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Austerity is a policy that aims to transfer resources away from the most disadvantaged and undermine social justice.
Why I Wrote Second Class Citizens
Stef Benstead found that many people, like Christian Conservatives, care about poverty but have false beliefs about why it exists, this inspired her to write Second Class…
Influences and Consequences
In the conclusion to the Preventable Harm Project Mo Stewart shows how US companies and right-wing ideology have savaged the lives of disabled people.
Canaries in the Coal Mine
Newcastle Council for Voluntary Service (NCVS) share their 2019 report on the state of the voluntary, community and social enterprise sector in Gateshead and Newcastle.
Crippled by Austerity
Simon Duffy reviews Frances Ryan's important book which describes the devastating impact of the UK Government's attack on disabled people since 2010.
Shameful Attack on Disabled People
Brian Collinge explains how the government's failure to update the Minimum Income Guarantee (MIG) for people entitled to social care acts as another form of theft.
Austerity's Victims
One million adults with a learning disability in the UK who have suffered because of government measures since 2010.
Cumulative Impact Assessment (CIA)
A statement from the Centre for the #WOWdebate on the Government's reasons for refusing to carry out a Cumulative Impact Assessment (CIA).
The Injustice of Benefit Sanctions
The welfare system has become punitive, even more bureaucratic and humiliating. It delivers pain instead of support and disregards people's basic needs.
US Corporate Influence on UK Welfare Reforms
Mo Stewart has been researching the damage caused by welfare reform and the malign influence of US private insurance companies.
Mental Health and Tentacled Snowballs
An anonymous article describing how medical and bureaucratic approaches to mental health undermine flexible and person-centred solutions - and make you a little crazy.
GaN Canny 2018
Over 168 voluntary and community organisations from Gateshead and Newcastle responded to a survey by Newcastle CVS on austerity and the voluntary sector.
Extreme Poverty in a Time of Austerity
This summary of the harm caused by the UK Government's austerity policies was submitted to the UN Special Rapporteur on Extreme Poverty and Human Rights.
Does Money Make You Mean?
In this TEDx film, Paul Piff shares his research into how people behave when they feel wealthy.
What is the alternative to neoliberalism?
Simon Duffy reflects on the intellectual and practical challenge facing thinkers opposed to the current neoliberal consensus.
Why Northamptonshire Went Bust
Simon Duffy explains why Northamptonshire went bust and what kind of thinking is required to return local government to its proper role.
A Constitution for Disability Rights
Claudia Gilberg, Geoff Jones and Gavin Barker explain why disability rights activists have every reason to support the campaign for constitutional reform.
How to Fund the NHS and Public Services
Gavin Barker summarises the arguments for Modern Monetary Theory and explains why government does not need to be bound by the limitations of tax.
Letters to the DWP
Correspondence between Mo Stewart, the independent disability researcher, and officials at the DWP, reveals the difficulty of holding a bureaucracy to account.
Workers' Rights Versus the Right to Care
Alain Catzeflis describes how UK social policy has created a severe, but unnecessary conflict between the rights of workers and disabled people.
Behind Relative Poverty
The stories in Relative Poverty address the imbalance of power; Les Monaghan describes the thinking behind his photographs.
A Grounded Theory Study of Disability Benefit Changes
Jessica Saffer carried out doctoral research into the psychological impact of Government changes to the disability benefit system - welfare reform.
Government Cuts are Slowly Killing Me
Lorraine Howard describes how the closure of the ILF and cuts in social care in Coventry are slowly killing her.
Deleted BBC News Item on Unum
In 2007 the BBC reported on the influence that a US insurance company was having on UK policy, in 2010 this item was deleted from BBC archives.
Don't Crowd Out People with Learning Disabilities
Alain Catzeflis argues that people with disabilities are being harmed by bad Government policy and people with learning disabilities are doubly excluded.


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Roman Serra
Profile  |  Artworks  |  Exhibitions  |  Network  |  Blog  |  Comments
Quick Facts
Detroit, MI
Birth year
Works in
Representing galleries
Hopefully You
gallery, non-profit, studio-lofts, Association, collective, arts-education mixed-media, landscape, modern, traditional, photography, figurative, sculpture, exhibition/performance
I want to make images that are full of energy. Abstraction has always interested me. I believe the psychologies of aesthetics do not rely on subjectivity but there still must be a relation present between the image and the natural world. My breath technique is something that I have found to mimic nature without getting to specific. I strive to make super-natural images.
Exhibited with these artists
Roman Serra has Exhibited with these artists:
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Roman Serra has Exhibited at these venues:
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Call Honey Do's of Holton, KS when you need a portable bathroom facility. Whether it's for your next special event, a park, or a construction site, we have the unit you need!
ADA Handicap accessible units
Commercial use
Hand wash stations available
Industrial use
Modern features
Residential use
Traditional units
We have what you need - from traditional units to our new exclusive pink units. Our new units are specifically designed for women with no urinals and more room for you to move around.
Whether you need a pickup or delivery of a portable toilet, or pumping of your septic unit, you can rely on Honey Do's to get the job done quickly and efficiently.
Daily, weekly, and monthly rentals.
Competitively priced portable toilets
for any occasion.


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Fastest Banking Options for New Zealand Players
For a lot of players in New Zealand, and around the world, choosing how to bank and manage their online casino funds is as important a decision as choosing where to play in the first place. In the world of cybercrime, where identity theft and fraud are unfortunate realities, this is understandable.
You need to know that your money and personal information is protected, so that you have the peace of mind you need to focus properly on winning your games. And the actual processes involved in the banking method you decide on needs to be simple and to work for your situation. Among the fastest and most popular options at New Zealand's mobile casinos are e-wallets, such as PayPal, Skrill and Neteller, eChecks and prepaid vouchers like Paysafecard.
Launched almost 20 years ago and having gone through a few changes as a company, PayPal is considered the granddaddy of e-wallets, the one who blazed the trails for the others to follow. These days PayPal is available in a huge range of currencies and can be used to transfer casino funds very quickly and easily.
Like any e-wallet, PayPal acts as an intermediary step as you are transferring funds between accounts. This can be between a bank account and a casino account, 2 different online casino accounts, your bank account and someone else's bank account, or your bank account and the account of another vendor.
You can set up your PayPal account or other e-wallet account by going to the company website and doing it online. No background checks are required and all you need is a valid bank account and e-mail address, so the system is open to everyone.
You'll move money between your e-wallet and your bank account on your bank account's website, and between your e-wallet and your online casino account on the cashier interface. Money clears into your PayPal account within a few hours and usually into other accounts from the e-wallet within 3 to 4 working days. It can take longer for the first few transfers until your security clearance is proven.
Skrill was previously called Moneybookers, so you might still see it listed as such at your chosen mobile casino. It works very similarly to PayPal and funds take 2 to 5 working days to clear. Its standout feature is its rewarding 4-level loyalty system which earns you points whenever you use your account. These add up and unlock great special perks.
The Neteller e-wallet also works very much like PayPal does. What sets this system apart and makes it such a favourite is that it is particularly security-conscious and transparent; you can even read the 1998 Data Protection Act on its website. Funds can take up to 6 working days to clear with Neteller, though it often happens much faster.
One of the things people appreciate about e-wallets is that none of your personal information is shared with the casino and thus your anonymity is assured. Prepaid voucher systems like Paysafecard are even more so. You can buy them from offline vendors or the Paysafecard website and receive a unique PIN number.
Following the prompts on your online casino's banking interface, you can transfer all or some of your Paysafecard funds. Your money is available immediately, there are no background checks to using Paysafecard and there is a fantastic Loyalty Programme. The only drawback is that you cannot use this system to cash out and make withdrawals.
Where prepaid vouchers and e-wallets are quite anonymous, electronic cheques, or eChecks, are not. They work in the same way that ordinary cheques do and you can make deposits and get withdrawals with them from online casinos. You need to enter in all your banking details and the eChecks can take up to 2 weeks to clear. The big attraction with this system is that all the established security practices of your bank are in place.


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There are multiple options to connect production signals from your machines to Evocon. The most common way is a new industrial sensor. You can also use a sensor that is already available on your production line or machine. Another standard method is to use a PLC output connection using a relay (e.g. with Andon lights). These signals connect to Evocon's device that sends the captured data to our cloud server in AWS.
If you have machines that already collect production data to a local database, then we can set up Evocon without using any additional hardware (data transfer is via HTTPS API requests).
You can read more about this in our post "How to get production signals from machines?".
If you are unsure what connection to use, contact our support and we will help sort everything out for you.


