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Une veuve de papier (French Edition) (ExLib) by John Irving
Current price $7.79
Listing type Fixed Price Item
Location Aurora, Illinois 60502 US
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Seller thrift.books (1741801)
Seller rating 99.3% positive feedback
Binding Hardcover
Author John Irving
Publisher Seuil
Publication Year 1999
Weight 1.54 lbs
Product Group Book
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Language french
Une veuve de papier (French Edition)
by John Irving
A copy that has been read, but remains in clean condition. All pages are intact, and the cover is intact. The spine may show signs of wear. Pages can include limited notes and highlighting, and the copy can include previous owner inscriptions. An ex-library book and may have standard library stamps and/or stickers. At ThriftBooks, our motto is: Read More, Spend Less.
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In this episode, we discuss the methodology, impact, and applications of the "Sprint" ideology as written about by Jake Knapp.
Editing and music by: John Bougioukos
visit us at: www.creativehoney.org
Join us in learning about Jérémie's journey from a comic book loving young boy, into a Graphic Designer who re-discovered his childhood passion for Illustration that brought him to a Freelance Illustration practice that he loves today.
Jérémie's website: www.jeremieclaeys.com/
Our Blog: www.creative honey.org
Music in this episode by: Dr. Doctor
Track: Semilanceata
Join us in learning about Jérémie's journey from a comic book loving young boy, into a Graphic Designer who re-discovered his childhood passion for Illustration that brought him to a Freelance Illustration practice that he loves today.
Jérémie's website: www.jeremieclaeys.com/
Our Blog: www.creative honey.org
Music in this episode by: Dr. Doctor
Track: Semilanceata
Time. It never feels like we have enough of it. Time can affect so many aspects of how we manage our lives, but how about our Creative practice? Today we talk about how you choose to view time can affect how smoothly your practice runs, the amount of income you can make, and even your client relationships.
Visit our blog: www.creativehoney.org
Music by: Iceland by napz
Meydan: Underwater
Intro Music by: Mockateel
Building a brand is more than just having a nice logo. It's about the process of research, discovery and analysis that goes into understanding a business or individual's needs and who they are most trying to target. The end result should be a beautiful visual identity and on-point messaging that lasts well into the future. In this episode we chat with Jain Karan, the CEO & Founder of Magfirst, a Publication Design Agency, and Enamus, a Branding Agency. He shares with us his masterful understanding of Branding & Identity, and how to properly approach the process, delivering information that is illuminating for aspiring Brand Strategists and businesses alike.
Check out what Jain's up to:
When someone gets to be a working Creative, it's easy to think that it's a dream come true. However, many Creatives can experience an insidious issue, that's not always easy to figure out. This issue is called Creative Burnout. In this episode we discuss what you can do to realize you might be burning yourself out, teach you how to spot the signs, how to heal from it and have a fulfilling creative Career.
Our Blog: www.creativehoney.org
Music By: Scott Holmes- Positive and Fun
Paul Fisko- Six Times Four & Little Glass Men- Sub Aqueonic
Many creatives may reach a point where they realize they want to try something different, that's outside of their current creative career education and experience, but are not sure how to make the leap. In this episode we talk to Mark Steiner founder of the successful startup, GigSalad, an online market place for entertainers of all types to land gigs for various types of events.
Mark started off being an Actor, then a Talent Agent, until one day he realized he wanted to combine his talent to form a startup. Mark tells us his story of his Creative career pivot, and how he got to where he is today.
Visit GigSalad: https://www.gigsalad.com/
Visit our Blog: www.creativehoney.org.
http://www.bensound.com : Jazz Comedy
The Atlas Room: Physika
When its time for the ball to drop every year, most of us have made resolutions that we want to implement for the New Year. In this episode we discuss some resolutions that are helpful for creatives, not only for 2017, but for the remainder of your creative practice.
Check out our newly designed blog: www.creativehoney.org
Music in this episode by: 4T Thieves
Many people are being struck with startup fever in recent years, and people from all disciplines are unexpectedly finding themselves gravitating towards this fast paced and innovative arena.
Recently we had the opportunity to be on a panel at CalArts, where we spoke to students about how to transition from being an artist, to being a part of the tech-heavy startup world. We also discussed the importance of understanding and implementing UX and UI when creating a digital product.
In this episode, Zach and I have a roundtable discussion with the 3rd member of the CalArts panel discussion, Damjan Krajacic (the founder of the design studio ActiveColor), continuing our conversation on these topics.
With technology innovation moving at the speed of light, devices we have grown accustomed to are now moving farther away from visual design and moving more towards Artificial Intelligence run interfaces. This is starting to reduce the way and capacity in which we interact and rely on the screens of our devices. Eventually technology will integrate with minimal graphics as we approach more advanced AI and augmented reality (AR) based experiences. What will UX and UI designers create when screen usage diminishes? We discuss our theories and predictions on this topic.
Check out our blog: www.creativehoney.org
Music By: Lee Rosevere

subset: commoncrawl


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In this blog we will give an overview for homeowners how a contractor's or construction professional's insurance relates to residential construction defects. This blog is[…]+ more
Colorado's Constitution guarantees a right to a jury trial in criminal cases, but not in civil cases. Whether a person is entitled to a jury[…]+ more
The Colorado Supreme Court issued its opinion in Hernandez v. Ray Domenico Farms, Inc. on Monday, March 5, 2018. The Colorado Supreme Court answered a question[…]+ more
The Colorado mechanics lien statute limits the lien of any person to the value of laborers, machinery, tools, or equipment supplied, or services rendered. A[…]+ more
Colorado unemployment law makes a distinction between termination for cause, and termination due to employee fault. A person may of course be terminated for cause,[…]+ more
Varsity Tutors LLC (Varsity) provided an online platform that connected tutors with students. Varsity had individual contracts with tutors, who advertised their services on Varsity's website. Students who[…]+ more
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A new unemployment law decision from the Colorado Supreme Court protects unemployment benefits for people who lose a job due to anxiety, depression or stress.[…]+ more


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Update - August 29, 2019
Fall 2019 Travel schedules are now available on the ECYSA site. Find your team's schedule at https://www.ecysa.org/ECYSA/full-schedule by filtering by the team name.
