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Accounts & Bookkeeping
Service charge accounts
Shionagh Gilchrist
When is a van not a van?
HMRC are being urged to provide clarity and consistency on the tax treatment of commercial vehicles such as VW Kombi Vans marketed as goods vehicles. The need for clarity follows the ruling in an important tax tribunal case involving "vans" provided to employees of Coca Cola.
The court has upheld the HMRC view that certain vehicles are not goods vehicles but motor cars for benefit in kind purposes. Consequently, the income tax and national insurance payable by employee and employer is significantly higher than if the vehicles had been classified as goods vehicles.
Certain vans are exempt from income tax
There is no assessable benefit in kind where the van is only used for business journeys or the private use of the vehicle is insignificant. Examples would include making a slight detour to pick up a newspaper on the way to work or taking an old mattress or other rubbish to the tip once or twice a year.
Income tax definition of "Goods Vehicle"
The income tax legislation defines a "goods vehicle" as "a vehicle of a construction primarily suited for the conveyance of goods or burden of any description…"
Although the VW Kombi vans failed this test the Tribunal held that Vauxhall Vivaro vans provided by Coca Cola did fall within the definition of goods vehicles!
It is understood that this case is due to be heard at the Court of Appeal which will provide legal precedent over the tax treatment. Until then it gives employers a dilemma as to how to report such vehicles on employees' form P11d and also whether the position in earlier years should be rectified. The tribunal had to seek evidence from automotive industry experts so how are employers expected to interpret the rules!
What is also particularly confusing, and thus difficult for businesses to deal with, is that the benefit in kind rules are not the same as the rules for capital allowances and VAT.
Capital allowances defintion of "motor car"
The definition of a "motor car" for plant and machinery allowances purposes is a mechanically propelled vehicle except a vehicle:
constructed in such a way that it is primarily suited for transporting goods of any sort, or
of a type which is not commonly used as a private vehicle and is not suitable for use as a private vehicle.
VAT definition of "motor car"
For VAT purposes the definition of a motor car has been amended several times over the years. The current definition states: "Motor car" means any motor vehicle of a kind normally used on public roads which has three or more wheels and either:
is constructed or adapted solely or mainly for the carriage of passengers; or
has to the rear of the driver's seat roofed accommodation which is fitted with side windows or which is constructed or adapted for the fitting of side windows;
There are a number of exceptions to this rule notably vehicles constructed to carry a payload of one tonne or more. A common example would be a "double cab" pick-up such as a Mitsubishi L200 or Toyota Hilux.
We can provide support
If you are unsure how this may affect you or want to look at purchasing some vans for your business get in touch on 0161 249 5040
What are service charge accounts?
Service charge accounts can be a complex part of property management. There is a lot to consider and they have become a bone of contention between leaseholders and freeholders or landlords and tenants in the past.
Our insight on the 2020 Spring Budget
How will the Spring Budget affect you and your business? Will you be left with less in your pocket, or more? Can you afford to make plans without knowing?
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My name is Michael Francis Heywood and I am the webmaster of this site. This site includes research done by Leroy Smithson, Frances Church, Helen Murphy, Ivo Lazzeroni, Peter Wood and myself. If you have any questions about this site, or the cumulative research on the Sumner, Jones-Wood, Wood, Heywood, Crawford, Finnerty, Lazzeroni, Smithson, Mariotti, Voigt or Carlos families click here to contact me. Our family tree is posted online on this site! There are 3414 names in our family site.
The site was last updated on Apr 15 2019, and it currently has 127 registered member(s). If you wish to become a member too, please click here.
Michael Francis Heywood added Lancelot Shackleford to family tree: Heywood Family Tree.
Michael Francis Heywood updated the details of Lancelot Shackleford , John Shackleford , John Sumner , Florence Sumner (born Lewis) and 1 other people in family tree Heywood Family Tree.
Michael Francis Heywood updated the details of Catherine Jones-Wood and Violet Marea Jackson (born Jones-Wood) in family tree Heywood Family Tree.
Michael Francis Heywood added <Private> Standish to family tree: Heywood Family Tree.
Michael Francis Heywood updated the details of <Private> Standish and Ann Tarleton (born Standish) in family tree Heywood Family Tree.
Michael Francis Heywood updated the details of <Private> Klein (born Myers) , Edward Donald Scruggs , <Private> Scruggs (born McCane) , Edward Donald Scruggs and 6 other people in family tree Heywood Family Tree.
Michael Francis Heywood added <Private> Klein (born Myers) , Edward Donald Scruggs , <Private> Scruggs (born McCane) , Edward Donald Scruggs and 5 other people to family tree: Heywood Family Tree.
Michael Francis Heywood updated the details of Merle Brugh , Anna Katherine Armbruster (born Kampen) , Stanley Joseph Armbruster and John W McFee in family tree Heywood Family Tree.
Michael Francis Heywood updated the details of Merle Brugh in family tree Heywood Family Tree.
Michael Francis Heywood added Martha Jane Crawford , Mary C. Massey (born Crawford) , Stephen Crawford , Sarah Hass (born Crawford) and 13 other people to family tree: Heywood Family Tree.
Michael Francis Heywood updated the details of Martha Jane Crawford , Mary C. Massey (born Crawford) , Stephen Crawford , Sarah Hass (born Crawford) and 20 other people in family tree Heywood Family Tree.


What do you think is the best self defense weapons for women? My best friend Ruthie used to carry this ballpen than converts to a mini knife back in college. Pretty useful, i think but scary. I learned from my cousin mitchie to bring along a pepper spray when going home late at night, so i bought one for myself and thank God i haven't used it for anyone. But how would you react if you're caught in a bad situation? I know it's scary and i never ever wanna go through that. Experts say don't try to fight off. If they want your cellphone…throw it to them then run as fast as you can. Their attention is to not to get you but your phone, then go to a place where there are lots of people…if there are guards nearby, go there quickly. 2 things to remember..keep a strong presence of mind and pray a lot! Keep safe everyone!
According to me, the best way is to carry self defense non lethal weapons. There is wide range of concealed carry bags available in the market which makes it easier to carry firearms or guns.


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TSB investigates crash of a small plane in Bonaventure
Paul Cherry, Montreal Gazette
A Surete du Quebec police car is parked in front of a warehouse as police check on maple syrup containers during a police search in St-Nicolas, a suburb of Levis, Que., Friday, October 12, 2012.	Jacques Boissinot / THE CANADIAN PRESS
The Transportation Safety Board has deployed a team of investigators to the Bonaventure Airport in the Gaspé region where a man died Friday night when the amateur-built aircraft he was flying in crashed.
"The TSB will gather information and assess the occurrence," the board said in a release on Saturday.
The one-seat small aircraft crashed near the airport, 850 kilometres northeast of Montreal, just before 9 p.m. Friday, said Sûreté du Québec Sgt. Audrey-Anne Bilodeau. She said the man who died is believed to be in his 40s and the SQ investigators were still on the scene of the crash Saturday morning and were attempting to find out what caused the crash.
Pointe-Claire bar co-owned by alleged head of drug trafficking ring faces... Suspect shot during breaking and entering

redpajama_set_name: RedPajamaCommonCrawl


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Smith Named Executive Director of Innovation & Commercialization Center
The new executive director of the Innovation and Commercialization Center (ICC) at Eastern Kentucky University is a familiar name and face to many in the central/eastern Kentucky business community.
Sultana Selected as Visiting Scholar by Consortium of Universities
Dr. Qaisar Sultana, professor emeritus of special education at Eastern Kentucky University, was chosen as one of six Visiting Scholars by a consortium of universities in Norway, Slovenia, Germany, Czech Republic, Uganda and Sudan.
Holmes Named Director of Office of International Education
Eastern Kentucky University has selected educator and former Peace Corps volunteer Bill Holmes as director of the Office of International Education.
Holmes, former director of Institutional Relations at CAPA International Education in Boston, joined the EKU staff on May 21.
50,000-Plus Attendees at Arts Center Events Boost Local Economy
The Center for the Arts at Eastern Kentucky University has played host during its inaugural season to more than 50,500 guests from more than 30 states and abroad.
Recent Graduate Earns Phi Kappa Phi National Fellowship; Third in Four Years for EKU
For the third time in four years, an Eastern Kentucky University graduate has received a Phi Kappa Phi National Fellowship for graduate study.
Garner Student Excellence Award Recipient Named
Katie Wiedmar, Louisville, a senior PGA golf management major at Eastern Kentucky University, received the 2011-12 S.J. Garner Student Excellence Award at the PGA Golf Management spring awards banquet in April.
Warrix Helps EKU, Ky. Music Hall of Fame Kick Off "Stars Over Appalachia" Program
Singer/songwriter Chad Warrix, who gained fame in the country music duo Halfway to Hazard, urged Rockcastle County High School students to never give up on their dreams.
Student's "Ethanol of Appalachia" Proposal Earns 2nd Place in Ideas Showcase
An Eastern Kentucky University student earned second place in the eighth annual Appalachian Ideas Network Showcase.
Gardner Named Dean of Libraries
Betina Gardner has been named dean of libraries at Eastern Kentucky University.
Gardner, who joined EKU Libraries in 1995, has served in a variety of capacities, including interim dean since July 2011.
Whitehouse Named Dean of College of Health Sciences
Dr. Deborah Whitehouse has been named dean of Eastern Kentucky University's College of Health Sciences.
A long-time chair of EKU's Department of Baccalaureate and Graduate Nursing, she had served as interim dean of the college since October, 2011.
Indiana Woman Receives President's Outstanding Senior Award
Avery Scherer, the daughter of Doug and Anne Scherer, of Jeffersonville, Ind., received the President's Outstanding Senior Award at Eastern Kentucky University's commencement ceremonies on May 5.
Philosophy Professor Receives National Grant from The Character Project
Dr. Mike Austin, associate professor of philosophy at Eastern Kentucky University, has received a one-year $50,666 grant to support work on a manuscript entitled "Humility: A Study in Analytic Moral Theology" from The Character Project at Wake Forest University.
Student Selected as "Inventors and Innovators" Ambassador
Junior Andrew Pennington, of Corbin, has been selected as the National Collegiate Inventors and Innovators Alliance student ambassador for Eastern Kentucky University.
WEKU's Technology-Related Racing Stories Enjoy Widespread Airing
A series of technology-related racing stories produced at WEKU-FM is getting widespread airplay nationwide.
WEKU News Director Charles Compton worked with the Innovation Trail network of stations in upstate New York to put the series together and to help edit and produce the freelance reporters' features.


