Medical Genetics Commons^™

Neurobehavioral Deficits And A Progressive Ictogenesis In The Tetrodotoxin Model Of Epileptic Spasms, John T Le, Carlos J Ballester-Rosado, James D Frost, John W Swann

Duncan NRI Faculty and Staff Publications

Objective: Our goal was to determine whether animals with a history of epileptic spasms have learning and memory deficits. We also used continuous (24/7) long-term electroencephalographic (EEG) recordings to evaluate the evolution of epileptiform activity in the same animals over time.

Methods: Object recognition memory and object location memory tests were undertaken, as well as a matching to place water maze test that evaluated working memory. A retrospective analysis was undertaken of long-term video/EEG recordings from rats with epileptic spasms. The frequency and duration of the ictal events of spasms were quantified.

Results: Rats with a history of epileptic spasms …

A Phase I/Ii Trial Of Nivolumab Plus Ipilimumab In Children And Young Adults With Relapsed/Refractory Solid Tumors: A Children's Oncology Group Study Advl1412, Kara L Davis, Elizabeth Fox, Emasenyie Isikwei, Joel M Reid, Xiaowei Liu, Charles G Minard, Stephan Voss, Stacey L Berg, Brenda J Weigel, Crystal L Mackall

Faculty, Staff and Students Publications

PURPOSE: In many cancers, nivolumab in combination with ipilimumab improves response rates compared with either agent alone, but the combination has not been evaluated in childhood cancer. We conducted a phase I/II trial of nivolumab plus ipilimumab in children and young adults with recurrent/refractory solid tumors.

PATIENTS AND METHODS: ADVL1412, Part C assessed safety of nivolumab plus ipilimumab at two dose levels (DL): DL1 1 mg/kg of each drug and DL2 3 mg/kg nivolumab plus 1 mg/kg ipilimumab. Part D evaluated response at the recommended phase II dose (RP2D) in Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma. Part E tested DL3 (1 …

A Cloning-Free Recyclable System For Crispr-Cas9 Mediated Mutant And Reversion Construction In Candida Albicans Clinical Isolates, Amanda K. Vogel

Theses and Dissertations (ETD)

Candida albicans is a ubiquitous opportunistic fungal pathogen and one of the most prevalent causes of fungal diseases worldwide. The reference isolate SC5314 is one of the most widely used strains for both experimental and genetic studies, but it is becoming increasingly evident that genetic diversity in clinical isolates plays an important role in antifungal resistance, virulence, and pathogenicity. These recent discoveries highlight the need for genetic tools that are capable of investigating genes in multiple strain backgrounds. Here we build on the SAT1-flipper method and combine it with CRISPR-Cas9 technology to achieve cloning-free homozygous deletion in a single transformation …

Methods Development In Inflammatory Bowel Disease, Andrew B. Steimke

Theses and Dissertations (ETD)

Inflammatory bowel disease (IBD) is a disease that is classified into two subtypes: ulcerative colitis (UC) and Crohn’s disease (CD). Symptoms can range from mild discomfort to requiring surgical intervention and affects approximately 1-in-200 adults in America alone, with global incidence rates increasing. While many treatments exist for IBD, perhaps the main reason for the lack of a cure is that there are many different pathogeneses that all lead to a very similar expression of symptoms. Over 240 IBD loci have been identified to date, yet the causative allele that drives the association has only been identified in ~60 of …

