Shimla is a tourist paraise that is visited all round the year by local as well as international travelers. It is surrounded by green pastures and snow capped peaks and is not too far from Delhi, the capital city of India. The city is also known as the summer capital of India with beautiful meadows and flowery valleys. It has become a hub of major adventure sports and other activities in the state of Himachal Pradesh. It is located on the north western ranges of Himalayas and is also known as Queen of Hills.
Shimla is easily accessible from Delhi and you can hire Delhi Shimla Taxi to reach there. These cabs provide hassle free trips. It is one of the tourist attractions that can be visited during any season and still retains the colonial charm. There are numerous tourist places that attract visitors from all over the world.
They include Dhengu Mata Temple, Wild Flower Hall, Tibetan Monastry, Christ Church, The Mall, and more. Mashobra is a place of unique beauty and Narkanda offers wonderful slopes for skiing.
When you hire Shimla to Delhi taxi service, you can see would pass through several places of importance on the way. The advantage of hiring cabs is that you can travel at your own pace. You can stop on the way, relax and see the places around and continue to travel to your destination at ease. The places such as Panipat, Karnal, Ambala and Panchkula would come on your way when you hire a Delhi to Shimla taxi. Among these Ambala is a wonderful destination that offers biggest natural lakes of Haryana and is truly a paradise.
You can stop on the way to visit these places and then continue with your journey.
The Delhi Shimla Taxi is available 24*7 and is just a phone call away. The cab service providers are also providing unique services for making bookings through the online mode as well. Keeping up with the modern advancement, these cab providers have developed their websites and provide all the information related to their services and tariffs here. You can select the most comfortable cab depending upon your budget. There are 4, 5 and 8 seater taxis available with these cab providers. Since they offer several advantages over the public transport vehicles, they are the most preferred way to travel to Shimla.
A 223-year-old law says foreigners can?file lawsuits in American courts for alleged violations of international law. But whether they can sue corporations remains a question for the Supreme Court.
The lawyer for a group of Nigerian villagers seeking to sue a multinational corporation for alleged human rights violations received a chilly reception at the US Supreme Court Tuesday.
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Paul Hoffman, a California appellate lawyer, endured a relentless barrage of blunt questions from the bench about whether a similar lawsuit could be filed in any other country in the world.
?I don?t know if this precise case could be brought,? Mr. Hoffman finally conceded.
?If there is no other country where this suit could have been brought ... isn?t it a legitimate concern that allowing the suit itself contravenes international law,? Chief Justice John Roberts asked.
The exchange came during an hour-long oral argument in a potential landmark case that could set the contours of corporate liability under an unusual 223-year-old American law.
The so-called Alien Tort Statute allows non-US citizens to file lawsuits in American courts for alleged violations of international law. Rather than filing their case in Nigeria, lawyers for the villagers decided to bring their fight to the US courts under the Alien Tort Statute.
There is just one problem. It is not clear that the enigmatic statute permits lawsuits against corporations.
A federal judge in New York allowed a portion of the suit to move forward, but a federal appeals court threw the entire case out. The Supreme Court agreed to take up the appeal.
At issue in Kiobel v. Royal Dutch Petroleum (10-1491) is whether international corporations may be held responsible in an American courtroom for allegedly aiding and abetting human rights abuses that take place in a foreign country.
Lawyers for Royal Dutch Petroleum maintain that the statute only permits lawsuits against individuals who personally perpetrate human rights violations, rather than the corporation that employs them.
The appeal stems from a 2002 civil lawsuit filed on behalf of 12 residents of the oil-rich Ogoni region of the Niger River delta.
The residents charge that from 1992 to 1995 Royal Dutch Petroleum and its subsidiaries aided and abetted the Nigerian military in conducting a campaign of terror and intimidation through the use of extrajudicial killings, torture, and other tactics to protect the oil company?s operations from the grassroots opposition of the Ogoni people. The company has denied involvement in atrocities.
Normally, such a suit would be filed in Nigeria, where the events took place, or in the Netherlands or the United Kingdom where the corporate subsidiaries are based.
But lawyers for the villagers decided to base their suit on the Alien Tort Statute which permits non-US citizen ?aliens? to sue other foreign residents for egregious violations of international law such as genocide, extra-judicial killing, torture, and slavery.
The Alien Tort Statute was adopted by the first Congress in 1789. It was largely ignored for nearly two centuries, but since 1980, lawyers have been trying to establish it as a vehicle to fight human rights abuses around the world.
At first, foreign plaintiffs went after individual foreign torturers and abusive officials. But since the late 1990s, the trend has been to target deep pocket corporations doing business in countries ruled by oppressive governments.
According to one analyst, 120 lawsuits have been filed in US courts against 59 corporations for alleged violations in 60 foreign countries.
Although four members of the high court?s conservative wing expressed significant skepticism about the tactic of charging corporations under the ATS, not all justices were openly opposed to the concept.
Justice Stephen Breyer hypothesized about a group of incorporated criminals operating as Pirates, Inc. Would they be immune from a civil lawsuit under ATS, he wondered.
Any experienced teacher will tell you that every class has a few: children who can?t focus, can?t sit still, who fight at the slightest provocation, or perhaps withdraw completely.
These kids are usually labeled as ?bad?, ?out of control? or ?willful?. But brain research has shown that these kids aren?t intentionally bad. Their brains are shorting out from an overload of toxic stress.
Prompted by results from a large study of Spokane, WA, schoolchildren that showed how childhood trauma is taking more of a toll than many imagined, an innovative project is underway that will test three types of intervention in 900 families that participate in Spokane?s Head Start program.
The study of 2,100 children was done in ten elementary schools in Spokane, WA, in late 2010. The study found not only that trauma is common in kids? lives ? trauma includes divorce, homelessness, witnessing family violence, involvement with child protective services, a family member abusing alcohol
or other drugs, neglect, or mental illness in a family ? but it?s also the main reason that children missed school or got into trouble. It?s the second-highest predictor of academic failure, after a child being in special education classes.
And the more stressors a kid had, the study showed, the more likely that child was to have failing grades, poor attendance, severe behavior problems and poor health.
