Medical Sciences Commons^™

Long-Term Morbidity And Mortality Among Survivors Of Neuroblastoma Diagnosed During Infancy: A Report From The Childhood Cancer Survivor Study, Danielle Novetsky Friedman, Pamela J Goodman, Wendy M Leisenring, Lisa R Diller, Susan L Cohn, Rebecca M Howell, Susan A Smith, Emily S Tonorezos, Suzanne L Wolden, Joseph P Neglia, Kirsten K Ness, Todd M Gibson, Paul C Nathan, Brent R Weil, Leslie L Robison, Kevin C Oeffinger, Gregory T Armstrong, Charles A Sklar, Tara O Henderson

Faculty, Staff and Student Publications

Purpose: To describe the risk of late mortality, subsequent malignant neoplasms (SMNs), and chronic health conditions (CHCs) in survivors of neuroblastoma diagnosed in infancy by treatment era and exposures.

Methods: Among 5-year survivors of neuroblastoma in the Childhood Cancer Survivor Study diagnosed age < 1 year between 1970 and 1999, we examined the cumulative incidence of late (> 5 years from diagnosis) mortality, SMN, and CHCs (grades 2-5 and 3-5). Multivariable Cox regression models estimated hazard ratios (HRs) and 95% CIs by decade and treatment (surgery-alone v chemotherapy with or without surgery [C ± S] v radiation with or without chemotherapy ± surgery [R ± C ± S]) among survivors and between survivors and 5,051 …

Towards A Biomarker For Acute Arterial Thrombosis Using Complete Blood Count And White Blood Cell Differential Parameters In Mice, Hee Jeong Jang, Dawid Schellingerhout, Jiwon Kim, Jinyong Chung, Dong-Eog Kim

Faculty, Staff and Student Publications

There is no blood biomarker diagnostic of arterial thrombosis. We investigated if arterial thrombosis per se was associated with alterations in complete blood count (CBC) and white blood cell (WBC) differential count in mice. Twelve-week-old C57Bl/6 mice were used for FeCl3-mediated carotid thrombosis (n = 72), sham-operation (n = 79), or non-operation (n = 26). Monocyte count (/µL) at 30-min after thrombosis (median 160 [interquartile range 140-280]) was ~ 1.3-fold higher than at 30-min after sham-operation (120 [77.5-170]), and twofold higher than in non-operated mice (80 [47.5-92.5]). At day-1 and -4 post-thrombosis, compared with 30-min, monocyte count decreased by about …

Overall Survival With Daratumumab, Lenalidomide, And Dexamethasone In Previously Treated Multiple Myeloma (Pollux): A Randomized, Open-Label, Phase Iii Trial, Meletios A Dimopoulos, Albert Oriol, Hareth Nahi, Jesus San-Miguel, Nizar J Bahlis, Saad Z Usmani, Neil Rabin, Robert Z Orlowski, Kenshi Suzuki, Torben Plesner, Sung-Soo Yoon, Dina Ben Yehuda, Paul G Richardson, Hartmut Goldschmidt, Donna Reece, Tahamtan Ahmadi, Xiang Qin, Wendy Garvin Mayo, Xue Gai, Jodi Carey, Robin Carson, Philippe Moreau

Faculty, Staff and Student Publications

Purpose: With the initial analysis of POLLUX at a median follow-up of 13.5 months, daratumumab in combination with lenalidomide and dexamethasone (D-Rd) significantly prolonged progression-free survival versus lenalidomide and dexamethasone (Rd) alone in patients with relapsed or refractory multiple myeloma (RRMM). We report updated efficacy and safety results at the time of final analysis for overall survival (OS).

Methods: POLLUX was a multicenter, randomized, open-label, phase III study during which eligible patients with ≥ 1 line of prior therapy were randomly assigned 1:1 to D-Rd or Rd until disease progression or unacceptable toxicity. After positive primary analysis and protocol amendment, …

Differential Spatial Gene And Protein Expression Associated With Recurrence Following Chemoradiation For Localized Anal Squamous Cell Cancer, Sharia Hernandez, Prajnan Das, Emma B Holliday, Li Shen, Wei Lu, Benny Johnson, Craig A Messick, Cullen M Taniguchi, John Skibber, Ethan B Ludmir, Y Nancy You, Grace Li Smith, Brian Bednarski, Larisa Kostousov, Eugene J Koay, Bruce D Minsky, Matthew Tillman, Shaelynn Portier, Cathy Eng, Albert C Koong, George J Chang, Wai Chin Foo, Jing Wang, Luisa Solis Soto, Van K Morris

