Digital Commons Network^™

Delayed-Interval Delivery In Multiple Gestation Pregnancies: Neonatal Mortality, Morbidity, And Development, Nicolas J Bouey, Shampa Saha, Deanne E Wilson-Costello, Matthew A Rysavy, Michele Walsh, Myra H Wyckoff, Anna Maria Hibbs

Faculty, Staff and Student Publications

OBJECTIVE: Delayed-interval delivery (DID) is the delivery of the first fetus in a multiple gestation pregnancy without prompt delivery of the remaining fetus(es). We aimed to assess infant outcomes of DID.

STUDY DESIGN: We performed a retrospective cohort study of infants born 22-28 weeks' gestation or weighing 401-1500 g. DID was defined as a passage of >24 h between the birth of firstborn and retained infants. Rates of mortality, morbidity, and developmental outcomes were compared within DID multiples, to other multiples not born by DID, and all infants in the Generic Database and follow-up datasets (excluding DID-born).

RESULTS: DID-born multiples …

Association Of Apremilast With Vascular Inflammation And Cardiometabolic Function In Patients With Psoriasis: The Vip-A Phase 4, Open-Label, Nonrandomized Clinical Trial, Joel M Gelfand, Daniel B Shin, April W Armstrong, Stephen K Tyring, Andrew Blauvelt, Scott Gottlieb, Benjamin N Lockshin, Robert E Kalb, Robert Fitzsimmons, Justin Rodante, Philip Parel, Grigory A Manyak, Laurel Mendelsohn, Megan H Noe, Maryte Papadopoulos, Maha N Syed, Thomas J Werner, Joy Wan, Martin P Playford, Abass Alavi, Nehal N Mehta

Faculty, Staff and Student Publications

IMPORTANCE: Psoriasis is an inflammatory condition associated with metabolic and cardiovascular disease. Apremilast, a phosphodiesterase 4 inhibitor, is commonly used for psoriasis and can cause weight loss.

OBJECTIVE: To determine the association between apremilast and aortic vascular inflammation as assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), cardiometabolic markers (primary outcomes at week 16), and abdominal fat composition.

DESIGN, SETTING, AND PARTICIPANTS: A single-arm, open-label, interventional, nonrandomized clinical trial in which the imaging and laboratory outcomes were measured by an investigator who was blinded to time was conducted between April 11, 2017, and August 17, 2021, at 7 dermatology sites …

Consensus Subtypes Of Hepatocellular Carcinoma Associated With Clinical Outcomes And Genomic Phenotypes, Sung Hwan Lee, Sun Young Yim, Yun Seong Jeong, Qi-Xiang Li, Sang-Hee Kang, Bo Hwa Sohn, Shwetha V Kumar, Ji-Hyun Shin, You Rhee Choi, Jae-Jun Shim, Hayeon Kim, Ji Hoon Kim, Shin Kim, Sheng Guo, Randy L Johnson, Ahmed Kaseb, Koo Jeong Kang, Yun Shin Chun, Hee Jin Jang, Byoung Gill Lee, Hyun Goo Woo, Min Jin Ha, Rehan Akbani, Lewis R Roberts, David A Wheeler, Ju-Seog Lee

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: Although many studies revealed transcriptomic subtypes of HCC, concordance of the subtypes are not fully examined. We aim to examine a consensus of transcriptomic subtypes and correlate them with clinical outcomes.

APPROACH AND RESULTS: By integrating 16 previously established genomic signatures for HCC subtypes, we identified five clinically and molecularly distinct consensus subtypes. STM (STeM) is characterized by high stem cell features, vascular invasion, and poor prognosis. CIN (Chromosomal INstability) has moderate stem cell features, but high genomic instability and low immune activity. IMH (IMmune High) is characterized by high immune activity. BCM (Beta-Catenin with high Male …

