When I first had my son, I was pretty young and didn't have any job prospects lined up. The good thing about my situation was that I was eager to work and had the opportunity to pursue whatever career field I wanted to earn an income.
I know it sounds backwards because most people associate becoming a parent with having to sacrifice and give up all your dreams but I never saw it that way and my son actually motivated me to work even harder and pursue jobs that paid me well.
My mom mentioned that I could go to school to become a medical biller and coder and it wouldn't take much time at all to learn and master the craft.
Medical billing and coding workers work in the healthcare field and are in charge of coding specific medical duties and processing patient data like treatment records and insurance information. Medical coding is actually different from medical billing, but the two are often grouped together as one job title. Whether it's a coding or billing position, the main requirement generally involves having technical knowledge of the software system required to do the job.
I was definitely interested and looked into some training programs but didn't go through with it in the end and chose a different path.
Within recent years, medical billing and coding has been associated with many scams and the Federal Trade Commission actually had to launch an investigation in an attempt to get to the bottom of some of the scams and hold certain companies responsible.
It's really a shame, but as a short answer to the popular question "Is medical billing and coding a scam?" my simple answer is no it's not. Unfortunately, it's a popular profession that scammers tend to target so it makes it extremely difficult for people who are interested in earning an honest and legitimate income.
It should be obvious these days that every piece of information or advertisement on the internet is not true. While the internet is still seen as a reliable source of information overall, literally anyone can create a website and post anything they want online.
Medical billing and coding jobs are actually in high demand and according to the Bureau of Labor Statistics, a medical coder can make $16.42/hr on average for an annual salary of $34,160.
When in doubt and someone is promising you that you'll make an extremely large amount of money by doing a specific job, always double check with the Bureau of Labor Statistics to view a realistic salary that you can expect.
Most advertisers will have you hooked with the 'work at home' part of the deal. While some medical billers and coders can actually work from home some do not and a doctor or medical office is not going to hire someone in this field with absolutely no experience.
Medical billing and coding is a crucial part of the healthcare reimbursement process. Medical billers deal with private patient information like social security numbers and detailed medical histories so it's highly unlikely that someone with no experience or references would be able to work from their home with this type of private information.
The medical billers who do work from home often have several years of experience under their belt.
While you don't need a college degree to get into this field, you need some sort of training or skillset to be able to find legitimate work and the same goes for any type of work-from-home job.
If it were so easy to work from home and earn a great income in 30 days or less with no training or skills, then we all would be doing it, but that's simply not the case.
Becoming certified for medical billing and/or coding can certainly help you find work in the field quicker. It can take anywhere from six month to one year to master the medical terminology, software systems and skill set required to be successful at the job. Anyone who promises you a certificate and job placement in less time than that is most likely running a scam.
There are some reputable online training programs that can help you get certified but there are also some fraudulent ones out there as well. It's important to make sure the service you are considering going with is accredited the Better Business Bureau and affiliated with major professional associations like the American Association of Professional Coders.
Hundreds of community colleges and technical schools offer training programs and may offer some online course options as well so it would be a good idea to start looking at institutions in your area.
Medical billing and coding is not just another dead end job and if you're interested in earning extra money or making a career out of it, you can definitely do it by avoiding common scams.
Have you ever come across a work-from-home scam? Do you think medical billing and training programs are worth it?
I always struggle with education courses that are advertised on TV, somehow it just seems to undermine their credibility. Interesting to hear your experience with this type of program though. Sounds like my bias isn't really correct!
I agree. I would've assumed that it's all a scam. Very good to know that there are actually legit medical billing jobs out there!
The other thing to be wary of is student loans. Many, not all, " For Profit" colleges are overpriced compared to a local community college. Some people have gotten a lame education that doesn't actually get them a job but they still have govt student loans that must be paid back. Which is hard to do if you didn't get a good enough education to get a job. These " For Profit" schools have a much higher default rate on student loans then a traditional public college.
They sound pretty sketchy to me. When in doubt, I'd always choose a community college or a public university. They might not be as fancy and high-tech, but you'll still get the education you need from an accredited institution.
Medical coding and billing and similar fields like medical and nursing assistant are perfect for families looking for a skilled career with reasonable education requirements, but you have to be very careful with the schools that offer the programs. For profit schools and advertising for easy loans is something to take a double look at. If you can find the right schools offering the programs, then you should be alright.
If you want to become a Certified Coder and make an average of $50,000 annually, all you need is a good coding prep course. Most Medical Billing and Coding Schools do not prepare you for the coding certification exam. They only prepare you for entry level billing positions at best, not the high paying remote medical coding positions that are in demand. Today, most employers require that their coders be certified. Also, you don't need a medical billing and coding degree or certificate to sit for the board exam. So if the program is not licensed by the AAPC (the coding certification for physicians), or AHIMA (for facilities), you may very likely be wasting your money. My advice, go to the certifying agencies and choose one of their coding preparation providers from their website. These coding prep courses are far less expensive too, and the prep courses affiliated with the certifying agencies have the only curriculum appropriate for students to pass their very complex board exams.
Medical billing is really a central pillar of any health care practice. It can help alleviate that burden, but it might end up being more expensive. In emergency conditions, insurance will still cover. The insurance company has a formula to calculating payment. Insurance is good for doctor and patient.
Has anyone heard of "American Career College"?
They currently offer the program and I am considering it. However, I just can't seem to find the right, un bias, review of them.
Medical billing and coding itself isn't a scam, but a lot of the schools that offer MB&C programs are scammy/low quality schools, so I think that's why it gets a bad rap.
Now is Penn Foster a good school for Medical billing and Coding?


The Municipal District of Bonnyville is currently seeking a dynamic individual to fulfill the role of Director of Infrastructure Services.
Our rural community (www.md.bonnyville.ab.ca) is a thriving municipality in northeastern Alberta, 2.5 hours northeast of Edmonton. The M.D. has a fantastic community base of 12,000 residents, and an excellent, growing economy consisting largely of agriculture and oil-related industries.
Reporting to the CAO, the Director of Infrastructure Services is responsible for the direction, and coordination of the activities of the M.D. Infrastructure department. This position oversees three direct reports, 55 full-time staff, approximately 50 seasonal, and is responsible to manage an estimated annual budget of $40M.
Provide leadership, adapt and integrate complex manners to ensure a clear understanding of Council objectives are reached in consultation with the CAO.
Provide recommendations to the CAO on the operating procedures required for fulfillment of municipal goals.
Control and monitor operating and capital budgets for the department.
Understand all relevant/applicable legislation and ensure the provisions of each are maintained.
Possess knowledge in strategic planning, and organizational development.
Provide the necessary skillset as an intricate member of the senior management team.
Develop positive team relations that encourage staff engagement within the department.
A competitive salary and comprehensive benefits package is available. Specifics will be discussed in a personal interview.
Please visit http://md.bonnyville.ab.ca/jobs.aspx for a full job description.


Last year I had the very great pleasure of meeting an inspirational young woman Kate at the BILD annual conference.
Kate works full time for the British Institute of Learning Disabilities and lives independently with support. Kate has Down's Syndrome, a social life you would be proud of, a house and mortgage, and told me how her Mum worried about her when she left home, but that she's just fine.
Read here about how meeting Kate and others really was life-changing for me.
Kate was recently chosen to take part in a TV show called The Undateables, a kind of dating agency programme for those with disabilities and learning disabilities.
Whatever you think of the programme (I for one can't get past the show's title) I urge you to watch to support the incredible Kate. The show airs at 9pm on Tuesday 22nd January. I just know Kate will shine and be an ambassador for us all.
She was also interviewed on ITV This Morning, Tuesday 8th January by Phillip and Holly.
I just saw this show last night and I think its awesome!I have worked with children with challeneges since I was achild myself.They all need love!The biggest disabbility is the way people react!


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Rand Paul Rails Against Pregnant Women and Medicaid
Oct 6, 2010, 4:46pm Amie Newman
In his latest rant, GOP candidate for U.S. Senate Rand Paul tells supporters that those pregnant women using Medicaid to access care may just be milking the system.
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I'm not sure what planet Rand Paul is living on but in his world, pregnant women in Kentucky who make 185 percent of the federal poverty level are taking advantage of Medicaid funded prenatal care.
Republican GOP candidate for U.S. Senate, told a group of business leaders on Monday that "we've made it too easy" for many of the lower income residents in his state to access Medicaid:
"Half of the people in Kentucky are not poor," he said. "We've made it too easy. And people are going to say, 'Oh, that's harsh, you can't say that.' Well, let's take care of those who are truly in need, which would be a small percentage of the public. Let's take care of them until they can take care of themselves.
Almost half of the 57,000 births in Kentucky are covered through Medicaid funding, notes the article. But it's not only pregnant women whom Rand targets – it's children, and senior citizens as well. Basically he's referring to all of those crooks who take advantage of a state's public health funding, who should apparently be able to "take care of themselves" when it comes to paying for health care.
"Let's not have intergenerational welfare, and that's what's been going on and that's a large part of this problem."
Considering Kentucky receives an "S-" (Satisfactory minus) for its maternal mortality rates from the CDC rating 22 out of 50 states, Rand may want to focus his efforts in another direction. And let's not forget that Rand Paul is one of the most radical candidate voices on restricting pregnant women's ability to make their own medical decisions; who believes that even rape and incest victims who become pregnant as a result, should be forced to bring the pregnancy to term.
birth, Kentucky, Medicaid, Pregnancy, Rand Paul, U.S. Senate

