Biomedical Informatics Commons^™

Asct Vs Cart For Patients With Relapsed Lbcl In Pr: Role Of Tmtv, Paolo Strati, Oren Pasvolsky, Lei Feng, Guofan Xu, Sanjit O Tewari, Jaimole Varghese, Karla Ow, Minifrida Santiago, Ajlan Al Zaki, Andrew Jallouk, Sattva S Neelapu, Partow Kebriaei, Elizabeth J Shpall, Sairah Ahmed

Faculty, Staff and Student Publications

No abstract provided.

Single Cell Clonotypic And Transcriptional Evolution Of Multiple Myeloma Precursor Disease, Minghao Dang, Ruiping Wang, Hans C Lee, Krina K Patel, Melody R Becnel, Guangchun Han, Sheeba K Thomas, Dapeng Hao, Yanshuo Chu, Donna M Weber, Pei Lin, Zuzana Lutter-Berka, David A Berrios Nolasco, Mei Huang, Hima Bansal, Xingzhi Song, Jianhua Zhang, Andrew Futreal, Luz Yurany Moreno Rueda, David E Symer, Michael R Green, Cristhiam M Rojas Hernandez, Michael Kroll, Vahid Afshar-Khargan, Libere J Ndacayisaba, Peter Kuhn, Sattva S Neelapu, Robert Z Orlowski, Linghua Wang, Elisabet E Manasanch

Faculty, Staff and Student Publications

Multiple myeloma remains an incurable disease, and the cellular and molecular evolution from precursor conditions, including monoclonal gammopathy of undetermined significance and smoldering multiple myeloma, is incompletely understood. Here, we combine single-cell RNA and B cell receptor sequencing from fifty-two patients with myeloma precursors in comparison with myeloma and normal donors. Our comprehensive analysis reveals early genomic drivers of malignant transformation, distinct transcriptional features, and divergent clonal expansion in hyperdiploid versus non-hyperdiploid samples. Additionally, we observe intra-patient heterogeneity with potential therapeutic implications and identify distinct patterns of evolution from myeloma precursor disease to myeloma. We also demonstrate distinctive characteristics of …

Leveraging Mid-Infrared Spectroscopic Imaging And Deep Learning For Tissue Subtype Classification In Ovarian Cancer, Chalapathi Charan Gajjela, Matthew Brun, Rupali Mankar, Sara Corvigno, Noah Kennedy, Yanping Zhong, Jinsong Liu, Anil K Sood, David Mayerich, Sebastian Berisha, Rohith Reddy

Faculty, Staff and Student Publications

Mid-infrared spectroscopic imaging (MIRSI) is an emerging class of label-free techniques being leveraged for digital histopathology. Modern histopathologic identification of ovarian cancer involves tissue staining followed by morphological pattern recognition. This process is time-consuming and subjective and requires extensive expertise. This paper presents the first label-free, quantitative, and automated histological recognition of ovarian tissue subtypes using a new MIRSI technique. This optical photothermal infrared (O-PTIR) imaging technique provides a 10× enhancement in spatial resolution relative to prior instruments. It enables sub-cellular spectroscopic investigation of tissue at biochemically important fingerprint wavelengths. We demonstrate that the enhanced resolution of sub-cellular features, combined …

Clinical Significance And Biology Of Circulating Tumor Dna In High-Risk Early-Stage Her2-Negative Breast Cancer Receiving Neoadjuvant Chemotherapy, Mark Jesus M Magbanua, Lamorna Brown Swigart, Ziad Ahmed, Rosalyn W Sayaman, Derrick Renner, Ekaterina Kalashnikova, Gillian L Hirst, Christina Yau, Denise M Wolf, Wen Li, Amy L Delson, Smita Asare, Minetta C Liu, Kathy Albain, A Jo Chien, Andres Forero-Torres, Claudine Isaacs, Rita Nanda, Debu Tripathy, Angel Rodriguez, Himanshu Sethi, Alexey Aleshin, Matthew Rabinowitz, Jane Perlmutter, W Fraser Symmans, Douglas Yee, Nola M Hylton, Laura J Esserman, Angela M Demichele, Hope S Rugo, Laura J Van 'T Veer

