Digital Commons Network^™

Gene Expression Dynamics Underlying Cell Fate Emergence In 2d Micropatterned Human Embryonic Stem Cell Gastruloids, Kyaw Thu Minn, Sabine Dietmann, Sarah E Waye, Samantha A Morris, Lilianna Solnica-Krezel

Open Access Publications

Human embryonic stem cells cultured in 2D micropatterns with BMP4 differentiate into a radial arrangement of germ layers and extraembryonic cells. Single-cell transcriptomes demonstrate generation of cell types transcriptionally similar to their in vivo counterparts in Carnegie stage 7 human gastrula. Time-course analyses indicate sequential differentiation, where the epiblast arises by 12 h between the prospective ectoderm in the center and the cells initiating differentiation toward extraembryonic fates at the edge. Extraembryonic and mesendoderm precursors arise from the epiblast by 24 h, while nascent mesoderm, endoderm, and primordial germ cell-like cells form by 44 h. Dynamic changes in transcripts encoding …

Manure Microbial Communities And Resistance Profiles Reconfigure After Transition To Manure Pits And Differ From Those In Fertilized Field Soil, Kimberley V Sukhum, Rhiannon C Vargas, Manish Boolchandani, Alaric W D'Souza, Sanket Patel, Akhil Kesaraju, Gretchen Walljasper, Harshad Hegde, Zhan Ye, Robert K Valenzuela, Paul Gunderson, Casper Bendixsen, Gautam Dantas, Sanjay K Shukla

Open Access Publications

In agricultural settings, microbes and antimicrobial resistance genes (ARGs) have the potential to be transferred across diverse environments and ecosystems. The consequences of these microbial transfers are unclear and understudied. On dairy farms, the storage of cow manure in manure pits and subsequent application to field soil as a fertilizer may facilitate the spread of the mammalian gut microbiome and its associated ARGs to the environment. To determine the extent of both taxonomic and resistance similarity during these transitions, we collected fresh manure, manure from pits, and field soil across 15 different dairy farms for three consecutive seasons. We used …

Perilipin 2 Downregulation In Β Cells Impairs Insulin Secretion Under Nutritional Stress And Damages Mitochondria, Akansha Mishra, Chen Kang, Rajan Sah, Et Al.

Open Access Publications

Perilipin 2 (PLIN2) is a lipid droplet (LD) protein in β cells that increases under nutritional stress. Downregulation of PLIN2 is often sufficient to reduce LD accumulation. To determine whether PLIN2 positively or negatively affects β cell function under nutritional stress, PLIN2 was downregulated in mouse β cells, INS1 cells, and human islet cells. β Cell-specific deletion of PLIN2 in mice on a high-fat diet reduced glucose-stimulated insulin secretion (GSIS) in vivo and in vitro. Downregulation of PLIN2 in INS1 cells blunted GSIS after 24-hour incubation with 0.2 mM palmitic acid. Downregulation of PLIN2 in human pseudoislets cultured at 5.6 …

Recovery Of Consciousness And Cognition After General Anesthesia In Humans, George A. Mashour, Ben J.A. Palanca, Wei Wang, Nan Lin, Maxwell Muench, Hannah Maybrier, Michael S. Avidan, Et Al

Open Access Publications

Understanding how the brain recovers from unconsciousness can inform neurobiological theories of consciousness and guide clinical investigation. To address this question, we conducted a multicenter study of 60 healthy humans, half of whom received general anesthesia for 3 hr and half of whom served as awake controls. We administered a battery of neurocognitive tests and recorded electroencephalography to assess cortical dynamics. We hypothesized that recovery of consciousness and cognition is an extended process, with differential recovery of cognitive functions that would commence with return of responsiveness and end with return of executive function, mediated by prefrontal cortex. We found that, …

Myocardial Lipin 1 Knockout In Mice Approximates Cardiac Effects Of Human Lpin1 Mutations, Kari T. Chambers, Michael A. Cooper, Alison R. Swearingen, Rita T. Brookheart, George G. Schweitzer, Carla J. Weinheimer, Attila Kovacs, Timothy R. Koves, Deborah M. Muoio, Kyle S. Mccommis, Brian N. Finck