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The Knowledge and Practice of Christianity Made Easy to the Meanest Capacities: Or, An Essay Towards an Instruction for the Indians ... In Twenty Dialogues. Together with Directions and Prayers ...
Printed; and sold by D. Dod, in Ave-Mary lane, bookseller to the Society for promoting Christian knowledge., 1759 - 300 páginas
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acknowlege Amen amongst Apostles assured Baptism believe beseech Thee Blesled Blessing cern Chri Christian Religion Church Commands convinced corrupt Creatures Death desire Divine Duty Earth endeavour eternal everlasting evil Spirits fafe Faith fame Father fave Favour Fear forget forgive forsake give Glory God's Gospel Grace gracious Happiness hath Heart Heathens Heaven Holy Ghost Holy Spirit Honour honour and obey hope Idolatry instruct Jesus Christ John xvii keep Knowlege known Labours lastly ligion live Lives End Lord's Lord's Prayer Lord's Supper Maker mand Mankind mean Mercy Miff Mijs Mind Misery Nature ness never Number obey offend ourselves Pardon Person Power pray Prayer promised punish Reason receive Redeemer remember Repentance Sacrament Salvation Saviour shew Sinners Sins Society Souls stians suffer sure Temptations Thanks thine Things Thou told true Truth unto wicked wonderful Word World worship
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Página 279 - LORD, our heavenly ,Father, Almighty > and everlasting God, who hast safely brought us to the beginning of this day ; De(fend us in the same with thy mighty power ; and grant » that this day we fall into no ,sin, neither run into ,any kind of danger ; but » that all our doings may be ordered by ,thy governance, to do always » that > is ,righteous in thy sight ; through Jesus ,Christ > our Lord.
Página 116 - Charge them that are rich in this world, that they be not highminded, nor trust in uncertain riches, but in the living God, who giveth us richly all things to enjoy; That they do good, that they be rich in good works, ready to distribute, willing to communicate; Laying up in store for themselves a good foundation against the time to come, that they may lay hold on eternal life.
Página 174 - Thou shalt not covet thy neighbour's house, thou shalt not covet thy neighbour's wife, nor his servant, nor his maid, nor his ox, nor his ass, nor any thing that is his.
Página 60 - Scriptures, they may learn, that in the beginning he made of one blood all nations of men, to dwell upon all the face of the earth ; and, that we all descended of one father and mother.
Página 38 - Christ, who at thy first coming didst send thy messenger to prepare thy way before thee ; Grant that the ministers and stewards of thy mysteries may likewise so prepare and make ready thy way, by turning the hearts of the disobedient to the wisdom of the just, that at thy second coming to judge the world we may be found an acceptable people in thy sight, who livest and reignest with the Father and the Holy Spirit, ever one God, world without end. Amen.
Página 185 - My duty towards my neighbour is to love him as myself, and to do to all men as I would they should do unto me ; to love, honour, and succour my father and mother; to honour and obey the king, and all that are put in authority under him...
Página 280 - THE grace of our Lord Jefus Chrift, and the love of God, and the fellowfhip of the Holy Ghoft be with us all evermore.
Página 277 - Lord hath brought us safe to the beginning of this day; let us therefore give thanks for this, and for all His mercies. Let us pray that we may live in the fear of God, and continue in love and charity with our neighbours. That His Holy Spirit may direct and rule our hearts, teaching us what we ought to do, and what to avoid.
Página 97 - LORD, we beseech thee mercifully to hear us; and grant that we, to whom thou hast given an hearty desire to pray, may, by thy mighty aid, be defended and comforted in all dangers and adversities, through JESUS CHRIST our Lord.
Página 59 - Grant that we may in fuch wife hear them, read, mark, learn, and inwardly digeft them, that by patience, and comfort of Thy holy Word, we may embrace, and ever hold faft the blefled hope of everlafting life, which Thou haft given us in our Saviour Jefus Chrift.


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During our interview, Wes discussed a powerful idea he had instituted at Citrix to ensure strong alignment and tight integration between the company's global marketing and sales departments. The idea was to create a single "playbook" that both the marketing and sales teams could use to formulate joint strategies, guide their activities, and drive increased revenue at Citrix.
Here are some excerpts from my interview with Wes about the marketing/sales playbook he has been using so effectively at Citrix.
Phil Fernandez: Wes, what was the genesis of your playbook idea?
Wes Wasson: My core philosophy from early on has been to think of sales and marketing in the context of a single demand chain, an integrated process. It starts with a belief that this really is a single chain. So, in thinking about the recipe for success with this integrated approach—and this was long before technology innovations started really changing things in our profession—the key was to have a common way to measure sales and marketing success. What that means is that success on the front end of the chain is a hundred percent irrelevant if the end of the chain doesn't deliver the finished product.
Think of a scenario like this: The marketing team at the front end of a bottling plant is celebrating and cheering and giving high-fives because it exceeded its quota in creating bottle caps and labels. Meanwhile, gallons of beer have been spilling onto the middle of ...
No credit card required


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2018 October: Siberian Lecture
Lecture by SVETLANA PANKOVA on one of the truly unique collections of The State Hermitage Museum!
Visiting curator from The State Hermitage Museum
Monday, 29 October 2018: 7 pm
Something you will never see anywhere else but in the Hermitage - the unique Siberian collections, with material from burials dating from the 4th to 3rd centuries BCE!!!
Svetlana Pankova is a Senior Research Fellow and Curator of the Siberian Collections at The State Hermitage Museum and is currently making a detailed study and re-evaluation of the Siberian burials of the 4th to 3rd centuries BCE. She will speak about her research and the latest findings.
In 1902 a shepherd accidentally fell into a tomb at a place called Oglakhty in the present-day Khakasia region of southern Siberia. Excavations quickly followed and revealed a series of subterranean tombs built like small log-cabins. Some contained spectacularly preserved organic materials, including fur coats, wooden bowls, Chinese silks and spectacular painted plaster masks adhering to the faces of the mummified dead. Next to the bodies were life-size mannequins made from grass, wrapped in leather and dressed in human clothes. The dating of the cemetery has been controversial, ranging from the first century BCE onwards, and the interpretation of the finds has also given rise to much discussion.


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About This Trip
This trip is for ages 18+
This trip supports Grace Churchs Outreach Partner ALARM, African Leadership & Reconciliation Ministries. This team will join the WLTI (Womens Leadership & Training Institute) team for their final conference and graduation ceremonies. This team will join the WLTI Facilitator's mid-week to provide a family conference including relationship health in marriages, how to support and integrate singles, and a children's camp. In addition, the team will offer a vision clinic to the WLTI participants families. The team will participate in the WLTI Graduation ceremonies, visit the Genocide memorial and spend time with the ALARM Rwanda staff visiting with other friends and components of ALARM, such as IWE (the girl's secondary school), a micro-finance coop, and the coffee plantation, a component peace, justice & reconciliation work.
Still have questions? Check out our short-term trip FAQs.


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Today brings a review of Trollbeads Limited Edition Pastel Agates. There is very little information available surrounding this mini release (which also included Ocean Jasper), with no official advertising of it from Trollbeads.
As far as I am aware, there are just two retailers in Denmark (Perlen and Diamonds4ever) and one retailer in the UK (Trollbeads Heaven) who will be receiving some of these beads. Three retailers in the US (including Trollbeads NYC and Trollbeads at South Park) are said to be receiving some of the Ocean Jasper, but I am unsure as to whether they will also receive the Pastel Agates.
Thanks to Perlen (Denmark), I was lucky enough to secure a beautiful pink, blue and green version of the Pastel Agates. They had individually photographed the beads which beautifully showed the detail, so I was lucky enough to get in early and choose the ones that I wanted. Later that day, I had another look on there site and there was only a couple remaining, which is a testimony as to how fast these beads have sold out.
These are dyed stones, however this does not detract from their beauty. As you will see from the individual photographs below, the subtle semi-opaque pattern within the stone gives them a soft appearance, even though the base colour of the stones are quite strong, and not what I would class as 'pastel'.
Worn together, they give a beautiful rainbow effect. I have put them with the Faceted Aurora beads from last year's 'Stories of You' release, which embrace the 'rainbow' theme and give a somewhat magical look.
I wish I had also invested in one of the yellow and purple versions now as I like these so much!
This is a release that I am so pleased I managed to add to my collection. I will review the Ocean Jasper separately in my next post!


