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News Item
Newsday: "Voxx International bets on iris-scanning technology"
Newsday: "Voxx International bets on iris-scanning technology"
Photo: James M. Demitrieus, chief executive of EyeLock, uses the iris-scan device for access to a company office in Manhattan. (Credit: Craig Ruttle)
. . . The biometrics market is increasingly competitive as proponents of fingerprints, facial recognition, voice recognition, and hand geometry vie for market share.
Michael Coakley, an adjunct professor of computer science and information systems at Pace University, said that researchers are busy seeking innovative biometric readings.
"Everything is fair game now," he said, "handprints, fingerprints, footprints, hair follicles. It seems like everybody is trying to find a body part to extract a biometric reading."
Read more: http://www.newsday.com/business/voxx-international-bets-on-iris-scanning...
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Disability Film Festival Marathon 2016
Disability Film Festival Marathon 2016
Pace University to host fourth annual Celebration of Individuals with Disabilities in Film, Tuesday, March 29
Panel discussion with leading advocates for people with disabilities in New York City
New York, NY – March 22, 2016 – Pace University will host its fourth annual Celebration of Individuals with Disabilities in Film on Tuesday, March 29, from 4 pm to 9 pm in the Aniello Bianco Room at One Pace Plaza in lower Manhattan. Pace's Disability Film Festival Marathon 2016 focuses on individuals with disabilities expressing dreams and hopes to be contributing members of society like other individuals without disabilities. The marathon highlights eight short documentary and narrative films from the Reel Abilities Film Festival in New York City, respecting the autonomy and the empowerment of people with disabilities. The event is free and open to the public.
What: The Disability Film Festival Marathon 2016 is sponsored through Pace's Dean for Students and the outreach programs of its Seidenberg School of Computer Science and Information Systems, in partnership with AHRC New York City, an organization for helping people with developmental and intellectual disabilities, and the Reel Abilities Film Festival in New York City. A panel of expert practitioners on the advocacy of disability rights in society will discuss the challenges and the opportunities highlighted in each of the films, with the panelists inviting engagement from guests. Following the panel discussion, moderators will engage in Q&A with audience guests in opinion polling on film themes.
Who: Panelists include Anita Altman, Founder, ReelAbilities: New York Disabilities Film Festival; Kathy Broderick; Associate Executive Director, AHRC New York City; Victor Calise, Commissioner for the New York City Mayor's Office for People with Disabilities; Allan B. Goldstein, Senior Lecturer, NYU Tandon School of Engineering; Maria Hodermarska, Parent and Teacher, New York University; and Marilyn Jaffe-Ruiz, Professor Emerita, Pace University. Moderators: Marijo Russell O'Grady, PhD, Dean for Students, Pace University; Melanie A. Greene, Seidenberg School of Computer Science and Information Systems, Pace University, Information Technology, June 2017; and Cassandra Raffucci, Kingsborough Community College – Melissa Riggio Program, June 2015, Self-Advocate.
Where: Pace University in the Aniello Bianco Room at One Pace Plaza (opposite City Hall), Manhattan. Enter at 3 Spruce Street.
When: Tuesday, March 29. Displays and Exhibits of Community Partners: 4 pm – 6 pm. Entertainment by the Zulu P Band, Reception and Refreshments: 5 pm – 6 pm. Discussion and Films: 6 pm – 9 pm.
For more information, contact James P. Lawler, DPS, Professor of Disability Studies and Information Technologies at Pace and Chair and Organizer of Film Festival Marathon 2016. Phone: (212) 346-1013; email: firstname.lastname@example.com.
Media contact: Bill Caldwell, Pace, 212-346-1597, email@example.com
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News Item
Associated Press: "FBI Official: Time Needed to Know If Phone Can Be Unlocked"
Associated Press: "FBI Official: Time Needed to Know If Phone Can Be Unlocked"
. . . Speculation about the source of the new method has centered on a little-known but thriving industry of computer forensics in which firms work with the FBI and other police agencies around the world.
While it could be an independent hacker, several experts said the proposed solution most likely came from one of those firms, possibly one that already works for the government.
"The FBI contracts out a lot of work, like every other government agency, and a lot of stuff gets shipped off to data-recovery contractors," said Jonathan Zdziarski, an independent iPhone forensics researcher.
He said the most straightforward possibility is that the FBI described the problem to a variety of contractors and one of them came forward with a proposed solution.
Other experts mentioned an Israeli company, Cellebrite Inc., that's a leader among several firms selling smartphone forensics services and software tools to U.S. police agencies. The programs can extract data from iPhones running older versions of Apple's operating system, but they have been stymied by the latest version, known as iOS 9. That's the version running on the San Bernardino iPhone.
Cellebrite hasn't announced any new product that works with iOS 9, but it's likely working on developing one, said Darren Hayes, a computer scientist and cybersecurity expert at Pace University in New York.
Cellebrite representatives couldn't be reached for comment Tuesday. The company did not respond to an email and phone message left at its U.S. offices in New Jersey.
Read more: http://abcnews.go.com/Technology/wireStory/fbi-attackers-phone-possibly-accessible-apple-37831413
News Item
Agence France-Presse: "Apple-FBI encryption showdown postponed, for now"
Agence France-Presse: "Apple-FBI encryption showdown postponed, for now"
- Paris, Brussels and encryption -
Darren Hayes, a Pace University professor specializing in computer forensics, said the issues will be seen as more urgent in the wake of attacks last year in Paris and on Tuesday in Brussels.
"If we hear more about iPhones used in terrorist attacks, people may side with the government a little more," he said.
The question of access to encrypted devices will probably be dealt with in the legislative arena in the United States and elsewhere, Hayes added.
"This is not just a struggle in the US," he said. "It's a toss-up on whether the US or EU implements legislation first."
Read more: http://www.afp.com/en/news/apple-fbi-encryption-showdown-postponed-now
News Item
Bankrate.com: "Watch a thief install a skimmer in 3 seconds"
Bankrate.com: "Watch a thief install a skimmer in 3 seconds"
News Item
Schools Chancellor Discusses Challenges of Educating 1.1 Million Students During Appearance at Pace University's InsideTrack
Schools Chancellor Discusses Challenges of Educating 1.1 Million Students During Appearance at Pace University's InsideTrack
Pace alumna talks with President Stephen J. Friedman about innovation, teaching as a growth industry, and the future of New York City's schools
New York, NY – March 17, 2016 -- As part of the university's InsideTrack speaker series, President Stephen J. Friedman and Pace University's School of Education hosted Carmen Fariña, New York City Schools Chancellor for a discussion on the state of education. The event was held in Pace's Schimmel Center at the University's Lower Manhattan campus.
The evening offered a behind-the-scenes look at running the nation's largest and most diverse school system. Chancellor Fariña discussed the ever changing state of education in New York and beyond, and examined what she feels some of the most important issues facing parents, students, and educators are today.
"There are probably very few people with more opportunity to shape the long-term future of New York City than Chancellor Fariña," said Pace President Stephen J. Friedman. "That is because in today's world, a great city is a platform for testing new ideas and new ways of doing things. And the critical players in that process are the men and women whom that city attracts and educates."
"I feel that people have to be treated with dignity so they can do the best work possible," Carmen Fariña said when asked about her most important objectives upon being appointed Chancellor. "First and foremost was to bring dignity back into the profession."
In her InsideTrack conversation, Fariña discussed her priorities and decisions related to key issues such as charter schools, Common Core, class size, teacher evaluations, and technology that will impact the City for years to come. She shared her experience for inspiring others and advocating for change in the New York City school system.
As Chancellor, Carmen Fariña has extended pre-kindergarten education to more than 68,000 four-year olds. She has also expanded the Community School model to provide more wrap-around services to students and families, and launched the Framework for Great Schools, a holistic, research-based approach to school improvement.
Under her leadership, the number of struggling city schools being reviewed for state takeover fell from 91 in 2015 to 27 in 2016.
Chancellor Fariña also discussed the challenges posed by a looming teacher shortage, but noted a silver lining for aspiring educators. With accelerated changes taking place in technology, how children are educated and other areas, the Chancellor sees teaching as a growth industry with an increasing demand for those specializing in pre-K, math, science, tech, language/ESL, the arts, and special needs education.
