Biomedical Informatics Commons^™

Mesoporous Silica Nanoparticles As A Gene Delivery Platform For Cancer Therapy, Nisar Ul Khaliq, Juyeon Lee, Joohyeon Kim, Yejin Kim, Sohyeon Yu, Jisu Kim, Sangwoo Kim, Daekyung Sung, Hyungjun Kim

Faculty, Staff and Student Publications

Cancer remains a major global health challenge. Traditional chemotherapy often results in side effects and drug resistance, necessitating the development of alternative treatment strategies such as gene therapy. Mesoporous silica nanoparticles (MSNs) offer many advantages as a gene delivery carrier, including high loading capacity, controlled drug release, and easy surface functionalization. MSNs are biodegradable and biocompatible, making them promising candidates for drug delivery applications. Recent studies demonstrating the use of MSNs for the delivery of therapeutic nucleic acids to cancer cells have been reviewed, along with their potential as a tool for cancer therapy. The major challenges and future interventions …

Immune Checkpoint Therapy Combinations In Adult Advanced Mit Family Translocation Renal Cell Carcinomas, Omar Alhalabi, Jonathan Thouvenin, Sylvie Négrier, Yann-Alexandre Vano, Luca Campedel, Elshad Hasanov, Ziad Bakouny, Andrew W Hahn, Mehmet Asim Bilen, Pavlos Msaouel, Toni K Choueiri, Srinivas R Viswanathan, Kanishka Sircar, Laurence Albiges, Gabriel G Malouf, Nizar M Tannir

Faculty, Staff and Student Publications

Background: There remains a paucity of data regarding the efficacy of immune checkpoint therapy (ICT) combinations ± vascular endothelial growth factor (VEGF) targeted therapy (TT) in translocation renal cell carcinoma (tRCC).

Methods: This is a retrospective study of patients with advanced tRCC treated with ICT combinations at 11 centers in the US, France, and Belgium. Only cases with confirmed fluorescence in situ hybridization (FISH) were included. Objective response rates (ORR) and progression-free survival (PFS) were assessed by RECIST, and overall survival (OS) was estimated by Kaplan-Meier methods.

Results: There were 29 patients identified with median age of 38 (21-70) years, …

Immune Checkpoint Therapy Combinations In Adult Advanced Mit Family Translocation Renal Cell Carcinomas, Omar Alhalabi, Jonathan Thouvenin, Sylvie Négrier, Yann-Alexandre Vano, Luca Campedel, Elshad Hasanov, Ziad Bakouny, Andrew W Hahn, Mehmet Asim Bilen, Pavlos Msaouel, Toni K Choueiri, Srinivas R Viswanathan, Kanishka Sircar, Laurence Albiges, Gabriel G Malouf, Nizar M Tannir

Faculty, Staff and Student Publications

Background: There remains a paucity of data regarding the efficacy of immune checkpoint therapy (ICT) combinations ± vascular endothelial growth factor (VEGF) targeted therapy (TT) in translocation renal cell carcinoma (tRCC).

Methods: This is a retrospective study of patients with advanced tRCC treated with ICT combinations at 11 centers in the US, France, and Belgium. Only cases with confirmed fluorescence in situ hybridization (FISH) were included. Objective response rates (ORR) and progression-free survival (PFS) were assessed by RECIST, and overall survival (OS) was estimated by Kaplan-Meier methods.

Results: There were 29 patients identified with median age of 38 (21-70) years, …

Integrative Molecular Subtypes Of Acute Myeloid Leukemia, Qianxing Mo, Seongseok Yun, David A Sallman, Nicole D Vincelette, Guang Peng, Ling Zhang, Jeffrey E Lancet, Eric Padron

Faculty, Staff and Student Publications

No abstract provided.

Medical-Legal Partnership Effects On Mental Health, Health Care Use, And Quality Of Life In Primary Care: A Randomized Clinical Trial, Winston Liaw, Thomas F Northrup, Angela L Stotts, Christine Bakos-Block, Robert Suchting, Alvin Chen, Abigail Hernandez, Lisandra Finzetto, Charles Green, Thomas Murphy

Faculty, Staff and Student Publications

Purpose: To determine whether an immediate referral to a medical-legal partnership (MLP), compared with a 6-month waitlist control, improved mental health, health care use, and quality of life.