redpajama_set_name: RedPajamaCommonCrawl


being little • bristol uk fashion & lifestyle blog.: festival glam.
This month's GlossyBox theme is "festival glam". What they see as the essentials for looking good at a festival. I can see all these products coming in very handy, and they're all little so they wouldn't take up much room in your backpack! Unfortunately, I'm not attending any festivals this year :( but I still enjoyed testing them out over the past week!
1. This can be used on lips or cheeks, but I'm quite wary of using some products on my face, so I just stuck to applying it to my lips. The smell is so yummy, I wanted to squirt the whole tube directly into my mouth. But I didn't, and I love the pink shine it gives to my lips!
2. I haven't noticed a great difference after using this, but I love the way the gel feels - it's so different to anything else I use and so I enjoy the texture. My skin is looking generally better at the moment (partly due to the sun, and partly to the Elizabeth Arden skincare, I think) and this is probably slightly boosting it further.. it's hard to tell!
3. This calming cream is supposed to neutralise the redness in skin. I've used it every day for the past week, and I can't say I've noticed much of a difference. This could be because I don't have much redness in my skin though..
4. I found this texturizing spray made my hair feel quite dry, but apart from that it did nothing whatsoever. I have very thick hair and it takes quite a lot of product to have an effect. I personally wouldn't buy this, but I'd be interested to know if it works on finer hair.
5. The coral-pink tone of this eyeshadow made me quite scared of using it, but when on the skin it's very subtle and pretty. It gives a slight shimmer and extra dimension to my eyelinered eyes. This has become a staple in my make up bag, and I will definitely buy another when this runs out!
6. The Elizabeth Arden samples were a bonus product this month! And I was very happy to receive them, as I've heard great things about their products. The exfoliating cleanser and optimizing skin serum are lovely to use, and make my skin feel lovely. The SPF lotion made my face an oily mess, however, so I won't be using that again!
Overall a very good box, I think! What do you think of the festival glam GlossyBox?
You can also now find them on instagram @glossyboxuk !
Massively tempted to order Glossybox after seeing this! I love the sound of the lip frosting!
oh my gosh! I've been wanting a glossybox! looks amazing!
i haven't used anything of those!


Continuing our coverage on the ultimate batshit-crazy cool sequel that is LittleBigPlanet 2, here's another shot at awesomeness with the sequel's game creator tools.
Sony and Media Molecule's LittleBigPlanet 2 continues to overachieve in an unprecedented way by thrashing us silly with their insanely fun and innovative game creation mode in the much anticipated sequel slated to to be released on 18th January.
In the below video, beta user POLLOIZARRARAZ43 mashes Sackboy in various outfits of well-known characters from Marvel, Capcom, and Sony (mainly Kratos, Solid Snake, and some of the big wigs you can find in PlayStation 3's catalogue) to create an ultimate cross-over fighting game, Sony Vs.Marvel Vs. Capcom.
And that's one incredibly innovative use of the many outfits of Sackboy.
And if you think that's pushing the game's ridiculously awesome game creator tools's limit, here's something else to knock your jaw off.
Here's Guile versus some the Street Fighter characters in his very own Street Fighter 2 stage.
As a drastic change of environment, here's Sackboy in his Wolfenstein adventure.
... As compared to the original Wolfenstein 3D, embedded below.
And here's Sackboy in Konami's Zone of the Enders!
Some "Black Ops" action in Vietnam as Sackboy engages in a pseudo-FPS adventure.
LittleBigPlanet 2 is scheduled to be released on January 18th, 2011.


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US launches airstrike on Taliban in Afghanistan for the first time in months
US forces in Afghanistan launched an airstrike on the Taliban for the first time since February. Last night's attack served to protect Afghan government forces, an army spokesman reported. Five Taliban fighters would have been killed.
The attack would not violate the agreements made by the US government and the Taliban at the end of February, the Americans said. The two sides then agreed to leave each other alone as much as possible and to work on the release of prisoners, a truce, and peace negotiations in Afghanistan. Washington aims to bring the remaining troops home with the deal with the Taliban.
President Trump's policy aims to diminish the US's role in foreign conflicts and, as far as possible, end costly foreign military intervention and spend less money on NATO.
The battle with the Taliban began with the US invasion of that country in 2001 and is now the longest war the United States has ever waged.
Since the agreements in February, the Taliban have spared the foreign military in the country, and the Americans have hardly launched any attacks on the Taliban. Earlier this month, however, the Taliban charged that US forces had done so in Helmand province.
Afghanistan Taliban United States
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text:
Subscriber Since
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TMBBQ Club
Top 50 BBQ Joints
Texas Monthly
Chief Accessory
Quanah Parker's majestic headdress.
Lonn Taylor
https://www.texasmonthly.com/the-culture/chief-accessory/
From the January 2016 Issue Subscribe
Photograph by Darren Braun
During the latter years of his life, Quanah Parker was the best known of all the Comanche, and his is still a name to conjure with in Texas more than a century after his death. He was born around 1852, the son of war chief Peta Nocona and a white woman named Cynthia Ann Parker, who was captured in 1836 during a raid at Fort Parker. Quanah grew up to become a warrior in a culture that measured a man by the number of horses and captives and scalps he took; he died an honored statesman who wore the white man's clothes and lived in a ten-room house. But he never abandoned the Comanche ways. As his biographer William T. Hagan writes, he had "one foot on the white man's road and the other on the old Comanche trail."
There is little reliable information about Quanah's early life. When he was approximately nine, Cynthia Ann was recaptured by whites at the Battle of Pease River, in present-day Foard County; two years after that his father died. In later life he recalled that he was a participant in the Second Battle of Adobe Walls, in June 1874, in which several hundred Comanche, Kiowa, Arapahoe, and Cheyenne attacked 28 buffalo hunters but were repelled after a five-day siege. The following May he was part of the Comanche band that surrendered to Colonel Ranald Mackenzie after the Red River War, agreeing to live on the reservation at Fort Sill, Oklahoma. Quanah was approximately 23 years old.
Reservation life for the Comanche meant subjecting themselves to the government's attempt to eradicate their free-range hunting and warring native culture and turn them into settled farmers. The first step in this process was abandoning their annual buffalo hunts and instead drawing government rations of beef, sugar, flour, and coffee. Quanah's inherent leadership qualities caught the eye of reservation agent James M. Haworth, who in 1875 appointed him head of a beef band, a group of families who drew their rations together.
Quanah rose in stature on the reservation. He realized the futility of continued Comanche resistance and saw that compromise with the federal government was the only path to survival. At the same time, he urged the preservation of as many Comanche customs as possible. He preached cooperation with the authorities in most matters, and in turn the authorities trusted him, describing him on one occasion as "a particularly progressive Indian." By 1878 he headed the third-largest band on the reservation, with 93 members. It was at about this time that he adopted his mother's surname, and a few years later the letterhead on his stationery proclaimed him to be "Quanah Parker, Principal Chief of the Comanche Indians."
Quanah's rise to chiefdom was by the assent of his fellow tribesmen, not by appointment or election. He first emerged as a defender of Comanche interests in the early 1880's, when he put together a shrewd alliance between his tribesmen and a group of Texas ranchers, including Burk Burnett and Dan Waggoner, to persuade the government to allow the tribe to lease its unused reservation grasslands. The leases brought income to every Comanche in the form of "grass money" and benefited Quanah personally, as he received a retainer from Burnett and Waggoner to ensure the leases' annual renewal. The alliance later helped Quanah delay efforts by Congress to turn the three-million-acre Comanche reservation over to white settlement, a fight he ultimately lost.
Quanah's defense of his native customs included the tribesmen's right to take as many wives as they could afford. Quanah himself had at least five at one time, and government officials continually harassed him about his polygamy. His position as presiding judge of the reservation's Court of Indian Offenses was threatened because of his plural marriages, and when he requested government funds to build his sprawling ten-room, two-story home, known as the Star House, he was told that no assistance would be granted to him unless he agreed to live with only one wife. He traveled to Washington, D.C., to discuss the matter with Thomas Morgan, the commissioner of Indian Affairs, and purportedly told him that he would agree to those conditions if Morgan would be the one to tell the other wives to leave. Eventually his Texas rancher friends paid for the house.
Quanah also sustained the use of peyote in religious ceremonies, a practice that increased in the 1880's and eventually became the foundation of the Native American Church. Starting in 1888, three successive agents at the Fort Sill reservation issued orders forbidding their Indian charges to use peyote in any form, and Quanah blandly assured each that his people were complying while he continued to function as a Road Man, or leader in the peyote ceremony. The secrecy that surrounded the ceremony made this deception possible. Quanah believed that peyote offered solace to his people and defended the practice by saying, "The white man goes into his church house and talks about Jesus, but the Indian goes into his tipi and talks to Jesus."
By the late 1890's Quanah had become a national celebrity. He made numerous well-publicized trips to Washington to represent Comanche interests, and in 1905 he rode down Pennsylvania Avenue in Theodore Roosevelt's inaugural parade, clad in buckskin and wearing a feathered headdress. He also led parades at the Fort Worth Fat Stock Show and the Texas State Fair, in Dallas, and he was much in demand for Fourth of July parades in Oklahoma. Quanah died in 1911, but the headdress he wore on these occasions is now in the Panhandle-Plains Historical Museum, in Canyon. It is a magnificent assemblage of 62 golden eagle feathers, each trimmed at the top with red turkey or rooster hackles and horsehair and attached to a felt cap and a trailer that falls nearly to the floor. It was a gift to the museum in 1960 from Topay, Quanah's last surviving wife, a fitting memento of a man who spent his life trying to guide his people along the white man's road while preserving their identity as Comanche.
Panhandle-Plains Historical Museum, 2503 Fourth Ave, Canyon (806-651-2244). Open Tue–Sat 9–5 from September through May; Mon–Sat 9–6 from June through August.
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Tags: History, The Culture, Artifact, commanche, fort parker, quanah parker
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My friend Doug Parker is a direct descendant of that great man… Thank you Doug for posting this informative piece.
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At a press conference today in Ottawa, members from the Standing Senate Committee on Banking, Trade and Commerce (Deputy Chair Joseph A. Day and Douglas Black) announced the release of their report on the operations and practices of the Copyright Board of Canada. The report, which was officially tabled in the Senate on November 30, follows two days of hearings held by the Committee earlier in November. The Committee heard from representatives from the Board, stakeholders, academics and experts. Music Canada took part in the hearings, with President & CEO Graham Henderson appearing before the committee on November 2.
The report, titled Copyright Board: A Rationale for Urgent Review, is a timely and insightful assessment of the current tariff-setting process and its shortcomings. The Report correctly notes that the Committee's witnesses agreed that the Board's biggest challenges are delay and unpredictability, while also highlighting potential areas for improvement, such as the imposition of deadlines, case management, simplified/expedited procedures, full-time members, and the elimination of retroactive decisions.
Music Canada applauds the Committee's leadership and recommendation for an urgent, in-depth review.
Music Canada looks forward to working with the government on this issue as we approach the 2017 review of the Copyright Act. A more efficient and predictable tariff-setting process is something that all Board stakeholders can aspire to, and we welcome the Committee's recognition of the urgency of this issue.


