Digital Commons Network^™

Shp2: A Redox-Sensitive Regulator Linking Immune Checkpoint Inhibitor Therapy To Cancer Treatment And Vascular Risk, Silvia Fernanda López Moreno, Stefania Assunto Lenz, Bernardo Casso-Chapa, Angelica Paniagua-Bojorges, Jung Hyun Kim, Nicolas L Palaskas, Kevin T Nead, Venkata S K Samanthapudi, Gilbert Mejia, Oanh Hoang, Jonghae Lee, Steven H Lin, Joerg Herrmann, Guangyu Wang, Syed Wamique Yusuf, Cezar A Iliescu, Noah I Beinart, Charlotte Manisty, Masuko Ushio-Fukai, Tohru Fukai, Pietro Ameri, Roza I Nurieva, Michelle A T Hildebrandt, Keri Schadler, Efstratios Koutroumpakis, Sivareddy Kotla, Nhat-Tu Le, Jun-Ichi Abe

Faculty, Staff and Student Publications

Src homology 2-domain containing protein tyrosine phosphatase 2 (SHP2), encoded by the Ptpn11 gene (Tyrosine-protein phosphatase non-receptor type 11), is a key downstream effector of PD-1/PD-L1 signaling and is likely important, in addition to immune modulation, in tumor development and vascular homeostasis. SHP2 conveys PD-1 mediated inhibitory signaling in T cells, and is emerging as a therapeutic target. Importantly, there is an association between immune checkpoint inhibitors (ICIs), immune-related adverse events (irAEs), and cardiovascular complications, underscoring the need to understand SHP2’s role in these processes. This review aims to summarize current knowledge on SHP2/PTPN11 biology, its role in immune …

Impact Of Peek Implant Surface Design On Postoperative Complications In Cranioplasty: A Retrospective Review, Carmen A Zavala, Laura Zima, Subhiksha Srinivasan, Sanjay V Neerukonda, Mark J Dannenbaum

Faculty, Staff and Student Publications

Background: The aim of this study was to evaluate and compare complication rates and clinical outcomes associated with smooth and perforated polyetheretherketone (PEEK) implants used in cranioplasty.

Methods: A retrospective analysis of 94 patients who underwent cranioplasty with either smooth (n = 45) or perforated (n = 49) PEEK implants over a five-year period was conducted. Patient demographics, comorbidities, reasons for initial craniectomy, time interval between craniectomy and cranioplasty, postoperative complications, hospital stays, and rates of revision surgeries were analyzed. Multivariate logistic regression was used to control for confounding factors.

Results: No statistically significant differences were observed in demographic characteristics, …

Liver-Directed Base Editing Of Abcc6 Prevents Ectopic Calcification In A Variant-Humanized Mouse Model Of Pseudoxanthoma Elasticum, Lauren C. Testa, Dora Obiri-Yeboah, Hooda Said, Ping Qu, Michael A. Levine, Mohamad-Gabriel Alameh, Kiran Musunuru, Qiaoli Li, Xiao Wang

Department of Biochemistry and Molecular Biology Faculty Papers

Pseudoxanthoma elasticum (PXE) is an autosomal recessive connective tissue disorder characterized by ectopic calcification of elastic fibers throughout the skin, retina, and arteries. It is caused by pathogenic variants in ABCC6 , which encodes a transmembrane transporter that primarily localizes to hepatocytes. Loss of ABCC6 function in hepatocytes leads to systemic deficiency of inorganic pyrophosphate (PPi), a potent inhibitor of calcification; such depletion of PPi from the circulation is responsible for multisystemic ectopic calcification seen in PXE. Therefore, liver-targeted variant correction by genome editing and subsequent restoration of systemic PPi may offer a one-and-done therapeutic approach for PXE. The ABCC6 …

Diras3-Derived Cyclic Peptides Disrupt Kras-Raf Interaction And Kras Nanoclustering, Suppressing Kras-Driven Pancreatic And Ovarian Tumors, Joshua P Gray, Gamze Bildik, Ha-Neul Kim, Margie N Sutton, Jing Wang, Amarachi O Osuji, Nefeli Batistatou, Hailing Yang, Weiqun Mao, Zhi Tan, Geneviève M C Gasmi-Seabrook, Junchen Liu, John F Hancock, Christopher B Marshall, Joshua A Kritzer, Mitsuhiko Ikura, Robert C Bast, Steven W Millward, Zhen Lu

Faculty, Staff and Students Publications

Mutations in KRAS drive 88% of pancreatic ductal adenocarcinomas (PDAC) and up to 40% of low-grade serous ovarian cancers (LGSOC), making KRAS a long-standing therapeutic target. We previously showed that DIRAS3 binds RAS, forming heterodimers that disrupt RAS clustering and downstream MAPK signaling. Building on this, we developed conformationally constrained DIRAS3-derived peptides using two cyclization strategies and characterized them by NMR and biolayer interferometry. These cyclic peptides attenuate the interaction between KRAS and the BRAF RAS-binding domain, penetrate cells efficiently, and inhibit KRAS nanoclustering on the inner leaflet of the plasma membrane. Functionally, they reduce cell viability and suppress PDAC …

