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eScholarship@UMassChan is a digital archive for UMass Chan Medical School's research and scholarship, including journal articles, theses, datasets and more. We welcome submissions from our faculty, staff, and students. eScholarship@UMassChan is a service of the Lamar Soutter Library, Worcester, MA, USA. See also our open access journal publishing services.
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Investigating the role of p16Ink4a in Alzheimer's Disease pathogenesisAdvancing age is the most significant risk factor for Alzheimer’s Disease (AD), but how aging contributes to AD development remains unclear. Human induced pluripotent stem cell (iPSC) technology has revolutionized AD modeling, enabling the study of AD cellular pathogenesis in patient-derived cells. However, the epigenetic landscape and aging clock are reset to the embryonic state in iPSCs during reprogramming. Thus, current iPSC-based models lack proper cellular aging and do not fully recapitulate AD hallmark pathologies, including amyloid- beta plaques and neurofibrillary tau tangles, observed in human AD brains. My thesis aims to introduce factors of cellular aging to improve iPSC-based modeling of AD pathogenesis. I focus on CDKN2A (p16Ink4a or p16), an important senescence regulator and aging biomarker. I demonstrated that robust induction of p16 in iPSCs reduces cell proliferation and triggers downstream pathways, including focal adhesion and extracellular matrix organization. The inducible approach enables temporal control of p16 expression during the differentiation of iPSCs to neurons. I found that inducible p16 increases tau phosphorylation in iPSC-derived neurons in a cell-autonomous manner, providing a direct link between p16 and an AD-related cell pathology. This robust system provides a powerful resource to improve AD disease modeling to advance our understanding of the impact of aging in AD and develop innovative AD therapeutic drug discovery.
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What is Community Participation?The Center for Community Inclusion and Reflective Collaboration (the CIRC Center) is a research and training center that aims to significantly advance community participation outcomes among young adults (14–26) with serious mental health conditions from populations that have been marginalized or minoritized. The term community participation is used in mental health services and research to refer to community-based activities that promote overall health and wellness. However, many people find this concept to be confusing, vague, and hard to understand. This tip sheet will define “community participation,” describe relevant experiences of young adults (ages 14–26) with serious mental health conditions (SMHC) from populations that have been marginalized, and provide reflections from our various advisory boards of young adults, family members, and professionals in the field.
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Demystifying Civic Engagement: How to Make Your Voice Heard (Beyond Voting!) & 5 Tips to Get StartedThe term “civic engagement” is less intimidating than it sounds! Civic engagement describes the process taken by individuals or groups to identify and address issues of concern within their communities. Civic engagement can take many forms, from individual events such as working the polls, to longer-term, sustained efforts such as joining an advocacy group and educating others around issues that matter to you. This tip sheet outlines 5 ways to get involved in civic engagement that are in addition to voting OR that can be done before you’re old enough to vote.
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UMCCTS Newsletter, October 2024This is the October 2024 issue of the UMass Center for Clinical and Translational Science Newsletter containing news and events of interest.
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iSPARC 2024 Annual Report to the Massachusetts Department of Mental HealthIn fiscal year 2024, iSPARC continued to leverage DMH’s investment to rapidly translate research findings into their implementation within best practices for individuals with lived experience, their families, and the providers who serve them across the Commonwealth. iSPARC’s work has focused on key strategic priorities for DMH. First, this year, the iSPARC Technical Assistance Program contributed to work on elucidating key factors involved in reducing the incidence of inpatient aggression at DMH-funded facilities. iSPARC also made substantial strides in targeting Diversity, Equity, and Inclusion (DEI) within our Center, including workforce enrichment and our research program. During fiscal year 2024, our Center has initiated several new and innovative projects to improve the behavioral health of individuals with mental health disorders.
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Disparate impact of risk assessment instruments: A systematic reviewObjective: One concern about the use of risk assessment instruments in legal decisions is the potential for disparate impact by race or ethnicity. This means that one racial or ethnic group will experience harsher legal outcomes than another because of higher or biased risk estimates. We conducted a systematic review of the literature to synthesize research examining the real-world impact of juvenile and adult risk instruments on racial/ethnic disparities in legal decision making. Hypotheses: Given the nature of research synthesis, we did not test formal hypotheses. Method: Our systematic literature search as of July 2023 identified 21 articles that investigated the disparate impact of 13 risk assessment instruments on various legal outcomes. Most of these instruments were actuarial pretrial screening instruments. Results: Our narrative synthesis indicated that there is not strong evidence of risk instruments contributing to greater system disparity. Ten articles indicated that adopting risk instruments did not create (or exacerbate preexisting) disparities, and eight articles found that instrument use reduced disparities in legal decision making. Three articles reported evidence of disparate impact of risk instruments; only one of these studies received a strong study quality assessment score. We observed a scarcity of high-quality articles that employed what we deem to be the gold standard approach for examining the disparate impact of risk instruments (i.e., pretest-posttest design). Conclusion: The evidence signals that risk instruments can contribute to reductions in disparities across multiple stages of legal decision making. Yet study quality remains low and most research has been conducted on decisions during the pretrial stage. More rigorous research on disparate impact across diverse legal decision points and approaches to risk assessment is needed.
