Now showing items 21-40 of 24701

    • Surveillance of Host and Pathogen Derived Metabolites Activates Intestinal Immunity

      Read Pukkila-Worley; Peterson, Nicholas D. (2022-06-30)
      Intestinal epithelial cells function, in part, to detect infection with pathogenic organisms and are key regulators of intestinal immune homeostasis. However, it is not fully understood how intestinal epithelial cells sense pathogen infection and coordinate the induction of protective immune defenses. Here, we define two new mechanisms of innate immune regulation in a metazoan host. First, we characterize the first bacterial pattern recognition receptor and its natural ligand in Caenorhabditis elegans. We show that the C. elegans nuclear hormone receptor NHR-86/HNF4 directly senses phenazine-1-carboxamide (PCN), a metabolite produced by pathogenic strains of Pseudomonas aeruginosa. PCN binds to the ligand-binding domain of NHR-86/HNF4, a ligand-gated transcription factor, and activates innate immunity in intestinal epithelial cells. In addition, we show that C. elegans NHR-86 senses PCN, and not other phenazine metabolites, as a marker of pathogen virulence to engage protective anti-pathogen defenses. Second, we show that a phase transition of the C. elegans Toll/interleukin-1 receptor domain protein (TIR-1) controls signaling by the C. elegans p38 PMK-1 MAPK pathway. Physiologic stress, both P. aeruginosa infection and sterol scarcity, induce multimerization of TIR-1 within intestinal epithelial cells. Like the mammalian homolog of TIR-1, SARM1, oligomerization and phase transition of C. elegans TIR-1 dramatically potentiate its NAD+ glycohydrolase activity. TIR-1/SARM1 multimerization and NAD+ glycohydrolase activity are required for activation of C. elegans p38 PMK-1 pathway signaling and pathogen resistance. These data uncover a mechanism by which nematodes interpret environmental conditions to prime innate immune defenses and promote survival in microbe rich environments. C. elegans animals augment these immune defenses by surveying for ligands specifically associated with toxigenic pathogens that are poised to cause disease. These findings define a new paradigm of intestinal immune control that informs the evolution of innate immunity in all metazoans.
    • The Impact of the COVID-19 Pandemic on the Clubhouse Model

      McKay, Colleen E.; Corcoran, Joel D (2022-06-29)
      The COVID-19 pandemic posed challenges to the traditional Clubhouse Model of Psychosocial Rehabilitation (Clubhouse). The COVID-19 pandemic forced many Clubhouses around the world to rapidly pivot from face-to-face services and support programs at the Clubhouse to hybrid or virtual services. The Clubhouse community quickly mobilized to establish new structures to maintain connections with Clubhouse members and provide them with essential supports. This brief describes adaptations that Clubhouses made during the COVID-19 pandemic. We also describe supports offered by Clubhouse International to inform their international network about innovative approaches and best practices for Clubhouses during the COVID-19 pandemic.
    • Super large-bore ingestion of clot (SLIC) leads to high first pass effect in thrombectomy for large vessel occlusion

      Massari, Francesco; Dabus, Guilherme; Cortez, Gustavo M.; Singh, Jasmeet; Kuhn, Anna L.; Naragum, Varun; Anagnostakou, Vania; Hanel, Ricardo A.; Gounis, Matthew J.; Puri, Ajit S. (2022-06-22)
      BACKGROUND: Super large-bore aspiration (SLBA) has shown high rates of complete clot ingestion. OBJECTIVE: To report the initial clinical feasibility, safety, and efficacy of this novel SLBA insert combination-super large-bore ingestion of clot (SLIC) technique for stroke. METHODS: We performed a retrospective review of three comprehensive stroke center databases. The SLIC technique entails a triaxial assembly of an 8 Fr 0.106'' Base Camp catheter, 0.088'' catheter extender (HiPoint), and an insert catheter (Tenzing 8) that completely consumes the inner diameter of the 0.088'' SLBA catheter. The HiPoint catheter is delivered over the Tenzing 8 to the face of the embolus, which is withdrawn, while aspirating through the Base Camp and HiPoint catheters as a single assembly. RESULTS: Thirty-three consecutive patients with large vessel occlusion were treated with SLIC. The median age was 70 years (30-91) and 17 were male (51.5%). The median presenting National Institutes of Health Stroke Scale score and Alberta Stroke Program Early CT score was 21 (1-34) and 8 (5-10), respectively. There was 100% success in delivering the 0.088'' catheter to the site of the occlusion. The successful revascularization rate (modified Thrombolysis in Cerebral Infarction (mTICI) score > /=2B) was 100% within a single pass in most cases (82%). Final mTICI > /=2C was achieved in 94.1% of occlusions, with 73.5% mTICI 3 recanalization. The rate of first pass effect in achieving excellent reperfusion (mTICI > /=2C) was 70.5%. There were no adverse events or postprocedural symptomatic hemorrhages. CONCLUSIONS: Our initial experience with the SLIC technique resulted in achieving a first pass effect (mTICI > /=2C) in 70.5%. Navigation of the SLBA catheter extender over the Tenzing insert was successful and safe in this early experience.
    • Vitamin, Mineral, and Multivitamin Supplementation to Prevent Cardiovascular Disease and Cancer: US Preventive Services Task Force Recommendation Statement

