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Red Orchestra: Ostfront 41-45 - Join your friends online or play single player in the epic struggle that was the Eastern Front during World War II
Please note
More details
Release Date: 03/11/2006
Red Orchestra: Ostfront 41-45 - Join your friends online or play single player in the epic struggle that was the Eastern Front during World War II. Fight as an infantry squad member, or crew one of many armored combat vehicles with up to two team-mates, including the most deadly and feared German and Soviet tanks.
Fight in lethal Combined-Arms teams including many specialized infantry roles or with heavy and light armored vehicles.
- 24 infantry weapons with real-world ballistics; pistols, rifles, SMGs, automatic rifles, and light machine-guns.
- Deploy anti-tank weapons, demolition charges and call in artillery strikes.
- Up to 32 Players online or command A.I. soldiers individually or in squads in single player.
- Vehicle weapon ballistics, optics and damage models from recently declassified intelligence files.
- In-game VOIP communications for teams, squads and vehicle crews.
- 13 maps of authentic Eastern Front combat environments.
- Sprint, crawl, lean and dive for cover and brace weapons for more accurate shooting.
- 14 crewable vehicles, with full interior and exterior renditions of all crew positions.
Pegi Rating:Suitable for people aged 16 and over.
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Created in this Craftsy class
Bag-Making Basics: Drawstring Bag & Bucket Bag taught by Kristin Link
In this free mini-class, Kristin Link of Sew, Mama, Sew! leads you through two fun and easy projects you're sure to love.
Other projects made as part of this class:
SewingKnitting and Crochet Bag.
SewingReversible tote
SewingBucket Bag
Offer some kudos...
Join the conversation...
Ask a question...
Add your comment...
This is a relatively easy pattern and something a beginner could make. While it's always important to measure and cut accurately, there is some forgiveness given these are scrunched at the top. The drawstrings are time consuming (compared to the rest of the parts), but a little practice does make them go quicker.
06/06/2014 Flag
You were on a roll! I agree the drawstring is the most time consuming but they turn out great & you must have had some happy grads!
11/05/2014 Flag

subset: commoncrawl


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esai, 11 Sep 2015 A very good companion of mine, Despite its age, I still love it, Unfortunately, mine was stol... morel think it is still on sale in some stores in some countries i think. If you cant find one in your area you can buy it online in several sites like amazon.
This mobile phone is one of the best I have ever had. I mean it has everything a mobile phone should have. Even better it can even function as a stereo radio/music player! Too bad mine has some issues on the navigation keys but that isn't serious at all, still works fine.
A very good companion of mine, Despite its age, I still love it, Unfortunately, mine was stolen! Can you help me on how to get another for purchase please? Thanks
incredible sound quality... great camera....great design... realy cute.. awesome hardwear..
why nokia did not make any more awesome hand set like this...
Great stereo speakers.they are almost as good as nokia 5800.
Great audio output.beats some good xpressmusic phones in this.
High video codec support.
Built in fm antena.
Dedicated music keys.
Battery backup is seriously weak.
No flash.
Display is 262k quality,while same specs nokia 5610's display is much better 16m quality.
It,s nice and cool mobile and also good features with strong metallic body. I really cool nice
Raghu, 22 Jan 2015Can we have whatsapp? Pleaseis whatsapp there in this mobile ?
ROHIT, 10 Nov 2014is whatpps downlodableplese updade my phone whatssapp
Anonymous, 17 Sep 2014is whatpps downlodableThera is a problem of slider ptta.
This is my all-time favourite phone. OK, it's not a smartphone and does not have WiFi or GPS, but it can access the internet on data, it has a huge battery life (days rather than hours) on standby, one-touch FM radio access, without the need for an aerial or headphones, and it's small. Boy, is it small: it really will fit easily into a shirt pocket.


text:
Latest News
Leahy, Sanders And Welch Issue Joint Statement On Rutland's Designation As A Refugee Resettlement Site
"We learned this morning that the City of Rutland will receive refugees who have fled the relentless violence in Syria and Iraq, sometimes with just the clothes on their backs.
September 27, 2016 Press Release
Bipartisan bill introduced today to address loophole in the 'orphan drug' program
Rep. Peter Welch (D-VT) today introduced bipartisan legislation with Rep. Morgan Griffith (R-VA) that would address a loophole in the Medicare 340B Drug Pricing Program that is contributing to the rising cost of health care for consumers and threatening access to lifesaving medications. The introduction of this legislation is the latest in Welch's efforts to fix the broken prescription drug market that has led to unrestrained price increases for consumers and providers.
Days After Welch and Duckworth's Request, Oversight Committee Calls Hearing on Prescription Drug Pricing
Oversight and Government Reform Committee to hold much-needed hearing
Less than a week after Rep. Peter Welch (D-VT) and Rep. Tammy Duckworth (D-IL) called on House Oversight and Government Reform Committee Chairman Jason Chaffetz to hold a hearing on recent prescription drug price hikes, the Chairman announced a hearing to investigate the cause of and potential solutions to prevent skyrocketing drug prices.


text:
Have you visited Dr. Stephen McIntyre? Rate you experience below.
Family Practice Physicians in Hickory, NC
Dr. Stephen McIntyre specializes in family practice in Hickory, North Carolina.
Dr. Stephen McIntyre has been compared 68 times. Details of Dr. McIntyre's 32 years experience as an MD, his hospital affiliation and education at Medical University of South Carolina are available on your free doctor report.
Dr. Stephen McIntyre has an average rating of 5 stars (out of 5) with a rating of Excellent based on 4 reviews.
Have you visited Dr. Stephen McIntyre? Rate you experience below.
Dr. Stephen McIntyre has been identified as specializing in Family Practice.
He is certified in Family Practice.
Insurance plans and networks accepted by a doctor are not necessarily universal across all locations at which the doctor practices. This can be affected by many factors such as different group practices, hospital affiliations and working arrangements at those locations. Checking that the doctor you are visiting and the facility they are at are in-network providers for your insurance plan can save you money and headaches later from surprise medical bills.
Dr. Stephen McIntyre accepts the following plans at 1940 Briarwood Dr, Hickory, NC
A hospital affiliation covers any doctor who has an affiliation, association or admitting privilege with a hospital. A doctor's particular affiliation to a specific hospital can translate to the overall quality of that provider.
Dr. McIntyre is affiliated with 1 hospital:
Dr. McIntyre attended medical school at Medical University of South Carolina College of Medicine and graduated in 1984 having 32 years experience.
While there is no proven correlation between the quality of one's educational institution and the quality of one's professional competence, it is often an indicator. Medical schools have various levels of selectivity (some are harder to get into than others), and both the quality of their clinical training and level of research are measured. Additional medical training in both residency and fellowships and the facilities they are conducted at also provide a history of the doctors' level of training and experience.
Patients may also know Dr. Stephen McIntyre MD as:
1170 Fairgrove Church Rd SE, Hickory, NC 28602
1170 Fairgrove Church Rd SE, Hickory, NC 28602
915 Tate Blvd SE, Suite 170 Hickory, NC 28602
1232 Shiloh Church Rd, Hickory, NC 28601
212 29th Ave NE, Hickory, NC 28601
Are you Dr. Stephen McIntyre?
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Joined: 28 December 2009
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Harshad Chopda shares about his first audition...
The show will bring you back the memories of your first love and the ...
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Thanks for helping us sort this video!
Thanks for helping us associate the correct Pornstars to this video!
Help Us: Do these Pornstars appear in this video?
Pornstar Name:
yeahhhh go drew you nail that bitch ahahhhahaahhaha
this dude just jizzed all over himself...the fuck
Those girls have wonderful bodies...don't be spiteful
these dudes are HOT
I would love to get a blowjob from her and a Handjob and a Footjob and Cum all over her feet.
that looks like a deathgrip at the end
And look at their non existent tits, I always see bitches like that with nothing going on. You all know you want my body more, I love my D cup boobies
Party looks lame . . .


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HourlyLess than 30 hrs/week
Start DateFebruary 4, 2013
Hello, if you are interested we are looking for a data minor to go through listing sites and social media sites such as linkedin to build us a lead list for certain industries and business professionals. If you are able please let me know how many leads an hour will be provided and what methods you will use to attain and make sure they are current. Thanks
Skills: linkedin
About the Client
United States
Birmingham 06:57 PM
Jobs Posted
40% Hire Rate, 1 Open Job
Total Spent
35 Hires, 3 Active
Avg Hourly Rate Paid
1,784 Hours


text:
Russian agency Megalicense has appointed Mikhail Kotov to the role of head of marketing and promotion.