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Single cell RNA-sequencing reveals molecular signatures that distinguish allergic from irritant contact dermatitisAllergic contact dermatitis (ACD) is a pruritic skin disease caused by environmental chemicals that induce cell-mediated skin inflammation within susceptible individuals. Irritant contact dermatitis (ICD) is caused by direct damage to the skin barrier by environmental insults. Diagnosis can be challenging as both types of contact dermatitis can appear similar by visual exam, and histopathological analysis does not reliably distinguish ACD from ICD. To discover specific biomarkers of ACD and ICD, we characterized the transcriptomic and proteomic changes that occur within the skin during each type of contact dermatitis. We induced ACD and ICD in healthy human volunteers and sampled skin using a non-scarring suction blister biopsy method that collects interstitial fluid and cellular infiltrate. Single cell RNA-sequencing analysis revealed that cell-specific transcriptome differences rather than cell type proportions best distinguished ACD from ICD. Allergy-specific genes were associated with upregulation of IFNG, and cell signaling network analysis implicated several other genes such as IL4, despite their low expression levels. We validated transcriptomic differences with proteomic assays on blister fluid and trained a logistic regression model on skin interstitial fluid proteins that could distinguish ACD from ICD and healthy control skin with 93% sensitivity and 93% specificity.
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Cohesin-mediated chromatin remodeling controls the differentiation and function of conventional dendritic cells [preprint]The cohesin protein complex extrudes chromatin loops, stopping at CTCF-bound sites, to organize chromosomes into topologically associated domains, yet the biological implications of this process are poorly understood. We show that cohesin is required for the post-mitotic differentiation and function of antigen-presenting dendritic cells (DCs), particularly for antigen cross-presentation and IL-12 secretion by type 1 conventional DCs (cDC1s) in vivo. The chromatin organization of DCs was shaped by cohesin and the DC-specifying transcription factor IRF8, which controlled chromatin looping and chromosome compartmentalization, respectively. Notably, optimal expression of IRF8 itself required CTCF/cohesin-binding sites demarcating the Irf8 gene. During DC activation, cohesin was required for the induction of a subset of genes with distal enhancers. Accordingly, the deletion of CTCF sites flanking the Il12b gene reduced IL-12 production by cDC1s. Our data reveal an essential role of cohesin-mediated chromatin regulation in cell differentiation and function in vivo, and its bi-directional crosstalk with lineage-specifying transcription factors.
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Means to an end: Characteristics and follow-up of emergency department patients with a history of suicide attempt via medication overdoseObjective: Availability and accessibility of a wide range of medications may be a contributing factor to rising medication-related overdose (OD) rates. Treatment for both suicide attempts (SAs) and ODs often occurs in the emergency department (ED), highlighting its potential as a screening and intervention point. The current study aimed to identify sociodemographic and clinical characteristics of individuals who reported SA via medication OD compared to other methods and to examine how these patients' suicide severity and behaviors differed over 12-month post-ED follow-up. Methods: Data were analyzed from Phases 1 and 2 of the Emergency Department Safety Assessment and Follow-up Evaluation multicenter study (N = 1376). Participants with a history of SA (n = 987) were categorized based on whether they indicated a past medication-related SA via OD. Results: Of participants with history of SA, 62.7% (n = 619) reported medication OD for either their most serious or their most recent SA. Multivariate analyses indicated female birth sex, diagnosis of bipolar disorder, and having some college education were significantly associated with membership in the medication OD attempt group (p <0.05). Of those who attempted suicide over the 12-month follow-up, nearly 60% of participants in the medication OD attempt group reported a subsequent SA via OD over follow-up. However, nearly half (46.5%) of participants with no medication OD at baseline also reported medication OD at follow-up. Conclusions: Among patients presenting to the ED, females, individuals with bipolar disorder, and patients with a college education, respectively, may be at highest risk for SAs via medication OD. Prospectively, medication OD appears to be a frequent method, even among individuals with no prior attempt via OD, as demonstrated by the high percentage of patients who did not have a medication OD at baseline, but reported a medication OD during follow-up.