Fariña, who holds a master's degree in Administration and Supervision from Pace, has spent half a century in the field of education -- dedicating her life to providing quality education to all children. The Chancellor oversees the education of more than one million students in New York City, the nation's largest school district.
Carmen Fariña grew up in Brooklyn, raised by parents who left Spain during the Spanish Civil War. As the first person in her family to attend college, she earned multiple degrees from New York area schools, including Pace University.
InsideTrack with President Stephen J. Friedman brings renowned thought leaders and policymakers to Pace for captivating discussions on topics that affect the greater New York community.
About Pace University: Pace University is a comprehensive, independent University with campuses in New York City and Westchester County. Nearly 13,000 students are enrolled in undergraduate and graduate degree programs in the Lubin School of Business, Dyson College of Arts and Sciences, Seidenberg School of Computer Science and Information Systems, School of Education, School of Law and College of Health Professions. http://www.pace.edu
Media contact: Bill Caldwell, Pace, 212-346-1597, email@example.com
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News Item
New York Times: "After Rough Campaign, Many Rubio Backers Will Stay Home"
New York Times: "After Rough Campaign, Many Rubio Backers Will Stay Home"
"What Marco Rubio's supporters will do now that he has exited the Republican primary, is a complicated question," writes Jessica Lavariega-Monforti, Professor and Chairperson of the Department of Political Science at Pace University, in the New York Times Room for Debate. "Some will move to support Donald Trump, as many people want to back a winner and many see his nomination as inevitable. But the majority will not."
Read more: http://www.nytimes.com/roomfordebate/2016/03/15/can-rubios-exit-stop-trump/after-rough-campaign-many-rubio-backers-will-stay-home


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Organic vegetables are grown without the use of pesticides, as they naturally repel pests by repeating everything they say in a singsong voice. Savor the taste of these wonder foods with today's Groupon from Full Circle. Choose from the following options:
- For $13, you get $28 worth of produce and grocery credit, good for any order. This amount is enough for a Sprout box, designed for 2–3 people, which provides 20–25 servings (regularly $27.95/week).
- For $22, you get $46 worth of produce and grocery credit, good for any order. This amount is enough for two Seed boxes, designed for 1–2 people, which each provide 15–20 servings (regularly $22.95 each/week).
- For $34, you get $70 worth of produce and grocery credit, good for any order. This amount is enough for two Garden boxes, designed for 2–4 people, which each provide 30–40 servings (regularly $34.95 each/week).<p>
Full Circle's 450 acres of Washington farmland cultivate a culture founded on sustainable, organic, and chemical-free food by delivering boxes of the season's bounty to homes and local communities. Each box encloses varieties of sustainably grown fruits, vegetables, and herbs, such as nantes carrots, golden beets, and white nectarines. Sprout boxes usually contain enough produce to satisfy a household of two adults and a young child or one Kareem Abdul-Jabbar, and Garden boxes can feed up to four. Alternatively, subscribers can collect a bevy of artisan groceries—such as einkorn-infused pasta, Organic Valley butter, and free-range poultry—into a personalized box.
The Full Circle process fosters benefits for all parties involved—customers can enjoy the health benefits of eating organically while supporting green farmers, whose eco-friendly practices create nutrient-rich produce, which will then be sold back to the customers, now dizzy from spinning.
Shipments can be delivered straight to homes or claimed at one of the community pickup sites scattered throughout the Spokane and Coeur d'Alene area. Click here to see pickup and delivery options in your area. Groupon customers automatically receive a recurring subscription for future orders, which will be billed automatically unless canceled. Membership is flexible and can be canceled any time without penalty. Credit will be applied to the membership account and can be used toward the examples above or any other grocery order.
Full Circle
Once an organic farm itself, Full Circle has expanded into a community of organic, like-minded farmers and producers dedicated to enriching the lives and health of its members through weekly delivery of organic produce and local, artisan groceries. Working closely with within the communities they serve, Full Circle delivers organic, pesticide-free and herbicide-free produce, as well as grass-fed meats, organic dairy, and a wide selection of locally-sourced artisan items.
The Full Circle process fosters benefits for all parties involved—customers can keep healthy by eating organically while supporting green farmers whose eco-friendly practices create nutrient-rich organic produce that will then be sold back to the customers.


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CORD provides a strong common voice to advocate for health policy and a healthcare system that works for those with rare disorders. CORD works with governments, researchers, clinicians and industry to promote research, diagnosis, treatment and services for all rare disorders in Canada.Learn More
MEDIA ALERT: Canadian Organization for Rare Disorders urges Ontario to implement Canada's first Rare Disease Strategy TORONTO, Feb. 27, 2017 /CNW/ - On International Rare Disease Day, patient representatives from the Canadian Organization for Rare Disorders (CORD) will meet with John Fraser, Parliamentary Assistant to the Minister of Health and Long-Term Care and other MPPs to share their experiences of living with rare disorders.
Rare Disease Day 2017 Annual Awards Gala
March 30, 2017
Sheraton Vancouver Wall Centre 1088 Burrard Street, Vancouver, BC
Date: March 30, 2017 Location: Sheraton Vancouver Wall Centre 1088 Burrard Street, Vancouver, BC Ticket Purchase Join us on Thursday evening, March 30th, when CORD will host its annual Rare Disease Day Awards Gala. We will recognize those individuals and organizations that have made extraordinary contributions to the Canadian rare disease community over this past year. Cocktail reception at 6:00 pm followed by dinner at 7:00 pm, with entertainment. Business or Smart Cocktail Attire Gala Ticket: $195 Patient Gala Ticket: $125 Tablet of 8: $150 CORD room rate at the Sheraton $199/night if booked by Feb 28th
Rare Disease Day 2017 Conference Registration: March 30 - 31 , 2017
March 30, 2017
Sheraton Vancouver Wall Centre, 1088 Burrard Street, Vancouver, BC
Date: March 30 - 31, 2017 Location: Sheraton Vancouver Wall Centre, 1088 Burrard Street, Vancouver, BC REGISTER HERE Living Rare: With Research, Possibilities are Limitless With Patients, Anything Imaginable is Achievable! 2-Day Conference: March 30-31, 2017 OBJECTIVES Share experiences of living ... enhanced by a rare condition Connect with groups that improve rare living Create inspired and inspiring solutions within Canada's Rare Disease Strategy Rare Disease Day 2017 UPDATED DRAFT AGENDA Through videos, testimonials, and facilitated discussions, we will provide an opportunity to get to know the people living with the rare conditions and their patient groups or organizations. Each of the four panels will be organized around one of the four core pillars of Canada's Rare Disease strategy: diagnosis, expert care, community support, and access to therapy. The fifth pillar, research, will be integral to addressing issues identified in each of the other areas. CORD is offering travel bursaries to patient group representatives to help offset the cost of travel to the Rare Disease Day 2017 Conference. Apply at: https://www.surveymonkey.com/r/rdd17application CORD room rate at the Sheraton $199/night if booked by Feb 28 REGISTER HERE Refund Policy: Cancellations received a minimum of 15 days prior to the event will receive a refund minus an administrative fee of $15.00. This fee covers the cost of processing the registration and refund. Cancellations received after the 15-day deadline and no-shows are non-refundable.
