Physician/Scientist Development Award Recipients

Heart failure (HF) is a highly comorbid syndrome that afflicts more than 6.7 million adults in America and about 60 million worldwide. A critical trend has now emerged highlighting an increase in heart failure incidence, prevalence, hospitalization, and death among Black men and women in the US. On top of social risks, there are complex genetic and epigenetic factors that influence the development and progression of heart disease. Serious underrepresentation of genetic data from non-European ancestry makes it difficult to generalize discoveries and leads to an inadequate understanding of genetic diversity. Lack of representation in genetics and genomics research poses critical scientific and moral dilemmas and has significant implications on the perpetuation of disparities. While race is a fallible proxy for biology, genetic ancestry can be leveraged to better investigate patterns of gene expression that increase susceptibility to or protect against cardiovascular disease (CVD).

These investigations represent the first of its kind to use single nuclear sequencing to perform an ancestry-based comparative analysis of the human cardiac transcriptome. Here, I use healthy donor heart tissue to study the cellular composition, gene expression, and niche-specific cellular communication within African and European individuals. I hypothesize that compositional and transcriptional differences impact response to myocardial stress, and additively, influence response to treatment. I anticipate that my findings may add to our fundamental understanding of CVD risk, allow for better stratification and surveillance of patient groups, and ultimately lead to the development of more precise therapies for patients living with heart failure.

Gene delivery using adeno-associated virus vectors has tremendous potential as treatment for congenital and acquired diseases of the nervous system. Understanding viral vector cellular transduction, crucial for optimizing drug design, has been hindered by the challenge of resolving nanoscale viral particles in living organisms. There is a critical need to develop imaging techniques that enable nanoscale imaging of thick tissues and living systems. Super-resolution microscopy provides a powerful tool for imaging fluorescent nanoscale targets in the nervous system. Heretofore, wide dissemination of these techniques has been hampered by the cost and demand of high laser power. In this proposal, we plan to develop an efficient Switching Laser Mode microscopy system to study viral vector gene delivery within cells of the murine nervous system. In Aim 1, an efficient super-resolution confocal microscope will be developed to study in vitro single virion trafficking in neuronal cells. In Aim 2, an efficient high-resolution multiphoton microscope will be developed to quantify transduction efficiency in the murine brain. If successful, this work carries potential to advance our understanding of viral vector trafficking by overcoming the delivery quantification limitation in this complex process, while demonstrating the potential of super-resolution microscopy to advance knowledge discovery in biomedicine.

The growing prevalence of obesity in women of childbearing age and associated complications are dramatically increasing. Glucagon-like peptide 1 receptor analogues (GLP-1 RAs) are a promising pharmacotherapeutic option for treatment of diabetes and obesity. In pregnancy, GLP-1 RAs are contraindicated based on animal toxicity. However, there is limited clinical guidance on the preconception use of GLP-1 RAs and pregnancy and postnatal outcomes. Rapid rebound weight gain occurs in non-pregnant individuals after stopping these agents. It is possible that discontinuing a GLP-1 RA shortly before pregnancy could lead to greater gestational weight gain and postnatal weight retention. Greater gestational weight gain is associated with postpartum weight retention and higher birth and childhood weights thus negating the potential long-term benefits of using these medications in the preconception period.

This proposal will use data from pregnant individuals with obesity in a large health system with robust infrastructure for electronic health record-based research to investigate the association between pre-pregnancy exposure to GLP-1 RA with pregnancy and postnatal outcomes. A complementary pilot study will gather prospective data to measure appetite and diet-related outcomes as well as adiposity in the postnatal period. Aim 1 will address pregnancy outcomes in women treated prior to conception with GLP1-RA. Aim 2 will address postpartum maternal outcomes. Aim 3 will address postnatal outcomes in the children born to mothers with GLP-1RA exposure pre-pregnancy.

Major depressive and anxiety disorders affects millions of adults in the U.S.. These disorders are often stigmatized. Stigma refers to negative attitudes or beliefs about mental illness, or negative behaviors directed toward persons with mental illness. Stigma is a fundamental cause of health inequities. The efficacy and precision of anti-stigma interventions to improve mental health outcomes among underserved Black adults are grossly limited and represent a critical public health gap. The aim of the award is to build a video library of Black adult narratives and integrate the narratives into a novel mobile mental health application that uses contact principles to reduce mental illness stigma and address medical mistrust. We aim to build a video library of Black adults living with mental illness sharing narratives on diagnosis, treatment and recovery. We will invite Black people from diverse backgrounds (across gender, ethnicity, and religion) who screen positive for mild, moderate, and severe depression and anxiety and who are in routine mental health care. We will also assess the feasibility and acceptability, and test the preliminary efficacy, of a self-administered, video-based mobile app in reducing mental illness stigma among Black adults with moderate to severe depression or anxiety.

Latinos have a 1.5x increased risk of developing Alzheimer’s disease and related dementias relative to non-Hispanic Whites. Latinos whose primary language is Spanish and who care for a family member with dementia (Spanish language dementia caregivers, SLDCs) have even more risk factors than the general Latino population. Although more SLDCs own a smartphone than a computer to access resources online, few caregiver resources are specifically developed for smartphones. We have developed a multicomponent mobile health (mHealth) intervention, the Spanish Resiliency and Cognition – engagement (SPARC-e) program. SPARC-e is accessible via smartphone for SLDCs and aims to help them increase healthy behaviors and reduce symptoms of caregiver distress. SPARC-e, provides healthy behavior information, and motivation to make changes via smartphone peer support group chat. In this study, we will test the feasibility and acceptability of SPARC-e for SLDCs in a randomized, controlled trial. We will assess whether SPARC-e increases healthy behavior adherence in SLDCs relative to a control that has all components except the peer support chat, and determine if SPARC-e is associated with candidate mediators (social support and self-efficacy). Finally, we will investigate whether SPARC-e improves cognition and psychological symptoms among SLDCs.

Spinal muscular atrophy (SMA) is a devastating neuromuscular disease and a leading genetic cause of infantile death worldwide. Despite exciting progress in the neuromuscular field that has resulted in novel therapies, there remains no permanent cure for SMA. Therefore, developing a permanent treatment that treats the underlying genetic perturbation and all systemic manifestations of this disease would transform patients’ life. SMA is caused by mutations in the Survival Motor Neuron 1 (SMN1) gene. An important modifier of SMA severity is the number of copies of a paralogous gene SMN2. The sequence of SMN2 mainly differs from SMN1 by a C•G-to-T•A transition in exon 7 (“C6T”), which causes the skipping of exon 7 in most SMN2 transcripts due to alternative splicing. While previous studies have demonstrated that antisense oligonucleotides (ASOs) or small molecules targeted to SMN2 gene can transiently increase full-length SMN protein expression, this approach requires repeated dosing and has incomplete penetrance that poses challenges for patients. Therefore, we are developing optimized base editors (BEs) that enable precise genetic alterations within defined regions of the SMN2 gene. In this proposal, we plan to extend this work by optimizing the most optimal genome editing approaches and investigating the use of adeno-associated viruses (AAVs) to deliver these novel editing technologies in SMA mouse models. In principle, this will create a lasting single-dose permanent treatment for SMA with several advantages compared to targeting mutations in the SMN1 gene or exogenous gene replacement. The success of this proposal will provide solutions to questions at the intersection of the fields of genome editing and neurogenetics, with broad implications for the entire neuromuscular scientific community. 

