Medical Genetics Commons^™

Allogeneic Chimeric Antigen Receptor T-Cell Products Cemacabtagene Ansegedleucel/Allo-501 In Relapsed/Refractory Large B-Cell Lymphoma: Phase I Experience From The Alpha2/Alpha Clinical Studies, Frederick L Locke, Javier L Munoz, Michael T Tees, Lazaros J Lekakis, Sven De Vos, Don A Stevens, Geoffrey P Shouse, Mehdi Hamadani, Olalekan O Oluwole, Miguel-Angel Perales, David B Miklos, Paul W Fisher, Amy Feng, Lynn Navale, John B Le Gall, Sattva S Neelapu

Faculty, Staff and Student Publications

Purpose: Off-the-shelf, allogeneic CD19 chimeric antigen receptor (CAR) T-cell products may improve access to treatment versus autologous ones. We report the phase I experience of the allogeneic CD19 CAR T-cell product cemacabtagene ansegedleucel (cema-cel) and its predecessor, ALLO-501, in CD19 CAR T-naïve patients with relapsed/refractory large B-cell lymphoma (R/R LBCL).

Methods: In the ALPHA2/ALPHA studies, the safety and efficacy of allogeneic CD19 CAR T cells were evaluated in CD19 CAR T treatment-naïve patients with R/R LBCL. Patients received healthy donor-derived, human leukocyte antigen-unmatched cema-cel/ALLO-501 following a 3-day lymphodepletion regimen of fludarabine (30 mg/m2 once daily), cyclophosphamide (300 or 500 mg/m2 …

Ligand-Activated Egfr/Mapk Signaling But Not Pi3k, Are Key Resistance Mechanisms To Egfr-Therapy In Colorectal Cancer, Xueping Qu, Habib Hamidi, Radia M Johnson, Ethan S Sokol, Eva Lin, Tae Won Kim, Smruthy Sivakumar, Benjamin Kaplan, Felipe De Sousa E Melo, Andrew Mancini, Matthew Wongchenko, Yi Shi, David Shames, Yibing Yan, Fortunato Ciardiello, Carlos Bais

Faculty, Staff and Student Publications

Understanding mechanisms of resistance to active therapies is crucial for developing more effective treatments. Here, we investigate resistance to anti-EGFR and anti-VEGF plus chemotherapy treatment in colorectal cancer (CRC) patients from the IMblaze370 trial (NCT02788279). While anti-VEGF does not select for secondary mutations, anti-EGFR leads to simultaneous mutations in EGFR and MAPK, but not PI3K pathway genes. Notably, we observe frequent acquired mutations in the EGFR extracellular but not intracellular domain and that patients with higher baseline expression of EGFR-ligands are prone to acquire resistant mutations. This data reveals a ligand-activated EGFR/MAPK-signaling dependency in CRC. We also observe enrichment for …

Zanidatamab Monotherapy Or Combined With Chemotherapy In Her2-Expressing Gastroesophageal Adenocarcinoma: A Phase 1 Trial, Funda Meric-Bernstam, Sun Young Rha, Erika Hamilton, Yoon-Koo Kang, Diana L Hanna, Keun-Wook Lee, Muralidhar Beeram, Do-Youn Oh, Jorge Chaves, Rachel A Goodwin, Jaffer A Ajani, Lin Yang, Rajen Oza, Elena Elimova

Faculty, Staff and Student Publications

There is a need for novel therapies for patients with previously treated HER2-positive gastroesophageal adenocarcinoma (GEA). This phase 1 (NCT02892123) dose-escalation and expansion trial evaluated zanidatamab (a dual HER2-targeted bispecific antibody) ± chemotherapy in previously treated patients with HER2-expressing, locally advanced/metastatic cancers. Here, we report the outcomes for GEA cohorts receiving zanidatamab monotherapy or with chemotherapy (paclitaxel or capecitabine). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rate (ORR), disease control rate, progression-free survival, pharmacokinetics, and immunogenicity. Seventy patients were enrolled (n = 29 monotherapy; n = 41 combination therapy); most received prior HER2-targeted agents (monotherapy, …

