Genetic Phenomena Commons^™

A Phase Ii Clinical Trial Of Pembrolizumab Efficacy And Safety In Advanced Renal Medullary Carcinoma, Chijioke Nze, Pavlos Msaouel, Mohamed H Derbala, Bettzy Stephen, Abdulrahman Abonofal, Funda Meric-Bernstam, Nizar M Tannir, Aung Naing

Faculty, Staff and Student Publications

Background: Renal medullary carcinoma (RMC) is one of most aggressive renal cell carcinomas and novel therapeutic strategies are therefore needed. Recent comprehensive molecular and immune profiling of RMC tissues revealed a highly inflamed phenotype, suggesting the potential therapeutic role for immune checkpoint therapies. We present the first prospective evaluation of an immune checkpoint inhibitor in a cohort of patients with RMC.

Methods: A cohort of patients with locally advanced or metastatic RMC was treated with pembrolizumab 200 mg intravenously every 21 days in a phase II basket trial (ClinicalTrials.gov: NCT02721732). Responses were assessed by irRECIST. Tumor tissues were evaluated …

Islet: Individual-Specific Reference Panel Recovery Improves Cell-Type-Specific Inference, Hao Feng, Guanqun Meng, Tong Lin, Hemang Parikh, Yue Pan, Ziyi Li, Jeffrey Krischer, Qian Li

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We propose a statistical framework ISLET to infer individual-specific and cell-type-specific transcriptome reference panels. ISLET models the repeatedly measured bulk gene expression data, to optimize the usage of shared information within each subject. ISLET is the first available method to achieve individual-specific reference estimation in repeated samples. Using simulation studies, we show outstanding performance of ISLET in the reference estimation and downstream cell-type-specific differentially expressed genes testing. We apply ISLET to longitudinal transcriptomes profiled from blood samples in a large observational study of young children and confirm the cell-type-specific gene signatures for pancreatic islet autoantibody. ISLET is available at https://bioconductor.org/packages/ISLET …

Dual Targeting Of Cdk4/6 And Bcl-2 Exhibits A Potent Antitumor Effect On Mantle Cell Lymphoma, Yuxuan Che, Yang Liu, Yijing Li, Joseph M Mcintosh, Alexa Jordan, Fangfang Yan, Wei Wang, Lei Nie, Heng-Huan Lee, Jingling Jin, Yixin Yao, Zhongming Zhao, Vivian Changying Jiang, Michael Wang

Faculty, Staff and Student Publications

No abstract provided.

Asian Americans In Stem Are Not A Monolith, Zer Vue, Chia Vang, Neng Vue, Vijayvardhan Kamalumpundi, Taylor Barongan, Bryanna Shao, Sunny Huang, Larry Vang, Mein Vue, Nancy Vang, Jianqiang Shao, Coohleenann Coombes, Prasanna Katti, Kaihua Liu, Kailee Yoshimura, Michelle Biete, Dao-Fu Dai, Mark A Phillips, Richard R Behringer

Faculty, Staff and Student Publications

Despite tremendous diversity, Asian Americans in STEM are grouped and viewed as a homogeneous monolith, facing stereotypes and disparities. We propose solutions that include disaggregating the Asian American grouping and recognizing the diverse individual ethnic subgroups that comprise Americans of Asian ancestry to implement change within the STEM field.

Structures Of Channelrhodopsin Paralogs In Peptidiscs Explain Their Contrasting K+ And Na+ Selectivities, Takefumi Morizumi, Kyumhyuk Kim, Hai Li, Elena G Govorunova, Oleg A Sineshchekov, Yumei Wang, Lei Zheng, Éva Bertalan, Ana-Nicoleta Bondar, Azam Askari, Leonid S Brown, John L Spudich, Oliver P Ernst

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Kalium channelrhodopsin 1 from Hyphochytrium catenoides (HcKCR1) is a light-gated channel used for optogenetic silencing of mammalian neurons. It selects K+ over Na+ in the absence of the canonical tetrameric K+ selectivity filter found universally in voltage- and ligand-gated channels. The genome of H. catenoides also encodes a highly homologous cation channelrhodopsin (HcCCR), a Na+ channel with >100-fold larger Na+ to K+ permeability ratio. Here, we use cryo-electron microscopy to determine atomic structures of these two channels embedded in peptidiscs to elucidate structural foundations of their dramatically different cation selectivity. Together with structure-guided mutagenesis, we show …