Sepsis is a common and deadly disease that causes about 11 million deaths worldwide annually. It is characterized by organ failure from dysfunctional immune responses to infection; yet the specifics of immune dysfunction are poorly understood and vary widely among different patients. Current management strategies for sepsis ignore this heterogeneity, instead relying on a “one-size-fits-all” approach to diagnostics and treatment that has been a major reason for limited progress in improving sepsis outcomes for decades.  

Transcriptional analysis of cells at single-cell resolution (single-cell sequencing) is a transformative new tool to probe disease pathogenesis. Recent studies in our laboratory using this methodology have made novel findings, including identification of a new immune cell subtype enriched in sepsis. In this project, we will use single-cell sequencing to investigate the immune cell heterogeneity within a cohort of sepsis patients. These studies will evaluate immune cell abundance and transcriptional changes over time, allowing us to discover the response of each individual immune cell type to infection. Ultimately, we anticipate that this project will expand our understanding of disease mechanisms in sepsis, allow precise distinction between sepsis and its mimics, and characterize patient subtypes to identify those that may respond favorably to certain therapies. 

Colorectal cancer (CRC) is the third leading cause of cancer death in Black men and women, with mortality rates that are 44% and 31% higher in Black men and women compared to White men and women. Approximately 40% of the difference in incidence and 20% of the difference in mortality are due to disparities in screening. Community health centers (CHCs) in urban areas serve a large share of racial and ethnic minority patients and have lower screening rates (41.9%) compared to the general population (69.7%). Low screening rates, and rising incidence and mortality from CRC in adults at younger ages also suggests that focusing on increasing screening uptake from 45 to 54 is a critical target. The objective of this study is to use equity-driven implementation strategies to initiate CRC screening in unscreened individuals aged 45 to 54 at Codman Square Health Center (CSHC) using principles of patient activation. This award leverages an existing partnership with CSHC, a predominantly Black CHC in inner-city Boston. This proposal has three scientific aims: (1) identify system-level and patient-level determinants of CRC screening in individuals 45 to 54 using mixed methods; (2) identify equity-driven implementation strategies to initiate CRC screening matched to determinants; and (3) conduct a randomized pilot evaluation to determine impact of implementation strategies on CRC screening. 

Study Design: The proposed project utilizes mixed methods and equity-driven implementation science methods to increase CRC screening in a predominantly Black CHC. To achieve this goal we will (1) identify patient and system-level determinants of CRC screening through an organizational survey and focus groups with patients and staff guided by an equity-driven CFIR framework; (2) develop implementation strategies matched to determinants using implementation roadmaps; and (3) perform a rapid cycle pilot evaluation to test implementation strategies at the patient- and system-level using an equity-driven RE-AIM framework. The combination of formal training and mentored research outlined in this application is designed to ensure that Dr. Anyane-Yeboa will emerge as a nationally recognized independent investigator with the skills and experience to reduce CRC inequities in marginalized patient populations. 

Acute kidney injury (AKI) is an important clinical disorder affecting many patients worldwide. Given its high prevalence and mortality, AKI is currently diagnosed only after renal injury has occurred, and there is no specific cure. Therefore, there is a clear need for the development of early markers of AKI and an associated therapy to reverse/prevent this complication. The current proposal addresses this clinical gap by leveraging novel mechanisms by which epithelial proton-secreting intercalated cells (ICs) communicate damage to immunocytes in the kidney. Uncontrolled inflammation is a leading cause of AKI. Our hypothesis is that the ICs are strategically positioned to interact with immunocytes, the so-called mononuclear phagocytes (MPs), to survey the renal epithelial barrier and regulate the balance between inflammation and tolerance. In the first aim, we will elucidate the major roles of ICs together with MPs after the ablation of immunotolerance. In the second aim, we will evaluate IC - MP crosstalk to mount an anti-inflammatory response during AKI, performing renal ischemia followed by reperfusion injury. The research proposed will use an innovative multidisciplinary approach to describe how specialized epithelial cells and immunocytes communicate in the kidney. Ultimately, such knowledge will fill gaps to understand the pathogenesis of AKI.

All mammalian embryos undergo a highly conserved sequence of developmental events, but different species complete this sequence at significantly different speeds. For instance, a mouse embryo is formed in 15 days, but a human embryo requires 56 days to complete the same process. How species-specific developmental rates are set represents a major unanswered question in developmental biology. We recently established an in vitro system that recapitulates the twofold difference in developmental rate between mouse and human embryos. This system provides a quantitative measure of developmental speed as revealed by the period of the segmentation clock, a molecular oscillator associated with the rhythmic production of vertebral precursors. Using this system, we uncovered that a higher cytosolic NAD+/NADH ratio in mouse cells compared to human cells gives rise to faster protein production, which ultimately allows mouse cells to proliferate and differentiate faster [5]. In the PSDA-funded project, we seek to elucidate the basis of cytosolic NAD+/NADH differences between mouse and human cells by investigating the activity of biochemical shuttles that transport reducing equivalents from the cytosol to mitochondria. Specifically, we will test the hypothesis that mouse cells feature increased activity of the glycerol phosphate shuttle compared to human cells, thereby underlying differences in cytosolic NAD+/NADH and developmental rate. We will then leverage this new understanding to develop approaches for the modulation of developmental rate in vitro by manipulating glycerol phosphate shuttle activity. Acceleration of developmental rate would allow faster production of mature cell types from human induced pluripotent stem cells (iPSCs) for cell-based therapies and disease modeling; whereas its deceleration would provide new avenues to halt tumor growth and to slow down the aging process. 

Genetic and environmental factors interact in the development of obesity from early life. However, research is still needed to understand how specific genes and environmental factors promote obesity development. The collection of microorganisms that live in our intestine is called the microbiota and is acquired after birth. Multiple lines of evidence have shown that the microbiota influences obesity development. In this project, we will define mechanistically how a genetic risk factor for obesity named Intelectin-1 regulates host metabolism potentially through the microbiota. Intelectin-1 is secreted to our gastrointestinal tract and interacts only with sugars found in the wall of microbes. We will study how Intelectin-1 in the gastrointestinal tract influences obesity using new genetically modified mice. This research project will enhance our understanding of Intelectin-1 on metabolic syndrome and will trailblaze the path to study the implications of Intelectin-1 interactions with the microbiota in humans with obesity. The proposed studies are relevant as they are expected to identify new insights into factors at the host and intestinal microbiome interface associated with metabolic syndrome, elucidate potential mechanisms, and, thus, novel therapeutic strategies for preventing obesity starting during the first years of life.