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Q: Changing order of records from the front end I am faced with a problem coding my next feature.  I want the user to be able to rearrange records and change the display_order value. I'm using Jquery UI's draggable and droppable to facilitate this.
I can see how a simple swap of display_order values would work. But I want to set a display order for a record and ideally have the others shuffle around so there are no repeated display_order values. Apart from not getting my head around how I would do that it seems like it would be hard to code and inefficient, shuffling every value around in the list.
So I am open to other suggestions of how this sort of thing is normally, or should be done.
I though of maybe using a value like 3.000 to represent the order and then when I want to make a record take its place make its value 3 - 0.001 so its 2.999 and will sort between 2 and 3. But I can see so many things wrong with that idea and doesn't seem like a good path to follow.
Thanks for any input!

A: *

*add a sorting column to your table, smallint,
mediumint or int depending on the
expected number of total entries

*A new entry is appended to the end, max(sorting) + 1

*when reordering an item, get the new position it will be in and alter the higher sorting entries accordingly:
mysql_query('UPDATE yourTable set sorting = '.$yourNewposition.' where id='.$yourUniqueId .' LIMIT 1');
mysql_query('UPDATE yourTable set sorting = sorting + 1 where sorting >= '.$yourNewposition.' AND id != '.$yourUniqueId );

redpajama_set_name: RedPajamaStackExchange


DMC Cotton Embroidery Floss, made from long staple Egyptian cotton and double mercerized for a brilliant sheen, is the most recommended floss in the world. This premium thread is made up of six size 25 easily separated strands, which allows you to customize the thickness of the thread by choosing the number of strands. DMC Embroidery Floss is 100% colorfast and fade resistant.
To separate the floss's strands, take your skein and find the tail that sticks out. Pull the tail out from the skein slowly until you have an 18" length of floss and cut it off. If you'd like to separate the thread into individual strands, pull one strand up and out slowly until it's fully separated from the others.
Care and Washing: DMC Embroidery Floss can be washed frequently without fading. It can be washed at a high temperature ( 95° C/203° F). Be sure to pay attention to the washing instructions on the fabric on which the thread was embroidered.


Tuesday night saw the Way Ahead Care Internal Care Awards in Bath recognising the staff and their achievements throughout the past 12 months.
This included recognising staff for their long service with the company (5 years or more) and a number of individual qualifications that had be undertaken by staff through Way Ahead Care's internal training department – Step Ahead Training Centre.
Dementia Awareness through City & Guilds. This involved, recognising, managing and communicating with those that live with Dementia.
Gold Standards Frame Work. This covered the planning of End of Life care packages and working with others involved in such packages of care.


Africa Aerospace & Defense Exhibition AAD 2014 launches its new website on 14 October 2013.
The Africa Aerospace & Defense Exhibition AAD 2014 will successfully launch its new website on 14 October 2013 presenting a renewed corporate image with the purpose to create a customer-centric experience and ensured that the navigation is customised and made easy for customers to find what they are looking for.
The 8th AAD Africa Aerospace & Defense Exhibition will take place at AFB Waterkloof, Centurion in the City of Tshwane, South Africa between 17 to 21 September 2014.
The site's homepage welcomes visitors with two enter sections, Trade & Exhibition and Airshow. It was important that the design of the website is clean, modern with a world map focused on Africa particularly South Africa showing a Gripen as one of the best leading fighter aircraft in the continent. We wanted our new website to reflect what we are 'The Premier Exhibition of Air, Sea and Land technologies in the African Continent' and in a global community.
Exhibitors, Media and Trade visitors will enter the website under the trade and exhibitor section on the home page for any exhibition related information such as VIP delegation information, how to exhibit, how to visit the show, news, layout etc.
The website also includes a 'University space' with information, targeting students that have interest in the industry and wish to meet with potential employers during AAD 2014. The AAD 2014 website will still allow Media and Trade visitors both national and international the opportunity to register online in an efficient manner.
Airshow enthusiasts will enter the website at the airshow section where the relevant information about the airshow will be available including ticket prices, roads to avoid, parking and how to get to AFB Waterkloof for the Airshow.
The AAD 2014 website is designed for a wide range of browsers, optimised for viewing on mobile devices such as smartphones and digital tablets. Be on the lookout closer to the time for the AAD2014 customised mobile application in order to help you use your time in the most efficient way and get the most possible out of the event. The service is optimised for Smartphone use (iPhone, Android and Mobile website) but is also available on all mobile phones that have internet capabilities. The redesigned website, created by Prospero South Africa team, embodies AAD's forward–thinking vision.
The Africa Aerospace and Defence (AAD) 2014 is one of the world's premier Aerospace and Defence exhibition that holds a prominent position within the Aviation and Defence calendar. This exhibition takes place biannually in September. The first three days of the exhibition are traditionally trade days, followed by two airshow days that are open to the public. The 8th AAD will take place at AFB Waterkloof, Centurion in the City of Tshwane, South Africa between 17 to 21 September 2014, and will once again bring together various industries from throughout the world so as to showcase the latest technological innovations within this sector.


Pay-to-play course on the top of the ski resort Skalka arena. This course has 12 holes and it is great for beginners and due to multiple tees also for skilled discgolfers. Definitely worth a visit. The owner also runs a stylish disc golf club house where you can have cold beer and some snacks.


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Can we use the asteroid apophis as an outpost
Thread starter 8603103a
Space Travel & SpaceX
Can we use the asteroid apophis as an outpost rather than deflecting it?
a_lost_packet_
Why? It's going to fly on by us anyway. Putting an outpost on it would simply be waving goodbye to a few lives and a lot of effort.
There's no intention to deflect Apophis. Despite what rumors you may here, it's not going to threaten us.
SteveCNC
It might be a good one to drop a probe on to though since it will be nearby .
how about move the asteroid to a lagrange point and we will acheive lagrange colonization,this is our oppurnityto acheive space colonization.
adrenalynn
We are a long way from that...
The more realistic direction is to drop a beacon or two on it, point at it as it goes past, and say "ooooh!" and "aahhhhh!".
MeteorWayne
8603103a":11ufh95b said:
It's moving far too fast and is far too massive to "move" anywhere. If it was a threat to earth we might be able to shove it a tiny bit so that it and earth aren't at the same spot at the same time... that's about all we could hope to do.
csmyth3025
SteveCNC":2co053q5 said:
I'm guessing that even though apophis will be nearby in its close approaches to Earth, the delta-v needed to land a probe on it - or to closely orbit it - would be about the same as that needed to put that same probe in it's own (similar) orbit. I may be worng about this.
It might be useful to put an RTG powered beacon or, at least, a reflector on it to make it easier to track. The cost for such a limited-purpose mission might be prohibitive, though (about $140 million according to Wikipedia). Still, if the thing bangs into a space rock or an iceball big enough to just slightly change its orbit, it would be nice to know about it early on - just in case.
This brings up a question: How much of apophis's orbit are we actually able to track?
csmyth3025":3oc4cy62 said:
SteveCNC":3oc4cy62 said:
My thinking is a small probe wouldn't require as much fuel to aquire delta V and would therefore be more doable being it could be remotely guided in for final approach with less lag due to the close proximity . This is the kind of mission the hybrid would be a good choice for the leo to neo run .
In order to plan a mission of any importance when it comes to an asteroid we need to know a few things to pick a good spot for touching down like is it tumbling and if so how . Wouldn't want to fly up to it and get smacked by it coming around or something , also would want access to regular sunlight for the solar panels and line of sight with earth for transmitting information so this would be important . Either that or a satelite has to go with and fly nearby on the same orbit to relay information but I think that raises the cost too much .
csmyth3025":1e39cdrt said:
SteveCNC":1e39cdrt said:
No, you are absolutely correct. It passes earth at relative speed of ~ 6 km/sec.
The biggest unknowns are actually various effects of solar radiation, the Yarkovsky and YORP effects. Having a radio transponder on the surface would allow considerable refinement of the orbit (though it is very well known) and continuous monitoring of the changes caused by these subtle radiation pressures.
Well, when it's close, and not behind the sun we can track it. The last visual obs were taken Jan 9, 2008, the discovery obs on Mar 15 2004 with a total of 1410 visual observations (and 6 rejected as outliers). In addition to the visual obs, Arecibo made 2 radar range observations, and 5 doppler velocity measurements between January 2005 and May 2006 at it's last close approach. These made the orbit extremely accurate, probably the most accurate for any asteroid.
There will be an opportunity for more such radar obs in 2013, assuming Arecibo hasn't been shut down by then. That will show any changes to the orbit due to the effects I mentioned above.
Thanks MW.
neilsox
Putting an outpost on apophis is likely no more difficult than putting an outpost on Mars or a moon of Mars. We could give the humans a 100 year supply of food and supplies. Apophis will do another close fly by of Earth in a few decades, so it is not like forever. Apophis is always closer than about 2 AU, so communications would be possible and practical, except briefly while apophis is behind the Sun. Neil
ROFL...a hundred year supply of food and water? Have you calculated the mass and cost????? :lol: :lol: :lol:
bdewoody
Again most people, even a lot in here don't understand the limited capability we have when it comes to moving humans around in space. Even just inside the orbit of Jupiter. Either you need a lot of power, which translates to massive amounts of fuel or a lot of time which isn't acceptable when it comes to humans in the equation. For example the mission to Pluto which will take 15 years and that is without a return trip. I'm sorry I'm not volunteering for a one way trip in space no matter what the scientific gains are.
MeteorWayne":d4z74awg said:
They would probably also want to take 100 years worth of spare parts and a couple of pairs of small children (male and female - not related) so that the children of those children can take care of their parents in their old age.
ok,we will move this asteroid into a suitable point and shave it small,we will renovate it and it will become our space colony,then ,we will make a giant leap into space.
We will build a telescope,bio center and a small town over there,i prefer the town name is Celestia, which means the space town always face the space.But , we have to acheive some tech to permanently providing oxygen on there.Can someone figure out how to provide the gas permanently to the colony.
Oh, is that all?
Well, when you put it that way, it's pretty trivially easy, cheap, and worthwhile. Why don't you just take care of it?
rubicondsrv
8603103a":2k44m6kz said:
how old are you???
Hi rubicondsrv,
Not very old I expect!!!!!!! :?
Andrew Brown.
Yuri_Armstrong
The concept of setting up a base on an asteroid has been around for a while. But why apophis? I'm sure there are better candidates than that.
raptorborealis
When I read a thread like this, my first hope is that it is intended to be a joke.
Are people really this ignorant of the level of our space technology?
Hey folks, we still cross our fingers when an astronaut exits the ISS to fasten a bolt.
I am 14 years old teenager but i am sure that the asteroid can be our revolutionary acheivement by colonizating it.Stephen Hawking had said that we have to acheive space colonization or we will extinct because of some earth related reasons.
raptorborealis":59ayv9o8 said:
Yeah,some folks are really ignorant.Maybe China or Russia ( they are rushing up ) will make it first if america still does not develop more advanced tech.
Things seem easy when you are 14 and don't have to consider the physics, or the staggering cost of the ideas you throw out there. Later on, you learn to be a little more realistic and pragmatic.
Still, don't stop dreaming, but do take the time to understand the science, and the way the world works when it comes to paying for things.
Psh. I could buy that asteroid and teach it to play fetch... If I didn't have this house payment.


