Posts Tagged ‘University of Pittsburgh Medical Center’

A Great University engaged in Drug Discovery: University of Pittsburgh


Reporter and Curator: Larry H. Bernstein, MD, FCAP


The US-based pharmaceutical companies have been consolidating and now are moving offshore to reduce taxes and other costs.  A part of the problem has been the large cost of clinical trials, the failure to detect toxicities in the early phases, and late phase failure or drug resistance conferring short term success.  This has been at a rate above 60%.  The result is that Big Pharma is looking to recycling old drugs for repurposing. Whatever success can be obtained from this, there is a larger problem in not having a comprehensive biological understanding of the problems imposed by the complexity on a deeper understanding.  I present here a major university, very well recognized in genetics, proteomics, and experimental pathology engaged in the drug development effort with reasonable promise of successes.


Perspective On: A Drug Discovery Lab

As lab manager at the University of Pittsburgh Drug Discovery Institute (UPDDI), Celeste Reese and her team use high-content imaging strategies and work with many other labs both within the university and outside the university on a wide range of projects.

By Rachel Muenz | July 03, 2014


We try to use new technologies and approaches and quantitative systems pharmacology (QSP) to complement the traditional drug discovery strategies

We try to use new technologies and approaches and quantitative systems pharmacology (QSP) to complement the traditional drug discovery strategies



Finding Clinically Relevant Solutions

Hard work, teamwork, and a whole lot of multitasking help this lab overcome a tough economic environment

“We try to use new technologies and approaches and quantitative systems pharmacology (QSP) to complement the traditional drug discovery strategies that are used by the large pharmacy companies,” she explains, adding that, on average, they have seven to ten active projects going on at any given time. “Right now we have a metastatic breast cancer program, a head and neck cancer project, and a Huntington’s disease project. We do some zebra fish modeling, some development of novel HIV diagnostics, liver modeling, and a variety of other things.”

Those projects take place in the institute’s 11,000 square feet of space, which covers two floors of the building the institute occupies and includes a large open lab on the top floor and an imaging lab, automation lab, and tissue culture facility on the floor below. Working in that space are 34 staff, including seven faculty, four graduate students, and five undergraduates, with the rest made up of technical specialists, administrative staff, and Reese herself. As in many other labs, staff members have a wide range of education levels—from high school for the undergrads all the way up to extensive post-doctoral experience for the faculty, Reese says, adding that staff receive quite a bit of training when they begin.

“The university has a lot of training modules that we send people to for such things as chemical hygiene, safety, and blood-borne pathogens, even things like safe shipping,” she says. “Then there are modules like conflict of interest training and research integrity training, which are also provided by the university. In-house, we train everyone on our equipment and on the procedures and protocols that we use within our institute.”

Training the grads and undergrads on those lab procedures is a big part of Reese’s role as lab manager, a task that she considers one of the highlights of the position.

“I really like working with the graduate students who come into the lab,” Reese says. “They always have a fresh perspective and they’re always challenging established protocols. They’re fresh and enthusiastic.”

The Catalyst Express robot is used to load plates onto a high-content imaging platform.It was a similar enthusiasm for science that led Reese to pursue the field in university, which led to a job in a pharmacology lab after graduation, getting her interested in the drug discovery field and—after 14 years staying home to raise her children—eventually brought her to the UPDDI, where she has worked for the past eight years.

“I’ve always loved science in general but then after college I got the job in the pharmacology lab and I just really liked experimental design and problem solving and implementation—which eventually led into the lab management position,” says Reese, who has now been lab manager at the UPDDI for four years.

Because of her enjoyment of experimenting, along with her other management duties of looking after supplies and equipment, Reese also likes to keep a hand in what’s going on in the lab.

“I keep an active role in at least one of the research projects that we have going on,” she explains. “I find that that’s very helpful in the lab management area as well, because I see key things while I’m doing experiments that I normally wouldn’t see on a walkthrough.”

Blocking out the day

Liquid nitrogen cell bank.

Liquid nitrogen cell bank.



Liquid nitrogen cell bank.For Reese, scheduling chunks of time for certain tasks is critical in ensuring she meets her goals for the day.

“Time management’s key when you’re trying to cover as many roles as it takes to do this job,” she says. “I try to keep the mornings for the lab management tasks and then the afternoons are usually taken up with meetings, experimental design and implementation, or data analysis.”

That means Reese’s mornings typically involve coming in, checking on what’s happening in the lab, looking after the ordering of supplies for the week, and attending to any equipment problems and emails. Along with meetings, her afternoons are usually taken up with running or designing experiments or analyzing data. Of course, the rest of the staff have a variety of different roles.

A few programs and regular inventory checks help keep everything organized.