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CAK Partners with Full Sail University
John Sessoms
An exciting partnership between CAK's digital media program, Warrior Network, and Full Sail University has been established!
The digital media program at Christian Academy of Knoxville has recently been named a Full Sail University High School Partnership Program for its emphasis on creative thinking and hands-on curricula encouraging students to pursue their dreams within the entertainment, media, arts, and technology industries.
The Full Sail University's High School Partnership Program identifies and supports distinguished high school programs nationwide focused on career and technical pathways. All qualifying programs exhibit a focused curriculum track, utilize industry tools, demonstrate project-based learning, and are led by distinguished educators who encourage creative communities.
The digital media program at Christian Academy of Knoxville is a tier-based program that allows students the opportunity to not only gain a solid foundation in the industry but to be fully immersed in it from day one. Students complete the multi-year program having had hands-on experience with audio, advanced lighting, editing, multi-camera productions, newscasts, cinematic short films, podcasts, interviews, live event broadcasting through the Warrior Network, and much more. Leading the digital media program is Johnathan Sessoms who taught at Full Sail University for seven years as well as has over 15 years of experience working in the entertainment industry.
"I am beyond excited to merge two of my favorite places together and partner Full Sail University with CAK. Having taught there myself, I can see that we're bringing something really special to our Digital Media Program through Full Sail's outstanding industry-leading education." says Sessoms.
CAK is thrilled to be partnering with Full Sail University by providing a pathway for our digital media students to further their education in this high-demand field.
A proud supporter of creativity throughout its over 40-year history, Full Sail University is dedicated to the encouragement and development of future generations of entertainment and media professionals. Therefore, graduates from CAK will qualify for a $15K Gateway Scholarship* for High School Seniors offered exclusively to High School Partnership Program students looking to further education at Full Sail University.
* Award recipients must also meet the University's admission requirements in order to qualify. See the University's Catalog for more information on the requirements for admission. Financial aid is available for those who qualify.


The Widdler at Little Harpeth Brewing in Nashville, Tennessee on Friday, August 17, 2018.
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I want to start off by making it clear that I am in no way an arsonist, or obsessed with fire. I don't even like it more than any other person, but along with water, it's one of the most profoundly important components of the universe. We need both of these two things to survive, even long before we could manipulate and control the former, or make the latter safe enough to drink. The control of fire is believed to have first been done by the ancestors of man between one and two million years ago. This marked a turning point in our history. It allowed us to keep warm, ward off predators, and cook our food. As I said in my Stepwisdom series, we do not know of a single civilization that did not cook its food. Wow, a lot of these entries are repeats. Does that make me wise? I don't know, you tell me...but yes. What I said about it there is that the intense heat is primarily good for killing off pathogens, but that's not all. Despite what you may have been told about the raw food craze, cooked food is not only perfectly acceptable, but healthy. Fad dietitians may claim our species has not had time to adapt to modern foods, and in some cases, this is true, especially when it comes to synthetic ingredients. But you would be surprised how quickly we can change in but a few generations. Our bodies have evolved to digest cooked food, and absorb the majority of its nutrients. Likewise, we've evolved out of the ability to live on a lot of raw foods, particularly meats. Meanwhile, our carnivorous animal brethren are completely fine with tearing the flesh off a fresh kill. I won't say anything further about it, nor will I go over yet again the benefits of drinking water. Both deserved to be on this list, but you don't need a master's thesis on them.