Methods: This trial randomly assigned individuals to an immediate referral or a wait-list control. The MLP involved a collaboration between the primary care clinic and a legal services organization. The primary outcome was stress (6 months) as measured by the Perceived Stress Scale (PSS). Secondary measures included the Center for Epidemiologic Studies Depression Scale; Generalized Anxiety Disorder scale (GAD-7); Patient-Reported Outcomes Measurement Information System (PROMIS); and emergency department (ED), urgent care, and …

Lifetime Ovulatory Years And Risk Of Epithelial Ovarian Cancer: A Multinational Pooled Analysis, Zhuxuan Fu, Maria Mori Brooks, Sarah Irvin, Susan Jordan, Katja K H Aben, Hoda Anton-Culver, Elisa V Bandera, Matthias W Beckmann, Andrew Berchuck, Angela Brooks-Wilson, Jenny Chang-Claude, Linda S Cook, Daniel W Cramer, Kara L Cushing-Haugen, Jennifer A Doherty, Arif B Ekici, Peter A Fasching, Renée T Fortner, Simon A Gayther, Aleksandra Gentry-Maharaj, Graham G Giles, Ellen L Goode, Marc T Goodman, Holly R Harris, Alexander Hein, Rudolf Kaaks, Lambertus A Kiemeney, Martin Köbel, Joanne Kotsopoulos, Nhu D Le, Alice W Lee, Keitaro Matsuo, Valerie Mcguire, John R Mclaughlin, Usha Menon, Roger L Milne, Kirsten B Moysich, Celeste Leigh Pearce, Malcolm C Pike, Bo Qin, Susan J Ramus, Marjorie J Riggan, Joseph H Rothstein, Joellen M Schildkraut, Weiva Sieh, Rebecca Sutphen, Kathryn L Terry, Pamela J Thompson, Linda Titus, Anne M Van Altena, Emily White, Alice S Whittemore, Anna H Wu, Wei Zheng, Argyrios Ziogas, Sarah E Taylor, Lu Tang, Thomas Songer, Nicolas Wentzensen, Penelope M Webb, Aocs Group, Harvey A Risch, Francesmary Modugno

Faculty, Staff and Student Publications

BACKGROUND: The role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC.

METHODS: LOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 control participants and 21 267 case patients from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models with …

Higher Dose Corticosteroids In Patients Admitted To Hospital With Covid-19 Who Are Hypoxic But Not Requiring Ventilatory Support (Recovery): A Randomised, Controlled, Open-Label, Platform Trial, Recovery Collaborative Group

Faculty, Staff and Student Publications

BACKGROUND: Low-dose corticosteroids have been shown to reduce mortality for patients with COVID-19 requiring oxygen or ventilatory support (non-invasive mechanical ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation). We evaluated the use of a higher dose of corticosteroids in this patient group.

METHODS: This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting adult patients with clinical evidence of hypoxia (ie, receiving oxygen or with oxygen saturation

FINDINGS: Between May 25, 2021, and May 13, 2022, 1272 patients with COVID-19 and hypoxia receiving no oxygen …

A Vlp-Based Vaccine Displaying Hbha And Mtp Antigens Of Mycobacterium Tuberculosis Induces Potentially Protective Immune Responses In M Tuberculosis H37ra Infected Mice, Juan Wang, Tao Xie, Inayat Ullah, Youjun Mi, Xiaoping Li, Yang Gong, Pu He, Yuqi Liu, Fei Li, Jixi Li, Zengjun Lu, Bingdong Zhu

Faculty, Staff and Student Publications

Heparin-binding hemagglutinin (HBHA) and M. tuberculosis pili (MTP) are important antigens on the surface of Mycobacterium tuberculosis. To display these antigens effectively, the fusion protein HBHA-MTP with a molecular weight of 20 kD (L20) was inserted into the receptor-binding hemagglutinin (HA) fragment of influenza virus and was expressed along with matrix protein M1 in Sf9 insect cells to generate influenza virus-like particles (LV20 in short). The results showed that the insertion of L20 into the envelope of the influenza virus did not affect the self-assembly and morphology of LV20 VLPs. The expression of L20 was successfully verified by transmission …