Metastatic Infiltration Of Nervous Tissue And Periosteal Nerve Sprouting In Multiple Myeloma-Induced Bone Pain In Mice And Human, Marta Diaz-Delcastillo, Oana Palasca, Tim T Nemler, Didde M Thygesen, Norma A Chávez-Saldaña, Juan A Vázquez-Mora, Lizeth Y Ponce Gomez, Lars Juhl Jensen, Holly Evans, Rebecca E Andrews, Aritri Mandal, David Neves, Patrick Mehlen, James P Caruso, Patrick M Dougherty, Theodore J Price, Andrew Chantry, Michelle A Lawson, Thomas L Andersen, Juan M Jimenez-Andrade, Anne-Marie Heegaard

Faculty, Staff and Student Publications

Multiple myeloma (MM) is a neoplasia of B plasma cells that often induces bone pain. However, the mechanisms underlying myeloma-induced bone pain (MIBP) are mostly unknown. Using a syngeneic MM mouse model, we show that periosteal nerve sprouting of calcitonin gene-related peptide (CGRP+) and growth associated protein 43 (GAP43+) fibers occurs concurrent to the onset of nociception and its blockade provides transient pain relief. MM patient samples also showed increased periosteal innervation. Mechanistically, we investigated MM induced gene expression changes in the dorsal root ganglia (DRG) innervating the MM-bearing bone of male mice and found alterations in pathways associated with …

Impact Of Mir196a-2 Genotypes On Colorectal Cancer Risk In Taiwan, Te-Cheng Yueh, Yun-Chi Wang, Yu-Ting Chin, Yi-Chih Hung, Mei-Chin Mong, Ya-Chen Yang, Jen-Sheng Pei, Jian Gu, Chia-Wen Tsai, Da-Tian Bau, Wen-Shin Chang

Faculty, Staff and Student Publications

We aimed to investigate the association between genotypes for

The Checkpoint Inhibitor Pd-1h/Vista Controls Osteoclast-Mediated Multiple Myeloma Bone Disease, Jing Fu, Shirong Li, Huihui Ma, Jun Yang, Gabriel M Pagnotti, Lewis M Brown, Stephen J Weiss, Markus Y Mapara, Suzanne Lentzsch

Faculty, Staff and Student Publications

Multiple myeloma bone disease is characterized by the development of osteolytic bone lesions. Recent work identified matrix metalloproteinase 13 as a myeloma-derived fusogen that induces osteoclast activation independent of its proteolytic activity. We now identify programmed death-1 homolog, PD-1H, as the bona fide MMP-13 receptor on osteoclasts. Silencing PD-1H or using Pd-1h-/- bone marrow cells abrogates the MMP-13-enhanced osteoclast fusion and bone-resorptive activity. Further, PD-1H interacts with the actin cytoskeleton and plays a necessary role in supporting c-Src activation and sealing zone formation. The critical role of PD-1H in myeloma lytic bone lesions was confirmed using a Pd-1h-/- myeloma bone …

Phase 1b Study Of Combined Selinexor And Eribulin For The Treatment Of Advanced Solid Tumors And Triple-Negative Breast Cancer, Blessie Elizabeth Nelson, Sadia Saleem, Senthil Damodaran, Neeta Somaiah, Sarina Piha-Paul, Julia Ann Moore, Bulent Yilmaz, Deby Ogbonna, Daniel D Karp, Ecaterina Dumbrava, Apostolia M Tsimberidou, David S Hong, Jordi Rodon Ahnert, Denái R Milton, Xiaofeng Zheng, Daniel J Booser, Nuhad K Ibrahim, Anthony P Conley, Priya Bhosale, Cristhiam M Rojas Hernandez, Debasish Tripathy, Aung Naing, Funda Meric-Bernstam

Faculty, Staff and Student Publications

BACKGROUND: Selinexor (KPT-330) is a potent inhibitor of exportin 1 (XPO1), in turn inhibiting tumor growth. Selinexor enhances the antitumor efficacy of eribulin in triple-negative breast cancer (TNBC) in vitro and in vivo. Given the unmet medical need in TNBC and sarcoma, the authors explored the safety and efficacy of this combination.