?The 248 kids with three or more adverse childhood experiences had three times the rate of academic failure, five times the rate of severe attendance problems, six times the rate of school behavior problems, and four times the rate of poor health compared with children with no known trauma,? says Christopher Blodgett, director of the Area Health Education Center of Eastern Washington at Washington State University.
Effects of ACEs on Spokane students' academic performance
Blodgett has been working on issues of family violence most of his career. About 10 years ago, he says, he began thinking about family violence as a set of public health concerns rather than as a medical issue. That was about the time that people in Washington State began learning about two areas of paradigm-shifting research:
The Adverse Childhood Experience Study (ACE Study), a joint research project by Dr. Vincent Felitti at Kaiser Permanente in San Diego, and Dr. Robert Anda of the Centers for Disease Control and Prevention, and
neurobiological research ? including studies by Dr. Martin Teicher, director of the Developmental Biopsychiatry Research Program at McLean Hospital; Dr. Bruce McEwen, director of the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at Rockefeller University; and Dr. Jack Shonkoff, director of the Center on the Developing Child at Harvard University ? that showed how toxic stress damaged the developing brains of children.
The CDC?s ACE Study measured 10 childhood traumas ? physical, emotional and sexual abuse; emotional and physical neglect; living with a parent who?s an alcoholic or addicted to other drugs; witnessing the abuse of a mother; a family member in prison or diagnosed with mental illness; and a loss of a parent through divorce or abandonment ? in 17,000 people in San Diego. (Of course, there are other possible traumatic events a child can experience ? such as severe illness, a catastrophic accident or homelessness ? but those were not measured.)
Researchers found a direct link between childhood trauma and adult onset of chronic disease, such as diabetes, heart disease, and some types of cancer. They also found that people with a higher ACE Score ? three or more types of childhood trauma ? had a significantly higher risk of chronic disease, suicide, drug use, engaging in violence or being a victim of violence.
The 17,000 people who participated in the study were 75 percent white, middle to upper-middle class, 76 percent had attended or graduated from college, and, since they were members of Kaiser through their employers, they had jobs and great health care.
In the last three years, 18 states have done their own ACE Studies, and those who have finished the analysis have found similar results.
The link between childhood trauma and adult onset of chronic disease was the damage that the toxic stress of chronic and severe trauma inflicts on a child?s developing brain. It essentially stunts the growth of some parts of the brain, and results in fried circuits in others. Children with toxic stress live their lives in fight, flight or fright mode ? unable to concentrate to learn, responding to the world as a place of constant danger, not trusting adults and unable to develop healthy relationships with peers. Failure, despair, blame, shame and frustration follow, and children transition into adulthood finding comfort by overindulging in food, alcohol, tobacco (nicotine is an anti-depressant), drugs (methamphetamines are anti-depressants), work, high-risk sports, a plethora of sexual partners?.anything to pump up feel-good moments to escape bad memories and feelings.
Christopher Blodgett
This knowledge ?started pushing us toward thinking about how we end up getting to the systems that universally serve children and families and how we can potentially bend the curve on risk and consequences of exposure to trauma,? says Blodgett.
To do that, he decided, communities needed to see local data, especially how trauma was affecting children?s performance in schools. That way, Blodgett believes, he could demonstrate ?how central ACEs and resulting risk of trauma are to the basic educational mission.?
So, in the spring of 2010, he and five other researchers obtained some funding from the Spokane County Community Network and the Washington State Family Policy Council. They worked with teachers and administrators to randomly choose 2,100 children from kindergarten through sixth grade in 10 elementary schools. They had asked school staff to identify the traumatic events that they knew the children had been exposed to without having to ask the children. The list included divorced or separated parents, homelessness or a risk of homelessness, witnessing family violence, having been involved with child protective services, a jailed family member, a family member abusing alcohol or other drugs, neglect, mental illness in a family member, exposure to community violence, or death of a parent or caregiver.
?This was a very conservative approach,? says Blodgett, ?but it still aligned well with the ACE Study. It showed the pervasive epidemic nature of risk common in all of our communities.?
After controlling for special education status, grade level, race, participation in the free and reduced meals program, teachers, school building and gender, the researchers found that childhood trauma significantly predicts academic risks and chronic health problems.
?ACE exposure may be the most powerful predictor of risk,? says Blodgett. ?This is not something schools can ignore; it?s basic to the academic mission. Schools have a fundamental stake in trying to respond to these problems.?
He hopes the data is helping educators understand that, with one in three or four children exposed to significant adverse childhood experiences, trauma may be impacting their ability to teach children.
Blodgett used the research as an impetus to provide tools for teachers to be able to help traumatized children learn. He and his team obtain a $1-million, 4.5-year grant from the Safe Start Center, funded by the U.S. Department of Justice to test out three types of intervention in 900 families that participate in the local Head Start program:
One intervention will train Head Start teachers to work with traumatized children.
A second intervention will train teachers and educate parents about parenting skills and how their own childhood trauma has affected their lives.
A third will train teachers and focuses on parent-child attachment skills, without delving into trauma history.
This project, which began last Fall, is in the process of recruiting families.
A separate grant from the Bill and Melinda Gates Foundation is testing trauma informed practices in elementary schools using similar practices. [ACEsTooHigh will do a separate story about this project.]
Blodgett has high hopes for how this knowledge of ACEs and the toxic effects of stress on developing children?s brains can change how educational systems handle traumatized children.
?I?ve been working on child maltreatment for 25 years, and I?ve never ever had a set of concepts catch fire with people in the community the way these ideas of ACEs and trauma have,? he says. ?This may start making things happen differently. That?s probably a really, really good thing.?
'It's a great thing to come into something that everybody's familiar with and knows each other very well,' new addition tells MTV News. By Kara Warner
Benedict Cumberbatch Photo: MTV News
With all the hullabaloo caused by the recently leaked photos from the "Star Trek 2" set, people are getting a wee bit distracted from the bigger picture surrounding the film: They're actually making the sequel, people! Let's be content with that happy news and the fact that all our favorite castmembers from the first film have returned, as well as a few very welcome additions, chief among them current actor-in-everything Benedict Cumberbatch.