GETTING TO ACCESS Innovative approaches to innovative medicines
March 29, 2017
Sheraton Vancouver Wall Centre 1088 Burrard Street, Vancouver, BC
INNOVATIVE MEDICINES OFFER OPPORTUNITIES AND CHALLENGES Why this forum matters: Innovative drug therapies are medicines that can: Offer a substantial improvement over existing therapies; for example, biologics can modify the underlying cause of a condition rather than just treat the symptoms; Address an unmet need; many drugs for rare disease are the first to be developed for that condition Target the (unique) characteristics of a subgroup of patients based on genetic makeup and/or other individual characteristics Cure the disease; for example, by eliminating the cause (hepatitis C virus), replacing abnormal cells (stem cell replacement), or modifying the faulty gene But innovative therapies come at a price that is often considered "unaffordable" under current assessment processes Individual high-cost therapies can have an identifiable impact on overall drug plan budgets, whether private or public DRAFT AGENDA Individual Registration: $995 early bird rate (before February 24) $1250 regular rate (after February 24) Patient Registration: $495 early bird rate (before February 24) $650 regular rate (after February 24) If you are a patient representative who would like to attend the forum but need financial assistants to cover the registration fee, please email us at email@example.com


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8 Dec 2009 // 9:00 PM
During the height of his career, Bill Monroe fielded a baseball team that would organize pickup games in each town in order to drum up publicity for that evening's concert.READ more
3 Nov 2009 // 8:00 PM
In the late '30s and '40s, Bill Monroe and His Blue Grass Boys were the biggest stars in country music, but when he appeared onstage at the 1963 Newport Folk Festival, he did so after a number of years spent toiling in relative obscurity.READ more
6 Oct 2009 // 9:00 PM
Johnny Cash was a serious scholar of music, and this knowledge was reflected in his own work, which included covers of everyone and everything from Jimmie Rodgers to Nine Inch Nails, oldtime hymns to reggae.READ more
7 Sep 2009 // 9:00 PM
Need more duets in your life? Loretta Lynn and Ernest Tubb are among country music's best partnerships.READ more
18 Aug 2009 // 9:00 PM
Country music ain't the sole purview of the southern part of the northern hemisphere: Canada has its share of fireside soul(ful) singers, too.READ more
5 Jul 2009 // 9:00 PM
With her honorary doctorate in hand, here's hoping she'll next broker peace in the Middle East, repair the economy, and explain the twisted plotlines of 'Lost' -- Lord knows, the woman is capable.READ more
18 May 2009 // 9:00 PM
What better way to soothe modern worries than by taking in classic country music with a side of hillbilly humor?READ more
5 Apr 2009 // 9:00 PM
Editing the original RCA tapes makes the songs on Naked Willie so much better that I'm remembering the reasons why I fell in love with Willie Nelson so many years ago.READ more
15 Mar 2009 // 9:00 PM
The Maddox Brothers and Rose recorded songs that would be considered controversial even today. But 60 years ago, they were incredibly groundbreaking, and paved the way for outspoken female singers like Loretta Lynn.READ more
8 Feb 2009 // 8:00 PM
- //Columns
The majority of us aren't coal miners, we don't know coal miners, and we wouldn't last a week in a coal mine. Are coal mining songs, then, still relevant?READ more
11 Jan 2009 // 8:00 PM
Steve Martin, Sufjan Stevens, and Kermit the Frog all know it and you should, too: the banjo is hands-down the coolest instrument out there.READ more
25 Nov 2008 // 9:00 PM
Poverty, crime, disenfranchisement, sinning, saving, and no-account women: Stereotypical subjects of the average country song, or the average hip-hop song?READ more
27 Oct 2008 // 10:00 PM
They might kick me out of the feminist club for this, but I love murder ballads, even the ones in which women get killed—though, to be fair, I am an equal opportunity advocate when it comes to a good killing narrative.READ more


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Compare broadband providers, deals and packages in Singapore all at one easy, quick and simple comparison website. Find the best broadband deals with the best speed Mbps and Gbps, monthly cost and if it includes a TV streaming service.
Enjoy the Freedom of No 12-month or 24-month Contract
Visit Site
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Broadband Provider
Show Broadband Providers
Broadband Speeds
Show Broadband Speeds
Broadband Monthly Cost
Show Monthly Costs
< s$40
s$41 - s$60
s$61 - s$80
s$81 - s$100
Broadband TV Bundle
Show with TV Packages
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Show Contract Duration
No Contract
12 Months
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Its important to ensure you have the best broadband deal and this can be a daunting prospect – there are so many technical terms and numbers used to explain the packages and it can be difficult to know where to start. Here at EnjoyCompare our guides will help you through the minefield, hopefully saving you both time and money in the process.
Technology moves so quickly and it's easy to get left behind. That's why EnjoyCompare has put together this quick and easy Broadband Guide to keep you up to date with the latest advances and to find the best deals for you, whatever your technical circumstances.
New to broadband technology? Keen to upgrade your existing broadband service to make better use of the internet? Are you a gaming enthusiast who needs a no-limits, super-fast broadband speeds? Whatever your needs, we've got the answers. Our simply, quick and clear broadband comparison tool does the work for you, comparing more than 100 deals and giving you all the information you need to make the right choice.
In Singapore you have two main ways to connect to the internet – through a fibre broadband connection, or through a slower cable service. With fibre broadband now available across the majority of Singapore, you can enjoy super fast speeds that are comparable to the fastest available globally. There are various ways of connecting to the internet using broadband. The most common is through an ADSL or cable line, but you can also connect through fibre-optic cable (up to six times faster than ADSL), mobile signal or even via satellite.
Its important to get the right broadband deal that suits your needs, therefore before you take out a broadband contract or consider switching to a new provider, ask yourself whether you're a high, medium or low internet household. This will help advise the kind of service you need. High-users, typically love the internet – they spend hours on it, streaming films, uploading photos and videos to Facebook, and downloading and sharing music with friends. If this sounds like you or your children, then you're going to need fast, unlimited fibre broadband.
Medium users use the net daily but they're not much into watching TV or films online, or downloading loads and loads of music. For them, a package with a moderate download limit, around should be fine. You'll be notified whenever you come close to exceeding your limit and you will be charged for additional usage so keep an eye on your costs. If you consistently go over your limit, you might be better off switching to a high-user service.
Low users use the internet for the basics, such as checking emails, paying bills and shopping. If you fit into this category, then you can go for the most economical, no-frills, package.
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Editorial Disclosure: The editorial content on this page is not provided by any of the companies mentioned, and has not been reviewed, approved or otherwise endorsed by any of these entities. Opinions expressed here are author's alone, not those of the companies mentioned, and have not been reviewed, approved or otherwise endorsed by any of these entities.
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Marjie Hartz says that life changes are inevitable and the one she most recently experienced has been one of the best. Marjie grew up on her family's Middletown, PA dairy farm, where she enjoyed raising and showing dairy animals for 4-H, but hasn't had cattle for many years. [Read more…]
PA Farm Bureau on court decision upholding EPA's actions in Chesapeake Bay Watershed
Pennsylvania Farm Bureau (PFB) is disappointed with the federal Third Circuit Court decision that upholds the Environmental Protection Agency's (EPA) implementation of a Total Maximum Daily Load (TMDL) in the Chesapeake Bay Watershed.
"We disagree with the court's decision that seems to give EPA employees the authority to trump local land use decisions in the watershed," said PFB President Rick Ebert. [Read more…]
The link between biodiversity and organic agriculture
by Karl H. Kazaks
NRCS recently hosted an online program on the importance of biodiversity to agriculture and how organic agriculture tends to support increased biodiversity. The event was part of a series exploring the environmental benefits of organic agriculture.
The occasion was part of the USDA's broader effort to educate the agriculture community and the public at large about organic agriculture, with the aim to increase organic production. [Read more…]
No-till drills now available through Soil and Water Districts
Crop growers are paying attention to the success that other farmers are reporting to have with no-till farming.
In response to the growing interest, Soil and Water Districts are bringing in no-till seed drills to rent out to farms that are interested, but have not had up close experience with the process and are concerned about paying out a large sum of money for machinery that they are unfamiliar with. [Read more…]
Breeding cattle for a growing market
Marshman Farms LLC, has come a long way since its founding in 1856. Today, sixth-generation owners David and John Marshman operate the Oxford, NY dairy farm that has garnered a following for high-quality purebred Holsteins under the name of Tiger Lily Holsteins. [Read more…]
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Our Partnerships
The Avaloq Group is the Swiss market leader for standardised banking software, and has branches in Luxembourg and Singapore. Over 35 banks worldwide rely on the Avaloq Banking System, which is geared consistently to the business processes and requirements of an innovative bank. Whether a bank is private, retail or universal, Avaloq increases banking efficiency and improves transparency. However, Avaloq is a lot more than a banking system: the Avaloq Academy ensures that all project team members receive in-depth training so they can leverage the full potential of the Avaloq Banking System. And the Avaloq Community brings together over 35,000 Avaloq users, customers and partners to share information on the Avaloq Banking System and banking software.
B-Source, a Swiss company, provides services for business process outsourcing (BPO) and IT outsourcing (ITO) for the private banking and asset management industry. Its clients include banks in Switzerland and a number of other countries. All services are certified according to ISO 9001 and ISO/IEC 27001:2005. B-Source has also been awarded an SAS 70 Level II Audit Report. B-Source works closely with its business partners the University of St. Gallen's Sourcing Competence Center, Avaloq and Orbium. B-Source's new BPO platform, the B-Source Master, is powered by Avaloq.
