Digital Commons Network^™

Nerves At Play: The Peripheral Nervous System In Extracranial Malignancies, Paola D Vermeer, Anthony C Restaino, Jeffrey L Barr, Dan Yaniv, Moran Amit

Faculty, Staff and Student Publications

The exponential growth of the cancer neuroscience field has shown that the host's immune, vascular, and nervous systems communicate with and influence each other in the tumor microenvironment, dictating the cancer malignant phenotype. Unraveling the nervous system's contributions toward this phenotype brings us closer to cancer cures. In this review, we summarize the peripheral nervous system's contributions to cancer. We highlight the effects of nerve recruitment and tumor innervation, the neuro-immune axis, glial cell activity, and neural regulation on cancer development and progression. We also discuss harnessing the neural control of peripheral cancers as a potential therapeutic approach in oncology. …

Combined Kras Inhibition And Immune Therapy Generates Durable Complete Responses In An Autochthonous Pdac Model, Yonghong Liu, Jincheng Han, Wen-Hao Hsu, Kyle A Labella, Pingna Deng, Xiaoying Shang, Paulino Tallón De Lara, Li Cai, Shan Jiang, Ronald A Depinho

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) resists conventional chemo/radiation and immunotherapy. In PDAC, oncogenic KRAS (KRAS*) drives glycolysis in cancer cells to consume available glucose and produce abundant lactate, creating profound immune suppression in the tumor microenvironment. Here, we combined KRAS* inhibition with agents targeting the major arms of the immunity cycle: CXCR1/2 inhibitor for myeloid cells, antagonistic anti-LAG3 antibody for T cells, and agonistic anti-41BB antibody for dendritic cells. This combination elicited robust anti-tumor regression in iKPC mice bearing large autochthonous tumors. While untreated mice succumbed within 3 weeks, sustained treatment led to durable complete tumor regression and prolonged survival in …

Neurocognitive Outcomes And Functional Independence In Adult Survivors Of Childhood Medulloblastoma Diagnosed Over 3 Decades, Chiara Papini, Sedigheh Mirzaei, Mengqi Xing, Ingrid Tonning Olsson, Ralph Salloum, Peter M K De Blank, Katharine R Lange, Tricia Z King, Deokumar Srivastava, Wendy M Leisenring, Rebecca M Howell, Kevin C Oeffinger, Leslie L Robison, Gregory T Armstrong, Kevin R Krull, Tara M Brinkman

Faculty, Staff and Student Publications

Background: Treatment of childhood medulloblastoma has evolved to reduce neurotoxicity while improving survival. However, the impact of evolving therapies on late neurocognitive outcomes and adult functional independence remains unknown.

Methods: Adult survivors of childhood medulloblastoma (n = 505; median [minimum-maximum] age, 29 [18-46] years) and sibling controls (n = 727; 32 [18-58] years) from the Childhood Cancer Survivor Study completed surveys assessing neurocognitive problems and chronic health conditions (CHCs). Treatment exposures were categorized as historical (craniospinal irradiation [CSI] ≥ 30 Gy, no chemotherapy), standard-risk (CSI > 0 to < 30 Gy + chemotherapy) and high-risk (CSI ≥ 30 Gy + chemotherapy) therapy. Latent class analysis identified patterns of functional independence using employment, independent living, assistance with routine/personal care needs, driver's license, and marital/partner status. Multivariable models estimated the risk of neurocognitive impairment in survivors versus siblings and by treatment exposure group, and associations between neurocognitive impairment, CHCs, and functional independence.