“One of the big tools we have is a purchasing program that we have developed in-house—an access program that we use and a similar one for equipment reservations and things like that,” Reese says. “We do a weekly inventory. We have two stockroom areas and we have two student workers who go out and stock all the individual work areas for people every day. And then we also have written protocols and established procedures for things like routine equipment maintenance and buffer preparations and such.”

She adds that the main challenge her lab faces is the same one that many other labs face—doing more with less in the current tough economic climate. For her lab, multitasking and teamwork are a big part of solving that issue.

“We just have really talented people here,” Reese says of her staff. “Everybody takes on a variety of roles. Everybody pitches in with things like routine equipment maintenance and … rather than having one person in each job, everybody covers a variety of tasks.” Because of that strong teamwork, Reese finds she doesn’t need to do much to motivate members of the lab.

“I don’t manage people—I just try to lead by example and try to take care of any issues that come up promptly rather than put things off,” she explains. “Everybody’s pretty self-motivated and hardworking here.”

An automated compound storage system is used to store the institute’s screening libraries.

An automated compound storage system is used to store the institute’s screening libraries.


six separate tissue culture facilities

six separate tissue culture facilities












An automated compound storage system is used to store the institute’s screening libraries. The UPDDI has six separate tissue culture facilities equipped with biosafety cabinets, incubators, and microscopes.

The tech side

Along with the aforementioned high-content imaging, Reese’s lab also uses automated liquid handling platforms, biosensors, microfluidics, and immunofluorescence and fluorescence microscopy, and they are starting to implement 3D cell culture strategies to tackle their many projects.

“These fluorescent proteins react to the physiological changes in the cell in real time,” Reese says of the lab’s work with biosensors. “And [with] microfluidics you actually have a moving system. The system is more clinically relevant— it’s a better model for the in vivo systems.”

By “clinically relevant” Reese says she basically means the center is trying to more closely model what is actually going on in the human body, rather than relying on traditional 2D cell culture models or high throughput methods. That focus on clinically relevant methods is a result of big changes in the pharmaceutical industry in recent years.

Top 5 Instruments in the Lab

  • GE InCell6000 Imaging System
  • Agilent (Velocity 11) Bravo Liquid Handling Platform
  • Thermo Scientific Multidrop Combi Dispenser
  • PerkinElmer EnVision 2103 Multilabel Plate Reader
  • Brooks (Matrical) Ministore Automated Compound  Management System

“In the drug discovery field in general, big pharma has been using the mass-scale high throughput screening for a long time and of course now we’re coming to the patent cliff for a lot of the pharmaceutical companies, when a lot of their moneymakers are going off patent,” Reese explains. “So here, we’re trying to move away from that high throughput screening toward a more high-content [screening] where we’re looking at more clinically relevant methods and QSP approaches for drug discovery.”

And the most interesting work the lab is doing right now?

“I would say the coolest thing we have going on is a liver microphysiology project,” Reese says. “We’re making a liver biomimetic, which will be integrated with other organ biomimetics to create a human-on-a-chip for use as a model for drug toxicity and other kinds of organ analysis.”

Categories: Research-Specific Labs

Tags: Drug Discovery Labs


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Effect of Hospital Characteristics on Outcomes of Endovascular Repair of Descending Aortic Aneurysms in US Medicare Population

Writer and Curator: Larry H. Bernstein, MD, FCAP 


Curator: Aviva Lev-Ari, PhD, RN 

Impact of hospital volume and type on outcomes of open and endovascular repair of descending thoracic aneurysms in the United States Medicare population.

Patel VI, Mukhopadhyay S, Ergul E, Aranson N, …., Cambria RP.
Journal of vascular surgery 2013;    http://dx.doi.org/10.1016/j.jvs.2013.01.035