Quantitative Apparent Diffusion Coefficients From Peritumoral Regions As Early Predictors Of Response To Neoadjuvant Systemic Therapy In Triple-Negative Breast Cancer, Benjamin C Musall, Beatriz E Adrada, Rosalind P Candelaria, Rania M M Mohamed, Abeer H Abdelhafez, Jong Bum Son, Jia Sun, Lumarie Santiago, Gary J Whitman, Tanya W Moseley, Marion E Scoggins, Hagar S Mahmoud, Jason B White, Ken-Pin Hwang, Nabil A Elshafeey, Medine Boge, Shu Zhang, Jennifer K Litton, Vicente Valero, Debu Tripathy, Alastair M Thompson, Clinton Yam, Peng Wei, Stacy L Moulder, Mark D Pagel, Wei T Yang, Jingfei Ma, Gaiane M Rauch

Faculty, Staff and Student Publications

BACKGROUND: Pathologic complete response (pCR) to neoadjuvant systemic therapy (NAST) in triple-negative breast cancer (TNBC) is a strong predictor of patient survival. Edema in the peritumoral region (PTR) has been reported to be a negative prognostic factor in TNBC.

PURPOSE: To determine whether quantitative apparent diffusion coefficient (ADC) features from PTRs on reduced field-of-view (rFOV) diffusion-weighted imaging (DWI) predict the response to NAST in TNBC.

STUDY TYPE: Prospective.

POPULATION/SUBJECTS: A total of 108 patients with biopsy-proven TNBC who underwent NAST and definitive surgery during 2015-2020.

FIELD STRENGTH/SEQUENCE: A 3.0 T/rFOV single-shot diffusion-weighted echo-planar imaging sequence (DWI).

ASSESSMENT: Three scans were …

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 …

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 …

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 …

Growth Parameters In Children With Achondroplasia: A 7-Year, Prospective, Multinational, Observational Study, Ravi Savarirayan, Melita Irving, Paul Harmatz, Borja Delgado, William R Wilcox, John Philips, Natalie Owen, Carlos A Bacino, Louise Tofts, Joel Charrow, Lynda E Polgreen, Julie Hoover-Fong, Paul Arundel, Ignacio Ginebreda, Howard M Saal, Donald Basel, Rosendo Ullot Font, Keiichi Ozono, Michael B Bober, Valerie Cormier-Daire, Kim-Hanh Le Quan Sang, Genevieve Baujat, Yasemin Alanay, Frank Rutsch, Daniel Hoernschemeyer, Klaus Mohnike, Hiroshi Mochizuki, Asako Tajima, Yumiko Kotani, David D Weaver, Klane K White, Clare Army, Kevin Larrimore, Keith Gregg, George Jeha, Claire Milligan, Elena Fisheleva, Alice Huntsman-Labed, Jonathan Day

Faculty, Staff and Students Publications

Purpose: This study was undertaken to collect baseline growth parameters in children with achondroplasia who might enroll in interventional trials of vosoritide, and to establish a historical control.

Methods: In this prospective, observational study, participants (≤17 years) underwent a detailed medical history and physical examination and were followed every 3 months until they finished participating in the study by enrolling in an interventional trial or withdrawing.

Results: A total of 363 children were enrolled (28 centers, 8 countries). Mean (SD) follow up was 20.4 (15.0) months. In participants < 1 year, mean annualized growth velocity (AGV) was 11.6 cm/year for girls and 14.6 cm/year for boys. By age 1 year, mean AGV decreased to 7.4 cm/year in girls and 7.1 cm/year in boys. By age 10 years, mean AGV decreased to 3.6 cm/year for both sexes. Mean height z-score in participants < 1 year was -2.5 for girls and -3.2 for boys and decreased up to the age 5 years (-5.3 for girls; -4.6 for boys). Girls and boys had a disproportionate upper-to-lower body segment ratio. Mean ratio was highest in participants aged < 1 year (2.9 for girls; 2.8 for boys) and decreased gradually to approximately 2 in both sexes from 4 years of age onward.