Never miss another review! Click the toggle above to be notified about new Wowcher never cease to amaze me. I have bought so many items from plants to online courses. Discount reviews. We promise not to send you unrelated messages.
"The products that are on this site completely wow me. Quality is in abundance. From clothes, courses and plants. Thank you wowcher."
"food products always top quality"


Currently the last checked firmware and manager are the release from 10-02-15.
For users who had bought their units in 2013 or earlier – MEGA32 not supported!
You should use the new manager (from this page or release from 10-02-15) after the firmware upgrade.
You should reset EEPROM after firmware upgrade!!!
Your parameters and settings will be lost, that is why you need to remember/note them beforehand.
Which firmware should I chose?
secu-3t_m644_rev9_hall – firmware for the synchronization from Hall sensor (HS) of distributor. Operating with this firmware you don't need the 60-2 pulleys and etc. It is used in the simplest and cheapest connection type.
secu-3t_m644_rev9_dwell – standard firmware for the synchronization from CKP sensor or Position sensor+Reference Point Sensor, the units are firmwared with it before sale. The distribution via distributor or "idle spark". Igniters don't support the calculation of the accumulation time (types BIP373, SECU-Igniters, VTN 0529.3734 or ignition units).
secu-3t_m644_rev9_dwell_phign – synchronization from CKP sensor or Position sensor+Reference Point Sensor, individual ignition coils (the support of ignition phase sensor). Igniters don't support the calculation of the accumulation time (types BIP373, SECU-Igniters, VTN 0529.3734 or ignition units).
There are also firmwares which allow to use two channel igniter controlled via one single wire. For its support perform the firmware unit using the version analogous to the abovementioned , which contains _2chig and doesn't contain _dwell.
Где взять прошивку с попарно-параллельным впрыском?
Менеджер файл *.exe – secu3man на Виндовс XP не запускается, где инструкция по установке и запуску менеджера?
Все запускается и работает. Не морочь людям голову, троль.
Внимание. Программа SECU-3 Manager не требует установки и доступна в двух вариантах: в виде одного единственного ехе-файла и 7z архива с файлами.
Если скачиваете 7z архив, то распакуйте его содержимое(библиотеки и ехе-файл) в отдельную папку и оттуда его и запускайте. Библиотеки должны находиться в одной папке с ехе-файлом, иначе программа не запустится.
Скачал 7z архив, распаковал его содержимое (библиотеки и ехе-файл) в отдельную папку и оттуда его запустил. Все работает. Система Windows 7 Professional SP1.


Should you clicked into this story, the truth that Coachella is correct across the nook just isn't information to you. You may have your ticket bought, your lodge booked, and your pre-festival playlist rigorously curated. However I can safely assume that regardless of all your proactive planning, your outfits have but to be set. As a substitute of doing what most of us are responsible of doing, which is ready till the final minute to plan our seems to be, leading to spending means an excessive amount of cash on issues we most likely do not want, this pageant season, head to Zara and store in peace.
The fast-fashion retailer at the moment has a complete part devoted to festival style, and since Coachella is the primary pageant within the lineup, we're assured the items from this Zara festival collection shall be noticed everywhere in the polo grounds. From palm tree-printed attire to shell anklets, beaded backpacks to cowboy boots, Zara's tackle 2019 pageant style is a step above the remaining (and will not value you greater than $100 on common).
Forward, store the perfect Coachella-ready objects at the moment out there at Zara.


The Confederation of Paper Industries (CPI) welcomes the focus that the Environmental Audit Committee (EAC) has brought on the issue of recycling, not just for used coffee cups, but also other 'on the go' packaging.
As a member of the Paper Cup Recovery & Recycling Group, CPI wholeheartedly supports its manifesto to improve the recycling of used paper cups. CPI members, such as James Cropper & ACE-UK/Sonoco, are already actively involved in the recycling of coffee cups at their own speciality mills. Furthermore, DS Smith, which operates the largest UK recycled paper mill in Sittingbourne, has just announced trials that will take place this month to evaluate the costs and technical issues of the bulk recycling of coffee cups in mainstream paper making processes.
The CPI and its members remain at the forefront of finding a solution to the challenges presented by recycling coffee cups. We recognise the need for both voluntary and legislative measures to help drive a solution that is in keeping with the UK's circular economy aspirations. We also recognise that the challenge is not limited to coffee cups and must ultimately embrace rapidly changing consumer lifestyle choices as more and more packaging is disposed of on the go in modern societies.
Investment in collection and recycling infrastructure goes hand in hand with technical developments in finding a solution. However, we need to take a holistic view of this challenge and fully understand the effects of embracing more and more coffee cups, and indeed similar on the go packaging, into our recycling systems.
For further information contact Mike Dobson, Communications and Public Affairs Manager on 01793 889612 or email mdobson@paper.org.uk.
CPI represents an industry with an aggregate annual turnover of £6.5 billion, 25,000 direct and more than 100,000 indirect employees.


text:
Cognigy Secures $44M in Series B Funding to Facilitate Global Customer and Employee Growth
Düsseldorf, Germany / San Francisco / Sydney / London – Cognigy, a global leader in omnichannel Customer and Employee Service Automation with its Conversational AI platform Cognigy.AI, announced today it has raised $44 million in Series B funding led by global venture capital and private equity firm, Insight Partners, and joined by existing investors DN Capital, Global Brain, Nordic Makers, Inventures and Digital Innovation and Growth. As part of the round, Insight Partners' Managing Director Teddie Wardi will join Cognigy's Board of Directors.
Founded in 2016 in Düsseldorf, Germany, Cognigy's customers now include global brands such as Lufthansa, Mobily, BioNTech, Vueling Airlines, Bosch, and Daimler. With Cognigy, they are leveraging the power of Conversational AI to pioneer a new era of Customer Service.
"We are thrilled to be leading Cognigy's Series B as the company continues on their ScaleUp journey," said Mr. Wardi. "Evident by their strong customer retention, Cognigy has created an essential product for global businesses to improve their customer experience in an efficient and effortless manner. With the new funding, Cognigy will be able to expand their leadership position to reach new markets and acquire more customers."
With the funding, Cognigy plans to accelerate its global customer growth, create new partnerships, and continue to enhance its market-leading platform capabilities for companies to speed up enterprise-grade AI adoption.
"The past four years have seen us emerge as a leader in the Enterprise Conversational AI space and we are extremely happy to be partnering with Insight Partners for the next phase of our journey," says Philipp Heltewig, CEO and Co-Founder of Cognigy. "This investment will enable us to significantly expand our operations in North America, Europe and Asia, whilst maintaining our clear product leadership position and building on our strong industry partnerships."
Cognigy.AI is strongly focused on Contact Center Automation, combining advanced natural language understanding (NLU) with strong low-code automation and integration capabilities, enabling the automation of conversation on both phone- and chat-channels. The low-code platform is built on the premise that any user could build cognitive bots without extensive coding experience and equips business users, conversation designers, data scientists and developers with an intuitive visual interface that makes designing and deploying multilingual virtual agents of varying complexity a breeze.
By combining these capabilities with analytics, live chat, and advanced API orchestration, Cognigy.AI is the platform of choice for many global enterprises to automate business processes ranging from customer service over HR and ITSM automation to outbound call scenarios.
As of 2021, Cognigy's customers have built and deployed thousands of virtual agents in more than 120 languages, leading to significant cost savings and increased customer satisfaction by lowering average handling and wait times and delivering answers quicker, wherever and whenever customers and employees need them.
About Insight Partners
Insight Partners is a leading global venture capital and private equity firm investing in high-growth technology and software ScaleUp companies that are driving transformative change in their industries. Founded in 1995, Insight Partners has invested in more than 400 companies worldwide and has raised through a series of funds more than $30 billion in capital commitments. Insight's mission is to find, fund, and work successfully with visionary executives, providing them with practical, hands-on software expertise to foster long-term success. Across its people and its portfolio, Insight encourages a culture around a belief that ScaleUp companies and growth create opportunity for all. For more information on Insight and all its investments, visit insightpartners.com or follow us on Twitter @insightpartners.
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Алексей Саввич Буцкий (1919—2004) — советский военачальник, генерал-лейтенант. Первый заместитель начальника Главного штаба РВСН СССР (1960—1976). Лауреат Ленинской премии (1974).

Биография
Родился 22 августа 1919 года на хуторе Козлов, Ставропольской губернии.

С 1936 году призван в ряды РККА и направлен для обучения в Московское артиллерийское училище РККА. С 1938 по 1941 год проходил службу в этом училище в должности командира взвода курсантов. С 1941 по 1945 год участник Великой Отечественной войны в составе 28-й стрелковой дивизии в должностях командира роты и артиллерийской батареи, командира дивизиона и начальника штаба 112-го артиллерийского полка. участвовал в Великолукской наступательной операции, Невельско-Городокской операции, Мадонской операции и Рижской операции. Воевал на Калининском, 1-м Белорусском и 2-м Прибалтийском фронтах.

С 1945 по 1947 год служил в составе ГСВГ в должностях старшего офицера и начальника оперативного отделения штаба артиллерии 47-й армии. С 1947 по 1952 год обучался на командном факультете наземной артиллерии Военной артиллерийской инженерной академии имени Ф. Э. Дзержинского. С 1952 по 1954 год — командир артиллерийского полка и начальник штаба артиллерийской дивизии РВГК. С 1954 по 1955 год — командир артиллерийской бригады РВГК. В 1955 году окончил академические курсы при Военной артиллерийской инженерной академии имени Ф. Э. Дзержинского. С 1955 по 1956 год — начальник штаба Научно-исследовательского испытательного полигона № 5 Министерства обороны СССР. С 1956 по 1959 год — начальник штаба Государственного центрального полигона Министерства обороны СССР. С 1959 по 1960 год — начальник 27-го Учебного артиллерийского полигона.

С 1960 по 1975 год — первый заместитель начальника Главного штаба РВСН СССР, занимался внедрением в войска РВСН средств управления и связи для применения космической техники, был одним из организаторов специальных частей
космического назначения. С 1961 года А. С. Буцкий являлся руководителем Государственной комиссии по испытаниям и принятию на вооружение космической системы связи «Корунд», за что в 1974 году был удостоен Ленинской премии. С 1962 году был участником секретной операции «Анадырь», за участие в которой был награждён орденом Красной Звезды.

С 1975 года в запасе. С 1975 года на научно-исследовательской работе в Московском научно-исследовательском институте радиосвязи и в Конструкторском бюро общего машиностроения при Министерстве общего машиностроения СССР.