Genetic Diversity Fuels Gene Discovery For Tobacco And Alcohol Use, Gretchen R B Saunders, Xingyan Wang, Fang Chen, Seon-Kyeong Jang, Mengzhen Liu, Chen Wang, Shuang Gao, Yu Jiang, Chachrit Khunsriraksakul, Jacqueline M Otto, Clifton Addison, Masato Akiyama, Christine M Albert, Fazil Aliev, Alvaro Alonso, Donna K Arnett, Allison E Ashley-Koch, Aneel A Ashrani, Kathleen C Barnes, R Graham Barr, Traci M Bartz, Diane M Becker, Lawrence F Bielak, Emelia J Benjamin, Joshua C Bis, Gyda Bjornsdottir, John Blangero, Eugene R Bleecker, Jason D Boardman, Eric Boerwinkle, Dorret I Boomsma, Meher Preethi Boorgula, Donald W Bowden, Jennifer A Brody, Brian E Cade, Daniel I Chasman, Sameer Chavan, Yii-Der Ida Chen, Zhengming Chen, Iona Cheng, Michael H Cho, Hélène Choquet, John W Cole, Marilyn C Cornelis, Francesco Cucca, Joanne E Curran, Mariza De Andrade, Danielle M Dick, Anna R Docherty, Ravindranath Duggirala, Charles B Eaton, Marissa A Ehringer, Tõnu Esko, Jessica D Faul, Lilian Fernandes Silva, Edoardo Fiorillo, Myriam Fornage, Barry I Freedman, Maiken E Gabrielsen, Melanie E Garrett, Sina A Gharib, Christian Gieger, Nathan Gillespie, David C Glahn, Scott D Gordon, Charles C Gu, Dongfeng Gu, Daniel F Gudbjartsson, Xiuqing Guo, Jeffrey Haessler, Michael E Hall, Toomas Haller, Kathleen Mullan Harris, Jiang He, Pamela Herd, John K Hewitt, Ian Hickie, Bertha Hidalgo, John E Hokanson, Christian Hopfer, Joukejan Hottenga, Lifang Hou, Hongyan Huang, Yi-Jen Hung, David J Hunter, Kristian Hveem, Shih-Jen Hwang, Chii-Min Hwu, William Iacono, Marguerite R Irvin, Yon Ho Jee, Eric O Johnson, Yoonjung Y Joo, Eric Jorgenson, Anne E Justice, Yoichiro Kamatani, Robert C Kaplan, Jaakko Kaprio, Sharon L R Kardia, Matthew C Keller, Tanika N Kelly, Charles Kooperberg, Tellervo Korhonen, Peter Kraft, Kenneth Krauter, Johanna Kuusisto, Markku Laakso, Jessica Lasky-Su, Wen-Jane Lee, James J Lee, Daniel Levy, Liming Li, Kevin Li, Yuqing Li, Kuang Lin, Penelope A Lind, Chunyu Liu, Donald M Lloyd-Jones, Sharon M Lutz, Jiantao Ma, Reedik Mägi, Ani Manichaikul, Nicholas G Martin, Ravi Mathur, Nana Matoba, Patrick F Mcardle, Matt Mcgue, Matthew B Mcqueen, Sarah E Medland, Andres Metspalu, Deborah A Meyers, Iona Y Millwood, Braxton D Mitchell, Karen L Mohlke, Matthew Moll, May E Montasser, Alanna C Morrison, Antonella Mulas, Jonas B Nielsen, Kari E North, Elizabeth C Oelsner, Yukinori Okada, Valeria Orrù, Nicholette D Palmer, Teemu Palviainen, Anita Pandit, S Lani Park, Ulrike Peters, Annette Peters, Patricia A Peyser, Tinca J C Polderman, Nicholas Rafaels, Susan Redline, Robert M Reed, Alex P Reiner, John P Rice, Stephen S Rich, Nicole E Richmond, Carol Roan, Jerome I Rotter, Michael N Rueschman, Valgerdur Runarsdottir, Nancy L Saccone, David A Schwartz, Aladdin H Shadyab, Jingchunzi Shi, Suyash S Shringarpure, Kamil Sicinski, Anne Heidi Skogholt, Jennifer A Smith, Nicholas L Smith, Nona Sotoodehnia, Michael C Stallings, Hreinn Stefansson, Kari Stefansson, Jerry A Stitzel, Xiao Sun, Moin Syed, Ruth Tal-Singer, Amy E Taylor, Kent D Taylor, Marilyn J Telen, Khanh K Thai, Hemant Tiwari, Constance Turman, Thorarinn Tyrfingsson, Tamara L Wall, Robin G Walters, David R Weir, Scott T Weiss, Wendy B White, John B Whitfield, Kerri L Wiggins, Gonneke Willemsen, Cristen J Willer, Bendik S Winsvold, Huichun Xu, Lisa R Yanek, Jie Yin, Kristin L Young, Kendra A Young, Bing Yu, Wei Zhao, Wei Zhou, Sebastian Zöllner, Luisa Zuccolo, 23andme Research Team, Biobank Japan Project, Chiara Batini, Andrew W Bergen, Laura J Bierut, Sean P David, Sarah A Gagliano Taliun, Dana B Hancock, Bibo Jiang, Marcus R Munafò, Thorgeir E Thorgeirsson, Dajiang J Liu, Scott Vrieze

Faculty, Staff and Student Publications

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1-4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power …