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Made Up provided 'total production' for the most innovative and energising live music tour of the last year, Jax Jones' House Work.
The approach set a new benchmark for dance music live performance, with surprising and inspiring details requiring impeccable standards of realisation.
Made Up built unusual, bespoke versions of party staples such as streamers and balloons. The stage set and floor brought to life Jax Jones' distinctive 'psychedelic grocery' images.
Dancers and MCs wielded CO2 and T-shirt guns crafter especially for the occasion.
It takes a lot of time, effort and professionalism to fabricate spontaneous, creative chaos!
Technical crew and other staffing
Bespoke balloons, flags, streamers and other FX
Unique projectile delivery vectors


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Paying Countries for Carbon Protects Forests, but Only if Payments Continue
climate mitigation. Under the Norway-Guyana REDD+ agreement signed in 2009, if deforestation rates ... prediction of deforestation rates without the REDD+ payments is called the "counterfactual," By ... quantifying the actual deforestation rates, measured from satellite imagery, and deforestation rates in the ...
Frequently Asked Questions
equals the higher of the market year average price (MYA) or the national average loan rate for the ... yields in certain counties. Payment rates for ARC will be calculated for irrigated and non-irrigated in ... irrigated and non-irrigated acres is applied to the associated payment rates to create a blended rate. For ...
CD Wire- November 4, 2019
the organization, which enables you to join at a reduced rate (using your funds) of $190. If you are ... membership rate. If you have any questions, please let me know. Congratulations I want to congratulate Gwynn ... proposal quality and competitiveness with the goal of increasing award success rates. Take advantage of ...
Ohio Agricultural Loan Delinquencies Have Stabilized in 2019
has been a slight uptick in delinquency rates, but they remain under 2%, which is a significant ... benchmark as delinquency rates remained above 2% for several years following the 2008 Farm Financial Crisis. ... The average delinquency rate for Ohio farm production loans for the recent 12 months was 1.06%, while ...
Taking Measure of Ohio's Opioid Crisis
per capita, a rate that continues to rise, overwhelming families, communities, and local governments ... growth and low economic mobility had higher drug overdose death rates. We also find that overdose deaths ... were strongly linked to educational attainment. In 2015, the drug overdose rate for those in Ohio with ...
CD Wire- October 21, 2019
with the goal of increasing award success rates. The GDSU offers blue, pink, red, and gold level ...
Middle Eastern Economic Development
exports, foreign debt and exchange rate policy. Prereq: 2001 (200) or Econ 2001 (200). Not open to students ...
Kenzie Johnston
publications Videos Forage Files (eFields Report page 170,171) Phosphorus Rate (eFields Report page 84,85) ... Files Phosphorus Rate Nitrogen Source Starter Fertilizer Nitrogen Timing Soybean Guys Delaware County ...
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programs, particular items of costs, OMB circulars, F&A rates and bases, and benefit rates. Register ... illness Ohio State News: Suicide rates climbing, especially in rural America © 2019, OSU Extension ...


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To the editor:
I first met Gerald Coppenrath in 2008. Unemployment had run out and I needed help. I faced eviction. Mr. Coppenrath got me a Chapter 115 veterans' benefit check to get set up in other living quarters.
I was working four part-time jobs. He had them adjust my 115 check with the hours from the jobs.
I had hard times again, with transportation problems, jobs lost, health issues. Still, Mr. Coppenrath was there to help.
There have been food baskets from the Veterans Outreach program, rides to appointments and being there during tough times.
So whenever he calls on me to help volunteer, I'm there. Whether it's putting up flags at the cemetery or delivering baskets to shut-ins. I'm amazed the selectmen are unaware of his efforts. He has assisted me in every turn of the road. He goes above and beyond. I'm proud to have him as a friend and veterans' service office.
I'm angry and disgusted at how these people are treating him. Maybe somebody selectmen knew wanted Mr. Coppenrath's job.
I have been coming into the veterans office since I was in the fifth grade. There was a full-time veterans officer and a full-time secretary. Over the years, I know cutbacks have been made. Now, it seems one person has to do the work of two.
The things involved in running the veterans' office have to be staggering. I couldn't imagine some of these so-called professionals doing it. It's a tremendous asset to the town having someone like Mr. Coppenrath in the veterans' office.
DL Tagg