METHODS: The authors conducted a phase 1b trial of combined selinexor and eribulin using a 3 + 3 dose-escalation design in patients who had advanced solid tumors and in those who had TNBC in a dose-expansion cohort.

RESULTS: Patients with TNBC (N = 19), sarcoma (N = 9), …

Actionability Classification Of Variants Of Unknown Significance Correlates With Functional Effect, Amber Johnson, Patrick Kwok-Shing Ng, Michael Kahle, Julia Castillo, Bianca Amador, Yujia Wang, Jia Zeng, Vijaykumar Holla, Thuy Vu, Fei Su, Sun-Hee Kim, Tara Conway, Xianli Jiang, Ken Chen, Kenna R Mills Shaw, Timothy A Yap, Jordi Rodon, Gordon B Mills, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Genomically-informed therapy requires consideration of the functional impact of genomic alterations on protein expression and/or function. However, a substantial number of variants are of unknown significance (VUS). The MD Anderson Precision Oncology Decision Support (PODS) team developed an actionability classification scheme that categorizes VUS as either "Unknown" or "Potentially" actionable based on their location within functional domains and/or proximity to known oncogenic variants. We then compared PODS VUS actionability classification with results from a functional genomics platform consisting of mutant generation and cell viability assays. 106 (24%) of 438 VUS in 20 actionable genes were classified as oncogenic in functional …

Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven By Different P53 Mutants, Dhruv Chachad, Lalit R Patel, Carlos Vera Recio, Rasoul Pourebrahim, Elizabeth M Whitley, Wenyi Wang, Xiaoping Su, An Xu, Dung-Fang Lee, Guillermina Lozano

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Missense mutations in the DNA binding domain of p53 are characterized as structural or contact mutations based on their effect on the conformation of the protein. These mutations show gain-of-function (GOF) activities, such as promoting increased metastatic incidence compared with p53 loss, often mediated by the interaction of mutant p53 with a set of transcription factors. These interactions are largely context specific. To understand the mechanisms by which p53 DNA binding domain mutations drive osteosarcoma progression, we created mouse models, in which either the p53 structural mutant p53R172H or the contact mutant p53R245W are expressed specifically in osteoblasts, yielding osteosarcoma …

Mettl3-Mediated M6a Modification Of Linc00839 Maintains Glioma Stem Cells And Radiation Resistance By Activating Wnt/Β-Catenin Signaling, Jianxing Yin, Fangshu Ding, Zhangchun Cheng, Xin Ge, Yanhui Li, Ailiang Zeng, Junxia Zhang, Wei Yan, Zhumei Shi, Xu Qian, Yongping You, Zhiliang Ding, Jing Ji, Xiefeng Wang

Faculty, Staff and Student Publications

Long noncoding RNAs (lncRNAs) are involved in glioma initiation and progression. Glioma stem cells (GSCs) are essential for tumor initiation, maintenance, and therapeutic resistance. However, the biological functions and underlying mechanisms of lncRNAs in GSCs remain poorly understood. Here, we identified that LINC00839 was overexpressed in GSCs. A high level of LINC00839 was associated with GBM progression and radiation resistance. METTL3-mediated m6A modification on LINC00839 enhanced its expression in a YTHDF2-dependent manner. Mechanistically, LINC00839 functioned as a scaffold promoting c-Src-mediated phosphorylation of β-catenin, thereby inducing Wnt/β-catenin activation. Combinational use of celecoxib, an inhibitor of Wnt/β-catenin signaling, greatly sensitized GSCs to …

Brentuximab Vedotin After Autologous Transplantation In Pediatric Patients With Relapsed/Refractory Hodgkin Lymphoma, Christopher J Forlenza, Jaclyn Rosenzweig, Audrey Mauguen, Ilia Buhtoiarov, Branko Cuglievan, Hema Dave, Rebecca J Deyell, Jamie E Flerlage, Anna K Franklin, Jennifer Krajewski, Kasey J Leger, Lianna J Marks, Robin E Norris, Martha Pacheco, Faye Willen, Adam Paul Yan, Paul D Harker-Murray, Lisa Giulino-Roth