Faculty, Staff and Student Publications

Circulating tumor DNA (ctDNA) analysis may improve early-stage breast cancer treatment via non-invasive tumor burden assessment. To investigate subtype-specific differences in the clinical significance and biology of ctDNA shedding, we perform serial personalized ctDNA analysis in hormone receptor (HR)-positive/HER2-negative breast cancer and triple-negative breast cancer (TNBC) patients receiving neoadjuvant chemotherapy (NAC) in the I-SPY2 trial. ctDNA positivity rates before, during, and after NAC are higher in TNBC than in HR-positive/HER2-negative breast cancer patients. Early clearance of ctDNA 3 weeks after treatment initiation predicts a favorable response to NAC in TNBC only. Whereas ctDNA positivity associates with reduced distant recurrence-free survival …

Paleoamerican Exploitation Of Extinct Megafauna Revealed Through Immunological Blood Residue And Microwear Analysis, North And South Carolina, Usa, Christopher R Moore, Larry R Kimball, Albert C Goodyear, Mark J Brooks, I Randolph Daniel, Allen West, Sean G Taylor, Kiersten J Weber, John L Fagan, Cam M Walker

Faculty, Staff and Student Publications

Previous immunological studies in the eastern USA have failed to establish a direct connection between Paleoamericans and extinct megafauna species. The lack of physical evidence for the presence of extinct megafauna begs the question, did early Paleoamericans regularly hunt or scavenge these animals, or were some megafauna already extinct? In this study of 120 Paleoamerican stone tools from across North and South Carolina, we investigate this question using crossover immunoelectrophoresis (CIEP). We find immunological support for the exploitation of extant and extinct megafauna, including Proboscidea, Equidae, and Bovidae (possibly Bison antiquus), on Clovis points and scrapers, as well as possible …

Human Papillomavirus And Rising Oropharyngeal Cancer Incidence In The United States, Anil K Chaturvedi, Eric A Engels, Ruth M Pfeiffer, Brenda Y Hernandez, Weihong Xiao, Esther Kim, Bo Jiang, Marc T Goodman, Maria Sibug-Saber, Wendy Cozen, Lihua Liu, Charles F Lynch, Nicolas Wentzensen, Richard C Jordan, Sean Altekruse, William F Anderson, Philip S Rosenberg, Maura L Gillison

Faculty, Staff and Student Publications

PURPOSE: Recent increases in incidence and survival of oropharyngeal cancers in the United States have been attributed to human papillomavirus (HPV) infection, but empirical evidence is lacking.

PATIENTS AND METHODS: HPV status was determined for all 271 oropharyngeal cancers (1984-2004) collected by the three population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Residual Tissue Repositories Program by using polymerase chain reaction and genotyping (Inno-LiPA), HPV16 viral load, and HPV16 mRNA expression. Trends in HPV prevalence across four calendar periods were estimated by using logistic regression. Observed HPV prevalence was reweighted to all oropharyngeal cancers within the cancer …

The Axis Of Complement C1 And Nucleolus In Antinuclear Autoimmunity, Shan Wu, Junjie Chen, Boon Heng Dennis Teo, Seng Yin Kelly Wee, Ming Hui Millie Wong, Jianzhou Cui, Jinmiao Chen, Khai Pang Leong, Jinhua Lu

Faculty, Staff and Student Publications

Antinuclear autoantibodies (ANA) are heterogeneous self-reactive antibodies that target the chromatin network, the speckled, the nucleoli, and other nuclear regions. The immunological aberration for ANA production remains partially understood, but ANA are known to be pathogenic, especially, in systemic lupus erythematosus (SLE). Most SLE patients exhibit a highly polygenic disease involving multiple organs, but in rare complement C1q, C1r, or C1s deficiencies, the disease can become largely monogenic. Increasing evidence point to intrinsic autoimmunogenicity of the nuclei. Necrotic cells release fragmented chromatins as nucleosomes and the alarmin HMGB1 is associated with the nucleosomes to activate TLRs and confer anti-chromatin autoimmunogenecity. …