Update - June 11, 2019
Registration for the fall 2019 soccer season is now open for both Travel and In Town programs. Travel team players please sign up now as we have to create teams and submit them to ECYSA in early July.
Travel Program:
Grades 3 to PG (grade 12+1), Boys and Girls Leagues.
Travel games will be played on Saturdays for Grades 3 to 8 and on Sundays for Grades 9 and up. Weekly practices will be set by teams' coaches. Please register before July 1, 2019.
Travel teams may only be submitted to the ECYSA travel league if they have a minimum number of players. We therefore encourage you to register your players as soon as possible. Extended registration after July 1, 2019 will only be available for age groups with teams formed before the deadline with available capacity.
In Town Program:
Instructional Leagues (Grades K and 1-2) and Junior League (Grades 3-5)
In Town games will be played on Sunday mornings. Registration is through August 2019.
$125 per player, not to exceed $300 per family. A late fee of $25 will apply after the registration deadlines of July 1, 2019 for the travel program and August 31, 2019 for the In Town program.
Register here.
Please email email@example.com with any questions.
Thank you for supporting Winthrop Youth Soccer!
Please visit us on Facebook!
"Like" and share!


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The world is now ready for dictatorship so get ready for the ride of your life folks what is happening now is a tiny foretaste of what is coming down the line like a loaded freight train on its way to a disastrous derailment. I and others have been saying […] Read more »
Dreams Read by Brain Scanner for the First Time
Dreams Read by Brain Scanner for the First Time Jessica Hamzelou, 14 Jan 2012 by Jessica Hamzelou: ______________________________________________ The secret world of dreams could soon be cracked open. Innovative neuroscientists have already begun to figure out the thoughts of awake people – now, a team reckon they can use similar […] Read more »


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Event Date: 29 Aug 17 :: Past Event
Celebrating the spirit of National Sports Day
"Good sports facilities are a blessing." - Kapil Dev
Meenakshi Public School, Sector 10- A Gurugram campus has best infrastructure for sports which include world class grounds, indoor and outdoor arenas, With its strategic location in the heart of Gurugram and its well equipped facilities in a number of sporting disciplines, the school also attracts for its sheer aesthetic value. Encompassed by lush green lawns, the school houses artificial synthetic green grass court for lawn tennis enthusiasts. The state-of –the-art half Olympic Size swimming pool is an added attraction. The schools's HCJ Academy for Cricket and Coaching for Football and Skating remain star attractions. A plethora of outdoor and indoor sporting activities include basketball, badminton, volleyball, table tennis and karate which inculcate perseverance, teamwork, discipline and punctuality. Our students have brought laurels by winning many interschool sports tournaments under the guidance of dedicated team of Physical Instructors.


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In this technology driven society, leaving people feeling more and more detached, women are finding themselves single late into their 30's and beyond, creating a sense of being forgotten by God. Their stress levels are compounded by the fact their "clock is ticking" and hopes of becoming a wife and mother, in their minds, are diminishing year after year. This can create a sense of low self-esteem, low self-worth and loneliness. These women are finding their identity in being single and alone, rather than in Christ.
The other group of women I address are the newly single. With divorce rates in the church being as prevalent as outside of the church, we have women in their 40's, 50's and beyond who are finding themselves feeling ostracized, isolated and left out, as they're becoming single once again after years, sometimes decades of marriage. This is a reality I faced over a decade ago when my marriage of 18 years ended. I share parts of my own story. From being asked to leave my church when I was going through my divorce, thoughts of abandoning my faith and reconciling I am who God says I am.
30-45 minutes
In this message, I talk about being stuck in the pain of your past. Using Scripture and some of my own stories, I remind women living a life wearing a mask to cover up their pain keeps them from experiencing all God has for them.
I've created this message based on Luke 9:62 and Philippians 3:12.
In this message, I will cove anything from broken marriages, sexual abuse of any kind, physical or extreme verbal abuse, being a victim of any kind of crime, dysfunctional families, death of a closed loved one and adultery.
This message is geared towards middle, high school and college age students. This talk is filled with the why's and how's of staying away from gang activity, smoking, drinking, drugs and sex outside of marriage.
I use many stories from students I've met and counseled and use humor throughout this message to keep them interested. I've shared this message with tens of thousands of students across the country and abroad. stories of why God says it's best to wait for sex until marriage.
30-45 minutes
Pro-Life, Abortion Healing, Adoption, Crisis Pregnancy and Mother/Daughter
Please provide a few details regarding the upcoming event so that we can better assist you.


