Medicine and Health Sciences Commons^™

The Hypothalamus For Whole-Body Physiology: From Metabolism To Aging, Tiemin Liu, Yong Xu, Chun-Xia Yi, Qingchun Tong, Dongsheng Cai

Children’s Nutrition Research Center Staff Publications

Obesity and aging are two important epidemic factors for metabolic syndrome and many other health issues, which contribute to devastating diseases such as cardiovascular diseases, stroke and cancers. The brain plays a central role in controlling metabolic physiology in that it integrates information from other metabolic organs, sends regulatory projections and orchestrates the whole-body function. Emerging studies suggest that brain dysfunction in sensing various internal cues or processing external cues may have profound effects on metabolic and other physiological functions. This review highlights brain dysfunction linked to genetic mutations, sex, brain inflammation, microbiota, stress as causes for whole-body pathophysiology, arguing …

Association Of Alcohol Use And Physical Activity With Body Mass Index In Mexican-Origin Adults, Natalia I Heredia, Qiong Dong, Shine Chang, Lorna H Mcneill

Faculty, Staff and Student Publications

BACKGROUND: Studies across racial/ethnic groups indicate that physical activity (PA) and alcohol consumption are positively associated, and that alcohol consumption is negatively associated with body mass index (BMI), but this relationship is less often evaluated in Hispanics. The purpose of this study was to assess the relationships between alcohol consumption, PA, and BMI in Hispanic adults.

METHODS: In this secondary data analysis of a Mexican-American cohort, we collected self-reported PA, alcohol consumption, and demographics, and measured height and weight. Linear regression assessed the association between PA and alcohol consumption with BMI, controlling for covariates. Total sample for analyses was n …

External Validation Of A Model Determining Risk Of Neoplastic Progression Of Barrett’S Esophagus In A Cohort Of Us Veterans, Theresa H Nguyen, Aaron P Thrift, Gyanprakash A Ketwaroo, Xianglin L Du, Luis Leon Novelo, Rollin George, Daniel G Rosen, Hashem B El-Serag

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: Risk of esophageal adenocarcinoma (EAC) in those with Barrett's esophagus (BE) is 11-fold greater than the general population. It remains unclear which BE patients are at highest risk of progression to EAC. We aimed to validate a predictive model risk-stratifying BE patients.

METHODS: We conducted a retrospective cohort study at the Houston Veteran Affairs Medical Center of consecutive patients with a new diagnosis of BE from November 1990 to January 2019. Study follow-up was through February 2020. Patients were excluded if they had no follow-up EGD with esophageal biopsy sampling after the initial BE-diagnosing EGD or evidence …

Responding To Natural And Industrial Disasters: Partnerships And Lessons Learned, Elaine Symanski, Heyreoun An Han, Inkyu Han, Michelle Mcdaniel, Kristina W Whitworth, Sheryl Mccurdy, William Brett Perkison, Amal Rammah, P Grace Tee Lewis, George L Delclos, Elena Craft, Melissa Bondy, Cheryl Lyn Walker, Loren Hopkins, José Guillermo Cedeño Laurent, Daisy James

Faculty, Staff and Student Publications

OBJECTIVES: The aim of this study was to provide insights learned from disaster research response (DR2) efforts following Hurricane Harvey in 2017 to launch DR2 activities following the Intercontinental Terminals Company (ITC) fire in Deer Park, Texas, in 2019.

METHODS: A multidisciplinary group of academic, community, and government partners launched a myriad of DR2 activities.

RESULTS: The DR2 response to Hurricane Harvey focused on enhancing environmental health literacy around clean-up efforts, measuring environmental contaminants in soil and water in impacted neighborhoods, and launching studies to evaluate the health impact of the disaster. The lessons learned after Harvey enabled rapid DR2 …

External Validation Of A Model Determining Risk Of Neoplastic Progression Of Barrett's Esophagus In A Cohort Of Us Veterans, Theresa H Nguyen, Aaron P Thrift, Gyanprakash A Ketwaroo, Xianglin L Du, Luis Leon Novelo, Rollin George, Daniel G Rosen, Hashem B El-Serag

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: Risk of esophageal adenocarcinoma (EAC) in those with Barrett's esophagus (BE) is 11-fold greater than the general population. It remains unclear which BE patients are at highest risk of progression to EAC. We aimed to validate a predictive model risk-stratifying BE patients.