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STING Gain-of-Function in Endothelial Cells Impairs Wound Healing ResponsesSTimulator of Interferon Genes (STING) gain-of-function (GOF) mutations, resulting in constitutive STING activation, have been linked to a rare autoinflammatory disease called STING-Associated Vasculopathy with onset in Infancy (SAVI). SAVI patients present with hallmark skin findings, including chilblains (cold-sensitive lesions on acral surfaces) and progressive ulcerative lesions. We used a murine model of SAVI, STING(V154M/WT)-(VM), to explore the impact of the VM mutant on wound repair using ultraviolet B (UVB) irradiation as a tool for skin injury. Following UVB-induced injury, we found that VM mice developed exacerbated skin inflammation that persisted for 21 days or more. Conversely, WT mice developed mild erythema and erosion, which resolved within 7 days. Despite a strikingly different phenotype, total immune cell infiltration in VM skin was the same as WT within the first 5 days post-UVB irradiation. However, there were differences in the immune composition, including a significant lack of macrophage expansion during healing in VM skin. Further, we discovered that the VM phenotype is independent of T-cell responses and type 1 interferon signaling, challenging prior expectations in the literature. To identify the cellular driver(s) of skin disease, we used busulfan chimera and conditional knock-in mouse models. We determined that STING GOF in endothelial cells was sufficient to induce ulcerative lesions in VM mice. The critical finding in this thesis work is that following UVB-induced skin injury, STING GOF mutation in endothelial cells prevented macrophage expansion and impaired wound healing responses.
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Youth Reoffending: Prevalence and Predictive Risk Factors in Two StatesThe Youth Protective Factors Study is an unprecedented multistate, multiyear examination of which risk and protective factors matter most when it comes to reoffending—particularly for more serious offenses that involve physical harm to another person (person offenses)—for youth ages 10 to 23 in the juvenile justice system. This brief is the first in a series that shares key findings to guide jurisdictions on research-based juvenile justice supervision, case planning, and service strategies to improve public safety and youth outcomes. These findings are especially pertinent during a time of rising concerns about youth crime, violence, and victimization. This brief is based on analysis of over 32,000 youth who had a new delinquency or status offense complaint over 3 years (2015–2017) in 2 states and received a risk assessment from the probation department. Most of the youth ended up on some form of supervision. Supervision could have included involvement in a diversion program, informal supervision, probation, a secure placement, or any combination of the above, and incorporates the time from their risk assessment until their case was closed (including any supervision extensions). Researchers obtained the records of all new juvenile court petitions and adult charges for these youth during supervision and for an average 2.5-year post-supervision follow-up period. The study analyzed recidivism during and after supervision, including for person offenses (offenses ranging from simple assault to robbery and homicide), and identified which risk factors were most associated with reoffending for youth overall and of different ages.
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Mapping the ALS Citrullinome: A Proteomic Perspective on Neurodegeneration, Aggregation, and Protein DysfunctionAmyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that is characterized by progressive motor neuron loss, muscle wasting, paralysis, and death. Ninety percent of the cases are sporadic (sALS), while the remaining ten percent are familial (fALS). A hallmark of ALS neuropathology is aberrant protein aggregation and inclusion body formation in neurons leading to eventual degeneration of motor neurons in the brain and spinal cord. Previously, we showed that protein citrullination (PC), a post-translational modification (PTM), and peptidyl arginine deiminase 2 (PAD2) expression are altered dynamically in the spinal cord during ALS disease progression, increasing in astrocytes while decreasing in neurons (PMID: 36076282, 38253209). Interestingly, the citrullinated proteins accumulate in myelin protein aggregates, suggesting a role of PC in protein aggregation. Here, we applied proteomic methods to identify citrullinated proteins in an ALS mouse model expressing mutant SOD1G93A. The ALS citrullinome profiles disease progression distinctly from normal aging in mice and highlighted an increase in citrullinated glial proteins and a decrease in citrullinated neuronal proteins, validating PC as a marker of reactive astrogliosis and neurodegeneration. Additional analyses found that soluble citrullinated proteins were enriched in inflammation, membrane traffic and metabolic pathways, whereas for insoluble citrullinated proteins, myelin proteins were enriched. The findings in the soluble fraction were validated in analysis of two human ALS proteomic datasets. Among the highly citrullinated proteins in ALS are heat shock proteins and MBP. PC severely compromises these proteins’ structure and function. These results demonstrate the impact of PC in protein function, and furthermore, suggest that PC could provide candidate biomarkers of early-stage ALS and be targeted with novel ALS therapeutics.