Faculty, Staff and Student Publications

Outcomes for children and adolescents with relapsed and refractory Hodgkin lymphoma (HL) are poor, with ∼50% of patients experiencing a subsequent relapse. The anti-CD30 antibody-drug conjugate brentuximab vedotin improved progression-free survival (PFS) when used as consolidation after autologous stem cell transplantation (ASCT) in adults with high-risk relapsed/refractory HL. Data on brentuximab vedotin as consolidative therapy after ASCT in pediatric patients with HL are extremely limited, with data of only 11 patients reported in the literature. We performed a retrospective analysis of 67 pediatric patients who received brentuximab vedotin as consolidation therapy after ASCT for the treatment of relapsed/refractory HL to …

Propensity Score Analysis With Local Balance, Yan Li, Liang Li

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Most propensity score (PS) analysis methods rely on a correctly specified parametric PS model, which may result in biased estimation of the average treatment effect (ATE) when the model is misspecified. More flexible nonparametric models for treatment assignment alleviate this issue, but they do not always guarantee covariate balance. Methods that force balance in the means of covariates and their transformations between the treatment groups, termed global balance in this article, do not always lead to unbiased estimation of ATE. Their estimated propensity scores only ensure global balance but not the balancing property, which is defined as the conditional independence …

Accumulation Of Chronic Disease Among Survivors Of Childhood Cancer Predicts Early Mortality, Adam J Esbenshade, Lu Lu, Debra L Friedman, Kevin C Oeffinger, Gregory T Armstrong, Kevin R Krull, Joseph P Neglia, Wendy M Leisenring, Rebecca Howell, Robyn Partin, Amy Sketch, Leslie L Robison, Kirsten K Ness

Faculty, Staff and Student Publications

Purpose: Cancer survivors develop cancer and treatment-related morbidities at younger than normal ages and are at risk for early mortality, suggestive of an aging phenotype. The Cumulative Illness Rating Scale for Geriatrics (CIRS-G) is specifically designed to describe the accumulation of comorbidities over time with estimates of severity such as total score (TS) which is a sum of possible conditions weighted by severity. These severity scores can then be used to predict future mortality.

Methods: CIRS-G scores were calculated in cancer survivors and their siblings from Childhood Cancer Survivor Study cohort members from two time points 19 years apart and …

A Functional Link Between Lariat Debranching Enzyme And The Intron-Binding Complex Is Defective In Non-Photosensitive Trichothiodystrophy, Brittany A Townley, Luke Buerer, Ning Tsao, Albino Bacolla, Fadhel Mansoori, Timur Rusanov, Nathanial Clark, Negar Goodarzi, Nicolas Schmidt, Sridhar Nonavinkere Srivatsan, Hua Sun, Reilly A Sample, Joshua R Brickner, Drew Mcdonald, Miaw-Sheue Tsai, Matthew J Walter, David F Wozniak, Alex S Holehouse, Vladimir Pena, John A Tainer, William G Fairbrother, Nima Mosammaparast

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The pre-mRNA life cycle requires intron processing; yet, how intron-processing defects influence splicing and gene expression is unclear. Here, we find that TTDN1/MPLKIP, which is encoded by a gene implicated in non-photosensitive trichothiodystrophy (NP-TTD), functionally links intron lariat processing to spliceosomal function. The conserved TTDN1 C-terminal region directly binds lariat debranching enzyme DBR1, whereas its N-terminal intrinsically disordered region (IDR) binds the intron-binding complex (IBC). TTDN1 loss, or a mutated IDR, causes significant intron lariat accumulation, as well as splicing and gene expression defects, mirroring phenotypes observed in NP-TTD patient cells. A Ttdn1-deficient mouse model recapitulates intron-processing defects and certain …

Feasibility And Safety Of Personalized, Multi-Target, Adoptive Cell Therapy (Ima101): First-In-Human Clinical Trial In Patients With Advanced Metastatic Cancer, Apostolia M Tsimberidou, Kerstin Guenther, Borje S Andersson, Regina Mendrzyk, Amir Alpert, Claudia Wagner, Anna Nowak, Katrin Aslan, Arun Satelli, Fabian Richter, Sabrina Kuttruff-Coqui, Oliver Schoor, Jens Fritsche, Zoe Coughlin, Ali S Mohamed, Kerry Sieger, Becky Norris, Rita Ort, Jennifer Beck, Henry Hiep Vo, Franziska Hoffgaard, Manuel Ruh, Linus Backert, Ignacio I Wistuba, David Fuhrmann, Nuhad K Ibrahim, Van Karlyle Morris, Bryan K Kee, Daniel M Halperin, Graciela M Nogueras-Gonzalez, Partow Kebriaei, Elizabeth J Shpall, David Vining, Patrick Hwu, Harpreet Singh, Carsten Reinhardt, Cedrik M Britten, Norbert Hilf, Toni Weinschenk, Dominik Maurer, Steffen Walter