Deletion Of Fibro-Adipogenic Progenitors-Specific Follistatin Impairs Muscle Function And Accelerates Skeletal Muscle Atrophy In Obese Mice, Muhammad Rahil Aslam, Muhammad Bilal, Allah Nawaz, Tomonobu Kado, Shinya Abe, Nguyen Quynh Phuong, Memoona, Sana Khalid, Le Duc Anh, Ayumi Nishimura, Yoshiyuki Watanabe, Yoshiko Igarashi, Naeem Iqbal, Maki Yokoyama, Yasuhiro Onogi, Kennichi Hirabayashi, Hiroyuki Miwa, Takumi Era, Martin M Matzuk, Seiji Yamamoto, Koichi Ikuta, Isao Usui, Kohta Kobayashi, Toshihiko Satake, Masaru Kato, Shiho Fujisaka, Kazuyuki Tobe

Faculty, Staff and Students Publications

Background: Follistatin is a potent regulator of various TGF-β superfamily members, including myostatin (MSTN) and activin A. Previous studies have shown that follistatin is crucial in enhancing myogenesis during acute muscle injury. The mechanism by which fibro-adipogenic progenitors (FAPs)-specific follistatin influences muscle homeostasis in obese mice remains unknown. Therefore, we investigated the physiological role of follistatin in PDGFRα-positive FAPs in the regulation of muscle homeostasis and exercise in obese mice.

Methods: A PDGFRα-specific follistatin knockout (follistatin KO) mouse model was generated using PDGFRα-GFP-CreERT2 (PDGFRα-GCE) and follistatinflox/flox mice. These mice were fed a 60% high-fat diet (HFD) for 20 weeks, followed …

The Effect Of Uterine Entry Technique On Chorioamniotic Membrane Separation In Fetoscopic Laser Photocoagulation For Twin-To-Twin Transfusion Syndrome: Protocol For A Randomized Controlled Trial, Brian A Burnett, Jessian L Munoz, Rebecca M Johnson, Christian M Parobek, Luis E Delgadillo Chabolla, Cara Buskmiller, Roopali V Donepudi, Magdalena Sanz Cortes, Michael A Belfort, Ahmed A Nassr

Faculty, Staff and Students Publications

Background: Chorioamniotic membrane separation (CAS) is a recognized complication of fetoscopic laser photocoagulation (FLP) for twin-to-twin transfusion syndrome (TTTS), associated with increased risks of preterm prelabor rupture of membranes (PPROM) and preterm birth (PTB). Although CAS is well described, its incidence and relationship to specific surgical techniques, particularly the method of uterine entry, are not well defined in the published literature. No randomized trials have evaluated whether entry technique influences the risk of CAS.

Methods: We present the protocol for a randomized controlled trial comparing sharp-trocar and Seldinger uterine entry techniques for FLP in TTTS diagnosed between 16 + 0 …

Identifying Compounds To Treat Opiate Use Disorder By Leveraging Multi-Omic Data Integration And Multiple Drug Repurposing Databases, Jeran K Stratford, Megan Ulmer Carnes, Caryn Willis, Melyssa S Minto, Logain Elnimeiry, Ravi Mathur, Matthew Schu, Bryan C Quach, Javan Carter, Tracy Nolen, Nathan Vandergrift, Thomas R Kosten, Eric Otto Johnson, Bradley T Webb

Faculty, Staff and Students Publications

Genes influencing opioid use disorder (OUD) biology have been identified via genome-wide association studies (GWAS), gene expression, and network analyses. These discoveries provide opportunities to identifying existing compounds targeting these genes for drug repurposing studies. However, systematically integrating discovery results and identifying relevant available pharmacotherapies for OUD repurposing studies is challenging. To address this, we've constructed a framework that uses existing results and drug databases to identify candidate pharmacotherapies. For this study, two independent OUD related meta-analyses were used including a GWAS and a differential gene expression (DGE) study of post-mortem human brain. Protein-Protein Interaction (PPI) sub-networks enriched for GWAS …

Alteration Of Gut Microbial Ecology By The Direct Activation Of The Brain: Inverse Gut-Microbiome-Brain Dynamics, I-Ching Wang, Jessica L Swanson, Jillian L Waters, Mikhail Y Kochukov, Shelly A Buffington, Sean W Dooling, Benjamin R Arenkiel, Mauro Costa-Mattioli