Results: Survivors in each treatment exposure group had a 4- to 5-fold elevated …

Dissecting The Binding Affinity Of Anti-Sars-Cov-2 Compounds To Human Transmembrane Protease, Serine 2: A Computational Study, Yue-Hui Shi, Jian-Xin Shen, Yan Tao, Yuan-Ling Xia, Zhi-Bi Zhang, Yun-Xin Fu, Ke-Qin Zhang, Shu-Qun Liu

Faculty, Staff and Student Publications

The human transmembrane protease, serine 2 (TMPRSS2), essential for SARS-CoV-2 entry, is a key antiviral target. Here, we computationally profiled the TMPRSS2-binding affinities of 15 antiviral compounds. Molecular dynamics (MD) simulations for the docked complexes revealed that three compounds exited the substrate-binding cavity (SBC), suggesting noncompetitive inhibition. Of the remaining compounds, five charged ones exhibited reduced binding stability due to competing electrostatic interactions and increased solvent exposure, while seven neutral compounds showed stronger binding affinity driven by van der Waals (vdW) interactions compensating for unfavorable electrostatic effects (including electrostatic interactions and desolvation penalties). Positive and negative hotspot residues were identified …

Conformational Switching Of Arp5 Subunit Regulates Ino80 Chromatin Remodeling, Shagun Shukla, Somnath Paul, Jeison Garcia, Yuan Zhong, Sara Sanz Juste, Karissa Beauchemin, Blaine Bartholomew

Faculty, Staff and Student Publications

The INO80 chromatin remodeler is a versatile enzyme capable of several functions, including spacing nucleosomes equal distances apart, precise positioning of nucleosomes based on DNA shape/sequence and exchanging histone dimers. Within INO80, the Arp5 subunit plays a central role in INO80 remodeling, evidenced by its interactions with the histone octamer, nucleosomal and extranucleosomal DNA, and its necessity in linking INO80's ATPase activity to nucleosome movement. We find two distinct regions of Arp5 binding near the acidic pocket of nucleosomes. One region has an arginine anchor that binds nucleosomes and is vital for INO80 mobilizing nucleosomes. The other region has a …

Integrating Ctla-4/Pd-1 Blockade Into Cervical Cancer Management: Results Of Compassion-16, Jeffrey A How, Amir A Jazaeri

Faculty, Staff and Student Publications

Although there is anti-tumor efficacy of dual CTLA-4/PD-1 blockade in advanced/recurrent cervical cancer, it is unclear whether combination with chemotherapy is synergistic. In COMPASSION-16, Wu et al. demonstrated improved survival outcomes of cadolinimab plus chemotherapy compared to chemotherapy alone for first-line systemic therapy for advanced/recurrent cervical cancer, suggesting a potential role of bispecific CTLA-4/PD-1 inhibitors in the frontline setting.

Pembrolizumab Plus Chemotherapy In Frontline Treatment Of Advanced Ovarian Cancer: Clinical And Translational Results From A Phase 2 Trial, Jeffrey A How, Minghao Dang, Sanghoon Lee, Bryan Fellman, Shannon N Westin, Anil K Sood, Nicole D Fleming, Aaron Shafer, Ying Yuan, Jinsong Liu, Li Zhao, Joseph Celestino, Richard Hajek, Margaret B Morgan, Edwin R Parra, Caddie D Laberiano Fernandez, Claudio A Arrechedera, Luisa Maren Solis Soto, Kathleen M Schmeler, Alpa Nick, Karen H Lu, Robert Coleman, Linghua Wang, Amir A Jazaeri

Faculty, Staff and Student Publications

Background: The efficacy and feasibility of pembrolizumab combined with chemotherapy in frontline management of advanced high-grade epithelial ovarian cancer (EOC) is unknown. Additionally, modification of the tumor microenvironment following neoadjuvant therapy is not well understood.

Methods: In this single-arm phase 2 trial (this study was registered at ClinicalTrials.gov: NCT02520154), eligible patients received up to 4 cycles of neoadjuvant chemotherapy followed by interval cytoreduction, 3 cycles of adjuvant intravenous carboplatin/weekly paclitaxel/pembrolizumab, and finally maintenance pembrolizumab until progression or toxicity (maximum 20 cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included feasibility, toxicity, and overall survival (OS). PD-L1 staining, …

