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Biotech / Medical : Ligand (LGND) Breakout! -- Ignore unavailable to you. Want to Upgrade?

To: DrJerry who wrote (15301)	2/19/1998 8:39:00 AM
From: Henry Niman	Respond to of 32384

Over the weekend there was a local news story in Pittsburgh on Leptin, but I just caught a few seconds. I suspect that the story came from the recent AAAS conference and the news summary mentioned both of LGND's approaches (controling leptin levels and signaling), but Ligand was not mentioned by name: techstocks.com

To: DrJerry who wrote (15301)	2/19/1998 8:49:00 AM
From: Henry Niman	Respond to of 32384

This is from the CBS news website today: Every year, millions of Americans battle with their weight. Some people are just a few pounds over the line, while others may have a more serious weight problem. What causes people to be overweight? An important new study with lab rats may prove that hormones are the cause. Watch the CBS Evening News with Dan Rather tonight at 6:30PM, ET, 5:30 CT/PT. Check your local listings.

To: DrJerry who wrote (15301)	2/19/1998 9:01:00 AM
From: Henry Niman	Respond to of 32384

Here's a description of the AAAS session on obesity: Obesity Update: Molecular Biology of Energy Regulation and Implications for Treatment and Public Policy Friday, February 13, 9:00am-12:00noon, Convention Center, Room TBA Organized by M. R. C. Greenwood, University of California-Santa Cruz SYNOPSIS Obesity is a major public health problem in the United States, affecting approximately 30% of the population. It is associated with co-morbidities such as Type II diabetes, hypertension, cardiovascular disease and some forms of cancer. It is notoriously difficult to treat successfully with a high rate of recidivism. Recent discoveries in obese animal models of genes that are involved in energy regulation have led to renewed optimism that new treatment options are on the horizon. Recent organized efforts by public advocacy groups and government policy makers emphasize the critical importance of providing physicians and other health professionals with guidelines for treatment and follow-up to reduce the human and economic cost to the nation. This symposium reviews the latest information on genes and their products that are involved in energy regulation and that are altered in obese animals and humans. Speakers will discuss prospects for new clinical approaches based upon these research findings. Speakers will review current efforts to provide guidance to physicians and health care professionals in respect to treatment of obese individuals.

To: DrJerry who wrote (15301)	2/19/1998 9:35:00 AM
From: Henry Niman	Respond to of 32384

Still looking for a recent Rat/Leptin article, but the current issue of Science has a paper advancing understanding in LGND's other core technology, STATs: Structure of the Amino-Terminal Protein Interaction Domain of STAT-4 Uwe Vinkemeier, Ismail Moarefi, * James E. Darnell Jr., John Kuriyan STATs (signal transducers and activators of transcription) are a family of transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors. The crystal structure of an NH2-terminal conserved domain (N-domain) comprising the first 123 residues of STAT-4 was determined at 1.45 angstroms. The domain consists of eight helices that are assembled into a hook-like structure. The N-domain has been implicated in several protein-protein interactions affecting transcription, and it enables dimerized STAT molecules to polymerize and to bind DNA cooperatively. The structure shows that N-domains can interact through an extensive interface formed by polar interactions across one face of the hook. Mutagenesis of an invariant tryptophan residue at the heart of this interface abolished cooperative DNA binding by the full-length protein in vitro and reduced the transcriptional response after cytokine stimulation in vivo. U. Vinkemeier, Laboratory of Molecular Cell Biology and Laboratories of Molecular Biophysics, The Rockefeller University, New York, NY 10021, USA. I. Moarefi and J. Kuriyan, Howard Hughes Medical Institute and Laboratories of Molecular Biophysics, The Rockefeller University, New York, NY 10021, USA. J. E. Darnell Jr., Laboratory of Molecular Cell Biology, The Rockefeller University, New York, NY 10021, USA. * Present address: Max-Planck-Institut fr Biochemie, Abteilung fr Zellul„re Biochemie, Am Klopferspitz 18, 82152 Martinsried, Germany. To whom correspondence should be addressed. E-mail: kuriyan@rockvax.rockefeller.edu