Conclusion: This study represents one of the largest datasets of prospectively collected …

Diptoindonesin G Is A Middle Domain Hsp90 Modulator For Cancer Treatment, Kristine Donahue, Haibo Xie, Miyang Li, Ang Gao, Min Ma, Yidan Wang, Rose Tipton, Nicole Semanik, Tina Primeau, Shunqiang Li, Lingjun Li, Weiping Tang, Wei Xu

2020-Current year OA Pubs

HSP90 inhibitors can target many oncoproteins simultaneously, but none have made it through clinical trials due to dose-limiting toxicity and induction of heat shock response, leading to clinical resistance. We identified diptoindonesin G (dip G) as an HSP90 modulator that can promote degradation of HSP90 clients by binding to the middle domain of HSP90 (K

Transferability Of Alzheimer Disease Polygenic Risk Score Across Populations And Its Association With Alzheimer Disease-Related Phenotypes, Sang-Hyuk Jung, Carlos Cruchaga, Et Al.

2020-Current year OA Pubs

IMPORTANCE: Polygenic risk scores (PRSs), which aggregate the genetic effects of single-nucleotide variants identified in genome-wide association studies (GWASs), can help distinguish individuals at a high genetic risk for Alzheimer disease (AD). However, genetic studies have predominantly focused on populations of European ancestry.

OBJECTIVE: To evaluate the transferability of a PRS for AD in the Korean population using summary statistics from a prior GWAS of European populations.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study developed a PRS based on the summary statistics of a large-scale GWAS of a European population (the International Genomics of Alzheimer Project; 21 982 AD cases …

Loss Of Wnt4 In The Gubernaculum Causes Unilateral Cryptorchidism And Fertility Defects, Abhishek Seth, Juan C Bournat, Olga Medina-Martinez, Armando Rivera, Joshua Moore, Hunter Flores, Jill A Rosenfeld, Liya Hu, Carolina J Jorgez

Faculty, Staff and Students Publications

Undescended testis (UDT) affects 6% of male births. Despite surgical correction, some men with unilateral UDT may experience infertility with the contralateral descended testis (CDT) showing no A-dark spermatogonia. To improve our understanding of the etiology of infertility in UDT, we generated a novel murine model of left unilateral UDT. Gubernaculum-specific Wnt4 knockout (KO) mice (Wnt4-cKO) were generated using retinoic acid receptor β2-cre mice and were found to have a smaller left-unilateral UDT. Wnt4-cKO mice with abdominal UDT had an increase in serum follicle-stimulating hormone and luteinizing hormone and an absence of germ cells in the undescended testicle. Wnt4-cKO mice …

Targeting The Mtor Pathway For The Prevention Of Er-Negative Breast Cancer, Abhijit Mazumdar, William M Tahaney, Jamal L Hill, Yun Zhang, Sumankalai Ramachandran, Jitesh Kawedia, Jing Qian, Alejandro Contreras, Michelle I Savage, Lana A Vornik, Shizuko Sei, Altaf Mohammed, Powel H Brown

Faculty, Staff and Student Publications

Our results show that everolimus delays mammary tumor formation in multiple mouse models, suggesting that mTOR inhibitors will be useful for the prevention of ER-negative and triple-negative breast cancer in humans. See related Spotlight, p. 787.

Lifespan Benefits For The Combination Of Rapamycin Plus Acarbose And For Captopril In Genetically Heterogeneous Mice, Randy Strong, Kerry Kornfeld, Et Al.

2020-Current year OA Pubs

Mice bred in 2017 and entered into the C2017 cohort were tested for possible lifespan benefits of (R/S)-1,3-butanediol (BD), captopril (Capt), leucine (Leu), the Nrf2-activating botanical mixture PB125, sulindac, syringaresinol, or the combination of rapamycin and acarbose started at 9 or 16 months of age (RaAc9, RaAc16). In male mice, the combination of Rapa and Aca started at 9 months and led to a longer lifespan than in either of the two prior cohorts of mice treated with Rapa only, suggesting that this drug combination was more potent than either of its components used alone. In females, lifespan in mice …

