Cancer Immunotherapy Where Are We Going?

The compelling concept of utilizing the patient's own immune system for a stronger and more effective way to attack cancer cells is not a new one. William Coley observed in 1891 that infections produced in patients with inoperable cancer following an injection of streptococcal organisms (Gram-positive bacteria) led to tumor shrinkage especially when the patients developed fever and other signs of a full-blown infection.1 Since then, research has embraced approaches to "train" the patient's own immune system to recognize certain biomarkers or proteins that are mainly found on cancer cells and to destroy the cells. After several setbacks the first cellular immunotherapy, Dendreon's Sipuleucel-T (Provenge(R)), was approved for the treatment of prostate cancer in 2010. Today, new promising cancer immunotherapy approaches are in clinical trials. Most recently, researchers at the 54th American Society of Hematology (ASH) meeting reported early success with a developmental-stage cell-based cancer vaccine for the treatment of leukemia and have shown remission in several patients 2,3, including a 7-year old girl who relapsed twice after chemotherapy. Cancer immunotherapy can be thought of as either active or passive immunotherapy. The most prominent passive immunotherapies, which have revolutionized cancer therapy, are monoclonal antibodies that either target tumor-specific antigens and receptors or block important pathways central to tumor growth and survival. Therapeutic monoclonal antibodies are the market leader in the targeted cancer therapy space and include blockbusters such as trastuzumab (Herceptin(R)) or rituximab (Rituxan(R)). In general, antibodies are significant elements of the body's adaptive immune system. They play a dominant role in the recognition of foreign antigens and the stimulation of the immune response. Therapeutic antibodies target and bind to antigens, usually proteins that are mainly expressed on diseased cells such as cancer cells. After binding, cancer cells can be destroyed by different mechanisms such as antibody-dependent cellular cytotoxicity, the activation of the complement system -- an important part of the immune system -- and triggering cell death. Although very successful, especially in oncology, therapeutic antibodies have a significant limitation: they don't generate a memory response by the immune system, and thus, repeated antibody infusions are required. Further, monoclonal antibodies are only able to recognize specific proteins present of the cell surface. Monoclonal antibodies are mostly produced in cell culture systems which are often costly. Humanization of murine monoclonal antibodies by replacing of certain parts of the antibody with human sequences has improved the tolerability of antibodies and made them less immunogenic, but even fully human sequence-derived antibodies can carry some immunological risk. Novel approaches in the passive immunization strategy include antibody drug conjugates, a combination of targeting antibody with a very potent drug such as the recently approved brentuximab vedotin (ADCETRIS(TM)) for Hodgkin lymphoma and anaplastic large cell lymphoma (ALCL). ADCETRIS comprises an anti-CD30 monoclonal antibodyanti-CD30 monoclonal antibody and a cytotoxic (cell-killing) agent that is released upon internalization into CD30-expressing tumor cells. Currently, the development of next generations of ADCs is underway. Alternatively, specific and durable cancer immunotherapies designed to actively "train" or stimulate the patient's intrinsic immune response have been more problematic; however, recent success stories, such as the cell-based immunotherapy Provenge, have revitalized this field. Dendreon's approach modifies the patients' own dendritic cells to present a protein specific to prostate cancer cells. Dendritic cells are the most potent, "professional" antigen-presenting cells. They process the antigen material and present it on their surface to other cells of the immune system. Once activated, the dendritic cells migrate to the lymphoid tissues where they interact with T-cells and B-cells -- white blood cells and important components of the immune system -- to initiate and shape the adaptive immune response. To develop Provenge, each patient's own dendritic cells are harvested and then loaded ex vivo with the tumor-associated antigen. Now "presenting" the antigen, the dendritic cells are administered back into the patient to induce a potent, cell-mediated anticancer immune response resulting in tumor shrinkage and clinical benefit. In another experimental approach for the treatment of leukemia, patients' own modified T-cells were infused back into the patients. Prior to this, the T-cells were transduced with a lentivirus to express