To: DrJerry who wrote (15301)	2/19/1998 5:05:00 PM
From: Henry Niman	Respond to of 32384

Hven't found much rat/leptin news (otther than AAAS convention). Here's one fairly recent paper: Leptin Causes Death Of Fat Cells ATHENS, GA. -- October 21, 1997 -- A team of researchers at the University of Georgia are the first to determine that the hormone leptin causes the programmed death of fat cells rather than simply reducing them in size. Their discovery helps explain why rats injected with leptin stay thin long after treatment has stopped, and could play a significant role in the use of leptin for the treatment of obesity, according to Clifton Baile, professor of foods and nutrition and animal science at UGA. Research on leptin has exploded in the two years since it was first discovered by Rockefeller University researchers. The hormone is produced by the body's fat cells and travels through the blood stream to the brain. Animals treated with leptin eat less, lose weight and expend energy at a higher rate. Pharmaceutical companies have invested hundreds of millions in research on the use of leptin to treat obesity and it's expected leptin-based medication will be available within five years. The UGA team's findings about leptin's effect on fat cells began after the arrival of Dr. Hao Qian, a post-doctoral fellow who joined UGA a year ago after spending several months researching apoptosis -- programmed death -- of cells in the spinal cord following spinal-cord injuries. In general, apoptosis is a routine process that occurs in most tissues. It is what causes leaves to fall from the trees in autumn and how the body eliminates diseased or unnecessary cells, such as a mother's milk-secreting mammary cells after a baby is weaned. Apoptosis was first introduced in the scientific literature in 1972. However, extensive research on the role it plays in a variety of organisms didn't begin until 1992, which explains why Qian's hypothesis about leptin's role in the destruction of fat cells was so novel. "When Hao first suggested that the fat cells' reaction to leptin looked like apoptosis, we didn't think he was right," Baile said. However, the team developed a series of experiments to test the hypothesis. In their research, the UGA scientists injected one group of rats with leptin, a second group was placed on a low-calorie diet, while a third was given normal amounts of food and not treated with leptin. In comparing the DNA of the fat cells of rats treated with leptin and the control groups, the fat cells of the leptin-treated rats clearly showed apoptosis. The DNA of the rats on the low-calorie diet and the control group failed to show any signs of apoptosis. "The only cells affected in the leptin-treated rats were the fat cells," Baile said. "Cells in the liver, kidney and heart, as well as both smooth and skeletal muscle were not affected. This was true in male and female rats, young rats and older rats. "A problem with most treatments for obesity is that once the treatment is stopped, the individual begins gaining weight almost immediately. However, with leptin, that's not the case." Baile said it takes weeks for the leptin-treated rats to recover the fat they lose. "We have had trouble finding any fat cells in rats within five days of treatment," he said. The scientists will present their results Oct. 27-28, 1997 in San Diego, CA. at the Annual Conference on Apoptosis. Some of the research also was presented at a September workshop sponsored by the National Institutes of Health that focused on the brain and fat cells.