Usp36 Promotes Tumorigenesis And Drug Sensitivity Of Glioblastoma By Deubiquitinating And Stabilizing Alkbh5, Guoqiang Chang, Gloria S Xie, Li Ma, Peng Li, Linlin Li, Hope T Richard

Faculty, Staff and Student Publications

Background: ALKBH5 is aberrantly activated and exerts critical roles in facilitating the development of glioblastoma. However, the underlying activation mechanism by which ALKBH5 protein is increased in glioblastoma is not completely understood. Our study aimed to elucidate the signaling pathways involved in mediating ALKBH5 protein stability.

Methods: The contribution of deubiquitinating enzymes (DUB) to the fluctuation of ALKBH5 protein expression was globally profiled with western blot analysis. Mass spectrometry and immunoprecipitation were performed to identify the USP36 and ALKBH5 interaction. The effects of USP36 on the stability of ALKBH5 were detected with in vivo and in vitro ubiquitination assays. Cell …

Prognosticators For Patients With Pancreatic Ductal Adenocarcinoma Who Received Neoadjuvant Folfirinox Or Gemcitabine/Nab-Paclitaxel Therapy And Pancreatectomy, Yi Tat Tong, Zongshan Lai, Matthew H G Katz, Laura R Prakash, Hua Wang, Deyali Chatterjee, Michael Kim, Ching-Wei D Tzeng, Jeffrey E Lee, Naruhiko Ikoma, Asif Rashid, Robert A Wolff, Dan Zhao, Eugene J Koay, Anirban Maitra, Huamin Wang

Faculty, Staff and Student Publications

Neoadjuvant FOLFIRINOX and gemcitabine/nab-paclitaxel (GemNP) therapies are increasingly used to treat patients with pancreatic ductal adenocarcinoma (PDAC). However, limited data are available on their clinicopathologic prognosticators. We examined the clinicopathologic factors and survival of 213 PDAC patients who received FOLFIRINOX with 71 patients who received GemNP. The FOLFIRINOX group was younger (p < 0.01) and had a higher rate of radiation (p = 0.049), higher rate of borderline resectable and locally advanced disease (p < 0.001), higher rate of Group 1 response (p = 0.045) and lower ypN stage (p = 0.03) than the GemNP group. Within FOLFIRINOX group, radiation was associated with decreased lymph node metastasis (p = 0.01) and lower ypN …

Igfbp2 Expressing Midlobular Hepatocytes Preferentially Contribute To Liver Homeostasis And Regeneration, Yu-Hsuan Lin, Yonglong Wei, Qiyu Zeng, Yunguan Wang, Chase A Pagani, Lin Li, Min Zhu, Zixi Wang, Meng-Hsiung Hsieh, Natasha Corbitt, Yu Zhang, Tripti Sharma, Tao Wang, Hao Zhu

Faculty, Staff and Student Publications

Although midlobular hepatocytes in zone 2 are a recently identified cellular source for liver homeostasis and regeneration, these cells have not been exclusively fate mapped. We generated an Igfbp2-CreER knockin strain that specifically labels midlobular hepatocytes. During homeostasis over 1 year, zone 2 hepatocytes increased in abundance from occupying 21%-41% of the lobular area. After either pericentral injury with carbon tetrachloride or periportal injury with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), IGFBP2+ cells replenished lost hepatocytes in zones 3 and 1, respectively. IGFBP2+ cells also preferentially contributed to regeneration after 70% partial hepatectomy, as well as liver growth during pregnancy. Because IGFBP2 labeling increased …

Patterns Of Oncogene Coexpression At Single-Cell Resolution Influence Survival In Lymphoma, Michal Marek Hoppe, Patrick Jaynes, Fan Shuangyi, Yanfen Peng, Shruti Sridhar, Phuong Mai Hoang, Clementine Xin Liu, Sanjay De Mel, Limei Poon, Esther Hian Li Chan, Joanne Lee, Choon Kiat Ong, Tiffany Tang, Soon Thye Lim, Chandramouli Nagarajan, Nicholas F Grigoropoulos, Soo-Yong Tan, Susan Swee-Shan Hue, Sheng-Tsung Chang, Shih-Sung Chuang, Shaoying Li, Joseph D Khoury, Hyungwon Choi, Carl Harris, Alessia Bottos, Laura J Gay, Hendrik F P Runge, Ilias Moutsopoulos, Irina Mohorianu, Daniel J Hodson, Pedro Farinha, Anja Mottok, David W Scott, Jason J Pitt, Jinmiao Chen, Gayatri Kumar, Kasthuri Kannan, Wee Joo Chng, Yen Lin Chee, Siok-Bian Ng, Claudio Tripodo, Anand D Jeyasekharan

