Methodology Newsletter Spring 2016

METHODOLOGYThe Research and Education Newsletter of Houston Methodist

SPRING 2016

A team of investigators from the Houston Methodist Research Institute may have transformed the treatment of metastatic triple negative

breast cancer by creating the first drug delivery system to successfully eliminate lung metastases in mice models. Results from this

landmark study appeared in Nature Biotechnology. Mauro Ferrari, Ph.D., president and CEO of the Houston Methodist Research Institute

and Haifa Shen, M.D., Ph.D., are co-senior authors on the paper.

In this study, 50 percent of the mice treated with the new drug delivery system had no trace of metastatic disease after eight months. That’s equivalent to about 24 years of long-term survival following metastatic disease for humans.

>> CONT. PAGE THREE

We invented a method that actually makes the nanoparticles inside the cancer and releases the drug at the site of the cellular nucleus. We were able to do what standard chemotherapy drugs, vaccines, radiation, and other nanoparticles have all failed to do.

“

”– Mauro Ferrari, Ph.D. President and CEO Houston Methodist Research Institute

by Gale Smith & Maitreyi Muralidhar

Landmark preclinical nanoparticle study shows efficacy for triple negative breast cancer treatment

Our physicians and scientists wake up every day with the goal of

transforming the lives of patients by developing more effective treatments

and cures. We invite you to learn about a few of the projects moving

closer to the clinic and examples of the collaborative approach we take

to solving medical challenges.

In a Nature Biotechnology paper that could mark a watershed moment

in the treatment of metastatic breast cancer, my coauthors and I

describe a novel multi-stage drug delivery system - injectable

nanoparticle generator (iNPG) - that generates nanoparticles inside

the tumor cells and releases the drug within the nucleus. For the first

time ever, we showed that 50 percent of mice treated with the iNPG

were free of metastatic disease after eight months which is equivalent

to almost 24 years of long-term survival in humans.

James M. Musser, M.D., Ph.D. and an international team of researchers have identified genetic

changes that increase virulence of group A streptococcus which could be targeted for vaccine development.

Under the direction of Philip Horner, Ph.D., our researchers are working on restoring movement to

paralyzed muscles using neuroregeneration. In a PLOS One report that has captured the attention of

both the medical community and the news media, John Cooke, M.D., Ph.D., and a team of scientists

from Houston Methodist and Stanford University report that adults who use proton pump inhibitors

are between 16-21 percent more likely to experience a heart attack than people who don’t – a finding

that could change the way these common antacids are used.

In this issue you will also read about how Michael Reardon, M.D., the world’s foremost expert in cardiac

autotransplantation for the treatment of complex cardiac tumors, is making use of 3-D printing to better

visualize these tumors. Our researchers are using nanotechnology to generate new blood vessels and a 4-D

lung cancer model to mimic tumor progression. We have also developed novel microfluidics-based platforms

and are using them to study mechanisms of aging.

The year 2015 also saw several key faculty recruitments in the priority areas identified in our strategic plan

- Biotherapeutics & Regenerative Medicine; Outcomes, Quality & Health Care Performance; and Precision

Medicine. An internationally recognized expert in the field of circulating tumor cells (CTCs) to combat cancer

metastasis, Dario Marchetti, Ph.D., joined us as the new director of the Biomarker Research Program.

Marc Garbey, Ph.D., joined Houston Methodist in August as the scientific director of the newly formed

Center for Computational Surgery. A computational science guru, Garbey will be working on creating an

intelligent operating room to improve patient safety, enhance real-time tracking of OR activities, and improve

patient outcomes. We are also pleased to announce the arrival of Adaani Frost, M.D., an expert in

pulmonary hypertension with extensive clinical research experience. Frost will be the director of the new

Lung Center. Please join me in welcoming these new faculty members.

On the education front, we graduated the first student from the collaborative doctoral program

between Swansea University and the Houston Methodist Research Institute.

As we celebrate these milestones, we are also acutely aware of the challenges ahead of us and the work

that still needs to be done. In August 2015, we were deeply saddened by the loss of David M. Bricker.

A science writer par excellence, David’s personal fight against cancer and that of many others across

the world, reinforces our commitment to take on some of the toughest challenges in medicine.

Mauro Ferrari, Ph.D.Ernest Cockrell Jr. Distinguished Endowed ChairPresident and CEO, Houston Methodist Research InstituteProfessor of Biomedical Engineering in MedicineDirector, Institute for Academic MedicineExecutive Vice President, Houston Methodist

Senior Associate Dean and Professor of MedicineWeill Cornell Medical College, New York, NY

Read more online: HoustonMethodist.org/hmrinews

Contents

FROM THE PRESIDENT

by xxxxxxxxxxxxxxxxFeatured News

Landmark preclinical nanoparticle study shows efficacy for triple negative breast cancer treatment ..... 1

Research Highlights: Neurosciences

Restoring movement to paralyzed muscles ...............................................4

Tracing Alzheimer’s disease with a cyclotron ...................................6

Study shows stroke and TIA patient outcomes best at experienced centers ...........................7

Research Highlights: Heart & Vascular

Leading the way in the surgical treatment of complex cardiac tumors .................................................8

The international Pumps & Pipes symposium .......................................10

Nanoneedles for generating new blood vessels in mice ......................12

Heart attack risk increases 16-21% with use of common antacid ..........14

Research Highlights: Cancer

Hundreds of cancer possibilities arise from common skin mole mutation ..............................................16

New “4-D” lung cancer model could quicken discoveries .............18

Research Highlights: Translational Research

Scientists identify molecular triggers for intercontinental epidemics of group A streptococcus ....................20

Tracking aging and delivering genes with high-throughput microfluidics ....22

Education News

Resident profile: Albert Huang, M.D. .........................24

First graduate from Swansea-Houston Methodist collaboration ..................25

Summer research student program ................................................25

Of Interest

New faculty members ....................26

In memory of David Bricker ...........27

Contents

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First injectable nanoparticle generator could radically transform metastatic breast cancer treatment

>> CONT. FROM PAGE ONE

The majority of cancer deaths are due to metastases to

the lung and liver, for which there is no cure. Existing

cancer drugs provide limited benefit due to their inability

to overcome biological barriers in the body and reach the

cancer cells in sufficient concentrations. Houston Methodist

nanotechnology and cancer researchers have solved this

problem by developing a drug that generates nanoparticles

inside the lung metastases in mice.

This new treatment strategy enables sequential passage

through the biological barriers to transport the drug into

the heart of the cancer. The active drug is only released

inside the nucleus of the metastatic disease cell, avoiding

the multidrug resistance mechanisms of the cancer cells.

This strategy effectively kills the tumor and provides significant

therapeutic benefit in all mice, including, never before seen

long-term survival in half of the animals.

Houston Methodist has developed good manufacturing

practices (GMP) for this drug and plans to fast-track the

research to obtain FDA-approval and begin safety and

efficacy studies in humans in 2017.

“I would never want to overpromise to the thousands of

cancer patients looking for a cure, but the data is astounding,”

said Ferrari, the Ernest Cockrell Jr. Presidential Distinguished

Chair at the Houston Methodist Research Institute and senior

associate dean and professor of medicine, Weill Cornell

Medicine. “We’re talking about changing the landscape of

curing metastatic disease, so it’s no longer

a death sentence.”

