Translational Research Institute for Metabolism and Diabetes (TRI)

The Translational Research Institute for Metabolism and Diabetes (TRI) is the product of an innovative affiliation between Florida Hospital and Sanford Burnham Medical Research Institute.
By linking the largest healthcare provider in Central Florida with a nationally renowned basic science leader, the TRI bridges the gap between the research bench and the patient’s bedside.

At the interim location on Lee Road in Winter Park, Florida, a talented team of brilliant researchers and experienced, caring medical professionals is bringing medical discoveries from the laboratory to the community for further testing, through clinical trials, in an effort to tackle some of today’s biggest health problems  obesity, diabetes, and cardiovascular disease.

What is “Translational Research”?

To improve human health, scientific discoveries must be translated into practical applications. These discoveries typically begin at “the bench” with basic research, in which scientists study disease at the molecular and cellular levels, then progress to the clinical level, or the patient’s “bedside.

”This “bench-to-bedside” approach in translational research is actually a two-way street. Basic scientists provide clinical researchers with new patient care tools to assess through clinical trials, and clinical researchers make novel observations about the nature and progression of disease that often stimulate basic scientists’ investigations.

The combined efforts of scientists, researchers, and physicians make translational research a true interdisciplinary approach to improving lives through innovation that leads to discoveries and ultimately cures

Cytomegalovirus (CMV) Researching

Bone marrow (stem cell) transplants have been a life-saving tool for patients with leukemia and lymphoma. However, like most cancer treatments, they come with significant risk.
Patients can be immune-compromised for as long as a year, making them vulnerable to pathogens that most people would fight off easily.

One such pathogen is cytomegalovirus (CMV), a member of the herpes virus family. People usually get CMV early in life (from childhood to early adulthood), experience mild symptoms and move on. However, for immune-compromised patients, CMV can be a serious and deadly complication.

While treating bone marrow transplant patients, Dr. Jaime Green, an Infectious Disease fellow at UC San Diego, became concerned that many were developing infections with CMV. She began researching this condition and realized she needed to learn more about specific immune system pathways to better understand what was happening to her patients. This led her to Sanford-Burnham’s Dr. Carl Ware.

“I started to get interested more in the immune system and what the T-cell responses were doing,” says Dr. Green. “I connected with Dr. Ware since he is an immunologist who specializes in herpes infections, and we came up with some interesting projects.”

Specifically, Dr. Green is interested in Dr. Ware’s research in type 1 interferons and how they link the innate and adaptive immune response—a link that is essential to control CMV.

“So we’re interested in identifying whether these type 1 interferon signatures are different in these patients,” says Dr. Green. “If the patient has an intact interferon signature pathway, are they less susceptible to getting the CMV infection, and would we treat these patients differently than the patients who do not have an interferon signature yet? So we’re looking for biomarkers in the short term and possible novel therapeutics in the long term.”

The quest for biomarkers is critical. The treatment for CMV is ganciclovir, which can be given preventively to all patients or only to those with active CMV. Unfortunately, ganciclovir increases the risk of bacterial infection and can endanger the bone marrow graft. Finding biomarkers could help physicians choose which patients should receive ganciclovir and when.

“We take weekly blood samples from these patients for the first three months after transplant, and then we draw a blood sample monthly up until the first year, and follow these patients clinically to determine who gets CMV infections and who has normal engraftment versus difficulties in engraftment,” says Dr. Green. All of these samples will be run to look at their interferon signatures in the lab at Sanford-Burnham.

This research could be a great benefit for patients. When Dr. Green looked at stem cell transplant recipients at UCSD, she found that 40 percent of patients in the past five years had CMV infection.

Studying for Metastasis Cancer Body

Dr. Courtneidge’s group has been studying invadopodia for a number of years with the goal of unraveling how they regulate tumor cell invasion.
Taking the study a step further, Drs. Courtneidge and Quintavalle and the team also worked out exactly how Cdk5 promotes invadopodia formation.
Metastasis the spread of cancer from the place where it first started to another place in the body is the most common reason that cancer treatments fail.

