Digital Commons Network^™

Ven In Combination With 10-Day Dec In Newly Diagnosed Elderly Or Relapsed/Refractory Acute Myeloid Leukemia, And High-Risk Myelodysplastic Syndrome: Long Term Follow-Up Of A Phase 2 Trial, Mahesh Swaminathan, Courtney D Dinardo, Abhishek Maiti, Naveen Pemmaraju, Maro Ohanian, Navel G Daver, Guillermo Garcia-Manero, Ghayas C Issa, Gautam Borthakur, Farhad Ravandi, Guillermo Montalban-Bravo, Tapan M Kadia, Yesid Alvarado, Elias J Jabbour, Nicholas J Short, William G Wierda, Nitin Jain, Steven M Kornblau, Lucia Masarova, Sherry A Pierce, Wei Qiao, Jing Ning, Hagop Kantarjian, Marina Y Konopleva

Faculty, Staff and Student Publications

No abstract provided.

The Relationship Between Physical Activity And Telomere Length In Women: A Systematic Review, Jeni Page, Catherine Stephens, Melissa Richard, Elizabeth Lyons, Elizabeth Baumler, M Terese Verklan, Elizabeth Lorenzo

Faculty, Staff and Student Publications

Telomere length (TL) is a biomarker of cellular aging with variations observed by sex, age, race, and ethnicity. Prior studies have suggested that physical activity (PA) may positively impact TL by potentially elongating telomeres and slowing cellular aging. However, research examining the optimal type and intensity of PA needed to elicit these changes specific to women remains limited. This systematic review aimed to investigate variations in TL in response to PA among women, exploring how these effects differ by age, race, or ethnicity. Following PRISMA guidelines, searches across five databases identified 17 relevant studies published from 2008 to 2022. A …

An Examination Of Ambulatory Care Code Specificity Utilization In Icd-10-Cm Compared To Icd-9-Cm: Implications For Icd-11 Implementation, Susan H Fenton, Cassandra Ciminello, Vickie M Mays, Mary H Stanfill, Valerie Watzlaf

Faculty, Staff and Student Publications

Objective: The ICD-10-CM classification system contains more specificity than its predecessor ICD-9-CM. A stated reason for transitioning to ICD-10-CM was to increase the availability of detailed data. This study aims to determine whether the increased specificity contained in ICD-10-CM is utilized in the ambulatory care setting and inform an evidence-based approach to evaluate ICD-11 content for implementation planning in the United States.

Materials and methods: Diagnosis codes and text descriptions were extracted from a 25% random sample of the IQVIA Ambulatory EMR-US database for 2014 (ICD-9-CM, n = 14 327 155) and 2019 (ICD-10-CM, n = 13 062 900). Code …

Llm-Ie: A Python Package For Biomedical Generative Information Extraction With Large Language Models, Enshuo Hsu, Kirk Roberts

Faculty, Staff and Student Publications

Objectives: Despite the recent adoption of large language models (LLMs) for biomedical information extraction (IE), challenges in prompt engineering and algorithms persist, with no dedicated software available. To address this, we developed LLM-IE: a Python package for building complete IE pipelines.

Materials and methods: The LLM-IE supports named entity recognition, entity attribute extraction, and relation extraction tasks. We benchmarked it on the i2b2 clinical datasets.

Results: The sentence-based prompting algorithm resulted in the best 8-shot performance of over 70% strict F1 for entity extraction and about 60% F1 for entity attribute extraction.

Discussion: We developed a Python package, LLM-IE, …

Frequency Of Variants In Mendelian Alzheimer’S Disease Genes Within The Alzheimer’S Disease Sequencing Project, Dongyu Wang, Alexandra Scalici, Yanbing Wang, Honghuang Lin, Achilleas Pitsillides, Nancy Heard-Costa, Carlos Cruchaga, Ellen Ziegemeier, Joshua C Bis, Myriam Fornage, Eric Boerwinkle, Philip L De Jager, Ellen Wijsman, Josée Dupuis, Alan E Renton, Sudha Seshadri, Alison M Goate, Alzheimer's Disease Neuroimaging Initiative (Adni), The Alzheimer's Disease Sequencing Project, Anita L Destefano, Gina M Peloso

Faculty, Staff and Student Publications

Background:

Prior studies examined variants within presenilin-2 (PSEN2), presenilin-1 (PSEN1), and amyloid precursor protein (APP) genes. However, previously-reported clinically-relevant variants and other predicted damaging missense (DM) variants have not been characterized in a newer release of the Alzheimer’s Disease Sequencing Project (ADSP).

