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Twin Perfos
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This season's sensation, Twin Perfos from Pierre Hardy, are two-tone calfskin brogues. With a blend of styles, these avant-garde, lace-up shoes pair the brogue style floral toe with the clean lines of the derby at the back. This model alternates silver and black tones. Two-toned down to the smallest detail, the soles are tinted tone on tone with the color of the body of the shoe.
- Heel height
0.8 inch
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50% leather capra hircus/ 50% leather bos taurus Lining : 100% leather


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Palazzo de Pero
An ancient watchtower. In 1300 an imposing building with a square plan and a mighty tower was built on this strip of land (570 metres above sea level) close to Arezzo, which marked the boundary between the two Italy, those of the Longobards and Byzantines.
The fascinating building of military origin, still visible in the traces of battlements and in a few slit windows, has been carefully restored and transformed into a comfortable holiday villa.
Thanks to this radical renovation the villa Torre di Vignale, that rises up majestically amongst thick oak and chestnut woods, has regained the importance and allure that had been eliminated by time.
The outdoor area and the panoramic swimming pool. The villa Torre di Vignale is surrounded by a large, panoramic garden full of flowers and equipped with garden furniture, barbecue and wood-burning oven. On one side of the garden, above the villa, there is a beautiful swimming pool ((URL HIDDEN)depth 1,20 - 2,20 m.).

subset: commoncrawl


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Right now, CBD is all the rage, but ten years ago it took a team effort of growers, researchers, breeders, and scientists to identify the few remaining high-CBD strains in existence and match them up with growers willing to take a chance on the then obscure cannabinoid. Next, they had to convince profit-minded dispensary buyers to stock their shelves with strains that don't get you high.
Not surprisingly, those efforts were met with much initial skepticism. But then it quickly became apparent that CBD-rich strains appeal to a lot of people, particularly those seeking the medicinal benefits of cannabis without any intoxicating effects'ÄĒincluding seriously ill children.
The earliest pioneers of cannabis horticulture (circa 10,000 years ago), though new to agriculture itself, would certainly have been capable of using selective breeding to enhance desired traits from generation to generation. If nothing else, then by simply culling out plants that grew poorly over the course of the season and planting seeds from crops that flourished.
So what are desired traits when it comes to cultivating cannabis?
Growers would want plants that thrive in their local climate, including resistance to mold, disease, insects, and drought. But that's just to ensure a reliable supply.
In a time long before modern science, the most observable and accurate way to gauge potency was by ingesting some of your harvest and seeing how high you got.
The point of it all is potency, and in a time long before modern science, the most observable and accurate way to gauge potency was by ingesting some of your harvest and seeing how high you got. Which is all pretty much any cannabis breeder had to go on until about ten years ago, when analytic testing labs became widely available in California and other states with legal medical cannabis.
Turns out the medicinal and psychoactive effects of a particular cannabis strain depends on a complex interplay of cannabinoids, terpenes, and flavonoids that researcher Ethan Russo has dubbed the entourage effect. In 2006, Russo led a team that published a fascinating paper titled Phytochemical and genetic analyses of ancient cannabis from Central Asia, which has an abstract that opens like something out of Indiana Jones.
'ÄúThe Yanghai Tombs near Turpan, Xinjiang-Uighur Autonomous Region, China have recently been excavated to reveal the 2700-year-old grave of a Caucasoid shaman whose accoutrements included a large cache of cannabis, superbly preserved by climatic and burial conditions.'ÄĚ
The samples were so 'Äúsuperbly preserved,'ÄĚ in fact, that Russo and his team were able to have them lab tested, and found through gas chromatography that the 2,700-year-old shaman stash appeared to be 'Äúa high-THC cannabis strain wherein CBD is only a minor component.'ÄĚ
It wasn't that ancient cannabis smokers had it out for CBD, they just didn't know such a thing existed. The compound wasn't isolated in a lab until 1940 and remained obscure long after that, largely because it doesn't get you noticeably high.
Since the 1980s, studies have hinted at CBD'Äôs potential for treating pain, insomnia, nausea, anxiety, spasticity, MS, Alzheimer'Äôs, cancer, seizure disorders and a host of other serious conditions. But for the general public, it was completely unknown'ÄĒand since CBD actually works to temper the high of THC, cannabis breeders had been unwittingly breeding it out of the cannabis gene pool for 10,000 years.
When Steep Hill Lab in Oakland opened in 2007, the first commercial medical cannabis testing lab in the United States found that the cannabis flowers they tested averaged over 15% THC, but only one in every 600 samples reached 4% CBD.
In 2010, journalist Fred Gardner (editor of O'Shaughnessy's: The Journal of Cannabis in Clinical Practice) and author Martin Lee (Smoke Signals, Acid Dreams) co-founded Project CBD, a non-profit educational clearinghouse for physicians, scientists, growers, cannabis-testing laboratories, patients, and retailers interested in learning more about the medical utility of CBD.
They fully understood that CBD has important benefits, but that finding CBD-rich cannabis in the underground market was virtually impossible.
Through years of careful research and reporting, they fully understood that CBD has important therapeutic benefits, but that finding CBD-rich cannabis in the underground market was virtually impossible. So they teamed with Steep Hill Labs and Harborside Health Center (then the nation's largest medical cannabis retailer) to begin immediately flagging any sample that tested high in CBD. Project CBD would then meet with the grower, and work to ensure that their particular strain proliferated and reached patients who could benefit.
Most of these growers understood their heirloom strains had unique properties, but didn'Äôt know why'ÄĒincluding Lawrence Ringo, the late proprietor of the Southern Humboldt Seed Collective. Ringo began growing cannabis while still a teenager, and 40 years later became the first California plant breeder to stabilize a CBD-rich strain with his much-beloved Sour Tsunami.
In 2015, Dr. Sanjay Gupta'ÄĒCNN'Äôs Chief Medical Officer'ÄĒreported on the Stanley Brothers in Colorado, who were having tremendous success treating pediatric seizure disorders with their high-CBD strain Charlotte'Äôs Web, named for their most famous patient.
'ÄúTake the case of [six-year-old] Charlotte Figi, who I met in Colorado,'ÄĚ Gupta said by way of introducing his mea culpa on medical cannabis. 'ÄúShe started having seizures soon after birth. By age 3, she was having 300 a week, despite being on seven different medications. Medical marijuana has calmed her brain, limiting her seizures to 2 or 3 per month.'ÄĚ
This after the poor girl endured five years of failed pharmaceutical cocktails, and a series of terribly painful procedures that left her unable to walk, talk, or eat.
So no wonder, once they saw that incredible story on CNN, other families facing similar circumstances began to agitate for access to CBD. Along the way, the rest of the world got let in on the secret that there'Äôs a lot more to weed than just THC. CBD is officially 'Äútrendy'ÄĚ now, but nearly a decade after the founding of Project CBD, there'Äôs still a relative dearth of CBD-rich strains.
Though that'Äôs changing'ÄĒquickly.
Scientifically, the plant you smoke to get high and the plant you use to make rope are the same species. But legally, hemp is defined as a Cannabis sativa plant that'Äôs less than 0.3% THC on a dry weight basis'ÄĒno matter how much CBD (or other cannabinoids) it produces.
But wait, does that mean anyone who registers with their state can legally grow a crop of hemp that's 15% CBD and looks just like any other budding resinous sinsemilla cannabis plant? Sure does. And if you don't believe me, here's the federal government's new definition of hemp, from the 2018 Farm Bill, with my emphasis added:
(1) HEMP.'ÄĒThe term 'Äėhemp'Äô means the plant Cannabis sativa L. and any part of that plant, including the seeds thereof and all derivatives, extracts, cannabinoids, isomers, acids, salts, and salts of isomers, whether growing or not, with a delta-9 tetrahydrocannabinol concentration of not more than 0.3 percent on a dry weight basis.
Andrew Gruver is the head of operations at Tweedle Farms in Oregon, a retailer of high-CBD hemp flower that currently ships 15 different varietals to (almost) all 50 states.
Andrew Gruver, Head of Operations at Tweedle
'ÄúThere are certain hemp strains,'ÄĚ he tells Leafly, 'Äúthat for me are pretty indistinguishable from high quality outdoor cannabis other than the lack of THC.'ÄĚ
His favorite at the moment is Sour Space Candy, a descendent of Lawrence Ringo's original Sour Tsunami with a cannabinoid content of 16.52% CBDA and .08% THC.
'ÄúIt'Äôs loud, it'Äôs resinous, and it tastes good,'ÄĚ Gruver says. 'ÄúAlso, it'Äôs high in terpinolene, which a lot hemp strains are not. Hemp typically exhibits high levels of myrcene, caryophyllene, or maybe some pinene. But we also get really interesting terpenes like bisabolol, farnesene, valencene.'ÄĚ
His other favorite strains include Hawaiian Haze from Oregon CBD, Berry Blossom from HGH, and Kush Hemp from Sovereign Fields. And we're just getting started.
The search for high-THC cannabis dates back millennia, but this current exploration of CBD-rich cannabis breeding remains in its infancy.
Source: https://www.leafly.com/news/strains-products/why-there-arent-more-cbd-strains