Enhanced Efficacy Of Ipilimumab Plus Nivolumab In Angiogenic Subtypes Of Metastatic Clear-Cell Renal Cell Carcinoma, Xiaofan Lu, Yann-Alexandre Vano, Xiaoping Su, Virginie Verkarre, Cheng-Ming Sun, Li Xu, Salma Kotti, Wolf Herman Fridman, Catherine Sautes-Fridman, Stéphane Oudard, Gabriel G Malouf

Faculty, Staff and Student Publications

In metastatic clear-cell renal cell carcinoma (mccRCC), choosing between immuno-oncology (IO) combinations and IO plus anti-VEGF therapies is uncertain. The BIONIKK trial revealed that ipilimumab plus nivolumab (Ipi/Nivo) achieved a 70% objective response rate in angiogenic cluster1/2 versus 41% in cluster4/5, which featured T-effector/cell-cycle signatures (p = 0.048). Complete responses were exclusively observed in cluster1/2 (p = 0.012), with longer progression-free survival (p = 0.014). Ipi/Nivo may particularly benefit angiogenic mccRCC, supporting molecular subtype-based treatment strategies.

Overconfidence And Financial Risk Tolerance In Older Age, Colleen C Frank, Gary R Mottola, Meiru Chen, Lei Yu, Patricia A Boyle, Kendra L Seaman

Faculty, Staff and Student Publications

Objectives: Excessive financial risk-taking in older age can have harmful consequences as opportunities to recover lost wealth are limited. Understanding financial risk-taking in older age is important for identifying vulnerabilities and developing interventions to empower aging investors to make wise financial choices. In this paper, we explore how overconfidence in financial knowledge affects financial risk-taking among older adults.

Methods: We examine this research question in older adults aged 58-101 (N = 1,242) using data from the Rush Memory and Aging Project (MAP).

Results: After controlling for demographics, overconfidence was associated with self-reported financial risk tolerance such that those who were …

Discovery Of Novel, Potent, And Orally Bioavailable Smarca2 Proteolysis-Targeting Chimeras With Synergistic Antitumor Activity In Combination With Kirsten Rat Sarcoma Viral Oncogene Homologue G12c Inhibitors, Sasikumar Kotagiri, Yawen Wang, Yanyan Han, Xiaobing Liang, Nicholas Blazanin, Manu Sebastian, Yongying Jiang, Yonathan Lissanu

Faculty, Staff and Student Publications

Cancer genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex, including SMARCA4 in nonsmall cell lung cancer with a frequency of up to 33% in advanced-stage disease, making it the most frequently mutated complex. We and others have identified SMARCA2 to be synthetic lethal to SMARCA4, indicating that SMARCA2 is a high-value therapeutic target. Here, we disclose the discovery and characterization of potent, selective, and orally bioavailable cereblon-based SMARCA2 PROTACs. Biochemically, we showed that YDR1 and YD54 are potent SMARCA2 degraders. Further, we showed the antitumor growth inhibitory activity of YDR1 and YD54 in SMARCA4 …

Metabolic Reprogramming Driven By Ant2 Deficiency Augments T Cell Function And Anti-Tumor Immunity In Mice, Omri Yosef, Leonor Cohen-Daniel, Oded Shamriz, Zahala Bar-On, Wajeeh Salaymeh, Ifat Abramovich, Veronika Lutz, Joseph Tam, Anna Permyakova, Eyal Gottlieb, Magdalena Huber, Michael Berger

Faculty, Staff and Student Publications

T cell activation requires a substantial increase in NAD+ production, often exceeding the capacity of oxidative phosphorylation (OXPHOS). To investigate how T cells adapt to this metabolic challenge, we generate T cell-specific ADP/ATP translocase-2 knockout (Ant2-/-) mice. Loss of Ant2, a crucial protein mediating ADP/ATP exchange between mitochondria and cytoplasm, induces OXPHOS restriction by limiting ATP synthase activity, thereby impeding NAD+ regeneration. Interestingly, Ant2-/- naïve T cells exhibit enhanced activation, proliferation and effector functions compared to wild-type controls. Metabolic profiling reveals that these T cells adopt an activated-like metabolic program with increased mitobiogenesis and anabolism. Lastly, pharmacological inhibition of ANT …