      US Preventive Services Task Force; Mangione, Carol M.; Pbert, Lori (2022-06-21)
      Importance: According to National Health and Nutrition Examination Survey data, 52% of surveyed US adults reported using at least 1 dietary supplement in the prior 30 days and 31% reported using a multivitamin-mineral supplement. The most commonly cited reason for using supplements is for overall health and wellness and to fill nutrient gaps in the diet. Cardiovascular disease and cancer are the 2 leading causes of death and combined account for approximately half of all deaths in the US annually. Inflammation and oxidative stress have been shown to have a role in both cardiovascular disease and cancer, and dietary supplements may have anti-inflammatory and antioxidative effects. Objective: To update its 2014 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a review of the evidence on the efficacy of supplementation with single nutrients, functionally related nutrient pairs, or multivitamins for reducing the risk of cardiovascular disease, cancer, and mortality in the general adult population, as well as the harms of supplementation. Population: Community-dwelling, nonpregnant adults. Evidence Assessment: The USPSTF concludes with moderate certainty that the harms of beta carotene supplementation outweigh the benefits for the prevention of cardiovascular disease or cancer. The USPSTF also concludes with moderate certainty that there is no net benefit of supplementation with vitamin E for the prevention of cardiovascular disease or cancer. The USPSTF concludes that the evidence is insufficient to determine the balance of benefits and harms of supplementation with multivitamins for the prevention of cardiovascular disease or cancer. Evidence is lacking and the balance of benefits and harms cannot be determined. The USPSTF concludes that the evidence is insufficient to determine the balance of benefits and harms of supplementation with single or paired nutrients (other than beta carotene and vitamin E) for the prevention of cardiovascular disease or cancer. Evidence is lacking and the balance of benefits and harms cannot be determined. Recommendation: The USPSTF recommends against the use of beta carotene or vitamin E supplements for the prevention of cardiovascular disease or cancer. (D recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the use of multivitamin supplements for the prevention of cardiovascular disease or cancer. (I statement) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the use of single- or paired-nutrient supplements (other than beta carotene and vitamin E) for the prevention of cardiovascular disease or cancer. (I statement).
    • Defining the substrate envelope of SARS-CoV-2 main protease to predict and avoid drug resistance

      Shaqra, Ala M.; Zvornicanin, Sarah N.; Huang, Qiu Yu J.; Lockbaum, Gordon J.; Knapp, Mark; Tandeske, Laura; Bakan, David T.; Flynn, Julia M.; Bolon, Daniel N.; Moquin, Stephanie; et al. (2022-06-21)
      Coronaviruses can evolve and spread rapidly to cause severe disease morbidity and mortality, as exemplified by SARS-CoV-2 variants of the COVID-19 pandemic. Although currently available vaccines remain mostly effective against SARS-CoV-2 variants, additional treatment strategies are needed. Inhibitors that target essential viral enzymes, such as proteases and polymerases, represent key classes of antivirals. However, clinical use of antiviral therapies inevitably leads to emergence of drug resistance. In this study we implemented a strategy to pre-emptively address drug resistance to protease inhibitors targeting the main protease (M(pro)) of SARS-CoV-2, an essential enzyme that promotes viral maturation. We solved nine high-resolution cocrystal structures of SARS-CoV-2 M(pro) bound to substrate peptides and six structures with cleavage products. These structures enabled us to define the substrate envelope of M(pro), map the critical recognition elements, and identify evolutionarily vulnerable sites that may be susceptible to resistance mutations that would compromise binding of the newly developed M(pro) inhibitors. Our results suggest strategies for developing robust inhibitors against SARS-CoV-2 that will retain longer-lasting efficacy against this evolving viral pathogen.
    • Interventional oncology update