Repair Of Noise-Induced Damage To Stereocilia F-Actin Cores Is Facilitated By Xirp2 And Its Novel Mechanosensor Domain, Elizabeth L Wagner, Jun-Sub Im, Stefano Sala, Maura I Nakahata, Terence E Imbery, Sihan Li, Daniel Chen, Katherine Nimchuk, Yael Noy, David W Archer, Wenhao Xu, George Hashisaki, Karen B Avraham, Patrick W Oakes, Jung-Bum Shin

Faculty, Staff and Student Publications

Prolonged exposure to loud noise has been shown to affect inner ear sensory hair cells in a variety of deleterious manners, including damaging the stereocilia core. The damaged sites can be visualized as 'gaps' in phalloidin staining of F-actin, and the enrichment of monomeric actin at these sites, along with an actin nucleator and crosslinker, suggests that localized remodeling occurs to repair the broken filaments. Herein, we show that gaps in mouse auditory hair cells are largely repaired within 1 week of traumatic noise exposure through the incorporation of newly synthesized actin. We provide evidence that Xin actin binding repeat …

Microcalcification Crystallography As A Potential Marker Of Dcis Recurrence, Sarah B Gosling, Emily L Arnold, Samantha K Davies, Hannah Cross, Ihssane Bouybayoune, Doriana Calabrese, Jayakrupakar Nallala, Sarah E Pinder, Liping Fu, Esther H Lips, Lorraine King, Jeffrey Marks, Allison Hall, Lars J Grimm, Thomas Lynch, Donna Pinto, Hilary Stobart, E Shelley Hwang, Jelle Wesseling, Kalotina Geraki, Nicholas Stone, Iain D Lyburn, Charlene Greenwood, Keith D Rogers, Grand Challenge Precision Consortium

Faculty, Staff and Student Publications

Ductal carcinoma in-situ (DCIS) accounts for 20-25% of all new breast cancer diagnoses. DCIS has an uncertain risk of progression to invasive breast cancer and a lack of predictive biomarkers may result in relatively high levels (~ 75%) of overtreatment. To identify unique prognostic biomarkers of invasive progression, crystallographic and chemical features of DCIS microcalcifications have been explored. Samples from patients with at least 5-years of follow up and no known recurrence (174 calcifications in 67 patients) or ipsilateral invasive breast cancer recurrence (179 microcalcifications in 57 patients) were studied. Significant differences were noted between the two groups including whitlockite …

Identification Of Key Elements In Prostate Cancer For Ontology Building Via A Multidisciplinary Consensus Agreement, Amy Moreno, Abhishek A Solanki, Tianlin Xu, Ruitao Lin, Jatinder Palta, Emily Daugherty, David Hong, Julian Hong, Sophia C Kamran, Evangelia Katsoulakis, Kristy Brock, Mary Feng, Clifton Fuller, Charles Mayo

Faculty, Staff and Student Publications

BACKGROUND: Clinical data collection related to prostate cancer (PCa) care is often unstructured or heterogeneous among providers, resulting in a high risk for ambiguity in its meaning when sharing or analyzing data. Ontologies, which are shareable formal (i.e., computable) representations of knowledge, can address these challenges by enabling machine-readable semantic interoperability. The purpose of this study was to identify PCa-specific key data elements (KDEs) for standardization in clinic and research.

METHODS: A modified Delphi method using iterative online surveys was performed to report a consensus agreement on KDEs by a multidisciplinary panel of 39 PCa specialists. Data elements were divided …

Prediction Of Disease Progression To Upfront Pembrolizumab Monotherapy In Advanced Non-Small-Cell Lung Cancer With High Pd-L1 Expression Using Baseline Ct Disease Quantification And Smoking Pack Years, Ali Silver, Cheryl Ho, Qian Ye, Jianjun Zhang, Ian Janzen, Jessica Li, Montgomery Martin, Lang Wu, Ying Wang, Stephen Lam, Calum Macaulay, Barbara Melosky, Ren Yuan

Faculty, Staff and Student Publications

Health Canada approved pembrolizumab in the first-line setting for advanced non-small-cell lung cancer with PD-L1 ≥ 50% and no EGFR/ALK aberration. The keynote 024 trial showed 55% of such patients progress with pembrolizumab monotherapy. We propose that the combination of baseline CT and clinical factors can help identify those patients who may progress. In 138 eligible patients from our institution, we retrospectively collected their baseline variables, including baseline CT findings (primary lung tumor size and metastatic site), smoking pack years, performance status, tumor pathology, and demographics. The treatment response was assessed via RECIST 1.1 using the baseline and first follow-up …

