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You know those FAMOUS Dole Whip treats that EVERYONE is talking about? The go to place for these coveted Dole Whips is Magic Kingdom's Aloha Isle. Located in Adventureland and sponsored by Dole, you can find chocolate, vanilla, and pineapple soft serve ice cream served in many different concoctions (all near and dear to the hearts of Disney fanatics everywhere). You can also get chips and pineapple slices here.
Many people make a stop at the Magic Kingdom JUST to get a Dole Whip! Why? Because you can't find anything like them anywhere else. Aloha Isle is on the Disney Dining Plan, and will be a snack credit. It's in a great location-you can take a seat in the shade and people watch while you enjoy your Dole Whip. You can check out their full menu HERE.
Overall, we give Aloha Isle an "A".
Thank you for visiting Chip and Co. Be sure to sign up for our Daily Newsletter where we deliver the best in Disney News & Planning Tips to your inbox! You can find us all over the internet at Twitter, Facebook, Instagram, Pinterest, and even our Tee Public Store!


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Innovation in Engineering
At Pentland Precision we are always looking to diversify the business, product innovation is where we thrive and this is highlighted by a project underway with Tornado Storage Systems for a more effective innovative warehousing process.
Pentland Precision continue to build our product innovation services by moving into new business sectors as shown by our work with the SRUC on the award winning 'GreenCow Project' to develop a world-class livestock greenhouse gas (GHG) emission research facility using respirometer chambers to measure methane output from cattle or sheep.
Our engineering innovation skills were utilised in the multi-million (£) construction of Heathrow Terminal 5 to supply specialist, complex, metalwork required in the prestigious new hub for BA.
We deliver a range of services, including:

subset: commoncrawl


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Sold Out
The Pool: Architecture, Culture and Identity in Australia
This companion publication to the Australian Exhibition at the Venice Architecture Biennale considers the pool in Australian life and architecture through the reminiscences and anecdotes of many: from children to teachers, swimmers to onlookers, architects to their clients. Eight prominent Australians have also shared their stories: Shane Gould, Ian Thorpe, Anna Funder, Christos Tsiolkas, Paul Kelly, Tim Flannery, Romance was Born and Hetti Perkins. In Australia, the pool takes many forms. In the bush, a waterhole, a dam, a billabong; on the coast, a concreted cavity gouged from the rocks over which the surf spills and crashes. Around the country, old-time municipal baths have steeply decked seating and supervisory signs about diving and running. In the suburbs, millions of tame blue rectangles adorn the back yards, as if plucked from the wild blue ocean. Mysterious and familiar, tame and wild, natural and man-made: a pool is where the communal and the personal intersect. The pool is revealed in these accounts as a vital force in Australian life, not only as the setting for formative childhood memories, but also as the stage for impressive sporting feats that fuel the nation's pride. A backdrop to many significant events in our communities, it is also a deeply contested space in the history of Australia, that has highlighted racial discrimination and social disadvantage. With a foreword by Margo Neale, Indigenous art curator and academic.
ed. Amelia Holliday, Isabelle Toland and Michelle Tabet
Australian Institute of Architects
192 pages. 112 colour illustrations.
21 x 21 cm
Our 1803 deer handle cheese knife has a small cleaver style blade. It is good to use with your befores. Hard cheese, soft cheese, salumi, charcuteries, that sort of thing. Hand forged for 1803 by the Canberra Cutlery Collective – a group of mates who...
$30.00 - Sold Out
Back in 1803 the first deer were introduced to Australia. The name of this range comes from that date, because in a way that's when their story began. Penny and her family have been sustainably and ethically farming red deer on rolling pastures near Orange,...
Challenge your friends and family to test their knowledge of 80's music with this fun quiz. Whether you're a Madonna fan, love Wham! or prefer Duran Duran, you'll be digging out your old mix-tapes by the end of the game. This gorgeous retro box contains...
How well do you remember the 90's? With a host of music questions spanning the decade you'll have fun casting your mind back to artists like the Spice Girls, Nirvana and huge hits such as MMMbop. This gorgeous gift box contains 140 question cards to...


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The Labor Ministry of Uzbekistan held a meeting with Japanese delegation comprised of representatives of Japanese Association «Chuo Sangyo Shinko», "Three Concier Co., Ltd.", social security corporation "Kinunokai", "Medical Brain Co., Ltd." corporation of social welfare "Wolf Аrden" and "PRIEM".
The meeting discussed issues of recruitment and involvement of citizens in institutions of social support of large Japanese companies, opening of Centre for training human resources to Japan in Ferghana region, and the signing of the Memorandum between the Agency for external labor migration and Japanese companies to attract citizens of Uzbekistan for implementation of labor activities in Japan.
Labor Minister A. Abduxakimov stressed that Uzbekistan and Japan set a dialogue based on trust, openness and mutual respect, which contributes to the deepening of cooperation.
Labor Minister in detail briefed the guests about the activities of the Ministry, development and potential of the labor market of Uzbekistan, the similarity in mentality between the two peoples, including the desire to expand your skills and experience.
In turn, the Japanese side expressed gratitude for the organization of this meeting. The guests briefed the Uzbek side about the demand in labor market of Japan.
Today in Japan there is a demand for medical specialists, and until November 2017, they are ready to admit 35 citizens of Uzbekistan to social welfare institutions, while by the end of this year – some 1 thousand.


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Versus to Reveal Hot Timepiece Trends at WWD Magic Show Las Vegas August 18-20 - Yahoo Finance
Surely the book will focus on the selfies that helped encapsulate big events from the life of Kim, Kanye and North in the last few years. With that in mind, heres our picks for seven selfies that must be in Selfish. 1. Pregnant Kim selfie No surrogacy rumors hereKim happily shows off her baby tirai jendela dari plastik bekas bump! Kims online pregnancy was a crucial step in the narrative that surrounded her romance with Kanye. It was the first sign that she was serious about this relationship.
"When buyers want to know what's next in timepieces for fashionistas, they come to Versus," she says. "They are conceived for the man and woman with style and taste who want to make a statement." The Versus Globe collection for men stands out by going against the grain. While watch diameters have been sizing down lately, the Globe watches defiantly announce themselves with a 50 mm diameter that transcends trend. The dial layout resembles a chronograph with its three subdials but like a plucky sibling who likes to be clever, the subdials are actually a day, date and 24-hour counter.


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Annual Fund 2016-2017
There's Nothing "New" about Their Commitment to GSL!
Suzanne and Erick New are all about GSL. Their two sons Garner (6th grade) and Gregory (4th grade) have kept these Midtowners actively involved at the school for nearly a decade. In fact, if you have attended an Anchor Auction in recent years, then you've seen the creative contributions of Erick, co-owner and director of operations of Garden District, a business that takes him all over the world. Suzanne, an alumna of Ole Miss with a graduate degree from the University of Memphis, keeps busy using at least two different skill sets: she teaches English as a Second Language (ESL) for Shelby County Schools, and she is also a stylist at Stella & Dot, jewelry and accessories. In addition to these interests, both Suzanne and Erick are fully engaged members of Grace-St. Luke's Episcopal Church.
What's not-so-new about the New family is their tireless commitment to GSL and the Annual Fund. Despite their diverse and busy schedules, they have always generously and enthusiastically found time to show their support of the school. Now they are stepping up to the plate again to lead the GSL community through another important fundraising campaign. They know first-hand that anyone - and everyone - can Make a Difference in the strength and success of GSL. Thank you, Suzanne & Erick - for all you do!
The Goal for the 2016-2017 Annual Fund is $250,000.
Annual Fund 101 – Know the Facts
- The Annual Fund is the single, largest fundraiser of the school year. (The Parents' Association's Anchor Auction is the second-largest money maker.)
- The Annual Fund is a supplemental source of income for the school. As with virtually all independent schools, tuition covers about 80% of GSL's operating budget. The Annual Fund makes up the difference (roughly $2,500 per student).
- GSL is a not-for-profit business. Our mission is education. By design, high-quality schools are labor-intensive and people-oriented. Where a for-profit company might consolidate employee duties and resources to save money, combining classrooms and reducing staff would not benefit our students. Teachers are our most important asset, yet most of them earn less than their public school peers. They choose to work at GSL because they value its commitment to children. The majority of your donations help us to recruit and retain these highly-qualified instructors, to pay for their advanced education and training, and to purchase classroom technologies and enhancements. In other words, your contributions have a direct impact on the quality of each child's experience while on campus.
- But that's not all! While most of the Annual Fund goes directly to faculty support, contributions are also used to pay for financial aid; facilities maintenance and improvements; for enhancements to the arts, the library, and other investments, as needed.
Basic Q & A
- Do other independent schools have annual funds? Yes. They ALL do.
- Who oversees the Annual Fund? The GSL Development Department (Denise DuBois Taylor, Sherry Emerson, and Kate Shelton) works with the Annual Fund chairs and volunteers to raise money each year. Under the watchful eye of the Head of School and the Board of Trustees, the day-to-day management of the dollars raised falls into the capable hands of GSL's Director of Finance, Daniel Fundo.
- How is the money used? Annual Fund dollars are used to maintain and improve the campus, to pay for advanced training for faculty, to provide financial aid to families, to upgrade technology, to expand After-School Care and Enrichment, and much more.
- Does GSL have an endowment? Yes. The school has a general Endowment Fund plus:
The Anchor Fund - Providing long-term stability through a variety of investment opportunities.
The Dennis Cain Facilities Fund - For the maintenance of school buildings and grounds.
The Scholarship Fund - Providing need-based financial assistance to families of current or prospective students.
The Library Fund - Promote and supporting the GSL School library.
The Technology Fund - Providing state-of-the-art technology to students and staff.
The Arts Fund - Promoting and supporting a variety of arts activities schoolwide.
- Can a small gift make a difference? Yes! Our school community is small with fewer supporters than a major high school or college. Because our donor base is limited, every gift counts!
All donations to the Annual Fund are tax-deductible!
We take Master Card, Visa, and American Express.
You may pledge now and pay later.
(Donors have until July 2017 to pay off their pledges.)
You may make a series of monthly installments.
You may pledge or pay using the enclosed remittance envelope.
You may pledge or pay on-line.
You may be a Lead Donor for as little as $42 a month!
(Lead Donors pledge a minimum of $500, which earns them an invitation to the hugely popular, annual Lead Donor Cocktail Party.)