      Newbury, Alex; Ferguson, Chantal M.; Valero, Daniel Alvarez; Kutcher-Diaz, Roberto; McIntosh, Lacey J.; Karamanian, Ara; Harman, Aaron (2022-06-20)
      Interventional Oncology (IO) is a subspecialty field of Interventional Radiology bridging between diagnostic radiology and the clinical oncology team, addressing the diagnosis and treatment of cancer. There have been many exciting advancements in the field of IO in recent years; far too many to cover in a single paper. To give each topic sufficient attention, we have limited the scope of this review article to four topics which we feel have the potential to drastically change how cancer is treated managed in the immediate future.
    • Clinical Diagnoses and Outcomes After Diagnostic Breast Ultrasound by Nurses and General Practitioner Physicians in Rural Rwanda

      Pace, Lydia E.; Dusengimana, Jean-Marie Vianney; Hategekimana, Vedaste; Rugema, Vestine; Umwizerwa, Aline; Frost, Elisabeth; Kwait, Dylan; Schleimer, Lauren E.; Huang, ChuanChin; Shyirambere, Cyprien; et al. (2022-06-20)
      PURPOSE: To scale up early detection of breast cancer in low- and middle-income countries, research is needed to inform the role of diagnostic breast ultrasound performed by nonradiologists in resource-constrained settings. The authors examined 2-year clinical follow-up and outcomes among women who underwent diagnostic breast ultrasound performed by nonradiologist clinicians participating in a breast ultrasound training and mentorship program at a rural Rwandan hospital. METHODS: Imaging findings, management plans, and pathologic results were prospectively collected during the training using a standardized form. Data on follow-up and outcomes for patients receiving breast ultrasound between January 2016 and March 2017 were retrospectively collected through medical record review. RESULTS: Two hundred twenty-nine breast palpable findings (199 patients) met the study's eligibility criteria. Of 104 lesions initially biopsied, 38 were malignant on initial biopsy; 3 lesions were identified as malignant on repeat biopsy. All 34 patients ultimately diagnosed with cancer received initial recommendations for either biopsy or aspiration by trainees. The positive predictive value of trainee biopsy recommendation was 34.8% (95% confidence interval, 24.8%-45.0%). The sensitivity of trainees' biopsy recommendation for identifying malignant lesions was 92.7% (95% confidence interval, 84.2%-100%). Of 46 patients who did not receive biopsy and were told to return for clinical or imaging follow-up, 37.0% did not return. CONCLUSIONS: Trained nonradiologist clinicians in Rwanda successfully identified suspicious breast lesions on diagnostic breast ultrasound. Loss to follow-up was common among patients instructed to return for surveillance, so lower biopsy thresholds, decentralized surveillance, or patient navigation should be considered for patients with low- or intermediate-suspicion lesions.
    • Comprehensive fitness landscape of SARS-CoV-2 M(pro) reveals insights into viral resistance mechanisms