Objective:

To characterize previously-reported clinically-relevant variants and DM variants in PSEN2, PSEN1, APP within the participants from the ADSP.

Methods:

We identified rare variants (MAF< 1%) in PSEN2, PSEN1, and APP in 14,641 individuals with whole genome sequencing and 16,849 individuals with whole exome sequencing available (Ntotal = 31,490). We additionally curated …

Learning Tracheal Intubation With A Hyperangulated Videolaryngoscopy Blade: Sub-Analysis Of A Randomised Controlled Trial, Sascha Ott, Lukas M Müller-Wirtz, Sergio Bustamante, Julian Rössler, Nikolaos J Skubas, Karan Shah, Daniel I Sessler, Alparslan Turan, Kurt Ruetzler

Faculty, Staff and Student Publications

Introduction: The number of tracheal intubation attempts required to reach proficiency in videolaryngoscopy with hyperangulated blades is unknown. Understanding this training requirement might guide training for clinicians who perform laryngoscopy. We therefore performed a planned sub-analysis of a randomised controlled trial comparing tracheal intubation success with videolaryngoscopy vs. direct laryngoscopy to determine the number of tracheal intubations with a hyperangulated videolaryngoscope blade needed to provide an acceptable first-attempt success rate.

Methods: We included clinicians from a randomised controlled trial who were familiar with direct laryngoscopy and Macintosh-blade videolaryngoscopy but inexperienced with hyperangulated videolaryngoscopy. Cumulative sum statistics were used to generate …

"When The Bills Keep On Coming:" The Experiences Of Seafood Processors During The Covid-19 Pandemic, Shannon Guillot-Wright, Laura Porterfield, Brenda Wilson, Lacy Davis

Faculty, Staff and Student Publications

Essential workers were at increased risk during the COVID-19 pandemic, including seafood processors who are often rendered invisible within the public sphere. To examine the health and safety concerns of seafood processors, many who are low income or im/migrant workers on H-2B visas, our team conducted qualitative research with 44 participants. We found that in addition to high occupational health hazards that existed before the pandemic, COVID-19 increased workers' financial risks, which put them in more dangerous health and safety positions, since they needed to work through physical and mental health illness. These financial risks can be seen through the …

Worldwide Policy, Surveillance, And Research On Physical Education And School-Based Physical Activity: The Global Observatory For Physical Education (Gope!) Conceptual Framework And Research Protocol, João Martins, Andrea Ramirez Varela, João Costa, Marcos Onofre, Dean Dudley, Rafael Cristão, Michael Pratt, Pedro C Hallal, Rafael Tassitano

Faculty, Staff and Student Publications

Introduction: The Global Observatory for Physical Education (GoPE!) builds on the Global Observatory for Physical Activity (GoPA!) to address gaps in surveillance, policy, and research on physical education (PE) and activity (PA). GoPE! is a worldwide surveillance system of quality PE and school-based PA that informs policy and interventions and allows comparative analysis so that each country and region can check their status and progress. This paper presents GoPE!'s conceptual framework and describes the research protocol as a cross-continental and evidence-based surveillance system.

Methods: Based on GoPA!'s framework and informed by the European Physical Education Observatory, as well as framed …