To metastasize, some types of cancer cells rely on invadopodia, cellular membrane projections that act like feet, helping them “walk” away from the primary tumor and invade surrounding tissues.
To determine how cells control invadopodia formation, Sanford-Burnham scientists screened a collection of pharmacologically active compounds to identify those that either promote or inhibit the process. They turned up several invadopodia inhibitors that target a family of enzymes called cyclin-dependent kinases (Cdks), revealing a previously unrecognized role for Cdks in invadopodia formation. These findings appeared online July 26 in Science Signaling.

The team was surprised to find that several of the newly identified compounds that blocked invadopodia (and therefore cancer cell invasion) targeted Cdks, a family of enzymes that were not previously associated with invadopodia. In follow-up experiments, they demonstrated that one of these enzymes, Cdk5, is required for the formation and function of invadopodia and for cellular invasion, both important steps in cancer metastasis. Cdk5 is highly expressed in neurons, where it’s involved in neuronal migration and outgrowth. This is the first time the enzyme has been implicated in invadopodia formation.

Cdk5’s action leads to the degradation of another protein called caldesmon. Caldesmon was previously shown to negatively regulate invadopodia, so Cdk5 essentially removes that brake. That’s why the Cdk inhibitors identified in the screening study also inhibited invadopodia.

Heart disease is the leading cause of death

Heart disease is the leading cause of death in all over the countries. While many factors work together to contribute to heart disease including environment, lifestyle, and genetics
To address the third factor (genetics), researchers at Sanford-Burnham recently turned to fruit flies.

Fly and human genes are so closely related that the sequences of newly discovered human genes, including many that contribute to disease, can often be matched up with fly counterparts.
Since fruit flies are relatively easy to work with (they’re small, breed quickly, and don’t require a lot of maintenance), they often give scientists clues to the functions of human genes and helps them develop drugs that target them.

As Dr. Rolf Bodmer, director of Sanford-Burnham’s Development and Aging Program, explains in the Journal of Cell Biology, “We use fruit flies to learn about the fundamental genetic mechanisms that are important for the development and function of the heart.”

Dr. Bodmer himself discovered early in his career that flies lacking Tinman, a protein that regulates the expression of other genes, fail to develop heart tissue during embryonic development. If Tinman is removed later during fly development, the flies’ hearts don’t function properly.

Now researchers in Dr. Bodmer’s lab, led by postdoctoral researcher Dr. Li Qian, uncovered a genetic network that controls heart development and function in fruit flies and mice, with additional clues that it might also play a role in human heart health.

In a study published June 20 in the Journal of Cell Biology, the researchers first found a genetic link between Tinman and a protein called Cdc42 in fruit flies. Cdc42 is well known to regulate actin filaments, which act like scaffolding to help cells maintain their shape. Without fully functioning Tinman and Cdc42, the flies’ hearts didn’t beat as regularly and heart muscle fibers weren’t arranged in a parallel, organized fashion like they are in normal flies.

But Dr. Bodmer, Dr. Qian, and colleagues didn’t stop with fruit flies—they also wanted to see if Tinman and Cdc42 affect heart development and function in mice. Indeed, they found that mice with reduced Tinman and Cdc42 levels experienced poor heart contraction and rhythm. But, in a final layer of complexity, the team also discovered how Tinman works—it inhibits microRNAs, small strands of genetic material that can influence protein production. More specifically, Tinman impairs one microRNA called miR1, which in turn decreases levels of Cdc42 and another gene. In other words, miR1 serves as the middleman in the interaction between Tinman and Cdc42, and the other genes they regulate.

Finally, to determine how their lab findings might translate into human disease, Dr. Qian and colleagues screened more than 600 heart disease patients to find mutations in the gene that codes for Cdc42. They found one patient with a Cdc42 mutation that was not found in healthy control patients, suggesting that malfunctions in this pathway might impact human health.

“Our next goal is to look for more genes that interact with Tinman or with other factors that we know are important for the heart,” says Dr. Bodmer.