Entertainment One has appointed Megalicense to represent its preschool series "Ben and Holly's Little Kingdom" throughout Russia and the Ukraine.
FremantleMedia Kids & Family Entertainment has appointed a number of new licensing agents for its preschool property "Kate & Mim-Mim."
Roi Visual continues to grow the Robocar Poli brand with a burgeoning traffic safety program, as well as new product and activations worldwide.
FremantleMedia Kids & Family Entertainment has appointed three new international agents for "Tree Fu Tom" in CIS, Benelux and Israel.
Rovio Entertainment has appointed Megalicense to represent licensing and retail initiatives for its Angry Birds brand in Russia.
Nerd Corps Entertainment has added a slew of new licensees for its action property Slugterra in Italy, Latin America, Russia, Turkey, Israel and South Africa.
Carte Blanche Greetings and iMegalicense have teamed up with the Russian search engine Yandex to offer Me to You-themed wallpaper.
Megalicense has taken over as licensing agent for "LazyTown" in Russia.
©2016 UBM. All rights reserved. A UBM Company.


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Quick Details
- Screen Size: 7"
- Placement: Dashboard
- Combination: Bluetooth-Enabled, Built-in GPS, CD Player, MP3 / MP4 Players, Radio Tuner, Touch Screen, TV, RDS,IPOD
- Certification: CE,ROHS
- Place of Origin: Guangdong, China (Mainland)
- Brand Name: BST /OEM
- Model Number: 7081 for BUICK ENCLAVE
- Resoultion: 800*480
Packaging & Delivery
|Packaging Details:
|Gift Box or neutral packing
|Delivery Detail:
|Within 20 days after receiving your payment.
Car DVD GPS player for BUICK ENCLAVE
- · In-dash Car GPS Navigator & Entertainment System Special for BUICK ENCLAVE
- · Display:
- o Touch screen
- o 7-inch HD digital color TFT screen. Professional digital image
processor makes the detail more modest and elegant
- o Resolution: 800*480 pixels
- o Aspect ratio: 16:9
- · Functions:
- o Built-in GPS navigation function, voice guide, route plan
- o DVD/VCD/CD/MP3/MP4/CD-R/WMA
- o Built-in Bluetooth: support handsfree call, dial-up and incoming
call automatic mute functions
- o Built-in AM/FM Radio, RDS for optional
- o iPod Connectivity
- o Analog TV, PAL/NTSC/SECAM (optional)
- o Digital TV Box DVB-T (optional)
- o Original steer wheeling compatibility (optional)
- o Supports Sanyo 6/10 discs and CD/DVD changer
- o Support dimmer mode(optional)
- o USB jack, SD card slot
- o Dual zone entertainment
- o Languages: English, Russian, Italian, Portuguese, Arabic,
Hebrew,Czech,Turkish and more menu languages can be
- o Interface : IPOD,USB, SD slot, A/V input,A/V output
- o Buit-in 4x45W hi-fi amplifier: international professional BBE
sound effect processing to strengthen audio ambience and
sound embellishment effects and make music more gentle
- o CAN BUS interface: support both foreground and background
- o Full function of infrared remote-control operation
- o Equipped with reversing video signal input ,can support many
kinds of reversing camera, automatic switch to reverse
- o Electronic and mechanical anti-shock system
Transaction History of the Supplier
Below is the information about the supplier's transactions conducted via Alibaba.com. If you require further details regarding the transaction data, please contact the supplier directly.
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text: At the southern tip of Norway, there is the country in miniature or so it has become titled. Stord has become known as "Norway in miniature" due to the variation of landscapes and coastlines on offer. If you're hiring a car in Stord then first and foremost you'll want to explore the island as a whole and you can easily drive to the mainland should you need to - there is Northern Europe's longest underwater tunnel to get you from A to B. There's a distinct divide between the industrial parts of the island and the more scenic and stunning nature to see, from fjords to glaciers, rugged landscape and a look across the waters to the rest of the archipelago of islands nearby.


text:
From Charleston, S.C. Dustin Clemons, AKA Big Dus was born a leader and a big thinker, with 10 years of polished talent composing, writing, producing, and engineering music. Big Dus has decided to take a different approach with his talents. With a degree in Entertainment Business Big Dus is a person with knowledge and skills that still understands the importance of bringing quality sounds to your ears
Google+ Tour
The Google+ project makes sharing online more like sharing in real life. Take the interactive tour for a quick look at five of the first key
Full Sail University
The official page for Full Sail University, an educational leader for careers in entertainment.
Big Dus - Big Dus Official Site
For exclusive up to date Music, Video, Tour Dates and Entertainment news from Recording Artist Big Dus - The Official Webpage - Slave Trade
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Manage another domain. -- Select --. » Customer Details. Name, Dustin Clemons. Email, email@example.com. Registration, 2010-02-13 16:
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BIG DUS (@BigDusBeenRaw) on Twitter
Sign up for Twitter to follow BIG DUS (@BigDusBeenRaw). Mr. Everything #RAW | Artist, Producer, and Songwriter | @BMI affiliated | Full Sail
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text:
• We examined the effect of cimetidine in altering gastric microflora in patients undergoing gastric resection for peptic ulcer disease. Ten patients had administration of cimetidine stopped at least six hours before surgery. Their mean gastric pH was 2.02 ± 1.51, and 0.4±0.97 organisms were isolated per patient. Ten patients were maintained on a regimen of cimetidine and their mean gastric pH was 5.69±1.80, with 3.2±1.62 organisms isolated per patient. We reached the following conclusions: cimetidine alters the gastric pH of preoperative patients; cimetidine therapy is associated with an increase in gastric flora; stopping administration of cimetidine six hours before surgery reacidifies the stomach, decreases the number of organisms isolated from the stomach, and decreases the risk of septic complications.
(Arch Surg 1983;118:1413-1415)
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Hello there gaming world. For this week is a busy week, but I will be doing a review in progress every day for Dishonered, and doing a full review of The Walking Dead part 4, and also do some demo reviews for XCOM enemt unkown, Fable Journy, and Forza Horizan. There will be no garrinted that I will be finshing all of the reviews by this Saturday, but I will try hard. I will also be bloging news on here, so be preared for some review in progrees, and demo revies. I hope that everybody have a nice gaming week. My gamertag is thebullSTL, PSN thebullSTL2006. Have some fun.
- Total Points:
- 17,275
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- Evil Genius
- Last Visit:
- 03/04/2014
- Currently:
- Offline
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- Location:
- XBox Live: thebullSTL
- PSN ID: thebullSTL2006
What I'm Playing
New games and demos this week
Oct 09, 2012 3:32PM PST
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40 years of experience
Accepting new patients
220 Arch St
Baltimore, MD 21201 Phone number & directions
A medical license is required for a doctor to practice medicine in a particular state. Requirements vary by state but most require, at a minimum, post-graduate training in the doctor's specific specialty. An NPI number is a national identifier unique to an individual health care provider and is managed by the Center for Medicare & Medicaid Services (CMS).
Learn more about Dr. Jay Perman:
View the full profile to get information on:
- Qualifications
- What's important to you
View full profile
Patient Reviews
The overall average patient rating of Dr. Jay Perman is Excellent.
|Patient Ratings
|Ease of Appointment
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|Accurate Diagnosis
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Prepare before visiting Dr. Perman
Seasonal Allergies Patient Education Vitals patient education guide for information about seasonal allergies such as hay fever, eye and mold allergies.Before Visiting Dr. Perman Learn More
Specialties & Research
Dr. Jay Perman, MD is board certified in Pediatrics and Pediatric Gastroenterology.
- He has special expertise in 10 areas:
- Acid Reflux Disease (Gastroesophageal Reflux / GERD)
- Celiac Disease
- Cystic Fibrosis
- Diarrhea
- Gastrointestinal Diseases (GI Diseases)
- HIV Infections
- Intestinal Diseases
- Lactose Intolerance
- Malabsorption Syndromes
- Nutritional Support
Education & Awards
Dr. Perman graduated from Northwestern University, Chicago. He has 1 awards.
Dr. Perman has 6 hospital affiliations:
- University Of Maryland Medical Center
- Mt Washington Pediatric Hosp
Similar doctors nearby
Dr. Darren DeWalt
Dr. Sang Park
Dr. Linda Jeng
Dr. Judith Rubin
Dr. Karen Kotloff
Dr. Mark Travassos
- Additional Information
- Dr. Jay Allan Perman MD is a male Pediatrician, has 40 years of experience and practices in Pediatrics and Pediatric Gastroenterology.
