Medicine and Health Sciences Commons^™

Assessing The Suitability Of A Virtual 'Pink Warrior' For Older Breast Cancer Survivors During Covid-19: A Pilot Study, Maria C Swartz, Michael C Robertson, Ursela Christopherson, Stephanie J Wells, Zakkoyya H Lewis, Jinbing Bai, Michael D Swartz, H Colleen Silva, Eloisa Martinez, Elizabeth J Lyons

Faculty, Staff and Student Publications

The COVID-19 pandemic impacted the conduct of in-person physical activity (PA) interventions among older survivors of BC, who need such interventions to stay active and prevent functional decline. We tested the feasibility of virtually delivering an exergame-based PA intervention to older BC survivors. We enrolled 20 female BC survivors ≥55 years and randomly assigned them to two groups. The intervention group (Pink Warrior 2) received 12 weekly virtual exergame sessions with behavioral coaching, survivorship navigation support, and a Fitbit for self-monitoring. The control group received 12 weekly phone-based survivorship discussion sessions and wore a Mi Band 3. Feasibility was evaluated …

The Use Of Automated Atrial Cmr Measures And A Novel Atrioventricular Coupling Index For Predicting Risk In Repaired Tetralogy Of Fallot, Megan Gunsaulus, Alejandra Bueno, Carley Bright, Katelyn Snyder, Nikkan Das, Craig Dobson, Mark Debrunner, Adam Christopher, Arvind Hoskoppal, Christopher Follansbee, Gaurav Arora, Laura Olivieri, Tarek Alsaied

Faculty, Staff and Student Publications

Atrial size and function have been recognized as markers of diastolic function, and diastolic dysfunction has been identified as a predictor of adverse outcomes in repaired tetralogy of Fallot (rTOF). This was a retrospective single-center study with the objective of investigating the use of atrial measurements obtained via CMR for predicting outcomes in rTOF patients. Automated contours of the left and right atria (LA and RA) were performed. A novel parameter, termed the Right Atrioventricular Coupling Index (RACI), was defined as the ratio of RA end-diastolic volume to right ventricle (RV) end-diastolic volume. Patients were risk-stratified using a previously validated …

Adjuvant Chemotherapy Versus Adjuvant Concurrent Chemoradiotherapy After Radical Surgery For Early-Stage Cervical Cancer: A Randomized, Non-Inferiority, Multicenter Trial, Danhui Weng, Huihua Xiong, Changkun Zhu, Xiaoyun Wan, Yaxia Chen, Xinyu Wang, Youzhong Zhang, Jie Jiang, Xi Zhang, Qinglei Gao, Gang Chen, Hui Xing, Changyu Wang, Kezhen Li, Yaheng Chen, Yuyan Mao, Dongxiao Hu, Zimin Pan, Qingqin Chen, Baoxia Cui, Kun Song, Cunjian Yi, Guangcai Peng, Xiaobing Han, Ruifang An, Liangsheng Fan, Wei Wang, Tingchuan Xiong, Yile Chen, Zhenzi Tang, Lin Li, Xingsheng Yang, Xiaodong Cheng, Weiguo Lu, Hui Wang, Beihua Kong, Xing Xie, Ding Ma

Faculty, Staff and Student Publications

We conducted a prospective study to assess the non-inferiority of adjuvant chemotherapy alone versus adjuvant concurrent chemoradiotherapy (CCRT) as an alternative strategy for patients with early-stage (FIGO 2009 stage IB-IIA) cervical cancer having risk factors after surgery. The condition was assessed in terms of prognosis, adverse effects, and quality of life. This randomized trial involved nine centers across China. Eligible patients were randomized to receive adjuvant chemotherapy or CCRT after surgery. The primary end-point was progression-free survival (PFS). From December 2012 to December 2014, 337 patients were subjected to randomization. Final analysis included 329 patients, including 165 in the adjuvant …