Sitravatinib In Combination With Nivolumab Plus Ipilimumab In Patients With Advanced Clear Cell Renal Cell Carcinoma: A Phase 1 Trial, Pavlos Msaouel, Kai Yu, Ying Yuan, Jianfeng Chen, Xinmiao Yan, Menuka Karki, Fei Duan, Rahul A Sheth, Priya Rao, Kanishka Sircar, Amishi Y Shah, Amado J Zurita, Giannicola Genovese, Min Li, Chih-Chen Yeh, Minghao Dang, Guangchun Han, Yanshuo Chu, Max Hallin, Peter Olson, Rui Yang, Daniela Slavin, Hirak Der-Torossian, Curtis D Chin, Nizar M Tannir, Linghua Wang, Jianjun Gao

Faculty, Staff and Student Publications

We conducted a phase I trial to determine the optimal dose of triplet therapy with the tyrosine kinase inhibitor sitravatinib plus nivolumab plus ipilimumab in 22 previously untreated patients with advanced clear cell renal cell carcinoma. The primary endpoint was safety. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), 1-year survival probability, and sitravatinib pharmacokinetics. Sitravatinib dose of 35 mg daily plus nivolumab 3 mg/kg and ipilimumab 1 mg/kg resulted in high frequency of immune-related adverse events. Subsequent dose reduction of ipilimumab to 0.7 mg/kg allowed safe …

Superstable Lipid Vacuoles Endow Cartilage With Its Shape And Biomechanics, Raul Ramos, Kim T Pham, Richard C Prince, Leith B Leiser-Miller, Maneeshi S Prasad, Xiaojie Wang, Rachel C Nordberg, Benjamin J Bielajew, Jerry C Hu, Kosuke Yamaga, Ji Won Oh, Tao Peng, Rupsa Datta, Aksana Astrowskaja, Axel A Almet, John T Burns, Yuchen Liu, Christian Fernando Guerrero-Juarez, Bryant Q Tran, Yi-Lin Chu, Anh M Nguyen, Tsai-Ching Hsi, Norman T-L Lim, Sandra Schoeniger, Ruiqi Liu, Yun-Ling Pai, Chella K Vadivel, Sandy Ingleby, Andrew E Mckechnie, Frank Van Breukelen, Kyle L Hoehn, John J Rasweiler, Michinori Kohara, William J Loughry, Scott H Weldy, Raymond Cosper, Chao-Chun Yang, Sung-Jan Lin, Kimberly L Cooper, Sharlene E Santana, Jeffrey E Bradley, Michael A Kiebish, Michelle Digman, David E James, Amy E Merrill, Qing Nie, Thomas F Schilling, Aliaksandr A Astrowski, Eric O Potma, Martín I García-Castro, Kyriacos A Athanasiou, Richard R Behringer, Maksim V Plikus

Faculty, Staff and Student Publications

Conventionally, the size, shape, and biomechanics of cartilages are determined by their voluminous extracellular matrix. By contrast, we found that multiple murine cartilages consist of lipid-filled cells called lipochondrocytes. Despite resembling adipocytes, lipochondrocytes were molecularly distinct and produced lipids exclusively through de novo lipogenesis. Consequently, lipochondrocytes grew uniform lipid droplets that resisted systemic lipid surges and did not enlarge upon obesity. Lipochondrocytes also lacked lipid mobilization factors, which enabled exceptional vacuole stability and protected cartilage from shrinking upon starvation. Lipid droplets modulated lipocartilage biomechanics by decreasing the tissue's stiffness, strength, and resilience. Lipochondrocytes were found in multiple mammals, including humans, …

Genome-Wide Association Study Reveals Shared And Distinct Genetic Architecture Of Fatty Acids And Oxylipins In The Hispanic Community Health Study/Study Of Latinos, Carolina G Downie, Heather M Highland, Mona Alotaibi, Barrett M Welch, Annie Green Howard, Susan Cheng, Nick Miller, Mohit Jain, Robert C Kaplan, Adam G Lilly, Tao Long, Tamar Sofer, Bharat Thyagarajan, Bing Yu, Kari E North, Christy L Avery