MTV News recently caught up with the "Sherlock," "Tinker Tailor Soldier Spy" and "War Horse" actor to find out how things are going on set and his thoughts about his castmates' very high praise for how the British actor has elevated their collective game.
"Well, it's very sweet to say," Cumberbatch told us at Elton John's Oscar viewing party in regards to Chris Pine's compliments. "I actually did a year at drama school, so I'm not that trained; I'm not that classical, but I'm flattered. I think they are brilliant on that show, and it's a real privilege to be on that set. There's a patter and a kind of knowledge of who they're playing and the other main characters, which I'm learning a lot from. It's just good fun. It's great to work with Chris. He's very professional. So is Zach [Quinto], who I've been working a lot with; I adore him, he's a brilliant, brilliant guy.
"I'm kinda getting busy with the film now," Cumberbatch teased of his villainous character's actions in and around deep space. "I've been away doing other things — 'The Hobbit,' which was fantastic. And so my part of the film is really sorta kicking in now. It's great fun, great, great fun. But what I'm trying to say is it's a great thing to come into something that everybody's familiar with and knows each other very well. So it's [in] a weird way a very easy thing to get up to speed with, because everybody is so welcoming and gets along with one another."
First person shooters are a staple of a gaming PC. If you are looking for some great first person shooters to add to your computer, you might get lost in the sea of games on the market. Here are the top 10 first person shooters for gaming PCs.?
?1)???? BattleField 3
?Known for it?s varied multiplayer environments and unbelievable graphics, Battlefield 3 take the cake in first person shooters for the PC. BF3 offers 6 co-op missions that you can play with your friends and enables up to 64 players in online multiplayer. BF3 also offers different vehicles to add to the carnage on the battlefield.
?2)???? Call of Duty: Modern Warfare 3
?The third chapter of the Modern Warfare series, COD 3 gives players different spec ops missions, a challenging and varied multiplayer environment and a campaign that could be confused with a live action movie. The graphics are unbelievable and the fight takes you from New York to Paris and London. MW3 has an upgrade in weaponry that is enough to wet the pallet of any serious gamer.
?3)???? Red Orchestra 2: Heroes Of Stalingrad
?A first person shooter centered on the Stalingrad conflict in WWII, Red Orchestra2: Heroes Of Stalingrad offers very well designed maps and authenticity to the battles of the era. If you were a fan of Call of Duty: Big Red One, you?re going to love this game.
?4)???? Call Of Duty: Black Ops
?Primarily set during the Cold War, Black Ops was released as a precursor to Modern Warfare 3. Black Ops gives users more freedom with their multiplayer attacks by adding the ability to select kill streak rewards.
?5)???? Call Of Duty: Modern Warfare 2
?A follow up to the original Modern Warfare, MW2 brought spec ops missions into the platform. Modern Warfare 2 is cut from the same cloth as COD4 and gives users a great multiplayer environment with challenging maps.
?6)???? Metro 2033
?The year is 2033 and you?re a fighter of humanity in the subway system after the apocalypse. Metro 2033 gives you a great atmosphere with dark corners and plenty of action. The environments are incredibly detailed and the weapons are not as cookie cutter as other first person shooters.
?7)???? Call Of Duty: Modern Warfare
?Call Of Duty: Modern Warfare revolutionized the first person shooter for consoles and PCs alike. Although the campaigned is a little short, the graphics and that action is enough to sustain the game. The multiplayer environments are detailed and the game offers tons of options to choose from when picking your objectives.
?8)???? Crysis
?Crysis is a Sci-Fi first person shooter where mankind must fight off an alien invasion. The graphics are stunning and the gameplay is dynamic. The multiplayer environment is open to a lot of players but it doesn?t offer team deathmatch, a staple of FPS multiplayer games.
?9)???? Singularity
?Singularity takes you from the present day back to 1950 where you must battle different creatures. This game gives you the power of time manipulation to keep the battles interesting. You get a diverse set of different weapons and the bosses are a lot of fun to take down.
?10) Team Fortress 2
?Primarily a multiplayer game, Team Fortress 2 gives the same signature style of its first installment. Team Fortress 2 stresses teamwork with objective based multiplayer gaming. Although this game doesn?t have a storyline, it?s still one of the better first person shooters on the market.
Cancer is often preventable and survivable, but not if you ignore it. ?We have to take cancer on like any other enemy. If you confront it you can beat it,? says Dr. David Perdue, Chickasaw, the medical director of the American Indian Cancer Foundation (AICAF).
AICAF Executive Director Kris Rhodes, a member of the Bad River Band of Lake Superior Chippewa and Fond du Lac Band of Lake Superior Chippewa, will attend the Reservation Economic Summit?s (RES) Celebrating Women in Business Luncheon and Fashion Show on March 1. The luncheon attracts about 2,500 people annually and features a different cause each year; this year?s focus is cancer awareness. Proceeds from a silent auction during the luncheon will benefit the AICAF, and Rhodes will have a booth where AICAF feather ribbon lapel pins will be sold for $5 each, with proceeds supporting cancer prevention and awareness in Indian country. A slide show will feature photographs of Native cancer survivors, those battling cancer and those lost to the disease, such as Elouise Cobell.
According to Rhodes, cancer has become the leading cause of death for American Indians, surpassing heart disease. Lung cancer is the leading cause of those deaths, followed closely by colorectal cancer. ?Disease rates vary by region and tribes, so what is true for the Northern Plains and Alaska may not be true for tribes in the Southwest,? she explains.
American Indians and Alaska Natives have higher rates of lung cancer and colorectal cancer than non-Hispanic white populations (NHW) in Alaska and the Northern Plains. This is attributed to smoking, poor access to health care and cancer screenings, underfunding of the Indian Health Service, a lack of ability to pay for medical treatment and poor awareness of early detection and treatment options.
Rates of stomach, gallbladder, kidney and liver cancers are also higher for American Indians and Alaska Natives than they are for NHWs in Alaska, the Plains regions and in the Southwest. (Reversing that trend, cancer rates overall for American Indians and Alaska Natives were lower than the rates for NHW populations in the Southwest, the Pacific Coast and the East regions, according to a 2008 Centers for Disease Control and Prevention study.)
