Medicine and Health Sciences Commons^™

Using Long-Read Cage Sequencing To Profile Cryptic-Promoter-Derived Transcripts And Their Contribution To The Immunopeptidome, Ju Heon Maeng, H Josh Jang, Alan Y Du, Shin-Cheng Tzeng, Ting Wang

2020-Current year OA Pubs

Recent studies have shown that the noncoding genome can produce unannotated proteins as antigens that induce immune response. One major source of this activity is the aberrant epigenetic reactivation of transposable elements (TEs). In tumors, TEs often provide cryptic or alternate promoters, which can generate transcripts that encode tumor-specific unannotated proteins. Thus, TE-derived transcripts (TE transcripts) have the potential to produce tumor-specific, but recurrent, antigens shared among many tumors. Identification of TE-derived tumor antigens holds the promise to improve cancer immunotherapy approaches; however, current genomics and computational tools are not optimized for their detection. Here we combined CAGE technology with …

Single-Pulse Electrical Stimulation Artifact Removal Using The Novel Matching Pursuit-Based Artifact Reconstruction And Removal Method (Mparrm), Tao Xie, Thomas J Foutz, Markus Adamek, James R Swift, Cory S Inman, Joseph R Manns, Eric C Leuthardt, Jon T Willie, Peter Brunner

2020-Current year OA Pubs

No abstract provided.

Development Of White Matter Fiber Covariance Networks Supports Executive Function In Youth, Joëlle Bagautdinova, Aristeidis Sotiras, Et Al.

2020-Current year OA Pubs

During adolescence, the brain undergoes extensive changes in white matter structure that support cognition. Data-driven approaches applied to cortical surface properties have led the field to understand brain development as a spatially and temporally coordinated mechanism that follows hierarchically organized gradients of change. Although white matter development also appears asynchronous, previous studies have relied largely on anatomical tract-based atlases, precluding a direct assessment of how white matter structure is spatially and temporally coordinated. Harnessing advances in diffusion modeling and machine learning, we identified 14 data-driven patterns of covarying white matter structure in a large sample of youth. Fiber covariance networks …

Cd62l Expression Marks A Functionally Distinct Subset Of Memory B Cells, Christopher H Hanson, Brittany Henry, Pradhnesh Andhare, Frank J Lin, Haley Pak, Jackson S Turner, Lucas J Adams, Tom Liu, Daved H Fremont, Ali H Ellebedy, Brian J Laidlaw

2020-Current year OA Pubs

The memory B cell response consists of phenotypically distinct subsets that differ in their ability to respond upon antigen re-encounter. However, the pathways regulating the development and function of memory B cell subsets are poorly understood. Here, we show that CD62L and CD44 are progressively expressed on mouse memory B cells and identify transcriptionally and functionally distinct memory B cell subsets. Bcl6 is important in regulating memory B cell subset differentiation with overexpression of Bcl6 resulting in impaired CD62L

Mecp2 Represses The Activity Of Topoisomerase Iiβ In Long Neuronal Genes, Sabin A Nettles, Yoshiho Ikeuchi, Katheryn B Lefton, Ladan Abbasi, Alyssa Erickson, Chibueze Agwu, Thomas Papouin, Azad Bonni, Harrison W Gabel

2020-Current year OA Pubs

A unique signature of neurons is the high expression of the longest genes in the genome. These genes have essential neuronal functions, and disruption of their expression has been implicated in neurological disorders. DNA topoisomerases resolve DNA topological constraints and facilitate neuronal long gene expression. Conversely, the Rett syndrome protein, methyl-CpG-binding protein 2 (MeCP2), can transcriptionally repress long genes. How these factors regulate long genes is not well understood, and whether they interact is not known. Here, we identify and map a functional interaction between MeCP2 and topoisomerase IIβ (TOP2β) in mouse neurons. We profile neuronal TOP2β activity genome wide, …

Genomic Loci Influence Patterns Of Structural Covariance In The Human Brain, Junhao Wen, Aristeidis Sotiras, Daniel S Marcus, Pamela Lamontagne, John C Morris, Et Al.

