Digital Commons Network^™

Molecular Profiles Of Serum-Derived Extracellular Vesicles In High-Grade Serous Ovarian Cancer, Li Zhao, Sara Corvigno, Shaolin Ma, Joseph Celestino, Nicole D Fleming, Richard A Hajek, Adrian Lankenau Ahumada, Nicholas B Jennings, Erika J Thompson, Hongli Tang, Shannon N Westin, Amir A Jazaeri, Jianhua Zhang, P Andrew Futreal, Anil K Sood, Sanghoon Lee

Faculty, Staff and Student Publications

Patients with high-grade serous ovarian cancer (HGSC) who have no visible residual disease (R0) after primary surgery have the best clinical outcomes, followed by patients who undergo neoadjuvant chemotherapy (NACT) and have a response enabling interval cytoreductive surgery. Clinically useful biomarkers for predicting these outcomes are still lacking. Extracellular vesicles (EVs) have been recognized as liquid biopsy-based biomarkers for early cancer detection and disease surveillance in other disease settings. In this study, we performed extensive molecular characterization of serum-derived EVs and correlated the findings with therapeutic outcomes in patients with HGSC. Using EV-DNA whole-genome sequencing and EV-RNA sequencing, we identified …

Two-Pore Channel Blockade By Phosphoinositide Kinase Inhibitors Ym201636 And Pi-103 Determined By A Histidine Residue Near Pore-Entrance, Canwei Du, Xin Guan, Jiusheng Yan

Faculty, Staff and Student Publications

Human two-pore channels (TPCs) are endolysosomal cation channels and play an important role in NAADP-evoked Ca2+ release and endomembrane dynamics. We found that YM201636, a PIKfyve inhibitor, potently inhibits PI(3,5)P2-activated human TPC2 with an IC50 of 0.16 μM. YM201636 also effectively inhibits NAADP-activated TPC2 and a constitutively-open TPC2 L690A/L694A mutant channel; whereas it exerts little effect when applied in the channel's closed state. PI-103, a YM201636 analog and an inhibitor of PI3K and mTOR, also inhibits human TPC2 with an IC50 of 0.64 μM. With mutational, virtual docking, and molecular dynamic simulation analyses, we found that YM201636 and PI-103 directly …

Genome-Wide Association Study In Minority Children With Asthma Implicates Dnah5 In Bronchodilator Responsiveness, Jaehyun Joo, Angel C. Y Mak, Shujie Xiao, Patrick M. Sleiman, Donglei Hu, Scott Huntsman, Celeste Eng, Mengyuan Kan, Avantika R. Diwakar, Jessica A. Lasky-Su, Scott T. Weiss, Joanne E. Sordillo, Ann C. Wu, Michelle Cloutier, Glorisa Canino, Erick Forno, Juan C. Celedón, Max A. Seibold, Hakon Hakonarson, Keoki L. Williams, Esteban G. Burchard, Blanca E. Himes

Center for Individualized and Genomic Medicine Research Articles

Variability in response to short-acting β(2)-agonists (e.g., albuterol) among patients with asthma from diverse racial/ethnic groups may contribute to asthma disparities. We sought to identify genetic variants associated with bronchodilator response (BDR) to identify potential mechanisms of drug response and risk factors for worse asthma outcomes. Genome-wide association studies of bronchodilator response (BDR) were performed using TOPMed Whole Genome Sequencing data of the Asthma Translational Genomic Collaboration (ATGC), which corresponded to 1136 Puerto Rican, 656 Mexican and 4337 African American patients with asthma. With the population-specific GWAS results, a trans-ethnic meta-analysis was performed to identify BDR-associated variants shared across the …

Regulated Dicing Of Pre-Mir-144 Via Reshaping Of Its Terminal Loop., Renfu Shang, Dmitry A Kretov, Scott I Adamson, Thomas Treiber, Nora Treiber, Jeffrey Vedanayagam, Jeffrey H Chuang, Gunter Meister, Daniel Cifuentes, Eric C Lai