- Where does Dr. Jay A. Perman practice?
- Dr. Jay Perman has 1 office location.
Dr. Jay Perman practices Pediatrics and Pediatric Gastroenterology near Baltimore, MD.
See Baltimore Pediatricians and Baltimore Gastroenterologists.


text:
Free shipping on orders over $75*
Visually upgraded for 2014, this sea kayaking inspired life jacket combines incredible fit, lightweight construction and ample, organized storage space. A great vest for any boater who likes to roam far from home. * Astral's Freestyle Tectonics system allows the outer front panel to move freely with…
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Designed with offshore sea kayakers in mind, the NRS cVest Life Jacket has pockets and attachment points for all the essentials. It also has lots of reflective tape and a cool mesh back that works great with high-back seats. * For touring comfort, convenience and safety, the cVest can't be beat.…
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…Chinook Life Jacket? Fishermen, sea kayakers and anyone who wants a vest with lots of storage will love this PFD. * Designed with anglers in mind, the Chinook features 7 front pockets for everything from small tackle boxes to tippet. * Perfect for kayak fishing, fly fishing and extended tours! * The…
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Make yourself visible with the Eco Flare™ personal locator light. An essential safety item for sea kayakers. * The Eco Flare includes two LED bulbs: one for constant area white light and a flashing red LED. * Runs on just 2 AAA alkaline batteries for over 500 hours of burn time. * IPX8…
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Experienced sea kayakers asked for it and Kokatat has built it - the Tropos Light Storm Cag. Defy foul weather with this innovative combination jacket and sprayskirt cover. * Fits over your existing garments and PFD to seal out spray and inclement weather. * The bottom of the garment cinches over…
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Wholesale Ganja Dealers Nabbed
By Express News Service - THIRUVANANTHAPURAM
Published: 12th December 2013 09:16 AM
Last Updated: 12th December 2013 09:16 AM
The Fort Police on Wednesday arrested two wholesale dealers of ganja, including a minor, from the city. The arrested have been identified as Naseer, 31, of Karimadom Colony and his helper, a student.
The police said that the two were under police surveillance for the last few days. Collection of the details regarding ganja lobbies and other dealers is in progress. "More arrests will take place in the coming days," said an official.
Chain-snatching:Man Arrested
A 30-year-old man was arrested by the Fort police on Wednesday in connection with a snatching case. The arrested has been identified as Muhammed Ismail.
According to the police, the accused had, on December 9, snatched a five-sovereign chain belonging to one Gomathy, a restaurant owner. Following her complaint, the police were searching for Ismail, who had been absconding after the incident.
The accused was produced before the court and remanded in judicial custody.
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In the news…
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translation Italian-German
This project received 8 bids from talented freelancers with an average bid price of €49 EUR.Get free quotes for a project like this
Skills Required
Project Budget€30 - €250 EUR
Total Bids8
Project Description
The document is in Italian, it contains common legal terms, it is an assembly report. the total number of characters, spaces included is 2195. I need the translation into German, a high quality one!
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f you're just getting to basketball or want a closer look, here's the resumes built so far in the ACC, and a closer statistical breakdown of the Tigers. Clemson Tigers – 5-3 Top-50 RPI Wins: 0 (Led at the half or in the second half on top-20 Arizona and Gonzaga, home and neutral site respectively – ended up losing by 10 per game).
Basketball Breakdown: Where Clemson, the ACC Stands a Month in
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Most Cited Journal of Controlled Release Articles
The most cited articles published since 2011, extracted from Scopus.
PLGA-based nanoparticles: An overview of biomedical applicationsFabienne Danhier | Eduardo Ansorena | Joana M. Silva | Régis Coco | Aude Le Breton | Véronique Préat
Volume 161, Issue 2, July 2012, Pages 505-522
Poly(lactic-co-glycolic acid) (PLGA) is one of the most successfully developed biodegradable polymers. Among the different polymers developed to formulate polymeric nanoparticles, PLGA has attracted considerable attention due to its attractive properties: (i) biodegradability and biocompatibility, (ii) FDA and European Medicine Agency approval in drug delivery systems for parenteral administration, (iii) well described formulations and methods of production adapted to various types of drugs e.g. hydrophilic or hydrophobic small molecules or macromolecules, (iv) protection of drug from degradation, (v) possibility of sustained release, (vi) possibility to modify surface properties to provide stealthness and/or better interaction with biological materials and (vii) possibility to target nanoparticles to specific organs or cells. This review presents why PLGA has been chosen to design nanoparticles as drug delivery systems in various biomedical applications such as vaccination, cancer, inflammation and other diseases. This review focuses on the understanding of specific characteristics exploited by PLGA-based nanoparticles to target a specific organ or tissue or specific cells. © 2012 Elsevier B.V. All rights reserved.
Doxil® - The first FDA-approved nano-drug: Lessons learnedYechezkel Barenholz
Volume 160, Issue 2, June 2012, Pages 117-134
Doxil®, the first FDA-approved nano-drug (1995), is based on three unrelated principles: (i) prolonged drug circulation time and avoidance of the RES due to the use of PEGylated nano-liposomes; (ii) high and stable remote loading of doxorubicin driven by a transmembrane ammonium sulfate gradient, which also allows for drug release at the tumor; and (iii) having the liposome lipid bilayer in a liquid ordered phase composed of the high-T m (53°C) phosphatidylcholine, and cholesterol. Due to the EPR effect, Doxil is passively targeted to tumors and its doxorubicin is released and becomes available to tumor cells by as yet unknown means. This review summarizes historical and scientific perspectives of Doxil development and lessons learned from its development and 20 years of its use. It demonstrates the obligatory need for applying an understanding of the cross talk between physicochemical, nano-technological, and biological principles. However, in spite of the large reward, ~ 2 years after Doxil-related patents expired, there is still no FDA-approved generic Doxil available. © 2012 Elsevier B.V.
Targeted drug delivery to tumors: Myths, reality and possibilityYou Han Bae | Kinam Park
Volume 153, Issue 3, August 2011, Pages 198-205
Endosomal escape pathways for delivery of biologicalsAmir K. Varkouhi | Marije Scholte | Gert Storm | Hidde J. Haisma
Volume 151, Issue 3, May 2011, Pages 220-228
Despite continuous improvements in delivery systems, the development of methods for efficient and specific delivery of targeted therapeutic agents still remains an issue in biological treatments such as protein and gene therapy. The endocytic pathway is the major uptake mechanism of cells and any biological agents, such as DNA, siRNA and proteins. These agents become entrapped in endosomes and are degraded by specific enzymes in the lysosome. Thus, a limiting step in achieving an effective biological based therapy is to facilitate the endosomal escape and ensure cytosolic delivery of the therapeutics. Bacteria and viruses are pathogens which use different mechanisms to penetrate the membranes of their target cells and escape the endosomal pathway. Different mechanisms such as pore formation in the endosomal membrane, pH-buffering effect of protonable groups and fusion into the lipid bilayer of endosomes have been proposed to facilitate the endosomal escape. Several viral and bacterial proteins have been identified that are involved in this process. In addition, chemical agents and photochemical methods to rupture the endosomal membrane have been described. New synthetic biomimetic peptides and polymers with high efficacy in facilitating the endosomal escape, low pathogenicity and toxicity have been developed. Each strategy has different characteristics and challenges for designing the best agents and techniques to facilitate the endosomal escape are ongoing. In this review, several mechanisms and agents which are involved in endosomal escape are introduced. © 2010 Elsevier B.V. All rights reserved.
Drug targeting to tumors: Principles, pitfalls and (pre-) clinical progressTwan Lammers | Fabian Kiessling | Wim E. Hennink | Gert Storm
Volume 161, Issue 2, July 2012, Pages 175-187
Many different systems and strategies have been evaluated for drug targeting to tumors over the years. Routinely used systems include liposomes, polymers, micelles, nanoparticles and antibodies, and examples of strategies are passive drug targeting, active drug targeting to cancer cells, active drug targeting to endothelial cells and triggered drug delivery. Significant progress has been made in this area of research both at the preclinical and at the clinical level, and a number of (primarily passively tumor-targeted) nanomedicine formulations have been approved for clinical use. Significant progress has also been made with regard to better understanding the (patho-) physiological principles of drug targeting to tumors. This has led to the identification of several important pitfalls in tumor-targeted drug delivery, including I) overinterpretation of the EPR effect; II) poor tumor and tissue penetration of nanomedicines; III) misunderstanding of the potential usefulness of active drug targeting; IV) irrational formulation design, based on materials which are too complex and not broadly applicable; V) insufficient incorporation of nanomedicine formulations in clinically relevant combination regimens; VI) negligence of the notion that the highest medical need relates to metastasis, and not to solid tumor treatment; VII) insufficient integration of non-invasive imaging techniques and theranostics, which could be used to personalize nanomedicine-based therapeutic interventions; and VIII) lack of (efficacy analyses in) proper animal models, which are physiologically more relevant and more predictive for the clinical situation. These insights strongly suggest that besides making ever more nanomedicine formulations, future efforts should also address some of the conceptual drawbacks of drug targeting to tumors, and that strategies should be developed to overcome these shortcomings. © 2011 Elsevier B.V. All rights reserved.