2020-Current year OA Pubs

Normal and pathologic neurobiological processes influence brain morphology in coordinated ways that give rise to patterns of structural covariance (PSC) across brain regions and individuals during brain aging and diseases. The genetic underpinnings of these patterns remain largely unknown. We apply a stochastic multivariate factorization method to a diverse population of 50,699 individuals (12 studies and 130 sites) and derive data-driven, multi-scale PSCs of regional brain size. PSCs were significantly correlated with 915 genomic loci in the discovery set, 617 of which are newly identified, and 72% were independently replicated. Key pathways influencing PSCs involve reelin signaling, apoptosis, neurogenesis, and …

A Distinct Human Cell Type Expressing Mhcii And Rorγt With Dual Characteristics Of Dendritic Cells And Type 3 Innate Lymphoid Cells, Alina Ulezko Antonova, Changxu Fan, Natalia Jaeger, Patrick Fernandes Rodrigues, Simone Brioschi, Tihana Trsan, José L Fachi, Khai M Nguyen, Ryan M Nunley, Ting Wang, Marina Cella, William Vermi, Marco Colonna, Et Al.

2020-Current year OA Pubs

Recent studies have characterized various mouse antigen-presenting cells (APCs) expressing the lymphoid-lineage transcription factor RORγt (Retinoid-related orphan receptor gamma t), which exhibit distinct phenotypic features and are implicated in the induction of peripheral regulatory T cells (Tregs) and immune tolerance to microbiota and self-antigens. These APCs encompass Janus cells and Thetis cell subsets, some of which express the AutoImmune REgulator (AIRE). RORγt

Improving Transparency In The Residency Application Process: Survey Study, Lindsey Ulin, Simone A Bernstein, Julio C Nunes, Alex Gu, Maya M Hammoud, Jessica A Gold, Kamran M Mirza

2020-Current year OA Pubs

BACKGROUND: Increasing numbers of residency applications create challenges for applicants and residency programs to assess if they are a good fit during the residency application and match process. Applicants face limited or conflicting information as they assess programs, leading to overapplying. A holistic review of residency applications is considered a gold standard for programs, but the current volumes and associated time constraints leave programs relying on numerical filters, which do not predict success in residency. Applicants could benefit from increased transparency in the residency application process.

OBJECTIVE: This study aims to determine the information applicants find most beneficial from residency …

Primary Care Clinicians' Prescribing Patterns Of Reduced-Dose Direct Oral Anticoagulants For Extended-Phase Venous Thromboembolism Treatment, Danielle Groat, Karlyn A Martin, Rachel P Rosovsky, Kristen M Sanfilippo, Manila Gaddh, Lisa Baumann Kreuziger, Elizabeth Federici, Scott C Woller

2020-Current year OA Pubs

The direct anticoagulants (DOACs), apixaban and rivaroxaban, are used for extended-phase treatment of venous thromboembolism (VTE) and have labeling for dose reduction for this indication. The objective of this study was to better understand primary care clinician prescribing patterns of apixaban and rivaroxaban for extended-phase anticoagulation. We conducted a 21-question survey targeting members of the American College of Physicians and United States Veterans Administration anticoagulation management services. Survey questions covered prescribing behaviors for dose reduction of apixaban and rivaroxaban for extended VTE treatment, as well as questions related to the respondent's practice setting. We used logistic regression to assess associations …

Pediatric Necrobiotic Xanthogranuloma As A Novel Phenotype Of Ikaros Gain Of Function, Rachel Guess, George Harocopos, Jeffrey J Bednarski, Lynn M Hassmann, Tarin M Bigley

2020-Current year OA Pubs

No abstract provided.