Скончался 7 февраля 2004 года в Москве, похоронен на Ваганьковском кладбище.

Высшие воинские звания
 Генерал-майор артиллерии (25.05.1959)
 Генерал-лейтенант (19.02.1968)

Награды
 четыре ордена Красного Знамени (29.03.1945, 19.05.1945, 30.12.1956, 24.11.1967)
 Орден Александра Невского (17.02.1943)
 Орден Отечественной войны I степени (12.10.1943)
 Орден Трудового Красного Знамени (21.02.1974)
 четыре ордена Красной Звезды (19.11.1951, 26.06.1959, 17.06.1961, 01.10.1963)
 Медаль «За боевые заслуги» (05.11.1946)
 Ленинская премия (1974 — за создание системы спутниковой связи «Корунд»).

Примечания

Литература
 Энциклопедия Ракетных войск стратегического назначения / М-во обороны Российской Федерации; под общ. ред. Соловцова Николая Евгеньевича. — Москва : РВСН ; Белгород : Белгородская обл. тип., 2009. — 859 с. — ISBN 978-5-86295-200-1
 Задача особой государственной важности: из истории создания ракетно-ядерного оружия и Ракетных войск стратегического назначения (1945—1959) : сборник документов / сост. В. И. Ивкин, Г. А. Сухина. — Москва : РОССПЭН, 2010. — 1205 с. — ISBN 978-5-8243-1430-4
 Ракетные войска стратегического назначения : истоки и развитие / Н. Е. Соловцов и др.; под общ. ред. Н. Е. Соловцова. — : ЦИПК, 2004. — 318 с.
 Стратеги: военачальники, ученые, испытатели ракетных войск стратегического назначения / Сост. Носов В. Т., АдамантЪ. : 2014. — 687 с. — ISBN 978-5-86103-125-7

Выпускники Военной академии РВСН имени Петра Великого

redpajama_set_name: RedPajamaWikipedia


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Ego or Alter Ego?
Constant battle between Ego and Alter ego.
There is a thin line between ego and esteem. Ego is the stepping stone to narcissism , while alter-ego is sheer closeness in friendship. Sometimes demarcation between the two becomes a formidable task to accomplish. Human behavior can be associated well with territories. Territories are prized possessions of their respective owners, and any transgression renders a feud. Now similarly, each human is unparalleled, when it comes to their attributes. No two individuals can be of twin characteristics, the differences are evident on the exterior and interior both. People do not like to be questioned about why they are behaving in a way that seems wrong to others, because that is their nature,and they do not want to change it. Superficial beaming is a gesture , when the concept of alter-ego is non existent. And heartfelt happiness is a sentiment, experienced in true friendship, where barricades of ego are put aside, and a companionship is intercalated to radiate warmth and credibility.
The differences and similarities of two individuals, if blended in equal proportions can lead to a blooming comradery, however if quantified wrongly, an imbalance prevails and ,a vengeful rivalry is bound to consummate. The animated prattle changes it's nature to a murky lull .The relation becomes akin to stretched rubber. The amicable gestures are reduced to contorted expressions. The fort of amiability crumbles into an estranged demeanor. A fumbling discourse takes place, where thoughts are churned and processed in a machine like manner, delivered in a monotonous tone. Each other's presence becomes painful like thorns of a rose. The rose which was earlier personified as blossoming companionship now serves as a symbol of affliction. The survival of friendship hangs by a thread. A single erroneous movement , and bang on ,the dart hits the target of animosity and hatred. This marks the victory of ego over alter-ego. Ego is a part of our existence, however if Ego becomes our existence then the harbingers of loyalty,faithfulness and concordance stop, visiting mankind.
The fruits of the precious and delicate bond, turn sour. SUGAR-COATEDNESS was never predominant, but now every single morsel of sweetness wanes away like the moon. The boat that sailed smoothly earlier, now takes a sharp turn and abruptly gets off course. It is destined to succumb to the currents or sail right through the unnerving and daunting waves, the endeavors to withstand the menacing currents is the conclusive factor. And they infer that whether the ship of friendship has sailed triumphantly, or has sunk into the fathomless sea of despair, grudges and ill-will. We confide in our alter ego, because our closest companions become confidantes after earning our confidence. Our deepest secrets, our fears capable of giving us goose-bumps, our strengths and weaknesses are now well comprehended by our trustworthy aides.
However, when the fire of misunderstanding is ignited in the hearts of friends, then a fiery battle between ego and alter-ego commences. Words are shot like arrows. We tend to take each other's weaknesses for granted. Touching one's underbelly ,is like opening Pandora's box and soliciting the spiteful demons.
Friendship is a maze, which can be be easily solved by putting two and two together, that is , by mutual " l "and "e" contract. Listening , lecturing, entrusting and endearing. It is a mystery of underlying sentiments that can be unraveled by jovial mateyness, open arms and selfless motives. Annihilation of the very foundation of this prestigious building renders a double whammy, loss of both the person and the relation creating a void incapable of being filled. Relationships should begin with a friendly footing, without haste, since it renders waste. Getting to know each other should be a sluggish movement, as this gradually accelerates the interlocking, and imbibes congeniality. Ego and alter-ego are both black and white respectively. The colour black absorbs all the vibrancy of our lives while white reflects the wavelengths of happiness. At times, when the key of the golden locker of friendship is handed over to ego, vanity supersedes all kind gestures, causing distress and grief.
Looking back with a thought that things will fall in the right place, is painstaking, it seems like a victory unachievable, however, we cannot prophesize, since destiny grapples our life, and turns it according to our actions and not wishful thinking. So the ray of hope should always be kept rejuvenated.
Ego and Alter- ego are synonymous with the Chinese symbol of Yin and yang, instead of complementing and fulfilling each other, like light and shadow ,they become contrasting characters, like fire and water, having a cut-throat war just like adversaries. Forging relationships is like smoldering our lives with the charcoal of fraud. Essence of living life is having relationships worthy of cherishing .
Friendship is being lunatic , going berserk, making a monkey out of ones self infront of each other, having fun at each other's expense, being a victim of mockery, serving as the venting and vending machine both . We humans with our alter-egos define the epitome of friendship. Life is too short to sow seeds of hatred . Hatching wicked plans , muttering in a stifled tone against the friend turned foe is like digging a hole in one's own delight.
Short term sadistic pleasures construct long term malice and wreck the walls of humanity. Practicality is practically everywhere. We tend to drown our mind and soul in the well of guilt, and cleansing the soul becomes a far fetched desire. Therefore sensibility lies in burying hatchets. Life is all about giving, it is about mutual insight of viewpoints, and comprehension of feelings. Life should be a lyrical melody, and not a composition of sardonic verses.