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156 Meriline Ave
156 Meriline Ave, Woodland Park, NJ 07424
1 year ago
It's a 1 bedroom apartment. I have a 4 yr old daughter and is becoming cluttered. I currently live with her father as well. I pay half the rent each month. Although, I really cant afford it due to the fact that i pay everything else.. I want to move because i hate this place, It feels small and tight. Walls need to be re painted, bathroom needs caulking, and tub needs to be replaced.


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New Video
#Video Vybz Kartel f. Toian – Ice Queen
Last night social media began to buzz as it was announced that Vybz Kartel & rising female songstress Toian released their new video titled 'Ice Queen'. The single 'Ice Queen' produced by TJ Records has garnered over half a million views on ...
January 3rd, 2015
#Video Prone Practice – Heaven
One year after the initial release of his debut project, rapper/producer, Prone Practice drops visuals for the self produced title track "Heaven" off of "Creative Control". Director Streets Beats lays the backdrop for this banger as Prone plays lead, rhyming over the distant
January 3rd, 2015
#Video Ne-Yo & Pitbull – Time Of Our Lives
#Video RizSelfMade – Final Destination
Harlem emcee Riz a.k.a. RIZSELFMADE is bringing in the New Year with a new video and EP!
#Video Jennifair – Lauryn Hill
#Video Wordsmith – Coco In December
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#Video OG Maco f. Skippa Da Flippa – How We Planned It
#Video Kid Ink – Hello World
#Video Troy Ave – Beneath Me
December 30th, 2014
#Video Shaggy – I Need Your Love
Over 10 million views and still going,Dancehall star Shaggy's new video "I Need Your Love"
December 30th, 2014


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Dr. Thomas Gonzales Joined Other Dentistry Experts At The Seminar Sponsored By NOBEL BIOCARE® And International Dental Consultants
Thomas Gonzales D.D.S., owner at Sedation and Implant Dentistry Irvine, an expert Conscious Sedation and Dental Implant Dentist in Orange County, recently spoke at the Annual International Dental Consultants Seminar. The event held on June 11th in San Diego, brought dentists from southern California to discuss integrating specialties to grow your dental practice.
"It was a pleasure to attend this seminar to discuss the collective goal to integrate other practice areas to grow your business, as well as the challenges and opportunities we all face," said Thomas Gonzales.
The event focused on exploring innovative solutions for growth and group practices in 2016. Topics included tactics that deliver leadership, case acceptance, new patient conversion and strategies galvanizing dental practices in improving their position within the market. Dr. Gonzales discussed the methods he uses to incorporate full mouth reconstruction, Sleep Apnea, IV Sedation and Hybrid 4 into his dental practice.
The event was sponsored by Nobel Biocare,® a world leader in the field of innovative implant-based dental restorations, and International Dental Consultants, a practice management innovator.
About the Doctor
Thomas Gonzales D.D.S. is the owner of Sedation and Implant Dentistry Irvine and Sedation and Implant Dentistry Las Vegas. He is board certified General and Conscious Sedation Dentist in California and Nevada. He taught TMJ Therapy for the Loma Linda Institute and Emergency Medicine and IV Sedation at the University of Nevada, Las Vegas School of Dental Medicine. In addition, Dr. Gonzales is a member of the American Academy of Cosmetic Dentistry, American Academy of Craniofacial Pain, American Academy of Implant Dentistry, American Dental Association, California Dental Association, Dental Implant Institute, Dental Organization for Conscious, Sedation, Hispanic Dental Association, International Association for Orthodontics, International Congress of Oral Implantologists, Latin American Institute of Dental Research and Education, Las Vegas Institute for Advanced Dental Studies, Nevada Dental Association and Orange County Dental Society. He is a graduate of the University of Southern California School of Dentistry and served in the United States Army and is a Vietnam War Veteran.
For more information, visit www.DentistOfficeIrvine.com Follow Sedation and Implant Dentistry Irvine on Facebook, on Twitter, Google+ and LinkedIn.


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ABUJA Mon Aug 11, 2014 6:18am EDT
Nigeria's Minister of Health Onyebuchi Chukwu addresses diplomatic envoys on the status of the Ebola disease control in Nigeria at the Foreign Affairs House in Abuja, August 7, 2014.Credit: Reuters/Afolabi Sotunde
ABUJA (Reuters) - Nigeria's Lagos has 10 confirmed cases of Ebola, up from seven at the last count, although only two so far have died, including the Liberian who brought the virus in, the health minister said on Monday.
All were people who had had primary contact with Patrick Sawyer, who collapsed on arrival at Lagos airport on July 25th and later died, Health Minister Onyebuchi Chukwu told a news conference. A nurse who treated him not knowing what it was and without protective gear also died.
"As at today, 77 primary and secondary contacts of the index case have been placed under surveillance or isolation," he added. The latest case was also a nurse who had had primary contact with Sawyer.
"When she got ill, we then brought her into isolation. We just tested her over the weekend."
She had been at home with her husband, who was also now under surveillance, Chukwu said.
The West African Ebola outbreak is the worst in history and the World Health Organization (WHO) said on Friday it represents an international health emergency that will likely continue spreading for months. It said 961 people have died during the outbreak and 1,779 have been infected.
The disease has strained health systems of affected states and governments have responded with measures including national emergencies declared in Sierra Leone, Liberia and Nigeria.
Nigeria faces the added problem that public doctors are on strike over pay and working conditions and have resisted calls by the government to end their strike to tackle the Ebola crisis.
The Nigerian Red Cross said it had provided 18 volunteers to work with the authorities to educate people on how Ebola is spread.
Ebola is one of the world's most deadly diseases, with no known vaccine or cure. The Zaire strain - the one currently spreading through West Africa - can kill up to 90 percent of sufferers, although in the latest outbreak the death toll has been around 55 percent.
(Reporting by Camillus Eboh; Writing by Tim Cocks; Editing by Jeremy Gaunt)
View the original article here
This post was made using the Auto Blogging Software from WebMagnates.org This line will not appear when posts are made after activating the software to full version.


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CERN Scientists Gagged On 'Politically Incorrect' Global Warming Data
Source: infowars.com
Physicists ordered not to draw conclusions from study which seeks to confirm that the sun drives climate change
In a shocking illustration of how the man-made climate change establishment has seized control of the scientific process, physicists at the CERN lab in Geneva were gagged from drawing conclusions about data that seeks to replicate studies which prove the sun is the main driver of climate change, after their boss told them that such heresy was politically incorrect.
"The chief of the world's leading physics lab at CERN in Geneva has prohibited scientists from drawing conclusions from a major experiment. The CLOUD ("Cosmics Leaving Outdoor Droplets") experiment examines the role that energetic particles from deep space play in cloud formation. CLOUD uses CERN's proton synchrotron to examine nucleation," reports the Register.