Glutathione-responsive nano-vehicles as a promising platform for targeted intracellular drug and gene deliveryRu Cheng | Fang Feng | Fenghua Meng | Chao Deng | Jan Feijen | Zhiyuan Zhong
Volume 152, Issue 1, May 2011, Pages 2-12
The past couple of years have witnessed a tremendous progress in the development of glutathione-responsive nano-vehicles for targeted intracellular drug and gene delivery, as driven by the facts that (i) many therapeutics (e.g. anti-cancer drugs, photosensitizers, and anti-oxidants) and biotherapeutics (e.g. peptide and protein drugs, and siRNA) exert therapeutical effects only inside cells like the cytosol and cell nucleus, and (ii) several intracellular compartments such as cytosol, mitochondria, and cell nucleus contain a high concentration of glutathione (GSH) tripeptides (about 2-10 mM), which is 100 to 1000 times higher than that in the extracellular fluids and circulation (about 2-20 μM). Glutathione has been recognized as an ideal and ubiquitous internal stimulus for rapid destabilization of nano-carriers inside cells to accomplish efficient intracellular drug release. In this paper, we will review recent results on GSH-responsive nano-vehicles in particular micelles, nanoparticles, capsules, polymersomes, nanogels, dendritic and macromolecular drug conjugates, and nano-sized nucleic acid complexes for controlled delivery of anti-cancer drugs (e.g. doxorubicin and paclitaxel), photosensitizers, anti-oxidants, peptides, protein drugs, and nucleic acids (e.g. DNA, siRNA, and antisense oligodeoxynucleotide). The unique disulfide chemistry has enabled novel and versatile designs of multifunctional delivery systems addressing both intracellular and extracellular barriers. We are convinced that GSH-responsive nano-carrier systems have enormous potential in targeted cancer therapy. © 2011 Elsevier B.V.
Albumin-based nanoparticles as potential controlled release drug delivery systemsAhmed O. Elzoghby | Wael M. Samy | Nazik A. Elgindy
Volume 157, Issue 2, January 2012, Pages 168-182
Albumin, a versatile protein carrier for drug delivery, has been shown to be nontoxic, non-immunogenic, biocompatible and biodegradable. Therefore, it is ideal material to fabricate nanoparticles for drug delivery. Albumin nanoparticles have gained considerable attention owing to their high binding capacity of various drugs and being well tolerated without any serious side-effects. The current review embodies an in-depth discussion of albumin nanoparticles with respect to types, formulation aspects, major outcomes of in vitro and in vivo investigations as well as site-specific drug targeting using various ligands modifying the surface of albumin nanoparticles with special insights to the field of oncology. Specialized nanotechnological techniques like desolvation, emulsification, thermal gelation and recently nano-spray drying, nab-technology and self-assembly that have been investigated for fabrication of albumin nanoparticles, are also discussed. Nanocomplexes of albumin with other components in the area of drug delivery are also included in this review. © 2011 Elsevier Ltd. All rights reserved.
"Nanoantibiotics": A new paradigm for treating infectious diseases using nanomaterials in the antibiotics resistant eraAe Jung Huh | Young Jik Kwon
Volume 156, Issue 2, December 2011, Pages 128-145
Despite the fact that we live in an era of advanced and innovative technologies for elucidating underlying mechanisms of diseases and molecularly designing new drugs, infectious diseases continue to be one of the greatest health challenges worldwide. The main drawbacks for conventional antimicrobial agents are the development of multiple drug resistance and adverse side effects. Drug resistance enforces high dose administration of antibiotics, often generating intolerable toxicity, development of new antibiotics, and requests for significant economic, labor, and time investments. Recently, nontraditional antibiotic agents have been of tremendous interest in overcoming resistance that is developed by several pathogenic microorganisms against most of the commonly used antibiotics. Especially, several classes of antimicrobial nanoparticles (NPs) and nanosized carriers for antibiotics delivery have proven their effectiveness for treating infectious diseases, including antibiotics resistant ones, in vitro as well as in animal models. This review summarizes emerging efforts in combating against infectious diseases, particularly using antimicrobial NPs and antibiotics delivery systems as new tools to tackle the current challenges in treating infectious diseases. © 2011 Elsevier B.V. All rights reserved.
The forthcoming applications of gold nanoparticles in drug and gene delivery systemsDakrong Pissuwan | Takuro Niidome | Michael B. Cortie
Volume 149, Issue 1, January 2011, Pages 65-71
The unique optical, chemical, and biological properties of gold nanoparticles have resulted in them becoming of clinical interest in several applications including drug and gene delivery. The attractive features of gold nanoparticles include their surface plasmon resonance, the controlled manner in which they interact with thiol groups, and their non-toxic nature. These attributes can be exploited to provide an effective and selective platform to obtain a targeted intracellular release of some substance. The use of gold nanoparticles can also increase the stability of the payload. Here we review recent advances in the use of gold nanoparticles in drug and gene delivery systems. The topics of surface modification, site-specificity and drugs and gene and gene delivery are discussed. © 2009 Elsevier B.V. All rights reserved.
Impact of albumin on drug delivery - New applications on the horizonBakheet Elsadek | Felix Kratz
Volume 157, Issue 1, January 2012, Pages 4-28
Over the past decades, albumin has emerged as a versatile carrier for therapeutic and diagnostic agents, primarily for diagnosing and treating diabetes, cancer, rheumatoid arthritis and infectious diseases. Market approved products include fatty acid derivatives of human insulin or the glucagon-like-1 peptide (Levemir ® and Victoza ®) for treating diabetes, the taxol albumin nanoparticle Abraxane ® for treating metastatic breast cancer which is also under clinical investigation in further tumor indications, and 99mTc-aggregated albumin (Nanocoll ® and Albures ®) for diagnosing cancer and rheumatoid arthritis as well as for lymphoscintigraphy. In addition, an increasing number of albumin-based or albumin-binding drugs are in clinical trials such as antibody fusion proteins (MM-111) for treating HER2/neu positive breast cancer (phase I), a camelid albumin-binding nanobody anti-HSA-anti-TNF- α (ATN-103) in phase II studies for treating rheumatoid arthritis, an antidiabetic Exendin-4 analog bound to recombinant human albumin (phase I/II), a fluorescein-labeled albumin conjugate (AFL)-human serum albumin for visualizing the malignant borders of brain tumors for improved surgical resection, and finally an albumin-binding prodrug of doxorubicin (INNO-206) entering phase II studies against sarcoma and gastric cancer. In the preclinical setting, novel approaches include attaching peptides with high-affinity for albumin to antibody fragments, the exploitation of albumin-binding gadolinium contrast agents for magnetic resonance imaging, and physical or covalent attachment of antiviral, antibacterial, and anticancer drugs to albumin that are permanently or transiently attached to human serum albumin (HSA) or act as albumin-binding prodrugs. This review gives an overview of the expanding field of preclinical and clinical drug applications and developments that use albumin as a protein carrier to improve the pharmacokinetic profile of the drug or to target the drug to the pathogenic site addressing diseases with unmet medical needs. © 2011 Elsevier B.V.