The Houston Methodist team used doxorubicin, a cancer

therapeutic that has been used for decades but has adverse

side effects to the heart and is not an effective treatment

against metastatic disease. In this study, doxorubicin was

packaged within the injectable nanoparticle generator that

is made up of many components.

Shen, a senior member of the department of nanomedicine

at Houston Methodist Research Institute, explains that each

component has a specific and essential role in the drug

delivery process. The first component is the nanoporous

silicon material that naturally degrades in the body. The second

component is a polymer made up of multiple strands that

contain doxorubicin. Once inside the tumor, the silicon

material degrades, releasing the strands. Due to natural

thermodynamic forces, these strands curl-up to form

nanoparticles that are taken up by the cancer cells. Once

inside the cancer cells, the acidic pH close to the nucleus

causes the drug to be released from the nanoparticles.

Inside the nucleus, the active drug acts to kill the cell.

Ferrari, who is considered one of the founders of

nanomedicine and oncophysics (physics of mass transport

within a cancer lesion), and the Houston Methodist team

are hopeful that this new drug could help cancer physicians

cure lung metastases from other origins, and possibly

primary lung cancers as well.

Xu R, Zhang G, Mai J, et al. An injectable nanoparticle generator enhances delivery

of cancer therapeutics. Nat Biotechnol. 2016 Mar 14. Epub ahead of print.

The work was supported by grants from Department of Defense (W81XWH-09-1-0212 and

W81XWH-12-1-0414), National Institute of Health (U54CA143837 and U54CA151668),

and The Cockrell Foundation.

This may sound like science fiction, like we’ve penetrated and destroyed the Death Star, but what we discovered is transformational. If this research bears out in humans and we see even a fraction of this survival time, we are still talking about dramatically extending life for many years. That’s essentially providing a cure in a patient population that is now being told there is none, said Ferrari.

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by Gale Smith

Philip Horner, Ph.D., an expert on the use of stem cells to replace damaged brain and spinal cord tissue, is the scientific director of the Houston Methodist Neurological Institute’s new Center for Neuroregeneration.

“Phil brings incredible experience in adult central nervous system regeneration, stem cells

and gene therapy,” said Gavin Britz, MBBCh, chair of the Department of Neurosurgery.

“His knowledge in cell repair and regenerative medicine will be a boon for our patients,

and also extend the reach of neurosurgery science at Houston Methodist.”

Horner comes to Houston Methodist from the University of Washington School of Medicine,

where he was a professor of stem cell biology and neural repair in the Department of

Neurological Surgery. He was also affiliated with UW’s Institute for Stem Cell & Regenerative

Medicine. His research focuses on the manipulation of a patient’s own stem cells to regenerate

cells damaged or lost following traumatic injuries.

Horner and his team use two methods to create healthy pathways for an impulse to follow.

The most common therapy is one in which a ball electrode is placed on the surface of the

brain or spinal cord to create a broad area of activity. The second, more challenging technique

requires implantation of wires in the brain or spinal cord. Ideally, the wires are placed in both

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Restoring Movement to Paralyzed Muscles

The Hebbian theory is correct: neurons that fire together, wire together.

What this means is that if you place these reprogrammed cells into an

injured environment, they will behave as injured cells. Therefore, it is

crucial that rehabilitative technologies are put into place to create a pattern

of movement, or deliberate action potentials that you want to restore.– Philip Horner, Ph.D. Scientific Director, Center for Neuroregeneration Houston Methodist

““

the brain and spinal cord since the brain controls the spinal

cord. “The problem with wires is their ultimate rejection by the

nervous system. In addition, we need to increase the power

fairly continuously to assure adequate operation,” says Horner.

The ultimate technology to create healthy neuronal pathways is

optigenetics, according to Horner. Close to FDA approval for

the restoration of sight in patients with macular degeneration,

optigenetics uses light to control the movement of neurons.

Optigenetics is a medical science gleaned through the study

of how ocean algae detected sunlight. Researchers learned

that algae move by way of their flagella, which are equipped

with channels that are sensitive to certain wavelengths of sunlight.

“Instead of putting wires in the central nervous system,

activity-driving neurons would be equipped with channels

that are light-sensitive. We could then install a series of

LEDs subcutaneously in the patient. For quadriplegia, for

example, we could begin with simply finding the pathways

that can be stimulated with light to get some hand function.

I think that’s very feasible,” says Horner.

Currently, Horner and colleagues are working on a clinical

trial in collaboration with the government of Andalusia, Spain.

The study will reprogram skin fibroblasts into new cells with

the capacity to make new connections in the spinal cord for

chronically paralyzed patients.

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Tracing Alzheimer’s Disease with a Cyclotron

The discovery of beta-amyloid, or β-amyloid, plaques in the brain inspired the design of a

pioneering class of radiotracers for Alzheimer’s diagnosis with positron emission tomography

(PET) imaging. Recent studies have shown that tau may be an even more effective marker

for Alzheimer’s disease than β-amyloid.

At Houston Methodist, physicians and scientists are developing a new class of radioactive biomarkers, or tracers, which can track abnormal

levels and tangles of abnormal tau protein in the brain with PET. Brain inflammation, another key player in the development and progression

of the disease, is also being measured with PET in a handful of centers around the world, including Houston Methodist. Together with

β-amyloid, these two disease indicators provide a powerful approach to assessing disease progression.

Houston Methodist is one of the few medical institutions in Texas to have a cyclotron and cGMP radiopharmaceutical lab for the production

of clinical grade radiotracers on-site. This aids in the production of clinically useful radiotracers that have a suitable half-life to decay quickly

and reach inert stability in the body to minimize patient exposure to radiation. This is important for Carbon-11 labelled tracers for amyloid

and inflammation with a half-life of 20.3 minutes, as well as the Flourine-18 labelled tracers for tau with a half-life of 109.8 minutes.

The Nantz National Alzheimer Center at Houston Methodist is currently conducting several studies that incorporate radionuclide neuroimaging

to detect abnormalities or injury to the brain. Dr. Masdeu is the principal investigator in majority of these studies that seek to clarify the

neurobiology of Alzheimer’s and other neurodegenerative disorders. “But I could not pursue any of these studies without the asset of the

Houston Methodist Cyclotron and Radiopharmaceutical Core, led by director Max Yu, Ph.D. says Masdeu.

In PET scans for Alzheimer’s disease we primarily use two radioactive particles–Carbon-11 and

Fluorine-18–and with them we label tracers to image amyloid, abnormal tau and inflammation.

In the Alzheimer’s brain, we see high levels of all three tracers. With PET imaging we can scan

people at the various stages of the disease, even before symptoms develop.

“

– Joseph C. Masdeu, M.D., Ph.D. Graham Family Distinguished Chair for Neurological Sciences Houston Methodist


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When we compared the frequencies of all known

baseline characteristics and stroke risk factors,

there were a few differences between high-enrolling

centers and low-enrolling centers but the only factor

that explained the disparity in outcomes between

the two groups was the center’s experience.

– David Chiu, M.D Elizabeth Blanton Wareing Chair of the Houston Methodist Eddy Scurlock Stroke Center Hosuton Methodist

Researchers from Houston Methodist Hospital and five partner institutions used data from a major stroke clinical study to show that medical centers with more experience and expertise in aggressive medical management had a significantly positive impact on patient outcomes. This, according to research published in Neurology.