Direct Cd32 T-Cell Cytotoxicity: Implications For Breast Cancer Prognosis And Treatment, Giuseppe Sconocchia, Giulia Lanzilli, Valeriana Cesarini, Domenico A Silvestris, Katayoun Rezvani, Roberto Arriga, Sara Caratelli, Ken Chen, Jinzhuang Dou, Carlo Cenciarelli, Gabriele Toietta, Silvia Baldari, Tommaso Sconocchia, Francesca De Paolis, Anna Aureli, Giandomenica Iezzi, Maria Irno Consalvo, Francesco Buccisano, Maria I Del Principe, Luca Maurillo, Adriano Venditti, Alessio Ottaviani, Giulio C Spagnoli

Faculty, Staff and Student Publications

The FcγRII (CD32) ligands are IgFc fragments and pentraxins. The existence of additional ligands is unknown. We engineered T cells with human chimeric receptors resulting from the fusion between CD32 extracellular portion and transmembrane CD8α linked to CD28/ζ chain intracellular moiety (CD32-CR). Transduced T cells recognized three breast cancer (BC) and one colon cancer cell line among 15 tested in the absence of targeting antibodies. Sensitive BC cell conjugation with CD32-CR T cells induced CD32 polarization and down-regulation, CD107a release, mutual elimination, and proinflammatory cytokine production unaffected by human IgGs but enhanced by cetuximab. CD32-CR T cells protected immunodeficient mice …

Statistical Process Control To Monitor Use Of A Web-Based Autoplanning Tool, Hunter Mehrens, Raphael Douglas, Mary Gronberg, Kelly Nealon, Joy Zhang, Laurence Court

Faculty, Staff and Student Publications

PURPOSE: To investigate the use of statistical process control (SPC) for quality assurance of an integrated web-based autoplanning tool, Radiation Planning Assistant (RPA).

METHODS: Automatically generated plans were downloaded and imported into two treatment planning systems (TPSs), RayStation and Eclipse, in which they were recalculated using fixed monitor units. The recalculated plans were then uploaded back to the RPA, and the mean dose differences for each contour between the original RPA and the TPSs plans were calculated. SPC was used to characterize the RPA plans in terms of two comparisons: RayStation TPS versus RPA and Eclipse TPS versus RPA for …

Radiomics In Abdominopelvic Solid-Organ Oncologic Imaging: Current Status, Xiaoyang Liu, Mohamed G Elbanan, Antonio Luna, Masoom A Haider, Andrew D Smith, Carl F Sabottke, Bradley M Spieler, Baris Turkbey, David Fuentes, Ahmed Moawad, Serageldin Kamel, Natally Horvat, Khaled M Elsayes

Faculty, Staff and Student Publications

Radiomics is the process of extraction of high-throughput quantitative imaging features from medical images. These features represent noninvasive quantitative biomarkers that go beyond the traditional imaging features visible to the human eye. This article first reviews the steps of the radiomics pipeline, including image acquisition, ROI selection and image segmentation, image preprocessing, feature extraction, feature selection, and model development and application. Current evidence for the application of radiomics in abdominopelvic solid-organ cancers is then reviewed. Applications including diagnosis, subtype determination, treatment response assessment, and outcome prediction are explored within the context of hepatobiliary and pancreatic cancer, renal cell carcinoma, prostate …

Clinically Significant Metachronous Colorectal Pathology Detected Among Young-Onset Colorectal Cancer Survivors: Implications For Post-Resection Surveillance Guidelines, Oliver Peacock, Eduardo Vilar, Montserrat Guraieb-Trueba, Selvi Thirumurthi, George J Chang, Y Nancy You

Faculty, Staff and Student Publications

No abstract provided.

Utility Of Measurable Residual Disease For Predicting Treatment Outcomes With Bcr- And Bcl2-Targeted Therapies In Patients With Cll, William G Wierda, Thomas J Kipps, Othman Al-Sawaf, Brenda Chyla, Juliana M L Biondo, Yong Mun, Yanwen Jiang, John F Seymour

Faculty, Staff and Student Publications

Inhibitors targeting B-cell receptor (BCR) signaling pathway proteins and B-cell lymphoma-2 (BCL2) in chronic lymphocytic leukemia (CLL) are recommended in the first-line and relapsed/refractory disease settings. Measurable residual disease (MRD) is an important prognostic tool in patients treated with the BCL2-targeted agent, venetoclax. We explored the relationship between MRD status and progression-free (PFS)/overall survival (OS) in patients with CLL, following treatment with novel BCR- and BCL2-targeted agents. Compared with chemoimmunotherapy, higher rates of undetectable (u)MRD were achieved with BCL2-targeted therapies; achieving uMRD status was associated with longer PFS and OS than MRD-positivity. Continuous treatment with BCR-targeted agents did not achieve …