Faculty, Staff and Students Publications

The gut-microbiome-brain axis is a bidirectional communication system influencing host physiology and overall fitness. While "bottom-up" effects-where gut microbes influence brain function and behavior-are well established, direct evidence for "top-down" modulation-where the brain shapes the gut microbial ecology-remains elusive. Here, we show that the selective expression of the bacterial ion channel mNaChBac in glutamatergic lateral habenula (LHb) neurons increases their bursting activity and leads to endophentypes associated with depression. Importantly, this chronic activation leads to changes in the gut microbiome composition over time, as reflected by shifts in alpha-diversity and alterations in specific microbial taxa. These findings provide direct evidence …

Genome-Wide Association Study Of 398,238 Women Unveils Seven Loci Associated With High-Grade Serous Ovarian Cancer, Daniel R Barnes, Jonathan P Tyrer, Joe Dennis, Goska Leslie, Manjeet K Bolla, Michael Lush, Amber M Aeilts, Kristiina Aittomäki, Nadine Andrieu, Irene L Andrulis, Hoda Anton-Culver, Adalgeir Arason, Banu K Arun, Judith Balmaña, Elisa V Bandera, Rosa B Barkardottir, Lieke P V Berger, Amy Berrington De Gonzalez, Pascaline Berthet, Katarzyna Białkowska, Line Bjørge, Amie M Blanco, Marinus J Blok, Kristie A Bobolis, Natalia V Bogdanova, James D Brenton, Henriett Butz, Saundra S Buys, Maria A Caligo, Ian Campbell, Carmen Castillo, Kathleen B M Claes, Sarah V Colonna, Linda S Cook, Mary B Daly, Agnieszka Dansonka-Mieszkowska, Miguel De La Hoya, Anna Defazio, Allison Depersia, Yuan Chun Ding, Jennifer A Doherty, Susan M Domchek, Thilo Dörk, Zakaria Einbeigi, Christoph Engel, D Gareth Evans, Lenka Foretova, Renée T Fortner, Florentia Fostira, Maria Cristina Foti, Eitan Friedman, Megan N Frone, Patricia A Ganz, Aleksandra Gentry-Maharaj, Gord Glendon, Andrew K Godwin, Anna González-Neira, Mark H Greene, Jacek Gronwald, Aliana Guerrieri-Gonzaga, Ute Hamann, Thomas V O Hansen, Holly R Harris, Jan Hauke, Florian Heitz, Frans B L Hogervorst, Maartje J Hooning, John L Hopper, Chad D Huff, David G Huntsman, Evgeny N Imyanitov, Louise Izatt, Anna Jakubowska, Paul A James, Ramunas Janavicius, Esther M John, Siddhartha Kar, Beth Y Karlan, Catherine J Kennedy, Lambertus A L M Kiemeney, Irene Konstantopoulou, Jolanta Kupryjanczyk, Yael Laitman, Ofer Lavie, Kate Lawrenson, Jenny Lester, Fabienne Lesueur, Carlos Lopez-Pleguezuelos, Phuong L Mai, Siranoush Manoukian, Taymaa May, Iain A Mcneish, Usha Menon, Roger L Milne, Francesmary Modugno, Jennifer M Mongiovi, Marco Montagna, Kirsten B Moysich, Susan L Neuhausen, Finn C Nielsen, Catherine Noguès, Edit Oláh, Olufunmilayo I Olopade, Ana Osorio, Laura Papi, Harsh Pathak, Celeste L Pearce, Inge S Pedersen, Ana Peixoto, Tanja Pejovic, Pei-Chen Peng, Beth N Peshkin, Paolo Peterlongo, C Bethan Powell, Darya Prokofyeva, Miquel Angel Pujana, Paolo Radice, Muhammad U Rashid, Gad Rennert, George Richenberg, Dale P Sandler, Naoko Sasamoto, Veronica W Setiawan, Priyanka Sharma, Weiva Sieh, Christian F Singer, Katie Snape, Anna P Sokolenko, Penny Soucy, Melissa C Southey, Dominique Stoppa-Lyonnet, Rebecca Sutphen, Christian Sutter, Yen Y Tan, Manuel R Teixeira, Kathryn L Terry, Liv Cecilie V Thomsen, Marc Tischkowitz, Amanda E Toland, Toon Van Gorp, Ana Vega, Digna R Velez Edwards, Penelope M Webb, Jeffrey N Weitzel, Nicolas Wentzensen, Alice S Whittemore, Stacey J Winham, Anna H Wu, Siddhartha Yadav, Yao Yu, Argyrios Ziogas, Andrew Berchuck, Fergus J Couch, Ellen L Goode, Marc T Goodman, Alvaro N Monteiro, Kenneth Offit, Susan J Ramus, Harvey A Risch, Joellen M Schildkraut, Mads Thomassen, Jacques Simard, Douglas F Easton, Michelle R Jones, Georgia Chenevix-Trench, Simon A Gayther, Antonis C Antoniou, Paul D P Pharoah