METHODS: We conducted a retrospective cohort study at the Houston Veteran Affairs Medical Center of consecutive patients with a new diagnosis of BE from November 1990 to January 2019. Study follow-up was through February 2020. Patients were excluded if they had no follow-up EGD with esophageal biopsy sampling after the initial BE-diagnosing EGD or evidence …

Integrative Analysis Of Clinical And Epigenetic Biomarkers Of Mortality, Tianxiao Huan, Steve Nguyen, Elena Colicino, Carolina Ochoa-Rosales, W David Hill, Jennifer A Brody, Mette Soerensen, Yan Zhang, Antoine Baldassari, Mohamed Ahmed Elhadad, Tanaka Toshiko, Yinan Zheng, Arce Domingo-Relloso, Dong Heon Lee, Jiantao Ma, Chen Yao, Chunyu Liu, Shih-Jen Hwang, Roby Joehanes, Myriam Fornage, Jan Bressler, Joyce B J Van Meurs, Birgit Debrabant, Jonas Mengel-From, Jacob Hjelmborg, Kaare Christensen, Pantel Vokonas, Joel Schwartz, Sina A Gahrib, Nona Sotoodehnia, Colleen M Sitlani, Sonja Kunze, Christian Gieger, Annette Peters, Melanie Waldenberger, Ian J Deary, Luigi Ferrucci, Yishu Qu, Philip Greenland, Donald M Lloyd-Jones, Lifang Hou, Stefania Bandinelli, Trudy Voortman, Brenner Hermann, Andrea Baccarelli, Eric Whitsel, James S Pankow, Daniel Levy

Faculty, Staff and Student Publications

DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10

Gene-Lifestyle Interactions In The Genomics Of Human Complex Traits, Vincent Laville, Timothy Majarian, Yun J Sung, Karen Schwander, Mary F Feitosa, Daniel I Chasman, Amy R Bentley, Charles N Rotimi, L Adrienne Cupples, Paul S De Vries, Michael R Brown, Alanna C Morrison, Aldi T Kraja, Mike Province, C Charles Gu, W James Gauderman, Charge Gene-Lifestyle Interactions Working Group, D C Rao, Alisa K Manning, Hugues Aschard

Faculty, Staff and Student Publications

The role and biological significance of gene-environment interactions in human traits and diseases remain poorly understood. To address these questions, the CHARGE Gene-Lifestyle Interactions Working Group conducted series of genome-wide interaction studies (GWIS) involving up to 610,475 individuals across four ancestries for three lipids and four blood pressure traits, while accounting for interaction effects with drinking and smoking exposures. Here we used GWIS summary statistics from these studies to decipher potential differences in genetic associations and G×E interactions across phenotype-exposure-ancestry combinations, and to derive insights on the potential mechanistic underlying G×E through in-silico functional analyses. Our analyses show first that …

Multi-Phenotype Analyses Of Hemostatic Traits With Cardiovascular Events Reveal Novel Genetic Associations, Gerard Temprano-Sagrera, Colleen M Sitlani, William P Bone, Miguel Martin-Bornez, Benjamin F Voight, Alanna C Morrison, Scott M Damrauer, Paul S De Vries, Nicholas L Smith, Maria Sabater-Lleal

Faculty, Staff and Student Publications

BACKGROUND: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes.

OBJECTIVES: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events.

