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Driven by the ongoing trough in oil prices, Chevron (CVX), Equinor (EQNR) and Eni (E) made announcements on spending cuts.
Chevron (CVX) closed the most recent trading day at $72.47, moving +0.72% from the previous trading session.
As the world fights a pandemic, top energy companies will have to reassess their payout strategies, either by slowing down share buybacks or reintroducing non-cash dividends.
One thing we could say about the analysts on Chevron Corporation (NYSE:CVX) - they aren't optimistic, having just made...
Investing.com - Chevron (NYSE:CVX) Stock rose by 3.63% to trade at $74.54 by 10:50 (14:50 GMT) on Tuesday on the NYSE exchange.
Investing.com - Chevron (NYSE:CVX) Stock rose by 3.14% to trade at $70.93 by 10:49 (14:49 GMT) on Monday on the NYSE exchange.
(Bloomberg) -- The American shale industry shocked the world with its rebound after the 2014-2016 bust, setting records for output that pushed the U.S. to the top spot among oil-producing countries. A handful of experts is saying that will happen again.The comeback trail would be steep and long. The spread of coronavirus is crushing demand while Saudi Arabia and Russia are creating a glut. Everybody agrees U.S. production will take a bigger hit than last time, when it dipped before soaring. As many as 70% of the 6,000 shale drillers may go bankrupt, and one-third of shale-patch workers are expected to lose their jobs. Wall Street, which financed the last boom, has cut off the cash spigot.But some experts are saying the future, however far off, will be better. They're looking past the dire forecasts and vertical chart lines and cautioning against despair. They're echoing a widespread view that's mostly unspoken during the market meltdown: Yes, America can shock the world again. The boom-and-bust cycle will shift, and shale is in a position, with its infrastructure, its ability to ramp-up quickly and its plentiful reserves, to rise from the ashes stronger than ever.When the dust settles in the Permian Basin and other American shale fields, the survivors will be leaner and more tech savvy, according to Daniel Yergin, a Pulitzer Prize-winning oil historian and vice chairman of IHS Markit Ltd. That means lower production costs and a greater ability to respond to the next price rebound with the last thing Moscow and Riyadh want -- another boom."Companies go bankrupt, but rocks don't go bankrupt," Yergin said in an interview. "When this all shakes out, there will be other people to develop shale."Noah Barrett also believes the growth engine of U.S. crude production will be humbled, but won't flicker out. That's because shale has extensive infrastructure that isn't going anywhere."The resource is still there, the pipeline capacity, the processing capacity," said Barrett, a Denver-based energy analyst at Janus Henderson Investors. "Those are still there."Even if predictions are correct, that overall American oil output will slide to 8 million or 9 million barrels a day, down about one-third from the current 13 million, the U.S. would still count among the world's very top producers, Barrett said.Bloomberg Intelligence is forecasting a more-modest production falloff of about 1.5 million barrels a day.The weakest companies "will go into stronger hands," said Vincent G. Piazza, BI's senior oil analyst. "The industry is going to be in a lot better shape than in 2014-2016. The balance sheet is in a lot better shape. I wouldn't underestimate the ability of this industry to re-create itself."Fereidun Fesharaki is a shale believer, too. The chairman of global energy consultant FGE said he also expects the price squeeze to force explorers to become more efficient and cost-competitive.Still, any rays of optimism must penetrate a very dense, dark cloud. In the market cataclysm that's still unfolding, crude and fuel prices around the world have sunk to levels not seen in nearly two decades.As if by evil magic, the Covid-19 outbreak has chased tens of millions of people from streets, stores, factories and travel hubs, suddenly degrading demand for gasoline, jet fuel and diesel across the world's largest economies.Veteran crude analyst Roger Diwan expects global consumption to plunge by more than 14 million barrels a day -- the biggest demand shock since the birth of the oil age. The pipeline that hauls 60% of the East Coast's gasoline supply from the Gulf Coast is cutting capacity by one-fifth. In Chicago, wholesale gasoline tumbled to 15 cents a gallon, the lowest since at least 1992.The virus-driven calamity has been compounded by the disintegration earlier this month of the Russia-Saudi cooperation pact that capped global crude supplies. Because of the rapidly expanding worldwide glut of crude, a barrel of oil in some parts of Texas recently fetched about $16. In Canada, oil traded for less than $10.The price plunge instantly made thousands of prospective shale sites money-losing propositions. Companies have been in such a hurry to cut losses that some have paid early-termination penalties on rigs and other gear to halt work before contracts are up.Slashing SpendingEven Chevron Corp. is retrenching. The California giant, widely recognized as holding some of the richest acreage in the Permian, said Tuesday it was slashing spending by $4 billion and halting share buybacks to conserve cash.In the final three months of 2019, nine explorers and six service companies filed for bankruptcy, according to Haynes and Boone LLC. That represented $13.5 billion in debt. This year's churn is just getting started. Mizuho Securities analyst Paul Sankey expects as many as 70% of the 6,000 or so shale drillers to go bankrupt before the cycle turns.But private-equity firms that swooped in to buy ailing explorers and tempting assets during the last bust won't be able to unfurl a safety net this time. The buy-and-flip model that underpinned their foray into shale has disappeared, forcing those firms to become oilfield operators, which in turn means tapping their own credit facilities, said Ian Rainbolt, vice president of finance at Warwick Energy Group, the biggest owner of non-operated U.S. shale assets.Only about one-third of the Permian and other U.S. fields count as sweet spots that can harvest oil profitably at $30 a barrel, he said. West Texas Intermediate traded at $21.42 on Friday."Private equity's going to be out of the game," Rainbolt said. "It's a very, very tough fund-raising market."In the meantime, service providers -- the hired hands of the oil industry who do everything from stack steel pipes to frack wells -- will experience extreme pressure, along with the explorers who are demanding price cuts, said Stacey Morris, director of research at Alerian, an indexing and research company. Pipeline owners are somewhat insulated because oil and natural gas still need to be shipped to refiners and export terminals, she said.Shale Threshold"The market is going to be out of balance for quite some time," Morris said.Yergin, the confidante of oil ministers and chief executives, sees the threshold for reinvigorating shale between $50 and $60 a barrel. U.S. crude was trading above the $50 level as recently as Feb. 26."At $50, we'll start to see a recovery and a step up in investment, so long as people feel safe about the price floor beneath them," he said.It's funny that Yergin should put it that way. A big part of shale's resilience lies in its unique geology. Unlike the so-called conventional fields in Saudi Arabia and Russia, North American shale is rock so dense that it doesn't degrade or collapse on itself if oil production is interrupted. In other parts of the world, disrupting output can do irreversible damage.That's why the bulk of Chevron's $4 billion spending cut will take place in the Permian, CEO Mike Wirth said Tuesday. It's a rare field where production can be turned off almost instantly without adverse long-term impacts.With shale, "the assets don't go away because you haven't destroyed the field," said Ken Medlock, senior director of Rice University's Center for Energy Studies. "We'll see a thinning of the herd but the assets will still be there."(Adds Bloomberg Intelligence analyst's comment in 10th paragraph.)For more articles like this, please visit us at bloomberg.comSubscribe now to stay ahead with the most trusted business news source.©2020 Bloomberg L.P.
The Zacks Analyst Blog Highlights: Chevron, Royal Dutch Shell, Diamondback Energy, Apache and Occidental
Investing.com - Chevron (NYSE:CVX) Stock fell by 6.27% to trade at $71.31 by 09:31 (13:31 GMT) on Friday on the NYSE exchange.