Faculty, Staff and Student Publications

Cancers often overexpress multiple clinically relevant oncogenes, but it is not known if combinations of oncogenes in cellular subpopulations within a cancer influence clinical outcomes. Using quantitative multispectral imaging of the prognostically relevant oncogenes MYC, BCL2, and BCL6 in diffuse large B-cell lymphoma (DLBCL), we show that the percentage of cells with a unique combination MYC+BCL2+BCL6- (M+2+6-) consistently predicts survival across four independent cohorts (n = 449), an effect not observed with other combinations including M+2+6+. We show that the M+2+6- percentage can be mathematically derived from quantitative measurements of the individual oncogenes and correlates with survival in IHC (n …

Insights Into The Formation And Diversification Of A Novel Chiropteran Wing Membrane From Embryonic Development, Neal Anthwal, Daniel J Urban, Alexa Sadier, Risa Takenaka, Simon Spiro, Nancy Simmons, Richard R Behringer, Chris J Cretekos, John J Rasweiler, Karen E Sears

Faculty, Staff and Student Publications

BACKGROUND: Through the evolution of novel wing structures, bats (Order Chiroptera) became the only mammalian group to achieve powered flight. This achievement preceded the massive adaptive radiation of bats into diverse ecological niches. We investigate some of the developmental processes that underlie the origin and subsequent diversification of one of the novel membranes of the bat wing: the plagiopatagium, which connects the fore- and hind limb in all bat species.

RESULTS: Our results suggest that the plagiopatagium initially arises through novel outgrowths from the body flank that subsequently merge with the limbs to generate the wing airfoil. Our findings further …

Twas_Sim, A Python-Based Tool For Simulation And Power Analysis Of Transcriptome-Wide Association Analysis, Xinran Wang, Zeyun Lu, Arjun Bhattacharya, Bogdan Pasaniuc, Nicholas Mancuso

Faculty, Staff and Student Publications

Genome-wide association studies (GWASs) have identified numerous genetic variants associated with complex disease risk; however, most of these associations are non-coding, complicating identifying their proximal target gene. Transcriptome-wide association studies (TWASs) have been proposed to mitigate this gap by integrating expression quantitative trait loci (eQTL) data with GWAS data. Numerous methodological advancements have been made for TWAS, yet each approach requires ad hoc simulations to demonstrate feasibility. Here, we present twas_sim, a computationally scalable and easily extendable tool for simplified performance evaluation and power analysis for TWAS methods.

Software and documentation are available at https://github.com/mancusolab/twas_sim.

Loss Of Lgr5 Through Therapy-Induced Downregulation Or Gene Ablation Is Associated With Resistance And Enhanced Met-Stat3 Signaling In Colorectal Cancer Cells, Tressie A Posey, Joan Jacob, Ashlyn Parkhurst, Shraddha Subramanian, Liezl E Francisco, Zhengdong Liang, Kendra S Carmon

Faculty, Staff and Student Publications

Leucine-rich repeat-containing, G protein-coupled receptor 5 (LGR5) is highly expressed in colorectal cancer and cancer stem cells (CSCs) that play important roles in tumor initiation, progression, and metastasis. Loss of LGR5 has been shown to enhance therapy resistance. However, the molecular mechanisms that mediate this resistance remain elusive. In this study, we demonstrate conversion of LGR5+ colorectal cancer cells to an LGR5- state in response to chemotherapy, LGR5- targeted antibody-drug conjugates (ADCs), or LGR5 gene ablation led to activation of STAT3. Further investigation revealed increased STAT3 activation occurred as a result of increased mesenchymal epithelial transition (MET) factor receptor activity. …

