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Emperor of Solo Play
Chapter 81 : Olf's Errand (2)
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Emperor of Solo Play
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Chapter 81 : Olf's Errand (2)
Chapter 81 – Olf's Errand (2)
– Level : 90
– Class : Magician
– Title : 47
– Stat : Strength(895)/Stamina(357)/Intelligence(538)/Magic(664)
After looking at his Stats, Hyrkan blinked as his eyes widened. Then he looked at his Stat Window once again.
'What's going on?'
A user of Hyrkan's caliber was well acquainted with his Stats. It was preposterous to not be able to recognize his own Stats. He would forget his phone number or home address before he would forget his Stats. It was unthinkable. Although Hyrkan wasn't that great at math, he was proficient enough to calculate the Stat values within his head.
'It seems all my Stats got a 3 percent increase? Am I seeing this wrong?'
Hyrkan quickly finished his calculation, then he checked the title.
[The First One to Meet Olf]
Title Effect : All Stat is increased by 3 percent.
Hyrkan stopped breathing.
All Stats increased by 3 percent!
'I knew the blacksmith Olf gave out a lot of good stuff, but I never expected such a good title.'
Olf didn't make make Rare or Unique Item. Olf was associated with making Epic Items, so he was a NPC that gave out a lot of title with good effects. The Epic Items also had a lot of ties with the Main Quests.
Hyrkan was well aware of this fact. However, Hyrkan had never been the main character to receive such Items or Titles until now.
'He really is an incredible bastard.'
Hyrkan rubbed his stomach.
'Although, his personality is bad, and he is annoying.'
He had received an unexpected present, and Hyrkan immediately checked the content of the Quest.
[Olf's Errand]
– Quest Rank : Unique
– Quest Level Range : None
– Quest Content : Deliver the item given to you by Olf to the Baheim Forest.
– Quest Reward : None
The Quest Content wasn't anything unique. It was a quest with no special rewards attached to it.
'He really is just using me as an errand boy.'
Essentially, it was a trash quest.
However, he had no choice but to carry this quest out, even if there was no reward.
Still, that didn't mean it was an easy quest.
'The Baheim Forest…… Isn't it at the Clapper Jungle?'
The Baheim Forest was actually a forest where one of the Elf tribe lived. It contained a village where the Baheim tribe lived.
The users enjoyed meeting the Elves in Warlord. Amongst the races, they enjoyed the highest popularity.
Weren't the Elves a race known for their beauty? Unless one was killed by being pierced by an Elf's arrow, there was no reason to hate the Elves.
Actually, the fondness for the Elves were a little bit overboard in some cases. There were some users that showed excessive interest in the Elves. Some did party play with an Elf NPC. Some even showed affection towards them. Moreover, there were users, who wanted to become a couple with an Elf NPC within the game. There were extremely disgraceful users whose life mission was to make this come true.
'Maybe I should have shown some some interest in the Elves in the past??'
Unfortunately, it was quite hard to meet the Elves in Warlord.
Like the blacksmith Olf, one needed a related Quest to be able to talk to the Elves.
Of course, the information regarding these Quests were released a little bit later on. However, at this point in the game, the information regarding the specific Quest Route for meeting the Elves were almost never traded.
Hyrkan also didn't have much information on the Elves.
He knew the Baheim Elf Tribe was at the Clapper Jungle. However, he didn't know that info, because he was interested in the Elves. He knew it since this had been part of the Main Scenario Quest content.
Basically, he would have to find out the specifics of the content by bumping his body against it.
'Even if I worry about it, I won't find an answer.'
Of course, it was meaningless to worry about it right now. Hyrkan turned his head. The Clapper Jungle was located north of the great Urugal mountain range. Hyrkan had his head turned northward.
'All right.'
Hyrkan reaffirmed his resolve.
It happened at that moment.
Kuhng kuhng!
A dog started barking with all its might from behind Hyrkan. He turned his head around in fright.
He caught sight of a single black dog.
Hyrkan started running, and the drooling Black Hound chased crazily after Hyrkan.
'When I advance in rank, I'll kill every one of those sons of bitches.'
Hyrkan left the great Urugal mountain range and headed towards the Clapper Jungle.
Clapper Jungle.
The enormous trees shot into the sky as if it didn't know the boundary of the sky. The Clapper Jungle was filled with the Clapper trees, and it was one of the most famous and magnificent view in Warlord.
Streams meandered to the middle of the Jungle, and it had formed a lake. It was majestic to see the Clapper trees from afar, but it was much more impressive within the jungle. The trees reached high into the sky, giving the illusion that there was a green colored sky above. The place held a profound and mysterious beauty. When the first user to find the Clapper Jungle recorded the video of the scenery, it drew 30 million views even though the footage was 3 hours long.
The Clapper Jungle was the main hunting ground used by users between level 100 to 110.
The most common monsters were the Tree Bark Snake, Hook Praying Mantis, and the Cursed Trapper Tree. It wasn't a place where one earned very good items or EXP, but it was a decent hunting ground.
The users, who used the Clapper Jungle as their stage, gathered at Clapper Village, which was located at the entrance of the jungle. The Clapper Village was quite large, and it even had a branch of the Subjugation Association there.
However, the most striking part of this place wasn't the village's size or the superb view of the Clapper Jungle. It was the users who used this place as their stage.
There was a clear difference between the users over level 100 and below 100. It was the difference between possessing a powerful power after finishing the Advancement and not having it.
Once one finishes one's Advancement, one's occupation that showed up on the Stat Window changed. One would then get a specialized Class instead of the Swordsman, Priest, Magician Class designation. There was the Fighter and Liner, Monk and Assister, Magic Swordsman and Mage, and etc…. Of course, the most distinguishable feature of these users was the experience and skill they had gained along the way.
The moment Hyrkan entered the Clapper Jungle's Subjugation Association, he could feel the difference.
Normally, if he entered a Subjugation Association in any castle he went to, most users would show surprise at Hyrkan with his Hahoe Mask on. Some put on an awed expression as if they had seen a celebrity.
However, it was different here.
"Is it really the Hahoe Mask?"
"A famous person has shown up here. Did he finish his Advancement?"
"We'll know once we see him in action. Anyways, the fact that the Hahoe Mask is here… There must be something interesting here?"
Instead of being surprised at seeing Hyrkan, these users thought about the potential profit they would be able to get their hands on.
Hyrkan received their gazes, and he was able to fully realize the situation he was in.
'Now I'll be playing with guys who really like playing this game.'
An adequate amount of nervousness sharpened Hyrkan's concentration and sharpness. At the same time, Hyrkan quickly turned his head to look at his surrounding. He first looked at the users equipped with the symbolic emblems.
At a glance, one could see several emblems present here. His eyes caught sight of several guild emblems. Hyrkan searched through his memories and discovered that many of them were from fairly famous guilds.
However, no one was from the 30 great guilds were present.
'I'll have to go with Plan A.'
In other words, no one from the 30 great guilds had yet to find out about the Baheim Elf Tribes within the Clapper Jungle. Even if the members of those guilds were present, Hyrkan had no plans to trade information with them.
Hyrkan had no choice but to go with his original idea.
'I have no choice, but to do all the Quests related to the Clapper Jungle.'
Hyrkan's hardships had just begun.
"Thanks to you, the Clapper Jungle will be a bit quieter now."
Hyrkan put on a forced smile as he heard words spoken by the Clapper Village's NPC.
'This is the 20th Quest. Please just let me move on. Please…'
This was the 10th day inside the Clapper Jungle.
During the 10 day period, Hyrkan had done all the Quests that was available to him.
Once he started doing all the Quest available in the Clapper Village, he formed a relationship with NPCs. This would lead to the higher rank Quests. In the end, he hoped he would get the Quest related to the Baheim Elves.
This was the most typical way for a user to get close to a hidden truth in Warlord.
Of course, people of the world preferred quality over quantity. It was the same for Hyrkan.
"Do you perhap have anything else for me to do?"
"Mmm. You can go see Chess at the Red Log Cabin. He is trying to acquire Tree Bark Snake's leather."
Hyrkan's face crumpled.
"Is it perhaps a task that requires gathering of the leathers?"
"The reward will be pretty good."
[Quest 'Chess' Request' has started.]
When he received the Quest, Hyrkan let out a forced laugh.
'Shit! I don't want to do this shit!'
Just by hearing the name of the Quest he could tell it was just a monster hunting Quest.
'I'm going to hit level 100 first if things keep going this way.'
The end to his patience had shown up 3 days ago. When the week was up, Hyrkan finally had to throw out a bait.
He put up a post to trade information. He put up a post saying he wanted information regarding the Elves within the Clapper Jungle.
It was a double-edged sword. He was basically telling other users that Elves existed inside the Clapper Jungle. This was why he hadn't wanted to take this route.
However, at this point, it was more important for him to get information regarding the Baheim Tribe. He couldn't worry about spreading information at this point. He had thrown out a big bait, yet no one was biting.
His anxiety deepened.
'The Stormhunters have already caught the Helm Ogre.'
It especially made him more restless knowing that the Stormhunters had already left the Parung Forest after catching the Helm Ogre.
