Digital Commons Network^™

Phase 1 Dose Escalation Study Of The Mdm2 Inhibitor Milademetan As Monotherapy And In Combination With Azacitidine In Patients With Myeloid Malignancies, Courtney D Dinardo, Rebecca Olin, Eunice S Wang, Barry Skikne, Joseph Rosenthal, Prasanna Kumar, Hiroyuki Sumi, Yoshiyuki Hizukuri, Ying Hong, Parul Patel, Takahiko Seki, Tao Duan, Arnaud Lesegretain, Michael Andreeff

Faculty, Staff and Student Publications

BACKGROUND: Mouse double minute-2 homolog (MDM2) plays a key role in downregulating p53 activity in hematologic malignancies, and its overexpression is associated with poor outcomes.

METHODS: This phase 1 study assessed the safety and efficacy of different dosing regimens of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine (AZA) in patients with relapsed or refractory acute myeloid leukemia or high-risk myelodysplastic syndromes.

RESULTS: Seventy-four patients (monotherapy, n = 57; milademetan-AZA combination, n = 17) were treated. The maximum tolerated dose of milademetan was 160 mg once daily given for the first 14-21 days of 28-day cycles as …

A Deep Catalogue Of Protein-Coding Variation In 983,578 Individuals, Kathie Y Sun, Xiaodong Bai, Siying Chen, Suying Bao, Chuanyi Zhang, Manav Kapoor, Joshua Backman, Tyler Joseph, Evan Maxwell, George Mitra, Alexander Gorovits, Adam Mansfield, Boris Boutkov, Sujit Gokhale, Lukas Habegger, Anthony Marcketta, Adam E Locke, Liron Ganel, Alicia Hawes, Michael D Kessler, Deepika Sharma, Jeffrey Staples, Jonas Bovijn, Sahar Gelfman, Alessandro Di Gioia, Veera M Rajagopal, Alexander Lopez, Jennifer Rico Varela, Jesús Alegre-Díaz, Jaime Berumen, Roberto Tapia-Conyer, Pablo Kuri-Morales, Jason Torres, Jonathan Emberson, Rory Collins, Regeneron Genetics Center, Rgc-Me Cohort Partners; Michael Cantor, Michael Cantor, Timothy Thornton, Hyun Min Kang, John D Overton, Alan R Shuldiner, M Laura Cremona, Mona Nafde, Aris Baras, Gonçalo Abecasis, Jonathan Marchini, Jeffrey G Reid, William Salerno, Suganthi Balasubramanian

Faculty, Staff and Student Publications

Rare coding variants that substantially affect function provide insights into the biology of a gene1-3. However, ascertaining the frequency of such variants requires large sample sizes4-8. Here we present a catalogue of human protein-coding variation, derived from exome sequencing of 983,578 individuals across diverse populations. In total, 23% of the Regeneron Genetics Center Million Exome (RGC-ME) data come from individuals of African, East Asian, Indigenous American, Middle Eastern and South Asian ancestry. The catalogue includes more than 10.4 million missense and 1.1 million predicted loss-of-function (pLOF) variants. We identify individuals with rare biallelic pLOF variants in 4,848 genes, 1,751 of …

Targeting Of Cyp2e1 By Mirnas In Alcohol-Induced Intestine Injury, Hyejin Mun, Sungyul Lee, Suyoung Choi, Ji-Hoon Jeong, Seungbeom Ko, Yoo Lim Chun, Benjamin Deaton, Clay T Yeager, Audrey Boyette, Juliana Palmera, London Newman, Ping Zhou, Soona Shin, Dong-Chan Kim, Cari A Sagum, Mark T Bedford, Young-Kook Kim, Jaeyul Kwon, Junyang Jung, Jeong Ho Chang, Je-Hyun Yoon

Faculty, Staff and Student Publications

Although binge alcohol-induced gut leakage has been studied extensively in the context of reactive oxygen species-mediated signaling, it was recently revealed that post-transcriptional regulation plays an essential role as well. Ethanol (EtOH)-inducible cytochrome P450-2E1 (CYP2E1), a key enzyme in EtOH metabolism, promotes alcohol-induced hepatic steatosis and inflammatory liver disease, at least in part by mediating changes in intestinal permeability. For instance, gut leakage and elevated intestinal permeability to endotoxins have been shown to be regulated by enhancing CYP2E1 mRNA and CYP2E1 protein levels. Although it is understood that EtOH promotes CYP2E1 induction and activation, the mechanisms that regulate CYP2E1 expression …

