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The Road to Discovery Runs through Mayo’s Clinical Research Unit

Posted on April 16th, 2014 by Bob Nellis

DE_CRU_Opening

The road to developments that change medicine is jammed with great ideas.  It meanders like a mountain trail in the early stages with many ideas failing and being discarded.  But once an innovative medical breakthrough reaches the point of clinic research, the road runs straight as a Midwest highway through a patient-study unit nestled in Mayo Clinic’s campus in Rochester, Minn.

The Clinical Research Unit (CRU) is the unsung waypoint through which any number of landmark patient studies have traveled en route to improving the lives of millions of people, including revolutionary discoveries in osteoporosis, gastrointestinal distress, sleep apnea and cardiovascular disease, and diseases related to physiology.  Here is a look at one from the CRU atlas of discoveries: diabetes.

 Diabetes

Fifty years ago, diabetes treatment involved considerable conjecture. How much insulin — the hormone required to move sugar from the bloodstream to the body’s cells for energy — did a patient need to maintain a safe glucose level? An error in either direction risked dangerously high or low blood sugar. Lacking a clear understanding of the mechanisms underlying diabetes, physicians weren’t sure.

In a series of clinical studies, Mayo Clinic researchers found answers that revolutionized diabetes treatment. By injecting tracers into the bloodstreams of study participants, the researchers were able to follow the intricate and previously unmapped pathways of metabolism. They learned that small amounts of stored glucose are released by the liver when blood sugar is low, keeping glucose concentrations constant between meals. More insulin is needed with a meal to metabolize food.

“Very quickly, we understood what needed to be done to bring glucose levels down, and the insulin doses necessary to accomplish that,” says Robert A. Rizza, M.D., an endocrinologist at Mayo Clinic who led the studies.

As a result of Dr. Rizza and colleagues’ “elegant” studies, the American Diabetes Association proclaimed “the most fundamental questions” about diabetes “were finally addressed.” Intensive insulin therapy, in which patients inject short-acting insulin before each meal and long-lasting insulin for coverage between meals, became standard treatment. Other research applications include the development of precise tools for measuring blood glucose as well as improved insulin and insulin pumps that provide constant therapy.

“To create therapies that benefit patients, we need to precisely measure glucose production and uptake, protein metabolism, the effects of diet and exercise — the list is long,” Dr. Rizza says. “These sophisticated studies could not be done without the Clinical Research Unit.”

To read the full story about Mayo Clinic's Clinical Research Unit, visit Discovery's Edge, Mayo Clinic's research magazine.

Cancer Researchers Begin Blog Series on Cures for Kidney Cancer

Posted on April 7th, 2014 by Bob Nellis

 

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Winston Tan, M.D.

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John Copland, III, Ph.D.

 

We’re Drs. Winston Tan and John “Al” Copland and we collaborate in pursuit of cures for kidney cancer.  Winston is a Mayo Clinic physician oncologist who treats kidney cancer patients and collaborates with Al, a Mayo scientist dedicated to kidney cancer research.

In talking with kidney cancer survivors and friends, we have been encouraged to begin a blog about our research efforts and discoveries in kidney cancer. Current FDA approved drugs are not cures.  They provide some survival benefit (in a small number of cases, long term). These treatments not only have a number of toxicities issues but also do not work permanently for patients. Thus, new therapies are desperately needed. In pursuit of new treatments, we have discovered new cancer genes (from the greater than 22,000 genes expressed in human body) that may lead to new treatments for kidney cancer and for other cancers where these genes occur. So much is still unknown for every cancer but we now have the technologies including genomic and functional genomic techniques to make impactful discoveries.

Today, we are introducing our blog series with new insights and discoveries into new genes and treatment options for kidney and related cancers. We will discuss with you cutting edge discoveries and share our struggles along the way as we make new discoveries. Join us in this new adventure as an interactive learning process. We all can participate together in asking and answering questions as well as bring new cutting edge data to this forum. We encourage you to post news & links of discoveries from around the world to this blog. Together, we’ll gain a better understanding of kidney cancer, cancer biology and move forward towards cures.

