University of Massachusetts Medical School
  • Worcester, Massachusetts, United States
Recent publications
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system characterized by focal and then generalized weakness leading to paralysis and death from respiratory failure. Symptoms arise from the loss of corticospinal (upper) and brainstem and spinal (lower) motor neurons. The cause of sporadic ALS (sALS) is unknown. Investigations of the 10% of cases that are familial (fALS) have identified over 30 genes whose mutations predispose to ALS. Expression of mutant ALS genes in rodents and cells has generated models that facilitate identification of molecular pathways in ALS. Three pathological processes appear to be central in this disease: (1) conformational instability and aberrant trafficking of critical proteins; (2) perturbations of processing of RNA and RNA-binding proteins; and (3) disruption of homeostasis. Related events include protein aggregation and disturbances of mitochondria, neuronal excitability and axonal transport. Elucidation of these pathways and events provides targets for treatment development.
Diet is a modifiable, noninvasive, inexpensive behavior that is crucial in shaping the intestinal microbiome. A microbiome "imbalance" or dysbiosis in inflammatory bowel disease (IBD) is linked to inflammation. Here, we aim to define the impact of specific foods on bacterial species commonly depleted in patients with IBD to better inform dietary treatment. We performed a single-arm, pre-post intervention trial. After a baseline period, a dietary intervention with the IBD-Anti-Inflammatory Diet (IBD-AID) was initiated. We collected stool and blood samples and assessed dietary intake throughout the study. We applied advanced computational approaches to define and model complex interactions between the foods reported and the microbiome. A dense dataset comprising 553 dietary records and 340 stool samples was obtained from 22 participants. Consumption of prebiotics, probiotics, and beneficial foods correlated with increased abundance of Clostridia and Bacteroides, commonly depleted in IBD cohorts. We further show that specific foods categorized as prebiotics or adverse foods are correlated to levels of cytokines in serum (i.e., GM-CSF, IL-6, IL-8, TNF-alpha) that play a central role in IBD pathogenesis. By using robust predictive analytics, this study represents the first steps to detangle diet-microbiome and diet-immune interactions to inform personalized nutrition for patients suffering from dysbiosis-related IBD.
Background Social communication is a key area of difficulty in fragile X syndrome (FXS) and there are not yet adequate outcome measurement tools. Appropriate outcome measures for FXS have been identified as a key area of research interest in order to evaluate future therapeutic trials. The Brief Observation of Social Communication Change-Minimally Verbal (BOSCC-MV), an outcome measure with strong psychometrics developed for autism spectrum disorder, has promise as an outcome measure to assess social communication change with FXS participants. Methods We examined the BOSCC-MV via central coders in this multi-site-trial to assess its appropriateness for FXS. Eighteen minimally verbal males ages 3–12 years were enrolled and assessed on two consecutive days and 7 participants completed a third visit 6 months later. We examined test-retest reliability, inter-rater reliability, and both convergent and divergent validity with standard clinical measures including the Autism Diagnostic and Observation Schedule-2, Vineland 3, Social Responsiveness Scale, and the Aberrant Behavior Checklist. Results The BOSCC-MV in FXS demonstrated strong inter-rater and test-retest reliability, comparable to previous trials in idiopathic ASD. Strong convergent validity was found with Autism Diagnostic Observation Schedule-2 and Vineland-3. Divergent validity was demonstrated between BOSCC-MV and unrelated measures. Conclusions The BOSCC-MV shows promise as a FXS social communication outcome measure, warranting further large-scale evaluation.