Faculty, Staff and Student Publications

The identification of transcriptomic and protein biomarkers prognosticating recurrence risk after chemoradiation of localized squamous cell carcinoma of the anus (SCCA) has been limited by a lack of available fresh tissue at initial presentation. We analyzed archival FFPE SCCA specimens from pretreatment biopsies prior to chemoradiation for protein and RNA biomarkers from patients with localized SCCA who recurred (N = 23) and who did not recur (N = 25). Tumor cells and the tumor microenvironment (TME) were analyzed separately to identify biomarkers with significantly different expression between the recurrent and non-recurrent groups. Recurrent patients had higher mean protein expression of …

Spectral Features Of Non-Nutritive Suck Dynamics In Extremely Preterm Infants, Steven M. Barlow, Chunxiao Liao, Jaehoon Lee, Seungman Kim, Jill L. Maron, Dongli Song, Priya Jegatheesan, Balaji Govindaswami, Bernard J. Wilson, Kushal Bhakta, John P. Cleary

United States Public Health Resources

Background: Non-nutritive suck (NNS) is used to promote ororhythmic patterning and assess oral feeding readiness in preterm infants in the neonatal intensive care unit (NICU). While time domain measures of NNS are available in real time at cribside, our understanding of suck pattern generation in the frequency domain is limited. The aim of this study is to model the development of NNS in the frequency domain using Fourier and machine learning (ML) techniques in extremely preterm infants (EPIs).

Methods: A total of 117 EPIs were randomized to a pulsed or sham orocutaneous intervention during tube feedings 3 times/day …

Engineering T Cells To Suppress Acute Gvhd And Leukemia Relapse After Allogeneic Hematopoietic Stem Cell Transplantation, Feiyan Mo, Norihiro Watanabe, Kayleigh I Omdahl, Phillip M Burkhardt, Xiaoyun Ding, Eiko Hayase, Angela Panoskaltsis-Mortari, Robert R Jenq, Helen E Heslop, Leslie S Kean, Malcolm K Brenner, Victor Tkachev, Maksim Mamonkin

Faculty, Staff and Student Publications

Acute graft-versus-host disease (aGVHD) limits the therapeutic benefit of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and requires immunosuppressive prophylaxis that compromises antitumor and antipathogen immunity. OX40 is a costimulatory receptor upregulated on circulating T cells in aGVHD and plays a central role in driving the expansion of alloreactive T cells. Here, we show that OX40 is also upregulated on T cells infiltrating GVHD target organs in a rhesus macaque model, supporting the hypothesis that targeted ablation of OX40+ T cells will mitigate GVHD pathogenesis. We thus created an OX40-specific cytotoxic receptor that, when expressed on human T cells, enables selective …

Disparity In Checkpoint Inhibitor Utilization Among Commercially Insured Adult Patients With Metastatic Lung Cancer, Meng Li, Kaiping Liao, Alice J Chen, Tina Cascone, Yu Shen, Qian Lu, Ya-Chen Tina Shih

Faculty, Staff and Student Publications

BACKGROUND: There is a lack of evidence from nationwide samples on the disparity of initiating immune checkpoint inhibitors (ICIs) after metastatic lung cancer diagnosis.

METHODS: We identified metastatic lung cancer patients diagnosed between 2015 and 2020 from a large, nationwide commercial claims database. We analyzed the time from metastatic lung cancer diagnosis to ICI therapy using Cox proportional hazard models. Independent variables included county-level measures (quintiles of percentage of racialized population, quintiles of percentage of population below poverty, urbanity, and density of medical oncologists) and patient characteristics (age, sex, Charlson comorbidity index, Medicare Advantage, and year of diagnosis). All tests …

Real-Time Liver Tumor Localization Via Combined Surface Imaging And A Single X-Ray Projection, Hua-Chieh Shao, Yunxiang Li, Jing Wang, Steve Jiang, You Zhang

Faculty, Staff and Student Publications

Objective. Real-time imaging, a building block of real-time adaptive radiotherapy, provides instantaneous knowledge of anatomical motion to drive delivery adaptation to improve patient safety and treatment efficacy. The temporal constraint of real-time imaging (< 500 milliseconds) significantly limits the imaging signals that can be acquired, rendering volumetric imaging and 3D tumor localization extremely challenging. Real-time liver imaging is particularly difficult, compounded by the low soft tissue contrast within the liver. We proposed a deep learning (DL)-based framework (Surf-X-Bio), to track 3D liver tumor motion in real-time from combined optical surface image and a single on-board x-ray projection.