It was at that moment.
[A Mail has arrived.]
The mail arrival alarm was heard.
Hyrkan immediately checked the address of the mail. It was a newly made mail address. Someone wanted trade information regarding the Baheim Elf Tribe.
The content was very brief.
[Would like to trade. The location will be in front of the Red Log Cabin.]
Hyrkan's expression unknotted.
He had spread the bait 3 days ago, and he had finally gotten a bite. Of course, he had no idea if the person who bit on the bait was a hustler, trash or a big fish.
First, Hyrkan immediately replied to the mail.
[Tell me about your appearance or distinct features. I'll go directly to you.]
Another mail came back immediately.
[I will look for you.]
Hyrkan was torn.
'Is this bastard trying to catch me instead?'
However, his indecision was brief.
'No. If I reveal myself as the Hahoe Mask, it might give credibility to the bait I put out. I've already spilled the beans about the Elves, and the fact that I'm hunting at the Clapper Jungle isn't a secret.'
Hyrkan didn't want to feel anymore anxiety, so he didn't think too hard on this decision.
Hyrkan decided to make a bold decision.
[Hahoe Mask]
Hyrkan sent another short mail. As he was sending it, he made a firm resolve.
'If this guy is trying to fish me, his wrist won't stay intact.'
The Red Log Cabin.
A merchant NPC named Chess used this place as his home. He was the NPC that gave out Quests that had gold rewards. He was popular amongst users who were aiming for the gold reward instead of the level up. There were about 3-4 users waiting for their turn in front of the Red Log Cabin.
Hyrkan stood a bit away from the other users. Of course, everyone's gaze headed toward Hyrkan.
On the other hand, Hyrkan didn't show any interest to the users. Hyrkan was on high alert, and he surveyed his surrounding.
'Why is he so late?'
In a flash, he had to determine if the person who took the bait was a snake or a big fish. If he confused a snake with a fish, then Hyrkan would be the one being bitten.
This was when the nervous Hyrkan caught sight of an extraordinary user.
It was a user with enough fame and reputation to make Hyrkan nervous in an instant. He was famous enough to grab the attention of users, who had been focusing on Hyrkan.
"It's Whistling."
"Whistling Pitbull!"
Hyrkan's eyes narrowed.
'Why is the Whistling Pit Bull here?'
Whistling Pitbull.
His appearance looked very similar to a pit bull. His face looked very fierce. Of course, he wasn't famous because of his ferocious look.
First, he was one of the first to put his name up in the top 100 Ranking Board during the early days of Warlord. He had exceptional abilities, and he also showed a great passion for this game. Of course, his name had long been pushed out from the top 100 Ranking Board by those who devoted their lives to Warlord. Still, his level was still sufficiently high.
'Currently, Whistling Pit Bull should be in the latter half of level 120 or early 130s?'
He was either at the latter stage of level 120 or he was in the early parts of 130.
It was on par with the level of the highest level users.
In other words, his level was too high to consider the Clapper Jungle as his hunting ground.
He had no reason to be here.
He might have another motive to be here instead of hunting.
Hyrkan was nervous.
'Is he here to catch me?'
Didn't Hyrkan have a lot of enemies? It was natural for him to be suspicious. Moreover, he had fought with the Whistling Pitbull before he had returned to the past. Of course, Hyrkan had won. However, amongst the users he had fought before, the Whistling Pitbull's capabilities and battle sense had left the biggest impression on him.
Moreover, he was part of a large guild that was close to entering the 30 great guilds. He was part of the Fighters Guild.
Of course, Hyrkan would be nervous at his appearance.
'He's coming towards me.'
He was clearly walking towards Hyrkan. Hyrkan discreetly put his hand into his pocket and started touching the Skeleton Fragments. If needed, he thought about doing a pre-emptive attack. At this point in time, Hyrkan hadn't gone through his advancement. It wouldn't be easy to fight Pitbull, who had over 30 levels on him.
The users in the surrounding tensed up.
'The Whistling Pitbull and the Hahoe Mask are together?'
'I think a good vid would come out of this?'
Everyone was probably getting ready to record when the two of them started fighting.
Every user in front of the natural looking Red Log Cabin was tense. In this anxious atmosphere, Pitbull stepped in front of Hyrkan. Hyrkan didn't even bother to greet him. The moment he spoke would be the brief window of opportunity Hyrkan needed. He just glared at Pitbull's face through the Hahoe Mask.
However, Pitbull didn't avoid his gaze. As befitting his nickname of Pitbull, his entire face gave off an impression of a fighting dog. His demeanor was very ferocious. If one didn't know him, others might think he was trying to start a fight just from looking at the Pitbull's face.
It was at that moment.
The Pit Bull spoke in a really low voice.
"Can you help me break open this Quest related to the Elves? It is my life's dream to meet the Elves…"
Whistling Pitbull.
He was a man with a romantic idea about the Elves. Please go to
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text:
Anticancer properties of the abietane diterpene 6,7-dehydroroyleanone obtained by optimized extraction.
Authors:Garcia, Catarina
Silva, Catarina Oliveira
Monteiro, Carlos M
Nicolai, Marisa
Viana, Ana
Andrade, Joana M
Barasoain, Isabel
Stanković, Tijana
Quintana, José
Hernández, Inmaculada
González, Ignacio
Estévez, Francisco
Díaz-Lanza, Ana M
Reis, Catarina P
Afonso, Carlos AM
Pešić, Milica
Rijo, Patrícia
Document Type:
Article (Published version)
© 2018 Newlands Press
MetadataShow full item record
AIM 6,7-dehydroroyleanone (DHR) is a cytotoxic abietane present in the essential oil of Plectranthus madagascariensis. METHODS/RESULTS Different extraction parameters were tested, and its extraction optimization was accomplished with a Clevenger apparatus-based hydrodistillation. After isolation, its effect on microtubules, P-glycoprotein and caspases was assessed on several cell lines and the compound was coupled with hybrid nanoparticles. The results show that DHR does not interfere with microtubule formation, but evades the resistance mechanisms of P-glycoprotein. Strong activation of caspases-3 and -9 indicates that DHR is able to induce apoptosis by triggering the intrinsic cell death pathway. Moreover, the assembly of DHR with hybrid nanoparticles was able to potentiate the effect of DHR in cancer cells. CONCLUSION DHR seems to be a promising starting material with anticancer properties to further be explored.
Keywords:6,7-dehydroroyleanone; Plectranthus; cytotoxicity; extraction; isolation; multidrug resistance; nanotechnology
Source:Future Medicinal Chemistry, 2018, 10, 10, 1177-1189
- Identification of predictive molecular markers for cancer progression, response to therapy and disease outcome (RS-41031)
- Fundação para a Ciência e a Tecnologia
DOI: 10.4155/fmc-2017-0239
PubMed: 29749759
WoS: 000433568500005
Scopus: 2-s2.0-85048107643

subset: commoncrawl


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Quarterly magazine for contemporary visual arts in Ireland. Includes current issue, back issues, paid downloads and subscription information.
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text:
Bigger freshwater bass are moving into this area from the St. Johns River.
ST. JOHNS RIVER: Capt. Bryn Adams at Highland Park Fish Camp in DeLand said largemouth bass fishing is gaining momentum. "Bass fishing is good," she said. "We are starting to see some real size coming in. Over the last couple of weeks we have had a few 10 pounders or better." Adams said she had hoped to provide a glowing report on speckled perch, but that magic has not started. "Speckled perch fishing remains mediocre at best," she said. "We have been hoping for improvements, but this year is just not up to par as of yet. Fishermen are still catching fish and we are seeing decent sizes coming in, you just have to work a little harder for them." Adams said the best catches of speck have been in the Norris Dead River by fishing in shallow water against vegetation.
SURF, PIERS: Gene Lytwyn, who mans The Fishin' Hole in downtown Daytona Beach, said weather has put a damper for anglers throwing a line in from the beach. "Reports are that surf fishing slowed up quite a bit," he said. "When conditions allowed, a few whiting were caught." The piers have been a different story. "The ocean piers have quite a few sheepshead and a few black drum along with the whiting."
OFFSHORE: "Offshore has been pretty much blown out," Lytwyn said. "Except for one day that a few boats got out. There were a couple of smaller wahoo caught and a couple of sailfish."
PONCE INLET, HALIFAX RIVER: Capt. Jeff Patterson (smallboatbigfish.com) said the current see-saw weather pattern has made inshore fishing a bit complicated. "We've had a lot of back and forth conditions with some beautiful days and some days with very strong north winds making for a choppy Intracoastal," he said. "There's been a bunch of big sheepshead around the area bridges and docks. These fish have been ranging from 1-pound on up to 6-pound fish." Capt. Fred Robert (fishing-guy.com) said he has been catching snook around the slot range, plus fat sheepshead and mangrove snapper in around the inlet. Patterson has been noodling around the inlet, too. "There's been a bunch of big sheepshead at the jetties," he said. "The redfish and black drum have been hit-or-miss there, but we have caught some nice fish when you find them. There are a few bluefish around the inlet as well."