      Flynn, Julia; Samant, Neha; Nachum, Gily S.; Bakan, David T.; Yilmaz, Nese Kurt; Schiffer, Celia A.; Moquin, Stephanie A.; Dovala, Dustin; Bolon, Daniel N. (2022-06-20)
      With the continual evolution of new strains of SARS-CoV-2 that are more virulent, transmissible, and able to evade current vaccines, there is an urgent need for effective anti-viral drugs SARS-CoV-2 main protease (M(pro)) is a leading target for drug design due to its conserved and indispensable role in the viral life cycle. Drugs targeting M(pro) appear promising but will elicit selection pressure for resistance. To understand resistance potential in M(pro), we performed a comprehensive mutational scan of the protease that analyzed the function of all possible single amino acid changes. We developed three separate high-throughput assays of M(pro) function in yeast, based on either the ability of M(pro) variants to cleave at a defined cut-site or on the toxicity of their expression to yeast. We used deep sequencing to quantify the functional effects of each variant in each screen. The protein fitness landscapes from all three screens were strongly correlated, indicating that they captured the biophysical properties critical to M(pro) function. The fitness landscapes revealed a non-active site location on the surface that is extremely sensitive to mutation making it a favorable location to target with inhibitors. In addition, we found a network of critical amino acids that physically bridge the two active sites of the M(pro) dimer. The clinical variants of M(pro) were predominantly functional in our screens, indicating that M(pro) is under strong selection pressure in the human population. Our results provide predictions of mutations that will be readily accessible to M(pro) evolution and that are likely to contribute to drug resistance. This complete mutational guide of M(pro) can be used in the design of inhibitors with reduced potential of evolving viral resistance.
    • School Nurse Perspectives on School-Supervised Asthma Therapy: A Qualitative Study

      Hoque, Shushmita; Luther, Janki; Mizrahi, Raphael; Gerald, Lynn B.; Phipatanakul, Wanda; Lemon, Stephenie C.; Rosal, Milagros C.; Byatt, Nancy; Pbert, Lori; Trivedi, Michelle K. (2022-06-16)
      Background: School-supervised asthma therapy improves asthma outcomes for children, yet this strategy is not widely utilized. School nurses play a vital role in this intervention, yet their perspectives on school-supervised asthma therapy have not been thoroughly examined. Objectives: To examine the perspectives of school nurses participating in school-supervised asthma therapy and identify key facilitators, barriers, and proposed solutions that will facilitate the uptake of this strategy. Methods: We used purposeful sampling to recruit 12 school nurses participating in Asthma Link, a real-world application of school-supervised asthma therapy, between 2017 and 2019. We performed semistructured interviews with school nurses to elicit their perspectives on the facilitators, barriers, and proposed solutions to barriers to Asthma Link implementation. Interview transcripts were analyzed using qualitative descriptive methodology to identify major themes. Results: School nurses identified facilitators for Asthma Link adoption, including the ease of integrating supervised therapy into school nurse routines, recognition of benefits for families with limited resources, and satisfaction participating in preventive care. School nurses identified barriers, including communication challenges with families and providers, families not reliably bringing medication to school, limited nursing staff in schools, and increased school nurse turnover. School nurses proposed specific solutions to these barriers, including appointing Asthma Link liaisons within pediatric practices, incentivizing families to bring medicine to school, and partnering new school nurses with those experienced in delivering Asthma Link to overcome staffing issues and promote program fidelity. Conclusions: School nurse perspectives on the facilitators, barriers, and solutions to barriers are important for understanding how to promote real-world implementation of school-supervised asthma therapy. The themes identified in this study will be utilized to refine our protocol for Asthma Link to facilitate real-world adoption of this evidence-based strategy.
    • Ultrasound of the Endometrium, Parts 1 and 2

      Harris, Robert D. (2022-06-16)
      This presentation is part of the PEER Liberia Radiology Lecture Series. It provides an overview for clinicians of ultrasound of the endometrium, including histology, accurate endometrial measurements, and endometrial abnormalities.
    • Design and Preliminary Findings of Adherence to the Self-Testing for Our Protection From COVID-19 (STOP COVID-19) Risk-Based Testing Protocol: Prospective Digital Study