Dimeric P53 Mutant Elicits Unique Tumor-Suppressive Activities Through An Altered Metabolic Program, Jovanka Gencel-Augusto, Xiaoping Su, Yuan Qi, Elizabeth M Whitley, Vinod Pant, Shunbin Xiong, Vrutant Shah, Jerome Lin, Encarnacion Perez, Marta L Fiorotto, Iqbal Mahmud, Abhinav K Jain, Philip L Lorenzi, Nicholas E Navin, Ellen R Richie, Guillermina Lozano

Faculty, Staff and Student Publications

Cancer-related alterations of the p53 tetramerization domain (TD) abrogate wild-type (WT) p53 function. They result in a protein that preferentially forms monomers or dimers, which are also normal p53 states under basal cellular conditions. However, their physiologic relevance is not well understood. We have established in vivo models for monomeric and dimeric p53, which model Li-Fraumeni syndrome patients with germline p53 TD alterations. p53 monomers are inactive forms of the protein. Unexpectedly, p53 dimers conferred some tumor suppression that is not mediated by canonical WT p53 activities. p53 dimers upregulate the PPAR pathway. These activities are associated with lower prevalence …

Impact Of Clonal Plasma Cells In Autografts On Outcomes In High-Risk Multiple Myeloma Patients, Oren Pasvolsky, Denái R Milton, Mikael Rauf, Sassine Ghanem, Adeel Masood, Ali H Mohamedi, Mark R Tanner, Qaiser Bashir, Samer Srour, Neeraj Saini, Paul Lin, Jeremy Ramdial, Yago Nieto, Guilin Tang, Hans C Lee, Krina K Patel, Partow Kebriaei, Sheeba K Thomas, Donna M Weber, Robert Z Orlowski, Katy Rezvani, Richard Champlin, Elizabeth J Shpall, Pei Lin, Muzaffar H Qazilbash

Faculty, Staff and Student Publications

Most patients with multiple myeloma (MM) undergoing autologous hematopoietic stem cell transplantation (autoHCT) eventually relapse, perhaps due to the presence of clonal plasma cells (CPC) in the autograft. We conducted a retrospective analysis to evaluate the impact of CPC in the autograft on the outcomes of high-risk chromosomal abnormalities (HRMM) patients undergoing autoHCT between 2008 and 2018. Patients were divided into CPC+ or CPC- in the autograft by next-generation flow cytometry (NGF). There were 75 CPC + autografts (18%) and 341 CPC- (82%). The CPC + group was less likely to achieve MRD-negative complete remission post-transplant (11% vs. 42%; p < 0.001). Median progression free survival (PFS) and overall survival (OS) were (12.8 vs. 32.1 months) and (36.4 vs. 81.2 months) in the CPC + and CPC- groups, respectively (both p < 0.001). Also in the subset of patients with MRD-negative ≥VGPR prior to autoHCT, those with CPC + autografts had inferior PFS (HR 4.21, p = 0.006) and OS (HR 7.04, p = 0.002) compared to CPC-. In multivariable analysis, the degree of CPC positivity in the autograft was independently predictive of worse PFS (HR 1.50, p = 0.001) and OS (HR 1.37, p = 0.001). In conclusion, both the presence and degree of CPC in the autograft were highly predictive of inferior PFS and OS.

Microparticle-Delivered Cxcl9 Prolongs Braf Inhibitor Efficacy In Melanoma, Gabriele Romano, Francesca Paradiso, Peng Li, Pooja Shukla, Lindsay N Barger, Olivia El Naggar, John P Miller, Roger J Liang, Timothy L Helms, Alexander J Lazar, Jennifer A Wargo, Francesca Taraballi, James C Costello, Lawrence N Kwong

Faculty, Staff and Student Publications

Patients with BRAF-mutant melanoma show substantial responses to combined BRAF and MEK inhibition, but most relapse within 2 years. A major reservoir for drug resistance is minimal residual disease (MRD), comprised of drug-tolerant tumor cells laying in a dormant state. Towards exploiting potential therapeutic vulnerabilities of MRD, we established a genetically engineered mouse model of BrafV600E-driven melanoma MRD wherein genetic BrafV600E extinction leads to strong but incomplete tumor regression. Transcriptional time-course analysis after BrafV600E extinction revealed that after an initial surge of immune activation, tumors later became immunologically "cold" after MRD establishment. Computational analysis identified candidate T-cell recruiting chemokines as …