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3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT) Positron Emission Tomography as an In Vivo Biomarker of inhibition of CDK 4/6-Rb pathway by Palbociclib in a patient derived bladder tumor
James L. Tatum ORCID: orcid.org/0000-0002-3217-24781,
Joseph D. Kalen ORCID: orcid.org/0000-0002-7163-46042,
Paula M. Jacobs ORCID: orcid.org/0000-0002-9423-64731,
Lisa A. Riffle ORCID: orcid.org/0000-0003-3975-30882,
Amy James3,
Lai Thang3,
Chelsea Sanders ORCID: orcid.org/0000-0001-8042-47833,
Melinda G. Hollingshead ORCID: orcid.org/0000-0002-1207-13974,
Falguni Basuli5,
Jianfeng Shi5 &
James H. Doroshow ORCID: orcid.org/0000-0002-4463-17901
Several new generation CDK4/6 inhibitors have been developed and approved for breast cancer therapy in combination with endocrine therapeutics. Application of these inhibitors either alone or in combination in other solid tumors has been proposed, but no imaging biomarkers of response have been reported in non-breast cancer animal models. The purpose of this study was to evaluate 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT) Positron Emission Tomography (PET) as in vivo biomarker of response to palbociclib in a non-breast cancer model.
Twenty-four NSG mice bearing patient derived xenografts (PDX) of a well-characterized bladder tumor were randomized into 4 treatment groups: vehicle (n = 6); palbociclib (n = 6); temozolomide (n = 6); and palbociclib plus temozolomide (n = 6) and treated with two cycles of therapy or vehicle. Tumor uptake of [18F]FLT was determined by micro-PET/CT at baseline, 3 days, and 9 days post initiation of therapy. Following the second cycle of therapy, the mice were maintained until their tumors reached a size requiring humane termination.
[18F]FLT uptake decreased significantly in the palbociclib and combination arms (p = 0.0423 and 0.0106 respectively at day 3 and 0.0012 and 0.0031 at day 9) with stable tumor volume. In the temozolomide arm [18F]FLT uptake increased with day 9 uptake significantly different than baseline (p = 0.0418) and progressive tumor growth was observed during the treatment phase. All groups exhibited progressive disease after day 22, 10 days following cessation of therapy.
Significant decreases in [18F]FLT uptake as early as three days post initiation of therapy with palbociclib, alone or in combination with temozolomide, in this bladder cancer model correlates with an absence of tumor growth during therapy that persists until day 18 for the palbociclib group and day 22 for the combination group (6 days and 10 days) following cessation of therapy. These results support early modulation of [18F]FLT as an in vivo biomarker predictive of palbociclib therapy response in a non-breast cancer model.
The D-cyclin-dependent kinase 4/6-INK4-retinoblastoma (D-CDK 4/6- Rb) pathway is a key pathway regulating the G1-S phase transition in the cell cycle. Abnormal activation of this pathway has been reported in numerous cancer types and it has been a high-profile target for therapeutic intervention, including high specificity inhibitors of the pathway [1, 2], which arrest tumor cells at G1. CDK 4/6 inhibitors are not new and have been employed effectively but were limited by dose toxicity. However, several new generation inhibitors have improved therapeutic indices and three, palbociclib, ribociclib, and abemaciclib, have been approved by FDA for the treatment of ER + /HER2- breast cancer in combination with endocrine therapy. [3].
Growing evidence supports expansion of these new CDK 4/6 inhibitors to other solid tumors [4], such as lung, melanoma, and head and neck cancers, with pre-clinical data showing response in human tumor xenografts. [5] Successful translation of a new therapy is highly dependent on robust biomarkers and a non-invasive response marker could be useful in translation of these inhibitors into other tumors. A recent preclinical study of six ER + breast cancer cell lines and one related xenograft reported that [18F]FLT and [18F]ISO-1 might be useful as predictive biomarkers for ER + breast cancer treated with the combination palbociclib/fulvestrant. [6] Another preclinical study [7] noted similar [18F]FLT responses in the presence of palbociclib in a triple negative breast cancer model with protein pRB and E2F levels significantly downregulated but not in a triple negative breast cancer model without this down regulation. However, no studies have been reported of [18F]FLT and CDK4/6 inhibitors in solid tumor models other than breast.
The PET tracer [18F]FLT was developed as an imaging biomarker for one of cancer's foundational characteristics proliferation. Unlike for [18F]FDG, [18F]FLT uptake is not a measure of general metabolism but instead reflects cell division activity. The mechanism of [18F]FLT uptake is well-established and occurs via nucleoside transporters. [8] Once intracellular, [18F]FLT is phosphorylated by thymidine kinase 1 (TK1), a cell cycle regulated enzyme and rate-limiting step of the thymidine salvage pathway. However, the [18F]FLT monophosphate cannot be further phosphorylated and incorporated into DNA and remains trapped in the cell. (Fig. 1). The [18F]FLT signal therefore reflects the enzymatic activity of TK1, which is linked to the cell cycle S phase.[9].
Uptake mechanism of thymidine and [18F]FLT. Like thymidine, FLT is transported across cell membranes by nucleotide transporters. After uptake, [18F]FLT is phosphorylated by TK 1 and trapped intracellularly. Incorporation into DNA is limited
[18F]FLT uptake has been compared with gold standard histological proliferation markers like Ki-67 with good but imperfect correlation. [18F]FLT has also been used as an in vivo marker to predict response to therapy. The modulation of tracer uptake can be affected by complex cell cycle alterations, but taking these variables into account, [18F]FLT is a good indirect measure of proliferation, derived from the number of cells in S phase and the activity level of thymidine kinase. Interestingly, the correlations of these more direct measures of proliferation [9] support the hypothesis that [18F]FLT should provide a valid in vivo biomarker of the status of the D-CDK 4/6 pathway in tumors with on-target modulation by CKD 4/6 inhibitors since these inhibitors are very specific to the G1/S checkpoint without other effects on the cell cycle.
In this study we employed a well characterized patient derived xenograft (PDX) bladder model in a drug challenge that included the D-CDK 4/6 inhibitor palbociclib to determine if early modulation of the [18F]FLT uptake was correlated with tumor response in a non-breast cancer model.
Animal studies were performed according to the National Cancer Institute (NCI) at Frederick (Frederick, MD) Institutional Animal Care and Use Committee guidelines (IACUC Protocol No. 19-0008-B).
Tumor fragments (8 mm3) were harvested from mice bearing BL0382-F1232 (The Jackson Laboratory, Bar Harbor, ME) and directly implanted into the right flank of 6-week-old female NOD-scid gamma NSG mice weighing approximately 26 g (Frederick National Laboratory for Cancer Research, Biological Testing Branch Animal Production, Frederick MD). This model is a well characterized Patient Derived Xenograft (PDX) of a myo-invasive bladder cancer with no prior chemotherapy and with a partial loss of function p53 E177 mutation but functional Rb1. [10] A total of 24 mice were enrolled in the study when their tumor sizes were approximately centered at 250 mm3 (252 ± 134 mm3) and were randomized into four groups as noted below. There was no blinding.
The drug therapy protocol was based on a prior unpublished study that demonstrated tumor response with a combination therapy of palbociclib and temozolomide in this model. In addition to the combination therapy, we added single drug arms to determine single agent efficacy. When the mice met enrollment criteria based on tumor size they were randomized into 4 groups: control [n = 6]—vehicle (Klucel and 50 mM sodium lactate pH4); TMZ [n = 6]—temozolomide (50 mg/kg in Klucel); PALB [n = 6]—palbociclib (50 mg/kg in 50 mM sodium lactate pH4), and Combo [n = 6]—temozolomide (50 mg/kg) plus palbociclib (50 mg/kg) in Klucel and 50 mM sodium lactate pH4. The treatment regimen was 5 days therapy followed by 2 days rest and a second round of 5 days therapy. All drugs were administered PO once a day. Following the second cycle of therapy, drug administration was discontinued, and the mice were maintained until their tumors reached a size requiring humane termination (ACUC guidance > 2 cm in any linear dimension by caliper) or their clinical status required euthanasia. Figure 2 details the study design.
Study Protocol. Twenty-four NSG mice bearing patient derived xenografts of a well-characterized bladder tumor were randomized into 4 treatment groups: Control (n = 6); palbociclib (n = 6); temozolomide (n = 6); and palbociclib plus temozolomide (n = 6) and treated with two cycles of therapy or vehicle
Xenograft tumor volume was calculated based on weekly caliper measurements. The volume was calculated from three dimensions measured. When the average tumor volume approached 250 mm3, baseline [18F]FLT positron emission tomography/computed tomography (PET/CT) imaging was initiated (NanoScan PET/CT, Mediso Medical Imaging Systems, Budapest, Hungary). [18F]FLT was prepared following the literature procedure [11]. The isolated radiochemical yields were in the range of 17–30% (n > 25, decay uncorrected) with a radiochemical purity > 99% and molar activity of 167–240 GBq/µmol.
Animal preparation and handling
Standard imaging and animal handling protocols required maintaining the rodent's temperature and anesthesia administration. The animal body temperature (thermostat controlled heated table at 34–37˚C) was maintained from the time the animal entered the imaging room, through anesthesia induction, imaging, and until recovery from anesthesia. Isoflurane anesthesia was administered via an induction chamber (3% pre-imaging) and nose cone (1.5–2% during imaging) with a carrier gas of oxygen at a flow of 1 l/min. Pulmonary function was monitored during scanning and the anesthesia (1.5–2% Isoflurane) was regulated to maintain a pulmonary rate between 50 and 90 breaths per minute (bpm).
PET/CT Protocol
Mice were injected IV via the tail-vein with [18F]FLT (6.22 ± 0.75 MBq) at the planned time points. PET-imaging commenced at approximately 1-h post injection. Mice were imaged in the prone position for a 3-min CT for PET attenuation correction, followed by a 20-min PET acquisition. CT acquisition parameters were: 50 kVp, 980 μA, 300 ms per step, covering 360-degrees, helical scan, and pitch of 1. PET list-mode data were acquired using an energy window of 400–600 keV and a < 2 ns coincidence timing window. CT images were reconstructed using a cone beam algorithm resulting in 192 × 192 matrix and PET utilized Ordered Subset Maximum-Likelihood Expectation Maximization (OS ML-EM) with 4 iterations and 4 subsets, with corrections for attenuation (CT based Monte Carlo), decay, Randoms, scatter, and noise reduction regularization [12], resulting in a 0.4 mm3 voxel.
[18F]FLT PET/CT DICOM images were displayed and fused on a MIM workstation (v 6.6.5, MIM Software Inc, Cleveland, OH). Tumor [18F]FLT uptake was acquired from a volume of interest defined by CT, and the maximum standardized uptake value normalized by body weight (SUVbw max) was calculated using the same commercial software. Since reproducibility is critical with imaging at multiple time points, SUVmax was chosen rather than SUVmean because it is more reproducible, especially for smaller tumors [13, 14].
Values for each mouse (SUV bw max and tumor volumes) were normalized to 100% at day 0 (baseline); group mean and standard deviation were evaluated for each time point. A paired t-test was used to determine significance compared to baseline with p value for significance set to ≤ 0.05.
Data were generated by the authors and are included in the supplementary tables.
A significant decrease in [18F]FLT uptake in the palbociclib and combination arms was accompanied by a suppression of tumor growth during and for a time after therapy cessation. A significant increase in tumor size in the control and TMZ arms at each time point was accompanied by increasing [18F]FLT uptake.
The tumor size at enrollment was 252 ± 134 mm3. No mice were terminated during the therapy and up to day 26 after study initiation.
The data are summarized in Table 1.
Table 1 [18F]FLT SUVbw Max and Volume Changes during drug treatment
At day three of therapy there was a statistically significant drop in [18F]FLT SUVbw max by 50% in both the palbociclib and combination therapy arms and uptake remained significantly depressed at day nine of therapy. [18F]FLT uptake in the TMZ and control arms increased but did not reach significance at day three. (Fig. 3a) [18F]FLT uptake continued to increase in both the TMZ and control arm at day nine with the TMZ arm reaching statical significance. The full SUV data set is presented in Additional file 1: Table S1 and is graphed in the Additional file 1: Figure S1.
[18F]FLT uptake as SUVbw max and tumor volumes, normalized to baseline SUVbw max (3a) and caliper volumes (3b and 3c) are shown with respect to dosing (QDx5, rest 2 days, and repeat). Study and dosing were initiated at day 0. Plot 3b displays the caliper tumor volumes for the same study range as the PET/CT study for easy comparison while 3c displays the full study range until mice reach ACUC endpoint. Figure 3d shows typical images of control and palbociclib treated mice at day 3
Tumor volumes in the control group increased significantly by 45% and in the TMZ group by 31% in the first three days of treatment and continued to increase significantly at day nine. The tumor volumes in the palbociclib and combo groups did not significantly change at days three and nine compared to baseline (Fig. 3b). Following completion of the second cycle of treatment at day 11 tumor volumes continued to be measured until the tumors reached the ACUC limit of > 2 cm in any linear dimension or the animals exhibited signs of physical stress and were humanely terminated. Tumor volume remained stable from cessation of therapy until day 19 for the palbociclib arm and day 23 for the combo and TMZ arm. (Fig. 3c). The full tumor volume data set is presented in supplementary table S2 and is graphed in the Additional file 1: Figure S1. Figure 3d shows typical PET images for animals treated with control and with drug.
The concept of using rapid modulation of PET uptake as an in vivo pharmacodynamic assay is not new. Numerous preclinical studies using both [18F]FDG and [18F]FLT PET have shown modulation of signals on repeat imaging after therapeutic intervention in 24–72 h predictive of future response based on volume changes. [15].
Clinically it has been shown that when treating metastatic colon cancer lacking K-RAS mutation a nearly 50% decrease in [18F]FDG uptake at 48 h following an initial dose of panitumumab was predictive of response at 8 weeks of therapy [16].
In this study we investigated the early modulation (day 3 and day 9) of [18F]FLT PET after initiation of therapy in a well characterized [10] PDX model of invasive bladder cancer responsive to the CDK4/6 inhibitor palbociclib and palbociclib/temozolomide combination. While palbociclib and other CDK4/6 inhibitors have been approved by FDA in breast cancer in combination with endocrine therapy [3], our goal was to determine if [18F]FLT should be considered a potential in vivo biomarker for predictive response in other tumors since CDK4/6 inhibitors are increasingly being considered in other solid cancers either as single agents or in combination therapy [17, 18]. Preclinical data suggesting the utility of [18F]FLT imaging includes a recent publication that demonstrated early decrease in [18F]FLT PET in a breast cancer model using combination palbociclib/fulvestrant therapy [6] and in another breast cancer model with single agent therapy [7] However, no studies have been reported in non-breast cancer models.
The CDK4/6 inhibitors act on the D-cyclin-dependent kinase 4/6-INK4-retinoblastoma (D-CDK 4/6- Rb) pathway, considered a key pathway regulating the G1-S phase transition in the cell cycle as shown in Fig. 4. Abnormal activation of this pathway has been reported in numerous cancer types. The retinoblastoma (RB) tumor suppressor regulates several processes associated with DNA repair and cell cycle progression [19]. RB suppresses the E2F family of genes that encode a collection of transcription factors involved in cell cycle regulation. Under standard conditions CDK4/6, directed by upstream signaling (PI3K/AKT/mTOR), phosphorylates RB1 promoting E2F transcription and cell cycle progression from G1 to S. While this pathway is important to DNA repair and genomic stability, it also is responsible for resistance to DNA-damaging therapeutics. In addition, this pathway is subject to abnormal deregulation of RB phosphorylation due to upregulated CDK4/6 from dysregulated input upstream. CDK4/6 inhibitors block the phosphorylation of RB1 and lead to G1 arrest [17].
Under standard conditions CDK4/6, directed by upstream signaling, phosphorylates RB1 promoting E2F transcription and cell cycle progression from G1 to S. CDK4/6 inhibitors block this pathway, causing cells to stall at G1. This blockage in the cell cycle reduces uptake of thymidine and therefore of [18F]FLT
[18F]FLT is a well-established PET imaging probe that reflects the status of cellular proliferation and has long been applied in oncology studies [20]. In a systematic review, Schelhass and co-authors found 102 papers investigating the correlation of [18F]FLT uptake to histological proliferation markers (mostly Ki67) and demonstrated correlation in the vast majority of studies [21]. Uptake of [18F]FLT occurs via nucleoside transporters notably nucleoside transporter 1 (hENT1) and once intracellular, it is phosphorylated by thymidine kinase 1 (TK1), a cell cycle regulated enzyme and rate-limiting step of the thymidine salvage pathway [22]. The [18F]FLT signal is therefore a measure of the enzymatic activity of TK1. Tumor accumulation of [18F]FLT strongly correlates with TK1 activity and percentage of cells in S phase [23, 24].
[18F]FLT PET should not be confused with [18F]FDG PET which measures aerobic glycolysis and correlates with tumor glycolytic reprogramming of the tumor metabolome. Rather [18F]FLT is a marker of DNA synthesis and reports on the status of the cell cycle especially correlated to S phase. [18F]FLT imaging in conjunction with a specific inhibitor of G1/S that rapidly down regulates TK1 and depletes S phase provides an in vivo measure of on target effect prior to measurable tumor volume change. Arrest of cells at G1 will cause a reduction in uptake of [18F]FLT compared to cells that are cycling normally. [18F]FLT imaging for prediction of therapeutic response in drug treatment models has shown a significant reduction in [18F]FLT uptake versus baseline as early as 24 h following initiation of therapy and has consistently shown reductions at 72 h [15]. Pre-clinical studies have shown that CDK4/6 inhibitor therapy leads to halt of G1/S, and the cells in S phase pass through G2/M with rapid washout. If the G1/S halt is persistent then cells will die primarily through senescence depending on p53 driven autophagy [24].
In this study we observed a significant reduction in [18F]FLT at both 3 and 9 days following initiation of therapy in both the palbociclib and palbociclib plus temozolomide therapy arms. During this time and persisting out to 19 days (12 days post end of therapy) there was significant suppression of tumor growth in these two groups. In the control group, we observed progressive growth and corresponding increase in [18F]FLT PET uptake. In the temozolomide group there was initially progressive growth as in the control arm with increased [18F]FLT uptake from day 3 to 9. By day 23, following cessation of therapy, all groups demonstrated progressive growth. Clearly the single agent palbociclib was driving the therapeutic response, consistent with the early [18F]FLT measures. On the other hand, temozolomide as a single agent was not effective and [18F]FLT uptake increased in line with control at day 3 and 9, as has been reported in a glioma study with TMZ resistant cells [26]. The fact that the combination therapy arm had prolonged suppression of growth over the palbociclib alone arm following cessation of therapy is interesting and warrants further investigation.
Our study is limited in that this was a single well characterized PDX model in a small number of animals. However, preclinical efficacy data has been reported [5] in other models, both responsive and non-responsive to CDK4/6 inhibitors, suggesting that further studies of [18F]FLT for response assessment to aid in development of this class of compounds in tumors other than breast is warranted. While [18F]FLT is not currently commercially available for clinical studies, it has been implemented in numerous clinical trials under active INDs in many institutions.
In this exploratory study we demonstrated that early decreased uptake of [18F]FLT PET occurred with suppression of tumor growth in a PDX model of invasive bladder disease treated with palbociclib or palbociclib/temozolomide. Temozolomide as a single agent was not effective and early increased [18F]FLT uptake was consistent with lack of therapeutic response. Based on these findings and supported by referenced preclinical publications, it appears [18F]FLT may serve as an in vivo biomarker for CDK4/6 inhibitor therapy in solid tumor histologies beyond breast. Subsequent studies are needed to confirm these results and to determine if other tumor types responsive to CDK4/6 inhibitors also demonstrate similar modulation of [18F]FLT uptake.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
[18F]FLT:
[18F]fluoro-3'-deoxythymidine
CDK4/6:
Cyclin-dependent kinase 4/6-INK4-retinoblastoma
X-ray computed tomography
E2F:
Genes encoding a family of transcription factors regulating cell cycle
Estrogen receptor
ERBB2:
Receptor tyrosine-protein kinase erbB-2
HER2:
Human epidermal growth factor receptor 2
PDX:
Patient derived xenograft
pRB, Rb, Rb1:
Retinoblastoma proteins
SUVbw max:
Maximum standardized uptake value normalized by body weight
TK1:
Thymidine kinase 1
TMZ:
Temozolomide
Knudsen ES, Shapiro GI, Keyomarsi K. Selective CDK4/6 inhibitors: biologic outcomes, determinants of sensitivity, mechanisms of resistance, combinatorial approaches, and pharmacodynamic biomarkers. Am Soc Clin Oncol Educ Book. 2020;40:115–26. https://doi.org/10.1200/EDBK_281085.
Liu M, Liu H, Chen J. Mechanisms of the CDK4/6 inhibitor palbociclib (PD 0332991) and its future application in cancer treatment (Review). Oncol Rep. 2018;39(3):901–11. https://doi.org/10.3892/or.2018.6221.
Wu Y, Zhang Y, Pi H, Sheng Y. Current therapeutic progress of CDK4/6 inhibitors in breast cancer. Cancer Manag Res. 2020;15(12):3477–87. https://doi.org/10.2147/CMAR.S250632.
Du Q, Guo X, Wang M, Li Y, Sun X, Li Q. The application and prospect of CDK4/6 inhibitors in malignant solid tumors. J Hematol Oncol. 2020;13(1):41. https://doi.org/10.1186/s13045-020-00880-8.
Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, Albassam M, Zheng X, Leopold WR, Pryer NK, Toogood PL. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004;3(11):1427–38. https://doi.org/10.1158/1535-7163.1427.3.11.
Elmi A, Makvandi M, Weng CC, Hou C, Clark AS, Mach RH, Mankoff DA. Cell-Proliferation imaging for monitoring response to CDK4/6 inhibition combined with endocrine-therapy in breast cancer: comparison of [18F] FLT and [18F]ISO-1 PET/CT. Clin Cancer Res. 2019;25(10):3063–73. https://doi.org/10.1158/1078-0432.CCR-18-2769.
Ma G, Liu C, Lian W, Zhang Y, Yuan H, Zhang Y, Song S, Yang Z. 18F-FLT PET/CT imaging for early monitoring response to CDK4/6 inhibitor therapy in triple negative breast cancer. Ann Nucl Med. 2021;35(5):600–7. https://doi.org/10.1007/s12149-021-01603-w.
Barthel H, Cleij MC, Collingridge DR, Hutchinson OC, Osman S, He Q, Luthra SK, Brady F, Price PM, Aboagye EO. 3'-deoxy-3'-[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography. Cancer Res. 2003;63(13):3791–8.
Been LB, Suurmeijer AJ, Cobben DC, Jager PL, Hoekstra HJ, Elsinga PH. [18F] FLT-PET in oncology: current status and opportunities. Eur J Nucl Med Mol Imaging. 2004;31(12):1659–72. https://doi.org/10.1007/s00259-004-1687-6.
Pan CX, Zhang H, Tepper CG, Lin TY, Davis RR, Keck J, Ghosh PM, Gill P, Airhart S, Bult C, Gandara DR, Liu E, de Vere White RW. Development and characterization of bladder cancer patient-derived xenografts for molecularly guided targeted therapy. PLoS ONE. 2015;10(8): e0134346. https://doi.org/10.1371/journal.pone.0134346.
Marchand P, Ouadi A, Pellicioli M, et al. Automated and efficient radiosynthesis of [18F]FLT using a low amount of precursor. Nucl Med Biol. 2016;43:520–7.
Magdics M, Szirmay-Kalos L, Toth B, Legradyy D, Cserkaszkyy A, Balkayz L, Domonkosx B, Volgyesx D, Patayx G, Majorx P, Lantosx J. Bukkix T Performance evaluation of scatter modeling of the GPU-based "Tera-Tomo" 3D PET reconstruction. IEEE Nuclear Science Symposium Conference Record. 2011;2011:4086–8. https://doi.org/10.1109/NSSMIC.2011.6153777.
Kinahan PE, Fletcher JW. Positron emission tomography-computed tomography standardized uptake values in clinical practice and assessing response to therapy. Semin Ultrasound CT MR. 2010;31(6):496–505. https://doi.org/10.1053/j.sult.2010.10.001.
Lee JR, Madsen MT, Bushnel D, Menda Y. A threshold method to improve standardized uptake value reproducibility. Nuclear Med Commun. 2000;21:685–90.
Soloviev D, Lewis D, Honess D, Aboagye E. [(18F ] FLT: an imaging biomarker of tumour proliferation for assessment of tumour response to treatment. Eur J Cancer. 2012;48(4):416–24. https://doi.org/10.1016/j.ejca.2011.11.035.
Krystal GW, Alesi E, Tatum JL. Early FDG/PET scanning as a pharmacodynamic marker of anti-EGFR antibody activity in colorectal cancer. Mol Cancer Ther. 2012;11(7):1385–8.
Thangavel C, Dean JL, Ertel A, Knudsen KE, Aldaz CM, Witkiewicz AK, Clarke R, Knudsen ES. Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer. 2011;18(3):333–45. https://doi.org/10.1530/ERC-10-0262.
Roberts PJ, Kumarasamy V, Witkiewicz AK, Knudsen ES. Chemotherapy and CDK4/6 Inhibitors: Unexpected Bedfellows. Mol Cancer Ther. 2020;19(8):1575–88. https://doi.org/10.1158/1535-7163.MCT-18-1161.
Choi YJ, Li X, Hydbring P, Sanda T, Stefano J, Christie AL, Signoretti S, Look AT, Kung AL, von Boehmer H, Sicinski P. The requirement for cyclin D function in tumor maintenance. Cancer Cell. 2012;22(4):438–51. https://doi.org/10.1016/j.ccr.2012.09.015.
Tehrani OS, Shields AF. PET imaging of proliferation with pyrimidines. J Nucl Med. 2013;54(6):903–12. https://doi.org/10.2967/jnumed.112.112201.
Schelhaas S, Heinzmann K, Bollineni VR, et al. Preclinical applications of 3'-Deoxy-3'-[18F]Fluorothymidine in oncology - a systematic review. Theranostics. 2017;7(1):40–50. https://doi.org/10.7150/thno.16676.
Rasey JS, Grierson JR, Wiens LW, Kolb PD, Schwartz JL. Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells. J Nucl Med. 2002;43(9):1210–7.
Sala R, Nguyen QD, Patel CB, Mann D, Steinke JH, Vilar R, Aboagye EO. Phosphorylation status of thymidine kinase 1 following antiproliferative drug treatment mediates 3'-deoxy-3'-[18F]-fluorothymidine cellular retention. PLoS ONE. 2014;9(7): e101366. https://doi.org/10.1371/journal.pone.0101366.
Grierson JR, Brockenbrough JS, Rasey JS, Wiens LW, Schwartz JL, Jordan R, Vesselle H. Evaluation of 5'-deoxy-5'-[F-18]fluorothymidine as a tracer of intracellular thymidine phosphorylase activity. Nucl Med Biol. 2007;34(5):471–8. https://doi.org/10.1016/j.nucmedbio.2007.03.004.
Vijayaraghavan S, Karakas C, Doostan I, Chen X, Bui T, Yi M, Raghavendra AS, Zhao Y, Bashour SI, Ibrahim NK, Karuturi M, Wang J, Winkler JD, Amaravadi RK, Hunt KK, Tripathy D, Keyomarsi K. CDK4/6 and autophagy inhibitors synergistically induce senescence in Rb positive cytoplasmic cyclin E negative cancers. Nat Commun. 2017;27(8):15916. https://doi.org/10.1038/ncomms15916.
Viel T, Schelhaas S, Wagner S, Wachsmuth L, Schwegmann K, Kuhlmann M, Faber C, Kopka K, Schäfers M, Jacobs AH. Early assessment of the efficacy of temozolomide chemotherapy in experimental glioblastoma using [18F]FLT-PET imaging. PLoS ONE. 2013;8(7): e67911. https://doi.org/10.1371/journal.pone.0067911.
We thank Dr. S. Difilippantonio for her supervision of the LASP core: Animal Research Technical Support.
Open Access funding provided by the National Institutes of Health (NIH). This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261201500003I. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
James L. Tatum, Paula M. Jacobs & James H. Doroshow
Small Animal Imaging Program, Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
Joseph D. Kalen & Lisa A. Riffle
Animal Research Technical Support, Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
Amy James, Lai Thang & Chelsea Sanders
Biological Testing Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institute of Health, Frederick, MD, United States
Melinda G. Hollingshead
Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
Falguni Basuli & Jianfeng Shi
James L. Tatum
Joseph D. Kalen
Paula M. Jacobs
Lisa A. Riffle
Amy James
Lai Thang
Chelsea Sanders
Falguni Basuli
Jianfeng Shi
James H. Doroshow
Conception/design: JLT, JDK, JHD, PMJ Acquisition of data: AJ, MGH, LT, CS, LR, FG, JS Analysis/interpretation: JLT, JDK, PMJ Draft/revise: JLT, JDK, PMJ Reviewed and approved: all. All authors read and approved the final manuscript.
Correspondence to Paula M. Jacobs.
Figure S1. Mean and standard deviation [18F]FLT SUVbw max) (A) and caliper measured tumor volumes (B) for individual mice in each cohort at each timepoint and normalized to baseline. The red horizontal line signifies the normalized baseline for easy comparison. Table S1. Individual animal data for [18F]FLT uptake [SUVbw max]. Table S2. Individual animal data for tumor volume (mm3).
Tatum, J.L., Kalen, J.D., Jacobs, P.M. et al. 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT) Positron Emission Tomography as an In Vivo Biomarker of inhibition of CDK 4/6-Rb pathway by Palbociclib in a patient derived bladder tumor. J Transl Med 20, 375 (2022). https://doi.org/10.1186/s12967-022-03580-8
Imaging biomarkers
Palbociclib
CDK4/6
FLT PET
Response biomarker
Translational Imaging


