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Contact Information
User Reception Desk's business hour is 8:30 a.m.-5:00 p.m. from Monday through Friday
(except national holidays and JAIST holidays).
If you have any question or trouble on computers, printers, and network
services, etc. that we provide, please check FAQ at first.
And if you couldn't find the solution, please make an inquiry using the query
forms below. You can contact us by e-mail to isc-query(at)jaist.ac.jp, too.
In case you have network trouble and cannot contact us on line, please
come to the Research Center for Advanced Computing Infrastructure
(2nd floor of Information Science Building 2) during the business hours.
If you are not sure whether the troubled machine is provided by the
Center, please ask your floor manager or supervisor before making an
inquiry to us.
We accept your inquiry from the query forms or e-mail 24 hours. Response
to non-emergency inquiries that reach us outside of business hours,
however, will be made on the next business day.
User Reception Desk
- Location: Information Science Bldg. II 2F (I-24)
- Business Hour: Monday to Friday, 8:30-17:00
- Ext: 1300
- E-mail: isc-query(at)jaist.ac.jp
- We may ask you to visit us again later when we are absent from the desk due to a meeting, lunch break, etc. and also an emergent troubleshooting.
Thank you for your cooperation.
Helpdesk Staff
We'are here 2Help!
The ISCenter Help Desk provides a visible and proactive avenue of help for our students, employees, and guests. Browse our IT services to view all of the resources available to help you excel in a way how to manage your own terminals.
If you are having problems and would like to submit an online help request, please send us an email.
Example 1 (During Help desk staff work hours)
I thought, "I do not knowhow to connect wireless Lan on my smartphone"!
Please send the OS information of the smartphone and ID (student number) of JAIST to
Then you will receive a reply saying that it is described in detail at www.jaist.ac.jp/iscenter/network/wireless.
If you do not understand how to follow the procedure described in the site above , please come to the 2nd floor of information science 2nd building (I-24 room).Then the help desk staff will carefully tell you how to connect the wireless Lan.


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A very accurate model of an Offroad Chassis .
The model comes in five formats: -.blend, rendered with cycles, as seen in the images; -.obj, with materials applied and textures; -.dae, with materials applied and textures; -.fbx; -.stl, ready to print in 3D;
This 3d model was originally created in Blender 2.75 and rendered with Cycles. The model has materials applied in all formats, and are ready to import and render. The model is built strictly out of quads and is subdivisable:
It comes in separate parts, named correctly for the sake of convenience.
For any problems please feel free to contact me.
Don't forget to rate and enjoy!

subset: commoncrawl


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Cruise secrets: Never touch this one thing on a cruise ship – you run a huge risk
By HARRIET MALLINSON Cruise ship holidays are an excellent opportunity to travel the world in comfort without ever having to unpack. Guests on cruises can enjoy all sorts of activities onboard as well as venture to shore on excursions. However, there are also things you shouldn't do on a cruise ship to prevent unpleasant consequences. Self-professed veteran cruiser… Read More »