Open Access Publications

Lipin 1 is a bifunctional protein that is a transcriptional regulator and has phosphatidic acid (PA) phosphohydrolase activity, which dephosphorylates PA to generate diacylglycerol. Human lipin 1 mutations lead to episodic rhabdomyolysis, and some affected patients exhibit cardiac abnormalities, including exercise-induced cardiac dysfunction and cardiac triglyceride accumulation. Furthermore, lipin 1 expression is deactivated in failing heart, but the effects of lipin 1 deactivation in myocardium are incompletely understood. We generated mice with cardiac-specific lipin 1 KO (cs-Lpin1-/-) to examine the intrinsic effects of lipin 1 in the myocardium. Cs-Lpin1-/- mice had normal systolic cardiac function but mild cardiac hypertrophy. Compared …

Waning Efficacy In A Long-Term Aav-Mediated Gene Therapy Study In The Murine Model Of Krabbe Disease, Gregory J Heller, Michael S Marshall, Yazan Issa, Jeffrey N Marshall, Duc Nguyen, Emily Rue, Koralege C Pathmasiri, Miriam S Domowicz, Richard B Van Breemen, Leon M Tai, Stephanie M Cologna, Stephen J Crocker, Maria I Givogri, Mark S Sands, Ernesto R Bongarzone

Open Access Publications

Neonatal AAV9-gene therapy of the lysosomal enzyme galactosylceramidase (GALC) significantly ameliorates central and peripheral neuropathology, prolongs survival, and largely normalizes motor deficits in Twitcher mice. Despite these therapeutic milestones, new observations identified the presence of multiple small focal demyelinating areas in the brain after 6-8 months. These lesions are in stark contrast to the diffuse, global demyelination that affects the brain of naive Twitcher mice. Late-onset lesions exhibited lysosomal alterations with reduced expression of GALC and increased psychosine levels. Furthermore, we found that lesions were closely associated with the extravasation of plasma fibrinogen and activation of the fibrinogen-BMP-SMAD-GFAP gliotic response. …

Genetic Causes Of Cardiomyopathy In Children: First Results From The Pediatric Cardiomyopathy Genes Study, Stephanie M Ware, Charles E Canter, Et Al

Open Access Publications

Background Pediatric cardiomyopathy is a genetically heterogeneous disease with substantial morbidity and mortality. Current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, but practice variations exist. Robust data on clinical testing practices and diagnostic yield in children are lacking. This study aimed to identify the genetic causes of cardiomyopathy in children and to investigate clinical genetic testing practices. Methods and Results Children with familial or idiopathic cardiomyopathy were enrolled from 14 institutions in North America. Probands underwent exome sequencing. Rare sequence variants in 37 known cardiomyopathy genes were assessed for pathogenicity using consensus clinical interpretation guidelines. …

Multi-Omic Analysis Elucidates The Genetic Basis Of Hydrocephalus, Andrew T Hale, Lisa Bastarache, Diego M Morales, John C Wellons Iii, David D Limbrick Jr., Eric R Gamazon

Open Access Publications

We conducted PrediXcan analysis of hydrocephalus risk in ten neurological tissues and whole blood. Decreased expression of MAEL in the brain was significantly associated (Bonferroni-adjusted p < 0.05) with hydrocephalus. PrediXcan analysis of brain imaging and genomics data in the independent UK Biobank (N = 8,428) revealed that MAEL expression in the frontal cortex is associated with white matter and total brain volumes. Among the top differentially expressed genes in brain, we observed a significant enrichment for gene-level associations with these structural phenotypes, suggesting an effect on disease risk through regulation of brain structure and integrity. We found additional support for these genes through analysis of the choroid plexus transcriptome of a murine model of hydrocephalus. Finally, differential protein expression analysis in patient cerebrospinal fluid recapitulated disease-associated expression changes in neurological tissues, but not in whole blood. Our findings provide convergent evidence highlighting the importance of tissue-specific pathways and mechanisms in the pathophysiology of hydrocephalus.

Postsurgical Presentation Of Zollinger-Ellison Syndrome After Resection Of Endometrioid Neuroendocrine Tumor, Aymen Almuhaidb, Nicholas O Davidson

Open Access Publications

Zollinger-Ellison syndrome is a functional neuroendocrine tumor with inappropriate gastrin secretion and hyperchlorhydria causing severe peptic ulcer disease and chronic diarrhea. Although 70% of primary gastrinomas occur in the region of the duodenum, the diagnosis and localization of gastrinomas can be challenging because of small lesions that may arise functionally as lymph node metastases at initial presentation. We report a 76-year-old woman presenting with Zollinger-Ellison syndrome several months after surgical resection of endometrioid small cell neuroendocrine carcinoma and endometrioid adenocarcinoma.