TOMOKA BASIN, RIVER: Patterson has thrown a line in this area over the past week. "The basin has been hit or miss on redfish for me it seems like they're moving around quite a bit," he said. "There are some nice schools of fish along the shorelines in the morning. If you catch a fish, hang out there because there are probably more."
MOSQ. LAGOON, INDIAN RIVER: Capt. Michael Savedow (edgewaterriverguide.com) said he has had a few charters in the Edgewater Backcountry. "First, the water temperature is cold again," Savedow said. "We've been catching small fish slams of snook, redfish and trout." Savedow said he has also caught bluefish, whiting, mangroves, black drum, jacks and ladyfish. "We're using live shrimp and shad tail jigs for bait," he said.
MATANZAS INLET, RIVER: The catch in this area has been sheepshead, black drum and trout. Lytwyn was quick to point out there are new trout regulations going into effect on Saturday. "Look up the appropriate regulations for your area," Lytwyn said. "We are right at the dividing line at the Volusia-Flagler county lines for two different bag limits."
SEND PHOTOS: We want to see your most recent catch. Email your fish photos to firstname.lastname@example.com. Be sure to include type of fish, size of fish (weight and/or length), where the fish was caught, first and last names and hometown of angler who caught the fish, and first and last name of person who took the photo. If a child is in the photo, please include their age. The News-Journal will use one or two photos in print each week and the other photos submitted will go into the online gallery called "Readers Fish Photos."


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text: Andrea Neumann is classically trained pianist, who – all of a sudden – got inside the instrument, and reduced it to strings, resonance board and metal frame; during the performance this remnant is connected to a mini mixer board by way of which sound is deformed, reformed and transformed. The truncated inside piano – Innenklavier in German – is no longer afraid of its limitations and rules, but instead offers an excellent starting-point. Andrea, a pioneer with a great ear for intonation, imagination and sound, employs this new instrument in such a manner that it is as a piano – as well as celesta, clavichord, harpsichord and the more distant Japanese koto – still recognisable in the background and all around, whereas the very focus builds up a completely unexpected and unfamiliar subject. Such a subtle use of electronics – which is unique also on the notorious 'Berlin scene' – reaches undreamed-of results. Such holds true for solos, and duos (with Annette Krebs, Burkhard Heins or Taku Sugimoto…), as well as larger ensembles (Phosphor, No Spaghetti Edition).


text:
Maggie Ann (Green) Brindle, 80, of Cooleemee, NC, entered her heavenly home on March 9, 2020 at Glenn A. Kiser Hospice House of Salisbury.
Maggie was born June 15, 1939, a daughter of the late George Thomas & Julia Ann (McIntyre) Green. She was also preceded in death by her husband Charlie Edward Brindle Jr., a son George William "Billy" Brindle, a sister Dora Green Yates.
Maggie attended Cabarrus County Schools. She married Charlie Edward Brindle Jr., on Nov. 12, 1955 and enjoyed fifty-nine years of marriage before his death in 2014. Maggie worked as an assistant teacher at Head Start, she worked for Wonder Knit, Ingersoll- Rand, and Fran Ray Rest Home. She was a member of First Baptist Church of Cooleemee, enjoyed reading, crafting, helping her community, and loved watching her children and grandchildren play sports.
Survivors include son Thomas "Tommy" Edward Brindle and fiancé Diana Badger, honorary son Shaun Stephen Chaffin, daughters Mary Ann Brindle Carter, Teresa "T" Lynette Brindle, grandchildren George Edward Carter(Leanne), Christopher Ryan Carter, Julia Ann "Annie" Benton, great grandchildren Charlie Edward Carter, Micah Ryan Carter, niece Peggy Love, cousin Jane Ellen VanHoy, special friend Hellen Daywalt.
Visitation will be held 6:00Pm-8:00PM Thursday March 12, 2020 at Davie Funeral Service. Graveside service will be held 2:00PM Friday March 13, 2020 at Legion Memorial Park in Cooleemee, NC, with Pastor Rodney Burton officiating.
Davie Funeral Service is honored to serve the family.
To send flowers to the family or plant a tree in memory of Maggie Ann (Green) Brindle, please visit our floral store.


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Review ARTICLE
Advancing Public Health Using Regulatory Science to Enhance Development and Regulation of Medical Products: Food and Drug Administration Research at the Center for Biologics Evaluation and Research
- CBER, FDA, Silver Spring, MD, United States
Center for Biologics Evaluation and Research enhances and supports regulatory decision-making and policy development. This work contributes to our regulatory mission, advances medical product development, and supports Food and Drug Administration's regulatory response to public health crises. This review presents some examples of our diverse scientific work undertaken in recent years to support our regulatory and public health mission.
The Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration (FDA) has regulatory oversight of blood, tissues, and complex medical products that include vaccines, allergenic products, blood-derived products, certain diagnostics and devices, live biotherapeutics, and novel medical products, such as stem cell-derived products, and other cell and gene therapies.
The complex biological products regulated by CBER present a variety of challenges:
(1) The challenge of ensuring product sterility, i.e., the absence of unwanted infectious agents, is compounded with the use of biological materials (e.g., cells, viruses, and bacteria) in the manufacture of biological products. Many of the products that CBER regulates comprise components of, or intact, biologically active cells, tissues, viruses, or bacteria. In most cases, this means that they cannot be subject to terminal sterilization. Quite often, other means of inactivating or removing potentially contaminating infectious agents also cannot be applied without compromising the biological activity of the product.
(2) There may not be a clear strategy for characterizing a manufactured product to verify that it is safe and potent before exposing study subjects in investigational clinical trials. Biological materials are generally not amenable to the type of straightforward analytical evaluation that might be used with a chemical drug for which the molecular structure is known and can be verified. Biological products by their very nature are complex mixtures.
(3) Biological products often elicit immune responses that, depending on the product, might be a desired outcome of the intervention (i.e., vaccine-induced protective immune response) or an unwanted outcome (i.e., immunogenicity of a recombinant protein, cell, or gene therapy). Preclinical models might not predict these effects in humans.
(4) The product's mechanism of action might not be sufficiently understood to identify appropriate biomarkers of clinical effect and/or to develop appropriate potency assays.
(5) Clinical trial designs need to optimize data collection that enables regulatory evaluation of safety and efficacy. Design must balance the desire to reduce the time and cost of product development with collection of sufficient data, while incorporating patient input and "real world evidence," as feasible and relevant. These issues are particularly difficult when conducting clinical trials of novel treatments for rare disease where the available pool of patients, and thus the clinical trial group sizes, is quite small.
(6) Evaluation of biological product safety and efficacy does not stop at licensure. Rather, it requires the development of means to accurately identify those post-licensure safety signals that might not have been apparent during clinical investigation, while also collecting additional supporting data on efficacy.
(7) The products within CBER's regulatory portfolio are often used to defend the public against emerging infectious disease (EID) outbreaks or acts of bioterrorism or burn/blast events. When addressing the threat of an EID, CBER must evaluate the risks to protect and maintain a robust and safe blood supply. CBER must also identify and develop tools to facilitate development and rapid deployment of promising investigational vaccines.
(8) Often the medical products for responding to EID or acts of bioterrorism cannot be ethically or practically evaluated in human clinical trials for efficacy, for ethical or practical reasons. This necessitates development of robust preclinical models for efficacy evaluation.
To meet these challenges, CBER relies on the best available science in its application of relevant laws through regulations and guidance. CBER engages the expertise and ingenuity of its intramural researcher–reviewers to identify and address major scientific gaps. The knowledge acquired facilitates regulatory evaluation and thus fosters development of innovative medical products. The outcomes of these efforts are made available to the public and product developers by publishing the results in peer-reviewed journals. In addition, CBER incorporates knowledge derived from its intramural research program into both informal and formal guidance to sponsors, other policy and regulatory decisions, and development of reference materials and standards to facilitate product evaluation by product developers.
Center for Biologics Evaluation and Research supports the science-based regulation of this diverse and complex product portfolio through a similarly diverse applied research program. The aim of this program is to fill knowledge gaps and develop more effective tools for regulatory decision-making and policy development. The unique perspective of scientists within this regulatory agency facilitates solutions to scientific problems that might benefit an entire class of products, rather than a specific product developed by a single sponsor.
Center for Biologics Evaluation and Research facilitates successful translation of early-stage medical product development into licensed safe and effective therapies. The results help to improve product manufacturing and identifying potential adverse events in marketed drugs and devices.
Center for Biologics Evaluation and Research has four major research goals through which they advance the scientific basis for regulation of biologics, human tissues, and blood.
Here, we provide recent examples from our diverse portfolio of research to demonstrate how CBER's research contributes to each goal.
Developing and Evaluating Technology, Reagents, and Standards to Inform and Improve Chemistry, Manufacturing, and Controls
Center for Biologics Evaluation and Research regulators must review the processes used in the manufacture of biologics and critically evaluate their quality and consistency, to ensure that they meet defined standards of safety, purity, and potency (CFR, Title 21 Part 601.2). This requires the use of validated methods and standards for evaluating products, including in-process and lot release tests.