Clinical Outcomes Of Immunotherapy Continued Beyond Radiographic Disease Progression In Older Adult Patients With Advanced Non-Small Cell Lung Cancer, Eric K Singhi, Frank Mott, Michelle Worst, Cheuk Hong Leung, J Jack Lee, Brett Carter, Carolyn J Presley, John V Heymach, Mehmet Altan

Faculty, Staff and Student Publications

Immunotherapy is an effective and generally well-tolerated treatment strategy for older adult patients (aged ≥70 years) with advanced non-small cell lung cancer (NSCLC). Unfortunately, most patients who receive immunotherapy eventually exhibit disease progression during treatment. The present study reports on a subset of older adult patients with advanced NSCLC who could effectively continue immunotherapy beyond radiographic disease progression due to perceived clinical benefit. Local consolidative radiotherapy may be used in select older adult patients to prolong the duration of immunotherapy they receive, with a particular consideration of their preexisting co-morbidities, performance status and tolerance of potential toxicities associated with combined …

Spatial Transcriptomics Depict Ligand-Receptor Cross-Talk Heterogeneity At The Tumor-Stroma Interface In Long-Term Ovarian Cancer Survivors, Sammy Ferri-Borgogno, Ying Zhu, Jianting Sheng, Jared K Burks, Javier A Gomez, Kwong Kwok Wong, Stephen T C Wong, Samuel C Mok

Faculty, Staff and Student Publications

Advanced high-grade serous ovarian cancer (HGSC) is an aggressive disease that accounts for 70% of all ovarian cancer deaths. Nevertheless, 15% of patients diagnosed with advanced HGSC survive more than 10 years. The elucidation of predictive markers of these long-term survivors (LTS) could help identify therapeutic targets for the disease, and thus improve patient survival rates. To investigate the stromal heterogeneity of the tumor microenvironment (TME) in ovarian cancer, we used spatial transcriptomics to generate spatially resolved transcript profiles in treatment-naïve advanced HGSC from LTS and short-term survivors (STS) and determined the association between cancer-associated fibroblasts (CAF) heterogeneity and survival …

A Geospatial Approach To Identify Patterns Of Antibiotic Susceptibility At A Neighborhood Level In Wisconsin, United States, Laurel Legenza, Kyle Mcnair, Song Gao, James P Lacy, Brooke J Olson, Thomas R Fritsche, Lucas T Schulz, Samantha Lamuro, Frances Spray-Larson, Tahmeena Siddiqui, Warren E Rose

Faculty, Staff and Student Publications

The global threat of antimicrobial resistance (AMR) varies regionally. This study explores whether geospatial analysis and data visualization methods detect both clinically and statistically significant variations in antibiotic susceptibility rates at a neighborhood level. This observational multicenter geospatial study collected 10 years of patient-level antibiotic susceptibility data and patient addresses from three regionally distinct Wisconsin health systems (UW Health, Fort HealthCare, Marshfield Clinic Health System [MCHS]). We included the initial Escherichia coli isolate per patient per year per sample source with a patient address in Wisconsin (N = 100,176). Isolates from U.S. Census Block Groups with less than 30 isolates …

Results Of Salvage Therapy With Mini-Hyper-Cvd And Inotuzumab Ozogamicin With Or Without Blinatumomab In Pre-B Acute Lymphoblastic Leukemia, Hagop Kantarjian, Fadi G Haddad, Nitin Jain, Koji Sasaki, Nicholas J Short, Sanam Loghavi, Rashmi Kanagal-Shamanna, Jeffrey Jorgensen, Issa Khouri, Partow Kebriaei, Yesid Alvarado, Tapan Kadia, Shilpa Paul, Guillermo Garcia-Manero, Bouthaina Dabaja, Musa Yilmaz, Jovitta Jacob, Rebecca Garris, Susan O'Brien, Farhad Ravandi, Elias Jabbour

Faculty, Staff and Student Publications

Background: Historically, adults with relapsed-refractory acute lymphoblastic leukemia (ALL) experienced poor outcomes with intensive chemotherapy. This mature analysis explores the benefit of the addition of sequential blinatumomab to low-intensity mini-Hyper-CVD chemotherapy with inotuzumab ozogamicin in this setting.