Founded in 1995, B-Source has offices in Lugano, Zurich, Nyon and St. Gallen. Its data centers are located in Lugano and Zurich. The current number of employees is about 556, half of which are banking professionals.
NetGuardians is a leading software company recognized for its revolutionary solutions to control all your operational risks from business operations to IT. Using smart behavioral analysis, our technology quickly identifies all atypical activity. It effectively controls data leaks, alerts you to potential internal fraud and provides the reporting and analysis to meet needs like audits and forensics. Founded in 2007, NetGuardians was the first company to emerge from the innovation incubator of the HEIG-VD Business School and Engineering Vaud, in Yverdon-les-Bains, Switzerland. Since then, the company has seen a steadily growing clientele in Europe, the Middle East and Africa.
BRP SA was founded in 2010 with the aim of assisting banks and financial institutions in managing constantly evolving regulatory constraints.
Today the team offers a unique combination of know-how acquired with supervisory authorities (Swiss and English), audit and consultancy firms, law firms and bodies within the financial sector. BRP's principal aim is to provide its clients with simple and pragmatic solutions.
Edgelab brings scientific rigour to risk mitigation. Using high-dimensional statistical modelling, scalable analytics and search, Edgelab provides fully compliant valuation and risk data, management apps and an automated investment solution. Using Edgelab technology, institutions achieve a clearer picture of their risk, allowing them to make smarter decisions.
Founded in 2013, Edgelab has offices in Lausanne and Pfaffikon, Switzerland.
Based in Switzerland and Silicon Valley, venture capital firm Polytech Ventures created and manages the Fusion fintech incubator in Geneva. Polytech specialises in early-stage investments, helping European SOFTWARE start-ups access the US. Working closely with its partners in academia and industry, it has an impressive record of value creation.
MyJob is the number one recruitment agency using social networks. Its innovative software allows companies to search, match and interview candidates as well as source references online, making recruitment faster and more efficient. Its platform links headhunters from every industry, offering the largest selection of potential candidates, while its software matches candidates to jobs according to qualifications and experience.
ACTICO is a leading international provider of software solutions and technologies for decision management. In a digital world it is necessary to process large volumes of data and make fast, consistent and auditable decisions; that is where our software solutions provide an advantage. Business rules and processes can be easily adapted and executed automatically, which improves the efficiency and agility of our customers in their competitive area. This also enables them to accelerate their growth, innovate effectively, stay compliant and as a result, increase profits. ACTICO's roots go back to 1997. It supports its international customers from locations in Germany, the U.S., and Singapore.
Indigita is BRP SA and Orbium joint venture providing banks with digitized regulatory smart data for cross-border banking. It is solving the problems faced by banks and financial advisers with international business when it comes to cross-border compliance. It takes the best from its parent companies BRP SA and Orbium, experts in regulatory and IT consultancy, to develop the perfect solution to meet ever-changing cross-border regulatory challenges. It is based in Geneva and Zurich.


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In 1953, Hilda Longinotti, a high school dropout from Queens, saw an ad in the New York Times that read "Wanted: Receptionist for a World Famous Architect." "I didn't know what an architect was," Longinotti, now a lively 80, says, "but it sounded shi shi." So she applied. Little did she know that said architect was George Nelson, design director of modernist furniture giant Herman Miller. The New York atelier hired the witty, impeccably styled (and fast-typing) Longinotti on the spot—for $55 a week—and thus began her 21-year career as Nelson's aide-de-campe.
Now, Longinotti's silver-tongued stories of her time at Herman Miller have been turned into a delightful new cartoon series: The Hilda Stories, animated by Damien Florébert Cuypers for Herman Miller's WHY. It's a first-hand account of working in New York during the age of real Mad Men, when the straightness of a woman's stocking seams could make or break her career. But, as Longinotti puts it, George Nelson "loved ballsy women."
"When I started with him, I had no balls. But over the 20 years, I grew them and grew them and grew them. So I think he'd be very proud of the ballsy woman I have become today," Longinotti says.
Despite the time's claustrophobically low glass ceiling, Longinotti developed a huge network in the design community and piloted a program to strengthen communication between Herman Miller and New York designers. This led to her appointment in 1979 as manager of design community programs, the offshoot of which is Herman Miller's current A+D efforts.
A nostalgic Longinotti describes the firm in the '50s as "a world of wonders," with a seemingly magical staff of eight doing furniture design, product design, interior design, graphic design, and architecture. The lucky Longinotti got a bespoke Herman Miller-designed reception area just for her: A purple felt wall, an orange-and-white clock by George Miller, and a purple daybed made the switchboard and typewriter seem like glamorous accessories.
"I think the major lesson I learned in my 21 years [at the Nelson Office] is: how to see," she says. "When you learn how to see, you learn to appreciate all that goes on around you—from the time you get up in the morning, to the time you go to bed at night."
Read more here.


text: This Awesome Music Video Thinks it's a Very Old Video GameLuke Plunkett2/09/12 4:30amFiled to: MusicPolinskispectrum33EditPromoteShare to KinjaToggle Conversation toolsGo to permalink After I posted Sole's new video yesterday, I was inundated with emails from people saying "OH YOU SHOULD CHECK OUT THIS MUSIC VIDEO THAT'S LIKE A VIDEO GAME". Most of them were rubbish, but this one, from Polinski, was great. The entire clip plays out like an old Spectrum game, down to the tape loading and the graphics having to pop in.Reply33 repliesLeave a reply


text:
Mammary epithelial cell transformation: insights from cell culture and mouse models
- Goberdhan Dimri1,
- Hamid Band2 and
- Vimla Band1Email author
DOI: 10.1186/bcr1275
© BioMed Central Ltd 2005
Published: 3 June 2005
Normal human mammary epithelial cells (HMECs) have a finite life span and do not undergo spontaneous immortalization in culture. Critical to oncogenic transformation is the ability of cells to overcome the senescence checkpoints that define their replicative life span and to multiply indefinitely – a phenomenon referred to as immortalization. HMECs can be immortalized by exposing them to chemicals or radiation, or by causing them to overexpress certain cellular genes or viral oncogenes. However, the most efficient and reproducible model of HMEC immortalization remains expression of high-risk human papillomavirus (HPV) oncogenes E6 and E7. Cell culture models have defined the role of tumor suppressor proteins (pRb and p53), inhibitors of cyclin-dependent kinases (p16INK4a, p21, p27 and p57), p14ARF, telomerase, and small G proteins Rap, Rho and Ras in immortalization and transformation of HMECs. These cell culture models have also provided evidence that multiple epithelial cell subtypes with distinct patterns of susceptibility to oncogenesis exist in the normal mammary tissue. Coupled with information from distinct molecular portraits of primary breast cancers, these findings suggest that various subtypes of mammary cells may be precursors of different subtypes of breast cancers. Full oncogenic transformation of HMECs in culture requires the expression of multiple gene products, such as SV40 large T and small t, hTERT (catalytic subunit of human telomerase), Raf, phosphatidylinositol 3-kinase, and Ral-GEFs (Ral guanine nucleotide exchange factors). However, when implanted into nude mice these transformed cells typically produce poorly differentiated carcinomas and not adenocarcinomas. On the other hand, transgenic mouse models using ErbB2/neu, Ras, Myc, SV40 T or polyomavirus T develop adenocarcinomas, raising the possibility that the parental normal cell subtype may determine the pathological type of breast tumors. Availability of three-dimensional and mammosphere models has led to the identification of putative stem cells, but more studies are needed to define their biologic role and potential as precursor cells for distinct breast cancers. The combined use of transformation strategies in cell culture and mouse models together with molecular definition of human breast cancer subtypes should help to elucidate the nature of breast cancer diversity and to develop individualized therapies.
More than 80% of adult human cancers are carcinomas, tumors originating from malignant transformation of epithelial cells. However, much of our understanding of oncogenic transformation comes from fibroblast transformation systems. Breast cancer is the second leading cause of cancer-related deaths among women in the USA [1]. The vast majority of breast cancers are carcinomas that originate from cells lining the milk-forming ducts of the mammary gland (for review [2]). Deliberate transformation of these cells provides a practical window into human epithelial oncogenesis. Malignant transformation represents a complex multistep process in which genetic, environmental, and dietary factors together are thought to alter critical cell growth regulatory pathways resulting in uncontrolled proliferation, which is a hallmark of tumorigenesis [3, 4]. Understanding the nature of these cellular pathways is of central importance in cancer biology.