A Honduran Prevalence Study On Soil-Transmitted Helminths Highlights Serological Antibodies To Tm-Wap49 As A Diagnostic Marker For Exposure To Human Trichuriasis, Neima Briggs, Leroy Versteeg, Rojelio Mejia, Jeroen Pollet, Maria Jose Villar, Graeme Segal, Patricia Lenihan, Paul Musgrave, Viviana Ellis, Carol Florencia Coello, K Jagannadha Sastry, Joe Craft, Peter J Hotez, Maria Elena Bottazzi

Faculty, Staff and Student Publications

Soil-transmitted helminth (STH) infections rank among the most prevalent communicable diseases of humans, yet detection of these parasites is mostly restricted to identifying active infection through fecal examinations. Currently, there are no commercial diagnostic tools to identify a prior whipworm or hookworm exposure, and the few serological assays for roundworm infection have not been well validated for crossreactivity or infections in humans. Such diagnostic restrictions limit the range of scientific and clinical questions that surround STH exposures and their implicated relationship to chronic diseases, such as autoimmunity, allergy, and cancer. The goal of this investigation was to evaluate the diagnostic …

Human Pain Neuroscience And The Next Generation Of Pain Therapeutics, Bryan A Copits, Michele Curatolo, Patrick M Dougherty, Robert W Gereau, Wenqin Luo, Hakan Olausson, William Renthal, Clifford J Woolf, Guoyan Zhao

Faculty, Staff and Student Publications

The recent approval of suzetrigine for acute pain treatment highlights both the success of targeting peripheral sensory neurons for pain management and the potential of developing new pain therapies primarily in human-based systems. To realize this transformative potential, further research into somatosensation and pain neuroimmunology in human systems is essential.

Axl Promotes Inflammatory Breast Cancer Progression By Regulating Immunosuppressive Macrophage Polarization, Lan T H Phi, Yating Cheng, Yohei Funakoshi, Francois Bertucci, Pascal Finetti, Fang Zou, Suguru Ogata, Savitri Krishnamurthy, James M Reuben, Jason M Foulks, Steven L Warner, Jennifer M Rosenbluth, Anil K Sood, Debu Tripathy, Naoto T Ueno, Xiaoping Wang

Faculty, Staff and Student Publications

Background: Tumor-associated macrophages (TAMs) are key promoters of inflammatory breast cancer (IBC), the most aggressive form of breast cancer. The receptor tyrosine kinase AXL is highly expressed in various cancer types, including IBC, but its role in TAMs remains unexplored.

Methods: We examined the effects of AXL inhibitor TP-0903 on tumor growth and tumor microenvironment (TME) component M2 macrophages (CD206+) in IBC and triple-negative breast cancer mouse models using flow cytometry and immunohistochemical staining. Additionally, we knocked out AXL expression in human THP-1 monocytes and evaluated the effect of AXL signaling on immunosuppressive M2 macrophage polarization and IBC cell growth …

Progressive Multifocal Leukoencephalopathy In Chimeric Antigen Receptor T-Cell Therapy Recipients: A Case Study, Michelly Abreu, Chirag B Patel, Krina Patel, Fareed Khawaja, Sudhakar Tummala

Faculty, Staff and Student Publications

Chimeric antigen receptor (CAR) T-cell therapy is a novel immunotherapy modality that has shown remarkable response rates in refractory hematologic malignancies, including multiple myeloma (MM). Cytokine release syndrome (CRS) and neurotoxicity are well-described side effects of this therapy. CAR T-cell therapy recipients are also at increased risk for infections due to immune dysfunction, history of multiple lines of therapy, history of lymphodepleting chemotherapy prior to cell infusion, and prolonged B-cell aplasia. Progressive multifocal leukoencephalopathy (PML) is an opportunistic disease of the central nervous system caused by the reactivation of JC virus (JCV) in the setting of immunosuppression, which leads to …

Language Mapping During Awake Brain Surgery In A Deaf Patient With A Brain Tumor: Illustrative Case, Ene Chibawanye I, Elizabeth Silva, Kyle Noll, Mariana Bradshaw, Katherine Connelly, Ravi Tummala, Frederick F Lang, Vinodh A Kumar

Faculty, Staff and Student Publications

Background: Signed language integrates complex sensorimotor processes involving visual and motor networks. The contribution of language regions such as Broca's and Wernicke's areas during signing is not well established. Here, the authors report the case of a 45-year-old right-handed male with congenital deafness, who communicates using American Sign Language (ASL) and Signed English, presenting with focal seizures. Imaging showed a diffuse infiltrative glioma in the right cerebral hemisphere.