Approach. Surf-X-Bio performs mesh-based deformable registration to track/localize liver tumors volumetrically via three steps. First, a DL model was built to estimate liver boundary motion from an optical surface image, using learnt motion correlations between the respiratory-induced external body surface and liver boundary. Second, the residual liver boundary motion estimation error was further corrected by a graph neural network-based DL model, using information extracted from a …

Mycorrhiza-Mediated Recruitment Of Complete Denitrifying Pseudomonas Reduces N2o Emissions From Soil, Xia Li, Ruotong Zhao, Dandan Li, Guangzhou Wang, Shuikuan Bei, Xiaotang Ju, Ran An, Long Li, Thomas W Kuyper, Peter Christie, Franz S Bender, Ciska Veen, Marcel G A Van Der Heijden, Wim H Van Der Putten, Fusuo Zhang, Klaus Butterbach-Bahl, Junling Zhang

Faculty, Staff and Student Publications

Background: Arbuscular mycorrhizal fungi (AMF) are key soil organisms and their extensive hyphae create a unique hyphosphere associated with microbes actively involved in N cycling. However, the underlying mechanisms how AMF and hyphae-associated microbes may cooperate to influence N2O emissions from "hot spot" residue patches remain unclear. Here we explored the key microbes in the hyphosphere involved in N2O production and consumption using amplicon and shotgun metagenomic sequencing. Chemotaxis, growth and N2O emissions of isolated N2O-reducing bacteria in response to hyphal exudates were tested using in vitro cultures and inoculation experiments.

Results: AMF hyphae reduced denitrification-derived N2O emission (max. 63%) …

Longitudinal Ultrasound Imaging And Network Modeling In Rats Reveal Sex-Dependent Suppression Of Liver Regeneration After Resection In Alcoholic Liver Disease, Benjamin K. Barnhart, Toshiki Kan, Ankita Srivastava, Corinne E. Wessner, John Waters, Manju Ambelil, John R. Eisenbrey, Jan B. Hoek, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Liver resection is an important surgical technique in the treatment of cancers and transplantation. We used ultrasound imaging to study the dynamics of liver regeneration following two-thirds partial hepatectomy (PHx) in male and female rats fed via Lieber-deCarli liquid diet protocol of ethanol or isocaloric control or chow for 5–7 weeks. Ethanol-fed male rats did not recover liver volume to the pre-surgery levels over the course of 2 weeks after surgery. By contrast, ethanol-fed female rats as well as controls of both sexes showed normal volume recovery. Contrary to expectations, transient increases in both portal and hepatic artery blood flow …

Optimization Of Cryo-Electron Microscopy For Quantitative Analysis Of Lipid Bilayers, Frederick A Heberle, Doug Welsch, Haden L Scott, M Neal Waxham

Faculty, Staff and Student Publications

Cryogenic electron microscopy (cryo-EM) is among the most powerful tools available for interrogating nanoscale structure of biological materials. We recently showed that cryo-EM can be used to measure the bilayer thickness of lipid vesicles and biological membranes with subangstrom precision, resulting in the direct visualization of nanoscopic domains of different thickness in multicomponent lipid mixtures and giant plasma membrane vesicles. Despite the great potential of cryo-EM for revealing the lateral organization of biomembranes, a large parameter space of experimental conditions remains to be optimized. Here, we systematically investigate the influence of instrument parameters and image postprocessing steps on the ability …

Pragmatic, Prospective Comparative Effectiveness Trial Of Carbon Ion Therapy, Surgery, And Proton Therapy For The Management Of Pelvic Sarcomas (Soft Tissue/Bone) Involving The Bone: The Prosper Study Rationale And Design, Bradford S Hoppe, Ivy A Petersen, Benjamin K Wilke, Todd A Dewees, Reiko Imai, Eugen B Hug, Maria Rosaria Fiore, Jürgen Debus, Piero Fossati, Shigeru Yamada, Ester Orlandi, Qing Zhang, Cihang Bao, Katharina Seidensaal, Byron C May, Anna C Harrell, Matthew T Houdek, Laura A Vallow, Peter S Rose, Michael G Haddock, Jonathan B Ashman, Krista A Goulding, Steven Attia, Sunil Krishnan, Anita Mahajan, Robert L Foote, Nadia N Laack, Sameer R Keole, Chris J Beltran, Eric M Welch, Mohammed Karim, Safia K Ahmed