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Marizza/Pilar/Mía || Hot mess
Tammy Age: 27. I'm ', lbs with waist length dark hair dark eyesI am sure we spend Nice time togheter And i will made you mad with my hot body
Busty blondies Kali & Taylor like sex in group sex scene
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Views: 3911 Date: 2018-06-21 Favorited: 18


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After you and your physician select the area(s) to be treated, the device is positioned on your body and controlled cooling is applied. A gel pad and applicator are applied to the targeted area. Vacuum applicators draw the tissue into the applicator cup. Applicators are secured to the treatment area. All applicators deliver controlled cooling to the targeted fat.
When diet and exercise efforts have been tried, tried again, and then exhausted, it can feel as achieving your dream figure is completely out of reach. However, modern medical technology and micro-body contouring techniques can open the doors that were once blocked by frustration and discouragement. Physicians at Athenix use these top three procedu...
CoolSculpting is a procedure that eliminates stubborn fat safe and effectively, without any surgery or downtime. The CoolSculpting treatment is the only FDA-cleared procedure to use controlled cooling to safely target and eliminate fat that is resistant to diet and exercise. With over 5 million treatments performed, the results are proven, noticeable and lasting. We can help you Achieve your goal of looking great at every angle.
I do not object to receiving regular marketing updates or promotions on the fitness, yoga, dining and retail services offered by the Pure Group. I hereby consent that Pure Group may use my personal data including name, mobile and other phone numbers and email address for such promotions via phone call, mobile, mailing and internet and I accept the privacy policy of Pure Group.


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Kenneth Paul Fletcher
Fletcher, Kenneth Paul 79, died March 19, 2019, in Colorado Springs, Colo. He was born July 6, 1939, to Randall & Mary (Nogowski) Fletcher in St. Paul, Minn.
Published on June 12, 2019
Guest Book
Star Tribune reviews all guest book entries to ensure appropriate content.
Our staff does not correct grammar or spelling. FAQ


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Do you have a hard time believing your friends when they tell you how talented you are? Is it difficult for you to accept compliments? Have you found yourself shrinking back from your dreams and playing it safe, just in case?
When we are terrified of our potential, we can feel brittle, exhausted, sluggish, trapped. Our "bright shadow", unexplored, becomes an anchor we drag behind us with every step.
This full-moon day will be given to the sacred-time experience of movement, meditation, art-making, and myth-telling, so that together we can experience what it feels like to step into our power with confidence and release our bright shadow into the world.
Come, dive deep into your own bright shadow and stretch with your whole body into the embodied feeling of sovereignty.
This world needs your power.
Space is limited. Registration is first-come, first-serve.
Retreat includes: yoga, all art supplies, herbal infusions, elixirs, and other treats, and a full organic, local lunch.
Feedback from past retreats...
"Amazing, genuine, talented facilitators. Very dynamic and diverse programming. It exceeded my expectations! Powerful, extraordinarily so."
"This was pretty magical and life-changing for one workshop! The most powerful part was the sharing of stories. Lissa and Maeve worked so well together, and everything flowed beautifully. And the ending circle was beyond amazing—a jewel to savor and take into my life."
"This retreat was like a brief but deeply felt therapy session and a boost to my personal growth. This open-hearted sharing allowed me to open, heal, cleanse, and even shake off some "stuff" I've been struggling with but challenged to identify. Also—amazing food! Thank you and much gratitude! "


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Related Keywords: Apparel One, boost exports, expansion to help make Indonesia, garment company, plan to invest in second factory, push for investment in labour intentive sectors, slowing economy, subsidiary of Bina Busana Internusa, the base for export-oriented products, Triputra Group
Apparel One, a subsidiary of Bina Busana Internusa, a Jakarta-based garments company controlled by tycoon T.P. Rachmat's Triputra Group plans to invest Rp 490 billion ($39 million) in a second factory in Semarang, Central Java, this year.
The plant, which covers a 2.4 hectare-area, would increase Apparel One's total production capacity to 21 million pieces of clothing, with an export value of $100 million per year, Apparel One Indonesia president director Lukman Widjaja said.
The factory will also employ 6,000 workers at the end of the year.


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A former professional dancer Elena discovered yoga was the perfect compliment to her rigorous rehearsal schedule. She loved that yoga allowed her to improve her strength and flexibility simply by slowing down and listening to her body.
200 hour Vinyasa Yoga teacher training certification San Diego, CA - 2013
Level 1Restorative Healing and Yin Yoga certification La Jolla, CA - 2014
100 hour certification in Blissology yoga with Eoin Finn Bali, Indonesia - 2015
Based in London whether teaching in offices, gyms, rooftops, or homes her classes are warm, grounded, and real. She is a firm believer that yoga is for everybody and especially enjoys introducing yoga to those who want to start but feel afraid or intimidated. Her goal is to make sure each student feels confident and comfortable while learning. Expect fun, eclectic playlists, high fives and laughter while still finding space for focus and quiet on your mat.


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"There is nothing like a room full of people singing along to the same song. In 2015, I put together a set of Tom Petty songs to be done bluegrass at a benefit for my local S.P.C.A. I had so much fun putting the project together, it brought a wave of joy over me singing these songs. With his untimely passing, these songs have been pushed to the forefront of my mind and is seems like as good a time as any to celebrate, publicly, the hits of Tom Petty. Luckily, The HillBenders share my passion for this music and it just so happens that they are kick ass pickers who have amazing attention to detail, you can see for yourself as they cover the entire rock opera of The Who's Tommy. These Petty songs lend themselves quite easily to bluegrass and by the end of the night, the audience will more than likely be singing in harmony."
– Keller Williams
The HillBenders have been playing their own brand of bluegrass for a decade!
2015 found them embarking on a journey with Louis Meyers to recreate The Who's rock opera "Tommy" in an acoustic fashion.
Find out more at www.HillBenders.com
Thanks Louis.