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Open Access This article is
- freely available
- re-usable
Int. J. Mol. Sci. 2017, 18(9), 1849; https://doi.org/10.3390/ijms18091849
Activation of Matrix Hyaluronan-Mediated CD44 Signaling, Epigenetic Regulation and Chemoresistance in Head and Neck Cancer Stem Cells
San Francisco Veterans Affairs Medical Center and Department of Medicine, University of California at San Francisco & Endocrine Unit (111N2), 4150 Clement Street, San Francisco, CA 94121, USA
Author to whom correspondence should be addressed.
Received: 11 July 2017 / Accepted: 22 August 2017 / Published: 24 August 2017
Head and neck squamous cell carcinoma (HNSCC) is a solid tumor composed by a genotypically and phenotypically heterogeneous population of neoplastic cells types. High recurrence rate and regional metastases lead to major morbidity and mortality. Recently, many studies have focused on cellular and molecular mechanisms of tumor progression that can help to predict prognosis and to choose the best therapeutic approach for HNSCC patients. Hyaluronan (HA), an important glycosaminoglycan component of the extracellular matrix (ECM), and its major cell surface receptor, CD44, have been suggested to be important cellular mediators influencing tumor progression and treatment resistance in head and neck cancer. HNSCC contains a small subpopulation of cells that exhibit a hallmark of CD44-expressing cancer stem cell (CSC) properties with self-renewal, multipotency, and a unique potential for tumor initiation. HA has been shown to stimulate a variety of CSC functions including self-renewal, clone formation and differentiation. This review article will present current evidence for the existence of a unique small population of CD44v3highALDHhigh-expressing CSCs in HNSCC. A special focus will be placed on the role of HA/CD44-induced oncogenic signaling and histone methyltransferase, DOT1L activities in regulating histone modifications (via epigenetic changes) and miRNA activation. Many of these events are essential for the CSC properties such as Nanog/Oct4/Sox2 expression, spheroid/clone formation, self-renewal, tumor cell migration/invasion, survival and chemotherapeutic drug resistance in HA-activated head and neck cancer. These newly-discovered HA/CD44-mediated oncogenic signaling pathways delineate unique tumor dynamics with implications for defining the drivers of HNSCC progression processes. Most importantly, the important knowledge obtained from HA/CD44-regulated CSC signaling and functional activation could provide new information regarding the design of novel drug targets to overcome current therapeutic drug resistance which will have significant treatment implications for head and neck cancer patients.
Keywords:cancer stem cells (CSCs); hyaluronan (HA); CD44; miR-10b; DOT1L; epigenetic regulation; HNSCC
1. Hyaluronan (HA) Metabolism in Head and Neck Cancer Progression
Head and Neck Squamous cell carcinoma (HNSCC) is an aggressive malignant neoplasm associated with major morbidity and mortality. The three-year survival rate for patients with advanced-stage HNSCC who are treated with standard therapy is only 30% to 50% [1,2,3,4]. Resistance to standard therapy continues to be a limiting factor in the treatment of HNSCC. Nearly 40% to 60% of patients with HNSCC subsequently develop locoregional recurrences or distant metastases [1,2,3,4]. Presently, very little information is available regarding the cellular and molecular mechanisms involved in regulating HNSCC cell signaling and chemotherapeutic responses.
Hyaluronan (HA), one of the major extracellular matrix (ECM) components, is known to contain repeating disaccharides units, d-glucuronic acid and N-acetyl-d-glucosamine (Figure 1) [5,6]. It is often accumulated at tumor cell–matrix attachment sites and is closely associated with tumorigenesis and metastasis [5,6]. HA synthesis or production is regulated by at least three mammalian HA synthase isozymes including HAS1 (HA synthase 1), HAS2 (HA synthase 2) and HAS3 (HA synthase 3) [7,8,9,10]. All three HAS genes are located on different chromosomes. Structurally, all three HAS isozymes appear to share a great deal of sequence homology [11,12,13]. Both HAS1 and HAS2 synthesize large-size of HA (~1 × 106–1 × 107 Da) [11,12] which are known to be important for cell proliferation, angiogenesis and development [13]. HAS3 synthesizes small-size HA (~1 × 105 Da) [11,12] which appears to contribute to many malignant behaviors of many different cell types [11,12]. HAS2 has been shown to express in head and neck cell lines [14]. Downregulation of HAS2 expression resulted in an inhibition of tumor cell growth and migration as well as an enhancement of cisplatin sensitivity, suggesting the importance of tumor cell HA production to promote in vitro tumor progression behaviors in oral cancer cells [14]. Overexpression of HAS2 in oral cavity carcinoma clinical specimens was also correlated with poor clinicopathologic characteristics and worse disease-free survival [14]. These observations strongly support the contention that HAS expression is closely associated with HNSCC progression. Thus, differential HAS expression/activities and unique HA-size production could selectively influence oncogenic signaling pathways and malignant properties leading to tumor progression.
Large-size HA polymers can be digested or degraded into smaller-sized HA fragments by acid-active hyaluronidases [15] (Figure 1). Overexpression of hyaluronidases has been associated with solid tumor metastases [16]. Presently, at least six hyaluronidase-like gene sequence products (e.g., Hyal-1, Hyal-2, Hyal-3, Hyal-4, PHYAL-1, and PH20 (or Spam1)) have been reported [17]. For example, the genes of Hyal-1 and Hyal-2 (the major hyaluronidases in human somatic tissues) are detected as tight clusters on chromosome 3p21.3. Hyal-1 is enriched in head and neck cancer [18]. Hyal-2 initially cleaves high-molecular-weight (HMW) large-size HA into ~20 kDa fragments, which are further digested into smaller size fragments by Hyal-1 [19,20]. Interestingly, low-molecular-weight (LMW) HA or small HA fragments, rather than high-molecular-weight (HMW) large HA, have been suggested to be essential for cancer progression in terms of invasion and metastasis [21]. Hyal-3 expression is detected in fibroblasts when they are undergone chondrocyte differentiation [17,22]. Hyal-4 could be a chondroitinase and PHYAL-1, a pseudogene appears to be untranslated in humans [23]. PH20 (or Spam1) belongs to a neutral-active hyaluronidase and is detected primarily in testes and in a variety of cancers including HNSCC tumors [18,24,25]. Most importantly, the unique HA-enriched microenvironment appears to serve as a stem cell niche and participates in cellular signaling and a variety of normal and cancer stem cell CSC)-specific functions [26,27].
2. CD44 (a HA Receptor) in Cancer Stem Cells (CSCs) and Tumor Progression
CD44, a family of transmembrane glycoproteins is expressed in a variety of cells and tissues including head and neck cells and HNSCC tissues [28,29,30,31]. The presence of high levels of CD44 variant (CD44v) isoforms is emerging as an important metastatic tumor marker in many cancers including head and neck cancer [28,29,30,31]. CD44 gene is known to undergo alternative splicing mechanisms and produces a variety of CD44 isoforms including CD44s, CD44v3, CD44v6, etc. [32,33] (Figure 2A). Mack and Gires showed that both CD44s and CD44v6 can be detected in 60–95% and 50–80%, respectively, of normal epithelia, whereas, in moderately differentiated carcinoma, the level of CD44s and CD44v6 only increase slightly [34]. Since CD44s and CD44v6 fail to distinguish normal from benign or malignant epithelia, these two CD44 isoforms cannot be used as reliable tumor markers for monitoring HNSCC progression. In contrast, CD44v3 can be detected in lymph metastasis and is closely involved in promoting metastasis and head and neck cancer progression [28,29,30,31]. The v3 exon (but not other variants) product of the CD44 molecule is unique, being the only exon that has a heparin sulfate (HS) assembly site (33). These v3 exon-containing variants carrying HS side chains bind and present heparin-binding growth factors and cytokines, such as FGF and heparin-binding epidermal growth factor (EGF), which may generate various functional consequences. These findings suggest that different CD44 isoforms may participate in distinct biological activities.
It has been well documented that all CD44 isoforms contain HA-binding domain located at the N-terminal region of the extracellular domain [35] (Figure 2A). The binding of CD44 isoforms to hyaluronan affects cell adhesion to extracellular matrix components and is implicated in the stimulation of aggregation, proliferation, migration, and angiogenesis [28,29,30,31,36]. The intracellular domain of CD44 isoforms (e.g., CD44v3) selectively interacts with cytoplasmic regulators (e.g., oncogenic molecules and cytoskeletal proteins) and effectively transmits cellular signaling [28,29,30,31,37,38,39,40]. Therefore, CD44 isoforms likely provide a close linkage between matrix components (HA) and cytoplasmic regulators (Figure 2B). Recent studies have shown that CD44 is also detected in tumor stem cells which have the unique ability to initiate tumor cell-specific properties [41]. In fact, CD44 is proposed to be one of the important surface markers for cancer stem cells [41]. Both CD44v isoforms and HA are overexpressed at sites of tumor attachment [42].
Accumulating evidence indicates that most tumors contain special subpopulations of cells, which appear to be highly tumorigenic and are involved in tumor progression. These "Cancer Stem Cells (CSCs)" or "Tumor-Initiating Cells (TICs)" share several common properties of normal stem cells [43,44]. However, some CSCs have altered their ability to regulate normal stem cell numbers, pluripotency, and lineage-dependent differentiation [43,44]. CSCs frequently undergo cell division/growth and/or clone formation and differentiation to expand the stem cell population [43,44]. They are also capable of generating self-renewal, maintaining quiescence, and displaying multipotentiality [43,44]. Consequently, CSC-derived tumor cells often display a variety of properties which are different from the parental tumor cells. These studies suggest that tumor formation could be a result of a variety of CSCS signaling modifications and/or functional alterations. Furthermore, CSCs have been shown to be chemoresistant and are possibly responsible for cancer relapse.
Head and neck cancer (HNSCC) tumors contain a subpopulation of CD44shigh-expressing CSCs which can generate phenotypically distinct cells [45]. When these CSCs were injected into immuno-deficient mice, the formation of heterogeneous tumors was observed [45]. These observations suggest that CD44shigh-expressing CSCs may exhibit stem cell-like properties (e.g., self-renewal, clone formation and differentiation) which are responsible for the generation of heterogeneous tumor cell populations. In fact, CD44s has been widely used as one of the most important stem cell surface markers in several studies [41,45]. Aldehyde dehydrogenase-1 (ALDH1), a detoxifying enzyme for intracellular aldehyde oxidation, has also been considered as a stem cell marker in both normal tissues and human HNSCC [46,47]. Recently, several studies indicate that overexpression of both CD44 variant isoform (CD44v3) and ALDH1 correlates well with tumor formation and HNSCC progression [28,29,30,31,46,47]. Specifically, a subpopulation characterized by overexpression of both CD44v3 and ALDH1 (so-called CD44v3highALDH1high cells) was isolated using anti-CD44v3 antibody plus ALDH1-specific reagent and FACS-fluorescence-activated cell sorter [48,49,50] (Figure 3A). Injection of CD44v3highALDH1high-expressing cells into NOD/SCID mice generated phenotypically distinct cells in heterogeneous tumors [48,49,50]. Most importantly, a high efficiency of tumor formation was detected by injecting as few as ~50 CD44v3highALDH1high cells (but not CD44v3lowALDH11ow cells or unsorted cells) into NOD/SCID mice [48,49,50]. These findings suggest that the high level of tumorigenic effect induced by CD44v3highALDH1high cells (but not CD44v3lowALDH11ow cells or unsorted cells) may be caused by unique tumor initiation properties of these subpopulations of HNSCC cells [48].
3. Hyaluronan–CD44 Interaction Stimulates Stem Cell Marker Expression, Stemness Properties and Chemoresistance in CD44v3highALDH1high Head and Neck Cancer Stem Cells (CSCs)
One of the common properties of CD44v3highALDH1high CSCs isolated from HNSCC is the upregulation of cancer stem cell markers (e.g., Nanog, Sox2 and Oct4) which are known to function as transcriptional factors [48,49,50]. These three regulatory factors often form a combinational complex to stimulate specific genes targeting for the expression of stem cell properties including proliferation, self-renewal, and differentiation [51]. Overexpression of Nanog/Sox2/Oct4 has also been closely correlated with higher histological grades and poorer clinical survival in head and neck cancer [48,52,53,54,55,56]. Nanog is an important transcription factor that renders the reprogramming adult stems into germ-line-competent induced pluripotent stem (iPS) cells [57]. It is expressed not only in germ cell tumors, but also in many other tumors including HNSCC cells and tissues [48,53]. In HNSCC, high expression of Nanog has been shown to be associated with advanced cancer stages and HNSCC progression [48,53,55,56]. Sox2 (Sex determining region Y-box (2)) is known to be involved in the maintenance of embryonic stem cell pluripotency and in multiple developmental processes [53,58,59,60]. Due to the weak DNA binding ability, Sox2 often forms complexes with other transcription factors [58]. Increasing numbers of studies regarding the association between SOX2 and malignant tumors (e.g., head and neck cancer) have been reported [59,60]. Overexpression of SOX2 is associated with lymph node metastasis in oral cancer [54]. Another stem cell marker, Oct4 is known to act as an important transcriptional factor which binds to an octameric sequence motif containing the AGTCAAAT consensus sequence to cause both the onset and maintenance of pluripotency during embryonic development [61]. Oct4 also interacts with other stem cell markers, such as Nanog and Sox2, by forming a large regulatory complexes or networks that stimulate pluripotency and/or block differentiation [58,62]. Moreover, stem cell profiling in head and neck cancer reveals an Oct-4 expressing subpopulation with properties of chemoresistance [63]. Most importantly, the expression of stem cell markers such as Nanog, Sox2 and Oct4 is closely associated with HNSCC patient's prognosis, pathological stages, cancer recurrence and therapy resistance [55,56]. Therefore, searching for new cancer stem cell targets or designing drugs to manipulate the known molecular targets in CSCs could be useful for improvements in clinical outcomes of the disease.
It has been reported that self-renewal, proliferation and differentiation regulated by Nanog/Sox2/Oct4 are the hallmark of stem cell properties that allow CSCs to produce both new cancer stem cells and phenotypically diverse cancer cells with different proliferative potential [43,44]. All three stem cell markers (i.e., Nanog, Oct4 and Sox2) have been shown to be upregulated (Figure 3B) and can be recruited into the CD44v3-associated membranes during HA-mediated signaling in these head and neck CSCs [48,49] (Figure 3E). Recent studies also indicate that HA binding to CD44 induces upregulation of Nanog, Sox2 and Oct4 expression and activates a variety of important target genes such as miR-302 and miR-21 in CD44v3highALDH1high head and neck CSCs and breast tumor cells, respectively [48,64,65] (Figure 3E). Most importantly, HA-mediated CD44 signaling promotes spheroid (Figure 3C) and clone formation (Figure 3D), as well as cell growth/self-renewal properties of CD44v3highALDH1high head and neck CSCs [48,49]. These findings strongly suggest that HA–CD44 interaction is tightly linked to the onset of stem cell marker (Nanog/Sox2/Oct4) expression and the subsequent stem cell functions in CSCs isolated from HNSCC.