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Homeobox domain-containing transcription factors are important regulators of hematopoiesis. Here we report that increased levels of non-clustered H2.0-like homeobox (HLX) lead to loss of functional hematopoietic stem cells and formation of aberrant progenitors with unlimited serial clonogenicity and blocked differentiation. Inhibition of HLX reduces proliferation and clonogenicity of leukemia cells, overcomes the differentiation block, and leads to prolonged survival. HLX regulates a transcriptional program, including PAK1 and BTG1, that controls cellular differentiation and proliferation. HLX is overexpressed in 87% of patients with acute myeloid leukemia (AML) and independently correlates with inferior overall survival (N=601, p=2.3×10−6). Our study identifies HLX as a key regulator in immature hematopoietic and leukemia cells, and a prognostic marker and therapeutic target in AML.
Transcription factors are critical for the regulation of normal hematopoiesis as well as leukemogenesis (Friedman, 2007; Laiosa, Stadtfeld and Graf, 2006; Tenen, 2003). Several members of the Hox (class I homeobox genes) family of transcription factors, which contain a conserved homeobox domain and are organized into 4 major gene clusters in humans, have been implicated in the functioning of hematopoietic stem and progenitor cells (HSPC) as well as in leukemic transformation and the generation of leukemia-initiating cells (Argiropoulos and Humphries, 2007; Krumlauf, 1994; Sitwala, Dandekar and Hess, 2008). Less is known about the role of non-clustered (class II) homeobox genes in hematopoiesis and leukemia. Members of the CDX family, for instance, have been found to be overexpressed in acute leukemias and to regulate Hox gene expression (Bansal, Scholl, et al, 2006; Scholl, Bansal, et al, 2007). Transcriptional analysis of purified stem and progenitor populations has recently been utilized as a powerful tool to identify critical regulators of stem and progenitor cell function and transformation to leukemia-initiating cells (Krivtsov, Twomey, et al, 2006; Majeti, Becker, et al, 2009; Passegué, Wagner and Weissman, 2004; Saito, Kitamura, et al, 2010; Somervaille and Cleary, 2006; Steidl, Rosenbauer, et al, 2006; Steidl, Steidl, et al, 2007). Our analysis of pre-leukemic HSPC in a murine model of AML revealed the non-clustered H2.0-like homeobox (Hlx) gene to be 4-fold upregulated compared to wild-type (WT) HSPC ((Steidl, Rosenbauer, et al, 2006); and data not shown), suggesting that Hlx may be involved in malignant transformation. HLX is the highly conserved human/murine homologue of the homeobox gene H2.0, which shows tissue-specific expression throughout development in Drosophila melanogaster (Allen, Lints, et al, 1991; Hentsch, Lyons, et al, 1996). Additional studies two decades ago detected HLX expression in hematopoietic progenitors and in leukemic blasts of patients with AML, and a study of HLX-deficient fetal liver cells suggested a decrease of colony-formation capacity (Deguchi and Kehrl, 1991; Deguchi, Kirschenbaum and Kehrl, 1992). However, the precise function of HLX in HSPC and its role in leukemia have not been studied, which was the objective of the present study. AML is a heterogeneous disease with overall poor clinical outcome (Marcucci, Haferlach and Dohner, 2011). Less than one third of patients with AML achieve durable remission with current treatment regimens. Furthermore, prognostication and risk stratification of individual patients remains very challenging, in particular in favorable and standard risk groups. New targets need to be identified for effective and individualized therapeutic intervention.
To examine the functional consequences of elevated HLX levels on hematopoiesis, we sorted lineage-negative (Lin−), Kit+ bone marrow (BM) cells from Ly5.2(CD45.2)+ WT mice, transduced them with a lentivirus expressing HLX and GFP, or GFP alone as a control (Fig. 1A+B), and transplanted them into lethally irradiated congenic Ly5.1(CD45.1)+ recipient mice. Transduction efficiency of control lentivirus and Hlx lentivirus was comparable, with both at approximately 50% (Fig. S1A). Twenty-four hours post-transplantation, both control and HLX-overexpressing GFP+ Ly5.2+ donor cells were detected in the BM at similar frequencies (42.8% and 41.6%, respectively) (Fig. 1C), indicating equal homing of the transplanted cells. Twelve weeks after transplantation, we evaluated hematopoietic multilineage reconstitution in the peripheral blood. Both groups engrafted robustly with an average donor chimerism of Ly5.2 cells of 80% (SD: 10%) and 85% (SD: 9%) in the control and Hlx groups, respectively. However, while mice transplanted with control cells showed 35% (SD: 17%) GFP+ cells in the peripheral blood 12 weeks after transplantation, mice transplanted with Hlx-transduced cells displayed drastically less GFP+ cells with only 0.07% (SD: 0.06%), demonstrating a severe defect of HLX-overexpressing cells in hematopoietic reconstitution (Fig. 1D). To determine the cellular compartments in which HLX was effective, we analyzed stem and progenitor cells in recipient BM. No GFP+ long-term hematopoietic stem cells (LT-HSC; Thy1loFlk2−LSK (Lin−Sca1+Kit+)) in mice transplanted with HLX-expressing cells were detected, while control mice displayed on average 42% (SD: 20%) GFP+ LT-HSC (Fig. 1E). Furthermore, in contrast to control animals, we could not find any GFP+ HLX-expressing short-term HSC (ST-HSCs; Thy1loFlk2+LSK), multipotent progenitors (MPP; Thy1− Flk2+LSK), common myeloid progenitors (CMP; Lin−Kit+Sca-1−FcγRII/IIIloCD34lo), granulocyte/monocyte progenitors (GMP; Lin−Kit+Sca-1−FcγRII/III+CD34+) or megakaryocyte/erythrocyte progenitors (MEP; Lin−Kit+Sca-1−FcγRII/III−CD34−), indicating that HLX acts at the level of the earliest hematopoietic stem cells (Fig. S1B). When we analyzed Hlx-GFP-transduced Lin−Kit+ (KL) cells by AnnexinV/DAPI staining, both control and HLX-overexpressing cells displayed the same low percentage of apoptotic/necrotic cells (Fig. S1C), indicating that HLX acts by a mechanism other than induction of apoptosis or necrosis. Further analysis for donor-derived cell populations persisting upon HLX overexpression revealed a small population of GFP+, CD45.2(Ly.5.2)+, Lin−, CD34−, and Kit− cells which were still present in the BM 12 weeks after transplantation (Fig. 1F). Analysis for additional surface markers revealed that these cells were characterized by intermediate expression of CD11b, as well as high expression of CD49b and CD44 (Fig. 1G, left panel), which is consistent with the surface phenotype of myeloid precursor cells slightly past the GMP stage (Novershtern, Subramanian, et al, 2011). This CD45+CD11bmidCD49b+CD44+ cell population was 16-fold expanded upon HLX expression in comparison to control (p=1.1×10−5) (Fig. 1G, right panel).
Next, we performed in vitro colony formation assays of transduced LSK cells. Hlx-transduced LSK cells formed slightly fewer and smaller colonies than control-transduced LSK cells in the initial plating (Fig. 2A, left panel, and Fig. S2A). To evaluate long-term clonogenic potential of HLX-overexpressing cells, we performed serial-replating assays. LSK cells overexpressing HLX showed greater clonogenic capacity in the 2nd to 5th plating in comparison to control-transduced cells, and maintained serial replating capacity through the 6th to 9th plating (Fig. 2A, right panel), showing a de facto immortalization of this clonogenic progenitor population by HLX. In addition, colonies were noticeably larger in size after five platings compared to control (Fig. 2B). Analysis of cells isolated from the initial plating revealed that HLX overexpression led to a decrease of Kit+ cells, similar to the in vivo phenotype, and an increased proportion of phenotypically more mature CD34−Kit− cells in comparison to control-transduced cells (Fig. 2C). To further characterize this persisting population, we examined a panel of cell surface markers. While the CD34−Kit− cells were negative for CD11c, CD25, FcγRII/III, CD61, CD115, and CD150 (Fig. S2B; and data not shown), they expressed CD49b and CD44, as well as intermediate levels of CD11b (Fig. S2B), similar to our observations in vivo (Fig. 1G). To determine which cellular subpopulation conferred the increased clonogenic capacity, we sorted equal numbers of CD34+Kit+ cells, CD34+Kit− cells, CD34− Kit+ cells, and CD34−Kit− cells from the first plating (populations I–IV, see Fig. 2C), and subjected each individual population to colony formation assays. Only CD34−Kit− cells derived from HLX-overexpressing cells formed a larger number of colonies in comparison to control cells, while all other populations did not display significant clonogenicity (Fig. 2D). Furthermore, the HLX-overexpressing GFP+CD34−Kit− cells showed serial replating capacity through 4 rounds, while all other populations exhausted significantly earlier (Fig. 2E). Finally, when we injected HLX-overexpressing GFP+CD34− Kit− cells from the fourth, sixth, or eighth plating into irradiated NOD-SCID-IL2Rgamma null (NSG) mice, GFP+ cells were detectable after 7 weeks in the peripheral blood (Fig. S2C; and data not shown). These data indicate that increased levels of HLX confer long-term clonogenicity to a population of CD34−Kit− cells.
To investigate the effect of HLX overexpression on differentiation capacity, we analyzed the clonogenic GFP+CD34−Kit− cells from the first colony assay for the expression of additional cell surface markers. The proportions of Gr1+Mac1+ and Gr1−Mac1+, as well as F4/80+Mac1+ expressing cells were significantly reduced (Gr1+Mac1+: from 29.7% (control) (SD: 6.6%) to 16.2% (Hlx) (SD: 1.9%), p=0.026; Gr1−Mac1+: from 30.7% (SD: 4.5%) to 11.2% (SD: 2.6%), p=0.003; F4/80+Mac1+: from 31.6% (SD: 4.9%) to 8.9% (SD: 2.8%), p=0.002; N=3), indicative of a defect in myelomonocytic differentiation (Fig. 3A). Expression of erythroid, B-lymphoid, and T-lymphoid markers was unchanged. Furthermore, almost half of the HLX-overexpressing GFP+CD34−Kit− population (47.6%, (SD: 2.8%)) was lineage-negative, in contrast to only 17% (SD: 1.2%) of GFP+CD34−Kit− control-transduced cells (p=0.005) (Fig. 3A). Sorted, HLX-overexpressing GFP+Lin− CD34−Kit− cells also showed a significant increase in clonogenicity compared with control-transduced cells (Fig. S3), indicating that HLX acts at the level of Lin−CD34−Kit− cells. To specifically test myelomonocytic differentiation, we carried out colony-formation assays with GM-CSF or M-CSF stimulation (Fig. 3B–E). Hlx-transduced cells gave rise to lower numbers of Gr1−Mac1+ and F4/80+Mac1+ cells compared to control-transduced cells, upon either GM-CSF or M-CSF stimulation (Fig. 3B, D). Cytomorphological evaluation of cells after stimulation showed an increased percentage of Hlx-transduced cells with immature progenitor morphology, in stark contrast to control-transduced cells which predominantly displayed mature monocytic morphology (Fig. 3C, E). Taken together, our findings show that HLX not only enhances clonogenicity of an increased population of Lin−CD34−Kit− cells, but also confers a partial myelomonocytic differentiation block.
To test whether HLX overexpression is functionally important for AML, we targeted Hlx by RNA interference. We transduced leukemia cells derived from the PU.1 UREΔ/Δ AML model (URE cells) as well as human AML cells with lentiviral constructs expressing either Hlx-directed (sh Hlx) or control shRNA (sh control). Knockdown of HLX by 80% led to significantly reduced cell proliferation in suspension culture, as well as reduced formation of colonies of URE cells in methylcellulose assays in comparison to control cells (p<0.00001) (Fig. 4A, B, C). Likewise, human KG1a, THP1, and MOLM13 AML cells showed 40–60% reduced growth (p=0.003, p=0.001, and p=0.014, respectively) in suspension culture, as well as significantly diminished clonogenicity (p=0.02, p=0.038, and p=0.004, respectively) (Fig. 4D). To test the anti-leukemic effect of HLX suppression in vivo, we performed murine transplantation assays. We found that reduction of HLX levels in transplanted URE cells significantly prolonged recipient survival in comparison to mice transplanted with control shRNA-transduced cells (p=0.0012, and p=0.0041) (Fig. 4E). Taken together, our findings demonstrate that HLX is functionally important for AML cells, and that targeting HLX can inhibit cellular growth, decrease clonogenicity, and lead to improved survival in a murine AML transplantation model. Of note, Hlx heterozygous mice, which show a 50% reduction of HLX protein levels in BM cells, did not show any noticeable effects on normal hematopoiesis, including hematopoietic stem cell functions such as capacity for hematopoietic reconstitution and serial transplantability (Fig. S4).
To obtain insight into the mechanism of action of HLX inhibition we studied the cell biological and molecular consequences of knockdown of HLX in leukemia cells. We found that HLX downregulation in URE cells led to a decrease in viable cells, and an increase in necrotic cells (Fig. 5A). This was accompanied by a lower number of cells in S phase (p=0.027), and a higher number of cells in G0/G1 phase of cell cycle (p=0.002) (Fig. 5B). In addition, reduction of HLX led to an increased population of cells expressing lower levels of Kit and higher levels of Gr-1 and Mac1, indicative of myeloid differentiation (Fig. 5C, D). Stimulation with GM-CSF further increased the number of Mac1 and Gr-1 expressing cells, and led to increased differentiation of AML cells upon sh Hlx treatment in comparison to control-treated cells, which retained an immature, leukemic morphology (Fig. 5E). This observation shows that inhibition of HLX can overcome the myeloid differentiation block of AML cells.
To gain insight into the molecular effects caused by HLX inhibition, we measured gene expression profiles of sh Hlx-transduced URE cells and control shRNA-transduced cells. Leukemia cells treated with Hlx-directed shRNAs displayed an altered gene expression pattern with 392 genes being significantly differentially expressed (mean difference > 0.5 (log2), p<0.05) (Fig. 5F). Gene set enrichment analysis (GSEA) showed that "leukocyte differentiation", "cell activation", and "cell proliferation" were among the most significantly affected cellular functions (Fig. 5G), which is consistent with the leukemia-inhibitory effect of HLX reduction in URE cells. We specifically found that several key genes involved in the regulation of cell cycle and proliferation, cell death, and myeloid differentiation, were significantly changed upon HLX downregulation (Fig. 5H). We confirmed differential expression of several genes, namely Btg1, FoxO4, Fyn, Gadd45a, RhoB, Trp63, Zfp36l1, Hdac7, and Pak1 by qRT-PCR (Fig. 5J and Fig. S5A). We also found enrichment of genes involved in pathways of other cellular functions (Fig. S5B). Further, we utilized GSEA to compare the Hlx knockdown data with the molecular signatures database (MSigDB) (Mootha, Lindgren, et al, 2003; Subramanian, Tamayo, et al, 2005), and found negative enrichment of several known leukemia- and stem cell-related gene signatures (Table S1). Taken together, these data are consistent with a model that HLX overexpression leads to activation of a specific transcriptional program in leukemia cells which affects processes critical for leukemogenesis such as cell differentiation and proliferation, and which can at least partially be reversed by inhibition of HLX.
We focused on two downstream genes modulated upon HLX inhibition in AML cells, Pak1 and Btg1, which have previously been implicated in the regulation of cell cycle and malignant proliferation (Ong, Jubb, et al, 2011; Kuo, Duncavage, et al, 2003). Knockdown of PAK1 in KG1a AML cells led to a significant inhibition of cell proliferation (p<0.05) and clonogenicity (p<0.03) (Fig. 5K, Fig. S5C), mimicking the effects we had observed by knockdown of HLX. Similarly, ectopic expression of BTG1 led to a significant inhibition of cell growth (p<0.01) and colony forming capacity (p<0.008) of KG1a cells (Fig. 5L, Fig. S5D). These findings suggest that downregulation of PAK1 and upregulation of BTG1 are functionally relevant for mediating the leukemia-inhibitory effects of HLX knockdown.
To examine whether HLX overexpression plays a role in human leukemia, we analyzed gene expression data of 354 patients with AML (Figueroa, Lugthart, et al, 2010; Wouters, Lowenberg, et al, 2009). HLX was overexpressed in 87% of patients with AML in comparison to CD34+ cells of healthy donors (Fig. 6A). On average, HLX expression was 2.03-fold higher in AML patients (p=1.9×10−9; Fig. 6B). 54% (190 out of 354) of patients with AML overexpressed HLX more than 2-fold, with the range extending up to 6.8-fold overexpression. These results demonstrate that HLX overexpression is a common feature in patients with AML. HLX overexpression was found across different French-American-British (FAB) classification subsets of AML (Table S2). Of note, high HLX expression was significantly more frequent in AML with myelomonocytic (M4) and monoblastic (M5) morphology, which is consistent with the observed myelomonocytic differentiation block caused by HLX overexpression in vitro.
We further sought to examine if HLX expression levels in patients were associated with known clinical or molecular parameters. We analyzed 4 published datasets of patients with AML, of whom gene expression and time-to-event data were available (NCBI GEO accessions GSE10358, GSE12417 (U133A), GSE12417 (U133plus2), and GSE14468 (Metzeler, Hummel, et al, 2008; Tomasson, Xiang, et al, 2008; Wouters, Lowenberg, et al, 2009)). As the lower 25% of patients had HLX expression levels very similar to CD34+ cells of healthy donors (Fig. 6B), we decided to use the 25th percentile to dichotomize patients into "HLX high" and "HLX low" expressers. We compared the overall survival of AML patients with low versus high HLX, and observed that in each of the 4 different data sets, high HLX expression was associated with inferior overall survival (Fig. S6A–D). Overall survival (irrespective of HLX status) in datasets GSE12417 (U133plus2.0), GSE14468 and GSE10358 was very similar, with superimposable survival curves (p=0.4636, log-rank test; Fig. S6E), suggesting that these cohorts and their clinical outcomes could be combined for further analyses. The GSE12417 (U133A) dataset showed a worse overall survival outcome compared with the other datasets (Fig. S6F) and was therefore not included in the combined analysis. Consistent with the analyses of the individual datasets, the evaluation of the combined set of patients from the GSE10358, GSE12417 (U133plus2.0) and GSE14468 datasets (N=601 total) confirmed that high HLX levels are associated with inferior overall survival (p=2.336 × 10−6 (log-rank); hazard ratio (HR)=0.57 (95% CI: 0.046–0.71); median survival: 17.05 months (HLX high), "not reached" (HLX low); 5-yr survival rate: 32.95% (HLX high), 55.85% (HLX low)) (Fig. 6C). To assess whether the impact of HLX expression on overall survival is independent of known prognostic factors for AML, we performed multivariate analysis based on the data of the GSE14468 dataset (Figueroa, Lugthart, et al, 2010; Wouters, Lowenberg, et al, 2009), using a Cox regression model. In this analysis, high HLX status remained an independent prognostic factor (p=0.0416, HR 1.521) along with FLT3 mutation status (p=0.0003, HR 1.925), NPM1 mutation status (p=0.0006, HR 0.518), CEBPA mutation status (p=0.0371, HR 0.693), and cytogenetic risk group (p=0.0109, HR 1.382). Of note, the relative blast percentage in the bone marrow was not correlated with HLX expression or overall survival (Fig. S6G–I). The independent prognostic role of HLX status led us to hypothesize that it may provide additional prognostic information for patients who belong to previously established, molecularly defined subtypes of AML. We indeed observed that among patients with FLT3 WT, NPM1 mutations, or CEBPA mutations, high HLX expression was associated with inferior overall survival (p=0.0175, p=0.0407 and p=0.0306, respectively) (Fig. 6D–F).