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Scottish set for kick-off
Thursday 7 August 2003
Article summary
The Scottish season gets under way this weekend with Rangers FC and Celtic FC once again likely to dominate.
Article body
No guarantees
However, manager Alex McLeish knows it would be folly for his treble-winners to expect to dominate the Scottish game for a second season. Last year's UEFA Cup finalists Celtic FC will be desperate to make sure silverware, as well as fantastic memories, are theirs to treasure at the end of the new campaign.
Memorable season
But there is no denying that last year was truly a memorable one for Scottish football. Rangers secured the Premier League title on goal difference in stoppage time of the final match of the season, while Glasgow rivals Celtic re-established themselves as a European force, reaching the UEFA Cup final in Seville.
Dramatic final
Some 80,000 Celtic fans descended on the Andalusian capital on 21 May to watch their team lose 3-2 after extra time to FC Porto. To make matters worse, three days later they had their broken hearts shattered into tiny pieces when Rangers emerged triumphant in the championship race. On that frantic last day, Rangers registered their 50th league title by the smallest of margins - only two goals separated the sides after 38 games left the old enemies tied on 97 points.
New signings
Rangers have since bolstered their ranks with four new signings. Georgian international Zura Khizanishvili arrived from Dundee FC and Nuno Capucho was prised from Porto after he helped defeat Celtic in his final game for that club. Just this week Norway's Henning Berg and former Bologna defender Paolo Vanoli also joined to reinforce a squad that has lost Neil McCann, Lorenzo Amoruso and Bert Konterman.
Strangely quiet
Celtic have been quiet in the transfer market - buying no one and letting only reserve keeper Javier Sánchez Broto depart Parkhead. Hoops fans will hope consistency of selection helps their initial form while manager Martin O'Neill looks to secure new talent before the close of the transfer window later this month.
Dominant duo
Such is the Old Firm's dominance, however, that it is almost inconceivable that they will be split by another side in the quest for the title. If they are to be pushed, then Heart of Midlothian FC - boosted by the signings of striker Dennis Wyness and winger Paul Hartley - are the most likely contenders as they look to build on their third place last term.
Outside contenders
Dundee United FC may be a renewed force with Ian McCall busy on the transfer scene signing Falkirk FC's Collin Samuel and Mark Kerr as well as Derek McInnes from England's West Bromwich Albion FC. Livingston FC have a Brazilian blend for the new campaign with Marcio Maximo in charge at Almondvale and Motherwell FC have retained the services of James McFadden despite intense transfer interest.
Invincible signing
Kilmarnock FC will hope that new arrival Danny Invincible lives up to his name on the pitch and Dunfermline Athletic FC will become one of four teams in Europe to benefit from a UEFA grant and play on a revolutionary plastic pitch.
Thrills and spills
But with the new season upon us, there is nothing artificial about the high hopes for a campaign to match the thrills and spills provided last time out.


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Monday, September 22, 2014
MILE WEBINAR | How do CEOs Overcome Leadership Challenges in Turbulent T...
Posted by Professor M S Rao at 3:09 PM
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© 2011 MSR Leadership Consultants India. All Rights Reserved. This is an educational blog for free sharing of knowledge, not for commercial use. The use of this material is free provided copyright is acknowledged and reference or link is made to the Blog http://profmsr.blogspot.com This material may not be sold, or published in any form, or used in the provision of business services to a third party without permission.


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I have an Acer A500 which I have been able to root using a dedicated app which allowed me to instali ClockWorkMod Recovery.
I have then been able to use Titanium Backup to save all apps and data to restore to whichever build I flash.
Is this possible on our Thrive7s?


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Save $3 on any shirt! Use code SHIRTSAVE3 at checkout.
A great quality Ladies V-Neck Shirt with standard sizing and a great feel. Sizes up to 4XL. 4.3-ounce, 100% ring spun combed cotton.
Free standard shipping to continental U.S.
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Recommendations for policy action
ERT wants Europe to still be an attractive place to live and work in 2025. It should continue to stand for a high quality of life for its citizens, offering prosperity and societal well-being. To turn this vision into reality, Europe in 2025 must achieve five major goals described in the document.
We believe that Europe should remain an attractive place to live and work in 2025, deeply integrated into the global economy as a respected partner. Europe should continue to stand for a high quality of life for its citizens. That is why prosperity and societal well-being are at the core of ERT's vision.
ERT's vision provides a perspective for a successful future for Europe. This can guide policy choices for the next decade. The publication contains specific recommendations providing guidance for policy action over the next five years:
1. A global champion of sustainable growth
2. Well-embedded and respected in global markets
3. Unleashing innovative power
4. People, education and culture drive productivity
5. Decisive, reliable and transparent governance
This document is based on a visioning project conducted by the ERT from April to June 2009 under the lead of the ERT Competitiveness Working Group. This visioning project also involved ERT Members, strategy and business planning experts from ERT companies, and external stakeholders from the policy-making community and civil society. It relied on the contributions of more than 200 participants.
ERT Chairman discusses ERT Vision (video): https://www.youtube.com/watch?v=bLL4UWHfOUY


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Search Results (201) - "Tag: web"
Web applets not loading
9 votes
Save to Google drive
Archived moga ● English ● Comments: 23 ● Reply 4 years ago by Michael B.
4 votes
Insert Image from Webcam
Archived Michael B. 7 years ago ● English ● No Comments
Export to HTML 5 works only in Google Chrome
Archived Werner K. ● English ● Comments: 1 ● Reply 6 years ago by Michael B.
Can I turn off the scroll zoom on GeoGebra on Chromebook?
[solved with r32579] expand the sub tool menu
Right-Click -> Object Properties Menu in HTML5: how?
CAS-Webversion übernehmen der Vorgängerzeile mit )
Answered Valentin W. ● German ● Comments: 3 ● Reply 1 year ago by Valentin W.
How do I hide the bottom left keyboard on the applet?
1 vote
Welcome to the GeoGebraWeb Beta-Release forum
Archived Michael B. 7 years ago ● English ● No Comments
1 vote


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Date: 1690, 1694, 1695, 1700, 1706
"When the Ideas that offer themselves, (for as I have observed in another place, whilst we are awake, there will always be a train of Ideas succeeding one another in our Minds,) are taken notice of, and, as it were, registred in the Memory, it is Attention."
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— Locke, John (1632-1704)
Date: 1691
"Who has so many English Dictionaries in his Study, and another in his Head bigger than all together (and yet there's still room to spare both for Brains and Projects) Does not he?--nay--now you ruffle his smooth Soul, alter his fair Body, and discompose him all over."
preview | full record
— Dunton, John (1659–1732)
Date: 1712
"The ready Phantomes at her Nod advance, / And form the busie Intellectual Dance: / While her fair Scenes to vary, or supply, / She singles out fit Images, that lye / In Memory's Records, which faithful hold / Objects immense in secret Marks inroll'd, / The sleeping Forms at her Command awake, / ...
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— Blackmore, Sir Richard (1654-1729)
Date: 1773
"Smooth like her verse her passions learned to move, / And her whole soul was harmony and love."
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— Barbauld, Anna Letitia [née Aikin] (1743-1825)
Date: 1800
"The pen is a pacifyer. It checks the mind's career; it circumscribes her wanderings."
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— Brown, Charles Brockden (1771-1810)
Date: November 15, 2016
"He [Trump] has set the worst human impulses marching. But there are no clean slates in the unconscious."
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— Rose, Jacqueline (b. 1949)