Faculty Research 2022

Although the route to generate microRNAs (miRNAs) is often depicted as a linear series of sequential and constitutive cleavages, we now appreciate multiple alternative pathways as well as diverse strategies to modulate their processing and function. Here, we identify an unusually profound regulatory role of conserved loop sequences in vertebrate pre-mir-144, which are essential for its cleavage by the Dicer RNase III enzyme in human and zebrafish models. Our data indicate that pre-mir-144 dicing is positively regulated via its terminal loop, and involves the ILF3 complex (NF90 and its partner NF45/ILF2). We provide further evidence that this regulatory switch involves …

Myt1l In The Making: Emerging Insights On Functions Of A Neurodevelopmental Disorder Gene, Jiayang Chen, Allen Yen, Colin P Florian, Joseph D Dougherty

2020-Current year OA Pubs

Large scale human genetic studies have shown that loss of function (LoF) mutations in MYT1L are implicated in neurodevelopmental disorders (NDDs). Here, we provide an overview of the growing number of published MYT1L patient cases, and summarize prior studies in cells, zebrafish, and mice, both to understand MYT1L's molecular and cellular role during brain development and consider how its dysfunction can lead to NDDs. We integrate the conclusions from these studies and highlight conflicting findings to reassess the current model of the role of MYT1L as a transcriptional activator and/or repressor based on the biological context. Finally, we highlight additional …

Influenza Activity And Composition Of The 2022-23 Influenza Vaccine - United States, 2021-22 Season, Angiezel Merced-Morales, Peter Daly, Anwar Isa Abd Elal, Noreen Ajayi, Ekow Annan, Alicia Budd, John Barnes, Arielle Colon, Charisse N Cummings, A Danielle Iuliano, Juliana Dasilva, Nick Dempster, Shikha Garg, Larisa Gubareva, Daneisha Hawkins, Amanda Howa, Stacy Huang, Marie Kirby, Krista Kniss, Rebecca Kondor, Jimma Liddell, Shunte Moon, Ha T Nguyen, Alissa O'Halloran, Catherine Smith, Thomas Stark, Katie Tastad, Dawud Ujamaa, Dave E Wentworth, Alicia M Fry, Vivien G Dugan, Lynnette Brammer

Faculty, Staff and Student Publications

Before the emergence of SARS-CoV-2, the virus that causes COVID-19, influenza activity in the United States typically began to increase in the fall and peaked in February. During the 2021-22 season, influenza activity began to increase in November and remained elevated until mid-June, featuring two distinct waves, with A(H3N2) viruses predominating for the entire season. This report summarizes influenza activity during October 3, 2021-June 11, 2022, in the United States and describes the composition of the Northern Hemisphere 2022-23 influenza vaccine. Although influenza activity is decreasing and circulation during summer is typically low, remaining vigilant for influenza infections, performing testing …

Integrated Dna Copy Number And Expression Profiling Identifies Igf1r As A Prognostic Biomarker In Pediatric Osteosarcoma., Aaron M Taylor, Jiayi M Sun, Alexander Yu, Horatiu Voicu, Jianhe Shen, Donald A Barkauskas, Timothy J Triche, Julie M Gastier-Foster, Tsz-Kwong Man, Ching C Lau

Faculty Research 2022

Osteosarcoma is a primary malignant bone tumor arising from bone-forming mesenchymal cells in children and adolescents. Despite efforts to understand the biology of the disease and identify novel therapeutics, the survival of osteosarcoma patients remains dismal. We have concurrently profiled the copy number and gene expression of 226 osteosarcoma samples as part of the Strategic Partnering to Evaluate Cancer Signatures (SPECS) initiative. Our results demonstrate the heterogeneous landscape of osteosarcoma in younger populations by showing the presence of genome-wide copy number abnormalities occurring both recurrently among samples and in a high frequency. Insulin growth factor receptor 1 (IGF1R) is a …

Integrated Dna Copy Number And Expression Profiling Identifies Igf1r As A Prognostic Biomarker In Pediatric Osteosarcoma, Aaron M Taylor, Jiayi M Sun, Alexander Yu, Horatiu Voicu, Jianhe Shen, Donald A Barkauskas, Timothy J Triche, Julie M Gastier-Foster, Tsz-Kwong Man, Ching C Lau