To obtain insight into the molecular consequences of elevated HLX levels we overexpressed HLX in sorted murine LSK cells and performed genome-wide transcriptional analysis. We found that 195 genes were significantly changed, resulting in a clearly distinguishable expression signature induced by HLX overexpression (Fig. S6J). Using GSEA we found enrichment of known leukemia- and stem cell-related gene signatures, consistent with our previous findings (Table S3).
Next, we tested whether this mouse LSK HLX overexpression gene set correlated with HLX expression in human AML patients. Specifically, we compared the human orthologs of the mouse gene set to HLX expression levels of AML patients in the different cohorts using globaltest (Goeman, van de Geer, et al, 2004). We found a highly significant correlation between the mouse gene signature and HLX expression in human AML samples (p=7.43×10−23 for GSE14468, p=2.13×10−08 for GSE10358, p=2.31×10−06 for GSE12417 (U133plus2.0), and p=5.01×10−10 for GSE12417 (U133A)). Further, we intersected differentially expressed genes from the HLX overexpression or inhibition studies with analogously differentially expressed genes in "HLX high" versus "HLX low" patients of the GSE14468 data set, and analyzed these genes for association with survival. Thereby, we were able to define an HLX-dependent core set of 17 genes (referred to as "HLX signature") correlating with HLX expression status in patients with AML (Fig. 6G). When we dichotomized patients into "HLX signature high" versus "HLX signature low" patients (defined by the genes of the signature, excluding HLX), we found that "HLX signature high" patients had significantly inferior overall survival (p=0.0089 (log-rank); hazard ratio (HR)=0.66 (95% CI: 0.48 to 0.90); median survival: 17.22 months for HLX signature high, "not reached" for HLX signature low; 5-yr survival rate: 34.5% for HLX signature high, 53.9% for HLX signature low) (Fig. 6H).
We subsequently validated the HLX signature in an independent cohort of patients, the GSE10358 data set, and found that the signature correlated strongly (p=7.8×10−11) with "HLX high" versus "HLX low" expression status in these AML patients as well (Fig. 6I). Furthermore, "HLX signature high" patients showed a strikingly inferior overall survival (p=1.89x10−05 (log-rank); hazard ratio (HR)=0.42 (95% CI: 0.28 to 0.62); median survival: 18.3 months (HLX signature high), "not reached" (HLX signature low); 5-yr survival rate: 29.0% (HLX signature high), 67.0% (HLX signature low)) (Fig. 6J). Taken together, these data suggest that elevated HLX levels cause a specific, functionally critical gene expression signature in human AML.
Interestingly, PAK1 was part of the HLX-induced prognostic signature. Given our finding that PAK1 mediates the leukemia-inhibitory effects of HLX knockdown in AML cells (Fig. 5K), we asked whether PAK1 expression levels alone may be functionally relevant in AML patients. We dichotomized AML patients into "PAK1 high" and "PAK1 low" expressers and analyzed clinical outcome. "PAK1 high" patients showed significantly inferior overall survival (p=0.00014 (log-rank)) than "PAK1 low" patients (median: 17.7 months (PAK1 high) vs. 109.1 months (PAK1 low); 5-yr survival rate: 34.0% (PAK1 high) vs. 50.5% (PAK1 low)) (Fig. S6K). Of note, high PAK1 expression was associated with inferior overall survival only in patients of the "HLX high" group (p=0.0005 (log-rank); hazard ratio (HR)= 0.62 (95% CI: 0.48 – 0.81)); median survival: 15.8 months (PAK1 high), 42.0 months (PAK1 low); 5-yr survival rate: 29.7% (PAK1 high), 48.1% (PAK1 low)), but not in "HLX low" patients (p=0.77 (log-rank); hazard ratio (HR)= 1.08 (95% CI: 0.65 – 1.78)); 5-yr survival rate: 55.0% (PAK1 high), 55.0% (PAK1 low)) (Fig. S6L,M). In addition, PAK1 expression levels were on average 1.5-fold higher (p=2.2×10−16) in "HLX high" patients compared to "HLX low" patients (Fig. S6N), and HLX and PAK1 expression levels in individual patients were also significantly correlated (p=8.8x10−15, R=0.31; Fig. S6O). Furthermore, experimental overexpression of HLX in LSK cells led to a significant increase in Pak1 mRNA expression (1.9-fold, p=0.017; Fig. S6P).
Utilizing both mouse and human model systems we have shown that the class II homeobox protein HLX affects hematopoietic stem cell function, as well as clonogenicity and differentiation of immature hematopoietic progenitor cells. We found that HLX is significantly overexpressed in the majority of patients with AML, and that high HLX expression levels are independently associated with inferior clinical outcome. Thereby, our study identifies HLX as a class II homeobox gene which is critically involved in the pathogenesis of acute myeloid leukemia. Our finding that increased HLX expression correlates with more aggressive disease, combined with the observation that HLX knockdown results in an inhibition of growth and clonogenicity of leukemia cells further suggest that HLX may be a promising prognostic and therapeutic target. Future studies evaluating HLX in the context of different therapies will be required to determine if HLX also has predictive relevance.
Many clustered (class I, or HOX) homeobox genes have been implicated in normal hematopoiesis as well as leukemia, but much less is known about the role of non-clustered (class II) homeobox transcription factors (for review see (Argiropoulos and Humphries, 2007)). Several HOX genes are expressed at high levels in subtypes of AML (Alcalay, Tiacci, et al, 2005; Ayton and Cleary, 2003; Bullinger, Dohner, et al, 2004; Horton, Grier, et al, 2005). Important roles in leukemic transformation have been demonstrated specifically for several members of the HOX-A and the HOX-B cluster (Fischbach, Rozenfeld, et al, 2005; Krivtsov, Twomey, et al, 2006; Kroon, Krosl, et al, 1998; Sauvageau, Thorsteinsdottir, et al, 1997; Somervaille and Cleary, 2006; Thorsteinsdottir, Sauvageau, et al, 1997). Also, the non-clustered homeobox gene CDX2 was recently reported to be implicated in leukemogenesis (Scholl, Bansal, et al, 2007). However, the clinical significance of these known HOX genes is largely unclear. Here, we report that expression levels of a homeobox gene are strongly associated with inferior overall survival in several large, independent cohorts of patients with AML. Furthermore, the prognostic value of HLX is a broad phenomenon across several molecular subsets of patients, and HLX holds up as an independent prognostic factor in a multivariate model. Gene expression analyses upon experimental overexpression and inhibition of HLX demonstrated that HLX regulates the expression of a specific subset of genes, and that part of this "HLX signature" is also detectable in AML patients and discriminates between patients with poor and favorable clinical outcome. Taken together, these observations suggest that HLX is a key regulator of a gene subset critical for AML pathogenesis, and that it may define a previously unrecognized molecular subtype of AML with distinct biological features and clinical outcome.
We identified PAK1 and BTG1 as two genes downstream of HLX in myeloid cells, and show that PAK1 and BTG1 are functionally relevant in AML cells. Notably, PAK1 is upregulated in human AML patients with high HLX expression, and it is also part of the HLX-induced core signature that independently predicts overall survival in AML patients. Interestingly, high PAK1 expression itself is associated with inferior overall survival, but only in patients with high HLX expression, indicating that there is an interaction of HLX and PAK1 with respect to their impact on overall survival. The correlation of HLX and PAK1 expression levels in the murine HLX knockdown model and in patients with AML, together with the observed induction of Pak1 expression upon HLX overexpression in stem cells strongly suggest that Pak1 is a downstream target of HLX and critically mediates, at least in part, the leukemia-promoting effects of HLX in patients in vivo. Further studies will be required to determine the exact nature of this regulation, and whether it is direct or indirect.
Several HOX genes, such as HOXB4, have been reported to be stimulators of HSC function and expansion (Antonchuk, Sauvageau and Humphries, 2002; Sauvageau, Thorsteinsdottir, et al, 1995). Our data show that HLX suppresses the function of normal immature HSC and progenitors, however leads to an increase of clonogenicity, as well as a differentiation block at the level of phenotypically more mature progenitors. As the loss of HSC does not seem to be mediated by induction of apoptosis or necrosis, one may speculate that HLX exerts this dual role by triggering initial differentiation of HSC and suppression of terminal differentiation at a more committed progenitor level. Further studies will be required to understand the molecular basis of this effect. While overexpression of HLX led to the formation of myeloid progenitors with unlimited serial clonogenicity, we so far did not observe development of leukemia upon transplantation, suggesting that HLX elevation alone may not be sufficient for full transformation. Like other homeobox genes, Hlx may function in concert with co-factors (Moens and Selleri, 2006; Pineault, Abramovich, et al, 2004). Such co-factors could confer cell type specificity to the effects of HLX overexpression, and also contribute to leukemic transformation. It is also possible that increase of HLX plays a role in leukemia maintenance rather than leukemia induction.
Several transcription factors that govern normal hematopoietic differentiation have been implicated in leukemogenesis by blocking differentiation and promoting self-renewal and clonogenicity (for review see (Rosenbauer and Tenen, 2007)). HLX may act similar to those factors by establishing a specific gene expression program in early HSPC, which results in increased long-term clonogenicity and a differentiation arrest, contributing to poor clinical outcome. Thus, HLX expression levels may be utilized to predict clinical outcome and improve risk stratification. Finally, inhibition of HLX may be a promising strategy for treatment of patients with AML.
FVB/nJ mice (Ly5.1), C57BL/6J (Ly5.2) mice, and B6.SJL-Ptprca Pepcb/BoyJ (Pep boy, Ly5.1), and NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were used for in vitro assays and in vivo transplantation assays. Mice with targeted disruption of the upstream regulatory element (URE) of the PU.1 gene have been previously described (Rosenbauer, Wagner, et al, 2004). All animal experiments were approved by the Institutional Animal Care and Use Committee of the Albert Einstein College of Medicine (protocol # 20080109). URE cells were established and maintained as described previously (Steidl,Rosenbauer, et al, 2006). Human AML cell lines THP1, MOLM13, and KG1a were cultured under standard conditions.
Mononuclear cells were purified by lysis of erythrocytes. For analysis and sorting we used antibodies directed against CD4[GK1.5], CD8a[53-6.7], CD19[eBio1D3], Gr-1[RB6-8C5], B220[RA3-6B2], F4/80[BM8], c-kit[ACK2], Sca-1[D7], CD34[RAM34], CD16/32[93], Flk-2[A2F10], Mac1[M1/70], Ter119[TER-119], and Thy-1.2[53-2-1]. To distinguish donor from host cells in transplanted mice, cells were additionally stained with anti-CD45.1[A20] and CD45.2[104]. Analysis and sorting were performed using a FACSAria II Special Order System (BD Biosciences, San Jose, CA). See Supplemental Experimental Procedures for more details.
For overexpression studies, we introduced the mouse Hlx coding sequence into the EcoRI site of a pCAD-IRES-GFP lentiviral construct (Steidl, Steidl, et al, 2007). For BTG1 overexpression we introduced the human BTG1 coding sequence into the EcoRI site of the pCAD-IRES-GFP construct. For murine knockdown studies, we inserted shRNA template oligonucleotides (target sense strand-loop-target antisense strand-TTTTT) into the pSIH1-H1-copGFP shRNA vector (System Biosciences, Mountain View, CA). For human knockdown studies we utilized the pGIPZ system from Open Biosystems, Huntsville, AL. See Supplemental Experimental Procedures for sequence information. For knockdown of PAK1 we utilized the plko.1-puro vector system (Sigma) with non-silencing control or human PAK1 target. Lentiviral particles were produced utilizing 293T cells, and concentrated by ultracentrifugation. For overexpression studies, we treated sorted Lin−Kit+ cells from WT C57BL/6J (Ly5.2) BM (for in vivo assays) or Lin−Kit+Sca-1+ cells from WT FVB/nJ BM (for in vitro assays) with control virus or Hlx virus. In brief, sorted cells were cultured with lentiviral supernatants in the presence of 8µg/ml polybrene. 24 hours after transduction, cells were washed with PBS and then used for experiments. After 40 hours, transduction efficiency was determined by flow-cytometry. For knockdown studies, cells were incubated with short-hairpin-containing lentivirus for 24 hours. GFP+ cells were sorted using a FACS Aria II sorter (BD Biosciences) and used for experiments.
We extracted total RNA from FACS-sorted cells or cultured cells using RNeasy Micro kit (Qiagen, Valencia, CA) and synthesized cDNA by Superscript II reverse transcriptase (Invitrogen, Carlsbad, CA). We performed real-time PCR using an iQ5 real-time PCR detection system (BIO-RAD, Hercules, CA) with 1 cycle of 50°C (2min) and 95°C (10min) followed by 40 cycles of 95°C (15sec) and 60°C (1min) using Power SYBR Green PCR master mix (AB, Carlsbad, CA) (see Supplemental Experimental Procedures for primer sequences).
Assays were performed in MethoCult M3434 (Stem Cell Technologies, Vancouver, BC) containing IL-3, IL-6, SCF, and EPO or in MethoCult M3234 supplemented with M-CSF or GM-CSF as previously described (Higuchi, O'Brien, et al, 2002;Huntly, Shigematsu, et al, 2004;Will, Kawahara, et al, 2009). GFP+ colonies were scored 8–10 days after plating using an AXIOVERT 200M microscope (Zeiss, Maple Grove, MN). After scoring, we resorted GFP+ cells after each round and then proceeded with serial replating assays. Cells were replated and colonies were again scored after 10–14 days.
For HLX overexpression studies, 5×104 lentivirus-transduced Lin−Kit+ cells (Ly5.2) together with 2.5×105 spleen cells from congenic WT recipients (Ly5.1) were transplanted into lethally irradiated age-matched congenic WT recipients (Ly5.1) by retroorbital vein injection. Total body irradiation was delivered in a single dose of 950 cGy using a Shepherd 6810 sealed-source 137Cs irradiator.
RNA was extracted from sorted GFP+ cells utilizing the RNeasy Micro Kit (Qiagen). After evaluation of the quality of RNA with an Agilent2100 Bioanalyzer, total RNA was used for amplification utilizing the Nugen Ovation pico WTA system according to the manufacturer's instructions. After labeling with the GeneChip WT terminal labeling kit (Affymetrix), labeled cRNA of each individual sample was hybridized to Affymetrix Mouse Gene 1.0ST microarrays (Affymetrix), stained, and scanned by GeneChip Scanner 3000 7G system (Affymetrix) according to standard protocols. For data analysis we utilized Multiple Experiment Viewer v.4 pilot2 (Saeed, Bhagabati, et al, 2006), DAVID bioinformatics tool (Huang da, Sherman and Lempicki, 2009a; Huang da, Sherman and Lempicki, 2009b), Enrichment Map Cytoscape plugin (Cline, Smoot, et al, 2007; Merico, Isserlin, et al, 2010), and Gene Set Enrichment Analysis v2.0 (GSEA) (Mootha, Lindgren, et al, 2003; Subramanian, Tamayo, et al, 2005). See Supplemental Experimental Procedures for details.
We analyzed the publicly available gene expression data sets with accession numbers GSE12417 (training set U133A and U133B; test set U133plus2.0), GSE14468, and GSE10358 (http://www.ncbi.nlm.nih.gov/geo/). Clinical outcome and mutational data for the GSE10358 dataset were obtained from a recent study of the same group (Ley, Ding, et al, 2010). Analyses of the gene expression profiles from GSE14468, GSE12417 training set and GSE10358 were performed based on published (Gentles, Plevritis, et al, 2010) and publicly available MAS5 files (GSE24006) with reanalyzed data. For analysis of the test set of the GSE12417 dataset, CEL files were processed using GenePattern (Broad Institute, Cambridge MA) for normalization (Expression File Creator algorithm). We utilized GraphPad Prism 5.0, R/Bioconductor sva package (R package version 3.2.0)(Leek, Johnson, et al.,2012), and SPSS 18.0 statistical package for further analyses. See Supplemental Experimental Procedures for details.
We utilized dChip (http://biosun1.harvard.edu/complab/dchip/), SAM (significance analysis of microarrays), as well as R/Bioconductor globaltest (Goeman, van de Geer, et al, 2004) for signature identification, followed by calculation of signature scores. See Supplemental Experimental Procedures for details.
AML is a heterogeneous disease with poor clinical outcome. Less than one third of patients achieve durable remission with current treatment regimens, and prognostication and risk stratification of individual patients is challenging. New molecular targets are desired for more effective therapeutic intervention. We identify the non-clustered homeobox gene Hlx as a key regulator in immature hematopoietic and leukemia cells. HLX is overexpressed in the majority of AML patients, and high levels of HLX correlate with inferior survival. Inhibition of HLX overcomes the differentiation block of AML, and prolongs survival in an in vivo model. As a key factor controlling malignant cell growth and differentiation, HLX may be a prognostic and therapeutic target in AML and possibly other types of cancer.
We thank the Einstein Human Stem Cell FACS and Xenotransplantation Facility for expert technical assistance (supported by NYSTEM, C024172). This work was supported by a new investigator award of the Leukemia Research Foundation, NYSTEM grant #CO24350, a Howard Temin Award of the NCI (R00CA131503), and a Medical Research Award of the Gabrielle's Angel Foundation for Cancer Research (to U.S.). U.S. is the Diane and Arthur B. Belfer Faculty Scholar in Cancer Research of the Albert Einstein College of Medicine.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Accession number
Complete array data are available in the Gene Expression Omnibus (GEO) of NCBI (Edgar, Domrachev and Lash, 2002), accession number GSE27947.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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A collection of stories from Ethos staff members traveling around the world.
Photographer Patrick Bryant took in the beauty of Iceland through the lens of his camera. Here are a few snapshots of his travels....Read More →
Football attracts both the young and old at a local, makeshift pitch in Ghana....Read More →
An account of one staff member's experience while visiting the infamous concentration camp. ...Read More →
One writer divulges everything you should know about Germany's famous Oktoberfest....Read More →