Methods: Mini-Hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 83% dose reduction) was combined with inotuzumab during the first 4 courses. From Patient #68 and onwards, inotuzumab was given in reduced and fractionated doses, and blinatumomab was added sequentially for 4 courses. Maintenance therapy with prednisone, vincristine, 6-mercaptopurine and methotrexate was given for 12 …

The Kynurenine Pathway In Major Depressive Disorder, Bipolar Disorder, And Schizophrenia: A Systematic Review And Meta-Analysis Of Cerebrospinal Fluid Studies, Mehmet Enes Inam, Brisa S Fernandes, Estela Salagre, Iria Grande, Eduard Vieta, João Quevedo, Zhongming Zhao

Faculty, Staff and Student Publications

INTRODUCTION: The kynurenine pathway has been attracting attention as a relevant pathway in schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). We conducted a systematic review and meta-analysis of the kynurenine pathway metabolites from cerebrospinal fluid (CSF) samples in SZ, BD, and MDD.

METHODS: PubMed and Scopus databases were systematically searched to identify peer-reviewed case-control studies until April 2022 that assessed kynurenine metabolites, namely, tryptophan (TRP), kynurenine (KYN), kynurenic acid (KA), quinolinic acid (QA), and 3- hydroxykynurenine (3-HK) in SZ, BD, or MDD subjects compared with healthy controls (HC). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses …

An Exploratory Simulation Study And Prediction Model On Human Brain Behavior And Activity Using An Integration Of Deep Neural Network And Biosensor Rabi Antenna, Nhat Truong Pham, Montree Bunruangses, Phichai Youplao, Anita Garhwal, Kanad Ray, Arup Roy, Sarawoot Boonkirdram, Preecha Yupapin, Muhammad Arif Jalil, Jalil Ali, Shamim Kaiser, Mufti Mahmud, Saurav Mallik, Zhongming Zhao

Faculty, Staff and Student Publications

The plasmonic antenna probe is constructed using a silver rod embedded in a modified Mach-Zehnder interferometer (MZI) ad-drop filter. Rabi antennas are formed when space-time control reaches two levels of system oscillation and can be used as human brain sensor probes. Photonic neural networks are designed using brain-Rabi antenna communication, and transmissions are connected via neurons. Communication signals are carried by electron spin (up and down) and adjustable Rabi frequency. Hidden variables and deep brain signals can be obtained by external detection. A Rabi antenna has been developed by simulation using computer simulation technology (CST) software. Additionally, a communication device …

Inferring Evolutionary Trajectories From Cross-Sectional Transcriptomic Data To Mirror Lung Adenocarcinoma Progression, Kexin Huang, Yun Zhang, Haoran Gong, Zhengzheng Qiao, Tiangang Wang, Weiling Zhao, Liyu Huang, Xiaobo Zhou

Faculty, Staff and Student Publications

Lung adenocarcinoma (LUAD) is a deadly tumor with dynamic evolutionary process. Although much endeavors have been made in identifying the temporal patterns of cancer progression, it remains challenging to infer and interpret the molecular alterations associated with cancer development and progression. To this end, we developed a computational approach to infer the progression trajectory based on cross-sectional transcriptomic data. Analysis of the LUAD data using our approach revealed a linear trajectory with three different branches for malignant progression, and the results showed consistency in three independent cohorts. We used the progression model to elucidate the potential molecular events in LUAD …

Structural Basis Of The Alkaline Ph-Dependent Activation Of Insulin Receptor-Related Receptor, Liwei Wang, Catherine Hall, Jie Li, Eunhee Choi, Xiao-Chen Bai

