Genetic Phenomena Commons^™

Srsf1 Haploinsufficiency Is Responsible For A Syndromic Developmental Disorder Associated With Intellectual Disability, Elke Bogaert, Aurore Garde, Thierry Gautier, Kathleen Rooney, Yannis Duffourd, Pontus Leblanc, Emma Van Reempts, Frederic Tran Mau-Them, Ingrid M Wentzensen, Kit Sing Au, Kate Richardson, Hope Northrup, Vincent Gatinois, David Geneviève, Raymond J Louie, Michael J Lyons, Lone Walentin Laulund, Charlotte Brasch-Andersen, Trine Maxel Juul, Fatima El It, Nathalie Marle, Patrick Callier, Raissa Relator, Sadegheh Haghshenas, Haley Mcconkey, Jennifer Kerkhof, Claudia Cesario, Antonio Novelli, Nicola Brunetti-Pierri, Michele Pinelli, Perrine Pennamen, Sophie Naudion, Marine Legendre, Cécile Courdier, Aurelien Trimouille, Martine Doco Fenzy, Lynn Pais, Alison Yeung, Kimberly Nugent, Elizabeth R Roeder, Tadahiro Mitani, Jennifer E Posey, Daniel Calame, Hagith Yonath, Jill A Rosenfeld, Luciana Musante, Flavio Faletra, Francesca Montanari, Giovanna Sartor, Alessandra Vancini, Marco Seri, Claude Besmond, Karine Poirier, Laurence Hubert, Dimitri Hemelsoet, Arnold Munnich, James R Lupski, Christophe Philippe, Christel Thauvin-Robinet, Laurence Faivre, Bekim Sadikovic, Jérôme Govin, Bart Dermaut, Antonio Vitobello

Faculty, Staff and Students Publications

SRSF1 (also known as ASF/SF2) is a non-small nuclear ribonucleoprotein (non-snRNP) that belongs to the arginine/serine (R/S) domain family. It recognizes and binds to mRNA, regulating both constitutive and alternative splicing. The complete loss of this proto-oncogene in mice is embryonically lethal. Through international data sharing, we identified 17 individuals (10 females and 7 males) with a neurodevelopmental disorder (NDD) with heterozygous germline SRSF1 variants, mostly de novo, including three frameshift variants, three nonsense variants, seven missense variants, and two microdeletions within region 17q22 encompassing SRSF1. Only in one family, the de novo origin could not be established. All individuals …

Using Cancer Proteomics Data To Identify Gene Candidates For Therapeutic Targeting, Diana Monsivais, Sydney E Parks, Darshan S Chandrashekar, Sooryanarayana Varambally, Chad J Creighton

Faculty, Staff and Students Publications

Gene-level associations obtained from mass-spectrometry-based cancer proteomics datasets represent a resource for identifying gene candidates for functional studies. When recently surveying proteomic correlates of tumor grade across multiple cancer types, we identified specific protein kinases having a functional impact on uterine endometrial cancer cells. This previously published study provides just one template for utilizing public molecular datasets to discover potential novel therapeutic targets and approaches for cancer patients. Proteomic profiling data combined with corresponding multi-omics data on human tumors and cell lines can be analyzed in various ways to prioritize genes of interest for interrogating biology. Across hundreds of cancer …

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

Faculty, Staff and Student Publications

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

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

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

Faculty, Staff and Student Publications

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

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

Faculty, Staff and Student Publications

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

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

Faculty, Staff and Student Publications

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

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

Nicotinamide Riboside And Beta-Hydroxybutyrate Activate Parallel Pathways For C. Elegans Lifespan Extension, Mckenzie Peters

Undergraduate Honors Theses

Supplementation with nicotinamide riboside (NR), a form of vitamin B3 and a precursor of nicotinamide adenine dinucleotide (NAD⁺) extends lifespan in the nematode C. elegans and delays aging-related pathologies in mammals. During aging, levels of NAD⁺ decline causing metabolic dysfunction and oxidative damage. Studies in C. elegans found that when NR was administered during larval development it induced the mitochondrial unfolded protein response (UPR^mt), which is frequently associated with lifespan extension. Both calorie restriction (CR) and ketogenic diets (KD) have been shown to extend lifespan, in part through increasing NAD⁺ and through increasing levels …

A Review Of Staphylococcus Aureus Pathogenesis, Global Impact, And The Rise Of Antibiotic-Resistant Clones, Anders Kleinbeck