Fat and glucose metabolism is a target for Diabetes

“When mice  or people  eat too much fat, they become obese and increasingly resistant to insulin, an early sign of type 2 diabetes,” explained Dr. Julio Ayala, assistant professor at Sanford-Burnham’s Lake Nona campus.

This study proposes a new role for the Glp1 receptor in regulating the balance between fat and glucose metabolism, making it an attractive target for new diabetes therapies.

Diabetes results from a lack of functioning insulin, a hormone that stimulates cells to take up glucose (a type of sugar) from the bloodstream. Cells need glucose as fuel to produce energy. 

Type 1 diabetics lack insulin because their immune systems destroy the pancreatic cells that produce it. In type 2 diabetics, cells no longer respond properly to insulin. Either way, without sugar that can be converted to energy, cells starve and glucose levels build up in the blood, which can lead to life-threatening complications such as heart disease.

Given their roles in diabetes, it stands to reason that insulin and glucose metabolism must be carefully regulated in order to keep the body running smoothly. One way our bodies do this is by producing a hormone called glucagon-like peptide 1 (Glp1) after we eat. The gut secretes Glp1, which travels through the bloodstream and is received by receptors in the pancreas.  This boosts production of insulin, thus telling cells to take up more glucose from the blood.

Dr. Ayala believes that Glp1 does more than just stimulate the pancreas to produce insulin. He studies how this gut hormone also affects glucose metabolism in the liver and glucose uptake by muscle cells. He and his colleagues at Vanderbilt University and Mt. Sinai Hospital in Toronto published a study earlier this month in the journal Endocrinology that provides further evidence that the Glp1 receptor regulates not only the production of insulin, but also how well it works.

If normal mice are fed a high-fat diet, their muscle and liver cells eventually become resistant to insulin. In this study, the researchers wondered what would happen if mice engineered to lack the Glp-1 receptor were fed a diet high in fat. They found that disrupting the Glp1 receptor was actually beneficial. When compared to normal mice on a high-fat diet, mice missing the hormone receptor were better at taking up glucose in muscle cells and insulin resistance at the liver was reduced.  This was accompanied by a decrease in fat accumulation in the muscle and liver – hallmarks of insulin resistance.

“We hypothesized that disrupting Glp1 signaling in mice on a high fat diet would be a double whammy – we thought they would experience both increased fat accumulation and impaired insulin action at the liver,” Dr. Ayala said. “But to our surprise, we got the completely opposite result. These mice actually have improved insulin action at the liver.”

Afinitor (everolimus), a medication for PNET (progressive neuroendocrine tumors)

Afinitor (everolimus), a medication for patients with PNET (progressive neuroendocrine tumors) in the pancreas whose tumor cannot be surgically removed or whose cancer has metastasized (spread), has been approved by the Food and Drug Administration (FDA).

Afinitor (everolimus) is a cancer medication that interferes with the growth of cancer cells and slows their spread in the body.

Afinitor also lowers your body’s immune system. The immune system helps your body fight infections. The immune system can also fight or “reject” a transplanted organ such as a liver or kidney. This is because the immune system treats the new organ as an invader.

Afinitor is used to treat advanced kidney cancer. Afinitor is usually given after sorafenib (Nexavar) or sunitinib (Sutent) have been tried without successful treatment of symptoms.

Afinitor may also be used for other purposes not listed in this medication guide.

Most important: You should not use Afinitor if you are allergic to everolimus, sirolimus (Rapamune), tacrolimus (Prograf), or temsirolimus (Torisel), or if you have problems digesting lactose or galactose (sugar).

Before taking Afinitor, tell your doctor if you have a breathing disorder such as asthma or COPD, liver disease, diabetes, high cholesterol, or a history of skin cancer.

Do not receive a “live” vaccine while using Afinitor. The vaccine may not work as well during this time, and may not fully protect you from disease. Live vaccines include measles, mumps, rubella (MMR), oral polio, typhoid, chickenpox (varicella), BCG (Bacillus Calmette and Guérin), and nasal flu vaccine. There are many other drugs that can interact with Afinitor. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

To be sure Afinitor is not causing harmful effects, your blood will need to be tested often. Your liver and kidney function may also need to be tested. Visit your doctor regularly.