the CD19-specific chimeric antigen receptor. CD19 is an antigen which is found on B-cell neoplasms, cancerous B-cells, and the lentivirus was the vehicle to transfer the genetic material for CD19 into the cells. A case report published in the New England Journal of Medicine stated that a patient with chronic lymphocytic leukemia (CLL) was in ongoing remission 10 months after treatment.3 These promising results have spurred continued research for new and safe ways to achieve effective tumor vaccination, and drug developers have explored many cancer immunotherapy strategies. To generate an effective antitumor immunity, therapeutic intervention should drive several functions; specifically, it should promote the antigen presentation functions of dendritic cells, promote the production of protective T-cell responses, stimulate B-cells and overcome immunosuppression characteristics that are common to tumor cells.4 Cell-based therapeutic vaccines are most frequently produced outside the patient's body and involve isolation of the specific cells, such as dendritic cells, and the introduction of preselected antigens, often with the use of specific vehicle, into the cells. The antigens can be encoded in viral vectors (frequently DNA) or administered as peptides or proteins in a suitable adjuvant and carrier through a long and cumbersome process. During my doctoral thesis, I conducted immunization experiments using RNA as a negative control, assuming that the RNA would be degraded during the experiment thus making it impossible to use as a vaccine. The physiological role of messenger (m) RNA is to transfer genetic information from the nucleus to the cytoplasm where this information is translated into the corresponding protein. mRNA is known to be very unstable and has a relatively short half-life. But astonishingly, we were able to measure a solid T-cell immune response. We repeated the experiment and confirmed that the RNA we had produced had the potential to be used as a vaccine. Importantly, we didn't need to isolate the patients' cells: mRNA-based vaccines can be injected directly into the skin (intradermal). The mRNA-based vaccines are then taken up by antigen-presenting cells, such as dendritic cells, and are then able to induce an immune response. Importantly, mRNA-vaccines can also be synthesized quickly for any antigen sequence identified.5 The first mRNA-based vaccines (RNActive(R)) are now in the clinic for the treatment of prostate cancer and lung cancer and have demonstrated that they do what they are supposed to do - induce a balanced humoral, as well as T cell-mediated, immune response that is entirely HLA independent. The HLA (human leukocyte antigen) system is used to differentiate the body's own cells (self) and non-self cells. Additionally, RNA-vaccines do not need a vehicle such as a virus for delivery to the cells, nor do they contain virus-derived elements that are often found in DNA-vaccines. These attributes make RNActive a very safe therapeutic. The risk of integration of the RNA into the host-genome is minimized (RNA would have been transcribed first to DNA, and then it has to be transported to the nucleus), as is the residual risk of DNA-based vaccines for inactivating or activating genes or affecting cellular regulatory elements, which can induce oncogenesis. Thus, the favorable safety profile of mRNA-based therapies broadens their potential use not only for the treatment of diseases but for use as prophylactic vaccinations. A recent proof-of-concept study using mRNA-based vaccines (RNActive) in animal models for influenza was published in Nature Biotechnology.6 Therapeutic cancer immunotherapies and vaccines have come a long way, and novel, promising approaches give hope for safe and effective treatment options. This may one day lead to the treatment of all cancers as chronic diseases. Literature 1Kirkwood JM, Butterfield LH, Tarhini AA, Zarour H, Kalinski P, Ferrone S: Immunotherapy of cancer in 2012. CA Cancer J Clin. 2012 2June CH, Blazar BR: T-Cell Infusions: A New Tool for Transfusion Medicine That Has Come of Age. Presentation at 54th ASH Annual Meeting 2013 3Porter DL, Levine BL, Kalos M, Bagg A, and June CH: Chimeric Antigen Receptor-Modified T Cells in Chronic Lymphoid Leukemia. N Engl J Med 2011 4Mellman I, Coukos G, Dranoff G: Cancer immunotherapy comes of age. Nature. 2011 Petsch B, Schnee M, Vogel AB, Lange E, Hoffmann B, Voss D, Schlake T, Thess A, Kallen KJ, 5Hoerr I, Obst R, Rammensee HG, Jung G: In vivo application of RNA leads to induction of specific cytotoxic T lymphocytes and antibodies. Eur J Immunol. 2000 6Petsch B, Schnee M, Vogel AB, Lange E, Hoffmann B, Voss D, Schlake T, Thess A, Kallen KJ, Stitz L, Kramps T: Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection. Nat Biotechnol. 2012