Faculty, Staff and Student Publications

Surgical treatment of pelvic sarcoma involving the bone is the standard of care but is associated with several sequelae and reduced functional quality of life (QOL). Treatment with photon and proton radiotherapy is associated with relapse. Carbon ion radiotherapy (CIRT) may reduce both relapse rates and treatment sequelae. The PROSPER study is a tricontinental, nonrandomized, prospective, three-arm, pragmatic trial evaluating treatments of pelvic sarcoma involving the bone. Patients aged at least 15 years are eligible for inclusion. Participants must have an Eastern Cooperative Oncology Group Performance Status score of two or less, newly diagnosed disease, and histopathologic confirmation of pelvic …

A New, Extremely Sensitive, Turn-Off Optical Sensor Utilizing Schiff Base For Fast Detection Of Cu(Ii), Lotfi M Aroua, Reham Ali, Abuzar E A E Albadri, Sabri Messaoudi, Fahad M Alminderej, Sayed M Saleh

Faculty, Staff and Student Publications

Throughout this research, a unique optical sensor for detecting one of the most dangerous heavy metal ions, Cu(II), was designed and developed. The (4-mercaptophenyl) iminomethylphenyl naphthalenyl carbamate (MNC) sensor probe was effectively prepared. The Schiff base of the sensor shows a "turn-off" state with excellent sensitivity to Cu(II) ions. This innovative fluorescent chemosensor possesses distinctive optical features with a substantial Stocks shift (about 114 nm). In addition, MNC has remarkable selectivity for Cu(II) relative to other cations. Density functional theory (DFT) and the time-dependent DFT (TDDFT) theoretical calculations were performed to examine Cu(II) chelation structures and associated electronic properties in …

Applications And Clinical Trial Landscape Using Toll-Like Receptor Agonists To Reduce The Toll Of Cancer, Christian Rolfo, Elisa Giovannetti, Pablo Martinez, Shannon Mccue, Aung Naing

Faculty, Staff and Student Publications

Toll-like receptors (TLRs), which serve as a bridge between innate and adaptive immunity, may be viable treatment targets. TLRs are the first line of defense against microbes and activate signaling cascades that induce immune and inflammatory responses. Patients with "hot" versus "cold" tumors may respond more favorably to immune checkpoint inhibition, and through their downstream effects, TLR agonists have the potential to convert "cold tumors" into "hot tumors" making TLRs in combination with immune checkpoint inhibitors, potential targets for cancer therapies. Imiquimod is a topical TLR7 agonist, approved by the FDA for antiviral and skin cancer treatments. Other TLR adjuvants …

Factors Affecting Variability In Vestibulo-Ocular Reflex Gain In The Video Head Impulse Test In Individuals Without Vestibulopathy: A Systematic Review Of Literature, Laurel Elise Money-Nolan, Ashley G. Flagge

Ashley Flagge Publications

The purpose of this systematic review was to summarize and synthesize published evidence examining variations in vestibulo-ocular reflex (VOR) gain outcomes for the Video Head Impulse Test (vHIT) in healthy individuals without vestibulopathy in order to describe factors that may influence test outcomes. Computerized literature searches were performed from four search engines. The studies were selected based on relevant inclusion and exclusion criteria, and were required to examine VOR gain in healthy adults without vestibulopathy. The studies were screened using Covidence (Cochrane tool) and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement standards (PRISMA-2020). A total of …

Poor Seizure Control Among Children Attending A Tertiary Hospital In South Western Uganda – A Retrospective Study, Martha Sajatovic

Faculty Scholarship

Background: Seizure control among children with epilepsy (CWE) receiving anti-seizure medications (ASMs) remains a challenge in low-resource settings. Uncontrolled seizures are significantly associated with increased morbidity and mortality among CWE. This negatively impacts their quality of life and increases stigma. Aim: This study determined seizure control status and described the factors associated among CWE receiving ASMs at Mbarara Regional Referral Hospital (MRRH). Methods: In a retrospective chart review study, socio-demographic and clinical data were obtained from 112 medical records. CWE receiving ASMs for at least six months and regularly attending the clinic were included in the study. Physical or telephone …