Faculty, Staff and Student Publications

The insulin receptor (IR) family is a subfamily of receptor tyrosine kinases that controls metabolic homeostasis and cell growth. Distinct from IR and insulin-like growth factor 1 receptor, whose activation requires ligand binding, insulin receptor-related receptor (IRR)-the third member of the IR family-is activated by alkaline pH. However, the molecular mechanism underlying alkaline pH-induced IRR activation remains unclear. Here, we present cryo-EM structures of human IRR in both neutral pH inactive and alkaline pH active states. Combined with mutagenesis and cellular assays, we show that, upon pH increase, electrostatic repulsion of the pH-sensitive motifs of IRR disrupts its autoinhibited state …

Family Caregiver Reports Of Their Own And Patient Symptoms In Cancer Home Hospice Approaching End-Of-Life, Maija Reblin, Eli Iacob, Djin L Tay, Hui Li, Megan C Thomas Hebdon, Anna Beck, Gary Donaldson, Kristin G Cloyes, Lee Ellington

Faculty, Staff and Student Publications

Context: Family caregivers assume the primary responsibility of assessing and managing hospice cancer patient symptoms while simultaneously managing their own wellbeing and symptoms. Objectives: Describe caregivers' assessment of hospice cancer patient and their own symptoms during the last 60 days of patient life, and assess the relationship between patient and caregiver symptoms over time.

Methods: Caregiver symptom report of self and cancer home hospice patient symptom data were collected via telephone in the final 60 days of patient life. Descriptive data on symptom severity and prevalence were summarized. Exploratory Factor Analysis was used to group individual symptoms. …

Incidence Of Primary End Point Changes Among Active Cancer Phase 3 Randomized Clinical Trials, Marcus A Florez, Joseph Abi Jaoude, Roshal R Patel, Ramez Kouzy, Timothy A Lin, Brian De, Esther J Beck, Cullen M Taniguchi, Bruce D Minsky, Clifton D Fuller, J Jack Lee, Michael Kupferman, Kanwal P Raghav, Michael J Overman, Charles R Thomas, Ethan B Ludmir

Faculty, Staff and Student Publications

IMPORTANCE: Primary end point (PEP) changes to an active clinical trial raise questions regarding trial quality and the risk of outcome reporting bias. It is unknown how the frequency and transparency of the reported changes depend on reporting method and whether the PEP changes are associated with trial positivity (ie, the trial met the prespecified statistical threshold for PEP positivity).

OBJECTIVES: To assess the frequency of reported PEP changes in oncology randomized clinical trials (RCTs) and whether these changes are associated with trial positivity.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used publicly available data for complete oncology phase 3 …

Multiparametric Magnetic Resonance Imaging Artificial Intelligence Pipeline For Oropharyngeal Cancer Radiotherapy Treatment Guidance, Kareem Wahid

Dissertations and Theses (Open Access)

Oropharyngeal cancer (OPC) is a widespread disease and one of the few domestic cancers that is rising in incidence. Radiographic images are crucial for assessment of OPC and aid in radiotherapy (RT) treatment. However, RT planning with conventional imaging approaches requires operator-dependent tumor segmentation, which is the primary source of treatment error. Further, OPC expresses differential tumor/node mid-RT response (rapid response) rates, resulting in significant differences between planned and delivered RT dose. Finally, clinical outcomes for OPC patients can also be variable, which warrants the investigation of prognostic models. Multiparametric MRI (mpMRI) techniques that incorporate simultaneous anatomical and functional information …

The Efficacy Of Selinexor (Kpt-330), An Xpo1 Inhibitor, On Non-Hematologic Cancers: A Comprehensive Review, Jennifer R Landes, Stephen A Moore, Brooke R Bartley, Hung Q Doan, Peter L Rady, Stephen K Tyring

Faculty, Staff and Student Publications

Purpose: Selinexor is a novel XPO1 inhibitor which inhibits the export of tumor suppressor proteins and oncoprotein mRNAs, leading to cell-cycle arrest and apoptosis in cancer cells. While selinexor is currently FDA approved to treat multiple myeloma, compelling preclinical and early clinical studies reveal selinexor's efficacy in treating hematologic and non-hematologic malignancies, including sarcoma, gastric, bladder, prostate, breast, ovarian, skin, lung, and brain cancers. Current reviews of selinexor primarily highlight its use in hematologic malignancies; however, this review seeks to summarize the recent evidence of selinexor treatment in solid tumors.

Methods: Pertinent literature searches in PubMed and the Karyopharm Therapeutics …