Study shows stroke and TIA patient outcomes best at experienced centers

Conducted from 2008-2013, Stenting and Aggressive

Medical Management for the Prevention of Recurrent

Ischemic Stroke (SAMMPRIS) was a National Institutes

of Health-funded randomized clinical trial. The study

enrolled 451 patients in 50 institutions, who had suffered

strokes or TIAs (also known as “mini-strokes”) attributed

to severe stenosis (blockage) of a major intracranial artery.

The effectiveness of aggressive medical management

or AMM versus stenting as a treatment was compared,

with the former resulting in lower rates of recurrence

and mortality.

Using the SAMMPRIS patient data, a team led by

David Chiu, M.D., Elizabeth Blanton Wareing Chair of

the Houston Methodist Eddy Scurlock Stroke Center

and professor of clinical neurology at Hosuton Methodist,

evaluated whether the experience of the stroke center

and the expertise of the staff in using AMM for strokes

and TIAs led to the better outcomes.

“We compared the rates of recurrent stroke or death for

patients receiving aggressive medical management at

the 12 centers with the highest study enrollment to

those who received the treatment at the 38 with the

lowest enrollment,” said Chiu. “We found a significant

difference in the rates after both 30 days—1.8 percent

for the high-volume centers and 9.8 percent for the

low-volume centers—and after 2 years—7.3 percent

versus 20.9 percent.”

The study, Chiu said, also found that

the rates of excellent blood pressure

and cholesterol control were superior

for patients who had undergone AMM

at the more experienced centers. As

for whether or not other factors

besides a center’s experience might

account for the better outcomes, he

believes his team’s findings make a strong case.

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”

Chiu D, Klucznik RP, Turan TN, et al. Enrollment volume effect on risk factor control

and outcomes in the SAMMPRIS trial. Neurology. 2015 Dec 15;85(24):2090-7.

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Leading the way in the surgical treatment of complex cardiac tumors

by Maitreyi Muralidhar

Cardiac tumors are rare and when malignant, are often associated with limited treatment options and dismal prognosis. They can either be primary tumors that arise from the heart or secondary tumors that have metastasized to the heart. For malignant and complex benign tumors, complete surgical resection is often the only optimal treatment option.

Michael Reardon, M.D. Allison Family Distinguished Chair of Cardiovascular Research Houston Methodist DeBakey Heart & Vascular Center

Photo: Robert Seale

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Houston Methodist cardiac surgeon, Michael

Reardon, M.D., the Allison Family Distinguished

Chair in Cardiovascular Research and chief of the

division of cardiac surgery, is forging new pathways

in the surgical treatment of cardiac tumors. In a

recent publication in the Annals of Thoracic Surgery,

Reardon et. al. report on their experience with

surgical treatment for 95 cases of primary cardiac

sarcomas between 1990−2015. To date, this is the

largest published surgical resection series of primary

cardiac sarcomas in the world. In comparison, the

Mayo Clinic comes in second with a published

record of 34 cases over a 32-year period.

Primary cardiac tumors that involve the left atrium

and the left ventricle are generally the most

challenging to treat using standard surgical

techniques. This is due to anatomical constraints

and inaccessibility associated with the location.

These limitations also make complete resection

technically difficult to achieve. Standard surgical

approaches are also associated with a high

incidence of recurrence in these tumors.

Cardiac autotransplantation is a surgical procedure

that can overcome limitations such as anatomic

inaccessibility to allow complete resection in complex

tumors. During autotransplantation, the patient is

first put on cardiopulmonary bypass. The heart is

removed and the surgeon then resects the tumor,

makes any necessary repairs to the heart structure,

inspects the heart, great vessels and left atrium

for tumor infiltration, and then implants the heart

back into the patient. This technique allows optimal

accessibility to the tumor for complete removal and

accurate reconstruction. In addition, unlike donor

heart transplantation that requires the timely availability

of a suitable donor heart, autotransplantation uses

the patient’s own heart, avoids lengthy wait time

for donor organs and the need for prolonged

immunosuppression.

Reardon is also making use of 3-D models to map out

anatomical and structural specifications of tumors before

embarking on such complex surgical procedures. MRI data

from a patient is fed into a specific computer program and

sent to a 3-D printer to create the patient-specific 3-D

models. Reardon recently used a 3-D model to better

visualize a secondary heart tumor whose location was

going to make the operation very challenging.

Using a 3-D model can take all the guess work out of

planning for a complex surgical procedure. Reardon believes

that in the future, surgeons will be able to look at a holographic

display of a person’s anatomy and virtually perform the

procedure even before opening up the patient.

Very few physicians or institutions

have the experience or expertise in

performing cardiac autotransplantation.

Reardon has performed more cardiac

autotransplants than any other surgeon

in the world. In a previous study

published in Annals of Thoracic

Surgery, Reardon et. al. have shown

that autotransplantation is a feasible

and safe technique to treat malignant

and complex benign left-sided cardiac

tumors that are inaccessible via

ordinary surgical resection.

Ramlawi B, Leja MJ, Abu Saleh WK, et al. Surgical Treatment of Primary Cardiac Sarcomas:

Review of a Single-Institution Experience. Ann Thorac Surg. 2016 Feb;101(2):698-702.

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The International Pumps & Pipes Symposium: Global Industries Compare Notes

Pumps & Pipes is about the transfer of knowledge between the energy world, the cardiovascular world and, more recently, the aerospace world. The other guy’s toolkit is something that we emphasize over and over because that’s where the solution often resides — we just need the opportunity to network and bring people together to explore ideas.

QUICK FACTSHOUSTON METHODIST

72,043

814,309 101,508

4,50020,000

Hospitals

Operating beds

Outpatient visits

Admissions

Physicians

Employees

1,607603567

4411,734

$47.8 M

1,001

Credentialed researchers

Faculty

Trainees (residents, postdoctoral fellows & students)

GME programs

CME, GME & MITIE learners

Annual extramural funding

Clinical protocols

440,000100,000

Sq.ft. dedicated research building with 12 stories and 150 lab benches

TOP 20

$131 M

U.S. domestic hospital based research institutes

Annual research expenditures

Additional sq.ft. research space embedded throughout the hospital

– Alan B. Lumsden, M.D. Walter W. Fondren III Distinguished Endowed Chair Houston Methodist DeBakey Heart & Vascular Center


The 9th annual Pumps & Pipes symposium

united professionals from the health care,

aerospace and energy sectors to examine current

cross-industry challenges and technologies.

The International Pumps & Pipes Symposium: Global Industries Compare Notes

The most recent gathering in December of 2015, themed

Discovery Pathways, featured several captivating presentations

including, a NASA presentation, Getting to Mars; a live

transcatheter aortic valve replacement broadcast from the

clinical hybrid operating room; a live webcast from Keele

University Observatory in England on the newly discovered

Jupiter-sized exoplanet, WASP-142B; and Making Sense of

Drilling Data, by ExxonMobil. A total of 280 people attended

the event at Houston Methodist. The 9-hour webcast was

streamed to 2900 connections in 27 states and 44 countries.

Pumps & Pipes is not only for industry professionals. The

symposium now offers a community outreach program for

science, technology, engineering and math (STEM) students.