Cd5 Expression By Dendritic Cells Directs T Cell Immunity And Sustains Immunotherapy Responses, Mingyu He, Kate Roussak, Feiyang Ma, Nicholas Borcherding, Vince Garin, Mike White, Charles Schutt, Trine I Jensen, Yun Zhao, Courtney A Iberg, Kairav Shah, Himanshi Bhatia, Daniel Korenfeld, Sabrina Dinkel, Judah Gray, Alina Ulezko Antonova, Stephen Ferris, David Donermeyer, Cecilia Lindestam Arlehamn, Matthew M Gubin, Jingqin Luo, Laurent Gorvel, Matteo Pellegrini, Alessandro Sette, Thomas Tung, Rasmus Bak, Robert L Modlin, Ryan C Fields, Robert D Schreiber, Paul M Allen, Eynav Klechevsky

Faculty, Staff and Student Publications

The induction of proinflammatory T cells by dendritic cell (DC) subtypes is critical for antitumor responses and effective immune checkpoint blockade (ICB) therapy. Here, we show that human CD1c+CD5+ DCs are reduced in melanoma-affected lymph nodes, with CD5 expression on DCs correlating with patient survival. Activating CD5 on DCs enhanced T cell priming and improved survival after ICB therapy. CD5+ DC numbers increased during ICB therapy, and low interleukin-6 (IL-6) concentrations promoted their de novo differentiation. Mechanistically, CD5 expression by DCs was required to generate optimally protective CD5hi T helper and CD8+ T cells; further, deletion of CD5 from T …

Exploiting Prmt5 As A Target For Combination Therapy In Mantle Cell Lymphoma Characterized By Frequent Atm And Tp53 Mutations, Yuxuan Che, Yang Liu, Yixin Yao, Holly A Hill, Yijing Li, Qingsong Cai, Fangfang Yan, Preetesh Jain, Wei Wang, Lixin Rui, Michael Wang

Faculty, Staff and Student Publications

Constant challenges for the treatment of mantle cell lymphoma (MCL) remain to be recurrent relapses and therapy resistance, especially in patients harboring somatic mutations in the tumor suppressors ATM and TP53, which are accumulated as therapy resistance emerges and the disease progresses, consistent with our OncoPrint results that ATM and TP53 alterations were most frequent in relapsed/refractory (R/R) MCL. We demonstrated that protein arginine methyltransferase-5 (PRMT5) was upregulated in R/R MCL, which predicted a poor prognosis. PRMT5 inhibitors displayed profound antitumor effects in the mouse models of MCL with mutated ATM and/or TP53, or refractory to CD19-targeted CAR T-cell therapy. …

Drug-Like Small Molecules That Inhibit Expression Of The Oncogenic Microrna-21, Matthew D Shortridge, Bhawna Chaubey, Huanyu J Zhang, Thomas Pavelitz, Venkata Vidadala, Changyan Tang, Gregory L Olsen, George A Calin, Gabriele Varani

Faculty, Staff and Student Publications

We report the discovery of drug-like small molecules that bind specifically to the precursor of the oncogenic and pro-inflammatory microRNA-21 with mid-nanomolar affinity. The small molecules target a local structure at the Dicer cleavage site and induce distinctive structural changes in the RNA, which correlate with specific inhibition of miRNA processing. Structurally conservative single nucleotide substitutions eliminate the conformational change induced by the small molecules, which is also not observed in other miRNA precursors. The most potent of these compounds reduces cellular proliferation and miR-21 levels in cancer cell lines without inhibiting kinases or classical receptors, while closely related compounds …

Exploiting Metabolic Vulnerabilities After Anti-Vegf Antibody Therapy In Ovarian Cancer, Deanna Glassman, Mark S Kim, Meredith Spradlin, Sunil Badal, Mana Taki, Pratip Bhattacharya, Prasanta Dutta, Charles V Kingsley, Katherine I Foster, Olamide Animasahun, Jin Heon Jeon, Abhinav Achreja, Anusha Jayaraman, Praveen Kumar, Minal Nenwani, Fulei Wuchu, Emine Bayraktar, Yutuan Wu, Elaine Stur, Lingegowda Mangala, Sanghoon Lee, Timothy A Yap, Shannon N Westin, Livia S Eberlin, Deepak Nagrath, Anil K Sood