Dr. Judith Kaur says getting patients to talk about cancer is key.
Perdue cites some other troubling statistics from that report: The number of new cases of colorectal cancer is 39 percent higher in Northern Plains tribes than it is in NHW populations, and Alaska Natives have double the colorectal cancer rate of NHWs. He says one reason those rates are so high could be that colorectal cancer screening rates for American Indians are half that of the NHW population. This is particularly disturbing, he explains, because that kind of cancer is one of the most preventable when patients undergo the proper screening processes and have access to quality care.
The AICAF is working as a subcontractor for the Shakopee Mdewakanton Sioux Community in Shakopee, Minnesota, which got a $625,000 two-year grant funded by the Centers for Disease Control and Prevention through the Indian Health Service to increase colorectal cancer screenings in Northern Plains tribes. Perdue says his team will be visiting 54 tribal health systems in the region to assess each system?s knowledge and procedures for colorectal cancer screenings.
Dr. Judith Kaur, a member of the Choctaw Nation of Oklahoma, is medical director for the Native American Programs of the Mayo Clinic Comprehensive Cancer Center, which provides outreach to American Indian communities. ?We have a tremendously vocal cancer survivor group across Indian country. They are telling family, friends and their communities that if you get screened, diagnosed and treated, there is a good chance you can beat this,? she says. ?In the past, people didn?t talk about cancer because of their fear of it, and it was the general assumption that if you were diagnosed with cancer it was already too late.?
Access to care and screenings are important elements of cancer prevention, detection and treatment, but they aren?t the only weapons in this fight. Mitigating the risk factors is also crucial. The number-one cancer risk factor in Indian country is smoking. The second, according to Perdue, is obesity. ?The biggest thing is: Don?t smoke,? he says. ?Going back to healthier, more traditional diets, cutting out foods high in fats and getting regular exercise will decrease cancer risk.?
Rhodes says cigarette smoke is linked to nine out of 10 cases of lung cancer and one out of three cases of all other cancers. ?We can all contribute to the health of our community by reserving tobacco for sacred purposes only,? she says. ?It is important to ask for help when quitting smoking?ask for help from the Creator, from your family, from your clinic and from your friends.?
Perdue says American Indians often have misconceptions that can be barriers to cancer screening and treatment. Some of his patients believed if they were to talk about cancer they would be more likely to get it. Or that cancer is infectious, or that it comes from breaking taboos. ?People need to understand that cancer is a biologic process and a lot of cancers are treatable and preventable,? he says.
Joy Rivera, Haudenosaunee, is the colon cancer?screening navigator at the AICAF?she is, according to Perdue, their ?face on the street,? the person who talks to tribal members about screenings and walks them through the process. Rhodes says Rivera has been incredibly successful in getting both men and women in following through with their medical providers to request and complete cancer screenings.
Rhodes says there are many barriers to detection and care, such as underfunded health systems, lack of data, lack of programs and professional staff shortages. American Indians in both rural and urban areas have less health-care coverage and less access to health care than the NHW population?added to that are fewer prevention programs, cancer screenings and specialist care targeted to American Indians.
Despite the formidable task she has undertaken, Kaur is hopeful. ?We have more resources today than even five or 10 years ago?but it?s not enough. We need to continually educate new leaders in health promotion and cancer prevention,? she says. ?Now that I am an elder with three grandchildren, I am very concerned that the next generation benefits from both traditional knowledge and western science. There needs to be a lot of dialogue about what new advances there are in cancer treatment.?
What this all boils down to is: don?t smoke, don?t abuse alcohol, don?t eat foods high in fat, do eat lean meats, fruits and vegetables?a more traditional diet. Exercise, even if that just means walking short distances during breaks at work. Do ask your medical providers questions and find cancer screenings appropriate for your risk factors and family history. Don?t ignore, forget, procrastinate or be stubborn about your health.
To learn more about AICAF, visit AmericanIndianCancer.org. To learn more about the resources available to American Indians and American Indian communities through the Mayo Clinic Comprehensive Cancer Center, visit NativeAmericanPrograms.org.
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Cancer therapy more potent when it hits 2 targetsPublic release date: 24-Feb-2012 [ | E-mail | Share ]
Contact: Jason Socrates Bardi jason.bardi@ucsf.edu 415-502-4608 University of California - San Francisco
UCSF research shows that 1-2 punch blocks tumor growth, invasion and metastasis in mice
Simultaneous targeting of two different molecules in cancer is an effective way to shrink tumors, block invasion, and stop metastasis, scientists at the University of California, San Francisco (UCSF) have foundwork that may improve the effectiveness of combination treatments that include drugs like Avastin.
The two-target approach, tested in mice with a type of cancer known as neuroendocrine pancreatic tumors, may have broad application for treating a wide variety of cancers, the UCSF team said. The drugs used in the tests belong to classes of pharmaceuticals that are either on the market or under development in clinical trials.
Clinical trials also are already underway to gauge effectiveness of the approach in humans with prostate cancer, breast cancer, and other tumor types. The UCSF study, described in the journal Cancer Discovery this week, is the first to show how the drug combination works in the laboratory.
The results are promising, said Donald McDonald, MD, PhD, a member of the UCSF Helen Diller Comprehensive Cancer Center and the Cardiovascular Research Institute and professor of anatomy, who led the research.
In the study, treating mice with the dual-target approach turned aggressive tumors with invasive fingers penetrating surrounding tissues and many metastases into tiny balls with few or no metastases.
"It's the combination of approachesthere's a synergy between the two," McDonald said. "You add two and two, and you get 10."
HOW EACH TARGET WORKS
The two targets are both proteins that scientists have known for years are involved in cancer. Both play important roles in malignant tumors.
The first, called c-MET, is involved in two processes associated with the most deadly cancers. A clinical marker of cancer aggressiveness, c-MET drives tumor invasion into surrounding tissues. It is also involved in metastasisthe spread of cancer cells to other parts of the body where they can establish new tumors.