Faculty, Staff and Student Publications

Bioactive fatty acid-derived oxylipin molecules play key roles mediating inflammation and oxidative stress. Circulating levels of fatty acids and oxylipins are influenced by environmental and genetic factors; characterizing the genetic architecture of bioactive lipids could yield new insights into underlying biology. We performed a genome-wide association study (GWAS) of 81 fatty acids and oxylipins in 11,584 Hispanic Community Health Study/Study of Latinos (HCHS/SOL) participants with genetic and lipidomic data measured at study baseline (58.6% female, mean age = 46.1 years (standard deviation 13.8)). Additionally, given the effects of central obesity on inflammation, we examined interactions with waist circumference using two-degree-of-freedom …

Nourishing Change In Houston, Texas: Exploring Grocery Shopping Behaviours And Fruit And Vegetable Consumption Among Low-Income Families In The Brighter Bites Program, Victoria Kwentua, Allison Marshall, Ru-Jye Chuang, Jessica Chen, Christine Markham, Mallika Mathur, Mike Pomeroy, Megan Hall, Shreela Sharma

Faculty, Staff and Student Publications

OBJECTIVE: We qualitatively examine the grocery shopping behaviours and fruit and vegetable consumption of low-income families participating in the Brighter Bites program in Houston, Texas.

DESIGN: We used a single-group observational study design. We used (1) purposive sampling of schools and (2) convenience sampling of parents/caregivers to recruit participants. Research staff conducted three face-to-face qualitative focus groups in Spanish and English. Transcripts were coded using deductive and inductive reasoning.

SETTING: Three elementary schools serving low-income families in Houston, Texas, in February-May of 2022.

PARTICIPANTS: Brighter Bites parents/caregivers from the 2021-2022 school year.

RESULTS: Three primary themes emerged: (1) child involvement …

Functional Characterization Of Qt Interval Associated Scn5a Enhancer Variants Identify Combined Additive Effects, Lavanya Gunamalai, Parul Singh, Brian Berg, Leilei Shi, Ernesto Sanchez, Alexa Smith, Ghislain Breton, Mark T Bedford, Darius Balciunas, Ashish Kapoor

Faculty, Staff and Student Publications

Several empirical and theoretical studies suggest the presence of multiple enhancers per gene that collectively regulate gene expression, and that common sequence variation impacting on the activities of these enhancers is a major source of inter-individual gene expression variability. However, for the vast majority of genes, enhancers and the underlying regulatory variation remains unknown. Even for the genes with well-characterized enhancers, the nature of the combined effects from multiple enhancers and their variants, when known, on gene expression regulation remains unexplored. Here, we have evaluated the combined effects from five SCN5A enhancers and their regulatory variants that are known to …

A Phase Ia Study Of A Novel Anti-Her2 Antibody-Drug Conjugate Gq1001 In Patients With Previously Treated Her2 Positive Advanced Solid Tumors, Chenfei Zhou, Bin Wang, Christina Teng, Hui Yang, Sarina A Piha-Paul, Gary Richardson, Ashanya Malalasekera, Yajun Sun, Wei Wang, Jieqiong Liu, Yan Shi, Xianbao Zhan, Charlotte Lemech

Faculty, Staff and Student Publications

Background: A novel anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate (ADC) GQ1001 was assessed in patients with previously treated HER2 positive advanced solid tumors in a global multi-center phase Ia dose escalation trial.

Methods: In this phase Ia trial, a modified 3 + 3 study design was adopted during dose escalation phase. Eligible patients were enrolled, and GQ1001 monotherapy was administered intravenously every 3 weeks. The starting dose was 1.2 mg/kg, followed by 2.4, 3.6, 4.8, 6.0, 7.2 and 8.4 mg/kg. Extra patients were enrolled into 6.0, 7.2, and 8.4 mg/kg cohorts as dose expansion phase. The primary …

Alleviation Of Liver Fibrosis By Inhibiting A Non-Canonical Atf4-Regulated Enhancer Program In Hepatic Stellate Cells, Li-Xian Yang, Chuangye Qi, Si Lu, Xiang-Shi Ye, Parnaz Merikhian, Du-Yu Zhang, Tao Yao, Jiang-Sha Zhao, Ying Wu, Yongshi Jia, Bo Shan, Jinghai Chen, Xiaozhou Mou, Jia You, Wenbo Li, Yu-Xiong Feng

