The Washington Post – For those who say that learning history can be dull, Making History: The Calm & the Storm attempts to rebut that by transporting players into leadership roles in the 1930s and ’40s. The original game only allows you to lead the major combat nations of World War II, but a recent patch allows almost any nation to be played.

You control almost every aspect of your chosen nation, including economic and production goals, scientific research, military strategy, foreign relations, world trade, infrastructure investment and its economy.

You’ll quickly learn that the geopolitical climate before World War II was not easy to navigate. Sure, you may want to take a stab at Germany before the Nazis begin their rampage, but they are already fairly strong. Nations that could oppose them directly, such as France, are in a terrible recession, so supporting a grand army isn’t really possible. Plus, nobody really wants to ally with anyone else. Instead, every nation is looking out for its own interests. That may seem shortsighted, but it makes perfect sense when you see the scenario unfolding.

Say you are playing Italy. England and France are your friends initially, but Germany’s emerging fascist government has borrowed many of your ideals. And requests for aid from fascists fighting a civil war in Spain can’t be ignored, even though that may weaken ties with friendly nations. It’s easy to see how Italy could be lured into the Axis sphere of power.

Or you could play as Germany or Japan. Perhaps you won’t attack right away, because diplomacy might be more useful at first. Perhaps you won’t strike at all, though playing a peaceful Germany or Japan is a sure route to a crashing economy, as you will find out if you try.

Making History is turn-based, so you won’t feel rushed to make decisions. Each turn represents one week, so it may take many turns to move armies and fleets, or to produce new units. As in real life, time often is not on your side.

Given the detailed economy and diplomacy interface, it’s surprising to find that combat is somewhat simplistic. It’s basically a numbers game with little player interaction once begun.

Making History isn’t the best war game, but it’s one of the best titles for learning why wars happen.
— John Breeden II

Making History: The Calm and the Storm; PC Windows XP/2000/Vista ($40)

North America CEO George Abercrombie discusses global and corporate preparedness.

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Mushrooms, ranging from the portobello to the cremini and white button, all contain beta-glucans, which can strengthen your ability to fight off a cold. The theory is that they help the immune system recognize and destroy disease-causing cells, says Chicago-based registered dietitian David Grotto. Mushrooms make a great side dish or addition to a stir fry.

Best Cold- And Flu-Fighting Foods

By Allison Van Dusen, January 23, 2008, – Every new year, Lisa Hark finds herself waiting for her kids at the bus stop with a bunch of other moms, most of whom have colds. Hark, on the other hand, can’t remember the last time she was sick.

Her secret? Hark, longtime director of the Nutrition Education and Prevention Program at the University of Pennsylvania School of Medicine, credits, in part, her well-balanced diet. She regularly eats a variety of citrus fruits and lean protein, which she says helps her immune system stay strong.

Seems she’s on to something. As colds and the flu make the rounds at your office this winter, Hark and other nutrition experts say there’s no reason to assume getting sick is inevitable. By regularly incorporating certain foods into your meals, in addition to maintaining good hygiene and an exercise regimen, you may be able to stave off illness or, at the least, shorten its duration.

“If we take a look at the common cold and influenza, these are bugs that we’ve been using drugs somewhat ineffectively to fight,” says David Grotto, a Chicago-based registered dietitian and author of 101 Foods That Could Save Your Life. “Now there’s really good research that shows foods can help with fighting virulent strains of bacteria.”
Grotto, who makes house calls for clients seeking nutrition makeovers, says eating foods such as cremini, portobello or white button mushrooms and barley can have a real impact. Sources of beta-glucan, they support the immune system. If you’re looking for an antibacterial boost, pour on the garlic. It contains phytochemicals, such as allicin, which can kill bacteria.

Top Superfoods

It turns out that many of the foods mom made when you were sick also can help you fight off a cold. Tea with honey is a combo that packs antibacterial and antiviral polyphenols and can aid in treating a sore throat or bacterial infection, Grotto says. Warm broth, full of phytochemicals leaked by steeping vegetables, may have antibacterial properties, too.