State of the art in PEGylation: The great versatility achieved after forty years of researchGianfranco Pasut | Francesco M. Veronese
Volume 161, Issue 2, July 2012, Pages 461-472
In the recent years, protein PEGylation has become an established and highly refined technology by moving forward from initial simple random coupling approaches based on conjugation at the level of lysine ε-amino group. Nevertheless, amino PEGylation is still yielding important conjugates, currently in clinical practice, where the degree of homogeneity was improved by optimizing the reaction conditions and implementing the purification processes. However, the current research is mainly focused on methods of site-selective PEGylation that allow t*he obtainment of a single isomer, thus highly increasing the degree of homogeneity and the preservation of bioactivity. Protein N-terminus and free cysteines were the first sites exploited for selective PEGylation but currently further positions can be addressed thanks to approaches like bridging PEGylation (disulphide bridges), enzymatic PEGylation (glutamines and C-terminus) and glycoPEGylation (sites of O- and N-glycosylation or the glycans of a glycoprotein). Furthermore, by combining the tools of genetic engineering with specific PEGylation approaches, the polymer can be basically coupled at any position on the protein surface, owing to the substitution of a properly chosen amino acid in the sequence with a natural or unnatural amino acid bearing an orthogonal reactive group. On the other hand, PEGylation has not achieved the same success in the delivery of small drugs, despite the large interest and several studies in this field. Targeted conjugates and PEGs for combination therapy might represent the promising answers for the so far unmet needs of PEG as carrier of small drugs. This review presents a thorough panorama of recent advances in the field of PEGylation. © 2011 Elsevier B.V. All rights reserved.
Macromolecular therapeutics in cancer treatment: The EPR effect and beyondHiroshi Maeda
Volume 164, Issue 2, December 2012, Pages 138-144
In this review, I have discussed various issues of the cancer drug targeting primarily related to the EPR (enhanced permeability and retention) effect, which utilized nanomedicine or macromolecular drugs. The content goes back to the development of the first polymer-protein conjugate anticancer agent SMANCS and development of the arterial infusion in Lipiodol formulation into the tumor feeding artery (hepatic artery for hepatoma). The brief account on the EPR effect and its definition, factors involved, heterogeneity, and various methods of augmentation of the EPR effect, which showed remarkably improved clinical outcomes are also discussed. Various obstacles involved in drug developments and commercialization are also discussed through my personal experience and recollections. © 2012 Elsevier B.V. All rights reserved.
Poly-ε-caprolactone based formulations for drug delivery and tissue engineering: A reviewTapan K. Dash | V. Badireenath Konkimalla
Volume 158, Issue 1, February 2012, Pages 15-33
Biodegradable polymer based novel drug delivery systems have provided many avenues to improve therapeutic efficacy and pharmacokinetic parameters of medicinal entities. Among synthetic biodegradable polymer, poly-ε- caprolactone (PCL) is a polymer with very low glass transition temperature and melting point. Owing to its amicable nature and tailorable properties it has been trialed in almost all novel drug delivery systems and tissue engineering application in use/investigated so far. This review aims to provide an up to date of drugs incorporated in different PCL based formulations, their purpose and brief outcomes. Demonstrated PCL formulations with or without drugs, intended for drug delivery and/or tissue engineering application such as microsphere, nanoparticles, scaffolds, films, fibers, micelles etc. are categorized based on method of preparation. © 2011 Elsevier B.V. All rights reserved.
Polymersomes for drug delivery: Design, formation and characterizationJung Seok Lee | Jan Feijen
Volume 161, Issue 2, July 2012, Pages 473-483
In the last past dozen years, polymersomes (Ps) have attracted tremendous attention as versatile carriers because of their colloidal stability, tunable membrane properties and ability in encapsulating or integrating a broad range of drugs and molecules. Relatively long blood circulation times of Ps can be accomplished when block copolymers with a poly(ethylene glycol) (PEG) are used for the formation of Ps. A number of Ps has been developed for new possibilities and applications in drug delivery, medical imaging, electronics and nanoreactors. In particular, Ps prepared by using biodegradable and/or stimuli-sensitive block copolymers that are responsive to various internal or external stimuli are of great interest for such applications. In this review, recent advances of Ps as drug delivery systems are discussed. Critical factors that influence the formation of Ps are also addressed. The review describes preparative methods and characterization techniques for Ps. Moreover, protein and cell interactions with Ps, in vivo circulation kinetics and biodistribution of Ps are addressed. © 2011 Elsevier B.V. All rights reserved.
Graphene-based nanomaterials for drug delivery and tissue engineeringSumit Goenka | Vinayak Sant | Shilpa Sant
Volume 173, Issue 1, January 2014, Pages 75-88
Nanomaterials offer interesting physicochemical and biological properties for biomedical applications due to their small size, large surface area and ability to interface/interact with the cells/tissues. Graphene-based nanomaterials are fast emerging as "two-dimensional wonder materials" due to their unique structure and excellent mechanical, optical and electrical properties and have been exploited in electronics and other fields. Emerging trends show that their exceptional properties can be exploited for biomedical applications, especially in drug delivery and tissue engineering. This article presents a comprehensive review of various types and properties of graphene family nanomaterials. We further highlight how these properties are being exploited for drug delivery and tissue engineering applications. © 2013 Elsevier B.V.
Polymeric micelles drug delivery system in oncologyJian Gong | Meiwan Chen | Ying Zheng | Shengpeng Wang | Yitao Wang
Volume 159, Issue 3, May 2012, Pages 312-323
Polymeric micelles (PM) system, as an efficient drug carrier, has received growing scientific attention in recent years owing to its solubilization, selective targeting, P-glycoprotein inhibition and altered drug internalization route and subcellular localization properties. Seven PM formulations of anti-tumor drugs being evaluated in clinical trials are reviewed in this paper, in terms of formulation study, in vitro cytotoxicity, in vivo pharmacokinetics, anti-tumor efficacy and safety as well as clinical trials, to shed new light on the discovery of novel PM formulations. In these seven PM formulations, PM system was employed to overcome the issues of low water solubility, high toxicity and (or) multidrug resistance accompanied with the conventional formulation, which greatly hampered their clinical application. Those promising preclinical and clinical results combined with rapid advancement and intense multidisciplinary collaboration enable the extension of the PM system to traditional Chinese medicine, imaging agents, gene and combination agent deliveries as well as some other administration routes, which facilitate the clinical translation of the PM drug delivery system. Copyright © 2012 Published by Elsevier B.V. All rights reserved.
Inorganic nanoparticles for cancer imaging and therapyHuang Chiao Huang | Sutapa Barua | Gaurav Sharma | Sandwip K. Dey | Kaushal Rege
Volume 155, Issue 3, November 2011, Pages 344-357
Inorganic nanoparticles have received increased attention in the recent past as potential diagnostic and therapeutic systems in the field of oncology. Inorganic nanoparticles have demonstrated successes in imaging and treatment of tumors both ex vivo and in vivo, with some promise towards clinical trials. This review primarily discusses progress in applications of inorganic nanoparticles for cancer imaging and treatment, with an emphasis on in vivo studies. Advances in the use of semiconductor fluorescent quantum dots, carbon nanotubes, gold nanoparticles (spheres, shells, rods, cages), iron oxide magnetic nanoparticles and ceramic nanoparticles in tumor targeting, imaging, photothermal therapy and drug delivery applications are discussed. Limitations and toxicity issues associated with inorganic nanoparticles in living organisms are also discussed. © 2011 Elsevier B.V. All rights reserved.
Opportunities and challenges for use of tumor spheroids as models to test drug delivery and efficacyGeeta Mehta | Amy Y. Hsiao | Marylou Ingram | Gary D. Luker | Shuichi Takayama
Volume 164, Issue 2, December 2012, Pages 192-204
Multicellular spheroids are three dimensional in vitro microscale tissue analogs. The current article examines the suitability of spheroids as an in vitro platform for testing drug delivery systems. Spheroids model critical physiologic parameters present in vivo, including complex multicellular architecture, barriers to mass transport, and extracellular matrix deposition. Relative to two-dimensional cultures, spheroids also provide better target cells for drug testing and are appropriate in vitro models for studies of drug penetration. Key challenges associated with creation of uniformly sized spheroids, spheroids with small number of cells and co-culture spheroids are emphasized in the article. Moreover, the assay techniques required for the characterization of drug delivery and efficacy in spheroids and the challenges associated with such studies are discussed. Examples for the use of spheroids in drug delivery and testing are also emphasized. By addressing these challenges with possible solutions, multicellular spheroids are becoming an increasingly useful in vitro tool for drug screening and delivery to pathological tissues and organs. © 2012 Elsevier B.V. All rights reserved.