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Welcome to DePaula Chevrolet, your Albany Chevrolet and Certified Pre-Owned dealer. Our convenient location on Central Avenue makes a great choice when you're looking for a Chevrolet dealer near Schenectady, Saratoga Springs or Troy, NY. We've been family owned since 1980 and have always put the customer first. Our dedication to you is what makes DePaula different from other car dealerships.
If you're looking for service for your new Chevrolet, DePaula Chevrolet's trained mechanics can help keep your new car running like new. So give them a call!
2521 out of 2589 people recommended this dealer
Reviewed by Brian in Albany
in Albany, NY
March 24, 2019
My wife and I (both DePaula customers) are absolutely beside ourselves with anger and frustration with the service department at this dealership. We've had nothing but headaches since purchasing our vehicles a few years ago. Prior to a recent incident, which is main subject of this review, most of the problems we've experienced with DePaula concerned customer service and communication (confusing my wife's account with my own for oil changes, etc.). However, most recently, my wife's vehicle suffered a fuel system malfunction. We had the vehicle towed to DePaula for repairs. At the very onset, the service representative misled her as to the nature of the problem and potential cost of repairs. It was confirmed by a seasoned mechanic friend of ours that she was given wrong information and we were being grossly overcharged in the quote. With little choice available to us given the prohibitive financial cost of having the vehicle towed elsewhere and limited time due to work obligations, etc., we decided that DePaula could perform initial repairs on the condition that they keep us apprised of the problem and estimated cost. They didn't do so. After four days in possession of the vehicle, we were told that the car was repaired and ready to be picked up. It was released back to my wife, ostensibly with the repairs completed. To our great dismay, the car died only minutes later in a store parking lot. My wife was stuck there in the freezing cold until 10 pm. She had the car towed back to DePaula the next morning, where it was examined again and started, or so we were told. The car was released back to her. Within several miles of the dealership, it died yet again. Upon trying to secure another tow from DePaula, they initially tried billing her for it. With the car back at DePaula for the third time in a week, it was explained that more costly repairs were needed, which was simply outrageous and unacceptable to us. My wife asked several times to speak to a service manager, but kept getting stonewalled. Phone calls weren't returned. Yet, the car remained with DePaula for further repairs. After 2 1/2 weeks without the vehicle and getting endless runaround, my wife was finally contacted to pick the vehicle up. Upon doing so, she found that the car was dirty, the fuel light was on and dirty dishes were left on the passenger floorboard (see photo). Sadly, we can't say we're the least bit surprised. It just adds to the list of ways in which we were terribly mistreated by this dealership. The lack of professionalism and competence and total disregard for the safety and wellbeing of customers is something that should be investigated and corrected immediately. The professional conduct and behavior we were shown is unethical and altogether reprehensible. We feel like we were taken advantage of and would even go as far as to say we could be the unfortunate victims of fraud. Update: My wife received her car back a couple of weeks ago and guess what? $1,500 later and it just died again. You can't make this stuff up, folks. This dealership is by far the worst business I've had the misfortune to deal with in my entire life.
Did you find this review helpful?
Reviewed by Mike Fountain
in Albany ny
December 14, 2018
After multiple attempts to coordinate individual appointments for my wife and I to look at a vehicle. After 3 days I was finally able to look at the vehicle. Please keep in mind that multiple emails and phones calls were exchanged. Upon arriving at the dealership to look at the vehicle I noticed a sold sign in the windshield. After talking with the sales rep, he stated the vehicle had been sold on the first day I inquired about it. Then when the manager Mike Fountain emailed me asking me if there was anything they coukd have done to improve, I provided him with the time line of events. The manager then promised to call my wife and I at mutually predetermined time. It's been 3 days and I am still waiting for a call from Mr. Fountain. The lack of quality customer service and responsiveness is astounding. Under no circumstances will I ever recommend that anyone work with this dealership.
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Reviewed by james
in albany
September 26, 2013
I visited two dealerships in the area and chose depaula chevy for its great customer service and large selection. Roger Kallop was a great sales person to deal with from start to finish and found just what I was looking for. Jay in finance got me an incredible rate on my loan far surpasing even my local credit union. The dealer overall was a great experience.
Did you find this review helpful?
DePaula Chevrolet
781 Central Ave
Albany, NY 12206
Sales: 518-293-4456
Used Cars: 518-293-4494


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Dr. Emma Patterson developed a passion for bariatric surgery during her fellowship in advanced laparoscopic surgery at Mount Sinai Hospital in New York City. She has over 15 years of experience and has performed over 3,500 bariatric surgeries. She was the first surgeon in the Northwest to specialize in laparoscopic bariatric surgery, and was also the first to perform a laparoscopic adjustable gastric banding with the Lap-Band.
In 2000, Dr. Patterson established herself in private practice in Portland, Oregon, and was the first Medical Director of the bariatric program at Legacy Good Samaritan. In her 14-year tenure as the Medical Director, Dr. Patterson led the program to become a nationally recognized Bariatric Surgery Center of Excellence.
As a recognized leader in U.S. laparoscopic bariatric surgery, she performs hundreds of procedures including the gastric balloon, laparoscopic adjustable gastric bands, laparoscopic gastric bypasses and laparoscopic sleeve gastrectomies. In addition to these primary procedures, she has mastered revisional bariatric procedures, is an investigator in the NIH funded consortium, Longitudinal Assessment of Bariatric Surgery (LABS) and is the principal investigator on many clinical trials.
Training surgeons from around the world in the techniques of laparoscopic bariatric surgery and publishing more than 100 journal articles, abstracts and book chapters are very important to Dr. Patterson. She also serves as an expert witness in medical malpractice cases nationwide. When Dr. Patterson isn't busy in clinic, she enjoys biking, skiing and spending time with her twin children and mini-dachshund, Biscuit.


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Ive been called by someone, but when I answer the phone, it makes digital noises and then my phone calls some Nissan dealership. It will literally, after making before stated noises start ringing on my end like I am calling someone. The Nissan dealership will then answer like I called them. What is happening.
closed as off-topic by Rory Alsop♦ Dec 20 '16 at 23:06
This question appears to be off-topic. The users who voted to close gave this specific reason:
- "This question does not appear to be about Information security within the scope defined in the help center." – Rory Alsop
It sounds like someone is calling you and then connecting you to a car dealership. This has nothing to do with your phone calling someone else, you are only accepting the call.
This is not new and nothing special. This is the default behavior of Google Voice, and other services. Some businesses offer queue call-backs that operate in this manner. There are some advertising businesses that will do this also.
I suggest not answering unknown numbers if you do not want to connect to random businesses.


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Cult "Dream Stash" Backpack
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Here it is–a collection of Forrest Mims's classic work from the original Popular Electronics magazine! Using commonly available components and remarkable. The Forrest Mims Circuit Scrapbook has 14 ratings and 0 reviews. Here it is–a collection of Forrest Mims's classic work from the original Popular Electr. The forrest mims circuit scrapbook. Published in: IEEE Transactions on Acoustics, Speech, and Signal Processing (Volume: 31, Issue: 4, Aug ). Article #.
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Fr. Bader named official spokesperson of papal visit
Fr. Bader named official spokesperson of papal visit
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Following is the text of the address by Fr. Rif'at Bader, director of the Catholic Center for Studies and Media and the official spokesperson of the upcoming papal visit to the Holy Land:
His Beatitude, Excellencies, dear colleagues,
This year is distinguished and it is conducive to consolidate dialogue, brotherhood and cooperation. These days, we mark the 50th anniversary of the visit of Pope Paul VI to the Holy Land, which started from Jordan, where he was received by His Majesty King Hussein, may his soul rest in peace, the East Catholic patriarchs, headed by Latin Patriarch of Jerusalem at the time Patriarch Alberto Gori.
Tomorrow, Monday, we will celebrate with the Lutheran Church in Jordan and the Holy Land, the launching of the new church built at the site of the Baptism Site, near the River Jordan.
On January 10, Catholic churches will celebrate pilgrimage to the Baptism Site, while Orthodox churches will mark the celebrations next week.
In the first week of February, the global week of harmony among religions will include several events. It is to be noted that Jordan is the side that took the initiative for this week while the United Nations adopted it unanimously.
On March 3, a memorial book will be launched. It marks the 50th anniversary of the visit of Pope Paul to the Holy Land and the 20th anniversary of the establishment of diplomatic relations between the Holy See-Vatican and the Hashemite Kingdom of Jordan on March 3, 1994.
On April 27, Pope John Paul II, who visited the Holy Land in 2000, will be proclaimed saint. Furthermore, this year is the 10th anniversary of the launching of the Amman Message.
This year marks the 50th anniversary of the founding of the Pontifical Council for Interreligious Dialogue which was launched by Pope Paul VI after his visit to the Holy Land. The Council has a permanent office for dialogue with Muslims, headed by a Jordanian priest, Father Khalid Akasheh.
In the spirit of the papal visit of Pope Francis, I invite you to share with us at the Catholic Center for Studies and Media these events. We will announce soon, in coordination with the Media Department at the Royal Court registration details to cover Pope Francis' visit to the Kingdom.
Please follow up the details on abouna.org site.
We welcome the guest of Abu Hussein, His Holiness Pope Francis.
Thank you for your cooperation.