Center for Biologics Evaluation and Research develops new methods and models to evaluate regulated medical products, evaluates or improves existing methods, and develops reagents, such as reference materials for assessing the reproducibility, sensitivity, and specificity of these test methods. The following examples illustrate our efforts to develop and evaluate models, methods, and reference materials and standards.
Detecting Contaminants in Biological Products
Many biological medical products are live viruses, bacteria, or mammalian cells. This means they are labile, and therefore, cannot be subjected to processes used for traditional biotechnology products, such as pathogen inactivation or removal; nor can they be subjected to terminal sterilization. Therefore, the raw materials and the products themselves must be thoroughly tested to ensure absence of contaminating infectious agents (adventitious agents). CBER scientists evaluated a technique for improving the sensitivity of detecting adventitious viruses. The technique, called tangential flow filtration, concentrates viruses from large volumes of cell substrate as a preliminary step before testing. The use of tangential flow filtration increases the ability to detect low level contaminants (1) and can be used by manufacturers to reduce the risk of contaminating infectious agents.
Center for Biologics Evaluation and Research regulates live biotherapeutic products when they are used to treat a specific condition. One of the challenges of determining the safety and purity of these products is that the live bacteria intended to have a beneficial therapeutic effect can interfere with testing for pathogenic contaminating microorganisms. To address this problem, CBER scientists developed a novel approach that uses viruses (bacteriophages) to selectively target and kill biotherapeutic bacteria in test samples, allowing unwanted pathogenic microbes to grow unimpeded. This enables use of standard laboratory methods to detect the harmful contaminants (2).
Improving Quality and Consistency of Biological Products
Many of CBER's products are complex and difficult to characterize. In fact, the critical attributes that correlate with safety, purity, and potency may not be known. Stem-cell-based therapies are an emerging class of products that are particularly challenging in this regard. Stem cell research holds the promise of innovative medical treatments for a variety of diseases, but also poses unique challenges to regulatory decision-making.
One major challenge facing regulators and industry is that we do not know the key, measurable properties of stem cells that correlate with specific, desired clinical outcomes. Several years ago, CBER assembled a consortium of scientists charged with addressing this challenge. The consortium uses different methods in an effort to identify critical stem cell attributes. In addition to evaluating some standard approaches, such as traditional flow cytometry for cell surface markers, CBER scientists are also developing new methods and using technological approaches such as proteomics, single-cell RT-PCR, epigenetics, and microarray.
To interpret the results of characterization assays, CBER is also developing ways to correlate assay results with functional assay outcomes, such as in vivo or in vitro models of wound repair, quantitative differentiation capacity, or immunosuppression (3–9). A recent example of the work being performed by the consortium is the development of a new method to predict differentiated functional capacity of human mesenchymal stem cells (multipotent mesenchymal stromal cells) after osteogenic induction. Using high-dimensional, single-cell morphological information, CBER scientists demonstrated that within 3 days, the morphological data correlated with 35-day mineralization assays with >90% accuracy (8). The development, evaluation, and communication of innovative methods, such as the one described above to identify bone differentiation capacity, provide a new stem cell-based tool to the community to facilitate development of innovative medical products.
Reference Materials and Standards
During an outbreak of an emerging transfusion-transmitted infectious disease (TTID), there is a delicate balance of priorities between maintaining the availability of blood for life-saving transfusions and reducing or eliminating the risk of TTID. In such situations, CBER uses a multipronged strategy to facilitate the complex decision-making required to ensure the availability of safe blood:
• Holding public workshops to discuss risk assessment for a given EID for blood and blood products (10)
• Developing new tools (e.g., modeling) to assess EID rates and risks
• Developing reference materials to facilitate evaluation of new assays to screen for EIDs.
In the last 15 years, the safety of the blood supply has been threatened by the agents of transmissible spongiform encephalopathy including variant Creutzfeldt–Jakob disease, as well as emerging and re-merging viruses and other pathogens: West Nile virus, chikungunya virus (ChikV), Babesia microti, dengue virus, and most recently, Ebola and Zika viruses.
Center for Biologics Evaluation and Research develops RNA reference standards that sponsors use to evaluate the sensitivity, specificity, and reproducibility of their nucleic acid-based tests intended for clinical diagnosis or blood screening for emerging and reemerging TT viruses. CBER typically characterizes these reference materials through multi-laboratory studies, such as those recently performed for West Nile virus (11), dengue virus (12), and ChikV (13). CBER then distributes these reference materials as CBER National Reference Reagents. CBER is currently developing reference standards to use in screening blood or tissue for transmissible spongiform encephalopathy (TSE) agents (14).
In spring 2016, CBER participated in a coordinated public health response to the emerging Zika virus outbreak. CBER scientists developed and coordinated a multi-laboratory effort to generate Zika virus RNA reference materials that were adopted by the World Health Organization. Other international standards organizations, such as the National Institute for Biological Standards and Control, have also adopted and distributed them worldwide.
In addition to protecting the blood supply from the risk of TTIDs, CBER laboratories actively support the development and lot release testing of seasonal and pandemic influenza vaccines in many ways (15):
(1) Early serology testing of circulating strains to identify strain prevalence
(2) Generation of candidate vaccine strains
(3) Generation of reagents that are distributed to manufacturers for lot release testing
(4) Independent verification of lot release testing results.
Center for Biologics Evaluation and Research prepares reagents to test influenza vaccine potency and ensure standardization of vaccine quality made by manufacturers. Traditionally, the vaccine strain is grown in eggs; bromelain is then used to purify the HA, which is used to immunize sheep. This technique is successful with most virus strains. However, in 2013, when novel H7N9 viruses emerged in China, the Center faced a major, unexpected bottleneck in preparing vaccine reagents when the traditional approach yielded substandard results. CBER scientists overcame that bottleneck by expressing H7N9 HA glycoprotein as a virus-like particle (VLP) using a vaccinia vector—a technique previously developed in our laboratories. Boosting sheep with the VLPs instead of the traditional HA yielded antiserum that significantly improved the quality of lot release assay results (16).
This type of innovation at CBER enables timely reagent production and might overcome future potential bottlenecks in influenza vaccine production that have occurred in the past for both seasonal and pandemic strains.
Developing and Assessing Non-Clinical Models and Methods Predictive of Clinical Performance with Respect to Toxicity and Effectiveness
Food and Drug Administration relies on data from non-clinical models and methods to support regulatory decisions on first-in-human clinical trials. In particular, before human, phase 1 clinical studies are initiated, the primary focus of FDA review is on safety. Non-clinical studies may identify candidates that should not proceed to human clinical trials. However, there are products for which issues are identified only after they progress into clinical testing, or even wider scale use on the market (for example, see the US FDA Report: 22 case studies that show divergent results between phase 2 and phase 3 trials1). These observations, combined with the finding that many products also fail in clinical trials due to lack of efficacy, suggest there is a need for improved non-clinical models and methods that more reliably predict product performance in humans. For the purpose of this discussion, non-clinical models and methods include in silico predictive models, as well as in vitro assays and in vivo animal models.
Learning from Medical Products That Fail in Clinical Trials
Immune responses to therapeutic protein products can compromise their therapeutic effects and trigger adverse events, some of which (e.g., anaphylaxis) can be life threatening. To ensure product developers consider this risk, FDA issued guidance for industry ("Immunogenicity Assessment for Therapeutic Products"). The guidance—a collaboration between CBER and Center for Drugs Evaluation and Research (CDER)—incorporates knowledge and improved mechanistic understanding gained from clinical trials, post-marketing adverse events, and laboratory and in silico studies, including CBER research (17–19).
The studies that informed the guidance continue today, providing improved mechanistic insights that lead to new ways to estimate risks of immunogenicity posed by recombinant protein products. Recently, CBER scientists began using a bioengineered analog of the clotting Factor VIIa to identify how neo-sequences introduced into protein drug analogs might induce development of antidrug antibodies (ADA). The work includes developing an approach to identify patients most likely to be affected by this adverse event. ADA impair the drug's therapeutic benefit and can also be life-threatening themselves. Therefore, improved methods to predict development of ADA can enhance safety and efficacy of innovative medical products.
In this case, the drug, vatreptacog alfa, had three minor changes engineered into its structure to improve its efficacy. While the parent drug had been used for two decades without reports of ADAs, the analog triggered ADAs during a Phase 3 clinical trial, ending its development. Using computational and experimental methods, CBER researchers found that in all 11 patients who had ADAs to vatreptacog alfa peptides, there was at least one HLA class II protein that was both predicted and then shown in vitro to bind avidly to one of the peptides with the same mutations as found in the analog. However, only 44% of patients without ADAs had an HLA allele specific for peptides from vatreptacog alfa (20).
This approach to analysis of bioengineered protein drugs and the patient characteristics that impact development of ADA could inform application of precision medicine to identify patients likely to benefit from the products without the risks of developing ADAs. With improved predictive tools, the resulting clinical trials of such products might become less costly and more efficient.