Effects Of Community-Based Antiretroviral Therapy Initiation Models On Hiv Treatment Outcomes: A Systematic Review And Meta-Analysis, Ingrid Eshun-Wilson, Ajibola A. Awotiwon, Ashley Germann, Sophia A. Amankwaa, Nathan Ford, Sheree Schwartz, Stefan Baral, Elvin H. Geng

Open Access Publications

BACKGROUND: Antiretroviral therapy (ART) initiation in the community and outside of a traditional health facility has the potential to improve linkage to ART, decongest health facilities, and minimize structural barriers to attending HIV services among people living with HIV (PLWH). We conducted a systematic review and meta-analysis to determine the effect of offering ART initiation in the community on HIV treatment outcomes.

METHODS AND FINDINGS: We searched databases between 1 January 2013 and 22 February 2021 to identify randomized controlled trials (RCTs) and observational studies that compared offering ART initiation in a community setting to offering ART initiation in a …

Epigenomic Regulation Of Human T-Cell Leukemia Virus By Chromatin-Insulator Ctcf, Xiaogang Cheng, Ancy Joseph, Victor Castro, Alice Chen-Liaw, Zachary Skidmore, Takaharu Ueno, Jun-Ichi Fujisawa, Daniel A. Rauch, Grant A. Challen, Michael P. Martinez, Patrick Green, Malachi Griffith, Jacqueline E. Payton, John R. Edwards, Lee Ratner

Open Access Publications

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that causes an aggressive T-cell malignancy and a variety of inflammatory conditions. The integrated provirus includes a single binding site for the epigenomic insulator, CCCTC-binding protein (CTCF), but its function remains unclear. In the current study, a mutant virus was examined that eliminates the CTCF-binding site. The mutation did not disrupt the kinetics and levels of virus gene expression, or establishment of or reactivation from latency. However, the mutation disrupted the epigenetic barrier function, resulting in enhanced DNA CpG methylation downstream of the CTCF binding site on both strands of …

Quantitative Signal Properties From Standardized Mris Correlate With Multiple Sclerosis Disability, Matthew R Brier, Abraham Z Snyder, Aaron Tanenbaum, Richard A Rudick, Elizabeth Fisher, Stephen Jones, Joshua S Shimony, Anne H Cross, Tammie L S Benzinger, Robert T Naismith

Open Access Publications

OBJECTIVE: To enable use of clinical magnetic resonance images (MRIs) to quantify abnormalities in normal appearing (NA) white matter (WM) and gray matter (GM) in multiple sclerosis (MS) and to determine associations with MS-related disability. Identification of these abnormalities heretofore has required specialized scans not routinely available in clinical practice.

METHODS: We developed an analytic technique which normalizes image intensities based on an intensity atlas for quantification of WM and GM abnormalities in standardized MRIs obtained with clinical sequences. Gaussian mixture modeling is applied to summarize image intensity distributions from T1-weighted and 3D-FLAIR (T2-weighted) images from 5010 participants enrolled in …

Obese Endometrial Cancer Survivors' Perceptions Of Weight Loss Strategies And Characteristics That May Influence Participation In Behavioral Interventions, Elise M Wilson, Abigail S Zamorano, Jingxia Liu, David Morris, Andrea Leon, Lindsay M Kuroki, Premal H Thaker, Carolyn K Mccourt, Katherine C Fuh, Matthew A Powell, David G Mutch, Graham A Colditz, Andrea R Hagemann

Open Access Publications

We aimed to evaluate obese endometrial cancer (EC) survivors' perceptions of weight loss barriers and previously attempted weight loss methods and to identify characteristics that predicted willingness to enroll in a behavioral intervention trial. We administered a 27-question baseline survey at an academic institution to EC survivors with body mass index ≥ 30 kg/m

Spatially Fractionated Stereotactic Body Radiation Therapy (Lattice) For Large Tumors, Sai Duriseti, James Kavanaugh, Sreekrishna Goddu, Alex Price, Nels Knutson, Francisco Reynoso, Jeff Michalski, Sasa Mutic, Clifford Robinson, Matthew B Spraker