In 2015, 40 students from eight Houston schools attended

the Pumps & Pipes symposium and hundreds of students

watched the symposium webcast in classrooms around the

city. At a new Mentors for Mentors symposium convened in

the first half of 2015, fifteen educators from seven Houston

Independent School District campuses attended a Pumps

& Pipes externship to learn how to apply concepts from

engineering and medicine to challenges in both disciplines.

“Technology and competence transfer is a high priority for

us, and there is a strong drive to explore an international

interactive platform between sectors to foster the sharing

of knowledge and innovation,” said Stephen R. Igo, executive

director of the Pumps & Pipes program.

Pumps & Pipes is growing internationally with plans for

an affiliate in Europe to be headquartered in Stavanger,

Norway. Visit pumpsandpipes.com for more information.

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Alan B. Lumsden, M.D. Walter W. Fondren III Distinguished Endowed Chair Houston Methodist DeBakey Heart & Vascular Center

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Associate Professor of Nanomedicine, Ennio Tasciotti, Ph.D., and his collaborators

from Imperial College London have developed a prototype of biodegradable

nanoneedles that are 1,000 times smaller

than a strand of human hair and are designed

to deliver nucleic acids to specific body parts.

This could be a new frontier in the treatment of degenerative diseases, damaged organs,

transplant rejection, and musculoskeletal injuries.


NANONEEDLES FOR GENERATING NEW BLOOD VESSELS

IN MICEby Maitreyi Muralidhar

NANONEEDLES FOR GENERATING NEW BLOOD VESSELS

IN MICE

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The biodegradable nanoneedles were fabricated at the

Houston Methodist Research Institute using photolithography

techniques, enabling precise control over the diameter

of the tip, pore size, and length of the needle. The pores

on the needle impart the nanoneedles with sponge-like

features that allow them to load, retain and release a

substantial amount of nucleic acids, nanoparticles, and

proteins, when compared to traditional, solid structures.

In addition, the size and shape of these nanoneedles

allow them to bypass and effectively penetrate the

outer membrane of a cell without causing any trauma.

In their study, featured on the cover of Nature Materials,

Tasciotti’s team describe how these nanoneedles could

co-deliver DNA and siRNA with greater than 90% efficiency,

while avoiding sub-cellular compartments designed to

degrade the payload of nucleic acids. Furthermore, they

demonstrated the unprecedented ability to efficiently

deliver genes to a localized area of tissue yielding a

significant increase in the generation of new blood vessels.

New blood vessel formation continued over a 14-day

period without any adverse effects or inflammation.

Given the inherent biodegradability and biocompatibility

of porous silicon, the use of nanoneedles is safe as

they dissolve leaving behind a harmless compound,

orthosalicilic acid, that is readily absorbed by the

human body.

Tasciotti who is also the director of the Center for

Biomimetic Medicine and his team are now aiming to

expand on these results. They envision developing

nano-based bandages that contain nanoneedles to

deliver specific genes for inducing local cell

programming, and to aid in rapid wound healing and

tissue response. In addition, they are exploring the

role of nanoneedles in providing mechanical cues

to cells to stimulate the regeneration of stem cell

populations without relying on the use of any bioactive

factor but relying only on the mechanical forces

imparted on the target cell population.

The ability to gain direct access to the cytoplasm and

induce high efficiency site-specific genetic reprograming

is an unmet need that could pave the way for new

treatment approaches.

This type of treatment will one day be able to provide

therapy for conditions like ischemic heart disease or to

prepare the local tissue microenvironment prior to the

implant of tissue engineering scaffolds.

Additional findings on the interface between cells and

nanoneedles were published in the April 2015 edition

of ACS Nano by Tasciotti and his collaborators from

Imperial College London.

Chiappini C, De Rosa E, Martinez JO, et al. Biodegradable silicon nanoneedles

delivering nucleic acids intracellularly induce localized in vivo neovascularization.

Nat Mater. 2015 May;14(5):532-9.

Chiappini, C. Martinez JO, De Rosa E et al. Biodegradable nanoneedles for

localized delivery of nanoparticles in vivo: exploring the biointerface. ACS Nano.

2015 May 26;9(5):5500-9.

Our experiments revealed the efficiency of nanoneedles to improve the vascularization of specific areas via the generation of new blood vessels. This could be expanded to provide personalized treatment for each patient by locally reprograming cells of interest to achieve any desired effect.

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– Ennio Tasciotti, Ph.D. Associate Professor of Nanomedicine Houston Methodist

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Adults who use proton pump inhibitors are between 16 and 21 percent more likely to experience a heart attack than people who don’t use the commonly prescribed antacid drugs, according to a massive new study by Houston Methodist and Stanford University scientists.

An examination of 16 million clinical documents representing 2.9 million patients also showed that patients who use a

different type of antacid drug called an H2 blocker have no increased heart attack risk. The findings, reported in PLOS

ONE, follow a Circulation report from 2013 in which scientists showed how -- at a molecular level -- PPIs might cause

long-term cardiovascular disease and increase a patient’s heart attack risk.

Our earlier work identified that the PPIs can adversely affect the endothelium, the

Teflon-like lining of the blood vessels. That observation led us to hypothesize that anyone

taking PPIs may be at greater risk for heart attack. Accordingly, in two large populations

of patients, we asked what happened to people that were on PPIs versus other

medications for the stomach.


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HEART ATTACK RISK INCREASES 16-21% WITH USE OF COMMON ANTACIDby David Bricker

Our earlier work identified that the PPIs can adversely affect the endothelium, the

Teflon-like lining of the blood vessels. That observation led us to hypothesize that anyone

taking PPIs may be at greater risk for heart attack. Accordingly, in two large populations

of patients, we asked what happened to people that were on PPIs versus other

medications for the stomach.

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– John Cooke, M.D., Ph.D. Joseph C. “Rusty” Walter and Carole Walter Looke Presidential Distinguished Chair in Cardiovascular Disease Research Houston Methodist

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The PLOS ONE study’s principal investigator was Stanford

vascular medicine specialist Nicholas J. Leeper, M.D. In the

present study, the researchers found a clear and significant

association between exposure to PPIs and the occurrences

of heart attack.

“By looking at data from people who were given PPI drugs

primarily for acid reflux and had no prior history of heart

disease, our data-mining pipeline signals an association with

a higher rate of heart attacks,” said the PLOS ONE report’s

lead author, Nigam H. Shah, M.B.B.S., Ph.D., an assistant

professor of biomedical informatics at Stanford, where the

work was done. “Our results demonstrate that PPIs appear

to be associated with elevated risk of heart attack in the

general population, and H2 blockers show

no such association.”

The estimated increase of heart attack risk ranges from

16 to 21 percent, because of uncertainty in the estimation

process, Shah said.

The FDA estimates about 1 in 14 Americans has used

proton pump inhibitors. In 2009, PPIs were the third-most

taken type of drug in the U.S., and are believed to account

for $13 billion in annual global sales. Doctors prescribe

PPIs to treat a wide range of disorders, including

gastro-esophageal reflux disease, or GERD, infection

by the ulcer-causing bacterium Helicobacter pylori,

Zollinger-Ellison syndrome, and Barrett’s esophagus.

The drugs can also be purchased over the counter.