Our laboratory has several technologies and capabilities that allow us to link clinical observations to functional cancer biology that may lead to new drugs to treat multiple cancers.

  1. Technologies to examine gene and protein expression in patients’ tumor tissues.
  2. Patient derived cell lines – originating from surgically resected tumor tissues
  3. shRNA technology – silence a gene and determine if that gene in a patient’s cells promotes tumor growth and metastasis
  4. In silico drug screening and drug synthesis allowing us to develop new compounds that may become tomorrow’s drugs.
  5. Cell based and in vitro models to test compound specificity.

Thus, we can determine if a gene is elevated in a patient’s cancer tissue. If it is, we can test the cell line (developed from that patient’s tumor tissue) by silencing the gene. We then determine if the cells grow slower, don’t survive or don’t metastasize.  If any of one of these three is true, then the gene is an important target to consider developing a drug that blocks its cancer promoting activity. Thus, using these step-wise methods allows us to validate many important new cancer genes.

We have discovered over 30 new genes in kidney cancer that promote tumor growth. We recently published one of these genes, SCD1. We showed an SCD1 inhibitor leads to massive cell death and it can be combined with an FDA approved drug, temsirolimus leading to greater cell death. In our next blog, we will share our thoughts on developing this combination therapy for clinical trials. And later, we will share with you discoveries of a second gene from the 30 plus genes. This gene is as exciting as SCD1 having never been described before as a cancer gene! You can see that we much to share from our laboratory discoveries on new gene targets along with insights to patient care from Winston and other topics that you may suggest important to our conversation.

We do envision that our discoveries will benefit other cancers. We know that SCD1 is over  expressed in many cancers along with our second discovered gene. We have access to different types of cancer tumor tissues. From these tumor tissues, we develop patient tumor derived cell lines in the laboratory for breast, ovarian, prostate, bladder, brain, head & neck, lung, pancreatic and colon cancers as well as melanoma. We will examine these cancer cell lines for antitumor activity and share our results with you. Thus, we can test our gene discoveries for benefit against other cancers. In our next blog, we will also share with you other cancers that are growth inhibited by SCD1.

So, come on the journey with us. We hope to inspire and educate one another along the way to solving some deadly mysteries. Like a detective, we have some very exciting leads but don’t know where they will ultimately lead us or if we will solve the ultimate crime -death by cancer- and catch the gang members (genes gone bad). We have to go for it! Did you know that over 1.665 million Americans will be told “You have cancer” in 2014.  About 585,720 Americans will die this year. There is 545,600 minutes in a year. Think about this – 3 people every minute will become a cancer victim and one person every minute will be die in the U.S.A. On the world stage, 2014 estimated new cancer diagnoses will be 1,665,540 made and cancer deaths will be 1,333,249 (http://www.medindia.net/patients/calculators/world_cancer_clock.asp). This calculates to 11.8 deaths per minute around the world.  The need is urgent. We are called to action.

 

The Connection Between Teeth and Heart Surgery

Posted on February 28th, 2014 by Bob Nellis

We want to pass on some published Mayo Clinic research as reflected in the media this week. This one, from the Annals of Thoracic Surgery is especially interesting and useful to both physicians and patients alike.

HealthDay, Getting Teeth Pulled Before Heart Surgery May Pose Serious Risks by Randy Dotinga…In a small, retrospective study, Mayo Clinic researchers found that 8 percent of heart patients who did not wait to have teeth pulled suffered major adverse health outcomes, such as a heart attack, stroke, kidney failure or death. "Guidelines from the American College of Cardiology and American Heart Association label dental extraction as a minor procedure, with the risk of death or non-fatal heart attack estimated to be less than 1 percent," study co-author Dr. Mark Smith said in a statement. Additional coverage:  KSAZ Ariz.US News & World ReportFOX NewsMedicineNet.comForbes.comWMCTV.comFox5Vegas.com19ActionNews.com,WDAM.comHHS HealthFinder.gov,

Reversing Breast Cancer With Injectable Nanoparticles

Posted on January 2nd, 2014 by Admin

A Mayo Clinic researcher, along with collaborators from Harvard Medical School, developed a method to first identify a breast-cancer-promoting gene and then specifically target this gene with a nanoparticle-based, injectable therapy that reverses breast cancer in mice.  The results, published this week in Science Translational Medicine, may provide a first step in developing a new non-surgical treatment option for patients diagnosed with early-stage breast cancer.   