Background: Oncogenic KRAS mutations are prevalent in human cancers, but effective treatment of KRAS-mutant malignancies remains a major challenge in the clinic. Increasing evidence suggests that aberrant metabolism plays a central role in KRAS-driven oncogenic transformation. The aim of this study is to identify selective metabolic dependency induced by mutant KRAS and to exploit it for the treatment of the disease. Method: We performed an integrated analysis of RNAi- and CRISPR-based functional genomic datasets (n = 5) to identify novel genes selectively required for KRAS-mutant cancer. We further screened a customized library of chemical inhibitors for candidates that are synthetic lethal with NOP56 depletion. Functional studies were carried out by genetic knockdown using siRNAs and shRNAs, knockout using CRISPR/Cas9, and/or pharmacological inhibition, followed by cell viability and apoptotic assays. Protein expression was determined by Western blot. Metabolic ROS was measured by flow cytometry-based quantification. Results: We demonstrated that nucleolar protein 5A (NOP56), a core component of small nucleolar ribonucleoprotein complexes (snoRNPs) with an essential role in ribosome biogenesis, confers a metabolic dependency by regulating ROS homeostasis in KRAS-mutant lung cancer cells and that NOP56 depletion causes synthetic lethal susceptibility to inhibition of mTOR. Mechanistically, cancer cells with reduced NOP56 are subjected to higher levels of ROS and rely on mTOR signaling to balance oxidative stress and survive. We also discovered that IRE1α-mediated unfolded protein response (UPR) regulates this process by activating mTOR through p38 MAPK. Consequently, co-targeting of NOP56 and mTOR profoundly enhances KRAS-mutant tumor cell death in vitro and in vivo. Conclusions: Our findings reveal a previously unrecognized mechanism in which NOP56 and mTOR cooperate to play a homeostatic role in the response to oxidative stress and suggest a new rationale for the treatment of KRAS-mutant cancers.
Background COVID-19 pandemic has a devastating impact on the economies and health care system of sub-Saharan Africa. Healthcare workers (HWs), the main actors of the health system, are at higher risk because of their occupation. Serology-based estimates of SARS-CoV-2 infection among HWs represent a measure of HWs’ exposure to the virus and could be used as a guide to the prevalence of SARS-CoV-2 in the community and valuable in combating COVID-19. This information is currently lacking in Ethiopia and other African countries. This study aimed to develop an in-house antibody testing assay, assess the prevalence of SARS-CoV-2 antibodies among Ethiopian high-risk frontline HWs. Methods We developed and validated an in-house Enzyme-Linked Immunosorbent Assay (ELISA) for specific detection of anti-SARS-CoV-2 receptor binding domain immunoglobin G (IgG) antibodies. We then used this assay to assess the seroprevalence among HWs in five public hospitals located in different geographic regions of Ethiopia. From consenting HWs, blood samples were collected between December 2020 and February 2021, the period between the two peaks of COVID-19 in Ethiopia. Socio-demographic and clinical data were collected using questionnaire-based interviews. Descriptive statistics and bivariate and multivariate logistic regression were used to determine the overall and post-stratified seroprevalence and the association between seropositivity and potential risk factors. Results Our successfully developed in-house assay sensitivity was 100% in serum samples collected 2- weeks after the first onset of symptoms whereas its specificity in pre-COVID-19 pandemic sera was 97.7%. Using this assay, we analyzed a total of 1997 sera collected from HWs. Of 1997 HWs who provided a blood sample, and demographic and clinical data, 51.7% were females, 74.0% had no symptoms compatible with COVID-19, and 29.0% had a history of contact with suspected or confirmed patients with SARS-CoV-2 infection. The overall seroprevalence was 39.6%. The lowest (24.5%) and the highest (48.0%) seroprevalence rates were found in Hiwot Fana Specialized Hospital in Harar and ALERT Hospital in Addis Ababa, respectively. Of the 821 seropositive HWs, 224(27.3%) of them had a history of symptoms consistent with COVID-19 while 436 (> 53%) of them had no contact with COVID-19 cases as well as no history of COVID-19 like symptoms. A history of close contact with suspected/confirmed COVID-19 cases is associated with seropositivity (Adjusted Odds Ratio (AOR) = 1.4, 95% CI 1.1–1.8; p = 0.015). Conclusion High SARS-CoV-2 seroprevalence levels were observed in the five Ethiopian hospitals. These findings highlight the significant burden of asymptomatic infection in Ethiopia and may reflect the scale of transmission in the general population.