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PHF21B overexpression promotes cancer stem cell-like traits in prostate cancer cells by activating the Wnt/β-catenin signaling pathway
Qiji Li1,2,
Liping Ye3,
Wei Guo1,2,
Min Wang1,2,
Shuai Huang1,2 &
Xinsheng Peng ORCID: orcid.org/0000-0001-7949-299X1,2
PHF21B is newly identified to be involved in the tumor progression; however, its biological role and molecular mechanism in prostate cancer have not been defined. This study is aimed to study the role of PHF21B in the progression of prostate cancer.
Real-time PCR, immunohistochemistry and western blotting analysis were used to determine PHF21B expression in prostate cancer cell lines and clinical specimens. The role of PHF21B in maintaining prostate cancer stem cell-like phenotype was examined by tumor-sphere formation assay and expression levels of stem cell markers. Luciferase reporter assay, western blot analysis, enzyme-linked immunosorbent assay and ChIP assay were used to determine whether PHF21B activates the Wnt/β-catenin signaling by transcriptionally downregulating SFRP1 and SFRP2.
Our results revealed that PHF21B was markedly upregulated in prostate cancer cell lines and tissues. High PHF21B levels predicted poorer recurrence-free survival in prostate cancer patients. Gain-of-function and loss-of-function studies showed that overexpression of PHF21B enhanced, while downregulation suppressed, the cancer stem cell-like phenotype in prostate cancer cells. Xenograft tumor model showed that silencing PHF21B decreased the ability of tumorigenicity in vivo. Notably, Wnt/β-catenin signaling was hyperactivated in prostate cancer cells overexpressing PHF21B, and mediated PHF21B-induced cancer stem cell-like phenotype. Furthermore, PHF21B suppressed repressors of the Wnt/β-catenin signaling cascade, including SFRP1 and SFRP2. These results demonstrated that PHF21B constitutively activated wnt/β-catenin signaling by transcriptionally downregulating SFRP1 and SFRP2, which promotes prostate cancer stem cell-like phenotype.
Our results revealed that PHF21B functions as an oncogene in prostate cancer, and may represent a promising prognostic biomarker and an attractive candidate for target therapy of prostate cancer.
Prostate cancer (PCa), one of the most lethal malignancies, constitutes 19% of all cancers diagnosed in men, with an estimated 161,360 new cases in the United States in 2017 [1]. While clinically localized PCa can be well controlled through radical prostatectomy, the 10-year recurrence rate in the intermediate and high risk localized PCa cases was 54% and 71%, respectively [2], leading to insurmountable obstacles for improving the survival rate [3, 4]. For patients with advanced prostate cancer, androgen deprivation therapy (ADT) has been the standard therapy. However, most patients relapse and develop castration-resistant prostate cancer within 18–24 months following ADT [5]. Cancer stem cells (CSCs), a small subpopulation of cancer cells, which possess self-renewal and multilineage differentiation potential, have been reported to play a critical role for PCa [6, 7]. CSCs are responsible for tumor initiation, chemotherapy resistance and become enriched after ADT treatment, which leads to poor outcomes and recurrence in PCa patients [8,9,10,11,12,13]. Therefore, unveiling the underlying molecular mechanism of prostate CSCs turns out to be the essential and profound topic for PCa treatment.
The Wnt/β-catenin signaling pathway, which is one of the most relevant pathways involved in CSCs, has been reported to be aberrantly activated in various types of cancers, including PCa [14,15,16]. Previous studies have shown that canonical Wnt signaling passway is associated with chemoresistance and recurrence of PCa [17,18,19,20]. Yun et al. reported that DAB2IP knockdown promotes PCa stem cell phenotypes through activation of Wnt/β-catenin signaling, and increases PCa cells chemoresistance [13]. Moreover, Huang et al. revealed that genetic variations of adenomatous polyposis coli (APC), tumor suppressor involved in the Wnt signaling pathway by regulating β-catenin degradation and nuclear export, are associated with recurrence of PCa following radical prostatectomy [18]. However, the underlying mechanism of how Wnt/β-catenin signaling regulates prostate CSCs remains to be elucidated.
Wnt/β-catenin signaling is initiated by the binding of Wnt to Frizzled (FZD) receptor and LRP-5/6, leading to the stabilization of cytosolic β-catenin [21, 22]. β-catenin then translocates to the nucleus and regulates the expression of a number of genes implicated in prostate CSCs regulation [13, 23]. On the other hand, there are several negative modulators involved in the Wnt/β-catenin signaling pathway for fine tuning the signaling. For instance, secreted Frizzled-related proteins (SFRPs), extracellular secreted Wnt inhibitors, can suppress Wnt ligands binding to frizzled receptor and block signal transduction [24]. Axin, GSK-3β and APC cause a robust suppression in the activity of Wnt/β-catenin signaling by forming a destruction complex and inducing β-catenin degradation [25]. Thus, understanding how these negative regulatory effects on the Wnt/β-catenin signaling pathway is clinically important for future development of PCa treatment.
Previous study has shown that proteins of the PHD zinc finger superfamily are capable of translocating to the nucleus and regulating transcription of genes, and involve in tumor progression in various types of cancers, including PCa [26,27,28,29]. High levels of PHF8 were associated with high Gleason grade and poor prognosis in PCa, and strengthened PCa cell migration and invasion in vitro [28]. Moreover, recently, Lapuk et al. found that PHF21A is differentially spliced in highly proliferative and aggressive neuroendocrine prostate cancer (NEPCa) versus PCa [29], in which these alternatively spliced genes were involved in EMT and important for cell shape and invasion. PHF21B, encoding the PHD finger protein 21B, is homologous to PHF21A and acts as a transcriptional repressor like PHF21A [30]. Previous study has reported that PHF21B was downregulated in head and neck squamous cell carcinomas (HNSCC), and reduced MDA-MB231 cells migration and colony formation in vitro [30]. However, the clinical implications and function of PHF21B in PCa have not been defined. In the present study, we found that PHF21B was significantly overexpressed in PCa and enhanced the stem cell-like traits of PCa cells by downregulating of negative modulators of the Wnt/β-catenin pathway, including SFRP1 and SFRP2. Therefore, our results suggest that PHF21B might serve as a novel therapeutic target in PCa.
RWPE-1, PC-3, DU145, C4-2B, VCaP and LNCaP cells were obtained from the ATCC (Manassas, VA, USA). RWPE-1 cells were cultured in defined keratinocyte-SFM (1×) (Invitrogen, Carlsbad, CA, USA). PC-3, C4-2B and LNCaP cells were cultured in RPMI 1640 medium (Invitrogen) supplemented with10% FBS (Invitrogen), while DU145 and VCaP cells were cultured in Dulbecco's modified Eagle's medium (Invitrogen) supplemented with10% FBS.
Patient information and tissue specimens
A total of 116 paraffin-embedded and archived PCa samples were collected for this study, which had been diagnosed histopathologically. Clinical information on the samples is summarized in detail in Additional file 1: Table S1. The fresh tissues including eight paired PCa tissues and adjacent non-tumor tissues were obtained from individuals who were diagnosed with PCa. All samples were collected from the First Affiliated Hospital of Sun Yat-sen University. Prior patient's consents were obtained to use these clinical specimens for research purposes. Our study was approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University according to the 1975 Declaration of Helsinki.
Plasmids, virus constructs and retroviral infection of target cells
A human PHF21B cDNA clone (EX-T2701-Lv105), as well as short hairpin RNA (shRNA) expression clone (HSH001525-CU6), was purchased from GeneCopoeia (Guangzhou, China). SMARTpool siRNA against human SFRP1, SFRP2, and β-catenin was purchased from RiboBio (Guangzhou, China). The reporter plasmids containing wild-type (CCTTTGATC; TOP flash) or mutated (CCTTTGGCC; FOP flash) TCF/LEF DNA binding sites were purchased from Upstate Biotechnology (New York, USA). Transfection of plasmids or siRNA was performed using the Lipofectamine 3000 reagent (Invitrogen, Carlsbad, CA, USA) according to the manufacturer's instruction. Stable cell lines expressing PHF21B and PHF21B-shRNA were generated by retroviral infection and selected with 0.5 μg/ml puromycin for 10 days.
RNA extraction, reverse transcription (RT) and real-time PCR
Total RNA was extracted from cultured cells and PCa tissues using the Trizol reagent (Invitrogen, Carlsbad, CA, USA) according to the manufacturer's instructions. A total of 2 μg of RNA was reverse transcribed to cDNA with M-MLV Reverse Transcriptase (Promega, Madison, US). qRT-PCR analysis was performed on an ABI Prism 7500 Sequence Detection System (Applied Biosystems, Texas, US). Expression data were normalized to the housekeeping gene GAPDH. Relative expression levels were calculated as 2-[(Ct of gene) - (Ct of GAPDH)], in which Ct represents the threshold cycle for each transcript. The PCR primer sequences are listed in Additional file 2: Table S2.
Western blotting was performed as described previously [31], using anti-PHF21B (ab70435, 1:1000; Abcam, Cambridge, UK), anti-β-catenin (#9562, 1:1000; Cell Signaling, Danvers, MA, USA), anti-phospho-β-Catenin (Ser33/37/Thr41) (#9561, 1:1000; Cell Signaling), and anti-p84 (ab102684, 1:500; Abcam) antibodies. Blotting membranes were stripped and re-probed with anti-α-tubulin antibody (T6199, 1:2000; Sigma-Aldrich, St. Louis, MO, USA) as a loading control. Nuclear extracts were prepared using the Nuclear Extraction kit (Active Motif), according to the manufacturer's instructions.
Immunohistochemical (IHC) analysis was conducted to study protein expression in clinical specimens. The procedure was carried out similarly to previously described methods [32]. After deparaffinization, the sections were immunohistochemically stained using anti-PHF21B (HPA053834, 1:2500; Sigma-Aldrich), and anti-β-catenin antibody (#9562, 1:200; Cell Signaling). The degree of immunostaining offormalin-fixed, paraffin-embedded sections was examined and scored independently by two pathologists. The scores were determined by combining the proportion of positively stained tumor cells and the intensity of the IHC signals. Tumor cell proportions were scored as follows: 0, no positive tumor cells; 1, 1%-25% positive tumor cells; 2, 25%-50% positive cells; 3, 50%-75% positive tumor cells; and 4, >75% positive tumor cells. Staining intensity was graded according to the following criteria: 0, no staining; 1, weak staining (light yellow); 2, moderate staining (yellow brown); and 3, strong staining (brown). The staining index (SI) was calculated as the staining intensity score × the proportion of positive tumor cells (ranging from 0 to 12). We evaluated protein expression by determining the SI. Samples with an SI ≥ 6 were classified as showing high expression, while samples with an SI < 6 were classified as showing low expression.
Enzyme-linked immunosorbent assay (ELISA)
Using a commercially available SFRP1 (E95880Hu) and SFRP2 (E95879Hu) ELISA Kit (USCN, Wuhan, China), the concentration of SFRP1 and SFRP2 in the conditioned media (CM) derived from the cells was determined. ELISA was performed according to the directions of the manufacturer.
Sphere formation assay
Cells (500/well) were seeded into 6-well ultra-low cluster plates (Corning, NY) and cultured in DMEM/F12 serum-free medium (Invitrogen) supplemented with 2% B27 (Invitrogen), 20 ng/ml EGF (PeproTech, Rocky Hill, NJ, USA), 20 ng/ml bFGF (PeproTech), 0.4% BSA (Sigma-Aldrich), and 5 μg/ml insulin (Sigma-Aldrich). After 10 days, the number of spheres was counted, and images of the spheres were photographed.
Luciferase activity assay