One way to make sure you’re getting enough of these types of foods in your diet is to avoid skipping meals, Hark says. If you always eat breakfast, you can regularly aid your immune system by eating oats. Skip it and you’re not giving yourself the fuel you need to recover from an overnight fast, potentially compromising your ability to fight off infection. When you’re feeling run down, you’re also more likely to grab whatever is available to keep you going, such as a nutritionally lacking donut, creating a vicious circle of bad eating.

.If you’re spending most of your time eating out, order a side salad packed with spinach leaves–not a Caesar. Skip the side of pasta and order a double helping of colorful veggies. Going out for drinks? Hark suggests having a screwdriver, which will at least give you a dose of vitamin C. While it’s not clear how much of an impact vitamin C has on the common cold, it is an antioxidant that the body uses to stay healthy.

What’s more, by adding nutritious fare to your diet, you might be getting a bigger benefit than you realize. Research is beginning to show that when some foods are combined they produce a healthy synergy, says Wendy Bazilian, a doctor of public health, registered dietitian and author of The SuperFoodsRx Diet. Pairing a tomato with a bit of olive oil, for instance, may improve absorption of the antioxidant lycopene, a powerful antioxidant that’s been demonstrated to have protective properties.

Susan Atkins, 50, a San Diego-based accountant, has been following a diet full of disease-fighting, healthy “superfoods,” such as peppers, nuts, grains and sweet potatoes, since May. Not only has the switch eliminated her acid reflux and gastrointestinal problems, but it’s also given her a lot more energy.

“Within a week,” she says, “I noticed a difference.”

But if you can’t stand cabbage, don’t force yourself to eat it just to keep a cold away. Focus on adding healthy foods you like to your diet. Many experts believe that the act of enjoying your food also can have a therapeutic effect on the body.
“Go for convenience, accessibility and, first and foremost,” Grotto says, “it’s got to taste good.”

List of Best Cold and Flu Fighting Foods

Virtually calorie-free, inexpensive and readily available, tea is full of polyphenols, which are protective antioxidants. Polyphenols are antibacterial, antiviral and act as anti-inflammatories, says Wendy Bazilian, a doctor of public health, registered dietitian and author of The SuperFoodsRx Diet. If you want to get the most out of your cup, be aware that milk may interfere with the absorption of disease-fighting catechins, says Chicago-based registered dietitian David Grotto.

It may not be good for your breath, but garlic is great for your body. That’s because it contains the phytochemicals that kill bacteria, soak up cholesterol and fight cancer, says David Grotto, a Chicago-based registered dietitian and author of 101 Foods That Could Save Your Life. To get the most out of your cloves, peel, crush and cut them, then let them sit for 15 minutes before cooking.

Mushrooms, ranging from the portobello to the cremini and white button, all contain beta-glucans, which can strengthen your ability to fight off a cold. The theory is that they help the immune system recognize and destroy disease-causing cells, says Chicago-based registered dietitian David Grotto. Mushrooms make a great side dish or addition to a stir fry.

Full of fiber, oats contain vitamins E and B, a number of minerals and immune system-boosting beta-glucans. They’ve been used to address everything from stomach discomfort and digestive ailments to cholesterol, says David Grotto, a Chicago-based registered dietitian and author of 101 Foods That Could Save Your Life. To up your intake, sneak oats into your meatloaf or meatballs or use them in chicken breading.

They’re not always easy to find but they’re worth the trouble. Elderberries contain more vitamin C than most fruits. They’re also packed with phytochemicals that have anti-inflammatory, antiviral and cancer-fighting properties, says Chicago-based registered dietitian David Grotto. Juice from these berries is also a traditional cold remedy. Grotto suggests adding elderberries to an apple pie.

A source of vitamin C, fiber and phytochemicals known as glucosinolates, cabbage is thought to prevent cancer and heal ulcers. Scientists also have reported that the leafy vegetable has helped animals recover from viruses, says David Grotto, a Chicago-based registered dietitian and author of 101 Foods That Could Save Your Life. Although it’s high in sodium, try adding sauerkraut to your hot dog to offset its processed contents.