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Ford Grand C-MAX
1.6 TDCi Zetec 5dr, FSH, 2 Owners, 2 Keys Bluetooth, AUX/USB, Park Assist, 62.8 mpg combined.
Vehicle Details
Vehicle Description
FULL SERVICE HISTORY, FREE 1 YEAR MOT, LOW MILES. WELL LOOKED AFTER WITH JUST 2 OWNERS AND HAS PASSED AN INDEPENDENT 50 POINT - IT IS IN GREAT CONDITION AND DRIVES SUPERB. EASY TO SEE WHY THESE REMAIN SO POPULAR - EXTREMELY ECONOMICAL FAMILY MPV WITH 7 SEATS AND REALLY EASY ACCESS. GIVES UP TO 63mpg AND CHEAP TO TAX AND INSURE. VERY GOOD SPECIFICATION LEVELS INCLUDING PARKING SENSORS, 16 inch ALLOYS, BLUETOOTH etc. COMES WITH 2 KEYS AND ALL PAPERWORK., 3 months warranty, Next MOT due 18/07/2019, Last serviced on 24/05/2019 at 58,663 miles, Full service history, Excellent bodywork, Black Cloth interior - Excellent Condition, Tyre condition Good, 7 seats, Metallic Brown, 2 owners, Upgrades - Metallic Paint, FREE AA BREAKDOWN COVER, AA APPROVED DEALER, HPI CLEAR, ALL PAPERWORK PRESENT, LOW RATE FINANCE, ALL MAJOR CARDS ACCEPTED WHY NOT TRY OUR FANTASTIC LOW RATE FINANCE PLAN? POOR CREDIT??, NO PROBLEM, WE HAVE A HUGE PANEL OF LENDERS TO FIT EVERYONE'S NEEDS, FAMILY BUSINESS TRADING 20 YEARS, GENEROUS PART EXCHANGE, ANY INSPECTION WELCOME, Standard Features - 16in x 5 5 Y-Spoke Alloy Wheels-215/55 R16 Tyres, Air Conditioning, Quickclear Heated Windscreen, Rear Parking Sensors, CD Player, Anti-Lock Brakes, Electric door mirrors, Electric windows, Front Fog Lights, Armrest, ISOFIX Child Safety Seat Attachments, Power-Assisted Steering, 3x3 point rear seat belts, Airbags, Bluetooth, AUX / USB, Multi-function Steering Wheel, £6,795 ovno
Vehicle Specification
- Alloy Wheels
- Colour Coded Bumpers
- Colour Coded Mirrors
- Front Fog Lamps
- Rear Wash Wipe
- Privacy Glass
- Air Conditioning
- Alarm
- Immobiliser
- Computer
- Central Locking
- Central Locking - Remote
- Climate Control
- Driver Airbag
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- Electric Mirrors
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- Lumbar Support
- Park Distance Control
- Power Assisted Steering
- Rear Head Rests
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Finance Deals
Financial Disclosure
Winchester Car Sales is Authorised and Regulated by the Financial Conduct Authority. (659963) Finance Subject to status. Other offers may be available but cannot be used in conjunction with this offer. We work with a number of carefully selected credit providers who may be able to offer you finance for your purchase. Winchester Car Sales - 251 Southey Green Road, Sheffield, South Yorkshire, S5 7QB. Companies House Number:. FCA number: 659963.
Full Tech Spec
Technical Specification
- Top Speed: 112mph
- Acceleration: 12.3seconds
- Engine Power: 115bhp
- Engine Torque: 199lbs/ft
- Fuel Type: Diesel
- Economy: 60.1mpg
- Driven Wheels:
- Engine: 1560
- Transmission: Manual
- Combined 60.1mpg
- Urban 51.4mpg
- Extra
- Height: 1684mm
- Width: 2067mm
- Seats: 7
- Length: 4520mm
- Doors: 5
- Braked: 1200kg
- Unbraked: 750kg
- Min Kerb Weight: 1504kg
- Insurance Group
- 6 Months £68.75
- 12 Months £125
- NCAP Overall 5
- NCAP Safety 71


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Frequently Asked Questions (FAQ's) - General
Ans: Our offices are open 0900 to 1700., Monday through Friday (except holidays). Appointments can be made by calling our (615) 342-0038 during office hours.
Where and when do your clinics operate?
Ans: We are open Monday to Friday (except holidays) between 0900 to 1700.
St. Thomas Medical Plaza East4230 Harding
Pike, Suite 900, Nashville, TN 37205
Click here for location map and driving directions.
Tel: (615) 342-0038
Fax: (615) 329-4469
What is Osteoarthritis?
Ans: Osteoarthritis is the most common form of arthritis. It is caused by the breakdown of cartilage. Cartilage is the tough elastic material that covers and protects the ends of bones. Bits of cartilage may break off
and cause pain and swelling in the joint between bones. This pain and
swelling is called inflammation. Over time the cartilage may wear away
entirely, and the bones will rub together. Osteoarthritis can affect any
joint but usually affects hips, knees, hands and spine.
Will physical therapy be required after surgery?
Ans: Major surgery on a joint may take two or three hours in the operating
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after surgery usually takes months. That's where pre-operative exercise and
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recovery after surgery. Together, such programs are among the most important determinants in the success of your surgery.


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In the meanwhile, Fertiplast SL focus their activity in packaging services. We are manufacturers of polypropylene woven sacks and bulk bags. Furthermore we supply a wide range of products as polyethilene strech film, thread and sewing machines, in order to meet all customer requirments.
Our 5.000 m2 factory is based in Alcalá de Guadaira, Sevilla.


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The following are the Terms and Conditions applicable in respect of the "The One" Pay-Monthly Mobile Plan ("the Tariff") being provided to a pay monthly customer ("the Customer") by Melita Limited ("Melita"). Access to and use of this Tariff is subject to the following Terms and Conditions. For more information, please contact Customer Care on 100 (call is free) from your Melita Mobile number, or +356 77100100 from any other network.
1.This Tariff will start from the 26th January 2015 and will continue thereafter unless and until it is terminated by Melita.
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16.Melita reserves the right to suspend, amend or otherwise alter this Tariff and these Terms and Conditions at any time by giving you 30 days' written notice of such amendments and such amendments shall automatically become part of these Terms and Conditions at the end of the said notice period. If you do not accept any such amendments, you have the right to migrate on to a different tariff plan or terminate the service without incurring any penalty during the 30 day notice period.
* Existing customers shall mean customers currently subscribed to the Magic Plan, customers within the last 6 months of their contract term on the Unlimited Value Plan and customers within last 12 months of their contract term on the Hybrid plan.
** As of the 17th June 2015 Customers subscribing to the €50 Tariff shall have the possibility of subscribing to an internet bundle as per clause 5 above.
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Any usage made shall be payable by the Customer. Customers may choose to benefit from the Handset Offer after the lapse of the first 30 days.
Discounts are not cumulative. The discount with the highest value shall be applicable.
NB – As of 20th of June 2016 to 17th of July Customers subscribing to the €50 Tariff shall further benefit from a €20 discount on the access fee for the first 3 months of the contract. Starting with the fourth month, the full access fee is applied.