Pancreatic ductal adenocarcinoma (PDAC) is the most found malignant tumor in the pancreas with an overall 5-year survival rate of 11%. Treatment options for PDAC are limited, and surgical resection remains the only curative option albeit only attainable in 15-20% of cases due to diagnosis at an advanced stage. Therapies for patients with advanced disease are limited to chemotherapeutics and immunotherapy. However, despite the profound success with immunotherapy in other cancers, it is ineffective in PDAC largely due to the barriers introduced by the desmoplastic and immunosuppressive PDAC tumor microenvironment (TME). The TME is infiltrated by tumor-associated macrophages, and neutrophils (TANs) aiding in PDAC immune evasion. It was recently shown that suppression of TANs by Lorlatinib attenuate PDAC growth and improves immunotherapy response in mouse models. Recently, we developed a Fe-based MRI probe, FePyC3A, that becomes MRI visible in the presence of reactive-oxygen species (ROS) by oxidation of Fe2+ to Fe3+. We’ve established that FePyC3A-enhanced MRI can detect TANs in a mouse PDAC model and that their suppression by Lorlatinib treatment is measurable by FePyC3A-enhanced MRI. The primary hypothesis of this proposal is that noninvasive imaging of ROS activity in PDAC will predict response to treatment with anti-PD1 blockade.

Major depressive disorder (MDD) has been associated with a significantly increased risk for cerebrovascular disease and dementia. Although the mechanisms for this association are multifactorial, dysregulation of cerebrovascular function, characterized by blunted cerebrovascular reactivity and reduced cerebral blood flow, has been proposed as a main contributing factor for the development and progression of cerebrovascular disease and cognitive impairment in patients with MDD. Given the key role that these alterations may play in the development of debilitating conditions such as stroke and dementia, the evaluation of interventions that target mechanisms responsible for cerebrovascular dysregulation could have a significant impact in the reduction of disability associated with these disorders in patients with MDD. The primary goal of this study is to evaluate the effects of a novel, non-invasive neuromodulatory technique of the vagus nerve on the regulation of cerebrovascular function in MDD individuals. We will administer expiratory-gated transcutaneous auricular vagus nerve stimulation during a functional magnetic resonance imaging session and will evaluate sex-dependent effects of this intervention on the regulation of cerebrovascular reactivity, peripheral autonomic function, and inflammatory response of midlife adults with recurrent MDD. This initial pilot study will provide relevant information for the development of a sex-selective intervention with beneficial effects prior to later-life health outcomes associated with MDD.

Initially thought to be an acute illness, resulting in death for some or full recovery in most, we are now appreciating that substantial numbers of COVID-19 illness survivors, including young and generally healthy people, experience persistent, significant, and often debilitating symptoms for months or years, known as Long-COVID or Post-Acute COVID-19 Syndrome (PASC). Symptoms range from neurological ("brain fog", headache) and neuropsychiatric (depression, poor sleep), to systemic symptoms (fatigue, pain). Symptoms, interfere with people's quality of life and daily functioning. It is hypothesized that these individuals may be at greater risk for neurodegenerative disease and dementia, including Alzheimer's disease. Yet, we do not understand why some people continue to experience cognitive difficulties and neurological symptoms, which are amongst the most common and debilitating PASC symptoms, and what this means for their future brain health. This three-year study aims to elucidate whether people with PASC, who have been experiencing "brain fog" and other symptoms for months after COVID-19 infection, may show evidence of inflammation and neural injury, as well as disrupted neural networks known to be important for memory and attention. Specifically, we will investigate, 1) the potential impact of PASC on blood markers of neuroinflammation and neural injury and degeneration; 2) the potential impact of PASC on the integrity of neural systems that underly cognitive functioning using resting-state functional connectivity; and 3) the relationship between markers of neuroinflammation and neural injury/degeneration and cognitive functioning in PASC. Findings will enlighten our understanding of the impact of PASC on the brain and its potential risk for future neurodegenerative disease, leading the way for better interventions and healthier aging.

Atrial fibrillation is a type of irregular heart rhythm caused by uncoordinated electrical signaling in the heart. This condition occurs commonly after cardiac surgery and is associated with elevated risk of further complications including stroke, heart failure and death. Atrial fibrillation occurring after cardiac surgery – Postoperative Atrial Fibrillation – is poorly understood with gaps in the knowledge about optimal prevention, duration of disease and patterns of presentation. We propose to advance knowledge in the field by performing a prospective randomized study to compare the rate of postoperative atrial fibrillation in cardiac surgery patients who receive standard of care versus those who receive a combination of two preventative interventions. The interventions include a) administering amiodarone (a drug that regulates electrical signaling in the heart), and b) performing a procedure called a posterior pericardiotomy (which improves blood drainage and can reduce the risk of atrial fibrillation). Integration of data from wearable biosensors placed on study participants at the time of discharge will delineate the duration and characteristics of atrial fibrillation in discharged patients. Overall, this project innovates clinically and technologically to advance our understanding of a major cause of morbidity and mortality in cardiac surgery.

Non-adherence to diabetes medications is a leading contributor to suboptimal diabetes management among Hispanic adults, who are nearly twice as likely to have diabetes-related complications as non-Hispanic White individuals. Digital health technology can improve medication adherence and is recommended by the American Diabetes Association to support diabetes self-care. Text message-based mobile health (mHealth) platforms, in particular, have the potential to engage Hispanic adults, who are more likely to own a cellphone than non-Hispanic White individuals and who are less likely to use other digital health tools, such as patient portals and app-based platforms. Interactive text message-based mHealth platforms with personalized content are features associated with higher user engagement. An mHealth tool with these key features is REACH (Rapid Encouragement/Education And Communications for Health), a low-cost, interactive text messaging platform shown to improve diabetes medication adherence and hemoglobin A1c in an English-speaking, low-income population, while achieving a retention rate of over 90% at 12 months. REACH has not yet been adapted to a Spanish-speaking context and could be a suitable mHealth tool to improve diabetes medication adherence among Hispanic adults with type 2 diabetes. In this proposal, we will adapt REACH to a Hispanic population (REACH-Español) using community-engaged research and mixed-methods in preparation for a randomized pilot study that will assess the feasibility, acceptability, and preliminary efficacy of REACH-Es among Hispanic adults with type 2 diabetes and suboptimal diabetes management.

Cardiovascular disease (CVD) represents the leading cause of death worldwide. While medications, such as statins, significantly reduce atherosclerotic CVD (ASCVD) risk by lowering low density lipoprotein levels, they may also have pleiotropic effects on inflammation. The immunomodulatory effects of these medications are relevant to ASCVD risk reduction given that inflammation plays a central role in atherosclerotic plaque formation (atherogenesis) and influences the development of vulnerable plaque morphology. Patients on statins, however, may have residual inflammation contributing to incident ASCVD despite the potent LDL-lowering effects of statins. While new therapies, such as proprotein convertase subtilisin/kexin type 9 (PSCK9) inhibitors, further reduce incident ASCVD and drastically reduce LDL-C below that achieved by statin therapy alone, PCSK9 inhibitors may also have pleiotropic effects on inflammation. Thus, PCSK9 inhibitors may help reduce arterial inflammation to a level closer to that of patients without ASCVD. This study will apply a novel targeted molecular imaging approach, technetium 99m (99mTc)-tilmanocept SPECT/CT, to determine if residual macrophage-specific arterial inflammation is present with statin therapy and the immunomodulatory effects of PSCK9 inhibition. Given the continued high mortality and morbidity attributable to ASCVD, strong imperatives exist to better understand the immunomodulatory effects of lipid lowering therapies and residual inflammatory risk. This understanding, in turn, will inform the development of new ASCVD preventative and treatment strategies as well as elucidate other indications for established therapies.

