Genetic Phenomena Commons^™

Cost-Effectiveness Of Sugammadex Versus Neostigmine To Reverse Neuromuscular Blockade In A University Hospital In Taiwan: A Propensity Score-Matched Analysis, Winnie Lan, Ka-Wai Tam, Jui-Tai Chen, Juan P Cata, Yih-Giun Cherng, Yun-Yun Chou, Li-Nien Chien, Chia-Li Chang, Ying-Hsuan Tai, Lu-Min Chu

Faculty, Staff and Student Publications

Sugammadex has several pharmacological advantages over neostigmine, including faster reversal of neuromuscular blockade and fewer adverse effects. However, the economic impact of sugammadex remains controversial due to the considerable heterogeneity of study designs and clinical settings in previous studies. In a post-hoc analysis of a randomized controlled trial, we evaluated patients who underwent elective surgeries and general anesthesia with endotracheal intubation in a medical center in Taiwan between March 2020 and August 2020. Patients were divided into either the sugammadex or neostigmine group based on the neuromuscular blocking drug used. Propensity score matching was used to balance the baseline patient …

Antibody-Drug Conjugates In Lung Cancer: Dawn Of A New Era?, Niamh Coleman, Timothy A Yap, John V Heymach, Funda Meric-Bernstam, Xiuning Le

Faculty, Staff and Student Publications

Antibody-drug conjugates (ADCs) are one of fastest growing classes of oncology drugs in modern drug development. By harnessing the powers of both cytotoxic chemotherapy and targeted therapy, ADCs are unique in offering the potential to deliver highly potent cytotoxic agents to cancer cells which express a pre-defined cell surface target. In lung cancer, the treatment paradigm has shifted dramatically in recent years, and now ADCs are now joining the list as potential options for lung cancer patients. Since 2020, the first ADC for NSCLC patients has been FDA-approved (trastuzumab deruxtecan) and two ADCs have been granted FDA Breakthrough Therapy Designation, …

Reconstructing Mutational Lineages In Breast Cancer By Multi-Patient-Targeted Single-Cell Dna Sequencing, Jake Leighton, Min Hu, Emi Sei, Funda Meric-Bernstam, Nicholas E Navin

Faculty, Staff and Student Publications

Single-cell DNA sequencing (scDNA-seq) methods are powerful tools for profiling mutations in cancer cells; however, most genomic regions sequenced in single cells are non-informative. To overcome this issue, we developed a multi-patient-targeted (MPT) scDNA-seq method. MPT involves first performing bulk exome sequencing across a cohort of cancer patients to identify somatic mutations, which are then pooled together to develop a single custom targeted panel for high-throughput scDNA-seq using a microfluidics platform. We applied MPT to profile 330 mutations across 23,500 cells from 5 patients with triple negative-breast cancer (TNBC), which showed that 3 tumors were monoclonal and 2 tumors were …

Diverticular Disease And Cancer Risk: More Than A Gut Feeling, Veronika Fedirko, Scott Kopetz, Carrie R Daniel

Faculty, Staff and Student Publications

No abstract provided.

Inhibition Of Ribosome Assembly Factor Pno1 By Crispr/Cas9 Technique Suppresses Lung Adenocarcinoma And Notch Pathway: Clinical Application, Sanjit K. Roy, Shivam Srivastava, Andrew Hancock, Anju Shrivastava, Jason Morvant, Sharmila Shankar, Rakesh K. Srivastava

School of Medicine Faculty Publications

Growth is crucially controlled by the functional ribosomes available in cells. To meet the enhanced energy demand, cancer cells re-wire and increase their ribosome biogenesis. The RNA-binding protein PNO1, a ribosome assembly factor, plays an essential role in ribosome biogenesis. The purpose of this study was to examine whether PNO1 can be used as a biomarker for lung adenocarcinoma and also examine the molecular mechanisms by which PNO1 knockdown by CRISPR/Cas9 inhibited growth and epithelial–mesenchymal transition (EMT). The expression of PNO1 was significantly higher in lung adenocarcinoma compared to normal lung tissues. PNO1 expression in lung adenocarcinoma patients increased with …