METHODS: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen …

Hiv Response Interventions That Integrate Hiv Molecular Cluster And Social Network Analysis: A Systematic Review, Daniel J Gore, Kellie Schueler, Santhoshini Ramani, Arno Uvin, Gregory Phillips, Moira Mcnulty, Kayo Fujimoto, John Schneider

Faculty, Staff and Student Publications

Due to improved efficiency and reduced cost of viral sequencing, molecular cluster analysis can be feasibly utilized alongside existing human immunodeficiency virus (HIV) prevention strategies. The goal of this paper is to elucidate how HIV molecular cluster and social network analyses are being integrated to implement HIV response interventions. We searched PubMed, Scopus, PsycINFO, and Cochrane Library databases for studies incorporating both HIV molecular cluster and social network data. We identified 32 articles that combined analyses of HIV molecular sequences and social or sexual networks. All studies were descriptive. Six studies described network interventions informed by molecular and social data …

Understanding Implementation Strategies To Support Classroom-Based Physical Activity Approaches In Elementary Schools: A Qualitative Study, Timothy J Walker, Jacob Szeszulski, Michael C Robertson, Paula M Cuccaro, Maria E Fernandez

Faculty, Staff and Student Publications

BACKGROUND: Classroom-based physical activity approaches can improve children's physical activity levels during school. However, the implementation of these approaches remains a challenge. The purpose of this study was to examine implementation strategies to support the delivery of classroom-based physical activity approaches from the perspectives of elementary school staff.

METHODS: We conducted individual interviews with elementary school staff from a mid-sized school district in Texas. Interviews lasted approximately 60 min and were audio recorded and transcribed for analyses. We used directed content analysis and an iterative categorization approach to identify emerging themes related to implementation strategies.

RESULTS: We interviewed 15 participants …

Midlife Determinants Of Healthy Cardiovascular Aging: The Atherosclerosis Risk In Communities (Aric) Study, Xiaoming Jia, Caroline Sun, Vijay Nambi, Salim S Virani, George Taffet, Eric Boerwinkle, Jan Bressler, Chiadi Ndumele, B Gwen Windham, James A De Lemos, Kunihiro Matsushita, John William Mcevoy, Ron C Hoogeveen, Elizabeth Selvin, Christie M Ballantyne

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: Risk factor cutoffs are derived from associations with clinical cardiovascular disease (CVD), but how these risk factors associate with preserved cardiovascular health into old age is not well studied. We investigated midlife determinants of healthy versus nonhealthy cardiovascular aging in the Atherosclerosis Risk in Communities (ARIC) study.

METHODS: ARIC participants were categorized by cardiovascular status in older age (mean age 75.8 ± 5.3 years, range 66-90): healthy, subclinical disease (assessed by biomarkers and left ventricular function), clinical CVD (coronary heart disease, stroke, or heart failure), or prior death. We examined associations of midlife (mean age 52.1 ± …

Better Care For Older Hispanics: Identifying Priorities And Harmonizing Care, Rafael Samper-Ternent, Mary Tinetti, Lee A Jennings, Rebeca Wong, Jennifer Arney, Aanand D Naik

Faculty, Staff and Student Publications

No abstract provided.

Assessment Of Oral And Overall Health Parameters Using The Sillha Oral Wellness System, Shawn S Adibi, Ryan Hanson, David F Fray, Tania Abedi, Brianna Neil, Danielle Maher, Gena Tribble, Ben F Warner, Mary C Farach-Carson

Faculty, Staff and Student Publications

OBJECTIVE: The study evaluated use of a multipoint saliva analyzer to assess patient wellness in a contemporary dental practice setting.

STUDY DESIGN: Unstimulated saliva from a diverse 104 patient cohort was analyzed using the SillHa Oral Wellness System. The device measures the following 7 analytes present in the patient's oral rinse: cariogenic bacteria, acidity, buffer capacity, blood, leukocytes, protein, and ammonia. Data obtained were compared with validated clinical assessment data independently provided by credentialed dental professionals.