The growth of normal human mammary epithelial cells (HMECs), which include luminal, myoepithelial and/or basal cells (described below), is tightly controlled. These cells grow for a finite life span and eventually senesce (for review [5–7]). Both cell culture and mouse models have provided evidence that essential initial steps in tumorigenesis involve the loss of senescence checkpoints and immortalization, which allow a cell to grow indefinitely and to go through further oncogenic steps, resulting in fully malignant behavior. In addition, cell culture model systems have identified a number of genes whose alterations are involved in HMEC immortalization and thereby have provided significant insights into the biology of early breast cancer [5, 7, 8]. Use of oncogene combinations has allowed researchers to create cell culture models of full HMEC transformation, thereby illuminating the process of breast cancer progression [9–11]. Additional insights have come from mouse models, using transgenic overexpression of oncogenesis-promoting genes and deletion of tumor suppressor genes, which often produce breast adenocarcinomas that closely resemble human breast cancers.
Studies using cell culture transformation models have pointed to the existence of HMEC subtypes with distinct susceptibilities to oncogenesis by different oncogenes [5, 8]. Remarkably, direct cDNA microarray profiling of human breast cancers has led to similar insights, identifying multiple subtypes of human breast cancer with distinct outcomes; phenotypic and genotypic characteristics of these breast cancer subtypes point to their possible origin from specific subtypes of HMECs, such as basal or luminal cells [12]. Finally, cell culture and mouse model systems have begun to identify mammary stem cells that may provide progenitors for oncogenic transformation [13] and have led to an appreciation of the microenvironment for oncogenesis [14, 15].
Thus, studies conducted over the past several years have established the importance of HMEC transformation models to our understanding of the pathways that control normal mammary cell growth, development, and oncogenesis. However, many challenges remain, including the identification of mammary cell subtypes or oncogenic strategies that result in cancers that resemble naturally occurring human breast cancers, and translation of new research to devise more specific diagnostic and treatment strategies for different subtypes of breast cancer.
Mammary gland and various epithelial cell subtypes
Histological examination of TDLU reveals two major types of cells: inner secretory luminal cells and outer contractile myoepithelial cells (Fig. 1). In addition to luminal and myoepithelial cells, there is emerging evidence that basal cells (presumed to be the progenitor for myoepithelial cells) and stem cells exist in the TDLU [17, 18]. Until recently it was believed that the vast majority of breast carcinomas arise from luminal epithelial cells [2]. This was based on the keratin expression and other phenotypic markers of cultured tumor cell lines, mostly derived from metastatic lesions [2]. Unfortunately, the great majority of primary breast tumors have proved difficult to establish in cultures, either on plastic or as three-dimensional cultures [5–7, 19–21]. However, recent molecular profiling studies clearly show the existence of multiple subtypes of breast cancers probably originating from luminal, basal, and possibly stem cell compartments [12] (described below in detail).
Culturing of various epithelial cell subtypes
For more than two decades, various investigators have attempted to develop cell culture models that lead to isolation of breast cancer cells resembling those found in human breast cancers. In order to establish such models, it was essential to culture normal HMECs. In 1980s, work from several laboratories showed that normal HMECs could be cultured in cell culture [22, 23] (for review [2, 5, 7]).
However, in some cases (not always) an occasional homogenous cell population emerges that continue to grow further for 30–60 PDs (Figs 2 and 3) [5–7] before senescence occurs (also called agonescence, described below) [25]. This process of emergence of cells that are able to proliferate for extended periods is also known as self-selection; before selection the cells are termed preselection cells, whereas those that emerge after selection are called postselection cells. The keratin profile of preselection cells (K-5, K-6, K-7, K-14, K-17, K-18 and K-19 positive) [8, 19, 26] suggests the existence of both luminal and basal (myoepithelial) cells. However, postselection cells generally exhibit a loss of expression of K-19 but retain the expression of all other keratins [8, 18, 25]. These cells also express α-smooth muscle actin (ASMA), suggesting that these may be of myoepithelial origin. Further development of cell sorting techniques and chemically defined media have helped in culturing of luminal and progenitor epithelial cells [14, 27] (described below in detail).
It has also been reported that postselection cells lose the expression of p16INK4a, a cyclin-dependent kinase (CDK) inhibitor [24, 25], and gain expression of cyclo-oxygenase (COX)-2, a gene that is thought to be involved in tumorigenesis [28]. As both of these genes are implicated in oncogenesis, it is conceivable that loss of p16 or gain of COX-2 expression may make these cells more susceptible to transformation, although it is unclear whether the loss of p16 and gain of COX-2 occur de novo during self-selection or represent selection of a minor population of cells with pre-existing high COX-2 and low p16 expression. Notably, p16-negative and COX-2-positive cells could be detected using immunohistochemistry in normal mammary tissue [28, 29].
Immortalization of various HMEC subtypes in culture
As alluded to above, normal mammoplasty-derived HMECs exhibit a limited life span, which is followed by replicative senescence. Replicative senescence acts as a strong tumor suppressor mechanism and prevents spontaneous immortalization of human cells [30–33]. A major determinant of replicative senescence is the enzyme telomerase, which maintains the length of telomere ends [30, 31]. Most somatic cells express little or no telomerase, resulting in telomere shortening with successive cell divisions, which eventually elicits a senescence checkpoint [30–32]. A senescence-like phenotype can also be induced by a variety of nontelomeric signals such as DNA-damaging agents, adverse cell culture conditions, and overexpression of certain oncogenes [30, 32]. The tumor suppressor protein p53 and its target gene product p21, and p16INK4a play a crucial role in senescence induced by telomeric as well as nontelomeric signals [30–33]. Much of our knowledge about senescence comes from studies conducted in human fibroblasts [30–34]. Only recently have we begun to elucidate the mechanisms of senescence in epithelial cells, in particular in HMECs [25].
The senescence associated with the 'selection' phase in HMEC cultures is accompanied by classic features of senescence, such as flat morphology, presence of vacuoles, and positive staining for senescence-associated β-galactosidase (SA-β-gal), a marker of senescence [34]. The block in cell proliferation at this stage is dependent on the pRb/p16 pathway [24, 35], because the human papillomavirus (HPV) oncogene E7, which binds and inactivates pRb, can overcome the M0/selection stage [36]. Similarly, a constitutively active p16-insensitive CDK4 mutant can overcome the M0 stage [37]. Thus, senescence of preselection cells appears to be telomere independent. At the end of their replicative life span, postselection HMECs exhibit senescence as well as cell death with a high level of genomic instability. This phenomenon is termed as agonescence, as opposed to replicative senescence [25]. Most importantly, unlike rodent cells, human HMECs derived from reduction mammoplasties or from milk do not exhibit spontaneous immortalization and thus provide suitable models of human cell transformation. Immortalization of HMECs in culture is characterized by their continuous growth beyond the agonescence checkpoint. It is thought that immortalization is an early step in human cancer, and continued proliferation of immortal cells allows the accumulation of additional genetic changes that promote malignant and metastatic behavior.
Stampfer and Bartley [38] presented initial evidence that HMECs could be immortalized in cell culture using benzo(a)-pyrene; however, the immortalization was a rare event in this case. Similar to carcinogen-induced immortalization, we found that γ-radiation induced the transformation of HMECs relatively infrequently [5, 8, 39]. In general, most viral oncogenes (including SV40 T antigen, adenovirus E1A and E1B, polyoma T antigen) have not proven very efficient as immortalizing genes for human cells [40]. While the introduction of the SV40 T antigen into breast tumor tissue-derived epithelial cells gave rise to immortal cell lines, SV40-transfected cells go through a long crisis period, and emergence of immortal cells is rare [19]. Over the past several years, our studies have defined a system to immortalize human HMECs efficiently and reproducibly, using the urogenital carcinoma-associated HPV oncogenes E6 and E7 [5, 8, 36].
Comparison of early (preselection) and late-passage (post-selection) cultures revealed that different HMEC subtypes exhibit a remarkably distinct susceptibility to E6 or E7, or their combination [8]. One HMEC subtype was exclusively immortalized by E6 but not by E7; such cells predominated the late-passage cultures but were rare at early passages. Surprisingly, a second cell type, present only in early passages of tissue-derived cultures, showed extension of life span and infrequent immortalization by E7 alone. Finally, E6 and E7 together were required to immortalize fully a large proportion of preselection HMECs [8].