Many People With Chronic Lymphocytic Leukemia Or Small Lymphocytic Lymphoma Benefit From Ibrutinib Treatment Up To 8 Years: A Plain Language Summary, Paul M Barr, Carolyn Owen, Tadeusz Robak, Alessandra Tedeschi, Osnat Bairey, Jan A Burger, Peter Hillmen, Claire Dearden, Sebastian Grosicki, Helen Mccarthy, Jian Yong Li, Fritz Offner, Carol Moreno, Mandy Jermain, Cathy Zhou, Emily Hsu, Anita Szoke, Thomas J Kipps, Paolo Ghia

Faculty, Staff and Student Publications

What is this summary about?: This is a plain language summary of a publication describing long-term results from the RESONATE-2 study with up to 8 years of follow-up. The original paper was published in Blood Advances in June 2022.

What were the results?: Researchers looked at 269 adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had not received any treatment for their CLL/SLL. Study participants were randomly divided into two groups: 136 participants received treatment with a drug called ibrutinib, and 133 participants received treatment with a drug called chlorambucil. Participants in the study were treated …

Hereditary Angioedema: Diagnosis, Clinical Implications, And Pathophysiology, Evan S. Sinnathamby, Peter P. Issa, Logan Roberts, Haley Norwood, Kevin Malone, Harshitha Vemulapalli, Shahab Ahmadzadeh, Elyse M. Cornett, Sahar Shekoohi, Alan D. Kaye

School of Medicine Faculty Publications

Hereditary angioedema (HAE) is an autosomal dominant disorder caused by a mutation in the C1 esterase inhibitor gene. HAE affects 1/50,000 people worldwide. Three main types of HAE exist: type I, type II, and type III. Type I is characterized by a deficiency in C1-INH. C1-INH is important in the coagulation complement, contact systems, and fibrinolysis. Most HAE cases are type I. Type I and II HAE result from a mutation in the SERPING1 gene, which encodes C1-INH. Formally known as type III HAE is typically an estrogen-dependent or hereditary angioedema with normal C1-INH activity. Current guidelines now recommend subdividing …

Predicting The Risk Of A Clinical Event Using Longitudinal Data: The Generalized Landmark Analysis, Yi Yao, Liang Li, Brad Astor, Wei Yang, Tom Greene

Faculty, Staff and Student Publications

Background: In the development of prediction models for a clinical event, it is common to use the static prediction modeling (SPM), a regression model that relates baseline predictors to the time to event. In many situations, the data used in training and validation are from longitudinal studies, where predictor variables are time-varying and measured at clinical visits. But these data are not used in SPM. The landmark analysis (LA), previously proposed for dynamic prediction with longitudinal data, has interpretational difficulty when the baseline is not a risk-changing clinical milestone, as is often the case in observational studies of chronic disease …

Antagonistic Effect Of Cyclin-Dependent Kinases And A Calcium-Dependent Phosphatase On Polyglutamine-Expanded Androgen Receptor Toxic Gain Of Function, Diana Piol, Laura Tosatto, Emanuela Zuccaro, Eric N Anderson, Antonella Falconieri, Maria J Polanco, Caterina Marchioretti, Federica Lia, Joseph White, Elisa Bregolin, Giovanni Minervini, Sara Parodi, Xavier Salvatella, Giorgio Arrigoni, Andrea Ballabio, Albert R La Spada, Silvio C E Tosatto, Fabio Sambataro, Diego L Medina, Udai B Pandey, Manuela Basso, Maria Pennuto

Duncan NRI Faculty and Staff Publications

Spinal and bulbar muscular atrophy is caused by polyglutamine (polyQ) expansions in androgen receptor (AR), generating gain-of-function toxicity that may involve phosphorylation. Using cellular and animal models, we investigated what kinases and phosphatases target polyQ-expanded AR, whether polyQ expansions modify AR phosphorylation, and how this contributes to neurodegeneration. Mass spectrometry showed that polyQ expansions preserve native phosphorylation and increase phosphorylation at conserved sites controlling AR stability and transactivation. In small-molecule screening, we identified that CDC25/CDK2 signaling could enhance AR phosphorylation, and the calcium-sensitive phosphatase calcineurin had opposite effects. Pharmacologic and genetic manipulation of these kinases and phosphatases modified polyQ-expanded AR …