Faculty, Staff and Student Publications

Despite modest clinical improvement with anti-vascular endothelial growth factor antibody (AVA) therapy in ovarian cancer, adaptive resistance is ubiquitous and additional options are limited. A dependence on glutamine metabolism, via the enzyme glutaminase (GLS), is a known mechanism of adaptive resistance and we aimed to investigate the utility of a GLS inhibitor (GLSi). Our in vitro findings demonstrated increased glutamine abundance and a significant cytotoxic effect in AVA-resistant tumors when GLSi was administered in combination with bevacizumab. In vivo, GLSi led to a reduction in tumor growth as monotherapy and when combined with AVA. Furthermore, GLSi initiated after the emergence …

Endothelial-To-Osteoblast Transition In Normal Mouse Bone Development, Song-Chang Lin, Guoyu Yu, Yu-Chen Lee, Jian H Song, Xingzhi Song, Jianhua Zhang, Theocharis Panaretakis, Christopher J Logothetis, Yoshihiro Komatsu, Li-Yuan Yu-Lee, Guocan Wang, Sue-Hwa Lin

Faculty, Staff and Student Publications

Metastatic prostate cancer (PCa) in bone induces bone-forming lesions. We have previously shown that PCa-induced bone originates from endothelial cells (ECs) that have undergone EC-to-osteoblast (OSB) transition. Here, we investigated whether EC-to-OSB transition also occurs during normal bone formation. We developed an EC and OSB dual-color reporter mouse (DRM) model that marks EC-OSB hybrid cells with red and green fluorescent proteins. We observed EC-to-OSB transition (RFP and GFP co-expression) in both endochondral and intramembranous bone formation during embryonic development and in adults. Co-expression was confirmed in cells isolated from DRM. Bone marrow– and lung-derived ECs underwent transition to OSBs and …

Functional Connectivity Signatures Of Nmdar Dysfunction In Schizophrenia—Integrating Findings From Imaging Genetics And Pharmaco-Fmri, Arnim J Gaebler, Nilüfer Fakour, Felix Stöhr, Jana Zweerings, Arezoo Taebi, Mariia Suslova, Juergen Dukart, Joerg F Hipp, Bhim M Adhikari, Peter Kochunov, Suresh D Muthukumaraswamy, Anna Forsyth, Thomas Eggermann, Florian Kraft, Ingo Kurth, Michael Paulzen, Gerhard Gründer, Frank Schneider, Klaus Mathiak

Faculty, Staff and Student Publications

Both, pharmacological and genome-wide association studies suggest N-methyl-D-aspartate receptor (NMDAR) dysfunction and excitatory/inhibitory (E/I)-imbalance as a major pathophysiological mechanism of schizophrenia. The identification of shared fMRI brain signatures of genetically and pharmacologically induced NMDAR dysfunction may help to define biomarkers for patient stratification. NMDAR-related genetic and pharmacological effects on functional connectivity were investigated by integrating three different datasets: (A) resting state fMRI data from 146 patients with schizophrenia genotyped for the disease-associated genetic variant rs7191183 of GRIN2A (encoding the NMDAR 2 A subunit) as well as 142 healthy controls. (B) Pharmacological effects of the NMDAR antagonist ketamine and the GABA-A …

A Deep Learning Approach To Identify Missing Is-A Relations In Snomed Ct, Rashmie Abeysinghe, Fengbo Zheng, Elmer V Bernstam, Jay Shi, Olivier Bodenreider, Licong Cui

Faculty, Staff and Student Publications

OBJECTIVE: SNOMED CT is the largest clinical terminology worldwide. Quality assurance of SNOMED CT is of utmost importance to ensure that it provides accurate domain knowledge to various SNOMED CT-based applications. In this work, we introduce a deep learning-based approach to uncover missing is-a relations in SNOMED CT.

MATERIALS AND METHODS: Our focus is to identify missing is-a relations between concept-pairs exhibiting a containment pattern (ie, the set of words of one concept being a proper subset of that of the other concept). We use hierarchically related containment concept-pairs as positive instances and hierarchically unrelated containment concept-pairs as negative instances …

Structural Basis Of Impaired Disaggregase Function In The Oxidation-Sensitive Skd3 Mutant Causing 3-Methylglutaconic Aciduria, Jose J Gorbea Colón, Leon Palao, Shin-Fu Chen, Hee Jong Kim, Laura Snyder, Yi-Wei Chang, Kuang-Lei Tsai, Kenji Murakami