Faculty, Staff and Student Publications

Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We meta-analyzed >22 million variants for 398,238 women from the Ovarian Cancer Association Consortium (OCAC), UK Biobank (UKBB) and Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA) to identify novel HGSOC susceptibility loci. Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was TP53 3’-UTR SNP rs78378222-T’s association with HGSOC (per-T-allele relative risk (RR) = 1.44, 95% CI:1.28–1.62, P = 1.76 × 10−9). Polygenic scores (PGS) were developed using OCAC and CIMBA data and trained on FinnGen data. The optimal PGS included 64,518 …

Acute Myeloid Leukemia With T(10; 17)(P15; Q21)/ Zmynd11::Mbtd1: A Subtype With Minimal Differentiation, Cd7/Cd56 Expression, And Generally Poor Outcomes In Adults, Qing Wei, Naveen Pemmaraju, Sa A Wang, Shimin Hu, Courtney Dinardo, Ghayas C Issa, Carlos E Bueso-Ramos, Jie Xu, Shaoying Li, Jeffrey L Medeiros, Guilin Tang

Faculty, Staff and Student Publications

No abstract provided.

Five-Year Follow-Up Analysis Of Zuma-5: Axicabtagene Ciloleucel In Relapsed/Refractory Indolent Non-Hodgkin Lymphoma, Sattva S Neelapu, Julio C Chavez, Alison R Sehgal, Narendranath Epperla, Matthew L Ulrickson, Emmanuel Bachy, Pashna N Munshi, Carla Casulo, David G Maloney, Sven De Vos, Ran Reshef, Lori A Leslie, Olalekan O Oluwole, Ibrahim Yakoub-Agha, Rashmi Khanal, Joseph D Rosenblatt, Jacob Wulff, Rhine R Shen, Wangshu Zhang, Soumya Poddar, Harry Miao, Olga Nikolajeva, Caron A Jacobson

Faculty, Staff and Student Publications

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL). Here, we report updated clinical outcomes from ZUMA-5 in 159 enrolled patients with R/R indolent non-Hodgkin lymphoma (iNHL; 127 with FL and 31 with marginal zone lymphoma) after a median follow-up of 64.6 months. Patients underwent leukapheresis and received lymphodepleting chemotherapy and axi-cel (2 × 106 CAR T cells/kg). The overall response rate was 90% (75% complete response rate). The median duration of response was 60.4 months, and the median progression-free survival (PFS) was 62.2 months; median time to next …

Early Tumor Volume Reduction By Breast Dce Mri Predicts Pathologic Complete Response To Neoadjuvant Therapy In Triple Negative Breast Cancer, Mary S Guirguis, Beatriz E Adrada, Clinton Yam, Debu Tripathy, Rosalind Candelaria, Wei Yang, Miral Patel, Tanya Moseley, Frances Perez, Gary J Whitman, Jessica W T Leung, Huong Le-Petross, Deanna L Lane, Lei Huo, Jennifer K Litton, Vicente Valero, Kelly K Hunt, Banu Arun, Rania Mohamed, Jia Sun, Anil Korkut, Zhan Xu, Sanaz Pashapoor, Jason White, Jong Bum Son, Alastair Thompson, Peng Wei, Jingfei Ma, Stacy Moulder, Gaiane M Rauch

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) is a heterogeneous disease with variable response to neoadjuvant systemic therapy (NAST). Patients with pathologic complete response (pCR) following NAST have improved survival. Our goal was to establish readily accessible imaging biomarker to identify which TNBC patients will have pCR. Building on prior favorable results in the literature, we hypothesized that manually measured tumor volume changes at DCE-MRI may predict pCR early during NAST. This prospective study included 287 stage I-III TNBC patients who underwent DCE-MRI at baseline, after two and four cycles of NAST, with pCR accessed at surgery (NCT02276443). Tumor volume and percentage tumor …

Disclosing A Pancreatic Cancer Diagnosis In An Era Of Immediate Electronic Result Release: A National Survey Of Endosonographers, Samuel Tanner, Fiyinfoluwa Abraham, Merrick Bay, R Tomas Davee, Daryl Ramai, Seth A Gross, Truptesh Kothari, Veeral M Oza, Somashekar G Krishna, Jorge D Machicado

Faculty, Staff and Student Publications

Background and aims: There are limited data in how U.S.-based endosonographers disclose pancreatic ductal adenocarcinoma (PDAC) diagnoses to patients. Therefore, we conducted a survey study across endosonographers to assess practice patterns, evaluate knowledge gaps and challenges, and explore perceptions of federal regulations that mandate immediate release of test results through electronic portals.

Methods: A 29-item electronic survey was distributed to 684 U.S.-based endosonographers between October and November 2024.