Honors Scholar Theses

Staphylococcus aureus is a pathogen of grave concern to global public health. The pathogen has shown an unrivaled propensity to obtain resistance to nearly every antibiotic drug approved and prescribed for its treatment. This review will provide an overview of the history and evolution of S. aureus, including an analysis of its transition from the nosocomial setting to the community and the factors contributing to the species’ innate pathogenicity. This paper will also discuss the molecular mechanisms by which resistance to a wide range of popular antibiotic substances was obtained and will provide insight into the evolutionary patterns exhibited by …

Pediatric Symptom Checklist-17: Factor Structure And Uniform Differential Item Functioning Across Gender And Age In Hiv Orphans And Vulnerable Children In Zambia, Nan Li, Mei Tan, Philip E Thuma, Elena L Grigorenko

Faculty, Staff and Students Publications

This study aimed to investigate the psychometric properties of the Pediatric Symptom Checklist-17 (PSC-17) in a sample of children orphaned or made vulnerable (OVC) by HIV in Zambia. Caregivers of 1,076 OVC (55.1% boys; M_age = 12.91 years) completed the PSC-17. Competing models, including confirmatory factor analysis (CFA), hierarchical CFA, bifactor CFA, exploratory structural equation modeling (ESEM), and bifactor ESEM, were tested to evaluate the optimal factor structure of the PSC-17. Results showed that the bifactor ESEM provided the best approximation of the PSC-17 data with a well-defined general psychosocial problems factor explaining 72% of the reliable variance in …

One Immune System Plays Many Parts: The Dynamic Role Of The Immune System In Chronic Pain And Opioid Pharmacology, Sanam Mustafa, Juliana E Bajic, Benjamin Barry, Samuel Evans, Kariel R Siemens, Mark R Hutchinson, Peter M Grace

Faculty, Staff and Student Publications

The transition from acute to chronic pain is an ongoing major problem for individuals, society and healthcare systems around the world. It is clear chronic pain is a complex multidimensional biological challenge plagued with difficulties in pain management, specifically opioid use. In recent years the role of the immune system in chronic pain and opioid pharmacology has come to the forefront. As a highly dynamic and versatile network of cells, tissues and organs, the immune system is perfectly positioned at the microscale level to alter nociception and drive structural adaptations that underpin chronic pain and opioid use. In this review, …

Communication In Phelan-Mcdermid Syndrome: Assessment And Genotype-Phenotype Correlation, Sarah Quadri

All Dissertations

Phelan McDermid Syndrome (PMS) is a rare genetic disorder caused by deletions or mutations of the SHANK3 gene on chromosome 22q13.3. Language and communication impairment are hallmark features of PMS, and this dissertation aims to address the lack of consensus on appropriate methods for assessing these abilities and genotype-phenotype correlations of language and communication impairments in PMS.

The first chapter introduces PMS and associated language and communication impairment, identifies gaps in the literature, and shows how this research fills those gaps to advance our understanding of this rare genetic disease. The second chapter identifies and analyzes practices for assessing speech, …

Secondary Validation Of An Ovarian Cancer-Specific Comorbidity Index In A Us Population, Chelsey Vranes, Hui Zhao, Mette Calundann Noer, Shuangshuang Fu, Charlotte C Sun, Ross Harrison, Pedro T Ramirez, Claus Kim Høgdall, Sharon H Giordano, Larissa A Meyer

Faculty, Staff and Student Publications

Objectives: The Ovarian Cancer Comorbidity Index (OCCI) is an age-specific index developed and previously found to be more predictive of overall and cancer-specific survival than the Charlson Comorbidity Index (CCI). The objective was to perform secondary validation of the OCCI in a US population.

Methods: A cohort of ovarian cancer patients undergoing primary or interval cytoreductive surgery from January 2005 to January 2012 was identified in SEER-Medicare. OCCI scores were calculated with the regression coefficients determined from the original developmental cohort for five comorbidities. Cox regression analyses were used to calculate associations between the OCCI risk groups and 5-year overall …

Endovascular Stroke Therapy For Posterior Circulation Acute Ischemic Stroke Has Diminishing Benefit With Additional Passes, Jerome A Jeevarajan, Hyun-Woo Kim, Muhammad Bilal Tariq, Sergio Salazar Marioni, Arash Niktabe, Rania Abdelkhaleq, Louise Mccullough, Sunil A Sheth

Faculty, Staff and Student Publications

Background: The relationship between pass number during endovascular stroke therapy (EST) and outcomes in anterior circulation large vessel occlusion (LVO) acute ischemic stroke (AIS) has been well studied. However, the association between EST attempts and outcomes for patients with posterior circulation LVO remains unclear.