Observations: Remarkably, preoperative functional MRI language activations were bihemispheric and overlapped for both traditional language paradigms and sign paradigms, suggesting that the same cortical regions of the brain are used for language …

Prognostic Value Of Serum And Bronchoalveolar Lavage Fluid Galactomannan Levels In Invasive Aspergillosis: An 8-Year Experience At A Tertiary Cancer Center, Saliba Wehbe, Anne-Marie Chaftari, Ray Hachem, Hiba Dagher, Andrea Haddad, Ying Jiang, Peter Bakht, Jishna Shrestha, Peter Lamie, Robin Sherchan, Jennifer Makhoul, Patrick Chaftari, Issam I Raad

Faculty, Staff and Student Publications

Background: Invasive aspergillosis (IA) is a life-threatening fungal infection that primarily affects immunocompromised individuals and has high morbidity and mortality rates, necessitating timely diagnosis and treatment. This study aimed to evaluate the prognostic utility of serum and bronchoalveolar lavage (BAL) fluid galactomannan levels, as well as galactomannan kinetics, in patients with IA.

Methods: We retrospectively reviewed the medical records of patients who were diagnosed with proven or probable IA from March 2016 to April 2024 at a tertiary cancer center. The collected data included patient characteristics, baseline and peak galactomannan levels in serum and BAL fluid, galactomannan trends, and …

Genomic Characterization Of High-Grade Serous Ovarian Carcinoma Reveals Distinct Somatic Features In Black Individuals, Katherine A Lawson-Michod, Jeffrey R Marks, Lindsay J Collin, David A Nix, Natalie R Davidson, Yao Yu, Courtney E Johnson, Lucas A Salas, Lauren C Peres, Casey S Greene, Joellen M Schildkraut, Jennifer A Doherty

Faculty, Staff and Student Publications

Black individuals experience worse survival after a diagnosis of high-grade serous ovarian carcinoma (HGSC) than White individuals and are underrepresented in ovarian cancer research. To date, the understanding of the molecular and genomic heterogeneity of HGSC is based primarily on the evaluation of tumors from White individuals. In the present study, we performed whole-exome sequencing on HGSC samples from 211 Black patients to identify significantly mutated genes and characterize mutational signatures, assessing their distributions by gene expression subtypes. The occurrence and frequency of somatic mutations and signatures by self-reported race were compared with historic data from The Cancer Genome Atlas …

Longitudinal Profiling Of Circulating Tumor Dna Reveals The Evolutionary Dynamics Of Metastatic Prostate Cancer During Serial Therapy, Yuehui Zhao, Naveen Ramesh, Ping Xu, Emi Sei, Min Hu, Patricia Troncoso, Christopher J Logothetis, Paul G Corn, Nicholas E Navin, Amado J Zurita

Faculty, Staff and Student Publications

Treatment decisions in metastatic castration-resistant prostate cancer are mostly guided by clinical variables, but efforts to molecularly monitor the disease remain hampered by challenges in acquiring tumor tissue repeatedly. In this study, we simultaneously profiled the genome copy number and exome in longitudinal plasma circulating tumor DNA (ctDNA) acquired before, during, and upon progression to serial treatments with androgen signaling inhibitors and taxane chemotherapy from 60 patients with metastatic castration-resistant prostate cancer (2-10 samples per patient). The genomic data were used to delineate the clonal substructure and evolutionary dynamics of each patient, and an evolutionary dynamic index was developed to …