The second target is a protein known as vascular endothelial cell growth factor (VEGF). VEGF is a protein that promotes the growth of new blood vessels. Growing tumors hijack this process to expand their network of blood vessels to provide nutrients. Drugs blocking VEGF have been developed based on the simple assumption that tumors cannot grow if you choke off their blood supply.
Drugs that target these molecules are in development, and a few are already on the market. The U.S. Food and Drug Administration (FDA) approved the first of these in 2004 to treat metastatic colon cancer. That drug, called Avastin, is manufactured by the South San Francisco-based company Genentech. Avastin was approved for metastatic breast cancer in 2008 under the FDA's accelerated approval program.
The FDA revoked approval of Avastin for breast cancer last year after further assessing the relative risks and benefits to women taking it. Blocking VEGF seemed to slow tumor growth for awhile, but the FDA determined that it did not significantly improve or extend the lives of most women taking it.
"It was not clear why some tumors responded and others did not. It was also unclear why some tumors would respond initially and then would stop responding," said McDonald, who has studied blood vessels in tumors and the effect of cancer drugs for years in his UCSF laboratory.
Two years ago former UCSF professor Douglas Hanahan and colleagues found in laboratory experiments that Avastin-like drugs would shrink tumors but unexpectedly did something else as well. The drugs also morphed tumors from roundish blobs into highly irregular growths with tendrils that penetrated surrounding tissues and even spread to other organssuggesting that the VEGF blockade could also make tumors more aggressive, invasive and metastatic.
McDonald's group confirmed Hanahan's findings and discovered that c-MET was involved. In their latest research, Barbara Sennino, PhD, with other investigators in his group set out to determine whether c-MET drove tumor aggressiveness during anti-VEGF therapy. What their paper shows is that blocking c-MET and VEGF together in mice is more powerful than blocking either alone because it not only slows tumor growth but also reduces invasion and metastasis.
They tested two inhibitors of VEGFa neutralizing antibody and sunitiniband three inhibitors of c-METcrizotinib, PF-04217903, and cabozantinib (XL184). Unlike the other agents, cabozantinib simultaneously inhibits both c-MET and VEGF. Inhibition of c-MET and VEGF together with a drug combination or with cabozantinib had more profound effects on tumors than any of the agents that blocked only one of the targets.
These promising laboratory results still need more tests of safety and effectiveness in the clinic, McDonald said, and it may be a year or more before the drugs are routinely available to patients.
###
The article, "Suppression of Tumor Invasion and Metastasis by Concurrent Inhibition of c-Met and VEGF Signaling in Pancreatic Neuroendocrine Tumors" by Barbara Sennino, Toshina Ishiguro-Oonuma, Ying Wei, Ryan M. Naylor, Casey W. Williamson, Vikash Bhagwandin, Sebastien P. Tabruyn, Weon-Kyoo You, Harold A. Chapman, James G. Christensen, Dana T. Aftab, and Donald M. McDonald appears in the March 1 issue of Cancer Discovery. After Feb. 24, the article will be available at http://cancerdiscovery.aacrjournals.org/
None of the UCSF authors has any financial interest in the companies that make the drugs used in the experiments, which also involved scientists at Pfizer and Exelixis. The work was funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute, both components of the National Institutes of Health. Additional support was provided by the companies Pfizer and Exelixis and by AngelWorks Foundation.
UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.
AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
Cancer therapy more potent when it hits 2 targetsPublic release date: 24-Feb-2012 [ | E-mail | Share ]
Contact: Jason Socrates Bardi jason.bardi@ucsf.edu 415-502-4608 University of California - San Francisco
UCSF research shows that 1-2 punch blocks tumor growth, invasion and metastasis in mice
Simultaneous targeting of two different molecules in cancer is an effective way to shrink tumors, block invasion, and stop metastasis, scientists at the University of California, San Francisco (UCSF) have foundwork that may improve the effectiveness of combination treatments that include drugs like Avastin.
The two-target approach, tested in mice with a type of cancer known as neuroendocrine pancreatic tumors, may have broad application for treating a wide variety of cancers, the UCSF team said. The drugs used in the tests belong to classes of pharmaceuticals that are either on the market or under development in clinical trials.
Clinical trials also are already underway to gauge effectiveness of the approach in humans with prostate cancer, breast cancer, and other tumor types. The UCSF study, described in the journal Cancer Discovery this week, is the first to show how the drug combination works in the laboratory.
The results are promising, said Donald McDonald, MD, PhD, a member of the UCSF Helen Diller Comprehensive Cancer Center and the Cardiovascular Research Institute and professor of anatomy, who led the research.
In the study, treating mice with the dual-target approach turned aggressive tumors with invasive fingers penetrating surrounding tissues and many metastases into tiny balls with few or no metastases.
"It's the combination of approachesthere's a synergy between the two," McDonald said. "You add two and two, and you get 10."
HOW EACH TARGET WORKS
The two targets are both proteins that scientists have known for years are involved in cancer. Both play important roles in malignant tumors.
The first, called c-MET, is involved in two processes associated with the most deadly cancers. A clinical marker of cancer aggressiveness, c-MET drives tumor invasion into surrounding tissues. It is also involved in metastasisthe spread of cancer cells to other parts of the body where they can establish new tumors.
The second target is a protein known as vascular endothelial cell growth factor (VEGF). VEGF is a protein that promotes the growth of new blood vessels. Growing tumors hijack this process to expand their network of blood vessels to provide nutrients. Drugs blocking VEGF have been developed based on the simple assumption that tumors cannot grow if you choke off their blood supply.
Drugs that target these molecules are in development, and a few are already on the market. The U.S. Food and Drug Administration (FDA) approved the first of these in 2004 to treat metastatic colon cancer. That drug, called Avastin, is manufactured by the South San Francisco-based company Genentech. Avastin was approved for metastatic breast cancer in 2008 under the FDA's accelerated approval program.
The FDA revoked approval of Avastin for breast cancer last year after further assessing the relative risks and benefits to women taking it. Blocking VEGF seemed to slow tumor growth for awhile, but the FDA determined that it did not significantly improve or extend the lives of most women taking it.