Chronic Conditions, Late Mortality, And Health Status After Childhood Aml: A Childhood Cancer Survivor Study Report, Lucie M Turcotte, Jillian A Whitton, Wendy M Leisenring, Rebecca M Howell, Joseph P Neglia, Rachel Phelan, Kevin C Oeffinger, Kirsten K Ness, William G Woods, E Anders Kolb, Leslie L Robison, Gregory T Armstrong, Eric J Chow

Faculty, Staff and Student Publications

Five-year survival following childhood acute myeloid leukemia (AML) has increased following improvements in treatment and supportive care. Long-term health outcomes are unknown. To address this, cumulative incidence of late mortality and grades 3 to 5 chronic health condition (CHC) were estimated among 5-year AML survivors diagnosed between 1970 and 1999. Survivors were compared by treatment group (hematopoietic cell transplantation [HCT], chemotherapy with cranial radiation [chemo + CRT], chemotherapy only [chemo-only]), and diagnosis decade. Self-reported health status was compared across treatments, diagnosis decade, and with siblings. Among 856 survivors (median diagnosis age, 7.1 years; median age at last follow-up, 29.4 years), …

The Lysosomal Ragulator Complex Activates Nlrp3 Inflammasome In Vivo Via Hdac6, Kohei Tsujimoto, Tatsunori Jo, Daiki Nagira, Hachiro Konaka, Jeong Hoon Park, Shin-Ichiro Yoshimura, Akinori Ninomiya, Fuminori Sugihara, Takehiro Hirayama, Eri Itotagawa, Yusei Matsuzaki, Yuki Takaichi, Wataru Aoki, Shotaro Saita, Shuhei Nakamura, Andrea Ballabio, Shigeyuki Nada, Masato Okada, Hyota Takamatsu, Atsushi Kumanogoh

Duncan NRI Faculty and Staff Publications

The cellular activation of the NLRP3 inflammasome is spatiotemporally orchestrated by various organelles, but whether lysosomes contribute to this process remains unclear. Here, we show the vital role of the lysosomal membrane-tethered Ragulator complex in NLRP3 inflammasome activation. Deficiency of Lamtor1, an essential component of the Ragulator complex, abrogated NLRP3 inflammasome activation in murine macrophages and human monocytic cells. Myeloid-specific Lamtor1-deficient mice showed marked attenuation of NLRP3-associated inflammatory disease severity, including LPS-induced sepsis, alum-induced peritonitis, and monosodium urate (MSU)-induced arthritis. Mechanistically, Lamtor1 interacted with both NLRP3 and histone deacetylase 6 (HDAC6). HDAC6 enhances the interaction between Lamtor1 and NLRP3, resulting …

Revision Of The Melanocytic Pathology Assessment Tool And Hierarchy For Diagnosis Classification Schema For Melanocytic Lesions: A Consensus Statement, Raymond L Barnhill, David E Elder, Michael W Piepkorn, Stevan R Knezevich, Lisa M Reisch, Megan M Eguchi, Boris C Bastian, Willeke Blokx, Marcus Bosenberg, Klaus J Busam, Richard Carr, Alistair Cochran, Martin G Cook, Lyn M Duncan, Rosalie Elenitsas, Arnaud De La Fouchardière, Pedram Gerami, Iva Johansson, Jennifer Ko, Gilles Landman, Alexander J Lazar, Lori Lowe, Daniela Massi, Jane Messina, Daniela Mihic-Probst, Douglas C Parker, Birgitta Schmidt, Christopher R Shea, Richard A Scolyer, Michael Tetzlaff, Xiaowei Xu, Iwei Yeh, Artur Zembowicz, Joann G Elmore

Faculty, Staff and Student Publications

Importance: A standardized pathology classification system for melanocytic lesions is needed to aid both pathologists and clinicians in cataloging currently existing diverse terminologies and in the diagnosis and treatment of patients. The Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) has been developed for this purpose.

Objective: To revise the MPATH-Dx version 1.0 classification tool, using feedback from dermatopathologists participating in the National Institutes of Health-funded Reducing Errors in Melanocytic Interpretations (REMI) Study and from members of the International Melanoma Pathology Study Group (IMPSG).