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Characterizing Colibactin Toxicity and the Resulting Cellular Response to DNA Damage in Mammalian and Bacterial SystemsThe bacterial toxin colibactin, produced primarily by the B2 phylogroup of Escherichia coli, crosslinks DNA and can promote colon cancer in human hosts, where it has been extensively studied. A systematic approach to identify the DNA damage response to colibactin-induced toxicity has yet to be applied and colibactin toxicity in bacteria remains underexplored. Using a genome-wide CRISPR screen in colon cancer cells, I found that colibactin activates most DNA repair pathways with key roles for Fanconi anemia/interstrand crosslink repair and fork quality control pathways. I also conducted a genome-wide loss-of-function screen in E. coli that identified a key role for homologous recombination in repairing colibactin-induced damage. I determined that colibactin induces a mutational pattern in E. coli in A/T rich regions, as it does in colon cells, but that the resulting mutational signature differs in E. coli. I then predicted that long- term colibactin exposure will culminate in a genomic bias based on this mutational signature, which may be detected in colibactin-producing bacteria. I tested this prediction by analyzing thousands of E. coli genomes andfound that colibactin-producing strains show skewness in trinucleotide composition. Finally, I used a sensitive DNA damage reporter assay to find that cell-cell contact is not required in bacteria as was previously suggested for both bacteria and mammalian cells, and that this needs to be reevaluated in mammalian cells. Taken together, this work revealed the DNA damage response to colibactin-induced damage in both colon and bacteria cells, a bacteria-specific mutation pattern, and that cell-cell contact is not required in bacteria.
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UMCCTS Newsletter, September 2024This is the September 2024 issue of the UMass Center for Clinical and Translational Science Newsletter containing news and events of interest.
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Pediatric and Adolescent Hypertension: A Multidisciplinary Call to ActionHeightened awareness and the rising prevalence of hypertension in children and adolescents has brought pediatric hypertension to the forefront of pediatric primary care. It has also made clear the need for public health programs and evidence-based lifestyle interventions to effectively prevent and manage this condition in youth. However, given that the ultimate aim of such efforts is to reduce rates of adult cardiovascular disease, how to best measure their success during childhood is unclear. In this perspective, we describe current challenges and gaps in research related to this dilemma while highlighting the need for multidisciplinary collaboration between pediatric primary care providers, researchers, public health practitioners, and hypertension experts to move toward effective prevention and management of this condition.
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PhD nursing programs: Where are we headed?Thank you for your timely editorial, The PhD in Nursing - Questions about a Credential at a Crossroads. We agree that the future of PhD education in nursing is in peril and needs rapid solutions. Low enrollment and threats of PhD program closures are on the rise. As three former Directors of PhD Programs, we feel it is essential that we do not walk away from PhD education. Here are some of our thoughts.
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Ketamine-assisted buprenorphine initiation: a pilot case seriesBackground: Many people with opioid use disorder who stand to benefit from buprenorphine treatment are unwilling to initiate it due to experience with or fear of both spontaneous and buprenorphine-precipitated opioid withdrawal (BPOW). An effective means of minimizing withdrawal symptoms would reduce patient apprehensiveness, lowering the barrier to buprenorphine initiation. Ketamine, approved by the FDA as a dissociative anesthetic, completely resolved BPOW in case reports when infused at a sub-anesthetic dose range in which dissociative symptoms are common. However, most patients attempt buprenorphine initiation in the outpatient setting where altered mental status is undesirable. We explored the potential of short-term use of ketamine, self-administered sublingually at a lower, sub-dissociative dose to assist ambulatory patients undergoing transition to buprenorphine from fentanyl and methadone. Methods: Patients prescribed ketamine were either (1) seeking transition to buprenorphine from illicit fentanyl and highly apprehensive of BPOW or (2) undergoing transition to buprenorphine from illicit fentanyl or methadone and experiencing BPOW. We prescribed 4-8 doses of sublingual ketamine 16 mg (each dose bioequivalent to 3-6% of an anesthetic dose), monitored patients daily or near-daily, and adjusted buprenorphine and ketamine dosing based on patient response and prescriber experience. Results: Over a period of 14 months, 37 patients were prescribed ketamine. Buprenorphine initiation was completed by 16 patients, representing 43% of the 37 patients prescribed ketamine, and 67% of the 24 who reported trying it. Of the last 12 patients who completed buprenorphine initiation, 11 (92%) achieved 30-day retention in treatment. Most of the patients who tried ketamine reported reduction or elimination of spontaneous opioid withdrawal symptoms. Some patients reported avoidance of severe BPOW when used prophylactically or as treatment of established BPOW. We developed a ketamine protocol that allowed four of the last patients to complete buprenorphine initiation over four days reporting only mild withdrawal symptoms. Two patients described cognitive changes from ketamine at a dose that exceeded the effective dose range for the other patients. Conclusions: Ketamine at a sub-dissociative dose allowed completion of buprenorphine initiation in the outpatient setting in the majority of patients who reported trying it. Further research is warranted to confirm these results and develop reliable protocols for a range of treatment settings.