Full of antioxidants, honey has long been used to help treat sore throats and other bacterial infections. It also can assist in the growth of friendly bacteria, improving gut health, and some research has shown it may help fight cancer, says Chicago-based registered dietitian David Grotto. Sneak more honey in your diet by using it to replace sugar in tea and coffee.

Whey Protein
It’s not just for body builders. Whey protein is full of branched chain amino acids, which aid in muscle repair and development, says Chicago-based registered dietitian David Grotto. Studies also have shown it can enhance the immune system, neutralizing the effects of free radicals. Grotto recommends adding whey protein to fruit smoothies.

Another source of fiber and beta-glucans, barley has been shown to improve immunity as well as lower cholesterol. The antioxidants found in barley also protect cells from damage, says David Grotto, a Chicago-based registered dietitian and author of 101 Foods That Could Save Your Life. Grotto. Barley can easily be added to soups, stews and salads.

Sweet Potato
Sweet potatoes are full of fiber and immune system-boosting betacarotene, says Chicago-based registered dietitian David Grotto. Pop one in the oven whole or thinly slice, season and bake them for a healthy bowl of chips. Look for potatoes with darker flesh, which have higher betacarotene content.

A novel cyclic signaling in the dermis in animal models has been identified that coordinates stem cell activity and regulates 1) ___ in large populations of hairs. The signaling switch involves the bone morphogenetic protein (Bmp) pathway. Conceptually, the findings have important implications for stem cell research and in understanding how stem cell activity is regulated during regeneration. The research presents a new dimension for the regulation of hair regrowth and ultimately 2) ___ regeneration. The hair is an important model for organ regeneration in 3) ___ because it is one of the few organs that regenerates regularly. Recent work in the field has established hair cycling as one of the mainstream models for organ regeneration. However, most of these works focus on the cyclic regeneration of one single hair 4) ___. Each of us has thousands of hair follicles. In this study, the coordinative behavior of cyclic regeneration in a population of organs, was analyzed. The research team found that hairs, even in normal mice, regenerate in waves, rather than 5) ___. The findings suggest that hair stem cells are regulated not only by the micro-environment within one hair follicle — as has previously been thought — but also by adjacent hair follicles, other skin compartments and systemic hormones, in a 6) ___ order. At the 7) ___ level, the findings showed that periodic expression of Bmp in the skin macro-environment appears to be at the center of the mechanism for coordinated hair stem cell activation. When many hairs regenerate, they must communicate activation signals among themselves. At different time points the macro-environment can be either permissive or suppressive for stem cell 8) ___.This research shows that the formation of new tissues or organs from stem cells — such as the formation of new hairs — can be more robust if it occurs in a permissive macro-environment. It is hoped that this research will draw more attention to the hair follicle as the model for physiological regeneration in mammals, and as an abundant source of adult stem cells for the purposes of stem cell therapy. The work also has critical implications for research using the mouse skin as a model for tumor growth or drug delivery. Many studies assume the mouse skin is a homogeneous and stable environment for testing, but variations in results have been obtained. Understanding the unexpected dynamics of the living mouse skin will help future experimental designs” (see January 17, 2008 issue of Nature).

ANSWERS: 1) regeneration; 2) organ; 3) mammals; 4) follicle; 5) individually; 6) hierarchical; 7) molecular; 8) activation

By Donald G. McNeil Jr., The New York Times – Last year, for the first time since avian flu emerged as a global threat, the number of human cases was down from the year before. As the illness receded, the scary headlines — with their warnings of a pandemic that could kill 150 million people — all but vanished.

But avian flu has not gone away. Nor has it become less lethal or less widespread in birds. Experts argue that preparations against it have to continue, even if the virus’s failure to mutate into a pandemic strain has given the world more breathing room.

There were 86 confirmed human cases last year compared with 115 in 2006, according to the World Health Organization, and 59 deaths compared with 79. Experts assume that the real numbers are several times larger, because many cases are missed, but that is still a far cry from a pandemic.