      Herbert, Carly; Broach, John P.; Gerber, Ben S.; Fahey, Nisha; Orvek, Elizabeth Aaker; Lazar, Peter; Ferranto, Julia M.; Noorishirazi, Kamran; Valpady, Shivakumar; Shi, Qiming; et al. (2022-06-16)
      BACKGROUND: Serial testing for SARS-CoV-2 is recommended to reduce spread of the virus; however, little is known about adherence to recommended testing schedules and reporting practices to health departments. OBJECTIVE: The Self-Testing for Our Protection from COVID-19 (STOP COVID-19) study aims to examine adherence to a risk-based COVID-19 testing strategy using rapid antigen tests and reporting of test results to health departments. METHODS: STOP COVID-19 is a 12-week digital study, facilitated using a smartphone app for testing assistance and reporting. We are recruiting 20,000 participants throughout the United States. Participants are stratified into high- and low-risk groups based on history of COVID-19 infection and vaccination status. High-risk participants are instructed to perform twice-weekly testing for COVID-19 using rapid antigen tests, while low-risk participants test only in the case of symptoms or exposure to COVID-19. All participants complete COVID-19 surveillance surveys, and rapid antigen results are recorded within the smartphone app. Primary outcomes include participant adherence to a risk-based serial testing protocol and percentage of rapid tests reported to health departments. RESULTS: As of February 2022, 3496 participants have enrolled, including 1083 high-risk participants. Out of 13,730 tests completed, participants have reported 13,480 (98.18%, 95% CI 97.9%-98.4%) results to state public health departments with full personal identifying information or anonymously. Among 622 high-risk participants who finished the study period, 35.9% showed high adherence to the study testing protocol. Participants with high adherence reported a higher percentage of test results to the state health department with full identifying information than those in the moderate- or low-adherence groups (high: 71.7%, 95% CI 70.3%-73.1%; moderate: 68.3%, 95% CI 66.0%-70.5%; low: 63.1%, 59.5%-66.6%). CONCLUSIONS: Preliminary results from the STOP COVID-19 study provide important insights into rapid antigen test reporting and usage, and can thus inform the use of rapid testing interventions for COVID-19 surveillance.
    • Interested in Peer Reviewing? Let’s Talk

      Raboin, Regina Fisher (2022-06-15)
      What does good peer review mean in the context of scholarly publishing? How can I be an effective peer reviewer? If I’ve never done it before, where would I start? Regina Raboin, Editor-In-Chief of the Journal of eScience Librarianship, will de-mystify peer review and answer your questions about this important process. In this presentation, both new and experienced peer reviewers can learn how to sharpen their skills and contribute to excellent scholarly communication. This webinar was sponsored by the RDAP Association Education and Resources Committee.
    • Development of a workflow process mapping protocol to inform the implementation of regional patient navigation programs in breast oncology

      Casanova, Nicole L.; LeClair, Amy M.; Xiao, Victoria; Mullikin, Katelyn R.; Lemon, Stephenie C.; Freund, Karen M.; Haas, Jennifer S.; Freedman, Rachel A.; Battaglia, Tracy A. (2022-06-14)
      BACKGROUND: Implementing city-wide patient navigation processes that support patients across the continuum of cancer care is impeded by a lack of standardized tools to integrate workflows and reduce gaps in care. The authors present an actionable workflow process mapping protocol for navigation process planning and improvement based on methods developed for the Translating Research Into Practice study. METHODS: Key stakeholders at each study site were identified through existing community partnerships, and data on each site's navigation processes were collected using mixed methods through a series of team meetings. The authors used Health Quality Ontario's Quality Improvement Guide, service design principles, and key stakeholder input to map the collected data onto a template structured according to the case-management model. RESULTS: Data collection and process mapping exercises resulted in a 10-step protocol that includes: 1) workflow mapping procedures to guide data collection on the series of activities performed by health care personnel that comprise a patient's navigation experience, 2) a site survey to assess program characteristics, 3) a semistructured interview guide to assess care coordination workflows, 4) a site-level swim lane workflow process mapping template, and 5) a regional high-level process mapping template to aggregate data from multiple site-level process maps. CONCLUSIONS: This iterative, participatory approach to data collection and process mapping can be used by improvement teams to streamline care coordination, ultimately improving the design and delivery of an evidence-based navigation model that spans multiple treatment modalities and multiple health systems in a metropolitan area. This protocol is presented as an actionable toolkit so the work may be replicated to support other quality-improvement initiatives and efforts to design truly patient-centered breast cancer treatment experiences. LAY SUMMARY: Evidence-based patient navigation in breast cancer care requires the integration of services through each phase of cancer treatment. The Translating Research Into Practice study aims to implement patient navigation for patients with breast cancer who are at risk for delays and are seeking care across 6 health systems in Boston, Massachusetts. The authors designed a 10-step protocol outlining procedures and tools that support a systematic assessment for health systems that want to implement breast cancer patient navigation services for patients who are at risk for treatment delays.
    • Orgo-Seq integrates single-cell and bulk transcriptomic data to identify cell type specific-driver genes associated with autism spectrum disorder

