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Research at Mass General
Snapshot of Science provides a quick look at recent publications, press releases and stories about the Mass General research community.
Here's a quick look at some of the recent publications, press releases and stories about the Mass General research community.
In this issue we highlight:
This is just a small snapshot of the incredible research that takes place at Mass General each day—there's lots more to find at massgeneral.org/research/news.
(Click on titles to see author-submitted summaries)
Allergens trigger eczema and asthma and thus insufferable itch and difficulty breathing. New work from the Lerner lab helps to explain these symptoms. While it has been known for decades that allergens turn on the immune system, their recent publication in the Journal of Biological Chemistry reveals that allergens also turn on the nervous system. This exciting finding makes sense, as the sensation of itch requires nerves, which has only recently been found for asthma. These observations suggest that targeting the nervous system could lead to new treatments for eczema and asthma.
Pseudomonas aeruginosa is a bacterium adept at infecting those already fighting illness or resolving injury, making bad situations worse. This microbe exacerbates burns, wounds, and airway distress by colonizing damaged tissue and manipulating inflammation towards its advantage. Researchers discovered a novel function of a toxin produced by Pseudomonas aeruginosa, known as ExoU. ExoU is injected into inflammatory cells recruited to the infectious site. Once inside, ExoU amplifies a key signal calling more inflammatory cells and intensifying things in a harmful way, while helping the microbe thrive. Impeding ExoU might recalibrate the inflammatory response towards benefiting the health of the patient.
Millions of patients treated with Warfarin and other anticoagulant drugs, have an increased risk of bleeding complications. Consequently, most patients require frequent laboratory testing to ensure safe anticoagulant dosing, imposing a staggering load on patients and primary care services. An optical sensor developed in the Nadkarni laboratory at the Wellman Center facilitates comprehensive coagulation profiling in whole blood and opens new opportunities for rapid and inexpensive coagulation testing in the doctor’s office and for patient self-testing. In a recent study by Tshikudi and co-authors, the team has demonstrated that dose-dependent anticoagulation can be quantified with excellent accuracy and precision within minutes using a drop of blood. Their optical sensing approach is poised to improve anticoagulation management in patients while reducing the burdensome need for frequent laboratory testing.
At the very foundation of life is the ability of each cell in the human body to perform sophisticated chemical reactions, broadly referred to as metabolism. Investigating metabolism is challenging in part because we lack methods to manipulate it in a defined way. Researchers at Mass General used structure-based protein design to invent a new genetic tool with which it is possible to manipulate one of the most central chemical co-factors in human metabolism. They anticipate that with the new tools it will be possible to investigate in much greater detail how cells cope with metabolic challenges under various disease conditions.
Genes in mammals are expressed as sums of signals from two alleles. Previous efforts to deconstruct these sums into individual alleles identified a number of genes with unequal expression from the two alleles. To better understand regulatory mechanisms behind this imbalance, researchers performed genome-wide analysis of epigenetic chromatin states of genes at the allele level, with the focus on autosomal genes with unequal levels of chromatin marks between two alleles. They identified approximately 4% of these autosomal genes that show imbalance between chromatin states of two alleles, analyze major sources of this imbalance, and show that it is predictive of allele-specific gene expression. The results provide a better understanding of this specific type of allelic imbalance which has important implications in cell biology and human disease.
In tumors, cancer cells are surrounded by a collection of proteins, enzymes, sugars, lipids, and minerals called the extracellular matrix (ECM). Many cancers have a fibrotic ECM making the tumor stiff and preventing delivery of anti-cancer drugs. The presence of a fibrotic ECM is often associated with poor prognosis. Researchers developed a new MRI method to detect tumor fibrosis non-invasively, and studied its effect in a mouse model of pancreatic cancer. The potential impact of this work is a new tool to stage the aggressiveness of tumors, guide treatment planning, and monitor the effectiveness of new tumor ECM altering treatments.
Glioblastoma is an invariably fatal brain cancer with no effective treatments. Immunotherapy has produced curative responses in a subset of cancers, but not glioblastoma. Here researchers show that curative therapy for glioblastoma requires multiple immunotherapeutic strategies (oncolytic viruses, immunomodulatory cytokine expression, and two distinct checkpoint inhibitors). This treatment strategy has highly interconnected effects on multiple immune cell types in the tumor microenvironment - namely an increase in T effector cells, a decrease in T regulator cells, and an infiltration of macrophages and their polarization to an anti-tumor phenotype. This reveals a new combination strategy to treat glioblastoma and other tumors that historically have been unresponsive to immunotherapy.