Milk ducts in cancer-prone mice are packed with tumor cells (deep purple cells, shown by arrow), causing the ducts to grow fatter. But milk ducts in mice treated with a gene-silencing nanoparticle remain mostly hollow (right, shown by arrows), like healthy ducts. Credit: Amy Brock

“Precancerous cells are at a tipping point, in which they could become full-blown cancer or not,"  says Mayo Clinic pharmacologist Hu Li, Ph.D., a co-first author on the study. "Our results show that, if we know the right target genes, it is possible to tip the balance in favor of a more normal cell state, preventing cancer progression, and improving survival outcomes.”

Identifying the Enemy

In order to identify the most-significant genes that were turning normal breast cells into tumor cells, the researchers developed a computational approach to identify cancer-related changes in regulatory genes which, in turn, control many other genes.  In theory, targeting such regulatory genes could have a dramatic effect, based on all of the downstream genes which would also be affected. The team zeroed in on a specific regulatory gene, HoxA1, as a driver of breast cancer in mice with a high rate of hereditary breast tumors.

A Nanoparticle Approach

To see if HoxA1 could be targeted to prevent further tumor development in these mice, the team decided to down-regulate HoxA1 within the breast tissue, specifically in the cells where the tumor develops.


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By injecting nanoparticles carrying a gene-silencing snippet of RNA directly into the nipple, Wyss Institute scientists delivered this therapy to the entire milk-duct network, breast cancer first gets started. Credit: Silva Krause and Amy Brock

To accomplish this, they used tiny, fat-based nanoparticles, which were coupled to molecules designed to specifically down-regulate HoxA1, and may be injected into the body.  Hoping to reduce toxicity, they decided to inject these nanoparticles directly into the breast ducts, specifically where the tumors form, rather than systemically, as others have tried in the past.

The result:  The researchers discovered that mice developed dramatically fewer tumors when treated with this novel therapy.  They also found that targeted depletion of HoxA1 appeared to reverse tumor characteristics, effectively tipping the cellular balance back to a normal cell state.

In the same way that HoxA1 was identified, the researchers say it may be possible to advance the technology to the point where doctors are able to identify the best therapeutic gene targets specific to an individual patient’s tumor, allowing for the design of tumor-specific and patient-specific therapeutic strategies.

The research was supported by the Department of Defense, SysCODE (Systems-based Consortium for Organ Design & Engineering), the National Institutes of Health, Susan G. Komen Foundation, the Wyss Institute at Harvad, and Mayo Clinic.

Study collaborators include Amy Brock, Ph.D., The University of Texas at Austin; Silva Krause, Ph.D., Michael S. Goldberg, Ph.D., Marek Kowalski, and Donald E. Ingber, M.D., Ph.D., all of Harvard University; James J. Collins, Ph.D., of Howard Hughes Medical Institute, Boston University, and Harvard University.

Dr. Hu Li, et al. Silencing HoxA1 by intraductal injection of siRNA lipidoid nanoparticles prevents mammary tumor progression in mice. 

-- by Debra Evans

Luring Cancer: Custom “Bait” Catches Recurrent Prostate Cancer

Posted on December 18th, 2013 by Admin

From Mayo Clinic's Discovery's Edge magazine

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Many prostate cancer survivors live in fear of being told that their cancer has returned. It’s even scarier to be told that the doctor knows the cancer is there because of rising PSA levels, but that he can’t find it. Doctors and patients alike know that early detection of the recurrent cancer is critical to the patient’s chance of beating it a second time.

The problem, however, is locating it.