To: DrJerry who wrote (15301)	2/19/1998 5:08:00 PM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Here's another one (it supports LGND's leptin signaling program): J Clin Invest 1997 Dec 1;100(11):2858-2864 Direct effects of leptin on brown and white adipose tissue. Siegrist-Kaiser CA, Pauli V, Juge-Aubry CE, Boss O, Pernin A, Chin WW, Cusin I, Rohner-Jeanrenaud F, Burger AG, Zapf J, Meier CA Unite de Thyroide, Division d'Endocrinologie et Diabetologie, Hopital Universitaire de Geneve, Geneva, Switzerland. Leptin is thought to exert its actions on energy homeostasis through the long form of the leptin receptor (OB-Rb), which is present in the hypothalamus and in certain peripheral organs, including adipose tissue. In this study, we examined whether leptin has direct effects on the function of brown and white adipose tissue (BAT and WAT, respectively) at the metabolic and molecular levels. The chronic peripheral intravenous administration of leptin in vivo for 4 d resulted in a 1.6-fold increase in the in vivo glucose utilization index of BAT, whereas no significant change was found after intracerebroventricular administration compared with pair-fed control rats, compatible with a direct effect of leptin on BAT. The effect of leptin on WAT fat pads from lean Zucker Fa/ fa rats was assessed ex vivo, where a 9- and 16-fold increase in the rate of lipolysis was observed after 2 h of exposure to 0.1 and 10 nM leptin, respectively. In contrast, no increase in lipolysis was observed in the fat pads from obese fa/fa rats, which harbor an inactivating mutation in the OB-Rb. At the level of gene expression, leptin treatment for 24 h increased malic enzyme and lipoprotein lipase RNA 1.8+/-0.17 and 1.9+/-0.14-fold, respectively, while aP2 mRNA levels were unaltered in primary cultures of brown adipocytes from lean Fa/fa rats. Importantly, however, no significant effect of leptin was observed on these genes in brown adipocytes from obese fa/fa animals. The presence of OB-Rb receptors in adipose tissue was substantiated by the detection of its transcripts by RT-PCR, and leptin treatment in vivo and in vitro activated the specific STATs implicated in the signaling pathway of the OB-Rb. Taken together, our data strongly suggest that leptin has direct effects on BAT and WAT, resulting in the activation of the Jak/STAT pathway and the increased expression of certain target genes, which may partially account for the observed increase in glucose utilization and lipolysis in leptin-treated adipose tissue. PMID: 9389752, UI: 98052590

To: DrJerry who wrote (15301)	2/19/1998 6:43:00 PM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Dan Rather just did the teaser for the obesity story, but CBS Evening news isn't on until 7:00 EST in Pittsburgh.

To: DrJerry who wrote (15301)	2/20/1998 12:14:00 AM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Here's the AP version of the CBS report: By Daniel Q. Haney The Associated Press B O S T O N, Feb. 19 - Scientists believe they have found the brain's hunger hormone, the stuff that triggers the overwhelming urge to say, "Another helping of mashed potatoes, please. And lots of gravy!" The discovery is likely to start a stampede of research intended to find medicines that can rein in this substance and help people say no to food. The researchers were led by Dr. Masashi Yanagisawa of Howard Hughes Medical Institute at the University of Texas Southwestern Medical Center. They are reporting the finding in Friday's issue of the journal Cell. The scientists called their discovery "orexin," a play on "orexis," the Greek word for hunger. "We believe that orexin is one of the important pathways in the regulation of hunger," said Yanagisawa. Come From Familiar Part of Brain The researchers found that two varieties of orexin are made by nerve cells in the lateral hypothalamus, a part of the brain already known to play a role in appetite. "It's an absolutely beautiful piece of work," said Dr. Jeffrey Friedman of Rockefeller University, "a very thorough and technically elegant set of studies that identify two new players in the system that controls weight." The work suggests that the brain churns out orexin when it senses a need to eat, such as after a drop in sugar levels in the blood. The same substance appears to be at work in rats as well as probably many other creatures. This allows the scientists to test its effects. They gave orexin to lab rats and found it made them ravenous. For an hour or two, they ate eight to 10 times more food than they ordinarily would. They also checked the brains of rats that had not eaten in a day and found that their orexin levels had gone up. An Eat-Don't Eat Feedback Loop "It really makes a nice feedback loop to regulate your appetite," said Yanagisawa. He said the possibility of harnessing this discovery to combat eating problems-both lack of appetite and its far more common opposite-are already being investigated by scientists at SmithKline Beecham Pharmaceuticals, which collaborated on the discovery. He said it should be possible to create drugs that mimic orexin and make people eat more. This could be helpful for cancer patients and others who have illnesses that rob their appetites. Even more important, perhaps, would be using this discovery to make drugs for treating obesity. The scientists know the exact spot on the surface of cells in the brain where orexin does its business. So it should also be possible to create medicines that block these spots, called receptors, so orexin cannot get in and trigger the munchies. The scientists believe many hormones besides orexin are involved in both creating and suppressing appetite. Leptin Already Known to be Factor One of these is leptin, an appetite-suppressing protein made by fat-filled adipose cells. While leptin is supposed to signal the brain to stop eating, the signal somehow does not get through properly in overweight people. Yanagisawa said that leptin-or the lack of it-could be one of the signals that triggers the brain to make orexin and whet the appetite. The discovery was made through a relatively new process called reverse endocrinology. Traditionally, scientists discover a hormone and then try to figure out what it does by searching for the receptor that it attaches to. In this case, however, the scientists discovered the receptor but had no idea what hormone acted on it or what it did. Working with the receptor, they figured out which protein fit into it. Still, they did not know at first that it was involved in appetite. Their first clue was the discovery that the protein was a hormone made by particular nerve cells in the hippocampus. "As soon as we saw the striking distribution of these neurons in that part of the brain, we guessed these hormones were doing something important in determining how much you eat," he said.