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USS Lexington CV-2
This kit will consist of 519 parts on 25sprues,
plus upper and lower hulls, Waterline plate
and display stand. You can build it as either a waterline or full hull kit. Markings for 1942
MS11 camouflage. Completed kit measures nearly 15" long.
Click the picture to enlarge!
Essential Skills Scale Modeling
displacement: 41,000 tons
length: 888 feet
beam: 105½ feet
draft: 32 feet
speed: 34¼ knots
complement: 2,122 crew
armament: 8 eight-inch and 12 five-inch guns
aircraft: 81
class: Lexington
From: Dictionary of American Fighting
Ships, published by the
Naval Historical Center
Full-screen images are linked from the images in the text below.
After fitting out and shakedown,
Lexington joined the battle fleet at San Pedro, Calif., 7 April 1928. Based
there, she operated on the west coast with Aircraft Squadrons, Battle Fleet, in
flight training, tactical exercises, and battle problems . Each year she
participated in fleet maneuvers in the Hawaiians, in the Caribbean, off the
Panama Canal Zone, and in the eastern Pacific. In the fall of 1941 she sailed
with the battle force to the Hawaiians for tactical exercises.
On 7 December 1941 Lexington was at sea with
Task Force 12 (TF 12) carrying marine aircraft from Pearl Harbor to reinforce
Midway when word of the Japanese attack on Pearl Harbor was received. She
immediately launched searchplanes to hunt for the Japanese fleet , and at
mid-morning headed south to rendezvous with USS Indianapolis (CA 35) and
USS Enterprise (CV 6) task forces to conduct a search southwest of Oahu
until returning Pearl Harbor 18 December.
Lexington sailed next day to raid Japanese
forces on Jaluit to relieve pressure on Wake; these orders were canceled 20
December, and she was directed to cover the
USS Saratoga force
in reinforcing Wake. When the island fell 23 December, the two carrier forces
were recalled to Pearl Harbor, arriving 27 December.
Lexington patrolled to block enemy raids In the
Oahu-Johnston-Palmyra triangle until 11 January 1942, when she sailed from Pearl
Harbor as flagship for Vice Adm. Wilson Brown commanding TF 11. On 16 February,
the force headed for an attack on Rabaul, New Britain, scheduled for 21
February. While approaching the day previous, Lexington was attacked by
two waves of enemy aircraft, nine planes to a wave. The carrier's own combat air
patrol and antiaircraft fire splashed 17 of the attackers. During a single
sortie Lt. E. H (Butch) O'Hare won the Medal of Honor by downing five planes.
Her offensive patrols in the Coral Sea continued until
6 March, when she rendezvoused with USS Yorktown's TF 17 for a thoroughly
successful surprise attack flown over the Owen Stanley mountains of New Guinea
to inflict heavy damage on shipping and installations at Salamaua and Lae 10
March. She now returned to Pearl Harbor, arriving 26 March 1942. Lexington's
task force sortied from Pearl Harbor 15 April, rejoining TF 17 on 1 May. As
Japanese fleet concentrations threatening the Coral Sea were observed,
Lexington and
USS Yorktown (CV 5)
moved into the sea to search for the enemy's force covering a projected troop
movement. The Japanese must now be blocked in their southward expansion, or sea
communication with Australia and New Zealand would be cut, and the dominions
threatened with invasion.
On 7 May 1942 search planes reported contact with an
enemy carrier task force, and Lexington's air group flew an eminently
successful mission against it, sinking light carrier Shoho. Later that
day, 12 bombers and 15 torpedo planes from still-unlocated heavy carriers
Shokaku and Zuikaku were intercepted by fighter groups from
Lexington and Yorktown, who splashed nine enemy aircraft.
On the morning of the 8th, a Lexington plane
located the Shokaku group. A strike was immediately launched from the
American carriers, and the Japanese ship was heavily damaged.
The enemy penetrated to the American carriers at
1100, and 20 minutes later Lexington was struck by a torpedo to port.
Seconds later, a second torpedo hit to port directly abreast the bridge. At the
same time, she took three bomb hits from enemy dive bombers, producing a seven
degree list to port and several raging fires. By 1300 her skilled damage control
parties had brought the fires under control and returned the ship to even keel.
Making 25 knots, she was ready to recover her air group. Then suddenly
Lexington was shaken by a tremendous explosion, caused by the ignition of
gasoline vapors below, and again fire raged out of control.
At 1558 Capt. Frederick C. Sherman, fearing for the
safety of men working below, secured salvage operations, and ordered all hands
to the flight deck. At 1707, he ordered, "abandon ship!", and the orderly
disembarkation began, men going over the side into the warm water, almost
immediately to be picked up by nearby cruisers and destroyers. Admiral Fitch and
his staff transferred to cruiser USS Minneapolis (CA 36); Captain Sherman
and his executive officer, Cmdr. M. T. Seligman insured all their men were safe,
then were the last to leave their ship.
Lexington blazed on, flames shooting hundreds of
feet into the air. The destroyer USS Phelps (DD 360) closed to 1500 yards
and fired two torpedoes into her hull. With one last heavy explosion,
Lexington sank at 1956 on 8 May 1942 at 15º 20' S., 155º 30' E. She was part
of the price that was paid to halt the Japanese overseas empire and safeguard
Australia and New Zealand, but perhaps an equally great contribution had been
her pioneer role in developing the naval aviators and the techniques which
played so vital a role in ultimate victory in the Pacific.
Lexington received two battle stars for World
War II service.


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From the moment Air Force One dropped down from the low cloud cover over Kanakanak bluff it was suddenly real. The President of the United States of America is really visiting my lifelong home.
Lindsey Bloom: Reflection on the President's visit to Dillingham
For President Obama his visit to Dillingham was another day on the job of leading the free world. It fit right into his job description of staying up to speed and making decisions on the most pressing issues, concerns and opportunities for American people. For those of us who fish salmon in Alaska and the residents of the Bristol Bay watershed, the President's visit was nothing less than extraordinary!
Tim Bristol: Reflection on the President's visit to Dillingham
's not out of the ordinary, the Dillingham flight back to Anchorage canceled. This time it turned out to be an unexpected source of pleasure, an opportunity to reflect on the incredible events of the previous 24 hours. Life happens fast. The fishing seasons pile up. The purpose of meetings are blurred by time, words scribbled in a notebook. The latest event or front page story quickly becoming yesterday's news. Yes, getting another "day in the Bay" was a gift.
Alannah Hurley: Reflection on the President's visit to Dillingham
Words escape me in times of overwhelming emotion and gratitude. The reality that the President of the United States visited our home and experienced the land our ancestors entrusted to us – is still sinking in. He didn't just "visit" like you would think the leader of the free world would "visit" a place. Barack Obama had a, "pick our fish, eat our food, and yuraq with our kids" kind of visit.


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Govt. Zirtiri Residential Science College has been established by the government to be the first science college with a view to cater to the need for undergraduate-level science education in Mizoram. The college has endeavoured to execute and disseminate quality education in various fields of science and technology.
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Copyright © Reserved ® 2018
Government Zirtiri Residential Science College
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The only Model Science College in Mizoram by RUSA


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1.Withdrawal is limited to a single course per semester.
2.The Course Withdrawal Application form is attached.
3.After Course Withdrawal the total number of credits should not be less than the minimum credits allowable.
4.Freshmen、Sophomores、Juniors no less than 12 credits,Seniors no less than 9 credits.
5.Master and Doctor no less than a single class.
6.Applicants should fill in this application form personally with the approval of their respective head of department. The application form must be submitted to the Office of Academic Affairs before the deadline.
7.Applicants are required to pay all credit fees in full, including for the course that is withdrawn. Those who have paid the credit fees but withdraw from any course later will not be refunded; those who have not paid for the credit fees are still required to make full payment for the credit fees of withdrawn course.