Wide Range Of Phenotypic Severity In Individuals With Late Truncations Unique To The Predominant Cdkl5 Transcript In The Brain, Laura Keehan, Isabel Haviland, Yoel Gofin, Lindsay C Swanson, Christelle Moufawad El Achkar, John Schreiber, Grace E Vannoy, Emily O'Heir, Anne O'Donnell-Luria, Richard Alan Lewis, Pilar Magoulas, Alyssa Tran, Mahshid S Azamian, Hsiao-Tuan Chao, Lisa Pham, Rodney C Samaco, Sarah Elsea, Erin Thorpe, Akanchha Kesari, Denise Perry, Brendan Lee, Seema R Lalani, Jill A Rosenfeld, Heather E Olson, Lindsay C Burrage

Faculty, Staff and Students Publications

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is caused by heterozygous or hemizygous variants in CDKL5 and is characterized by refractory epilepsy, cognitive and motor impairments, and cerebral visual impairment. CDKL5 has multiple transcripts, of which the longest transcripts, NM_003159 and NM_001037343, have been used historically in clinical laboratory testing. However, the transcript NM_001323289 is the most highly expressed in brain and contains 170 nucleotides at the 3' end of its last exon that are noncoding in other transcripts. Two truncating variants in this region have been reported in association with a CDD phenotype. To clarify the significance and range …

Identification Of Patients With Ovarian Cancer Experiencing The Highest Benefit From Bevacizumab In The First-Line Setting On The Basis Of Their Tumor-Intrinsic Chemosensitivity (Kelim): The Gog-0218 Validation Study, Benoit You, David Mutch, Et Al.

2020-Current year OA Pubs

PURPOSE: In patients with high-grade ovarian cancer, predictors of bevacizumab efficacy in first-line setting are needed. In the ICON-7 trial, a poor tumor intrinsic chemosensitivity (defined by unfavorable modeled cancer antigen-125 [CA-125] ELIMination rate constant K [KELIM] score) was a predictive biomarker. Only the patients with high-risk disease (suboptimally resected stage III, or stage IV) exhibiting unfavorable KELIM score < 1.0 had overall survival (OS) benefit from bevacizumab (median: 29.7

METHODS: In GOG-0218, 1,873 patients were treated with carboplatin-paclitaxel ± concurrent-maintenance bevacizumab/placebo. Patient KELIM values were calculated with CA-125 kinetics during the first 100 chemotherapy days by the Lyon University team. The association between KELIM score (favorable ≥ 1.0, or unfavorable …

Association Of Leukocyte Telomere Length With Perceived Physical Fatigability, Rain Katz, Emma L Gay, Allison L Kuipers, Joseph H Lee, Lawrence S Honig, Kaare Christensen, Mary F Feitosa, Mary K Wojczynski, Nancy W Glynn, Llfs Research Group

2020-Current year OA Pubs

BACKGROUND: Leukocyte telomere length (LTL) is a potential genomic marker of biological aging, but its relation to fatigability, a prognostic indicator of phenotypic aging (e.g., functional decline) is unknown. We hypothesized shorter LTL would predict greater perceived physical fatigability, but that this association would be attenuated by adjusting for chronological age.

METHODS: Two generations of participants (N = 1997; 309 probands, 1688 offspring) were from the Long Life Family Study (age = 73.7 ± 10.4, range 60-108, 54.4 % women), a longitudinal cohort study of aging. LTL was assayed at baseline. Perceived physical fatigability was measured 8.0 ± 1.1 years …

Cic Missense Variants Contribute To Susceptibility For Spina Bifida, Xiao Han, Xuanye Cao, Vanessa Aguiar-Pulido, Wei Yang, Menuka Karki, Paula Andrea Pimienta Ramirez, Robert M Cabrera, Ying Linda Lin, Bogdan J Wlodarczyk, Gary M Shaw, M Elizabeth Ross, Cuilian Zhang, Richard H Finnell, Yunping Lei