Stiff Knee Gait Disorders As Neuromechanical Consequences Of Spastic Hemiplegia In Chronic Stroke, Sheng Li

Faculty, Staff and Student Publications

Stiff knee gait (SKG) is defined as decreased knee flexion during the swing phase. It is one of the most common gait disorders following stroke. Knee extensor spasticity is commonly accepted as the primary cause. Clinical management has focused on the reduction in knee extensor spasticity. Recent advances in understanding of post-stroke hemiplegic gait suggest that SKG can present as mechanical consequences between muscle spasticity, weakness, and their interactions with ground reactions during walking. Various underlying mechanisms are presented through sample cases in this article. They include ankle plantar flexor spasticity, knee extensor spasticity, knee flexor and extensor coactivation, and …

A Comprehensive And Integrative Approach To Mecp2 Disease Transcriptomics, Alexander J Trostle, Lucian Li, Seon-Young Kim, Jiasheng Wang, Rami Al-Ouran, Hari Krishna Yalamanchili, Zhandong Liu, Ying-Wooi Wan

Faculty, Staff and Students Publications

Mutations in MeCP2 result in a crippling neurological disease, but we lack a lucid picture of MeCP2's molecular role. Individual transcriptomic studies yield inconsistent differentially expressed genes. To overcome these issues, we demonstrate a methodology to analyze all modern public data. We obtained relevant raw public transcriptomic data from GEO and ENA, then homogeneously processed it (QC, alignment to reference, differential expression analysis). We present a web portal to interactively access the mouse data, and we discovered a commonly perturbed core set of genes that transcends the limitations of any individual study. We then found functionally distinct, consistently up- and …

Multifaceted Role For P53 In Pancreatic Cancer Suppression, Stephano S Mello, Brittany M Flowers, Pawel K Mazur, James J Lee, Fabian Müller, Sarah K Denny, Sofia Ferreira, Kathryn Hanson, Seung K Kim, William J Greenleaf, Laura D Wood, Laura D Attardi

Faculty, Staff and Student Publications

The vast majority of human pancreatic ductal adenocarcinomas (PDACs) harbor TP53 mutations, underscoring p53's critical role in PDAC suppression. PDAC can arise when pancreatic acinar cells undergo acinar-to-ductal metaplasia (ADM), giving rise to premalignant pancreatic intraepithelial neoplasias (PanINs), which finally progress to PDAC. The occurrence of TP53 mutations in late-stage PanINs has led to the idea that p53 acts to suppress malignant transformation of PanINs to PDAC. However, the cellular basis for p53 action during PDAC development has not been explored in detail. Here, we leverage a hyperactive p53 variant-p5353,54-which we previously showed is a more robust PDAC suppressor than …

Preparation And Synergy Of Supported Ru0 And Pd0 For Rapid Chlorate Reduction At Ph 7, Jinyu Gao, Shaohua Xie, Fudong Liu, Jinyong Liu

Faculty, Staff and Student Publications

Chlorate (ClO3–) is a common water pollutant due to its gigantic scale of production, wide applications in agriculture and industry, and formation as a toxic byproduct in various water treatment processes. This work reports on the facile preparation, mechanistic elucidation, and kinetic evaluation of a bimetallic catalyst for highly active ClO3– reduction into Cl–. Under 1 atm H2 and 20 °C, PdII and RuIII were sequentially adsorbed and reduced on a powdered activated carbon support, affording Ru0–Pd0/C from scratch within only 20 min. The Pd0 particles significantly accelerated the reductive immobilization of RuIII as >55% dispersed Ru0 outside Pd0. At …

Hiv Screening Among Immigrants Establishing Care In Maine, 2017-2021, Elizabeth Mazzeo, Elizabeth Danielson, Benjamin Felix, Kimberly Toomire, Elizabeth Eisenhardt, Evelyn Roach, Katlyn Breton, Karen Thompson, Stephen Digiovanni, Kathleen M. Fairfield

Journal of Maine Medical Center

No abstract provided.