Implications Of Ras Mutational Status In Subsets Of Patients With Newly Diagnosed Acute Myeloid Leukemia Across Therapy Subtypes, Daniel Rivera, Kunhwa Kim, Rashmi Kanagal-Shamanna, Gautam Borthakur, Guillermo Montalban-Bravo, Naval Daver, Courtney Dinardo, Nicholas J Short, Musa Yilmaz, Naveen Pemmaraju, Koichi Takahashi, Elias J Jabbour, Sherry Pierce, Marina Konopleva, Kapil Bhalla, Guillermo Garcia-Manero, Farhad Ravandi, Hagop Kantarjian, Tapan M Kadia

Faculty, Staff and Student Publications

Activating mutations in RAS have been reported in about 10-15% of patients with AML; previous studies have not identified a prognostic significance. However, RAS mutations have emerged as a potential resistance mechanism to treatment with inhibitors of FLT3, IDH, and BCL2. We aimed to determine the characteristics and outcomes of patients with RAS-mutated (RAS-mut) AML across therapy subsets of 1410 patients newly diagnosed (ND AML). RAS-mut was observed in 273 (20%) patients. Overall, patients with RAS-mut AML had an estimated 3-year survival rate of 38% vs. 28% in those with RAS wild type (RAS-wt), p = .01. Among patients with …

Pet/Mr Imaging Of A Lung Metastasis Model Of Clear Cell Renal Cell Carcinoma With (2s,4r)-4-[18f]Fluoroglutamine, Alyssa C Pollard, Vincenzo Paolillo, Bhasker Radaram, Sarah Qureshy, Li Li, Tapati Maity, Lei Wang, Md Nasir Uddin, Christopher G Wood, Jose A Karam, Mark D Pagel, David Piwnica-Worms, Steven W Millward, Natalie Wall Fowlkes, William Norton, Brian J Engel, Federica Pisaneschi, Niki M Zacharias

Faculty, Staff and Student Publications

Purpose: Metabolic reprogramming plays an important role in the tumorigenesis of clear cell renal cell carcinoma (ccRCC). Currently, positron emission tomography (PET) reporters are not used clinically to visualize altered glutamine metabolism in ccRCC, which greatly hinders detection, staging, and real-time therapeutic assessment. We sought to determine if (2S,4R)-4-[18F]fluoroglutamine ([18F]FGln) could be used to interrogate altered glutamine metabolism in ccRCC lesions in the lung.

Procedures: We generated a novel ccRCC lung lesion model using the ccRCC cell line UMRC3 stably transfected with GFP and luciferase constructs. This cell line was used for characterization of [18F]FGln uptake and retention by transport …

Genetic Landscape Of Indolent And Aggressive Kaposi Sarcomas, G G Malouf, X Lu, R Mouawad, J-P Spano, P Grange, F Yan, S Aractingi, X Su, N Dupin

Faculty, Staff and Student Publications

Background: Kaposi sarcoma (KS) is a rare skin tumour caused by herpesvirus 8 infection and characterized by either indolence or an aggressive course necessitating systemic therapies. The genetic basis of this difference remains unknown.

Objectives: To explore the tumour mutational burden in indolent and aggressive KS.

Methods: We performed whole-exome sequencing on a cohort of 21 KS patients. We compared genetic landscape including tumor mutational burden between the two forms of indolent and agressive KS.

Results: Aggressive KS tumours had a significantly higher TMB and a larger cumulative number of deleterious mutations than indolent KS tumours. In addition, all aggressive …

A Phase Ii Randomized Double Blinded Trial Evaluating The Efficacy Of Curcumin With Pre-Operative Chemoradiation For Rectal Cancer, Jillian R Gunther, Awalpreet S Chadha, Sushovan Guha, Gottumukkala S Raju, Dipen M Maru, Mark F Munsell, Yan Jiang, Peiying Yang, Edd Felix, Marilyn Clemons, Geena George Mathew, Pankaj K Singh, John M Skibber, Miguel A Rodriguez-Bigas, George J Chang, Cathy Eng, Marc E Delclos, Christopher H Crane, Prajnan Das, Sunil Krishnan

Faculty, Staff and Student Publications

Background: In vivo studies demonstrate that curcumin increases radioresponse of colorectal cancers. To demonstrate efficacy in humans, we performed a randomized double-blind study of locally advanced rectal cancer (LARC) patients receiving pre-operative chemoradiation therapy (CRT) ± curcumin. We used pathologic complete response (pCR) rate as a surrogate for clinical outcome.

