The 9th Awards Term
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2015-2016
The topics of the 9th term, 2015-2016 were selected to be for Grand Hamdan International Award -Gastroenterology, and for Hamdan Award for Medical Research Excellence - Liver Disorders, Colon Disorders, Pancreatic Diseases

Topics

Gastroenterology

A pioneer in the investigation into the gastrointestinal system was the American physician William Beaumont (1785-1853), a student of the prestigious London and Edinburgh Universities. He worked in the Army Hospital in Fort Mackinok on the American-Canadian border where he saw a patient with an abdominal gunshot wound and a stomach fistula. Beaumont sought the permission of the patient to leave open the fistula to enable him to study the stomach and examine its contents. In July of 1822 Beaumont became the first to perform experiments in the physiology of digestion. As a result he was able to isolate hydrochloric acid from the stomach juice, and discover the connection between the stomach secretion and emotional changes and made the first attempt to describe stomach motility. He wrote a book entitled The Physiology of Digestion which at the time was seen as a breakthrough work in the field of experimental gastrology.

 

In the 19th century the foundations of a new physiological school were established. It happened mainly thanks to the support of French and German scientists who were connected with the greatest schools and institutes. In 1813, François Magendie (1783-1855), professor of pathology in College de France gave a detailed description of the swallowing and vomiting mechanism and in 1844 showed that food is first digested in the bowel and then is transported through the portal vein to the liver.

 

Claude Bernard (1813-1878), who was a student of Magendi, is known as the creator of

modern physiology, studied endocrine secretion, neurophysiology, the methodology of experiments and experimental pharmacology, which became new medical disciplines. Examining physiological function of the liver he discovered its ability to synthesize and store glycogen. In 1849 he performed the first glucose injection into the fourth chamber of the brain (so called the Claude Bernard injection), causing a rapid and significant increase in the blood sugar level, due to the sudden glycogenolysis in the liver. His very impressive achievements include, chronologically, the investigations of the enzymatic functions of the liver and the pancreas, the discovery of the digestive function of the pancreas (1856) and the reflux of the bowel contents to the pancreatic duct, which causes severe acute inflammatory changes in the gland.

 

The isolation of the spiral, rod bacterium, which is characteristic of gastric cancer and peptic ulcer disease, was another very important discovery made in 1889 by a Polish scientist, Professor  Walery Jaworski (1849-1924), of the Jagiellonian University. He called the newly discovered bacteria Vibrio rugula and also found them in the sediment of specimens from the gastric contents. In 1983 two Australian scientists from Royal Perth Hospital - Robin Warren and Barry Marshall - proved that the stomach mucosa could be colonized by the spiral bacteria named Helicobacter pylori which were capable of developing inflammatory changes and cause disturbances in the gastric juice secretion. Many other seminal discoveries were made including the proton pump by John Forte.

Colon Disorders

Medical works written by ancient Chinese civilization approximately 6000 years ago proposed different herbs to treat colonic cancer. There have been descriptions of causes, symptoms and treatments for colon cancer from the Middle Ages as well. The ancient Greek civilization from that timeline proposed olive oil for their colon health as a form of preventive care. Ancient Indian civilization also proposed mustard to treat diseases that had similar symptoms to the modern colon cancer.
 
 
 
.Aldred Scott Warthin, an American medical researcher and pathologist was the first person to discover the association between heredity and colon cancer in 1913. In the field of medical science, this discovery was officially known as the Lynch Syndrome I and II. Later Cuthbert Duke, a British medical researcher and pathologist discovered the development process of colon cancer. He also provided a classification system to describe the different level or stages of this colon cancer. This was considered as one of the most significant discovery on this disease.
 
 
 
Despite improvements in the treatment of colon cancer, detection often does not occur until the disease is in an advanced stage, which increases mortality. For instance, once colon cancer has spread to distal organs, the five-year survival is only approximately 12 percent. A recent study has established the TXA2 pathway’s importance in the development of colorectal cancer and lays the groundwork for introducing a strategy to target TXA2 for the prevention, early detection and management of this deadly disease. The TXA2 pathway is constitutively activated during colorectal carcinogenesis and is required for anchorage-independent growth of colon cancer cells. Overall, the results indicate that lowering circulating TXA2 levels or interfering with the TXA2 pathway might be a promising strategy for colorectal cancer prevention and/or treatment in the future.
 
 
 
Over the past decade, there has been increased interest in investigating molecular pathways that affect the activation and suppression of oncogenes, or genes with the potential to lead to cancer. Identification of oncogene signaling pathways may be particularly informative for altering their genetic transcription. In colon cancer, a family of transcription factors called GLI — and specifically GLI1 and GLI2 — have become a novel and potentially important focus of molecular research to possibly improve therapeutic intervention and hence prognosis. GLI1 and GLI2 are oncogenes, so when aberrantly activated, they can transform cells, can cause cancer, they drive proliferation and they turn on genes involved in cell growth. GLI 1 and 2 are activated in epithelial cancers, like GI cancer and colon cancer, as well as in lung cancers, pancreatic cancers, brain tumors, melanoma and pediatric solid cancers. GLI are located at the distal end of a signaling pathway called Hedgehog, which plays a vital role in embryonic cellular function and organ development and is expressed at low levels in adult tissues: two genes called KRAS and BRAF. These genes are mutated in colon cancer in about 50 percent of cases, and these directly activate GLI genes. So this could impact a wide variety of cancers because not only are GLI1 and 2 present in many cancers and constituently activated by KRAS, but KRAS mutations also are in one-third of all human cancers. People have been trying to develop inhibitors of KRAS, and it’s just been very elusive.
 