"It was not clear why some tumors responded and others did not. It was also unclear why some tumors would respond initially and then would stop responding," said McDonald, who has studied blood vessels in tumors and the effect of cancer drugs for years in his UCSF laboratory.
Two years ago former UCSF professor Douglas Hanahan and colleagues found in laboratory experiments that Avastin-like drugs would shrink tumors but unexpectedly did something else as well. The drugs also morphed tumors from roundish blobs into highly irregular growths with tendrils that penetrated surrounding tissues and even spread to other organssuggesting that the VEGF blockade could also make tumors more aggressive, invasive and metastatic.
McDonald's group confirmed Hanahan's findings and discovered that c-MET was involved. In their latest research, Barbara Sennino, PhD, with other investigators in his group set out to determine whether c-MET drove tumor aggressiveness during anti-VEGF therapy. What their paper shows is that blocking c-MET and VEGF together in mice is more powerful than blocking either alone because it not only slows tumor growth but also reduces invasion and metastasis.
They tested two inhibitors of VEGFa neutralizing antibody and sunitiniband three inhibitors of c-METcrizotinib, PF-04217903, and cabozantinib (XL184). Unlike the other agents, cabozantinib simultaneously inhibits both c-MET and VEGF. Inhibition of c-MET and VEGF together with a drug combination or with cabozantinib had more profound effects on tumors than any of the agents that blocked only one of the targets.
These promising laboratory results still need more tests of safety and effectiveness in the clinic, McDonald said, and it may be a year or more before the drugs are routinely available to patients.
###
The article, "Suppression of Tumor Invasion and Metastasis by Concurrent Inhibition of c-Met and VEGF Signaling in Pancreatic Neuroendocrine Tumors" by Barbara Sennino, Toshina Ishiguro-Oonuma, Ying Wei, Ryan M. Naylor, Casey W. Williamson, Vikash Bhagwandin, Sebastien P. Tabruyn, Weon-Kyoo You, Harold A. Chapman, James G. Christensen, Dana T. Aftab, and Donald M. McDonald appears in the March 1 issue of Cancer Discovery. After Feb. 24, the article will be available at http://cancerdiscovery.aacrjournals.org/
None of the UCSF authors has any financial interest in the companies that make the drugs used in the experiments, which also involved scientists at Pfizer and Exelixis. The work was funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute, both components of the National Institutes of Health. Additional support was provided by the companies Pfizer and Exelixis and by AngelWorks Foundation.
UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.
AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
ScienceDaily (Feb. 23, 2012) ? Could blind, buck-toothed, finger-sized naked mole-rats harbor in their brain cells a survival secret that might lead to better heart attack or stroke treatments?
University of Illinois at Chicago biologist Thomas Park and colleagues at UIC and the University of Texas Heath Science Center at San Antonio think the subterranean lifestyle of the pasty-looking rodents may indeed hold clues to keeping brain cells alive and functioning when oxygen is scarce. The key may lie in how brain cells regulate their intake of calcium.
"Normally, calcium in brain cells does wonderful things, including forming memories," says Park, who is professor of biological sciences at UIC. "But too much calcium makes things go haywire."
Brain cells starved of oxygen can't regulate calcium entry, and too much calcium in the cell is lethal. When a heart attack or stroke prevents oxygenated blood from reaching the brain, brain damage or death results.
Naked mole-rats, however, are very tolerant to oxygen deprivation, or hypoxia -- as are human newborns, whose brain cells have calcium channels that close during oxygen deprivation, protecting the cells from calcium overdose. With age, these calcium channels no longer close, which normally isn't a problem -- except during a heart attack.
Naked mole-rats retain a tolerance for oxygen deprivation into adulthood. Park and his colleagues measured calcium entry in brain tissue that had been kept under oxygen-poor conditions, reporting their findings online Feb. 21 in PLoS One.
"We knew the adults of this unusual mammal had brains that, like infant humans, were very tolerant to oxygen deprivation," he said. "We wanted to know if the adult naked mole-rats used the same strategy as babies to prevent calcium entry. This is exactly what we found."
Park thinks this strategy is an evolutionary adaptation by mole-rats, which live in the hundreds underground in tight, oxygen-deprived conditions.
"Imagine 200 mice living in a shoe box buried four feet under the ground -- things are going to get bad fast," he said.
The researchers think they have identified a novel mechanism for protecting the adult brain in times of oxygen deprivation.
"Developing this target into a clinical application is our next goal," he said. "We need to find a way to rapidly up-regulate the infant-type of calcium channels. Adult humans actually have some of these channels already, but far fewer than infants."
Park, who for years has studied naked mole-rats and their unusual adaptations, thinks the latest findings "are just the tip of the iceberg" of what we can learn from the rodents. Their homes are not only oxygen-poor, but rich in carbon dioxide and ammonia -- conditions that would make most animals ill. Yet mole-rats have evolved to suppress pain and even cancer.
"The more we study these creatures," said Park, "the more we learn."
Co-authors include Rochelle Buffenstein, of the University of Texas Health Science Center in San Antonio; Bethany Peterson, a UIC doctoral student in Park's lab; John Larson, UIC associate professor of psychiatry; and Christopher Fall, UIC visiting research associate professor of bioengineering.
The study was funded by the National Science Foundation and the National Institutes of Health-National Institute of Mental Health Neurotechnology Program.
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The above story is reprinted from materials provided by University of Illinois at Chicago, via Newswise.
Note: Materials may be edited for content and length. For further information, please contact the source cited above.
Journal Reference:
Bethany L. Peterson, John Larson, Rochelle Buffenstein, Thomas J. Park, Christopher P. Fall. Blunted Neuronal Calcium Response to Hypoxia in Naked Mole-Rat Hippocampus. PLoS ONE, 2012; 7 (2): e31568 DOI: 10.1371/journal.pone.0031568
Note: If no author is given, the source is cited instead.
Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.