The most commonly reported side effects for Afinitor were stomatitis (inflammation of the mouth), rash, fatigue, diarrhea, edema, abdominal pain, fever, headache and nausea.

Afinitor is already approved for treating advanced renal cell carcinoma (kidney cancer) after the patient did not respond properly to Sutent or Nexavar. It is also administered to patients with a type of brain cancer (subependymal giant cell astrocytoma) whose tumor cannot be surgically removed.

Zortress, another trade name for Afinitor, is used as an immunosuppressant for kidney transplantation recipients.

Benadryl, good for Insomnia problem

Benadryl is used to treat sneezing; runny nose; itching, watery eyes; hives; rashes; itching; and other symptoms of allergies and the common cold.

Benadryl is also used to suppress coughs, to treat motion sickness, to induce sleep, and to treat mild forms of Parkinson’s disease.

Benadryl is an antihistamine. Diphenhydramine blocks the effects of the naturally occurring chemical histamine in the body.

Benadryl may also be used for purposes other than those listed in this medication guide.

Most important: Use caution when driving, operating machinery, or performing other hazardous activities. Benadryl may cause dizziness or drowsiness. If you experience dizziness or drowsiness, avoid these activities. Use alcohol cautiously. Alcohol may increase drowsiness and dizziness while taking Benadryl.

Apidra SoloStar for diabetes disease & Treatment

Apidra SoloStar is used to treat diabetes in adults and children who are at least 4 years old. It is usually given together with a long-acting insulin.
Apidra SoloStar is a hormone that is produced in the body. It works by lowering levels of glucose (sugar) in the blood. Apidra SoloStar is a faster-acting form of insulin than regular human insulin.

Apidra SoloStar may also be used for other purposes not listed in this medication guide.

Most important: Apidra SoloStar is a fast-acting insulin that begins to work very quickly. You should use it within 15 minutes before or 20 minutes after you start eating a meal.

Take care to keep your blood sugar from getting too low, causing hypoglycemia. Symptoms of low blood sugar may include headache, nausea, hunger, confusion, drowsiness, weakness, dizziness, blurred vision, fast heartbeat, sweating, tremor, or trouble concentrating. Carry a piece of non-dietetic hard candy or glucose tablets with you in case you have low blood sugar. Also be sure your family and close friends know how to help you in an emergency.

Also watch for signs of blood sugar that is too high (hyperglycemia). These symptoms include increased thirst, loss of appetite, increased urination, nausea, vomiting, drowsiness, dry skin, and dry mouth. Check your blood sugar levels and ask your doctor how to adjust your insulin doses if needed.

Never share an injection pen or cartridge with another person. Sharing injection pens or cartridges can allow disease such as hepatitis or HIV to pass from one person to another.

Apidra SoloStar is only part of a complete program of treatment that may also include diet, exercise, weight control, foot care, eye care, dental care, and testing your blood sugar. Follow your diet, medication, and exercise routines very closely. Changing any of these factors can affect your blood sugar levels.

Zoladex to treat prostate & Breast cancer

Zoladex is used in men to treat symptoms of prostate cancer, and in women to treat breast cancer or endometriosis. It is also used in women to prepare the lining of the uterus for endometrial ablation (a surgery to correct abnormal uterine bleeding).

If you are receiving Zoladex to treat prostate cancer, use any other medications your doctor has prescribed to best treat your condition. Goserelin treats only the symptoms of prostate cancer but does not treat the cancer itself.

Zoladex may also be used for other purposes not listed in this medication guide.

Most important: Zoladex can harm an unborn baby or cause birth defects and should not be used during pregnancy. Use effective non-hormonal (barrier) birth control during treatment and for at least 12 weeks after treatment ends. Tell your doctor right away if you become pregnant during treatment. Do not use Zoladex if you are pregnant or breast-feeding. You should not use this medication if you are allergic to goserelin or to similar hormone medications such as leuprolide (Lupron, Eligard, Viadur), nafarelin (Synarel), or ganirelix (Antagon). Do not use Zoladex if you are pregnant or breast-feeding.