A Mayo Clinic research team has developed a new imaging technique that can often find the recurrent disease months, if not years, earlier than other imaging techniques. Prostate cancer uses choline, a B-complex vitamin, as a building block. So when a minute amount of radioactively-labeled choline (choline C-11) is injected into a patient, it is quickly taken up by the cancer — like a fish rising to the bait.

The prostate cancer then emits radiation, allowing doctors to pinpoint its location. A positron emission tomography (PET) scanner is “able to tell where in the body this radiation is being emitted,” explains Mayo Clinic radiologist Val Lowe, M.D..

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Val Lowe, M.D.

Choline C-11 isn’t toxic, and the radioactive element is so minimal, it’s really not much of a pharmacologic safety issue, explains Dr. Lowe. “If you take a grain of sugar and divide it into 100 pieces, one of those pieces is enough to do a PET scan.”

As well as being safe, the PET scan takes little time. Once the radioactive element is added to the choline C-11, it has a very short shelf-life. The half-life of choline C-11 is only 20 minutes, meaning it loses half of its radioactivity every 20 minutes. Because the radioactivity is the imaging agent that allows the PET scanner to see the cancer, the agent must be used shortly after it’s made. It cannot be stored and shipped. It essentially must be manufactured on-site.

All told, it takes about 45 minutes to make choline C-11, and the scan itself takes only about 20 minutes. The results are analyzed and a report is typically ready half an hour after the scan is completed.


PET scan on right using choline C-11 makes early tumors highly visible compared to traditional image on left.

PET scan on right using choline C-11 makes early tumors highly visible compared to traditional image on left.

“For the first time ever, we will have a clear blueprint of where the patient stands, at a far earlier course in treatment failure,” says Eugene Kwon, M.D., a Mayo Clinic urologist. “It has basically ripped the curtain off the Wizard of Oz.”

At this time, Mayo Clinic is the only health care provider in the country authorized to do this test. But when filing with the FDA, Mayo Clinic waived all exclusivity. It wanted other sites in the country to be able to manufacture and use the drug to better serve their own patients.

Mayo Clinic Debuts Two New Blogs Focused on Celiac Disease and Inflammatory Bowel Disease (IBD)

Posted on December 9th, 2013 by Admin

 

We are excited to unveil Mayo Clinic’s newest blogs, which focus on celiac disease and inflammatory bowel disease (IBD, which includes Crohn’s disease and ulcerative colitis).

The blogs feature commentary from Mayo Clinic experts about most recent news and advances within each disease, specifically:

  • Study findings
  • News alerts
  • Clinical trials
  • Upcoming events
  • Disease management tips from clinicians

The content produced on these blogs is meant to spur discussion and our contributors look forward to answering any questions left in the comment section of blog posts or YouTube videos.

We also encourage our readers to use the comment section of posts to propose any topics they would like to see discussed in future posts.

Thanks for your continued interest and we look forward to expanding our collection of content focused on these conditions.

Celiac Blog: http://celiacblog.mayoclinic.org/
IBD Blog: http://ibdblog.mayoclinic.org/

The Radiation Limbo: How Low Can We Go?

Posted on December 2nd, 2013 by Admin

From Mayo Clinic's Discovery's Edge magazine

Reducing radiation exposure from CT scans has become one of the primary goals of Mayo Clinic’s CT Clinical Innovation Center. Dr. Cynthia McCollough and her colleagues are doing the Radiation Limbo: How low can they go without sacrificing image quality.

At a time when CT scans are being used with greater frequency, the work of Mayo researchers has cut the risk of exposure without sacrificing image quality or diagnostic capability.

Dr. McCollough is continually looking for ways to lower radiation exposures while maintaining the needed quality. A critical step in that process includes better defining what level of image quality is needed.

“We don’t always need pretty pictures,” says Dr. McCollough.  “We only need pictures that clearly show the disease or injury. For some conditions, a really low exposure of radiation can be used.”

To reduce the amount of radiation patients are exposed to, the CT Clinical Innovation Center takes several routes. “The most basic, low-tech thing we can do is to ‘right-size’ the dose,” says Dr. McCollough.