Effectiveness And Safety Of Different Estradiol Regimens In Transgender Women (Treat Study): Protocol For A Randomized Controlled Trial, Samuel Cortez, Dominic Moog, Christopher Lewis, Kelley Williams, Cynthia Herrick, Melanie Fields, Teddi Gray, Zhaohua Guo, Ginger Nicol, Thomas Baranski

2020-Current year OA Pubs

BACKGROUND: Current guidelines for gender-affirming hormone therapy (GAHT) for transgender women are mostly based on clinical experience from experts in the field and treatments used on postmenopausal women. While care is currently provided with the best available evidence, there is a critical gap in knowledge about the safest and most effective estradiol routes of administration for GAHT in transgender women; this statement is supported by the World Professional Association for Transgender Health on their Standards of Care for the Health of Transgender and Gender Diverse People, version 8. Furthermore, the reported rates of cardiometabolic adverse events in transgender women highlight …

Leveraging Mhealth To Mitigate The Impact Of Covid-19 In Black American Communities: Qualitative Analysis, Kelly M Harris, Tilicia Mayo Gamble, Madelyn G Yoo, Lindsay A Spell, Timira N Minor, Holly Jones, Donald Lynch

2020-Current year OA Pubs

BACKGROUND: COVID-19 remains an ongoing public health crisis. Black Americans remain underrepresented among those vaccinated and overrepresented in both COVID-19 morbidity and mortality. Medical misinformation, specifically related to COVID-19, has exacerbated the impact of the disease in Black American communities. Communication tools and strategies to build relationships and disseminate credible and trustworthy diagnostic and preventative health information are necessary to improve outcomes and equity for historically oppressed populations.

OBJECTIVE: As the initial phase of a larger mixed methods project to develop, pilot, and evaluate a mobile health (mHealth) intervention among a population at high risk for COVID-19 and cardiovascular comorbidities, …

Efficacy And Safety Of Teprotumumab In Patients With Thyroid Eye Disease Of Long Duration And Low Disease Activity, Raymond S Douglas, Steven Couch, Sara T Wester, Brian T Fowler, Catherine Y Liu, Prem S Subramanian, Rosa Tang, Quang T Nguyen, Robi N Maamari, Shoaib Ugradar, Kate Hsu, Michael Karon, Marius N Stan

2020-Current year OA Pubs

CONTEXT: Early inflammatory thyroid eye disease (TED) can lead to symptomatic chronic disease, including disabling proptosis. Teprotumumab, an insulin-like growth factor-1 receptor (IGF-1R) inhibitor, previously demonstrated efficacy in acute, high-inflammation TED trials.

OBJECTIVE: We present data from the first placebo-controlled trial with teprotumumab in chronic/low disease activity TED.

METHODS: This randomized double-masked, placebo-controlled trial, conducted at 11 US centers, enrolled adult participants with TED duration of 2 to 10 years, Clinical Activity Score (CAS) ≤ 1 or no additional inflammation or progression in proptosis/diplopia for ≥1 year, proptosis ≥3 mm from before TED and/or from normal, euthyroid/mildly hypo/hyperthyroid, no prior …

Pharmacokinetics Of Dacarbazine And Unesbulin And Cyp1a2-Mediated Drug Interactions In Patients With Leiomyosarcoma, Lan Gao, Diksha Kaushik, Brian A Van Tine, Matthew A Ingham, Steven Attia, Christian F Meyer, Gary K Schwartz, Pius Maliakal, John D Baird, Jiyuan Ma, Rosemary Barrett, Dhiren D'Silva, Kylie O'Keefe, Ronald Kong

2020-Current year OA Pubs

Unesbulin is being investigated in combination with dacarbazine (DTIC) as a potential therapeutic agent in patients with advanced leiomyosarcoma (LMS). This paper reports the pharmacokinetics (PK) of unesbulin, DTIC, and its unreactive surrogate metabolite 5-aminoimidazole-4-carboxamide (AIC) in 29 patients with advanced LMS. Drug interactions between DTIC (and AIC) and unesbulin were evaluated. DTIC (1000 mg/m