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Cell therapy in acute respiratory distress syndrome
Acute respiratory distress syndrome (ARDS) is a multifactorial syndrome of severe lung injury causing hypoxemia, loss of lung compliance, pulmonary oedema, that can in some instances progress to multiple organ failure (1,2), and results in death in 30–45% of cases (3). ARDS occurs in 10% of all ICU patients and in 23% of all mechanically ventilated patients, with 5.5 ARDS cases per ICU bed each year globally (4). ARDS can develop in response to multiple predisposing factors including pneumonia, systemic infection, and major surgery or multiple traumas (5). This pathology is strongly associated with pulmonary sepsis and/or with a disordered immune response to a major insult (6). Severe lung inflammation is perpetrated by an invasion of neutrophils and macrophages into the alveolar space, which together with the production of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-1β, IL-8 and tumour necrosis factor-alpha (TNF-α), results in damage to the endothelial and epithelial lung layers (7). This inflammatory environment enhances the production of reactive oxygen species, impairs lung barrier function and increases vascular permeability, and, where ARDS is prolonged or unresolved, it can lead to fibrosis (7) (Figure 1).
Current therapies and their shortfalls
There are no direct therapies for ARDS currently, while management strategies such as protective mechanical ventilation and fluid-restrictive strategies minimize iatrogenic harm while providing organ support. Patients with ARDS by definition are extremely hypoxic and require mechanical ventilation, which can exacerbate the acute lung injury (ALI). This is commonly caused by the initial volutrauma that intensifies the inflammatory response and is known clinically as ventilator-induced lung injury (VILI) (8). In ARDS which has developed from a pulmonary or systemic infection, early broad-spectrum antibiotics and source control where possible, are the treatment of choice. Antibiotic therapy presents a low success rate in the treatment of ARDS due to the ongoing inflammatory response which continues to cause injury even after eradication of the pathogen. The emergence of antibiotic-resistant strains and the timing of antibiotic administration can also contribute to this low success (9). Pharmacologic treatments, including glucocorticoids, surfactants, inhaled nitric oxide, antioxidants, protease inhibitors, and a variety of other anti-inflammatory treatments have been tested in clinical trials (10). Unfortunately, these pharmacologic treatments have proven to be completely ineffective (11). In contrast, protective lung ventilation strategies (low tidal volume or limited driving pressure strategy) are currently the accepted gold standard for improving mortality rates in ARDS.
Rationale for cell-based therapies for ARDS
There is a pressing need for a safe and effective treatment for ARDS and attention has turned to the use of cell therapy. The first successful use of cell therapy involved the use of bone marrow (BM) aspirates in a transplant procedure for leukaemia patients (12,13). Originally thought to be the definitive solution for the replacement of damaged tissues by differentiating to replace the damaged cells, further investigations have highlighted that in fact this is not a major mechanism of adult stromal/stem cell action. However, other investigations have highlighted an array of capabilities that some of these cells possess. Their immune-modulating effects, anti-bacterial action, lack of rejection molecules as well as relative ease of isolation and characterisation make these cells an ideal therapeutic for ARDS. In fact, several different cell types have been examined for therapeutic potential.
Stem cell candidates for ARDS
Embryonic stem cells (ESCs)
ESCs are pluripotent cells derived from the inner blastocyst cell mass of the developing embryo (14).These cells can differentiate into all other progenitor cell types (15,16) and their capacity for self-renewal makes them a viable treatment option for tissue regeneration. Studies using human ESCs have shown efficacy in a number of disease models including diabetes mellitus (17), Parkinson's disease (18), ischemic stroke (19) and some have progressed to clinical trial (20,21). A study by Wang et al., observed that ESC- derived alveolar-epithelial type II cells (AECII) attenuated bleomycin-induced lung injury in mice and thus showed potential promise as a therapeutic (22). There are ethical concerns with the use of this cell type however, and in many countries their use is limited or banned. Another major limiting factor is the safety concerns of ESC-based therapy. The pluripotency of ESCs is a double-edged sword; the same plasticity that permits ESCs to generate hundreds of different cell types also makes them difficult to control after in vivo transplantation, with one of the definitions of ESCs being that after implantation they form teratomas containing cells from all three primary germ layers (23).
Induced pluripotent stem cells (iPSCs)
iPSCs are originally somatic cells of animal or human origin that undergo an induced differentiation treatment, resulting in the overexpression of Oct3/4, Sox2, Klf-4 and c-Myc transcription factors that licence pluripotency (24). iPSCs solve the ethical concerns of ESCs, retaining plasticity and also allowing for autologous transplants. However, iPSCs still present the risk of teratoma formation, for example c-Myc activity has been linked to tumorigenesis (25) while mutagenesis may occur due to the use of lentivirus and adenovirus during the reprogramming process (26). Recent studies have focused on identifying new molecular strategies that can increase cell reprogramming efficiency and that avoid the use of viral transduction (27). A recent study showed that iPSCs significantly alleviated histological damage and cell leakage in a murine model of endotoxin-induced lung injury (28). There are several phase I clinical trials using iPSCs in the treatment of Leukemia (NCT02564484), chronic granulomatous disease (NCT02926963) and retinoblastoma (NCT02193724) for example. iPSCs represent a promising strategy for the therapeutic use of a pluripotent cell type, however much research remains to be conducted to ascertain the safety and enhanced benefits (if any) of these cells over multipotent stem cells.
Mesenchymal stromal/stem cells
MSCs are multipotent adult progenitor cells that can be isolated from numerous sources, including BM, umbilical cord (UC) and adipose tissue (AD), and can be differentiated into mesenchymal lineage cells (29). MSCs are considered to be hypoimmunogenic because they exhibit low levels of MHC-I expression, and no expression of either MHC class II markers or costimulatory molecules, which allows them to avoid immunosurveillance (30) and thus allows allogenic and autologous transplantation (31,32). MSCs have already shown therapeutic efficacy in preclinical models and exhibited safety clinically in a number of phase I trials. Their therapeutic potential, low immunogenicity, ease of harvest and isolation, and low production costs compared with other stem cells have made them the focus of research and consequently, the rest of this review.