Faculty, Staff and Student Publications

Liver fibrosis is a critical liver disease that can progress to more severe manifestations, such as cirrhosis, yet no effective targeted therapies are available. Here, we identify that ATF4, a master transcription factor in ER stress response, promotes liver fibrosis by facilitating a stress response-independent epigenetic program in hepatic stellate cells (HSCs). Unlike its canonical role in regulating UPR genes during ER stress, ATF4 activates epithelial-mesenchymal transition (EMT) gene transcription under fibrogenic conditions. HSC-specific depletion of ATF4 suppresses liver fibrosis in vivo. Mechanistically, TGFβ resets ATF4 to orchestrate a unique enhancer program for the transcriptional activation of pro-fibrotic EMT genes. …

Application Of Core Functions And Forms In Complex Health Intervention Research: A Scoping Review Protocol, Katelyn Fox, Debbie Passey, Eunyoung Kang, Laura Zeigen, Erin Kenzie, Jessica D Austin, Rachel J Meadows, Maria E Fernandez, Monica Perez Jolles

Faculty, Staff and Student Publications

Introduction: The ability of healthcare, community and public health systems to effectively implement and disseminate research innovations depends on contextual factors at multiple interconnected levels of influence (eg, the innovation, individual, provider/implementor, organisation and health system). Recently, there has been an increase in the development of complex interventions designed to target multiple levels, designed for or adapted to the context in which they are delivered. Two concepts from complex systems thinking have been increasingly used to operationalise such interventions-core functions (theory and evidence-driven purposes of interventions) and forms (adaptable activities that perform each core function). However, there is a gap …

Society For Immunotherapy Of Cancer: Updates And Best Practices For Multiplex Immunohistochemistry (Ihc) And Immunofluorescence (If) Image Analysis And Data Sharing, Janis M Taube, Joel C Sunshine, Michael Angelo, Guray Akturk, Margaret Eminizer, Logan L Engle, Cláudia S Ferreira, Sacha Gnjatic, Benjamin Green, Shirley Greenbaum, Noah F Greenwald, Cyrus V Hedvat, Travis J Hollmann, Daniel Jiménez-Sánchez, Konstanty Korski, Ana Lako, Edwin R Parra, Marlon C Rebelatto, David L Rimm, Scott J Rodig, Jamie Rodriguez-Canales, Jeffrey S Roskes, Kurt A Schalper, Emanuel Schenck, Keith E Steele, Michael J Surace, Alexander S Szalay, Michael T Tetzlaff, Ignacio I Wistuba, Jennifer H Yearley, Carlo B Bifulco

Faculty, Staff and Student Publications

Objectives: Multiplex immunohistochemistry and immunofluorescence (mIHC/IF) are emerging technologies that can be used to help define complex immunophenotypes in tissue, quantify immune cell subsets, and assess the spatial arrangement of marker expression. mIHC/IF assays require concerted efforts to optimize and validate the multiplex staining protocols prior to their application on slides. The best practice guidelines for staining and validation of mIHC/IF assays across platforms were previously published by this task force. The current effort represents a complementary manuscript for mIHC/IF analysis focused on the associated image analysis and data management.

Methods: The Society for Immunotherapy of Cancer convened a task …

Clinical And Imaging Features Of Head And Neck Metastasis Of High-Grade Glioma: A Single-Center Case Series, Rami W Eldaya, Diana Kaya, Michelle Williams, Susana Calle, Dawid Schellingerhout

Faculty, Staff and Student Publications

High-grade gliomas are the most frequent primary brain tumors, yet extraneural metastasis is exceedingly rare. This is in part secondary to the relatively poor survival of these patients and likely the shielding effect of the blood-brain barrier. Given the rarity of extraneural metastasis, the pathophysiology and imaging appearance of extraneural metastasis is under-reported and poorly understood. In this case series we present 6 patients with pathology-confirmed high-grade glioma and extraneural head and neck metastasis. We highlight imaging features of metastasis on CT, MRI, and PET/CT. We also explore potential correlations and pathophysiology of high-grade glioma metastasis to the head and …

Genetic Variations In Mdm2 Gene Contribute To Renal Cell Carcinoma Susceptibility: A Genotype–Phenotype Correlation Study, Shu-Yu Chang, Wen-Shin Chang, Hou-Yu Shih, Chao-Hsiang Chang, Hsi-Chin Wu, Chia-Wen Tsai, Yun-Chi Wang, Jian Gu, Da-Tian Bau

Faculty, Staff and Student Publications

Background: This study aimed to investigate the polymorphic genotypes of MDM2 rs937282, rs937283, rs2279744, and rs769412, as well as the combined effects of MDM2 genotypes and environmental factors on RCC susceptibility.