H2 blockers are another type of antacid drug. They are

not believed to be associated with increased risk of heart

attack or cardiovascular disease. Examples of the drug are

cimetidine and ranitidine. Brand examples of H2 blockers

are Zantac and Tagamet.

The researchers collected data from two repositories

– STRIDE (Stanford Translational Research Integrated

Database Environment), which contains information about

1.8 million Stanford hospital and clinic patients, and a

subset of information for 1.1 million patients from the

Web-based electronic medical records company Practice

Fusion, Inc. Both sources of patient information were

anonymized before the researchers accessed the data.

The group scanned the databases for patients who were

prescribed proton pump inhibitors or other drugs, such as

H2 blockers, and also looked to see if a given patient had

a mention of having experienced a major cardiovascular

event, such as myocardial infarction (heart attack), in their

medical record.

Patients who had used PPIs were found to be at

1.16-1.21-fold-increased risk of heart attack.

A 2013 report to Circulation by several of the present

report’s coauthors, including Cooke, raised the possibility

that PPIs could lead to cardiovascular disease in the

general population.

In the future, the researchers say they hope to conduct a

large, prospective, randomized trial to determine whether

PPIs are harmful to a broader population of patients.

PPIs come in a variety of slightly different

chemical forms, always ending with the

suffix “-prazole,” for example, omeprazole

or lansoprazole. Brand examples of PPIs

are Nexium, Prilosec, and PrevAcid.

Shah, NH, Lependu, P, Bauer-Mehren. A. et al. PLoS One. 2015 Jun 10;

10 (6): e 0124653.

Research Highlights

An initial mutation, called BrafV600E, is found in 70 percent or more of benign birthmarks

and moles in humans, and has long been believed to precede the development of melanomas,

even though the Braf mutation alone does not seem to be enough to cause cancer.

What skin cancer researchers have not had – until the present report in Nature Genetics

– is a list of genes or genetic pathways that, once altered, work with the Braf mutation to

cause cancer.

The mutation BrafV600E is found in 70 percent or more of benign birthmarks and moles in

humans. Scientists believe the Braf mutation alone isn’t enough to cause cancer. A variety

of subsequent mutations identified in the present study, however, make melanomas possible.

“We want to know what exactly must happen after someone acquires this mutation in Braf

that causes something even worse to happen,” said Houston Methodist Research Institute

cancer geneticist Michael Mann, Ph.D., the Nature Genetics report’s lead author. “We want

to understand how this Braf mutation makes people vulnerable, susceptible to melanoma,

so that we can help identify new targets for slowing or stopping growth.”

16


A Houston Methodist-led team of international scientists has identified

hundreds of possible new genes in mice that could transform benign skin

growths into deadly melanomas.

Hundreds of cancer possibilities arise from common skin mole mutationby David Bricker

The scientists used a genetic tool, a

transposon called “Sleeping Beauty”

that was developed by Houston

Methodist cancer geneticists

Nancy Jenkins, Ph.D., and

Neal Copeland, Ph.D., and an

animal model developed by UC

San Francisco cancer geneticist

Martin McMahon, Ph.D., to identify

the candidate cancer genes, or

CCGs, that unleash BrafV600E’s

terrible potential.

- Michael Mann, Ph.D. Cancer Geneticist Houston Methodist Research Institute

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By letting Sleeping Beauty loose in the model’s genome and

looking for meaningful outcomes, the scientists were able

to identify 1,232 altered CCGs that, with BrafV600E, led to

melanomas.

A comparison of human genes equivalent to those the

scientists identified in mice showed that more than 500

human genes, sampled from melanoma patients, were

“enriched” for mutations and that these mutations appeared

to be related to patient survival. A genetic survey of human

melanoma patients whose skin biopsies already contain

BrafV600E and other relevant mutations could be helpful

to oncologists in predicting patient outcomes.

Last, the researchers found that one human gene, CEP350,

appears to be required for tumor suppression. CEP350 had

not previously been named a melanoma tumor suppressor

gene. CEP350 encodes a protein believed to be crucial

for cell division.

Mann MB, Black MA, Jones DJ, et al. Transposon mutagenesis identifies

genetic drivers of Braf(V600E) melanoma. Nat Genet. 2015 May;47:486-95.

By using Sleeping Beauty transposon mutagenesis

strategically, our group was able to identify an incredible

number of genes that may cause nevi — moles and other

skin marks — to become cancerous. As we expected,

we haven’t just identified single genes that respond to

the Braf mutation, but whole pathways that appear to

contribute to cancer development. This is important,

because if you look at it tumor by tumor, the same

pathways may appear to be engaged, but not because

of changes to the same genes. If you looked only at

singular genes, you could miss what is really going

on, biologically.

“

”

Research Highlights

18


Researchers at Houston Methodist have invented a new, ex vivo lung

cancer model that mimics the process of tumor progression. Tests of

the model are published in The Annals of Thoracic Surgery. The model

developed by Min P. Kim, M.D. and colleagues produces results quickly

and solves the problems of existing models used to study cancer

progression. “Our model truly captures the phenomenon of cancer

metastasis,” said Houston Methodist thoracic surgeon and Assistant

Professor of Surgery Kim, the report’s principal investigator.

The model can be used to study the progression of other cancers

besides lung. The “4-D” model is created by removing all the cells

from a vertebrate lung, leaving the enveloping matrix, which provides

support for cell growth and development. The native lung matrix,

once cells are removed, is further modified and placed in a bioreactor

to allow for human tumor cells to grow.

Without good models to study cancer metastasis -- the spread of cancer cells from one organ to another — cancer researchers have struggled to understand tumor progression fully, and new therapies targeting the main causes of death are slow to come.

NEW “4-D” LUNG CANCER MODEL COULD QUICKEN DISCOVERIESby David Bricker

Unlike other tumor models, the 4-D model allows the tumor

cells to form 3-D nodules that grow over time. Kim called

an earlier version of the model “3-D ex vivo.” The new model’s

fourth dimension is flow, Kim explained, as the latest version

incorporates the movement of fluids between lungs through

blood vessels. This fourth dimension allows the model to show

the growth of primary tumors, the formation of circulating tumor

cells (CTCs) and formation of metastatic lesions. These three

steps of cancer progression aren’t a part of any single in vitro

or ex vivo model. And unlike in vivo models of metastasis,

which often require researchers to wait months for information

about metastasis progression, the 4-D model can provide

data in a matter of days.

Kim and his colleagues also investigated gene expression in

cancer cells during different phases of tumor progression.

They found the gene signatures of experimental CTCs were

associated with poor survival in lung cancer patients.

“The model allowed for the isolation of unique gene signature

of circulating tumor cell phase of metastasis, which may provide

a clue to the mechanism of tumor progression,” Kim said.

In future experiments, Kim said his group will focus on the unique

gene signatures of circulating tumor cells to better understand

the mechanism of tumor progression. Kim said this may provide

ideas for new therapies that stop metastatic spread in patients

with lung cancer.

Also contributing to the Annals paper were Dhruva Mishra, Ph.D.

(lead author), and Michael J. Thrall, M.D. (Houston Methodist),

and Chad J. Creighton, Ph.D., Yiqun Zhang, and Fengju

Chen (Baylor College of Medicine). The coauthors received

funding support from the American Association for Thoracic

Surgery Graham Research Foundation, the Houston Methodist

Foundation, the National Institutes of Health, and the Cancer

Research & Prevention Institute of Texas.