(Bloomberg Opinion) -- Under the watchful eye of Beijing's energy hawks, China's oil and gas majors have splurged for more than a decade, first on deals abroad and then drilling at home. Yet with crude prices at less than half where they were at the start of the year and demand battered by a coronavirus epidemic, they're preparing to cut back.Cnooc Ltd. signaled Wednesday it might reduce its 2020 capital expenditure budget, which was set at as much as $13 billion, the highest since 2014. PetroChina Ltd., the country's largest oil producer with a market value of $117 billion, suggested Thursday that it would do the same. Given the delicate politics involved, it's a welcome hint of rational frugality.Energy security has always been a top concern for China's leadership. Overseas deals peaked at $28 billion in 2012, the year Cnooc bid for Canada's Nexen. Local production growth has been less exuberant, and China has been importing ever more. As trade tensions with Washington rose in 2018, President Xi Jinping urged the country's state-owned titans to drill. That set off a frenzy from deepwater fields in the South China Sea to shale gas in Sichuan, where China Petroleum & Chemical Corp., known as Sinopec, has led. Performing national service is fine when oil is at $60 a barrel, even if the improvements are unimpressive compared to the capital spent. It's a different matter when West Texas Intermediate is just coming off an 18-year low of less than $20. That's a price at which no one can make money — not even Cnooc, with an all-in production cost of less than $30 per barrel of oil equivalent. Cnooc's adventures in U.S. onshore and Canadian oil sands look terrible; its buccaneering domestic ventures are little better.Overseas, oil majors from Chevron Corp. to Saudi Aramco are cutting spending to preserve capital. Dividends are precarious. Logic dictates that China's producers, even with healthier balance sheets, will follow the same pattern. The question is whether they can put financial logic ahead of political necessity. So far, the message is cautious: Cnooc executives pointed out that 2020 spending targets were drawn up when oil was at $65, so adjustments would be made. It gave no specifics. PetroChina, meanwhile, didn't disclose precise targets for the year. That's no accident, given a volatile market. After a string of personnel changes, there are new bosses across the industry. Political priorities haven't been set in stone, given the delay in the annual National People's Congress meeting. Still, the official message has been clear: Life is returning to normal after a devastating shutdown. Announcing a drastic spending cut, or anything that might hint at job losses or a weak economy, simply isn't on the cards. PetroChina employed 476,000 at the end of 2018.That doesn't mean that there won't be mild cuts followed by steeper ones later in the year, a pattern seen before.How steep? Unlike during the last price crunch, in 2014 and 2015, the forward curve suggests prices will remain low, with little prospect for a quick solution to the Russia-Saudi spat that has worsened a global supply glut. Demand, meanwhile, is in the doldrums. China's economy, and therefore its own appetite for oil and gas, is recovering only slowly, and the rest of the world is ailing as more lockdowns, factory closures and travel restrictions are imposed to limit the spread of the coronavirus. Analysts at UBS Group AG forecast Cnooc's capex could come down 25% over the next two years, a cut that could be far deeper if oil averages closer to $30 this year. Overall, they project Chinese state-owned oil producers could cut spending by over a third, dragging production down 8% to 9%. Exploration budgets may be trimmed, though domestic production — where job preservation remains key — will mostly be spared. That leaves refining and other downstream activities, plus projects abroad, to bear the brunt. Low energy prices aren't all bad for China, which imports more than 70% of the crude it consumes. Even liberalization of the domestic gas market becomes easier when prices are low enough for consumers to cope with change, Michal Meidan of the Oxford Institute for Energy Studies points out. Cheaper oil could eventually stimulate demand. For now, a little less drilling all round. This column does not necessarily reflect the opinion of Bloomberg LP and its owners.Clara Ferreira Marques is a Bloomberg Opinion columnist covering commodities and environmental, social and governance issues. Previously, she was an associate editor for Reuters Breakingviews, and editor and correspondent for Reuters in Singapore, India, the U.K., Italy and Russia.For more articles like this, please visit us at bloomberg.com/opinionSubscribe now to stay ahead with the most trusted business news source.©2020 Bloomberg L.P.
(Bloomberg) -- High inventories of oil and low prices are forcing Venezuela to consider shutting wells, adding a dire context for Nicolas Maduro's handling of an economy already under stress from the coronavirus crisis.Overall production plummeted to 464,000 barrels of oil a day last week, according to two people with access to the data who asked not to be named because the information is private. That's down about 38% from February. Meanwhile, inventories of about 30.9 million barrels are sitting with no buyers on the coasts of Venezuela, Togo, Singapore, Malaysia, India and China.That's forcing Maduro's government to consider shutting wells, one person said. It's a decision that would come as ventures that make up more than half of Venezuela's output have dwindled over the past weeks.According to four people with knowledge of these operations, state-controlled Petroleos de Venezuela S.A. and Chevron Corp.'s Petropiar was at 50,000 barrels a day last week, down from 120,000 in January while Rosneft PJSC's main venture, Petromonagas, dropped to 20,000 barrels a day last week, a quarter of their January production.Expatriates and local employees at international oil companies including Chevron and Repsol SA were sent home in compliance with Maduro's nationwide quarantine measures on March 12, according to two of the people.Chevron declined to comment, while representatives for PDVSA, Rosneft and Repsol didn't respond to requests for comment.There are about 91 cases of the virus in Venezuela. Caracas and cities nationwide are in a lockdown and the only transportation allowed is for food, health, security and government business. Flights to Europe, Colombia and other destinations have been canceled.For more articles like this, please visit us at bloomberg.comSubscribe now to stay ahead with the most trusted business news source.©2020 Bloomberg L.P.
Dow Jones registered its best single-day gain since 1933. These stocks of the Dow ETF logged a superb rally on Mar 24.
Oil companies are already beginning to pare back their activity in the Permian, with cutbacks coming not just from smaller drillers, but also the oil majors
Apart from cost containment, Chevron (CVX) stalls its $5-billion share buyback program to ride out the current oil price rout.
The world's biggest oil and gas firms should break an industry taboo and consider cutting dividends, rather than taking on any more debt to maintain payouts as they weather the fallout from the coronavirus pandemic, investors say. The top five so-called oil majors have avoided reducing dividends for years to keep investors sweet and added a combined $25 billion to debt levels in 2019 to maintain capital spending, while giving back billions to shareholders. The strategy was designed to maintain the appeal of oil company stocks as investors came under increased pressure from climate activists to ditch the shares and help the world move faster towards meeting carbon emissions targets.
Shares of leading oil majors are rallying hard after they suspended buybacks and cut CAPEX--but maintained the all-important dividend
Oil has experienced one of the most vicious selloffs in history, with WTI crude plunging over 60% since the beginning of the year
Crude oil prices have crashed by 60% since January as Saudi Arabia and Russia pump full bore to grab share in a dwindling market, and gasoline and jet fuel use has slumped. The reset is being felt across the industry, as Chevron was joined on Tuesday in reducing expenses by oilfield service leaders Halliburton and Schlumberger , independent refiner Phillips 66 , and Canada's Suncor . "This is as unprecedented an oil price environment as I can recall seeing," Chevron Chief Executive Michael Wirth said in an interview.
Chevron is slashing capital expenditures, especially in the Permian, and is also about to suspend its share buyback program
(Bloomberg Opinion) -- The critical element when ripping off a Band-Aid is speed. Chevron Corp.'s cut to its spending budget and suspension of buybacks, announced Tuesday morning, hurts of course. Looked at another way, though, it merely acknowledges the injuries inflicted already. It also leaves a certain large rival whose name rhymes with MexxonObil looking like a laggard again, so that probably helps.No Western oil company's economics balance at $25-ish a barrel. The market knows this; hence, energy stocks currently vie with the similarly challenged Materials sector for the title of smallest in the S&P 500. Under such circumstances, and with oil demand having dropped into a chasm of pestilence, the prudent thing is to abandon even minimal growth and conserve as much cash as possible without wrecking the business or one's relationship with investors altogether. Chevron is cutting its capex budget by 20% and, having bought back $1.75 billion of stock in the first quarter, suspending repurchases until further notice.Cutting guidance isn't pleasant, but given the drop in the stock already, there's no need to disburse more cash: Even without the buyback, Chevron yields more today on pure dividend than it did on its analyst day. There's little point funneling more cash to investors if they aren't valuing it. A similar situation exists for ConocoPhillips, which trimmed capex and cut, but didn't suspend, its buyback program last week. That leaves one mega-cap U.S. oil and gas producer that is yet to adjust course.Exxon Mobil Corp. had the unfortunate timing of defending its counter-cyclical spending splurge the day before OPEC+ broke up in acrimony and sealed the oil market's fate. The company has since indicated it is evaluating potentially big cuts to spending, having suffered a credit-rating downgrade from Standard & Poor's in the meantime. But details are yet to come, and Chevron's move leaves Exxon looking flat-footed.Exxon now yields more purely on its dividend, but that indicates higher stress. Forecasts for 2020 are in flux to say the least. Still, using Ebitda as a proxy for cash from operations, current consensus figures imply Chevron needing to borrow a little to cover capex and payouts and Conoco covering from cash flow. Both have strong balance sheets. Exxon, on the other hand, has been borrowing or selling assets to cover dividends for a while. And consensus forecasts indicate cash flow won't cover capex, let alone the roughly $15 billion dividend payout.Despite Tuesday morning's bounce in oil prices, the market still faces the prospect of storage potentially being maxed out within a couple of months or so — which would precipitate a further crash. It is, therefore, perhaps too early to speculate on which oil stocks offer relative safety and gains on the other side of this crisis. Yet Chevron's and Conoco's yields, post spending cuts, look relatively robust. Chevron's stock is up 17% as of writing this. Exxon's yield may be higher, but the Band-Aid hasn't come off yet.This column does not necessarily reflect the opinion of Bloomberg LP and its owners.Liam Denning is a Bloomberg Opinion columnist covering energy, mining and commodities. He previously was editor of the Wall Street Journal's Heard on the Street column and wrote for the Financial Times' Lex column. He was also an investment banker.For more articles like this, please visit us at bloomberg.com/opinionSubscribe now to stay ahead with the most trusted business news source.©2020 Bloomberg L.P.