Methods: From our prospectively maintained multicenter registry, we identified consecutive patients with LVO AIS who underwent EST. The number of thrombectomy passes and per-pass reperfusion grades (thrombolysis in cerebral infarction) were recorded prospectively at the time of procedure. The primary outcome was the association of number of EST passes and functional independence (modified Rankin scale 0-2) …

N-Terminal Egfp-Tagging Of Rabbit Apolipoprotein A-I Decreases Expression And Impairs Cholesterol-Efflux Activity, Bradley K Wacker, Lianxiang Bi, Li Liu, Mary G Sorci-Thomas, Philip Ng, Donna J Palmer, Chongren Tang, David A Dichek

Faculty, Staff and Students Publications

No abstract provided.

Nonlinear Propagation Of Quasiplanar Shear Wave Beams In Soft Elastic Media With Transverse Isotropy, John M Cormack, Mark F Hamilton

Faculty, Staff and Student Publications

Model equations are developed for shear wave propagation in a soft elastic material that include effects of nonlinearity, diffraction, and transverse isotropy. A theory for plane wave propagation by Cormack [J. Acoust. Soc. Am. 150, 2566 (2021)] is extended to include leading order effects of wavefront curvature by assuming that the motion is quasiplanar, which is consistent with other paraxial model equations in nonlinear acoustics. The material is modeled using a general expansion of the strain energy density to fourth order in strain that comprises thirteen terms defining the elastic moduli. Equations of motion for the transverse displacement components are …

Impact Of Biomarker-Matched Therapies On Outcomes In Patients With Sarcoma Enrolled In Early-Phase Clinical Trials (Samba 101), Roberto Carmagnani Pestana, Justin T Moyers, Jason Roszik, Shiraj Sen, David S Hong, Aung Naing, Cynthia E Herzog, Siqing Fu, Sarina A Piha-Paul, Jordi Rodon, Timothy A Yap, Daniel D Karp, Apostolia M Tsimberidou, Shubham Pant, Maria A Zarzour, Ravin Ratan, Vinod Ravi, Robert S Benjamin, Alexander J Lazar, Wei-Lien Wang, Najat Daw, Jonathan B Gill, Douglas J Harrison, Valerae O Lewis, Christina L Roland, Shreyaskumar R Patel, J Andrew Livingston, Neeta Somaiah, Joseph A Ludwig, Anthony P Conley, Nelson Hamerschlak, Richard Gorlick, Funda Meric-Bernstam, Vivek Subbiah

Faculty, Staff and Student Publications

Purpose: Developing new therapeutics for any of the more than 100 sarcoma subtypes presents a challenge. After progression from standard therapies, patients with sarcoma may be referred for enrollment in early-phase trials. This study aimed to investigate whether enrollment in biomarker-matched early-phase clinical trials leads to better outcomes for patients with advanced sarcoma.

Experimental design: In this retrospective analysis, investigational treatment characteristics and longitudinal survival outcomes were analyzed in patients with biopsy-confirmed sarcoma enrolled in early-phase trials at MD Anderson Cancer Center from May 2006 to July 2021.

Results: Five hundred eighty-seven patients were included [405 soft tissue, 122 bone, …

Late-Onset Cognitive Impairment And Modifiable Risk Factors In Adult Childhood Cancer Survivors, Nicholas S Phillips, Kayla L Stratton, Annalynn M Williams, Tim Ahles, Kirsten K Ness, Harvey Jay Cohen, Kim Edelstein, Yutaka Yasui, Kevin Oeffinger, Eric J Chow, Rebecca M Howell, Leslie L Robison, Gregory T Armstrong, Wendy M Leisenring, Kevin R Krull

Faculty, Staff and Student Publications

Importance: Long-term survivors of childhood cancer may be at elevated risk for new neurocognitive impairment and decline as they age into adulthood.

Objective: To determine whether aging adult childhood cancer survivors report more new-onset neurocognitive impairments compared with their siblings and to identify risk factors associated with such impairments.