text:
Recommend some depressing jazz!
DVsickgirlDV June 27, 2006, 8:57pm #1
So I just heard Billie Holiday's "Strange Fruit" and the song just sent chills up my spine with the melancholy piano and haunting lyrics. Can anyone else recommend good jazz to listen to on a rainy day when you're feeling down in the dumps?
Bosda_Di_Chi_of_Tricor June 27, 2006, 11:22pm #2
Smile, darn ya! Smile!
You don't need to be depressed!
Go listen to Louis Armstrong's "What a Wonderful World". Life looks better, afterwards.
Or listen to Yoko Kanno & The Seatbelts, off the Cowboy Bebop soundtrack, belting out "Tank!". Sets the blood pumpin'.
MovieMogul June 27, 2006, 11:24pm #3
Addressing the OP, there's something mournful about just about everything Nina Simone sang. Any one of her albums should do the trick.
Gatopescado June 27, 2006, 11:25pm #4
See also "Blues" and "Fado".
teela_brown June 27, 2006, 11:45pm #5
I seem to remember "'Round Midnight" being a good suicide anthem.
Dead_Badger June 27, 2006, 11:52pm #6
"Goodbye Pork Pie Hat" by Charles Mingus. Beautiful track, and one of my favourites; written after the death of Lester Young, the saxophonist who wore the eponymous hat (I love the name of the track). I can practically see the guys sitting in a smoky bar when they hear the news, and writing that for him. Just make sure to listen to "Better git it in your soul" too to stop you killing yourself.
Specific Nina Simone suggestion: "I loves you Porgy", from Porgy and Bess. Gorgeous. Or "Ne me quitte pas".
AncientHumanoid June 28, 2006, 12:04am #7
Just about anything by Chieli Minucci and his band Special EFX. I really like Hands of the Healer and Rainy Sunday off of the Mystique album.
Elendil_s_Heir June 28, 2006, 4:34pm #8
Bosda Di'Chi of Tricor:
…Go listen to Louis Armstrong's "What a Wonderful World". Life looks better, afterwards…
Agreed, although it was used in two movies in an ironic way, juxtaposed with scenes of death and devastation: in Good Morning, Vietnam (as U.S. troops wage war) and in Twelve Monkeys (about a looming pandemic that will kill most of the world's population).
mojave66 June 28, 2006, 4:42pm #9
Try Holliday's "Gloomy Sunday" if you want depressing. All about joyfully contemplating suicide.
Bosda_Di_Chi_of_Tricor June 28, 2006, 5:28pm #10
Elendil's Heir:
3 movies.
The Anime version of Metropolis used it to devasting effect. Even horrifying effect!
AncientHumanoid June 28, 2006, 5:41pm #11
It was used for the closing credits of an 80s BBC sci-fi miniseries about a doomed planet and the doomed future/past survivor of said doomed planet.
ZipperJJ June 28, 2006, 6:52pm #12
For something newer (well, 1999) check out the songs "Self Inflicted" and "Mope" from the Heretic Blues album by Kevin O'Donnell's Quality Six.
The singer, Andrew Bird, will rip your heart out.
Unforunately, the Amazon preview doesn't give too much in the way of lyrics
MovieMogul June 28, 2006, 7:14pm #13
NoClueBoy:
Five. It was also used in Fahrenheit 9/11.
Linty_Fresh June 28, 2006, 8:09pm #14
ArchiveGuy:
Six, it was also used in Madagascar to highlight the brutality of nature.
gigi June 28, 2006, 8:16pm #15
These aren't are depressing as **Strange Fruit ** (Cassandra Wilson does a version as well) but a couple from **Mo' Better Blues ** are quietly sad:
Harlem Blues – with vocal
Mo' Better Blues – instrumental
Talon_Karrde June 29, 2006, 12:14am #16
I remember when I first heard Strange Fruit. It was in literature class. I was in a serious funk for the rest of the day.
Tom Waits can have some depressing songs, and musically he can be kinda close to Billie Holiday. The song Poor Edward is a major downer.