(Bloomberg) -- Chevron Corp. became the latest major oil company to take an ax to its budget after halting its $5 billion-a-year share buyback and halving spending in the Permian Basin, which means a large decrease in projected output from America's biggest shale region.The California-based oil giant said Tuesday it's lowering projected 2020 capital spending by 20%, or $4 billion. The Permian will account for the largest single element of that reduction, translating into 125,000 fewer barrels of oil equivalent per day than previously forecast, a quantity equal to about 2.5% of the basin's total current production."The largest single piece is in the Permian Basin, which we've indicated is a flexible portion of our portfolio," Chief Executive Officer Mike Wirth said in a Bloomberg Television interview. "The strength of Chevron's business is the ability to flex our capital if there were market signals indicating that was the right thing to do."European rivals Royal Dutch Shell Plc and Total SA this week also cut their buybacks until further notice as the oil majors scramble to save money wherever they can to protect their massive dividends, which have become central to their investment case in a world that's exploring alternatives to fossil fuels. Wirth said Chevon's payout is his "top priority" and emphasized that it hasn't been cut since the Great Depression.The global energy industry is slashing spending in the face of the major demand shock caused by the coronavirus and the price war between Saudi Arabia and Russia. Chevron's response was bigger than expected, which is "positive" for sentiment toward the stock, Biraj Borkhataria, an analyst at RBC Capital Markets, wrote in a note to clients.There was no mention in Chevron's statement of any reductions at Tengiz, its over-budget megaproject in Kazakhstan. Wirth had previously indicated that Chevron's Permian oil is among the profitable parts of its portfolio, meaning the cuts announced Tuesday may reduce its overall returns on capital employed, a key metric for the industry.Exxon Mobil Corp., the biggest Western oil major, had no buyback even before this month's collapse in oil prices and has yet to announce its response to the crisis. At $77 a barrel, it needs the highest crude price among all the majors to fund its capital spending and dividend from cash flow, according to RBC Capital Markets.Chevron was up 15% at $62.32 at 9:41 a.m. in New York amid broad gains for the stock market.Chevron's overall production this year is now seen as roughly flat relative to 2019.(Updates share price in eighth paragraph)For more articles like this, please visit us at bloomberg.comSubscribe now to stay ahead with the most trusted business news source.©2020 Bloomberg L.P.
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Content :Florence, the cradle of the Renaissance, houses wonderful works of art known throughout all the world, created by personalities such as Michelangelo, Giotto, Botticelli, Della Robbia, Pontormo, just to name a few of them.
City Sightseeing Florence offers you the opportunity to enjoy the views of the historic centre of the Medieval and Renaissance town, the small craft workshops, its gastronomic specialities and the stylish boutiques.
Details :Highlights
- Hop on and off as many times as you want.
- Discover the city from another point of view.
- Free admission for children from 0 to 4 years.
- 24h/48h/72h city sightseeing
- Public transport ticket
- Free app 'Sightseeing Experience', perfect to keep track of times and position of the buses
- Free walking tour
- Audio-guide
- Free WiFi
- Assistance on board
Commentary: Portuguese, Italian, English, French, German, Spanish, Japanese, Russian
Voucher details :Mobile tickets are NOT currently accepted. Print and present this ticket to the driver at any stops or exchange at City Sightseeing Experience Visitor Centre (Firenze Santa Maria Novella (SMN Station) platform 16. Open: Apr to Oct, 08.00 to 18.00).
Stop 1: Line A (Via Fiume); Line B (Michelangelo)
Duration: 60 to 120 mins
Frequency: 30 to 60 mins
Schedule: first tour at 09.30; last tours vary, please check on arrival.
Season: All year round.
Voucher general :TICKET INCLUDES ATAF PUBLIC TRANSPORT TICKET VALID THE SAME PERIOD OF YOUR CITY SIGHTSEEING TICKET! YOU MUST WRITE YOUR NAME ON ATAF TICKET.
NB: Pets are accepted on board subject to conditions. Bulky and heavy luggage is NOT accepted on board.
Come da accordi, pagabile da:
4 Elmwood, Crockford Lane
Chineham Park, Basingstoke
RG24 8WG, Regno Unito

subset: commoncrawl


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Technologically advanced 3 wheeled auto in stunning white, can be ridden on a car licence * congestion charge and Ulez friendly, has a FULL service history, 1 owner from new, fitted windscreen, Usb charger, comes with all books and manuals, 2 keys, hpi clear, sold serviced with a new mot and 3 months warranty, finance available, White, SELLING WHAT WE ARE HAPPY TO RIDE OURSELVES,UK-WORLDWIDE DELIVERY
We offer UK wide delivery, charged at £2.00 per mile - however this will be discounted where we can add your delivery to an existing delivery run. Our minimum delivery fee is £50. All delivery prices are subject to VAT.
Motorcycle Giant has partnered up with BikeSure - one of the UK's leading Motorcycle & Scooter insurance providers and winner of the Motorcycle Trader 2015 Industry Award for Motorcycle Insureance.
For best BikeSure rates ring 0800 089 8070 and quote reference G3748 to get our partnered prices!


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This is a guest post from Chris Hnin, of Tufts University, who went out as part of a group to talk to hotel and motel owners in Boston about how to identify and report child sex trafficking.
"Hi, would you like to hear about how you can help fight sex trafficking in your hotel?"
It was quite the perfect morning; the sun painted the sky clear blue and Boston was waking up to a beautiful Saturday. It was the day of an outreach effort to hotels and motels for us here at Love146 Tufts Chapter. In groups of no more than four, we headed to Downtown Boston, Alewife, and Fenway.
Prior to this date, we had put together a hospitality packet and some posters from Love146 to be distributed to each hotel and motel. In this neatly bound folder, you could find essential guidelines and hotlines for hospitality professionals – answering questions like: How do you identify potential trafficking activity? How can you provide aid? What are the available resources?
We then generated a list of hotels with two or three stars on Yelp.com and contacted them in advance.
As we made our way to the hotels we had successfully contacted before this date, our little box of folders and posters became lighter and lighter. And so did the weight of our initial worries.
We had been wary about how these hotels would respond to a bunch of college students. Would they take us seriously? Would they be apprehensive about our intents? Much to our relief, the managers and staff we met with were mostly receptive, and gave us the confidence that they were on our side.
There was an instance where a manager shared enthusiasm and knowledge about anti-trafficking efforts. It was encouraging to hear that the hotel already includes some abolitionist education in their staff training. The manager further assures us that he was aware of the same hotlines.
This was a great morale-boost for the team, and what we took away was the importance of increased efforts in upper management to actually integrate anti-trafficking education in its training curriculum.
While most of us had pleasant experiences, my friend Kenia recounts a particularly interesting interaction. According to Kenia, a manager at one of the more inexpensive hotels reacted quite adamantly to her explanations of the material, insisting that it was in the better and more luxurious hotels that the sex trade flourished. Though a bold (and ungrounded) claim, it definitely made us wonder whether our efforts were directed correctly at the lower-tier hotels.
Perhaps this manager knew better; perhaps the sex trade was immune to the differing standards of hotels.
We ended the day with a high. Knowing that we had brought attention to the issue to hospitality staff in the hotels we visited was a rewarding experience for all of us. Knowing that this attention – even if for a moment, even if for a day – could translate to further actions is what gives us hope and keeps us going.
Moving forward, what we think will be even more effective is to consider targeting outreach to hospitality executives in the Greater Boston area; to pass a kind reminder that they are the people who are more able to make or break an environment that welcomes the sex trade.
Want to talk to hotel owners in your city?
We've got everything you need!


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Everyone needs to understand nutrition. Seeking good nutrition is intimidating though. Thankfully, it is not necessary to completely upend your diet at once. The following tips are easy, yet effective, ideas to try.
Every sound dietary plan must incorporate riboflavin. We need it to release the energy found in food. Riboflavin also plays a major role in metabolism, as well as in the transportation of iron throughout the body. Products in which Riboflavin is found contain dairy, whole grains, and enriched grains, just to name a few.
Meat is not the only source of protein available. Many foods other than meat contain protein. Try eating things like soy, tofu, nuts and beans for a good source of nutritious protein. You can add these to an established dish, or just make a meal out of them. Eat more than one type of protein so that you do not get bored with your diet.
A multi-vitamin is a very important addition to your diet. This vitamin can give you the foundation for the minerals that you need during the course of the day.
Take as much salt out of your diet as possible. Junk foods, especially fast food menu items, are typically high in salt content. If you can decrease your salt intake in your daily diet, you may discover that you more easily notice its flavor occurring. Unhealthy foods will start to taste more salty. Your body will adjust, and your cravings will go away in time.
