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Glioblastoma (GBM) is a disease of the whole brain, with infiltrative tumor cells protected by an intact blood-brain barrier (BBB). GBM has a poor prognosis despite aggressive treatment, in part due to the lack of adequate drug permeability at the BBB. Standard of care GBM therapies include radiation and cytotoxic chemotherapy that lead to DNA damage. Subsequent activation of DNA damage response (DDR) pathways can induce resistance. Various DDR inhibitors, targeting the key regulators of these pathways such as ataxia telangiectasia mutated and Rad3-related (ATR), are being explored as radio- and chemosensitizers. Elimusertib, a novel ATR kinase inhibitor, can prevent repair of damaged DNA, increasing efficacy of DNA-damaging cytotoxic therapies. Robust synergy was observed in vitro when elimusertib was combined with the DNA-damaging agent temozolomide; however, we did not observe improvement with this combination in in vivo efficacy studies in GBM orthotopic tumor-bearing mice. This in vitro–in vivo disconnect was explored to understand factors influencing central nervous system (CNS) distribution of elimusertib and reasons for lack of efficacy. We observed that elimusertib is rapidly cleared from systemic circulation in mice and would not maintain adequate exposure in the CNS for efficacious combination therapy with temozolomide. CNS distribution of elimusertib is partially limited by P-glycoprotein efflux at the BBB, and high binding to CNS tissues leads to low levels of pharmacologically active (unbound) drug in the brain. Acknowledging the potential for interspecies differences in pharmacokinetics, these data suggest that clinical translation of elimusertib in combination with temozolomide for treatment of GBM may be limited.

Anna Marie, Chris, and Kelley are joined by special guest Ryan Radcliff! Chris swears every time E3 fails, an angel gets its wings. Anna Marie refuses to play games she's in. Kelley wants to pet the cat cream roll. And Ryan is dragging around Paws's corpse as he spins all the wheels.

The post RPG Cast – Episode 589: “Chaos Never Sleeps” appeared first on RPGamer.

Kelley needs a good toilet game. Chris wonders where to hold the sword-chucks. Josh discovers the Trails series gets more anime the further it goes. And Jason wonders if Dory has ADHD. What's his name again? Oh right, Wyl.

The post RPG Cast – Episode 689: “Enthusiasm Crushed” appeared first on RPGamer.

It's rare that you'll find discounts on Apple products through the company's own retail channels, but other storefronts are often happy to slash prices on such wares. You can find early Black Friday deals on a bunch of Apple products, including MacBooks. The M3 MacBook Air with 16GB of RAM has dropped to its lowest price to date at Amazon. The laptop will run you $899, which is $200 off the list price.

This is a 13-inch MacBook Air with 256GB of storage. Other configurations with more storage space are on sale too. One with 8GB of RAM and a 512GB SSD is $300 off at $999, though we'd recommend having at least 16GB of memory. It's not possible to upgrade the RAM in an Apple Silicon MacBook, but you can always add external storage if need be.

To that end, you can snag a 13-inch M3 MBA with 16GB of RAM and 512GB of built-in storage for $1,099. If a model with 24GB and the same SSD is what you're looking for, you can snap one up for $1,299. Both are $200 off.

Apple just released its first M4-powered Macs, but it has yet to slot the latest chip into the MacBook Air. To that end, we reckon the 13-inch M3 MacBook Air is the best laptop for most people. It's our pick for the best laptop for college students too.

The 13-inch MBA's blend of power and portability makes it a potent choice and we gave it a score of 90 in our review. It delivers fast performance and has a killer display. The design is sleek and sturdy and it sounds great thanks to a quad-speaker array. We like the trackpad and keyboard as well, while the upgrade to Wi-Fi 6E connectivity is a definite plus. Our main quibble is that the USB-C ports are on the same side of the unit as the one for the charger — having even one USB-C on the right side would be handy. But that's a minor complaint about an otherwise excellent laptop.

Check out all of the latest Black Friday and Cyber Monday deals here.

During a March 28 meeting with Assistant Secretary or South and Central Asian Affairs Boucher, Foreign Minister-designate Shah Mehmood Qureshi confirmed that the new government wanted to work with the U.S. to combat extremism, increase trade and extend cooperation with India and Afghanistan.

The bottom line is that Pakistan cannot afford the $2 billion required to complete this F-16 program.

The �Design Smart, Live Beautifully� Home Tour coincides with the launch of the 2014 model of Blu�s award-winning�Breezehouse, which is�packed with luxurious features and an even more spacious floor plan

National Dog Bite Prevention Week is May 18-24. Any dog can bite, regardless of breed. Be a responsible pet owner.

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Blu Homes Breezehouse is the Real Simple and This Old House "2014 Dream Home of the Year."

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EY�s Natalie Deak on how hedge fund managers are pursuing growth

Edmunds.com�s roundup of new vehicles at the 2014 LA Auto Show

Celebrate My Drive� thanks all who committed to drive safe!

Christy Turlington en vid�o

Ramco's SMS based Employee Self Service redefines 'Inclusive Computing'

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This #AutismAwarenessMonth we encourage families with special needs to take steps now to plan for their loved ones� futures. Our Director of Advanced Planning, Ruthann Driscoll, discusses the importance of planning to secure long-term security and quality of life for your family. Learn more: http://u.nm.com/1AQBAsN

Interview Jean Jouzel, Pr�sident du jury

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The Patriot offers modern amenities along with brand-name appliances. For each unit sold, Clayton will donate $100 to Hope for the Warriors�.

Introducing CEB�s Global Talent Monitor

Les tendances du march� neuf

Barclaycard Travel Community presents the #IHAVEARRIVED contest. Sign up and tell us your most memorable travel story for a chance to win an unforgettable vacation experience!

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Northwestern Mutual, presenting sponsor of the Rose Bowl Game�, revealed renderings of its Tournament of Roses� Parade float, inspired by Peyton Richardson, a teenage ballerina who is fighting cancer.

D�couvrez la tour EQHO en vid�o

ITW Fr�d�ric Verdavaine

Lee and Lucille Allen share the story of how their Clayton Home changed their lives.

Algiz-RT7 rugged tablet product presentation

Global (INTERNET) sensation Joseph Griffin will make his triumphant return to Las Vegas on Thursday, Nov. 19, to properly capture the sights and sounds of the iconic Las Vegas Strip. This time, he�ll film a few familiar sites from his original �selfie� video paired with a selection of only-in-Vegas surprises for this Irish Dad.

Actor/comedian Rob Riggle announces his next breakfast move as the Holiday Inn Express brand�s Creative Director � BREAKFA-mojis!

The new HomeKit-enabled Onelink by First Alert� Wi-Fi Smoke + Carbon Monoxide (CO) Alarm pairs First Alert�s legacy of safety and innovation with Apple�s revolutionary HomeKit technology.

Eden Party by Perrier-Jou�t