Methods: From 2008-2010, LARC patients were randomized to placebo/curcumin in a 1:2 ratio. Patients received CRT [50.4 gray in 28 fractions; capecitabine (825 mg/m2 twice daily)] followed by surgery. Curcumin (4 grams orally, twice daily) or placebo was given throughout CRT and 6 weeks afterward. Toxicity was monitored weekly. Blood …

Lymphocyte Sparing Normal Tissue Effects In The Clinic (Lymphotec): A Systematic Review Of Dose Constraint Considerations To Mitigate Radiation-Related Lymphopenia In The Era Of Immunotherapy, Bhanuprasad Venkatesulu, Prashanth Giridhar, Lincoln Pujari, Brian Chou, Jae Han Lee, Alec M Block, Rituraj Upadhyay, James S Welsh, Matthew M Harkenrider, Sunil Krishnan, Vivek Verma, Cheng En Hsieh, Satyajit Pradhan, William Small, Abhishek A Solanki

Faculty, Staff and Student Publications

Background: Radiation-related lymphopenia has been associated with suboptimal tumor control rates leading to inferior survival outcomes. To date, no standardized dose constraints are available to limit radiation dose to resident and circulating lymphocyte populations. We undertook this systemic review of the literature to provide a synopsis of the dosimetric predictors of radiation-related lymphopenia in solid malignancies.

Methodology: A systematic literature review of PubMed (National Institutes of Health), Cochrane Central (Cochrane collaboration), and Google Scholar was conducted with the following keywords: "radiation", "lymphopenia", "cancer", "dosimetric predictors" with an inclusion deadline of May 31, 2022. Studies that met prespecified inclusion criteria were …

Monitoring Pd-L1 Expression On Circulating Tumor-Associated Cells In Recurrent Metastatic Non-Small-Cell Lung Carcinoma Predicts Response To Immunotherapy With Radiation Therapy, Jillian A Moran, Daniel L Adams, Martin J Edelman, Pablo Lopez, Jianzhong He, Yawei Qiao, Ting Xu, Zhongxing Liao, Kirby P Gardner, Cha-Mei Tang, Steven H Lin

Faculty, Staff and Student Publications

Purpose: Current diagnostic methods to determine programmed death 1 (PD-1) receptor and its ligand (PD-L1)/PD-1 immunotherapy (immune checkpoint inhibitor [ICI]) efficacy in recurrent or metastatic non-small-cell lung carcinoma (rmNSCLC) are imprecise. Although previously shown that patients with high tumor PD-L1 (≥ 50%) demonstrate clinical benefit in the form of disease reduction and improved survival, patients with low PD-L1 (< 50%) sometimes benefit from treatment. Since the PD-L1/PD-1 pathway is dynamic, monitoring PD-L1 levels during treatment may be more accurate than a static baseline tumor biopsy; however, rebiopsying the primary or metastatic disease is rarely feasible. Liquid biopsies that measure the upregulation of PD-L1 on tumor-associated cells (TACs), ie, cancer-associated macrophage-like cells and circulating tumor cells, have been performed, but their predictive value for ICI therapy efficacy is unknown.

Materials and methods: We initiated a single-blind prospective study to evaluate TAC PD-L1 expression changes in rmNSCLC from blood samples before (T0) and after (T1) treatment with ICI (ICI, n = 41) or without ICI (no ICI, n = 41). Anonymized …

Tertiary Lymphoid Structure Signatures Are Associated With Immune Checkpoint Inhibitor Related Acute Interstitial Nephritis, Shailbala Singh, James P Long, Amanda Tchakarov, Yanlan Dong, Cassian Yee, Jamie S Lin

Faculty, Staff and Student Publications

Tertiary lymphoid structures (TLSs) are associated with anti-tumor response following immune checkpoint inhibitor (ICI) therapy, but a commensurate observation of TLS is absent for immune related adverse events (irAEs) i.e. acute interstitial nephritis (AIN). We hypothesized that TLS-associated inflammatory gene signatures are present in AIN and performed NanoString-based gene expression and multiplex 12-chemokine profiling on paired kidney tissue, urine and plasma specimens of 36 participants who developed acute kidney injury (AKI) on ICI therapy: AIN (18), acute tubular necrosis (9), or HTN nephrosclerosis (9). Increased T and B cell scores, a Th1-CD8+ T cell axis accompanied by interferon-g and TNF …