Before you receive Zoladex, tell your doctor if you have osteoporosis, diabetes, urination problems, a condition affecting your spine, or if you have abnormal bleeding that your doctor has not checked.

Zoladex can decrease bone mineral density, which may increase your risk of developing osteoporosis. This risk may be greater if you smoke, drink alcohol frequently, have a family history of osteoporosis, or use certain drugs such as seizure medications or steroids. Talk to your doctor about your individual risk of bone loss.

Call your doctor at once if you have a serious side effect such as severe numbness or tingling in your legs or feet, muscle weakness, problems with balance or coordination, loss of bladder or bowel control, urinating more or less than usual, pain or burning when you urinate, feeling like you might pass out, pale skin, easy bruising, trouble breathing, chest pain or heavy feeling, or changes in heart rate.

If you are using Zoladex to treat prostate cancer, use any other medications your doctor has prescribed to best treat your condition. Zoladex treats only the symptoms of prostate cancer but does not treat the cancer itself.

Megace (Megestrol), Breast Cancer Drugs

Megace is used in the treatment of advanced breast cancer and endometrial cancer. Exactly how it works to treat loss of appetite and weight loss is unknown and it is also used to treat loss of appetite and weight loss because of disease. 

Megace is a man-made chemical similar to the female hormone progesterone.

Megace may also be used for purposes other than those listed in this medication guide.

Most important: Notify your doctor if you develop any side effects while taking Megace

Treatment Methods for Skin Cancer

Skin Cancer Treatment is dependent on type of cancer, location of the cancer, age of the patient, and whether the cancer is primary or a recurrence. One should look at the specific type of skin cancer (basal cell carcinoma, squamous cell carcinoma, or melanoma) of concern in order to determine the correct treatment required. 

An example would be a small basal cell cancer on the cheek of a young man, where the treatment with the best cure rate (Mohs surgery or CCPDMA) might be indicated.

 In the case of an elderly frail man with multiple complicating medical problems, a difficult to excise basal cell cancer of the nose might warrant radiation therapy (slightly lower cure rate) or no treatment at all. Topical chemotherapy might be indicated for large superficial basal cell carcinoma for good cosmetic outcome, whereas it might be inadequate for invasive nodular basal cell carcinoma or invasive squamous cell carcinoma. In general, melanoma is poorly responsive to radiation or chemotherapy.

For low-risk disease, radiation therapy (external beam radiotherapy or brachytherapy), topical chemotherapy (imiquimod or 5-fluorouracil) and cryotherapy (freezing the cancer off) can provide adequate control of the disease; both, however, may have lower overall cure rates than certain type of surgery.

Other modalities of treatment such as photodynamic therapy, topical chemotherapy, electrodessication and curettage can be found in the discussions of basal cell carcinoma and squamous cell carcinoma.

Mohs’ micrographic surgery (Mohs surgery) is a technique used to remove the cancer with the least amount of surrounding tissue and the edges are checked immediately to see if tumor is found. This provides the opportunity to remove the least amount of tissue and provide the best cosmetically favorable results. This is especially important for areas where excess skin is limited, such as the face. Cure rates are equivalent to wide excision. Special training is required to perform this technique. An alternative method is CCPDMA and can be performed by a pathologist not familiar with Mohs surgery.

In the case of disease that has spread (metastasized), further surgical procedures or chemotherapy may be required.

Scientists have recently been conducting experiments on what they have termed “immune- priming”. This therapy is still in its infancy but has been shown to effectively attack foreign threats like viruses and also latch onto and attack skin cancers. More recently researchers have focused their efforts on strengthening the body’s own naturally produced “helper T cells” that identify and lock onto cancer cells and help guide the killer cells to the cancer. Researchers infused patients with roughly 5 billion of the helper T cells without any harsh drugs or chemotherapy. This type of treatment if shown to be effective has no side effects and could change the way cancer patients are treated.