Dr. David Nabarro, the senior United Nations coordinator for human and avian flu, recently conceded that he worried somewhat less than he did three years ago. “Not because I think the threat has changed,” he quickly added, but because the response to it has gotten so much better.”

The world is clearly more prepared. Vaccines have been developed. Stockpiles of Tamiflu and masks have grown. Many countries, cities, companies and schools have written pandemic plans. The European Center for Disease Prevention and Control, created in Stockholm in 2005, just estimated that the European Union needed “another two to three years of hard work and investment” to be ready for a pandemic, but that is improving because previous estimates were for five years.

In the worst-hit countries — all poor — laboratories have become faster at flu tests. Government veterinarians now move more quickly to cull chickens. Hospitals have wards for suspect patients, and epidemiologists trace contacts and treat all with Tamiflu — a tactic meant to encircle and snuff outbreaks before the virus can adapt itself to humans.

Bernard Vallat, director general of the World Organization for Animal Health, recently called the virus “extremely stable” and, thus, less likely to mutate into a pandemic form. Many prominent virologists would vehemently disagree. But others who argued three years ago that H5N1 would not “go pandemic” are feeling a bit smug.

Dr. Paul A. Offit, a vaccine specialist at Children’s Hospital in Philadelphia, was one of those who, he jokes, “dared to be stupid” by bucking the alarmist trend in 2005.

“H5 viruses have been around for 100 years and never caused a pandemic and probably never will,” he said.

But Dr. Offit said he backed all preparedness efforts because he expected another pandemic from an H1, H2 or H3, the subtypes responsible for six previous epidemics, including the catastrophic one in 1918.

“What I worry is that this has been a ‘boy who cried wolf’ phenomenon,” he said. “When the next pandemic comes, people will say, ‘Yeah, yeah, we heard that last time.’ ”

Some who were Cassandras in 2005 still are.

The fact that human cases fell slightly last year is “pretty much meaningless,” argued Michael T. Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota. The virus is still circulating and has evolved 10 clades and hundreds of variants.

World preparations thus far are “incremental,” he said, “like sending 10 troops to a war when you need 10,000.”

He noted that the H3N8 flu found in horses in the 1960s took 40 years to adapt to dogs, but that since 2004 it has spread to kennels all over the country.

The most worrisome aspect of H5N1, virtually all scientists agree, is that it persists in birds without becoming less lethal to them.

“This is the most serious bird flu virus that has ever been known,” Dr. Nabarro said. “By 2007, it was in 60 countries. It must be dealt with.”

Despite the culling of hundreds of millions of birds and the injection of billions of doses of poultry vaccine, the virus is out of control in some of the most populous countries — though exactly which ones are in dispute, because some are touchy about conceding that they cannot rid their flocks of it.

Dr. Vallat has named three countries where it is now endemic in local birds: Egypt, Indonesia and Nigeria.

Dr. Nabarro added Bangladesh, Vietnam and parts of China. Reports of recurrent outbreaks also persist in parts of India, Myanmar and Pakistan. Last week, villagers in India were reported to be killing and eating their flocks before government cullers, who paid less than a third of market value, could seize them.

Dr. Henry L. Niman, a biochemist in Pittsburgh whose Web site tracks mutations, argues that there is a separate reservoir in wild birds that extends across Eurasia. Late each fall, fresh outbreaks appear across Europe and down into the Middle East as geese and swans migrate from Asia toward Africa.

In December, dying birds were found in Poland and Russia, in Saudi Arabia and even in a kindergarten petting zoo in Israel.

On Jan. 8, it reached one of England’s most famous swan-breeding grounds, the Abbotsbury Swannery, which has been around since the 11th century.

The Western Hemisphere is in less danger, according to a study published in the journal PloS Pathogens, which analyzed viruses found in migratory birds sampled from 2001 to 2006 in Alberta and along the Jersey Shore. It found that none carried whole viruses from Eurasian bird pathways.