Head and neck cancer treatment commonly involves the use of cisplatin-related chemotherapeutic drugs. HNSCC tumor resistance to chemotherapy is often caused by the presence of anti-apoptotic regulators [31,66]. IAP family (e.g., cIAP-1, cIAP-2 and XIAP) appears to play an important role in suppressing apoptosis and promoting oncogenesis [66]. IAPs not only block the activities of several caspases and pro-caspases such as caspase-3 and caspase-7 [67], but also prevent anti-cancer drug-induced tumor cell death [67]. Even though some attention has been paid to the involvement of other anti-apoptotic proteins (e.g., Bcl-xL) in anti-apoptosis and chemoresistance of breast tumor cells in the presence of HA [68], recently, there is a significant interest of investigating a possible role of IAPs in HA-treated HNSCC tumor resistance [69]. Recent results show that there is a significant elevation of IAP protein (e.g., cIAP-1, cIAP-2 and XIAP) expression in CD44v3highALDH1high head and neck CSCs following HA treatment [48,49,50]. Upon treatment of cisplatin, these CSCs show a reduction in apoptosis and cell death (possibly due to an increase of IAP production and tumor cell survival) and a significant increase in cisplatin-resistance [48,49,50] (Figure 3E). Taken together, these findings strongly suggest that HA–CD44 interaction plays an important role in promoting Nanog/Oct4/Sox2 upregulation, stemness properties, tumorigenesis and chemoresistance in CD44v3highALDH1high head and neck CSCs, which are important contributors to HNSCC progression. Another cell surface marker is the single-chain sialoglycoprotein CD24, which is also associated with cancer stem cell characteristics in colorectal and pancreatic cancer, while head and neck cancer cells and breast cancer cells with CD44+CD24−/low expression are highly tumorigenic [70,71,72]. However, the question of whether HA displays any effect on CD44+CD24−/low cancer stem cells is presently unknown.
4. Hyaluronan (HA) Promote miRNA-10b Expression, Tumor Cell Invasion and Chemoresistance in Head and Neck Cancer Stem Cells (CSCs)
It has been well-documented that cytoskeleton functions are directly involved in tumor cell invasion of surrounding tissue, and metastasis [73]. During the search for cellular regulators that are involved in controlling cytoskeleton function and cell migration/invasion in HNSCC, certain microRNAs (miRNAs) (~22 nucleotides) known to function as RNA interference for gene regulation [74] were identified. Alterations of miRNAs are often associated with the pathogenesis of HNSCC [75]. Several previous studies demonstrated that certain oncogenic microRNAs promote the cell functions of CD44v3highALDH1high (CSC-like) subpopulation isolated from HNSCC (HSC-3) [48,49,50]. However, the information regarding the regulation of miRNA production by matrix component(s) in head and neck cancer CSCs is very limited.
One general concept that has emerged from recent studies is that HA fragments (small vs. mid-size HAs) and their larger precursor molecules (i.e., intact HA) may be involved in regulating distinct biological activities including miRNAs [48,49,50,76,77]. For example, the generation of different sizes of HA fragments from large/intact HA in the ECM occurs during periods of cell growth, migration, differentiation and development as well as injury-related repairs [9,10]. Several studies indicate that there is a selective activation of transcriptional activation and differentiation by large HA fragments, but not small HA fragments. Other cellular functions such as cell proliferation and migration appear to be preferentially regulated by small-size HA fragments, but not large-size HA. [49,76,77]. Recently, a panel of stem cell-related miRNAs including miR-10b, miR-27b, miR-373, miR-181, miR-34a and miRNA-145 has been shown to be preferentially up-regulated by 200 kDa-HA in head and neck CSCs [49]. In contrast, the other sizes of HA (e.g., 5 kDa-HA, 20 kDa-HA and 700 kDa-HA) fail to induce stem cell-specific miRNA production in the CD44v3highALDH1high (CSC-like) subpopulation from HNSCC cells [49]. Most noticeably, miR-10 has been shown to undergo the highest level of stimulation by 200 kDa-HA in CSCs isolated from HNSCC [49]. In a previous study, miRNA-10b was found to be overexpressed in malignant glioma in addition to the overexpression of RhoC and uPAR which are contributors to glioma invasion and migration [78]. Most importantly, 200 kDa-HA/CD44-activated miR-10b production also plays an important role in upregulating the cytoskeleton regulator, RhoC and CSC migration/invasion [49,50]. Treatment of CSCs with an anti-miR-10 inhibitor significantly decreases RhoC expression and blocks CSC migration/invasion [49,50]. These findings suggest that miR-10 is closely involved in regulating cytoskeleton function required for CSC migration/invasion and the miR-10b inhibitor may be considered as a promising new anti-cancer agent.
Treatment of head and neck cancer CSCs with 200 kDa-HA also causes cisplatin resistance [49]. Survival proteins such as Inhibitors of Apoptosis Proteins (IAPs) are frequently upregulated in CSCs following HA treatment [48,49,50]. Importantly, high levels of IAPs in CSCs increase cell survival due to the binding of IAPs to caspases and the suppression of apoptosis [48,49,50]. A recent study indicates that the expression of IAPs such as c-IAP-1 significantly increased in CD44v3highALDH1high head and neck cancer CSCs treated with 200 kDa-HA [49]. There is only a relatively low level of c-IAP-1 expression detected with other sizes of HAs (e.g., 5 kDa-HA, 20 kDa-HA or no HA treatment) [49]. These findings clearly indicate that the survival proteins such as c-IAP-1 is up-regulated in the CSC subpopulation isolated from HNSCC cells following 200 kDa-HA treatment. Further analyses show that the addition of 200 kDa-HA in CSCs not only significantly increases miR-10b expression, but also greatly decreases the ability of cisplatin to induce tumor cell death [49]. These observations strongly suggest that 200 kDa-HA causes both a decrease in tumor cell death and an increase in tumor cell survival leading to the enhancement of chemoresistance [49]. Moreover, downregulation of miR-10b using anti-miR-10b inhibitor significantly reduces the survival and increases cisplatin sensitivity in 200 kDa-treated CSCs [49]. These findings clearly suggest that downregulation of the 200 kDa-HA-induced miR-10 b function (by anti-miR-10 b treatment) may represent a new target for therapeutic agents designed to cause head and neck cancer CSCs to undergo cell death and remain chemotherapy sensitive.
5. HA–CD44 Interaction Promotes Histone Methyltransferase, DOT1L Expression and Epigenetic Modification in Head and Neck Cancer Stem Cells
Epigenetic changes such as histone methylation have emerged as one of the important regulatory processes in the chromatin structural modifications and the gene expression alterations during cancer progression [79]. Methylation of histone H3 at lysine 79 (H3K79) is highly conserved among most eukaryotic species. In budding yeast, nearly 90% of histone H3 displays either monomethylation (H3K79me1), dimethylation (H3K79me2) or trimethylation (H3K79me3) at lysine 79, all catalyzed exclusively by the histone methyltransferase, DOT1 [80,81]. In Saccharomyces cerevisiae, DOT1 was initially identified as a disruptor of telomeric silencing. The orthologs of DOT1 appear to be evolutionarily conserved from yeast to mammals [80,81]. Both DOT1 and the mammalian DOT1L (DOT1-like protein) function as H3K79 methyltransferases in the regulation of histone H3K79 methylation and transcriptional activation [82]. Specifically, DOT1/DOT1L-mediated H3K79 methylation is known to be involved in the control of transcriptional activity required for cell cycle, meiotic checkpoint and the DNA damage checkpoint [83]. An earlier study indicated that mammalian DOT1L participates in proliferation and differentiation in embryonic stem (ES) cells [84]. It has also been reported that aberrant H3K79 methylation by DOT1L occurs in Mixed Lineage Leukemia (MLL) [85]. Treatment of MLL-rearranged leukemia with EPZ00477 or EPZ-5676 (potent and selective amino nucleoside inhibitors of DOT1L histone methyltransferase activity) causes cell death in acute leukemia lines bearing MLL translocations [86,87]. Furthermore, downregulation of H3K79 methyltransferase, DOT1L, using specific DOT1LsiRNA also reduced proliferation of lung cancer cells [88]. These findings indicate that H3K79 methyltransferase, DOT1L, plays an important role in promoting cancer formation.
A recent study indicates that histone methyltransferase, DOT1L can be upregulated by HA in CD44v3highALDH1high head and neck CSCs [50]. Previously, tumor invasion and migration-associated miR-10b has been shown to contain several predicted E-box elements at its upstream promoter region [89]. DOT1L-activated H3K79 methylation appears to be directly involved in the binding of the E-box elements at the miR-10b promoter leading to miR-10b gene expression and production in head and neck cancer CSCs treated with HA [50]. Further analyses indicate that the stimulation of microRNA-10b (miR-10b) expression is DOT1L-specific and HA/CD44-dependent in CD44v3highALDH1high CSCs. This process subsequently results in the overexpression of RhoGTPases and survival proteins leading to tumor cell invasion and cisplatin resistance. These findings suggest that HA/CD44-activated miR-10 production plays an important role in upregulating the cytoskeleton regulator, RhoC in CSC-like cells. Most importantly, we found that downregulation of HA-activated DOT1L signaling or miR-10b production by treating CSCs with DOT1L siRNA or anti-miR-10b inhibitor, respectively, not only reduces RhoGTPase (RhoC) expression and impairs tumor cell migration/invasion but also enhances chemosensitivity [50]. These observations clearly establish a causal link between DOT1L/H3K79 methylation and miR-10b function including cytoskeleton-regulated CSC invasion and chemoresistance in HA-treated CSCs. Taken together, these findings strongly support the contention that histone methyltransferase, DOT1L-associated epigenetic changes induced by HA play pivotal roles in miR-10 production leading to upregulation of RhoGTPase and survival proteins. These events are critically important for the acquisition of cancer stem cell properties including tumor cell invasion and chemotherapy resistance in HA/CD44-activated CD44v3highALDH1high head and neck cancer CSCs (Figure 4).
6. Conclusions
This review has placed a special focus on the properties of a unique subpopulation of HNSCC cells (i.e., CD44v3highALDH1high), which displays CSC characteristics with high tumorigenic potential and chemoresistance. These CD44v3highALDH1high-expressing CSCs appear to be closely involved in the pathobiology of head and neck squamous cell carcinomas. Most importantly, matrix hyaluronan (HA) interaction with CD44v3 plays a pivotal role in regulating stem cell marker expression, stemness properties (e.g., spheroid formation, clone formation, self-renewal, differentiation) and chemoresistance in these head and neck cancer stem cells. Moreover, histone methyltransferase, DOT1L/H3K79 methylation-associated epigenetic changes induced by matrix HA has been shown to directly regulate miR-10 production leading to up-regulation of RhoGTPase and survival proteins as well as migration/invasion and chemoresistance in CD44v3highALDH1high-expressing CSCs. In the future, cancer stem cell-based signaling perturbation therapies may be developed to downregulate stem cell transcription factors and/or histone methyltransferase, DOT1L (using Nanog/Oct4/Sox2/DOT1L-specific siRNA and shRNA vector approaches or DOT1L inhibitors) and/or to silence miR-10b (using anti-miR-10b inhibitor) for blocking HA/CD44v3-mediated Nanog/Oct4/Sox2 signaling and DOT1L/miR-10b expression/function as well as chemoresistance and HNSCC progression. Taken together, these recently discovered matrix hyaluronan (HA)/CD44v3-mediated signaling pathways and DOT1L-specific epigenetic regulation in head and neck CSCs could provide unique molecular targets and specific therapeutic drugs for the treatment of head and neck cancer.
This work was supported by Veterans Affairs (VA) Merit Review Awards (RR & D-1I01 RX000601 and BLR & D-5I01 BX000628) and United States Public Health grants (R01 CA66163). Lilly Y. W. Bourguignon is a VA Senior Research Career Scientist.
Author Contributions
Lilly Y. W. Bourguignon wrote the paper. Lilly Y. W. Bourguignon, Christine Earle and Marisa Shiina contributed to the data presentation of the manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
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Figure 2. Illustration of CD44 gene and alternative spliced variants (e.g., CD44v3 and CD44v6 isoforms) which contain several structural domains including external domain, transmembrane (TM) and intracellular domain (A); and demonstration of CD44v3 protein which displays the HA binding domain at the external N-terminal region and the signaling regulator binding sites at the cytoplasmic domain (B).
Figure 3. Characterization of cancer stem cell-like population from tumor-derived HNSCC (HSC-3 cells). (A) Flow cytometry analyses of HSC-3 tumor cell populations: Specifically, HSC-3 cells were stained with both allophycocyanin (APC)-labeled anti-CD44v3 antibody (recognizing the v3-specific domain of CD44) and ALDEFLUOR (measuring an ALDH1 enzymatic activity) followed by processing through multicolor fluorescence-activated cell sorter (FACS) and cell sorting. (Top right quad represents CD44v3highALDH1high cells (15%); Top left quad represents CD44v3highALDH1low cells (7%); Bottom right quad represents CD44v3lowALDH1high cells (2%); and Bottom left quad represents CD44v3lowALDH1low cells (76%). A FACS-fluorescence-activated cell sorter was then used to isolate CD44v3highALDH1high cells or CD44v3lowALDH1low cells for the study; (B) detection of stem cell markers Nanog, Oct4 and Sox2 in CD44v3highALDH1high cells (treated with no HA or with HA) using immunoblot analyses. (C) Sphere formation of CD44v3highALDH1high cells in: the absence of HA; or the presence of HA. (D) Clone formation of CD44v3highALDH1high cells in: the absence of HA; or the presence of HA. (E) A proposed HA-induced CD44v3 signaling in CD44v3highALDH1high cells. The binding of HA to CD44v3-expressing CSCs promotes Nanog/Oct4/Sox2 association with CD44v3 first followed by Nanog/Oct4/Sox2 translocation to the promoter sites of target genes. Subsequently, Nanog/Oct4/Sox2-specific target genes (e.g., miR-302 and miR-21) are expressed leading to stemness properties (e.g., sphere formation, self-renewal, cell proliferation, survival and chenoresistance) and tumor progression.
Figure 4. A summary for DOT1L-H3K79 methylation signaling in influencing miRNA-10 gene expression and production as well as Cancer Stem Cell (CSC) functions in HA-treated CD44v3highALDH1high cells. The binding of HA (Step 1) to CD44v3-expressing CSCs enhances DOT1L upregulation (Step 2) and DOT1L/H3K79 methylation-mediated epigenetic changes (Step 2), resulting in methyl-H3K79 binding to miR-10b promoter (Step 3), and miR-10b gene expression/production (Step 4). The expressed miR-10b then promotes upregulation of RhoC (cytoskeleton activator) and CSC-mediated invasion (Step 5). Moreover, miR-10b also induces survival protein, IAP (cIAP-1/cIAP-2 and XIAP) expression, HNSCC cell anti-apoptosis/survival and chemoresistance (Step 6). Red dot represents DOT1L/H3K79-mediated histone modifications (via epigenetic changes). Taken together, these findings suggest that targeting HA-mediated DOT1L/H3K79 methylation pathways and miR-10b function may provide a new drug target to sensitize cancer stem cell apoptosis/death and overcome cisplatin resistance in CSC-derived HNSCC cells.
© 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).