Ghcu, A Molecular Chaperone, Regulates Leaf Curling By Modulating The Distribution Of Kngh1 In Cotton, Yihao Zang, Chenyu Xu, Lishan Yu, Longen Ma, Lisha Xuan, Sunyi Yan, Yayao Zhang, Yiwen Cao, Xiaoran Li, Zhanfeng Si, Jieqiong Deng, Tianzhen Zhang, Yan Hu

Faculty, Staff and Student Publications

Leaf shape is considered to be one of the most significant agronomic traits in crop breeding. However, the molecular basis underlying leaf morphogenesis in cotton is still largely unknown. In this study, through genetic mapping and molecular investigation using a natural cotton mutant cu with leaves curling upward, the causal gene GHCU is successfully identified as the key regulator of leaf flattening. Knockout of GHCU or its homolog in cotton and tobacco using CRISPR results in abnormal leaf shape. It is further discovered that GHCU facilitates the transport of the HD protein KNOTTED1-like (KNGH1) from the adaxial to the abaxial …

Genetic Analysis Of Seven Patients With Inherited Ichthyosis And Nagashima-Type Palmoplantar Keratoderma, Jing Zhang, Yue Yao, Ya Tan, Hua-Ying Hu, Lin-Xi Zeng, Guo-Qiang Zhang

Faculty, Staff and Student Publications

Inherited ichthyosis comprises a series of heterogeneous dermal conditions; it mainly manifests as widespread hyperkeratosis, xerosis and scaling of the skin. At times, overlapping symptoms require differential diagnosis between ichthyosis and several other similar disorders. The present study reports seven patients with confirmed or suspected to be associated with ichthyosis by conducting a thorough clinical and genetic investigation. Genetic testing was conducted using whole-exome sequencing, with Sanger sequencing as the validation method. The MEGA7 program was used to analyze the conservation of amino acid residues affected by the detected missense variants. The enrolled patients exhibited ichthyosis-like but distinct clinical manifestations. …

Change In Trust In Us Government Health Agencies For Cancer Information In The Covid-19 Era, Onyema G Chido-Amajuoyi, Rajesh Talluri, Henry K Onyeaka, Itunu Sokale, Gideon T Dosunmu, Noelle Loconte, Sanjay Shete

Faculty, Staff and Student Publications

This cross-sectional study assesses changes in levels of public trust in US government health agencies providing cancer information.

Machine Learning Identifies Prognostic Subtypes Of The Tumor Microenvironment Of Nsclc, Duo Yu, Michael J Kane, Eugene J Koay, Ignacio I Wistuba, Brian P Hobbs

Faculty, Staff and Student Publications

The tumor microenvironment (TME) plays a fundamental role in tumorigenesis, tumor progression, and anti-cancer immunity potential of emerging cancer therapeutics. Understanding inter-patient TME heterogeneity, however, remains a challenge to efficient drug development. This article applies recent advances in machine learning (ML) for survival analysis to a retrospective study of NSCLC patients who received definitive surgical resection and immune pathology following surgery. ML methods are compared for their effectiveness in identifying prognostic subtypes. Six survival models, including Cox regression and five survival machine learning methods, were calibrated and applied to predict survival for NSCLC patients based on PD-L1 expression, CD3 expression, …

Mutation Order In Acute Myeloid Leukemia Identifies Uncommon Patterns Of Evolution And Illuminates Phenotypic Heterogeneity, Matthew Schwede, Katharina Jahn, Jack Kuipers, Linde A Miles, Robert L Bowman, Troy Robinson, Ken Furudate, Hidetaka Uryu, Tomoyuki Tanaka, Yuya Sasaki, Asiri Ediriwickrema, Brooks Benard, Andrew J Gentles, Ross Levine, Niko Beerenwinkel, Koichi Takahashi, Ravindra Majeti

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) has a poor prognosis and a heterogeneous mutation landscape. Although common mutations are well-studied, little research has characterized how the sequence of mutations relates to clinical features. Using published, single-cell DNA sequencing data from three institutions, we compared clonal evolution patterns in AML to patient characteristics, disease phenotype, and outcomes. Mutation trees, which represent the order of select mutations, were created for 207 patients from targeted panel sequencing data using 1 639 162 cells, 823 mutations, and 275 samples. In 224 distinct orderings of mutated genes, mutations related to DNA methylation typically preceded those related to …