Thirty thousand cells were cultured in triplicate in 48-well plates for 24 h. Then, 100 ng of luciferase reporter plasmids containing the SFRP1 and SFRP2 promoter, TOP-Flash or FOP-Flash luciferase reporter, plus 3 ng of pRL-TK Renilla plasmid (Promega), were transfected into cells using the Lipofectamine 3000 reagent (Invitrogen, Carlsbad, CA, USA) according to the manufacturer's recommendations. Luciferase and Renilla signals were measured 36 h after transfection using the Dual Luciferase Reporter Assay Kit (Promega) according to the manufacturer's protocol.
Specific primers used for promoter luciferase reporter were presented in Additional file 3: Table S3.
The promoter sequences of SFRP1/2 were obtained from the UCSC Genome Browser (http://genome.ucsc.edu) referring the enrichment of H3K27Ac mark (often found near active regulatory elements) on seven cell lines as determined by ChIP-seq assays provided by the website. Each of the cell lines including GM12878, H1-hESC, HSMM, HUVEC, K562, NHEK, NHLF in this track is consistent across the ENCODE (Encyclopedia of DNA Elements) Regulation super-track.
Chromatin immunoprecipitation (ChIP)
The SimpleChIP Enzymatic Chromatin IP Kit with magnetic beads (#9003, Cell Signaling, Danvers, MA, USA) was used according to the manufacturer's protocol. Cells (4 × 106) transfected with Flag-tagged PHF21B (EX-T2701-Lv102; GeneCopoeia, Guangzhou, China) in a 100 mm culture dish were treated with formaldehyde to cross-link proteins to DNA. 1× Glycine was added to terminate cross-linking. A total of 5 μg of anti-FLAG antibody (SAB4200071; Sigma, St Louis, MO, USA),) or anti-IgG antibody was incubated with 10 μg of sheared chromatin overnight at 4 °C. ChIP-grade protein G magnetic beads were added and incubated for 2 h at 4 °C with rotation. Immunoprecipitated chromatin was then washed with low- and high-salt ChIP buffer. After reverse cross-linking of protein/DNA complexes to free DNA, PCR was performed. Primers used for ChIP are presented in Additional file 4: Table S4–S5.
Xenograft tumor model
All experimental procedures were approved by the Institutional Animal Care and Use Committee of Sun Yat-Sen University. Male BALB/c-nude mice (4–6 weeks old, 18–20 g) were purchased from the Slac-Jingda Animal Laboratory (Hunan, China) and housed in barrier facilities on a 12-h light/dark cycle. Mice were randomly allocated into groups (n = 6 per group). The indicated cells at three doses (1 × 106, 1 × 105, and 1 × 104) were inoculated subcutaneously with Matrigel (final concentration of 25%) into the inguinal folds of the mice. Tumor volume was determined using an external caliper and calculated using the equation (L × W2)/2. After mice were sacrificed, the tumors were excised, weighed and subjected to pathologic examination. The frequency of tumor-initiating cells (TICs) was calculated using the Extreme Limiting Dilution Analysis (ELDA) program (http://bioinf.wehi.edu.au/software/elda/) [33].
All statistical analyses were carried out using the SPSS 17.0 statistical software package (SPSS Inc, Chicago, IL, USA). The relationship between PHF21B expression and the clinicopathological characteristics was tested by the χ 2 test. Bivariate correlations between study variables were calculated using Spearman's rank correlation coefficients. Survival curves were plotted with the Kaplan-Meier method and compared by the log-rank test. Other comparisons were analyzed by unpaired two-sided independent Student's t-test without equal variance assumption. P < 0.05 was considered statistically significant.
Expression of PHF21B is upregulated in PCa cell lines and tissues
By analysis of the RNA expression data from The Cancer Genome Atlas (TCGA), we found that PHF21B levels were significantly upregulated in human PCa tissues (n = 497) compared with that in normal prostate tissues (n = 52) (P < 0.001) (Fig. 1a). Overexpression of PHF21B in PCa was confirmed by analyzed prostate cancer GEO dataset GSE21032 (Fig. 1b). We further verified this result in PCa cell lines and paired tissues using realtime PCR and western blotting analysis. As shown in Fig. 1c-f, PHF21B expression levels were differentially increased in five PCa cell lines than that in normal prostate epithelial cell (RWPE-1), and in 8 PCa tissues (T) compared to that in the paired adjacent normal tissues (ANT). Collectively, these results suggested that PHF21B was upregulated and might be involved in human PCa progression.
PHF21B is overexpressed in PCa cell lines and tissues. a PHF21B mRNA levels in PCa tissues were assessed by analyzing the TCGA prostate adenocarcinoma mRNA dataset (PRAD, Normal, n = 52; Tumor, n = 497 (Left panel) and 52 paired adjacent non-tumor tissues (Normal) and PCa tissues (Tumor) (Right panel). Data were acquired from the TCGA data portal (https://portal.gdc.cancer.gov/). b PHF21B mRNA levels in PCa tissues were assessed by analyzing the GSE21032 PCa mRNA dataset (Normal prostate tissue (Normal), n = 29; Clinically localized primary PCa tissue (Tumor), n = 131; Data were acquired from the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/)). c-d Real-time PCR (c) and Western blotting (d) analyses to detect PHF21B expression in normal human prostate epithelial cell (RWPE-1) and cultured PCa cell lines. e-f Real-time PCR (e) and Western blotting (f) analyses of PHF21B expression in paired primary PCa tissues (T) and the matched adjacent non-tumor tissues (ANT) from eight prostate cancer patients (P1-P8). mRNA expression was normalized to GAPDH, and α-tubulin was used as a protein loading control. Data represent the mean ± SD of three independent experiments; *P < 0.05
Upregulation of PHF21B correlates with progression and poor prognosis in PCa
To investigate the clinical significance of upregulation of PHF21B in PCa, PHF21B protein expression was examined in 116 paraffin-embedded, archived PCa tissues using IHC. As shown in Fig. 2a-b and Additional file 1: Table S1, expression of PHF21B correlated significantly with tumor stage (P = 0.011), total PSA level (P = 0.005) and Gleason score (P = 0.001) in PCa. We further assessed the correlation between PHF21B expression and the prognosis of the patient by analyzing the TCGA prostate adenocarcinoma (PRAD) dataset. Notably, Kaplan-Meier survival analysis revealed that patients with high PHF21B expression had poorer recurrence-free survival (RFS) than patients with low PHF21B expression in TCGA (Fig. 2d, P = 0.022), indicating that PHF21B may have potential as an independent prognostic marker in PCa.
Upregulation of PHF21B correlates with progression and poor prognosis in PCa. a Representative IHC analyses of PHF21B expression in normal prostate tissue, low- and high-grade PCa specimens. b Percentage of PCa specimens showing low- and high-grade PCa relative to the level of PHF21B. c Kaplan-Meier analysis of recurrence-free survival curves for PCa patients with low PHF21B expression (PHF21B-L; n = 312) versus high PHF21B expression (PHF21B-H; n = 184) by analyzing the TCGA prostate adenocarcinoma dataset (P = 0.022, log-rank test)
PHF21B regulates the stem cell-like phenotype in PCa cells
It has been noted that obtaining a stem-like phenotype of PCa cells is critical for malignant tumor and high frequency of recurrence [8, 9]. We then investigated the role of PHF21B upregulation in the self-renewal ability of PCa cells. PCa cell lines C4-2B and PC-3 were engineered to overexpress or silence PHF21B via lentivirus infection (Fig. 3a-b). Sphere-formation assays showed that upregulating PHF21B increased, while downregulating PHF21B decreased, the number and size of tumor spheroids in C4-2B and PC-3 cells (Fig. 3c). In addition, pluripotency-associated markers, including NANOG, OCT4, SOX2, Bmi1 and c-Myc, showed significantly higher mRNA expression in PHF21B-transduced cells but much lower in PHF21B-silenced cells than in the control group (Fig. 3d-e). Thus, our results indicated that PHF21B promoted the stem cell-like phenotype in PCa.
PHF21B regulates the stem cell-like phenotype in PCa cells in vitro. a-b Western blotting of PHF21B protein expression in the constructed C4-2B (a) and PC-3 (b) cells. α-Tubulin was used as a loading control. c Representative images of spheres formed by the indicated cells. Histograms show the mean number of spheres. d-e Real-time PCR analysis of the expression of pluripotency-associated markers, including NANOG, OCT4, SOX2, Bmi1, and c-Myc, in the indicated cells. The expression of different stem cell markers in different groups was normalized to that in the PHF21B vector control group. Error bars represent the means ± SD of 3 independent experiments. * P < 0.05. Original magnification, c, ×100
PHF21B promotes PCa cells tumorigenicity in vivo
To further confirm the effect of PHF21B on PCa cell stemness, we subcutaneously inoculated different numbers of cells mixed with matrigel into the inguinal folds of BALB/c-nude mice. As shown in Fig. 4a-d, the tumors formed by PHF21B-transduced PCa cells, at both amount of 1 × 106, 1 × 105 or 1 × 104 cells, were dramatically larger than the vector control tumors. Conversely, PHF21B-silenced cells formed much smaller tumors and presented lower rates of tumorigenicity (Fig. 4a-d). Importantly, only PHF21B-transduced cells could form tumors when 1 × 104 cells were implanted (Fig. 4d). These results indicated that PHF21B strongly promoted PCa tumorigenicity in vivo.
PHF21B promotes PCa tumorigenicity in vivo. a Xenograft model in nude mice (n = 6/group). Tumors formed by PHF21B-overexpressing PC-3 cells were larger than vector-control tumors in the group receiving 1 × 106 cells. Conversely, tumors formed by PHF21B-silenced cells were smaller than tumors formed by control cells. Only PHF21B-overexpressing cells formed visible tumors following the implantation of 1 × 104 cells. Representative images of the tumors are shown. b Histograms showing the mean tumor weights of each group. c Growth curves of tumor formation after implantation. Mean tumor volumes are plotted. d Effect of PHF21B on the tumorigenic capacity of PC-3 cells. The frequency of TICs was calculated using the ELDA program. Error bars represent the means ± SD. * P < 0.05. P values were based on t-test unless otherwise indicated
PHF21B activates Wnt/β-catenin signaling pathway
Since Wnt/β-catenin signaling is one of the most important pathways in maintaining stem cell phenotype and frequently activates in PCa [16, 23], we then examined the role of PHF21B in Wnt/β-catenin signaling pathway. As shown in Fig. 5a, cellular fractionation and western blot analysis revealed that overexpression of PHF21B increased, while silencing of PHF21B reduced nuclear β-catenin expression. In addition, we found that PHF21B overexpression significantly increased, but silencing PHF21B reduced the TCF/LEF activities in PCa cell lines (Fig. 5b). Consistently, the expression of MYC, CD44, SOX9, MMP7, CCND1, LEF1, and NRCAM, which are well-characterized downstream targets of Wnt/β-catenin, were significantly increased in PHF21B-transduced cells but reduced in PHF21B-silenced cells (Fig. 5c). Collectively, our results suggested that PHF21B activated Wnt/β-catenin signaling pathway in PCa.
PHF21B activates Wnt/β-catenin signaling pathway. a PHF21B overexpression promoted the stabilization of cytosolic β-catenin, and increased β-catenin nuclear accumulation in indicated cells, as confirmed by western blot analysis. α-Tubulin and P84 were used as loading controls. b Luciferase-reported TCF/LEF transcriptional activity in the indicated cells. c Fold change of indicated genes mRNA expression in Real-time PCR analysis comparing cells overexpressing PHF21B versus Vector (V) or PHF21B-RNAi versus RNAi-vector (RNAi-V). d Knockdown of β-catenin with specific siRNA in PHF21B-overexpressing cells, as confirmed by western blot analysis. e Luciferase-reported TCF/LEF transcriptional activity in the indicated cells. f Histograms showing the mean number of spheres formed by the indicated cells. Each bar represents the mean ± SD of three independent experiments.*P < 0.05