Open Access Publications

Purpose: Stereotactic body radiation therapy (SBRT) has demonstrated clinical benefits for patients with metastatic and/or unresectable cancer. Technical considerations of treatment delivery and nearby organs at risk can limit the use of SBRT in large tumors or those in unfavorable locations. Spatially fractionated radiation therapy (SFRT) may address this limitation because this technique can deliver high-dose radiation to discrete subvolume vertices inside a tumor target while restricting the remainder of the target to a safer lower dose. Indeed, SFRT, such as GRID, has been used to treat large tumors with reported dramatic tumor response and minimal side effects. Lattice is …

Crohn's Disease-Associated Atg16l1 T300a Genotype Is Associated With Improved Survival In Gastric Cancer, Changqing Ma, Chad E Storer, Uma Chandran, William A Laframboise, Patricia Petrosko, Madison Frank, Douglas J Hartman, Liron Pantanowitz, Talin Haritunians, Richard D Head, Ta-Chiang Liu

Open Access Publications

BACKGROUND: A non-synonymous single nucleotide polymorphism of the ATG16L1 gene, T300A, is a major Crohn's disease (CD) susceptibility allele, and is known to be associated with increased apoptosis induction in the small intestinal crypt base in CD subjects and mouse models. We hypothesized that ATG16L1 T300A genotype also correlates with increased tumor apoptosis and therefore could lead to superior clinical outcome in cancer subjects.

METHODS: T300A genotyping by Taqman assay was performed for gastric carcinoma subjects who underwent resection from two academic medical centers. Transcriptomic analysis was performed by RNA-seq on formalin-fixed paraffin-embedded cancerous tissue. Tumor apoptosis and autophagy were …

A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With Als, Jeremy M. Shefner, Timothy M. Miller, Et Al

Open Access Publications

No abstract provided.

Placental Sampling For Understanding Viral Infections - A Simplified Protocol For The Covid-19 Pandemic, Guilherme De Moraes Nobrega, José Paulo Siqueira Guida, Rodolfo Rosa Japecanga, Arthur Antolini-Tavares, Indira Mysorekar, Maria Laura Costa

Open Access Publications

OBJECTIVE:  The coronavirus disease 2019 (COVID-19) is a pandemic viral disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The impact of the disease among the obstetric population remains unclear, and the study of the placenta can provide valuable information. Adequate sampling of the placental tissue can help characterize the pathways of viral infections.

METHODS:  A protocol of placental sampling is proposed, aiming at guaranteeing representativity of the placenta and describing the adequate conservation of samples and their integrity for future analysis. The protocol is presented in its complete and simplified versions, allowing its implementation in different complexity settings. …

Taz-Camta1 And Yap-Tfe3 Alter The Taz/Yap Transcriptome By Recruiting The Atac Histone Acetyltransferase Complex, Nicole Merritt, Keith Garcia, Dushyandi Rajendran, Zhen-Yuan Lin, Xiaomeng Zhang, Katrina A. Mitchell, Nicholas Borcherding, Colleen Fullenkamp, Michael S. Chimenti, Anne-Claude Gingras, Kieran F. Harvey, Munir R. Tanas

Open Access Publications

Epithelioid hemangioendothelioma (EHE) is a vascular sarcoma that metastasizes early in its clinical course and lacks an effective medical therapy. The TAZ-CAMTA1 and YAP-TFE3 fusion proteins are chimeric transcription factors and initiating oncogenic drivers of EHE. A combined proteomic/genetic screen in human cell lines identified YEATS2 and ZZZ3, components of the

Oncolytic Hsv-1 G207 Immunovirotherapy For Pediatric High-Grade Gliomas, Gregory K Friedman, Mohamed S Abdelbaki, Et Al

Open Access Publications

BACKGROUND: Outcomes in children and adolescents with recurrent or progressive high-grade glioma are poor, with a historical median overall survival of 5.6 months. Pediatric high-grade gliomas are largely immunologically silent or "cold," with few tumor-infiltrating lymphocytes. Preclinically, pediatric brain tumors are highly sensitive to oncolytic virotherapy with genetically engineered herpes simplex virus type 1 (HSV-1) G207, which lacks genes essential for replication in normal brain tissue.