RESULTS: Measured leukocyte and protein levels were higher in patients with periodontal disease and/or deep gingival pockets. Patients with a history of cancer and/or …

Host And Gut Microbial Tryptophan Metabolism And Type 2 Diabetes: An Integrative Analysis Of Host Genetics, Diet, Gut Microbiome And Circulating Metabolites In Cohort Studies, Qibin Qi, Jun Li, Bing Yu, Jee-Young Moon, Jin C Chai, Jordi Merino, Jie Hu, Miguel Ruiz-Canela, Casey Rebholz, Zheng Wang, Mykhaylo Usyk, Guo-Chong Chen, Bianca C Porneala, Wenshuang Wang, Ngoc Quynh Nguyen, Elena V Feofanova, Megan L Grove, Thomas J Wang, Robert E Gerszten, Josée Dupuis, Jordi Salas-Salvadó, Wei Bao, David L Perkins, Martha L Daviglus, Bharat Thyagarajan, Jianwen Cai, Tao Wang, Joann E Manson, Miguel A Martínez-González, Elizabeth Selvin, Kathryn M Rexrode, Clary B Clish, Frank B Hu, James B Meigs, Rob Knight, Robert D Burk, Eric Boerwinkle, Robert C Kaplan

Faculty, Staff and Student Publications

OBJECTIVE: Tryptophan can be catabolised to various metabolites through host kynurenine and microbial indole pathways. We aimed to examine relationships of host and microbial tryptophan metabolites with incident type 2 diabetes (T2D), host genetics, diet and gut microbiota.

METHOD: We analysed associations between circulating levels of 11 tryptophan metabolites and incident T2D in 9180 participants of diverse racial/ethnic backgrounds from five cohorts. We examined host genome-wide variants, dietary intake and gut microbiome associated with these metabolites.

RESULTS: Tryptophan, four kynurenine-pathway metabolites (kynurenine, kynurenate, xanthurenate and quinolinate) and indolelactate were positively associated with T2D risk, while indolepropionate was inversely associated with …

On The Front Lines Of The Covid-19 Pandemic: Occupational Experiences Of The Intimate Partner Violence And Sexual Assault Workforce, Leila Wood, Rachel Voth Schrag, Elizabeth Baumler, Dixie Hairston, Shannon Guillot-Wright, Elizabeth Torres, Jeff R Temple

Faculty, Staff and Student Publications

In the face of increasing risk for intimate partner violence (IPV) and sexual assault during the COVID-19 pandemic, there is an urgent need to understand the experiences of the workforce providing support to survivors, as well as the evolving service delivery methods, shifting safety planning approaches, and occupational stress of frontline workers. We addressed this gap by conducting an online survey of members of IPV and sexual assault workforce using a broad, web-based recruitment strategy. In total, 352 staff from 24 states participated. We collaborated with practitioner networks and anti-violence coalitions to develop the brief survey, which included questions about …

Statins Enhance The Chemosensitivity Of R-Chop In Diffuse Large B-Cell Lymphoma, Sushanth Gouni, Paolo Strati, Gokce Toruner, Akanksha Aradhya, Ralf Landgraf, Daniel Bilbao, Francisco Vega, Nitin Kumar Agarwal

Faculty, Staff and Student Publications

The beneficial effect of statins on the anti-lymphoma activity of the rituximab-based chemotherapy regimen is controversial. Here, we retrospectively reviewed patients with naïve-treated advanced diffuse large B-cell lymphoma (DLBCL) receiving frontline R-CHOP, and for whom data regarding differential statins use was available at the time of initiation of treatment. We observe that patients treated with statins and R-CHOP experienced a significantly higher CR rate as compared to those who received R-CHOP only. We further show that patients receiving medium or high intensity statins and R-CHOP experienced a significantly higher CR as compared to those treated with R-CHOP. Six-year progression free …

Grief Symptoms Promote Inflammation During Acute Stress Among Bereaved Spouses, Ryan L Brown, Angie S Leroy, Michelle A Chen, Robert Suchting, Lisa M Jaremka, Jia Liu, Cobi Heijnen, Christopher P Fagundes