Background The Supplemental Nutrition Assistance Program (SNAP) has well-established positive impacts on child health outcomes, including increased birth weight and decreased likelihood of underweight status. Studies in adult populations suggest that SNAP is associated with lower health care costs, although less is known in children. Methods Retrospective analysis of U.S. children (age <18 years) living in low-income households (< 200% of the federal poverty level) in the 2013-2017 Medical Expenditure Panel Survey. We used multivariable regression, adjusting for sociodemographic and clinical covariates, to model the effect of continuous SNAP enrollment on health expenditures as compared to non-enrollees at 12 and 24 months. Results The sample included 5,626 children, of whom 49.2% consistently received SNAP for the entire two-year survey period. Compared with SNAP non-recipients, SNAP-recipient households more often had incomes below 100% FPL (78.3% vs 37.9%), and children in SNAP-recipient households were more often publicly insured (94.9% vs 64.5%). Unadjusted expenditures were lower for children in SNAP-recipient households at 12 ($1222 vs $1603) and 24 months ($2447 vs $3009). However, when adjusting for sociodemographic and clinical differences, no statistically significant differences in health care expenditures, including emergency department, inpatient, outpatient, and prescription costs, were identified. Conclusion SNAP participant children experience heightened social hardships across multiple domains. There were no differences in short term health care costs based on SNAP enrollment when accounting for differences in sociodemographic and clinical factors. Despite demonstrated child health benefits, we found that sustained enrollment in SNAP over a two-year period did not generate significant short- term health care cost reductions. Our findings suggest that although SNAP is intended to act as a benefit towards the health and well-being of its recipients, unlike among adults, it may not reduce health care costs among children.
Background DNA methylation-based GrimAge acceleration (GrimAA) is associated with a wide range of age-related health outcomes including cardiovascular disease. Since DNA methylation is modifiable by external and behavioral exposures, it is important to identify which of these exposures may have the strongest contributions to differences in GrimAA, to help guide potential intervention strategies. Here, we assessed the relative contributions of lifestyle- and health-related components, as well as their collective association, to GrimAA. Results We included 744 participants (391 men and 353 women) from the Coronary Artery Risk Development in Young Adults (CARDIA) study with blood DNA methylation information at CARDIA Exam Year (Y) 20 (2005–2006, mean age 45.9 years). Six cumulative exposures by Y20 were included in the analysis: total packs of cigarettes, total alcohol consumption, education years, healthy diet score, sleep hours, and physical activity. We used quantile-based g-computation (QGC) and Bayesian kernel machine regression (BKMR) methods to assess the relative contribution of each exposure to a single overall association with GrimAA. We also assessed the collective association of the six components combined with GrimAA. Smoking showed the greatest positive contribution to GrimAA, accounting for 83.5% of overall positive associations of the six exposures with GrimAA (QGC weight = 0.835). The posterior inclusion probability (PIP) of smoking also achieved the highest score of 1.0 from BKMR analysis. Healthy diet and education years showed inverse contributions to GrimAA. We observed a U-shaped pattern in the contribution of alcohol consumption to GrimAA. While smoking was the greatest contributor across sex and race subgroups, the relative contributions of other components varied by subgroups. Conclusions Smoking, alcohol consumption, and education showed the highest contributions to GrimAA in our study. Higher amounts of smoking and alcohol consumption were likely to contribute to greater GrimAA, whereas achieved education was likely to contribute to lower GrimAA. Identifying pertinent lifestyle- and health-related exposures in a context of collective components can provide direction for intervention strategies and suggests which components should be the primary focus for promoting younger GrimAA.
Background Patient navigation is an evidence-based intervention for reducing delays in oncology care among underserved populations. In order to address the financial sustainability of this intervention, information is needed on the cost of implementing patient navigation in diverse healthcare settings. Because patient navigation programs and care settings are highly variable, this paucity of cost data creates difficulties in identifying best practices and decisions about the feasibility of implementing navigation programs within a health care system. One barrier to collecting these cost data is the lack of assessment tools available to support patient navigation programs. These tools must be relevant to the wide variety of navigation activities that exist in health care settings, and be flexible enough to collect cost data important to stakeholders in fee-for-service and value-based care environments. Methods and results We present a novel approach and methods for assessing the cost of a patient navigation program implemented across six hospital systems to enhance timely entry and uptake of breast cancer care and treatment. These methods and tools were developed in partnership with breast oncology patient navigators and supervisors using principles of stakeholder engagement, with the goal of increasing usability and feasibility in the field. Conclusions This methodology can be used to strengthen cost analysis and assessment tools for other navigation programs for improving care and treatment for patients with chronic conditions. Trial registration NCT03514433