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The world is changing. We're here to help you change with it. Apply for FREE for a limited time. | Click to learn more | Additional COVID-19 Updates
For a limited time, use the discount code TOGETHER and we'll waive the $25 application fee. | Apply Today!
Fill out the form below and we'll contact you and answer all of your questions.
As a CPA you can either work independently or help entire organizations to run more efficiently and successfully. You'll stay on top of changes to financial-related laws and regulations, and reduce costs and improve profits for clients. An accounting professional may be responsible for the following:
The Master's in Professional Accounting program is designed to prepare you to be a Certified Public Accountant (CPA), as well as an effective leader in public accounting, corporations, government agencies, and other fields. By becoming a licensed accountant by your state's Board of Accountancy, you can advance quickly within your field.
In addition to the institutional graduate admission standards, students seeking admission to the MPAcc program must have an undergraduate degree with a major or concentration in accounting, which includes a minimum of 21 credit hours of upper-division accounting coursework. If this requirement is not met, students can seek admission with the program chair approval as long as they meet one of the following conditions:
To gain full admission to the MPAcc program, provisionally admitted students must complete the above coursework within 12 months of starting and maintain a 3.0 grade point average without receiving a grade lower than a C in any coursework.
The prerequisite coursework is designed to prepare students for the program. Students seeking to become CPAs may need to take additional courses to meet state requirements. Other courses may need to be taken to comply with the prerequisites of some electives.
This program consists of 8 three-credit core courses as part of a full 30-credit master's degree.
* Master's Plus - Some Master of Professional Accounting students may also be required to take BUS500 and/or RES501 as part of their coursework if they have an undergraduate GPA below 3.00/do not earn an accredited ACBSP-degree in business courses and/or accounting, finance, or business statistics. In this case, the degree is 33 credits.
** Students who do not have a previous degree from an an ACBSP-accredited program must complete BUS500 before completing other program requirements. Once the undergraduate program evaluation is completed, students whose prior degree does not meet the requirements will complete BUS500, rather than RES500 or RES501. Provisionally admitted students whose undergraduate degree meets the requirements will complete RES500 or RES501, rather than BUS500.
The Data Analytics Emphasis is designed for those who want to acquire advanced analytical skills in addition to having in-depth accounting knowledge. Using various data analytics tools, students learn how to collect and categorize voluminous data as well as how to analyze and prioritize relevant data to make them useful for decision-making.
Data Analytics is a skill that can apply to many facets of accounting including taxation, auditing, consulting, and risk management. Hence, it is important for accountants who work or plan to work in these areas to know how to undertake and analyze data analytics-related activities. Students in the Master of Professional Accounting who select this emphasis with be equipped with such versatile and valuable skills by the end of their coursework. Students declaring Data Analytics Emphasis should have prior coursework and/or experience in statistics and basic programming.
Courses in the Data Analytics Emphasis include:
Increased occurrences and awareness of fraudulent activities have resulted in increased demand for fraud investigators and forensic accountants. Forensic accounting extends beyond uncovering and investigating fraud. Forensic accountants utilize their accounting skills to provide investigative, litigation, and valuation support in cases involving financial statement fraud, mergers and acquisitions, bankruptcy and insolvency, and divorce. Consequently, forensic accountants can work in public accounting, consulting, and forensic accounting service firms. Forensic accountants can also provide expert services to lawyers, law enforcement agencies, insurance companies, governmental entities, non-profit organizations, and financial institutions.
Students who select this emphasis may be interested in obtaining the Certified Fraud Examiner (CFE) designation. CSU Global does not provide or prepare students for the CFE designation.
Courses in the Fraud Investigations & Forensic Emphasis include:
Auditing and assurance service is a vital accounting niche. Auditors play important roles in the financial reporting process. Audit and assurance service informs users by painting a true picture of where an organization's financial information stands, providing relevant insights about financial and non-financial information, changes that are needed as well as how the changes happens so users can make sound decisions. The emphasis is designed for students interested in pursuing careers in internal audit, assurance services, and information technology auditing. Students will learn how to evaluate internal controls and best practices in auditing using computer-based accounting systems.
Students who select this emphasis can further benefit by obtaining the Certified Internal Auditor (CIA) or Certified Information Systems Auditor(CISA) designation. CSUGlobal does not provide or prepare students for the CIA or CISA designation.
Courses in the Auditing & Assurance Emphasis include:
The taxation emphasis builds on students' previous conceptual understanding of taxation, awareness of tax professionals' responsibilities, technical competence as tax professionals, and understanding of tax laws and policies. Students will also learn tax research tools and policies.
Tax professionals are in demand in public accounting, corporations, and governmental entities. Students who select this emphasis can further benefit by earning the Enrolled Agent designation. CSU Global does not provide or prepare students for the Enrolled Agent Designation.
Courses in the Taxation Emphasis include:
This emphasis is designed for students who want to take diverse courses for career growth or for meeting the education requirements of the CPA and other professional licenses' examinations. In addition to the eight required core courses, students can select two courses from the following list.
Courses in the Professional Accounting Emphasis include:
Your education should increase your earning potential, not your monthly bills.
Your employer may be one of 3,000+ we partner with to offer a 10% discount on tuition.
You may be eligible to receive financial aid to help cover the cost of your education.
Regional accreditation by the Higher Learning Commission (HLC) means your degree comes from a top quality, trusted university.
Your Bachelor's in Accounting from CSU Global is accredited by the Accreditation Council for Business Schools & Programs (ACBSP)
CSU Global was ranked #1 Accounting by Intelligent.
CSU Global was ranked #1 of 25 in Forensic Accounting by Best Masters Programs.
CSU Global's online Master's in Accounting was ranked number 9 by Online Accounting Degree Programs.
In Best Colleges' Schools of Distinction standings, CSU Global earns one of only 15 gold rankings, out of more than 2,000 online degree programs.
Guide to Online Schools identifies CSU Global as one of the top military-friendly online institutions.
"CSU Global enables you to finish and further your education with a very flexible and workable platform. I am married with a full time job and a toddler at home and I have been able to go back to school so that I can further my professional career and truly achieve my educational dreams."
Earning your online master's degree through CSU Global provides you with more than just the diploma you need to get noticed. With an emphasis on real world concepts and career-relevant skills, you get training and experience along with your credit hours. Additionally, CSU Global strives to make your education as affordable as possible. With our Tuition Guarantee, your tuition rate won't increase over time! Instead, you'll enjoy the same low rate for the duration of your enrollment at CSU Global.
Students will learn how to develop accounting strategies to solve organizational problems, apply qualitative and quantitative analyses in decision-making, evaluate and manage ethical and legal conflicts, and adapt accounting methods and practices to best meet the needs of both employees and leaders within an organization. As a bonus, CSU Global students receive discounted access to the Wiley CPAexcel® Gold Course, helping fully prepare you for the CPA exam. Additional outcomes include the following:
Download this fun infographic to discover things like where most accountants work, skills of successful accountants, and other random information about the profession.
Bachelor's of Accounting alumni from CSU Global report extremely high rates of working in the field of accounting after completing the program.
The average annual salary for budget analysts is more than $76k. (BLS, 2019)
Top three titles as reported by Bachelor's of Accounting alumni from CSU Global.