Human milk is an easily available source of relatively pure HMECs that are thought to be differentiated luminal cells [2, 19]. However, these cells can be cultured for only a limited number of passages (typically two to three passages, or five to nine PDs), which has precluded their detailed biochemical study [2, 18]. Most of the work on milk cells has been carried out in Taylor-Papadimitriou's laboratory and has demonstrated that these cells can be immortalized by SV40 T antigen [41]. Interestingly, neither E6 nor E7 alone could induce the immortalization of milk-derived HMECs, whereas a combination of E6 and E7 was effective [8].
The reproducibility and relatively high efficiency with which E6 (in postselection HMECs) or E6 and E7 combined can induce immortalization of human HMECs have therefore yielded a practical approach to elucidate the biochemical mechanisms of HMEC immortalization. In recent years, using Yeast Two-hybrid analysis, we identified several novel targets of the E6 oncogene in HMECs. These targets represent novel mediator of HMEC immortalization [5]. These include ADA3 (alteration/deficiency in activation 3), a novel coactivator of p53 and steroid receptors (estrogen receptor [ER] and retinoic acid receptor) [42–44]; E6 targeted protein 1 (E6TP1), a novel GTPase activating Rap small G protein; and protein kinase N (PKN), an effector for Rho small G protein [5]. We recently found that MamL1, a human homolog of the Drosophila mastermind gene and a known coactivator for Notch [45], also interacts with E6 (I Bhat, V Band, unpublished data). These studies have implicated the p53, Notch, ER, Rho, and Rap signaling pathways in early transformation of human HMECs. Consistent with these analyses, we have shown that expression of mutant p53 [46] or activated Rho (X Zhao, V Band, unpublished data) induces immortalization of HMECs. Furthermore, several studies support a role for p53 mutations as an early event in breast cancer [47]. Taken together, these studies demonstrate that E6 is the most efficient immortalizing gene for postselection HMECs and that E6 immortalizes the HMECs by concurrently altering multiple biochemical pathways. Future studies will need to address the precise role played by these novel oncogene targets in early breast cancer.
In addition to viral oncogenes, alterations in the expression of cellular genes can also help to overcome senescence and promote HMEC immortalization. Among the cellular genes, we recently reported that Bmi-1, a member of the polycomb group of transcriptional repressors, could immortalize postselection HMECs [48]. Although the detailed mechanism of immortalization induced by Bmi-1 remains to be explored, Bmi-1 does not appear to immortalize these cells by down-regulating the INK4a/ARF locus. Interestingly, recent studies have implicated Bmi-1 in stem cell function and renewal [49, 50], suggesting that Bmi-1 could function as a potential breast cancer stem cell marker [50]. Another study showed that ZNF217, a zinc finger protein that is overexpressed in breast cancers, can promote immortalization of postselection HMECs [51]. Furthermore, introduction of hTERT also induces immortalization of postselection cells [5]. Interestingly, induction of telomerase has been documented early after E6 was introduced into HMECs [52], although the cause and effect relationship between telomerase induction and E6-induced immortalization continues to be debated. Recently, the E6 and E6-AP binding protein NFX-91 was implicated in E6-mediated induction of telomerase [53].
Cell culture models of full transformation of HMECs
Although these studies have thus far relied on the use of known oncogenes, future studies using the cell culture transformation models with gene libraries should help identify novel cellular genes that participate at various steps of breast cancer progression. Vast majority of human breast cancers are adenocarcinomas, and only a small portion of breast cancers are poorly differentiated carcinomas. Hence, it appears that HMEC transformation in culture system is not optimal because the tumors produced by these transformed HMECs have usually been poorly differentiated carcinomas rather than adenocarcinomas. Breast cancer is associated with overexpression of various cellular proto-oncogenes such as ErbB2, epidermal growth factor receptor, Src family kinases, Bmi-1, cyclin D1, cyclin E, CDK4, and other potential growth regulators. Use of these oncogenes in the multistep model described above and the use of other HMEC subtypes (such as luminal cells, potential stem cells, or those derived from milk) as a starting population may help to achieve full transformation of HMECs that develop into adenocarcinomas in a nude mouse model. Thus, future studies must focus on developing models that will lead to breast tumors that faithfully reproduce the pathological characteristics of human breast cancers.
Transgenic mouse models of breast cancers
Mouse models of breast cancers have provided a wealth of knowledge about the molecular pathways involved in breast cancers. Initial studies in these models used carcinogens to induce breast carcinomas [55]. Later studies targeted a wide variety of genes expressed under either the MMTV (mouse mammary tumor virus) or the WAP (whey acidic protein) promoter to target genes to the mammary gland. Importantly, such studies invariably produced breast adenocarcinomas in mice that resembled human breast cancers. These include viral proteins, such as SV40 large T, polyoma virus T antigen [56–58], or cellular proteins such as c-Myc, ErbB2/neu, cyclin D1, cyclin E, ERs, mutant p53, c-Ha-ras, and Wnt-1 [59–63]. Recent studies have focused on mouse models with either a global or a mammary-specific knockout of specific genes to examine the function of obvious players, such as cell cycle related proteins and tumor suppressors, either by themselves or after these deficiencies were combined with transgenic neu or other oncogenes. For example, cyclin D1-deficient mice are resistant to mammary carcinomas induced by c-neu/ ErbB2 and Ha-ras but not to those induced by c-Myc or Wnt-1 [63]. These findings define a pivotal role for cyclin D1 in selective mammary cancers in a mouse model and imply a functional role for cyclin D1 overexpression in a subset of human breast cancers. In another study, Cre-mediated deletion of exons 3 and 4 of the mouse Brca2 gene in mice with a loxP-modified and null Brca2 allele resulted in high incidence of breast adenocarcinomas [64]. Similarly, the telomere attrition in aging telomerase-deficient and p53-mutant mice promoted the development of breast adenocarcinomas [65]. Another study showed that loss of Stat5a delays mammary cancer progression in a WAP-TAg transgenic mouse model [66].
Collectively, these models have defined a role for p53, pRb, BRCA1/2, cyclins, CDKs, ErbB2, c-Myc, Wnt-1, ER, and progesterone receptor in mammary cell growth and development of breast cancers. Finally, these different oncogenes and the pathways in which they work seem to target different progenitors or cell types in mammary gland to develop mammary tumors [67]. For example, the Wnt signaling pathway targets both luminal and myoepithelial cells, whereas Neu, H-Ras, and polyoma T antigen target only luminal epithelial cells [67]. The take-home lesson here is that the majority of these mouse models result in tumors that resemble human breast adenocarcinomas pathologically. The lack of development of adenocarcinomas from cells transformed in culture models may thus reflect the cell type that was used as the starting normal cell, rather than any peculiarity associated with the use of mouse as a host.
Molecular classification of breast cancers: cues from cell culture studies
A vast body of clinical literature indicates that breast tumors exhibit diverse phenotypes as judged by their distinct clinical course, pathological features, and responsiveness to various therapies. However, it has not been clear whether this diversity reflects cancers arising from distinct subtypes of HMECs. Consistent with such a possibility, several years ago we reported the presence of different subtypes of cells in reduction mammoplasty specimens and in milk that exhibited differential susceptibility to viral oncogenes [5, 8]. Direct evidence for the conclusions derived from these cell culture studies was provided by recent work utilizing gene expression patterns in primary human breast cancers, using cDNA microarrays. These studies identified distinct gene expression profiles or molecular portraits based on which breast tumors could be subclassified into groups that appear to reflect the original cellular subtypes found in the mammary gland [12]. Five categories of breast cancers were described [12]: a basal epithelial-like group, an ErbB2-overexpressing group, a normal breast epithelial-like group, luminal epithelial cell type A, and luminal epithelial cell type B. A slightly different classification was proposed by Sotiriou and coworkers [68]. The breast tumors were first divided into ER-positive and ER-negative categories. The ER-negative tumors were further subgrouped into basal-like 1, basal-like 2, and ErbB2/neu tumors, whereas ER-positive tumors were subdivided into luminal-like 1, luminal-like 2, and luminal-like 3 subtypes. Sotiriou and coworkers also re-examined data from the study by Sorlie and coworkers [12] and suggested that luminal-like breast cancer could be classified as luminal A, B, and C subtypes corresponding to luminal-like 1, luminal-like 2, and luminal-like 3 subtypes.