Center for Medical Ethics and Health Policy Staff Publications

Osteosarcoma is a primary malignant bone tumor arising from bone-forming mesenchymal cells in children and adolescents. Despite efforts to understand the biology of the disease and identify novel therapeutics, the survival of osteosarcoma patients remains dismal. We have concurrently profiled the copy number and gene expression of 226 osteosarcoma samples as part of the Strategic Partnering to Evaluate Cancer Signatures (SPECS) initiative. Our results demonstrate the heterogeneous landscape of osteosarcoma in younger populations by showing the presence of genome-wide copy number abnormalities occurring both recurrently among samples and in a high frequency. Insulin growth factor receptor 1 (IGF1R) is a …

Tumor Microenvironment In Pancreatic Ductal Adenocarcinoma: Implications In Immunotherapy, Caitlyn Smith, Wei Zheng, Jixin Dong, Yaohong Wang, Jinping Lai, Xiuli Liu, Feng Yin

2020-Current year OA Pubs

Pancreatic ductal adenocarcinoma is one of the most aggressive and lethal cancers. Surgical resection is the only curable treatment option, but it is available for only a small fraction of patients at the time of diagnosis. With current therapeutic regimens, the average 5-year survival rate is less than 10% in pancreatic cancer patients. Immunotherapy has emerged as one of the most promising treatment options for multiple solid tumors of advanced stage. However, its clinical efficacy is suboptimal in most clinical trials on pancreatic cancer. Current studies have suggested that the tumor microenvironment is likely the underlying barrier affecting immunotherapy drug …

Kathryn V. Holmes: A Career Of Contributions To The Coronavirus Field, Aurelio Bonavia, Samuel R Dominguez, Gabriela Dveksler, Sara Gagneten, Megan Howard, Scott Jeffers, Zhaohui Qian, Mary Kathryn Smith, Larissa B Thackray, Dina B Tresnan, David E Wentworth, David R Wessner, Richard K Williams, Tanya A Miura

2020-Current year OA Pubs

Over the past two years, scientific research has moved at an unprecedented rate in response to the COVID-19 pandemic. The rapid development of effective vaccines and therapeutics would not have been possible without extensive background knowledge on coronaviruses developed over decades by researchers, including Kathryn (Kay) Holmes. Kay's research team discovered the first coronavirus receptors for mouse hepatitis virus and human coronavirus 229E and contributed a wealth of information on coronaviral spike glycoproteins and receptor interactions that are critical determinants of host and tissue specificity. She collaborated with several research laboratories to contribute knowledge in additional areas, including coronaviral pathogenesis, …

Changes In Health Care Access During The Covid-19 Pandemic: Estimates Of National Japanese Data, June 2020-October 2021, Yuta Tanoue, Cyrus Ghaznavi, Takayuki Kawashima, Akifumi Eguchi, Daisuke Yoneoka, Shuhei Nomura

2020-Current year OA Pubs

The COVID-19 pandemic has disrupted health care access around the world, both for inpatients and outpatients. We applied a quasi-Poisson regression to national, monthly data on the number of outpatients, number of inpatients, length of average hospital stay, and the number of new hospitalizations from March 2015 to October 2021 to assess how these outcomes changed between June 2020 to October 2021. The number of outpatient visits were lower-than-predicted during the early phases of the pandemic but normalized by the fall of 2021. The number of inpatients and new hospitalizations were lower-than-predicted throughout the pandemic, and deficits in reporting continued …

Proteomic Biomarkers Of The Apnea Hypopnea Index And Obstructive Sleep Apnea: Insights Into The Pathophysiology Of Presence, Severity, And Treatment Response, Katie L J Cederberg, Yo-El S Ju, Et Al

2020-Current year OA Pubs

Obstructive sleep apnea (OSA), a disease associated with excessive sleepiness and increased cardiovascular risk, affects an estimated 1 billion people worldwide. The present study examined proteomic biomarkers indicative of presence, severity, and treatment response in OSA. Participants (

Effect Of Race On Prediction Of Brain Amyloidosis By Plasma Aβ42/Aβ40, Phosphorylated Tau, And Neurofilament Light, Suzanne E Schindler, Rachel L Henson, Yan Li, Benjamin Saef, Krista L Moulder, David Bradford, Anne M Fagan, Brian A Gordon, Tammie L S Benzinger, Joyce Balls-Berry, Randall J Bateman, Chengjie Xiong, John C Morris, Et Al

2020-Current year OA Pubs

BACKGROUND AND OBJECTIVES: To evaluate whether plasma biomarkers of amyloid (Aβ42/Aβ40), tau (p-tau181 and p-tau231), and neuroaxonal injury (neurofilament light chain [NfL]) detect brain amyloidosis consistently across racial groups.