Genome-Wide Association Study Meta-Analysis Provides Insights Into The Etiology Of Heart Failure And Its Subtypes, Albert Henry, Xiaodong Mo, Chris Finan, Mark D Chaffin, Doug Speed, Hanane Issa, Spiros Denaxas, James S Ware, Sean L Zheng, Anders Malarstig, Jasmine Gratton, Isabelle Bond, Carolina Roselli, David Miller, Sandesh Chopade, A Floriaan Schmidt, Erik Abner, Lance Adams, Charlotte Andersson, Krishna G Aragam, Johan Ärnlöv, Geraldine Asselin, Anna Axelsson Raja, Joshua D Backman, Traci M Bartz, Kiran J Biddinger, Mary L Biggs, Heather L Bloom, Eric Boersma, Jeffrey Brandimarto, Michael R Brown, Søren Brunak, Mie Topholm Bruun, Leonard Buckbinder, Henning Bundgaard, David J Carey, Daniel I Chasman, Xing Chen, James P Cook, Tomasz Czuba, Simon De Denus, Abbas Dehghan, Graciela E Delgado, Alexander S Doney, Marcus Dörr, Joseph Dowsett, Samuel C Dudley, Gunnar Engström, Christian Erikstrup, Tõnu Esko, Eric H Farber-Eger, Stephan B Felix, Sarah Finer, Ian Ford, Mohsen Ghanbari, Sahar Ghasemi, Jonas Ghouse, Vilmantas Giedraitis, Franco Giulianini, John S Gottdiener, Stefan Gross, Daníel F Guðbjartsson, Hongsheng Gui, Rebecca Gutmann, Sara Hägg, Christopher M Haggerty, Åsa K Hedman, Anna Helgadottir, Harry Hemingway, Hans Hillege, Craig L Hyde, Bitten Aagaard Jensen, J Wouter Jukema, Isabella Kardys, Ravi Karra, Maryam Kavousi, Jorge R Kizer, Marcus E Kleber, Lars Køber, Andrea Koekemoer, Karoline Kuchenbaecker, Yi-Pin Lai, David Lanfear, Claudia Langenberg, Honghuang Lin, Lars Lind, Cecilia M Lindgren, Peter P Liu, Barry London, Brandon D Lowery, Jian'an Luan, Steven A Lubitz, Patrik Magnusson, Kenneth B Margulies, Nicholas A Marston, Hilary Martin, Winfried März, Olle Melander, Ify R Mordi, Michael P Morley, Andrew P Morris, Alanna C Morrison, Lori Morton, Michael W Nagle, Christopher P Nelson, Alexander Niessner, Teemu Niiranen, Raymond Noordam, Christoph Nowak, Michelle L O'Donoghue, Sisse Rye Ostrowski, Anjali T Owens, Colin N A Palmer, Guillaume Paré, Ole Birger Pedersen, Markus Perola, Marie Pigeyre, Bruce M Psaty, Kenneth M Rice, Paul M Ridker, Simon P R Romaine, Jerome I Rotter, Christian T Ruff, Marc S Sabatine, Neneh Sallah, Veikko Salomaa, Naveed Sattar, Alaa A Shalaby, Akshay Shekhar, Diane T Smelser, Nicholas L Smith, Erik Sørensen, Sundararajan Srinivasan, Kari Stefansson, Garðar Sveinbjörnsson, Per Svensson, Mari-Liis Tammesoo, Jean-Claude Tardif, Maris Teder-Laving, Alexander Teumer, Guðmundur Thorgeirsson, Unnur Thorsteinsdottir, Christian Torp-Pedersen, Vinicius Tragante, Stella Trompet, Andre G Uitterlinden, Henrik Ullum, Pim Van Der Harst, David Van Heel, Jessica Van Setten, Marion Van Vugt, Abirami Veluchamy, Monique Verschuuren, Niek Verweij, Christoffer Rasmus Vissing, Uwe Völker, Adriaan A Voors, Lars Wallentin, Yunzhang Wang, Peter E Weeke, Kerri L Wiggins, L Keoki Williams, Yifan Yang, Bing Yu, Faiez Zannad, Chaoqun Zheng, Folkert W Asselbergs, Thomas P Cappola, Marie-Pierre Dubé, Michael E Dunn, Chim C Lang, Nilesh J Samani, Svati Shah, Ramachandran S Vasan, J Gustav Smith, Hilma Holm, Sonia Shah, Patrick T Ellinor, Aroon D Hingorani, Quinn Wells, R Thomas Lumbers

Faculty, Staff and Student Publications

Heart failure (HF) is a major contributor to global morbidity and mortality. While distinct clinical subtypes, defined by etiology and left ventricular ejection fraction, are well recognized, their genetic determinants remain inadequately understood. In this study, we report a genome-wide association study of HF and its subtypes in a sample of 1.9 million individuals. A total of 153,174 individuals had HF, of whom 44,012 had a nonischemic etiology (ni-HF). A subset of patients with ni-HF were stratified based on left ventricular systolic function, where data were available, identifying 5,406 individuals with reduced ejection fraction and 3,841 with preserved ejection fraction. …

Environmental Health Disparities In Pediatric Cancer: A Report From The Fourth Symposium On Childhood Cancer Health Disparities, Thanh T Hoang, Zdenko Herceg, Don W Coulter, Adam De Smith, Manish Arora, William E Funk, David Haynes, Stephen H Linder, Leticia M Nogueira, Amy E Hughes, Lindsay A Williams, Jeremy M Schraw, Michael E Scheurer, Philip J Lupo