Cerebrovascular Reactivity Mapping Using Resting-State Functional Mri In Patients With Gliomas, Mei-Yu Yeh, Henry S Chen, Ping Hou, Vinodh A Kumar, Jason M Johnson, Kyle R Noll, Sujit S Prabhu, Sherise D Ferguson, Donald F Schomer, Hsu-Hsia Peng, Ho-Ling Liu

Faculty, Staff and Student Publications

Background: Recently, a data-driven regression analysis method was developed to utilize the resting-state (rs) blood oxygenation level-dependent signal for cerebrovascular reactivity (CVR) mapping (rs-CVR), which was previously optimized by comparing with the CO2 inhalation-based method in health subjects and patients with neurovascular diseases.

Purpose: To investigate the agreement of rs-CVR and the CVR mapping with breath-hold MRI (bh-CVR) in patients with gliomas.

Study type: Retrospective.

Population: Twenty-five patients (12 males, 13 females; mean age ± SD, 48 ± 13 years) with gliomas.

Field strength/sequence: Dynamic T2*-weighted gradient-echo echo-planar imaging during a breath-hold paradigm and during the rs on a 3-T …

Allergic Fungal Rhinosinusitis: The Role And Expectations Of Biologics, Amber U Luong, Andy Chua, Bader M Alim, Petter Olsson, Amin Javer

Faculty, Staff and Student Publications

Allergic fungal rhinosinusitis (AFRS) is a noninvasive subtype of chronic rhinosinusitis with nasal polyps (CRSwNP) that usually develops in immunocompetent atopic individuals and is more common in geographic regions characterized by warm temperatures and high humidity, conducive to higher environmental fungal presence. Allergic fungal rhinosinusitis usually presents with unique computed tomography findings and significant polyp burden, yet patients often report minimal sinus symptoms. Patients with AFRS often have extremely elevated serum total and fungal-specific IgE levels. Treatment almost always requires surgery, in which adjuvant medical therapy is critical to success. However, until recently the choice of adjuvant therapy has consisted …

Airway Mucus Dysfunction In Covid-19, Burton F Dickey, Jichao Chen, R Stokes Peebles

Faculty, Staff and Student Publications

No abstract provided.

The Circadian Nobiletin-Ror Axis Suppresses Adipogenic Differentiation And Iκbα/Nf-Κb Signaling In Adipocytes, Ji Ye Lim, Eunju Kim, Collin M Douglas, Marvin Wirianto, Chorong Han, Kaori Ono, Sun Young Kim, Justin H Ji, Celia K Tran, Zheng Chen, Karyn A Esser, Seung-Hee Yoo

Faculty, Staff and Student Publications

Numerous molecular and physiological processes in the skeletal muscle undergo circadian time-dependent oscillations in accordance with daily activity/rest cycles. The circadian regulatory mechanisms underlying these cyclic processes, especially at the post-transcriptional level, are not well defined. Previously, we reported that the circadian E3 ligase FBXL21 mediates rhythmic degradation of the sarcomere protein TCAP in conjunction with GSK-3β, and Psttm mice harboring an Fbxl21 hypomorph allele show reduced muscle fiber diameter and impaired muscle function. To further elucidate the regulatory function of FBXL21 in skeletal muscle, we investigated another sarcomere protein, Myozenin1 (MYOZ1), that we identified as an FBXL21-binding protein from …

Bcl11b And Atoh8 Coordinate Cellular Plasticity For Reprogramming And Transformation, Mo-Fan Huang, Rachel Shoemaker, Dung-Fang Lee

Faculty, Staff and Student Publications

By dissecting and comparing the transcriptional trajectories and epigenomic traits of reprogramming and transforming cells at the single-cell resolution, Huyghe et al discovered Bcl11b and Atoh8, two key transcription factors controlling cell plasticity during pluripotent reprogramming and oncogenic transformation.