Faculty, Staff and Student Publications

Most eukaryotic promoter regions are divergently transcribed. As the RNA polymerase II pre-initiation complex (PIC) is intrinsically asymmetric and responsible for transcription in a single direction, it is unknown how divergent transcription arises. Here, the Saccharomyces cerevisiae Mediator complexed with a PIC (Med-PIC) was assembled on a divergent promoter and analyzed by cryoelectron microscopy. The structure reveals two distinct Med-PICs forming a dimer through the Mediator tail module, induced by a homodimeric activator protein localized near the dimerization interface. The tail dimer is associated with ∼80-bp upstream DNA, such that two flanking core promoter regions are positioned and oriented in …

Genome-Wide Identification, Characterization, And Expression Analysis Of Spiral1 Family Genes In Legume Species, Qianxia Yu, Junjie Liu, Jiayu Jiang, Fudong Liu, Zhen Zhang, Xiaoye Yu, Mengru Li, Intikhab Alam, Liangfa Ge

Faculty, Staff and Student Publications

The SPIRAL1 (SPR1) gene family encodes microtubule-associated proteins that are essential for the anisotropic growth of plant cells and abiotic stress resistance. Currently, little is known about the characteristics and roles of the gene family outside of Arabidopsis thaliana. This study intended to investigate the SPR1 gene family in legumes. In contrast to that of A. thaliana, the gene family has undergone shrinking in the model legume species Medicago truncatula and Glycine max. While the orthologues of SPR1 were lost, very few SPR1-Like (SP1L) genes were identified given the genome size of the two …

Using Artificial Intelligence To Improve Pain Assessment And Pain Management: A Scoping Review, Meina Zhang, Linzee Zhu, Shih-Yin Lin, Keela Herr, Chih-Lin Chi, Ibrahim Demir, Karen Dunn Lopez, Nai-Ching Chi

Faculty, Staff and Student Publications

CONTEXT: Over 20% of US adults report they experience pain on most days or every day. Uncontrolled pain has led to increased healthcare utilization, hospitalization, emergency visits, and financial burden. Recognizing, assessing, understanding, and treating pain using artificial intelligence (AI) approaches may improve patient outcomes and healthcare resource utilization. A comprehensive synthesis of the current use and outcomes of AI-based interventions focused on pain assessment and management will guide the development of future research.

OBJECTIVES: This review aims to investigate the state of the research on AI-based interventions designed to improve pain assessment and management for adult patients. We also …

A Human Stem Cell-Derived Neuronal Model Of Morphine Exposure Reflects Brain Dysregulation In Opioid Use Disorder: Transcriptomic And Epigenetic Characterization Of Postmortem-Derived Ipsc Neurons, Emily F Mendez, Sandra L Grimm, Laura Stertz, Damian Gorski, Sai V Movva, Katherine Najera, Karla Moriel, Thomas D Meyer, Gabriel R Fries, Cristian Coarfa, Consuelo Walss-Bass

Faculty, Staff and Student Publications

INTRODUCTION: Human-derived induced pluripotent stem cell (iPSC) models of brain promise to advance our understanding of neurotoxic consequences of drug use. However, how well these models recapitulate the actual genomic landscape and cell function, as well as the drug-induced alterations, remains to be established. New

METHODS: We engineered a novel induced pluripotent stem cell-derived model of neural progenitor cells and neurons from cultured postmortem human skin fibroblasts, and directly compared these to isogenic brain tissue from the donor source. We assessed the maturity of the cell models across differentiation from stem cells to neurons using RNA cell type and maturity …

A Retrospective Study Of Cladribine And Low-Dose Cytarabine-Based Regimens For The Treatment Of Chronic Myelomonocytic Leukemia And Secondary Acute Myeloid Leukemia, Alexandre Bazinet, Faezeh Darbaniyan, Tapan M Kadia, Sangeetha Venugopal, Rashmi Kanagal-Shamanna, Courtney D Dinardo, Gautam Borthakur, Elias J Jabbour, Naval G Daver, Naveen Pemmaraju, Marina Y Konopleva, Farhad Ravandi, Koji Sasaki, Kelly S Chien, Danielle Hammond, Sherry A Pierce, Hagop M Kantarjian, Guillermo Garcia-Manero, Guillermo Montalban-Bravo

Faculty, Staff and Student Publications

Background: Patients with higher risk chronic myelomonocytic leukemia (CMML) have limited therapeutic options beyond hydroxyurea and hypomethylating agents (HMAs). Regimens based on a backbone of cladribine (CLAD), low-dose cytarabine (LDAC), and an HMA are effective low-intensity therapies for acute myeloid leukemia (AML).