Transport of drugs across the blood-brain barrier by nanoparticlesStefanie Wohlfart | Svetlana Gelperina | Jörg Kreuter
Volume 161, Issue 2, July 2012, Pages 264-273
The central nervous system is well protected by the blood-brain barrier (BBB) which maintains its homeostasis. Due to this barrier many potential drugs for the treatment of diseases of the central nervous system (CNS) cannot reach the brain in sufficient concentrations. One possibility to deliver drugs to the CNS is the employment of polymeric nanoparticles. The ability of these carriers to overcome the BBB and to produce biologic effects on the CNS was shown in a number of studies. Over the past few years, progress in understanding of the mechanism of the nanoparticle uptake into the brain was made. This mechanism appears to be receptor-mediated endocytosis in brain capillary endothelial cells. Modification of the nanoparticle surface with covalently attached targeting ligands or by coating with certain surfactants enabling the adsorption of specific plasma proteins are necessary for this receptor-mediated uptake. The delivery of drugs, which usually are not able to cross the BBB, into the brain was confirmed by the biodistribution studies and pharmacological assays in rodents. Furthermore, the presence of nanoparticles in the brain parenchyma was visualized by electron microscopy. The intravenously administered biodegradable polymeric nanoparticles loaded with doxorubicin were successfully used for the treatment of experimental glioblastoma. These data, together with the possibility to employ nanoparticles for delivery of proteins and other macromolecules across the BBB, suggest that this technology holds great promise for non-invasive therapy of the CNS diseases. © 2011 Elsevier B.V. All rights reserved.
Designing the nanoparticle-biomolecule interface for "targeting and therapeutic delivery"Eugene Mahon | Anna Salvati | Francesca Baldelli Bombelli | Iseult Lynch | Kenneth A. Dawson
Volume 161, Issue 2, July 2012, Pages 164-174
The endogenous transport mechanisms which occur in living organisms have evolved to allow selective transport and processing operate on a scale of tens of nanometers. This presents the possibility of unprecedented access for engineered nanoscale materials to organs and sub-cellular locations, materials which may in principle be targeted to precise locations for diagnostic or therapeutic gain. For this reason, nano-architectures could represent a truly radical departure as delivery agents for drugs, genes and therapies to treat a host of diseases. Thus, for active targeting, unlike the case of small molecular drugs where molecular structure has evolved to promote higher physiochemical affinity to specific sites, one aims to exploit these energy dependant endogenous processes. Many active targeting strategies have been developed, but despite this truly remarkable potential, in applications they have met with mixed success to date. This situation may have more to do with our current understanding and integration of knowledge across disciplines, than any intrinsic limitation on the vision itself. In this review article we suggest that much more fundamental and detailed control of the nanoparticle-biomolecule interface is required for sustained and general success in this field. In the simplest manifestation, pristine nanoparticles in biological fluids act as a scaffold for biomolecules, which adsorb rapidly to the nanoparticles' surface, conferring a new biological identity to the nanoparticles. It is this nanoparticle-biomolecule interface that is 'read' and acted upon by the cellular machinery. Moreover, where targeting moieties are grafted onto nanoparticles, they may not retain their function as a result of poor orientation, and structural or conformational disruption. Further surface adsorption of biomolecules from the surrounding environment i.e. the formation of a biomolecule corona may also obscure specific surface recognition. To transfer the remarkable possibilities of nanoscale interactions in biology into therapeutics one may need a more focused and dedicated approach to the understanding of the in situ (in vivo) interface between engineered nanomaedicines and their targets. © 2012 Elsevier B.V. All rights reserved.
The journey of a drug-carrier in the body: An anatomo-physiological perspectiveNicolas Bertrand | Jean Christophe Leroux
Volume 161, Issue 2, July 2012, Pages 152-163
Recent advances in chemistry and material sciences have witnessed the emergence of an increasing number of novel and complex nanosized carriers for the delivery of drugs and imaging agents. Nevertheless, this raise in complexity does not necessarily offer more efficient systems. The lack of performance experienced by several colloidal drug carriers during the preclinical and clinical development processes can be explained by inadequate pharmacokinetic/biodistribution profiles and/or unacceptable toxicities. A comprehensive understanding of the body characteristics is necessary to predict and prevent these problems from the early stages of nanomaterial conception. In this manuscript, we review and discuss the anatomical and physiological elements which must be taken into account when designing new carriers for delivery or imaging purposes. This article gives a general overview of the main organs involved in the elimination of nanosized materials and briefly summarizes the knowledge acquired over more than 30 years of research and development in the field of drug targeting. © 2011 Elsevier B.V. All rights reserved.
Magnetic resonance imaging of high intensity focused ultrasound mediated drug delivery from temperature-sensitive liposomes: An in vivo proof-of-concept studyMariska De Smet | Edwin Heijman | Sander Langereis | Nicole M. Hijnen | Holger Grüll
Volume 150, Issue 1, February 2011, Pages 102-110
Temperature-sensitive liposomes (TSLs) co-encapsulating doxorubicin and 250 mM [Gd(HPDO3A)(H2O)] were evaluated for HIFU-mediated drug delivery under MR image guidance. In vitro studies showed simultaneous and quantitative release of the drug and the MRI contrast agent from the lumen of the TSLs at 42°C, while no leakage was observed over 1 h at 37°C. In a proof-of-concept study, local hyperthermia has been applied for 30 min in 9L rat tumors using a clinical MR-HIFU system. The local temperature-triggered release of [Gd(HPDO3A)(H2O)] was monitored with interleaved T1 mapping of the tumor tissue. A good correlation between the ΔR 1, the uptake of doxorubicin and the gadolinium concentration in the tumor was found, implying that the in vivo release of doxorubicin from TSLs can be probed in situ with the longitudinal relaxation time of the co-released MRI contrast agent. © 2010 Elsevier B.V.
Modeling of diffusion controlled drug deliveryJuergen Siepmann | Florence Siepmann
Volume 161, Issue 2, July 2012, Pages 351-362
Mathematical modeling of drug release can be very helpful to speed up product development and to better understand the mechanisms controlling drug release from advanced delivery systems. Ideally, in silico simulations can quantitatively predict the impact of formulation and processing parameters on the resulting drug release kinetics. The aim of this article is to give an overview on the current state of the art of modeling drug release from delivery systems, which are predominantly controlled by diffusional mass transport. The inner structure of the device, the ratio "initial drug concentration:drug solubility" as well as the device geometry determine which type of mathematical equation must be applied. A straightforward "road map" is given, explaining how to identify the appropriate equation for a particular type of drug delivery system. The respective equations for a broad range of devices are indicated, including reservoir and matrix systems, exhibiting or not an initial excess of drug and the geometry of slabs, spheres and cylinders. The assumptions the models are based on as well as their limitations are pointed out. Practical examples illustrate the usefulness of mathematical modeling of diffusion controlled drug delivery. Due to the advances in information technology the importance of in silico optimization of advanced drug delivery systems can be expected to significantly increase in the future. © 2011 Elsevier B.V. All rights reserved.
Administration of resveratrol: What formulation solutions to bioavailability limitations?A. Amri | J. C. Chaumeil | S. Sfar | C. Charrueau
Volume 158, Issue 2, March 2012, Pages 182-193
Resveratrol (3,5,4′-trihydroxystilbene), a naturally occurring polyphenol, has attracted considerable interest for its beneficial potentials for human health, which include anti-oxidant, anti-inflammatory, cardioprotective and anti-tumor activities. However, the in vivo biological effects of resveratrol appear strongly limited by its low bioavailability, which is a barrier to the development of therapeutic applications. In this context, an increasing number of recent studies have aimed at designing novel resveratrol formulations to overcome its poor solubility, limited stability, high metabolization and weak bioavailability. This review outlines physicochemical and pharmacokinetic limitations to resveratrol bioavailability, describes formulations tested for resveratrol administration, controlled release and targeting, and identifies future opportunities for resveratrol delivery. © 2011 Elsevier B.V. All rights reserved.
Analysis on the current status of targeted drug delivery to tumorsIl Keun Kwon | Sang Cheon Lee | Bumsoo Han | Kinam Park
Volume 164, Issue 2, December 2012, Pages 108-114
Targeted drug delivery to tumor sites is one of the ultimate goals in drug delivery. Recent progress in nanoparticle engineering has certainly improved drug targeting, but the results are not as good as expected. This is largely due to the fact that nanoparticles, regardless of how advanced they are, find the target as a result of blood circulation, like the conventional drug delivery systems do. Currently, the nanoparticle-based drug delivery to the target tumor tissues is based on wrong assumptions that most of the nanoparticles, either PEGylated or not, reach the target by the enhanced permeation and retention (EPR) effect. Studies have shown that so-called targeting moieties, i.e., antibodies or ligands, on the nanoparticle surface do not really improve delivery to target tumors. Targeted drug delivery to tumor sites is associated with highly complex biological, mechanical, chemical and transport phenomena, of which characteristics vary spatiotemporally. Yet, most of the efforts have been focused on design and surface manipulation of the drug carrying nanoparticles with relatively little attention to other aspects. This article examines the current misunderstandings and the main difficulties in targeted drug delivery. © 2012 Elsevier B.V. All rights reserved.