METHODS: Individuals enrolled in studies of memory and aging who self-identified as African American (AA) were matched 1:1 to self-identified non-Hispanic White (NHW) individuals by age,

RESULTS: There were 76 matched pairs of AA and NHW participants (n = 152 total). For both AA and NHW groups, the median age was 68.4 years, 42% were

DISCUSSION: Models predicting brain amyloidosis using a high-performance plasma Aβ42/Aβ40 assay may provide an accurate and …

Hippo-Taz Signaling Is The Master Regulator Of The Onset Of Triple-Negative Basal-Like Breast Cancers, Hirotoshi Soyama, Miki Nishio, Junji Otani, Toshiko Sakuma, Shintaro Takao, Shigeo Hara, Takaaki Masuda, Koshi Mimori, Shinya Toyokuni, John P Lydon, Kazuwa Nakao, Hiroshi Nishina, Takumi Fukumoto, Tomohiko Maehama, Akira Suzuki

Faculty, Staff and Students Publications

A universal oncogenic driver of basal-like breast cancer (BLBC) has resisted identification. We show that continuous transcriptional coactivator with PDZ-binding motif (TAZ) activation in precancerous murine luminal cells generates luminal cancers that later become BLBCs. Subsequent TP53 alteration, a feature of invasive human BLBCs, accelerates tumor progression. Because BLBC development is inhibited by TAZ inactivation in vivo, our work provides a sound rationale for targeting Hippo-TAZ signaling as therapy for human BLBC. Our mouse model of BLBC represents a powerful tool for evaluating such drugs.

Adipose Methylome Integrative-Omic Analyses Reveal Genetic And Dietary Metabolic Health Drivers And Insulin Resistance Classifiers., Colette Christiansen, Max Tomlinson, Melissa Eliot, Emma Nilsson, Ricardo Costeira, Yujing Xia, Sergio Villicaña, Olatz Mompeo, Philippa Wells, Juan Castillo-Fernandez, Louis Potier, Marie-Claude Vohl, Andre Tchernof, Julia El-Sayed Moustafa, Cristina Menni, Claire J. Steves, Karl Kelsey, Charlotte Ling, Elin Grundberg, Kerrin S. Small, Jordana T. Bell

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: There is considerable evidence for the importance of the DNA methylome in metabolic health, for example, a robust methylation signature has been associated with body mass index (BMI). However, visceral fat (VF) mass accumulation is a greater risk factor for metabolic disease than BMI alone. In this study, we dissect the subcutaneous adipose tissue (SAT) methylome signature relevant to metabolic health by focusing on VF as the major risk factor of metabolic disease. We integrate results with genetic, blood methylation, SAT gene expression, blood metabolomic, dietary intake and metabolic phenotype data to assess and quantify genetic and environmental drivers …

A Narrative Review On Yoga: A Potential Intervention For Augmenting Immunomodulation And Mental Health In Covid-19, Indranill Basu-Ray, Kashinath Metri, Dibbendhu Khanra, Rishab Revankar, Kavitha M Chinnaiyan, Nagaratna Raghuram, Mahesh Chandra Mishra, Bhushan Patwardhan, Manjunath Sharma, Ishwar V Basavaraddi, Akshay Anand, Shrinath Reddy, K K Deepak, Marian Levy, Sue Theus, Glenn N Levine, Holger Cramer, Gregory L Fricchione, Nagendra R Hongasandra

Faculty, Staff and Students Publications

BACKGROUND: The ongoing novel coronavirus disease 2019 (COVID-19) pandemic has a significant mortality rate of 3-5%. The principal causes of multiorgan failure and death are cytokine release syndrome and immune dysfunction. Stress, anxiety, and depression has been aggravated by the pandemic and its resultant restrictions in day-to-day life which may contribute to immune dysregulation. Thus, immunity strengthening and the prevention of cytokine release syndrome are important for preventing and minimizing mortality in COVID-19 patients. However, despite a few specific remedies that now exist for the SARS-CoV-2virus, the principal modes of prevention include vaccination, masking, and holistic healing methods, such as …