Transcranial Direct Current Stimulation Of The Dorsolateral Prefrontal Cortex Does Not Improve Handgrip Time-To-Failure Or Alter Central Or Peripheral Hemodynamics, Yousef Qadumi

All NMU Master's Theses

Age-related deviations to the neuromuscular system negatively impact motor function and performance. Transcranial direct current stimulation (tDCS) has been linked to improvements in the neuromuscular system. The purpose of this study was to determine if tDCS delivered to the dorsolateral prefrontal cortex (DLPFC) would improve handgrip time-to-failure in adults 60 years old and older. Twenty-five participants completed five maximal voluntary contractions, followed by 20-minutes of a-tDCS or SHAM conditions. Next, participants completed a handgrip time-to-failure task by maximally squeezing an electronic handgrip dynamometer until they could no longer maintain 50% of their maximal voluntary contraction. Pairwise t-test revealed a non-significant …

Effects Of Diazepam, D-Amphetamine, And Morphine On Rats’ Choices Between Food Alone And Food With Delayed Shock, Mackenzie Baranski

All NMU Master's Theses

Repeated choices that result in immediate reinforcing consequences followed by delayed aversive consequences are commonly associated with failures in “self-control”. The present study evaluated acute effects of diazepam, d-amphetamine, and morphine on rats’ choices using a variable-delay procedure that arranged choices involving conflicting-valence consequences. Rats pressed response levers to choose between a single-valence consequence (1 food pellet) and a conflicting-valence consequence (3 food pellets followed by a delayed shock). In each condition, the delay to shock varied systematically in a fixed sequence across blocks of trials of a session. After choice was stable, rats were exposed to acute administration …

Evaluation Of Current Redating Guidelines For Pregnancies ≤9 6/7 Weeks' Gestation, Grace Chen, Clara Choi, Allyson Nguyen, Mark Brunk-Grady, Tuan Nguyen

Conference Presentation Abstracts

Objectives: The aim was to evaluate the validity of the current redating guidelines for pregnancies ≤9 6/7 weeks’ gestation. We postulated that visually apparent discrepancies between crown-rump length (CRL) measured by ultrasound (US) and CRL by last menstrual period (LMP) were statistically significant. Methods: This is a retrospective, cross-sectional study conducted between January 2019 and June 2023 at a tertiary referral center. Individuals who had singleton gestations between ≥6 0/7 and ≤9 6/7 weeks by known LMP were reviewed. For estimated gestational age (EGA) by LMP ≥6 0/7 and ≤8 6/7 weeks, a 3–5 day discrepancy between EGA by LMP …

Table Of Contents

Journal of Youth Development

No abstract provided.

Volunteer Training, Tenure, And Facilitation Of Essential Elements In 4-H: Examining Conditions That Promote Positive Youth Development Practices, Kimber Sarver, Kate Fogarty, Tracy Johns, Sarah Thomas Hensley, Dale W. Pracht

Journal of Youth Development

The 4-H program relies on trained volunteers to facilitate youths’ acquisition of life skills in relevant subject matter areas (STEM, Healthy Living). A large part of the 4-H professionals’ objective is to undergird their volunteers in program delivery. The content of volunteers’ training emphasizes the 4 essential elements for youth development programming, namely: 1. Creating an atmosphere of belonging for diverse youth; 2. Promoting generosity through service to their families and communities; 3. Supporting youth mastery of globally applicable life skills and specific skills within subject matter areas of expertise; and 4. Facilitating youths’ sense of independence by self-selecting topics …

Making Sense Of The Arab State, Steven Heydemann, Marc Lynch

Middle East Studies: Faculty Books

Book abstract:

No region in the world has been more hostile to democracy, more dominated by military and security institutions, or weaker on economic development and inclusive governance than the Middle East. Why have Arab states been so oppressively strong in some areas but so devastatingly weak in others? How do those patterns affect politics, economics, and society across the region? The state stands at the center of the analysis of politics in the Middle East, but has rarely been the primary focus of systematic theoretical analysis. Making Sense of the Arab State brings together top scholars from diverse theoretical …