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Hearing aids in 48327, Waterford, MI
We found 28 hearing clinics with 103 reviews within 33.4 miles of 48327, Waterford, MI.
Featured hearing professionals near you
Nancy Maranto, Au.D., CCC-A
Dr. Nancy Maranto serves patients at West Bloomfield. She earned her M.A. from Michigan State (read more)
Paulette McDonald, MA, CCC-A
Paulette is the Director of Audiology as well as the Cochlear Implant team coordinator. She oversees (read more)
Malcolm McAdam, M.S., CCC-A
Malcolm McAdam has an extensive background in clinical, educational, and industrial audiology for (read more)
Noel Rendelman, AuD
Licensed doctor of audiology Noel Rendelman has nearly two decades of experience in the audiology (read more)
Steve Smith, HIS
Steve Smith is a licensed Hearing Instrument Specialist with experience in solving even the most (read more)
Jeffrey Anderson, HIS
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Michigan Hearing at Livonia Center for Specialty Care Audiology
Julie Carlson, AuD, CCC-A
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Linda Vassallo, MA
Linda Vassallo joined the PHS family in March 2011. Along with her contageous laugh, she brought her (read more)
Jeffrey Anderson, HIS
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Karen Butchart, BC-HIS
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Valerie Ketchum, Au.D., CCC-A
Valerie A. Ketchum earned her Doctor of Audiology from Central Michigan University and holds her (read more)
Steve Smith, HIS
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John Selley, HIS
John Selley helps our customers with the selection and fitting of today's most advanced digital (read more)
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Julie Carlson, AuD, CCC-A
Doctor of Audiology Julie Carlson earned her Doctorate in Audiology from the University of Florida (read more)
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Joel Stutz, Au.D., CCC-A
Joel earned his Doctorate in Audiology at the University of Florida after attending Central Michigan (read more)
John Selley, HIS
John Selley helps our customers with the selection and fitting of today's most advanced digital (read more)
Thomas O'Connor, M.A., CCC-A, FAAA
Thomas O'Connor offers over 25 years of experience in audiometric testing and fitting hearing (read more)
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CHICAGO – It's 3am on Saturday night/Sunday morning on August 20th, and you're just not ready to quit. How about indulging in the 2016 "Abbie Hoffman Died for Our Sins" Theater Festival? The three-day theater marathon is in its 28th edition, and will be sponsored for the final time by the Mary-Arrchie Theatre Company, and hosted by the "Godfather of Storefront Theater," Rich Cotovsky. It all takes place at the Den Theatre, 1333 N. Milwaukee in Chicago (details below).
Little House on the Prairie
Exclusive Portraits: Melissa Gilbert Still Wows Them on the PrairieSubmitted by PatrickMcD on October 31, 2014 - 1:08pm
- Alison Arngrim
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- HollywoodChicago.com Content
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- Joe Arce
- Little House on the Prairie
- Melissa Gilbert
- Melissa Sue Anderson
- Michael Landon
- My Prairie Cookbook: Memories and Frontier Food from My Little House to Yours
- Naperville
- North Central College
- Patrick McDonald
CHICAGO – Melissa Gilbert has grown up a bit since portraying Laura Ingalls on the 1970s TV classic "Little House on the Prairie," but her roots aren't far behind. She's just released "My Prairie Cookbook: Memories and Frontier Food from My Little House to Yours," and appeared last month at North Central College in Naperville, Ill. – at an event sponsored by Anderson's Bookshop – to greet admirers and sign her new menu planner.
Alison Arngrim Interview: Nasty Nellie on 'Little House on the Prairie'Submitted by PatrickMcD on September 11, 2010 - 5:58am
CHICAGO – For every nice girl on the prairie, there needed to be an evil opposite who wasn't so nice. Nellie Oleson was that nasty girl on the NBC-TV legend "Little House on the Prairie, and Alison Arngrim portrayed her. She has parlayed that long ago child actor part into a stand-up routine and new memoir about her experiences.
Interview: Melissa Sue Anderson, 'Little House on the Prairie' DaysSubmitted by PatrickMcD on June 6, 2010 - 12:24pm
CHICAGO – The NBC TV show legend, "Little House on the Prairie," evokes an era of the family drama that Melissa Sue Anderson, who played Mary Ingalls, says could never be on the air today. Anderson was in Chicago recently, promoting her new book, "The Way I See It: A Look Back on My Life on Little House."


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Legislation would allow the families of victims to sue Saudi Arabia for the kingdom's alleged backing of the attackers
Should the vote fail, both departments expect significant layoffs
House Speaker Paul Ryan says deal "will help unlock" short-term spending bill
Voters see presidential pair side-by-side during opening discussion.
Ex-president tells 800 at Waite that she will bring people together, Trump will divide.
Officials have said they believe attacks were orchestrated by those backed by the Russian government.
Will be first ambassador to country in more than 50 years.
Area to be bounded by Lafayette, Erie, Adams, and Summit streets.
Debate between Clinton, Trump beat a 36-year record of viewers.
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Jazz Band
Jazz Band
Are you tired of only getting to play the notes on the page? Do you wish you could express yourself through the magic of musical improvisation? Do you think you have what it takes to get an audience on their feet dancing?
If you answered "yes" to any of the above, then jazz band might be for you!
Open to all instruments. No prior jazz experience necessary. A background in music theory is preferred but not required.
Music of a variety of styles will be studied, including swing, funk, rock, blues, and Latin jazz.
Music scholarships available beginning in Fall 2017.


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7 posts tagged with DoctorWho and writing.
Displaying 1 through 7 of 7. Subscribe:
Zeppelin Vs Pterodactyl
At first glance it may seem mediocre but over time you see why such a vehicle would inspire so much loyalty and devotion.
During the month of December, tor.com has been publishing essays on the Twelve Doctors of Christmas. Today artist Pia Guerra gives us the gift of an extended metaphor: the fifth Doctor as a Volvo. [more inside]
Doctor Who and the Overthrow of the Thatcher Goverment
"My exact words were: I'd like to overthrow the government. I was a young firebrand and I wanted to answer honestly. I was very angry about the social injustice in Britain under Thatcher and I'm delighted that came into the show." - former Doctor Who script editor Andrew Cartmel on the shows 80s political stance. Terrance Dicks and Andrew Cartmel on Newsnight. Meanwhile former Doctor David Tennant gives his veiws on the Master-like characteristics of Tory leader David Cameron.
Doctor Who and the Auton Invasion of your Nightmares
The 21 Scariest Doctor Who Moments Ever, according to SFX magazine. Waters of Mars, which aired in the UK this weekend and airs in the US on December 20th, may add to that list. Meanwhile, in other formats, Michael Moorcock is writing a Doctor Who novel.
"A lot of writers are mad."
Long interview with Doctor Who showrunner Russel T Davies on his writing and producing career (at the BBC's Writersroom).
The Who we never knew
The Russell T. Davis papers – As he prepares to leave the role of Doctor Who show runner (previously) he's releasing a book of email exchanges with Doctor Who Magazine writer Benjamin Cook about his time on the longstanding British SF series, revealing the younger face of Who he's like to see, and plans for a Doctor Who/Harry Potter crossover which never materialized.
Script-Doctorin' the TARDIS
As of 2010 Steven Moffat will be replacing Russell T. Davies as lead writer and executive producer of Doctor Who. In 2005 Davies revived the series, which had been dormant (bar the odd US co-production or audiodrama) since 1989, for BBC Wales. It won awards and was successful enough to spawn the spin-offs Sarah Jane Adventures and the popular-in-America Torchwood. He is replaced by Moffat, one of the regular writers on the show, whose highly acclaimed episodes have won a number of awards and nominations. "I applied before but I got knocked back 'cos the BBC wanted someone else. Also I was seven. Anyway, I'm glad the BBC has finally seen the light and it's a huge honour to be following Russell into the best - and the toughest - job in television. I say toughest 'cos Russell's at my window right now, pointing and laughing."