Prognostic Impact Of Breslow Thickness In Acral Melanoma: A Retrospective Analysis, Xiaoting Wei, Yu Chen, Hong Yao, Di Wu, Hang Li, Rui Zhang, Zhihong Chi, Chuanliang Cui, Xue Bai, Lili Mao, Zhonghui Qi, Ke Li, Shijie Lan, Lizhu Chen, Rui Guo, Xinyu Yao, Bin Lian, Yan Kong, Jie Dai, Bixia Tang, Xuan Wang, Jeffrey E Gershenwald, Charles M Balch, Jun Guo, Lu Si

Faculty, Staff and Student Publications

Background: Evidence for the prognostic importance of tumor thickness in acral melanoma (AM) patients is limited.

Objective: The objective of the study was to determine the prognostic impact of Breslow thickness in AM.

Methods: This multicenter study enrolled patients diagnosed with localized AM between January 1, 2000 and December 31, 2017. Melanoma-specific survival (MSS) in different tumor thickness strata (T1-T4: ≤1, >1-2, >2-4, >4 mm, respectively) was estimated by the Kaplan-Meier method. Comparisons were performed by the log-rank test and multivariable Cox regression.

Results: A total of 853 patients with clinical N0 (cN0) AM were included in the analysis. The …

Factors Modulating 99mtc-Maa Planar Lung Dosimetry For 90y Radioembolization, Benjamin P Lopez, Armeen Mahvash, James P Long, Marnix G E H Lam, S Cheenu Kappadath

Faculty, Staff and Student Publications

Purpose: To investigate the accuracy and biases of predicted lung shunt fraction (LSF) and lung dose (LD) calculations via 99m Tc-macro-aggregated albumin (99m Tc-MAA) planar imaging for treatment planning of 90 Y-microsphere radioembolization.

Methods and materials: LSFs in 52 planning and LDs in 44 treatment procedures were retrospectively calculated, in consecutive radioembolization patients over a 2 year interval, using 99m Tc-MAA planar and SPECT/CT imaging. For each procedure, multiple planar LSFs and LDs were calculated using different: (1) contours, (2) views, (3) liver 99m Tc-MAA shine-through compensations, and (4) lung mass estimations. The accuracy of each planar-based LSF and LD …

Bayesian Hierarchical Random-Effects Meta-Analysis And Design Of Phase I Clinical Trials, Ruitao Lin, Haolun Shi, Guosheng Yin, Peter F Thall, Ying Yuan, Christopher R Flowers

Faculty, Staff and Student Publications

We propose a curve-free random-effects meta-analysis approach to combining data from multiple phase I clinical trials to identify an optimal dose. Our method accounts for between-study heterogeneity that may stem from different study designs, patient populations, or tumor types. We also develop a meta-analytic-predictive (MAP) method based on a power prior that incorporates data from multiple historical studies into the design and conduct of a new phase I trial. Performances of the proposed methods for data analysis and trial design are evaluated by extensive simulation studies. The proposed random-effects meta-analysis method provides more reliable dose selection than comparators that rely …

Identity-Related Experiences Of Asian American Trainees In Gynecologic Oncology, Jhalak Dholakia, Yeon Woo Lee, Karen H Lu, Warner K Huh, S Diane Yamada, Katherine C Fuh, Amanika S Kumar, Margaret I Liang, Navya Nair, Kenneth H Kim

Faculty, Staff and Student Publications

Background: Anti-Asian violence increased during the COVID-19 pandemic. Asian American/Pacific Islanders (AAPI) represent a diverse population experiencing a long history of stereotyping and exclusionism; however, this group is often left out of diversity/inclusion conversations. In academic medicine, AAPI are under-represented in leadership. We characterized the personal/professional experiences of AAPI gynecologic oncology trainees and assessed the impact of a virtual panel discussion with leaders in the field.

Methods: An anonymous survey was disseminated online to trainees in/interested in gynecologic oncology fellowship who identified as AAPI, using modified snowball sampling. A virtual session with AAPI leaders in gynecologic oncology discussed themes emerging …

Development Of A Distributed International Patient Data Registry For Hairy Cell Leukemia, Leslie A Andritsos, Mirela Anghelina, Jasmine Neal, James S Blachly, Puneet Mathur, Omkar Lele, Claire Dearden, Sunil Iyengar, Matthew Cross, Clive S Zent, Kerry A Rogers, Narendranath Epperla, Gerard Lozanski, Christopher C Oakes, Eric Kraut, Amy S Ruppert, Qiuhong Zhao, Seema A Bhat, Francesco Forconi, Versha Banerji, Sasanka Handunnetti, Constantine S Tam, John F Seymour, Monica Else, Robert J Kreitman, Alan Saven, Timothy Call, Sameer A Parikh, Farhad Ravandi, James B Johnston, Enrico Tiacci, Xavier Troussard, Martin S Tallman, Sascha Dietrich, Tamar Tadmor, Alessandro Gozzetti, Pier Luigi Zinzani, Tadeusz Robak, Graeme Quest, Judit Demeter, Kanti Rai, Soledad A Fernandez, Michael Grever