text:
Deschamps Says Mbappe's Current Champions League Goal Drought Should Not be a Concern
Paris Saint-Germain forward Kylian Mbappe is currently on a rare UEFA Champions League goals drought. The French talent has not scored a Champions League goal in 2020. Mbappe failed to find the back of the net earlier this year in PSG's Champions League knockout stage run, and he has not yet scored in the group stage this season.
While many have pointed out Mbappe's sluggish Champions League performances this year, French national team manager Didier Deschamps is not among those bashing the forward for his slight struggles. Deschamps knows very well how quickly Mbappe can turn the tide with his play. Deschamps explained (via RMC Sport) his reasoning for not being overly concerned with Mbappe's current goal drought in the biggest club football competition in the continent.
"Kylian is always a player who makes the differences," Deschamps said. "Obviously he needs to score, it's been a while since he scored [in the UCL]. It happens, all top attackers can experience a period when they have a little less success and efficiency.
"I'm not asking myself questions or having concerns about Kylian. He wants to stop this series of course but that does not prevent him from doing decisive things for his club."
Mbappe will have one final chance to score a Champions League goal in the calendar year when PSG takes on Istanbul Basaksehir next week in the team's last group stage fixture of the season.
Tags Champions League Didier Deschamps Kylian Mbappé
'I Am Very Proud of the Work I Did in Paris' – Emery Discusses His Time as PSG's Manager, Champions League, and Pochettino's Hiring


The Fareast Club Optimist Package is a reliable option for a sailor entering into a junior sailing program.
Fareast Race Hull: Economically suitable hull for a beginner sailor.
North Sails Club Sail: High quality with a low price tag. The club sail is class strong and durable to last until your sailor is ready to move to the next level.
Fareast Club Spars: Club spars work in pair with the club sail. The sail and spars are designed to be rolled using the "snow cone" rolling technique.
Fareast Race Blades: The rudder and daggerboard are class legal race blades. These blades may be slightly nicer than a beginner will need, but if properly maintained will come in handy when your sailor starts to race.
Overall the Fareast Club Package is the best value on the Optimist market. You will not find a better price for this quality boat.


text:
Desmia pentodontalis is a moth of the family Crambidae described by George Hampson in 1989. It is found in Ecuador.