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Florida man sentenced to 10 years in "hackerazzi" case

A Florida man who pleaded guilty to hacking into the email accounts of celebrities to gain access to nude photos and private information was sentenced to 10 years in prison by a federal judge in Los Angeles on Monday. Former office clerk Christopher Chaney, 36, said before the trial that he hacked into the accounts of film star Scarlett Johansson and other celebrities because he was addicted to spying on their personal lives. Prosecutors said Chaney illegally gained access to email accounts of more than 50 people in the entertainment industry, including Johansson, actress Mila Kunis, and singers Christina Aguilera and Renee Olstead from November 2010 to October 2011. Chaney, who was initially charged with 28 counts related to hacking, struck a plea deal with prosecutors in March to nine felony counts, including wiretapping and unauthorized access to protected computers. "I don't know what else to say except I'm sorry," Chaney said during his sentencing. "This will never happen again." Chaney was ordered to pay $66,179 in restitution to victims. Prosecutors recommended a 71-month prison for Chaney, who faced a maximum sentence of 60 years. TEARFUL JOHANSSON Prosecutors said Chaney leaked some of the private photos to two celebrity gossip websites and a hacker. Johansson said the photos, which show her topless, were taken for her then-husband, actor Ryan Reynolds. In a video statement shown in U.S. District Court in Los Angeles, a tearful Johansson said she was "truly humiliated and embarrassed" when the photos appeared online, asking Judge S. James Otero to come down hard on Chaney. Prosecutors said Chaney also stalked two unnamed Florida women online, one since 1999 when she was 13 years old. Chaney, a native of Jacksonville, Florida, was arrested in October 2011 after an 11-month FBI investigation dubbed "Operation Hackerazzi" and he continued hacking after investigators initially seized his personal computers. Shortly after his arrest, Chaney told a Florida television station that his hacking of celebrity email accounts started as curiosity and later he became "addicted." "I was almost relieved months ago when they came in and took my computer ... because I didn't know how to stop," he said.

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Actor Depardieu hits back at French PM over tax exile

Actor Gerard Depardieu, accused by French government leaders of trying to dodge taxes by buying a house over the border in Belgium, retorted that he was leaving because "success" was now being punished in his homeland. A popular and colourful figure in France, the 63-year-old Depardieu is the latest wealthy Frenchman to seek shelter outside his native country after tax increases by Socialist President Francois Hollande. Prime Minister Jean-Marc Ayrault described Depardieu's behavior as "pathetic" and unpatriotic at a time when the French are being asked to pay higher taxes to reduce a bloated national debt. "Pathetic, you said pathetic? How pathetic is that?" Depardieu said in a letter distributed to the media. "I am leaving because you believe that success, creation, talent, anything different must be sanctioned," he said. An angry member of parliament has proposed that France adopt a U.S.-inspired law that would force Depardieu or anyone trying to escape full tax dues to forego their nationality. The "Cyrano de Bergerac" star recently bought a house in Nechin, a Belgian village a short walk from the border with France, where 27 percent of residents are French nationals, and put up his sumptuous Parisian home up for sale. Depardieu, who has also inquired about procedures for acquiring Belgian residency, said he was handing in his passport and social security card. Culture Minister Aurelie Filippetti said she was outraged by Depardieu's letter, adding that he had for years been supported financially by public money for the film industry. "When we abandon the ship and desert in the middle of an economic war, you don't then come back and give morality lessons," she told BFM-TV. "One can only regret that Gerard Depardieu doesn't make a comeback in silent movies." He said he had paid 145 million euros ($190.08 million) in taxes since beginning work as a printer at the age of 14. "People more illustrious than me have gone into (tax) exile. Of all those that have left none have been insulted as I have." The actor's move comes three months after Bernard Arnault, chief executive of luxury giant LVMH and France's richest man, caused an uproar by seeking to establish residency in Belgium - a move he said was not for tax reasons. Belgian residents do not pay wealth tax, which in France is now levied on those with assets over 1.3 million euros ($1.7 million). Nor do they pay capital gains tax on share sales. "We no longer have the same homeland," Depardieu said. "I sadly no longer have a reason to stay here. I'll continue to love the French and this public that I have shared so much emotion with." Hollande is pressing ahead too with plans to impose a 75-percent supertax on income over 1 million euros. "Who are you to judge me, I ask you Mr. Ayrault, prime minister of Mr. Hollande? Despite my excesses, my appetite and my love of life, I remain a free man."

