Digital Commons Network^™

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 …

Statins And Middle Meningeal Artery Embolization: A Literature Review In The Treatment Of Chronic Subdural Hematoma, Basel Musmar, Joanna M. Roy, Samantha Spellicy, Stavropoula I. Tjoumakaris, Michael R. Gooch, Robert H. Rosenwasswer, David Hasan, Pascal Jabbour

Department of Neurosurgery Faculty Papers

Chronic subdural hematoma (cSDH) presents a multifaceted challenge in contemporary neurological practice, necessitating innovative therapeutic strategies. This comprehensive review explores the convergence of two promising interventions: statins and middle meningeal artery (MMA) Embolization. With cSDH incidence on the rise, particularly among the aging population and those with long-term anticoagulant usage, the traditional surgical avenues face limitations in recurrence rates and associated risk factors. Statins, heralded for their anti-inflammatory, vasculogenic, and angiogenic properties, are emerging as potential allies in cSDH management. Concurrently, MMA embolization offers a nuanced approach to target the neomembrane's blood supply, with evidence supporting its efficacy and safety. …

Rhythm Is Essential: Unraveling The Relation Between The Circadian Clock And Cancer, Olajumoke Ogunlusi, Abantika Ghosh, Mrinmoy Sarkar, Kayla Carter, Harshini Davuluri, Mahul Chakraborty, Kristin Eckel-Mahan, Alex Keene, Jerome S Menet, Deborah Bell-Pedersen, Tapasree Roy Sarkar

The Brown Foundation: Institute of Molecular Medicine

Physiological processes such as the sleep-wake cycle, metabolism, hormone secretion, neurotransmitter release, sensory capabilities, and a variety of behaviors, including sleep, are controlled by a circadian rhythm adapted to 24-hour day-night periodicity. Disruption of circadian rhythm may lead to the risks of numerous diseases, including cancers. Several epidemiological and clinical data reveal a connection between the disruption of circadian rhythms and cancer. On the contrary, oncogenic processes may suppress the homeostatic balance imposed by the circadian clock. The integration of circadian biology into cancer research offers new options for making cancer treatment more effective, and the pharmacological modulation of core …

Epigenome-Wide Association Study Of Incident Type 2 Diabetes In Black And White Participants From The Atherosclerosis Risk In Communities Study, Sowmya Venkataraghavan, James S Pankow, Eric Boerwinkle, Myriam Fornage, Elizabeth Selvin, Debashree Ray

The Brown Foundation: Institute of Molecular Medicine

Aims/hypothesis: DNA methylation studies of incident type 2 diabetes in US populations are limited and to our knowledge none include individuals of African descent. We aimed to fill this gap by identifying methylation sites (CpG sites) and regions likely influencing the development of type 2 diabetes using data from Black and White individuals from the USA.

Methods: We prospectively followed 2091 Black and 1029 White individuals without type 2 diabetes from the Atherosclerosis Risk in Communities study over a median follow-up period of 17 years, and performed an epigenome-wide association analysis of blood-based methylation levels with incident type 2 diabetes …

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

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 …

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 …

Frozen Section Mohs: A Hybrid Technique And One Plastic Surgeon's Experience With 1714 Consecutive Skin Cancer Removals, Michael L. Chang, Steven L. Chang, Fady Gerges, Matthew M. Delancy, Amanda C. Yang, Lawrence D. Chang

Student Papers, Posters & Projects

While US nonmelanoma skin cancer (NMSC) mortality rate has decreased in the past decade, its incidence is rising. Traditional surgical treatments include wide local excision, intraoperative frozen section analysis (IFSA), and Mohs micrographic surgery (MMS). IFSA and MMS are techniques that provide intraoperative analysis allowing the surgeon to confirm margins clear of malignancy and minimize tissue damage, especially in cosmetically sensitive subunits. MMS, with cure rates up to 99%-100%, is considered the gold standard but is limited geographically and financially because of specialized training. We report a hybrid surgical technique that effectively excises cutaneous malignancy but can be utilized by …

Evaluating Artifact-Free Four-Dimensional Computer Tomography With 16 Cm Detector Array, Inhwan Yeo, Wei Nie, Jiajin Fan, Mindy Joo, Michael Correa, Qianyi Xu

Department of Radiation Oncology Faculty Papers

PURPOSE: To evaluate a 16 cm-array axial four-dimensional computer tomography (4DCT) in comparison with a 4 cm-array 4DCT in the presence of respiration irregularity.