 
 
Given its prominent role in Hedgehog signaling and in oncogenic KRAS and BRAF function, a novel compound was investigated to directly target GLI, called GANT61. In seven human colon carcinoma cell lines, GANT61 successfully induced extensive cell death, thus inhibiting GLI transcription and oncogenic signaling via convergence on GLI.

Liver Disorders

Galen identified the gall bladder and spleen as the two crucial subsidiary organs of the liver. In the Middle Ages, the strength of the Galenic model of the body is amply apparent in descriptions of all three organs.  Calling the liver "the seat of the nutritive or vegetative faculties," the Islamic medical philosopher Ibn Sina (Avicenna) observed, "Physicians regard the liver as the seat of manufacture of the dense part of the humors."  He further specified the liver's uniquely heavy and moist condition as a function of the fact that the organ itself was nothing more than a dense concentration of blood rather than being made of actual tissue.  He also noted that the primary function of uroscopy -- reading urine -- was to understand the health of the liver.  Thus by the early eleventh century, medical practitioners had consolidated their views of the importance of the liver into an elaborate regime of diagnosis and therapy.
 
Between the 1640s and 1660s, increased numbers of animal vivisections allowed anatomists to look more closely at the relationship between the liver and the newly discovered lymphatic system.  In his Lymphatic Vessels (1653), the great Danish anatomist and discoverer of the lymphatic system, Thomas Bartholin,  confidently declared the end of the liver's role as "ruler of the abdomen" and the death of the "sanguine empire."  Bartholin ultimately decided that the role of the liver was to form bile rather than blood.  In 1654, the English physician Thomas Glisson was the first scholar to publish a book devoted exclusively to the Anatomy of the Liver.  
 
 Although it has long been recognized that a key event leading to development of type 2 diabetes is uncontrolled glucose production from the liver, underlying mechanisms have been elusive. aP2 has been identified as a novel hormone released from fat cells that controls this critical function. The communication system between adipose tissue and liver may have evolved to help fat cells command the liver to supply the body with glucose in times of nutrient deprivation. However, when the engorged fat cells lose control over this signal in obesity, the blood levels of aP2 rise, glucose is poured into the bloodstream and cannot be cleared by other tissues. The result is high blood glucose levels and type 2 diabetes. The majority of cases of type 2 diabetes are related to failure of insulin action in the body. However, for decades researchers and physicians have been faced with a conundrum: not all who are obese or resistant to insulin develop type 2 diabetes. In fact, many patients who are severely obese never develop the disease. As a result scientists have theorized that an unknown factor is involved in regulating glucose metabolism in the liver, and perhaps the presence or absence of this element might determine who gets the disease. The consequences of this discovery are profound, and the potential therapeutic applications by switching this protein off have the capability to reshape the way physicians treat diabetes.
 

Pancreatic Diseases

People probably think least about the pancreas. This lack of interest is not a new phenomenon: the pancreas was missed by early anatomists because it is deeply seated and lost in the fat of the mesentery; it was not studied by early physiologists because of the difficulty in accessing the pancreatic duct; it was not operated on by surgeons because of the extremely high mortality associated with pancreatic surgery; and it was not analyzed by molecular biologists because of inadequate numbers of specimens. The last two decades, however, has witnessed a revolution in our understanding of pancreatic diseases.
 
The history of the healthy pancreas goes back to the description of the organ by the Greek anatomist and surgeon Herophilus (335-280 BC), through the discovery of the pancreatic duct system by Johann Wirsüng (1642) and Giovanni Santorini (1681-1737), to the early descriptions of pancreas histology by Moyse and Langerhans. When Wirsüng sent a letter to his old teacher Riolan suggesting that he study the pancreatic duct, Riolan replied that he could not because of a shortage of hanged criminals! Similarly, the authors describe how Claude Bernard, the father of pancreatic physiology, was almost arrested when one of the dogs he was experimenting on escaped and its angry master called the police.
 
Trousseau described the association of pancreatic cancer with migratory thrombophlebitis, and he in fact made a self-diagnosis of pancreatic cancer after he himself developed migratory thrombophlebitis. Giovanni Morgagni, a pathologist associated with congenital diaphragmatic hernia, also was the first to describe pancreatic cancer in 1761. Allen Whipple was responsible for the 2-stage pancreatoduodenectomy which later evolved into 1-stage en bloc resection of the head of the pancreas. Scott Kern at Johns Hopkins discovered the pancreatic cancer gene DPC4 and helped discover the breast cancer gene (BRCA2) in a pancreatic cancer. 
 
The pancreas has been long ignored because of the difficulties inherent in studying this hidden organ. Nonetheless, diseases of the pancreas—including diabetes, pancreatitis, and pancreatic cancer—cause significant human suffering and death.
 

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