Faculty, Staff and Student Publications

The 4th Symposium on Childhood Cancer Health Disparities was held at Texas Children's Hospital in Houston, Texas, on September 26, 2023. The symposium registered 94 attendees from different backgrounds (e.g. clinicians, epidemiologists, exposure assessment scientists, geospatial experts) with an interest in environmental health disparities of pediatric cancer susceptibility and treatment outcomes. The focus of the symposium was to provide an overview of the role of environmental risk factors in studies of pediatric cancer, introduce novel exposure assessment tools that can be applied to the field, and highlight opportunities to study the impact of environmental health disparities in pediatric cancer susceptibility …

An Application Of Minimization For Ensuring Balanced Study Arms In A Group-Randomized Covid-19 Educational Intervention Trial, Xu Zhang, Mohammad H Rahbar, Amirali Tahanan, Cici Bauer, Marcia C De Oliveira Otto, Alanna C Morrison, Belinda Reininger, Maria E Fernandez

Faculty, Staff and Student Publications

BACKGROUND: Our institution carried out a multi-center, group-randomized controlled trial to evaluate the effectiveness of two community-based interventions on promoting the uptake of COVID-19 testing and vaccination in three regions with high levels of health disparities in Texas. We selected Census Block Groups (CBGs) with high disparity for randomization. In each study region, selected CBGs were randomized into two intervention groups and one control group. An important goal was to ensure balanced distributions of two continuous covariates, the disparity index and population size, across study arms. In this paper, we describe a novel minimization method used to ensure balanced study …

Intraoperative Goal-Directed Haemodynamic Therapy: A Systematic Review And Meta-Analysis Stratified By Trial Size, Dominik X Müller, Daniel I Sessler, Bernd Saugel

Faculty, Staff and Student Publications

No abstract provided.

Individualized Blood Pressure Regulation And Acute Kidney Injury In Older Patients Having Major Abdominal Surgery: A Pilot Randomized Trial, Zhaohua Pang, Shuang Liang, Nannan Zhou, Xiaoyan Zhu, Qulian Guo, Daniel I Sessler, Wangyuan Zou

Faculty, Staff and Student Publications

Background: Acute kidney injury (AKI) is a common postoperative complication, and hypotension may contribute. We therefore tested the primary hypothesis that individualized intraoperative blood pressure regulation reduces postoperative AKI in older surgical patients.

Methods: We enrolled patients ≥60 years old scheduled for elective major abdominal surgery with invasive arterial pressure monitoring. All had goal-directed fluid management based on stroke volume variation cardiac output, and administration of a starch. Participants were randomly assigned to: (1) individualized blood pressure management targeting a systolic blood pressure (SBP) within -20% and +10% if baseline SBP was ≥130 mmHg or diastolic blood pressure was ≥80 …

A Phase I Study Of The Pharmacokinetics, Pharmacodynamics, And Safety Of Liposomal Bupivacaine For Sciatic Nerve Block In The Popliteal Fossa For Bunionectomy, Daniel I Sessler, Xiaodong Bao, David Leiman, Jia Song, Jason Chittenden, Alexander Voelkner, Alparslan Turan, Jeffrey Gadsden

Faculty, Staff and Student Publications

This trial assessed the pharmacokinetics, pharmacodynamics, and safety of liposomal bupivacaine given via ultrasound-guided popliteal sciatic nerve block with or without immediate-release bupivacaine hydrochloride in adults having bunionectomies. Forty-five adults were enrolled into four sequential cohorts: (1) liposomal bupivacaine 266 mg with bupivacaine hydrochloride 50 mg; (2) liposomal bupivacaine 133 mg with bupivacaine hydrochloride 50 mg; (3) liposomal bupivacaine 266 mg; or (4) bupivacaine hydrochloride 100 mg. Outcomes included pharmacokinetics (e.g., bupivacaine maximum plasma concentration [C

Measles Is Just A Harbinger, Catherine Troisi

Faculty, Staff and Student Publications

No abstract provided.

Apoe And Alzheimer’S Disease And Related Dementias Risk Among 12,221 Hispanics/Latinos, Sandra Barral, Zikun Yang, Nicole Phillips, Robert C Barber, Adam M Brickman, Lawrence S Honig, Basilio Cieza, Dolly Reyes-Dumeyer, Richard Mayeux, Farid Rajabli, Michael L Cuccaro, Jeffery M Vance, Silvia Mejia Arango, Rafael Samper-Ternent, Alejandra Michaels Obregon, Rosa Montesinos, Marcio Soto-Añari, Juan Carlos Duran, Maria Cusicanqui, Ivonne Z Jimenez Velazquez, Victoria Marca, Maryenela Illanes-Manrique, Mario Cornejo-Olivas, Margaret Pericak-Vance, Rebeca Wong, Sid O'Bryant, Nilton Custodio, Giuseppe Tosto

Faculty, Staff and Student Publications

Background: Effect of apolipoprotein E (APOE) on Alzheimer's disease and related dementias (ADRD) risk is heterogeneous across populations, with scarce data on Hispanics/Latinos.