METHOD: Ten traces of lung tumor motion from CyberKnife treatments were imported to move the lung cylinder, containing a spherical target, of a phantom. Images were acquired for the lung that moved to each of the 10-positions/phases (1) step-wisely by nominal helical scan at each movement (ground truth), (2) continuously by 4D scan with the 16 cm array, and (3) the same with the 4 cm array, involving table shift. Irregularities, consisting of baseline shift and/or …

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+ …

Safety Outcomes Of Antiplatelet Therapy During Endovascular Treatment Of Tandem Lesions In Acute Ischemic Stroke Patients, Mudassir Farooqui, Afshin A Divani, Milagros Galecio-Castillo, Ameer E Hassan, Mouhammad A Jumaa, Marc Ribo, Michael Abraham, Nils Petersen, Johanna Fifi, Waldo R Guerrero, Amer M Malik, James E Siegler, Thanh N Nguyen, Sunil A Sheth, Albert J Yoo, Guillermo Linares, Nazli Janjua, Darko Quispe-Orozco, Asad Ikram, Wondewossen G Tekle, Syed F Zaidi, Cynthia B Zevallos, Federica Rizzo, Tiffany Barkley, Reade De Leacy, Jane Khalife, Mohamad Abdalkader, Sergio Salazar-Marioni, Jazba Soomro, Weston Gordon, Aaron Rodriguez-Calienes, Juan Vivanco-Suarez, Charoskhon Turabova, Maxim Mokin, Dileep R Yavagal, Santiago Ortega-Gutierrez

Faculty, Staff and Student Publications

Risk of hemorrhage remains with antiplatelet medications required with carotid stenting during endovascular therapy (EVT) for tandem lesion (TLs). We evaluated the safety of antiplatelet regimens in EVT of TLs. This multicenter study included anterior circulation TL patients from 2015 to 2020, stratified by periprocedural EVT antiplatelet strategy: (1) no antiplatelets, (2) single oral, (3) dual oral, and (4) intravenous IV (in combination with single or dual oral). Primary outcome was symptomatic intracranial hemorrhage (sICH). Secondary outcomes were any hemorrhage, favorable functional status (mRS 0-2) at 90 days, successful reperfusion (mTICI score ≥ 2b), in-stent thrombosis, and mortality at 90 …

Lysyl Hydroxylase 2 Glucosylates Collagen Vi To Drive Lung Cancer Progression, Shike Wang, Houfu Guo, Reo Fukushima, Masahiko Terajima, Min Liu, Guan-Yu Xiao, Lenka Koudelková, Chao Wu, Xin Liu, Jiang Yu, Emma Burris, Jun Xu, Alvise Schiavinato, William K Russell, Mitsuo Yamauchi, Xiaochao Tan, Jonathan M Kurie

Faculty, Staff and Student Publications

Lysyl hydroxylase 2 (LH2) is highly expressed in multiple tumor types and accelerates disease progression by hydroxylating lysine residues on fibrillar collagen telopeptides to generate stable collagen cross links in tumor stroma. Here, we show that a galactosylhydroxylysyl glucosyltransferase (GGT) domain on LH2-modified type-VI collagen (Col6) to promote lung adenocarcinoma (LUAD) growth and metastasis. In tumors generated by LUAD cells lacking LH2 GGT domain activity, stroma was less stiff, and stable types of collagen cross links were reduced. Mass spectrometric analysis of total and glycosylated peptides in parental and GGT-inactive tumor samples identified Col6 chain α3 (Col6a3), a component of …

Symptom Documentation In Unstructured Palliative Care Notes Of Children And Adolescents With Cancer., Katherine Bernier Carney, Jacob Wilkes, Tumilara Aderibigbe, Kristin Stegenga, Holly Spraker-Perlman, Lauri A. Linder

Manuscripts, Articles, Book Chapters and Other Papers

CONTEXT: Children and adolescents with cancer experiencing complex symptoms can benefit from subspeciality palliative care. However, standardized methods of symptom documentation by pediatric palliative care teams are lacking. Understanding current approaches to symptom documentation will inform next steps to optimize symptom support.