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IMA101 is an actively personalized, multi-targeted adoptive cell therapy (ACT), whereby autologous T cells are directed against multiple novel defined peptide-HLA (pHLA) cancer targets. HLA-A*02:01-positive patients with relapsed/refractory solid tumors expressing ≥1 of 8 predefined targets underwent leukapheresis. Endogenous T cells specific for up to 4 targets were primed and expanded in vitro. Patients received lymphodepletion (fludarabine, cyclophosphamide), followed by T-cell infusion and low-dose IL2 (Cohort 1). Patients in Cohort 2 received atezolizumab for up to 1 year (NCT02876510). Overall, 214 patients were screened, 15 received lymphodepletion (13 women, 2 men; median age, 44 years), and 14 were treated with …

The Swi/Snf Chromatin-Remodeling Subunit Dpf2 Facilitates Nrf2-Dependent Antiinflammatory And Antioxidant Gene Expression, Gloria Mas, Na Man, Yuichiro Nakata, Concepcion Martinez-Caja, Daniel Karl, Felipe Beckedorff, Francesco Tamiro, Chuan Chen, Stephanie Duffort, Hidehiro Itonaga, Adnan K Mookhtiar, Kranthi Kunkalla, Alfredo M Valencia, Clayton K Collings, Cigall Kadoch, Francisco Vega, Scott C Kogan, Ramin Shiekhattar, Lluis Morey, Daniel Bilbao, Stephen D Nimer

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During emergency hematopoiesis, hematopoietic stem cells (HSCs) rapidly proliferate to produce myeloid and lymphoid effector cells, a response that is critical against infection or tissue injury. If unresolved, this process leads to sustained inflammation, which can cause life-threatening diseases and cancer. Here, we identify a role of double PHD fingers 2 (DPF2) in modulating inflammation. DPF2 is a defining subunit of the hematopoiesis-specific BAF (SWI/SNF) chromatin-remodeling complex, and it is mutated in multiple cancers and neurological disorders. We uncovered that hematopoiesis-specific Dpf2-KO mice developed leukopenia, severe anemia, and lethal systemic inflammation characterized by histiocytic and fibrotic tissue infiltration resembling a …

Fast Inference Of Genetic Recombination Rates In Biobank Scale Data, Ardalan Naseri, William Yue, Shaojie Zhang, Degui Zhi

Faculty, Staff and Student Publications

Although rates of recombination events across the genome (genetic maps) are fundamental to genetic research, the majority of current studies only use one standard map. There is evidence suggesting population differences in genetic maps, and thus estimating population-specific maps, are of interest. Although the recent availability of biobank-scale data offers such opportunities, current methods are not efficient at leveraging very large sample sizes. The most accurate methods are still linkage disequilibrium (LD)-based methods that are only tractable for a few hundred samples. In this work, we propose a fast and memory-efficient method for estimating genetic maps from population genotyping data. …

Sox11 Is An Effective Discriminatory Marker, When Used In Conjunction With Ck20 And Ttf1, For Merkel Cell Carcinoma: Comparative Analysis Of Sox11, Ck20, Pax5, And Ttf1 Expression In Merkel Cell Carcinoma And Pulmonary Small Cell Carcinoma, Woo Cheal Cho, Kaitlin Vanderbeck, Priyadharsini Nagarajan, Denái R Milton, Pavandeep Gill, Wei-Lien Wang, Jonathan L Curry, Carlos A Torres-Cabala, Doina Ivan, Victor G Prieto, Phyu P Aung

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Context.—: Distinction between Merkel cell carcinoma (MCC) and pulmonary small cell carcinoma (PSmCC) can be challenging, even with the aid of immunohistochemistry (IHC) analysis of CK20 and TTF1, as these tumors occasionally lack classic immunophenotypes (CK20+/TTF1- in MCC and CK20-/TTF1+ in PSmCC).