Therefore, the authors argued, it is more likely that any importation of the virus would be in “birds moved legally or illegally by humans.”

It may be even more likely that a human will be the first carrier. There was a close call in early December, when six members of one family in northern Pakistan fell ill, probably infected by a brother who had culled sick poultry.

Another brother, who lived on Long Island, went to Pakistan for the funeral and felt sick when he returned home. He turned out not to have H5N1, but it showed how easily the virus could have reached the Western Hemisphere.
Pakistan had its first human cases last year, as did Laos, Myanmar and Nigeria.

Many small mutations have been recorded that seem to make the virus more adaptable to humans and more resistant to known drugs, but no combination of those producing a superstrain has yet emerged.

Ninety percent of cluster cases have been among blood relatives, and Dr. Arnold S. Monto, an avian flu expert at the University of Michigan School of Public Health, said that suggested a genetic susceptibility that has not yet been defined.

It has long been known that the virus has difficulty attaching to receptors in human noses. A team at M.I.T. has refined that, showing that those receptors come in two shapes, cones and umbrellas, and that avian viruses attach more easily to the cones.

Rapid progress has been made in vaccines. The newest, Dr. Monto said, need just small amounts of antigen — 4 micrograms an injection instead of 90 micrograms — making them much more practical to produce.

Some scientists argue for vaccinating millions of people as a precaution. One dose, even if it is based on a three-year-old strain, might protect against death, if not infection. A second, fully protective dose could be made up from whatever strain has gone pandemic.

Right now, said Dr. Klaus Stöhr, who was chief of flu vaccines for the W.H.O. and now does the same for Novartis, it would take manufacturers about one year to produce a billion doses of any vaccine based on a new pandemic strain. But the pandemic would have circled the globe within three months.

“The peak would be over, and, principally, you’d be vaccinating survivors,” Dr. Stöhr said. Switzerland, he added, has a vaccine stockpile and plans to test it on soldiers, police officers and health care workers before deciding whether to offer it to all Swiss.

Because of the American swine flu debacle of 1976, in which a vaccine made against a pandemic that never emerged harmed more people than the flu did, experts say they think it is unlikely that many Americans would be willing to take such precautions.

By Donald G. McNeil Jr., The New York Times – Avian flu in Pakistan nearly touched the United States this month when a 38-year-old Nassau County resident returned from visiting family members who were later confirmed to be part of Pakistan’s first cluster of human infections.

But the resident, who landed at Kennedy International Airport on Dec. 5 and visited his family doctor the next day, tested negative for flu, both at a state laboratory and at the Centers for Disease Control and Prevention, the New York State Health Department and the C.D.C. said.

The cluster of human cases in Pakistan — which apparently began in November — was described last week in Pakistani press reports, which were picked up by flu-watcher Web sites.

But only on Saturday did the World Health Organization say that Pakistan had detected H5N1 virus in eight people, two of whom had died. The H5N1 virus is the strain of avian flu that has international health officials most worried about the threat of a pandemic.

All the cases occurred in the remote North-West Frontier Province, near the Afghan border, where outbreaks of H5N1 in poultry have been reported for months.

Exactly how the Long Island resident was connected to the cluster was vague.

Pakistani media reports said a man who had attended the funerals of his two brothers in late November had returned to the United States. State and federal officials could not confirm that on Monday.

While some reports said he visited his doctor because he felt ill, a State Health Department spokeswoman said he had not.
Another family member on Long Island had flu symptoms even before his relative returned from Pakistan, but both tested negative, the spokeswoman said.

Early local reports of avian flu clusters have routinely been confusing.

The Pakistani cluster appears to be the largest to be detected since May 2006, when seven confirmed cases in one family were found in Karo, a village in Indonesia. Others have occurred in Egypt, Turkey and Azerbaijan. In some cases, limited human-to-human transmission has appeared likely because relatives fell sick well after others had contact with birds.
There have been 340 confirmed cases of H5N1 flu in the world since 2003, 208 of which have been fatal, according to the World Health Organization. There have been fewer cases this year than in 2006, but the flu season has just begun.