In Vitro and Animal Models Identify Mechanisms of Product Toxicity or Reduced Efficacy; Outcomes Guide Future Product Development
Adenovirus vectors are often used in clinical trials of gene therapy because they possess two major desired traits:
• Ability to be manufactured and purified to high concentration and purity
• High expression levels of the potentially therapeutic protein in host cells
In spite of these positive traits, clinical development of adenovirus vector-mediated gene therapy has been hampered by the low targeting efficiency of vectors.
Center for Biologics Evaluation and Research scientists are combining animal model and in vitro studies to investigate how the vector interacts with the immune system. They made the novel observation that adenovirus vectors of serotype 5 (Ad5, the first serotype used in gene therapy clinical trials) forms complexes with the coagulation factor X (FX) that shield the vector from antibodies and complement. This shield facilitates vector transduction of hepatocytes. In contrast, vectors unable to form complexes with FX showed significantly lower levels of infection of and gene expression in, the liver and lung (21).
The researchers subsequently showed that replacing the FX shield with a polyethylene glycol shield prevented macrophages from neutralizing the vector in vitro and demonstrated significantly improved transduction in murine models (22). These findings suggest that such shielding could greatly improve the clinical efficiency of Ad5 in human gene therapies.
Center for Biologics Evaluation and Research also develops and uses animal models to evaluate vaccines for safety and effectiveness. For example, in the face of a resurgence of pertussis (whooping cough) in the past decade, CBER developed a baboon model. The model is being used for studies aimed at improving the safety and effectiveness of pertussis vaccines.
Following introduction of the whole-cell pertussis vaccine in the 1950s, the occurrence of pertussis in the US decreased by over 90%. However, whole-cell pertussis vaccine caused soreness at the injection site and fevers in children (described as reactogenicity). Therefore, the US replaced whole-cell pertussis vaccine with the acellular pertussis (ACP) vaccine in 1997. Subsequently, there was a steady rise in cases, which peaked at nearly 50,000 in 2012, according to the Centers for Disease Control and Prevention.2
To investigate the cause of this rising trend of pertussis cases in the face of ACP vaccination, CBER developed the first animal model to recapitulate the disease and provide scientific evidence of airborne transmission (23). Studies with this baboon model demonstrated that third-trimester maternal vaccination with ACP protected neonates from disease when challenged at 5 weeks of age (24). However, even in the absence of disease, vaccinated animals showed evidence of bacterial infection, colonization, and ability to transmit to vaccinated animals (25).
Additional studies using the baboon model showed significant differences in the type of immune responses to natural infection, whole-cell vaccine, and ACP. Specifically, unlike the ACP vaccine, any of the three whole-cell vaccines currently approved for use outside the US significantly accelerated the clearance of the causative organism, Bordetella pertussis, from the nose and throat. Moreover, whole-cell vaccines boosted production of the immune system protein IL-17, which suggests this molecule plays a role in clearing the infection (26).
This finding is important because it provides the scientific basis for improving the pertussis vaccine: the use of novel adjuvants to boost Th17 responses to ACP vaccines. Thus, this work provides a roadmap for designing the next generation of pertussis vaccine. The goal is to develop a vaccine that has low reactogenicity but retains the protective immune responses that are associated with protection against infection and disease.
Improving Clinical Evaluation Pre- and Post-Licensure through Use of Big Data, Innovative Designs, and Statistical, Analytical, and Modeling Approaches
A large study of clinical development programs between 2006 and 2015 found that the likelihood that a drug candidate would progress from phase 1 through licensure was 9.6%. Some of the factors that impacted success rates were patient population and selection, especially in rare disease studies, as well as clinical trial complexity in large heterogeneous patient populations (27). These observations underscore the need to improve clinical trial designs.
Improving Clinical Trial Design Pre-Licensure
Similar to the larger study from Bio, Biomedtracker, and Amplion, CBER studied the problems seen in regulated clinical trials, focusing initially on adaptive designs, i.e., clinical trials that enable knowledge gained during the research to affect ongoing conduct or analysis of the trial. We subsequently published a 6-year analysis (2008–2013) of adaptive design proposals from product sponsors. The paper provides recommendations to sponsors for developing such proposals, with the aim of encouraging optimal design (28).
In another project, CBER statisticians used a novel version of a Bayesian two-stage adaptive design to analyze a hypothetical Phase II trial of immune globulin (intravenous; IGIV)—an antibody-based product used as replacement therapy in patients with humoral immunodeficiencies. The study confirmed the validity of using this statistical technique to end a clinical trial early due to either treatment futility or efficacy, an approach that can save developers of novel medical products both time and money (29).
Developing New Approaches to Identify Post-Licensure Safety Signals
Center for Biologics Evaluation and Research also works to improve safety surveillance using large databases, such as the US Vaccine Adverse Event Reporting System and the FDA Adverse Event Reporting System for drugs. Optimal use of these databases requires automated retrieval of information useful for reviewer analysis. The current natural language processing systems are often hampered by low quality text (e.g., poor grammar, many abbreviations). CBER developed an algorithm for analyzing low quality texts that is minimally dependent on grammatical and syntactic information (30). This will speed reviewer extraction and analysis of important information, and accelerate recommendations about post-marketing adverse events related to medical product use. It might also contribute to future research in text mining of electronic health records.
Additionally, a major limitation to timely tracking of vaccine adverse events using reporting databases, such as those used in the FDA's Sentinel System, is that the most recent data are 6–9 months old. While these "mature" data give a broad, long-term view of events, it does not allow for timely regulatory responses to adverse events. CBER developed a way to access, use, and evaluate "fresh" data for timely influenza vaccine safety surveillance in the Sentinel System. This approach is now being used to develop an infrastructure that works for other FDA-regulated medical products, such as blood products, that require faster access to safety information and a review response that is closer to "real-time." (31).
Preparing for Future Regulatory and Public Health Challenges
Changes in science and technology are occurring rapidly, impacting many of the products CBER regulates. This means that the Center's research program must evolve and anticipate, when feasible, developments that are likely to yield innovative medical products.
As resources permit, CBER expands capabilities in key technologies, such as high resolution analytical instrumentation (NMR and mass spectrometry), "next-generation sequencing" (NGS), multiparameter analytic and sorting flow cytometry, high resolution microimaging of fixed and living cells and tissues, and tools for sequential imaging of living animals, such as digital X-ray, ultrasound, and a 4.7 T MRI.
In addition, CBER developed hardware infrastructure and a bioinformatics team to support transfer, storage, and analysis of large, complex datasets. This high-performance integrated virtual environment (HIVE) supports analysis of NGS data generated not only by our own researchers but also provided by sponsors in regulatory submissions. In addition, CBER is adopting the advanced computational platform provided by HIVE for analysis of other complex data, such as high resolution mass spectra, and integration of product, preclinical, and clinical data. These new tools enable improved regulatory evaluation of medical products. The underlying code supporting HIVE is open source,3 and the team of HIVE developers and research scientists using HIVE publish the tools, applications, and results of using HIVE (32–40).
To keep pace with new technology and to anticipate innovative product development, CBER needs scientists with state-of-the-art knowledge. CBER recruits scientists to develop and establish new research programs that respond to emerging public health challenges, new technology, and regulatory needs. New programs that have been initiated in the past 3 years include the following:
• Vaccine development for emerging pathogens (e.g., norovirus)
• Using the microbiome to treat infection with antibiotic-resistant bacterial pathogens
• Using microphysiologic systems to improve safety and effectiveness of tissue-engineered medical products
• Mechanistic studies of cellular differentiation of induced pluripotent stem cells (iPSCs)
• Effects of the gene editing endonucleases (i.e., Cas9) on genome integrity and function of human iPSCs
• Factors that influence T cell activation and how that might inform evaluation of CAR-T cell-based therapies (chimeric antigen receptor)
Center for Biologics Evaluation and Research makes critical contributions to FDA's efforts to fulfill its regulatory mission. The Center's active intramural research program provides three important capabilities: (1) rapid responses to urgent public health needs, such as a newly identified post-marketing safety signal or EID outbreak; (2) development and evaluation of new methods to advance development of products by providing better tools for evaluating safety, effectiveness, or product quality; (3) preparation for future products by evaluating potential safety concerns or developing new methods and models to characterize complex new products that enhance effectiveness and product quality.
Center for Biologics Evaluation and Research's scientists play a dual role: they not only perform applied research relevant to key regulatory needs but also participate in the review of submitted regulatory files, perform inspections, participate and organize timely advisory committees and workshops, and inform development of guidance and regulatory decision-making. This dual role of the researcher–reviewer allows CBER to rapidly incorporate the findings of our research program into daily informal guidance provided to sponsors. It also enables the center to share the outcome of our research with both the public and the scientific and regulated communities by publishing in peer-reviewed scientific journals and presenting our research findings at public workshops, advisory committees, and relevant scientific and professional meetings. Essentially, the capabilities resulting from an active intramural research program enable CBER to be prepared, flexible, proactive, and responsive in support of its regulatory mission and its efforts to facilitate development of safer and more effective innovative medical products.