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Medically reviewed by C.H. Weaver M.D. updated 7/2019
In general treatment for non-small cell lung (NSCLC) may require surgery, radiation, and/or systemic therapy with chemotherapy, immunotherapy or precision cancer medicines. The specific treatment for each person is individualized and is based on the stage of the cancer and its genomic profile.(1,2,3)
For patients with NSCLC have cancer that is limited to the chest surgical resection is not only an important therapeutic modality, but in many cases, the most effective method of controlling the disease. Patients with stages I-II localized cancer without spread to lymph nodes are considered to have early stage lung cancer and are almost always treated with a thoracotomy, which is a surgical procedure to open the chest and remove cancerous lung tissue. This surgical procedure is performed under general anesthesia. Some individuals with stage IIIA NSCLC can be treated with surgery as well however surgery for stage IIIB and IV disease is ineffective because the lung cancer has already spread.(1,2,3)
Radiation therapy uses high-powered energy beams, such as X-rays or protons, to kill cancer cells. Radiation therapy may be used alone or with chemotherapy before surgery to shrink a tumor or after surgery to kill any remaining cancer cells.(1-6)
Systemic Therapy: Precision Cancer Medicine, Chemotherapy
Systemic therapy is any treatment directed at destroying cancer cells throughout the body. Many patients with NSCLC already have small amounts of cancer that have spread outside the lungs that cannot be treated with surgery or radiation. These cancer cells cannot be detected with any of the currently available tests and are referred to as micrometastases. The presence of micrometastases causes NSCLC recurrence following local treatment with surgery and/or radiation therapy alone. An effective systemic treatment is needed to cleanse the body of micrometastases in order to improve a patient's duration of survival and potential for cure.
Systemic therapies commonly used in the treatment of NSCLC include:
Precision Cancer Medicines
The purpose of precision cancer medicine is to define the genomic alterations in the cancers DNA that are driving that specific cancer. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer's genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.
Large-scale screening for epidermal growth factor receptor (EGFR) PD-1, ROS1, ALK, RET, BRAF, MET, TRK and other mutations in lung cancer is feasible and allows for customization of treatment leading to improved outcomes.(7-16)
Chemotherapy uses medications that can be taken orally as a pill or are injected into a vein to kill cancer cells. In some situations chemotherapy is combined with radiation therapy or other precision cancer medicines to achieve the best results.
Treatment of Non Small Cell Lung Cancer by Stage
Stage II: The cancer has not spread to the lymph nodes but is larger than 5 centimeters or involves structures near the lung such as the chest wall or diaphragm. NSCLC is also considered to be Stage II if it measures 7 centimeters or less and involves the lymph nodes within the lung or near the bronchus.
Stage IIIA: The cancer involves lymph nodes in the space between the lungs (mediastinum) or near where the windpipe divides; is large or extensive but the only lymph node involvement is within the lung or near the bronchus; or there is no lymph node involvement but the cancer extends to other organs or tissues such as the heart, great vessels, trachea, or other lobes of the lung.
Stage IIIB: The cancer involves lymph nodes on the opposite side of the chest or above the collar bone, or is extensive (involves organs such as the heart or trachea) and also involves lymph nodes in the center of the chest (mediastinum) or near where the windpipe divides.
Stage IV: Cancer is found in both lungs, in the fluid that surrounds the lungs or heart, or has spread to other parts of the body such as the liver, brain, or bones.
Recurrent/Relapsed: Cancer has progressed or returned (recurred/relapsed) following an initial treatment with surgery, radiation therapy and/or chemotherapy.
Radiation Therapy
Radiation therapy uses high-powered energy beams, such as X-rays or protons, to kill cancer cells. Radiation therapy may be used as part of an overall strategy to treat stage III disease, treat single metastases, or control the cancer in individuals unable to undergo surgery systemic chemotherapy treatment.
Some patients with NSCLC are not able to undergo the surgery to remove their cancer. Advanced age and other medical conditions such as heart disease and diminished lung capacity make it more difficult for these patients to withstand surgery. Studies have demonstrated that patients with stages IIIA NSCLC who are not able to, or do not wish to undergo surgery may be treated with radiation therapy alone. Results indicated that radiation therapy alone produced an average survival time of over 30 and 34 months, respectively.(2,4)
Prophylactic brain radiation: Researchers have found that the most common site for cancer to spread in patients is the brain.[3] These patients may benefit from radiation treatment to the brain during their initial therapy, which is called prophylactic treatment. Results of a clinical trial indicate that prophylactic brain radiation reduced the rate of cancer recurrence in the brain from 30% to 8% and the overall chance of relapse in the brain from 54% to 13%. Researchers reported that patients who received prophylactic brain radiation did not experience impaired attention or visual memory after treatment.(2,5,6)
Surgical Treatment
The role of surgery in the management of lung cancer consists of obtaining a biopsy to make a correct diagnosis, determining the correct stage of the cancer in order to ensure optimal treatment and treating the cancer by surgical removal in selected situations. The decision to treat lung cancer surgically depends on the type of lung cancer, as well as several prognostic factors. Surgery is a common form of treatment for non-small cell lung cancer (NSCLC), whereas, it is not as commonly used with small cell lung cancer (SCLC).(1,2)
Types of Surgical Procedures for Diagnosing Lung Cancer
In order to accurately diagnose a lung cancer, a biopsy, or small piece of tissue, must be obtained and examined under a microscope. Because of the use of computed tomography (CT) screening, the detection of small abnormal areas in the lung that may or may not be cancer has become more common. There are several procedures that can be used to perform a biopsy.
CT Guided Fine Needle Aspiration Biopsy: CT guided fine needle aspiration biopsy is the most common way to evaluate possible cancers. A CT scan takes a very detailed picture of a patient's suspected cancer, allowing the insertion of a thin needle to remove a sample of the tissue. This gives doctors the most information without resorting to a more invasive surgery (thoracotomy) and direct biopsy.
Thoracotomy: During a thoracotomy, a surgeon makes a large incision in a patient's chest in order to directly access the mass and directly remove part or all of the suspicious area. In some patients with a peripheral lung mass and no evidence of mediastinal or systemic cancer, a wedge resection of the lesion is sometimes performed and diagnosis made on a frozen-section of tissue. If lung cancer is confirmed, a formal cancer resection is then performed.
Endoscopic Ultrasound Guided Fine Needle Aspiration Biopsy: The mediastinum is the area behind the breast bone and consists of blood vessels, lymph nodes and other structures. Because lung cancer frequently spreads to lymph nodes in the mediastinum, biopsies to this area are often necessary. An endoscopic ultrasound guided fine needle aspiration biopsy is often used to evaluate the mediastinum. This technique is performed in order to avoid the more invasive procedures of mediastinoscopy or thoracotomy. Using this technique, more invasive methods of diagnosis can be avoided in approximately 50% of patients. An ultrasound machine is used to take pictures of the mediastinum, allowing a small biopsy needle to be directly inserted into the suspicious area without making an incision in the chest.
Cervical Mediastinoscopy: Mediastinoscopy is another diagnostic procedure used to determine whether mediastinal lymph nodes contain cancer. This procedure is used in cases where endoscopic ultrasound guided fine needle aspiration biopsy is not indicated or was not successful. Medianstinoscopy requires general anesthesia, a small anterior neck incision and insertion of an endoscope, which is a thin, lighted tube. A complete procedure includes extensive sampling of lymph nodes in the upper and lower mediastinum.