Phase II NECTAR Trial for Triple Negative Breast Cancer

Houston Methodist will be the lead site on a

Phase II multi-center clinical trial called NECTAR,

designed to test Everolimus and Cisplatin

combination therapy as a treatment for triple

negative breast cancer (TNBC).

Jenny C. Chang, Emily Herrmann Chair in Cancer

Research and director of the Houston Methodist

Cancer Center, initiated the original pilot study

that identified Everolimus, a drug commonly used

to treat kidney cancer, as a potential treatment

for TNBC. The drug is thought to work by blocking

enzymes needed for cell growth and blood flow

to the tumor.

The Triple Negative Breast Cancer Program at

Houston Methodist is designed to integrate care

for all women diagnosed with TNBC, and the

NECTAR trial delivers on their commitment to

fighting the most aggressive form of breast cancer.

Mishra DK, Compean SD, Thrall MJ, et al. Human Lung Fibroblasts Inhibit

Non-Small Cell Lung Cancer Metastasis in Ex Vivo 4D Model. Ann Thorac Surg.

2015 Oct;100(4):1167-74.

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by Gale Smith

According to James M. Musser, M.D., Ph.D., principal investigator

and the Fondren Presidential Distinguished Chair Houston

Methodist Research Institute, the research showed, at the

individual nucleotide level, factors that contributed to epidemics

of group A streptococcus (GAS).

“People may say, ‘So what?’ The answer to the ‘so what?’ is

that this now gives us the opportunity to begin thinking about

what we call translational medicine tools,” said Musser. “We

can use this information in developing therapeutics, advanced

diagnostic techniques and new ways to prevent, or at least to

dampen, epidemics.”

According to the World Health Organization, GAS causes more

than 600 million cases of human disease every year. The majority

of cases are group A streptococcus pharyngitis, more commonly

known as strep throat. But group A strep is also the major cause

of preventable pediatric heart disease caused by rheumatic fever

and rheumatic heart disease. On the far end of the spectrum,

group A strep also causes necrotizing fasciitis.

Musser and team found that group A strep is a model organism

to study the molecular basis of epidemic disease. Researchers

have known for more than a century that this organism can

cause epidemics, but no one has been able to fully address the

cause. Now with next generation sequencing, scientists are able

to sequence the entire genome of the bacteria, just as we do

in humans. Group A streptococcus was selected as the model

organism for study due to the high quality of its strain sample

and its very small genome, which allows it to be sequenced

in its entirety in thousands of isolates.

The researchers’ original hypothesis, which turned out to be

correct, was predicated on changes in the GAS pathogen.

To address this hypothesis, Musser and the international team

sequenced the genome of thousands of strains, precisely

defining every base pair in the strain.

Scientists identify molecular triggers for intercontinental epidemics of group A streptococcus

For the first time, scientists from the United

States, Finland, and Iceland have pinpointed

molecular genetic events that contribute to

epidemics of group A Streptococcus, which

can cause everything from strep throat to

“flesh-eating” disease. Researchers from

Houston Methodist, the National Institute

of Allergy and Infectious Diseases, and

international collaborators report their findings

in the Journal of Clinical Investigation.


Houston Methodist Receives $2.8 Million to Identify Lung Cancer Therapy Targets

by Erika Hayes and Rebecca Hall, Ph.D.

Stephen Wong, Ph.D., John S. Dunn, Presidential Distinguished Chair in Biomedical

Engineering was awarded a $2.8 million 5-year UO1 grant from the National Cancer

Institute (NCI) to identify non-small cell lung cancer (NSCLC) therapy targets critical

for tumor-stroma crosstalk.

The supporting stromal tissue of the lung contains tumor suppressing properties,

but as a tumor develops, the stroma adapts to promote tumor growth and invasion.

This collusive relationship relies on communication between the tumor and stroma

known as crosstalk pathways. The proposed research exploits these tumor-stroma

crosstalk pathways as a largely untapped source of drug targets.

Strong candidate targets would be critical for crosstalk, and when they are checked,

would stop the stroma from nurturing tumor growth. This is the focus of the NCI

funded project that will be done in collaboration with Vivek Mittal, director of the

Neuberger Berman Foundation Lung Cancer Laboratory at Weill Cornell Medical

College. Wong’s lab will use a novel multi-cellular network model (P2GWAS) to

predict tumor-stroma crosstalk signaling pathways based on RNA-Seq data

generated from clinical NSCLC specimens in Mittal’s lab.

Wong , who is also the Chief Research Information Officer of the Houston Methodist

Hospital, says that the work has tremendous potential for the development of novel

therapeutic strategies that may complement existing cancer treatments. The goal

is to accelerate clinical trials either as monotherapies or as complements to existing

conventional treatments for lung cancer.

More collaborations are in the works including a partnership with Baylor College of

Medicine to apply this approach to breast cancer and with M. D. Anderson Cancer

Center for application to ovarian cancer.

Stephen Wong, Ph.D.John S. Dunn, Presidential Distinguished Chair in Biomedical Engineering Houston Methodist

Ultimately, the goal is to provide more efficient

and cost-effective treatments for the patients.

This focus always benefits from collaboration.

“

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“The surprise was that the changes involved

alterations in the genes encoding two potent toxins

that contribute to human infections,” said Musser.

The researchers found that in the epidemic form

of group A streptococcus, which manifests as

necrotizing fasciitis or the “flesh-eating” disease,

there were three significant changes within the

genetic regulatory region of the pathogenic bacteria.

The regulatory region is involved in how genes are

transcribed and proteins are made. These specific

genetic changes resulted in the creation of single

nucleotide polymorphisms, or SNPs.

Musser’s team found that two of those SNPs

result in the increased production of two important

toxins called streptolysin O and Streptococcus

pyogenes NAD-glycohydrolase. The third SNP

creates a form of one of those toxins that becomes

more active than the original form. All three SNPS

contribute to building an organism that is a more

virulent machine.

Think about the thermostat in your house controlling temperature. If you want to make your house hotter, or if group A strep wants to make itself hotter or more virulent, it just turns up the heat a little bit via these two toxin genes.

– James M. Musser, M.D., Ph.D. Fondren Presidential Distinguished Chair Houston Methodist

“

”

Zhu L, Olsen RJ, Nasser W, et al. A molecular trigger for

intercontinental epidemics of group A Streptococcus.

J Clin Invest. 2015 Sep;125(9):3545-59.

22

A team of researchers at the Houston

Methodist Research Institute, led by

Associate Professor of Nanomedicine,

Lidong Qin, Ph.D., has been developing

microfluidics-based platforms that

enable rapid and high-throughput

molecular and cellular assays for

applications ranging from aging

research to gene therapy.

Delivering GenesHigh-Throughputwith

and

Tracking

Microfluidics

Aging


Microfluidic devices contain microsize channels generated

through photolithography techniques that allow control or

manipulation of small volumes of fluids (microliters to

picoliters). In a recent publication in the Proceedings of the

National Academy of Sciences, Qin and his team report

on a microfluidic system that could have a significant

impact on understanding the effect of calorie restriction

on longevity and aging.