Faculty, Staff and Student Publications

The death of a spouse is associated with maladaptive immune alterations; grief severity may exacerbate this link. We investigated whether high grief symptoms were associated with an amplified inflammatory response to subsequent stress among 111 recently bereaved older adults. Participants completed a standardized psychological stressor and underwent a blood draw before, 45 min after, and 2 hr after the stressor. Those experiencing high grief symptoms (i.e., scoring > 25 on the Inventory of Complicated Grief) experienced a 45% increase in interleukin-6 (IL-6; a proinflammatory cytokine) per hour, whereas those experiencing low grief symptoms demonstrated a 26% increase. In other words, high …

Experimental Models Of Undifferentiated Pleomorphic Sarcoma And Malignant Peripheral Nerve Sheath Tumor, Angela D Bhalla, Sharon M Landers, Anand K Singh, Jace P Landry, Michelle G Yeagley, Gabryella S B Myerson, Cristian B Delgado-Baez, Stephanie Dunnand, Theresa Nguyen, Xiaoyan Ma, Svetlana Bolshakov, Brian A Menegaz, Salah-Eddine Lamhamedi-Cherradi, Xizeng Mao, Xingzhi Song, Alexander J Lazar, Ian E Mccutcheon, John M Slopis, Joseph A Ludwig, Dina C Lev, Kunal Rai, Keila E Torres

Faculty, Staff and Student Publications

Undifferentiated pleomorphic sarcoma (UPS) and malignant peripheral nerve sheath tumor (MPNST) are aggressive soft tissue sarcomas that do not respond well to current treatment modalities. The limited availability of UPS and MPNST cell lines makes it challenging to identify potential therapeutic targets in a laboratory setting. Understanding the urgent need for improved treatments for these tumors and the limited cellular models available, we generated additional cell lines to study these rare cancers. Patient-derived tumors were used to establish 4 new UPS models, including one radiation-associated UPS-UPS271.1, UPS511, UPS0103, and RIS620, one unclassified spindle cell sarcoma-USC060.1, and 3 new models of …

A Roadmap To Clinical Trials For Flash, Paige A Taylor, Jean M Moran, David A Jaffray, Jeffrey C Buchsbaum

Faculty, Staff and Student Publications

While FLASH radiation therapy is inspiring enthusiasm to transform the field, it is neither new nor well understood with respect to the radiobiological mechanisms. As FLASH clinical trials are designed, it will be important to ensure we can deliver dose consistently and safely to every patient. Much like hyperthermia and proton therapy, FLASH is a promising new technology that will be complex to implement in the clinic and similarly will require customized credentialing for multi-institutional clinical trials. There is no doubt that FLASH seems promising, but many technologies that we take for granted in conventional radiation oncology, such as rigorous …

Assessment Of Clinical Response Following Atezolizumab And Bevacizumab Treatment In Patients With Neuroendocrine Tumors: A Nonrandomized Clinical Trial, Daniel M Halperin, Suyu Liu, Arvind Dasari, David Fogelman, Priya Bhosale, Armeen Mahvash, Jeannelyn S Estrella, Laura Rubin, Ajaykumar C Morani, Mark Knafl, Tim A Overeem, Szu-Chin Fu, Luisa M Solis, Edwin Parra Cuentas, Anuj Verma, Hong-Lei Chen, Swati Gite, Priya Subashchandrabose, Shannon Dervin, Katja Schulze, Walter C Darbonne, Cindy Yun, Ignacio I Wistuba, P Andrew Futreal, Scott E Woodman, James C Yao

Faculty, Staff and Student Publications

Importance: Therapies for patients with advanced well-differentiated neuroendocrine tumors (NETs) have expanded but remain inadequate, with patients dying of disease despite recent advances in NET therapy. While patients with other cancers have seen long-term disease control and tumor regression with the application of immunotherapies, initial prospective studies of single-agent programmed cell death 1 inhibitors in NET have been disappointing.