Dsm-5 Conduct Disorder And Symptoms In Youths At High Risk Of Psychosis In Kenya With Dsm-5 Mental Disorders And Substance Use: Towards Integrated Management, David M Ndetei, Victoria Mutiso, Christine Musyimi, Reinpeter Momanyi, Pascalyne Nyamai, Peter Tyrer, Daniel Mamah

2020-Current year OA Pubs

Little is known about the prevalence of Conduct Disorder (CD) and symptoms of CD in high risk psychosis persons at both clinical and community populations in LMICs and in particular Kenya. This study aimed to document (1) the prevalence of CD diagnosis and symptoms in youth who screened positive for psychosis and (2) the associated mental disorders and substance use in the same cohort in LMIC. The sample size was 536 students who had screened positive on the Washington Early Recognition Center Affectivity and Psychosis (WERCAP) from a population of 9,742 high school, college and university students, but had not …

Distinct Gene Expression Signatures Comparing Latent Tuberculosis Infection With Different Routes Of Bacillus Calmette-Guérin Vaccination, Richard F Silver, Mei Xia, Chad E Storer, Jessica R Jarvela, Michelle C Moyer, Azra Blazevic, David A Stoeckel, Erin K Rakey, Jan M Tennant, Johannes B Goll, Richard D Head, Daniel F Hoft

2020-Current year OA Pubs

Tuberculosis remains an international health threat partly because of limited protection from pulmonary tuberculosis provided by standard intradermal vaccination with Bacillus of Calmette and Guérin (BCG); this may reflect the inability of intradermal vaccination to optimally induce pulmonary immunity. In contrast, respiratory Mycobacterium tuberculosis infection usually results in the immune-mediated bacillary containment of latent tuberculosis infection (LTBI). Here we present RNA-Seq-based assessments of systemic and pulmonary immune cells from LTBI participants and recipients of intradermal and oral BCG. LTBI individuals uniquely display ongoing immune activation and robust CD4 T cell recall responses in blood and lung. Intradermal BCG is associated …

Comparative Genomics Reveals The Correlations Of Stress Response Genes And Bacteriophages In Developing Antibiotic Resistance Of Staphylococcus Saprophyticus, Kailun Zhang, Robert F Potter, Jamie Marino, Carol E Muenks, Matthew G Lammers, Jennifer Dien Bard, Tanis C Dingle, Romney Humphries, Lars F Westblade, Carey-Ann D Burnham, Gautam Dantas

2020-Current year OA Pubs

No abstract provided.

Instrumental Variables For Implementation Science: Exploring Context-Dependent Causal Pathways Between Implementation Strategies And Evidence-Based Interventions, Aaloke Mody, Lindsey M Filiatreau, Charles W Goss, Byron J Powell, Elvin H Geng

2020-Current year OA Pubs

BACKGROUND: The impact of both implementation strategies (IS) and evidence-based interventions (EBI) can vary across contexts, and a better understanding of how and why this occurs presents fundamental but challenging questions that implementation science as a field will need to grapple with. We use causal epidemiologic methods to explore the mechanisms of why sharp distinctions between implementation strategies (IS) and efficacy of an evidence-based intervention (EBI) may fail to recognize that the effect of an EBI can be deeply intertwined and dependent on the context of the IS leading to its uptake.

METHODS: We explore the use of instrumental variable …

The Faculty-To-Faculty Mentorship Experience: A Survey On Challenges And Recommendations For Improvements, Sarvenaz Sarabipour, Natalie M Niemi, Steven J Burgess, Christopher T Smith, Alexandre W Bisson Filho, Ahmed Ibrahim, Kelly Clark

2020-Current year OA Pubs

Faculty at research institutions play a central role in advancing knowledge and careers, as well as promoting the well-being of students and colleagues in research environments. Mentorship from experienced peers has been touted as critical for enabling these myriad roles to allow faculty development, career progression, and satisfaction. However, there is little information available on who supports faculty and best ways to structure a faculty mentorship programme for early- and mid-career academics. In the interest of advocating for increased and enhanced faculty mentoring and mentoring programmes, we surveyed faculty around the world to gather data on whether and how they …

Advanced Structural Brain Aging In Preclinical Autosomal Dominant Alzheimer Disease, Peter R Millar, Brian A Gordon, Julie K Wisch, Tammie L.S. Benzinger, Carlos Cruchaga, Jason J Hassenstab, Laura Ibanez, Celeste Karch, Jorge J Llibre-Guerra, John C Morris, Richard J Perrin, Charlene Supnet-Bell, Chengjie Xiong, Randall J Bateman, Beau M Ances, Eric M Mcdade, Et Al.