Faculty, Staff and Students Publications

Neural tube defects (NTDs) are congenital malformations resulting from abnormal embryonic development of the brain, spine, or spinal column. The genetic etiology of human NTDs remains poorly understood despite intensive investigation. CIC, homolog of the Capicua transcription repressor, has been reported to interact with ataxin-1 (ATXN1) and participate in the pathogenesis of spinocerebellar ataxia type 1. Our previous study demonstrated that CIC loss of function (LoF) variants contributed to the cerebral folate deficiency syndrome by downregulating folate receptor 1 (FOLR1) expression. Given the importance of folate transport in neural tube formation, we hypothesized that CIC variants could contribute to increased …

Racial And Ethnic Disparities In Access To Minimally Invasive Mitral Valve Surgery, Laurent G Glance, Karen E Joynt Maddox, Michael Mazzefi, Peter W Knight, Michael P Eaton, Changyong Feng, Miklos D Kertai, James Albernathy, Isaac Y Wu, Julie A Wyrobek, Marisa Cevasco, Nimesh Desai, Andrew W Dick

2020-Current year OA Pubs

IMPORTANCE: Whether people from racial and ethnic minority groups experience disparities in access to minimally invasive mitral valve surgery (MIMVS) is not known.

OBJECTIVE: To investigate racial and ethnic disparities in the utilization of MIMVS.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used data from the Society of Thoracic Surgeons Database for patients who underwent mitral valve surgery between 2014 and 2019. Statistical analysis was performed from January 24 to August 11, 2022.

EXPOSURES: Patients were categorized as non-Hispanic White, non-Hispanic Black, and Hispanic individuals.

MAIN OUTCOMES AND MEASURES: The association between MIMVS (vs full sternotomy) and race and ethnicity …

Hdac2 In Primary Sensory Neurons Constitutively Restrains Chronic Pain By Repressing Α2Δ-1 Expression And Associated Nmda Receptor Activity, Jixiang Zhang, Shao-Rui Chen, Meng-Hua Zhou, Daozhong Jin, Hong Chen, Li Wang, Ronald A Depinho, Hui-Lin Pan

Faculty, Staff and Student Publications

α2δ-1 (encoded by the Cacna2d1 gene) is a newly discovered NMDA receptor-interacting protein and is the therapeutic target of gabapentinoids (e.g., gabapentin and pregabalin) frequently used for treating patients with neuropathic pain. Nerve injury causes sustained α2δ-1 upregulation in the dorsal root ganglion (DRG), which promotes NMDA receptor synaptic trafficking and activation in the spinal dorsal horn, a hallmark of chronic neuropathic pain. However, little is known about how nerve injury initiates and maintains the high expression level of α2δ-1 to sustain chronic pain. Here, we show that nerve injury caused histone hyperacetylation and diminished enrichment of histone deacetylase-2 (HDAC2), …

Synaptic Development In Diverse Olfactory Neuron Classes Uses Distinct Temporal And Activity-Related Programs, Michael A. Aimino, Alison T. Depew, Lucas Restrepo, Timothy J. Mosca

Farber Institute for Neuroscience Faculty Papers

Developing neurons must meet core molecular, cellular, and temporal requirements to ensure the correct formation of synapses, resulting in functional circuits. However, because of the vast diversity in neuronal class and function, it is unclear whether or not all neurons use the same organizational mechanisms to form synaptic connections and achieve functional and morphologic maturation. Moreover, it remains unknown whether neurons united in a common goal and comprising the same sensory circuit develop on similar timescales and use identical molecular approaches to ensure the formation of the correct number of synapses. To begin to answer these questions, we took advantage …