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Dag Hjalmar Agne Carl Hammarskjöld ( Dag Hammarskjöld (help·info)) (29 July 1905 – 18 September 1961) was a Swedish diplomat, economist and author. He was the second Secretary-General of the United Nations. He served from April 1953 until his death in a plane crash in September 1961. He is the only person to have been awarded the Nobel Peace Prize posthumously. Hammarskjöld remains the only U.N. Secretary-General to die in office.
U.S. President John F. Kennedy called Hammarskjöld "the greatest statesman of our century."
Dag Hammarskjöld was born in Jönköping, Sweden, but he lived most of his childhood in Uppsala. He was the fourth and youngest son of Hjalmar Hammarskjöld, prime minister of Sweden from 1914 to 1917, and Agnes Hammarskjöld (née Almquist). His ancestors had served the Swedish Crown since the 17th century. He studied first at Katedralskolan and then at Uppsala University where he graduated with a Master's degree in Political Economy and a Bachelor of Law degree. During this time he served for a year as the first Curator at Uplands Nation. He then moved to Stockholm.


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John Martin is Senior Security Architect & Security Practice Leader at IBM New Zealand and President of the New Zealand Chapter of ISC2. He spoke to NZSM about how 'new collar' recruitment, micro-skills training and AI can solve the cyber skills shortage.
There is a global cyber security skills crisis, and it's not getting any better. In New Zealand – as with many other countries – the rate of demand for cybersec professionals continues to outstrip supply. And with Bachelor degrees the minimum qualification preferred by most employers, a resolution looks remote.
NZSM: All reports point to a lack of skilled professionals in the cyber security labour market and a lack of graduates being produced by training programs. What are your thoughts on this?
JM: Our understanding of the current market is that there is a high demand for cyber security practitioners and looking across the recruitment agencies you can see that on both the commercial and government sides.
There is a lack of these specialists available in New Zealand, and worldwide there is a huge shortage. The latest statistics are pointing to the fact that by 2022 there will be 1.8 million unfilled cyber security jobs. This is why in IBM we're actually advocating more of a 'new collar' approach to security hiring.
NZSM: What initiatives are you aware of in terms of addressing that challenge in the government and private sectors?
JM: From an IBM perspective, we are trying to change the perception of where the talent comes from away from the traditional methods. We're using a 'new collar' approach, which is characterised by new employee profiles, new roles and new relationship perspectives. A recruit needn't have a degree, but they obviously need to have an aptitude towards security and a mindset that puts them in those roles.
This approach has already had some success, especially in our security operations centres in the US. Since 2015 these 'new collar' cyber security professionals have actually accounted for about 20 percent of IBM's hiring. We've brought them in and placed them into a working environment, mentored them and coached them to become professionals.
From that perspective, we would advocate that other organisations – especially in New Zealand – redefine their hiring models to identify people with the right attributes and skills – and give them a chance.
Because we're realising that we can't limit ourselves to just universities, we've identified the need to expand to community colleges and other education programs – so we now, for example, have a relationship with Unitec. It's really about creating new partnerships to recruit the people we need.
We've also placed a real emphasis on 'micro-skills' and earning 'badges' to get the skills you need rather than completing a whole degree. IBM has partnered with Acclaim, and one of the things we have in IBM is something we call the 'Think 40'. [It's a program in which] everybody is encouraged to do at least 40 hours of personal development per year, if not more, for our certification.
During this digital transformation that all organisations are currently facing, it's quite dynamic and we need a new skills sets – like data science and cyber security – and we need to invest in people to get the best of people.
Enjoying this article? Consider a subscription to the print edition of New Zealand Security Magazine.
NZSM: Can one say that the idea of a three-year degree no longer appears to be something of continuing relevance for the sector, or is that perspective mistaken?
JM: Because of the levels of demand we need to build up the right skills and aptitude. Traditionally, people coming from the military or government-type roles have the right talent, and they have the right mindset, which in turn means they have the right level of integrity, ethics and trust.
What we're saying is "let's turn things upside down and encourage these people to stay with an organisation and then [at some point later] go on to university."
Taking things a step further, this is where we see IBM's Watson and security and artificial intelligence coming into play – the technology can supplement the people skills.
You can bring in 'new collar' people and using Watson you can augment their current capabilities and mentor, train and guide them.
NZSM: So, is the idea that we meet the skills shortfall by developing these people but at the same time increasing their effectiveness via AI capabilities such as Watson?
JM: Absolutely. Take the example of security analysts. From our last two years of doing this we have been able to measure a 60 percent increase in the effectiveness and efficiency of a security analyst's ability to cope with the number of security events [they're having to manage].
We've actually trained this system to understand the language of cyber security. It's actually ingested more than a million documents on cyber security, intelligence etc. We've had to train it from the level of a toddler to a Phd and to be able to relate information directly to a human being using the natural language process we've applied.
The fact is that there are about 10,000 security research papers published each year and about 60,000 security blogs. If a security analyst can only read even a small percentage of these, you can see the great demand in terms of being able to holistically grab that information.
Watson can actually digest information and remember it, unlike you and me. It can look for the patterns and for different perspectives of what is happening within an organisation. It can understand structured and unstructured information and return that information in a natural language that a human being can actually process.
The key thing here is the quicker you identify that there has been an indicator of cyber compromise to your organisation you can analyse the impact on the organisation very quickly and therefore you can respond and avoid the significant financial impact of the organisation having to clean up afterwards.
Basically, Watson has a more holistic perspective. Where a security analyst may have identify "I've detected something in front of me," Watson returns in a few minutes or a few seconds and says "In fact, the impact on your organisation is this".
NZSM: One of the major issues in terms of cyber breaches is that lag time between the breach occurring and it being identified and treated. Can Watson play a role in actually identifying a breach or is it more in terms of working out what actually happened?
JM: We've had use cases whereby during the beta testing (with eight universities and about 40 beta partners) the security analyst actually detected a DDoS attack on the organisation. What the security analyst didn't realise was that attack was actually a 'blinder' – a misdirection.
Watson was able to indicate to the security analyst "in fact you've been compromised, and this is how you've been compromised." It gave a very full indication of how they'd actually been compromised – what the original attack did – despite the security analyst being unable to see it.