Objective.—: To evaluate the diagnostic utility of SOX11 and PAX5 IHC for distinguishing MCCs from PSmCCs and compare it with that of CK20 and TTF1 IHC.

Design.—: SOX11, PAX5, CK20, and TTF1 expression (pattern, intensity, and proportion of tumor cells expressing protein) was assessed in 31 primary and 16 metastatic MCCs and 20 primary and 9 metastatic PSmCCs. …

A Cre Driver Line For Genetic Targeting Of Kappa Opioid Receptor Expressing Cells, Franciely Paliarin, Chelsea Duplantis, Andrea F Jones, Jessica Cucinello-Ragland, Samhita Basavanhalli, Emily Blaze, Evan Doré, Anna Isabella Neel, Haiguo Sun, Rong Chen, Scott Edwards, Nicholas W Gilpin, Robert O Messing, Rajani Maiya

Faculty, Staff and Student Publications

Here we describe the generation and characterization of a Cre knock-in mouse line that harbors a Cre insertion in the 3′UTR of the κ opioid receptor gene (Oprk1) locus and provides genetic access to populations of κ opioid receptor (KOR)-expressing neurons throughout the brain. Using a combination of techniques including RNA in situ hybridization and immunohistochemistry, we report that Cre is expressed with high fidelity in KOR-expressing cells throughout the brain in this mouse line. We also provide evidence that Cre insertion does not alter basal KOR function. Baseline anxiety-like behaviors and nociceptive thresholds are unaltered in Oprk1-Cre …

Author Correction: Multiscale Reorganization Of The Genome Following Dna Damage Facilitates Chromosome Translocations Via Nuclear Actin Polymerization, Jennifer Zagelbaum, Allana Schooley, Junfei Zhao, Benjamin R Schrank, Elsa Callen, Shan Zha, Max E Gottesman, André Nussenzweig, Raul Rabadan, Job Dekker, Jean Gautier

Faculty, Staff and Student Publications

No abstract provided.

Invited Commentary: Mri Clear Cell Likelihood Score For Indeterminate Solid Renal Masses: Is There A Path For Broad Clinical Adoption?, Ivan Pedrosa

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No abstract provided.

The Promise And Future Of Radiomics For Personalized Radiotherapy Dosing And Adaptation, Rachel B Ger, Lise Wei, Issam El Naqa, Jing Wang

Faculty, Staff and Student Publications

Quantitative image analysis, also known as radiomics, aims to analyze large-scale quantitative features extracted from acquired medical images using hand-crafted or machine-engineered feature extraction approaches. Radiomics has great potential for a variety of clinical applications in radiation oncology, an image-rich treatment modality that utilizes computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) for treatment planning, dose calculation, and image guidance. A promising application of radiomics is in predicting treatment outcomes after radiotherapy such as local control and treatment-related toxicity using features extracted from pretreatment and on-treatment images. Based on these individualized predictions of treatment outcomes, radiotherapy …

Characteristics, Treatment, And Outcome Of Diverticulitis After Immune Checkpoint Inhibitor Treatment In Patients With Malignancies, Austin R Thomas, Mostafa Eyada, Miho Kono, Krishnavathana Varatharajalu, Yang Lu, Guofan Xu, Kavea Panneerselvam, Malek Shatila, Mehmet Altan, Jennifer Wang, John A Thompson, Hao Chi Zhang, Muhammad Ali Khan, Gottumukkala S Raju, Anusha S Thomas, Yinghong Wang

Faculty, Staff and Student Publications

Purpose: Immune checkpoint inhibitors (ICIs) are efficacious for treating various malignancies. In addition to immune-related adverse events (irAEs), growing evidence suggests that ICIs might also be associated with diverticulitis. We aim to assess the clinical presentations and management of colonic diverticulitis among cancer patients after ICI treatment.

Methods: A retrospective study was conducted on ICI-treated adult cancer patients between 01/2010 and 06/2020. Patients were grouped based on when diverticulitis developed relative to ICI treatment, either before (controls) or after (cases). Patient clinical characters, treatment, and outcomes were compared between both groups.