Heart failure (HF) with preserved ejection fraction (HFpEF) is a poorly understood syndrome that is projected to become the leading cause of HF in the next decade. Twenty years of research and numerous clinical trials with over 15,000 patients have failed to produce any effective therapies. A major hurdle in HFpEF drug development is the lack of methods that can sensitively detect and diagnose HFpEF, and the clinical diagnosis of HFpEF remains challenging. One of the central features of HFpEF is the development of scar tissue (fibrosis) in the heart. We have previously demonstrated that fibrogenesis-targeted MRI contrast agents can sensitively detect early stages of lung fibrosis and distinguish between active and stable remodeling. The aim of this proposal is to use a targeted imaging agent to detect active fibrosis in the heart in a mouse model of HFpEF. This approach has the potential to address many of the challenges we face in HFpEF research and clinical care. Molecular imaging of a biochemical feature of HFpEF would enable quantification of disease burden at the molecular level, which in turn enables diagnosis, grading/staging of the disease as well as monitoring its progression. The outcomes of this work have the potential to accelerate our understanding of HFpEF and provide more effective approaches to development of HFpEF therapies.

Lung cancer remains the leading cause of cancer-related death among Latinos, and existing disparities in lung cancer outcomes have been exacerbated by the COVID-19 pandemic. Lung cancer screening (LCS) can serve as a pillar to bridge disparities in lung cancer outcomes through early detection among Latino communities. However, despite the proven benefits of LCS in reducing lung cancer mortality, only 10-20% of the eligible population has been screened; the proportion of eligible Latinos participating in LCS is likely to be lower. This proposal seeks to reduce LCS disparities among Spanish speaking Latinos and Latinos with limited English proficiency served by our health care system by implementing a multimodal digital outreach intervention to increase LCS engagement among eligible Latino individuals using a 3-tiered approach: 1) Accurate identification of smoking history to increase LCS opportunities; 2) Digital outreach tailored for Latino communities to increase LCS awareness; 3) Measuring efficacy to increase LCS participation among Latino patients. The specific aims of this proposal are to 1) assess the community needs and emerging barriers to LCS through conducting a survey with Latino communities served by our healthcare system and (2) to employ a mixed-methods approach to explore preferences for message source, channel, and content about LCS during the ongoing COVID-19 to inform a future, culturally tailored LCS outreach intervention among Latino communities. The overarching goal of this proposal is to increase LCS participation and decrease lung cancer disparities by developing a framework to identify barriers to LCS, engage the Latino community in the development of a multimodal digital outreach intervention, and determine the best approach to increase LCS participation among eligible Latino individuals.

Intraductal papillary mucinous neoplasia (IPMN) is a cystic tumor of the pancreas seen in 10% of the population. Retrospective data shows that >1/3 of patients with IPMN are at risk of developing invasive pancreatic ductal adenocarcinoma (PDA), one of the deadliest malignancies. Unfortunately, current clinical and imaging criteria are inadequate for predicting the likelihood of IPMN becoming malignant. The only treatment for IPMN or resulting PDA is surgical resection, which carries significant morbidity (40-50%) and mortality (2%).

Thus, critical challenges include the need to identify patients who are at risk for developing PDA and to improve diagnostic methods and develop preventive therapies, as well as to develop more targeted treatments for IPMN-derived PDA.

We have developed a series of novel genetically engineered mouse models (GEMMs) and have access to one of the largest surgically resected IPMN biorepositories in the world. From these models, we discovered that IPMNs have a distinct immune microenvironment that is rich in tumor suppressive cells and is controlled by specific genetic mutations found only in IPMNs. In this proposal, we aim to further classify these tumor subtypes and identify factors related to cancer progression so that we may uncover strategies for early intervention or treatment of advanced disease.

The COVID-19 pandemic highlighted how vulnerable we are to disease without vaccination. A year into the pandemic, there are several approved vaccines. However, little is known about how cancer patients respond to vaccination. I am a leukemia specialist and treat patients with leukemias called myeloproliferative neoplasms (MPN). MPN patients are immunosuppressed, and studies show that only 45% develop immunity to the yearly influenza vaccine. For this proposal, I collected blood from MPN patients and healthy volunteers before and after receiving COVID-19 vaccines to learn how they respond to vaccination. First, we measured antibody titers before and after vaccination. Specifically, we assessed cumulative IgG, IgA and IgM anti-spike by ELISA (binding site) and we performed quantitation of spike-specific IgG. Second, T-cell responses to COVID-19 vaccinations were measured utilizing interferon gamma ELISpot assays. These studies demonstrated that patients with more indolent MPNs essentially have normal immune response to vaccination, patients with myelofibrosis had a significantly impaired to vaccination. Our results were published in Leukemia in 2022. Lastly, we will use mass cytometry to get an in depth look at how different cells in the immune system interact in response to vaccination. Our goal is to gain a deeper understanding of the immune status of patients with leukemia and to learn how they respond to vaccination. Ultimately, we will continue to investigate how leukemia patients, and immunocompromised patients, respond to vaccination to better guide the care of our patients.

Disruptions to the myelin sheath, the protective layer that covers nerve cells in the brain and spinal cord, can affect neuronal ability to propagate action potentials needed for the proper function of motor, sensory and cognitive skills. Demyelination is a hallmark in a wide range of neurological pathologies, including multiple sclerosis (MS), leukodystrophies, Alzheimer’s disease, traumatic brain (TBI) and spinal cord injury (SCI) and stroke, among others. However, demyelination is not a stand-alone feature in these disorders, being usually accompanied by other processes including neuroinflammation. It is therefore attractive to identify and develop methods that can accurately quantify and assess myelin status in order to diagnose and monitor disease progression and treatment.

Currently, myelin content in demyelinating diseases is evaluated with MRI. However, while MRI is highly sensitive to demyelination, it cannot discriminate between demyelination and other simultaneous processes present in these pathologies, such as inflammation and axonal loss. Due to its biochemical specificity and quantification ability, positron emission tomography (PET) can serve as a complementary technique to MRI. [18F]3F4AP, a recently developed 4-aminopyridine (4AP) based PET tracer that binds to voltage-gated K+ channels, has been proven to visualize demyelination in rodent models of multiple sclerosis. The proposed research project seeks to assess the potential utility of this radiotracer to identify white matter injury in a variety of pathologies, namely models of traumatic injury.