METHODS: We conducted a phase 1 trial of G207, which used a 3+3 design with four dose cohorts of children and adolescents with biopsy-confirmed recurrent or progressive supratentorial brain tumors. Patients underwent stereotactic placement …

A Target-Agnostic Screen Identifies Approved Drugs To Stabilize The Endoplasmic Reticulum-Resident Proteome, Mark J Henderson, Fumihiko Urano, Et Al

Open Access Publications

Endoplasmic reticulum (ER) dysregulation is associated with pathologies including neurodegenerative, muscular, and diabetic conditions. Depletion of ER calcium can lead to the loss of resident proteins in a process termed exodosis. To identify compounds that attenuate the redistribution of ER proteins under pathological conditions, we performed a quantitative high-throughput screen using the Gaussia luciferase (GLuc)-secreted ER calcium modulated protein (SERCaMP) assay, which monitors secretion of ER-resident proteins triggered by calcium depletion. We identify several clinically used drugs, including bromocriptine, and further characterize them using assays to measure effects on ER calcium, ER stress, and ER exodosis. Bromocriptine elicits protective effects …

Phenotype Of Peripheral Nk Cells In Latent, Active, And Meningeal Tuberculosis, José Alberto Choreño-Parra, Shabaana A. Khader, Et Al

Open Access Publications

No abstract provided.

Her2 And Apc Mutations Promote Altered Crypt-Villus Morphology And Marked Hyperplasia In The Intestinal Epithelium, Elisa Murray, Xiaoqing Cheng, Anagha Krishna, Xiaohua Jin, Takahiro E Ohara, Thaddeus S Stappenbeck, Ron Bose

Open Access Publications

BACKGROUND AND AIMS: The Cancer Genome Atlas (TCGA) project has identified HER2 mutations or amplification in 7% of colon cancers. In addition to HER2 mutations, colon cancer patients also possess co-occurring mutations in genes such as APC. Here, we investigated the role of HER2 and APC mutations on the crypt-villus architecture of the intestinal epithelium, localization of secretory cells, and expression of intestinal stem cell markers.

METHODS: We generated a HER2 transgenic mouse (HER2

RESULTS: HER2

CONCLUSIONS: We established an epithelial intrinsic role for HER2

Sars-Cov-2 Requires Cholesterol For Viral Entry And Pathological Syncytia Formation, David W. Sanders, Alex S. Holehouse, Et Al

Open Access Publications

Many enveloped viruses induce multinucleated cells (syncytia), reflective of membrane fusion events caused by the same machinery that underlies viral entry. These syncytia are thought to facilitate replication and evasion of the host immune response. Here, we report that co-culture of human cells expressing the receptor ACE2 with cells expressing SARS-CoV-2 spike, results in synapse-like intercellular contacts that initiate cell-cell fusion, producing syncytia resembling those we identify in lungs of COVID-19 patients. To assess the mechanism of spike/ACE2-driven membrane fusion, we developed a microscopy-based, cell-cell fusion assay to screen ~6000 drugs and >30 spike variants. Together with quantitative cell biology …

Immune Activation During Paenibacillus Brain Infection In African Infants With Frequent Cytomegalovirus Co-Infection, Albert M Isaacs, Qiang Zhang, Diego M Morales, R Reid Townsend, David D Limbrick Jr, Et Al

Open Access Publications

Inflammation during neonatal brain infections leads to significant secondary sequelae such as hydrocephalus, which often follows neonatal sepsis in the developing world. In 100 African hydrocephalic infants we identified the biological pathways that account for this response. The dominant bacterial pathogen was a

Integrating Neuroimaging Biomarkers Into The Multicentre, High-Dose Erythropoietin For Asphyxia And Encephalopathy (Heal) Trial: Rationale, Protocol And Harmonisation, Jessica L Wisnowski, Robert C Mckinstry, Et Al

Open Access Publications

INTRODUCTION: MRI and MR spectroscopy (MRS) provide early biomarkers of brain injury and treatment response in neonates with hypoxic-ischaemic encephalopathy). Still, there are challenges to incorporating neuroimaging biomarkers into multisite randomised controlled trials. In this paper, we provide the rationale for incorporating MRI and MRS biomarkers into the multisite, phase III high-dose erythropoietin for asphyxia and encephalopathy (HEAL) Trial, the MRI/S protocol and describe the strategies used for harmonisation across multiple MRI platforms.

METHODS AND ANALYSIS: Neonates with moderate or severe encephalopathy enrolled in the multisite HEAL trial undergo MRI and MRS between 96 and 144 hours of age using …

A Microbiota-Directed Food Intervention For Undernourished Children, Robert Y Chen, Matthew C Hibberd, Arjun S Raman, Daniel Webber, Cyrus Zhou, Vinaik Sundaresan, Kazi Ahsan, Martin F Meier, Michael J Barratt, Jeffrey I Gordon, Et Al

Open Access Publications

BACKGROUND: More than 30 million children worldwide have moderate acute malnutrition. Current treatments have limited effectiveness, and much remains unknown about the pathogenesis of this condition. Children with moderate acute malnutrition have perturbed development of their gut microbiota.