2020-Current year OA Pubs

BACKGROUND: "Brain-predicted age" estimates biological age from complex, nonlinear features in neuroimaging scans. The brain age gap (BAG) between predicted and chronological age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD), in which AD progression is highly predictable with minimal confounding age-related co-pathology.

METHODS: We modeled BAG in 257 deeply-phenotyped ADAD mutation-carriers and 179 non-carriers from the Dominantly Inherited Alzheimer Network using minimally-processed structural MRI scans. We then tested whether BAG differed as a function of mutation and cognitive status, or estimated years until symptom onset, and whether it was associated with established …

Autophagy Gene-Dependent Intracellular Immunity Triggered By Interferon-Γ, Michael R Mcallaster, Jaya Bhushan, Dale R Balce, Anthony Orvedahl, Arnold Park, Seungmin Hwang, Meagan E Sullender, L David Sibley, Herbert W Virgin

2020-Current year OA Pubs

Interferon-γ (IFNγ) is a critical mediator of cell-intrinsic immunity to intracellular pathogens. Understanding the complex cellular mechanisms supporting robust interferon-γ-induced host defenses could aid in developing new therapeutics to treat infections. Here, we examined the impact of autophagy genes in the interferon-γ-induced host response. We demonstrate that genes within the autophagy pathway including

A Broadly Reactive Antibody Targeting The N-Terminal Domain Of Sars-Cov-2 Spike Confers Fc-Mediated Protection, Lucas J Adams, Laura A Vanblargan, Zhuoming Liu, Pavlo Gilchuk, Haiyan Zhao, Rita E Chen, Saravanan Raju, Zhenlu Chong, Bradley M Whitener, Swathi Shrihari, Prashant N Jethva, Michael L Gross, James E Crowe Jr., Sean P J Whelan, Michael S Diamond, Daved H Fremont

2020-Current year OA Pubs

Most neutralizing anti-SARS-CoV-2 monoclonal antibodies (mAbs) target the receptor binding domain (RBD) of the spike (S) protein. Here, we characterize a panel of mAbs targeting the N-terminal domain (NTD) or other non-RBD epitopes of S. A subset of NTD mAbs inhibits SARS-CoV-2 entry at a post-attachment step and avidly binds the surface of infected cells. One neutralizing NTD mAb, SARS2-57, protects K18-hACE2 mice against SARS-CoV-2 infection in an Fc-dependent manner. Structural analysis demonstrates that SARS2-57 engages an antigenic supersite that is remodeled by deletions common to emerging variants. In neutralization escape studies with SARS2-57, this NTD site accumulates mutations, including …

Vodka2: A Fast And Accurate Method To Detect Non-Standard Viral Genomes From Large Rna-Seq Data Sets, Emna Achouri, Sébastien A Felt, Matthew Hackbart, Nicole S Rivera-Espinal, Carolina B López

2020-Current year OA Pubs

During viral replication, viruses carrying an RNA genome produce non-standard viral genomes (nsVGs), including copy-back viral genomes (cbVGs) and deletion viral genomes (delVGs), that play a crucial role in regulating viral replication and pathogenesis. Because of their critical roles in determining the outcome of RNA virus infections, the study of nsVGs has flourished in recent years, exposing a need for bioinformatic tools that can accurately identify them within next-generation sequencing data obtained from infected samples. Here, we present our data analysis pipeline, Viral Opensource DVG Key Algorithm 2 (VODKA2), that is optimized to run on a parallel computing environment for …