The Pakistan press reported that the first case was in a veterinarian in Abbottabad who culled sick birds. He recovered but was reported to have infected two of his brothers, who died. However, the Pakistan government denied that human-to-human transmission had occurred.

India: Bird Flu Spread ‘Alarming’

By Donald G. McNeil Jr., January 19, 2008, The New York Times – India’s third outbreak of avian flu among poultry is the worst it has faced, the World Health Organization said. The chief minister of West Bengal State, which is trying to cull 400,000 birds, called the virus’s spread “alarming.” Uncooperative villagers, angry at being offered only 75 cents a chicken by the government, have been selling off their flocks and throwing dead birds into waterways, increasing the risk. New outbreaks were also reported this week in Iran and Ukraine.

Avian influenza – situation in Indonesia – update 32
21 January 2008

The Ministry of Health of Indonesia has announced a new case of human infection of H5N1 avian influenza. An 8-year-old male from Tangerang District, Banten Province developed symptoms on 7 January 2008, was hospitalized on 16 January and died in an AI referral hospital on 18 January. Investigations into the source of his infection are ongoing, however initial reports indicate the case lived in close proximity to a chicken slaughter house.

Of the 119 cases confirmed to date in Indonesia, 97 have been fatal.

Avian influenza – situation in Egypt – update 3
3 January 2008

The Ministry of Health and Population of Egypt has announced the death of a previously confirmed case of H5N1 infection. The 50 years old female from Domiatt governorate died on 31 December.

Of the 43 cases confirmed to date in Egypt, 19 have been fatal.

Avian influenza – situation in Pakistan – update
27 December 2007

The first case of human infection with H5N1 avian influenza has been confirmed in Pakistan. Laboratory tests conducted by the WHO H5 Reference Laboratory in Cairo, Egypt and WHO Collaborating Center for Reference and Research on Influenza, in London, United Kingdom have confirmed the presence of avian influenza virus strain A(H5N1) in samples collected from one case in an affected family. The H5N1 positive case was a 25 year old male from the Peshawar area who developed febrile respiratory illness on 21 November, was hospitalized on 23 November, and died on 28 November. Additional laboratory analysis, including gene sequencing, is ongoing.

At the request of the Pakistan Government, a WHO team traveled to Pakistan to participate with national authorities in the ongoing investigations of several suspected cases of human H5N1 infections. The following conclusions have been made accordingly:

The preliminary risk assessment found no evidence of sustained or community human to human transmission.
All identified close contacts including the other members of the affected family and involved health care workers remain asymptomatic and have been removed from close medical observation.

The Ministry of Health in Pakistan has taken timely steps to investigate and contain this event including case isolation, contact tracing and monitoring, detailed epidemiological investigations, increasing the availability of personal protective equipment, dedicating hospital facilities for any new suspected cases, and other infection control measures. In addition, agricultural authorities, including the Ministry of Food, Agriculture and Livestock and FAO, have been active technical partners for the effective control of this limited outbreak.

Avian influenza – situation in Myanmar
14 December 2007

The Ministry of Health in Myanmar has confirmed the country’s first case of human infection with the H5N1 avian influenza virus. The case is a 7-year-old female from Kyaing Tone Township, Shan State (East).

The case was detected through routine surveillance following an outbreak of H5N1 in poultry in the area in mid-November. She developed symptoms of fever and headache on 21 November 2007 and was hospitalized on 27 November. She has now recovered. Samples taken from the case tested positive for H5N1 at the National Health Laboratory in Yangon, and the National Institute of Health in Thailand. The diagnosis was further confirmed at the WHO Collaborating Centre for Reference and Research on Influenza, National Institute of Infectious Diseases in Tokyo, Japan.

A team from the Ministry of Health, the Ministry of Livestock and Fisheries and the WHO Country Office are conducting investigations to confirm the source of her infection. Initial findings indicate poultry die off in the vicinity of the case’s home in the week prior to the onset of illness. To date, all identified contacts of the case remain healthy and ongoing surveillance activities in the area have not detected any further cases.