METHODS: In this study, we provided a microbiota-directed complementary food prototype (MDCF-2) or a ready-to-use supplementary food (RUSF) to 123 slum-dwelling Bangladeshi children with moderate acute malnutrition between the ages of 12 months and 18 months. The supplementation was given twice daily for 3 months, followed by 1 month of monitoring. We obtained weight-for-length, weight-for-age, and length-for-age z scores and mid-upper-arm circumference …

Evolution Of Genetic Networks For Human Creativity, I Zwir, C Del-Val, C R Cloninger, Et Al

Open Access Publications

The genetic basis for the emergence of creativity in modern humans remains a mystery despite sequencing the genomes of chimpanzees and Neanderthals, our closest hominid relatives. Data-driven methods allowed us to uncover networks of genes distinguishing the three major systems of modern human personality and adaptability: emotional reactivity, self-control, and self-awareness. Now we have identified which of these genes are present in chimpanzees and Neanderthals. We replicated our findings in separate analyses of three high-coverage genomes of Neanderthals. We found that Neanderthals had nearly the same genes for emotional reactivity as chimpanzees, and they were intermediate between modern humans and …

A Single Intranasal Dose Of Chimpanzee Adenovirus-Vectored Vaccine Protects Against Sars-Cov-2 Infection In Rhesus Macaques, Ahmed O Hassan, Friederike Feldmann, Haiyan Zhao, David T Curiel, Atsushi Okumura, Tsing-Lee Tang-Huau, James Brett Case, Kimberly Meade-White, Julie Callison, Rita E Chen, Jamie Lovaglio, Patrick W Hanley, Dana P Scott, Daved H Fremont, Heinz Feldmann, Michael S Diamond

Open Access Publications

The deployment of a vaccine that limits transmission and disease likely will be required to end the coronavirus disease 2019 (COVID-19) pandemic. We recently described the protective activity of an intranasally administered chimpanzee adenovirus-vectored vaccine encoding a pre-fusion stabilized spike (S) protein (ChAd-SARS-CoV-2-S [chimpanzee adenovirus-severe acute respiratory syndrome-coronavirus-2-S]) in the upper and lower respiratory tracts of mice expressing the human angiotensin-converting enzyme 2 (ACE2) receptor. Here, we show the immunogenicity and protective efficacy of this vaccine in non-human primates. Rhesus macaques were immunized with ChAd-Control or ChAd-SARS-CoV-2-S and challenged 1 month later by combined intranasal and intrabronchial routes with SARS-CoV-2. …

Contextual Cues From Cancer Cells Govern Cancer-Associated Fibroblast Heterogeneity, Neus Bota-Rabassedas, Gregory D Longmore, Et Al

Open Access Publications

Cancer cells function as primary architects of the tumor microenvironment. However, the molecular features of cancer cells that govern stromal cell phenotypes remain unclear. Here, we show that cancer-associated fibroblast (CAF) heterogeneity is driven by lung adenocarcinoma (LUAD) cells at either end of the epithelial-to-mesenchymal transition (EMT) spectrum. LUAD cells that have high expression of the EMT-activating transcription factor ZEB1 reprogram CAFs through a ZEB1-dependent secretory program and direct CAFs to the tips of invasive projections through a ZEB1-driven CAF repulsion process. The EMT, in turn, sensitizes LUAD cells to pro-metastatic signals from CAFs. Thus, CAFs respond to contextual cues …

Psychosocial Syndemics And Multimorbidity In Patients With Heart Failure, Kenneth E Freedland, Judith A Skala, Robert M Carney, Brian C Steinmeyer, Michael W Rich

Open Access Publications

Heart failure (HF) is a common cause of hospitalization and mortality in older adults. HF is almost always embedded within a larger pattern of multimorbidity, yet many studies exclude patients with complex psychiatric and medical comorbidities or cognitive impairment. This has left significant gaps in research on the problems and treatment of patients with HF. In addition, HF is only one of multiple challenges facing patients with multimorbidity, stressful socioeconomic circumstances, and psychosocial problems. The purpose of this study is to identify combinations of comorbidities and health disparities that may affect HF outcomes and require different mixtures of medical, psychological, …