Mayo Clinic has developed a computerized set of electronic protocols that are centrally managed.  If an adjustment is made to a protocol, the correct, new information is instantly available at all 25 CT scanners on the Mayo Clinic campus in Rochester, Minn., as well as at all Mayo Clinic Health System sites, and the Mayo practices in Florida and Arizona.

A CT scan of a patient with a small, non-obstructing kidney stone. In the left image, the stone is visible (arrow); in the right image from a follow-up exam, acquired using 60 percent less radiation, the stone is still easily detected (arrow).

Much like the automatic exposure feature on a camera, CT scanners can now automatically adjust the radiation exposure that the patient receives based on the type of exam and the size of the patient. “Everything we're doing with dose reduction is to make sure patients get the exams they need at the lowest radiation doses,” says Dr. McCollough.

One area where use of medical radiation has increased dramatically in recent years is in cardiology.  It is also one of the areas that has seen significant decreases in the levels of radiation exposure. Dr. Charanjit Rihal, a cardiologist at Mayo Clinic, says the results have been encouraging. “We reduced the amount of radiation by at least 40 percent, and in some cases, by as much as 70 percent.”

Charanjit S. Rihal, M.D., the William S. and Ann Atherton Professor of Cardiology Honoring Robert L. Frye, M.D., is chair of cardiovascular diseases at Mayo Clinic.

Another of Dr. McCollough’s colleagues, Dr. Joel Fletcher a radiologist and the medical director of the CT Clinical Innovation Center, worked with the pediatric oncology group to lower the radiation dose for follow-up CT scans for children diagnosed with cancer who had completed treatment.

“We just kept turning down the dose until finally it was down to the lowest setting the scanner would run at,” says Dr. McCollough. With each setting, a pediatric radiologist would look at the scan to ensure that the image was still clear. “We try to do the limbo: you know, ‘How low can you go?’”

With education, new technology, and collaboration between physicists, radiologists, and other physicians, Mayo Clinic is answering that question.

Mayo Clinic's Fifty Years of Kidney Transplants – Part IV

Posted on November 25th, 2013 by Admin

Pioneers of Kidney Transplantation at Mayo Clinic

James H. DeWeerd, M.D.

The first transplant of a kidney took place in Saint Marys Hospital on Nov. 25, 1963. Surgeons George A. Hallenbeck, M.D., and James DeWeerd, M.D., headed a medical team that performed the first transplant, placing a kidney in a female patient. The patient’s half-sister was the donor. Mayo’s operation reflected a common theme in the early development of transplant medicine. The donor providing the kidney was a close relative of the recipient. That was important at the time to minimize rejection of the organ by the recipient’s body.

George A. Hallenbeck, M.D.

George Hallenbeck, M.D., had acquired a deep knowledge of physiology and an interest in experimental surgeries before he stood at that operating table. Dr. Hallenbeck also designed Mayo’s initial kidney transplant program. Once it began, he was named to direct Mayo’s Section of Tissue and Organ Transplantation. He subsequently headed the surgical teams for more than 40 kidney transplants.

Dr. Hallenbeck was among Mayo’s most accomplished surgeons and researchers. Besides a medical degree, he held a doctorate in physiology with specialty work in gastric secretions. During World War II, Dr. Hallenbeck worked on the physiology of acceleration for Mayo, and served on the U.S. Army’s development team for the famed “G-suit.” It was created to protect fighter pilots from blackouts under extreme flight conditions.

Frank C. Mann, M.D.

Frank C. Mann, M.D., and his Mayo Clinic laboratory were probing the science of kidney transplants in the 1920s, decades before surgeons performed the first patient operations. A surgical resident working with the laboratory drew several insights from the failure of transplanted kidneys. Carl S. Williamson, M.D., was among the early scientists to recognize a “blood-borne” factor that needed to be overcome to prevent rejections. In later remarks, Dr. Mann observed: “The successful transplantation of a healthy organ for a diseased one awaits the discovery of those biologic factors which prevent the survival of tissues of one individual when transplanted into the body of another individual.” Dr. Mann and his associates also pioneered surgical techniques for kidneys. Among them was the method developed by Dr. Williamson, which was used in the first kidney transplants on humans. Dr. Mann came to Mayo Clinic in 1914 as director of experimental medicine and retired in 1952.