Methods: The authors conducted a retrospective chart review to evaluate the efficacy of CLAD/LDAC/HMA in CMML and secondary acute myeloid leukemia (sAML) arising from CMML. Responses were evaluated according to the 2006 International Working Group criteria for CMML and the 2017 European LeukemiaNet criteria for AML. The overall survival (OS), leukemia-free survival (LFS), and duration of response were …

A Phase 1 Study To Evaluate The Safety, Pharmacology, And Feasibility Of Continuous Infusion Nelarabine In Patients With Relapsed And/Or Refractory Lymphoid Malignancies, Prajwal C Boddu, Jayastu Senapati, Farhad Ravandi-Kashani, Elias J Jabbour, Nitin Jain, Mary Ayres, Yuling Chen, Michael J Keating, Hagop M Kantarjian, Varsha Gandhi, Tapan M Kadia

Faculty, Staff and Student Publications

Background: Nelarabine is a purine nucleoside analogue prodrug approved for the treatment of relapsed and refractory T-cell acute lymphoblastic leukemia (R/R T-ALL) and lymphoblastic lymphoma (T-LBL). Although effective in R/R T-ALL, significant neurotoxicity is dose-limiting and such neurotoxicity associated with nucleoside analogues can be related to dosing schedule.

Methods: The authors conducted a phase 1 study to evaluate the pharmacokinetics and toxicity of nelarabine administered as a continuous infusion (CI) for 5 days (120 hours), rather than the standard, short-infusion approach.

Results: Twenty-nine patients with R/R T-ALL/LBL or T-cell prolymphocytic leukemia (T-PLL) were treated, with escalating doses of nelarabine from …

Brainstorm-Duneuro: An Integrated And User-Friendly Finite Element Method For Modeling Electromagnetic Brain Activity, Takfarinas Medani, Juan Garcia-Prieto, Francois Tadel, Marios Antonakakis, Tim Erdbrügger, Malte Höltershinken, Wayne Mead, Sophie Schrader, Anand Joshi, Christian Engwer, Carsten H Wolters, John C Mosher, Richard M Leahy

Faculty, Staff and Student Publications

Human brain activity generates scalp potentials (electroencephalography - EEG), intracranial potentials (iEEG), and external magnetic fields (magnetoencephalography - MEG). These electrophysiology (e-phys) signals can often be measured simultaneously for research and clinical applications. The forward problem involves modeling these signals at their sensors for a given equivalent current dipole configuration within the brain. While earlier researchers modeled the head as a simple set of isotropic spheres, today's magnetic resonance imaging (MRI) data allow for a detailed anatomic description of brain structures and anisotropic characterization of tissue conductivities. We present a complete pipeline, integrated into the Brainstorm software, that allows users …

Lewy Body-Like Pathology And Loss Of Dopaminergic Neurons In Midbrain Organoids Derived From Familial Parkinson’S Disease Patient, Andrea Becerra-Calixto, Abhisek Mukherjee, Santiago Ramirez, Sofia Sepulveda, Tirthankar Sinha, Rabab Al-Lahham, Nicole De Gregorio, Camila Gherardelli, Claudio Soto

Faculty, Staff and Student Publications

Progressive accumulation of α-Synuclein (αSyn) in Lewy bodies (LBs) and loss of dopaminergic (DA) neurons are the hallmark pathological features of Parkinson's disease (PD). Although currently available in vitro and in vivo models have provided crucial information about PD pathogenesis, the mechanistic link between the progressive accumulation of αSyn into LBs and the loss of DA neurons is still unclear. To address this, it is critical to model LB formation and DA neuron loss, the two key neuropathological aspects of PD, in a relevant in vitro system. In this study, we developed a human midbrain-like organoid (hMBO) model of PD. …