OBJECTIVE: To explore the documentation of symptom prevalence and characteristics in unstructured clinical notes by pediatric palliative care clinicians caring for children and adolescents with cancer.

METHODS: We reviewed unstructured clinical notes documented by the pediatric palliative care team for 115 children and adolescents with cancer. Symptom-related data were abstracted and evaluated using content analysis based on the …

Prediction Of Hepatitis C Virus Perinatal Transmission In Pregnant Individuals With Hepatitis C Virus Infection, Grecio J Sandoval, George R Saade, Brenna L Hughes, Rebecca G Clifton, Uma M Reddy, Anna Bartholomew, Ashley Salazar, Edward K Chien, Alan T N Tita, John M Thorp, Torri D Metz, Ronald J Wapner, Vishakha Sabharwal, Hyagriv N Simhan, Geeta K Swamy, Kent D Heyborne, Baha M Sibai, William A Grobman, Yasser Y El-Sayed, Brian M Casey, Samuel Parry, George A Macones, Mona Prasad

Faculty, Staff and Student Publications

Our objective was to develop a prediction model for hepatitis C virus (HCV) infection perinatal transmission to improve triage for neonatal follow-up. This was a secondary analysis of HCV antibody-positive participants who were enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network multicenter observational study of HCV infection in pregnancy. Among 432 participants, the perinatal transmission rate was 6.0% (95% CI, 4.0-8.7%). The prediction model was developed and included two factors: maternal HCV RNA titer greater than 10 6 international units/mL and having had any antepartum bleeding. Using this model, the …

Importance Of Postreduction Ct Scans In Posterior And Transverse Posterior Wall Acetabular Fracture-Dislocations, Samantha R Gardner, Douglas R Haase, Nikhil Gattu, Stephen J Warner, Milton L Chip Routt, Patrick Kellam, Jonathan G Eastman

Faculty, Staff and Student Publications

Objectives: To report the frequency of patients with pre-reduction and postreduction computed tomography (CT) scans associated with acetabular fracture-dislocations and the change in position of associated intra-articular fragments occurring with joint reduction.

Design: Retrospective case series.

Setting: Regional Level 1 trauma center.

Patient selection criteria: Patients who sustained Arbeitsgemeinschaft fur Osteosynthesefragen/Orthopedic Trauma Association 62A1 and 62B1 posterior wall or transverse posterior wall acetabular fracture-dislocations with pre-reduction and postreduction CT imaging from February 2020 to July 2023.

Outcome measures and comparisons: Intra-articular fragments were identified, and change in position (fossa to cranial, intra-articular to extra-articular, etc.) was noted from pre-reduction to …

Acute Pain Trajectories In Elderly Patients With Fragility Hip Fractures, Paul Potnuru, Christina Goehl, Katherine S Becker, Alejandro Juul, Madison Aycock, Johanna Blair De Haan, Sudipta Sen, Michelle Ge, Stephen J Warner, Nadia Hernandez

Faculty, Staff and Student Publications

Background: Pain management for hospitalized elderly patients with fragility hip fractures (FHF) remains challenging. This study aims to distinguish acute pain trajectories in FHF patients that can inform personalized analgesia management.