Mayo Clinic and 50 Years of Kidney Transplants – Part II

Posted on November 25th, 2013 by Admin

[Editor's note: We recently looked at benchmarks in kidney transplant history. Today more on the kidney and why it's so important.]

The Kidney’s Critical Role

The kidney’s well-being is essential for the rest of the body. It acts as the main filtering system for wastes and the major factor in excreting them from the body.

With each heartbeat, about one-fifth of the blood supply floods into the kidney. The organ contains enormous numbers of “nephrons’’ containing microscopic tubes. They are sized precisely to strain undesirable waste chemicals from the blood stream.

Each human has two kidneys and easily can survive with a single one. But various genetic diseases, infections or poisons can destroy the nephrons in both kidneys.

Once the kidneys are incapacitated, the damage is life- threatening. Doctors today can offer two main treatments to patients with terminal renal disease – transplantation or dialysis.

Although individual cases differ, Mayo Clinic doctors tend to favor transplants because of better and longer-lasting results. Kidney transplants can be performed at almost any age.

Medical Advances that Made a Difference Over 50 Years

Kidney transplant surgeries are possible due to ongoing, significant biomedical advances. Perhaps the single most important advance involves preventing the recipient’s immune system from rejecting the donated kidney.

Immunosuppressant drugs

• Prednisone – a steroid used in the early days of transplantation and still used today

• Azathioprine – introduced in 1968

• Cyclosporine – approved in 1983 and in wide use today

Blood treatments

Doctors today can “precondition” the recipient’s blood to remove antibodies that would trigger rejection of a donated kidney.

Antibiotics, antimicrobial and related medicines – These drugs help ward off infections in patients with weakened immune systems.

Surgical techniques

Laparoscopy has greatly reduced the size of incisions and shortened recovery times for kidney donors. Mayo surgeons first started using the technique in 1999. It’s sometimes called “bellybutton surgery.” The surgeon inserts a long instrument with a camera through narrow holes in the donor’s abdomen, snips away a healthy kidney and recovers it through another small opening. Previously, the operation involved a much larger incision on one side of the donor’s back.

Detecting and Treating Cancer Recurrence in Time

Posted on November 22nd, 2013 by Admin

A Mayo Clinic laboratory study has revealed a possible mechanism to stop recurrence of cancer in mice. The approach, involving screening and a second-line treatment, prevented cancer from coming back in most of the mice in the study in which recurrence would have happened. The findings appear in Nature Medicine.

It’s been long known that cancer tumors change their appearance or phenotype, as well as their genomic characteristics, to avoid the natural immune response from the host body. A collaborative international team led by Richard Vile, Ph.D., Mayo Clinic molecular medicine researcher, attempted to detect or anticipate that shift and then initiate a “pre-emptive strike” before the tumor fully evolves, thus preventing a relapse.

The researchers say the findings may lead to new methods of early cancer detection and “appropriately timed, highly targeted treatment of tumor recurrence irrespective of tumor type or initial treatment.”

The research was supported by the Richard M. Schulze Family Foundation, Mayo Clinic, Cancer Research UK, the National Institutes of Health, and a grant from Terry and Judith Paul.

Other collaborators in the research are: Timothy Kottke, Nicolas Boisgerault, Ph.D., Rosa Maria Diaz Ph.D, Diana Rommelfanger-Konkol Ph.D, Jose Pulido, M.D., Jill Thompson, Debabrata Mukhopadhyay, Ph.D., of Mayo Clinic; Oliver Donnelly, M.D., Alan Melcher, M.D. Ph.D., and Peter Selby, M.D. Ph.D., of Cancer Research UK; Roger Kaspar, Ph.D., TransDerm, Santa Cruz; Matt Coffey, Ph.D., Oncolytics Biotech, Calgary; Hardev Pandha, M.D. Ph.D., University of Surrey; Kevin Harrington, M.D. Ph.D., The Institute of Cancer Research, London.