Genome-Wide Analyses Characterize Shared Heritability Among Cancers And Identify Novel Cancer Susceptibility Regions, Sara Lindström, Lu Wang, Helian Feng, Arunabha Majumdar, Sijia Huo, James Macdonald, Tabitha Harrison, Constance Turman, Hongjie Chen, Nicholas Mancuso, Theo Bammler, Breast Cancer Association Consortium (Bcac), Steve Gallinger, Stephen B Gruber, Marc J Gunter, Loic Le Marchand, Victor Moreno, Kenneth Offit, Colorectal Transdisciplinary Study (Corect), Colon Cancer Family Registry Study (Ccfr), Genetics And Epidemiology Of Colorectal Cancer Consortium (Gecco), Immaculata De Vivo, Tracy A O'Mara, Amanda B Spurdle, Ian Tomlinson, Endometrial Cancer Association Consortium (Ecac), Rebecca Fitzgerald, Puya Gharahkhani, Ines Gockel, Janusz Jankowski, Stuart Macgregor, Johannes Schumacher, Jill Barnholtz-Sloan, Melissa L Bondy, Richard S Houlston, Robert B Jenkins, Beatrice Melin, Margaret Wrensch, Paul Brennan, David C Christiani, Mattias Johansson, James Mckay, Melinda C Aldrich, Christopher I Amos, Maria Teresa Landi, Adonina Tardon, International Lung Cancer Consortium (Ilcco), D Timothy Bishop, Florence Demenais, Alisa M Goldstein, Mark M Iles, Peter A Kanetsky, Matthew H Law, Ovarian Cancer Association Consortium (Ocac), Laufey T Amundadottir, Rachael Stolzenberg-Solomon, Brian M Wolpin, Pancreatic Cancer Cohort Consortium (Panscan), Alison Klein, Gloria Petersen, Harvey Risch, Pancreatic Cancer Case-Control Consortium (Panc4), The Practical Consortium, Stephen J Chanock, Mark P Purdue, Ghislaine Scelo, Paul Pharoah, Siddhartha Kar, Rayjean J Hung, Bogdan Pasaniuc, Peter Kraft

Faculty, Staff and Student Publications

BACKGROUND: The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci.

METHODS: We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel …

Plumbing Mysterious Rnas In “Dark Genome” For The Conquest Of Human Diseases, Lisa A Huang, Chunru Lin, Liuqing Yang

Faculty, Staff and Student Publications

Next-generation sequencing has revealed that less than 2% of transcribed genes are translated into proteins, with a large portion transcribed into noncoding RNAs (ncRNAs). Among these, long noncoding RNAs (lncRNAs) represent the largest group and are pervasively transcribed throughout the genome. Dysfunctions in lncRNAs have been found in various diseases, highlighting their potential as therapeutic, diagnostic, and prognostic targets. However, challenges, such as unknown molecular mechanisms and nonspecific immune responses, and issues of drug specificity and delivery present obstacles in translating lncRNAs into clinical applications. In this review, we summarize recent publications that have explored lncRNA functions in human diseases. …

Non-Melanoma Skin Cancer Detection In The Age Of Advanced Technology: A Review, Haleigh Stafford, Jane Buell, Elizabeth Chiang, Uma Ramesh, Michael Migden, Priyadharsini Nagarajan, Moran Amit, Dan Yaniv

Faculty, Staff and Student Publications

Skin cancer is the most common cancer diagnosis in the United States, with approximately one in five Americans expected to be diagnosed within their lifetime. Non-melanoma skin cancer is the most prevalent type of skin cancer, and as cases rise globally, physicians need reliable tools for early detection. Artificial intelligence has gained substantial interest as a decision support tool in medicine, particularly in image analysis, where deep learning has proven to be an effective tool. Because specialties such as dermatology rely primarily on visual diagnoses, deep learning could have many diagnostic applications, including the diagnosis of skin cancer. Furthermore, with …