Selenium is very important in your diet. Selenium is a helpful antioxidant that helps with tissue elasticity, along with battling premature skin aging. Selenium can also neutralize the harmful effects of free radicals and protect the skin from sun damage. Wheat germ, tuna, brown rice, eggs, garlic, and brazil nuts are all high in selenium.
Try eating a vegetarian meal two or three times a week, even if you are not a vegetarian. You can enjoy a meal without meat just as much as a meat-based one, and you will reduce the amount of animal fat in your diet.
Eating Habits
Changing your diet can be overwhelming. Luckily, you can gradually transition to healthier eating habits rather than make a sudden drastic change. Every small change gets you closer to your big goal– a healthy diet full of good nutrition. The information here can assist you with developing better eating habits.
You should be professional when dealing with romance from now on. By using the above advice, you will not only have a better understanding, but you'll see it's much simpler than you may have realized. Just take things slow and you will end up being successful.


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The recent patch applied to LinuxSampler causes it to crash Ardour 3.
Could you please back that out and replace it with the one found at
http://tracker.ardour.org/view.php?id=4462? The second version there,
called linuxsampler-patch-3.patch, is the one you want, but it's missing
a file, lv2_state.h, that belongs in the src/hostplugins/lv2 directory,
and can also be found there. That patch was created by user cth103,
and was derived from drobilla's original patch, and works great with
Ardour 3 with no crashes. Thanks.
I should have mentioned that this is when the Ardour session being loaded
was saved with anything besides a GIG file (i.e. SF2 or SFZ). Also, it
seems that that patch was only a partial fix even though I had thought it
was complete before. For some reason, if I use an older release (2290)
with the patch I referred to, it now works with SFZ's, but still crashes
with SF2's, which I thought I had tested before, but I can't get it to
work now even if I go back to a prior release of Ardour, so either I
didn't test the patch with SF2's like I thought I remembered doing, or
something else has changed, and I don't know what it is. The current
release of LinuxSampler (2294), however, crashes Ardour with both SFZ's
and SF2's.
*** Bug 176 has been marked as a duplicate of this bug. ***


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Revised Common Lectionary: 2 Kings 2:1-2, 6-14 and Psalm 77:1-2, 11-20; 1 Kings 19:15-16, 19-21 and Psalm 16; Galatians 5:1, 13-25; Luke 9:51-62
Narrative Lectionary: Series on Psalms, Psalm 27:1-6 (Matthew 6:25-34)
Our first selection of the Hebrew scriptures in this season after Pentecost follows the prophets. We began with Elijah last week, and now, the mantle is passed to Elisha in 2 Kings 2:1-2, 6-14. Twice Elijah told Elisha to remain behind, but Elisha refused to leave him. Elijah used his mantle to strike the river Jordan and to pass through, as the Israelites passed through on dry ground when they came to the promised land. Before Elijah was taken up by the whirlwind, Elisha asked for a double portion of his spirit. Elisha mourned when Elijah was taken up, tearing his clothes, but afterward, he picked up Elijah's mantle, struck the Jordan and crossed back over, taking up Elijah's role as prophet over Israel.
In Psalm 77:1-2, 11-20, the psalmist calls to God in their distress, but also takes comfort in the work of God. The psalmist meditates on the greatness and holiness of God, recalling God's mighty act of delivering the people of Israel out of Egypt, leading them by the hand of Moses and Aaron. The psalmist sees God as a warrior, holding back the waters with arrows, and the waters trembled in fear. God is the one who works wonders and redeems the people from destruction.
The second selection of the Hebrew scriptures takes place before our first selection. In 1 Kings 19:15-16, 19-21, God told Elijah to anoint a new king of Aram along with a new king over Israel, and to anoint Elisha as prophet in his place. When Elijah found Elisha, he threw his mantle over him, but Elisha wanted to go say goodbye to his parents first. Elijah told him to go home, but Elisha returned only to slaughter his oxen, boil them and serve it to the people. Then he followed Elijah.
The psalmist calls out to God for protection in Psalm 16. Though others may choose other gods, the psalmist has chosen the Lord, their God, who instructs them and is present with them. God has kept them from death and has shown them the good way of life.
In Galatians 5, Paul speaks of living by the Spirit instead of the ways of flesh, to bear spiritual fruit. In arguing that they were no longer under the law, but that all were children of God by faith, Paul warns against using this as an excuse for self-indulgence. Rather, by the Spirit, all the faithful will show the work of the Spirit in their lives, of love, kindness, gentleness, and peace. For those led by the Spirit are guided by the Spirit.
In Jesus' ministry, he and the disciples traveled to different villages. In Luke 9:51-62, they entered a village of Samaritans, but they were not welcomed, because Jesus was already focusing on Jerusalem. However, James and John (known as Sons of Thunder in Mark 3:17) ask Jesus if they ought to call down fire on the village. Jesus rebukes them instead. As they travel on the road, others want to follow Jesus, but something is holding them back. Jesus warns they will have no home, and they cannot look back, if they truly want to follow him.
The Narrative Lectionary continues its series on the Psalms with Psalm 27:1-6. As enemies drawn near, the psalmist sings of their trust in God, that God is their light and salvation. The psalmist is assured of God's presence and deliverance and sings to the congregation that they will dwell with God forever, for God is faithful.
Jesus tells the disciples not to worry in Matthew 6:25-34. God has provided for all of creation, surely God will provide for all. Worrying does not do anything to help; instead, as Jesus teaches, work for the kingdom of God. When we are working together for the reign of God, when we care for other's needs, we find our own needs are met. God knows what they are, and when we work together for God's beloved community, we take care of each other.
Following Jesus comes at a cost. It is a commitment of our whole life, all of who we are. It is not a job that we leave at the end of the day, but a way of being. If we live by the Spirit, we are led by the Spirit, and we produce spiritual fruit. We are known by our love, by our actions, if we follow Jesus. The Way, as it once was known, must become our way of life.
Call to Worship
The Spirit is moving us,
To care for the world God has given us, as stewards of God's gifts.
The Spirit is moving us,
To follow Christ's call to love our neighbors as ourselves.
The Spirit is moving us,
To boldly proclaim God's reign of justice and peace.
The Spirit is moving us now, in this time of worship:
May we be filled with the Holy Spirit, for the holy work of God.
Prayer of Brokenness/Confession
Holy One, we confess that we have failed to care for the gifts You have given us. We've consumed more than we need and misused the resources entrusted to us for generations. We've failed to love our neighbors as ourselves, when love is the greatest gift from You. We've hoarded our gifts instead of using them for the good of all. At times, we have denied our gifts, refused to believe we have anything of use. Forgive us, O God, and call us into accountability. Forgive us, O God, and restore our faith and spirit. Forgive us, O God, and lead us into mutual responsibility to care for all You have given us. In the name of Christ we pray. Amen.
The Giver of all Good Gifts needs you. God made you with intention, to love and care for others. You are a blessing. You are a gift. Share who you are with others, knowing God's love, forgiveness, and mercy are always yours to have, and to share. Amen.
God Who Knows Us by Name, speak to us above the noise of the world. Speak to us through the love and wisdom of others. Speak to us in our grieving so we may recognize Your presence, as you did with Mary in the garden. Speak to us in our struggles and wandering, as you did with Paul. Speak to us so we may lead with boldness into Your ways, as you did to Moses and Miriam, Deborah and Elijah. Speak our names, and send us into Your world with Your love, justice, and mercy. Amen.
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Release Date: October 8th, 2019


text: SUGGESTION: Check-In ("What Are You Playing?") Category & Channels Folgen Dartis 20. Januar 2020 00:03 First up, i tried searching for check in and found mostly how to check things or change settings - nothing as to what I'm suggesting... Now for the actual post: A Check-In Feature - "What Are You Playing?" Category & Channels Basically in servers where a group of friends play multiple games and normally in groups seem to have a Voice Channel for each game - leaving the Voice Chat Category very cluttered. I feel this is simply a way of letting others know (without the notification under their name - as some disable it and on mobile you cant see it without looking specifically) what we are playing and whether you'd like to join seeing there's a group of players already in game. How this would work would be a custom named channel (for the games played in that server) that has no data usage but shows all members in that channel in a list. This way we can have simply say a few Voice Chat channels (simply named Game Chat 1 - 4) and a series of check in channels for the games played on that server - this would make "Show what You're Playing" completely opt-in without needing to change settings each time - which most simply either leave on or off. This might be over the top for everyone else - but i could definitely see it being used... And not just for Games - but maybe even Discord Servers that hold Tournaments - You'd Check-In before your match sort of thing... 0


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Change My Name
The team is called to Forks Washington to solve a case involving a serial killer who only targets brunette females. Meanwhile, Reid is acting very strange around a young female professor named Bella Swan.