Therapeutic Targeting Of Macrophage Plasticity Remodels The Tumor-Immune Microenvironment, Hee-Jin Jang, Hyun-Sung Lee, Wendong Yu, Maheshwari Ramineni, Cynthia Y Truong, Daniela Ramos, Taylor Splawn, Jong Min Choi, Sung Yun Jung, Ju-Seog Lee, Daniel Y Wang, Joel M Sederstrom, Massimo Pietropaolo, Farrah Kheradmand, Christopher I Amos, Thomas M Wheeler, R Taylor Ripley, Bryan M Burt

Center for Medical Ethics and Health Policy Staff Publications

Although the majority of patients with advanced lung adenocarcinoma (LUAD) are eligible to receive immune checkpoint blockade, approximately 80% of these tumors are resistant to this therapeutic approach. Insights at the single-cell level into mechanisms that drive LUAD tumorigenesis and the relationship of LUAD histologic heterogeneity to response to immune checkpoint blockade could help identify biomarkers and potential combinational approaches to improve immunotherapy efficacy. Here we used a genetically engineered mouse model that replicates the development of human LUAD through a spectrum of pre-invasive to invasive adenocarcinoma histologic subtypes. A systems onco-immunology approach of integrating the analytical power and unique, …

A Method For Bridging Population-Specific Genotypes To Detect Gene Modules Associated With Alzheimer's Disease, Yulin Dai, Peilin Jia, Zhongming Zhao, Assaf Gottlieb

Faculty, Staff and Student Publications

BACKGROUND: Genome-wide association studies have successfully identified variants associated with multiple conditions. However, generalizing discoveries across diverse populations remains challenging due to large variations in genetic composition. Methods that perform gene expression imputation have attempted to address the transferability of gene discoveries across populations, but with limited success.

METHODS: Here, we introduce a pipeline that combines gene expression imputation with gene module discovery, including a dense gene module search and a gene set variation analysis, to address the transferability issue. Our method feeds association probabilities of imputed gene expression with a selected phenotype into tissue-specific gene-module discovery over protein interaction …

Cranial Base Synchondrosis: Chondrocytes At The Hub, Shawn A Hallett, Wanida Ono, Renny T Franceschi, Noriaki Ono

Faculty, Staff and Student Publications

The cranial base is formed by endochondral ossification and functions as a driver of anteroposterior cranial elongation and overall craniofacial growth. The cranial base contains the synchondroses that are composed of opposite-facing layers of resting, proliferating and hypertrophic chondrocytes with unique developmental origins, both in the neural crest and mesoderm. In humans, premature ossification of the synchondroses causes midfacial hypoplasia, which commonly presents in patients with syndromic craniosynostoses and skeletal Class III malocclusion. Major signaling pathways and transcription factors that regulate the long bone growth plate-PTHrP-Ihh, FGF, Wnt, BMP signaling and Runx2-are also involved in the cranial base synchondrosis. Here, …

Impairing Proliferation Of Glioblastoma Multiforme With Cd44+ Selective Conjugated Polymer Nanoparticles, Dorota Lubanska, Sami Alrashed, Gage T. Mason, Fatima Nadeem, Angela Awada, Mitchell Dipasquale, Alexandra Sorge, Aleena Malik, Monika Kojic, Mohamed A. R Soliman, Ana C. De Carvalho, Abdalla Shamisa, Swati Kulkarni, Drew Marquardt, Lisa A. Porter, Simon Rondeau-Gagné

Neurosurgery Articles

Glioblastoma is one of the most aggressive types of cancer with success of therapy being hampered by the existence of treatment resistant populations of stem-like Tumour Initiating Cells (TICs) and poor blood-brain barrier drug penetration. Therapies capable of effectively targeting the TIC population are in high demand. Here, we synthesize spherical diketopyrrolopyrrole-based Conjugated Polymer Nanoparticles (CPNs) with an average diameter of 109 nm. CPNs were designed to include fluorescein-conjugated Hyaluronic Acid (HA), a ligand for the CD44 receptor present on one population of TICs. We demonstrate blood-brain barrier permeability of this system and concentration and cell cycle phase-dependent selective uptake …