Author Contributions
MK and EB: provided input into the overall organization, content, and approach for the article. Provided substantive input into the draft of the article at each stage. Wrote initial drafts of some sections of the article. CW: primary author who wrote the initial draft of the article, coordinating input from coauthors, and finalized the article for submission.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors thank the following colleagues for critical reading of the manuscript: Drs. Peter Marks, Konstantin Chumakov, Chintamani Atreya, and Suzanne Epstein. The research that was described in this review was primarily supported by the Center for Biologics Evaluation and Research, Food and Drug Administration.
1. Furtak VA, Dabrazhynetskaya A, Volokhov DV, Chizhikov V. Use of tangential flow filtration for improving detection of viral adventitious agents in cell substrates. Biologicals (2015) 43(1):23–30. doi:10.1016/j.biologicals.2014.10.005
2. Dreher-Lesnick SM, Schreier JE, Stibitz S. Development of phage lysin LysA2 for use in improved purity assays for live biotherapeutic products. Viruses (2015) 7(12):6675–88. doi:10.3390/v7122965
3. Lynch PJ, Thompson EE, McGinnis K, Rovira Gonzalez YI, Lo Surdo J, Bauer SR, et al. Chromatin changes at the PPAR-gamma2 promoter during bone marrow-derived multipotent stromal cell culture correlate with loss of gene activation potential. Stem Cells (2015) 33(7):2169–81. doi:10.1002/stem.1967
4. Mindaye ST, Lo Surdo J, Bauer SR, Alterman MA. The proteomic dataset for bone marrow derived human mesenchymal stromal cells: effect of in vitro passaging. Data Brief (2015) 5:864–70. doi:10.1016/j.dib.2015.10.020
5. Mindaye ST, Lo Surdo J, Bauer SR, Alterman MA. System-wide survey of proteomic responses of human bone marrow stromal cells (hBMSCs) to in vitro cultivation. Stem Cell Res (2015) 15(3):655–64. doi:10.1016/j.scr.2015.09.013
6. Pripuzova NS, Getie-Kebtie M, Grunseich C, Sweeney C, Malech H, Alterman MA. Development of a protein marker panel for characterization of human induced pluripotent stem cells (hiPSCs) using global quantitative proteome analysis. Stem Cell Res (2015) 14(3):323–38. doi:10.1016/j.scr.2015.01.009
7. Bellayr IH, Marklein RA, Lo Surdo JL, Bauer SR, Puri RK. Identification of predictive gene markers for multipotent stromal cell proliferation. Stem Cells Dev (2016) 25(11):861–73. doi:10.1089/scd.2015.0374
8. Marklein RA, Lo Surdo JL, Bellayr IH, Godil SA, Puri RK, Bauer SR. High content imaging of early morphological signatures predicts long term mineralization capacity of human mesenchymal stem cells upon osteogenic induction. Stem Cells (2016) 34(4):935–47. doi:10.1002/stem.2322
9. Stultz BG, McGinnis K, Thompson EE, Lo Surdo JL, Bauer SR, Hursh DA. Chromosomal stability of mesenchymal stromal cells during in vitro culture. Cytotherapy (2016) 18(3):336–43. doi:10.1016/j.jcyt.2015.11.017
10. Gallagher LM, Ganz PR, Yang H, Kessler DA, O'Brien SF, Custer BS, et al. Advancing risk assessment for emerging infectious diseases for blood and blood products: proceedings of a public workshop. Transfusion (2013) 53(2):455–63. doi:10.1111/j.1537-2995.2012.03808.x
11. Grinev A, Anez G, Rios M. Complete genome sequence of West Nile virus strains used for the formulation of CBER/FDA RNA reference reagents and lot release panels for nucleic acid testing. Genome Announc (2014) 2(5):1–2. doi:10.1128/genomeA.00811-14
12. Anez G, Heisey DA, Volkova E, Rios M. Complete genome sequences of dengue virus type 1 to 4 strains used for the development of CBER/FDA RNA reference reagents and WHO International Standard Candidates for Nucleic Acid Testing. Genome Announc (2016) 4(1):1–2. doi:10.1128/genomeA.01583-15
13. Anez G, Jiang Z, Heisey DA, Kerby S, Rios M, Chikungunya virus Collaborative Study Group. Collaborative study for the characterization of a chikungunya virus RNA reference reagent for use in nucleic acid testing. Vox Sang (2015) 109(4):312–8. doi:10.1111/vox.12297
14. McDowell KL, Nag N, Franco Z, Bu M, Piccardo P, Cervenak J, et al. Blood reference materials from macaques infected with variant Creutzfeldt-Jakob disease agent. Transfusion (2015) 55(2):405–12. doi:10.1111/trf.12841
15. Weir JP, Gruber MF. An overview of the regulation of influenza vaccines in the United States. Influenza Other Respir Viruses (2016) 10(5):354–60. doi:10.1111/irv.12383
16. Schmeisser F, Jing XH, Joshi M, Vasudevan A, Soto J, Li X, et al. A novel approach for preparation of the antisera reagent for potency determination of inactivated H7N9 influenza vaccines. Influenza Other Respi Viruses (2016) 10(2):134–40. doi:10.1111/irv.12365
17. Jefferis R, Lefranc MP. Human immunoglobulin allotypes possible implications for immunogenicity. MAbs (2009) 1(4):332–8. doi:10.4161/mabs.1.4.9122
18. Pandey GS, Yanover C, Howard TE, Sauna ZE. Polymorphisms in the F8 gene and MHC-II variants as risk factors for the development of inhibitory AntiFactor VIII antibodies during the treatment of hemophilia A: a computational assessment. PLoS Comput Biol (2013) 9(5):1–11. doi:10.1371/journal.pcbi.1003066
19. Pandey GS, Yanover C, Miller-Jenkins LM, Garfield S, Cole SA, Curran JE, et al. Endogenous factor VIII synthesis from the intron 22-inverted F8 locus may modulate the immunogenicity of replacement therapy for hemophilia A. Nat Med (2013) 19(10):1318–24. doi:10.1038/nm.3270
20. Lamberth K, Reedtz-Runge SL, Simon J, Klementyeva K, Pandey GS, Padkjaer SB, et al. Post hoc assessment of the immunogenicity of bioengineered factor VIIa demonstrates the use of preclinical tools. Sci Transl Med (2017) 9(372):1–11. doi:10.1126/scitranslmed.aag1286
21. Xu Z, Qiu Q, Tian J, Smith JS, Conenello GM, Morita T, et al. Coagulation factor X shields adenovirus type 5 from attack by natural antibodies and complement. Nat Med (2013) 19(4):452–7. doi:10.1038/nm.3107
22. Krutzke L, Prill JM, Engler T, Schmidt CQ, Xu Z, Byrnes AP, et al. Substitution of blood coagulation factor X-binding to Ad5 by position-specific PEGylation: preventing vector clearance and preserving infectivity. J Control Release (2016) 235:379–92. doi:10.1016/j.jconrel.2016.06.022
23. Warfel JM, Beren J, Merkel TJ. Airborne transmission of Bordetella pertussis. J Infect Dis (2012) 206(6):902–6. doi:10.1093/infdis/jis443
24. Warfel JM, Papin JF, Wolf RF, Zimmerman LI, Merkel TJ. Maternal and neonatal vaccination protects newborn baboons from pertussis infection. J Infect Dis (2014) 210(4):604–10. doi:10.1093/infdis/jiu090
25. Warfel JM, Zimmerman LI, Merkel TJ. Acellular pertussis vaccines protect against disease but fail to prevent infection and transmission in a nonhuman primate model. Proc Natl Acad Sci U S A (2014) 111(2):787–92. doi:10.1073/pnas.1314688110
26. Warfel JM, Zimmerman LI, Merkel TJ. Comparison of three whole-cell pertussis vaccines in the baboon model of pertussis. Clin Vaccine Immunol (2015) 23(1):47–54. doi:10.1128/CVI.00449-15
27. Thomas DW, Burns J, Audette J, Carrol A, Dow-Hygelund C, Hay M. Clinical Development Success Rates 2006-2015. Washington, DC: Biotechnology Industry Organization (2016).