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motorcycle parts in Clearfield, UT
Xtm Motorsports Xtreme5528 S 1900 W, Roy, UT map
I took my little kids atv to this shop from another shop. The other shop had it over a week and could not... more
K & T Performance4836 S 3200 W, Roy, UT map
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I took my yamaha roadstar there because they are a dealer , What a HUGE MISTAKE that was . I gave the sho... more
Monarch Honda398 W 800 N, Orem, UT map
Monarch Honda has been a family owned and operated dealership for over thirty years!All Honda All the Tim... more
The Quad & Cycle Shop3550 Riverdale Rd, Ogden, UT map
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d'bi. Toronto, Ontario
dubpoet, playwright, educator & scholartist, d'bi. is an int'l Jamaican-dancehall-diva-womxnist-warrior-chanting-conscious- fyah on the mic. Her lyricism stems from the socio-political genre of dub poetry fused with dancehall reggae, hiphop, punk rock, blues & performance art; producing a pepperpot of theatricality that crosses cultural boundaries, reconfigures social norms & inspires r/evolution. ... more
Streaming and Download help


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2015/2016 USST Independent Enrollment of Chinese Government Scholarship Students
In accordance with the document of International Cooperation and Exchange Department of MOE, specific enrollment regulations are currently established as follows:
1. Category of Enrollment
Full-time postgraduates (Master, PH.D)
2. Target Students
Regarding freshman*: We will only admit students who have not already studied in China.
3. Qualifications
Applicants should be non-Chinese citizens.
Applicants who study for a master degree should be under 35 years old and have a bachelor's degree.
Applicants who study for a doctoral degree should be under 45 years old and have a master's degree.
4. Details Of Scholarship
Registration fee, tuition fee, basic teaching materials and accommodation fees are exempted.
Living allowance: (PH.D 2000 RMB/month Master 1700RMB/month) and one-off settlement fee.
Comprehensive medical care insurance for International Students
5. Application documents
Include the original and a copy, and fill out in Chinese or English.
(1)Application Form for Chinese Government Scholarship (filled in Chinese or in English)
Those who are able to apply online shall fill in and print the application form after submitting it online,then sign their names on the form.
The CSC Online Application for Study in China is available in http://laihua.csc.edu.cn
Those who cannot apply online shall download from http://isoe.usst.edu.cn for the application form. Fill in the form, print out and sign their names.
Note: the [
Agency No
.] shall be filled in with [
When choose major of the university, please refer to
http://isoe.usst.edu.cn/s/17/t/69/p/1/c/411/d/428/list.htm or
(2)Valid highest education certificate and transcript, i.e., copy of degree diploma and transcript, and notarized Chinese or English translation. If the verification is written in a language other than Chinese or English, it must be translated into either English or Chinese and sealed with official notarization. If applicants are either students about to graduate by 2014/2015 school year or have been employed, they must submit appropriate verification.
(3)Applicant's study plan in China (at least 800 words) written in Chinese or English.
(4)2 recommendation letters from either full professors or associate professors.
(5)Copy of valid Foreigner's Physical Examination Record and blood test report if any, the originals should be carried about to China
6. Application materials should be submitted by post to
International Students Office,
Rm.202, International Affairs Office,
No.516, Jun gong Rd., Shanghai
Zip code: 200093
phone: +86-21-55270783 Fax: +86-21-55270783
Email: firstname.lastname@example.com firstname.lastname@example.com
Web: http://isoe.usst.edu.cn
Deadline: Mar 20
, 2015