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Leah Remini sued by former managers over "Family Tools" commissions

Leah Remini's new TV gig is already giving her a headache, months before it even starts. Former "King of Queens" star Remini is being sued by her former managers, the Collective Management Group, which claims that it's owed $67,000 in commissions relating to her upcoming ABC comedy "Family Tools," which debuts May 1. In a complaint filed with Los Angeles Superior Court on Tuesday, the Collective says that it entered into an agreement with the actress in November 2011 that guaranteed the company 10 percent of the earnings that emerged from projects that Remini "discussed, negotiated, contemplated, or procured/booked during Plaintiff's representation of Remini," regardless of whether the income was earned after she and the Collective parted ways. According to the lawsuit, that would include the $1 million that it says Remini will earn for the first season of "Family Tools." (The suit allows that it isn't owed commission on a $330,000 talent holding fee that Remini received from ABC prior to officially being booked on the show.) Remini, pictured above wearing the self-satisfied smirk of someone who just might stiff her former managers out of their commission, terminated her agreement with the Collective "without warning or justification" in October, the suit says. Alleging breach of oral contract among other charges, the suit is asking for an order stipulating that it's owed the $67,000, plus unspecified damages, interest and court costs. Remini's agent has not yet responded to TheWrap's request for comment.

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Thousands mourn U.S.-Mexican singer Jenni Rivera

Thousands of mourners on Wednesday packed a Los Angeles theater to pay their final respects to Mexican-American singer Jenni Rivera more than a week after her death in a plane crash. Rivera, 43, best known for her work in the Mexican folk Nortena and Banda genres, died after the small jet she was traveling in crashed in northern Mexico on December 9. Rivera's family, dressed in white, led the memorial service eulogizing the singer. A bank of white roses was displayed in front of Rivera's bright red coffin and a brass band performed musical interludes. More than 6,000 people crowded into the theater about 30 miles north of her childhood home in Long Beach, California. Tickets for the service at the Gibson Amphitheatre sold out within minutes, organizers said. The daughter of Mexican immigrants, Rivera was called the "Diva de la Banda." She sold about 15 million albums and earned a slew of Latin Grammy nominations during her 17-year career. "Jenni made it OK for women to be who they are," her manager Pete Salgado said at the service. "Jenni also made it OK to be from nothing, with the hopes of being something." Rivera had five children, the first at age 15, and was married three times. Her third husband was baseball pitcher Esteban Loaiza. Rivera's private life influenced her songs, which often referenced living through hardship. "She's a fighter and she knows it's in all of us," Rivera's son Michael said between video tributes. In recent years, Rivera branched out into television, appearing on a reality television show and serving as a judge on the Mexican version of the singing competition "The Voice." Television broadcaster ABC was reported to be developing a comedy pilot for the singer. Rivera's plane crashed in mountains south of Monterrey killing all seven on board. The singer was to perform in the city of Toluca, 40 miles southwest of Mexico City, in central Mexico after a concert in Monterrey. It is not clear what caused the crash.

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Putin offers French tax row actor Depardieu a Russian passport