Decoding The Regulatory Roles Of Non-Coding Rnas In Cellular Metabolism And Disease, Yuru Zong, Xuliang Wang, Bing Cui, Xiaowei Xiong, Andrew Wu, Chunru Lin, Yaohua Zhang

Faculty, Staff and Student Publications

Non-coding RNAs, including long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are being studied extensively in a variety of fields. Their roles in metabolism have received increasing attention in recent years but are not yet clear. The regulation of glucose, fatty acid, and amino acid metabolism is an imperative physiological process that occurs in living organisms and takes part in cancer and cardiovascular diseases. Here, we summarize the important roles played by non-coding RNAs in glucose metabolism, fatty acid metabolism, and amino acid metabolism, as well as the mechanisms involved. We also summarize the therapeutic advances for non-coding …

Noncoding Rnas: Hope And Hype At 30 Years, George A Calin

Faculty, Staff and Student Publications

No abstract provided.

A Nurse-Led Telehealth Program For Diabetes Foot Care: Feasibility And Usability Study, Hsiao-Hui Ju, Rashmi Momin, Stanley Cron, Jed Jularbal, Jeffery Alford, Constance Johnson

Faculty, Staff and Student Publications

BACKGROUND: Diabetes mellitus can lead to severe and debilitating foot complications, such as infections, ulcerations, and amputations. Despite substantial progress in diabetes care, foot disease remains a major challenge in managing this chronic condition that causes serious health complications worldwide.

OBJECTIVE: The primary aim of this study was to examine the feasibility and usability of a telehealth program focused on preventive diabetes foot care. A secondary aim was to descriptively measure self-reported changes in diabetes knowledge, self-care, and foot care behaviors before and after participating in the program.

METHODS: The study used a single-arm, pre-post design in 2 large family …

Achondroplasia Natural History Study (Clarity): 60-Year Experience In Orthopedic Surgery From Four Skeletal Dysplasia Centers, Nickolas J Nahm, W G Stuart Mackenzie, William G Mackenzie, Ethan Gough, S Shahrukh Hashmi, Jacqueline T Hecht, Janet M Legare, Mary Ellen Little, Peggy Modaff, Richard M Pauli, David F Rodriguez-Buritica, Maria Elena Serna, Cory J Smid, Julie Hoover-Fong, Michael B Bober

Faculty, Staff and Student Publications

BACKGROUND: The purpose of this study was to describe the frequency and risk factors for orthopedic surgery in patients with achondroplasia. CLARITY (The Achondroplasia Natural History Study) includes clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the United States from 1957 to 2018. Data were entered and stored in a Research Electronic Data Capture (REDCap) database.

RESULTS: Information from one thousand three hundred and seventy-four patients with achondroplasia were included in this study. Four hundred and eight (29.7%) patients had at least one orthopedic surgery during their lifetime and 299 (21.8%) patients underwent multiple procedures. …

Effect Of Porosity In Activated Carbon Supports For Silicon-Based Lithium-Ion Batteries (Libs), Yun Jeong Choi, Jeong Bin Choi, Ji Sun Im, Ji Hong Kim

Faculty, Staff and Student Publications

Activated carbon supports for Si deposition with different porosities were prepared, and the effect of porosity on the electrochemical characteristics was investigated. The porosity of the support is a key parameter affecting the Si deposition mechanism and the stability of the electrode. In the Si deposition mechanism, as the porosity of activated carbon increases, the effect of particle size reduction due to the uniform dispersion of Si was confirmed. This implies that the porosity of activated carbon can affect the rate performance. However, excessively high porosity reduced the contact area between Si and activated carbon, resulting in poor electrode stability. …

Achondroplasia Natural History Study (Clarity): 60-Year Experience In Orthopedic Surgery From Four Skeletal Dysplasia Centers, Nickolas J Nahm, W G Stuart Mackenzie, William G Mackenzie, Ethan Gough, S Shahrukh Hashmi, Jacqueline T Hecht, Janet M Legare, Mary Ellen Little, Peggy Modaff, Richard M Pauli, David F Rodriguez-Buritica, Maria Elena Serna, Cory J Smid, Julie Hoover-Fong, Michael B Bober

Faculty, Staff and Student Publications

BACKGROUND: The purpose of this study was to describe the frequency and risk factors for orthopedic surgery in patients with achondroplasia. CLARITY (The Achondroplasia Natural History Study) includes clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the United States from 1957 to 2018. Data were entered and stored in a Research Electronic Data Capture (REDCap) database.