Background People with opioid use disorder experience high burden of disease from medical comorbidities and are increasingly hospitalized with medical complications. Medications for opioid use disorder are an effective, life-saving treatment, but patients with an opioid use disorder admitted to the hospital seldom initiate medication for their disorder while in the hospital, nor are they linked with outpatient treatment after discharge. The inpatient stay, when patients may be more receptive to improving their health and reducing substance use, offers an opportunity to discuss opioid use disorder and facilitate medication initiation and linkage to treatment after discharge. An addiction-focus consultative team that uses evidence-based tools and resources could address barriers, such as the need for the primary medical team to focus on the primary health problem and lack of time and expertise, that prevent primary medical teams from addressing substance use. Methods This study is a pragmatic randomized controlled trial that will evaluate whether a consultative team, called the Substance Use Treatment and Recovery Team (START), increases initiation of any US Food and Drug Administration approved medication for opioid use disorder (buprenorphine, methadone, naltrexone) during the hospital stay and increases linkage to treatment after discharge compared to patients receiving usual care. The study is being conducted at three geographically distinct academic hospitals. Patients are randomly assigned within each hospital to receive the START intervention or usual care. Primary study outcomes are initiation of medication for opioid use disorder in the hospital and linkage to medication or other opioid use disorder treatment after discharge. Outcomes are assessed through participant interviews at baseline and 1 month after discharge and data from hospital and outpatient medical records. Discussion The START intervention offers a compelling model to improve care for hospitalized patients with opioid use disorder. The study could also advance translational science by identifying an effective and generalizable approach to treating not only opioid use disorder, but also other substance use disorders and behavioral health conditions. Trial registration: NCT05086796, Registered on 10/21/2021.
This study aimed to explore ultrasonography as a single imaging modality for the initial assessment of parotid lesions compared to computed tomography (CT) and magnetic resonance imaging (MRI). A retrospective cross‐sectional study was performed on 264 parotid gland lesions evaluated in a dedicated point‐of‐care ultrasound (POCUS) clinic with concurrent fine needle biopsy (FNB). Two hundred and nine of these lesions also underwent CT or MRI imaging. Histopathology results, when available, were recorded and compared to imaging impressions. Surgeon‐performed POCUS classified parotid masses accurately when compared to final histopathology (90/96, 94%). Using predefined criteria, POCUS determined the nature of parotid lesions more definitively than the descriptive CT or MRI radiology reports (p <.001). Sub‐analysis showed that ultrasonography was able to distinguish between benign pathologies with high degree of accuracy (Warthin tumor—82%, pleomorphic adenoma—64%). POCUS can accurately distinguish between benign and malignant parotid lesions. POCUS may suffice as the only imaging study for benign lesions, obviating the need for additional cross‐sectional imaging. This can be combined with fine needle or core biopsy in the same visit, resulting in expedient diagnosis, low cost, and lack of radiation exposure. 2b, individual cross‐sectional cohort study. Our study compares the performance of point of care ultrasound (POCUS) with cross sectional imaging in diagnosis and management of Parotid tumors.
The accumulation of somatic DNA mutations over time is a hallmark of aging in many dividing and nondividing cells but has not been studied in postmitotic human cardiomyocytes. Using single-cell whole-genome sequencing, we identified and characterized the landscape of somatic single-nucleotide variants (sSNVs) in 56 single cardiomyocytes from 12 individuals (aged from 0.4 to 82 years). Cardiomyocyte sSNVs accumulate with age at rates that are faster than in many dividing cell types and nondividing neurons. Cardiomyocyte sSNVs show distinctive mutational signatures that implicate failed nucleotide excision repair and base excision repair of oxidative DNA damage, and defective mismatch repair. Since age-accumulated sSNVs create many damaging mutations that disrupt gene functions, polyploidization in cardiomyocytes may provide a mechanism of genetic compensation to minimize the complete knockout of essential genes during aging. Age-related accumulation of cardiac mutations provides a paradigm to understand the influence of aging on cardiac dysfunction.
Reducing the microbial diversity in a type of fermented tea reveals the core metabolic interactions responsible for the drink’s signature taste and characteristics.