Methods: We conducted a prospective observational study of patients aged 65 and older with FHF at a Level I trauma center. The primary outcome was daily average pain assessed for five days post-injury using the Brief Pain Inventory (BPI). We used group-based trajectory modeling (GBTM) to distinguish acute pain trajectories. Then, factors and secondary outcomes (opioid use and hospital length of stay [LOS]) associated with more severe pain trajectories …

Cell-Free Dna Results Indicating Mosaic Monosomy X Of Likely Maternal Origin: Impact On Genetic Counseling Practices And Patient Experiences, Audrey Mcbride, Ashley Cannon, Siddharth Prakash, Aaron W Roberts, Angela Seasely, Anna C E Hurst, Laura Hendon

Faculty, Staff and Student Publications

Objective: To investigate the current genetic counseling practices involving a cfDNA result indicating mosaic monosomy X of likely maternal origin, and to better understand the perspectives of patients who have received this result.

Method: A total of 60 prenatal genetic counselors completed surveys about their experiences with this result, cfDNA consenting practices, and management practices. In addition, qualitative interviews were conducted with 5 patients to gain insight into their experiences with result disclosure and follow-up care.

Results: 95% of genetic counselors reported feeling prepared to counsel on these results. However, responses to current practices varied. Of the genetic counselors surveyed, …

Thrombotic Complications Associated With Right Atrial Lines In Neonates And Infants Undergoing Cardiac Surgery. Is Calcium Chloride A Culprit?, Vy A Tran, Evelyn M Griffin, Jehan D Elliott, Rebecca L Scholl, Robert B Hill, Kelbie Kerr, Hala Khan, Jonathan Bates, Xu Zhang, Sepideh Saroukhani, Jorge Salazar, Olga I Pawelek

Faculty, Staff and Student Publications

Objectives: To determine if a change from calcium chloride to calcium gluconate infusion resulted in a decreased incidence of atrial thrombi and thrombotic events in neonates undergoing cardiac surgery.

Design: A single-center, retrospective cohort analysis.

Setting: A single center in Houston, TX.

Participants: 135 neonates undergoing cardiac surgery who had either a central venous catheter or tunneled atrial catheter placed and received infusions of either calcium chloride or calcium gluconate in the perioperative period.

Interventions: Patients either received a calcium chloride or calcium gluconate infusion in the perioperative period.

Measurements and main results: The study cohort consisted of 93 procedures …

In Vivo Antibody Labeling Route And Fluorophore Dictate Labeling Efficiency, Sensitivity, And Longevity, Natalie B Hagan, Charles Inaku, Nikesh Kunder, Tayleur White, Thierry Iraguha, Anna Meyer, Kristen E Pauken, Jason M Schenkel

Faculty, Staff and Student Publications

Leukocytes migrate through the blood and extravasate into organs to surveil the host for infection or cancer. Recently, we demonstrated that intravenous (IV) anti-CD45.2 antibody labeling allowed for precise tracking of leukocyte migration. However, the narrow labeling window can make this approach challenging for tracking rare migration events. Here, we show that altering antibody administration route and fluorophore can significantly extend the antibody active labeling time. We found that while both IV and intraperitoneal (IP) anti-CD45.2 antibody labeled circulating leukocytes after injection, they had different kinetic properties that impacted labeling time and intensity. Quantification of circulating antibody revealed that while …

Unleashing The Power Of Multiomics: Unraveling The Molecular Landscape Of Peripheral Neuropathy, Julie Choi, Zitian Tang, Wendy Dong, Jenna Ulibarri, Elvisa Mehinovic, Simone Thomas, Ahmet Höke, Sheng Chih Jin

Faculty, Staff and Student Publications

Peripheral neuropathies (PNs) affect over 20 million individuals in the United States, manifesting as a wide range of sensory, motor, and autonomic nerve symptoms. While various conditions such as diabetes, metabolic disorders, trauma, autoimmune disease, and chemotherapy-induced neurotoxicity have been linked to PN, approximately one-third of PN cases remain idiopathic, underscoring a critical gap in our understanding of these disorders. Over the years, considerable efforts have focused on unraveling the complex molecular pathways underlying PN to advance diagnosis and treatment. Traditional methods such as linkage analysis, fluorescence in situ hybridization, polymerase chain reaction, and Sanger sequencing identified initial genetic variants …