Objective: To evaluate the response rate following treatment with the combination of the vascular endothelial growth factor inhibitor bevacizumab with the programmed cell death 1 ligand 1 inhibitor atezolizumab in patients with advanced NETs.

Design, setting, and participants: This single-arm, open-label …

A First-In-Human Phase I Trial Of The Oral P-Stat3 Inhibitor Wp1066 In Patients With Recurrent Malignant Glioma, John De Groot, Martina Ott, Jun Wei, Cynthia Kassab, Dexing Fang, Hinda Najem, Barbara O'Brien, Shiao-Pei Weathers, Carlos Kamiya Matsouka, Nazanin K Majd, Rebecca A Harrison, Gregory N Fuller, Jason T Huse, James P Long, Raymond Sawaya, Ganesh Rao, Tobey J Macdonald, Waldemar Priebe, Michael Decuypere, Amy B Heimberger

Faculty, Staff and Student Publications

No abstract provided.

Non-Coding Rnas And Ferroptosis: Potential Implications For Cancer Therapy, Amar Balihodzic, Felix Prinz, Michael A Dengler, George A Calin, Philipp J Jost, Martin Pichler

Faculty, Staff and Student Publications

Ferroptosis is a recently defined form of regulated cell death, which is biochemically and morphologically distinct from traditional forms of programmed cell death such as apoptosis or necrosis. It is driven by iron, reactive oxygen species, and phospholipids that are oxidatively damaged, ultimately resulting in mitochondrial damage and breakdown of membrane integrity. Numerous cellular signaling pathways and molecules are involved in the regulation of ferroptosis, including enzymes that control the cellular redox status. Alterations in the ferroptosis-regulating network can contribute to the development of various diseases, including cancer. Evidence suggests that ferroptosis is commonly suppressed in cancer cells, allowing them …

Knowledge-Based Planning For The Radiation Therapy Treatment Plan Quality Assurance For Patients With Head And Neck Cancer, Wenhua Cao, Mary Gronberg, Adenike Olanrewaju, Thomas Whitaker, Karen Hoffman, Carlos Cardenas, Adam Garden, Heath Skinner, Beth Beadle, Laurence Court

Faculty, Staff and Student Publications

This study aimed to investigate the feasibility of using a knowledge-based planning technique to detect poor quality VMAT plans for patients with head and neck cancer. We created two dose-volume histogram (DVH) prediction models using a commercial knowledge-based planning system (RapidPlan, Varian Medical Systems, Palo Alto, CA) from plans generated by manual planning (MP) and automated planning (AP) approaches. DVHs were predicted for evaluation cohort 1 (EC1) of 25 patients and compared with achieved DVHs of MP and AP plans to evaluate prediction accuracy. Additionally, we predicted DVHs for evaluation cohort 2 (EC2) of 25 patients for which we intentionally …

Distinct Immune Gene Programs Associated With Host Tumor Immunity, Neoadjuvant Chemotherapy, And Chemoimmunotherapy In Resectable Nsclc, Pedro Rocha, Jiexin Zhang, Raquel Laza-Briviesca, Alberto Cruz-Bermúdez, Neus Bota-Rabassedas, Beatriz Sanchez-Espiridon, Katsuhiro Yoshimura, Carmen Behrens, Wei Lu, Ximing Tang, Apar Pataer, Edwin R Parra, Cara Haymaker, Junya Fujimoto, Stephen G Swisher, John V Heymach, Don L Gibbons, J Jack Lee, Boris Sepesi, Tina Cascone, Luisa M Solis, Mariano Provencio, Ignacio I Wistuba, Humam Kadara

Faculty, Staff and Student Publications

Purpose: Our understanding of the immunopathology of resectable non-small cell lung cancer (NSCLC) is still limited. Here, we explore immune programs that inform of tumor immunity and response to neoadjuvant chemotherapy and chemoimmunotherapy in localized NSCLC.