Intouch Week Of March 6, 2023, New York Medical College

InTouch

• The Family Health Center Celebrates Three Years at NYMC
• NYMC and Union Community Health Center Partner for Clinical and Allied Health Profession Training Program
• NYMC Forms Academic Affiliation with St. Mary’s General Hospital and Saint Clare’s Hospitals

Whole-Exome Sequencing Study Identifies Four Novel Gene Loci Associated With Diabetic Kidney Disease, Yang Pan, Xiao Sun, Xuenan Mi, Zhijie Huang, Yenchih Hsu, James E Hixson, Donna Munzy, Ginger Metcalf, Nora Franceschini, Adrienne Tin, Anna Köttgen, Michael Francis, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium Topmed Kidney Function Working Group, Jennifer A Brody, Bryan Kestenbaum, Colleen M Sitlani, Josyf C Mychaleckyj, Holly Kramer, Leslie A Lange, Xiuqing Guo, Shih-Jen Hwang, Marguerite R Irvin, Jennifer A Smith, Lisa R Yanek, Dhananjay Vaidya, Yii-Der Ida Chen, Myriam Fornage, Donald M Lloyd-Jones, Lifang Hou, Rasika A Mathias, Braxton D Mitchell, Patricia A Peyser, Sharon L R Kardia, Donna K Arnett, Adolfo Correa, Laura M Raffield, Ramachandran S Vasan, L Adrienne Cupple, Daniel Levy, Robert C Kaplan, Kari E North, Jerome I Rotter, Charles Kooperberg, Alexander P Reiner, Bruce M Psaty, Russell P Tracy, Richard A Gibbs, Alanna C Morrison, Harold Feldman, Eric Boerwinkle, Jiang He, Tanika N Kelly, Cric Study Investigators

Faculty, Staff and Students Publications

Diabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease and diabetes. Our two-stage WES study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort and Atherosclerosis Risk in Communities studies (stage 1) and 11 487 multi-ancestry Trans-Omics for Precision Medicine participants (stage 2). Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex and ancestry, were used to test associations between …

A Gene Regulatory Network Approach Harmonizes Genetic And Epigenetic Signals And Reveals Repurposable Drug Candidates For Multiple Sclerosis, Astrid M Manuel, Yulin Dai, Peilin Jia, Leorah A Freeman, Zhongming Zhao

Faculty, Staff and Student Publications

Multiple sclerosis (MS) is a complex dysimmune disorder of the central nervous system. Genome-wide association studies (GWAS) have identified 233 genetic variations associated with MS at the genome-wide significant level. Epigenetic studies have pinpointed differentially methylated CpG sites in MS patients. However, the interplay between genetic risk factors and epigenetic regulation remains elusive. Here, we employed a network model to integrate GWAS summary statistics of 14 802 MS cases and 26 703 controls with DNA methylation profiles from 140 MS cases and 139 controls and the human interactome. We identified differentially methylated genes by aggregating additive effects of differentially methylated …

Qualification Of Hemophilia Treatment Centers To Enable Multi-Center Studies Of Gene Expression Signatures In Blood Cells From Pediatric Patients, Birgit M Reipert, Christoph J Hofbauer, Bagirath Gangadharan, Verena Berg, Elizabeth Donnachie, Shannon Meeks, Maria Elisa Mancuso, Joel Bowen, Deborah L Brown

Faculty, Staff and Student Publications

Hemophilia A is a rare congenital bleeding disorder caused by a deficiency of functionally active coagulation factor VIII (FVIII). Most patients with the severe form of the disease require FVIII replacement therapies, which are often associated with the development of neutralizing antibodies against FVIII. Why some patients develop neutralizing antibodies while others do not is not fully understood. Previously, we could demonstrate that the analysis of FVIII-induced gene expression signatures in peripheral blood mononuclear cells (PBMC) obtained from patients exposed to FVIII replacement therapies provides novel insights into underlying immune mechanisms regulating the development of different populations of FVIII-specific antibodies. …

Mechanosensitive Membrane Proteins: Usual And Unusual Suspects In Mediating Mechanotransduction, Miriam B Goodman, Elizabeth S Haswell, Valeria Vásquez

Faculty, Staff and Student Publications

This Viewpoint, which accompanies a Special Issue focusing on membrane mechanosensors, discusses unifying and unique features of both established and emerging mechanosensitive (MS) membrane proteins, their distribution across protein families and phyla, and current and future challenges in the study of these important proteins and their partners. MS membrane proteins are essential for tissue development, cellular motion, osmotic homeostasis, and sensing external and self-generated mechanical cues like those responsible for touch and proprioception. Though researchers' attention and this Viewpoint focus on a few famous ion channels that are considered the usual suspects as MS mechanosensors, we also discuss some of …