Methods: APOE genotype was studied in 12,221 Hispanics/Latinos (per cohort and via metanalysis): Caribbean-Hispanics, Mexicans, Mexican-Americans, and Peruvians/Bolivians. A subsample had longitudinal assessment and plasma p-tau. We tested the modifying effects of global and local ancestries. Results were replicated in an independent Peruvian cohort and brain samples.

Results: APOE ε4 effect was strongest in Peruvians/Bolivians (odds ratio [OR] = 6.13, 95% confidence interval [CI] = 2.71-13.83), followed by Mexicans (OR = 4.31, 95% CI = 1.58-11.74), Mexican-Americans …

Development And Evaluation Of An Automated Multimodal Mobile Detection Of Oral Cancer Imaging System To Aid In Risk-Based Management Of Oral Mucosal Lesions, Ruchika Mitbander, David Brenes, Jackson B Coole, Alex Kortum, Imran S Vohra, Jennifer Carns, Richard A Schwarz, Ida Varghese, Safia Durab, Sean Anderson, Nancy E Bass, Ashlee D Clayton, Hawraa Badaoui, Loganayaki Anandasivam, Rachel A Giese, Ann M Gillenwater, Nadarajah Vigneswaran, Rebecca Richards-Kortum

Faculty, Staff and Student Publications

Oral cancer is a major global health problem. It is commonly diagnosed at an advanced stage, although often preceded by clinically visible oral mucosal lesions, termed oral potentially malignant disorders, which are associated with an increased risk of oral cancer development. There is an unmet clinical need for effective screening tools to assist front-line healthcare providers to determine which patients should be referred to an oral cancer specialist for evaluation. This study reports the development and evaluation of the mobile detection of oral cancer (mDOC) imaging system and an automated algorithm that generates a referral recommendation from mDOC images. mDOC …

External Validation Of An Algorithm To Detect Vertebral Level Mislabeling And Autocontouring Errors, Tucker J Netherton, Didier Duprez, Tina Patel, Gizem Cifter, Laurence E Court, Christoph Trauernicht, Ajay Aggarwal

Faculty, Staff and Student Publications

Background and purpose: This work performs external validation of a previously developed vertebral body autocontouring tool and investigates a post-processing method to increase performance to clinically acceptable levels.

Materials and methods: Vertebral bodies within CT scans from two separate institutions (40 from institution A and 41 from institution B) were automatically 1) localized and enumerated, 2) contoured, and 3) screened as a means of quality assurance (QA) for errors. Identification rate, contour acceptability rate, and QA accuracy were calculated to assess the tool's performance. These metrics were compared to those calculated on CTs from the model's original training dataset, and …

A New Cure Model Accounting For Longitudinal Data And Flexible Patterns Of Hazard Ratios Over Time, Can Xie, Xuelin Huang, Ruosha Li, Yu Shen, Nicholas J Short, Kapil N Bhalla

Faculty, Staff and Student Publications

With the advancement of medical treatments, many historically incurable diseases have become curable. An accurate estimation of the cure rates is of great interest. When there are no clear biomarker indicators for cure, the estimation of cure rate is intertwined with and influenced by the specification of hazard functions for uncured patients. Consequently, the commonly used proportional hazards (PH) assumption, when violated, may lead to biased cure rate estimation. Meanwhile, longitudinal biomarker measurements for individual patients are usually available. To accommodate non-PH functions and incorporate individual longitudinal biomarker trajectories, we propose a new joint model for cure, survival, and longitudinal …

Diet And Survival After A Diagnosis Of Ovarian Cancer: A Pooled Analysis From The Ovarian Cancer Association Consortium, Christina M Nagle, Torukiri I Ibiebele, Renhua Na, Elisa V Bandera, Daniel Cramer, Jennifer A Doherty, Graham G Giles, Marc T Goodman, Gillian E Hanley, Holly R Harris, Allan Jensen, Susanne K Kjaer, Alice Lee, Valerie Mcguire, Roger L Milne, Bo Qin, Jean Richardson, Naoko Sasamoto, Joellen M Schildkraut, Weiva Sieh, Kathryn L Terry, Linda Titus, Britton Trabert, Nicolas Wentzensen, Anna H Wu, Andrew Berchuck, Malcolm C Pike, Celeste Leigh Pearce, Penelope M Webb, Multidisciplinary Ovarian Cancer Outcomes Group And Ovarian Cancer Association Consortium

Faculty, Staff and Student Publications

Background: Prognosis after a diagnosis of invasive epithelial ovarian cancer is poor. Some studies have suggested modifiable behaviors, like diet, are associated with survival but the evidence is inconsistent.