Efficacy And Safety Of Larotrectinib In Patients With Trk Fusion Gastrointestinal Cancer, Changsong Qi, Lin Shen, Thierry Andre, Hyun Cheol Chung, Timothy L Cannon, Antoine Italiano, Tianshu Liu, Domnita-Ileana Burcoveanu, Natascha Neu, Chiara E Mussi, Rui-Hua Xu, David S Hong, Alexander Drilon, Jordan Berlin

Faculty, Staff and Student Publications

Background: Larotrectinib is the first-in-class, highly selective TRK inhibitor with demonstrated efficacy in various TRK fusion solid tumours. We report the efficacy and safety of larotrectinib in patients with TRK fusion gastrointestinal (GI) cancer.

Methods: Patients with TRK fusion GI cancer from NAVIGATE (NCT02576431) were included. Response was independent review committee (IRC)-assessed per RECIST v1.1.

Results: As of July 2023, 44 patients were enrolled. Tumour types included colorectal (CRC; n = 26), pancreatic (n = 7), cholangiocarcinoma (n = 4), gastric (n = 3), and one each of appendiceal, duodenal, oesophageal and hepatic cancers. Of the 26 patients …

Immune Landscape Of Early Liver Metastatic Lesions In A Novel Immunocompetent Murine Colorectal Cancer Metastasis Model, Alaa Mohamed

Dissertations and Theses (Open Access)

Colorectal cancer minimal residual disease (MRD) represents a major clinical problem for colorectal cancer patients, with failure rates of surgery and adjuvant chemotherapy between 5% to 40% depending on stage of disease. In our study, we simulated MRD using genetically engineered organoids with precise somatic editing of APC and TP53, creating a murine model that mimics human liver metastatic colorectal cancer. By implementing a meticulously timed experimental metastatic model, we could detect microscopic tumor lesions. Through genomic and transcriptomic analyses, we pinpointed the importance of macrophages, particularly those expressing high levels of CSF1R, in these microscopic metastatic focal lesions. We …

Elucidating The Multi-Omics Of Early-Onset Colorectal Cancer, Jumanah Alshenaifi

Dissertations and Theses (Open Access)

The incidence and mortality rates of sporadic early-onset colorectal cancer have increased in recent decades, but there is no clear etiological basis for this trend. EOCRC is commonly defined as colon and rectal cancers diagnosed before the age of 50 years. The rising incidence of EOCRC has made it the second most common cancer and the third leading cause of cancer death in this age group. The rising incidence of EOCRC is also documented internationally in more than 20 countries across different continents. Clinically, EOCRC has a distinct, more aggressive clinical profile than LOCRC. While approximately 15% of EOCRC cases …

Enhancing The Safety And Efficacy Of Cell Therapy With Programmed Sense-And-Respond Function, Andrew J Walters, Xiaoyu Yang, Scott D Olson, Caleb J Bashor

Faculty, Staff and Student Publications

No abstract provided.

Imaging In Pelvic Exenteration-A Multidisciplinary Practice Guide From The Esgar-Sar-Esur-Pelvex Collaborative Group, Stephanie Nougaret, Doenja M J Lambregts, Geerard L Beets, Regina G H Beets-Tan, Lennart Blomqvist, David Burling, Quentin Denost, Maria A Gambacorta, Benedetta Gui, Ann Klopp, Yulia Lakhman, Kate E Maturen, Riccardo Manfredi, Iva Petkovska, Luca Russo, Atul B Shinagare, James A Stephenson, Damian Tolan, Aradhana M Venkatesan, Aaron J Quyn, Rosemarie Forstner

Faculty, Staff and Student Publications

Pelvic exenteration (PE) is a radical surgical approach designed for the curative treatment of advanced pelvic malignancies, requiring en-bloc resection of multiple pelvic organs. While the procedure is radical, it has shown promise in enhancing long-term survival and is now comparable in surgical mortality to elective resections for primary pelvic cancers. Imaging plays a crucial role in preoperative planning, with MRI, CT, and PET/CT being pivotal in assessing the extent of cancer and formulating a surgical roadmap. This paper presents clinical practice guidelines for imaging in the context of PE, developed jointly by ESGAR, SAR, ESUR, and the PelvEx Collaborative. …