Avian influenza – situation in China – update 5
9 December 2007

The Ministry of Health in China has reported a new case of human infection with the H5N1 avian influenza virus in Jiangsu Province. The case was confirmed by the national laboratory on 6 December.

The 52-year old male is the father of the 24-year old man who died from H5N1 infection on 2 December 2007. He is one of the close contacts placed under medical observation by national authorities. He developed symptoms on 3 December and was sent immediately to hospital for treatment.

Of the 27 cases confirmed to date in China, 17 have been fatal.

January 2008, Howard Hughes Medical Institute researchers have identified small pieces of ribonucleic acid (RNA) that suppress the spread of breast cancer to the lungs and bone. The new research shows that the most invasive and aggressive human breast cancer tumors are missing three critical microRNA molecules. When the researchers put those molecules back into human breast cancer tumors in mice, the tumors lost their ability to spread.

“The tiny RNAs prevent the spread of cancer by interfering with the expression of genes that give cancer cells the ability to proliferate and migrate,” said senior author Joan Massagué, a Howard Hughes Medical Institute researcher at Memorial Sloan-Kettering Cancer Center.

“The gene signature we have identified could offer another tool for assessing the likelihood that a cancer will progress.”
Joan Massagué

The researchers said their new research findings add to the growing number of cellular targets for drugs designed to prevent breast cancer metastasis. The scientists are also optimistic that their work could spur the development of new clinical tests to assess the likelihood that breast tumors will metastasize. Metastasis of breast cancer is the leading cause of death from the disease.

Metastasis occurs when cells from a primary tumor break off and invade another organ. It is the deadliest transformation that a cancer can undergo, and therefore researchers have been looking for specific genes that propel metastasis. If they can identify distinctive metastatic gene programs for different cancers, it may be possible to slow or halt metastases by targeting the proteins produced by those genes.

Massagué, his postdoctoral fellow Sohail Tavazoie, and colleagues at Sloan-Kettering, published their findings in the January 10, 2008, issue of the journal Nature.

In the experiments reported in Nature, the researchers explored the role that microRNAs play in controlling the expression of genes that trigger the spread of breast cancer. MicroRNAs, which are no more than 20-22 nucleotides in length, play an important role in development, cancer, stress responses and viral infections. Unlike the large messenger RNA (mRNA) molecules that code for cellular proteins, the microRNAs regulate gene activity by repressing or enhancing the translation of mRNAs.

Messenger RNA molecules are the genetic templates for proteins. In constructing proteins, the mRNA template is transcribed from DNA genes and transported to the ribosomes – the cell’s protein factories that are large complexes of protein and RNA. Given the importance of mRNA as an information-carrying molecule, the machinery that regulates mRNA levels and destroys faulty mRNA is critical in ensuring that errors in the genetic code are not passed on to proteins.
Massagué and his colleagues have focused on identifying the driving forces behind the spread of breast cancer, and have, in previous work, identified distinct genetic signatures associated with metastasis to the bone and the lungs. They decided to explore the role of microRNAs in breast cancer shortly after other researchers published data showing that certain tumors, including breast cancers, had decreased levels of microRNA expression. These observations suggested to Massagué and others that loss of the gene-suppressing molecules might well play a key role in the growth and spread of tumors.

To follow up on that hunch, Tavazoie and others in Massagué’s lab set their sights on identifying microRNAs that were suppressed only in aggressive, metastatic human breast cancers. They first analyzed cultured metastatic human breast cancer cells to create a genetic profile of the array of microRNAs produced by the cancerous cells. When they compared this microRNA profile to that from non-metastatic cancer cells, they found that a small subset of microRNAs was greatly reduced only in the metastatic cells.

They next found that when they restored normal levels of three of these microRNAs—miR-335, miR-126 and miR-206—in the cultured human breast cancer cells, it greatly reduced the cells’ ability to spread to the lungs or bones of mice. They also obtained a sample of metastatic cells from a breast cancer patient and found that those cells had lost the same three microRNAs identified in the cell culture experiments.