Mortality And Major Adverse Cardiovascular Events In Hospitalized Patients With Atrial Fibrillation With Covid-19, Lucas Wang, Lawrence Hoang, Kristopher Aten, Mujahed Abualfoul, Victor Canela, Sri Prathivada, Michael Vu, Yi Zhao, Manavjot Sidhu

Faculty, Staff and Student Publications

COVID-19 results in increased incidence of cardiac arrhythmias, including atrial fibrillation (AF). However, little is known about the combined effect of AF and COVID-19 on patient outcomes. This study aimed to determine if AF, specifically new-onset AF (NOAF), is associated with increased risk of mortality and major adverse cardiovascular events (MACEs) in hospitalized patients with COVID-19. This multicenter retrospective analysis identified 2,732 patients with COVID-19 admitted between March and December 2020. Data points were manually reviewed in the patients' electronic health records. Multivariate logistic regression was used to assess if AF was associated with death or MACE. Patients with AF …

Triple Combination Targeting Methyltransferase, Bcl-2, And Pd-1 Facilitates Antileukemia Responses In Acute Myeloid Leukemia, Zhihong Zeng, Abhishek Maiti, Shelley Herbrich, Tianyu Cai, Antonio Cavazos, Taylor Manzella, Helen Ma, Kala Hayes, Jairo Matthews, Courtney D Dinardo, Naval G Daver, Marina Y Konopleva

Faculty, Staff and Student Publications

Background: A recent breakthrough therapy combining the BCL-2 inhibitor venetoclax with hypomethylating agents (HMAs) targeting DNA methyltransferase has improved outcomes for patients with acute myeloid leukemia (AML), but the responses and long-term survival in older/unfit patients and in patients with relapsed/refractory AML remain suboptimal. Recent studies showed that inhibition of BCL-2 or DNA methyltransferase modulates AML T-cell immunity.

Methods: By using flow cytometry and time-of-flight mass cytometry, the authors examined the effects of the HMA decitabine combined with the BCL-2 inhibitor venetoclax (DAC/VEN therapy) on leukemia cells and T cells in patients with AML who received DAC/VEN therapy in a …

Waking Immune-Resistant Tumors With Neddylation, Kristin Huntoon, Wen Jiang, Betty Ys Kim

Faculty, Staff and Student Publications

The CD47/signal regulatory protein α (SIRPα) axis, which functions as an inhibitory phagocytosis checkpoint, also serves as a key mediator in cancer immune evasion. Many cancers, including colorectal cancer (CRC), exploit the expression of CD47 to escape phagocytic clearance and activate the innate immune system. Previous work has indicated that distinct paradigms of posttranslational modifications mediate the regulatory mechanisms of the CD47/SIRPα axis. In this issue of the JCI, Li et al. show that neddylation, a ubiquitin-like modification, inactivates Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2), a downstream target of this pathway. They further show that inhibition of …

Combination Of Epha2- And Wee1-Targeted Therapies In Endometrial Cancer, Santosh K Dasari, Robiya Joseph, Sujanitha Umamaheswaran, Lingegowda S Mangala, Emine Bayraktar, Cristian Rodriguez-Aguayo, Yutuan Wu, Nghi Nguyen, Reid T Powell, Mary Sobieski, Yuan Liu, Mamur A Chowdhury, Paola Amero, Clifford Stephan, Gabriel Lopez-Berestein, Shannon N Westin, Anil K Sood

Faculty, Staff and Student Publications

EphA2 tyrosine kinase is upregulated in many cancers and correlated with poor survival of patients, including those with endometrial cancer. EphA2-targeted drugs have shown modest clinical benefit. To improve the therapeutic response to such drugs, we performed a high-throughput chemical screen to discover novel synergistic partners for EphA2-targeted therapeutics. Our screen identified the Wee1 kinase inhibitor, MK1775, as a synergistic partner to EphA2, and this finding was confirmed using both in vitro and in vivo experiments. We hypothesized that Wee1 inhibition would sensitize cells to EphA2-targeted therapy. Combination treatment decreased cell viability, induced apoptosis, and reduced clonogenic potential in endometrial …