Precision Proteogenomics Reveals Pan-Cancer Impact Of Germline Variants, Fernanda Martins Rodrigues, Nadezhda V Terekhanova, Kathleen J Imbach, Karl R Clauser, Myvizhi Esai Selvan, Isabel Mendizabal, Yifat Geffen, Yo Akiyama, Myranda Maynard, Tomer M Yaron, Yize Li, Song Cao, Erik P Storrs, Olivia S Gonda, Adrian Gaite-Reguero, Akshay Govindan, Emily A Kawaler, Matthew A Wyczalkowski, Robert J Klein, Berk Turhan, Karsten Krug, D R Mani, Felipe Da Veiga Leprevost, Alexey I Nesvizhskii, Steven A Carr, David Fenyö, Michael A Gillette, Antonio Colaprico, Antonio Iavarone, Ana I Robles, Kuan-Lin Huang, Chandan Kumar-Sinha, François Aguet, Alexander J Lazar, Lewis C Cantley, Urko M Marigorta, Zeynep H Gümüş, Matthew H Bailey, Gad Getz, Eduard Porta-Pardo, Li Ding

Faculty, Staff and Student Publications

We investigate the impact of germline variants on cancer patients' proteomes, encompassing 1,064 individuals across 10 cancer types. We introduced an approach, "precision peptidomics," mapping 337,469 coding germline variants onto peptides from patients' mass spectrometry data, revealing their potential impact on post-translational modifications, protein stability, allele-specific expression, and protein structure by leveraging the relevant protein databases. We identified rare pathogenic and common germline variants in cancer genes potentially affecting proteomic features, including variants altering protein abundance and structure and variants in kinases (ERBB2 and MAP2K2) impacting phosphorylation. Precision peptidome analysis predicted destabilizing events in signal-regulatory protein alpha (SIRPA) and glial …

A Stakeholder-Informed Conceptual Framework For Evaluating Genomics In Precision Oncology, Julie A. Wiedower

All Dissertations

This dissertation explores the value of genomic testing in precision oncology with an emphasis on how US payers conceptualize and prioritize elements of value. This research aims to address gaps in understanding payer perspectives and proposes a stakeholder-informed framework for evaluating genomic testing in oncology. To achieve this aim, the presented research investigates payer perspectives, value-based cancer care priorities, and the conceptual understanding of the value of a genetic diagnosis to establish a framework for value with the payer audience in mind. Chapter 1 outlines relevant background information relating to the genomic revolution and challenges in translating genomic testing technologies …

The Genomic Landscape And Prognostic Impact Of Kras, Stk11, And Smarca4 Mutations And Co-Mutations On Survival Outcomes In Non-Small Cell Lung Cancer, Peter Manolakos

All Dissertations

Non-small lung cancer (NSCLC) accounts for 85% of lung cancer cases, and Kirsten rat sarcoma viral oncogene homolog (KRAS), Serine/Threonine Kinase 11 (STK11), and SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4) mutations and co-mutations have been increasingly recognized for their potential prognostic significance. However, clear knowledge gaps remain regarding which treatments should be selected for patients who present clinically with KRAS/STK11 or KRAS/SMARCA4 co-mutations, as outlined in Chapter 1. Despite significant clinical development advancements in immunotherapy and targeted therapy, a deeper understanding of the influence of these genomic …

Development Of A Treatment Decision Aid For Patients With Dysplastic Nevi Who Are Candidates For Re-Excision, Jaclyn N Roland-Mcgowan, Steven Caleb Freeman, Wenelia Baghoomian, Bryan T Carroll, Caroline Choi Kim, Emily Y Chu, Kelly Carter Nelson, Kevin P White, Michael E Ming, Rebecca I Hartman, Sancy A Leachman, Stephanie Mengden-Koon, Suephy C Chen, Susan M Swetter, Victor G Prieto, Elizabeth Berry, Wesley Y Yu

Faculty, Staff and Student Publications

No abstract provided.