Experimental design: Targeted immune gene sequencing using the HTG Precision Immuno-Oncology panel was performed in localized NSCLCs from three cohorts based on treatment: naïve (n = 190), neoadjuvant chemotherapy (n = 38), and neoadjuvant chemoimmunotherapy (n = 21). Tumor immune microenvironment (TIME) phenotypes were based on the location of CD8+ T cells (inflamed, cold, excluded), tumoral PD-L1 expression (<1% and ≥1%), and tumor-infiltrating lymphocytes (TIL). Immune programs and signatures were statistically analyzed on the basis of tumoral PD-L1 expression, immune phenotypes, and pathologic response and were cross-compared across the three cohorts.

Results: PD-L1-positive tumors exhibited increased …

Histone Chaperone Asf1 Acts With Rif1 To Promote Dna End Joining In Brca1-Deficient Cells, Mengfan Tang, Zhen Chen, Chao Wang, Xu Feng, Namsoo Lee, Min Huang, Huimin Zhang, Siting Li, Yun Xiong, Junjie Chen

Faculty, Staff and Student Publications

Replication timing regulatory factor 1 (RIF1) acts downstream of p53-binding protein 53BP1 to inhibit the resection of DNA broken ends, which plays critical roles in determining the DNA double-strand break repair pathway choice between nonhomologous end joining and homologous recombination (HR). However, the mechanism by which this choice is made is not yet clear. In this study, we identified that histone chaperone protein ASF1 associates with RIF1 and regulates RIF1-dependent functions in the DNA damage response. Similar to loss of RIF1, we found that loss of ASF1 resulted in resistance to poly (ADP-ribose) polymerase (PARP) inhibition in BRCA1-deficient cells with …

Long-Term Outcomes Among Adolescent And Young Adult Survivors Of Acute Leukemia: A Surveillance, Epidemiology, And End Results Analysis, Amy M Berkman, Clark R Andersen, Branko Cuglievan, David C Mccall, Philip J Lupo, Susan K Parsons, Courtney D Dinardo, Nicholas J Short, Nitin Jain, Tapan M Kadia, J A Livingston, Michael E Roth

Faculty, Staff and Student Publications

Background: There is a growing population of adolescent and young adult (AYA, age 15-39 years) acute leukemia survivors in whom long-term mortality outcomes are largely unknown.

Methods: The current study utilized the Surveillance, Epidemiology, and End Results (SEER) registry to assess long-term outcomes of AYA acute leukemia 5-year survivors. The impact of diagnosis age, sex, race/ethnicity, socioeconomic status, and decade of diagnosis on long-term survival were assessed utilizing an accelerated failure time model.

Results: A total of 1,938 AYA acute lymphoblastic leukemia (ALL) and 2,350 AYA acute myeloid leukemia (AML) survivors diagnosed between 1980 and 2009 were included with a …

Comprehensive Quantitative Evaluation Of Variability In Magnetic Resonance-Guided Delineation Of Oropharyngeal Gross Tumor Volumes And High-Risk Clinical Target Volumes: An R-Ideal Stage 0 Prospective Study, Carlos E Cardenas, Sanne E Blinde, Abdallah S R Mohamed, Sweet Ping Ng, Cornelis Raaijmakers, Marielle Philippens, Alexis Kotte, Abrahim A Al-Mamgani, Irene Karam, David J Thomson, Jared Robbins, Kate Newbold, Clifton D Fuller, Chris Terhaard

Faculty, Staff and Student Publications

Purpose: Tumor and target volume manual delineation remains a challenging task in head and neck cancer radiation therapy. The purpose of this study was to conduct a multi-institutional evaluation of manual delineations of gross tumor volume (GTV), high-risk clinical target volume (CTV), parotids, and submandibular glands on treatment simulation magnetic resonance scans of patients with oropharyngeal cancer.