28. Lin M, Lee S, Zhen BG, Scott J, Horne A, Solomon G, et al. CBER's experience with adaptive design clinical trials. Ther Innov Regul Sci (2016) 50(2):195–203. doi:10.1177/2168479015604181
29. Hand AL, Scott JA, Young PD, Stamey JD, Young DM. Bayesian adaptive two-stage design for determining person-time in phase II clinical trials with Poisson data. J Appl Stat (2016) 43(9):1625–35. doi:10.1080/02664763.2015.1117588
30. Wang W, Kreimeyer K, Woo EJ, Ball R, Foster M, Pandey A, et al. A new algorithmic approach for the extraction of temporal associations from clinical narratives with an application to medical product safety surveillance reports. J Biomed Inform (2016) 62:78–89. doi:10.1016/j.jbi.2016.06.006
31. Yih WK, Kulldorff M, Sandhu SK, Zichittella L, Maro JC, Cole DV, et al. Prospective influenza vaccine safety surveillance using fresh data in the Sentinel System. Pharmacoepidemiol Drug Saf (2016) 25(5):481–92. doi:10.1002/pds.3908
32. Pan Y, Karagiannis K, Zhang H, Dingerdissen H, Shamsaddini A, Wan Q, et al. Human germline and pan-cancer variomes and their distinct functional profiles. Nucleic Acids Res (2014) 42(18):11570–88. doi:10.1093/nar/gku772
33. Shamsaddini A, Pan Y, Johnson WE, Krampis K, Shcheglovitova M, Simonyan V, et al. Census-based rapid and accurate metagenome taxonomic profiling. BMC Genomics (2014) 15:918. doi:10.1186/1471-2164-15-918
34. Laassri M, Zagorodnyaya T, Plant EP, Petrovskaya S, Bidzhieva B, Ye Z, et al. Deep sequencing for evaluation of genetic stability of influenza A/California/07/2009 (H1N1) vaccine viruses. PLoS One (2015) 10(9):e0138650. doi:10.1371/journal.pone.0138650
35. Sauder CJ, Ngo L, Simonyan V, Cong Y, Zhang C, Link M, et al. Generation and propagation of recombinant mumps viruses exhibiting an additional U residue in the homopolymeric U tract of the F gene-end signal. Virus Genes (2015) 51(1):12–24. doi:10.1007/s11262-015-1204-y
36. Wan Q, Dingerdissen H, Fan Y, Gulzar N, Pan Y, Wu TJ, et al. BioXpress: an integrated RNA-seq-derived gene expression database for pan-cancer analysis. Database (Oxford) (2015) 2015:1–13. doi:10.1093/database/bav019
37. Zhang W, Soika V, Meehan J, Su Z, Ge W, Ng HW, et al. Quality control metrics improve repeatability and reproducibility of single-nucleotide variants derived from whole-genome sequencing. Pharmacogenomics J (2015) 15(4):298–309. doi:10.1038/tpj.2014.70
38. Goldweber S, Theodore J, John Torcivia-Rodriguez J, Simonyan V, Mazumder R. Pubcast and Genecast: browsing and explor-ing publications and associated curated content in biology through mobile devices. IEEE/ACM Trans Comput Biol Bioinform (2016) 14(2):498–500. doi:10.1109/TCBB.2016.2542802
39. Novatt H, Theisen TC, Massie T, Massie T, Simonyan V, Voskanian-Kordi A, et al. Distinct patterns of expression of transcription factors in response to interferonbeta and interferonlambda1. J Interferon Cytokine Res (2016) 36(10):589–98. doi:10.1089/jir.2016.0031
40. Simonyan V, Chumakov K, Dingerdissen H, Faison W, Goldweber S, Golikov A, et al. High-performance integrated virtual environment (HIVE): a robust infrastructure for next-generation sequence data analysis. Database (Oxford) (2016) 2016:1–16. doi:10.1093/database/baw022
Keywords: regulatory science, biologics, vaccines, blood safety, cell and gene therapy, clinical trial design, bioinformatics, plasma proteins
Citation: Kusinitz M, Braunstein E and Wilson CA (2017) Advancing Public Health Using Regulatory Science to Enhance Development and Regulation of Medical Products: Food and Drug Administration Research at the Center for Biologics Evaluation and Research. Front. Med. 4:71. doi: 10.3389/fmed.2017.00071
Received: 30 March 2017; Accepted: 23 May 2017;
Published: 12 June 2017
Edited by:Jan Willem Van Der Laan, College ter Beoordeling van Geneesmiddelen, Netherlands
Reviewed by:Christine Gispen-de Wied, European Medicines Agency, United Kingdom
Christine Keipert, Paul Ehrlich Institut, Germany
James Whiteford McBlane, Medicines & Healthcare Products Regulatory Agency (MHRA), United Kingdom
Copyright: © 2017 Kusinitz, Braunstein and Wilson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Carolyn A. Wilson, email@example.com


text:
Update 12:09 p.m., March 30: 911 dispatchers will be eligible for priority testing for COVID-19 as first responders, the Department of Emergency Management said Sunday.
Original story: Emergency officials were not surprised to learn Thursday that one of San Francisco's 911 dispatchers had tested positive for the coronavirus.
The dispatcher had not come to work since last Friday after experiencing symptoms related to COVID-19, said Rob Smuts, a director with the Department of Emergency Management.
"It is not a surprise that a dispatcher has tested positive, and it will almost certainly happen again," Smuts said in an internal email obtained by the San Francisco Examiner.
Smuts urged employees to "redouble" efforts to mitigate the spread of the virus by cleaning and social distancing.
The test results have escalated health concerns for dispatchers who work at the 911 Call Center on Turk Street.
While Mayor London Breed announced Friday that first responders who show symptoms of the virus would be eligible for priority testing, it's unclear if that includes dispatchers.
But Burt Wilson, president of the dispatchers union, said they should be considered first responders because they direct fire and police services to help people in need.
"Working in close quarters at our center," Wilson said, "It only makes sense to keep our dispatchers healthy and give them the priority test that is being given to first responders for COVID-19 so that we are able to work to keep our city safe."
Wilson has called not only for his peers who show symptoms to be tested, but all dispatchers.
There is currently a national shortage of testing kits, and the CDC has recommended that people who do not show symptoms related to the virus are not tested.
The Mayor's Office and DEM did not immediately respond to a request for comment.
On Thursday, DEM implemented temperature checks for anyone entering the operations floor of the dispatch center, Smuts said. DEM is also notifying people who may have been exposed to the dispatcher within 48 hours of him showing symptoms.
"Because the dispatcher's last presence at work was six days ago, there is no risk of continued presence of the virus on surfaces from this case," Smuts said. "But this should be a reminder of the importance of our cleaning."
Mary Ellen Carroll, the executive director of DEM, reacted to the news in another email obtained by the Examiner.
"In spite of all of our efforts, even with temp screening, it is still likely we will have additional cases," Carroll said. "We will continue to work to protect everyone at DEM, supporting each other and still provide the essential service for the safety of the public."
Bay Area NewsCoronavirussan francisco news
Find out more at www.sfexaminer.com/join/


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A client is in a row with a salon after a treatment which she says left her with the 'world's sh*ttest eyebrows'.
Melissa Ryan, 21, from Kent, visited Cavendish Aesthetics to get lip fillers but claimed she was pressured into getting her brows laminated by a member of staff who 'wasn't fully qualified'.
Melissa took to social media to share her frustrations.
But now the owner, Amanda Cavendish, has spoken out against the 'constant barrage of abuse' she says she has received in response.
The business owner, 56, claimed she has received more than 700 messages in the wake of the viral post.
She even says she has reported the alleged harassment to the police.
In the post, Melissa wrote: 'My eyebrows were completely unsatisfactory and nothing like the photos that are advertised on social media.
'I was left looking like I complete fool. I probably could've done a better job myself, blindfolded.'
'I literally came home and cried, this has made me feel even worse about myself and my appearance.
'I was allowed to leave the shop with my eyebrows in the worst state possible, people in public were staring at me and laughing at me, it was so embarrassing!'
About half an hour after leaving, Melissa decided to contact the salon to air her concerns, but said she was dealt with 'completely unprofessionally'.
Melissa and Amanda then shared a series of messages, with Amanda offering a refund of £25 to be collected. But Melissa said she would prefer a bank transfer as the journey to the salon would render the money redundant.
Amanda says her regular clients have been quick to support the salon, which has three employees.
She also said she wasn't worried about the future of her business amid the social media uproar.
Amanda says she clearly explained Melissa's treatment was being done by someone in training. This is something Melissa denies.
Amanda told Kent Live: 'All I said at the time was, "we do brow lamination, you've got lovely big brows, would you like to have your brows laminated?"
'I explained that we were looking for models at the moment, for someone in training, and asked if she would be happy to help. She said "go on then" – those were her words.'
After the treatment was done, Amanda said she explained to her client how staining of the skin was to be expected. Melissa was then told to keep them dry for 24 hours.
Melissa said her skin had become irritated and itchy after the treatment and insisted in her post she should have been offered a patch test
But Amanda claims the products she uses are 'very mild' and only need a patch test if the person involved has pre-existing skin sensitivity or allergies.
Amanda admitted they didn't look perfect when the treatment was done but said Melissa had opportunity to voice her concerns.
Melissa has defended her social media post, claiming it was the only way she could get in touch with Amanda after their Whatsapp exchange.
She said: 'I've tried to contact Amanda but haven't gotten anywhere, this whole situation didn't have to get out of hand like this if she didn't allow unqualified people to do work.
'She hasn't taken any sort of responsibility for what went on in her salon or what her employee did, she blocked my number so I couldn't contact her. That's why I took to social media.
'I haven't even received any sort of apology or my refund, I live in London, I only went there for my treatment.'
MORE: 28 images from largest crowdsourced photo exhibition show life for millennials in modern Britain
MORE: Black women are being targeted with 'disgusting' misogynoir in online gaming forums


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KUALA LUMPUR, 11th March 2020: If the Irish are known for one thing, it's that they know how to throw a celebration. From big events to the smallest of reasons, the Irish will always find an excuse to celebrate. It's March, and that means it's time for the biggest Irish celebration of them all, St. Patricks! That's why Guinness, Ireland and Malaysia's No. 1 stout, is giving Malaysian drinkers 10,000 reasons to celebrate this month.