The specific goals of this proposal are to study [18F]3F4AP as a tool to evaluate demyelination with PET imaging in rodent traumatic injury models for open-head and spinal cord injury. Mice will be subjected to a well-characterized model of TBI, open-head controlled cortical impact (CCI) and monitored in a longitudinal PET imaging study with the radiotracer to evaluate focal changes in myelin content, followed by corroboration with histopathological and histochemical characterization of the brain tissue. Additionally, the study will expand to a rat model of SCI to study the pathology of demyelination with imaging, histology, and behavioral methodologies.

A majority of the approximately six million children who undergo anesthesia annually in the United States will experience preoperative anxiety, putting them at risk for poor postoperative outcomes. Several studies have suggested that Black non-Latino and Latino children may receive different treatment for preoperative anxiety than White non-Latino patients: specifically, Black and Latino patients may be less likely to receive midazolam (a benzodiazepine) and more likely to have parental presence at induction (PPAI). However, these findings derive from single-institution studies which neither used established disparities methodology nor considered mediating factors or associated clinical outcomes.

To address this knowledge gap, we will perform a mixed-methods study within the Mass General Brigham Health System to explore the magnitude, mechanisms, associated clinical consequences, and provider perspectives of racial/ethnic disparities in treatment of pediatric preoperative anxiety. We will first characterize the extent by which management of preoperative anxiety varies by patient race/ethnicity and is explained by provider and hospital level factors. We will also determine whether specific treatments (PPAI or midazolam) are associated with any of four pre-identified poor clinical outcomes and evaluate the potential for heterogeneity of treatment effect by patient race/ethnicity. Finally, we will conduct semi-structured interviews to identify as-yet unexplored clinicians’ perspectives on treatment of pediatric preoperative anxiety. Our findings are expected to inform interventions such as protocolized clinical pathways and educational interventions for informing clinicians.

Type 1 diabetes (T1D) is characterized by autoimmune-mediated destruction of insulin-producing beta cells of pancreatic islets. Currently without a cure, diagnosis with T1D necessitates lifelong exogenous insulin replacement therapy. Although this is life-sustaining, physiological glucose control is hardly attainable, with most patients ultimately succumbing to cardiovascular complications. The incidence of this incurable disease is on a global rise, affecting 64, 000 Americans annually and accounts for an annual loss in income and healthcare expenditure of $14.4 billion to the US alone. The bone marrow is the predominant residence of hematopoietic stem cells (HSCs) that regenerate all immune cells throughout life. Additionally, the BM is endowed with other stem and progenitor cells and regulatory T cells (Tregs) that have superior immunoregulatory ability and can abrogate the autoimmune response that destroys beta cells, while supporting tissue regeneration. Unfortunately, the BM is also “sick” in T1D, causing dysregulation of immune cell production, as well as impaired function and peripheral mobilization of immunoregulatory stem/progenitor and regulatory T cells. This promotes disease development and associated cardiovascular complications. The overall goal of this PSDA research project is to use single cell sequencing analysis to understand how autoimmune diabetes impacts the BM microenvironment and to design novel therapeutic strategies to rescue BM function and induce mobilization of stem/progenitor cells and Tregs mobilization into the blood circulation and pancreatic islets to treat autoimmune diabetes. These studies may uncover new pathogenic mechanisms in T1D and treatment strategies.

Lung cancers with anaplastic lymphoma kinase (ALK) rearrangements are defined by an initial dependence on ALK signaling that renders these tumors markedly sensitive to ALK targeted therapies. However, the majority of ALK+ lung cancer will eventually develop refractoriness to ALK targeted therapy due to adaptations that promote dependence on other growth signals. In current practice, "ALK-independent" growth signals are most often identified through direct analysis of biopsies obtained through invasive procedures or laboratory studies of cell lines derived from these biopsies. In this grant, we are exploring whether less invasive strategies, i.e. plasma analysis, can identify genetic alterations that are critical to survival of resistant ALK-positive lung cancers. Furthermore, we will conduct a clinical trial to assess the activity of several combination therapies in patients with ALK-positive lung cancer with ALK-independent resistance. As there are no approved selective regimens for ALK-independent resistance and understanding of the molecular drivers of this important form of resistance is limited, these analyses have the potential to immediately impact patient care and inform future treatment strategies.

Aortic aneurysm is a common human condition, accounting for greater than 17,000 deaths annually in the United States. Aortic aneurysm places individuals at risk for aortic dissection (AoD), a life-threatening complication of aortic dilation, a malady with mortality rates measured at 1-2% per hour. During aortic aneurysm progression, vascular smooth muscle cells (VSMC) undergo dramatic changes in cellular phenotype. Large scale rearrangements in cellular metabolism, impaired autophagy signaling, loss of cellular contractile elements and expansion of synthetic capacity. Our previous work has found that HDAC9 mediates the epigenetic downregulation of VSMC contractile genes via recruitment of the methyltransferase EZH2, the catalytic subunit of the PolyComb Repressive complex 2 (PRC2). Interestingly EZH2 is a negative regulator of autophagy activity with detrimental effects on VSMC survival. Autophagy is an evolutionarily conserved, tightly regulated process through which cells deliver unnecessary or potentially dangerous cellular materials in double-membrane vesicles for degradation via fusion with lysosomal compartments. Our preliminary data indicates that in TAA models, HDAC9 binds to chromatin regions at autophagy-related gene-loci which associates with the accumulation of autophagy vesicle and cytotoxic materials (matrix proteases), indicating abnormal autophagy flux. We expect that this study will lead to an in-depth mechanistic understanding of the regulation and function of autophagy in normal vascular tissue and aneurysm disease and will provide insights into precise targeting of autophagy for aortic aneurysm treatment.

End-stage liver disease (ESLD) is an irreversible condition marked by poor quality of life, high symptom burden, and a median survival of less than 2 years in the absence of liver transplantation. While liver transplantation improves outcomes for transplant candidates, the diagnosis of ESLD remains a terminal one for thousands of patients annually who die while awaiting a donor organ or are deemed ineligible for transplant. Despite their poor prognosis, the majority of patients with ESLD have frequent hospitalizations and receive intensive care in their last months of life.

Specialty palliative care clinicians are experts in managing complex symptoms, helping patients cope with their illness, enhancing patients’ illness and prognostic understanding, and supporting patients with advance care planning. However, palliative care is underutilized for patients with ESLD, despite studies showing that palliative care improves quality of life and symptom burden and reduces healthcare utilization in patients with serious illnesses.

We have developed a longitudinal inpatient palliative care intervention tailored to the unique physical, psychological, and end-of-life care needs of patients with ESLD. In this proposal, we will conduct a prospective randomized study to assess the feasibility, acceptability, and preliminary efficacy of this intervention versus usual care alone on improving quality of life and symptom burden and reducing healthcare utilization for 100 patients with ESLD.