Cd11b Suppresses Tlr Activation Of Nonclassical Monocytes To Reduce Primary Graft Dysfunction After Lung Transplantation, Melissa Querrey, Stephen Chiu, Emilia Lecuona, Qiang Wu, Haiying Sun, Megan Anderson, Megan Kelly, Sowmya Ravi, Alexander V. Misharin, Daniel Kreisel, Ankit Bharat, G. R. Scott Budinger

2020-Current year OA Pubs

Primary graft dysfunction (PGD) is the leading cause of postoperative mortality in lung transplant recipients and the most important risk factor for development of chronic lung allograft dysfunction. The mechanistic basis for the variability in the incidence and severity of PGD between lung transplant recipients is not known. Using a murine orthotopic vascularized lung transplant model, we found that redundant activation of Toll-like receptors 2 and 4 (TLR2 and -4) on nonclassical monocytes activates MyD88, inducing the release of the neutrophil attractant chemokine CXCL2. Deletion of Itgam (encodes CD11b) in nonclassical monocytes enhanced their production of CXCL2 and worsened PGD, …

Kras Mutations As Essential Promoters Of Lymphangiogenesis Via Extracellular Vesicles In Pancreatic Cancer, Radu Pirlog, George A Calin

Faculty, Staff and Student Publications

Kirsten rat sarcoma virus (KRAS) gene mutations are present in more than 90% of pancreatic ductal adenocarcinomas (PDACs). KRASG12D is the most frequent alteration, promoting preneoplastic lesions and associating with a more aggressive phenotype. These tumors possess increased intratumoral lymphatic networks and frequent lymph node (LN) metastases. In this issue of the JCI, Luo, Li, et al. explored the relationship between the presence of the KRASG12D mutation and lymphangiogenesis in PDAC. The authors used in vitro and in vivo models and an elegant mechanistic approach to describe an alternative pathway for lymphangiogenesis promotion. KRASG12D induced SUMOylation of heterogenous nuclear ribonucleoprotein …

Cryo-Em Structure Of The Human Kv3.1 Channel Reveals Gating Control By The Cytoplasmic T1 Domain, Gamma Chi, Qiansheng Liang, Akshay Sridhar, John B Cowgill, Kasim Sader, Mazdak Radjainia, Pu Qian, Pablo Castro-Hartmann, Shayla Venkaya, Nanki Kaur Singh, Gavin Mckinley, Alejandra Fernandez-Cid, Shubhashish M M Mukhopadhyay, Nicola A Burgess-Brown, Lucie Delemotte, Manuel Covarrubias, Katharina L Dürr

Department of Neuroscience Faculty Papers

Kv3 channels have distinctive gating kinetics tailored for rapid repolarization in fast-spiking neurons. Malfunction of this process due to genetic variants in the KCNC1 gene causes severe epileptic disorders, yet the structural determinants for the unusual gating properties remain elusive. Here, we present cryo-electron microscopy structures of the human Kv3.1a channel, revealing a unique arrangement of the cytoplasmic tetramerization domain T1 which facilitates interactions with C-terminal axonal targeting motif and key components of the gating machinery. Additional interactions between S1/S2 linker and turret domain strengthen the interface between voltage sensor and pore domain. Supported by molecular dynamics simulations, electrophysiological and …

Neuronal Activity Induces Glucosylceramide That Is Secreted Via Exosomes For Lysosomal Degradation In Glia, Liping Wang, Guang Lin, Zhongyuan Zuo, Yarong Li, Seul Kee Byeon, Akhilesh Pandey, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

Recessive variants in GBA1 cause Gaucher disease, a prevalent form of lysosome storage disease. GBA1 encodes a lysosomal enzyme that hydrolyzes glucosylceramide (GlcCer) into glucose and ceramide. Its loss causes lysosomal dysfunction and increased levels of GlcCer. We generated a null allele of the Drosophila ortholog Gba1b by inserting the Gal4 using CRISPR-Cas9. Here, we show that Gba1b is expressed in glia but not in neurons. Glial-specific knockdown recapitulates the defects found in Gba1b mutants, and these can be rescued by glial expression of human GBA1. We show that GlcCer is synthesized upon neuronal activity, and it is transported …

An Updated Assessment Of 43,110 Patients Enrolled In The Childhood Cancer Research Network: A Children’S Oncology Group Report, Austin L Brown, Pagna Sok, Michael E Scheurer, Karen R Rabin, Erin L Marcotte, Douglas S Hawkins, Logan G Spector, Philip J Lupo

Center for Medical Ethics and Health Policy Staff Publications

Background: The Childhood Cancer Research Network (CCRN) was established by the Children's Oncology Group (COG) as a resource for epidemiologic studies of childhood cancer. The objective of this study was to evaluate the representativeness of CCRN and identify factors associated with enrollment.