Results: One hundred sixteen endosonographers participated (17% response rate). Endosonographers often deliver PDAC diagnoses via phone calls (75%), of 6 to 10 minutes (60%), and without following published protocols (81%). One-third of …

Single Cell Long Read Whole Genome Sequencing Reveals Somatic Transposon Activity In Human Brain, Michal B Izydorczyk, Ester Kalef-Ezra, Dominic W Horner, Xinchang Zheng, Nadine Holmes, Marco Toffoli, Zeliha Sahin, Yi Han, Heer H Mehta, Sonja W Scholz, Clifton L Dalgard, Donna M Muzny, Adam Ameur, Fritz J Sedlazeck, Christos Proukakis

Faculty, Staff and Students Publications

The advent of single cell DNA sequencing revealed astonishing dynamics of genomic variability, but failed at characterizing smaller to mid size variants that on the germline level have a profound impact. In this work we discover previously uncharacterized genomic dynamics in 18 cells from three human brains utilizing single cell long-read whole genome sequencing. This provides key insights into the dynamic of the genomes of individual cells and further highlights brain specific activity of transposable elements, but requires validation in larger studies.

Tca Cycle Mode Switch Determines The Fate Of Pirtobrutinib-Tolerant Persister Cells In Mantle Cell Lymphoma, Wei Wang, Qingsong Cai, Yang Liu, Lei Nie, Heng-Huan Lee, Fangfang Yan, Yue Fei, Yixin Yao, Yijing Li, Lin Tan, Philip L Lorenzi, Ying-Nai Wang, Jun Yao, Zhihong Chen, Joseph Mitchell Mcintosh, Cheng-Tai Yu, Preetesh Jain, Vivian C Jiang, Jovanny Vargas, Xiaolin Li, Tianci Zhang, Shaoying Li, David Santos, Selvi Thirumurthi, Erin Heather Seeley, Lukas Mikolaj Simon, Christopher Flowers, Chi Young Ok, Michael Wang

Faculty, Staff and Student Publications

Bruton tyrosine kinase inhibitors (BTKis) and cell therapy have successfully been used to treat mantle cell lymphoma (MCL). However, therapy resistance inevitably emerges. Cancer cells can progressively develop stable resistance by traversing through a transient drug-tolerant persister (DTP) state. The mechanisms enabling DTP cells to reversibly adapt to therapies and evolve to acquire heterogeneity remain poorly understood, and characterizing DTP cells in MCL continues to pose a challenge for clinic translation. Here, using pirtobrutinib, a recently US Food and Drug Administration-approved noncovalent BTKi, we identified pirtobrutinib-tolerant persister cells exhibiting morphological variability by presenting a unique population of enlarged cells (giant …

Conjunctival Melanoma Genomic Analysis Reveals Intermediate Tumor Mutation Burden And Genomic Overlap With Cutaneous Melanoma, Florentia Dimitriou, Xiaogang Wu, Priyadharsini Nagarajan, Isabella C Glitza, Li Zhao, Jing Ning, Sapna P Patel, Jennifer A Wargo, Andrew Futreal, Scott Woodman, Jennifer L Mcquade, Bita Esmaeli

Faculty, Staff and Student Publications

Conjunctival melanoma (CJM) is a rare and aggressive malignancy. Mainly attributed to its rarity, the genomic features of CJM have not been well characterized. In the present study, we sequenced the exomes of primary and metastatic CJM tumors with the aim to unravel their genomic landscape. The results of the study suggest that CJM is a molecularly distinct melanoma subtype with mixed genotype and targetable mutations. Notably, there were features overlapping with both mucosal, and mainly cutaneous melanoma. Of note, some genetic alterations were found in association with specific subsets of CJM, such as bulbar anatomical localization. CJM tumors had …

Infection And Nonunion Rates In Open Fractures: Description Of 6,042 Fractures From The Flow And Prep-It Trials, Roman M Natoli, Lucas S Marchand, Sofia Bzovsky, Jennifer E Hagen, Mark J Gage, Christina A Stennett, Nathan N O'Hara, Kyle J Jeray, Brad Petrisor, Sheila Sprague, Gerard P Slobogean

Faculty, Staff and Student Publications

Background: Infection and nonunion are common sequelae of open fractures. Studies have shown infection and nonunion rates ranging from 2% to 52% and 12% to 17%, respectively. The present article describes the rates of surgical site infection (SSI) and delayed union/nonunion following open fractures in a large contemporary series of patients from prospective clinical trials with adjudicated outcomes.