We further investigated the functional significance of Wnt/β-catenin signaling activation in PHF21B-mediated self-renewal of PCa cells by silencing β-catenin in PHF21B-overexpressing PCa cell lines (Fig. 5d). As expected, the stimulatory effect of PHF21B on TOP/FOP luciferase reporter activity was impaired by silencing β- catenin (Fig. 5e). Moreover, sphere formation assays indicated that silencing β- catenin abrogated the promotive effects of PHF21B on self-renewal of PCa cells (Fig. 5f). Thus, these results reveal that activation of Wnt/β-catenin signaling was essential for PHF21B-promoted stem cell-like phenotype in PCa.
PHF21B suppresses the repressors of Wnt/β-catenin signaling pathway
PHF21B, with a PHD zinc finger domain, localizes to the nucleus and acts as a transcriptional repressor like PHF21A [30]. To investigate the mechanism by which PHF21B activates Wnt/β-catenin signaling passway, we examined whether PHF21B regulates the transcription of negative modulators in Wnt/β-catenin signaling. Indeed, SFRP1 and SFRP2 mRNA and protein expression were both downregulated in PHF21B-transduced PCa cells but upregulated in PHF21B-silenced PCa cells compared with control cells, revealing that SFRP1 and SFRP2 might be transcriptionally downregulated by PHF21B in PCa cells (Fig. 6a-d). As expected, luciferase reporter assays revealed that overexpression of PHF21B attenuated, whereas downregulation of PHF21B activated, the luciferase activity of SFRP1 and SFRP2 promoters in PCa cells in a dose-dependent manner (Fig. 6e-f). Furthermore, ChIP assays revealed that PHF21B was capable of binding to different fragment regions within the SFRP1 and SFRP2 promoters (Fig. 6e-f), suggesting that PHF21B transcriptionally downregulated SFRP1 and SFRP2 expression by directly targeting the SFRP1 and SFRP2 promoters.
PHF21B suppresses the repressors of Wnt/β-catenin signaling pathway. a-b Real-time PCR analysis of SFRP1(a) and SFRP2 (b) expression in the indicated cells. c-d ELISA analysis of SFRP1(c) and SFRP2 (d) expression in the indicated cells. e-f Left panel: Luciferase activity assays in PC-3 and C4-2B cells showed trans-inactivation of the SFRP1(e) and SFRP2(f) promoters by PHF21B overexpression and trans-activation by PHF21B silencing. Right panel: ChIP enrichment assay confirmed that Flag-tagged PHF21B binds to the promoter of SFRP1 (e) and SFRP2 (f); IgG was used as a negative control. Schematic illustration of the indicated nucleotide regions of the SFRP1 and SFRP2 promoters. H3K27Ac enrichment, indicating high transcription activity, is observed in the promoter elements according to Genome Browser Gateway website. g Luciferase-reported TCF/LEF transcriptional activity in the indicated cells. h Histograms showing the mean number of spheres formed by the indicated cells. Each bar represents the mean ± SD of 3 independent experiments.*P < 0.05
In addition, individual silencing of SFRP1 or SFRP2 potently rescued the TOP/FOP luciferase reporter activity and self-renewal ability in PHF21B-silenced cells (Fig. 6g-h and Additional file 5: Figure S1a-b), revealing that SFRP1 and SFRP2 were functional effectors of PHF21B on regulating Wnt/β-catenin signaling and stem cell-like phenotype in PCa. Moreover, as shown in the Figure S1a-b, SFRP1 was not significantly affected by SFRP2 siRNA, and SFRP1 siRNA had no effect on the SFRP2 levels, in PHF21B-RNAi#1 PCa cells, suggesting that either SFRP1 or SFRP2 siRNA rescued TOPflash activity and self-renewal ability in PHF21B-silenced cells was not attributed to the siRNA cross-reaction. Collectively, our results suggested that PHF21B activated Wnt/β-catenin signaling to enhance stem cell-like phenotype in PCa by transcriptionally downregulated SFRP1 and SFRP2.
Clinical relevance of PHF21B and β-catenin in human PCa
IHC analysis of PCa tissue specimens showed that PHF21B was positively correlated with β-catenin expression levels (P < 0.001, Fig. 7a). Collectively, these data further support the notion that PHF21B upregulation in PCa activates canonical Wnt/β-catenin signaling, ultimately leading to PCa progression.
Clinical relevance of PHF21B and β-catenin in human PCa. a Left panel: PHF21B expression was positively correlated with β-catenin expression levels in PCa tissue specimens. Two representative cases are shown. Negative controls for IHC analysis by substitution of the primary antibody with PBS were provided. Original magnification, ×400. Right panel: Percentage of PCa specimens showing low or high PHF21B expression relative to the level of β-catenin
Despite many recent advances, PCa continues to be the leading cause of male cancer-related mortality and morbidity. Most of PCa patients diagnosed with clinically localized disease can be successfully controlled by definitive treatments-radical prostatectomy or radiotherapy alone or in combination with androgen ablation. However, the 10-year recurrence rate is very high [2, 34]. In addition, almost all advanced PCa patients relapse and progress to lethal castration-resistant disease after initial response to androgen ablation [5]. The CSC has been proposed to be responsible for the high rate of relapse and subsequent resistance of advanced PCa to ADT. CSCs have been identified in many solid malignancies, including PCa [6], and have significant clinical implications, as targeting the CSC population may be essential in preventing the recurrence and progression of castration-resistant PCa [13, 17, 35].
Herein, we found that PHF21B acted as a potent CSC-promoting factor in PCa. Overexpression of PHF21B promoted, while downregulation reduced, the self-renewal of PCa cells and the expression of pluripotency-associated markers, including NANOG, OCT4, SOX2, Bmi1 and c-Myc. In addition, inhibition of PHF21B potentially reduced PCa cells tumorigenicity in vivo. Thus, our results suggested that upregulation of PHF21B is involved in the malignant progression of PCa, and proposed that PHF21B might be a potential therapeutic target for human PCa.
Wnt/β-catenin signaling pathway plays a key role in the regulation of CSC self-renewal and is aberrantly activated in PCa [14, 23]. In addition, the functions of Wnt/β-catenin signaling in PCa development and progression have been well documented. Mesd, a general Wnt inhibitor, suppressed Wnt/β-catenin signaling induced by Wnt1 in PC-3 cells, and inhibited PC-3 cells tumorigenicity in vivo [36]. Unlike in colon cancer, the mutations in β-catenin are rare, but the expression and/or nuclear localization of β-catenin are often abnormal in PCa, suggesting a constitutive activation of Wnt/β-catenin signaling [20, 37, 38]. However, how cancer cells escape the negative regulation by Wnt/β-catenin signaling cascade, leading to constitutively activated β-catenin/TCF remains unclear. Herein, we found that PHF21B was upregulated in PCa and induced activation of Wnt/β-catenin signaling via directly transcriptionally downregulating SFRP1 and SFRP2. Therefore, our findings not only confirmed activation of Wnt/β-catenin pathway contributes to the malignant behavior of PCa, but also revealed a novel mechanism for activation of Wnt/β-catenin pathway involving PHF21B in PCa.
In our result, we found that PHF21B was positively correlated with β-catenin expression levels in PCa tissue specimens (P < 0.001) (Fig. 7a). However, we also observed that 12 of 49 cases (~24%) of PCa with high PHF21B exhibited low protein level of β-catenin. Previous studies have found that human cancers exhibit substantial intra-tumor heterogeneity in transcriptional identities and gene expression [39]. Therefore, the mechanisms by which β-catenin protein is reduced in PCa tissues with high PHF21B might be attributed to tumor heterogeneity. Moreover, there might be some transcriptional cofactors [40] that bind PHF21B or block associations between PHF21B and the SFRP1 and SFRP2 promoters, under certain circumstances, thus inhibit trans-inactivation of SFRP1 and SFRP2. In addition, recruitment of chromatin-modifying factors might be another reason [41]. In this respect, further investigation of the mechanisms by which β-catenin protein is reduced in PCa with high PHF21B will eventually lead to the development of a new therapeutic strategy for the treatment of PCa.
PHF21B has been reported to be downregulated in HNSCC, and overexpression of PHF21B reduced MDA-MB231 cells migration and colony formation in vitro, suggesting it might act as a tumor suppressor in HNSCC and breast cancer [30]. However, in the current study, PHF21B was significantly upregulated in PCa, and enhanced the stem cell-like traits of PCa cells by activating the Wnt/β-catenin pathway. Therefore, the PHF21B may display both tumor suppressive and oncogenic properties depending on the tissue types and cellular conditions.
In summary, this study provided the first report of the expression of PHF21B in PCa cell lines and tissues, and demonstrated that upregulation of PHF21B may contribute to the progression and poor prognosis of human PCa. Moreover, these data suggests that PHF21B functioned as an oncogene in PCa and may represent a promising prognostic biomarker for PCa. Therefore, this study elucidated the precise role of PHF21B in PCa, and may help to identify more effective therapeutic strategies for PCa.
ADT:
Androgen deprivation therapy
APC:
Adenomatous polyposis coli
CSC:
Cancer stem cell
ELISA:
PCa:
SFRPs:
Frizzled-related proteins
shRNA:
Short hairpin RNA
The Cancer Genome Atlas.
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Li K, Mao Y, Lu L, Hu C, Wang D, Si-Tu J, Gao X, et al. Silencing of CDC20 suppresses metastatic castration-resistant prostate cancer growth and enhances chemosensitivity to docetaxel. Int J Oncol. 2016;49:1679–85.
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This work was supported by grants from the National Natural Science Foundation of China (No. 81472505) and Science and Technology Planning Project of Guangzhou, China (No.201607010213).
All data are fully available without restriction.
Department of Orthopaedic Surgery, the First Affiliated Hospital of Sun Yat-sen University, 510080, Guangzhou, Guangdong Province, China
Qiji Li
, Wei Guo
, Min Wang
, Shuai Huang
& Xinsheng Peng
Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, 510080, China
Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, 510060, Guangzhou, Guangdong Province, China
Liping Ye
Search for Qiji Li in:
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XP designed and conceived the study. QL and LY were responsible for most of the experiments, data collection, and analysis. WG, MW, and SH conducted the molecular cloning, data analysis, reviewing. MW and WG performed the immunohistochemical staining. XP supervised the project. QL and LY wrote the manuscript. All authors read and approved the manuscript.
Correspondence to Xinsheng Peng.
All samples and clinical data were collected from the First Affiliated Hospital of Sun Yat-sen University. Prior patient's consents were obtained to use these clinical specimens for research purposes. Our study was approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University according to the 1975 Declaration of Helsinki. All animal experiments were approved by the Institutional Animal Care and Use Committee of Sun Yat-Sen University.
All contributing authors agree to the publication of this article.
Correlation between PHF21B expression and clinicopathological characteristics of prostate cancer patients. (DOC 38 kb)
Real-time PCR primers. (DOC 37 kb)
The primers used for promoter luciferase reporter. (DOC 29 kb)
Additional file 4: Table S4-S5.
The primers used for ChIP assay. (DOC 50 kb)
SFRP1 and SFRP2 protein expression in the indicated cells. (A-B) Enzyme-linked immunosorbent assay (ELISA) analysis of protein levels of SFRP1 (A) and SFRP2 (B) in the supernatants of PHF21B-RNAi#1-C4-2B and -PC-3 cells treated with SFRP1 or SFRP2 siRNA. Error bars represent the means ± SD of 3 independent experiments. *P < 0.05. Not significant, n.s.. (TIF 103 kb)
Li, Q., Ye, L., Guo, W. et al. PHF21B overexpression promotes cancer stem cell-like traits in prostate cancer cells by activating the Wnt/β-catenin signaling pathway. J Exp Clin Cancer Res 36, 85 (2017) doi:10.1186/s13046-017-0560-y
DOI: https://doi.org/10.1186/s13046-017-0560-y
PHF21B
Wnt/β-catenin signaling