The microfluidic, single-cell analysis chip, enables the

visualization and analysis of the lifespan of a single yeast

cell. Budding yeast or Saccharomyces cerevisiae, has long

been used as a model system for studying aging due to its

short lifespan and the ease with which it can be genetically

manipulated. In the traditional lifespan assay, mother yeast

cells were grown on agar plates and daughter cells were

separated and removed manually by microdissection.


Delivering Genes


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The process of removing daughter cells is critical for

accurately tracking the lifespan of mother cells. However,

the traditional manual microdissection method is inefficient

(repeated every hour for 3 days) and incompatible with high

resolution microscopy tracking. Qin’s microfluidic single-cell

analysis chip overcomes these limitations by retaining only

the mother cells inside the microfluidic chambers while

washing off daughter cells automatically.

This chip has allowed them to view and track single cells

throughout their lifespan by fluorescence microscopy.

With this technique, Qin and his team were able to confirm

that yeast on a low-calorie diet live much longer than yeast

on a standard diet.

Qin and his team have also designed another

microfluidic device that could facilitate novel

approaches for gene therapy delivery. In a recent

issue of Science Advances, Qin and team address

gene knockdown in hard-to-transfect cells. By squeezing

cells through microposts or barriers in the device, they

forced open transient pores in the cell membrane. Through

these open pores, molecules added to the cell media can

passively diffuse into the cell. This process of deforming the

membrane and opening up transient pores can be used to

deliver a range of materials such as proteins, transcription

factors, single-stranded DNA, siRNAs, and large-sized

plasmids into almost any cell type, including hard-to-

transfect cells. Qin and his team used this membrane

deformation method to deliver sgRNA and Cas9 to

achieve successful genome editing.

With their wide-ranging applications, microfluidics devices

developed by Qin and his group have provided a fast,

high-throughput, and accurate approach that opens up

new avenues for research in several areas.

Jo MC, Liu W, Gu L et al. High-throughput analysis of yeast replicative aging using a microfluidic system. Proc Natl Acad Sci U S A. 2015 Jul 28;112(30):9364-9.

Han X, Liu Z, Jo M et al. CRISPR-Cas9 delivery to hard-to-transfect cells via membrane deformation. Science Advances. 2015 Aug 14;1(7):e1500454.

Our device can track around 100

mother cells. In 2-3 days, we can

assay the lifespan of 10 different

strains-that corresponds to analyzing

around 1,000 mother cells and

performing 30,000 micro-dissections.

If we were using the traditional

method, this would take 4-5 skilled

individuals almost 3-4 weeks

to complete.

“

” – Lidong Qin, Ph.D.

Associate Professor of Nanomedicine Houston Methodist

The microfluidics device, termed High-throughput-Yeast-Aging-Analysis chip (HYAA-chip) provides automated whole-lifespan tracking with fine spatiotemporal resolution and large-scale data quantification of single yeast cell aging.

Education News

24

Albert Huang, M.D., a general surgery resident at Houston Methodist, is in his third year of research with the

Houston Methodist Institute for Technology, Innovation & Education (MITIESM) and the Department of Surgery

where his work has focused on medical device design and computational surgery.

During his research fellowship, he worked under the guidance of Brian Dunkin, M.D., the John F., Jr. and Carolyn

Bookout Chair in Surgical Innovation and Technology, Marc Garbey, Ph.D., the scientific director of the Center for

Computational Surgery, and Barbara Bass, M.D., the John F., Jr. and Carolyn Bookout Presidential Distinguished

Chair of the Department of Surgery. Together, they are designing an intelligence system for the operating room.

The system will create an enhanced awareness of the many simultaneous activities taking place, help improve

surgeon performance and increase patient safety and comfort.

Huang and Dunkin also filed a provisional patent for a novel medical device that allows a surgeon to maintain a

greater sense of direction within the body while performing flexible endoscopic procedures. The device works

similarly to a compass, but uses gravity rather than magnetism to assess orientation. This allows surgeons to

see where they are circumferentially within a body cavity.

Huang notes, “Performing a dissection in a straight line during an endoscopic procedure like POEM, when all you

have is pink tissue to look at, can be really difficult. If you very gradually start to deviate from a straight line, you

may not even know it.” POEM, which stands for Per-Oral Endoscopic Myotomy, is a minimally invasive, natural

orifice procedure where a small incision is made in the mucosa of the esophagus and the stomach to relax

the lower esophageal sphincter and allow food to pass properly.

This appealed to Huang, who has always had a passion for innovation and thinking outside the box. His interest

in surgery was originally prompted, when he began working on tissue engineering and organ fabrication in the

lab of Joseph Vacanti, M.D. at Harvard Medical School. This experience provided his first exposure to surgery and

his subsequent medical schooling served as an inspiration for the design of his clothing line, Collateral Concepts.

His designs consider the concepts of human anatomy and take into account lines of movement, vascular structures,

and neurological structures for coming up with innovative approaches to garment construction. As he heads back

to the clinic for his residency, Huang plans to continue his passion for medtech innovation in and out of the OR,

and he hopes to continue to innovate with his colleagues at Houston Methodist throughout his career.

a general surgery resident at Houston Methodist

RESIDENT PROFILE

Albert Huang, M.D.

Opportunities to innovate in the clinical setting inspired Huang to make Houston Methodist his first choice for surgical residency. He noted Bass’s speech during his interview as having a particularly strong influence. Bass described Houston Methodist as a place that supports resident individuality and helps them become the best at what they are interested in, rather than fitting them into a set mold.

Albert Huang, M.D.General Surgery Resident

by Thomas Ellington

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On July 23, 2015, Matthew Ware earned his

Ph.D. in Nanotechnology and became the first

student to graduate from the collaborative

doctoral program between Swansea University

and the Houston Methodist Research Institute.

Under the guidance of faculty mentors Paul Rees,

Ph.D., of Swansea University, and Biana Godin

Vilentchouk, Ph.D., MScPharm of the Houston

Methodist Research Institute, Ware’s work in the

four-year program culminated in a dissertation

entitled Development of Engineering Approaches

to Studying Dose Response In Vitro for

Nanomedicine Applications.

The program, which began in 2012, has two

students currently at Houston Methodist and

two more are expected to join in early 2016.

In summer of 2015, the Houston Methodist Research Institute welcomed 60 students

to take part in the annual Summer Student Program. This year’s cohort hailed from

renowned universities, both domestic and international, including Harvard, Massachusetts

Institute of Technology and Imperial College London .

During the ten-week program, students were assigned a Houston Methodist faculty mentor

who guided them through a research project. Students also attended a weekly lecture

series, attended a variety of social events, and presented their research at a public exhibition.

New this year was the inclusion of surgery as one of the research areas. The inaugural

Fields Rosenberg Summer Surgical Internship Program is a revival of the DeBakey

Program, which was disbanded in 2005. The Fields Rosenberg program sponsors five

undergraduate students to spend ten weeks working under the guidance of Houston

Methodist surgical faculty, where they observe surgical cases and explore surgically

oriented research questions. Topics this year ranged from bloodless lung transplantation

to gastric bypass revision surgery.

