tissue resident regulatory T cell subsets are maintained within nonlymphoid tissues and are optimally positioned to suppress localized pro-inflammatory responses. However, knowledge of the signaling pathways regulating the development of tissue …

Author Correction: Drugnomeai Is An Ensemble Machine-Learning Framework For Predicting Druggability Of Candidate Drug Targets, Arwa Raies, Ewa Tulodziecka, James Stainer, Lawrence Middleton, Ryan S Dhindsa, Pamela Hill, Ola Engkvist, Andrew R Harper, Slavé Petrovski, Dimitrios Vitsios

Faculty, Staff and Students Publications

No abstract provided.

When A Calorie Is Not Just A Calorie: Diet Quality And Timing As Mediators Of Metabolism And Healthy Aging, Maria M Mihaylova, Amandine Chaix, Mirela Delibegovic, Jon J Ramsey, Joseph Bass, Girish Melkani, Rajat Singh, Zheng Chen, William W Ja, Michele Shirasu-Hiza, Mary N Latimer, Julie A Mattison, Anna E Thalacker-Mercer, Vishwa Deep Dixit, Satchidananda Panda, Dudley W Lamming

Faculty, Staff and Student Publications

An epidemic of obesity has affected large portions of the world, increasing the risk of developing many different age-associated diseases, including cancer, cardiovascular disease, and diabetes. In contrast with the prevailing notion that "a calorie is just a calorie," there are clear differences, within and between individuals, in the metabolic response to different macronutrient sources. Recent findings challenge this oversimplification; calories from different macronutrient sources or consumed at different times of day have metabolic effects beyond their value as fuel. Here, we summarize discussions conducted at a recent NIH workshop that brought together experts in calorie restriction, macronutrient composition, and …

High Throughput Single Cell Long-Read Sequencing Analyses Of Same-Cell Genotypes And Phenotypes In Human Tumors, Cheng-Kai Shiau, Lina Lu, Rachel Kieser, Kazutaka Fukumura, Timothy Pan, Hsiao-Yun Lin, Jie Yang, Eric L Tong, Gahyun Lee, Yuanqing Yan, Jason T Huse, Ruli Gao

Faculty, Staff and Student Publications

Single-cell nanopore sequencing of full-length mRNAs transforms single-cell multi-omics studies. However, challenges include high sequencing errors and dependence on short-reads and/or barcode whitelists. To address these, we develop scNanoGPS to calculate same-cell genotypes (mutations) and phenotypes (gene/isoform expressions) without short-read nor whitelist guidance. We apply scNanoGPS onto 23,587 long-read transcriptomes from 4 tumors and 2 cell-lines. Standalone, scNanoGPS deconvolutes error-prone long-reads into single-cells and single-molecules, and simultaneously accesses both phenotypes and genotypes of individual cells. Our analyses reveal that tumor and stroma/immune cells express distinct combination of isoforms (DCIs). In a kidney tumor, we identify 924 DCI genes involved in …

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

Faculty, Staff and Student Publications

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

A Global Study For Acute Myeloid Leukemia With Rarg Rearrangement, Hong-Hu Zhu, Ya-Zhen Qin, Zhang-Lin Zhang, Yong-Jing Liu, Li-Jun Wen, M James You, Cheng Zhang, Esperanza Such, Hong Luo, Hong-Jian Yuan, Hong-Sheng Zhou, Hong-Xing Liu, Reng Xu, Ji Li, Jian-Hu Li, Jian-Ping Hao, Jie Jin, Liang Yu, Jing-Ying Zhang, Li-Ping Liu, Le-Ping Zhang, Rui-Bin Huang, Shu-Hong Shen, Su-Jun Gao, Wei Wang, Xiao-Jing Yan, Xin-You Zhang, Xin Du, Xiao-Xia Chu, Yan-Fang Yu, Yi Wang, Ying-Chang Mi, Ying Lu, Zhen Cai, Zhan Su, David Christopher Taussig, Suzanne Macmahon, Edward D Ball, Huan-You Wang, John S Welch, C Cameron Yin, Gautam Borthakur, Miguel A Sanz, Hagop M Kantarjian, Jin-Yan Huang, Jiong Hu, Su-Ning Chen

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) with retinoic acid receptor γ (RARG) rearrangement has clinical, morphologic, and immunophenotypic features similar to classic acute promyelocytic leukemia. However, AML with RARG rearrangement is insensitive to alltrans retinoic acid (ATRA) and arsenic trioxide (ATO) and carries a poor prognosis. We initiated a global cooperative study to define the clinicopathological features, genomic and transcriptomic landscape, and outcomes of AML with RARG rearrangements collected from 29 study groups/institutions worldwide. Thirty-four patients with AML with RARG rearrangements were identified. Bleeding or ecchymosis was present in 18 (54.5%) patients. Morphology diagnosed as M3 and M3v accounted for 73.5% and …

Lessons Learned Creating Microbiology Laboratory Demonstration Videos, Marnie Imhoff, Linsey Donner

Innovations in Health Sciences Education Journal

Microbiology laboratory classes are designed to allow students to apply knowledge gained during lectures and become proficient in laboratory skills. Students are introduced to procedures for working with and identifying microorganisms. Instructors must prepare students to perform and interpret the necessary testing procedures to be successful. Laboratory demonstration videos provide students with a first-person, unobstructed demonstration on how to perform laboratory techniques. The videos can be used as a visual learning tool to supplement courses with an in-person laboratory session or as a component in online learning. This article describes the creation of instructional microbiology laboratory demonstration videos.