      Lim, Elaine T.; Chan, Yingleong; Dawes, Pepper; Erdin, Serkan; Reichert, Julia M.; Burns, Mannix J.; Church, George M. (2022-06-10)
      Cerebral organoids can be used to gain insights into cell type specific processes perturbed by genetic variants associated with neuropsychiatric disorders. However, robust and scalable phenotyping of organoids remains challenging. Here, we perform RNA sequencing on 71 samples comprising 1,420 cerebral organoids from 25 donors, and describe a framework (Orgo-Seq) to integrate bulk RNA and single-cell RNA sequence data. We apply Orgo-Seq to 16p11.2 deletions and 15q11-13 duplications, two loci associated with autism spectrum disorder, to identify immature neurons and intermediate progenitor cells as critical cell types for 16p11.2 deletions. We further applied Orgo-Seq to identify cell type-specific driver genes. Our work presents a quantitative phenotyping framework to integrate multi-transcriptomic datasets for the identification of cell types and cell type-specific co-expressed driver genes associated with neuropsychiatric disorders.
    • Agenda: UMCCTS Research Symposium 2022

      UMass Center for Clinical and Translational Science (2022-06-10)
      Agenda for the UMass Center for Clinical and Translational Science Research Symposium held virtually on Friday, June 10, 2022.
    • Videorecording: UMCCTS Research Symposium 2022

      UMass Center for Clinical and Translational Science (2022-06-10)
      Click on the "Link to Full Text" button to view a video recording of the UMass Center for Clinical and Translational Science Research Symposium held virtually on Friday, June 10, 2022. This recording is restricted to current UMass Chan Medical School users only.
    • Modifiable Resources and Resilience in Racially and Ethnically Diverse Older Women: Implications for Health Outcomes and Interventions

      Springfield, Sparkle; Qin, Feifei; Hedlin, Haley; Eaton, Charles B.; Rosal, Milagros C.; Taylor, Herman; Staudinger, Ursula M.; Stefanick, Marcia L. (2022-06-09)
      Introduction: Resilience-which we define as the "ability to bounce back from stress"-can foster successful aging among older, racially and ethnically diverse women. This study investigated the association between psychological resilience in the Women's Health Initiative Extension Study (WHI-ES) and three constructs defined by Staudinger's 2015 model of resilience and aging: (1) perceived stress, (2) non-psychological resources, and (3) psychological resources. We further examined whether the relationship between resilience and key resources differed by race/ethnicity. Methods: We conducted a secondary analysis on 77,395 women aged 62+ (4475 Black or African American; 69,448 non-Hispanic White; 1891 Hispanic/Latina; and 1581 Asian or Pacific Islanders) who enrolled in the WHI-ES, which was conducted in the United States. Participants completed a short version of the Brief Resilience Scale one-time in 2011. Guided by Staudinger's model, we used linear regression analysis to examine the relationships between resilience and resources, adjusting for age, race/ethnicity, and stressful life events. To identify the most significant associations, we applied elastic net regularization to our linear regression models. Findings: On average, women who reported higher resilience were younger, had fewer stressful life events, and reported access to more resources. Black or African American women reported the highest resilience, followed by Hispanic/Latina, non-Hispanic White, and Asian or Pacific Islander women. The most important resilience-related resources were psychological, including control of beliefs, energy, personal growth, mild-to-no forgetfulness, and experiencing a sense of purpose. Race/ethnicity significantly modified the relationship between resilience and energy (overall interaction p = 0.0017). Conclusion: Increasing resilience among older women may require culturally informed stress reduction techniques and resource-building strategies, including empowerment to control the important things in life and exercises to boost energy levels.
    • Single cell transcriptomics reveals dysregulated cellular and molecular networks in a fragile X syndrome model