Thrombotic disorders of the pulmonary circulation, including pulmonary embolism (PE) and chronic thromboembolic pulmonary hypertension (CTEPH), are estimated to affect over 1 million people in the United States every year, accounting for 1 in 8 deaths worldwide and costing over $1.5 billion U.S. dollars annually. The current standard of care treatment is anticoagulant or thrombolytic drugs; however, these therapies do not target molecular mechanisms underlying pulmonary thrombosis specifically and are associated with a high rate of major adverse clinical events due to off-target drug complications such as life-threatening hemorrhage in other vascular beds. Therefore, developing a therapy that is selective to the pulmonary circulation is anticipated to provide a superior therapeutic advantage compared to the current standard of care. We demonstrated that NEDD9 is a hypoxia-sensitive protein that is selectively upregulated on the luminal aspect of human pulmonary artery endothelial cells and binds directly to platelet-surface P-Selectin to promote pulmonary thrombosis. We developed a novel antibody that targets the NEDD9-P-Selectin binding region to prevent platelet-endothelial adhesion in vitro. We now aim to demonstrate if it can prevent pulmonary thrombosis and pulmonary hypertension in vivo with the goal of translating this into a novel therapeutic strategy for patients.

Prostate cancer (PC) is the most common malignancy among men in the United States. Prostate-directed radiation therapy is an effective treatment for localized PC but it can be associated with long-term bladder, bowel, and sexual toxicities that adversely impact quality of life (QOL) in PC survivors. Long-term QOL is key in this population given high cure rates and long natural history. There is a need for biomarkers that can accurately predict individualized radiation toxicity risk and thus enable tailoring of treatment. Emerging data suggest that inherited genetic differences may impact radiosensitivity. Single nucleotide polymorphisms (SNPs) have been reported as predictors of toxicity after radiation but have not been independently validated in prospective, prostate-specific cohorts. The overarching hypothesis of this project is that individual genetic variations through SNPs mediate normal tissue toxicities induced by radiation. Using samples from patients prospectively enrolled on an ongoing multicenter national randomized phase III trial evaluating proton- versus photon-beam radiation therapy in early-stage PC, we seek to validate previously identified SNPs associated with radiation toxicities using high-quality, prospectively collected toxicity and patient-reported outcome data. Validated SNPs can serve as biomarkers for predictors of radiation-specific toxicity and patient-reported long-term QOL that can guide and personalize PC treatment.

Cerebral Adrenoleukodystrophy is a devastating inherited disease that causes inflammatory cells to infiltrate the brain, leading to progressive degeneration, vegetative state and death in months to years. Unfortunately, current therapies either fail to prevent cerebral disease or carry high toxicity and mortality. In this project we will study how the gene defect changes the brain vessel permeability to allow access of inflammatory cells to the brain using laboratory tools at the bench. If validated by this study, our approach sets forth a successful strategy for identifying factors that contribute to the development of cerebral degeneration and a laboratory tool urgently needed to screen for new therapies that are more targeted and less toxic.

Adherence to hormonal therapy (HT) among women with hormone receptor positive breast cancer (HR+) is suboptimal, contributing to preventable deaths and health disparities. American Society of Clinical Oncology practice guidelines recommend that women with HR+ breast cancer complete at least five, and up to 10, years of adjuvant tamoxifen and/or aromatase inhibitor therapy, depending on menopausal status. Data suggest that up to 50% of women do not complete five years of endocrine therapy, and this may be even worse among lower-income and minority women and may contribute to persistent racial and socioeconomic disparities in breast cancer survival. Previous interventions to address gaps in HT initiation, adherence and persistence have focused on education and cognitive behavioral training among patients, with limited success. However, a small but growing body of evidence demonstrates system-level interventions that may be effective. In this proposal, we build on a city-wide implementation trial to improve care to vulnerable women across Boston. Translating Research into Practice (TRIP) is a three-pronged city-wide patient navigation intervention targeted at breast cancer patients who are at risk for delays in care due to their race/ethnicity, language, or insurance status. We propose to:

1. Determine the feasibility and validity of an online medication database compared to EMR data abstraction to measure HT adherence and persistence
2. Evaluate the impact of TRIP on HT early discontinuation and adherence among 342 intervention patients and 263 historic controls with HR+ breast cancer

Despite initially effective chemotherapy for ovarian cancer, around two-thirds of patients diagnosed will succumb to this disease. As such, novel efficacious treatments are critically needed. The presence of MUC16 (CA-125 antigen) on the surface of most epithelial ovarian cancer cells provides an opportunity for immunotherapy-based approaches that target this cancer. This project aims to exploit the MUC16 antigen via the design and testing of bispecific engager T cell molecules that bind to the cancer cell and recruit the patient’s immune system to destroy the tumor. In addition, we aim to understand the role of unfavorable elements of the tumor microenvironment and engineer countermeasures to improve the clinical efficacy of bispecific engagers. We will rationally combine other chemotherapeutics, and immunotherapeutic modalities with bispecific engagers to promote a comprehensive immune attack against cancer.

Six million Americans suffer from heart failure and the prevalence is expected to increase 46% by 2030. Increased heart size (cardiac hypertrophy) commonly precedes heart failure. Indeed, clinical studies show that even partial regression of hypertrophy improves major clinical outcomes. We understand little about how to mechanistically promote beneficial cardiac size normalization (or regression) and hypothesize is that there are adaptive and maladaptive regression states that conceptually parallel the adaptive physiological and maladaptive pathological growth states of cardiac hypertrophy. We are using extreme models to gain new insights into the process of cardiac remodeling. In the Burmese python, the heart undergoes repeated regression episodes after feeding. We anticipate that identification of pathways promoting beneficial regression rather than maladaptive atrophy will provide new biological insights as well as novel therapeutic targets against heart failure. We will identify transcriptional signatures of regression using multiple models that include the Burmese Python and mammalian models. We focus on a class of molecules known as microRNA because they are known key regulators of cardiac development and disease; have been largely unexplored in this context; are highly conserved across species; and are amenable to therapeutic targeting.

Gestational diabetes mellitus (GDM), the most common metabolic complication of pregnancy, is associated with an increased risk of adverse perinatal outcomes and future maternal type 2 diabetes (T2D). Randomized trials demonstrate that GDM treatment reduces the risk of complications, yet standard GDM treatment is burdensome and crude, relying on frequent blood glucose self-monitoring and trial-and-error (as glycemic responses to both diet and pharmacotherapy, prescribed when dietary treatment fails, vary greatly between individuals). GDM, until now, has been treated as one disease, but we recently demonstrated that all GDM is not the same: genetics and pregnancy outcomes differ according to the predominant late pregnancy physiologic defect leading to hyperglycemia. The goal of this project is to define and characterize GDM subtypes using physiology and genetics to develop novel personalized approaches for this increasingly common condition. We will link samples from women with prior GDM in the MGH Obstetrical Maternal Study and the Partners Biobank to clinical data from their GDM-affected pregnancies. We will test whether GDM subtypes, defined based on physiology or genetics differ in their risk for adverse perinatal outcomes, dietary treatment failure, and future maternal T2D. Our work will set the stage for novel precision approaches to the treatment of hyperglycemia and prevention of T2D in women with GDM.