Sets up cost control system, monitors and controls costs and schedules on contracts requiring validated cost schedule control system. Performs analyses and prepares reports in order to ensure that contracts are within negotiated and agreed-upon parameters and government cost control guidelines. Prepares budgets and schedules for contract work and performs and/or assists in financial analyses such as funding profiles, sales outlook, and variance analysis. Prepares program plans to ensure program requirements and statement of work are captured and scheduled. Performs schedule risk assessments to identify and mitigate program cost and scheduling risks. Ensures adequate funding availability by maintaining accurate records of expenditures, directing preparation of expenditure projections, and submitting timely requests for additional funding. Incorporates contractual changes into control systems by staying aware of outstanding work against each contract in order to maintain realistic contract cost and schedule baselines.
Program Planning & Control responsibilities include:
Generate customer cost reports as required by CDRLs/SDRLs Provide recurring and ad hoc project reporting and analyses Assist Managers in preparation of budgets and forecasts Monitor projects to ensure costs are within budget, negotiated contract value and funding Assist in performing analyses of actual costs and estimates to complete Coordinate and participate in program reviews Support, interact and communicate effectively with individuals in remote locations and other support organizations (Finance, Purchasing and Material Control)
Pricing responsibilities include:
Assist in the preparation and review of Government, Commercial and intercompany proposals, quotes, ROMs and white papers. Support proposal managers in generating adequate costing for internal review and external submission. Ensure cost proposal is consistent with the Request for Proposal (RFP) requirements. Assemble and coordinate all cost proposal inputs. Provide pricing support for all phases of the proposal process including proposal development, pricing reviews, fact-finding meetings, contract negotiations and pricing certification. Utilize, create and maintain Excel based costing files for proposal pricing. Ensure Government proposals subject to TINA are prepared consistent with the FAR, agency supplements, applicable regulations, the company?s disclosed practices, policies and procedures, and the customer?s RFP requirements. Provide support for proposal re-pricing, fact-finding, data-sweeps and negotiations
[unable to retrieve full-text content]Reuters - An alleged al Qaeda operative from Maryland held at Guantanamo Bay has entered into a plea agreement with U.S. military prosecutors that calls for him to testify against other detainees, The Washington Post reported on Wednesday.
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ScienceDaily (Feb. 20, 2012) ? Inhibiting telomerase, an enzyme that rescues malignant cells from destruction by extending the protective caps on the ends of chromosomes, kills tumor cells but also triggers resistance pathways that allow cancer to survive and spread, scientists report in the Feb. 17 issue of Cell.
"Telomerase is overexpressed in many advanced cancers, but assessing its potential as a therapeutic target requires us to understand what it does and how it does it," said senior author Ronald DePinho, M.D., president of The University of Texas MD Anderson Cancer Center.
"We exploited the experimental merits of mice to model and study more precisely telomere crisis, telomerase reactivation and telomerase extinction in cancer development, progression and treatment," DePinho said. "This elegant model exposed two mechanisms, including one unexpected metabolic pathway, used by cancer cells to adapt to loss of telomerase.
"These findings allow us to anticipate how tumor cells might respond to telomerase inhibition and highlight the need to develop drug combinations that target telomerase and these adaptive resistance mechanisms," DePinho said.
Researchers evaluated telomerase as a therapeutic target in experiments that originated in DePinho's lab at the Dana-Farber Cancer Institute in Boston. He became MD Anderson's fourth full-time president in September.
Telomerase activity is low or absent in normal cells, which have segments of repeat nucleotides called telomeres at the ends of their chromosomes that protect DNA stability during cell division, said first author Jian Hu, Ph.D., an instructor in MD Anderson's Department of Cancer Biology.
With each division the telomeres shorten, leading eventually to genomic instability and cell death, a period termed "telomere crisis," Hu said. In cancer, telomerase becomes active during telomere crisis and rescues the genomically abnormal cells by lengthening telomeres.
In a series of experiments in a lymphoma mouse model, the team found:
Telomerase reactivation in malignant cells after genomic instability causes cancer progression.
Inhibiting telomerase caused tumor cell death but also led to alternative lengthening of telomeres (ALT) independent of telomerase.
ALT-positive cells increase both the expression and copy number of a gene called PGC-1?, a key regulator of mitochondrial function, to compensate for mitochondrial and reactive oxygen species defense deficiencies.
Targeting PGC-1? to weaken mitochondria function enhances anti-telomerase therapy.
To study the impact of reactivated telomerase, DePinho and colleagues genetically modified mice to develop T cell lymphomas and to have telomerase reactivated when the mice are treated with 4-hydroxytamoxifen (4-OHT). They crossed the mice for several generations, treating some with 4-OHT and others with a control vehicle that did not trigger TERT activation.
Telomerase reactivation causes aggressive cancer
Third- and fourth-generation mice with telomerase activated by 4-OHT had a median survival of 30 days and more frequent tumor infiltration to the spleen, kidney, liver, lung, bone marrow and brain than did control-treated mice, 70 percent of which lived beyond 50 days. Tumor cells in control-treated mice were more likely to be detected and destroyed by tumor-suppressing p53 signaling.
"These findings are consistent with telomere crisis leading to genomic instability during early stage cancer, with reactivated telomerase protecting malignant cells later to ensure tumor progression," Hu said.
Later-generation mice with activated telomerase had 4,928 amplified genes and 2,297 deletions. The team compared these changes to those in human lymphoma tumors and found 565 matching amplified genes and 300 deletions.
These cross-species copy number alterations included several known tumor-suppressing genes and oncogenes, suggesting that initial telomere dysfunction not only drives primary tumor development but also confers malignant traits such as invasiveness.
Telomerase extinction works -- at first
The team then took tumor cells from late-generation mice with activated telomerase -- the aggressive tumors -- and passaged them four times through groups of mice treated with either 4-OHT to trigger telomerase production or the control vehicle that leaves the enzyme off.
During the first two rounds, survival for the two groups was about the same. In the third round, the control mice had a major improvement in survival over the telomerase arm, indicating that telomere erosion had allowed cellular defense mechanisms to pick off genomically unstable cells.
However, in the fourth passage, survival of the control-treated mice fell back toward that of mice with active telomerase. The tumors had become resistant without relying on telomerase.