Methods: A descriptive analysis was performed with use of patient data from the FLOW, Aqueous-PREP, and PREPARE-Open studies. These studies, published within the past 10 years, included multiple international trauma centers and shared definitions for SSI and delayed union/nonunion. SSI and delayed …

14,441 Genomics-Based Validated Automated Comprehensive Clinicopathologic Correlations For Myeloid Neoplasms., Ahmed Elsafty, Yomna Ahmed, Taher F Halawa, Shaoguang Li, Dongguang Li, Elena Agranovsky, Ahmed Soliman, Howida Talaat, Mohamed Montaser, Omar Elnady, Deyaa Elnady, Mohamed Mahmoud Moustafa, Nourhan Ibrahim, Maryana Gumenyak, Yasmin Soliman, Samah Ali, Elshaimaa Abdelrahman, Hatem M S Alahwal, Ahmed S Barefah, Ashraf Abdelghany, Sherif Ammar, Nermeen Abdel-Haleem, Osama Abdel-Kareem, Samir N Shamma, Naglaa Husein, Maha M Sakr, Heba-Allah E Abdelrhman, Menatalla Nadim, Hany Girguis, Manal Othman, Ola Soliman, Walaa H Behery, Lamis Eltoukhy, Heldez A Mohamed, Aya M Hassan, Fatma-Elzahraa A Bebers, Marwa Abdel-Zaher, Sara A Abbas, Shady Attia, Mohamed A Saada, Amira S Eid, Soha E Khorshed, Khaled Talaat, Mohamed Saad Hamed Mahmoud, Mahmoud M S Mahmoud, Ola M S Mahmoud, Abdel-Rahman O Abdel-Kareem, Ahmed K Talaat, Haitham Heneish, Ibrahim I Samaha, Mones Safwat, Mohamed K Talaat, Alaa O Abdel-Kareem, Hadeel Abdel-Monem, Ramy Abaza, Hazem Abaza, Nora Ahmad, May A Maarouf, Iman A Shaheen, Ahmed S Abdelhafiz, Amera Rabee, Yara M Montaser

Faculty, Staff and Student Publications

The dataset (Elsafty_Reports_of_Myeloid_Neoplasms_2024) consists of 14,441 comprehensive clinicopathologic correlations (CPCs) for myeloid neoplasms (MN) with corresponding laboratory results. Specialized online platform utilizing these laboratory results automatically generated the diagnostic and prognostic CPCs. These results include complete blood counts (CBC), peripheral blood smear (PBS) findings, blast/promyelocyte count with dysplasia screening by flow cytometry, and molecular results by NGS/PCR. Two Hematopathologists, who performed the CBC and PBS review, collected their 10,794 real-world reports of cases served in Egypt with molecular studies performed in the USA and Europe. These newly-diagnosed cases included 243 chronic myeloid leukemia (CML) cases with 257 mutations/aberrations; 4,567 non-CML …

Response Of Ipsc-Derived Neurons From Individuals With Treatment-Resistant Depression To (2 R, 6 R)-Hydroxynorketamine And Reelin: An Exploratory Study, Jenessa N Johnston, Peixiong Yuan, Bashkim Kadriu, Nirmala Akula, Brandi Quintanilla, Shiyong Peng, Greg H Jones, Anton Schulmann, Mani Yavi, Ioline D Henter, Francis J Mcmahon, Lisa E Kalynchuk, Carlos A Zarate, Hector J Caruncho

Faculty, Staff and Student Publications

Treatment-resistant depression (TRD) is associated with worse clinical outcomes and longer course of illness. However, TRD is more difficult to model in animal phenotypes, suggesting that other experimental and translational models must be considered to properly address and research novel therapeutics. Reelin, an endogenous glycoprotein downregulated in depression, has shown rapid antidepressant-like effects akin to those of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine. Interestingly, the antidepressant-like effects of both ketamine and reelin affect mechanistic target of rapamycin complex 1 (mTORC1) activity and that of its related downstream signalers. (2 R,6 R)-hydroxynorketamine (HNK) is a major metabolite of ketamine that, at …

Implementation And Assessment Of The Openbci Platform As An Accessible Brain- Computer Interface, Jewell Norris

Honors Theses

OpenBCI is a low-cost, open-source platform for alternative brain-computer interface (BCI) software and hardware. This thesis evaluates OpenBCI’s electroencephalogram (EEG) and electromyography (EMG) capabilities by constructing and testing a 16-channel EEG system using the Ultracortex Mark IV headset and Cyton + Daisy biosensing board. The viability of the system was assessed through real-time BCI control and comparison to a clinical-grade EEG system. Real-time BCI control of an online falling-block game was tested via the use of eye blinks EMG (channels Fp1/Fp2) and head-tilt accelerometer inputs. The BCI game demonstrated reliable control despite minor latency and artifact sensitivity. For clinical comparison, …

Aqueous Humor Biomarkers In Ocular Oncology: Insights And Advances, Lara Cheslow, Signe Caksa, Rachel E. Cain, Scott A. Waldman, Andrew A. Aplin

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Ocular malignancies, though relatively rare, pose significant risks to patients' vision, quality of life, and potential for developing metastatic disease. Due to the eye's complicated and delicate anatomy, diagnosing ocular malignancy and monitoring its progression can be technically challenging. Current approaches include direct tumor biopsy, vitreous humor sampling, and imaging. However, these techniques are associated with rare, yet potentially severe, side effects and can be invasive or limited in detecting microscopic disease. Recent studies have introduced aqueous humor sampling as a promising, minimally invasive alternative to diagnose ocular malignancy, guide therapeutic management, monitor response to treatment, and track early recurrence. …