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Spring of Shixiang Lake
Adjacent to Tianfu New Zone, Pujiang County is located at the junction between Chengdu, Meishan and Ya'an city and within the half hour economic circle of Chengdu. It is a strategic point en route to Tibet and Yunnan with convenient transportation. Pujiang County, established backed in 554AD, is both home to Wei Liaoweng, the neo-Confucian in Song Dynasty, and Li Jiayu, a revered solider who fought in the Sino-Japanese War. Pujiang County encompasses an area of 583 km2 and governs eight towns and four villages, with a total population of 265,000. Its forest coverage rate reaches 50.08% while the quality of its surface water is listed at the national level 3 standard and air quality at the national level 2 standard. Pujiang County has been granted several statuses including National Ecological County, National Hygienic County, and National Leisure Agriculture and Rural Tourism Demonstration County.
The Pujiang government has thoroughly implemented a scientific method of development and firmly centering on the overall strategy of "reform and innovation, transformation and improvement". Based on the current state of Pujiang county, it has a determined functional orientation of building a green and ecological city according to the strategy of "a new city with three bases", meaning to create an ecological industrial base, recreation base and organic agricultural base of international standards, as well as a new environmental city that is pleasant to live, to visit and to work. The Pujiang government spares no effort to cultivate local eco-industry, strengthen urban-rural integration, brand Pujiang County as new and harmonious, and accelerate the characteristic development unique to the County.
Through painstaking effort and perseverance, Pujiang County is now well-known as a national demonstration area for quality and safety of export in tea and kiwi fruit. Pujiang Queshe Tea, Pujiang Kiwi and Pujiang Cereal Bar have been named national PGI products, while Pujiang Hybrid Citrus is authenticated as national AGI product. There are nine leading agricultural corporations of national and provincial level in Pujiang and one famous brand of China. More than 90% of the county's agricultural production have adopted standardized production system, with over 60% authentication rate of pollution-free and green organic product. Constructions of the new towns of Shou'an and Chengya, the launch of Shenpu industrial zone, and creation of China's second and western China's first Sino-German cooperative demonstration park for SMEs were launched with strict implementation of the urban-industrial integration and interaction strategy. The layout of "Taicang in the east and Pujiang in the west" is taking shape. Relying on the establishment of a functional eco-tourism area in Longmen Mountain, the recreational tourism in villages will be pushed toward a higher and more international level, while construction of Stone Elephant Lake and the Big Valley Tourist Area has commenced. Pujiang County now has one provincial scenic spot and three AAA-leveled scenic regions, and has preliminary formed a tourism business model of top-class recreation, vacation, relaxation and exploration.
1、Functional orientation: the green and ecological city of Pujiang
2、reputations and honors:
National Ecological County
National Hygienic County
Sichuan Provincial Civilized City
Hometown of Chinese Green Tea
Hometown of Chinese Hybrid Citrus
National Demonstration Area for Quality and Safety of Export Tea and Kiwi Fruit
Chinese Industrial Base of Package Printing
National Demonstration Base of Agricultural Products Processing
National Leisure Agriculture and Rural Tourism Demonstration County