Results: 77 eligible patients were included: 63 patients developed …

Route Of Delivery Does Not Impact Postnatal Surgical Morbidity In Pregnancies Affected By Fetal Achondroplasia, Bobby K Brar, Michael B Bober, Ethan Gough, S Shahrukh Hashmi, Jacqueline T Hecht, Lorena Dujmusic, Mary E Little, Peggy Modaff, Richard M Pauli, David F Rodriguez-Buritica, Maria E Serna, Cory Smid, Janet M Legare, Julie E Hoover-Fong

Faculty, Staff and Student Publications

Purpose: Pregnancies affected by maternal or fetal achondroplasia present unique challenges. The optimal route of delivery in fetuses with achondroplasia has not been established. Our objective was to determine whether the route of delivery affects postnatal achondroplasia-related surgical burden.

Methods: We conducted a secondary analysis of Achondroplasia Natural History Study (CLARITY), which is a multicenter natural history cohort study of patients with achondroplasia. Achondroplasia-related surgical morbidity, which we defined as the need for one or more postnatal achondroplasia-related surgeries, was assessed in relation to the route of delivery and whether the mother also had achondroplasia. Rate of each individual surgery …

Mrtx-500 Phase 2 Trial: Sitravatinib With Nivolumab In Patients With Nonsquamous Nsclc Progressing On Or After Checkpoint Inhibitor Therapy Or Chemotherapy, Kai He, David Berz, Shirish M Gadgeel, Wade T Iams, Debora S Bruno, Collin M Blakely, Alexander I Spira, Manish R Patel, David M Waterhouse, Donald A Richards, Anthony Pham, Robert Jotte, David S Hong, Edward B Garon, Anne Traynor, Peter Olson, Lisa Latven, Xiaohong Yan, Ronald Shazer, Ticiana A Leal

Faculty, Staff and Student Publications

Introduction: Sitravatinib, a receptor tyrosine kinase inhibitor targeting TYRO3, AXL, MERTK receptors, and vascular epithelial growth factor receptor 2, can shift the tumor microenvironment toward an immunostimulatory state. Combining sitravatinib with checkpoint inhibitors (CPIs) may augment antitumor activity.

Methods: The phase 2 MRTX-500 study evaluated sitravatinib (120 mg daily) with nivolumab (every 2 or 4 wk) in patients with advanced nonsquamous NSCLC who progressed on or after previous CPI (CPI-experienced) or chemotherapy (CPI-naive). CPI-experienced patients had a previous clinical benefit (PCB) (complete response, partial response, or stable disease for at least 12 weeks then disease progression) or no PCB (NPCB) …

Ai In Drug Discovery And Its Clinical Relevance, Rizwan Qureshi, Muhammad Irfan, Taimoor Muzaffar Gondal, Sheheryar Khan, Jia Wu, Muhammad Usman Hadi, John Heymach, Xiuning Le, Hong Yan, Tanvir Alam

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The COVID-19 pandemic has emphasized the need for novel drug discovery process. However, the journey from conceptualizing a drug to its eventual implementation in clinical settings is a long, complex, and expensive process, with many potential points of failure. Over the past decade, a vast growth in medical information has coincided with advances in computational hardware (cloud computing, GPUs, and TPUs) and the rise of deep learning. Medical data generated from large molecular screening profiles, personal health or pathology records, and public health organizations could benefit from analysis by Artificial Intelligence (AI) approaches to speed up and prevent failures in …

Snakes And Ladders: A Potential Therapy Of Hepatocyte Growth Factor And Pigment Epithelium-Derived Factor In Pulmonary Hypertension, Joseph M Zambelas, Harry Karmouty-Quintana

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No abstract provided.

Early Stage Gastric Adenocarcinoma: Clinical And Molecular Landscapes, Yuki Hirata, Ayesha Noorani, Shumei Song, Linghua Wang, Jaffer A Ajani

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Gastric adenocarcinoma, even when diagnosed at an early (localized) disease stage, poses a major health-care burden with cure rates that remain unsatisfactorily low, particularly in Western countries. This lack of progress reflects, among other aspects, the impracticality of early diagnosis, considerable variations in therapeutic approaches that is partly based on regional preferences, and the ingrained heterogeneity of gastric adenocarcinoma cells and their associated tumour microenvironment (TME). Clinical trials have long applied empirical interventions with the assumption that all early stage gastric adenocarcinomas are alike. Despite certain successes, the shortcomings of these approaches can potentially be overcome by targeting the specific …