Evaluative Analysis Of The Incorporation Of Ict In The Solving Of Mathematical Problems In Primary Education Students With The Help Of Neutrosophic Statistics On Fuzzy Data, Gladys Martha Flores-Choque, Beker Maraza-Vilcanqui, Nain Maraza-Vilcanqui, Queke Maraza-Vilcanqui, Jesús Ttito-Quispe, Elizabeth Norma Calixto-Arias, Liliana Huaranga-Rivera, Aniceto Elías Aguilar-Polo

Neutrosophic Sets and Systems

This paper aims to determine the influence of incorporating Information and Communication Technologies (ICT) in solving mathematical problems in students of the Primary Educational Institution N° 70656 Ricardo Palma Puno, Peru. To collect the information, a pre-test and a post-test were applied in the variable "resolution of mathematical problems" to an experimental group that received classes with the help of the use of ICT. The test was applied to a control group of the same age that followed the traditional method of learning mathematics. Teachers were asked to evaluate children using a linguistic scale because it is simpler and more …

Community Midwives Plus Project In Sindh: Introducing Group Antenatal Care (Ganc) At The Community Level Through Community Midwives, Population Council Pakistan

Sexual and Reproductive Health, Rights, and Choices

No abstract provided.

Alternative Dispute Resolution In Agency Administrative Programs, Kristen Blankley, Kathleen Claussen, Judith Starr

Articles

This Article studies how federal agencies use and might better use different types of alternative dispute resolution (ADR)-including mediation, conciliation, facilitation, factfinding, minitrials, arbitration, and the use of ombuds-in the programs Congress has entrusted them to administer. The use of ADR by the executive branch of the federal government to resolve disputes with or among private actors has deep historical roots. ADR related to managerial agency matters such as employment or procurement is well-established across the government and performed under a uniform set of laws. Much less has been known, however, about the scope and reach of ADR in the …

Schrodinger's Dissent: The Hybrid Authority Of A Dissenting Opinion, Christina Frohock

Articles

A dissenting opinion is the Schrodinger's cat of authorities: both the law and not the law simultaneously. Courts and scholars often clarify that a dissenting opinion is not binding. Outside the universe of precedent, that authority defies easy description. Emerging from the pen of a judge wearing a black robe and acting in an official capacity, a dissenting opinion exhibits the form of the law. Yet, beneath that lofty sheen, a dissent exhibits the substance of commentary. A dissenting judge writes to undercut the law, providing a case law coda. This Article describes the traditional categories of authority, primary and …

A Closer Look: Understanding Endometriosis And Pelvic Health Through The Lens Of Occupational Therapy, Brenda Vergara

Occupational Therapy Student Capstones

No abstract provided.

Dance For Children W/ Disabilities, Alex Zamora

Occupational Therapy Student Capstones

No abstract provided.

Sensory Reeducation In The Upper Extremity, Angela Vides

Occupational Therapy Student Capstones

No abstract provided.

Increasing Restroom Accessibility For Transgender College Students: An Occupational Justice Effort, Gabriel Soto

Occupational Therapy Student Capstones

No abstract provided.

Postpartum Health And Wellness, Estephanie Huerta

Occupational Therapy Student Capstones

No abstract provided.

A Day In The Life Of A Sci, Jeffrey Garcia

Occupational Therapy Student Capstones

No abstract provided.

Optimizing Eating Performance Among Individuals With Dementia: A Sensory-Based Approach, Nazifa Fazli

Occupational Therapy Student Capstones

No abstract provided.

Exploring The Role Of Occupational Therapy In The Criminal Justice System At The County Level, Marisa Given

Occupational Therapy Student Capstones

No abstract provided.

Imposter Syndrome Management And Strategies For Ot Graduate Students, Lauren Magat

Occupational Therapy Student Capstones

No abstract provided.

Integrating Social Connectedness Within Community Programs, Staphany Jimenez

Occupational Therapy Student Capstones

No abstract provided.

Sensory Education Program For Speech Therapy Graduate Students, And Caregivers Of Children With Support Needs, Julie Jones

Occupational Therapy Student Capstones

No abstract provided.

Exploring Occupational Therapy’S Role With Unhoused Individuals In A Community-Based Setting: An Emerging Practice Area, Mckayla Wallace Mccarthy

Occupational Therapy Student Capstones

No abstract provided.