Design, setting, and participants: Participants of this cohort study included adult survivors of childhood cancer from the Childhood Cancer Survivor Study and their siblings as a control group. The original cohort included survivors who received a diagnosis between January 1, 1970, and December 31, 1986, for whom longitudinal neurocognitive assessment was …

Technique For Robotic Pancreaticojejunostomy, Derek J Erstad, Yuji Hatanaka, Samuel Cass, Jessica Maxwell, Hop Tran Cao, Michael Kim, Ching-Wei Tzeng, Jeffrey E Lee, Matthew Katz, Naruhiko Ikoma

Faculty, Staff and Student Publications

Background:: Minimally invasive, robotic techniques for hepatobiliary procedures offer the potential for accelerated recovery and reduced opioid usage. Robotic pancreaticoduodenectomy is a technically challenging procedure with a complex reconstruction. In this regard, standardization of the pancreaticojejunostomy technique is critical for safe adoption of robotic technology in pancreatic surgery.

Study Design:: In this video, we demonstrate the primary steps and associated principles to perform a robotic pancreaticojejunostomy using a modified Blumgart/Nagakawa technique.

Results:: Key steps to this procedure include: 1) exposure and positioning of the pancreatic remnant and jejunal limb; 2) transpancreatic suture placement using augmented sutures with bulldog clamps for …

Disclosing Quantitative Rt-Pcr Raw Data During Manuscript Submission: A Call For Action, Andreas Untergasser, Jan Hellemans, Michael W Pfaffl, Jan M Ruijter, Maurice J B Van Den Hoff, Mihnea P Dragomir, Douglas Adamoski, Sandra Martha Gomes Dias, Rui Manuel Reis, Manuela Ferracin, Emmanuel Dias-Neto, Ian Marsh, Mikael Kubista, Muller Fabbri, Ajay Goel, Ondřej Slabý, Erik Knutsen, Baoqing Chen, Massimo Negrini, Koshi Mimori, Martin Pichler, Maria Papatriantafyllou, Simone Anfossi, Thomas D Schmittgen, Jim Huggett, Stephen Bustin, Jo Vandesompele, George A Calin, Heroic (The Initiative Group On Qrt Disclosure) Consortium

Faculty, Staff and Student Publications

Accuracy and transparency of scientific data are becoming more and more relevant with the increasing concern regarding the evaluation of data reproducibility in many research areas. This concern is also true for quantifying coding and noncoding RNAs, with the remarkable increase in publications reporting RNA profiling and sequencing studies. To address the problem, we propose the following recommendations: (a) accurate documentation of experimental procedures in Materials and methods (and not only in the supplementary information, as many journals have a strict mandate for making Materials and methods as visible as possible in the main text); (b) submission of RT‐qPCR raw …

Emp1+ Tumor Cells Drive Metastatic Relapse, Oscar E Villarreal, Scott Kopetz

Faculty, Staff and Student Publications

No abstract provided.

Falciform Ligament Hernia: Combination Of Key Ct Findings, Tomonori Matsuura, Nozomi Satani, Ryo Tamura, Yuriko Kagaya, Takayuki Yamada

Faculty, Staff and Student Publications

A male patient in his early 90s with no history of abdominal surgery was referred to us for abdominal pain and vomiting. An abdominal computed tomography (CT) demonstrated dilated small bowel with a double beak sign and poorly enhanced wall, which indicated a closed-loop obstruction that leads to strangulation. A closed-loop bowel was located in front of the anterior and medial segments of the liver and to the right of the round ligament of the liver on axial images. Sagittal images revealed that the round ligament has deviated downward and 2 adjacent narrowed intestines were located at its cranial side. …

Multi-Institutional Study Of Pathologist Reading Of The Programmed Cell Death Ligand-1 Combined Positive Score Immunohistochemistry Assay For Gastric Or Gastroesophageal Junction Cancer, Aileen I Fernandez, Charles J Robbins, Patricia Gaule, Diana Agostini-Vulaj, Robert A Anders, Andrew M Bellizzi, Wei Chen, Zongming Eric Chen, Purva Gopal, Lei Zhao, Mikhail Lisovsky, Xiuli Liu, Jinru Shia, Huamin Wang, Zhaohai Yang, Leena Mccann, Yvonne G Chan, Jodi Weidler, Michael Bates, Xuchen Zhang, David L Rimm