RESULTS: Information from one thousand three hundred and seventy-four patients with achondroplasia were included in this study. Four hundred and eight (29.7%) patients had at least one orthopedic surgery during their lifetime and 299 (21.8%) patients underwent multiple procedures. …

Targeting Cxcr4 Abrogates Resistance To Trastuzumab By Blocking Cell Cycle Progression And Synergizes With Docetaxel In Breast Cancer Treatment, Shuying Liu, Shelly M Xie, Wenbin Liu, Mihai Gagea, Ariella B Hanker, Nguyen Nguyen, Akshara Singareeka Raghavendra, Gloria Yang-Kolodji, Fuliang Chu, Sattva S Neelapu, Adriano Marchese, Samir Hanash, Johann Zimmermann, Carlos L Arteaga, Debasish Tripathy

Faculty, Staff and Student Publications

Background: Although trastuzumab and other HER2-targeted therapies have significantly improved survival in patients with HER2 overexpressed or amplified (HER2+) breast cancer, a significant proportion of patients do not respond or eventually develop clinical resistance. Strategies to reverse trastuzumab resistance remain a high clinical priority. We were the first to report the role of CXCR4 in trastuzumab resistance. The present study aims to explore the therapeutic potential of targeting CXCR4 and better understand the associated mechanisms.

Methods: Immunofluorescent staining, confocal microscopy analysis, and immunoblotting were used to analyze CXCR4 expression. BrdU incorporation assays and flow cytometry were used to analyze dynamic …

17Β-Estradiol Promotes Extracellular Vesicle Release And Selective Mirna Loading In Erα-Positive Breast Cancer, Rares Drula, Barbara Pardini, Xiao Fu, Mireia Cruz De Los Santos, Ancuta Jurj, Lan Pang, Sherien M El-Daly, Linda Fabris, Erik Knutsen, Mihnea P Dragomir, Recep Bayraktar, Yongfeng Li, Meng Chen, Filippo Del Vecchio, Léa Berland, Jessica Dae, Daniel Fan, Masayoshi Shimizu, Anh M Tran, Mercedes Barzi, Carlotta Pioppini, Angelica M Gutierrez, Cristina Ivan, Salyna Meas, Carolyn S Hall, Suresh K Alahari, Ioana Berindan-Neagoe, Muller Fabbri, Anthony Lucci, Banu Arun, Simone Anfossi, George A Calin

Faculty, Staff and Student Publications

The causes and consequences of abnormal biogenesis of extracellular vesicles (EVs) are not yet well understood in malignancies, including in breast cancers (BCs). Given the hormonal signaling dependence of estrogen receptor-positive (ER+) BC, we hypothesized that 17β-estradiol (estrogen) might influence EV production and microRNA (miRNA) loading. We report that physiological doses of 17β-estradiol promote EV secretion specifically from ER+ BC cells via inhibition of miR-149-5p, hindering its regulatory activity on SP1, a transcription factor that regulates the EV biogenesis factor nSMase2. Additionally, miR-149-5p downregulation promotes hnRNPA1 expression, responsible for the loading of let-7's miRNAs into EVs. In multiple patient cohorts, …

Non-Homologous End-Joining Pathway Genotypes Significantly Associated With Nasopharyngeal Carcinoma Susceptibility, Chia-Wen Tsai, Liang-Chun Shih, Wen-Shin Chang, Che-Lun Hsu, Jie-Long He, Te-Chun Hsia, Yun-Chi Wang, Jian Gu, Da-Tian Bau