Variation In Human Water Turnover Associated With Environmental And Lifestyle Factors, Yosuke Yamada, Xueying Zhang, Mary E T Henderson, Hiroyuki Sagayama, Herman Pontzer, Daiki Watanabe, Tsukasa Yoshida, Misaka Kimura, Philip N Ainslie, Lene F Andersen, Liam J Anderson, Lenore Arab, Issad Baddou, Kweku Bedu-Addo, Ellen E Blaak, Stephane Blanc, Alberto G Bonomi, Carlijn V C Bouten, Pascal Bovet, Maciej S Buchowski, Nancy F Butte, Stefan G Camps, Graeme L Close, Jamie A Cooper, Richard Cooper, Sai Krupa Das, Lara R Dugas, Simon Eaton, Ulf Ekelund, Sonja Entringer, Terrence Forrester, Barry W Fudge, Annelies H Goris, Michael Gurven, Lewis G Halsey, Catherine Hambly, Asmaa El Hamdouchi, Marije B Hoos, Sumei Hu, Noorjehan Joonas, Annemiek M Joosen, Peter Katzmarzyk, Kitty P Kempen, William E Kraus, Wantanee Kriengsinyos, Robert F Kushner, Estelle V Lambert, William R Leonard, Nader Lessan, Corby K Martin, Anine C Medin, Erwin P Meijer, James C Morehen, James P Morton, Marian L Neuhouser, Theresa A Nicklas, Robert M Ojiambo, Kirsi H Pietiläinen, Yannis P Pitsiladis, Jacob Plange-Rhule, Guy Plasqui, Ross L Prentice, Roberto A Rabinovich, Susan B Racette, David A Raichlen, Eric Ravussin, Leanne M Redman, John J Reilly, Rebecca M Reynolds, Susan B Roberts, Albertine J Schuit, Luis B Sardinha, Analiza M Silva, Anders M Sjödin, Eric Stice, Samuel S Urlacher, Giulio Valenti, Ludo M Van Etten, Edgar A Van Mil, Jonathan C K Wells, George Wilson, Brian M Wood, Jack A Yanovski, Alexia J Murphy-Alford, Cornelia U Loechl, Amy H Luke, Jennifer Rood, Klaas R Westerterp, William W Wong, Motohiko Miyachi, Dale A Schoeller, John R Speakman

Children’s Nutrition Research Center Staff Publications

Water is essential for survival, but one in three individuals worldwide (2.2 billion people) lack access to safe drinking water. Water intake requirements largely reflect water turnover (WT), the water used by the body each day. We investigated the determinants of human WT in 5,604 people from the ages of 8 days to 96 years from 26 countries using isotope tracking (2H) methods. Age, body size, and composition were significantly associated with WT as were physical activity, athletic status, pregnancy, socioeconomic status, and environmental characteristics (latitude, altitude, air temperature, and humidity). People in countries with low human development index (HDI) …

Premature Ovarian Insufficiency In Clpb Deficiency: Transcriptomic, Proteomic And Phenotypic Insights, Elena J Tucker, Julia T Warren, Et Al.

2020-Current year OA Pubs

CONTEXT: Premature ovarian insufficiency (POI) is a common form of female infertility that usually presents as an isolated condition but can be part of various genetic syndromes. Early diagnosis and treatment of POI can minimize comorbidity and improve health outcomes.

OBJECTIVE: We aimed to determine the genetic cause of syndromic POI, intellectual disability, neutropenia, and cataracts.

METHODS: We performed whole-exome sequencing (WES) followed by functional validation via RT-PCR, RNAseq, and quantitative proteomics, as well as clinical update of previously reported patients with variants in the caseinolytic peptidase B (CLPB) gene.

RESULTS: We identified causative variants in CLPB, encoding a mitochondrial …

Myc Regulates A Pan-Cancer Network Of Co-Expressed Oncogenic Splicing Factors., Laura M Urbanski, Mattia Brugiolo, Sunghee Park, Brittany Lynn Angarola, Nathan Leclair, Marina Yurieva, Phil Palmer, Sangram Keshari Sahu, Olga Anczuków

Faculty Research 2022

MYC is dysregulated in >50% of cancers, but direct targeting of MYC has been clinically unsuccessful. Targeting downstream MYC effector pathways represents an attractive alternative. MYC regulates alternative mRNA splicing, but the mechanistic links between MYC and the splicing machinery in cancer remain underexplored. Here, we identify a network of co-expressed splicing factors (SF-modules) in MYC-active breast tumors. Of these, one is a pan-cancer SF-module correlating with MYC activity across 33 tumor types. In mammary cell models, MYC activation leads to co-upregulation of pan-cancer module SFs and to changes in >4,000 splicing events. In breast cancer organoids, co-overexpression of the …