Faculty, Staff and Student Publications

The assessment of the expression of programmed cell death ligand-1 (PD-L1) using immunohistochemistry (IHC) has been controversial since its introduction. The methods of assessment and the range of assays and platforms contribute to confusion. Perhaps the most challenging aspect of PD-L1 IHC is the combined positive score (CPS) method of interpretation of IHC results. Although the CPS method is prescribed for more indications than any other PD-L1 scoring system, its reproducibility has never been rigorously assessed. In this study, we collected a series of 108 gastric or gastroesophageal junction cancer cases, stained them using the Food and Drug Administration-approved 22C3 …

Publisher Correction: Comprehensive Molecular Characterization Of Mitochondrial Genomes In Human Cancers, Yuan Yuan, Young Seok Ju, Youngwook Kim, Jun Li, Yumeng Wang, Christopher J Yoon, Yang Yang, Inigo Martincorena, Chad J Creighton, John N Weinstein, Yanxun Xu, Leng Han, Hyung-Lae Kim, Hidewaki Nakagawa, Keunchil Park, Peter J Campbell, Han Liang, Pcawg Consortium

Faculty, Staff and Student Publications

No abstract provided.

Integrated Circulating Tumor Dna And T Cell Repertoire Predict Radiotherapeutic Response And Outcome In Non-Small Cell Lung Cancer Patients With Brain Metastasis, Ling Peng, Yawen Bin, Peng Ding, Lingjuan Chen, Hao Zeng, Zelong Xu, Liyan Ji, Xuan Gao, Pian Liu, Ye Wang, Sheng Zhang, Zhongxing Liao, Xuefeng Xia, Ruiguang Zhang, Fan Tong, Xiaorong Dong

Faculty, Staff and Student Publications

No abstract provided.

Potent Antitumor Activity Of Ensartinib In Met Exon 14 Skipping-Mutated Non-Small Cell Lung Cancer, Yang Xia, Rui Jin, Miao Li, Fen Lan, Hao Zhu, Yinghui Yu, Da Miao, Qiyuan Wang, Yi Zhou, Giovanni Selvaggi, Songmin Ying, Jianjun Zhang, Huahao Shen, Xiuning Le, Wen Li

Faculty, Staff and Student Publications

Met proto-oncogene exon 14 skipping (METex14) mutations are targetable driver genes in approximately 3% of non-small-cell lung cancers (NSCLCs). Ensartinib, a type Ia MET inhibitor, is a multi-kinase inhibitor that has been approved for ALK-positive NSCLCs. Ensartinib was administered for compassionate use (cohort 1) and in a phase II clinical trial (cohort 2) to patients with METex14 mutant NSCLCs, with ORR as a primary endpoint. Molecular simulation was conducted to evaluate ensartinib c-MET interaction, and cell lines, patient-derived organoids (PDOs), and xenograft models were used to test the effectiveness of ensartinib. Among 29 evaluable patients, the ORR and DCR of …

Younger Haploidentical Donor Versus Older Matched Unrelated Donor For Patients With Aml/Mds, Curtis Marcoux, David Marin, Jeremy Ramdial, Gheath Alatrash, Amin M Alousi, Betul Oran, Partow Kebriaei, Uday R Popat, Katayoun Rezvani, Richard E Champlin, Elizabeth J Shpall, Rohtesh S Mehta

Faculty, Staff and Student Publications

Optimal donor selection is fundamental to successful allogeneic hematopoietic cell transplantation (HCT), and donor age influences survival after both matched unrelated donor (MUD) and haploidentical donor HCT. Though recent studies have shown similar outcomes between MUD and haploidentical HCT, it is unknown if outcomes differ following HCT with younger haploidentical donors compared to HCT with older MUDs. Therefore, we performed a retrospective analysis comparing outcomes of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients who underwent HCT with younger (≤35 years) haploidentical donors (n = 494) or older (>35 years) MUDs (n = 1005). Patients in the haploidentical …