Objectives: This study aims to pool data from studies conducted around the world to evaluate the relationships among dietary indices, foods, and nutrients from food sources and survival after a diagnosis of ovarian cancer.

Methods: This analysis from the Multidisciplinary Ovarian Cancer Outcomes Group within the Ovarian Cancer Association Consortium included 13 studies with 7700 individuals with ovarian cancer, who completed food-frequency questionnaires regarding their prediagnosis diet. Adjusted hazard ratios (aHRs) …

Immunotherapy Targeting A Leader Sequence Cathepsin G-Derived Peptide, Chunhua Shi, Ze Tian, Jun Yan, Mao Zhang, Pariya Sukhumalchandra, Edward Chang, Guojun Yang, Junping You, Meng Cui, Qing Shi, Celine Kerros, Anne Philips, Na Qiao, Hiroki Torikai, Sathvik Patchametla, Anna Sergeeva, Lisa St John, Helen He, Dmitri Wiederschain, Benjamin H Lee, Geraldine L C Paulus, Dongxing Zha, Jeffrey Molldrem, Gheath Alatrash

Faculty, Staff and Student Publications

Myeloid azurophil granules provide a rich source of intracellular leukemia antigens. Cathepsin G (CG) is a serine protease that has higher expression in acute myeloid leukemia (AML) blasts in comparison to normal myeloid progenitors. Based on the unique biology of HLA-A*0201 (HLA-A2), in which presentation of leader sequence (LS)-derived peptides is favored, we focused on the LS-CG-derived peptide CG1 (FLLPTGAEA). We previously detected CG1/HLA-A2 complexes on the surface of primary HLA-A2+ AML blasts and cell lines, and immunity targeting CG1/HLA-A2 in leukemia patients. T cell receptor (TCR)-mimic (m) antibodies are immunotherapeutic antibodies that target peptide-HLA (pHLA) complexes. Here we report …

Crowd-Sourced Benchmarking Of Single-Sample Tumor Subclonal Reconstruction, Adriana Salcedo, Maxime Tarabichi, Alex Buchanan, Shadrielle M G Espiritu, Hongjiu Zhang, Kaiyi Zhu, Tai-Hsien Ou Yang, Ignaty Leshchiner, Dimitris Anastassiou, Yuanfang Guan, Gun Ho Jang, Mohammed F E Mootor, Kerstin Haase, Amit G Deshwar, William Zou, Imaad Umar, Stefan Dentro, Jeff A Wintersinger, Kami Chiotti, Jonas Demeulemeester, Clemency Jolly, Lesia Sycza, Minjeong Ko, Pcawg Evolution And Heterogeneity Working Group, Smc-Het Participants, David C Wedge, Quaid D Morris, Kyle Ellrott, Peter Van Loo, Paul C Boutros

Faculty, Staff and Student Publications

Subclonal reconstruction algorithms use bulk DNA sequencing data to quantify parameters of tumor evolution, allowing an assessment of how cancers initiate, progress and respond to selective pressures. We launched the ICGC-TCGA (International Cancer Genome Consortium-The Cancer Genome Atlas) DREAM Somatic Mutation Calling Tumor Heterogeneity and Evolution Challenge to benchmark existing subclonal reconstruction algorithms. This 7-year community effort used cloud computing to benchmark 31 subclonal reconstruction algorithms on 51 simulated tumors. Algorithms were scored on seven independent tasks, leading to 12,061 total runs. Algorithm choice influenced performance substantially more than tumor features but purity-adjusted read depth, copy-number state and read mappability …

Daratumumab/Lenalidomide/Dexamethasone In Transplant-Ineligible Newly Diagnosed Myeloma: Maia Long-Term Outcomes, Thierry Facon, Philippe Moreau, Katja Weisel, Hartmut Goldschmidt, Saad Z Usmani, Ajai Chari, Torben Plesner, Robert Z Orlowski, Nizar Bahlis, Supratik Basu, Cyrille Hulin, Hang Quach, Michael O'Dwyer, Aurore Perrot, Caroline Jacquet, Christopher P Venner, Noopur Raje, Mourad Tiab, Margaret Macro, Laurent Frenzel, Xavier Leleu, Gordon Cook, George Wang, Huiling Pei, Maria Krevvata, Robin Carson, Fredrik Borgsten, Shaji K Kumar