A Comparison Of Carbon Ions Versus Protons For Integrated Mode Ion Imaging, Mikaël Simard, Ryan Fullarton, Lennart Volz, Christoph Schuy, Daniel G Robertson, Colin Baker, Christian Graeff, Charles-Antoine Collins Fekete

Faculty, Staff and Student Publications

Background: Incorporating image guidance into ion beam therapy is critical for minimizing beam range uncertainties and realizing the modality's potential. One promising avenue for image guidance is to capture transmission ion radiographs (iRads) before and/or during treatment. iRad image quality is typically maximized using a single-event imaging system, which involves tracking individual ions, albeit the approach is generally not suited to clinical beam settings. An alternative faster and clinically compatible method is integrated mode imaging, where individual pencil beam data is acquired, rather than single ion data. To evaluate the usefulness of transmission ion imaging for image guidance, it is …

Advancing Understanding And Therapeutic Strategies For Nut Sarcomas: Comprehensive Review Of The Literature And Two Cases, Carlos Torrado, Elise Nassif Haddad, Neeta Somaiah, Pavlos Msaouel, Alexander J Lazar

Faculty, Staff and Student Publications

Soft tissue sarcomas (STSs) are a group of rare cancers, among which nuclear protein in testis (NUT) sarcomas represent an ultra-rare subset driven by NUTM1 gene fusions. This article presents two unique cases of NUT sarcomas and conducts a comprehensive review of the literature to include an additional 61 cases. Our review reveals that NUT sarcoma exhibits a slightly higher incidence among women (male-to-female ratio of 1:1.03) and tends to manifest at a relatively young age (median age of 40 years). The most prevalent NUT partner genes were the MAD family in 52% of patients (33 of 63 patients, including …

Summary Of Research: Efficacy Of Trastuzumab Deruxtecan In Her2-Expressing Solid Tumors By Enrollment Her2 Ihc Status: Post Hoc Analysis Of Destiny-Pantumor02, Ana Oaknin, Jung-Yun Lee, Vicky Makker, Do-Youn Oh, Susana Banerjee, Kyung Hae Jung, Luis Manso, Aránzazu Manzano, Bohuslav Melichar, Salvatore Siena, Daniil Stroyakovskiy, Anitra Fielding, Soham Puvvada, Ann Smith, Funda Meric-Bernstam

Faculty, Staff and Student Publications

of the original article, 'Efficacy of Trastuzumab Deruxtecan in HER2-Expressing Solid Tumors by Enrollment HER2 IHC Status: Post Hoc Analysis of DESTINY-PanTumor02'. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate, which is a chemotherapy with a linker (deruxtecan) joined to an antibody (trastuzumab). Trastuzumab binds to the human epidermal growth factor receptor 2 (HER2) protein on cancer cells, where it releases the chemotherapy to kill these cells. The DESTINY-PanTumor02 clinical study tested the effectiveness of T-DXd for people with various HER2-expressing cancers and the safety of treatment. Previous results from DESTINY-PanTumor02 showed that T-DXd had antitumor activity, and the greatest effects …

Further Delineation Of The Scaf4-Associated Neurodevelopmental Disorder, Cosima M Schmid, Anne Gregor, Anna Ruiz, Carmen Manso Bazús, Isabella Herman, Urania Kotzaeridou, Lucie Dupuis, Katharina Steindl, Anaïs Begemann, Anita Rauch, Aude-Annick Suter, Bertrand Isidor, Sandra Mercier, Mathilde Nizon, Benjamin Cogné, Wallid Deb, Thomas Besnard, Tobias B Haack, Ruth J Falb, Amelie J Müller, Tobias Linden, Chad R Haldeman-Englert, Charlotte W Ockeloen, Francesca Mattioli, Alexandre Reymond, Nazia Ibrahim, Shagufta Naz, Elodie Lacaze, Jennifer A Bassetti, Julia Hoefele, Theresa Brunet, Korbinian M Riedhammer, Houda Z Elloumi, Richard Person, Fanggeng Zou, Juliette J Kahle, Kirsten Cremer, Axel Schmidt, Marie-Ange Delrue, Pedro M Almeida, Fabiana Ramos, Siddharth Srivastava, Aisling Quinlan, Stephen Robertson, Eva Manka, Alma Kuechler, Stephanie Spranger, Malgorzata J M Nowaczyk, Reem M Elshafie, Hind Alsharhan, Paul R Hillman, Leslie A Dunnington, Hilde M H Braakman, Shane Mckee, Angelica Moresco, Andrea-Diana Ignat, Ruth Newbury-Ecob, Guillaume Banneau, Olivier Patat, Jeffrey Kuerbitz, Susan Rzucidlo, Susan S Sell, Patricia Gordon, Sarah Schuhmann, André Reis, Yosra Halleb, Radka Stoeva, Boris Keren, Zainab Al Masseri, Zeynep Tümer, Sophia Hammer-Hansen, Sofus Krüger Sølyst, Connolly G Steigerwald, Nicolas J Abreu, Helene Faust, Amica Müller-Nedebock, Frédéric Tran Mau-Them, Heinrich Sticht, Christiane Zweier