Interestingly, survival analyses conducted in a subcohort of patients with locally advanced breast cancer uniformly treated in a prospective study showed significantly different outcomes for the patients belonging to the various groups, with the basal-like subtype correlating with worst outcome, followed by ErbB2 overexpressing, normal cell type and luminal cell type groups [12, 68]. Interestingly, a significant difference in outcome for the two ER-positive groups was also noticed [68]. These studies strongly support the idea that many of the breast tumor subtypes may represent malignancies of biologically distinct cell types producing distinct disease entities that may require different treatment strategies. Importantly, these analyses provide a strong rationale for further definition of various mammary epithelial subtypes and expansion of immortalization and full transformation strategies to derive models that may faithfully reproduce the histological and molecular diversity encountered in human breast cancers.
Do breast cancers arise from stem cells?
Stem cells have enormous replicative potential and capacity for self-renewal, and give rise to different lineages of cells. Although still a controversial notion, many cancers are thought to originate from cancer stem cells [69]. This idea has also attracted a great interest in the field of breast cancer research, and investigators have begun to examine whether there are mammary stem cells [13, 17, 27, 70–73]. The cellular milieu of the mammary gland undergoes significant changes during pregnancy, lactation, and involution. These include bursts of proliferation of existing cells during pregnancy, continued differentiation during lactation, and apoptosis during involution at the end of the cycle. This cyclical behavior predicts the presence of a stem cell-like population in the mammary gland, which would meet the demand of a pregnancy cycle. The existence of adult mammary epithelial stem cells has therefore been proposed. Direct evidence for the existence of such cells has come from clear fat-pad transplantation, retroviral tagging, and X-chromosome inactivation studies in rodent model [13, 16, 17, 70–73].
Recently, using various putative stem cell and cell surface markers, such as sialomucin (Muc), epithelial-specific antigen (ESA), various cytokeratins, ASMA, and CALLA or CD10, attempts have been made to identify the mouse and human mammary epithelial stem cells [13, 27, 70–73]. Using immuno-magnetic cell sorting based on surface antigen markers (Muc and ESA) and subsequent immortalization with E6 and E7, Gudjonsson and coworkers [27] separated Muc-/ESA+/ K-19+ cells that were able both to self-renew and to give rise to Muc-/ESA+ epithelial cells and ASMA+ myoepithelial cells, thus exhibiting characteristic of breast stem cells. Dontu and coworkers [13] isolated undifferentiated mammospheres from single cell suspensions of HMECs obtained by mechanical and enzymatic dissociations. Primary mammo-spheres can be further passaged to generate secondary mammospheres. Primary as well as secondary mammo-spheres were highly enriched in early progenitor or stem cells capable of differentiating along multiple lineages and of self-renewal. Immunostaining of these mammospheres showed the presence of CD10, α6 integrin and K-5 on early progenitors, and ESA and K-14 on late progenitor cells [13]. However, MUC1, K-18, and ASMA were not expressed in cells present in mammospheres [13]. Detailed expression profiling of mammospheres suggests the presence of additional markers that are upregulated in mammospheres such as stem cell growth factor, hepatocyte growth factor antagonist, stem cell growth factor B and apolipoprotein E. Some markers are exclusively expressed in mammospheres such as FZD2 (frizzled homolog 2), glypican 4, interleukin-6, CXCR4 (CXC chemokine receptor), and FGFR1 (fibroblast growth factor receptor 1). Several genes that are expressed in mammospheres are also expressed in similar structures derived from other cell types (such as neurospheres formed by neural stem cells) [13].
Thus, culture of human HMECs in mammospheres may provide a tool with which to isolate and study mammary epithelial stem cells and their oncogenic susceptibilities. Based on the above and other related studies [13, 17, 27], the candidate mammary stem cells appear to be ESA+, MUC1-, α6 integrin+, and CD10+, and the mammary stem cell niche appears to be at the suprabasal location within the luminal cell layer. Further work by other laboratories and adoption of the schemes employed by Gudjonsson [27] and Dontu [13] and their groups should help in determining the general feasibility of these novel approaches.
Apart from normal mammary stem cells, the possible existence of a breast cancer stem cell has been reported in the literature [74, 75]. In a NOD/SCID xenotransplants model, Al-Hajj and coworkers [75] used four cell surface markers, CD44, CD24, ESA and B38.1 (a Breast/ovarian cancer specific marker), and lineage markers to sort different populations of breast cells from breast tumor tissues. All mice injected with Lin-/CD44+/B38.1+/CD24-/low generated tumors, whereas none of the mice injected with CD44-/B38.1- cells developed tumors. Lin-/CD44+/B38.1+ fractions were further subdivided based on ESA expression. When used in numbers as low as 200, Lin-/ESA+/CD44+/CD24-/low cells in xenotransplants generated tumors that were similar to initial tumors in term of phenotypic heterogeneity [75]. The presence of such a population in breast tumor tissue, which is able to self-renew and differentiate, supports the stem-cell model of breast tumorigenesis.
Our ability to culture and immortalize normal HMECs has provided a wealth of knowledge about the behavior of mammary cells and the genes involved in normal cell growth and oncogenesis. Characterization of these cells has provided novel markers that may permit early diagnosis and prognosis of breast cancers, and has yielded knowledge about potential precursor cells for breast cancers. Transformation analyses in cell culture models have also proven important to our understanding of the multistep nature of breast cancer. Transgenic mouse models have identified the roles played by various tumor suppressors, cell cycle proteins, and other proto-oncogenes in breast cancers. Recent studies using three-dimensional models have proven useful to our understanding of the normal and tumor mammary stem cells and the relationship of microenvironment to epithelial cell growth. Finally, using gene profiling, we have begun to appreciate that breast cancers do not originate only from luminal cells but also from basal and myoepithelial cells, and that there are subtypes of breast cancers that possibly originate from distinct normal precursors that have distinct clinical outcomes and may require different treatment strategies.
However, a number of critical questions remain. What are breast stem cells and what is their role in breast cancer? Are myoepithelial cells and basal cells similar or distinct? Why can we not culture most of the primary breast cancers? How can we develop transformed breast cells in culture that would give rise to breast tumors that resemble human breast cancer -adenocarcinomas as opposed to poorly differentiated carcinomas? How do different subtypes of breast cancer originate?
In conclusion, experimental immortalization and transformation models have led to substantial progress in our understanding of the biology of breast cancer. Future studies in these model systems should go a long way toward elucidating the nature of breast cancer heterogeneity and thus facilitate the development of more individualized therapies for breast cancer patients.
α-smooth muscle actin
cyclin-dependent kinase
estrogen receptor
epithelial-specific antigen
human mammary epithelial cell
human papillomavirus
- hTERT:
catalytic subunit of human telomerase
population doubling
- Ral-GEF:
Ral guanine nucleotide exchange factor
terminal ductal-lobular unit.
We apologize to many of our colleagues whose original work could not be cited due to space constrains.
We thank past and present members of our respective laboratories for their contribution to work published from our laboratories. Work in our laboratories was supported by the NIH Grants CA94143, CA96844, CA81076, and DAMD BC010093 (VB); CA 87986, CA 76118, CA 99900, CA99163, and DAMD17-02-1-0303 (HB); and CA 094150 and DAMD17-02-1-0509 (GD). VB and HB gratefully acknowledge the support of the Duckworth Family Chair in Breast Cancer Research and Jean Ruggles-Romoser Chair for Cancer Research, respectively.
Authors' Affiliations
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text:
User Agent: Mozilla/5.0 (X11; Linux x86_64; rv:10.0) Gecko/20100101 Firefox/10.0
Build ID: 20120205184700
Steps to reproduce:
Install Firefox 12.0a2 and create fresh profile.
Install extension at
and restart.
Go to http://code.google.com/p/ff-html5notifications/ and test notifications.
Actual results:
Firefox says functionnality is not available.
Expected results:
Firefox should have asked for notification permission.
After a second restart, Firefox does ask for notification permission.