Faculty, Staff and Student Publications

Defects in the non-homologous end-joining (NHEJ) DNA repair pathway lead to genomic instability and carcinogenesis. However, the roles of individual NHEJ genes in nasopharyngeal carcinoma (NPC) etiology are not well-understood. The aim of this study was to assess the contribution of NHEJ genotypes, including XRCC4 (rs6869366, rs3734091, rs28360071, rs28360317, rs1805377), XRCC5 (rs828907, rs11685387, rs9288518), XRCC6 (rs5751129, rs2267437, rs132770, rs132774), XRCC7 rs7003908, and Ligase4 rs1805388, to NPC risk, with 208 NPC patients and 416 controls. Genotype-phenotype correlations were also investigated by measuring mRNA and protein expression in adjacent normal tissues and assessing the NHEJ repair capacity in blood lymphocytes from 43 …

Variant Spectrum Of Von Hippel-Lindau Disease And Its Genomic Heterogeneity In Japan, Kenji Tamura, Yuki Kanazashi, Chiaki Kawada, Yuya Sekine, Kazuhiro Maejima, Shingo Ashida, Takashi Karashima, Shohei Kojima, Nickolas F Parrish, Shunichi Kosugi, Chikashi Terao, Shota Sasagawa, Masashi Fujita, Todd A Johnson, Yukihide Momozawa, Keiji Inoue, Taro Shuin, Hidewaki Nakagawa

Faculty, Staff and Student Publications

Von Hippel-Lindau (VHL) disease is an autosomal dominant, inherited syndrome with variants in the VHL gene, causing predisposition to multi-organ neoplasms with vessel abnormality. Germline variants in VHL can be detected in 80-90% of patients clinically diagnosed with VHL disease. Here, we summarize the results of genetic tests for 206 Japanese VHL families, and elucidate the molecular mechanisms of VHL disease, especially in variant-negative unsolved cases. Of the 206 families, genetic diagnosis was positive in 175 families (85%), including 134 families (65%) diagnosed by exon sequencing (15 novel variants) and 41 (20%) diagnosed by multiplex ligation-dependent probe amplification (MLPA) (one …

Bk Channel Modulation By Positively Charged Peptides And Auxiliary Γ Subunits Mediated By The Ca2+-Bowl Site, Guanxing Chen, Qin Li, Timothy I Webb, Mark A Hollywood, Jiusheng Yan

Faculty, Staff and Student Publications

The large-conductance, Ca2+-, and voltage-activated K+ (BK) channel consists of the pore-forming α (BKα) subunit and regulatory β and γ subunits. The γ1-3 subunits facilitate BK channel activation by shifting the voltage-dependence of channel activation toward the hyperpolarization direction by about 50-150 mV in the absence of Ca2+. We previously found that the intracellular C-terminal positively charged regions of the γ subunits play important roles in BK channel modulation. In this study, we found that the intracellular C-terminal region of BKα is indispensable in BK channel modulation by the γ1 subunit. Notably, synthetic peptide mimics of the γ1-3 subunits' C-terminal …

Irinotecan- Vs Oxaliplatin-Based Doublets In Krasg12c-Mutated Metastatic Colorectal Cancer—A Multicentre Propensity-Score-Matched Retrospective Analysis, Vincenzo Formica, Cristina Morelli, Veronica Conca, Maria Alessandra Calegari, Jessica Lucchetti, Emanuela Dell'aquila, Marta Schirripa, Marco Messina, Lisa Salvatore, Federica Lo Prinzi, Giovanni Dima, Giovanni Trovato, Silvia Riondino, Mario Roselli, Ferdinandos Skoulidis, Hendrik-Tobias Arkenau, Chiara Cremolini

Faculty, Staff and Student Publications

Background: KRASG12C-mutated metastatic colorectal cancer (mCRC) has recently been recognized as a distinct druggable molecular entity; however, there are limited data on its sensitivity to standard chemotherapy. In the near future, the combination of chemotherapy plus a KRASG12C-inhibitor might become the standard of care; however, the optimal chemotherapy backbone is unknown.