Open surgery for thoracic aortic aneurysm has had success, but it carries complication risks.  In 2004, a much less invasive procedure, thoracic endovascular repair (TEVAR) was introduced. It eliminated a need for open surgery in many patients, but not all were suitable candidtes .  The advances in endovascular technology and procedural breakthroughs  since it was introduced has contributed to a dramatic transformation of the specialty of thoracic aortic surgery. The decision of which patients require open surgery is necessarily determined by the limitations of the procedure and the condition of the patient.
Thoracic endovascular aortic repair (TEVAR) is a minimally invasive alternative to conventional open surgical reconstruction for the treatment of thoracic aortic aneurysm. TEVAR procedures can be challenging and, at times, extraordinarily difficult.  Meticulous assessment of anatomy and preoperative procedure planning are absolutely paramount to produce optimal outcomes. The rapidly Increased use of TEVAR has produced favorable outcomes of TEVAR compared with open abdominal repair for descending thoracic aortic aneurysms (DTAs).   But the success of these procedure depends on requisite skills, and following guidelines intended for use in quality-improvement programs that assess the standard of care expected from all physicians who perform TEVAR procedures.
Currently, there is a diverse array of endografts that are commercially available to treat the thoracic aorta. Multiple studies have demonstrated excellent outcomes of thoracic endovascular aortic repair for the treatment of thoracic aortic aneurysms, with less reported perioperative morbidity and mortality in comparison with conventional open repair. Additionally, similar outcomes have been demonstrated for the treatment of type B dissections. However, the technology remains relatively novel, and larger studies with longer term outcomes are necessary to more fully evaluate the role of endovascular therapy for the treatment of thoracic aortic disease.
The MGH/Partners vascular surgeons evaluated the effect of case volume and hospital teaching status on clinical outcomes of intact DTA repair to gain an insight into whether there was a variability in DTAs outcomes based on hospital size, patient mix, number of procedures, staff characteristics, and teaching status.  This study was needed for establishing the type of procedure most suited to the type of patient, and to obtain the most accurate analysis of cost requirements based on resource allocation for reimbursement purposes.
The Medicare Provider Analysis and Review (MEDPAR) data set (2004 to 2007) was queried to identify open repair or TEVAR for DTA. Hospitals were stratified by DTA volume into high volume (HV; ≥8 cases/y) or low volume (LV; <8 cases/y) and teaching or nonteaching. The effect of hospital variables on the primary study end point of 30-day mortality and secondary end points of 30-day complications and long-term survival after open repair and TEVAR DTA repair were studied using univariate testing, multivariable regression modeling, Kaplan-Meier survival analysis, and Cox proportional hazards regression modeling.
They identified 763 hospitals performing 3554 open repairs and 3517 TEVARs. Overall DTA repair increased (P < .01) from 1375 in 2004 to 1987 in 2007. The proportion of hospitals performing open repair significantly decreased from 95% in 2004 to 57% in 2007 (P < .01), whereas
  • those performing TEVAR increased (P < .01) from 24% to 76%.
Overall repair type shifted from open (74% in 2004, the year before initial commercial availability of TEVAR) to TEVAR (39% open in 2007; P < .01). The fraction of open repairs at LV hospitals
  • decreased from 56% in 2004 to 44% in 2007 (P < .01), whereas
  • TEVAR increased from 24% in 2004 to 51% in 2007 (P < .01).
Overall mortality during the study interval for
  •  open repair was 15% at LV hospitals vs 11% at HV hospitals (P < .01), whereas
  • TEVAR mortality was similar, at 3.9% in LV vs 5.5% in HV hospitals (P = .43).
LV was independently associated with increased mortality after open repair (odds ratio, 1.4; 95% confidence interval, 1.1-1.8; P < .01) but not after TEVAR. There was no independent effect of hospital teaching status on mortality or complications after open repair or TEVAR repair.
The total number of DTA repairs significantly increased after the introduction of TEVAR for DTA. Operative mortality for TEVAR is independent of hospital volume and type, whereas
  • mortality after open surgery is lower at HV hospitals.
While the TEVAR mortality is significantly less than that of open surgery, the mortality in open surgery is higher for LV hospitals.  The data suggests that TEVAR can be safely performed across a spectrum of hospitals, whereas open surgery should be performed only at HV hospitals.
  1. Standard of Practice for the Endovascular Treatment of Thoracic Aortic Aneurysms and Type B Dissections. Fanelli F, and  Dake MD.  Cardiovasc Intervent Radiol. 2009 September; 32(5): 849–860.  http://dx.doi.org/10.1007/s00270-009-9668-6  PMCID: PMC2744786
  2. Thoracic aortic aneurysms and dissections: endovascular treatment. Baril DT, Cho JS, Chaer RA, Makaroun MS. Division of Vascular Surgery, University of Pittsburgh Medical Center, Pittsburgh, PAMt Sinai J Med. 2010 May-Jun;77(3):256-69.  http://dx.doi.org/10.1002/msj.20178.

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Histopathological image of dissecting aneurysm...

Histopathological image of dissecting aneurysm of thoracic aorta in a patient without evidence of Marfan syndrome. The damaged aorta was surgically removed and replaced by artificial vessel. Victoria blue & HE stain. (Photo credit: Wikipedia)

Diagram of aortic aneurysm Figure A shows a no...