One: Called In
Spencer Reid awoke to the sound of his alarm clock. He sighed and sat up in his bed, rubbing the sleep out of his eyes. Once again, his mind had decided to bring back the memories of his childhood before it flashed forward to the time he had been taking drugs. He grunted, running his hands through his mess of curls before removing himself from bed. He made his way into his kitchen and proceeded to make coffee, but found he was fresh out. He sighed again before heading back into his bedroom and getting ready for today.
As he finished placing on his vest, he walked towards his dresser and pulled out a picture. The picture was of a little boy, no older than three years old, grinning up at the camera, his eyes, one blue and the other green, were filled with nothing but glee. A small smile crossed Reid's lips before he slipped the picture into his back pocket and walked out the door. He walked to the coffee shop and ordered his usual order of black with two lumps of sugar and just a pinch of cream, paid and left. He took the elevator to the office and bypassed Prentiss and Morgan on the way, his mind on other matters.
"Hey Reid!" He stopped when he heard Morgan's voice and turned. The older agent walked up to the twenty-six year old genius and smiled warmly, "Good morning Pretty Boy."
"Morning Morgan, Prentiss."
They all walked into the briefing room and sat down. JJ walked into the room and cleared her throat, waiting for Hotch and Rossi to show up. It took them a total of five minutes for them to come in. JJ began then. She clicked the clicker and a picture of a woman of at least twenty-four popped up, her throat slit and blood everywhere. "This is Izzie Welsh. She was found murdered in an alleyway in a small town in Washington State. This is the third victim this month."
"Who were the others?"
JJ clicked and two more pictures appeared on the screen. "Zoey Tyler and Isabelle Fields. Same victimology: brunette, five foot four, slender, green or hazel eyes and they all had a three year son waiting for them when they got home."
"So the unsub targets single mothers and slits their throats?" Morgan asked.
"More than that, he stabs them in their chest and genital area before carving onto their arm the words 'You'll pay'."
"So what we're dealing with is a sexual sadist?" Rossi asked.
"Possibly," Hotchner stated. "JJ, what's the name of this town?"
"A small town called Forks. About two hours away from Seattle." JJ clarified. No one seemed to notice that Spencer hadn't spoke once since JJ started speaking, nor that he paled at the mention of the name.
"Well gang, pack your bags. We're going to Forks." Hotch confirmed and stood up.
Reid was the last to stand and his hand went for the picture in his pocket. He gazed down at the picture with a sigh before shoving it back into his pocket. As he walked past the calander on his desk he noticed the date, December 14, was circled in red.
Two days.


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For the health and safety of the Grand Valley community, remote academic instruction will continue through April 25. The Admissions office is available to answer calls Mon.-Fri. from 8 a.m. to 5 p.m. at 616-331-2025 or 1-800-748-0246 or email email@example.com. Additional instructions and updates at www.gvsu.edu/coronavirus
GV Now
18-year-old will earn computing degree at Saturday's commencement
Posted on December 05, 2019
Alec Betancourt will participate in the fall commencement ceremony December 7 at Van Andel Arena, earning a bachelor's degree in computing and information systems.
He is 18 years old.
Betancourt said he always knew he wanted to finish school early. He completed seventh and eighth grade as a homeschool student, then started high school in the Forest Hills Public Schools district at age 12.
"I found out pretty young that I was not a fan of school," Betancourt said. "My thought was to either put in extra years doing this or get it done early. I had a little fire under me, so to speak."
Aside from standing out academically, Betancourt has many hobbies, including playing the guitar and drums, cooking and coding. Coding became more than just a hobby when he decided his major would be computer science.
"I started coding when I was really young," he said. "I picked up Java and C. I was generally pretty familiar with computers."
By taking Advanced Placement courses, then dual-enrollment courses through Grand Rapids Community College, Betancourt earned a diploma from Forest Hills Central High School when he was 15 years old. By 16, he earned an associate's degree from GRCC and was a first-year student at Grand Valley, living on his own.
His senior computing internship last summer took him to Toledo, Ohio, where he helped with data and analytics for Owens Corning, a Fortune 500 company.
"I started searching for internships at the career fair and I got the offer the next day," Betancourt said. "So it was kind of one of those things I couldn't really turn down."
After graduation, Betancourt's next adventure will be leaving for the U.S. Army's infantry and airborne training on December 30.
"It's kind of the family business," he said. "Both my mom and my dad were officers. My granddad came to this country from Colombia and two months later got a draft notice in the mail. He got drafted on a residency visa. My great-granddad was in the Colombian Army — uncles, aunts, cousins, you name it."
And while his accomplishments deserve to be recognized, Betancourt insists he is just like any other student who aspires to earn a college degree.
"I think people look at my life and put it on a pedestal," he said. "Really, I think it's a little more boring. I have all the same hobbies, trials, tribulations and friends as any other person. I think my life is a little more normal than people would imagine."
Commencement begins at 10 a.m. The event will be webcast; watch the live stream online at gvsu.edu/commencement.
The keynote speaker will be A.C. Grayling, an author, professor of philosophy, and the master of London's New College of the Humanities.
Grayling was named the first master of New College, an independent undergraduate college, in 2011. The author of more than 30 books, Grayling also served as a columnist for theGuardian, Times, and Prospect magazine.
Grayling has served as judge for the Booker Prize, annually awarded to the best novel of the year published in the UK or Ireland.
The student speaker will be Nina Nguyen, a graduating student who will receive a bachelor's degree in integrated science and education.
— written by Olivia Conaty, student writer


text:
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Desktop-as-a-Service Designed for Any Cloud ? Nutanix Frame
IBM will take aim at Sun Microsystems Monday with the launch of
two new midrange servers -- the deskside p620 and rack-mounted p660
-- as part of its overall strategy to catch up to Sun, which leads
the U.S. in UNIX server market share. It also will open up things a
bit in the UNIX market by introducing its AIX 5L, which is primed
for Linux, in an effort to gain an edge over the closed systems of
its competitors.
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text:
Jquery Dialog Syntax Error Unrecognized Expression
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The Maze (3d blu-ray edition) (Blu-ray)
Directed by William Cameron Menzies
Veronica Hurst
Katherine Emery
Michael Pate
John Dodsworth
Hilary Brooke
Newly Restored in 3-D by 3-D Film Archive from 4K scans by Paramount Pictures Archives! The Maze is a 1953 atmospheric horror film in 3-D, directed by William Cameron Menzies (Invaders from Mars, Things to Come) and starring Richard Carlson (The Magnetic Monster) as Scotsman Gerald MacTeam (Carlson) who abruptly breaks off his engagement to pretty Kitty Murray (Veronica Hurst) after receiving word of his uncle's death and inheriting a mysterious castle in the Scottish Highlands. Kitty refuses to accept the broken engagement and travels with her aunt (Katherine Emery) to the castle. When they arrive, they discover that Gerald has suddenly aged and his manner has changed significantly. After a series of mysterious events occur in both the castle and the hedge maze outside, they invite a group of friends, including a doctor, to the castle, hoping they can help Gerald with whatever ails him. Menzies was known for his very dimensional style, focusing many shots in layers – The Maze was his final film as production designer and director.
Blu-ray Extras Include:
Interview with Star Veronica Hurst
Audio Commentary by Film Historian Tom Weaver
Restored three-channel stereophonic sound by Eckhard Büttner
Original 3-D Trailer
Reversible Art
"Another Golden Age 3D gem The Maze has been redeemed by the 3-D Film Archive for fans of subtle Gothic suspense complete with a really superb 3D rendering, a most effective new soundtrack mix, and some bonus features fans of the movie won't want to be without. Kudos!"
"This was so much fun - the best vintage 3D I've seen on Blu-ray and a wild, bizarre sci-fi horror gem. For fans of the 3D process this is essential, for everyone else it is simply warmly recommended!"
"Another restoration treat from the 3-D Film Archive."
"This Blu-ray is the beneficiary of a startlingly intense and highly enjoyable 3D restoration by Greg Kintz, Bob Furmanek, and everyone at the 3-D Film Archive. Also boasting quality sound and a couple of excellent extras including a must-listen commentary, this release of course comes very highly recommended and is an early contender for a spot on the year-end top-10 list. "
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Images added / Abbildungen hinzugefügt 02.05.2019
Generally Sonography Atlas of Dogs →
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S. Shor, B.A. Fadl-Alla, H.C. Pondenis, X. Zhang, K.L. Wycislo, S. Lezmi, and T.M. Fan "Expression of Nociceptive Ligands in Canine Osteosarcoma", Published online 2015 Jan 8. doi: 10.1111/jvim.12511
Canine osteosarcoma (OS) is associated with localized pain as a result of tissue injury from tumor infiltration and peritumoral inflammation. Malignant bone pain is caused by stimulation of peripheral pain receptors, termed nociceptors, which reside in the localized tumor microenvironment, including the periosteal and intramedullary bone cavities. Several nociceptive ligands have been determined to participate directly or indirectly in generating bone pain associated with diverse skeletal abnormalities.