While MSCs are traditionally isolated from BM, they can also been found in many other adult tissues such as lung, liver, cord blood, placenta, dental pulp and AD (33), providing alternative, more readily available and cheaper sources of MSCs. These cells have some common morphological and immunophenotypic properties and studies have shown that MSCs derived from UC and AD tissue among others have demonstrated therapeutic efficacy in pre-clinical models of ARDS (34-36). It was recently demonstrated that UC-MSCs could protect against LPS-induced lung injury in a mouse model, with examination of the MSC secretome and identification of factors responsible for the immune regulation leading to a beneficial outcome (37). A study using human AD-MSCs in a mouse model of bleomycin-induced pneumonia has also shown these cells to play a role in immune regulation whereby they reduce the production of pro-inflammatory cytokines and also reduce the proliferation and differentiation of Th2-type CD4+ T-cells, the major T-cell population involved in inflammation (38). The most recent and relevant research studies using MSCs from different tissues are shown in Table 1.
Full table
Progenitor cell candidates for ARDS
Progenitor cells are tissue-specific cells with a limited differentiation capacity, distinguishing them from stem cells. They are found in most tissues and can differentiate and replace injured/damaged cells within organ systems. These cells reside within specific tissue/organ niches; accordingly preclinical studies suggest their therapeutic potential for disease conditions relating to their source tissue, having properties most associated with the repair and regeneration of that tissue (47).
Pulmonary epithelial progenitor cells (EpPCs)
EpPCs have the potential to be used as a therapy in pulmonary diseases both as a direct treatment and also as a potential target in vivo due to their involvement and disruption in certain syndromes (48). A Wnt-responsive alveolar epithelial progenitor cell population expressing AECII surface markers has been recently demonstrated to enhance lung alveoli regeneration in a mouse model of influenza (49).
AEC-IIs, the pulmonary surfactant-producing cells of the lung (48), are a sub-population of EpPCs and their therapeutic potential stems from their ability to rapidly differentiate to AEC-Is, which regulate and control the fluid homeostasis in the alveolar wall and express diverse ion and water channels, and tight junction proteins (50). Intratracheal administration of AEC-IIs aided lung repair through AEC-I transformation and regulated the immune response by synthesizing surfactant and other anti-inflammatory proteins and lipids such as prostaglandin E2 (PGE2) and surfactant protein A (SPA) in a rodent LPS injury model (46). However, the isolation of these cells can be difficult, and the number of cells obtained low.
Endothelial progenitor cells (EnPCs)
EnPCs are circulating cells and their role, isolation and identification has not been fully elucidated. EnPCs express the surface marker CD34 (hematopoietic marker) and seem to have a pivotal role in the repair of the endothelium, adhering to it and other areas under hypoxia or ischemia, releasing growth factors that induce angiogenesis (51,52). One study showed that autologous transplantation of EnPCs improved endothelial function and ameliorated pulmonary oedema following oleic acid- induced ALI in rabbits (53), while another study observed that higher counts of circulating EnPCs correlated to higher survival rates in patients with ALI (54,55). These cells have also shown potential therapeutic use for vascular diseases such as pulmonary arterial hypertension (PAH) as demonstrated during a clinical study by Zhu and colleagues (56). A more recent study has examined the effects of EnPCs transfected to express endothelial nitric oxide synthase in patients with PAH (57). This phase I trial demonstrated the therapeutic potential and safety of this treatment, however further investigations are required to understand the exact mechanism of action of these cells.
Effects of MSCs on the immune system in ARDS
Modulation of the inflammatory response
Cytokine networks between immune and non-immune cells of the alveolar-capillary membrane are necessary for cellular communication during pulmonary inflammation. The subsequent events of these cellular/humoral interactions are pivotal to the initiation and propagation of the inflammatory response leading to pulmonary injury (58). Several studies demonstrate a reduction of the pro-inflammatory cytokines (IL-1α, -1β, -6, -12, -17, TNF-α, TNF-γ and IFN-γ) and an increase in the concentration of anti-inflammatory cytokines and molecules (IL-1 receptor antagonist, IL-10, cyclooxygenase-2 and PGE2) in the lung environment after MSC treatment (41,59-65). Miao et al., demonstrated that MSCs can regulate the NLRP3 inflammasome which regulates the activation of caspase-1 and a subsequent inflammatory response to infectious microbes and molecules in Kupffer cells via secretion of PGE2, leading to increased Kupffer cell production of IL-10. This ameliorated the inflammatory response and ensuing organ dysfunction (66).
Effects on neutrophil response
Upon infection, a series of chemical signals are released, which induce the activation and recruitment of neutrophils to the site of injury (67). Neutrophils kill microorganisms that cause the infection via: phagocytosis, the release of antibacterial peptides, and by creating neutrophil extracellular traps (NETs) (67). If the infection or injury is not resolved, over-stimulation of neutrophils causes the overproduction of inflammatory cytokines at the site of injury (68), thus leading to more damage than resolution (69).
Neutrophils can also migrate from inflamed tissues to other tissues and organ systems causing widespread host injury and organ dysfunction (69). NETs are structures released from neutrophils comprising a core of chromatin DNA and histones, surrounded by specific antimicrobial proteins (lactoferrin, cathepsin G, defensins, LL-37, and bacterial permeability increasing protein), proteases (neutrophil elastase, proteinase-3, and gelatinase), and reactive oxygen species-generating enzymes (myeloperoxidase) (67). However, excessive increases in the release of NETs can also cause damage to lung tissue. Pedrazza et al. demonstrated that MSC treatment enhanced survival in a LPS injury model by reducing NETs, formation (39,40). Numerous pre-clinical ARDS and sepsis studies have shown that MSCs reduce the infiltration of neutrophils to the damaged tissue (64,70) while also enhancing neutrophil-mediated phagocytosis and thus bacterial clearance (71). Németh et al. showed that PGE2 released by MSCs increases the production of IL-10, reducing neutrophil trans-endothelial migration, protecting the organ function and reducing pathogen load (64).