Conditions such as heart attack and heart failure are conventionally regarded as diseases of the heart muscle. There is profound scientific interest and study of the many other cell types in the heart that interact with the heart muscle and can contribute to heart disease. Pericytes are unique cells that line the outer walls of the smallest blood vessels in the heart and are thought to have many roles in regulating blood flow and maintaining the local health of the tissue. The organization and many functions of these cells are not well understood, however, in part due to a lack of scientific tools to measure them in their native environment. This project seeks to utilize state-of-the art optical microscopy techniques and transgenic reporter mice to profile the structure and dynamic physiology of pericytes in the living, beating heart in a model of myocardial infarction or heart attack. The ultimate goal is to better understand the ways that these cells contribute to ischemic heart disease in order to develop improved pharmacologic therapies.

Obesity rates continue to rise in adolescents and young adults in the US. To date, weight loss surgery is the most effective tool to treat moderate to severe obesity and its associated co-morbidities. This proposal seeks to understand predictors of referrals to tertiary weight management and subsequent weight loss surgery in adolescents and young adults. We will assess shared decision-making surrounding weight loss surgery and develop a decision aid (DA) to help adolescents and young adults with moderate to severe obesity decide if weight loss surgery might be a useful tool to treat their obesity.

Motor Functional Neurological Disorder (a.k.a. Conversion Disorders) is a highly prevalent and disabling neuropsychiatric disorder, comprising about 16% of outpatient neurology referrals; this includes patients with Functional Seizures, Functional Movement Disorders and Functional Limb Weakness. Motor Functional Neurological Disorder and other brain-mind-body conditions are exceedingly costly to the U.S. health care system, with an estimated $256 billion/year spent in caring for medically unexplained illness. To date, very little is known about the underlying biological mechanisms of this disorder at the intersection of Neurology and Psychiatry. This study seeks to identify structural and functional magnetic resonance imaging biomarkers of symptom severity, disease-subtype and prognosis across the spectrum of motor Functional Neurological Disorder. The aim of this research is to advance our pathophysiologic understanding of this condition and subsequently catalyze the development of biologically informed treatment studies. It is hypothesized that structural and functional circuit changes in specific brain regions that mediate the convergence of emotional, viscero-somatic, cognitive and motor functions are associated with symptom severity, disease-subtype and prognosis in motor Functional Neurological Disorder. This research leverages a large and relatively unique patient cohort in the newly established Functional Neurological Disorder Unit at the Massachusetts General Hospital in the Department of Neurology.

For the first time since Alzheimer’s disease (AD) was discovered, amyloid-modifying treatments are being evaluated in clinical trials, while other disease-modifying treatments, including anti-tau antibodies, are in preclinical development. These holds promise to modify the course of AD, and even prevent its clinical manifestation if administered early enough.

We will work with an extraordinary family of approximately 5,000 individuals in Antioquia, Colombia, which contains roughly 1,800 carriers of the autosomal-dominant presenilin1 (PSEN1) E280A mutation. These carriers are virtually certain to develop AD, and have a well-characterized disease course, with dementia occurring at a mean age of 51. We are currently using cross-sectional data to characterize associations of preclinical biomarker changes with age and temporal distance to the kindred’s mean age of clinical onset. The addition of the longitudinal data proposed for this PSDA will greatly improve our understanding of the trajectory of these biomarker changes in preclinical AD and their role in subsequent cognitive decline.

It is increasingly clear that there can be significant genetic and epigenetic variability within a single tumor in a single patient. This intra-tumor heterogeneity has implications both for understanding the biology of tumor development, and for effective patient management since clinical decisions are based on pathological diagnosis of a small biopsy that may not represent the entirety of the tumor. While pathologists have long recognized morphological variability within tumors, high-throughput molecular techniques have until recently been limited to bulk ‘averaged’ tissue measurements, which obscure cell-to-cell variability. We are working in collaboration with labs that are developing techniques for in-situ genomic profiling of biomolecules including RNA and protein. These approaches will allow the simultaneous study of changes in tissue architecture and cell state in diseases such as cancer. While proof-of-principle experiments have demonstrated the feasibility of in-situ transcriptional profiling, adoption of the techniques will be hampered by the lack of established bioinformatics tools. We plan to develop a publicly available computational analysis tool set for spatially resolved genomics data. These data can be layered on top of traditional morphology-based pathology images to dramatically improve our ability to characterize cellular states and diversity in tumors and other tissues.

Sub-Saharan Africa contributes a staggering 71% of the global population living with HIV. Nigeria, the most populous country in Africa, has an estimated 3.5 million people with HIV, the second largest worldwide. Despite the tremendous gains of antiretroviral therapy (ART) scale-up in Nigeria and other countries in the past decade, loss to follow-up (LTFU) and unplanned care interruption continue to undermine the clinical and transmission benefits of ART. One in four patients are lost-to-follow-up one year after initiating ART, resulting in loss of the survival gains of treatment. While some patients are completely lost from HIV care, about one-third interrupt but then return to care. Studies among this group are extremely limited. 1 Patient retention in care is likely influenced by a combination of health-system factors, driven by the facility and healthcare environment, and patient-factors, driven by individuals and community.

With support from the Physician Scientist Development Award, I aim to address important gaps in knowledge on patient retention. I have developed a collaboration with the AIDS Prevention Initiative in Nigeria (APIN), a large, multi-site HIV treatment program in Nigeria now caring for over 100,000 patients, to launch the Care4Life Study. Our team is enrolling a prospective patient cohort, which will consist of 750 patients newly enrolled in care and initiated on ART. We will investigate a range of factors informing patient decisions to remain in care over time, including clinical status, socio-demographic factors along with competing priorities on healthcare, stigma, religious/traditional beliefs, and levels of decisional conflict. I will also lead an effort to study APIN’s large retrospective database at 36 HIV treatment centers to identify health-system characteristics associated with patient retention. These studies will inform the development of novel interventions to improve retention for HIV-infected patients in Nigeria, and other resource-limited settings.

This four-year project proposal seeks to build upon my experience with nanomedicine and published work using novel nanosensing technologies developed at MGH to profile cancer protein markers across the spectrum of human specimens: fine needle aspirates (FNAs), ascites, and peripheral blood.The project intends to optimize and translate validated micro- nuclear magnetic resonance (µNMR) into patient-oriented research efforts. Specifically, µNMR will be explored as a practical strategy for robustly quantitating 1) baseline signal transduction pathway activity; and 2) drug modulation of the targeted pathway in FNAs attained from subjects treated with one or more targeted drug therapies. Since conventional protein testing is limited by the amount of tissue procured, µNMR works within these limitations by extracting more information from an FNA – which yields fewer cells but is a less morbid procedure than excisional or core biopsies. Implementing

a tactic that could potentially 1) provide clinical investigators with same visit readouts of pathway activity; and 2) enable drug combination trials in patients with inadequate pathway inhibition to monotherapies, could improve subject selection and streamline the drug testing process.The proposed project will focus on the biologically important and therapeutically relevant PI3K-Akt and Raf-MEK-ERK pathways. If successful, µNMR could be positioned as a companion tool for use with the growing number of targeted therapy studies at MGH and beyond.