Engineering E. Coli Strains Using Antibiotic-Resistance-Gene-Free Plasmids, Matthew B Amrofell, Sunaina Rengarajan, Steven T Vo, Erick S Ramirez Tovar, Larissa Lobello, Gautam Dantas, Tae Seok Moon

2020-Current year OA Pubs

We created a generalizable pipeline for antibiotic-resistance-gene-free plasmid (ARGFP)-based cloning using a dual auxotrophic- and essential-gene-based selection strategy. We use auxotrophic selection to construct plasmids in engineered E. coli DH10B cloning strains and both auxotrophic- and essential-gene-based selection to (1) select for recombinant strains and (2) maintain a plasmid in E. coli Nissle 1917, a common chassis for engineered probiotic applications, and E. coli MG1655, the laboratory "wild-type" E. coli strain. We show that our approach has comparable efficiency to that of antibiotic-resistance-gene-based cloning. We also show that the double-knockout Nissle and MG1655 strains are simple to transform with plasmids …

Integrative Analysis Of Clinicopathological Features Defines Novel Prognostic Models For Mantle Cell Lymphoma In The Immunochemotherapy Era: A Report From The North American Mantle Cell Lymphoma Consortium, Julie M Vose, Brad S Kahl, Et Al.

2020-Current year OA Pubs

BACKGROUND: Patients with mantle cell lymphoma (MCL) exhibit a wide variation in clinical presentation and outcome. However, the commonly used prognostic models are outdated and inadequate to address the needs of the current multidisciplinary management of this disease. This study aims to investigate the clinical and pathological features of MCL in the immunochemotherapy era and improve the prognostic models for a more accurate prediction of patient outcomes.

METHODS: The North American Mantle Cell Lymphoma Project is a multi-institutional collaboration of 23 institutions across North America to evaluate and refine prognosticators for front-line therapy. A total of 586 MCL cases diagnosed …

Diversity And Dissemination Of Viruses In Pathogenic Protozoa, Senne Heeren, Ilse Maes, Mandy Sanders, Lon-Fye Lye, Vanessa Adaui, Jorge Arevalo, Alejandro Llanos-Cuentas, Lineth Garcia, Philippe Lemey, Stephen M Beverley, James A Cotton, Jean-Claude Dujardin, Frederik Van Den Broeck

2020-Current year OA Pubs

Viruses are the most abundant biological entities on Earth and play a significant role in the evolution of many organisms and ecosystems. In pathogenic protozoa, the presence of viruses has been linked to an increased risk of treatment failure and severe clinical outcome. Here, we studied the molecular epidemiology of the zoonotic disease cutaneous leishmaniasis in Peru and Bolivia through a joint evolutionary analysis of Leishmania braziliensis and their dsRNA Leishmania virus 1. We show that parasite populations circulate in tropical rainforests and are associated with single viral lineages that appear in low prevalence. In contrast, groups of hybrid parasites …

A Single C-Terminal Residue Controls Sars-Cov-2 Spike Trafficking And Incorporation Into Vlps, Debajit Dey, Enya Qing, Yanan He, Yihong Chen, Benjamin Jennings, Whitaker Cohn, Suruchi Singh, Lokesh Gakhar, Nicholas J Schnicker, Brian G Pierce, Julian P Whitelegge, Balraj Doray, John Orban, Tom Gallagher, S Saif Hasan

2020-Current year OA Pubs

The spike (S) protein of SARS-CoV-2 is delivered to the virion assembly site in the ER-Golgi Intermediate Compartment (ERGIC) from both the ER and cis-Golgi in infected cells. However, the relevance and modulatory mechanism of this bidirectional trafficking are unclear. Here, using structure-function analyses, we show that S incorporation into virus-like particles (VLP) and VLP fusogenicity are determined by coatomer-dependent S delivery from the cis-Golgi and restricted by S-coatomer dissociation. Although S mimicry of the host coatomer-binding dibasic motif ensures retrograde trafficking to the ERGIC, avoidance of the host-like C-terminal acidic residue is critical for S-coatomer dissociation and therefore incorporation …