Faculty, Staff and Student Publications

In the MAIA study, daratumumab plus lenalidomide and dexamethasone (D-Rd) improved progression-free survival (PFS) and overall survival (OS) versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). We report updated efficacy and safety from MAIA (median follow-up, 64.5 months), including a subgroup analysis by patient age (< 70, ≥70 to < 75, ≥75, and ≥80 years). Overall, 737 transplant-ineligible patients with NDMM were randomized 1:1 to D-Rd or Rd. The primary endpoint, PFS, was improved with D-Rd versus Rd (median, 61.9 vs 34.4 months; hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.45-0.67; P <  0.0001). Median OS was not reached in the D-Rd group versus 65.5 months in the Rd group (HR, 0.66; 95% CI, 0.53-0.83; P = 0.0003); estimated 60-month OS rates were 66.6% and 53.6%, respectively. D-Rd achieved higher rates of complete response or better (≥CR; 51.1% vs 30.1%), minimal residual disease (MRD) negativity (32.1% vs 11.1%), and sustained MRD negativity (≥18 months: 16.8% vs 3.3%) versus Rd (all P <  0.0001). D-Rd demonstrated clinically meaningful efficacy benefits across age groups. No new safety concerns were observed. Updated results (median follow-up, >5 years) continue to support frontline use of D-Rd in transplant-ineligible patients with NDMM.

Staged Screening Identifies People With Biomarkers Related To Neuronal Alpha-Synuclein Disease, Ethan G Brown, Lana M Chahine, Andrew Siderowf, Caroline Gochanour, Ryan Kurth, Micah J Marshall, Chelsea Caspell-Garcia, Michael C Brumm, Craig E Stanley, Monica Korell, Bridget Mcmahon, Maggie Kuhl, Kimberly Fabrizio, Laura Heathers, Luis Concha-Marambio, Claudio Soto, Sohini Chowdhury, Christopher S Coffey, Tatiana M Foroud, Tanya Simuni, Kenneth Marek, Caroline M Tanner

Faculty, Staff and Student Publications

Objective: Remote identification of individuals with severe hyposmia may enable scalable recruitment of participants with underlying alpha-synuclein aggregation. We evaluated the performance of a staged screening paradigm using remote smell testing to enrich for abnormal dopamine transporter single-photon emission computed tomography imaging (DAT-SPECT) and alpha-synuclein aggregation.

Methods: The Parkinson's Progression Markers Initiative (PPMI) recruited participants for the prodromal cohort who were 60-years and older without a Parkinson's disease diagnosis. Participants were invited to complete a University of Pennsylvania Smell Identification Test (UPSIT) independently through an online portal. Hyposmic participants were invited to complete DAT-SPECT, which determined eligibility for enrollment in …

Nicotinic Acetylcholine Receptor Expression In Merkel Cell Carcinoma Is Associated With Clinical And Histopathologic Parameters, Christopher R Cunningham, Yiannis P Dimopoulos, Ian M García-Quiñones, Denái R Milton, Manuel Delgado-Vélez, Woo Cheal Cho, Victor G Prieto, José A Lasalde-Dominicci, Leomar Y Ballester, Phyu P Aung

Faculty, Staff and Student Publications

Background: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy with neuroendocrine differentiation. Several molecular pathways have been implicated in MCC development and multiple cell-of-origin candidates have been proposed, including neural crest cells, which express acetylcholine receptors (AChRs). The role of nicotinic acetylcholine receptors (nAChRs) in MCC has not been explored. In this study, we investigated if MCC expresses nAChRs and if nAChR expression correlates with patient characteristics.

Methods: The study included 71 MCC cases diagnosed with sufficient tissue available to perform immunohistochemical analysis. The median follow-up was 29.8 months (range, 2.7-234.1). We performed immunohistochemistry using antibodies against the …

Nicotinic Acetylcholine Receptor Expression In Merkel Cell Carcinoma Is Associated With Clinical And Histopathologic Parameters, Christopher R Cunningham, Yiannis P Dimopoulos, Ian M García-Quiñones, Denái R Milton, Manuel Delgado-Vélez, Woo Cheal Cho, Victor G Prieto, José A Lasalde-Dominicci, Leomar Y Ballester, Phyu P Aung

Faculty, Staff and Student Publications

Background: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy with neuroendocrine differentiation. Several molecular pathways have been implicated in MCC development and multiple cell-of-origin candidates have been proposed, including neural crest cells, which express acetylcholine receptors (AChRs). The role of nicotinic acetylcholine receptors (nAChRs) in MCC has not been explored. In this study, we investigated if MCC expresses nAChRs and if nAChR expression correlates with patient characteristics.

