PHILADELPHIA INTERNATIONAL MEDICINE® NEWS BUREAU
Contact: Leonard N. Karp
lkarp@philadelphiamedicine.com
215-735-3989
In this month's edition of the PIM News Bureau:
1. Children's Hospital Team Successful in Treating Focal Congenital Hyperinsulinism
2. Temple Study: Rb2 Gene May Play Significant Role in Determining Effectiveness of Drug Therapies Against Breast Cancer
3. Penn Researchers Breed Most to Model "Jumping Genes"
Children's Hospital Team Successful in Treating Focal Congenital
Hyperinsulinism
Philadelphia - Researchers from The Children's Hospital of Philadelphia successfully cured 91 percent of infants of a rare but serious condition called focal congenital hyperinsulinism (HI). In this condition, excess levels of insulin cause low blood sugar, which may lead to irreversible brain damage in children. Children's Hospital is a member of Philadelphia International Medicine®.
Using a team approach combining medical tests, operative biopsies and precise, technically demanding surgery, the physicians were able to cure newborns of focal congenital HI without causing diabetes, a common complication of conventional HI surgery.
N. Scott Adzick, MD, surgeon-in-chief at The Children's Hospital of Philadelphia, described this research today at the annual meeting of the American Pediatric Surgical Association.
Dr. Adzick reported results from a study of 34 children with a median age of
7 weeks who underwent surgery from 1999 to 2002 at The Children's Hospital of
Philadelphia. As determined by both preoperative testing and an operative
biopsy, all the children had the focal form of congenital HI, in which the
abnormal tissue is confined to a limited area of the pancreas, the organ that
produces insulin.
Of the 34 patients, 31 did not subsequently require medication to control their
insulin levels. The remaining three children continued to require medical
treatment for low blood sugar, but like all 34 patients, did not develop
diabetes.
Both HI and diabetes involve an imbalance of insulin: hyperinsulinism results from excess insulin; diabetes from insufficient insulin. While some forms of HI in infants are transient and relatively common, congenital HI is a rare genetic disease, with several subtypes, based on specific mutations.
The most severe forms of congenital HI affect an estimated 100 to 200 infants annually in the U.S. Of that number, approximately two-thirds may have the focal type, as found by the Children's Hospital team.
The Children's Hospital team uses medical tests performed by interventional radiologists to guide the diagnosis and the delicate surgery on the infant's pancreas, an organ the size of an adult's little finger.
The surgical team performed a partial pancreatectomy, removing the diseased portion of the pancreas while leaving the rest of the organ intact. In contrast, in the other form of congenital HI, diffuse HI, abnormal tissue permeates the pancreas, and 98 percent of that organ must usually be removed. This near-total pancreatectomy leaves the child at risk for diabetes.
At most centers where surgery is performed for HI, near-total pancreatectomies are the norm, because physicians are unable to accurately differentiate between diffuse and focal HI. Children's Hospital is the only center in the United States, and one of only two in the world, to perform partial pancreatectomies for focal HI.
The physicians use interventional radiology techniques to help distinguish focal HI from diffuse HI before the surgery. These are selective stimulation and sampling of blood vessels in different parts of the pancreas to help pinpoint the location of the abnormal cells. During the surgery, they use pancreatic biopsies, analyzed rapidly by a pathologist, to confirm that diseased tissue is removed.
"We draw on the talents of a full team -- pediatric endocrinologists, radiologists, pathologists and surgeons -- to achieve these results," said Charles A. Stanley, MD, chief of Endocrinology at Children's Hospital. "This team approach enables us to distinguish focal disease from diffuse disease, identify the specific site of the focal lesion and perform a surgical cure for the vast majority of children with focal hyperinsulinism."
Dr. Adzick's and Dr. Stanley's co-authors from The Children's Hospital of Philadelphia were Robin D. Kaye, MD, chief of Interventional Radiology; and Eduardo Ruchelli, MD, an attending pathologist.
Temple Study: Rb2 Gene May Play Significant Role in Determining Effectiveness
of Drug Therapies Against Breast Cancer
The tumor suppressing gene pRb2/p130 may play a significant role in determining the effectiveness of drug therapies against breast cancer in women, according to a study by researchers at Temple University's Sbarro Institute for Cancer Research and Molecular Medicine. Temple University Hospital is a member of Philadelphia International Medicine.
The study, "pRb2/p130-E2F4/5-HDAC1-SUV39H1-p300 and
pRb2/p130-E2F4/5-HDAC1-SUV39H1-DNMT1 Multimolecular Complexes Mediate the
Transcription of Estrogen Receptor-a in Breast Cancer," was presented at an
international scientific lecture June 5 by Antonio Giordano, MD, PhD, director
of the Sbarro Institute. It will also be published in the June 5 issue of
Oncogene (http://www.nature.com/onc/).
In the study, led by Dr. Giordano, researchers at the Sbarro Institute looked at the estrogen receptor gene alpha, which plays a crucial role in normal breast development in women and has been linked to the development and progression of mammary carcinoma, or breast cancer.
The study found that in estrogen receptor-positive and estrogen receptor-negative mammary cell lines of women who have been affected with breast cancer, pRb2/p130 binds with the estrogen receptor gene alpha and sends out signals to engage or recruit a number of molecules.