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Counseling Skills for Teachersby Jeffrey A. Kottler Ellen Kottler
By necessity, today's teachers do much more than deliver instruction. In the classroom, on the playground, or even in the parking lot, teachers are often called upon to respond quickly and appropriately to students' social and emotional needs, drawing from instinct more than anything else. In this second edition of the bestselling Counseling Skills for Teachers, Jeffrey and Ellen Kottler expertly guide preservice and inservice teachers to be effective helpers in the context of today's most common challenges, highlighting issues related to homelessness, grief and loss, and bullying and harassment. The book also discusses: - Responding to a range of behaviors in formal and informal school settings - Building a culture of tolerance and respect in the classroom - Motivating disengaged students - Communicating effectively with counseling professionals and parents With an entirely new chapter on "Counseling Yourself," the book offers teachers surefire techniques for taking better care of themselves and the students in their schools.
The Mummy at the Dining Room Table: Eminent Therapists Reveal Their Most Unusual Cases and What They Teach Us About Human Behaviorby Jeffrey A. Kottler Jon Carlson
insightful and entertaining... and you thought you were weird!
Nuts and Bolts of Helpingby Jeffrey A. Kottler
This book is intended to give students in various professions a basic overview of the theory, process, and skills of helping methods.
On Being a Master Therapistby Jeffrey A. Kottler Jon Carlson
Learn from master therapists and bring your skills to the next levelBringing a breath of fresh air to the therapy profession, this compelling and thoughtful resource urges readers to move from competency to full mastery in the mental health field. Combining the findings of hundreds of previous studies, interviews with a wide range of master therapists, own unique experiences and perspectives, Jeffery A. Kottler and Jon Carlson have devised a guide that takes therapists out of their comfort zones.Professionals in the fields of psychology, counseling, social work, and human services, as well as graduate students studying for these professions, will find a level of honesty and candor in this resource, which tackles a range of essential topics in a frank, personal tone, and closes with a meaningful discussion about the challenges of striving for mastery. Master therapists and authors Kottler and Carlson explore a range of hot-button topics, such as:Cultural misunderstandingsDisliking your clients (or having clients dislike you)Receiving negative feedback from clientsInjecting creativity into the therapeutic processFinding time for social justice and advocacyOn Being a Master Therapist provides a much-needed look at a range of topics that aren't often given such genuine and insightful treatment, with the goal of helping you attain the attributes that truly distinguish excellence in clinical practice. Start on your journey toward mastery with this thoughtful resource.
On Being a Therapist (4th edition)by Jeffrey A. Kottler
According to Kottler (counseling, California State U., Fullerton), much has changed in the field since the 1986 edition was published. The book includes updated research and treats issues related to the challenges of increasing client diversity and complaints, managed care, and new technology. New chapters address therapists' reciprocal relationship with their clients, struggles with negative outcomes, forbidden admissions, and responsibility to promote social justice in the broader world.
Secrets for Secondary School Teachersby Jeffrey A. Kottler Cary J. Kottler Ellen Kottler
Teach like a pro from day one!In this updated version of the successful Secrets for Secondary School Teachers, you will learn tangible ways to supercharge your teaching skills, while avoiding the pitfalls common to beginning teachers. Offering a unique blend of perspectives and "insider" insights into secondary education, a seasoned high school teacher, a long-time educator and counselor, and a recent high school graduate join forces to impart proven tips and tools.This indispensable guide combines practical applications of your preservice coursework with straightforward portrayals of what you can expect during your first days, weeks, semesters, and years in the classroom.Already packed with winning ideas and real-life scenarios, this newest edition has added: A new chapter on developing plans for instruction and assessment Rubrics-both holistic and analytic A-to-Z list of assessments Expanded information on multiple intelligences and diverse learning populations Suggestions for students with attention deficits Stress source chart Technology tipsReduce your stress, hone your skills, and be "in the know" with this invaluable resource.
Stress Management and Preventionby Jeffrey A. Kottler David D. Chen
Stress Management and Prevention, Second Edition offers a fun and exciting way to learn about stress, its causes, and ways to deal with and prevent it. Not only will you enjoy reading it, but you'll also find yourself motivated to continue incorporating what you learn into your life long after your class is over. You'll explore both Western and Eastern views of stress to learn about its nature, what can trigger it, and the impact it can have on your body and your life. Numerous coping strategies are explored, including problem solving and time management skills, psychological and spiritual relaxation methods, and healthy nutritional and lifestyle choices. Self-reflection and self-awareness exercises, activities, and hands-on techniques will show you how to effectively and easily manage your stress and, most importantly, prevent it from reoccurring. A collection of 17 videos to accompany the text are available here: www.youtube.com/user/routledgetherapy.
Students Who Drive You Crazyby Jeffrey A. Kottler
Outlines strategies teachers can use to succeed with difficult and hard to motivate young people.
The Therapist in the Real World: What You Never Learn in Graduate School (But Really Need to Know)by Jeffrey A. Kottler
Advice and inspiration for the real-life challenges of being a mental health professional. Graduate school and professional training for therapists often focus on academic preparation, but there's a lot more that a therapist needs to know to be successful after graduation. With warmth, wisdom, and expertise, Jeffrey A. Kottler covers crucial but underaddressed challenges that therapists face in their professional lives at all levels of experience. PART I , "More Than You Bargained For," covers the changing landscape of the mental health profession and the limits and merits of professional training. PART II , "Secrets and Neglected Challenges," explores important issues that are often overlooked during training years, including the ways our clients become our greatest teachers, the power of storytelling, and the role of deception in psychotherapy. And in PART III , "Ongoing Personal and Professional Development," Kottler focuses on areas in which even the most experienced therapists can continue to hone their talents and maximize their potential, laying out effective tips to navigate organization politics, write and publish books and articles, cultivate creativity in clinical work, maintain a private practice, present and lecture to large and small audiences, sustain passion for the work of helping others, plan for the future, and much more. As honest and inspiring as it is revealing, this book offers therapists and counselors at all levels of experience key ideas for thriving after formal education.
The Therapist's Workbookby Jeffrey A. Kottler
Mental health professionals spend their days helping others, but who is there to help them when stress and burnout threaten their own well-being? Filled with self-assessments, journaling exercises, and activities designed to facilitate renewal, growth, and change, this timely book helps clinicians help themselves with coverage of career threatening issues, such as fear of failure, loss of confidence, and the financial stress and loss of autonomy that many clinician's experience as a result of managed care and its constraints.
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Local History" Ghosts of the past aren't so far away
First in a continuing series
William Faulkner wrote in Requiem for a Nun, "The past is never dead. It's not even past."
As Halloween approaches, there are some "ghosts" from Tunica County's past that we can visit in our area cemeteries, without even getting a scare.
Here are some of their stories:
Tunica County received official recognition from the state of Mississippi in October of 1837 just a few years after the Treaty of Pontotoc ceded the last of the Chickasaw lands east of the Mississippi to the federal government.
Latest News
'Highway killer' convicted in retrial A man who went on...
Fifteen Years Later One Tunican's special...
A Flag Folding and Bell Ceremony for 9/11 Tuesday, September 11,...
TA presents Homecoming Court Tunica Academy's Homecoming...
Revival stirs churches to act as one in Christ Jesus By turns smiling and...
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The SurgiCenter is the first outpatient surgical facility of its kind in the state of Kentucky accredited by the American Association for the Accreditation of Ambulatory Surgical Facilities (AAAASF) in 1998; the highest measure of quality and safety. To date, over 1600 cosmetic surgical procedures have been performed in the SurgiCenter.
Offering a wide range of cosmetic services and procedures, this modern 4200 square foot facility offers the most advanced technology available, with the personal care, privacy, safety, and convenience of an accredited operating room suite without hospital hassles. We are staffed by board certified anesthesiologists as well as surgical technologists and operating room nurses, who are especially trained in cosmetic surgical procedures, assuring the highest level of personal care and satisfaction.
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Recent Blog Posts
Premier High School
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On August 18, 2013 Scheherazade (Sherry) Perkins was the keynote speaker at the TSTC commencement ceremony at...read more
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Waco Independent School District recognized SIBSolutions L.L.C. and two scholarship winners from the Make...read more
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SIBSolutions L.L.C. worked with University High School's freshmen class of 2017 with 9th grade transition...read more


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We've arrived at the end of season one of Cartoon Brew TV and we're going out with a bang. This week's offering, To the Moon (2008), by Jacob Ospa is one of the finest examples of cartoon animation we've seen in a long time. That it was animated by a 21-year-old reaffirms our faith in the future of animation. The Flash-animated thesis film was created at the School of Visual Arts. Watch To the Moon only on Cartoon Brew TV.
Cartoon Brew TV: To the Moon
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