Background: Free flap autologous breast reconstruction (f-ABR) improves quality of life in cancer survivors but has a 5-47% higher postoperative complication (PCs) rate in vulnerable patients, such as those with obesity or the elderly. Given the high (respectively: 43% and 16%) and rising prevalence of these conditions, operative risk prediction is critical to guide targeted care. Age, BMI, and ASA class have shown inaccuracies as predictive factors of PCs in f-ABR. Since frailty, a measure of vulnerability, was reported to be a reliable predictor of PCs in multiple other surgical fields, we hypothesized that it would be an accurate predictor of PCs also in f-ABR. Methods: Patients undergoing f-ABR (CPT: 19364) were identified using the ACS-NSQIP (American College of Surgeons-National Surgical Quality Improvement Program) database (01/2010-12/2018). Frailty was calculated using the validated modified Frailty Index (mFI). Rates of wound complications, bleeding episodes, readmissions, returns to operating room (ROR), and DVTs were compared across mFI score, BMI, age, and ASA class. Results: mFI ≥ 2 was associated with 22.22% (p <0.001) wound complications; 15.79% (p <0.001) bleeding episodes; 8.20% (p <0.001) readmissions; 17.19% (p <0.001) ROR; and 1.81% (p <0.05) DVTs. Higher BMI, age, and ASA class did not significantly correlate with increased rates in one or more PCs. Only a high mFI was consistently associated with significantly higher odds of complications in all complication types. Conclusions: As a reliable and accurate predictor of PCs in f-ABR, frailty could be used preoperatively to counsel patients and guide surgical care.
Bacillus thuringiensis crystal proteins are widely and safely used as insecticides. Recent studies have shown they also can cure gastrointestinal parasitic worm (nematode) infections when ingested.
The complex genomic landscape of prostate cancer evolves across disease states under therapeutic pressure directed toward inhibiting androgen receptor (AR) signaling. While significantly altered genes in prostate cancer have been extensively defined, there have been fewer systematic analyses of how structural variation shapes the genomic landscape of this disease across disease states. We uniformly characterized structural alterations across 531 localized and 143 metastatic prostate cancers profiled by whole genome sequencing, 125 metastatic samples of which were also profiled via whole transcriptome sequencing. We observed distinct significantly recurrent breakpoints in localized and metastatic castration-resistant prostate cancers (mCRPC), with pervasive alterations in noncoding regions flanking the AR, MYC, FOXA1, and LSAMP genes enriched in mCRPC and TMPRSS2-ERG rearrangements enriched in localized prostate cancer. We defined nine subclasses of mCRPC based on signatures of structural variation, each associated with distinct genetic features and clinical outcomes. Our results comprehensively define patterns of structural variation in prostate cancer and identify clinically actionable subgroups based on whole genome profiling.
Visual components of trauma memories are often vividly re-experienced by survivors with deleterious consequences for normal function. Neuroimaging research on trauma has primarily focused on threat-processing circuitry as core to trauma-related dysfunction. Conversely, limited attention has been given to visual circuitry which may be particularly relevant to posttraumatic stress disorder (PTSD). Prior work suggests that the ventral visual stream is directly related to the cognitive and affective disturbances observed in PTSD and may be predictive of later symptom expression. The present study used multimodal magnetic resonance imaging data (n = 278) collected two weeks after trauma exposure from the AURORA study, a longitudinal, multisite investigation of adverse posttraumatic neuropsychiatric sequelae. Indices of gray and white matter were combined using data fusion to identify a structural covariance network (SCN) of the ventral visual stream 2 weeks after trauma. Participant’s loadings on the SCN were positively associated with both intrusion symptoms and intensity of nightmares. Further, SCN loadings moderated connectivity between a previously observed amygdala-hippocampal functional covariance network and the inferior temporal gyrus. Follow-up MRI data at 6 months showed an inverse relationship between SCN loadings and negative alterations in cognition in mood. Further, individuals who showed decreased strength of the SCN between 2 weeks and 6 months had generally higher PTSD symptom severity over time. The present findings highlight a role for structural integrity of the ventral visual stream in the development of PTSD. The ventral visual stream may be particularly important for the consolidation or retrieval of trauma memories and may contribute to efficient reactivation of visual components of the trauma memory, thereby exacerbating PTSD symptoms. Potentially chronic engagement of the network may lead to reduced structural integrity which becomes a risk factor for lasting PTSD symptoms.
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2,772 members
Javier A. Jaimes
  • Program in Molecular Medicine
Sharone Green
  • Division of Infectious Disease and Immunology
Javier E Irazoqui
  • Department of Microbiology and Physiological Systems
  • Department of Neurology
Hong Wei Yang
  • Neurosurgery
55 Lake Avenue North, 01655, Worcester, Massachusetts, United States
Head of institution
Chancellor Michael F. Collins MD, FACP