This extension uses no binary code, but (among others) Javascript XPCOM and javascript global property with chrome.manifest registration
category JavaScript-global-property webkitNotifications @paxal.net/html5notifications/notification-center;1
Addons Log after first restart :
*** LOG addons.xpi: startup
*** LOG addons.xpi: checkForChanges
*** LOG addons.xpi: Found updated metadata for email@example.com in app-profile
*** LOG addons.xpi: Processing install of email@example.com in app-profile
*** LOG addons.xpi: Opening database
*** LOG addons.xpi: New add-on email@example.com installed in app-profile
*** LOG addons.xpi: Updating database with changes to installed add-ons
*** LOG addons.xpi: Updating add-on states
*** LOG addons.xpi: Writing add-ons list
See issue @ http://code.google.com/p/ff-html5notifications/issues/detail?id=36
Regression window
Cannot reproduce:
Mozilla/5.0 (Windows NT 6.1; WOW64; rv:12.0a1) Gecko/20120111 Firefox/12.0a1 ID:20120111082226
Can reproduce:
Mozilla/5.0 (Windows NT 6.1; WOW64; rv:12.0a1) Gecko/20120111 Firefox/12.0a1 ID:20120111083049
Suspected: Bug 675221
This extension needs to be fixed. What's happening is:
We hit the line "category JavaScript-global-property webkitNotifications @paxal.net/html5notifications/notification-center;1" in chrome.manifest. When we process this line, before the patch we would post an event to the event loop to notify observers. The new behavior is that we immediately notify observers. Both behaviors are correct, but the new behavior is much more efficient.
This ends up immediately at http://hg.mozilla.org/mozilla-central/annotate/e0d9c8ddd5bd/dom/base/nsScriptNameSpaceManager.cpp#l724 which fails because the contractID isn't registered yet.
This would be solved by reordering chrome.manifest so that you register the contractid/CID *before* you add the category.
It's not clear to me why this works correctly on non-first runs, but that actually sounds like a bug that we need to fix; the behavior should be consistent.
The reason this doesn't happen on second-startup is that we initialize the nsScriptNameSpaceManager later in startup, so that it doesn't have to cache the results.
Thank you for such quick replies.
I reordered chrome.manifest lines, but the problem is still here.
The components are accessible, but the JavaScript global-property is not.
Extract of chrome.manifest :
# notification center object
interfaces components/nsIPXLNotificationCenter.xpt
component {d931339b-60b1-4559-9459-a69ed1396561} components/nsIPXLNotificationCenter.js
contract @paxal.net/html5notifications/notification-center;1 {d931339b-60b1-4559-9459-a69ed1396561}
category JavaScript-global-property webkitNotifications @paxal.net/html5notifications/notification-center;1
I will ask other AMO Editors if they can find other addons that could be concerned with this issue. Maybe it's a problem with mine only.
Created attachment 595321 [details]
Extension with reordered chrome.manifest file : category command at the end
I tested 3 (mine + 2) of the 12 addons with JavaScript-global-property in chrome.manifest (thank you AMO editors for the list) :
https://addons.mozilla.org/fr/firefox/addon/js-print-setup/ (11.0b1 OK, 12.0a2 NOT OK)
Javascript property : jsPrintSetup
chrome.manifest : ordered
https://addons.mozilla.org/fr/firefox/addon/openid-for-firefox/ (11.0b1 OK, 12.0a2 NOT OK)
Javascript property : openid
chrome.manifest : ordered
All addons with Global JS Property stop working after 1st restart, and work again after second restart (even the addons that were already installed).
Small interface to test if a window.javascriptProperty exists :
(In reply to Benjamin Smedberg [:bsmedberg] from comment #2)
> This would be solved by reordering chrome.manifest so that you register the
> contractid/CID *before* you add the category.
Reordering will not have any effect as contracts are special cased in the manifest parser to be registered last:
A viable work-around would be to register components in a separate manifest and link that from the main manifest, as the Parser will only delay contract registration on a per manifest basis.
manifest components.manifest
category ...
interfaces ...
component ...
contract ...
Right now nsScriptNameSpaceManager.cpp - the global javascript components - and the nsIStringBundleService (checking for nsIStringBundleOverride.idl) are the only code bits in core code that observe "xpcom-category-entry-added".
The only addons mxr listed add-on observing the notification is AdBlock Plus, using this as a way for other extensions to load modules conditionally on ABP being installed:
ABP hg is down ATM, at least for me, so here are the commits from a clone:
There are no addons mxr listed add-ons registering themselves to the "adblock-plus-module-location" category.
If this bug does not get fixed, this definitively needs a note regarding js globals, stringbundle overrides and the xpcom-category-entry-added notification in the compatibility report Jorge publishes on the addons blog.
Hrmph. I guess we should always asynchronously dispatch this notification. Patch forthcoming :-(
Created attachment 595456 [details] [diff] [review]
Patch, make category delivery always be asynchronous, rev. 1
Created attachment 595457 [details] [diff] [review]
Comment on attachment 595456 [details] [diff] [review]
Patch, make category delivery always be asynchronous, rev. 1
I have same problem, but can't solve by restart twice
I totally screwed up the bug number in parts of this :-(
Target Milestone set to mozilla13, is that mean only in firefox 13?
so, firefox 12a2 won't enjoy the fix, right?
*** Bug 696117 has been marked as a duplicate of this bug. ***
Comment on attachment 595456 [details] [diff] [review]
Patch, make category delivery always be asynchronous, rev. 1
This is pretty low-risk, it reverts this specific case to the previous behavior and comes with a test.
Comment on attachment 595456 [details] [diff] [review]
Patch, make category delivery always be asynchronous, rev. 1
[Triage Comment]
This low-risk patch fixes a reproducible bug when an add-on needs notification permissions. Approved for Aurora 12.
This hasn't yet landed on Aurora 12 - can we do that soon so that this doesn't land right before the cutover to beta?
Mozilla/5.0 (X11; Linux x86_64; rv:12.0) Gecko/20100101 Firefox/12.0
Mozilla/5.0 (Macintosh; Intel Mac OS X 10.6; rv:12.0) Gecko/20100101 Firefox/12.0
Verified with steps from comment 0 on Ubuntu 11.10 x86_64 and Mac OS 10.6. Notifications appear after restarting.


text:
MENUOur real tasty food INTRODUCING EN MASSE SOMETHING EXHILIRATING, SOMETHING SPECTACULAR
Getting to Know Us
The Dockside Restaurant, located overlooking beautiful Seneca Lake is the most popular restaurant in the area for the summer. We offer breakfast, lunch, and dinner dining. Our full menu has something for families, large groups, as well as the individual appetite.
Father's Day Buffet
Hey dad's - come celebrate your day at the Dockside Restaurant!.
Buffet Menu
BBQ Riblets
Oven Baked Chicken
Mashed Potatoes & Gravy
Country Style Green Beans
Buttered Corn
Grandma's Noodles
Salad Bar
Rolls & Butter
Adults - $13.95, Kids under 9 - $9.95, Kids under 5 - Free
* Free 5x7 photos available for Father's Day with Seneca Lake backdrop - by Hannah's Photography.
Weekly Specials
Join us every Friday night for our fish fry
Every Friday and Saturday, we will have mouth-watering BBQ.
We Serve Breakfast
Full breakfast menu available. Big Breakfast Brunch offered June-Sept
Memorial Day through Labor Day weekend stop by for a fresh ribeye loin slow roasted. 4PM to Close.


text:
"Beauty is just kind of an accident. Beauty is just a happenstance. Beauty is the remainders of being a painter."
"I love Hiroshi Sugimoto's work, and I've always paid close attention to his horizons- always at the same place. But that was not my interest. I saw a helicopter coming down, and the idea of photographing it just before it hit the horizon became of utmost importance tome. This reinforces the idea of the helicopter flying, just floating on air. That's what they do, of course, but this visually reinforces that idea or describes it in a way that I hadn't seen before."
- An-My Lê


text:
Rating: 0.0/5 (Total votes: 0)
Private Web browser, encrypted file manager, Flash downloader, and media player. ArmorSurf protects and encrypts user files, cookies, browsing history and activity so no traces are left on a computer. Includes IP masking, secret installation, password protection, panic keys, pop-up protection, and a forced confession feature. ArmorSurf lets you download and keep any type of content, including streaming Flash videos. It can also burn video DVDs or export videos to an iPod or other mobile device.
What is new in this release:
Version 18.104.22.168 supports Windows 7 and high definition flash videos.
Some features disabled
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