Methods and materials: We retrospectively collected pretreatment T1-weighted, T1-weighted with gadolinium contrast, and T2-weighted magnetic resonance imaging scans for 4 patients with oropharyngeal cancer under an institution review board-approved protocol. We provided the scans to 26 radiation oncologists from 7 international cancer centers …

Success And Outcomes Following A Second Salvage Attempt For Free Flap Compromise In Patients Undergoing Head And Neck Reconstruction, Allison A Slijepcevic, Gavin Young, Justin Shinn, Steven B Cannady, Matthew Hanasono, Matthew Old, Jeewanjot S Grewal, Tamer Ghanem, Yadranko Ducic, Joseph M Curry, Mark K Wax

Faculty, Staff and Student Publications

Importance: Incidence of perioperative free flap compromise is low, with successful salvage in up to 70%. When the flap is compromised a second time, the value of intervening is unknown.

Objective: To assess the outcomes of a second revascularization attempt for compromised free flaps.

Design, setting, and participants: This multicenter retrospective medical record review included patients undergoing head and neck reconstruction with free flaps at 6 US medical centers from January 1, 2000, through December 30, 2020. Patients were 18 years or older with a history of head and neck defects from cancer, osteoradionecrosis, or other wounds. Of 3510 flaps …

Axl/Mertk Inhibitor Ono-7475 Potently Synergizes With Venetoclax And Overcomes Venetoclax Resistance To Kill F Lt 3-Itd Acute Myeloid Leukemia, Sean M Post, Huaxian Ma, Prerna Malaney, Xiaorui Zhang, Marisa J L Aitken, Po Yee Mak, Vivian R Ruvolo, Tomoko Yasuhiro, Ryohei Kozaki, Lauren E Chan, Lauren B Ostermann, Marina Konopleva, Bing Z Carter, Courtney Dinardo, Michael D Andreeff, Joseph D Khoury, Peter P Ruvolo

Faculty, Staff and Student Publications

FMS-like Tyrosine Kinase 3 (FLT3) mutation is associated with poor survival in acute myeloid leukemia (AML). The specific Anexelekto/MER Tyrosine Kinase (AXL) inhibitor, ONO-7475, kills FLT3-mutant AML cells with targets including Extracellular- signal Regulated Kinase (ERK) and Myeloid Cell Leukemia 1 (MCL1). ERK and MCL1 are known resistance factors for Venetoclax (ABT-199), a popular drug for AML therapy, prompting the investigation of the efficacy of ONO-7475 in combination with ABT-199 in vitro and in vivo. ONO-7475 synergizes with ABT-199 to potently kill FLT3-mutant acute myeloid leukemia cell lines and primary cells. ONO-7475 is effective against ABT-199-resistant cells including cells that …

Maximal Activation Of Apoptosis Signaling By Cotargeting Antiapoptotic Proteins In Bh3 Mimetic-Resistant Aml And Aml Stem Cells, Bing Z Carter, Po Yee Mak, Wenjing Tao, Qi Zhang, Vivian Ruvolo, Vinitha M Kuruvilla, Xiangmeng Wang, Duncan H Mak, Venkata L Battula, Marina Konopleva, Elias J Jabbour, Paul E Hughes, Xiaoyue Chen, Phuong K Morrow, Michael Andreeff

Faculty, Staff and Student Publications

MCL-1 is known to play a major role in resistance to BCL-2 inhibition, but the contribution of other BCL-2 family proteins has not been fully explored. We, here, demonstrate the ineffectiveness of MCL-1 inhibitor AMG176 in venetoclax-resistant, and conversely, of venetoclax in AMG176-resistant acute myelogenous leukemia (AML). Like cells with acquired resistance to venetoclax, cells with acquired resistance to AMG176 express increased MCL-1. Both cells with acquired resistance to venetoclax and to AMG176 express increased levels of BCL-2 and BCL-2A1, decreased BAX, and/or altered levels of other BCL-2 proteins. Cotargeting BCL-2 and MCL-1 was highly synergistic in AML cell lines …