      Donnard, Elisa; Shu, Huan; Garber, Manuel (2022-06-08)
      Despite advances in understanding the pathophysiology of Fragile X syndrome (FXS), its molecular basis is still poorly understood. Whole brain tissue expression profiles have proved surprisingly uninformative, therefore we applied single cell RNA sequencing to profile an FMRP deficient mouse model with higher resolution. We found that the absence of FMRP results in highly cell type specific gene expression changes that are strongest among specific neuronal types, where FMRP-bound mRNAs were prominently downregulated. Metabolic pathways including translation and respiration are significantly upregulated across most cell types with the notable exception of excitatory neurons. These effects point to a potential difference in the activity of mTOR pathways, and together with other dysregulated pathways, suggest an excitatory-inhibitory imbalance in the Fmr1-knock out cortex that is exacerbated by astrocytes. Our data demonstrate that FMRP loss affects abundance of key cellular communication genes that potentially affect neuronal synapses and provide a resource for interrogating the biological basis of this disorder.
    • Integrated Multi-omics Characterization of Human Disease Models

      Erik J. Sontheimer; Rodríguez, Tomás (UMass Chan Medical School, 2022-06-07)
      Animal and cell-based models of human disease offer simplified biological systems for studying the basis of more complex pathologies under well-controlled conditions. An ever-expanding suite of genomic and transcriptomic tools allows us to thoroughly characterize these models, highlighting disease-driving molecular features and exposing novel therapeutic targets. Here, we integrate diverse DNA- and RNA-sequencing strategies to describe the gene-regulatory chromatin landscape of models for hepatoblastoma and retrovirally-infected CD4+ T-cells. We first developed a conditional hepatoblastoma mouse model using doxycycline-inducible YAP1 overexpression and constitutive β-cateninDelN90. We found that YAP1 withdrawal alone is sufficient to trigger tumor regression and substantially increase survival. We reasoned that a thorough chromatin profile of this tumor model during YAP1 withdrawal could reveal YAP1-driven mechanisms of hepatoblastoma tumorigenesis. Our integrated approach revealed 31 novel YAP1-targeted cis-regulatory element-gene pairs. Subsequent validation confirmed that regulation of Jun-Dimerization Protein 2, among others, is both YAP1-dependent and functionally consequential for the hepatoblastoma phenotype in human cells and in hepatic malignancies. To expand our efforts to apply multi-omics technologies to disease models, we next engineered a fluorophore-containing murine leukemia virus (MLV-GFP) stably integrated into Jurkat CD4+ T-cells to report on defective transcriptional silencing by the retroelement-silencing complex, HUSH. A CRISPR knockout screen identified DHX29 as essential for HUSH-mediated silencing of newly-integrated retroviruses. Profiling genomic and transcriptomic features of MLV-GFP Jurkat cells after HUSH and DHX29 knockout revealed their epistatic roles in silencing, and revealed a suite of loci targeted by HUSH. Finally, we used site-specific proteomics and chromatin profiling to identify HUSH-associated factors at the newly integrated proviral reporter.
    • Imaging response assessment for oncology: An algorithmic approach

      Ruchalski, Kathleen; Dewan, Rohit; Sai, Victor; McIntosh, Lacey J.; Braschi-Amirfarzan, Marta (2022-06-07)
      Treatment response assessment by imaging plays a vital role in evaluating changes in solid tumors during oncology therapeutic clinical trials. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 is the reference standard imaging response criteria and provides details regarding image acquisition, image interpretation and categorical response classification. While RECIST 1.1 is applied for the majority of clinical trials in solid tumors, other criteria and modifications have been introduced when RECIST 1.1 outcomes may be incomplete. Available criteria beyond RECIST 1.1 can be explored in an algorithmic fashion dependent on imaging modality, tumor type and method of treatment. Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) is available for use with PET/CT. Modifications to RECIST 1.1 can be tumor specific, including mRECIST for hepatocellular carcinoma and mesothelioma. Choi criteria for gastrointestinal stromal tumors incorporate tumor density with alterations to categorical response thresholds. Prostate Cancer Working Group 3 (PCWG3) imaging criteria combine RECIST 1.1 findings with those of bone scans. In addition, multiple response criteria have been created to address atypical imaging responses in immunotherapy.