text:
General elections were held in Ecuador on 15 October 2006 to elect a new President and National Congress.

As no presidential candidate received a majority of the vote in the first round, a run-off was held on 26 November, which was won by Rafael Correa of the PAIS Alliance.

Noteworthy lack of reporting of null votes
According to the Supreme Electoral Tribunal, the first-round total of null and blank votes was 1,091,833, which is less than the vote for either of the top two candidates.

Run-off
On November 28, 2006, Correa was declared the winner, although Noboa did not accept defeat, and suggested that he might challenge the validity of the ballot.

According to the Supreme Electoral Tribunal (TSE), out of 97.29% of the votes counted, 57.07% were for Correa and 42.96% for Noboa. Among others, the Organization of American States, US ambassador Linda Jewell, and representatives of many South American countries have recognised Correa as the winner of the election. However, as of November 29, 2006, Álvaro Noboa had still not admitted defeat.

Rafael Correa was duly sworn in as president for a four-year term on January 15, 2007.

Opinion polls

First round

Second round

Results

President

Congress

References

External links
Tribunal Supremo Electoral
Ecuadorian Election 2006 - Election news from Angus Reid Global Monitor
Correa likely to win Ecuador elections, NDTV.com
Ecuador candidate defends Chavez ties, seattlepi.com
Washington frets over 'Bolivarian' candidate, Green Left Weekly

Presidential elections in Ecuador
Elections in Ecuador
Ecuador
General election
Election and referendum articles with incomplete results
Ecuador

redpajama_set_name: RedPajamaWikipedia


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Censorship in the American Jewish community
By +972 Magazine November 5, 2014 | Edit
Support for groups like JVP has grown significantly since the latest war against Gaza. Disenfranchising this ever-growing segment of concerned American Jews will only escalate the decline in our community.
By Seth Morrison
A protest condemning the Israeli assault on Gaza outside the Israeli consulate in downtown Chicago, July 16, 2014. (Photo by Tess Scheflan/Activestills.org)
The past year has seen increasing efforts within the American Jewish community to censor anybody who believes that boycott, divestment and sanctions (BDS) are the way to end the occupation — censorship that is most often targeted at Jewish Voice for Peace. And yet, JVP continues to grow.
JVP is not anti-Israel, it is anti-occupation. Our belief that that the people living in Israel-Palestine are the ones who must decide on their own political formulations does not negate that we are committed Jews acting according to Jewish teachings of how to treat your neighbors. We support any solution that fully recognizes and respects the human rights and aspirations of both peoples — and that includes people with varying political visions for the end of the conflict.
Within JVP I have met many people who like me think that a two-state solution is best, many who believe in a single state with strong guarantees for all, and an increasing number who would like to see a two-state solution but believe that Israel has closed that door in the last few years.
Read also: 'As U.S. Jews, we need to figure out what leverage we have in ending the occupation'
Whenever I have expressed my support for a two-state solution to JVP members, responses have always been respectful. I have never been shut down, accused of being anti-Palestinian or called names. Yet some of my Jewish friends have totally cut me off, refuse to interact with me online or in person and have called me a traitor, accused me of ignoring the Holocaust or called me names that I won't repeat. I expected some pushback and honest debate, but censorship and alienation are dangerous to the future of the American Jewish community.
JVP Boston activists protest the Veolia transportation company for operating bus lines serving settlements in the West Bank. November 14, 2012. (Tess Scheflan/ Activestills.org)
In recent weeks we have seen enhanced efforts by AIPAC to circumvent the Obama administration, as well as increased fundraising in the U.S. by settler organizations like Elad to evict Palestinians from their homes in Jerusalem. To me these groups are the real danger to Israel's future, not Jewish Voice for Peace.
Last spring, writing in +972 I explained my decision to support JVP:
There is no longer any doubt that Israel has become addicted to settlements, occupation of Palestinian territory and to treating the 23 percent of Israelis who are not Jewish as second class citizens.
Many of us have friends or family who suffer from addiction, and all-too-often it is only when we cut them off, stop enabling their negative behavior that things can actually change. It is that model of "tough love" that led me to become a strong BDS supporter.
The Jewish community's efforts to censor JVP's ideas and to exclude JVP members are alienating large numbers of American Jews, especially college students and young adults. Last year's Pew Center Study reported that 48 percent of Jewish Americans don't think Israel is making a sincere attempt to make peace. A quarter of all Jews ages 18-29 believes the U.S. is too supportive of Israel. The next iteration of this study is sure to show even lower support for Israel's government.
It is sad to see that our Jewish tradition of learning through debate and respecting opposing opinions has completely shut down regarding Israel. JVP, J Street, ACRI and the New Israel Fund are all victims of this censorship – but it hits JVP members the hardest because we are the least welcome.
JVP supports boycott, divestment and sanctions because we believe that this tough love approach is the only way to bring both sides together on an equal footing to end the occupation. Israel is afraid of BDS because it works, and because deep down Israeli leaders know that the occupation and the settlements are wrong.
Support for JVP has grown significantly since the latest war against Gaza. With 36 percent growth in online supporters we are now larger than J Street. Disenfranchising this ever-growing group of concerned American Jews will only escalate the decline in our community.
The future of our American Jewish Community and the future of Israel as a democracy depend on openness and full debate of tough issues.
'U.S. Jews: Figure out what leverage we have in ending the occupation'
At Open Hillel conference, Jews demand their spot at the communal table
'Open Hillel' seeks to redefine U.S. Jewish debate on Israel-Palestine
Seth Morrison has held leadership posts in various local, regional and national Jewish organizations starting in college as a youth leader in Young Judea. In 2011 Mr. Morrison resigned from the Washington DC Board of the Jewish National Fund in protest over repeated evictions of Palestinians from their homes in East Jerusalem. He is also active in LGBTQ organizations and local politics in Northern Virginia. Professionally Morrison is a consultant specializing in marketing and strategic planning.
Jewish Voice for Peace
American Jewry
diaspora Jewry