The wingspan is about 34 mm. The forewings are black-brown with a cupreous tinge and with a hyaline (glass-like) spot in the cell, as well as a lunulate (crescent-shaped) spot in the end of the cell and a lunulate spot below the cell with a whitish mark below it. There is a hyaline postmedial band. There is irregular medial hyaline band on the hindwings, as well as an irregular postmedial line.

References

Moths described in 1898
Desmia
Moths of South America


text:
If You Experience Any of These Symptoms of Rhabdo, Seek Professional Treatment ASAP
Symptoms of Rhabdomyolysis
13 June, 2018 by Christina Stiehl
You've likely heard about rhabdomyolysis, or rhabdo for short, in relation to indoor cycling or CrossFit. It's a dangerous condition that can do serious damage to your kidneys and be life-threatening if you're not careful. And while it's caused by exercise, even healthy, fit people who work out regularly can still get it.
POPSUGAR talked to experts who broke down the symptoms to watch out for and how to prevent it. If you're embarking on a particularly tough workout, such as CrossFit's Murph, be sure to pay attention to the signs you may be getting rhabdo.
This Is Exactly What Happens to Your Body When You Don't Take a Rest Day
What Is Rhabdo?
Rhabdomyolysis is the rapid breakdown of skeletal muscle tissue. When this happens, a protein from your muscle tissue called myoglobin enters into your bloodstream. And since myoglobin is a waste your body doesn't need, your kidneys have to work overtime to filter it out. The problem is that your kidneys can only do so much; the amount of waste that enters your bloodstream can overload your kidneys, which can lead to kidney damage or kidney failure, which is potentially fatal.
Overexerting yourself in a workout can lead to exertional rhabdomyolysis, but other causes of rhabdo include trauma, such as getting in a car accident or a fall; illegal drugs, such as cocaine, amphetamines, or heroin; viral infections; or diseases of the muscles, such as congenital muscle enzyme deficiency.
After an intense workout, you should expect to be sore. But with exertional rhabdo, you will experience soreness and pain unlike any that you've had before. Vijay Jotwani, MD, the primary care sports medicine physician at Houston Methodist, said this pain is the biggest symptom. If you overworked your biceps or triceps, for example, you may not be able to fully extend your arms.
Another symptom is the darkening of your urine, sometimes to the point of it looking like cola, thanks to the myoglobin entering your urine. You may also feel generally fatigued or uneasy. If you get to the point of kidney damage, you may experience nausea, vomiting, lethargy, or confusion, Dr. Jotwani said.
Since exertional rhabdo is caused by overexerting yourself, it's important to pay attention to your body during your workouts, especially if you're embarking on something tougher than normal. "Rhabdomyolysis is completely preventable and occurs when you exceed your body's limits," Dr. Jotwani said. "It's important to gradually increase the intensity of your workouts to avoid rhabdo." This is especially important if you're an inexperienced exerciser and working out at an intense level for the first time.
But it's not just inexperienced athletes who are susceptible to rhabdo; fit people and frequent exercisers can still get it, too.
"Even the most skilled, well-trained and physically fit athletes are potentially vulnerable to rhabdo," said Todd S. Cutler, MD, a hospitalist at New York-Presbyterian/Weil Cornell Medical Centre and author of a 2016 study about rhabdomyolysis published in the Clinical Journal of Sports Medicine.
"This is especially true if they're pushed hard enough at a rigorous, high-intensity physical activity or workout they've never tried before and that their body has never experienced," he said. "In this instance, the emphasis is less on a person's fitness level. Instead, it's about whether or not they've been properly trained, prepared, and are ready to be physically active at a high intensity level or not."
You should also be sure to hydrate before and after a particularly difficult workout. Although you may want to celebrate that Murph or intense Spin class with a beer afterward, be sure you drink plenty of water and possibly an electrolyte-rich beverage, such as Gatorade.
How Should I Seek Treatment?
As soon as you notice any of these symptoms, especially muscle pain and dark urine, you should seek professional help immediately. Dr. Jotwani recommends going to the ER, where they'll perform a blood and/or urine test to diagnose (or rule out) rhabdo.
Fortunately, you can expect a full recovery from rhabdo if you're treated early and properly. If you don't seek treatment early enough, it may lead to lasting kidney damage or kidney failure. You'll be treated with intravenous (IV) fluids to prevent kidney failure. Depending on how severe your rhabdo is, you may need to be hospitalized or return every few days for treatment.
Although rahbdo sounds scary, it is preventable; just be sure you are paying attention to your body, keeping an eye out for symptoms, and always mindful of how hard you are actually pushing yourself in the gym.
Image Source: POPSUGAR Photography / Kathryna Hancock
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Oakland McDonald's Ordered to Improve Worker Safety After Coronavirus Outbreak
All workplaces across California should prioritize worker safety no matter what, whether it involves purchasing protective equipment or providing special training. The ongoing COVID-19 pandemic, however, has required employers to take extra steps to ensure employees are safe on the job.
Workers at a McDonald's restaurant in Oakland recently spoke up after a lack of safety measures resulted in a workplace COVID-19 outbreak last year. A group of cooks and cashiers filed a public nuisance lawsuit against their employer in June 2020.
Around 25 McDonald's workers and their family members, including a 10-month-old baby, were infected with COVID-19 during the outbreak in spring 2020. Employees claimed management told them to use dog diapers and coffee filters as face masks during the outbreak. Managers also used an inaccurate thermometer when conducting pre-shift temperature checks of workers and failed to enforce physical distancing.
An Alameda County Superior Court judge ordered the Telegraph Avenue McDonald's franchise to implement 11 health and safety measures. As part of the August 12 settlement, the restaurant agreed to set up a safety committee.
Managers will be required to follow new worker safety measures. Recommendations include allowing paid sick leave, providing proper masks and gloves, mandating physical distancing, deep cleaning surfaces and carrying out contact tracing if a worker tests positive for the coronavirus.
The safety committee is believed to be the first of its kind at a McDonald's restaurant. It will consist of monthly meetings between management and staff to discuss how to maintain worker safety.
The McDonald's corporation itself was not named in the lawsuit. According to a report in SFGATE, franchises received handbooks that contained safety policies for the COVID-19 pandemic.
Angely Lambert, one of the lawsuit's five plaintiffs, highlighted the change that can come about when workers speak up. Lambert said, "We joined together and fought for our dignity as human beings — and we won… We will keep fighting to make sure that every worker, in fast food and beyond, has a voice on the job."
If your employer is violating your right to a safe workplace, you should not tolerate the dangerous working conditions. Discuss your situation with an experienced Oakland employment lawyer. Erlich Law Firm can provide legal advice on how to get your employer to take workplace safety seriously. Contact us today to learn more.


This April, Protect Your Eyes – inside and out!
*Some conditions may apply. Sales and promotions cannot be combined with any other offers or packages. Sale pricing applies to in-stock product with the purchase of fully coated lenses. See in-store, call, or email us for more details.
Double-sided UV protection Airwear provides 100% UV protection from the front. Broad Spectrum technology from Crizal provides unique protection against UV reflections off the back side of the lens.
Crizal Prevencia filters out harmful UV and Blue-Violet light while allowing essential light to pass through.
Virtually unbreakable Airwear is 12 times more impact resistant than standard plastic and is 35% thinner and 50% lighter than standard plastic lenses.
Transitions Lenses: a convenient choice for children! Transitions reduce glare and risk of breakage. Your child may not lose their glasses since they don't have to switch back and forth between sunglasses and glasses! 9 out of 10 children prefer them to regular lenses. If your child tries Transitions, and does not enjoy them, we can switch them back to regular lenses within the first 60 days– at no extra charge!
One-time lens replacement warranty if your child's prescription changes within 15 months!
Is your child in kindergarten and requires their first pair of glasses? Your child could be eligible for a free pair of glasses! Eye Etiquette is proud to be a participant in the Eye See … Eye Learn® children's vision program! Eye See provides Kindergarten students with eye exams and, if prescribed, one free pair of eyeglasses!
Good eye health and vision are essential for academic and developmental success during children's early learning years. However, statistics show that 1 in 4 school-age children has an underlying vision problem that can affect performance.
Families of Kindergarten children in participating school districts receive a letter from school staff introducing them to the program. Book an eye exam with us online or call us today to see one of our optometrists!
For more information about ESEL, email PR@optometrists.bc.ca or call 604-737-9907 or 1-888-393-2226 (outside of BC). Information on this webpage is courtesy of Eye See Eye Learn.


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Kira Wynne
https://kwphotographyanddesign.com/
Kira Wynne was born and raised in Houston, TX and moved to MD with her family in 1991. She now resides in Middletown, MD with her loving and supportive husband and crazy talented daughter. She studied psychology in college and worked in the mental health field for about 5 years before she changed career goals and decided to turn her passion into her profession. Kira is a completely self-taught Graphic and Web Designer, as well as a very talented Photographer. Kira has been working in the field for almost 20 years. Most of her career was spent working in the corporate field for companies that were DoD contractors. Due to recent health issues however, she had to leave the daily 9-5 grind behind and now works as a photographer and graphic/ web contractor from the comforts of her home. Kira Wynne is the designer and administrator of The Tentacle website.
Caroling For Freedom
Caroling For Freedom on December 19th at 4:30PM as we sing in protest of the continued restrictions of our FREEDOM! We will fellowship and celebrate the holiday season together while letting the Former Governor Hogan know that WE WILL NOT COMPLY!!!
The Police Abandoned Me
By now most people are probably already aware of the shootings that took place in CHOP — or "Capitol Hill Occupied Protest" zone — near Cal Anderson Park in Seattle, Washington on June 20th.
The Viral Mauling At Macy's
Another brutal video is flooding social media - this video was filmed on Monday at the Macy's at the Genessee Valley Center mall in Flint Township in Michigan. The video shows a black man punching a white store employee and knocking him to the ground. He then hits him twice more as the man tries to crawl away, begging his assailant to stop.
Rioting – The Coronavirus Cure
I don't know how many of you engage in social media but up until recently I only used Facebook to post family pictures and trivial things like that. Then the pandemic started and everything changed.
MHS production of Annie
Tickets for the MHS production of Annie are now on sale! Visit www.showtix4u.com to reserve your seats today!
By John Ashbury
On January 15, 1883, William Nelson Pendleton, former rector of All Saints Episcopal Church, and a general in the Confederate Army, died in Lexington, VA. He also designed an East Patrick Street bridge that replaced one destroyed by a Carroll Creek flood in October 1847. The bridge was used until 1926.
On January 15, 1903, a special five-car train left Frederick, taking the members of the Society of Jesus from its Frederick Novitiate to a new one on the Hudson River in New York State, ending 150 years of their work in Frederick.
On January 15, 1908, The Peoples Fire Insurance Company of Frederick began doing business. It had been incorporated on December 10, 1907.
On January 15, 1977, President Gerald R. Ford visited Camp David just days before his presidency ended.
Dan Bogino's Podcast
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