Faculty, Staff and Student Publications

While mostly de novo truncating variants in SCAF4 were recently identified in 18 individuals with variable neurodevelopmental phenotypes, knowledge on the molecular and clinical spectrum is still limited. We assembled data on 50 novel individuals with SCAF4 variants ascertained via GeneMatcher and personal communication. With detailed evaluation of clinical data, in silico predictions and structural modeling, we further characterized the molecular and clinical spectrum of the autosomal dominant SCAF4-associated neurodevelopmental disorder. The molecular spectrum comprises 25 truncating, eight splice-site and five missense variants. While all other truncating variants were classified as pathogenic/likely pathogenic, significance of one C-terminal truncating variant, one …

The Multilayered Transcriptional Architecture Of Glioblastoma Ecosystems, Masashi Nomura, Avishay Spitzer, Kevin C Johnson, Luciano Garofano, Djamel Nehar-Belaid, Alissa C Greenwald, Young Taek Oh, Frederick S Varn, Fulvio D'Angelo, Simon Gritsch, Kevin J Anderson, Simona Migliozzi, L Nicolas Gonzalez Castro, Tamrin Chowdhfury, Nicolas Robine, Catherine Reeves, Jong Bae Park, Anuja Lipsa, Frank Hertel, Anna Golebiewska, Simone P Niclou, Labeeba Nusrat, Sorcha Kellet, Sunit Das, Hyo Eun Moon, Sun Ha Paek, Franck Bielle, Alice Laurenge, Anna Luisa Di Stefano, Bertrand Mathon, Alberto Picca, Marc Sanson, Shota Tanaka, Nobuhito Saito, David M Ashley, Stephen T Keir, Keith L Ligon, Jason T Huse, W K Alfred Yung, Anna Lasorella, Roel G W Verhaak, Antonio Iavarone, Mario L Suvà, Itay Tirosh

Faculty, Staff and Student Publications

In isocitrate dehydrogenase wildtype glioblastoma (GBM), cellular heterogeneity across and within tumors may drive therapeutic resistance. Here we analyzed 121 primary and recurrent GBM samples from 59 patients using single-nucleus RNA sequencing and bulk tumor DNA sequencing to characterize GBM transcriptional heterogeneity. First, GBMs can be classified by their broad cellular composition, encompassing malignant and nonmalignant cell types. Second, in each cell type we describe the diversity of cellular states and their pathway activation, particularly an expanded set of malignant cell states, including glial progenitor cell-like, neuronal-like and cilia-like. Third, the remaining variation between GBMs highlights three baseline gene expression …

From Epithelium To Therapy: Transitional Cells In Lung Fibrosis, Sarah Y Shin, Jichao Chen, Irit Milman Krentsis, Yair Reisner, Rodeo Abrencillo, Danielle Wu

Faculty, Staff and Student Publications

Patients with idiopathic pulmonary fibrosis and lung fibrosis secondary to infections such as influenza A and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have limited treatment options outside of supportive therapy and lung transplantation. Multiple lung stem cell populations have been implicated in the pathogenesis of lung fibrosis, and more progenitor cell populations continue to be discovered and characterized. In this review, we summarize the functions and differentiation pathways of various cells that constitute the lung epithelium. We then focus on two subpopulations of KRT5