Evidence review: Practicing dermatopathologists recruited from 40 US states participated in the 2-year REMI study …

Evaluation Of Proton Therapy Reirradiation For Patients With Recurrent Head And Neck Squamous Cell Carcinoma, Anna Lee, Robbie Woods, Amgad Mahfouz, Sarin Kitpanit, Olivia Cartano, Nader Mohamed, Irini Youssef, Kathryn Marqueen, Kevin Sine, Dennis Mah, Brian Neal, Kaveh Zakeri, Jung J Kang, Nadeem Riaz, Yao Yu, Sean M Mcbride, Linda D Chen, C Jillian Tsai, Daphna Y Gelblum, Robert H Press, Loren S Michel, Eric J Sherman, David Pfister, Lara A Dunn, Alan L Ho, James Fetten, Richard J Wong, Jay O Boyle, Bhuvanesh Singh, Jennifer R Cracchiolo, Ian Ganly, Marc A Cohen, Nancy Y Lee

Faculty, Staff and Student Publications

Importance: Use of proton therapy reirradiation (PT-ReRT) for head and neck cancer is increasing; however, reports are heterogenous and outcomes can be difficult to interpret.

Objective: To evaluate outcomes and toxic effects following PT-ReRT in a uniform and consecutive cohort of patients with head and neck squamous cell carcinoma.

Design, setting, and participants: This retrospective cohort study included patients with recurrent primary head and neck squamous cell carcinoma who were treated with PT-ReRT from January 1, 2013, to December 31, 2020, at a single institution. Patient, clinical, and treatment characteristics were obtained, and multidisciplinary review was performed to record and …

An Initial Experience Of Completion Hemispherotomy Via Magnetic Resonance-Guided Laser Interstitial Therapy, Vijay M Ravindra, Lucia Ruggieri, Nisha Gadgil, Angela P Addison, Ilana Patino, David D Gonda, Jason Chu, Laura Whitehead, Anne Anderson, Gloria Diaz-Medina, Kimberly Houck, Akshat Katyayan, Laura Masters, Audrey Nath, Michael Quach, James John Riviello, Elaine Seto, Krystal Elizabeth Sully, Latanya Agurs, Sonali Sen, Maureen Handoko, Rohini Coorg, Irfan Ali, Daniel Ikeda, Howard Weiner, Daniel J Curry

Duncan NRI Faculty and Staff Publications

Introduction: In carefully selected patients with medically refractory epilepsy, disconnective hemispherotomy can result in significant seizure freedom; however, incomplete disconnection can result in ongoing seizures and poses a significant challenge. Completion hemispherotomy provides an opportunity to finish the disconnection. We describe the use of magnetic resonance-guided laser interstitial thermal ablation (MRgLITT) for completion hemispherotomy.

Methods: Patients treated with completion hemispherotomy using MRgLITT at our institution were identified. Procedural and seizure outcomes were evaluated retrospectively.

Results: Five patients (3 males) underwent six MRgLITT procedures (one child treated twice) for completion hemispherotomy at a median age of 6 years (range 1.8-12.9). Two …

Upregulation Of The Escrt Pathway And Multivesicular Bodies Accelerates Degradation Of Proteins Associated With Neurodegeneration, Ron Benyair, Sai Srinivas Panapakkam Giridharan, Pilar Rivero-Ríos, Junya Hasegawa, Emily Bristow, Eeva-Liisa Eskelinen, Merav D Shmueli, Vered Fishbain-Yoskovitz, Yifat Merbl, Lisa M Sharkey, Henry L Paulson, Phyllis I Hanson, Samarjit Patnaik, Ismael Al-Ramahi, Juan Botas, Juan Marugan, Lois S Weisman

Duncan NRI Faculty and Staff Publications

Many neurodegenerative diseases, including Huntington’s disease (HD) and Alzheimer’s disease (AD), occur due to an accumulation of aggregation-prone proteins, which results in neuronal death. Studies in animal and cell models show that reducing the levels of these proteins mitigates disease phenotypes. We previously reported a small molecule, NCT-504, which reduces cellular levels of mutant huntingtin (mHTT) in patient fibroblasts as well as mouse striatal and cortical neurons from an HdhQ111 mutant mouse. Here, we show that NCT-504 has a broader potential, and in addition reduces levels of Tau, a protein associated with Alzheimer’s disease, as well as other tauopathies. We …

Cytosolic Dna Sensing Protein Pathway Is Activated In Human Hearts With Dilated Cardiomyopathy, Leila Rouhi, Sirisha M Cheedipudi, Benjamin Cathcart, Priyatansh Gurha, Ali J Marian