Alternative lengthening of telomeres rescues cancer cells
An analysis showed that telomere lengths of tumor cells with active telomerase remained largely unchanged across the four passages. Telomeres shortened in cells lacking telomerase through the first two passages followed by a sharp increase during the third and fourth passages.
Other molecular evidence pointed to alternative lengthening of telomeres in telomerase-absent cells.
They found that ALT-positive tumors had different gene expression patterns -- 891 genes with increased expression, 1,345 with decreased -- compared to telomerase-positive tumors.
Key gene in mitochondrial pathway active in ALT cells
Many genes were found in networks regulating mitochondrial biology and oxidative stress regulation. PGC-1? was the only gene in both pathways with increased expression and copy number gain in the ALT-positive tumors.
PGC-1? is a master regulator of both pathways, which turn out to be dysfunctional in ALT-positive tumors. When the researchers knocked down PGC-1?, mice with ALT-positive tumors survived much longer than those with intact PGC-1? and than those with activated telomerase in their tumors.
In normal cells, power-generating mitochondria process fatty acids to produce ATP, a molecule that serves as the major energy source for the cell. Cancer cells generally rely more on sugar processing to generate energy. However, DePinho and colleagues note their genetic evidence suggests that mitochondria play a role supporting cancer cells.
This research was funded by grants from the National Cancer Institute, the Leukemia and Lymphoma Society, the Fundaci?n Ram?n Areces, and Helen Hay Whitney Fellowship, the Ellison Foundation for Medical Research and the American Cancer Society.
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The above story is reprinted from materials provided by University of Texas M. D. Anderson Cancer Center, via Newswise.
Note: Materials may be edited for content and length. For further information, please contact the source cited above.
Journal Reference:
Jian Hu, Soyoon?Sarah Hwang, Marc Liesa, Boyi Gan, Ergun Sahin, Mariela Jaskelioff, Zhihu Ding, Haoqiang Ying, Adam?T. Boutin, Hailei Zhang, Shawn Johnson, Elena Ivanova, Maria Kost-Alimova, Alexei Protopopov, Yaoqi?Alan Wang, Orian?S. Shirihai, Lynda Chin, Ronald?A. DePinho. Antitelomerase Therapy Provokes ALT and Mitochondrial Adaptive Mechanisms in Cancer. Cell, 2012; 148 (4): 651 DOI: 10.1016/j.cell.2011.12.028
Note: If no author is given, the source is cited instead.
Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.
How to cook: TOMATO SALAD IN A SAVOURY TUILE BASKET TOPPED WITH A BASIL SORBET
Ingredients:
25g (scant 1oz) basil leaves, plus extra shredded leaves to garnish 7-8 tbsp extra virgin olive oil 32 red cherry tomatoes 16 yellow cherry tomatoes
FOR THE SORBET
100g (31/2 oz) caster sugar small bunch of basil leaves squeeze of lemon juice
FOR THE BASKETS
1 small garlic clove coarse sea salt 50g (13/4 oz) unsalted butter 30g (1oz) plain flour 2 tbsp caster sugar 1 large egg, white only 100g (31/2 oz) Parmesan cheese, finely grated 1 tbsp finely chopped rosemary leaves
Directions:
To create the sorbet, dissolve the sugar in 200ml (7fl oz) drinking water more than moderate warmth. Stir in the basil and lemon juice. Blend inside a foodstuff processor, then pass through a fine sieve. Line a second sieve with muslin and set more than a bowl. Pour inside the basil syrup and leave to drain.
Pour the syrup into an maker and churn for one hour. Line a baking sheet with baking parchment. Using two dessert spoons condition quenelles of sorbet, location around the tray, and freeze.
To generate the baskets, preheat the oven to 200/C (400/F/Gas 6) and line 2 baking sheets with baking parchment. Grease the outsides of eight medium dariole moulds and sit them upturned on yet another baking sheet. Crush and mince the garlic to a great paste with the sea salt using the back again of the knife. Conquer the butter until finally pale then defeat during the flour, sugar, and garlic. Gradually conquer within the egg white and Parmesan to kind a sticky paste.
Draw four 12cm (5in) circles on each and every sheet of baking parchment, nicely spaced apart. Dollop 2-3 spoonfuls with the combination into every single circle and thinly pass on that has a palette knife to fill the circle. Sprinkle over some rosemary and bake for 6-8 minutes or till tinged brown throughout the edges. Drape about the moulds, and return to your oven for 3-4 minutes. Neat to get a couple of seconds, then launch through the moulds and depart to chill.
For the salad, blend the basil with 5-6 tbsp of the oil. Pour by way of a sieve set above a bowl. Peel the tomatoes (see left) and put into a bowl. Season with salt and a splash of olive oil.
To serve, cautiously set a tuile basket on each and every plate and divide the cherry tomatoes between each. Place a quenelle of sorbet on leading and garnish using the shredded basil leaves.
Changes are inevitable while you progress like a psychic. Aside from the preferred psychic characteristic of comprehending the world better and feeling psychic powers directly, common physical signs and symptoms of psychic awakening range from the following:
- Yawning. You will probably discover that your previous shallow breathing designs simply don?t work any longer. You would like more air and insisting on higher quality (fresh, not stale) air. Through yawning additionally you adjust for any greater increase of psychic powers. Begin taking walks in character if you are not doing the work already.
- Nutritional changes. Some meals you cannot stand any longer plus some meals you eat in mass amounts. The physical body needs to reflect and sustain the alterations from the psychic body. Should you ignore the nutritional needs of the physical body, the body will discover ways to show you. (Should you stubbornly cling to old eating routine, it may get uncomfortable.)
- Flu-like signs and symptoms. By dealing with many alterations in a almost no time the body discovers to organize ahead and anticipate more changes. Make certain to eliminate a myriad of biological, emotional and mental waste out of your psychic being.
- Feeling tired/vitalized. While you switch to a new default psychic condition, the mixture of recent and old psychic oscillations might influence you diversely. Give consideration to yourself as well as your atmosphere to be able to adjust.
These are the common psychic signs and symptoms. For the way you explore the psychic area, chances are that you?ll also experience uncommon signs and symptoms for or less specific or unique for you being an individual.
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Public release date: 24-Feb-2012
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