Insights Into The Relevance Of Targeting Fibroblasts To Control Cancer, Viktoria Boeker, Raghu Kalluri

Faculty, Staff and Student Publications

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) have garnered significant research attention in the last decade. As key stromal cells of the TME, studies have explored them as a potential target for controlling cancer. Using high-throughput technologies like single-cell RNA sequencing coupled with proteomics, the classification of different CAF subgroups reveals a complex system that varies by cancer type. Unraveling novel big data, potentially through AI platforms, will be key to identifying the role of CAFs in tumor progression and therapy escape mechanisms, enabling new therapies that manipulate CAFs to increase patients' survival. We summarize and discuss new developments …

Accounting For Population Structure In Genomic Prediction Of Strawberry Sweetness At A Global Scale, Mulusew Fikere, Jason D Zurn, Sujeet Verma, Iraida Amaya, Pilar Muñoz, José F Sánchez-Sevilla, Helen M Cockerton, Richard J Harrison, Lise L Mahoney, Thomas M Davis, James F Hancock, Chad E Finn, Megan M Mathey, Jodi Neal, Hian-Lien Ko, Vance M Whitaker, Nahla V Bassil, Craig Hardner

Faculty, Staff and Student Publications

Genomic prediction models that fit multiple environments globally are valuable tools for assessing cultivar performance across diverse and variable growing conditions. We analyzed 2,064 strawberry (Fragaria × ananassa) accessions genotyped with 12,591 SNP markers. Soluble solids content (SSC) was measured in multi-year trials conducted at seven locations spanning the U.S., Europe, and Australia. Population structure analysis grouped accessions into two major clusters corresponding to subtropical and temperate origins, which was confirmed by significant differences in allele frequency distributions. To improve prediction accuracy across environments, we developed factor analytic models focusing on genotype-by-environment interactions rather than covariance between sub-populations. We compared …

Read The Data For Diverse Truths-And Quantitative Myocardial Perfusion Versus Angiography, Kenneth Lance Gould, Nils P Johnson

Faculty, Staff and Student Publications

No abstract provided.

Sex Differences In Atherosclerotic Coronary Artery Disease Patterns, Kazumasa Ikeda, Daniel Munhoz, Sofie Brouwers, Jeroen Sonck, Hitoshi Matsuo, Toshiro Shinke, Hirohiko Ando, Brian Ko, Simone Biscaglia, Fernando Rivero, Thomas Engstrøm, Ketina Arslani, Antonio Maria Leone, Domenico Galante, Lokien X Van Nunen, William F Fearon, Evald Høj Christiansen, Stephane Fournier, Liyew Desta, Andy Yong, Julien Adjedj, Javier Escaned, Masafumi Nakayama, Ashkan Eftekhari, Frederik M Zimmermann, Koshiro Sakai, Tatyana Storozhenko, Bruno R Da Costa, Gianluca Campo, Colin Berry, Damien Collison, Thomas Johnson, Tetsuya Amano, Divaka Perera, Allen Jeremias, Ziad Ali, Bernard De Bruyne, Frederic Bouisset, Takashi Kubo, Nobuhiro Tanaka, Kazuhiro Satomi, Nils P Johnson, Carlos Collet, Takuya Mizukami

Faculty, Staff and Student Publications

Background: Sex differences in coronary artery disease (CAD) have been increasingly recognized, as women present with distinct clinical characteristics and outcomes compared with men. This study investigated the impact of sex on pathophysiological CAD patterns (focal versus diffuse) in stable patients undergoing percutaneous coronary interventions (PCI).

Methods: We conducted a subanalysis of the PPG Global (Pullback Pressure Gradient Global Registry) study, a multicenter, prospective trial including 993 patients (236 [23.8%] women and 757 [76.2%] men) with hemodynamically significant CAD, defined as fractional flow reserve ≤0.80. The pullback pressure gradient metric categorized CAD patterns as focal or diffuse. Patient-reported outcomes were …

Vessel-Specific Myocardial Mass In Patients With Stable Coronary Artery Disease, Nikolaos Stalikas, Takuya Mizukami, Frederic Bouisset, Kazumasa Ikeda, Atomu Tajima, Daniel Munhoz, Thabo Mahendiran, Adriaan Wilgenhof, Koshiro Sakai, Bjarne Noorgard, Thomas Engstroem, Jonathon Leipsic, Giulio Stefanini, Antonio Bartorelli, Timothy Fairbairn, Alan Bagnall, Brian Ko, Nils P Johnson, Colin Berry, Divaka Perera, Evald Høj Christiansen, Toshiro Shinke, Hiromase Otake, Bon Kwon Koo, Emanuele Barbato, Salvatore Brugaletta, Damien Collison, Gianluca Campo, Eric Van Belle, Tommaso Goori, Lokien Van Nunen, Adam Witkowski, Patricio Astudillo, James Spratt, Tetsuya Amano, Hirohiko Ando, Georgios Sianos, Jeroen Sonck, Daniele Andreini, Bernard De Bruyne, Carlos Collet

Faculty, Staff and Student Publications

Background: Assessing the myocardial mass at risk is essential in evaluating patients with coronary artery disease. This study aims to establish reference values for vessel-specific myocardial mass derived from coronary computed tomography angiography, providing a quantitative assessment of the myocardial mass subtended by each epicardial vessel.