Bronchoscopy: During a bronchoscopy, a physician inserts a bronchoscope (thin, lighted tube) through the nose or mouth into the trachea (windpipe) and bronchi (air passages that lead to the lung). Through this tube, the surgeon can examine the inside of the trachea, bronchi and lung and collect cells or small tissue samples.
Thorascopy: During this procedure, an endoscope called a thorascope is inserted through a small incision in the chest wall. Thorascopy is a limited surgical procedure that allows the lining of the chest wall and the lungs to be examined and biopsied to determine if cancer is present.
Surgical Treatment
Small cell lung cancer is not typically treated with surgery because the disease is usually widespread at the time of diagnosis. Once a diagnosis of SCLC is made and the amount of disease is characterized as either limited or extensive, patients typically receive treatment with systemic therapy and possibly radiotherapy. However, good results from surgery alone have been reported in a small subgroup of patients that have a small primary cancer and no lymph node involvement. Sometimes surgery is used in conjunction with chemotherapy and/or radiation therapy, but the contribution of surgery to overall outcome is not clear in this setting.(2)
Approximately 45% of all patients with NSCLC have cancer that is limited to the chest. For these patients, surgical resection is not only an important therapeutic modality, but in many cases, the most effective method of controlling the disease. Patients with stages I-II localized cancer without spread to lymph nodes are considered to have early stage lung cancer and are almost always treated with surgery.
Patients with stage III NSCLC may be treated with either neoadjuvant chemotherapy followed by surgery or combined treatment with chemotherapy and radiation therapy.(2) The following are the types of surgical procedures that may be performed in patients with stage I-III NSCLC. For patients with stage IV disease, surgery is usually not indicated.
Thoracotomy: Thoracotomy is a surgical procedure to open the chest and remove cancerous lung tissue. This surgical procedure is performed under general anesthesia.
During a thoracotomy the surgeon may remove part or all of a lung. There are two operations to remove a small part of the lung. A wedge resection removes a very small part of the lung and segmentectomy removes a slightly larger part of lung based on anatomical segments. These types of operation are used when the cancer has been diagnosed early and is only in one very small area. A lobectomy is the removal of one lobe of the lung and is the most frequent operation performed for early stage NSCLC. A pneumonectomy is the removal of the entire lung. This procedure is performed when the cancer is found to involve more than one lobe. Pneumonectomy is associated with more than twice the mortality rate of lobectomy, as well as more long-term pulmonary side effects.
Video-Assisted Thorascopic Surgery (VATS): This is a form of minimally invasive surgery that utilizes a television camera. The advantages of the camera-aided procedures are that smaller incisions can be used and there is no need to cut through a rib, which is necessary for conventional thoracotomy. This results in quicker, less intrusive surgery, with a much smaller scar. However, using these new procedures requires significant skill and a great deal of training. There is less, or at least different, visibility with VATS. If a serious problem arises, VATS can be converted to an open or traditional procedure, creating a small additional risk.
Chest Tube Thoracostomy: This is a procedure performed to drain fluid, blood or air from the space around the lungs (pleural space).
Precision Cancer Medicine - Not all cancer cells are alike
Lung cancers may differ from one another based on what genes have mutations. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer's genome. This "genomic testing" is performed on a biopsy sample of the cancer and sometimes with a "blood biopsy"
Once a genetic abnormality is identified that is driving the growth of the lung cancer, a specific precision cancer medicine or targeted therapy can be developed to attack that specific mutation or other cancer-related change in the DNA programming of the cancer cells.
Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the specific genetic mutation that is driving the lung cancers growth. Precision cancer medicines can be used both instead of and in addition to chemotherapy to improve treatment outcomes.
Lung Cancer Biomarkers & Medicines to Target Them
Testing an individual's lung cancer for specific biomarkers and genomic alterations allow doctors to identify cancer driving genetic mutations and offer the most personalized treatment approach utilizing precision medicines. Individuals with lung cancer should undergo genomic testing to determine whether newer precision cancer medicines are a treatment option.(2,6,7)
- NSCLC: EGFR, MET, ALK, TRK, RET, BRAF, ROS1 mutations can be treated with a specific precision cancer medicine.
- Squamous and non-squamous NSCLC with high levels of PD-L1 can benefit from treatment with immunotherapy.
PD-1 Checkpoint Inhibitors
Checkpoint inhibitors are a novel precision cancer immunotherapy that helps to restore the body's immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD -L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade an attack by the body's immune cells. Checkpoint inhibitor drugs that block the PD-1 pathway enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 ligand these drugs restore an immune cells' ability to recognize and fight the lung cancer cells.
Overall two thirds of lung cancer patients have some expression of PD-1, and one third are "high expressers" meaning over 50% of the tested tumor expresses PD-1. A diagnostic test to measure the level of PD-L1 is available and checkpoint inhibitors are effective in the management of many lung cancers.(9,10)
Keytruda® (pembrolizumab) was the first checkpoint inhibitor to have received FDA approval in the U.S for the treatment of NSCLC and Keytruda® improves survival rates among patients with certain lung cancers.(8)
- Keytruda® (pembrolizumab)
- Opdivo (nivolumab)
- Imfinzi (durvalumab)
- Tecentriq® (atezolizumab)
Epidermal growth factor receptor (EGFR): The EGFR pathway is a normal biologic pathway found in healthy cells. It is involved in regular cellular division and growth. However, certain mutations within the EGFR gene can lead to an overactive EGFR pathway, leading to the development and/or spread of cancer. These cancers are referred to as EGFR-positive, and there are several FDA-approved medications know as tyrosine kinase inhibitors (TKI) that block the activity of EGFR and slow cancer growth for EGFR-positive cancers.
EGFR mutations are most common in individuals who never smoked, woman, people of Asian ethnicity, and those with a type of lung cancer known as adenocarcinoma.(11,12) There are several FDA approved TKI inhibitors and others in development. In depth overview of TKI's here
- Tagrisso (Osimertinib)
- Tarceva (Erlotinib)
- Erbitux (Cetuximab)
- Iressa (Gefitinib)
- Gilotrif (Afatinib)
- Vectibix (Panutumamab)
ALK+ Lung Cancer: Approximately 5% of all NSCLC have an identified mutation referred to as the anaplastic lymphoma kinase (ALK) mutation. The ALK mutation is responsible for initiating and promoting cancer growth. Individuals with ALK+ lung cancer tend to be non-smokers or former light smokers; younger, and are a type of NSCLC referred to as adenocarcinoma (based upon the cells affected); and respond worse to standard chemotherapy regimens than patients who do not have the ALK mutation.(13,14) There are several FDA approved medications that target ALK and others in development.
- Zykadia® (ceritinib)
- Alecensa (alectinib)
- Alunbrig (brigatinib)
- Xalkori (crizotinib)
- Alunbrig (brigatinib)
ROS-1+ Lung Cancer: The ROS-1 mutation is an uncommon mutation found in only 1% of individuals with NSCLC. Research has indicated that the ROS-1 mutation plays a role in the development and progression of some lung cancers, and patient characteristics are similar to those who have ALK+ NSCLC and can be targeted with Xalkori.(14,20)
- Rozlytrek (entrectinib)
BRAF & MEK Kinase Inhibitors: The BRAF and MEK genes are known to play a role in cell growth, and mutations of these genes are common in several types of cancer. Lung cancers may carry the BRAF mutation known as V600E. This mutation produces an abnormal version of the BRAF kinase that stimulates cancer growth. Another mutation known as V600K may also be present. BRAF and MEK inhibitors are precision cancer medicines that block the activity of the V600E and V600K mutations respectively.(16)
- Zelboraf®(vemurafenib) BRAF V600E kinase inhibitor
- Tafinlar®(dabrafenib) BRAF V600E kinase inhibitor
MEK inhibitors
- Mekinist®(trametinib) MEK V600 kinase inhibitor
- Cotellic® (cobimetinib) MEK V600 kinase inhibitor