Canine OS cells actively produce nociceptive ligands with the capacity to directly or indirectly activate peripheral pain receptors residing in the bone tumor microenvironment.
Ten dogs with appendicular OS.
Expression of nerve growth factor, endothelin‐1, and microsomal prostaglandin E synthase‐1 was characterized in OS cell lines and naturally occurring OS samples. In 10 dogs with OS, circulating concentrations of nociceptive ligands were quantified and correlated with subjective pain scores and tumor volume in patients treated with standardized palliative therapies.
Canine OS cells express and secrete nerve growth factor, endothelin‐1, and prostaglandin E2. Naturally occurring OS samples uniformly express nociceptive ligands. In a subset of OS‐bearing dogs, circulating nociceptive ligand concentrations were detectable but failed to correlate with pain status. Localized foci of nerve terminal proliferation were identified in a minority of primary bone tumor samples.
Canine OS cells express nociceptive ligands, potentially permitting active participation of OS cells in the generation of malignant bone pain. Specific inhibitors of nociceptive ligand signaling pathways might improve pain control in dogs with OS.
Under normal physiologic conditions, pain serves as a protective mechanism and is generated by depolarization of specialized peripheral neurons called nociceptors.1 Anatomically, nociceptors densely innervate tissues of cutaneous, musculoskeletal, and visceral origin, providing a comprehensive afferent neuronal network for the detection of noxious stimuli and early adaptive responses to avert severe tissue damage. Nociceptors can be stimulated by mechanical, chemical, and thermal activating pathways with the molecular drivers of painful sensations being categorized as nociceptive, neuropathic, or inflammatory in nature.2
In diseases such as cancer, the protective function of pain can become maladaptive, resulting in aberrant and dysregulated afferent nociceptor stimulation.3 Direct infiltration of tumor cells into connective and neuronal tissues can generate sensations of nociceptive and neuropathic pain by secretion of chemical mediators and spatial compressive effects, respectively. In addition, cancer cells can promote immune cell chemotaxis into the local microenvironment with consequent secretion of cytokines and degradative proteases to generate inflammatory pain. By virtue of chronic and pathologic nociceptor activation, pain is a common clinical manifestation in cancer patients and has been reported to affect up to 85% of people diagnosed with advanced stage cancers.4
Although the actual incidence of cancer pain in companion animals is unreported, painful behaviors can be observed in dogs and cats diagnosed with tumors involving the oronasal cavity, urogenital tract, alimentary tract, skin, and musculoskeletal system. Bone cancers, such as canine appendicular osteosarcoma (OS), frequently are associated with pain and lameness given the role of the skeleton for withstanding cyclical compressive forces during weight‐bearing activities. Specifically for bone tumors such as OS, nociceptors residing principally within the periosteum and medullary cavity can be pathologically activated by both mechanical and chemical stimulation.5 As a consequence of malignant osteolysis, regional skeletal integrity is compromised and physical distortion of bone can induce pain by activating skeletal mechanotransducers of the transient receptor potential vanilloid receptor family.6 Furthermore, a variety of chemical mediators produced and secreted by cancer, stromal, and migratory immune cells within the immediate bone tumor microenvironment have the capacity to directly activate nociceptors and induce pain.7
Although several chemical nociceptive ligands likely participate in the generation of bone cancer pain, arguably the most biologically relevant for OS progression would be ligands that not only have the capacity to activate nociceptors but also confer potential protumorigenic activities for malignantly transformed osteoblasts. Nerve growth factor (NGF), endothelin‐1 (ET‐1), and prostaglandin E2 (PGE2) are 3 well‐documented nociceptive ligands,8, 9, 10 which act as drivers of bone cancer pain and also participate in normal osteoblast activities including proliferation, migration, and survival.11, 12, 13 Given the potential duality for specific mediators to orchestrate both nociception and osteoblast biology, as well as the clinical need for confirming the presence of drug targets to improve analgesia in cancer‐bearing dogs, the purpose of this study was to investigate the expressions of NGF, ET‐1, and PGE2 in canine OS. The specific aims of this study were (1) to characterize the expression and secretion of nociceptive ligands in OS cell lines and tumor samples; (2) to study the relationships between subjective pain scores and circulating nociceptive ligand concentrations in dogs with OS; and, (3) to identify and characterize the existence of disorganized peripheral neuronal proliferation networks in primary OS bone lesions.
Four dog (Abrams, D17, HMPOS, and POS), 1 human (143B), and 1 murine (K7M2) OS cell lines, 1 human prostate carcinoma cell line (DU145), 1 human pulmonary carcinoma cell line (A549), and 1 rat pheochromocytoma cell line (PC12) were used in this study. The HMPOS and POS cell lines were provided by James Farese, University of Florida; the Abrams cell line was provided by Doug Thamm, Colorado State University; and all other cell lines were purchased commercially.1
Antibodies used in this investigation were rabbit monoclonal NGF antibody (Anti‐NGF antibody2 ), rabbit polyclonal ET‐1 antibody (Anti‐Endothelin 1 antibody2), rabbit polyclonal mPGES‐1 antibody (Prostaglandin E Synthase‐1 antibody3 ), rabbit polyclonal peripherin antibody (Peripherin antibody2), mouse monoclonal βIII tubulin (Anti‐βIII Tubulin antibody4 ) and mouse monoclonal β‐actin antibody (Anti‐beta Actin antibody2).
Protein from 6 OS cell lines (4 canine OS, 1 human OS, and 1 murine OS) were extracted with a standard reagent (M‐PER5 ) and quantified using a commercial kit (BCA Assay).5 In addition to OS cell lines, proteins from positive control cell lines were processed similarly. For detection of NGF, ET‐1, or mPGES‐1, membranes were incubated with a rabbit monoclonal NGF antibody (1 : 500), rabbit polyclonal ET‐1 antibody (1 : 1,000), or rabbit polyclonal mPGES‐1 antibody (1 : 50), respectively, in 5% nonfat dry milk TBS‐Tween overnight at 4°C. Subsequently, membranes were stripped and reprobed with a rabbit polyclonal β‐actin antibody (1 : 5,000) and HRP‐conjugated secondary antibody (1 : 1,000).
Sixteen canine appendicular OS tissue blocks were provided by Dr Luke Borst (North Carolina State University) for immunohistochemical assessment. Blocked slides were incubated with rabbit primary antibodies against NGF (1 : 400), ET‐1 (1 : 2,000), or mPGES‐1 (1 : 250) for 1 hour at room temperature. Slides were incubated with a biotinylated secondary antibody for 20 minutes at room temperature, then washed in buffer before incubation for 20 minutes with a streptavidin–biotinylated horseradish peroxidase complex, and developed with DAB substrate for 5 minutes and counterstained with hematoxylin. Staining intensity for each naturally occurring OS sample was scored by a single investigator (KLW) based on a previously published methodology.14
Five OS cell lines and respective positive control cell lines for NGF, ET‐1, and PGE2 were incubated in 6‐well plates at a cell density of 2.5 × 105 per well in 1% FBS DMEM for 48 hours. After 48 hours, cell culture supernatants were assessed for NGF, ET‐1, and PGE2 concentrations using NGF,6 ET‐1,7 and PGE2 (Prostaglandin E2 EIA3) ELISA kits, previously described for the assessment of canine ligands.15, 16, 17 Concentrations of secreted nociceptive ligands were normalized for in vitro cell metabolic activity assessed by a colorimetric MTS assay (CellTiter 96 Aqueous One Solution4), and expressed as an arbitrary ratio (concentration/optical density).
In 10 untreated dogs with appendicular OS, serial plasma and serum were collected at day 0 (pretreatment), day 28, day 84, and at the time of localized pain progression (failure) after institution of standardized palliative treatment including ionizing radiation (10 Gy on days 1 and 2), IV zoledronate (0.1 mg/kg IV as 15‐minute constant rate infusion q28d), and a combination of PO analgesics including deracoxib (2 mg/kg q24h), tramadol (2 mg/kg evq8h), and gabapentin (5 mg/kg q24h). Concentrations of circulating NGF, ET‐1, and PGE2 were quantified using commercially available NGF,6 ET‐1,8 and PGE23 ELISA kits.
In 10 untreated dogs with appendicular OS, serial assessment of pain was subjectively characterized by pet owners by use of the visual analogue scale (VAS) pain score questionnaire18 at day 0 (pretreatment), day 28, day 84, and at the time of localized pain progression (failure) after institution of standardized palliative treatment.