Oleuropein Suppresses Endometriosis Progression And Improves The Fertility Of Mice With Endometriosis, Yuri Park, Yeon Jean Cho, Nuri Sung, Mi Jin Park, Xiaoming Guan, William E Gibbons, Bert W O'Malley, Sang Jun Han

Faculty, Staff and Students Publications

BACKGROUND: Endometriosis is an estrogen-dependent inflammatory reproductive disease. Therefore, systematic estrogen depletion and anti-inflammatory drugs are the current treatment for endometriosis. However, current endometriosis treatments have low efficacy and cause adverse effects in endometriosis patients. Consequently, alternative endometriosis treatments targeting endometriosis-specific factors are in demand. In this context, ERβ was selected as a druggable target for endometriosis due to its critical role in progression. Therefore, selective targeting of ERβ without inhibiting ERα activity would be a new paradigm for endometriosis treatment to overcome the low efficacy and adverse effects of hormonal endometriosis therapy.

METHODS: Cell-based ERβ and ERα activity assay …

Copy Number Variants Are Ovarian Cancer Risk Alleles At Known And Novel Risk Loci, Amber A Devries, Joe Dennis, Jonathan P Tyrer, Pei-Chen Peng, Simon G Coetzee, Alberto L Reyes, Jasmine T Plummer, Brian D Davis, Stephanie S Chen, Felipe Segato Dezem, Katja K H Aben, Hoda Anton-Culver, Natalia N Antonenkova, Matthias W Beckmann, Alicia Beeghly-Fadiel, Andrew Berchuck, Natalia V Bogdanova, Nadja Bogdanova-Markov, James D Brenton, Ralf Butzow, Ian Campbell, Jenny Chang-Claude, Georgia Chenevix-Trench, Linda S Cook, Anna Defazio, Jennifer A Doherty, Thilo Dörk, Diana M Eccles, A Heather Eliassen, Peter A Fasching, Renée T Fortner, Graham G Giles, Ellen L Goode, Marc T Goodman, Jacek Gronwald, Opal Study Group, Aocs Group, Niclas Håkansson, Michelle A T Hildebrandt, Chad Huff, David G Huntsman, Allan Jensen, Siddhartha Kar, Beth Y Karlan, Elza K Khusnutdinova, Lambertus A Kiemeney, Susanne K Kjaer, Jolanta Kupryjanczyk, Marilyne Labrie, Diether Lambrechts, Nhu D Le, Jan Lubiński, Taymaa May, Usha Menon, Roger L Milne, Francesmary Modugno, Alvaro N Monteiro, Kirsten B Moysich, Kunle Odunsi, Håkan Olsson, Celeste L Pearce, Tanja Pejovic, Susan J Ramus, Elio Riboli, Marjorie J Riggan, Isabelle Romieu, Dale P Sandler, Joellen M Schildkraut, V Wendy Setiawan, Weiva Sieh, Honglin Song, Rebecca Sutphen, Kathryn L Terry, Pamela J Thompson, Linda Titus, Shelley S Tworoger, Els Van Nieuwenhuysen, Digna Velez Edwards, Penelope M Webb, Nicolas Wentzensen, Alice S Whittemore, Alicja Wolk, Anna H Wu, Argyrios Ziogas, Matthew L Freedman, Kate Lawrenson, Paul D P Pharoah, Douglas F Easton, Simon A Gayther, Michelle R Jones

Faculty, Staff and Student Publications

BACKGROUND: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort.

METHODS: Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types.

RESULTS: We identified …

Molecular Subclasses Of Clear Cell Ovarian Carcinoma And Their Impact On Disease Behavior And Outcomes, Kelly L Bolton, Irenaeus C C Chan, Brian J Wiley, Et Al.

2020-Current year OA Pubs

PURPOSE: To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes.

EXPERIMENTAL DESIGN: We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival.