"These key molecules together are recruited by pRb2/p130 onto the receptor gene alpha, which when expressed on mammary cell lines makes the breast tumors more responsive to treatment," says Dr. Giordano, who discovered the Rb2 gene while working at Temple's Fels Cancer Institute in the early 1990s.
The researchers discovered that in estrogen receptor-negative cell lines, pRb2/p130's signal is damaged or mutated and it recruits a different sequence of molecules which cause Rb2 to silence the expression of the estrogen receptor and block drug therapies from being successful against the cancer cells.
"There is a lack of success in therapies because the drug does not recognize the tumor cells anymore," says Dr. Giordano. "It cannot distinguish between the good cells and the bad cells. One gene on its own doesn't mean anything," he adds. "It's the dialogue among the genes that are writing the sentences, and this finding really writes a very important sentence in the book that we are authoring on uncovering the understanding of how a normal cell functions and why some therapies work or some therapies don't work. It also clearly shows that cancer is not the event of one gene, but an army of genes and it looks like pRb2/p130 is one of the generals."
"During the development of cancer, many genes that suppress the transformation of normal cells to a malignant cell are inactivated or shut off. In this regard, Dr. Giordano's group has made a very important discovery on how the estrogen receptor alpha gene is shut off in breast cancer cells," says Dr. Richard L. Momparler, professor of pharmacology at the University of Montreal and Research Center, Hôpital Sainte-Justine. "This gene plays a key role in dictating the response to therapy in women with breast cancer. A better understanding of how gene inactivation occurs in tumor cells can lead to the design of more effective therapy and early diagnosis of breast cancer."
Giordano, who was joined in this study by lead author Dr. Marcella Macaluso, a research associate at the Sbarro Institute and a member of the Center for the Biomolecular Characterization of Neoplasms and Genetic Screening of Hereditary Tumors at the University of Palermo, says the next step for researchers is to figure out how they can restore pRb2/p130's correct communication or dialogue with the molecules in order to have the estrogen receptor alpha correctly expressed on the tumor cells. By understanding this mechanism of how Rb2 recruits molecules, he says, researchers will be able to eventually design drugs that are very precise in the target they recognize.
Penn Researchers Breed Most to Model "Jumping Genes"
Researchers at the University of Pennsylvania School of Medicine have bred a
mouse to model human
L1 retrotransposons, the so-called "jumping genes." The University of
Pennsylvania Medical Center is a member of Philadelphia International Medicine.
Retrotransposons are small stretches of DNA that are copied from one location in the genome and inserted elsewhere, typically during the genesis of sperm and egg cells. The L1 variety of retrotransposons, in particular, are responsible for about one third of the human genome.
The mouse model of L1 retrotransposition is expected to increase our understanding of the nature of jumping genes and their implication in disease. According to the Penn researchers, the mouse model may also prove to be a useful tool for studying how a gene functions by knocking it out through L1 insertion. Their report is in the December issue of Nature Genetics and currently available online.
"There are about a half million L1 sequences in the human genome, of which 80 to 100 remain an active source of mutation," said Haig H. Kazazian, Jr., MD, chair of Penn's Department of Genetics and senior author in the study. "This animal model will help us better understand how this happens, as well as provide a useful tool for discovering the function of known genes."
In humans, retrotransposons cause mutations in germ line cells, such as
sperm, which continually divide and multiply. Like an errant bit of computer
code that gets reproduced and spread online, retrotransposons are adept at being
copied from one location and placed elsewhere in the chromosomes. When
retrotransposons are inserted into important genes, they can cause disease,
such as hemophilia and muscular dystrophy. On the other hand, retrotransposons
have been around for 500 to 600 million years, and have contributed a lot to
evolutionary change.
"In the grand scheme of evolution, retrotransposons have behaved like fickle gods, arbitrarily wreaking havoc in some and benefiting others," said Dr. Kazazian. "Retrotransposons can cause new genes to emerge that may benefit an organism - or they can kill by knocking out important genes. Overall, however, it seems that they are neutral and add to the apparent sloppiness of the genome."
For some time, researchers have been trying to understand how retrotransposons affect the genome and, in addition, what science may learn from the techniques they employ. According to Dr. Kazazian and his colleagues, the mouse model displays high-frequency chromosome to chromosome retrotransposition of human L1s, which behave in exactly the same way as they do in humans. While the current tissue culture model works well, it does not mimic the way retrotransposons jump in chromosomes.
The researchers believe that by understanding the mechanics of retrotransposition, they might be able to use similar techniques for genetic therapies in humans. They also hope to learn more about the basic mysteries behind retrotransposition, such as why L1 retrotransposons only seem to effect the germ line and not any other type of cell in the body.
As science refines the content of the mouse genome database, Dr. Kazazian foresees that this model will also be useful for determining the function of different genes. As new genes are identified, their purpose can be resolved by using retrotransposons to knock them out of commission. "Such knowledge has direct impact in humans," said Dr. Kazazian, "Information important to determining the nature of human diseases and developing new therapeutics can be extrapolated from our knowledge of the mouse genome."
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