Absolute tumor volume (ATV) of primary bone OS tumors was calculated using a previously described methodology.19
Ten primary bone OS and 2 normal bone samples were histologically sectioned at 5 μm thickness, placed onto pretreated glass slides, dewaxed, rehydrated in water, and then used for immunohistochemical analyses as previously described.20 Each section was incubated with primary antibodies recognizing either βIII tubulin (1 : 200) or peripherin (1 : 1,000). A secondary biotinylated antibody9 (1 : 500) and avidin–biotin–peroxidase complex system10 were used. Slides were scanned for "hot spots" consistent with disorganized nerve endings sprouting within periosteal tissues immediately adjacent to viable OS bone lesions and compared to normal bone sections, and the number of nerve endings was counted in a total of 5 fields (135,000 μm2/field) per sample.
In dogs with OS, changes in an experimental variable (VAS, NGF, ET‐1, and PGE2) with respect to time either were analyzed by a repeated measures 1‐ANOVA and posthoc Dunnet's test or by a Friedman test and posthoc Dunn test. Significant changes in either subjective pain scores or circulating nociceptor mediators were compared with day 0 (pretreatment). Spearman rank correlation was performed to analyze the existence of any relationship between VAS and ET‐1 or PGE2 concentrations, as well as relationships between ATV and VAS, ET‐1, or PGE2. Significance was defined as P < .05.
Osteosarcoma cells derived from human, murine, and canine origin expressed NGF and ET‐1 (Fig 1A,B). In addition, all OS cell lines expressed the rate‐limiting enzyme, mPGES‐1, required for production of PGE2 (Fig 1C). Unlike the relatively uniform protein expressions detected by western blot analysis, the active secretions of nociceptive ligands were divergent. For NGF (Fig 2A), the average concentration secreted by positive control human prostatic carcinoma cells was 29.8 ± 1.5 pg/mL/OD, which was within the limits of analyte detection. In addition, the 143B human OS cell line released low but measurable concentrations of NGF (15.9 ± 1.1 pg/mL/OD). Of the 4 canine OS cell lines, only HMPOS actively secreted higher concentrations of NGF (44.0 ± 6.7 pg/mL/OD), whereas the remaining 3 canine OS cell lines questionably secreted NGF at concentrations approaching or below the manufacturer reported level of analyte detection, being 5.3 ± 1.1 pg/mL/OD, 3.1 ± 0.4 pg/mL/OD, and 11.7 ± 2.7 pg/mL/OD, respectively. For ET‐1 (Fig 2B), all cell lines released measurable quantities of ET‐1 within the sensitivity limits of the assay, with the positive control cell line DU145 producing 23.7 ± 0.4 pg/mL/OD. For the 5 OS cell lines, ET‐1 secretion varied with the HMPOS cell line producing the lowest quantity of 1.4 ± 0.1 pg/mL/OD, whereas the Abrams cell line actively secreted ET‐1 at a concentration of 100.3 ± 0.8 pg/mL/OD. The release of PGE2 was relatively uniform among 4 of the 5 OS cell lines screened, ranging from 111.2 ± 12.1 pg/mL/OD to 2,676.2 ± 93.1 pg/mL/OD. The HMPOS cell line secreted substantially greater concentrations of PGE2 at 89,112.0 ± 4,577.0 pg/mL/OD.
Figure 1: In a panel of cell lines inclusive of known positive controls (far left lane) and 6 osteosarcoma cell lines (human, murine, and canine), cellular proteins for (A) NGF, (B) ET‐1, and (C) mPGES‐1 are detected by western blot analysis. Species of origin: Human‐143B; Murine‐K7M2; Canine‐Abrams, D17, HMPOS, and POS.
Figure 2: In a panel of cell lines inclusive of known positive secretory controls (far left) and 5 osteosarcoma cell lines (human and dog), active secretions of (A) NGF, (B) ET‐1, and (C) PGE2 into the cell culture supernatants are quantified by ELISA after 48 hours of incubation and normalized for differences in metabolic activity.
All tumor samples demonstrated diffuse cytoplasmic staining for all 3 nociceptive ligands (Fig 3A). Among the 3 nociceptive ligands, ET‐1 was most robustly and consistently expressed with 16/16 samples demonstrating a 3+ staining score, whereas NGF and mPGES‐1 staining was 3+ positive in 9 and 10 samples, respectively (Fig 3B). Although all nociceptive ligands demonstrated cytoplasmic subcellular localization, immunohistochemical detection of mPGES‐1 also was identified within the nucleus in approximately 10–15% of malignant osteoblast cells.
Figure 3: (A) Microscopic appearance of a representative spontaneous canine OS sample by H&E staining and confirmed protein expressions of NGF, ET‐1, and mPGES‐1 by immunohistochemistry. (B) Tabulated immunohistochemical staining summary for NGF, ET‐1, and mPGES‐1 expression in 16 spontaneously arising OS samples.
In 10 untreated dogs with OS (Table S1), serial changes in VAS pain scores and circulating nociceptive ligand concentrations were characterized after effective pain alleviation. The median pretreatment (day 0) VAS pain score was 3.5 (range, 0.0–7.0), which decreased after the institution of treatment to 1.5 (range, 0.0–6.0) at day 28 and 2.5 (range, 0.0–6.0) at day 84, and subsequently increased to 6.0 (range, 1.0–9.0) at time of bone pain progression (Fig 4A). Median VAS pain scores on days 28 (P < .05) and 84 (P < .05) were significantly decreased in comparison with day 0.
Figure 4: Serial changes as a function of time in (A) VAS pain scores and plasma concentrations of (B) NGF, (C) ET‐1, and (D) PGE2 derived from 10 OS‐bearing dogs treated with standardized palliative therapies. Data expressed as median and interquartile range for (A–C) and mean ± SEM for (D). Significant differences relative to Day 0 denoted with either *P < .05 or **P < .01.
In the same 10 dogs, circulating NGF, ET‐1, and PGE2 concentrations were serially quantified. In 7 dogs, NGF concentrations were below the limits of detection (Table S1), but the remaining 3 dogs had quantifiable NGF concentrations with median values of 132.6 pg/mL (range, 59.3–228.2), 152.6 pg/mL (range, 44.0–187.4), 139.6 pg/mL (range, 21.6–142.1), and 128.0 pg/mL (range, 24.6–174.4) at days 0, 28, 84, and failure, respectively (Fig 4B). Based on these 3 dogs, NGF concentrations did not appear to change after institution of effective palliative treatment, but statistical analysis was not performed because of the limited sample size. For ET‐1, 7 dogs had ET‐1 concentrations between 4.0 and 12.0 fmol/mL, whereas 3 dogs had higher concentrations of ET‐1 ranging from 45.0 to 84.5 fmol/mL (Table S1). The median concentrations of ET‐1 at days 0, 28, 84, and failure was 8.8 fmol/mL (range, 4.0–84.5), 6.6 fmol/ml (range, 4.4–62.6), 6.5 fmol/mL (range, 4.0–60.3), and 9.2 fmol/mL (range, 4.3–57.3), respectively. Compared to pretreatment (day 0), ET‐1 concentrations were significantly decreased on day 84 (P < .05; Fig 4C). The average plasma concentrations of PGE2 were 368.7 ± 73.5 pg/mL, 134.1 ± 20.5 pg/mL, 122.7 ± 17.5 pg/mL, and 129.7 ± 11.8 pg/mL on days 0, 28, 84, and failure, respectively (Fig 4D). Decreases in plasma PGE2 concentrations in comparison with day 0 were significant for all time points: day 28 (P < .01), day 84 (P < .01), and failure (P < .01).
No correlations between individual VAS pain score and ET‐1 or PGE2 concentrations at each respective time point (days 0, 28, 84, and failure) were identified. The ability to assess for any correlation between individual VAS pain score and NGF concentrations was precluded given the limited number of dogs (n = 3) with measurable NGF concentrations. Relative primary bone tumor burden in dogs with OS was expressed as ATV, and among the 10 OS‐bearing dogs was calculated to be 107.0 ± 13.6 cm3. No correlation between ATV and any individual pain parameter at baseline was identified.
To investigate if sensory nerve fiber sprouting occurs in canine OS, 10 archived primary OS samples were stained for 2 neuronal markers: class III β tubulin and peripherin (Fig 5A,B). Systematic evaluation of 5 microscopic fields (135,000 μm2/field) containing periosteal tissues adjacent to viable malignant osteoblasts identified positive staining for both class III β tubulin and peripherin in 20% of tumor samples (Fig 5C,D), whereas periosteum from normal bone (data not shown) and the majority of OS samples did not show any significant immunolabeling (Fig 5E,F). Quantitatively, in 2 of the 10 OS samples, the number of positively labelled nerve foci per microscopic field ranged from 0 to 25, with a median value of 3 nerve termini/field. In the remaining 10 bone samples (8 OS and 2 normal bone), no obvious detectable nerve termini were identified within the periosteum.