Cell-Free Rna Signatures Predict Alzheimer's Disease, Alejandro Cisterna-García, Aleksandra Beric, Muhammad Ali, Jose Adrian Pardo, Hsiang-Han Chen, Maria Victoria Fernandez, Joanne Norton, Jen Gentsch, Kristy Bergmann, John Budde, Joel S Perlmutter, John C Morris, Carlos Cruchaga, Juan A Botia, Laura Ibanez

2020-Current year OA Pubs

There is a need for affordable, scalable, and specific blood-based biomarkers for Alzheimer's disease that can be applied to a population level. We have developed and validated disease-specific cell-free transcriptomic blood-based biomarkers composed by a scalable number of transcripts that capture AD pathobiology even in the presymptomatic stages of the disease. Accuracies are in the range of the current CSF and plasma biomarkers, and specificities are high against other neurodegenerative diseases.

T1 And Flair Signal Intensities Are Related To Tau Pathology In Dominantly Inherited Alzheimer Disease, Farzaneh Rahmani, Matthew R Brier, Brian A Gordon, Nicole Mckay, Shaney Flores, Sarah Keefe, Russ Hornbeck, Beau Ances, Nelly Joseph-Mathurin, Chengjie Xiong, Guoqiao Wang, Cyrus A Raji, Jorge J Libre-Guerra, Richard J Perrin, Eric Mcdade, Alisha Daniels, Celeste Karch, John C Morris, Randall J Bateman, Tammie L S Benzinger, Et Al.

2020-Current year OA Pubs

Carriers of mutations responsible for dominantly inherited Alzheimer disease provide a unique opportunity to study potential imaging biomarkers. Biomarkers based on routinely acquired clinical MR images, could supplement the extant invasive or logistically challenging) biomarker studies. We used 1104 longitudinal MR, 324 amyloid beta, and 87 tau positron emission tomography imaging sessions from 525 participants enrolled in the Dominantly Inherited Alzheimer Network Observational Study to extract novel imaging metrics representing the mean (μ) and standard deviation (σ) of standardized image intensities of T1-weighted and Fluid attenuated inversion recovery (FLAIR) MR scans. There was an exponential decrease in FLAIR-μ in mutation …

Combining The Tyrosine Kinase Inhibitor Cabozantinib And The Mtorc1/2 Inhibitor Sapanisertib Blocks Erk Pathway Activity And Suppresses Tumor Growth In Renal Cell Carcinoma, Yige Wu, Siqi Chen, Xiaolu Yang, Kazuhito Sato, Preet Lal, Andrew T Shinkle, Michael C Wendl, Tina M Primeau, Yanyan Zhao, Alanna Gould, Hua Sun, Jacqueline L Mudd, Jeremy Hoog, R Jay Mashl, Matthew A Wyczalkowski, Chia-Kuei Mo, Ruiyang Liu, John M Herndon, Sherri R Davies, Di Liu, Xi Ding, Ramaswamy Govindan, Shunqiang Li, James Hsieh, Ryan C Fields, Kian-Huat Lim, Cynthia X Ma, Li Ding, Feng Chen, Et Al.

2020-Current year OA Pubs

UNLABELLED: Current treatment approaches for renal cell carcinoma (RCC) face challenges in achieving durable tumor responses due to tumor heterogeneity and drug resistance. Combination therapies that leverage tumor molecular profiles could offer an avenue for enhancing treatment efficacy and addressing the limitations of current therapies. To identify effective strategies for treating RCC, we selected ten drugs guided by tumor biology to test in six RCC patient-derived xenograft (PDX) models. The multitargeted tyrosine kinase inhibitor (TKI) cabozantinib and mTORC1/2 inhibitor sapanisertib emerged as the most effective drugs, particularly when combined. The combination demonstrated favorable tolerability and inhibited tumor growth or induced …