Genomic And Transcriptomic Analysis Of Checkpoint Blockade Response In Advanced Non-Small Cell Lung Cancer, Arvind Ravi, Matthew D Hellmann, Monica B Arniella, Mark Holton, Samuel S Freeman, Vivek Naranbhai, Chip Stewart, Ignaty Leshchiner, Jaegil Kim, Yo Akiyama, Aaron T Griffin, Natalie I Vokes, Mustafa Sakhi, Vashine Kamesan, Hira Rizvi, Biagio Ricciuti, Patrick M Forde, Valsamo Anagnostou, Jonathan W Riess, Don L Gibbons, Nathan A Pennell, Vamsidhar Velcheti, Subba R Digumarthy, Mari Mino-Kenudson, Andrea Califano, John V Heymach, Roy S Herbst, Julie R Brahmer, Kurt A Schalper, Victor E Velculescu, Brian S Henick, Naiyer Rizvi, Pasi A Jänne, Mark M Awad, Andrew Chow, Benjamin D Greenbaum, Marta Luksza, Alice T Shaw, Jedd Wolchok, Nir Hacohen, Gad Getz, Justin F Gainor

Faculty, Staff and Student Publications

Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of …

Prioritizing Clinical Trial Quality Assurance For Photons And Protons: A Failure Modes And Effects Analysis (Fmea) Comparison, Paige A Taylor, Elizabeth Miles, Lone Hoffmann, Sarah M Kelly, Stephen F Kry, Ditte Sloth Møller, Hugo Palmans, Kamal Akbarov, Marianne C Aznar, Enrico Clementel, Coreen Corning, Rachel Effeney, Brendan Healy, Alisha Moore, Mitsuhiro Nakamura, Samir Patel, Maddison Shaw, Markus Stock, Joerg Lehmann, Catharine H Clark

Faculty, Staff and Student Publications

Background and purpose: The Global Clinical Trials RTQA Harmonization Group (GHG) set out to evaluate and prioritize clinical trial quality assurance.

Methods: The GHG compiled a list of radiotherapy quality assurance (QA) tests performed for proton and photon therapy clinical trials. These tests were compared between modalities to assess whether there was a need for different types of assessments per modality. A failure modes and effects analysis (FMEA) was performed to assess the risk of each QA failure.

Results: The risk analysis showed that proton and photon therapy shared four out of five of their highest-risk failures (end-to-end anthropomorphic phantom …

Vestigial-Like 1 (Vgll1): An Ancient Co-Transcriptional Activator Linking Wing, Placenta, And Tumor Development, Heather M Sonnemann, Barbara Pazdrak, Dinler A Antunes, Jason Roszik, Gregory Lizée

Faculty, Staff and Student Publications

Vestigial-like 1 (VGLL1) is a recently discovered driver of proliferation and invasion that is expressed in many aggressive human malignancies and is strongly associated with poor prognosis. The VGLL1 gene encodes for a co-transcriptional activator that shows intriguing structural similarity to key activators in the hippo pathway, providing important clues to its functional role. VGLL1 binds to TEAD transcription factors in an analogous fashion to YAP1 but appears to activate a distinct set of downstream gene targets. In mammals, VGLL1 expression is found almost exclusively in placental trophoblasts, cells that share many hallmarks of cancer. Due to its role as …

Gwas And Meta-Analysis Identifies 49 Genetic Variants Underlying Critical Covid-19, Erola Pairo-Castineira, Konrad Rawlik, Andrew D Bretherick, Ting Qi, Yang Wu, Isar Nassiri, Glenn A Mcconkey, Marie Zechner, Lucija Klaric, Fiona Griffiths, Wilna Oosthuyzen, Athanasios Kousathanas, Anne Richmond, Jonathan Millar, Clark D Russell, Tomas Malinauskas, Ryan Thwaites, Kirstie Morrice, Sean Keating, David Maslove, Alistair Nichol, Malcolm G Semple, Julian Knight, Manu Shankar-Hari, Charlotte Summers, Charles Hinds, Peter Horby, Lowell Ling, Danny Mcauley, Hugh Montgomery, Peter J M Openshaw, Colin Begg, Timothy Walsh, Albert Tenesa, Carlos Flores, José A Riancho, Augusto Rojas-Martinez, Pablo Lapunzina, Genomicc Investigators, Scourge Consortium, Isaricc Investigators, 23andme Covid-19 Team, Jian Yang, Chris P Ponting, James F Wilson, Veronique Vitart, Malak Abedalthagafi, Andre D Luchessi, Esteban J Parra, Raquel Cruz, Angel Carracedo, Angie Fawkes, Lee Murphy, Kathy Rowan, Alexandre C Pereira, Andy Law, Benjamin Fairfax, Sara Clohisey Hendry, J Kenneth Baillie

Faculty, Staff and Student Publications

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a …