A cream used to treat pre-cancerous skin lesions also reverses signs of aging, a study released in April 2009 indicated. In March 2010 academics from Dundee University in Scotland announced they had devised a new, less-painful method of treating skin cancer, which could be administered from the home.

What causes Skin Cancer (Skin neoplasms) ?

The three most common skin cancers are basal cell cancer, squamous cell cancer, and melanoma, each of which is named after the type of skin cell from which it arises. Skin neoplasms are growths on the skin which can have many causes. 

Skin cancer generally develops in the epidermis (the outermost layer of skin), so a tumor is usually clearly visible. This makes most skin cancers detectable in the early stages. Unlike many other cancers, including those originating in the lung, pancreas, and stomach, only a small minority of those afflicted will actually die of the disease. In fact, though it can be disfiguring, except for melanoma, skin cancer is rarely fatal. Skin cancer represents the most commonly diagnosed cancer, surpassing lung, breasts, colorectal, and prostate cancer. 

Melanoma is less common than basal cell carcinoma and squamous cell carcinoma, but it is the most serious—for example, in the UK there are 9,500 new cases of melanoma each year, and 2,300 deaths. It is the most common cancer in the young population (20 – 39 age group). 

Most cases are caused by long periods of exposure to the sun. Non-melanoma skin cancers are the most common skin cancers. The majority of these are basal cell carcinomas. These are usually localized growths caused by excessive cumulative exposure to the sun and do not tend to spread.

Ultraviolet (UV) light exposure, most commonly from sunlight, is overwhelmingly the most frequent cause of skin cancer.

Other important causes of skin cancer include the following:

• Use of tanning booths
• Immunosuppression-impairment of the immune system, which protects the body from foreign entities, such as germs or substances that cause an allergic reaction. This may occur as a consequence of some diseases or can be due to medications prescribed to combat autoimmune diseases or prevent organ transplant rejection.
• Exposure to unusually high levels of x-rays
• Contact with certain chemicals-arsenic (miners, sheep shearers, and farmers), hydrocarbons in tar, oils, and soot (may cause squamous cell carcinoma)

The following people are at the greatest risk:

• People with fair skin, especially types that freckle, sunburn easily, or become painful in the sun
• People with light (blond or red) hair and blue or green eyes
• Those with certain genetic disorders that deplete skin pigment such as albinism, xeroderma pigmentosum
• People who have already been treated for skin cancer
• People with numerous moles, unusual moles, or large moles that were present at birth
• People with close family members who have developed skin cancer
• People who had at least one severe sunburn early in life

Basal cell carcinomas and squamous cell carcinomas are more common in older people. Melanomas are more common in younger people. For example, melanoma is the most common cancer in people 25-29 years of age.

The New Drug Approved for Advanced Skin Cancer

The drug was approved to treat melanoma tumors with a gene mutation called BRAF V600E. Zelboraf was not studied in melanoma cases that did not include this abnormal gene, the FDA said in a news release.

The drug was approved along with a novel diagnostic test called the cobas 4800 BRAF V600 Mutation Test, which helps determine if melanoma cells have the gene mutation, the FDA said.

Zelboraf (vemurafenib) has been approved by the U.S. Food and Drug Administration to treat a certain form of metastatic (spreading) melanoma, or cases that cannot be removed surgically, the agency said Wednesday.

Zelboraf, a BRAF inhibitor, was evaluated in a clinical study of 675 people with late-stage melanoma that included the mutated gene. Of those who received Zelboraf, 77 percent were still living as of the agency's news release, compared with 64 percent still living who took a different anti-cancer drug.

The most common side effects among those who took Zelboraf included joint pain, rash, hair loss, fatigue, nausea, and skin sensitivity to the sun. About 26 percent of those treated with Zelboraf developed a form of skin cancer called cutaneous squamous cell carcinoma, which was treated with surgery, the FDA said.

People treated with Zelboraf should avoid exposure to the sun, the agency advised.

Both the drug and the screening test are manufactured by member companies of the Roche Group, based in Switzerland.