Faculty, Staff and Student Publications

Hairy cell leukemia (HCL) is a rare lymphoproliferative disorder, comprising only 2% of all leukemias. The Hairy Cell Leukemia Foundation (HCLF) has developed a patient data registry to enable investigators to better study the clinical features, treatment outcomes, and complications of patients with HCL. This system utilizes a centralized registry architecture. Patients are enrolled at HCL Centers of Excellence (COE) or via a web-based portal. All data are de-identified, which reduces regulatory burden and increases opportunities for data access and re-use. To date, 579 patients have been enrolled in the registry. Efforts are underway to engage additional COE's to expand …

Neoadjuvant Chemo-Immunotherapy For Lung Cancer: How Much Is Too Much?, Nathaniel Deboever, Jianjun Zhang

Faculty, Staff and Student Publications

No abstract provided.

Long Read Sequencing And Expression Studies Of Ahdc1 Deletions In Xia-Gibbs Syndrome Reveal A Novel Genetic Regulatory Mechanism, Varuna Chander, Medhat Mahmoud, Jianhong Hu, Zain Dardas, Christopher M Grochowski, Moez Dawood, Michael M Khayat, He Li, Shoudong Li, Shalini Jhangiani, Viktoriya Korchina, Hua Shen, George Weissenberger, Qingchang Meng, Marie-Claude Gingras, Donna M Muzny, Harsha Doddapaneni, Jennifer E Posey, James R Lupski, Aniko Sabo, David R Murdock, Fritz J Sedlazeck, Richard A Gibbs

Faculty, Staff and Students Publications

Xia-Gibbs syndrome (XGS; MIM# 615829) is a rare mendelian disorder characterized by Development Delay (DD), intellectual disability (ID), and hypotonia. Individuals with XGS typically harbor de novo protein-truncating mutations in the AT-Hook DNA binding motif containing 1 (AHDC1) gene, although some missense mutations can also cause XGS. Large de novo heterozygous deletions that encompass the AHDC1 gene have also been ascribed as diagnostic for the disorder, without substantial evidence to support their pathogenicity. We analyzed 19 individuals with large contiguous deletions involving AHDC1, along with other genes. One individual bore the smallest known contiguous AHDC1 deletion (∼350 Kb), encompassing eight …

Tceal1 Loss-Of-Function Results In An X-Linked Dominant Neurodevelopmental Syndrome And Drives The Neurological Disease Trait In Xq222 Deletions, Hadia Hijazi, Linda M Reis, Davut Pehlivan, Jonathan A Bernstein, Michael Muriello, Erin Syverson, Devon Bonner, Mehrdad A Estiar, Ziv Gan-Or, Guy A Rouleau, Ekaterina Lyulcheva, Lynn Greenhalgh, Marine Tessarech, Estelle Colin, Agnès Guichet, Dominique Bonneau, R H Van Jaarsveld, A M A Lachmeijer, Lyse Ruaud, Jonathan Levy, Anne-Claude Tabet, Rafal Ploski, Małgorzata Rydzanicz, Łukasz Kępczyński, Katarzyna Połatyńska, Yidan Li, Jawid M Fatih, Dana Marafi, Jill A Rosenfeld, Zeynep Coban-Akdemir, Weimin Bi, Richard A Gibbs, Grace M Hobson, Jill V Hunter, Claudia M B Carvalho, Jennifer E Posey, Elena V Semina, James R Lupski

Faculty, Staff and Student Publications

An Xq22.2 region upstream of PLP1 has been proposed to underly a neurological disease trait when deleted in 46,XX females. Deletion mapping revealed that heterozygous deletions encompassing the smallest region of overlap (SRO) spanning six Xq22.2 genes (BEX3, RAB40A, TCEAL4, TCEAL3, TCEAL1, and MORF4L2) associate with an early-onset neurological disease trait (EONDT) consisting of hypotonia, intellectual disability, neurobehavioral abnormalities, and dysmorphic facial features. None of the genes within the SRO have been associated with monogenic disease in OMIM. Through local and international collaborations facilitated by GeneMatcher and Matchmaker Exchange, we have identified and herein report seven de novo variants involving …