Effects on macrophages
Macrophages are present in almost all tissues, where they coordinate developmental, metabolic, and immunologic functions and thus contribute to the maintenance of homeostasis (72). Upon activation, macrophages develop into two broad phenotypes: M1 or pro-inflammatory macrophages are involved in initiating and sustaining inflammation in response to injury or infection and are required for bacterial killing and clearance, and M2 macrophages, involved in the clearance of dead/injured host cells and tissue repair and immune resolution (73,74). Thus, they play a pivotal role in most aspects of pathologies occurring in the lung. Research has focused on the ability of MSCs to modulate macrophage function by inducing their differentiation to different phenotypes (75,76). Studies suggest that MSCs favour the differentiation of macrophages to the M2 phenotype thus improving the resolution of inflammation and enhancing repair while MSC promotion of the M1 phenotype leads to enhanced phagocytic activity (59,77-79).
Effects on the T-cell response
Regulatory T-cells are a subpopulation of T-cells that modulate the immune system, maintaining self-antigen tolerance and preventing autoimmune disease (80). MSCs promote regulatory T-cell expansion, which causes the suppression of the proliferation of effector T-cells and dampens the immune response, potentially providing a mechanism by which MSCs may enhance ARDS resolution (80). Furthermore, MSCs can modify T-cells, dendritic cells, and natural killer cells, decreasing pro-inflammatory cytokine release and enhancing anti-inflammatory molecule release (81). These effects may be direct or may occur indirectly via effects on dendritic cells and/or other antigen presenting cells (82).
Therapeutic efficacy of MSCs in pre-clinical models of ARDS
As previously described, MSCs offer therapeutic promise for ARDS for several reasons including their immunomodulating ability, reprogramming the immune system to reduce host tissue damage while preserving the immune response to microorganisms and also their capacity to enhance tissue repair after lung injury (83). A study demonstrated that in a septic cecal ligation and puncture (CLP) murine model, MSC therapy modulates transcription of up to 13% of the genome, with immune response–related effects including; down-regulation of toll-like receptor and nuclear factor-κB (NF-κB) activation, a decrease in IL-6 signalling pathways, up-regulation of nuclear factor of activated T-cell (NFAT)-related genes, and genes involved in antigen presentation and cell-to-cell interactions which regulates endothelial integrity, increased phagocytosis and bacterial killing, decreased complement activation, and coagulation regulation including platelet activation (58,84). Furthermore, the long-term effects of MSCs are mitigated by the fact that they disappear from the tissue within days of administration.
Means by which MSCs exert effects
Cell-to-cell contact mediated effects
MSCs can migrate to the damaged lung, and without the need to engraft in the tissue, perform their antimicrobial and tissue repair functions, residing in the tissue for a limited time (85). Liu et al. demonstrated that in ALI, MSCs migrate to the lung, reducing inflammation through direct cell-cell contact (86). Specifically, MSCs showed enhanced therapeutic efficacy after pulmonary lung injury (LPS) versus extra-pulmonary lung injury (LPS/zymosan) due to greater cell recruitment to the lung (86). Islam et al. demonstrated that MSCs in the lung transfer cellular products, including mitochondria via gap junctions to epithelial cells, elevating the ATP levels and improving their function and survival (87). Recently, Jackson et al. demonstrated that MSCs conducted a transfer of mitochondria to macrophages in EVs, via cell-cell contact through tunnelling nanotubules (TnTs), which induced the transformation of these macrophages to a highly phagocytic phenotype and ameliorated E. coli-induced lung injury in vivo (88).
Soluble MSC secretome
Numerous studies have shown that MSCs exert part of their therapeutic efficacy via paracrine mechanisms through the release of an array of soluble molecules known as the 'MSC secretome'. Curley et al. demonstrated that MSC conditioned medium (MSC-CM) containing the MSC secretome attenuated injury and enhanced repair in a VILI rat model partly by a keratinocyte growth factor (KGF)-dependent mechanism (63). However, Hayes et al. demonstrated in the same animal model, that MSCs produced a better early phase recovery in blood oxygenation and respiratory compliance, and reduction in lung edema when compared to the MSC-CM (89). In another study, MSC-CM caused the down-regulation of inflammatory NF-κB signalling in the lung, which reduced the expression of Bcl-x and Mcl-1 in neutrophils and induced apoptosis of these cells in an endotoxin-induced ALI mouse model (90). In an LPS-induced ALI mouse study it was further demonstrated that MSC-CM produces an improvement in the physiology and histology of the lung (91). Furthermore, this study showed that MSC-CM can induce the differentiation of monocytes to an M2 macrophage phenotype, enhancing the anti-inflammatory and pro-healing environment in part due to the production of insulin-like growth factor (IGF-1) from MSCs (91).
MSC-derived EVs and exosomes
As mentioned previously, MSCs release EVs which incorporate cellular components including mitochondria (87), and gene products such as mRNA and microRNAs (miRNA) (92). Zhu et al. demonstrated that these EVs reduced extravascular lung water and protein levels, decreased pulmonary edema, reduced the alveolar influx of neutrophils, and decreased alveolar macrophage inflammatory protein-2 concentrations after endotoxin-induced ALI in mice (93). Monsel et al. observed that human MSC-derived EVs enhanced survival in a mouse model of E. coli pneumonia, increased ATP levels of epithelial cells, reduced bacterial load, and decreased protein and inflammatory cytokine concentrations—effects that were mediated in part by KGF secretion (92). In recent ARDS research, MSCs were shown to promote an anti-inflammatory and highly phagocytic macrophage phenotype through EV-mediated mitochondrial transfer, reducing lung damage (94,95). Song et al. showed that MSCs stimulated with IL-1β, produce exosomes with high concentration of miR-146a, an anti-inflammatory micro-RNA. This exosomal miR-146a was transferred to macrophages and resulted in M2 polarization. When these exosomes were administered to septic CLP mouse models they lead to an increased survival and were internalised by macrophages in vivo (96). These properties suggest a potential use of stem cell derived EVs for therapy in lung diseases and gives insight to the mechanism of action of MSCs in vivo.