General anesthesia is drug-induced reversible neurophysiological phenomenon comprised of five distinct behavioral states: hypnosis (loss of consciousness), amnesia (loss of memory), analgesia (loss of pain sensation), akinesia (immobility), and the maintenance of physiological stability. Over 100,000 patients receive general anesthesia in the United States each day for surgical and diagnostic procedures. Despite its widespread use, the neural-circuit mechanisms by which anesthetic drugs induce the state of general anesthesia are not well understood. By studying anesthesia-induced unconsciousness and recovery of consciousness in controlled human experiments with high-density electroencephalography, and simultaneous positron emission tomography/functional magnetic resonance imaging, we are identifying the neural circuit mechanisms implicated in general anesthesia-induced brain states. This understanding has direct implications for a precise neurophysiological definition of anesthetic brain states, improved brain function monitoring, and risk stratification of patients.

The project funded by the award was focused on the application of immuno-proteomics to the study of protective immunity in human cholera infection, an infection that remains endemic in over 50 countries. An estimated 3-5 million individuals develop cholera each year, resulting in approximately 100,000 deaths. Although cholera vaccines do induce a protective immune response, immunity is short-lived, lasting approximately 6-24 months. In comparison, natural infection with cholera results in protective immunity that lasts years or decades. The mediators of this protective immune response to cholera are poorly understood. In this project, Dr. Charles used a high-throughput protein-based platform to characterize serum and mucosal anti-V. cholerae immune responses in cholera patients and vaccinees. The results of these studies have provided important insights into protective immunity of human cholera infection, and could lead to improved vaccination strategies against cholera.

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Dr. Louissaint aims to contribute significantly to the diagnosis and treatment of lymphoma by identifying molecular alterations that help us to understand their pathogenesis, serve as prognostic indicators of outcome, and potentially represent therapeutic targets. In 2010, Dr. Louissaint was awarded an ECOR MAO physician-Scientist Development award in support of his work on follicular lymphoma. Follicular lymphoma (FL) is the second most common type of non-Hodgkin’s lymphoma (NHL). Its clinical course and prognosis are highly variable, and at present, we do not have optimal clinical or pathological prognostic indicators of outcome to assess risk and make individualized treatment choices. Therefore, there is a need to identify biological markers that can be used in practice to predict outcome and direct therapy in patients with FL.

Dr. Louissaint characterized and defined "Pediatric-Type follicular lymphoma" (PTFL), a novel type of follicular lymphoma known for its distinctly indolent course. He received the 2013 Benjamin Castleman award by the United States & Canadian Academy of Pathology. He later received the 2014 Harold Amos Medical Faculty Development Program Award by the Robert Wood Johnson Foundation and the American Society of Hematology (ASH), the 2014 Harvard Catalyst PFDD Fellowship and an American Cancer Society grant in support of his work. Dr. Louissaint defined the genetic landscape of PTFL, discovering that PTFLs harbor recurrent somatic activating mutations in MAP kinase pathway genes in almost 60% of cases. On the basis of this work and the work of others, PTFL is now defined a distinct entity in the recent 2016 WHO Classification of Hematopoietic neoplasms. Dr. Louissaint is currently using next-generation sequencing to define the genomic features of other non-Hodgkin B-cell lymphomas. To this end, he has created and leads a lymphoma repository at MGH in which lymphoma samples are viably frozen for later genetic and functional studies. Dr. Louissaint has created patient-derived models of follicular lymphoma and is currently investigating questions about the role of microenvironment in lymphomagenesis, lymphoma progression and transformation.

Wilms tumor is the most common pediatric kidney cancer and is closely connected to kidney development. Mutations in two genes, WT1 and beta-catenin, are present in 5-10% of tumors but the genetic basis of the remaining cases is unknown. Using high resolution DNA arrays Dr. Rivera identified a new tumor suppressor gene, WTX, which is inactivated in 30% of Wilms tumors. WTX is the first example of a tumor suppressor that, due to its location on the X-chromosome, is inactivated by “single hit” events targeting the single X chromosome in males or the active X chromosome in females. During development, WTX is expressed in specialized kidney stem cells and is thus likely to have an important role in both Wilms tumor and in normal developmental processes. Dr. Rivera is now studying the function of WTX in several model systems in order to identify molecular mechanisms that are important in early kidney development and that could be widely applicable to cancer and other diseases.

Genome-wide association studies (GWAS) have identified novel diabetes-associated loci with high statistical confidence. How these variants affect response to anti-diabetes medications is not known. We propose to mine recent GWAS for diabetes-associated variants in a three-pronged approach. First, we will attempt to replicate novel associations discovered in recent GWAS for type 2 diabetes and related glycemic traits in a new MGH diabetes case/control sample totaling 1,812 subjects and in the Diabetes Prevention Program (DPP), in which 2,994 participants at high risk of diabetes were randomized to a lifestyle intervention, metformin or placebo. Second, we will mine these GWAS for polymorphisms in genes that encode diabetic drug targets, and assess their effects in the DPP. And third, all high-likelihood variants will be tested in the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH), and in a retrospective patient cohort treated with monotherapy culled from Partners electronic databases. With this project we hope to determine whether polymorphisms in genes that encode drug targets have an effect on diabetes risk and response to intervention.

Malignant glioma is a relentlessly progressive and universally fatal disease. Median survival is only 14 months, and there is no known effective treatment for recurrent disease. Immunotherapy represents a promising approach by which to target these intracranial tumors; however, for such therapy to be effective, we must overcome the systemic and local immunosuppression associated both with these tumors and their treatments.

They are conducting a phase I clinical study in which glioma cells are harvested from patients at surgery, irradiated, mixed with a GM-CSF – producing cell line and implanted subcutaneously in patients for a scheduled six vaccinations. measured outcomes in this study include safety, feasibility, and biological effect, including development of antitumor immunity. We are performing detailed serological analyses of antibody and T lymphocyte responses to patient brain tumors in an effort to uncover antigenic tumor epitopes and to further unravel the basic mechanisms by which the immune system responds to human brain tumors.

The United States is experiencing a significant increase in the prevalence of Type 2 diabetes mellitus (T2DM). Communities of color are especially affected. Vitamin D deficiency (VDD), also more prevalent in minority populations, appears to contribute to insulin resistance (IR). However, no large clinical trials of the impact of treating VDD on IR exist. We hypothesized that treatment of VDD would decrease IR. We randomized 90 vitamin D deficient (25-OHD < 20 ng/mL), healthy men and women of diverse racial background to vitamin D 50,000 international units, or placebo, QWK for 12 weeks. The primary endpoint was the change in IR as assessed by modified IVGTT. While we observed the previously reported negative association between insulin resistance and vitamin D levels, repletion of vitamin D deficiency over 12 weeks did not change insulin secretion or resistance in any subjects (Mitchell et al, American Journal of Clinical Nutrition 2015; 102: 1-8). It will be important to follow-up these results with longer term interventional studies that include glucose tolerant and intolerant subjects. However, these findings suggest that there is not a benefit to repleting vitamin D deficiency from an insulin resistance perspective.