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...and maybe one goal.
A season that started on October 7, 2010 is ending, finally on June 15, 2011...that's a long time for hockey. It's pretty much summer now, even in Canada. But we're still playing (and cheering wildly for) a winter sport.
Regardless of the outcome of tonight's game, I am glad to see this craziness come to an end. It's been two months of elevated heart rates and blood pressure, gnawed off finger nails, ground down teeth, queasy tummies, late-night horns honking, lack of concentration and focus craziness.
Don't get me wrong, it's been spectacular! But I'm ready for normal (and hoping that normal now includes a Stanley Cup for the Vancouver Canucks). My daughter is ready for regular bedtimes - they have been few and far between since the playoffs started because we live on a major street and jubilant fans walk by cheering and drive by honking their horns. I learned early on not to fight this and now J hangs out at her window or sometimes on the deck and yells GoCanucksGo to them.
I am certain employers will be glad to have productive employees back...the early game times haven't affected me much because I start early and leave early to pick J up at daycare, but I know lots of people who have been leaving work half an hour to two hours early, pretty much every other day since April. That's a lot of missed time to make up...
And days like today, well, I know my mind keeps flitting back to questions of what will happen tonight...what if...what if not...
Seventeen years ago I was seventeen. I had been away at boarding school for the first part of the playoffs in a state where hockey isn't really followed. But my dorm mother graciously allowed me and the other lone hockey fan (who was cheering for Chicago...we made a deal, as long as our teams weren't playing each other, we'd cheer together) to watch our beloved teams in her apartment on her tv during study hall. I came home in time for the last two series. Our house was full of yelling, cheering, screaming people. I was at my friend Michelle's the night of game 7. It was heart wrenching, then heartbreaking, then devastating [I know, I know, first world problems] but we recovered. And the Canucks recovered. And seventeen years later, here we are again. It's not the same team, but it is the same team.
And so, I am leaving my desk now. Yes. Early. Yes, I'm blogging from work. Yes, my boss told me to leave over half an hour ago. [I didn't...I have to wait for J to wake up from her nap at daycare] I'm going home to cheer loudly for the Canucks with J and with AndreaClaire who is here to cheer all the way from Victoria. And we might venture into the party zone. And hopefully we'll have lots to be excited about. And tonight, tonight I hope the noise and honking and cheering lasts well into the wee hours of tomorrow. And I hope there is a parade for us to go to later this week.
So, boys in blue and green, please:
Play hard
Play safe
Play clean
Win it for the ones you've lost through these series and the late season - Samuelsson, Hamhuis, Rome, Raymond. Win it for the seventh man on the ice - Bourdon. Win it for the fans who have cheered for you since before they really understood the game. Win it for the fans who jumped on the bandwagon, drawn by the excitement and insanity of the playoffs. Win it for the guys of 1982 and the guys of 1994. Win it for yourselves. And your families. And your friends. Heck, just go out there and win it! I believe!
And fans, please:
Cheer hard
Cheer loud
Cheer long and late (or is it early)
Cheer respectfully
Ignore the Boston trolls and welcome the more respectful Boston fans [but let them know we're going to win]
Have fun
And please, please, please, no matter the outcome of the game, don't ruin our city or all the good feelings that have piled up and grown through this playoff run.