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Role: WISERD Co-Director
Institution: Bangor University
Email: email@example.com
Telephone: 01248 382123
Howard Davis was appointed Professor of Social Theory and Institutions at Bangor University in 1997 and was Head of the School of Social Sciences from 1999-2007. He worked previously at the universities of Kent, Glasgow and Edinburgh.
Research Interests
Howard is interested in social theories of culture and creativity; cultural formations and transitions in post-Soviet societies; social implications of new technologies; the formation of social identities at local, national and international levels; research methods for the sociological analysis of culture, media and communications
Current Research
2008-11 The Evolution of European Identity: Using biographical methods to study the development of European identity (EU 7th Framework Programme)
Howard is the leader of Bangor team which includes Dr Sally Baker (Research Fellow) and Marta Kowalska (researcher assistant). This three year project is coordinated by Professor Robert Miller from Queen's University, Belfast. The other partners are from the Institute of Sociology, Magdeburg, Germany; the Department of European Culture Studies, University of Lodz, Poland; the School of Economics and Business Administration, Tallinn University of Technology, Estonia; the Institute of Sociology, Bulgarian Academy of Sciences, Bulgaria; and the Department of Sociology, 'Frederico II' University, Naples, Italy. The project website can be found here.
Click here to view Howard's official Bangor University bio page
Recent Publications
Davis H, Day G, Baker S, Eichsteller M, 2012, 'International Education in the Life Course' in The Evolution of European Identities: Biographical Approaches Ed(s) R Miller, G Day (Palgrave Macmillan, Basingstoke)
Davis H, Erofeev S, 2011, 'Reframing Society and Culture in Post-Soviet Russia' Comparative Sociology 10(5) pp 710-734 (Available here)
Davis H, 2009, "Revisiting the concept of the public intellectual" in Intellectuals and their Publics Eds C Fleck, A Hess, ES Lyon (Ashgate, London) pp 261-69 (Available here)
Davis H, Sosnovskaya A, 2009, "Representations of Otherness in Russian Newspapers: the theme of migration as a counterpoint to Russian national identity" Journal of Intercultural Communication 21, ISSN 1404-1634 (Available here)
Davis H, Day G , Drakakis-Smith A, 2008, "Migrating to North Wales: the 'English' experience'" Contemporary Wales 21 pp 101-12, ISSN 0951-4937
Davis H, Day G , Drakakis-Smith A, 2008, "Portrait of a Locality? The local press at work in North West Wales 2000-2002" Contemporary Wales 21 pp 25-26, ISSN 0951-4937
Davis H, Yerofeyev S, 2007, "The Regional and the Global in the Context of Changing Cultural Production" Regionologiia 4 pp 5-14, ISSN 0131-5706
7th August 2017
Are pupils who attend Welsh-medium schools in south-east Wales mostly from middle-class backgrounds and does it matter?
31st July 2017
WISERD has been delighted to host five undergraduate students this summer for work placements exploring dementia research, the intergenerational transmission of family values and data mapping.


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Is pro gay theology a sound biblical doctrine? Alan Shlemon discusses this in his monthly newsletter. Original article is here Two thousand years ago, Paul sounded a warning to his protégé Timothy. He said that a time will come when people will no longer "endure sound doctrine; but wanting to have their ears tickled, they will accumulate for themselves …
How Were People Saved Before Christ?
"If Old Testament saints can go to heaven without knowing or trusting Jesus, why can't people today get to heaven by simply obeying the Ten Commandments?" J Warner Wallace explores this in the article below. Original article is here The "exclusivity" of Christianity is a stumbling block for many skeptics. How can Jesus be the only way to heaven? …
The Knudson's Testimonies
Aaron and his wife Jessica share their Christian testimony at the E-Free church in Wall Drug.
The STR Seminar For You
Join Brian Johnson, Matt Irwin, Peter Irwin and Justin Hornbaker as they update our listeners on SD Apologetics events as well as the free upcoming Stand To Reason conference in September. You can register for the STR event here: REGISTRATION PAGE LINK
New Testament Reliability Part 2
In Part 2 of our podcast with Rob Ward we continue our discussion on whether or not the New Testament is reliable and what evidence there is that we can evaluate.


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Customer Reviews Of:
Columbia Sportswear Whitefield Winter Boots - Waterproof (For Women)
Closeouts. Survive the snowy winter months with warm, dry feet in Columbia Sportswear's Whitefield winter boots. An Omni-Tech® waterproof breathable membrane provides wet weather protection, and 200g insulation keeps toes cozy.
Average Rating based on 17 reviews 3.941176 0 5
Verified Buyer Reviewed by Dog lover from Indianapolis, IN on Thursday, January 3, 2013I use these boots to take my dog out. I attached the snow & ice traction cleats and I was good to go. A little bulky and stiff but I'm sure that will give with time.
Verified Buyer Reviewed by Jane from Maricopa, AZ on Monday, December 10, 2012My prior boots, Bugaboos, cracked across the top of the boot after a winter in Fairbanks. So, I am trying these which seem a bit more stout. I think they will be perfect for warmth and comfort just to and from the car but also for recreational activities.
Verified Buyer Reviewed by Montana mom from Montana on Sunday, November 25, 2012Great product for adventuring in the snow. Not comfortable enought to want to wear around town, but great to play outside.
Verified Buyer Reviewed by Horse talkin' lady from Brighton, co on Saturday, November 10, 2012Bulky, heavy, klunky. Dug into the outside aspect of my ankle. I wanted these as they had no fluff to attract/stick to hay, but they weigh a ton awkward. 6 horses in snow and down to zero degrees, I need more manuverability.
- Best Uses: Cold Weather, Slippery Terrain, Snow, Wet Conditions
- Cons: Bulky, Difficult Entry & Exit, Heavy, Not Comfortable
- Describe Yourself: Casual/ Recreational
- Gear Usage: Cold Weather Living, Winter Sports
- Pros: Waterproof
- Was this a gift?: No
Verified Buyer Reviewed by Aiya from Chicago, IL on Tuesday, September 11, 2012These are the best boots I have ever purchased. They are really well made and keep your feet warm and dry. Awesome traction.....and the tongue is connected to the rest of the boot so they are super easy to get on and off.
Take the recommendation and order a little larger than your regular size.....I made this mistake last time I bought winter boots and I got a great pair of boots then but ordered my regular size and the pain was unbearable as my toes got crushed so I had to use lifts.
These boots are not about vanity...they are about winter survival...and if you order the right size.....they won't let you down. Pair them with some acorn socks and your feet will be toasty all winter even if your outside a lot.
- Best Uses: Cold Weather, Slippery Terrain, Snow, Wet Conditions
- Describe Yourself: Avid Adventurer
- Gear Usage: Cold Weather Living, Outdoor work, Winter Sports
- Pros: Comfortable, Easy Entry & Exit, Good Traction, Lightweight, Stylish, Warm, Waterproof
- Was this a gift?: No
Verified Buyer Reviewed by fede from Chile on Monday, June 25, 2012they are really usefull for gardening in the winter
- Best Uses: After Skiing/Snowboarding, Cold Weather, Wet Conditions
- Cons: Heavy
- Describe Yourself: Casual/ Recreational
- Gear Usage: Cold Weather Living
- Pros: Comfortable, Warm, Waterproof
- Was this a gift?: Yes
Verified Buyer Reviewed by elenyou from NJ on Monday, March 12, 2012Dress for a walk with your child
- Best Uses: Cold Weather, Snow
- Describe Yourself: Casual/ Recreational
- Gear Usage: Cold Weather Living
- Pros: Comfortable, Warm, Waterproof
- Was this a gift?: Yes
Verified Buyer Reviewed by Katy from Portland, OR on Saturday, February 11, 2012Thick, sturdy boots. Nothin's getting through them. Ever.
A Little clumsy at first, but you get used to the stiff-ness of the design. Good for snowshoeing.
- Best Uses: Snowshoeing
Verified Buyer Reviewed by Eileen from New York on Monday, February 6, 2012I love these boots! But they were a half-size too big and too warm (at least for this year). We've had a really mild winter and they were just more boot than I need right now.
- Cons: For really cold weather, Ran big
- Pros: Extremely comfortable, Great price, Solid boot, Stylish, Warm and waterproof
Verified Buyer Reviewed by ColoradoSun from Colorado on Wednesday, February 1, 2012I did not have a chance to use these because returned them because they run small and the toe box is very small and narrow. I have a narrow foot so these are really narrow.
- Cons: Runs Small, Toe box is very narrow