Methods: A total of 135 RCC patients and 590 controls were recruited for MDM2 genotyping using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Quantitative PCR was performed to assess MDM2 mRNA levels among 30 healthy individuals and 22 RCC patients.

Results: MDM2 rs2279744, but not other polymorphisms, was significantly associated with an increased RCC risk (p = 0.0133). The MDM2 rs2279744 G allele was identified as …

Gene Signatures Derived From Transcriptomic-Causal Networks Stratify Colorectal Cancer Patients For Effective Targeted Therapy, Akram Yazdani, Heinz-Josef Lenz, Gianluigi Pillonetto, Raul Mendez-Giraldez, Azam Yazdani, Hanna Sanoff, Reza Hadi, Esmat Samiei, Alan P Venook, Mark J Ratain, Naim Rashid, Benjamin G Vincent, Xueping Qu, Yujia Wen, Michael Kosorok, William F Symmans, John Paul Y C Shen, Michael S Lee, Scott Kopetz, Andrew B Nixon, Monica M Bertagnolli, Charles M Perou, Federico Innocenti

Faculty, Staff and Student Publications

Background: Gene signatures derived from transcriptomic-causal networks offer potential for tailoring clinical care in cancer treatment by identifying predictive and prognostic biomarkers. This study aimed to uncover such signatures in metastatic colorectal cancer (CRC) patients to aid treatment decisions.

Methods: We constructed transcriptomic-causal networks and integrated gene interconnectivity into overall survival (OS) analysis to control for confounding genes. This integrative approach involved germline genotype and tumor RNA-seq data from 1165 metastatic CRC patients. The patients were enrolled in a randomized clinical trial receiving either cetuximab or bevacizumab in combination with chemotherapy. An external cohort of paired CRC normal and tumor …

Venetoclax-Based Combination Regimens In Acute Myeloid Leukemia, Hannah Goulart, Hagop Kantarjian, Naveen Pemmaraju, Naval Daver, Courtney D Dinardo, Caitlin R Rausch, Farhad Ravandi, Tapan M Kadia

Faculty, Staff and Student Publications

In recent years, there has been tremendous interest surrounding the integration of venetoclax into both non-intensive and intensive chemotherapy regimens for AML. However, with this increasing utilization of venetoclax, considerable questions surrounding key issues such as dosing strategies and the practicality of venetoclax administration have arisen. This review highlights the evolution of venetoclax-based regimens in AML and provides a commentary on notable practical considerations when utilizing this agent.

Toward Personalized Digital Experiences To Promote Diabetes Self-Management: Mixed Methods Social Computing Approach, Tavleen Singh, Kirk Roberts, Kayo Fujimoto, Jing Wang, Constance Johnson, Sahiti Myneni

Faculty, Staff and Student Publications

BACKGROUND: Type 2 diabetes affects nearly 34.2 million adults and is the seventh leading cause of death in the United States. Digital health communities have emerged as avenues to provide social support to individuals engaging in diabetes self-management (DSM). The analysis of digital peer interactions and social connections can improve our understanding of the factors underlying behavior change, which can inform the development of personalized DSM interventions.