Methods: The study included 71 MCC cases diagnosed with sufficient tissue available to perform immunohistochemical analysis. The median follow-up was 29.8 months (range, 2.7-234.1). We performed immunohistochemistry using antibodies against the …

Adoptively Transferred Tumor-Specific Il-9-Producing Cytotoxic Cd8+ T Cells Activate Host Cd4+ T Cells To Control Tumors With Antigen Loss, Liuling Xiao, Rui Duan, Wendao Liu, Chuanchao Zhang, Xingzhe Ma, Miao Xian, Qiang Wang, Qi Guo, Wei Xiong, Pan Su, Lingqun Ye, Yabo Li, Ling Zhong, Jianfei Qian, Yong Lu, Zhongming Zhao, Qing Yi

Faculty, Staff and Student Publications

Host effector CD4+ T cells emerge as critical mediators for tumor regression but whether they can be activated by adoptively transferred CD8+ T cells remains unknown. We previously reported that adoptive transfer of interleukin 9 (IL-9)-producing cytotoxic CD8+ T (Tc9) cells achieved long-term control of tumor growth. Here, we demonstrate that murine tumor-specific Tc9 cells control the outgrowth of antigen-loss relapsed tumors by recruiting and activating host effector CD4+ T cells. Tc9 cells secreted IL-24 and recruited CCR7-expressing conventional type 2 dendritic cells (cDC2 cells) into tumor-draining lymph nodes to prime host CD4+ T cells against relapsed tumors. Host CD4+ …

Pulmonary Disease Caused By Mycobacterium Marseillense In Colombia, Darío Sebastián López-Delgado, Gabriel Alonso Rodríguez-Caicedo, Diego Fernando Taramuel-Gómez, Peter Houck, Martha Isabel Murcia-Aranguren, Roberto C Arduino, Alfonso J Rodriguez-Morales

Faculty, Staff and Student Publications

No abstract provided.

Fungal Infections In People Who Use Drugs, Jose Portugal Gonzales, Luis Ostrosky-Zeichner

Faculty, Staff and Student Publications

Illicit drug use in the United States continues to rise, alongside an increasing number of severe infections associated with drug use. Surveillance studies report that 28%–34% of candidemia cases are linked to intravenous drug use, with Candida albicans being the most commonly isolated species, followed by Candida parapsilosis and Candida glabrata. Marijuana use is associated with lung infections caused by Aspergillus and the Mucorales, showing a 3.5-fold increased risk of mold infections and a 2.2-fold increased risk for other fungal infections. Intravenous drug use also presents a recognized risk factor for Aspergillus and Mucorales infections. Additionally, substances like …

Uric Acid Stroke Cerebroprotection Transcended Sex, Age, And Comorbidities In A Multicenter Preclinical Trial, Rakesh B Patel, Mariia Kumskova, Hanish Kodali, Ivan Budnik, Vitalii Kuznetsov, Aditi Jain, Abhishek Jha, Daniel Thedens, Nirav Dhanesha, Brijesh Sutariya, Karisma A Nagarkatti, Jessica Lamb, Pradip Kamat, Yanrong Shi, Brooklyn Avery, Takahiko Imai, Xuyan Jin, Anjali Chauhan, Ligia S B Boisserand, Mohammad B Khan, Krishnan Dhandapani, Basavaraju G Sanganahalli, Lauren H Sansing, David C Hess, Raymond C Koehler, Louise D Mccullough, Jaroslaw Aronowski, Cenk Ayata, Márcio A Diniz, Patrick D Lyden, Anna M Planas, Angel Chamorro, Anil K Chauhan, Enrique C Leira, Span Investigators

Faculty, Staff and Student Publications

Background: Past failures in translating stroke cerebroprotection provoked calls for a more rigorous methodological approach, leading to the stroke preclinical assessment network SPAN (Stroke Preclinical Assessment Network), where uric acid (UA) treatment exceeded a prespecified efficacy boundary for the primary functional outcome. Still, successful translation to humans requires confirmation of the effect of UA across key biological variables relevant to patients with stroke.

Methods: We measured the effects of intravenous UA treatment (16 mg/kg) versus intravenous saline in groups of animals enrolled in the SPAN network with diverse comorbidities, sex, and age. The masked study drug or placebo was administered …