Roving Methyltransferases Generate A Mosaic Epigenetic Landscape And Influence Evolution In Bacteroides Fragilis Group, Michael J Tisza, Derek D N Smith, Andrew E Clark, Jung-Ho Youn, Pavel P Khil, John P Dekker

Faculty, Staff and Students Publications

Three types of DNA methyl modifications have been detected in bacterial genomes, and mechanistic studies have demonstrated roles for DNA methylation in physiological functions ranging from phage defense to transcriptional control of virulence and host-pathogen interactions. Despite the ubiquity of methyltransferases and the immense variety of possible methylation patterns, epigenomic diversity remains unexplored for most bacterial species. Members of the Bacteroides fragilis group (BFG) reside in the human gastrointestinal tract as key players in symbiotic communities but also can establish anaerobic infections that are increasingly multi-drug resistant. In this work, we utilize long-read sequencing technologies to perform pangenomic (n = …

Accumulation Of Chronic Disease Among Survivors Of Childhood Cancer Predicts Early Mortality, Adam J Esbenshade, Lu Lu, Debra L Friedman, Kevin C Oeffinger, Gregory T Armstrong, Kevin R Krull, Joseph P Neglia, Wendy M Leisenring, Rebecca Howell, Robyn Partin, Amy Sketch, Leslie L Robison, Kirsten K Ness

Faculty, Staff and Student Publications

Purpose: Cancer survivors develop cancer and treatment-related morbidities at younger than normal ages and are at risk for early mortality, suggestive of an aging phenotype. The Cumulative Illness Rating Scale for Geriatrics (CIRS-G) is specifically designed to describe the accumulation of comorbidities over time with estimates of severity such as total score (TS) which is a sum of possible conditions weighted by severity. These severity scores can then be used to predict future mortality.

Methods: CIRS-G scores were calculated in cancer survivors and their siblings from Childhood Cancer Survivor Study cohort members from two time points 19 years apart and …

Mct4-Dependent Lactate Secretion Suppresses Antitumor Immunity In Lkb1-Deficient Lung Adenocarcinoma, Yu Qian, Ana Galan-Cobo, Irene Guijarro, Minghao Dang, David Molkentine, Alissa Poteete, Fahao Zhang, Qi Wang, Jing Wang, Edwin Parra, Apekshya Panda, Jacy Fang, Ferdinandos Skoulidis, Ignacio I Wistuba, Svena Verma, Taha Merghoub, Jedd D Wolchok, Kwok-Kin Wong, Ralph J Deberardinis, John D Minna, Natalie I Vokes, Catherine B Meador, Justin F Gainor, Linghua Wang, Alexandre Reuben, John V Heymach

Faculty, Staff and Student Publications

Inactivating STK11/LKB1 mutations are genomic drivers of primary resistance to immunotherapy in KRAS-mutated lung adenocarcinoma (LUAD), although the underlying mechanisms remain unelucidated. We find that LKB1 loss results in enhanced lactate production and secretion via the MCT4 transporter. Single-cell RNA profiling of murine models indicates that LKB1-deficient tumors have increased M2 macrophage polarization and hypofunctional T cells, effects that could be recapitulated by the addition of exogenous lactate and abrogated by MCT4 knockdown or therapeutic blockade of the lactate receptor GPR81 expressed on immune cells. Furthermore, MCT4 knockout reverses the resistance to PD-1 blockade induced by LKB1 loss in syngeneic …

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

Faculty, Staff and Students Publications

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

Structural Insights Into Rna Bridging Between Hiv-1 Vif And Antiviral Factor Apobec3g, Takahide Kouno, Satoshi Shibata, Megumi Shigematsu, Jaekyung Hyun, Tae Gyun Kim, Hiroshi Matsuo, Matthias Wolf

Computational Medicine Center Faculty Papers

Great effort has been devoted to discovering the basis of A3G-Vif interaction, the key event of HIV's counteraction mechanism to evade antiviral innate immune response. Here we show reconstitution of the A3G-Vif complex and subsequent A3G ubiquitination in vitro and report the cryo-EM structure of the A3G-Vif complex at 2.8 Å resolution using solubility-enhanced variants of A3G and Vif. We present an atomic model of the A3G-Vif interface, which assembles via known amino acid determinants. This assembly is not achieved by protein-protein interaction alone, but also involves RNA. The cryo-EM structure and in vitro ubiquitination assays identify an adenine/guanine base …