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Implementing virtual desktops for clinical research at an academic health center: a case reportObjectives: To address the challenges of sharing clinical research data through the implementation of cloud-based virtual desktops, enhancing collaboration among researchers while maintaining data security. Materials and methods: This case study details the deployment of virtual desktops at UMass Chan Medical School (UMass Chan). The process involved forming a Research Informatics Steering Executive workgroup, identifying key requirements, implementing Amazon WorkSpaces, and establishing configurable data management for research support. Results: Key lessons include the significance of collaboration, balancing user-friendliness and functionality, flexibility in data management, maximizing virtual desktop efficiency within budget constraints, and continuous user feedback. The implementation of virtual desktops supports secure collaborative research, advancing medical knowledge and improving healthcare outcomes. Discussion: The structured approach to implementing virtual desktops addresses data security, regulatory compliance, and real-time collaboration challenges. Continuous feedback and iterative improvements have enhanced the system's effectiveness. Conclusion: The successful implementation of virtual desktops at UMass Chan demonstrates the potential for such systems to support secure, collaborative research, offering insights for similar initiatives in other academic health centers.
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Randomized non-inferiority trial comparing an asynchronous remotely-delivered versus clinic-delivered lifestyle interventionObjective: Lifestyle interventions are effective, but those delivered via in-person group meetings have poor scalability and reach. Research is needed to establish if remotely delivered lifestyle interventions are non-inferior to in-person delivered lifestyle interventions. Methods: We conducted a randomized non-inferiority trial (N = 329) to compare a lifestyle intervention delivered remotely and asynchronously via an online social network (Get Social condition) to one delivered via in-person groups (Traditional condition). We hypothesized that the Get Social condition would result in a mean percent weight loss at 12 months that was not inferior to the Traditional condition. Additional outcomes included intervention delivery costs per pound lost and acceptability (e.g., convenience, support, modality preferences). Results: At 12 months, no significant difference in percent weight change was observed between the Get Social and Traditional conditions (2.7% vs. 3.7%, p = 0.17) however, criteria for non-inferiority were not met. The Get Social condition costs $21.45 per pound lost versus $26.24 for the Traditional condition. A greater percentage of Get Social condition participants rated participation as convenient (65% vs 44%; p = 0.001). Conclusions: Results revealed a remotely-delivered asynchronous lifestyle intervention resulted in slightly less weight loss than an in-person version but may be more economical and convenient. Trial registration: ClinicalTrials.gov NCT02646618; https://clinicaltrials.gov/ct2/show/NCT02646618 .
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A minimally invasive endovascular approach to the cerebellopontine angle cistern enables broad CNS biodistribution of scAAV9-CB-GFPNeurological disorders pose a challenge for targeted therapy due to restricted access of therapeutic agents to the central nervous system (CNS). Current methods are limited by procedure-related risks, invasiveness, and insufficient CNS biodistribution. A novel percutaneous transvenous technology, currently in clinical trials for communicating hydrocephalus, offers a minimally invasive approach by providing endovascular access to the cerebrospinal fluid-filled cerebellopontine angle (CPA) cistern. We hypothesized that drug delivery to the CPA cistern could yield widespread CNS distribution. Using an ovine model, we compared the biodistribution of scAAV9-CB-GFP following CPA cistern infusion with previously reported cisterna magna (CM) administration. Targeting both the CPA cistern and CM in sheep, we employed a lumbar spine-inserted microcatheter under fluoroscopy. CPA delivery of AAV9 demonstrated biodistribution and transduction in the cerebral cortices, striatum, thalamus, midbrain, cerebellum, and spinal cord, with minor liver distribution comparable to CM. The favorable safety profile in humans with hydrocephalus suggests that percutaneous endovascular injection into the CPA could offer a clinically safer and minimally invasive delivery system for CNS gene and cell-based therapies.