It seems like a lot of the tactical gear and camo uniforms that are currently available use a lot of Velcro? Now new Velcro has it place for some uses it is quick and convenient. But it's also noisy, and when the going gets real dirty and muddy, it just doesn't stick together anymore.
For a couple of years, I have been carrying two multi tools, a Leatherman Wave and an older Gerber. Multi Tools are They Worth Carrying? Both have served me well and have helped me in many situations. Over the years, some people have scoffed and wondered why I carried them.
This morning my wife and I decided to go for a four-mile hike. Now this is a trail that we hike on regularly and normally have no problems. Lately my wife has been complaining about her ankles and so she decided to wear boots instead of athletic shoes. This led to a major boot failure.
I recently received a new knife and today I took it out for a test run. The knife is the Condor Primitive Bush Knife that is a copy of the one Matt Graham uses on Duel Survivor. It is an interesting knife and has some pro and con.
This morning I got up early and planted a couple of fruit trees before it got to hot. Now the area in which we live is in the foothills of the Sierra Nevada Mountains and the soil can be very rocky in places. One of the holes went pretty easy; the soil was good and still contained enough moisture to make digging easy. But the other one was hard and I needed a digging bar.
This morning I found a comment on small engines from Tim V. one of our readers that I thought deserved to be put up as a post in order for it to get wider distribution. There is some good information on mothballing and maintaining small engines. I have added a link for clarity.


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We're excited to announce that registration for CamMUN 2019 will open end of October. The registration is not first come, first served, so we welcome registration whenever you're ready and as soon as we are ready to receive you! We will start accepting delegates in late October, the date has not been finalised yet but check back here to stay updated.


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Man accused of allegedly plotting next US massacre is charged
Rodolfo Montoya faces four felony charges; Montoya, a California Marriott hotel cook, allegedly told a coworker that he planned to attack coworkers and guests, authorities said.
Transcript for Man accused of allegedly plotting next US massacre is charged
The alleged plot to shoot up that hotel, targeting workers and guests. And the suspect was charged and in court just moments ago. Tonight, new details coming in about the alleged plot. The hotel cook arrested. The arsenal seized at his home. Hundreds of rounds of ammunition, an ar-15 among the weapons. This all comes amid two more cases today, two young people arrested. But we begin with that hotel plot in California, and ABC's will Carr leads us off. Reporter: Tonight, the man accused by authorities of plotting America's next massacre appeared in court for the first time. 37-year-old Rodolfo Montoya behind that glass divider, now charged with four felonies. Police say they found a stash of weapons inside Montoya's home, including hundreds of rounds of ammunition, tactical gear and an automatic rifle and high capacity magazines, both are illegal in California. Authorities say on Monday, Montoya, a hotel cook, told a hotel worker about his planned attack. He was going to shoot up fellow employees and people coming into the hotel. Reporter: That coworker told hotel management, who then called police. Montoya was arrested at his home, with authorities allegedly found that arsenal of weapons. Tonight, employees at the Marriott are grateful that hotel management called police after learning about the alleged plot. So blessed that I'm alive and I'm -- that I'm fine and everybody's here is fine, because that's horrible. Reporter: Since the tragedies in Dayton and El Paso, there have been more than a dozen Ares for alleged threats of mass shootings across the country, including in Ohio, where this man, who police say wanted to shoot up a jewish community center, was arrested after posting this disturbing video online. In Florida, a mother pleads with police after her teenage son is arrested. He didn't do anything wrong. Yes, he's 15, but he's still a little boy and he's not one of the crazy people out there doing stuff. Reporter: And today, also in Florida, at least two students in separate schools arrested for alleged threats at the start of the school year. And will Carr with us live again tonight in the case of that California hotel cook. I know police now investigating how he allegedly obtained some of those weapons, will? Reporter: That's right, David. We know that ar-15 he allegedly had was illegal here authorities now want to know exactly where he got it from. And we've heard across the country that saying, if you see something, say something. Tonight, authorities are strengthening their language, saying if you see, hear or even read something suspicious, you should report it. David? Will Carr leading us off. Will, thank you.
Beto O'Rourke says he's changed after massacre in hometown El Paso
O'Rourke shares about pausing his campaign to spend time in the city that raised him after a gunman murdered 22 innocent people there. "Nightline" explores his life and history in politics.
It's Morning, America: Wednesday, Aug. 21, 2019
New arrests in alleged mass shooting plots, President Trump appears to contradict his positions, thousands arrested in Kashmir and more.
Now Playing: Beto O'Rourke says he's changed after massacre in hometown El Paso
Now Playing: It's Morning, America: Wednesday, Aug. 21, 2019
Now Playing: Who will President Trump pardon before he leaves office?
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text:
Police refute video clip of herdsmen expulsion in Enugu
Jan Vertonghen commits to Tottenham, but not a new contract
Home Topics Zimbabwean Politician
Zimbabwean Politician
Report: Zimbabwean politician 'reclaims seized farm from Robert Mugabe's daughter'
A Zimbabwean politician has reportedly reclaimed his farm from former president Robert Mugabe's daughter Bona and her in-laws after they allegedly seized it from him four years ago.
The Police Command in Enugu State has refuted the video clip showing youths of Oduma Community in Aninri Local Government Area of the state chasing herdsmen away from the community.
Jan Vertonghen believes Tottenham are "the best club to play for at the moment", but has not committed to penning a new contract in north London.
Nigeria's inflation rate drops
The National Bureau of Statistics, Monday, has said that Nigeria's inflation rate dropped by 0.18 percent in the month of June.
WHO raises concern over global negligence on measles vaccination
The World Health Organisation (WHO) has expressed concern over worldwide negligence of vaccination against measles and some other diseases.
Coalition lauds President Buhari, Nigerian Army for promoting officers
The Coalition Against Terrorism and Extremism (CATE) has reacted to the recent promotion of two senior officers of the Nigerian Army.
Real Madrid left 'stunned' by teen sensation Takefusa Kubo
Real Madrid coaches have been left 'stunned' by Takefusa Kubo and could hand the teenager a place in the first team squad for this coming season.


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Epicor Software Names New CFO
Samuel Monti takes over finance at the enterprise resource planning software company.
Vincent RyanJanuary 26, 2021
On Tuesday, Epicor Software announced that it appointed a new finance chief in the wake of its purchase by private equity firm Clayton Dubilier & Rice last year.
Samuel Monti, former CFO of Khoros, will be joining Epicor's executive team as chief financial officer. Monti has more than 25 years of experience in corporate finance.
At Austin, Texas-based Epicor, a provider of enterprise resource planning software to the manufacturing and distribution industries, including cloud-based ERP, Monti will be responsible for the leadership and management of all aspects of Epicor's financial organization, including accounting, tax, treasury, financial reporting, and analysis.
CFO Samuel Monti
"Given Sam's impressive track record, we know he is the best addition to our team to further accelerate growth and results on a global scale," said Epicor CEO Steve Murphy. "As a seasoned CFO, Sam has experience successfully leading and closing complex acquisitions and company transactions, as well as deep operational finance leadership expertise."
Monti had been CFO of Khoros, a customer engagement software company, since April 2018. The company provides software for online community management, social media marketing, and social media analytics. Before Khoros, Monti was finance chief at Mitratech, a compliance solution provider to corporate legal professionals. Earlier in his career, he was a finance director at Rockwell Automation.
"I am incredibly excited to join Epicor and its talented leadership team," said Monti. "As a highly regarded enterprise software company, Epicor is seeing significant growth. I look forward to continuing to build on the momentum created and adding value to the organization for both employees as well as current and future customers."
In the press announcement about Monti's appointment, Epicor underscored his experience providing financial expertise critical to organic sales growth and significant merger, acquisition, and integration projects. The company also noted his experience in giving "financial guidance essential to increasing manufacturing capacity; improving manufacturing cost structure; and automating manual processes."
Monti replaces David Mehok, who spent two-and-a-half years at Epicor. Mehok left after KKR sold Epicor to CD&R for $4.7 billion, a deal that closed in October 2020. In November, Mehok was named CFO of Q2, a publicly held company that sells banking-as-a-service products to financial institutions.
The CD&R deal came four years after KKR acquired Epicor from British private-equity firm Apax Partners for $3.3 billion.
Epicor made several acquisitions under KKR, including data interchange software maker 1 EDI Source and warehouse-management software provider Majure Data.
Epicor Software, Khoros, Rockwell Automation
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Biden Names 3 Nominees to Fed's Board of Governors
The nominees could significantly increase the board's diversity and push banking regulation in a more progressive direction.
By CFO Editorial Staff	| January 18, 2022
Supreme Court Rejects Workplace Vaccine Mandate
The U.S. Supreme Court delivered a major blow to the Biden administration's anti-COVID 19 efforts on Thursday, striking down its vaccine-or-test mandate for large businesses. The court's six conservative justices said the mandate exceeded the authority of the Occupational Safety and Health Administration to issue emergency regulations to protect workers from "grave danger" that is
Coinbase Buys Crypto Futures Platform FairX
The deal positions Coinbase to offer crypto derivative products to U.S. investors as part of a "robust and holistic trading environment."