Method: The number of US childhood patients with cancer diagnosed < 20 years of age enrolled in CCRN (2008-2015) was compared to expected counts, calculated from Surveillance, Epidemiology, and End Results incidence rates and US Census population estimates. Observed-to-expected ratios and corresponding 95% confidence intervals (CI) were estimated across sex, race, diagnosis age, calendar year, and cancer diagnosis groups. Multivariable linear regression models were generated to evaluate the association between open COG phase 3 therapeutic trials and CCRN enrollment rates.

Result: The 43,110 cases enrolled in CCRN represented 36% of the expected childhood cancers diagnosed from 2008 to 2015 (N = 120,118). CCRN enrollment ratios [95% CI] were highest among males (0.38 [95% CI, 0.37-0.38]), non-Hispanics (0.35 [95% CI, 0.35-0.36]), and those diagnosed from 1 to 4 years …

The Role Of Natural Products And Their Multitargeted Approach To Treat Solid Cancer, Naoshad Muhammad, Darksha Usmani, Mohammad Tarique, Huma Naz, Mohammad Ashraf, Ramesh Raliya, Shams Tabrez, Torki A Zughaibi, Ahdab Alsaieedi, Israa J Hakeem, Mohd Suhail

2020-Current year OA Pubs

Natural products play a critical role in the discovery and development of numerous drugs for the treatment of various types of cancer. These phytochemicals have demonstrated anti-carcinogenic properties by interfering with the initiation, development, and progression of cancer through altering various mechanisms such as cellular proliferation, differentiation, apoptosis, angiogenesis, and metastasis. Treating multifactorial diseases, such as cancer with agents targeting a single target, might lead to limited success and, in many cases, unsatisfactory outcomes. Various epidemiological studies have shown that the steady consumption of fruits and vegetables is intensely associated with a reduced risk of cancer. Since ancient period, plants, …

Reports Of Adverse Events Associated With Use Of Novel Psychoactive Substances, 2017-2020: A Review, Amanda L A Mohr, Barry K Logan, Melissa F Fogarty, Alex J Krotulski, Donna M Papsun, Sherri L Kacinko, Marilyn A Huestis, Jeri D Ropero-Miller

Institute of Emerging Health Professions Faculty Papers

An important role of modern forensic and clinical toxicologists is to monitor the adverse events of novel psychoactive substances (NPS). Following a prior review from 2013 to 2016, this critical literature review analyzes and evaluates published case reports for NPS from January 2017 through December 2020. The primary objective of this study is to assist in the assessment and interpretation of these cases as well as provide references for confirmation methods. Chemistry, pharmacology, adverse events and user profiles (e.g., polypharmacy) for NPS are provided including case history, clinical symptoms, autopsy findings and analytical results. Literature reviews were performed in PubMed …

Long-Term Outcomes For Ibrutinib-Rituximab And Chemoimmunotherapy In Cll: Updated Results Of The E1912 Trial, Tait D Shanafelt, Amanda F Cashen, Et Al.