Ush2a Mutation And Specific Driver Mutation Subtypes Are Associated With Clinical Efficacy Of Immune Checkpoint Inhibitors In Lung Cancer, Dexin Yang, Yuqin Feng, Haohua Lu, Kelie Chen, Jinming Xu, Peiwei Li, Tianru Wang, Dajing Xia, Yihua Wu

Faculty, Staff and Student Publications

This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors (ICIs) by conducting systematic literature search in electronic databases up to May 31, 2021. The main outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and durable clinical benefit (DCB) were correlated with tumor genomic features. A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies. The Kirsten rat sarcoma viral oncogene homolog

Itch And Janus Kinase Inhibitors, Yujin Han, Yu Ri Woo, Sang Hyun Cho, Jeong Deuk Lee, Hei Sung Kim

Faculty, Staff and Student Publications

Itch is a common skin symptom, with complex aetiology and pathogenesis. It is mediated by 2 pathways, the histaminergic and non-histaminergic pathways. Chronic itch is understood to be processed by the latter and is difficult to treat with traditional pruritus therapies. The Janus kinase and signal transducer and activator of transcription pathway is a signalling mechanism that regulates gene expression through various cytokines. Janus kinase inhibitors, which have been tested and used for several autoimmune diseases, have also been shown to be effective for itch through clinical trials and case reports. Janus kinase inhibitors could be a good choice for …

Baseline Extracellular Vesicle Tgf-Β Is A Predictive Biomarker For Response To Immune Checkpoint Inhibitors And Survival In Non-Small Cell Lung Cancer, Diego De Miguel-Perez, Alessandro Russo, Muthukumar Gunasekaran, Francesco Buemi, Lisa Hester, Xiaoxuan Fan, Brandon A Carter-Cooper, Rena G Lapidus, Ariel Peleg, Marisol Arroyo-Hernández, Andres F Cardona, Aung Naing, Fred R Hirsch, Philip C Mack, Sunjay Kaushal, Maria Jose Serrano, Vincenzo Adamo, Oscar Arrieta, Christian Rolfo

Faculty, Staff and Student Publications

Background: Immune-checkpoint inhibitors (ICIs) are an effective therapeutic strategy, improving the survival of patients with lung cancer compared with conventional treatments. However, novel predictive biomarkers are needed to stratify which patients derive clinical benefit because the currently used and highly heterogenic histological PD-L1 has shown low accuracy. Liquid biopsy is the analysis of biomarkers in body fluids and represents a minimally invasive tool that can be used to monitor tumor evolution and treatment effects, potentially reducing biases associated with tumor heterogeneity associated with tissue biopsies. In this context, cytokines, such as transforming growth factor-β (TGF-β), can be found free in …

Curq+, A Next-Generation Formulation Of Curcumin, Ameliorates Growth Plate Chondrocyte Stress And Increases Limb Growth In A Mouse Model Of Pseudoachondroplasia, Jacqueline T Hecht, Alka C Veerisetty, Mohammad G Hossain, Frankie Chiu, Karen L Posey

Faculty, Staff and Student Publications

Mutations in cartilage oligomeric matrix protein (COMP) causes protein misfolding and accumulation in chondrocytes that compromises skeletal growth and joint health in pseudoachondroplasia (PSACH), a severe dwarfing condition. Using the MT-COMP mice, a murine model of PSACH, we showed that pathological autophagy blockage was key to the intracellular accumulation of mutant-COMP. Autophagy is blocked by elevated mTORC1 signaling, preventing ER clearance and ensuring chondrocyte death. We demonstrated that resveratrol reduces the growth plate pathology by relieving the autophagy blockage allowing the ER clearance of mutant-COMP, which partially rescues limb length. To expand potential PSACH treatment options, CurQ+, a uniquely absorbable …

Staphylococcus Aureus Breast Implant Infection Isolates Display Recalcitrance To Antibiotic Pocket Irrigants, Jesus M Duran Ramirez, Jana Gomez, Blake M Hanson, Taha Isa, Terence M Myckatyn, Jennifer N Walker