Tag Archives: guinness
Flavour by Fire
Guinness Flavour by Fire festival celebrates all things roasted, grilled and BBQ'd; thousands of foodies turn up to feast on specially-curated dishes paired with cold, smooth Guinness Draught.
Fire is a force with an awesome transformative power. When it comes to food, fire is what turns simple raw ingredients into mouth-watering meals. Guinness, Malaysia's No. 1 Stout1, understands this better than anyone – the barley used to brew Guinness is roasted at exactly 232° Celsius, which gives the beer its distinctive dark colour and delicious roasted flavour notes.
Have you ever realised that we spend more time with our colleagues than our family or friends? Eight hours a day, five days a week – and yet, most of us don't know each other as well as we'd like. In a recent survey commissioned by Guinness, Malaysia's favourite stout1, more than 85% of young working adults said they'd like to get to know their colleagues and friends better – and Guinness has the solution with the launch of 'Guinness Time'. Continue reading
The taste of Guinness infuses WIP and SOULed OUT outlets with Saint Patrick's Day spirit
March marks the celebration of Ireland's foremost patron saint, also known as the 'Apostle of Ireland'. Popularized across the globe by the ever-expanding Irish diaspora, Saint Patrick's Day is celebrated in more countries than any other national festival and Malaysians across the Nation, known worldwide for our love of parties, have adopted the tradition with typical enthusiasm.Continue reading
Sláinte with GUINNESS this March
Get together with GUINNESS to celebrate St. Patrick's Day with various activities and amazing promotions leading up to the two-day festival.
KUALA LUMPUR, 28 February 2019 – GUINNESS, Malaysia's – and Ireland's – favourite stout is set to celebrate the famous Irish festival, St. Patrick's, throughout the month of March. The two-day festival promises St. Patrick's fun all weekend long for everyone at The Gasket Alley, Petaling Jaya. People from other regions who are unable to join the ultimate two-day festival are in for a treat too, as they can get together with their friends to celebrate St. Patrick's Day at various events happening in Ipoh, Penang, and Johor for the rest of the month. GUINNESS beer lovers can enjoy their favorite brew with amazing promotions as they join the worldwide St. Patrick's party.Continue reading
Ever wondered what makes Guinness Malaysia's – and the world's – favourite stout?[1] You'll get a chance to find out over the next few months in bars and pubs up and down the country. Guinness Expert and Brand Ambassador Cian Hulm, from the home of Guinness – the legendary St. James Gate in Dublin – has come to Malaysiato lead a special series of in-outlet activations from now until January 2019.
Excitement was at its peak as GUINNESS, Malaysia's favourite stout, announced the winners of its Perfect Pour contest, today. Over the past month, trainers from the HEINEKEN Malaysia Star Academy have travelled the length and breadth of the country, teaching hundreds of bartenders the methods to pouring a great pint of GUINNESS. Continue reading
GUINNESS 'paints the town green' for St. Patrick's, transforming bars across Malaysia into 'Irish Pubs' for the month of March; 10,000 GUINNESS up for grabs for you and your friends to get you into the St. Patrick's mood.
Guinness – THE ART OF POUR
Heineken Malaysia has revealed the winners of the inaugural Guinness Perfect Pour contest, at a prize-giving session at The Tavern, Sungei Way brewery. The winners, representing four regions in Malaysia – Central, North, South, and East Malaysia – faced stiff competition from more than 1,000 entrants across the country in search of the perfectly-poured pint of Guinness.
The Brand New Guinness Bright
The future's bright for Malaysian beer lovers – Guinness, Malaysia's favourite black brew, has launched a brand new stout especially for the Malaysian market: Guinness Bright. A smooth and fresh stout infused with invigorating coffee, ginger, and lemongrass extracts, Guinness Bright is stout as you've never seen it before. Continue reading


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from The Conservative Treehouse:
There was once a time, not that long ago, when the mainstream left was highly critical of the CIA, and scrutiny of dubious claims by U.S. intelligence was a common occurrence. Of course all of that changed when those same intelligence agencies were weaponized to target a political enemy that was also the enemy of the left, namely Donald Trump.
Now, in the era of modern political narratives, no intelligence claim against the Trump administration is too outlandish. Regardless of dubious sourcing, it's all pushed as fact so long as the target of the claim is President Donald Trump.
As a result it is not a surprise how targeted weaponization became the cornerstone of the Russian narrative, and sketchy intelligence claims of Russian involvement in elections became the mortar that binds the bricks. The end product is tenuous at best; and if anyone starts to scrutinize the instability of the construct they too become a target.
Last year U.S. Attorney John Durham and U.S. Attorney General Bill Barr were reported to be spending time on a narrowed focus looking carefully at CIA activity in the 2016 presidential election. That CIA activity is directly related to the construction of the December 2016 Joint Analysis Report (JAR), and January 2017 Intelligence Community Assessment (ICA). Both constructs are so critical to the Russia narrative that anyone who dare question the information becomes an immediate risk and target.
Using information from U.K. media, and looking closer at yesterday's New York Times report about investigations of the CIA, in this outline we will explain where corrupt U.S. and U.K. interests merge; what specific action was taken, & why the mortar is crumbling.
2019 – "One British official with knowledge of Barr's wish list presented to London commented that "it is like nothing we have come across before, they are basically asking, in quite robust terms, for help in doing a hatchet job on their own intelligence services"". (Link)
The U.K. Independent ran the above quote last year based on British intelligence officials who were concerned about scrutiny on their aligned activity with the U.S. CIA during the 2016 election. More recently, yesterday the New York Times ran an article breathless with concern about DOJ inquiry and Attorney John Durham questioning the CIA directly.
2020 […] The Justice Department has declined to talk about Mr. Durham's work in meaningful detail, but he has been said to be interested in how the intelligence community came up with its analytical judgments — including its assessment that Russia was not merely sowing discord, but specifically sought to help Mr. Trump defeat Hillary Clinton in the 2016 election.
[…] The analysts could have been engaged in standard bureaucratic behavior like obeying the filtering process or hoarding sensitive information. Or perhaps they were trying to cover something up. The questions asked by Mr. Durham and his team suggest they are looking for any potential basis to support making the latter reading, officials said.
[…] Mr. Durham has interviewed F.B.I. officials and agents who worked on the bureau's Russia investigation, called Crossfire Hurricane, and for the special counsel who took over the inquiry, Robert S. Mueller III. They have also interviewed C.I.A. analysts.
Mr. Durham and his team also interviewed around a half-dozen current and former officials and analysts at the National Security Agency, including its former director, the retired Adm. Michael S. Rogers, last summer and again last fall. The Intercept first reported the interviews of Admiral Rogers.
But Mr. Durham has not interviewed the former F.B.I. director James B. Comey, his onetime deputy Andrew G. McCabe or Mr. Brennan. Mr. Durham has requested Mr. Brennan's emails, call logs and other documents from the C.I.A. to learn what he told other officials, including Mr. Comey, about his and the C.I.A.'s views of a notorious dossier of assertions about Russia and Trump associates. (NYT Link)
It is important to remember how critical the Russian interference narrative is to the activity that took place in 2016. If you take away the mortar, the building collapses. If the concrete evidence is not there to support the intelligence claims of 2016/2017, then all justification for the downstream "investigations" is lost.
Without the Russia narrative, those who weaponized intelligence for political surveillance are naked to the world. The Russia narrative is essential for their justification of everything. In a world with a functioning media the high importance of a key detail would mean even more scrutiny on that detail was warranted. Alas, in the world of orange-man-bad, the concept of a functioning media is as visible as a rotary phone.
The two-year investigation that generated the Weissmann/Mueller report contains claims that Russia hacked the DNC servers as the central element to the Russia interference narrative in the 2016 U.S. election. This claim is perhaps the sketchiest.
It is also important to remember just how extensive the operations of the CIA were in 2016; because it is within the network of foreign and domestic operations where FBI Agent Peter Strzok is noted as a bridge between the CIA and FBI operations.
Read More @ TheConservativeTreehouse.com


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From Bulbapedia, the community-driven Pokémon encyclopedia.
Due primarily to my only basic understanding of coding, I can't seem to fix the fact that this links to Charizard, a disambig, while still keeping simply "Charizard" in the text box. Anyone? --P o L i 17:43, 15 October 2010 (UTC)
- If you find any more like this, use
displayname#, where # is the number used for name. There should be quite a few more out there using glitchevobox which link to redirects. --SnorlaxMonster 11:32, 19 October 2010 (UTC)
This glitch Pokémon's cry is a slowed down Champion Theme with channels missing, but it doesn't freeze the game like ♀'s cry as seen here: http://www.youtube.com/watch?v=mfjsYoL1Uk0 The video was found under unknown circumstances, and it only freezes because, apparently, Super Glitch was in effect. SkyEmerald (talk) 21:53, 14 July 2013 (UTC)