President Vladimir Putin offered French actor Gerard Depardieu a Russian passport on Thursday, saying he would welcome the 63-year-old celebrity who is embroiled in a bitter tax row with France's socialist government. Weighing into a dispute over a hike in taxes, Putin heaped praise on Depardieu, making the offer of citizenship in response to a question during his annual televised press conference. "If Gerard really wants to have either a residency permit in Russia or a Russian passport, we will assume that this matter is settled and settled positively," Putin said. French daily Le Monde reported on Tuesday that Depardieu had told his close friends he was considering three options to escape France's new tax regime: moving to Belgium, where he owns a home, relocating to Montenegro, where he has a business, or fleeing to Russia. "Putin has already sent me a passport," Le Monde quoted the actor as jokingly saying. Depardieu is well-known in Russia where he has appeared in many advertising campaigns, and in 2012 he was one of several Western celebrities invited to celebrate the birthday of Ramzan Kadyrov, Chechnya's Kremlin-backed leader. He also worked in Russia last year on a film about the life and times of the eccentric Russian monk Grigory Rasputin. He has already inquired about how to obtain Belgian residency rights and said he plans to hand in his French passport and social security card. In what has become an ugly public dispute, France's Prime Minister Jean-Marc Ayrault criticized Depardieu's announcement as "pathetic" and unpatriotic. The actor hit back, accusing France of punishing success and talent. But Putin said he thought the feud was the result of a "misunderstanding". The 60-year-old former KGB spy said he was very friendly with Depardieu, saying he thought the actor considered himself a Frenchman who loved the culture and history of his homeland. Belgian residents do not pay a wealth tax, which in France is now levied on those with assets over 1.3 million euros ($1.7 million). Nor do they pay capital gains tax on share sales. Hollande is also pressing ahead with plans to impose a 75-percent super tax on income over 1 million euros. Russia has a flat income tax rate of 13 percent.

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"Fiscal cliff" drag on economy less than feared so far

WASHINGTON (Reuters) - The U.S. economy showed surprising signs of resilience in November despite the approach of the so-called fiscal cliff as consumer spending rose by the most in three years and a gauge of business investment jumped. Consumer spending rose 0.6 percent when adjusted for inflation, while new factory orders for capital goods outside the defense and aerospace sectors - a proxy for business spending plans - jumped 2.7 percent, the Commerce Department said on Friday. Economists had pinned earlier weakness in investment plans on worries lawmakers and the White House might fail to strike a deal to avoid the brunt of tax hikes and government spending cuts scheduled to begin in January. They also worried consumers would hold back as the end-of-the-year deadline approached with both parties far apart on how to avoid the potential hit to the economy. But Friday's data suggested both consumers and businesses had mostly shrugged off the cliff, at least in November. "It appears that the looming fiscal cliff hasn't been nearly as disruptive as we had feared," said Paul Ashworth, an economist at Capital Economics in Toronto. Still, another report provided ample reason for caution as U.S. consumer sentiment slumped in December, with households apparently rattled by on-going negotiations to lessen the fiscal tightening that could easily trigger a recession next year. The Thomson Reuters/University of Michigan's final index of consumer sentiment in December tumbled more than expected to 72.9 from 82.7 a month before. U.S. stocks fell sharply after a Republican proposal for averting the fiscal cliff was abandoned late on Thursday, eroding optimism that a deal could be reached quickly. At the same time, U.S. government debt prices rallied and the dollar gained ground as investors sought a safe haven. Economists still expect economic growth to cool in the fourth quarter as companies slow the pace at which they have been re-stocking their shelves, but the data on Friday suggested consumers are offsetting some of that drag. Consumer spending is on track to grow at a 2.2 percent annual rate in the fourth quarter, faster than during the prior three months, said Michael Feroli, an economist at JPMorgan in New York. Forecasting firm Macroeconomic Advisers raised its forecast for fourth-quarter economic growth by four tenths of a point to a 1.4 percent annual rate. In the third quarter, the economy expanded at a 3.1 percent rate. "The economy is holding in here at the end of the year despite the concerns about the fiscal cliff," said Gary Thayer, an economic strategist at Wells Fargo Advisors in St. Louis. WORRIES AHEAD Those concerns are not going away. In November, many analysts on Wall Street said they expected Washington would largely avert the fiscal cliff, and optimism had grown over the last week that a deal was within reach. Since Wednesday, however, negotiations have fallen into disarray. If Congress and the White House do not reach a deal in time, taxes will go up for all Americans beginning in January and the government will cut spending on a host of programs. Running off the fiscal cliff would slash the nation's trillion-dollar budget deficit nearly in half in just one year. The impact would only come gradually, but economists expect it would be enough to knock the country into recession in the first half of the year. So far, uncertainty over the talks appears to have had only a limited impact on the economy. New orders for durable goods, items meant to last three years or more, rose a greater-than-expected 0.7 percent in November due to gains in machinery, fabricated metal products, and computer and electronic products. Those increases were offset by a decline in volatile aircraft orders. The report also showed a rise in shipments, brightening the prospects for fourth-quarter economic growth. Shipments of non-defense capital goods orders excluding aircraft, used to calculate equipment and software spending in the government's measures of gross domestic product, gained 1.8 percent, after rising by a softer 0.6 percent in October.