2020-Current year OA Pubs

Herein, we present the long-term follow-up of the randomized E1912 trial comparing the long-term efficacy of ibrutinib-rituximab (IR) therapy to fludarabine, cyclophosphamide, and rituximab (FCR) and describe the tolerability of continuous ibrutinib. The E1912 trial enrolled 529 treatment-naïve patients aged ≤70 years with chronic lymphocytic leukemia (CLL). Patients were randomly assigned (2:1 ratio) to receive IR or 6 cycles of FCR. With a median follow-up of 5.8 years, median progression-free survival (PFS) is superior for IR (hazard ratio [HR], 0.37; P < .001). IR improved PFS relative to FCR in patients with both immunoglobulin heavy chain variable region (IGHV) gene mutated CLL (HR: 0.27; P < .001) and IGHV unmutated CLL (HR: 0.27; P < .001). Among the 354 patients randomized to IR, 214 (60.5%) currently remain on ibrutinib. Among the 138 IR-treated patients who discontinued treatment, 37 (10.5% of patients who started IR) discontinued therapy due to disease progression or death, 77 (21.9% of patients who started IR) discontinued therapy for adverse events (AEs)/complications, and 24 (6.8% of patients who started IR) withdrew for other reasons. Progression was uncommon among patients able to remain on ibrutinib. The median time from ibrutinib discontinuation to disease progression or death among those who discontinued treatment for a reason other than progression was 25 months. Sustained improvement in overall survival (OS) was observed for patients in the IR arm (HR, 0.47; P = .018). In conclusion, IR therapy offers superior PFS relative to FCR in patients with IGHV mutated or unmutated CLL, as well as superior OS. Continuous ibrutinib therapy is tolerated beyond 5 years in the majority of CLL patients. This trial was registered at www.clinicaltrials.gov as #NCT02048813.

Antiphospholipid Antibodies And Vitamin D Deficiency In Covid-19 Infection With And Without Venous Or Arterial Thrombosis: A Pilot Case-Control Study, Ruchi Shah, Yaqub Nadeem Mohammed, Tracy J Koehler, Jasmeet Kaur, Margarita Toufeili, Priyanjali Pulipati, Ahmed Alqaysi, Ali Khan, Mahrukh Khalid, Yi Lee, Parveen Dhillon, Anna Thao Dan, Nicholas Kumar, Monica Bowen, Anupam A Sule, Geetha Krishnamoorthy

Faculty, Staff and Student Publications

BACKGROUND: Coronavirus disease-2019 (COVID-19) is associated with thromboembolism. Antiphospholipid antibody (APLa) formation is one of the mechanisms. Vitamin D deficiency has been associated with thrombosis in antiphospholipid antibody syndrome.

OBJECTIVE: Measure APLa and vitamin D in hospitalized COVID-19 patients with and without thrombosis to evaluate if thromboembolism is associated with concomitant APLa and vitamin D deficiency.

METHODS: Case-control study. Hospitalized COVID-19 patients with a thromboembolic event (ischemic stroke, myocardial infarction, deep venous thrombosis/pulmonary embolism, Cases n = 20). Controls (n = 20): Age, sex-matched without thromboembolic events. Patients with autoimmune disorders, antiphospholipid antibody syndrome, thrombophilia, anticoagulation therapy, prior thromboembolism, chronic …

Triplet Therapy, Transplantation, And Maintenance Until Progression In Myeloma, Paul G Richardson, Susanna J Jacobus, Edie A Weller, Hani Hassoun, Sagar Lonial, Noopur S Raje, Eva Medvedova, Philip L Mccarthy, Edward N Libby, Peter M Voorhees, Robert Z Orlowski, Larry D Anderson, Jeffrey A Zonder, Carter P Milner, Cristina Gasparetto, Mounzer E Agha, Abdullah M Khan, David D Hurd, Krisstina Gowin, Rammurti T Kamble, Sundar Jagannath, Nitya Nathwani, Melissa Alsina, R Frank Cornell, Hamza Hashmi, Erica L Campagnaro, Astrid C Andreescu, Teresa Gentile, Michaela Liedtke, Kelly N Godby, Adam D Cohen, Thomas H Openshaw, Marcelo C Pasquini, Sergio A Giralt, Jonathan L Kaufman, Andrew J Yee, Emma Scott, Pallawi Torka, Amy Foley, Mariateresa Fulciniti, Kyle Hebert, Mehmet K Samur, Kelly Masone, Michelle E Maglio, Andrea A Zeytoonjian, Omar Nadeem, Robert L Schlossman, Jacob P Laubach, Claudia Paba-Prada, Irene M Ghobrial, Aurore Perrot, Philippe Moreau, Hervé Avet-Loiseau, Michel Attal, Kenneth C Anderson, Nikhil C Munshi, Determination Investigators

Faculty, Staff and Students Publications

BACKGROUND: In patients with newly diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown.

METHODS: In this phase 3 trial, adults (18 to 65 years of age) with symptomatic myeloma received one cycle of RVD. We randomly assigned these patients, in a 1:1 ratio, to receive two additional RVD cycles plus stem-cell mobilization, followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Both groups received …