Faculty, Staff and Student Publications

INTRODUCTION: The genome is constantly exposed to numerous stressors, which induce DNA lesions, including double-stranded DNA breaks (DSBs). DSBs are the most dangerous, as they induce genomic instability. In response to DNA damage, the cell activates nuclear DNA damage response (DDR) and the cytosolic DNA sensing protein (CDSP) pathways, the latter upon release of the DSBs to the cytosol. The CDSP pathway activates NFκB and IRF3, which induce the expression of the pro-inflammatory genes. There is scant data on the activation of the CDSP pathway in human hearts with dilated cardiomyopathy (DCM).

AIM: We aimed to determine expression levels of …

Effects That The Methylenetetrahydrofolate Gene Mutation (Both The C677t And A1298c Polymorphisms) Have On Both Men And Women’S Fertility Abilities And Subsequent Fetal Development, As Well As What Nutritional Changes Can Possibly Do To Aid In Reversing These Supposed Negative Effects., Elizabeth Simkanin

Williams Honors College, Honors Research Projects

This study discusses the perceived negative effects of variants (C677T and A1298C) of the methylenetetrahydrofolate (MTHFR) gene on male and female fertility and fetal development, as well as the potential for nutrition changes to aid in reversing these negative effects. This research project was completed in order to discuss the possible association with and connection between nutrition and fertility in both male and female individuals who have either of the two most common MTHFR gene polymorphisms, 677C>T and 1298A>C. These two polymorphisms are of particular interest because they are associated with the most decreased activity of the MTHFR …

Methodological Considerations In Pisces 3: A Randomized, Placebo-Controlled Study Of Intracerebral Stem Cells In Subjects With Disability Following An Ischemic Stroke, Daniel T Laskowitz, Keith W Muir, Sean I Savitz, Lawrence R Wechsler, Julie G Pilitsis, Scott Y Rahimi, Richard L Beckman, Vincent Holmes, Peng R Chen, Laura Juel, Deborah Koltai, Brad J Kolls

Faculty, Staff and Student Publications

Background and hypothesis: At present, there are no medical interventions proven to improve functional recovery in patients with subacute stroke. We hypothesize that the intraparenchymal administration of CTX0E03, a conditionally immortalized neural stem cell line, linked with a standardized rehabilitation therapy regimen for the upper limb, would improve functional outcomes in patients 6-12 months after an index ischemic stroke.

Study design: PISCES III was designed as a multicenter prospective, sham-controlled, outcome-blinded randomized clinical trial. Eligibility required a qualifying ischemic stroke 6-12 months prior to surgical intervention. Patients must be between 35 and 75 years of age and have residual moderate …

Development Of A Chemical Biology Approach To Uncover The Influence Of Sequence Variations On Ces1 Activity In Live Cells, Samuel James Knebel

Masters Theses

Drug metabolism is the biochemical process of modifying drugs to detoxify and remove them through enzymatic transformations. These biotransformation’s occur primarily in the liver and are critical to understanding how pharmaceutical compounds are chemically altered inside the human body. Human carboxylesterases (CESs) catalyze the hydrolysis of esters, amides, thioesters, and carbamates. CES-mediated hydrolysis plays an important role in the metabolism of many drugs including the first FDA approved antiviral treatment for COVID-19, remdesivir (Veklury), the seizure control medication rufinamide (Banzel), and the flu antiviral drug oseltamivir (Tamiflu). CES activity is known to be influenced by a variety of factors including …

Cerebellar Dysfunction In Rodent Models With Dystonia, Tremor, And Ataxia, Meike E Van Der Heijden, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Dystonia is a movement disorder characterized by involuntary co- or over-contractions of the muscles, which results in abnormal postures and movements. These symptoms arise from the pathophysiology of a brain-wide dystonia network. There is mounting evidence suggesting that the cerebellum is a central node in this network. For example, manipulations that target the cerebellum cause dystonic symptoms in mice, and cerebellar neuromodulation reduces these symptoms. Although numerous findings provide insight into dystonia pathophysiology, they also raise further questions. Namely, how does cerebellar pathophysiology cause the diverse motor abnormalities in dystonia, tremor, and ataxia? Here, we describe recent work in rodents …