Lung inflammation can be beneficial or harmful depending on degree and context. White blood cell neutrophils rapidly breach protective airway linings to confront microbes, but can be quite destructive. The research team of immunologists, pediatricians, bioengineers, and stem cell biologists developed a new model of inflamed human airway mucosa. Airway stem cells from biopsy were cultured to develop beating cilia and secrete mucus. Neutrophils from blood donors were applied to infected airway cultures and live imaged to reveal rapid mobilization and migration through airways in response to identified signals. This model has enormous potential for investigating inflammation and evaluating new therapies.
Positron emission tomography (PET) imaging, a very useful imaging method for disease diagnosis, treatment monitoring, and drug development, is particularly known for its high cost, which has been the key roadblock for its widespread routine use. The need to produce and prepare chemicals used in PET imaging on-site (called on-site synthesis) weightily contributes to the high cost. In this report, researchers demonstrated that synthesis-free PET imaging is feasible, and has the potential to significantly reduce the cost of PET imaging. Specifically, step-wise injection of 64CuCl2 and disulfiram, a FDA approved drug for alcoholism, could be used to avoid the on-site synthesis and be applied for imaging brown adipose tissue (BAT), which is very important for maintaining the energy balance of the whole body.
Positron emission tomography (PET) allows visualization of numerous biological processes. Many PET studies require arterial blood sampling, a complicated and invasive procedure. One such type of PET data (“TSPO PET”) is used to assess brain inflammation, but recent evidence suggests traditional arterial blood methods are suboptimal for these data. Therefore, researchers investigated alternative methods to analyze TSPO PET data without arterial sampling. They found that a ratio technique identified inflammation in patients with chronic pain and Lou Gehrig’s Disease similarly to traditional methods. These results suggest that TSPO PET studies, if properly validated, may be conducted without arterial catheters, an attractive prospect for studies where traditional methods are impractical or unavailable.
When a person is at wakeful rest, his/her brain activity will not drift into random noise. Instead, there are robust dynamical interactions between brain regions. It remains unclear how the long-range interactions may relate to local brain activity. Recently, investigators at Mass General combined fMRI and MEG to study the relationship between the anterior and the posterior cingulate cortex (ACC and PCC), two core regions of the default-mode network that is important for self-referential thoughts, and discovered that local activity of the ACC changes according to its interactions with the PCC. This covariation between long-rage connectivity and local activity provides important insights into the neural underpinnings of human cognition, which is driven by complex interactions between different brain regions.
A 68-year-old woman with chemotherapy-refractory diffuse large B-cell lymphoma (DLBCL) with a brain metastasis was treated with CAR T-cell therapy (tumor-targeting immune cells) as part of a clinical trial. Mass General researchers observed that treatment induced complete remission of the brain and all other sites of disease - the first report of a response to CAR T-cells in a central nervous system (CNS) lymphoma. In addition, when a subcutaneous tumor began to recur two months after CAR T-cell therapy and a surgical biopsy was performed, the CAR T-cells spontaneously re-expanded and the tumor again went into remission, a phenomenon that had also not previously been reported. These observations have implications for multiple types of CNS lymphoma, for which treatment options are limited, and few patents are cured.
Type 1 diabetes (T1D) is an autoimmune disease where insulin producing cells are destroyed. Inflammation in islets of human patients has been hard to evaluate, given the challenging access to material. Now, researchers at the MGH Research Institute and Harvard Medical School have discovered how the different cellular players interact. They created new reporter mice and new imaging agents where cells of interest (lymphocytes, macrophages, dendritic cells, beta cells) are fluorescent and can be observed by imaging. They were able to observe the intricate “dance” of different immune cells interacting with each other as diabetes develops. Throughout the process, Tregs (a unique type of T-lymphocyte) control the activation of many cell types. The “dynamic geography” of events uncovered here provide important clues to immunoregulation that underlies diabetes development.
Alzheimer’s disease (AD) is the most frequent cause of severe memory loss in the elderly. Early detection of AD is the key to preventing, slowing or stopping the disease. Near-infrared spectroscopy (NIRS) is a non-invasive neuroimaging technique capable of monitoring brain activation. Here, researchers investigated the utility of fNIRS in measuring brain activity of healthy adults during memory encoding and retrieval under a face-name paired-associate learning task. Their study demonstrates that fNIRS can robustly measure memory encoding and retrieval-related brain activity. Future work will include similar measurements in populations with progressing memory deficits. Their approach, if successful, will introduce a non-invasive, inexpensive and easily accessible tool for identifying early stages of AD.
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