OBJECTIVE: Our objective is to apply our methodology using a mixed methods approach to (1) characterize the role of context-specific social influence patterns in DSM and (2) derive interventional targets that enhance individual …

Evaluating The Effects Of High-Throughput Structural Neuroimaging Predictors On Whole-Brain Functional Connectome Outcomes Via Network-Based Matrix-On-Vector Regression, Tong Lu, Yuan Zhang, Vince Lyzinski, Chuan Bi, Peter Kochunov, Elliot Hong, Shuo Chen

Faculty, Staff and Student Publications

The joint analysis of multimodal neuroimaging data is vital in brain research, revealing complex interactions between brain structures and functions. Our study is motivated by the analysis of a vast dataset of brain functional connectivity (FC) and multimodal structural imaging (SI) features from the UK Biobank. Specifically, we aim to investigate the effects of SI features, such as white matter microstructure integrity (WMMI) and cortical thickness, on the whole-brain functional connectome network. This analysis is inherently challenging due to the extensive structural-functional associations and the intricate network patterns present in multimodal high-dimensional neuroimaging data. To bridge methodological gaps, we developed …

Organizational Readiness For Implementation: A Qualitative Assessment To Explain Survey Responses, Maria Mcclam, Lauren Workman, Timothy J Walker, Emanuelle M Dias, Derek W Craig, Joe R Padilla, Andrea E Lamont, Abraham Wandersman, Maria E Fernandez

Faculty, Staff and Student Publications

BACKGROUND: One factor considered essential to successful implementation is organizational readiness. The purpose of this study was to explore ways to improve the measurement of organizational readiness, and in particular to refine a preliminary measure based on the Readiness = Motivation x innovation Specific Capacity x General Capacity (R = MC2) heuristic. We assessed the experiences of staff in Federally Qualified Health Centers (FQHC) implementing evidence-based interventions (EBIs) designed to increase colorectal cancer screening (CRCS) who previously completed the survey and aimed to understand their perspectives on why our data were positively skewed.

METHODS: We conducted a series of qualitative …

The Gip Receptor Activates Futile Calcium Cycling In White Adipose Tissue To Increase Energy Expenditure And Drive Weight Loss In Mice, Xinxin Yu, Shiuhwei Chen, Jan-Bernd Funcke, Leon G Straub, Valentina Pirro, Margo P Emont, Brian A Droz, Kyla Ai Collins, Chanmin Joung, Mackenzie J Pearson, Corey M James, Gopal J Babu, Vissarion Efthymiou, Ashley Vernon, Mary Elizabeth Patti, Yu A An, Evan D Rosen, Matthew P Coghlan, Ricardo J Samms, Philipp E Scherer, Christine M Kusminski

Faculty, Staff and Student Publications

Obesity is a chronic disease that contributes to the development of insulin resistance, type 2 diabetes (T2D), and cardiovascular risk. Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) co-agonism provide an improved therapeutic profile in individuals with T2D and obesity when compared with selective GLP-1R agonism. Although the metabolic benefits of GLP-1R agonism are established, whether GIPR activation impacts weight loss through peripheral mechanisms is yet to be fully defined. Here, we generated a mouse model of GIPR induction exclusively in the adipocyte. We show that GIPR induction in the fat cell protects mice from diet-induced …

A Regularized Bayesian Dirichlet-Multinomial Regression Model For Integrating Single-Cell-Level Omics And Patient-Level Clinical Study Data, Yanghong Guo, Lei Yu, Lei Guo, Lin Xu, Qiwei Li

Faculty, Staff and Student Publications

The abundance of various cell types can vary significantly among patients with varying phenotypes and even those with the same phenotype. Recent scientific advancements provide mounting evidence that other clinical variables, such as age, gender, and lifestyle habits, can also influence the abundance of certain cell types. However, current methods for integrating single-cell-level omics data with clinical variables are inadequate. In this study, we propose a regularized Bayesian Dirichlet-multinomial regression framework to investigate the relationship between single-cell RNA sequencing data and patient-level clinical data. Additionally, the model employs a novel hierarchical tree structure to identify such relationships at different cell-type …

Causal Models And Prediction In Cell Line Perturbation Experiments, James P Long, Yumeng Yang, Shohei Shimizu, Thong Pham, Kim-Anh Do