Combination Therapy
A combination of a BRAF and a MEK inhibitor appears to decrease the emergence of disease resistance that occurs in patients treated with a BRAF mutation. The combination of Taflinar plus Mekinist has been evaluated and FDA approved.(16)
RET + Lung Cancer: Genetic alternations in the RET ( rearranged during transfection) receptor tyrosine kinase are present in 1-2% of NSCLC's and drive their development and growth.(17)
- Vandatenib
- Cabozantinib
MET + Lung Caner: The mesenchymal-epithelial transition (MET) cancer driving mutation occurs in up to 5% of individuals with NSCLC and can be targeted with MET inhibitor medications.
TRK + Lung Cancer: Tropomyosin receptor kinases (TRK) fusions are rare chromosomal abnormalities that occur when one of the NTRK genes (NTRK1, NTRK2, NTRK3) becomes abnormally connected to another, unrelated gene (e.g. ETV6, LMNA, TPM3). This abnormality results in uncontrolled TRK signaling that can lead to cancer. (18,19)
- Vitrakvi (larotrectinib)
- Rozlytrek (entrectinib)
Immunologic Therapy or Immuno-oncology
Immunotherapy treatment of NSCLC has also progressed considerably over the past few decades and has now become a standard treatment. The immune system is a network of cells, tissues, and biologic substances that defend the body against viruses, bacteria, and cancer. Doctors have been trying for years to find ways to harness an individual's immune system to fight cancer.
The immune system recognizes cancer cells as foreign and can eliminate them or keep them in check—up to a point. Cancer cells are very good at finding ways to avoid immune destruction however, so the goal of immunotherapy is to help the immune system eliminate cancer cells by either activating the immune system directly or inhibiting the mechanisms of suppression of the immune system.
Recent promising clinical results have generated an explosion of interest and research in the field of immuno-oncology. Researchers are mainly focused on two promising types of immunotherapy. One type creates a new, individualized treatment for each patient by removing some of the person's immune cells, altering them genetically to kill cancer, and then infusing them back into the bloodstream. This procedure has been pioneered mainly in the treatment of leukemia or lymphoma.
The second type of immunotherapy is a group of drugs that do not have to be tailored to each patient; these are called checkpoint inhibitors. These drugs block a mechanism, called a checkpoint, that cancer uses to shut down the immune system. These drugs have been approved by the US Food and Drug Administration (FDA) to treat several types of cancer, including NSCLC.(8,9)
Checkpoint inhibitors work on killer T-cells—the white blood cells that are often described as the soldiers of the immune system. T-cells have built-in brakes, or checkpoints, to turn them off and keep them from attacking normal tissue, which could result in autoimmune diseases. One checkpoint stops T-cells from multiplying; another weakens them and shortens their life span.
Several checkpoint inhibitors have already been approved for treatment of patients with more-advanced NSCLC, based on clinical trials showing they were superior to chemotherapy. Keytruda has shown prolonged survival and an increased time to cancer recurrence compared with standard chemotherapy in patients with newly diagnosed advanced NSCLC whose tumors expressed high levels of PD-L1. Patients had to have PD-L1 expression greater than 50 percent to participate in the trial.(8)
This is in contrast to the checkpoint inhibitor Opdivo, which, in another clinical trial in newly diagnosed patients, did not improve outcomes for PD-L1–positive NSCLC when compared with chemotherapy.vThis came as a bit of a surprise to many in the oncology community, but the results may be explained by the fact that the Opdivo trial did not require participants' cancers to have as high a level of PD-L1 expression.(9)
Researchers suspect that checkpoint inhibitors might work better if they are combined with treatments that kill tumor cells because debris from dead cancer cells may help the immune system recognize its target. Studies are under way to test checkpoint inhibitors in combination with chemotherapy. But it is a delicate balance to adjust the timing and doses because in addition to killing cancer cells, chemotherapy treatments can knock out the immune system just when it is needed most.
One significant side effect of checkpoint inhibitors will require further research: in addition to causing lung inflammation, checkpoint inhibitors can lead to autoimmune disease, including colitis and rheumatoid arthritis, which result from an attack on other tissues by the revved-up immune system.
More-detailed and in-depth results of the recent clinical trials evaluating checkpoint inhibitors will is forth coming, and this will provide better guidance regarding their optimal use in the treatment of NSCLC. Importantly, there are also ongoing clinical trials evaluating these and other novel targeted and immunotherapies for the management of NSCLC; patients should discuss the potential role of these trials with their treating physician.
- American Cancer Society. Cancer Facts & Figures 2017.
- https://oncolife.com.ua/doc/nccn/Non-Small_Cell_Lung_Cancer.pdf
- cancer.gov/types/lung/patient/non-small-cell-lung-treatment-pdq
- Jeremic B, Calssen J, Bamberg M. Radiotherapy alone in technically operable, medically inoperable, early-stage (I/II) non-small-cell lung cancer. International Journal of Radiation Oncology, Biology, Physics 2002;54:119.
- Stuschke M, Eberhardt W, Pottgen C, Stamatis G, Wilke H, Stuben G, Stoblen F, Wilhelm HH, Menker H, Teschler H, Muller RD, Budach V, Seeber S, Sack H. Prophylactic cranial irradiation in locally advanced non-small-cell lung cancer after multimodality treatment: long-term follow-up and investigations of late neuropsychologic effects. Journal of Clinical Oncology. 1999 Sep;17(9):2700-9.
- Mamon H, Yeap B, Jänne P, et al. High Risk of Brain Metastases in Surgically Staged IIIA Non–Small-Cell Lung Cancer Patients Treated With Surgery, Chemotherapy, and Radiation. Journal of Clinical Oncology. 2005; 23: 1530-1537.
- Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. New England Journal of Medicine. [early online publication]. August 19, 2009.
- Quest Diagnostics Press Release. Quest Diagnostics Introduces Dako's PD-L1 Complementary Diagnostic Test to Support Bristol-Myers Squibb's OPDIVO® Anti-PD-1 Therapy for Non-squamous Non-small Cell Lung Cancer. The new Quest test service is based on the first FDA-approved complementary diagnostic. Available online at: . Accessed November 8, 2015.
- Keytruda (pembrolizumab) demonstrates superior progression-free and overall survival compared to chemotherapy as first line treatment in patients with advanced non-small cell lung cancer. [Press release.] http://www.mercknewsroom.com/news-release/oncology-newsroom/mercks-keytruda%C2%A0pembrolizumab-demonstrates-superior-progression-free- Accessed June 21, 2016.
- Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer. New England Journal of Medicine. 2015; 373:1627-1639.
- OSI Pharmaceuticals. FDA Approves Tarceva as a Maintenance Therapy for Advanced Non-small Cell Lung Cancer. Available at: http://investor.osip.com/releasedetail.cfm?ReleaseID=460783. Accessed April 19, 2010.
- Zhou C, Wu Y-L, Chen G et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomized, phase 3 study. Lancet Oncology. Early online publication July 22, 2011.
- Shaw AT, Kim DW, Mehra R, et al: Ceritinib in ALK-rearranged non–small-cell lung cancer. New England Journal of Medicine. 2014; 370: 1189-1197.
- Leighl NB, Rekhtman N, Biermann WA, et al. Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Guideline. Journal of Clinical Oncology. 2014;32(32):3673-79. Available at: <a href="http://jco.ascopubs.org/content/32/32/3673.">http://jco.ascopubs.org/content/32/32/3673.</a> Accessed September 30, 2016.
- United States Food and Drug Administration (FDA). FDA expands use of Xalkori to treat rare form of advanced non-small cell lung cancer. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm490329.htm. Accessed March 11, 2016.
- <a href="https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm564331.htm?source=govdelivery&utm\_medium=email&utm\_source=govdelivery">https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm564331.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery</a>
- Gainor JF, et al. Abstract 9008. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
- www.nejm.org/doi/full/10.1056/NEJMoa1714448?query=featured_home
- https://www.targetedonc.com/news/entrectinib-granted-priority-review-by-fda-for-ntrk-tumors-and-ros1-nsclc
- US Food and Drug Administration. FDA approves third oncology drug that targets a key genetic driver of cancer, rather than a specific type of tumor. August 15, 2019.