The program is named for the families of Wade Rosenberg, M.D., Assistant Professor of

Clinical Surgery at Houston Methodist, and his wife, Amy Fields Rosenberg, who cultivated

the revival effort. Rosenberg, who participated in the original DeBakey program, understands

the value of early exposure to the field of surgery as a catalyst to pursuing a surgical career.

“I wouldn’t be who I am today if I had not had the opportunity,” Rosenberg stated in reference

to his participation in the DeBakey Program.

The Rosenbergs worked to establish the structure of the program, recruit surgical faculty

at Houston Methodist to participate as mentors and reached out to the M.B. & Edna Zale

Foundation to garner support for the program. In response to a match challenge by the

Zale Foundation, additional support was provided by the Houston Texans and individual

donor Keith Rutherford. Their contributions will ensure the program continues to run for

future generations.

Summer Research Student Program

Matthew Ware, pictured second from right, after his graduation ceremony, surrounded by his family, faculty mentors, and Houston Methodist staff.

FIRST GRADUATE FROM SWANSEA-HOUSTON METHODIST COLLABORATION

OF INTEREST

26

Dario Marchetti, Ph.D., joined Houston Methodist in September 2015 as the new Director

of the Biomarker Research Program. Previously, Marchetti was at Baylor College of Medicine

where he held the “Jack L. Titus” Endowed Professorship in the Department of Pathology &

Immunology. At Houston Methodist, Marchetti will be managing an interdisciplinary translational

research laboratory and will develop a collaborative biomarker program with faculty across numerous

disciplines. Marchetti’s main priorities will be to better understand why cancer recurs and

how to decipher the molecular heterogeneity of circulating tumor cell subsets shed from

tumors and responsible for metastases. He has held academic appointments of increasing

responsibilities since 1979, and served on the editorial boards of journals, as a grant reviewer

for national and international funding agencies, and as a consultant for biotechnology

companies. His research has received continued peer-reviewed funding for more than 25

years from federal, state, institutional and private organizations.

Adaani Frost, M.D., has been appointed as the Director of the new Lung Center at

Houston Methodist. An expert in pulmonary hypertension, Frost joins us from Baylor

College of Medicine where she was the Director of their Pulmonary Hypertension

Center since 2002. Frost brings with her extensive clinical research experience in

pulmonary diseases including pulmonary arterial hypertension and idiopathic pulmonary

fibrosis. She has an M.D. from the Memorial University of Newfoundland, Canada

and was qualified as a fellow of the Royal College of Physicians and Surgeons of

Canada in 1990.

Marc Garbey, Ph.D., has joined Houston Methodist as scientific director of the Center for

Computational Surgery. He was previously professor in the Department of Computer

Science and the Department of Biology and Biochemistry at the University of Houston.

Garbey, who specializes in applied mathematics, is working with Houston Methodist Hospital

surgeons and the Houston Methodist Institute of Technology, Education and Innovation

(MITIE) to create an intelligent operating room (OR). The primary goal is to rethink operating

room functions and integrated technologies to improve patient safety during surgery, enhance

real-time tracking of OR activities, and improve patient outcomes. This project uses devices

to collect and process operating room and surgical technology data to optimize the OR setting.

Devices include sensors placed on anesthesia machines to detect when a patient is under

anesthesia. Other sensors track a patient’s location in real time, from the pre-operation area

to the operating and recovery rooms.

Dario Marchetti, Ph.D.Director, Biomarker Research Program

Adaani Frost, M.D.Director, Lung Center

Marc Garbey, Ph.D.Director, Center for Computational Surgery

Houston Methodist recruits New Director of the Biomarker Research Program

Adaani Frost, M.D., joins Houston Methodist as Director of the Lung Center

Garbey, establishes Center for Computational Surgery at Houston Methodist

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David M. Bricker, research and science

publications manager for Houston Methodist

passed away after a battle with cancer on

August 16, 2015. An exceptional science

writer, David used his background in science

and journalism to convey abstract scientific

discoveries in simple language, making him

invaluable for communicating Houston

Methodist research discoveries to the masses.

Anyone who had the opportunity of working

with David came away impressed by his

zeal and enthusiasm for making science

accessible and interesting for the non-scientific person. His writing inspired us to

seek knowledge through science, and break through the boundaries of medicine.

David’s articles were a mainstay of Methodology and some of the last articles

written by him are featured in this issue.

In his memory, the Houston Methodist Research

Institute has established the Bricker Award for

Science Writing in Medicine. The award recognizes

talented and respected writers who have the skill

to craft technical medical research advances into

must-read stories, and the tenacity to place them

in the public spotlight.

We are accepting donations through "The David

M. Bricker Memorial Fund" to carry on David’s legacy

of mentorship by supporting his fellow science

writers in their education and careers. To make donations,

go to www.houstonmethodist.org/brickeraward

and click on "Donate Now". Choose “Other” as the

option in the “Please use my gift for” section and

specify “In memory of David M. Bricker.”

In memory of David Bricker

BOARD OF DIRECTORSHouston Methodist Research Institute

Steven D. Arnold

John F. Bookout

John F. Bookout, III

Marc L. Boom, M.D.

Timothy Boone, M.D., Ph.D.

Giorgio Borlenghi

Joseph R. "Rod" Canion

Albert Chao

Ernest D. Cockrell, II

John P. Cooke, M.D., Ph.D.

Dan O. Dinges

Mauro Ferrari, Ph.D.

Joe B. Foster

Laurie H. Glimcher, M.D.

Antonio M. Gotto, M.D., D.Phil

Mark A. Houser

Catherine S. Jodeit

Evan H. Katz

Rev. Kenneth R. Levingston

Vidal G. Martinez

Gregory V. Nelson

Stuart W. Stedman

Andrew C. Von Eschenbach, M.D.

Martha Walton

Elizabeth B. Wareing

Ewing Werlein, Jr.

Houston Methodist Research Institute

6670 Bertner Ave.Houston | TX 77030

Editor-in-Chief Rebecca Hall, Ph.D.

Managing Editor and Writer Maitreyi Muralidhar, MS

Design & Creative Lead Doris T. Huang

METHODOLOGYThe Research and Education Newsletter of Houston Methodist

Contributing Writers David Bricker Thomas Ellington Erika Hayes Gale Smith Public Relations Contact Gale Smith 832.667.5843 [email protected]

Read more online: houstonmethodist.org/hmrinews

Office of Communications and External RelationsInstitute for Academic MedicineHouston MethodistEmail: [email protected]

IAMNEWS-005 | 03.2016 | 1730

UPCOMING EVENTS

Go to houstonmethodist.org/hmrievents for more information.

April 1, 2016 Second Annual David M. Underwood Center for

Digestive Disorders: Exploring Frontiers in the

Management of Digestive and Liver Disorders 2016

CME credit available

April 2, 2016 Below the Beltline: 2016 - Insider's Guide to Male

and Female Pelvic Health Across the Lifespan


April 9, 2016 5th Annual Symposium on Enhancing Geriatric

Understanding and Education (SEGUE):

Geriatric Ophthalmology for Non-Geriatricians


April 11, 2016 International Leadership Experience and Development (ILEAD)


April 29, 2016 Southwest Valve Summit IV


May 9, 2016 Deciphering Human Immune Responses to

Cancer Immunotherapy

June 17, 2016 Orthopedics for the Primary Care Physician


UPCO

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Methodology Newsletter Spring 2016

Documents