To study a broader sample of cancers, the researchers measured levels of the microRNAs in cancer cells from 20 patients with breast cancer. They found lower levels of the microRNAs in patients whose breast cancers had metastasized than in those whose cancers had not metastasized.

Additional biological analyses revealed that miR-126 influences the proliferation rate of the metastatic cells, whereas miR-335 and miR-206 influence the cancer cells’ ability to migrate into lungs or bone.

The researchers found a particularly strong association between loss of miR-335 and cancer relapse, so they next sought to determine which genes were regulated by that particular microRNA. Their genetic analyses revealed a set of six genes whose activity greatly increased with loss of miR-335 in metastatic cells. Two genes in particular, SOX4 and TNC, were known to regulate cell migration, which is critical for cancer invasion of other tissues. When the scientists knocked down the activity of those two genes, they reduced the cancer cells’ ability to spread.

Taking the analysis a step further, Massagué’s team sifted through genetic data from 368 patients with breast cancer. Those data showed that tumors with a higher level of expression of the six miR-335-regulated genes were much more likely to metastasize than those tumors with a lower level of expression of the six genes.

According to Massagué, identification of the microRNAs and the metastasis-controlling genes they regulate could prove valuable for both breast cancer prognosis and treatment. “The gene signature we have identified could offer another tool for assessing the likelihood that a cancer will progress,” he said. “There are quite a few of these signatures, and the most useful ones are those that consist of genes that are not just markers, but are actually mediators of metastasis. And in this gene signature, we have identified just such a set of mediators.

“Secondly, these findings reveal still more genes that could be targets of drugs to interfere with metastasis,” he said. “Researchers in this field are currently accumulating an inventory of clinically significant genes to explore, and the set we identified has shown such significance.”

Massagué said his group is now designing experiments to ask whether the breast cancer genes regulated by the microRNAs they identified also control metastasis of other types of cancer. “We have basically opened a window into a major future inquiry into such genes,” he said. “And my hope is that this paper will lead to findings that are even more important and useful than the ones contained in this first installment.”

By Melanie Lindner, – Business service and software companies IBM and SAP are joining up to create a new technology that includes the best of both worlds.

International Business Machines (nyse: IBM – news – people ) and SAP (nyse: SAP – news – people ) announced on Monday that the two companies will launch their first joint software product in the fourth quarter of 2008. The product, codenamed “Atlantic,” will integrate IBM’s Lotus Notes software with SAP’s Business Suite, according to a statement released by IBM.
While on opposite sides of the Atlantic Ocean, Armonk, N.Y-based IBM and Waldorf, Germany-based SAP have been partners in technology for some time now. SAP was founded by five former IBM employees, and the two companies have been collaborating for about 35 years. For instance, IBM is the world’s largest integrator of SAP’s business-management software, which is certified for IBM users. Also, SAP often uses IBM’s development database.

The two companies have dodged rumors of a merger, though they noted that their mutual customers have requested the specific functions that the “Atlantic” software will provide. IBM’s Lotus Notes, currently used by more than 135 million people around the globe, is a system of accessing business email, calendars and instant messages. SAP’s contribution will include programs that help companies to back office work such as payroll, inventory management and accounting.

Michael Rhodin, general manager of IBM Lotus Software said of the joint technological venture: “Businesses are looking to find better ways to collaborate and manage their business processes. This IBM-SAP solution addresses both challenges in one seamless package for millions of users.”

“Atlantic” will be sold by both IBM and SAP. If customization is required, IBM Global Business Services will offer consulting services. SAP practitioners will provide customization services to meet individual

Dr Mitchel will again be consulting for NIH in the area of Drug Development and Regulatory Affairs. It is our way of giving back, as no one gets rich doing this, and to assure that awards are only given to highly qualified contractors. Target e*CRF® is currently being used in 2 NIH programs.

For more information, please contact Dr. Jules T. Mitchel or Joyce Hays. For new business opportunities, contact Dr. Jules T. Mitchel .

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