Figure 5: Microscopic appearance of a peripheral sensory nerve traversing through control tissue as indicated by positive immunohistochemical staining for (A) class III β tubulin and (B) peripherin. Haphazard and disorganized proliferation of neuronal endings identified within OS‐associated periosteum as determine by positive immunohistochemical staining for (C) class III β tubulin and (D) peripherin. Representative OS‐associated periosteum which is devoid of excessive neuronal end proliferations based upon the absence of (E) class III β tubulin and (F) peripherin immunohistochemical staining.
Although various nociceptive ligands likely participate in generating OS bone cancer pain, the current investigation focused on NGF, ET‐1, and PGE2 given their potential roles in not only malignant osteolytic nociception but also OS protumorigenic biology. In particular, NGF and ET‐1 have been intensively evaluated as drug targets for the alleviation of bone cancer pain in murine preclinical models. In these studies, the neutralization of NGF with blocking antibodies or small molecule inhibitors decreased nociceptive guarding behaviors in mice implanted with prostatic carcinoma or osteolytic sarcoma cells within the bone medullary cavity.21, 22, 23 Similarly, ET‐1 signaling blockade with small molecule inhibitors in tumor‐bearing mice alleviated painful sensations induced by the osteolytic growth of prostatic carcinoma or bone sarcoma cells.24, 25 Although inflammatory eicosanoids, particularly PGE2, have long been recognized to participate in nociceptor sensitization associated with inflammatory disorders, recent investigations have directly linked PGE2 with tumor‐induced osteolysis and bone cancer pain.26, 27, 28 Importantly, the rate limiting enzyme involved in PGE2 generation (mPGES‐1) has been demonstrated to enhance bone tumor growth and malignant osteolytic pain behaviors in preclinical murine models,29 and provides a biologic rationale for inhibiting mPGES‐1 enzymatic activities to ameliorate pain associated with malignant osteolysis. Despite many studies defining the drivers of malignant bone pain in murine preclinical models, canine OS‐associated bone pain remains incompletely defined and warrants studies to identify pathways involved in the development and maintenance of bone cancer pain in dogs.
Although localized pain is a salient hallmark in dogs diagnosed with OS, the clinical spectrum of pain symptomatology is heterogeneous among affected patients, and likely reflects the complex interplay among several tumor‐ and host‐related factors including degree of osteolysis, tumor volume and location, skeletal mass and physical activity. Findings in this study suggest that additional tumor‐specific factors also could contribute to the variable spectrum of malignant bone pain, specifically the inherent capacity of OS cells to express and actively secrete nociceptive ligands. Malignant osteoblast cell lines demonstrated a wide variability in the secretion of nociceptive ligands, with the magnitude of difference between the highest and lowest secreted concentrations ranging approximately 10‐fold, 100‐fold, and 800‐fold for NGF, ET‐1, and PGE2, respectively. In addition, all naturally occurring OS samples demonstrated uniform and positive staining for NGF, ET‐1, and mPGES‐1, and if malignant osteoblasts retain divergent capacities for localized nociceptive ligand secretion within the bone tumor microenvironment, it is plausible that the severity of bone pain in dogs could be partially mediated by the existence of different clonal populations with variable secretory capacities.
In this study, the relationship between VAS pain scores and plasma concentrations of NGF, ET‐1, and PGE2 were explored in OS‐bearing dogs receiving standardized palliative treatment. As expected, the alleviation of pain after effective palliative treatment decreased the median VAS pain scores on days 28 and 84 in comparison with day 0 and, upon recurrence of breakthrough pain, VAS pain scores rebounded back to pretreatment levels. Plasma concentrations of NGF, ET‐1, and PGE2 tended to decrease after palliative treatment, but strong correlations between VAS pain scores and circulating nociceptive ligand concentrations were not identified in the limited population of dogs evaluated. As such, the preliminary data generated from the current investigation do not support the utility of plasma NGF, ET‐1, and PGE2 concentrations as surrogates of bone pain or absolute tumor volume in dogs with OS. Corroborating the imperfect association between pain intensity and circulating nociceptive ligands identified in this study, correlations between plasma NGF concentrations and pain intensity in people suffering from various pathologic conditions including chronic migraine, interstitial cystitis, and temporomandibular joint and myofascial pain also have yielded conflicting results.30, 31, 32
Although circulating concentrations of NGF, ET‐1, and PGE2 were not correlated with pain status in dogs with OS, ours is the first report to serially characterize pre‐ and posttreatment plasma concentrations of nociceptive ligands in dogs with OS. For NGF and ET‐1, it is noteworthy that systemic concentrations of both ligands could be dichotomously categorized as being either marginally or robustly detectable, and the observed pattern could be consistent with differing secretory capacities of canine OS cells as demonstrated in vitro. Among the 3 ligands, plasma PGE2 concentrations were most consistently detectable in dogs with OS, and demonstrated expected decreases after administration of nonsteroidal anti‐inflammatory drugs (NSAIDs), findings consistent with historical studies in tumor‐bearing dogs treated with NSAIDs.33
Gradual intensification of bone pain is a frequent clinical observation in dogs diagnosed with OS, and is a consequence of progressive mechanical, chemical, and neuronal perturbations within the immediate bone tumor microenvironment. In murine preclinical models of malignant bone pain, aberrant nerve sprouting has been identified as a driver of pathologic pain intensification,34, 35 yet whether an analogous process is operative in naturally occurring bone tumors such as canine OS has not been reported previously. Of 10 primary OS samples, excessive proliferation of nerve endings within tumor‐associated periosteum was definitively observed in 2 cases, suggesting that aberrant nerve sprouting might contribute to progressive pain intensification in some affected dogs. Given that only a small fraction of the periosteal surface area was microscopically evaluated in this study, the percentage of bone samples recognized to exhibit aberrant nerve sprouting likely underestimates the true frequency of neuropathologic alterations induced by OS‐associated chronic bone pain. Based upon these findings, it would be reasonable to suggest that treatment strategies that inhibit pathologic neuronal sprouting, such as NGF blockade, might attenuate the severity of bone pain in dogs with OS.
Despite the novel findings of this study, there are several investigative limitations that should be recognized. First, the mere demonstration of nociceptive ligand expression by OS cells does not provide evidence for the direct or indirect participation of OS cells in pain generation, rather it can only be stated that OS cells are capable of producing ligands with recognized nociceptive functions. Second, although NGF, ET‐1, and PGE2 were chosen for investigation based on their known involvement in nociception, these molecules can be produced by a broad range of cell types and also exert diverse effects completely unrelated to pain sensation. In fact, within the bone tumor microenvironment, nonmalignant resident cells including osteoclasts, mature osteocytes, and trafficking immune cells were identified to stain positively for some of the nociceptive ligands characterized. Hence, their evaluation in dogs with OS as exclusive biomarkers of bone pain would be erroneous given their involvement in diverse homeostatic processes including cardiovascular, neuronal, and cell membrane physiology. Third, rather than measuring systemic circulating nociceptive ligands, assessment of their intratumoral concentrations would have been expected to correlate better with localized bone pain status, as supported by preclinical murine tumor models.28
In summary, the descriptive findings reported here provide incremental advancements in identifying potential driver pathways that might participate in malignant bone pain generation in dogs with OS. Improving treatment outcomes in people suffering from bone cancer pain has been possible only by the initial identification of key cellular processes involved in malignant osteolysis and pathologic nociceptor activation, with several novel analgesic targets being validated and consequently translated into clinical practice.24, 36, 37 The rational development and clinical institution of superior analgesic regimens for dogs suffering from OS‐associated bone pain will require a similar discovery path. The findings of thist study might serve as an initial catalyst to stimulate future research into the functional pathways responsible for pathologic nociception in dogs suffering from malignant bone pain.
Conflict of Interest Declaration: Dr Timothy Fan is an associate editor at the Journal of Veterinary Internal Medicine.
Off‐label Antimicrobial Declaration: The authors declare no off‐label use of antimicrobials.
1American Tissue Culture Collection, Manassas, VA
2Abcam, Cambridge, MA
3Cayman Chemical, Ann Arbor, MI
4Promega, Madison, WI
5Pierce, Rockford, IL
6ChemiKine NGF, Sandwich ELISA, EMD Millipore, Billerica, MA
7Endothelin‐1 ELISA, Immuno‐Biological Labs Co, Hamburg, Germany
8Endothelin ELISA (1‐21), ALPCO, Salem, NH
9Jackson Laboratories, Bar Harbor, MA
10ABC Vector Laboratories, Burlingame, CA
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