Faculty, Staff and Student Publications

Breast implant-associated infections (BIAIs) are the primary complication following placement of breast prostheses in breast cancer reconstruction. Given the prevalence of breast cancer, reconstructive failure due to infection results in significant patient distress and health care expenditures. Thus, effective BIAI prevention strategies are urgently needed. This study tests the efficacy of one infection prevention strategy: the use of a triple antibiotic pocket irrigant (TAPI) against Staphylococcus aureus, the most common cause of BIAIs. TAPI, which consists of 50,000 U bacitracin, 1 g cefazolin, and 80 mg gentamicin diluted in 500 mL of saline, is used to irrigate the breast implant …

Influence Of County-Level Geographic/Ancestral Origin On Glioma Incidence And Outcomes In Us Hispanics, Kyle M Walsh, Corey Neff, Melissa L Bondy, Carol Kruchko, Jason T Huse, Christopher I Amos, Jill S Barnholtz-Sloan, Quinn T Ostrom

Faculty, Staff and Student Publications

BACKGROUND: Glioma incidence is 25% lower in Hispanics than White non-Hispanics. The US Hispanic population is diverse, and registry-based analyses may mask incidence differences associated with geographic/ancestral origins.

METHODS: County-level glioma incidence data in Hispanics were retrieved from the Central Brain Tumor Registry of the United States. American Community Survey data were used to determine the county-level proportion of the Hispanic population of Mexican/Central American and Caribbean origins. Age-adjusted incidence rate ratios and incidence rate ratios (IRRs) quantified the glioma incidence differences across groups. State-level estimates of admixture in Hispanics were obtained from published 23andMe data.

RESULTS: Compared to predominantly …

Curq+, A Next-Generation Formulation Of Curcumin, Ameliorates Growth Plate Chondrocyte Stress And Increases Limb Growth In A Mouse Model Of Pseudoachondroplasia, Jacqueline T Hecht, Alka C Veerisetty, Mohammad G Hossain, Frankie Chiu, Karen L Posey

Faculty, Staff and Student Publications

Mutations in cartilage oligomeric matrix protein (COMP) causes protein misfolding and accumulation in chondrocytes that compromises skeletal growth and joint health in pseudoachondroplasia (PSACH), a severe dwarfing condition. Using the MT-COMP mice, a murine model of PSACH, we showed that pathological autophagy blockage was key to the intracellular accumulation of mutant-COMP. Autophagy is blocked by elevated mTORC1 signaling, preventing ER clearance and ensuring chondrocyte death. We demonstrated that resveratrol reduces the growth plate pathology by relieving the autophagy blockage allowing the ER clearance of mutant-COMP, which partially rescues limb length. To expand potential PSACH treatment options, CurQ+, a uniquely absorbable …

Depatuxizumab Mafodotin In Egfr-Amplified Newly Diagnosed Glioblastoma: A Phase Iii Randomized Clinical Trial, Andrew B Lassman, Stephanie L Pugh, Tony J C Wang, Kenneth Aldape, Hui K Gan, Matthias Preusser, Michael A Vogelbaum, Erik P Sulman, Minhee Won, Peixin Zhang, Golnaz Moazami, Marian S Macsai, Mark R Gilbert, Earle E Bain, Vincent Blot, Peter J Ansell, Suvajit Samanta, Madan G Kundu, Terri S Armstrong, Jeffrey S Wefel, Clemens Seidel, Filip Y De Vos, Sigmund Hsu, Andrés F Cardona, Giuseppe Lombardi, Dmitry Bentsion, Richard A Peterson, Craig Gedye, Véronique Bourg, Antje Wick, Walter J Curran, Minesh P Mehta

Faculty, Staff and Student Publications

BACKGROUND: Approximately 50% of newly diagnosed glioblastomas (GBMs) harbor epidermal growth factor receptor gene amplification (EGFR-amp). Preclinical and early-phase clinical data suggested efficacy of depatuxizumab mafodotin (depatux-m), an antibody-drug conjugate comprised of a monoclonal antibody that binds activated EGFR (overexpressed wild-type and EGFRvIII-mutant) linked to a microtubule-inhibitor toxin in EGFR-amp GBMs.

METHODS: In this phase III trial, adults with centrally confirmed, EGFR-amp newly diagnosed GBM were randomized 1:1 to radiotherapy, temozolomide, and depatux-m/placebo. Corneal epitheliopathy was treated with a combination of protocol-specified prophylactic and supportive measures. There was 85% power to detect a hazard ratio (HR) ≤0.75 for overall survival …