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Find the perfect drink!
Browse by categories or ingredients
Read what others had to say about each recipe
››› Go to the Top 10
Trendy and popular cocktails for girls. They are usually sweet and colorful.
A fruity, rich flavored cocktail.
By uribecano
A tropical green monster with red eye garnish!
By lcmdmtwo
A sweet twist to a popular classic
By Athena
Long Drink
By gcasta
Elegant drink to start the night off. The Ellison is a delicious mix of cucumber and mint - always a hit with the ladies
By Harvs
A blue refreshing cocktail
By David
Tastes just like the candy of the same name
By David
Sweet and nutty!
By David
A taste of the tropics
By David
The brandy bring a refreshing warmth to the bubbly.
By David
A blue version of the che che
By AMIR
A very easy non alcoholic but very tasty margarita. Serves 4.
By Angus
A simple and delicious drink, very popular in Kenya
By David
A simple and delicious tropical cocktail drink.
By David
A sweet and glowing red cocktail that tastes just like candy.
By David
Page [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ]


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Surgery, Neurological Jobs
Browse For Surgery, Neurological Jobs. Find The Job Of Your Dreams On JAMA Career Center Today!
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- Endovascular (7)
- Neurosurgeon (89)
- Other (2)
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- Spine Surgeon (2)
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- Sanford Health – North Division
- Fargo, ND United States
- 07/23/2017
- Surgery, Neurological
Sanford Health is currently seeking a Board Certified or Board Eligible Neurosurgeon to join its neurosurgical team practicing in Fargo, North Dakota. Join a practice of 6 neurosurgeons and 8 advanced practice providers in a rapidly growing, high volume practice. Sanford Medical Center in Fargo is... More Details
- HCA - The Healthcare Company
- Anchorage, AK United States
- 07/23/2017
- Surgery, Neurological
Anchorage Neurosurgical Associates is a well-established comprehensive Neurosurgical practice specializing in a broad range of cranial, spine, and peripheral conditions. We are looking to add an experienced or well-trained Neurointerventional Surgeon to our group. Strong candidates will have endovas... More Details
- HCA - The Healthcare Company
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- Surgery, Neurological
We currently have an opening for a Neurosurgeon to join an expanding neurosurgery practice in the Los Angeles valley area. The call is 1:3. There are a two Neuro-Intensivists along with 5 critical care specialists at the hospital to handle the care of ICU patients. There are 2 Neuro-Interventionalis... More Details
- HCA - The Healthcare Company
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- 07/23/2017
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A well-established neurosurgery group in Las Vegas is seeking a fellowship trained endoscopic skull base surgeon. In addition to this unique surgery, candidates can and will be encouraged to build a general neurosurgery practice of as well. The group offers an employed opportunity with competitive ... More Details
- Saint Luke's Health System
- Kansas City, MO United States
- 07/24/2017
- Surgery, Neurological
The nationally prominent Saint Luke's Marion Bloch Neurosciences Institute is seeking a neurosurgeon with advanced clinical training and a post-graduate fellowship in spine from a prestigious institution to join the comprehensive neurosciences program at Saint Luke's Hospital, a 600-bed, regional te... More Details


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|Reviews for Star of Dreams
| Elf141 chapter 1 . 6/30/2016
I love your writing but I think you are a little confused in one matter, in no place in the Lord of the Rings Appendices Hobbit or Silmarillion is there mention of Legolas having a daughter or wife for that matter. Don't get me wrong your work is amazing and I love heaps of your story's for their originality, humour and general content but I think you might want to find proof of Legolas' daughters existence before you state that it's a fact from the trilogy. (Please don't kill me)
| TheDarkLordsFabulousDaughter chapter 1 . 4/25/2012
Is it safe to say I cried?...beautiful story:)
| brittany1989 chapter 1 . 2/27/2012
Sorry to say but legolas didn't have a daughter don't know where you got that from but it wasn't from the books.
| CandySmile chapter 1 . 5/22/2011
So sweet! Bravo! :) She did an amazing job! Fanfiction is missing out on such a great writer! _ Is she still profile-less?
| WankerLoL chapter 1 . 4/30/2011
tolkien made no mention of whether or not legolas had any children in any of his books, and especially not in the LOTR trilogy.
| Agena K chapter 1 . 3/18/2011
Ai! Mellon-nin,
you have touched my heart, have caused the love to overflow from my tired body and made me feel the deep joy of Legolas and Rima. Thank you so much.
May you always be blessed.
and keep writing you are good.


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Our photography style is natural and relaxed but most of all beautiful, simple and stylish. We believe good quality photography does not require a great deal of digital manipulation, our images speak for themselves.
For us beautiful portraiture is about capturing the subjects personality thus evoking emotions in the viewer of the final image.
In the galleries below you will find a selection of our favourite photographs.


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High School Diploma / Child Care Professional
Penn Foster
Program Overview
Take the first steps towards a career in child care while you earn your high school diploma online with Penn Foster High School. The Child Care Professional Career Pathway program allows you to work toward a diploma or degree in child care and early childhood education. Your concentration electives in the High School Diploma with Child Care Professional program are transferable to the Penn Foster Child Care Professional Career Diploma program.
Program Details
Degree Level: Diploma
Delivery Format:
Accelerated Degree:
Accreditation & Licensing
Penn Foster Career School, Penn Foster High School, and Penn Foster College are nationally accredited by the Distance Education Accrediting Commission (DEAC), recognized by the U.S. Department of Education and the Council for Higher Education Accreditation.
School Overview
Penn Foster's expertise in distance learning and genuine desire to help students meet their educational aspirations has helped students worldwide for over a century. More than 13,000,000 people have benefitted from Penn Foster programs, and more than 130,000 students are actively enrolled in studies. Penn Foster offers online career-focused and blended learning opportunities completely at a distance, and retains headquarters in Scranton, Pennsylvania.
Penn Foster supports distance education students with:
- Open enrollment
- Self-paced online courses
- 24/7 online support
- A Penn Foster Study Planner that organizes study plans and due dates
- Exams provided through the online Student Portal
- Career services
Penn Foster offers a broad scope of degrees, careers diplomas, and certificates ranging from high school diplomas to undergraduate certificates to associate and bachelor's degrees. Three schools make up Penn Foster.
- Penn Foster College awards associate and bachelor's degrees.
- Penn Foster Career School provides career diploma and certificate opportunities.
- Penn Foster High School gives students the choice to earn a traditional high school diploma, or opt to complete diplomas with career concentrations.
Degree programs offered at Penn Foster College include studies in:
- Business Management
- Finance
- Graphic Design
- Medical Assistant
- Human Resources Management.
Many of the programs can be finished within two years; however, completion time depends upon the degree program as well as each student's schedule.
There are over 70 vocational training programs and 20 associate degrees. Industrial courses allow students to build their skill set in a variety of fields such as:
- Construction
- Vehicle Maintenance
- Mechanical Maintenance
- Industrial Safety.
Though Penn Foster does not have a physical campus, some courses may blend online learning with more traditional forms of correspondence courses, including textbooks and print materials for study purposes.
In addition to national accreditation, Penn Foster is recognized by:
- Regional accreditation by the Commission on Secondary Schools of the Middle States Association of Colleges and Schools for Penn Foster Career School non-degree granting postsecondary programs
- Regional accreditation by the Commission on Secondary Schools of the Middle States Association of Colleges and Schools for Penn Foster High School grades 9 through adult
- An Authorized Provider by the International Association for Continuing Education and Training (IACET)
- State licensure by the Pennsylvania State Board of Private Licensed Schools for Penn Foster Career School and Penn Foster High School
- State licensure by the Arizona State Board for Private Postsecondary Education for Penn Foster College, with authorization to award Associate of Science Degrees, Bachelor of Science Degrees, and Undergraduate Certificates
- ACE CREDIT, of the American Council on Education, for many of Penn Foster College courses
Penn Foster upholds a strong, military-friendly relationship and retains a 2016 Military Friendly School® designation by G.I. Jobs. Penn Foster supports the military and veterans with discounts and VA benefits.
Students who are interested in more details on specific programs and requirements should request more information.
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