Methods: Left ventricular (LV) and vessel-specific myocardial mass were calculated from coronary computed tomography angiography using the Voronoi method in patients with stable coronary artery disease. Myocardial mass was quantified for each epicardial coronary artery with a diameter >1.5 mm.

Results: We included 948 patients with 9228 epicardial coronary artery branches. Mean age was …

Role Of Endoscopy In The Diagnosis And Management Of Esophageal Cancer, Jennifer Ma, Sharon Pan, Rachel Mortan, Faisal Shaukat Ali, Nirav Thosani, Vaibhav Wadhwa

Faculty, Staff and Student Publications

Esophageal cancer cases are predicted to reach 957,000 by 2040. Prior mortality rates average 6.5% in men and 2.2% in women, with a poor 5-year prognosis of 20%. A deficiency in screening guidelines, an incomplete understanding of pathophysiology, and limited treatment options contributed to this poor prognosis. Now, as technology and knowledge evolve, endoscopy serves a primary role in improving morbidity and mortality around esophageal cancer, in which early detection and treatment play a profound role. Advances in diagnostic modalities, including higher frequency ultrasound, acquisition of larger specimens, and nodal characterization, all improve esophageal cancer diagnostic accuracy and treatment planning. …

Prognosis And Treatment Response Stratification According To Loss Of Proofreading (Lop), Giulia Maddalena, Fadl A Zeineddine, Saikat Chowdhury, Mohammad A Zeineddine, Abdelrahman M Yousef, Francesca Bergamo, Sara Lonardi, Timothy A Yap, Michael Geoffrey White, Michael J Overman, Scott Kopetz, John Paul Shen

Faculty, Staff and Student Publications

Background: Only a subset of polymerase epsilon (POLE) mutations is associated with hypermutant phenotype; we hypothesized that only loss-of-proofreading (LOP) POLE mutations are associated with favorable immunotherapy response.

Methods: This retrospective cohort study included a pan-cancer cohort of 69,223 patients from cBioPortal and a cohort of patients with 41 POLE mutant metastatic colorectal (CRC) treated with immunotherapy at the MD Anderson Cancer Center between January 2017 and May 2023. We evaluated prognosis according to POLE mutation functionality.

Results: In the pan-cancer cBioPortal cohort (n=69,223) POLE was mutated in 2.8% (1,965) of tumors; of these, only 7.5% (n=148) had …

Voices: Future Directions In Targeting The Tumor Microenvironment, Tanja De Gruijl, Catherine Sautès-Fridman, Daniela S Thommen, Michael A Curran

Faculty, Staff and Student Publications

What do you envision as the most promising future directions for therapeutic strategies aimed at modulating the tumor microenvironment?

Identification Of Therapeutic Targets For Renal Medullary Carcinoma Via Integrated Genomic And Transcriptomic Profiling, Pavlos Msaouel, Nizar M Tannir, Funda Meric-Bernstam, Jennifer M King, Martin H Voss, Jessica P Cheng, Susan S Thomas, Zita D Lim, Menuka Karki, Rong He, Giannicola Genovese, Rahul A Sheth, Davis R Ingram, Diana Shamsutdinova, Khalida M Wani, Wei-Lien Wang, Alexander J Lazar, Dominique Knipper-Davis, Amber Berlinski, Tayla Soares, Danil Stupichev, Kirill Kryukov, Suren Davitavyan, Anna Novokreshchenova, Dmitry Lebedev, Stanislav Kurpe, Andrey Kravets, Dmitrii Belousov, Michael Hensley, Alexander Bagaev, Francesca Paradiso, Vladimir Kushnarev

Faculty, Staff and Student Publications

Renal medullary carcinoma (RMC) is a rare but highly aggressive kidney cancer that resists conventional therapies. To identify therapeutic targets, this study employs histopathologic, genomic, and transcriptomic profiling of 25 RMC samples. TROP2, EPCAM, CLDN6, and CDH6 are significantly overexpressed compared with other renal and solid tumors. Pathway analyses indicate Hippo pathway upregulation and a tumor microenvironment rich in fibroblasts and neutrophils. We subsequently explore treatment of four heavily pretreated patients, all with high TROP2 expression, using sacituzumab govitecan, a TROP2-targeted antibody-drug conjugate. Of these four patients, one patient achieves a partial response with symptom improvement, two patients maintain stable …