Methods: A multicentre retrospective analysis was conducted including KRASG12C-mutated mCRC patients treated with first-line FOLFIRI or FOLFOX +/- bevacizumab. Both unmatched and propensity-score-matched analysis (PSMA) were conducted, with PSMA controlling for: previous adjuvant chemotherapy, ECOG PS, use of bevacizumab in first line, timing of metastasis appearance, time from diagnosis …

Tubectomy With Delayed Oophorectomy As An Alternative To Risk-Reducing Salpingo-Oophorectomy In High-Risk Women To Assess The Safety Of Prevention: The Tuba-Wisp Ii Study Protocol, Miranda P Steenbeek, Majke H D Van Bommel, Joanna Inthout, Christine B Peterson, Michiel Simons, Kit C B Roes, Marleen Kets, Barbara M Norquist, Elizabeth M Swisher, Rosella P M G Hermens, Tuba-Wisp Ii Consortium, Karen H Lu, Joanne A De Hullu

Faculty, Staff and Student Publications

Background: Risk-reducing salpingectomy with delayed oophorectomy has gained interest for individuals at high risk for tubo-ovarian cancer as there is compelling evidence that especially high-grade serous carcinoma originates in the fallopian tubes. Two studies have demonstrated a positive effect of salpingectomy on menopause-related quality of life and sexual health compared with standard risk-reducing salpingo-oophorectomy.

Primary objective: To investigate whether salpingectomy with delayed oophorectomy is non-inferior to the current standard salpingo-oophorectomy for the prevention of tubo-ovarian cancer among individuals at high inherited risk.

Study hypothesis: We hypothesize that postponement of oophorectomy after salpingectomy, to the age of 40-45 (BRCA1) …

Studies On Diketopiperazine And Dipeptide Analogs As Opioid Receptor Ligands, Siavash Shahbazi Nia, Mohammad Anwar Hossain, Guangchen Ji, Sravan K Jonnalagadda, Samuel Obeng, Md Ashrafur Rahman, Ali Ehsan Sifat, Saeideh Nozohouri, Collin Blackwell, Dhavalkumar Patel, Jon Thompson, Scott Runyon, Takato Hiranita, Christopher R Mccurdy, Lance Mcmahon, Thomas J Abbruscato, Paul C Trippier, Volker Neugebauer, Nadezhda A German

Faculty, Staff and Student Publications

Using the structure of gliotoxin as a starting point, we have prepared two different chemotypes with selective affinity to the kappa opioid receptor (KOR). Using medicinal chemistry approaches and structure-activity relationship (SAR) studies, structural features required for the observed affinity were identified, and advanced molecules with favorable Multiparameter Optimization (MPO) and Ligand Lipophilicity (LLE) profiles were prepared. Using the Thermal Place Preference Test (TPPT), we have shown that compound2 blocks the antinociceptive effect of U50488, a known KOR agonist. Multiple reports suggest that modulation of KOR signaling is a promising therapeutic strategy in treating neuropathic pain (NP). As a …

The Role Of Native Cysteine Residues In The Oligomerization Of Kcnq1 Channels, Alison Bates, Rebecca B Stowe, Elizabeth M Travis, Lauryn E Cook, Carole Dabney-Smith, Gary A Lorigan

Faculty, Staff and Student Publications

KCNQ1, the major component of the slow-delayed rectifier potassium channel, is responsible for repolarization of cardiac action potential. Mutations in this channel can lead to a variety of diseases, most notably long QT syndrome. It is currently unknown how many of these mutations change channel function and structure on a molecular level. Since tetramerization is key to proper function and structure of the channel, it is likely that mutations modify the stability of KCNQ1 oligomers. Presently, the C-terminal domain of KCNQ1 has been noted as the driving force for oligomer formation. However, truncated versions of this protein lacking the C-terminal …

Utility Of Patient-Reported Symptom And Functional Outcomes To Indicate Recovery After First 90 Days Of Radical Cystectomy: A Longitudinal Study, Xin Shelley Wang, Kelly K Bree, Neema Navai, Mona Kamal, Shu-En Shen, Elizabeth Letona, Charles S Cleeland, Qiuling Shi, Vijaya Gottumukkala

Faculty, Staff and Student Publications

This is a longitudinal prospective study that tracked multiple symptom burden and functioning status for bladder cancer (BLC) patients for 3 months post-radical cystectomy at The University of Texas MD Anderson Cancer Center, using a validated disease-specific patient-reported outcome measure (PROM) tool, the MD Anderson Symptom Inventory (the MDASI-PeriOp-BLC). The feasibility of collecting an objective measure for physical functioning, using "Timed Up & Go test" (TUGT) and PRO scores at baseline, discharge and end of study, was tested. Patients (