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IMF extends zero interest loans to poor nations

WASHINGTON (Reuters) - Poor countries with loans from the IMF can continue to pay no interest until the end of 2014, the Fund's board said on Friday, as their economies are still recovering from the global economic crisis. The IMF's zero-interest loan program for low-income countries had been set to expire at the end of this year. "The executive board decision to keep interest rates at zero ... is testament to the Fund's continued support for low-income countries since the global economic crisis hit in 2009," IMF Managing Director Christine Lagarde said in a statement. The IMF decided in 2009 to allow countries eligible for its anti-poverty loan program to pay zero interest on loans in light of the financial crisis. The Fund also set a target to raise $17 billion to lend to the poorest countries, which are threatened by the risk of euro-zone contagion and by a drop-off in foreign aid after the global recession. IMF's Lagarde has pushed to meet that goal, seeking to ease concerns that the IMF and donor nations may turn a blind eye to the world's poor as they focus on containing the euro zone crisis. In September, the IMF said it would distribute a $3.8 billion windfall from gold sales to its 188 member countries if they agreed to commit most of the money to the anti-poverty loan program.

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Top business story in '12: Sluggish global economy

This would be the year when the global economy finally regained its vigor. At least that's what many had hoped. It didn't happen. The three largest economies — the United States, China and Japan — struggled again in 2012. The 17 countries that use the euro endured a third painful year in their financial crisis and slid into recession. Emerging economies slowed. President Barack Obama defied predictions by sailing to re-election. And his landmark health care plan surprisingly survived Supreme Court review. Obama's re-election triggered a face-off with Republicans over averting the "fiscal cliff" — the drastic spending cuts and tax increases that were set to kick in Jan. 1. The tech world dueled over smartphones and tablets and saw Facebook's IPO sour as fast as it had sizzled. The housing market inched toward recovery. And Americans suffered both a catastrophic drought and a catastrophic superstorm. Least surprisingly, perhaps, another gallery of rogues brought investigative scrutiny to Wall Street. The achingly slow global economic recovery was chosen as the top business story of the year by business editors at The Associated Press. The U.S. presidential election came in second, followed by the Supreme Court's upholding Obama's health-care plan. 1. THE GLOBAL ECONOMY: Worldwide growth was slack again in 2012. The global economy grew just 3.3 percent, down from 3.8 percent in 2011 and 5.1 percent in 2010, the International Monetary Fund estimates. The U.S. economy, the world's largest, failed to gain traction. Five years after a recession seized the economy and more than three years after it ended, growth in the United States was only about 2 percent. Unemployment remained a high 7.7 percent. Europe fared worse. Its financial crisis did stabilize, thanks in part to the European Central Bank's plan to buy government bonds to help countries manage their debts. But the euro alliance sank into recession. Europeans, in turn, held back China, the world's No. 2 economy, by cutting back on Chinese goods. China's economy grew at a 7.4 percent annual rate in the July-September quarter. Though a scorching pace for developed countries, that marked a 3½-year low for China. And at year's end, Japan's economy, the world's third-largest, was shrinking. 2. U.S. PRESIDENTIAL ELECTION: Obama vaulted to a re-election victory over Mitt Romney, who had staked his bid on the weakest U.S. economic rebound since the Great Depression and had pledged to slash taxes. Unemployment under Obama topped 8 percent for 43 straight months. Yet he won despite the highest unemployment rate of any president seeking re-election since World War II. Voters assigned him higher marks on the economy as the year progressed, perhaps encouraged by job gains. As the fiscal cliff neared, Obama fought to raise taxes on the highest-earning Americans. He also demanded aid for the long-term unemployed and money for roads, bridges and other infrastructure. Economists raised hopes that if the fiscal cliff was averted, the gloom would lift in Obama's second term. 3. OBAMA HEALTH CARE PLAN UPHELD: The Supreme Court caught many by surprise when it backed Obama administration's health care reform in a 5-4 vote. The law requires Americans to buy insurance or pay a tax, while subsidizing the needy. Hospitals and health insurers will likely benefit from 30 million new customers. Medical device makers, though, will face a new sales tax. And some small businesses say the law will discourage hiring because it requires companies to provide health care once they employ more than 50. 