RESULTS: We detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). …

Antibody-Drug Conjugates For The Treatment Of Her2-Positive Breast Cancer, Mariana K Najjar, Sara G Manore, Angelina T Regua, Hui-Wen Lo

Faculty, Staff and Student Publications

Human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase is overexpressed in 20–30% of breast cancers and is associated with poor prognosis and worse overall patient survival. Most women with HER2-positive breast cancer receive neoadjuvant chemotherapy plus HER2-targeted therapies. The development of HER2-directed therapeutics is an important advancement in targeting invasive breast cancer. Despite the efficacy of anti-HER2 monoclonal antibodies, they are still being combined with adjuvant chemotherapy to improve overall patient outcomes. Recently, significant progress has been made towards the development of a class of therapeutics known as antibody-drug conjugates (ADCs), which leverage the high specificity of HER2-targeted …

A Randomized Pilot Study Of Oncology Massage To Treat Chemotherapy-Induced Peripheral Neuropathy, Gabriel Lopez, Cathy Eng, Michael Overman, David Ramirez, Wenli Liu, Curtiss Beinhorn, Pamela Sumler, Sarah Prinsloo, Yisheng Li, Minxing Chen, Eduardo Bruera, Lorenzo Cohen

Faculty, Staff and Student Publications

This pilot randomized controlled trial investigated massage therapy for symptomatic relief of chemotherapy-induced peripheral neuropathy (CIPN) to determine the ideal weekly frequency and number of weeks of providing massage. We evaluated the feasibility and initial efficacy of a Swedish massage protocol to treat lower extremity (LE) CIPN. Inclusion criteria: LE neuropathy attributed to oxaliplatin, paclitaxel, or docetaxel, with no other attributable causes; ≥ 6 months since last chemotherapy; self-reported neuropathy score ≥ 3, 0-10 scale; age ≥ 18. Participant randomization (2:2:1:1) to one of four groups: LE (2) or head/neck/shoulder (control; 1) massage 3 times (3X) a week for 4 …

Omics Analyses Of A Somatic Trp53r245w/+ Breast Cancer Model Identify Cooperating Driver Events Activating Pi3k/Akt/Mtor Signaling, Xiaojie Yu, Yun Zhang, Shunbin Xiong, Joy M Mcdaniel, Chang Sun, Gilda P Chau, Jovanka Gencel-Augusto, Dhruv Chachad, Rhiannon L Morrissey, Xiayu Rao, Jing Wang, Guillermina Lozano

Faculty, Staff and Student Publications

Alterations of the tumor suppressor

Hormonal Therapies Up-Regulate Manf And Overcome Female Susceptibility To Immune Checkpoint Inhibitor Myocarditis, Yaohua Zhang, Chengcao Sun, Yajuan Li, Juan Qin, Kaushik Amancherla, Ying Jing, Qingsong Hu, Ke Liang, Zhao Zhang, Youqiong Ye, Lisa A Huang, Tina K Nguyen, Sergey D Egranov, Zilong Zhao, Andrew Wu, Yutao Xi, Jun Yao, Mien-Chie Hung, George A Calin, Jie Cheng, Bora Lim, Lorenz H Lehmann, Joe-Elie Salem, Douglas B Johnson, Michael A Curran, Dihua Yu, Leng Han, Radbod Darabi, Liuqing Yang, Javid J Moslehi, Chunru Lin

Faculty, Staff and Student Publications

Immune checkpoint inhibitors (ICIs) have been increasingly used in combination for cancer treatment but are associated with myocarditis. Here, we report that tumor-bearing mice exhibited response to treatment with combinatorial anti-programmed cell death 1 and anti-cytotoxic T lymphocyte antigen-4 antibodies but also presented with cardiovascular toxicities observed clinically with ICI therapy, including myocarditis and arrhythmia. Female mice were preferentially affected with myocarditis compared to male mice, consistent with a previously described genetic model of ICI myocarditis and emerging clinical data. Mechanistically, myocardial tissue from ICI-treated mice, the genetic mouse model, and human heart tissue from affected patients with ICI myocarditis …