The Fly Homolog Of Supt16h, A Gene Associated With Neurodevelopmental Disorders, Is Required In A Cell-Autonomous Fashion For Cell Survival, Mengqi Ma, Xi Zhang, Yiming Zheng, Shenzhao Lu, Xueyang Pan, Xiao Mao, Hongling Pan, Hyung-Lok Chung, Hua Wang, Hong Guo, Hugo J Bellen

Faculty, Staff and Students Publications

SUPT16H encodes the large subunit of the FAcilitate Chromatin Transcription (FACT) complex, which functions as a nucleosome organizer during transcription. We identified two individuals from unrelated families carrying de novo missense variants in SUPT16H. The probands exhibit global developmental delay, intellectual disability, epilepsy, facial dysmorphism and brain structural abnormalities. We used Drosophila to characterize two variants: p.T171I and p.G808R. Loss of the fly ortholog, dre4, causes lethality at an early developmental stage. RNAi-mediated knockdown of dre4 in either glia or neurons causes severely reduced eclosion and longevity. Tissue-specific knockdown of dre4 in the eye or wing leads to the loss …

Assigning Pathogenicity For Tab2 Variants Using A Novel Scalable Functional Assay And Expanding Tab2 Disease Spectrum, Weiyi Xu, Andrea Graves, Monika Weisz-Hubshman, Lamees Hegazy, Christina Magyar, Zian Liu, Eleni Nasiotis, Md Abul Hassan Samee, Thomas Burris, Seema Lalani, Lilei Zhang

Faculty, Staff and Students Publications

Haploinsufficiency of TGF-beta-activated kinase 1 (MAP3K7) binding protein 2 (TAB2) has been associated with congenital heart disease and more recently multiorgan structural abnormalities. Missense variant represents a major proportion of non-synonymous TAB2 variants reported in gnomAD (295/576) and Clinvar (16/73), most of which are variants of uncertain significance (VUSs). However, interpretation of TAB2 missense variants remains challenging because of lack of functional assays. To address this issue, we established a cell-based luciferase assay that enables high-throughput screening of TAB2 variants to assess the functional consequence for predicting variant pathogenicity. Using this platform, we screened 47 TAB2 variants including five pathogenic …

Treatment Outcomes For Newly Diagnosed, Treatment-Naïve Tp53-Mutated Acute Myeloid Leukemia: A Systematic Review And Meta-Analysis, Naval G Daver, Shahed Iqbal, Camille Renard, Rebecca J Chan, Ken Hasegawa, Hao Hu, Preston Tse, Jiajun Yan, Michael J Zoratti, Feng Xie, Giridharan Ramsingh

Faculty, Staff and Student Publications

Background: TP53 mutations, which are present in 5% to 10% of patients with acute myeloid leukemia (AML), are associated with treatment resistance and poor outcomes. First-line therapies for TP53-mutated (TP53m) AML consist of intensive chemotherapy (IC), hypomethylating agents (HMA), or venetoclax combined with HMA (VEN + HMA).

Methods: We conducted a systematic review and meta-analysis to describe and compare treatment outcomes in newly diagnosed treatment-naïve patients with TP53m AML. Randomized controlled trials, single-arm trials, prospective observational studies, and retrospective studies were included that reported on complete remission (CR), CR with incomplete hematologic recovery (CRi), overall survival (OS), event-free survival (EFS), …

Microbiome Influencers Of Checkpoint Blockade-Associated Toxicity, Yinghong Wang, Robert R Jenq, Jennifer A Wargo, Stephanie S Watowich

Faculty, Staff and Student Publications

Immunotherapy has greatly improved cancer outcomes, yet variability in response and off-target tissue damage can occur with these treatments, including immune checkpoint inhibitors (ICIs). Multiple lines of evidence indicate the host microbiome influences ICI response and risk of immune-related adverse events (irAEs). As the microbiome is modifiable, these advances indicate the potential to manipulate microbiome components to increase ICI success. We discuss microbiome features associated with ICI response, with focus on bacterial taxa and potential immune mechanisms involved in irAEs, and the overall goal of driving novel approaches to manipulate the microbiome to improve ICI efficacy while avoiding irAE risk.