4. THE FISCAL CLIFF: A dreaded package of tax increases and deep spending cuts to domestic and defense programs loomed over the economy in the year's final months. Negotiators struggled to forge a budget deal to avert those measures. If they failed, the tax increases and spending cuts would kick in Jan. 1. That threat was intended to be so chilling that it would force Congress and the White House to take the painful budgetary steps needed to avoid it. Economists warned that if the fiscal cliff measures remained in place for much of 2013, they would cause a recession. 5. FACEBOOK's IPO: Years of anticipation led to Facebook's initial public offering of stock — the hottest Internet IPO since Google's in 2004. Many of the billion or so users of the world's largest online social network craved a chance to buy in early. On the eve of its first trading day, Facebook's market value was $104 billion — more than Amazon.com's or McDonald's at the time. Yet the IPO bombed. Its debut was marred by technical glitches with the Nasdaq exchange, allegations that a revenue gap wasn't publicly disclosed and complaints that the IPO had been priced too high. Traders lost confidence fast. Within three months, Facebook's stock had shed more than half its IPO value. 6. HOUSING RECOVERY: After a six-year slump that sent more than 4 million homes into foreclosure and shrank home prices about one-third nationwide, the U.S. housing market began to recover in mid-year. Modest job gains and record-low mortgage rates fueled demand. And the supply of available homes sank. By June, prices began rising. And builders broke ground on the most homes in four years. Housing boosted economic growth this year for the first time since 2005. 7. THE RETURN OF BIG OIL: Domestic crude oil production achieved its biggest one-year gain since 1951, driven by output in North Dakota and Texas. The United States is on pace to pass Saudi Arabia as the world's top oil producer within two years. Credit goes to drilling improvements, like those that have fed a boom in domestic natural-gas production — horizontal drilling combined with hydraulic fracturing, or fracking. The new production helped cut natural gas prices to their lowest levels in more than a decade. Higher oil production helped reduce oil imports to 1992 levels and hand record profits to U.S. refiners. Gasoline prices declined in the last three months of the year. But for all of 2012, the average gallon was a record $3.63. 8. BANKS BEHAVING BADLY: It was a banner year for bank drama. JPMorgan Chase lost $6 billion in a complex series of trades. And one of its bankers in London grew famous for big bets and became known as the "London whale." Morgan Stanley was accused of botching Facebook's IPO. An ex-banker trashed Goldman Sachs for putting profits ahead of customers and for mocking clients as "muppets." Barclays and UBS were fined for their roles in manipulating a key global interest rate. And HSBC agreed to pay $1.9 billion to settle charges that it enabled money laundering by Mexican drug traffickers. 9. MOTHER NATURE: There wasn't enough rain in much of the nation. Then, suddenly there was much too much. The nation suffered its worst drought since the 1950s, covering 80 percent of U.S. farmland. Grain and food prices soared. Then a storm so destructive it was dubbed a "superstorm" walloped the Northeast. Sandy blasted coastal New Jersey and New York and put 8.5 million customers in 21 states in the dark. Sandy will likely end up as the second-costliest U.S. storm ever after Hurricane Katrina. 10. MOBILE-GADGET WARS: Competition in mobile technology intensified. Apple maintained its worldwide dominance. But the use of Google's Android software on competing smartphones and tablets spread faster than Apple's market share. Forty-four percent of U.S. adults own smartphones, up from about 35 percent a year ago. Tablet ownership doubled in 2012. Taking on Apple's iPad, Microsoft unleashed its Surface tablet and began selling Windows 8, a tablet-friendly operating system. Amazon and Barnes & Noble rushed out high-definition-screen tablets. Each priced its premium model less than the entry-level iPad. Apple struck back with the iPad Mini. Struggling to compete, once-formidable Nokia and BlackBerry-maker Research In Motion floundered.

