A Snapshot of Science at Mass General: A New Approach to Targeted Cancer Treatments, Identifying Genes that Help Protect the Gut and Much More!

We wanted to share some recent Massachusetts General Hospital research that has been published in high impact, top-tier journals. This is just a small snapshot of the incredible research that takes place at Mass General each day — there’s lots more to find on the Mass General website!


Cognitive Decline, Tau and β-Amyloid in Healthy Older Adults
(Summary submitted by Rachel Buckley, PhD, and Rebecca Amariglio, PhD, both of the Martinos Center for Biomedical Imaging)

We published findings from the Harvard Aging Brain Study (Department of Neurology, Massachusetts General Hospital) investigating the link between subjective memory complaints (when a patient reports a worsening of their thinking abilities, including memory) and Alzheimer’s disease pathology in individuals who are otherwise cognitively normal. We found that increasing memory complaints were linked with greater amounts of tau in the brain, a naturally occurring protein that is associated with neuron loss in Alzheimer’s disease. We posit that memory complaints are a very early marker of disease, as they relate to tau build up before clinical tests can detect memory impairment.

Region-Specific Association of Subjective Cognitive Decline With Tauopathy Independent of Global β-Amyloid Burden
Buckley RF, Hanseeuw B, Schultz AP, Vannini P, Aghjayan SL, Properzi MJ, [et al.] Amariglio RE
Published in JAMA Neurology on October 2, 2017


New Approach to Targeted Cancer Treatment 
(Summary submitted by Conor L. Evans, PhD, of the Wellman Center for Photomedicine)

We have created a promising new light-activated, cancer-targeting therapeutic. Cancer drugs often cannot reach every cell in a tumor, leaving behind cells that can become resistant to treatment. At the same time, these drugs can cause unwanted systemic problems, such as weight and hair loss, elsewhere in the patient’s body. Our therapeutic was built to diffuse throughout tumors, target cancer cells, and kill these cells only when activated by light to avoid unwanted and burdensome side effects. We hope that this approach could one day find use in the fight against treatment-resistant cancers, like breast and lung.

An Integrin-Targeted, Highly Diffusive Construct for Photodynamic Therapy
Klein OJ, Yuan H, Nowell NH, Kaittanis C, Josephson L, Evans CL
Published in Scientific Reports on October 17, 2017


Identifying Genes that Help Protect the Gut 
(Summary submitted by Javier Elbio Irazoqui, PhD, formerly of the Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease)

The intestinal epithelium is a single layer of cells that protects the gut from environmental insult. Defects in this layer are linked to many diseases, including inflammatory bowel disease. Despite its critical importance, very little is known about the genes in the epithelium involved in this function. We found that transcription factor TFEB, a master regulator of lysosomal gene expression, provides a protective effect, and this function is mediated by expression of apolipoprotein A1, the major constituent of HDL, aka “good” cholesterol. Our findings suggest that enhancement of TFEB activity in the intestinal epithelium could be a therapeutic approach to enhance Apolipoprotein A1 expression for the treatment of inflammatory bowel disease.

Transcription Factor TFEB Cell-Autonomously Modulates Susceptibility to Intestinal Epithelial Cell Injury In Vivo
Murano T, Najibi M, Paulus GLC, Adiliaghdam F, Valencia-Guerrero A, Selig M, [et al.] Xavier RJ, Lassen KG, Irazoqui JE
Published in Scientific Reports on October 24, 2017


Patient Resistance to Immune Checkpoint Blockade Therapies
(Summary submitted by Nir Hacohen, PhD, of the Cancer Center)

Cancer therapy has been transformed in the last few years by immune-based therapies, called ‘checkpoint blockade’ therapies. An important question is why some people respond and others do not respond to this therapy. By analyzing the DNA of tumors from patients who developed resistance to checkpoint therapy, we found changes in the DNA of a key gene that is critical for tumors to be detected by the immune system. In this way, the tumor has learned how to hide from the immunotherapy. Knowing this will help us decide which patients would benefit from immune therapy. Finding ways to make these resistant tumors visible to the immune system is an important goal for the coming years.

Resistance to Checkpoint Blockade Therapy Through Inactivation of Antigen Presentation
Sade-Feldman M, Jiao YJ, Chen JH, Rooney MS, Barzily-Rokni M, Eliane JP, [et al.] Flaherty KT, Sullivan RJ, Hacohen N
Published in Nature Communications on October 26, 2017

A Snapshot of Science: Detection of Alzheimer’s Disease, Development of Type 1 Diabetes, and Much More

We wanted to share some recent Mass General research that has been published in high impact, top-tier journals. 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!

 

DETECTING AND TREATING STIFF TUMORS
Published in Nature Scientific Reports on August 14, 2017
(Summary submitted by Peter Caravan, PhD, of the Martinos Center for Biomedical Imaging)

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. We 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.