To: DrJerry who wrote (15301)	2/20/1998 6:48:00 AM
From: Henry Niman	Respond to of 32384

Here's the Reuter's version of the CBS News report: Study finds new hormones that affect appetite February 19, 1998 Web posted at: 6:20 p.m. EST (2320 GMT) BOSTON (Reuters) -- Texas researchers have found two new hormones that seem to influence eating behavior and could lead to new treatments for obesity and help adults with diabetes control the disease. The scientists' finding is published in Friday's issue of Cell magazine. "It could also be of value for people suffering from the effects of emaciation such as cancer patients or AIDS patients," said Dr. Masashi Yanagisawa of the University of Texas Southwestern Medical Center at Dallas. The hormones, dubbed orexin-A and orexin-B, are released by nerve cells in the region of the brain known to play a key role in appetite. When Yanagisawa and his colleagues injected the hormones into the brains of rats, the animals began eating more. When they starved the animals, brain levels of the hormones increased. The team also pinpointed proteins studding the surface of nerve cells that react to the presence of orexin-A and orexin-B. That reaction sparks a chemical cascade that affects eating behavior. Finding a way to prevent or slow the release of the hormones, or blocking the protein receptors that are sensitive to them could lead to a new way to control appetite. The process could also be turned around to encourage eating in people who have become dangerously thin. Weight control is believed to be important for preventing or controlling a host of health problems, the most prominent of which are heart disease and the form of diabetes that appears in adulthood. "For the treatment of adult diabetes, one of the most important aspects is to lose weight," Yanagisawa said. The team is now trying to genetically engineer rats that lack one of the orexin hormones and both protein receptors to see if the defect affects their appetites. Yanagisawa said researchers at SmithKline Beecham were already trying to create an oral medicine that will block the protein receptors. The newly discovered hormones are two of about a dozen chemicals in the body known to affect eating behavior, Yanagisawa said. Whether the two forms of orexin are more important than the others "is something we have to study from now on," he said. The hormones get their name from the Greek word orexis, which means appetite.

To: DrJerry who wrote (15301)	2/20/1998 6:49:00 AM
From: Henry Niman	Respond to of 32384

Here's the Title and Authors of the Cell paper: Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior Takeshi Sakurai, Akira Amemiya, Makoto Ishii, Ichiyo Matsuzaki, Richard M. Chemelli, Hirokazu Tanaka, S. Clay Williams, James A. Richardson, Gerald P. Kozlowski, Shelagh Wilson, Jonathan R. S. Arch, Robin E. Buckingham, Andrea C. Haynes, Steven A. Carr, Roland S. Annan, Dean E. McNulty, Wu-Schyong Liu, Jonathan A. Terrett, Nabil A. Elshourbagy, Derk J. Bergsma, and Masashi Yanagisawa