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Russia clashes over energy with Belarus, Ukraine, EU

MINSK/MOSCOW (Reuters) - Russia plunged back into the disputes over energy with Ukraine and Belarus that have repeatedly disrupted oil and gas supplies to European Union countries, and it also termed EU energy policy as "uncivilized". Russia on Friday denied remarks by Belarussian President Alexander Lukashenko that it had agreed to increase its crude oil supplies to Minsk, vital for the Belarus economy, and said that it still intended to cut them next year. On Thursday, Russian President Vladimir Putin criticized Ukraine for failing to agree on a deal, in return for cheaper gas, under which it would lease its pipeline network to Moscow and the European Union. Russia, the world's top energy producer, supplies over a quarter of Europe's gas and oil needs. Ukraine ships around two thirds of Europe's imports of Siberian gas through pipelines across its territory, while Belarus is mainly responsible for oil deliveries Clashes over energy pricing and pipeline transit with Ukraine and Belarus have led over the past decade to cuts or halts in Russian oil and gas supplies to Central and Western Europe. These have most often happened over the New Year, when Russia failed to agree on energy supply terms with the two countries. The European Union has accused the Kremlin of using its energy might as a political tool, while Moscow has argued it wants its neighbors to pay fair prices promptly for energy. On Friday, Belarussian state news agency BelTA quoted Lukashenko as saying Russia had agreed to increase oil supplies next year to 23 million tonnes (460,000 barrels per day) from 21.5 million this year. "We have really agreed on the supply ... We will get the oil without any issues," he said. Moscow was quick to deny the report, insisting it was offering 18.5 million tonnes, an effective cut in supplies. "As of today, an agreement on supplies to Belarus in 2013 has not been signed," Russia's Energy ministry said in a statement. "The Russian side's offer is supplying 18.5 million tonnes of oil. Supplies in the first quarter of 2013 will be based on the suggested volume." Russian oil is crucial for the economy of Belarus and is supplied free of Russia's normally hefty export duties as Moscow seeks to keep the country within its political orbit. Belarus has two large oil refineries that process Russian crude and export gasoline and diesel to the West. The refining business earns vital hard currency, but Moscow has occasionally bridled over supply terms, part of a complex arrangement that also covers pipeline supplies of Russian oil and gas to Europe via Belarussian pipelines. Belarus, which suffered from a balance-of-payments crisis in 2011, faces a foreign debt repayment crunch next year when about $3 billion of its liabilities fall due. UNCIVILISED DECISION The stand-off with Belarus comes as Moscow is struggling to reach a deal with Ukraine over gas deliveries. Ukraine's reluctance to strike a deal on its gas transit system led to the last-minute cancellation of a visit to Moscow by its President Viktor Yanukovich this week. Although Moscow has regularly been at odds with both neighbors, it has never faced a situation of simultaneous cuts through both countries to Europe. At the same time tensions between Moscow and the European Union have risen over economic, political and human rights issues. Putin, in Brussels on Friday for a Russian-EU summit, said it was unacceptable that EU rules were applied retroactively. He was particularly referring to the Third Energy Package of EU legislation to create a single energy market and prevent those that dominate supply from also dominating distribution. An EU antitrust case against Russia's gas export monopoly Gazprom as well as EU attempts to diversify its energy suppliers away from Russia and legislation to encourage competition have angered Moscow. "Of course the EU has the right to take any decisions, but ... we are stunned by the fact that this decision is given retroactive force," Putin told reporters in Brussels. "It is an absolutely uncivilized decision." Russia presented the European Commission with new proposals on the legal status of its gas pipeline infrastructure to accommodate its export projects in Europe, Energy Minister Alexander Novak told reporters. Russia has been seeking exemptions from EU regulation that would allow it to make full use of pipelines bringing gas to Europe by routes that skirt around Ukraine.

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