Diagram of aortic aneurysm Figure A shows a normal aorta. Figure B shows a thoracic aortic aneurysm (which is located behind the heart). Figure C shows an abdominal aortic aneurysm located below the arteries that supply blood to the kidneys. (Photo credit: Wikipedia)

Thoracic aorta

Thoracic aorta (Photo credit: Wikipedia)

Open Heart Surgery

Open Heart Surgery (Photo credit: Wikipedia)

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First-of-Its-Kind FDA Approval for ‘AUI’ Device with Endurant II AAA Stent Graft: Medtronic Expands in Endovascular Aortic Repair in the United States

Reporter: Aviva Lev-Ari, PhD, RN


Medtronic, Inc. (MDT) Expands Endovascular Aortic Portfolio With Two New Devices

5/30/2013 8:39:47 AM

Medtronic Garners First-Of-Its-Kind FDA Approval for ‘AUI’ Device with Endurant II AAA Stent Graft 

MINNEAPOLIS — May 30, 2013 — Medtronic, Inc. (NYSE: MDT) is expanding its market-leading portfolio of products for endovascular aortic repair in the United States with two new medical devices: the company recently received approval from the U.S. Food and Drug Administration (FDA) for the Endurant II Aorto-Uni-Iliac (AUI) Stent Graft System and the FDA’s 510(k) clearance for the Sentrant Introducer Sheath; both devices will be on exhibit at the Medtronic booth during the Society for Vascular Surgery‘s “Vascular Annual Meeting,” which runs May 30-June 2 in San Francisco.

Endurant II AUI Stent Graft System

The Endurant II AUI Stent Graft System is the only FDA-approved AUI device in the United States indicated for the primary endovascular treatment of infrarenal abdominal aortic or aorto-iliac aneurysms in patients whose anatomy does not allow for the use of a bifurcated device. Both the bifurcated and AUI configurations of the Endurant Stent Graft System provide a new pathway for blood flow through the iliac arteries in abdominal aortic aneurysms, thereby reducing risk of aneurysm rupture.

Whereas use of the bifurcated device requires access to both iliac arteries, the AUI device requires access to only one iliac artery (Endurant II Aorto-Uni-Iliac (AUI)). In published studies of endovascular abdominal aortic aneurysm (AAA) repair.

Current global usage of AUI stent graft configurations averages

  • 5 percent (range 0-26%) for intact AAA and
  • 39 percent (range 0-91%) for ruptured AAA.[i],[ii]

“The new Endurant II Aorto-Uni-Iliac Stent Graft extends the proven performance of the Endurant System to patients with difficult access,” said Dr. Michel Makaroun, chief of vascular surgery at the University of Pittsburgh Medical Center and co-director of the UPMC Heart and Vascular Institute. “By maintaining the deliverability, conformability and deployment accuracy of the bifurcated Endurant device, the AUI configuration offers aneurysm patients with challenging outflow anatomies a better option for a successful endovascular aortic repair.”

As with the bifurcated Endurant II Stent Graft, distinguishing features of the Endurant II AUI Stent Graft include a low delivery profile, tip capture for easy and accurate deployment and compatibility with contralateral iliac limbs and aortic extensions for ultimate patient applicability.

Sentrant Introducer Sheath

The Sentrant Introducer Sheath complements Medtronic’s market-leading portfolio of stent grafts for endovascular aortic repair. It is specially designed for use with the Endurant II AAA and Valiant Captivia Stent Graft Systems and is also compatible with competitive systems. The Sentrant Introducer Sheath is inserted at the access site

in the patient’s femoral artery and advanced upwards into the iliac arteries to facilitate the implant procedure and enable smooth passage of the stent graft delivery system en route to the treatment site in the aorta.

The Sentrant Introducer Sheath can accommodate a wide range of anatomies, with diameters of 12-26 French and shaft lengths of 28cm. Other distinguishing features of the accessory device include:

  • optimal seal for superior hemostasis,
  • reinforced coil for kink resistance,
  • hydrophilic coating and
  • flexibility for easy tracking through tortuous and calcified iliacs and a
  • dilator locking mechanism for secure positioning.

The Sentrant Introducer Sheath received the CE (Conformité Européenne) mark in April 2013. Its FDA clearance expands the accessory device’s availability to endovascular specialists in the United States.

In collaboration with leading clinicians, researchers and scientists, Medtronic offers the broadest range of innovative medical technology for the interventional and surgical treatment of cardiovascular disease and cardiac arrhythmias. The company strives to offer products and services that deliver clinical and economic value to healthcare consumers and providers worldwide.


Medtronic, Inc. (www.medtronic.com), headquartered in Minneapolis, is the global leader in medical technology-alleviating pain, restoring health and extending life for millions of people around the world.

Any forward-looking statements are subject to risks and uncertainties such as those described in Medtronic’s periodic reports on file with the Securities and Exchange Commission. Actual results may differ materially from anticipated results.


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