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4 Ways Men Can Take On More Emotional Labor In Relationships (And Why They Should Do It) Whether it's romantic, sexual, platonic, or professional, emotions will always play a large part in how successful or unsuccessful any relationship ends up.
Relationships, by definition, require two or more parties to put forth some amount of emotional effort in order to keep the relationship afloat. Oftentimes one person takes on the brunt of the emotions—especially the negative or stressful emotions—that are produced in their relationships. Wonder Woman is Your Zionist, White Feminist Hero. "I am sending my love and prayers to my fellow Israeli citizens, especially to all the boys and girls who are risking their lives protecting my country against the horrific acts conducted by Hamas, who are hiding like cowards behind women and children…We shall overcome!!!
#weareright (Image: screenshot from Facebook) The assault in question was widely condemned and took place between July 8 through Aug. 27. More than 2,100 Palestinians were killed along the Gaza strip along with 66 Israeli soldiers, and seven civilians in Israel. The majority of the Palestinian deaths were civilians including 495 children and 253 women. But this isn't new, Israel maintains a brutal grip on Palestinians and their daily lives. A feminist glossary because we didn't all major in gender studies. We've broken down some words you should know when discussing feminism or other gender topics.
USA TODAY. The "Day Without A Woman" Strike Details Are Out, And Here Are 3 Ways To Participate. After the Women's Marches across the country and the world last month, many wondered what the next step would be in the resistance.
In early February, the organizers of the Women's March announced they would stand with the grassroots organizers putting together a one-day strike on March 8, 2017 called "A Day Without A Woman. " Although we've known about the date for a little over a week now, few details were available about the strike itself. On Thursday, though, the Women's March organizers announced the "Day Without A Woman" strike details. There are three fairly simple ways to get involved and make an impact, so read on for how you can participate in the strike. The date of the "Day Without A Woman" strike coincides with another important event: International Women's Day — which is no coincidence. The Women's March website suggests three ways to participate in the strike: Reflecting on one very, very strange year at Uber — Susan J. Fowler. Nova Scotia town's tiny Women's March a big deal online. On Saturday in a tiny Nova Scotian town, 12 women, a toddler and two men took to the street with posters, instruments and high spirits to walk in solidarity with the millions marching for women's rights in the United States and around the world.
Jan. 21 dawned misty and chilly in Sandy Cove, a town of 65 perched on Digby Neck peninsula in Nova Scotia. The group took off from the town's 22-student school and ended up at the fire station, about a mile away. 7 real actions you can take after the Women's March and 1 you shouldn't. Sexist men have psychological problems. (BigStock) Psychologists looking at 10 years of data from nearly 20,000 men found that those who value having power over women and endorse playboy behavior and other traditional notions of masculinity are more likely to suffer from psychological problems — and less likely to seek out help.
Turns out that cultural norms that hurt half of a society's members aren't too good for the other half, either. Who'd have thunk it? The new meta-analysis, which was published Monday in the Journal of Counseling Psychology, synthesized 78 studies on masculinity and mental health gathered between 2003 and 2013. The participants ranged in age from 12 to over 65, and the vast majority were men.
In general, the men who stuck more strongly to these norms were more likely to experience problems such as depression, stress, body image issues, substance abuse and negative social functioning. [Sexism in science: Peer editor tells female researchers their study needs a male author] Lead author Y. Yes Men, All Women Really Have Been Taught to Politely Tolerate Your Bullsh*t. Yes Men, All Women Really Have Been Taught to Politely Tolerate Your Bullsh*t By Courtney Enlow | Think Pieces | September 27, 2016 | Comments (660 View.
Gossip as an act of resistance. When we talk about women and gossip, we must speak, first, about the bathroom stall.
Brown University, 1990. A list springs up on campus.
Division of Labour. Beware These 10 Types of Feminist Men. Trying to Avoid Burnout and Still Help Others? How Intersectionality Is the Key. Panel 1 (Woman #1 is carrying a basket labelled Feminist Activism, which is filled with "activism pieces," which are different blocks and shapes that are labelled with things like "pamphlets," "101 education," "organizing protests," "writing blog posts," "research," "awareness protests," "ignoring trolls," and "writing anti-harassment policies.")
Voice-over: Sometimes it feels like feminism asks a lot from us. A men's centre at Simon Fraser University raises questions - Canada. Against sexist Olympic advertising. The Olympics started as an über-macho, male-only competition in ancient Greece.
While a lot has changed since then, women are still facing sexism when it comes to the Games. Much of the hype surrounding the 2012 Summer Games in London (which kick off Friday, July 27th ed.'s note: look for our coverage!) Has centered on the achievements of female athletes. The Olympics have been very empowering for women: the U.S. is sending its first ever female-majority team to the games, tennis pro Maria Sharapova is going to be Russia's first female athlete to carry her country's Olympic flag, women's boxing is being allowed for the first time, and—in the biggest news since women were first allowed to compete in 1900—for the first time ever, every single country in the Games is sending women to compete.
At the 2008 Bejing summer Olympics, Saudi Arabia, Qatar, and Brunei were the only three countries in the world that did not send female athletes to the Games. Beach Volleyball Q.R. ESPN's "Body Issue" 14 Badass Historical Women To Name Your Daughters After. Not language but a map — just shut up. Opposing Ontario's New Sex Ed Curriculum is Not Only Stupid, It's Dangerous to Children. A demonstrator holds up a sign while gathering in front of Queen's Park to protest against Ontario's new sex education curriculum in Toronto on Tuesday, February 24, 2015. Photo courtesy Canadian Press/Darren Calabrese A group of Ontario parents is protesting the province's new sex-ed curriculum.
"Our children, our choice," they chant, in what comes off as a chilling parody of the feminist war cry "Our bodies our choice! " These parents, seemingly, are outraged that their children will be learning about consent, different sexual orientations beyond heterosexuality, oral and anal sex, and the proper names for their penises and vaginas. Thousands of parents are keeping their kids out of school this week. Looking for Proof of Male Privilege in Your Daily Life? Here Are 7 Undeniable Examples. How to Compliment Women without Objectifying Them. Editor's Note: This article is focused on the problematic ways that men are socialized to approach women they find attractive.
These men may be straight, bisexual, pansexual, or queer and may be cis or trans. Ah, the stereotypical man-to-women come on attempt. Boy sees girl. Boy finds girl attractive. Boy approaches girl and attempts to get into her pants by telling her how sexy she looks in her lime green halter top and skinny jeans, and how if she sleeps with him, he'll treat her to a breakfast in bed consisting of homemade Eggs Benedict with a side of Cajun sausage and juice made from freshly-squeezed oranges. Girl finds boy creepy and tells him to f*ck off.
Pop culture. Appearance. Economic/career/opportunity. CND politics. Health. Gender equity team. Assault/violence. Slut shaming/society. Pics/videos. Not actually funny. Satire/laughs.
Young Feminists Blogging, Organizing, Kicking Ass. Where have all the radicals gone? When feminism gets moderate. | April 15, 2011 Where have all the Radicals gone? When feminism gets moderate.mp3. How the West uses women's rights as an excuse for military intervention.