Faculty, Staff and Student Publications

In cell line perturbation experiments, a collection of cells is perturbed with external agents and responses such as protein expression measured. Due to cost constraints, only a small fraction of all possible perturbations can be tested in vitro. This has led to the development of computational models that can predict cellular responses to perturbations in silico. A central challenge for these models is to predict the effect of new, previously untested perturbations that were not used in the training data. Here we propose causal structural equations for modeling how perturbations effect cells. From this model, we derive two estimators for …

Genetics And Biology Of Pancreatic Ductal Adenocarcinoma, Haoqiang Ying, Alec C Kimmelman, Nabeel Bardeesy, Raghu Kalluri, Anirban Maitra, Ronald A Depinho

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) poses a grim prognosis for patients. Recent multidisciplinary research efforts have provided critical insights into its genetics and tumor biology, creating the foundation for rational development of targeted and immune therapies. Here, we review the PDAC genomic landscape and the role of specific oncogenic events in tumor initiation and progression, as well as their contributions to shaping its tumor biology. We further summarize and synthesize breakthroughs in single-cell and metabolic profiling technologies that have illuminated the complex cellular composition and heterotypic interactions of the PDAC tumor microenvironment, with an emphasis on metabolic cross-talk across cancer and …

Sstr2-Targeted Theranostics In Hepatocellular Carcinoma, Majid Momeny, Solmaz Aghaamiri, Servando Hernandez Vargas, Belkacem Acidi, Sukhen C Ghosh, Tyler M Bateman, Jack T Adams, Vahid Khalaj, Ahmed O Kaseb, Hop S Tran Cao, Ali Azhdarinia

Faculty, Staff and Student Publications

Background: While the clinical use of radiolabeled somatostatin analogs is well established in neuroendocrine tumors, there is growing interest in expanding their application to other somatostatin receptor 2 (SSTR2)-expressing cancers. This study investigates the potential utility of SSTR2-targeted theranostics in hepatocellular carcinoma (HCC).

Methods: SSTR2 expression in HCC cell lines and clinical samples was evaluated using qRT-PCR, Western blot analysis, and a public dataset. 67Ga-DOTATATE uptake was measured, 177Lu-DOTATATE cytotoxicity was assessed, and 68Ga-DOTATATE tumor targeting was evaluated in HCC animal models and a patient via PET/CT imaging.

Results: SSTR2 expression was confirmed in HCC cell lines and clinical samples. …

Targeted Inhibition Of Aurora Kinase A Promotes Immune Checkpoint Inhibition Efficacy In Human Papillomavirus-Driven Cancers, Soma Ghosh, Madison P O'Hara, Pragya Sinha, Tuhina Mazumdar, Lacin Yapindi, Jagannadha K Sastry, Faye M Johnson

Faculty, Staff and Student Publications

Background: Human papillomavirus (HPV)-driven cancers include head and neck squamous cell carcinoma and cervical cancer and represent approximately 5% of all cancer cases worldwide. Standard-of-care chemotherapy, radiotherapy, and immune checkpoint inhibitors (ICIs) are associated with adverse effects and limited responses in patients with HPV-driven cancers. The integration of targeted therapies with ICIs may improve outcomes. In a previous study, we demonstrated that Aurora kinase A (AURKA, Aurora A) inhibitors lead to apoptosis of human HPV-positive cancer cells in vitro and in vivo. Here, we explored the potential of Aurora A inhibition to enhance response to ICIs in immune-competent …

Development Of Sacb-Based Counterselection For Efficient Allelic Exchange In Fusobacterium Nucleatum, Peng Zhou, Bibek G C, Bo Hu, Chenggang Wu

Faculty, Staff and Student Publications

Fusobacterium nucleatum, prevalent in the oral cavity, is significantly linked to overall human health. Our molecular comprehension of its role in oral biofilm formation and its interactions with the host under various pathological circumstances has seen considerable advancements in recent years, primarily due to the development of various genetic tools for DNA manipulation in this bacterium. Of these, counterselection-based unmarked in-frame mutation methods have proved notably effective. Under suitable growth conditions, cells carrying a counterselectable gene die, enabling efficient selection of rare, defined allelic exchange mutants. The sacB gene from Bacillus subtilis, encoding levansucrase, is a widely used …