Strategies to enhance MSC therapeutic potential for ARDS
Different methods have been employed to improve the therapeutic effect of MSCs. MSCs treated with poly (I:C), a toll-like receptor-3 ligand, inhibited micro-RNA-143 which increased MSC expression of cyclooxygenase-2, leading to increased PGE2 production and enhanced MSC effects on macrophage function in an in vivo CLP sepsis model (97). Human MSCs overexpressing soluble IL-1 receptor-like-1, the IL-33 antagonist, attenuated endotoxin-induced ALI (65). Recently, Han et al. demonstrated that MSCs transduced with the E-prostanoid 2 receptor enhanced their migration to the injured lung, decreased lung inflammation and reduced endothelial permeability (98). Cai et al. showed that overexpression of orphan receptor tyrosine kinase (ROR2) facilitates MSCs to repair lung injury, enhancing their retention in the lung, and reducing inflammation and pathological impairment (99). MSCs overexpressing the anti-inflammatory cytokine IL-10 resulted in enhanced migration and engraftment, increased wound healing and improved survival rates in a murine model of endotoxin-induced ALI (44).
Another strategy being investigated is the overexpression of proteins that may have a key function in tissue repair. Wang et al. found that human placental MSCs overexpressing platelet-derived growth factor (PDGF) receptor (PDGFR)-β exhibited greater proliferation rates, expressed higher levels of pro-angiogenic factors such as Ang1, VEGF, bFGF and PDGF, and thus enhanced wound repair (100). Overexpression of ANG-1 in MSCs was more effective than naïve MSCs in reducing endotoxin-induced alveolar inflammation and lung permeability (101). Min et al. demonstrated that MSCs overexpressing angiotensin-converting enzyme 2 (ACE2) caused an enhanced reduction in inflammation, and reduced lung edema, collagen deposition and fibrosis after bleomycin-induced lung injury in mice (36). The overexpression of other genes, such as fibroblast growth factor 2 (FGF-2) or KGF have been demonstrated to enhance MSC efficacy in attenuating endotoxin-induced lung injury (102,103).
Other studies have also aimed to improve MSC functionality or longevity; Liu Y et al. showed that inhibition of miRNA-24a enhances survival of BM-MSCs under oxidative stress (104), however the functionality of these MSCs after rescue was not ascertained. Zhang et al., demonstrated that nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transfection of human amniotic mesenchymal stem cells enhances the efficacy of these stem cells to reduce lung damage in an LPS ALI model by decreasing epithelial apoptosis and inflammatory cytokine production (43). Further to this, combination therapies have been investigated to complement and enhance the MSC effect in vivo. The use of a sphingosine 1 phosphate (S1P) analogue FTY720, previously shown to be effective in murine lung injury models (105), administered with UC-MSCs has been demonstrated to yield a better outcome than either treatment alone in terms of mortality and lung injury indices (45). While Chen et al. showed the enhanced effective protection against ARDS with peritoneal sepsis by combined administration of AD-MSCs and pre-activated disaggregated platelets (106). Other substances which may prove beneficial in combination therapy with MSCs include nebulized heparin which has been shown to inhibit coagulation and inflammatory pathways and modulate alveolar macrophages in ALI (107), or using targeting molecules such as glycogen synthase kinase 3 beta inhibitor (GSK-3β) which improves indices of lung injury and promotes the differentiation of MSCs to AT-II cells in in vivo pre-clinical ALI (108)
Progress and challenges
Clinical studies in ARD
Based on their therapeutic promise in pre-clinical studies, MSCs have entered early phase clinical testing in patients with ARDS. Zheng et al. administered allogeneic MSCs to 12 ARDS patients in an intravenous dose of 1 million cells per kilogram, or placebo in a 1:1 ratio (NCT01902082). A study by Wilson et al. included nine patients that received 1, 5, or 10 million cells per kilogram of a single intravenous dose of allogeneic human BM-MSCs, using a three-by-three dose escalation design (NCT01775774). Both studies have shown that MSCs appear to be well tolerated by ARDS patients (Table 2). Zheng et al. also measured IL-6, IL-8, and surfactant protein D levels and found that surfactant protein D concentrations were lower after MSC delivery at day 5 but that MSC administration had no effects on IL-6 or IL-8 levels. There were no significant differences in total length of hospital stay, ICU–free days, and ventilator–free days between treatment arms (Table 2) (109). Another study reported beneficial results of MSCs when administered to two patients in a compassionate use setting (110).
Full table
Barriers to clinical translation
Despite these important advances, several issues must still be investigated before MSCs can be considered as a potential "off the shelf" treatment. Robust assays of MSC batch potency for ARDS are lacking. Factors such as the stage of ARDS, type of MSCs, viability and purity of MSCs, and donor variability, are all poorly understood. The timing of MSC therapy is also relevant, with pre-clinical studies to date generally focused on early MSC delivery. A concern regarding delivery is that during intravenous administration due to the risk of MSC clumping into micro emboli, an obstruction of the pulmonary circulation could occur. The longer-term effects of MSC administration should also be considered with a concern that MSCs could potentially enhance tumorigenesis either by direct malignant transformation or indirectly by facilitating growth of tumor cells, although studies suggest that this is quite unlikely. Frozen cells are often used in studies, as this is necessary for cell transport to clinical sites. In contrast, the majority of preclinical studies use freshly harvested cells. The optimization of cryopreservation strategies for MSCs that maintain cell viability, potency, and efficacy is an important translational challenge.
Commercial production of MSC for the clinical setting
The number of patients receiving MSC based therapies is growing and this increasing demand must be managed legitimately to avoid complications in production and use. The challenges facing the successful marketing of cell therapies has been discussed in several articles (111) which highlight critical hurdles including the scalability, manufacturing and distribution concerns, navigating regulation, cost management, and indeed dealing with the complexity of the cells themselves. In addition to this, focus must be placed on patient safety with regulations needed to avoid exploitation of patients who partake in what is termed 'stem cell tourism' and regarding the unlicensed use of stem cell-based therapies (112).