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Mind in London is the largest Third Sector service delivery network across London.
The network is made up of local Mind charities run by local people, for local people. Together we provide over 200 different services each year to meet the needs of more than 34,000 people of all ages across the capital. We involve over 1,300 volunteers, extending our reach and impact. We empower those who use our services, their carers, supporters and neighbourhoods, promoting positive social action and challenging the stigma and discrimination all too often associated with mental health problems.
For details of what Mind is doing in your borough click on the map. Please note the boroughs shaded in blue do not have a local Mind association situated within them. However, some local Mind associations provide services to neighbouring boroughs. To find out more, please email us below.
To find out more about Mind in London please contact: firstname.lastname@example.com.
For general information about Mind please visit: www.mind.org.uk.


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With a powerful V6 engine, a comfortable ride, and a features galore, the new 2017 GMC Terrain promises top-notch performance and an appealing performance. Some of the defining 2017 fetes include an adjustable backseat, a comfortable highway ride, an agile V6 ride, and spacious cabin. Its release date should be expected mid this year.
For 2017, buyers should look forward to new safety features which include but not limited to lane departure control, a blind-spot monitoring, and hill assist. Also, we should expect better styling on its rear and front as well as updated daytime running lights.
This year marks the seventh year for this truck and will undoubtedly mark yet another successful year for this small-to-midsize crossover class. The Terrain still stands out from the rest of the group through its unique square shouldered body and larger-than-average body style. However, newer and more powerful models threaten it some ways.
To its credit, the new GMC Terrain still offers some of the best features and appealing qualities that have defined its long existence in its segment. However not everything is a bed of roses for the Terrain. Some of the vehicle's shortcomings include an unavailable Bluetooth audio control, less cargo space than its formidable rivals, a sluggish four-cylinder engine, unintuitive touchscreen interface, and less impressive EPA fuel economy ratings.
Available Trims – GMC Terrain
The 2017 Terrain is available in a walloping five trims: base SL, mid-trims SLE-1, SLE-2, and SLT, and the top-of-the-line Denali trim.
Exterior Colors & Interior Reviews – 2017 GMC Terrain
The redesigned 2017 GMC Terrain SL trim comes standard with full-power accessories, a height-adjustable steering wheel, an auto-dimming rearview camera, cruise control, 17" alloy wheels, a 60/40-split folding rear seat, a reclining and sliding functions, a telescopic-and-tilt steering wheel, a power-adjustable steering wheel, Bluetooth audio and phone connectivity, USB port, six-speaker sound system, a 7" touchscreen interface, and an auxiliary audio jack.
Next up is the SLE-1 trim that tacks on several feature packages, an all-wheel-drive powertrain, a rear carpeted floor mat, satellite radio, and heated exterior mirrors.
Building upon what the above trim comes with is the SLE-2 trim that comes equipped with a Pioneer eight-speaker sound system, LED daytime running lights, voice command functionality, an eight-speaker sound system, smartphone app integration, Bluetooth audio and phone connectivity, a leather-wrapped steering wheel, automatic climate control, heated front seats, an eight-way power driver seat, and exterior heated mirrors.
The SLT comes equipped with a rear parking sensors, chrome exterior accents, heated front seat, leather upholstery, and remote engine start. Additionally, the Driver Alert package is available for both the SLE-2 and SLT trims. The package come bundled with an adjustable power liftgate, forward collision warning, rear-cross traffic alert, and a blind-spot monitoring.
The top-of-the-line 2017 GMC Terrain Denali tacks everything the SLT trim comes with plus a navigation system, unique 19" wheels, Denali-specific comfort-oriented suspension set-up, and lots of packages.
Engine Specs – 2017 GMC Terrain
Offered as the standard engine is a 2.4L four-cylinder engine rated at 182 horsepower and 172 pounds of torque. Also, an optional 3.6L engine is available for the SLE-2, SLT, and Denali trims. It is rated at 301 horsepower and 272 pounds of torque.
Both engines come standard with a front wheel drive, as is the six-speed automatic transmission system.
EPA fuel economy ratings for the front wheel drive, four-cylinder engine stand at 22/32/26 mpg in the city/highway/combined, and 20/29/23 mpg for the 4WD.
During our won test drive, the FWD sprinted from 0-60 mph in 9.1 seconds. An AWD V6-equipped Denali trim dashed the same distance but clocked 7.0 seconds.
When properly equipped, a four-cylinder-equipped Terrain comes with a maximum towing capacity of 1,500 pounds. The V6 tows up to 3,500 pounds.
Safety wise, some of the standard features include front-seat side-impact, traction and stability control, antilock disc brakes, side-curtain airbags, and automatic crash notification.
Price & 2017 GMC Terrain Release Date
Expect to pay an MSRP starting from $23,975 for the 2017 GMC Terrain SUV. As for its release date, expect the new Terrain mid this year, according to reliable information from our sources privy of GMC's operations.
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Company Details
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Pattern: Can Be Customized
Packaging: carton with foam
Brand: ShengRong
Transportation: Ocean,Land
Place of Origin: China
Certificate: ISO9001
Port: ShenZhen
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