 

IMPACT OF BLOOD AND URINE FILTRATION IN LEAKY KIDNEY FILTERS
Published in Scientific Reports on August 16, 2017
(Summary submitted by Hua A. Jenny Lu, MD, PhD, of the Nephrology Division)

One major function of the kidney is filtering blood through an intricate “glomerular filter”. Disruption of any components of this highly sophisticated and dynamic filter’s structure leads to proteinuria (protein in the urine), a condition frequently seen in diabetic nephropathy and many other glomerular diseases. How blood filters though the glomerular filter and how proteinuria develops when the filter becomes leaky has not been well understood. This paper reports the application of a novel and powerful scanning microscopy technology, the Helium Ion microscopy (HIM) to identify previously unrecognized ultrastructural abnormalities of proteinuric glomerulopathy in animals. These newly discovered abnormalities provide important insight into the molecular and cellular mechanism underlying proteinuria kidney diseases.

 

OBSERVING THE DEVELOPMENT OF TYPE 1 DIABETES
Published in PNAS on August 24, 2017
(Summary submitted by Ralph Weissleder, MD, PhD, Director of the Center for Systems Biology)

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, our research team has discovered how the different cellular players interact. We 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. We 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.

 

NON-INVASIVE MEASUREMENT OF BRAIN ACTIVITY AND MEMORY ENCODING
Published in Scientific Reports on August 25, 2017
(Summary submitted by Meryem Yucel, PhD, of the Martinos Center for Biomedical Imaging)

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, we investigated the utility of fNIRS in measuring the 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.

A Snapshot of Science: Zebrafish, Steroid Replacements, and Much More

We wanted to share some recent Mass General research that has been published in high impact, top-tier journals. 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!

Exploring the Formation of the Aorta in Zebrafish

Summary submitted by Caroline Burns, PhD, d’Arbeloff MGH Research Scholar, and Geoff Burns, PhD, both researchers in the Cardiovascular Research Center at Mass General, and co-senior authors of the study

Zebrafish
Image of the head region of a zebrafish embryo (head is to the left)

The aorta and its branches are large arteries in the human body that carry oxygen-rich blood from the heart to the rest of the circulatory system. Structural malformations of the aorta are common birth defects that even in the mildest cases require life-saving surgery at birth.  During fetal life, the aorta is built from transient blood vessels termed the pharyngeal arch arteries (PAAs). However, the mechanisms regulating formation of the PAAs remain poorly understood. This paper reports that TGFb signaling, a molecular pathway that controls cellular proliferation and differentiation in other contexts, initiates and is essential for PAA development in zebrafish. Despite this important advance, further research is needed to identify additional molecular pathways that control PAA establishment and to learn if mutations that affect TGFb signaling in humans result in similar aortic deficiencies. This information can be leveraged to develop new therapies for preventing or treating congenital malformations that involve the aorta and its branches.

Managing Consciousness with Anesthesia Drugs

Summary submitted by Patrick Purdon, PhD, from the Department of Anesthesia, Critical Care, and Pain Medicine, at Mass General, and senior author of the study

This study finds evidence that propofol, an anesthetic drug frequently used in clinical practice, disrupts activity in the parts of the brain responsible for awareness and coordination by inducing highly synchronized oscillations within and between these brain structures. The study also found that during recovery of consciousness, these synchronized oscillations dissipate in a distinct “boot-up” sequence, one that did not simply mirror loss of consciousness. This implies that recovering consciousness is not just a passive process, but an active one involving a different set of brain areas responsible for “waking up” the brain. Overall, this study advances understanding of what it means to be unconscious under anesthesia, and establishes principled neurophysiological markers to monitor and manage this state.

Impact of Genetic Disease on Metabolism and Exercise

Summary submitted by Rohit Sharma, PhD, from the Department of Molecular Biology at Mass General, and co-investigator of the study

Human metabolism is “wired” to allow us to go from rest to running by efficiently burning sugars, fats and proteins to harness their energy.  However, patients with certain genetic conditions like McArdle disease who cannot access glycogen stores or mitochondrial disease who have broken respiratory chains have symptoms that are exacerbated by exercise.  Scientists from the Mootha lab studied the exercise-induced changes that occur in hundreds of plasma metabolites in healthy individuals, patients who have McArdle disease and mitochondrial disease patients.  By comparing these disorders they shed light on the typical metabolic processes that allow us to exercise and also revealed potential disease biomarkers.

Treating Blood Vessel Inflammation Without Steroids

Summary submitted by John Stone, MD, MPH, Director of the Clinical Rheumatology in the Rheumatology Unit at Mass General, and lead author of the study

Giant cell arteritis (GCA) is the most common form of blood-vessel inflammation. Complications include blindness and aneurysm. Up to now, the only known effective treatment was a steroid called prednisone which caused many complications. Now a phase 3 clinical trial has confirmed for the first time in the history of this disease that regular treatment with a drug called tocilizumab successfully reduces the need for high-dose steroid treatment. Patients who received tocilizumab plus a prednisone taper were nearly four times more likely to achieve disease remissions compared to those who received prednisone alone. Results of the trial were the basis for the Food and Drug Administration’s approval of tocilizumab to treat GCA in May 2017.