For cell therapy to be viable in patients with critical illnesses, cells must be available within hours and in sufficient numbers from a reproducible production process and be available at relatively low cost. Therefore, there is a need for a strict production process which is highly regulated and licenced by an international authority, however it has been stated that due to complexities of disease states, cell types, and administration procedures, a strict repeatable, reproducible process in cell production may be unfeasible (113). A recent study was conducted to better understand the relationships between commercial and regulatory environments regarding cell-based therapies and products in Canada (114) concluding that there is a 'reverse governance process' whereby the regulatory authority relies on the scientific input of researchers and developers to develop the framework. Currently, commercially produced MSCs are manufactured to the companies own (often patented) protocols and are thus the preferred method of MSC acquisition for research rather than 'in house' production due to a reduction in variability and an availability of large quantities of cells. However, there are then concerns regarding commercial interests from company entities, the discrepancies in protocols between products, and the ability for research groups to fund and manage clinical trials without vested interests coming into play. The efficacy of MSCs in ARDS has yet to be proven in a large scale clinical trial, requiring the availability of huge quantities of clinical-grade, validated MSCs which would necessitate the involvement of a commercial process. Indeed, there are many issues that need to be addressed to aid in the progress of the development and routine use of cell therapies.
Many challenges remain before MSC therapy becomes the "go to" treatment for ARDS. Further effort is required to optimise their isolation, preparation, and administration in addition to having a better understanding of their mechanism of action. The need for a more abundant source of MSCs is apparent, with UC- and AD-derived MSCs potentially filling this need. Preclinical studies have demonstrated the abundant therapeutic potential of MSCs in ARDS, specifically their capacity to modify the inflammatory response and promote repair. Although MSC treatment seems encouraging in patients in different phase I and II clinical trials, there are still significant hurdles to overcome before these cells can be a truly viable therapy in the clinical setting. The therapeutic efficacy of MSCs can be enhanced by various methods including pre-activation and gene therapy but a complete understanding of their mechanism of action will clarify specific targets to create the most effective phenotype. In understanding the mechanism of action of MSCs, markers of cell potency can be identified, making selection and batch testing more reliable and repeatable, thus ultimately paving the way to an enhanced MSC therapy for the ARDS patient. In an ideal clinical scenario MSCs will constitute a readily available, off the shelf product, with reliable, reproducible effects, that can be tailored to the condition and patient being treated, at an affordable price. In some aspects we are not far from this reality, however some critical hurdles must be overcome to fulfil the criteria of an 'ideal medicine'.
Conflicts of Interest: The authors have no conflicts of interest to declare.
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text:
Climate law and developing countries : legal and policy challenges for the world economy /
- Author:
- Publication info:
- Cheltenham, UK ; Northampton, MA : Edward Elgar, c2009.
- Format:
- Book
Osgoode Hall Law School Library
|Call Number
On the Shelf
International environmental law and policy / by David Hunter, Professor of Law, Director, Program on International and Comparative Environmental Law, Director, International Legal Studies Program, Washington College of Law, American University; James Salzman, Donald Bren Distinguished Professor of Environmental Law, University of California, Los Angeles School of Law, University of California, Santa Barbara Bren School of Environmental Science & Management; Durwood Zaelke, President, Institute for Governance and Sustainable Development, Director, International Network for Environmental Compliance and Enforcement, Adjunct Professor of Law, Washington College of Law, American University, Co-Director, Program on Governance for Sustainable Development, University of California, Santa Barbara.
Le droit à un environnement humain : proposition pour un protocole additionnel à la Convention européenne des Droits de l'Homme : The right to a humane environment : Das Recht auf eine menschenwürdige Umwelt / par le Groupe de travail pour le Droit de l'Environnement (Bonn) ; Rapporteur : Heinhard Steiger.
- Subject:
- Subject:
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More Details
- Title:
- Climate law and developing countries : legal and policy challenges for the world economy / edited by Benjamin J. Richardson ... [et al.].
- Other Authors:
- Language:
- Published:
Cheltenham, UK ; Northampton, MA : Edward Elgar, 2009
- Series:
- Local Note:
Osgoodiana copy in original publisher's hardcover binding.
- Item Description:
Other editors: Yves Le Bouthilier, Heather McLeod-Kilmurray, Stepan Wood.
- Physical Description:
xv, 425 pages ; 24 cm.
- Bibliography:
Includes bibliographical references and index.
Table of Contents
- Introduction: climate law and developing countries / Benjamin J. Richardson, Yves Le Bouthillier, Heather McLeod-Kilmurray and Stepan Wood
- . Climate change, differentiated responsibilities and state responsibility: devising novel legal strategies for damage caused by climate change / Sumudu Atapattu
- India?s constitutional challenge: a less visible climate change catastrophe / Deepa Badrinarayana
- Promoting justice within the international legal system: prospects for climate refugees / Angela Williams
- Climate change and indigenous peoples in the South Pacific: the need for regional and local strategies / Eric Kwa
- . Supporting adaptation in developing countries at the national and global levels / Jolene Lin
- . Designing a REDD mechanism: The TDERM triptych / Claire Stockwell, William Hare and Kirsten Macey
- The role of marine ?forests? and soils as carbon sinks: enhanced bio-sequestration as a mitigation strategy to help avoid dangerous climate change / Robert Fowler
- Adaptation to climate change to save biodiversity: lessons learned from African and European experiences / Saja Erens, Jonathan Verschuuren and Kees Bastmeijer
- The deadlock of the clean development mechanism: caught between sustainability, environmental integrity and economic efficiency / Christina Voigt
- Beautifying Africa for the clean development mechanism: legal and institutional issues considered / Damilola S. Olawuyi
- Policy and legal dimensions of CDM projects in the forestry sector: implications for climate change mitigation and adaptation in Uganda / Emmanuel B. Kasimbazi
- Brazilian policy on biodiesels: a sound means of mitigating climate change? / Solange Teles da Silva and Carolina Dutra
- Improving citizen responsibility in the North and its consequences for the South: voluntary carbon offsets and government involvement / Marjan Peeters
- Climate and trade in a divided world: can measures adopted in the North end up shaping climate change legislative frameworks in the South? / Francesco Sindico
- Climate change in the European Union development cooperation policy / Marie-Pierre Lanfranchi and Sandrine Maljean-Dubois.