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Top Shopped: 11/14/15
Our top shopped items on gordmans.com show that gift shopping is in full swing! Awesome NFL and team gear? Check. Adorable boots for the season? Check, check. The most popular toys around for up to 60% less than department stores? Check, check, ch….you get the point.
1. Little hands will be off to the races with this cool, Hot Wheels Race Case.
2. Snow ready and out for adventure, these fleece-lined boots are just begging for snow.
3. The force is awakening, and we've got Star Wars Legos that will have imaginations soaring!
4. Win or lose, this Broncos zip-up hoodie is ready for game day.
5. Your guests will never want to leave when the holidays, and this 9-piece bedroom set, are at your house!
6. Never stop celebrating when you're wearing this awesome Royals World Series Champions sweatshirt.
7. Elsa and Anna are still enchanting kids with this wondrous Frozen Ice Palace.
8. Paired with leggings, denim or dresses, these suede boots are a wardrobe must!
9. Smiles will be abundant when this Thomas & Friends Turbo Flip Train is unwrapped!


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Pedestrian Accidents in Burlington, North Carolina occur more often than most people think. Every 111 minutes a pedestrian is killed in an accident. These accidents can happen for any number of reasons but the result is usually the same. The pedestrian involved is left with severe personal injuries.
Pedestrians and motorists both must obey the traffic lights at all times. Some common causes for Pedestrian Accidents include:
- Stepping out into the street
- Crossing street without Crosswalk
- Vehicle driving through Crosswalk
If you have been injured or involved in a pedestrian accident, contact an attorney today. An experienced pedestrian accident attorney can ease the healing process by filing claim against the drivers insurance company and researching medical records. Two tasks vital to your case and may be difficult to accomplish if seriously injured.
If you have been personally injured or involved in a pedestrian accident contact Whited Doby & Ray Attorneys at Law today. Our pedestrian accident attorneys are licensed in all 3 Federal Districts in North Carolina. And, if you've been seriously injured in a pedestrian accident, we can come and meet you.


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Princess Cruises to air Royal Wedding across its fleet
Princess Cruises is to air the forthcoming Royal Wedding live on all 17 of its ships. Prince Harry and Meghan Markle's marriage on Saturday May 19 will be shown on the ships' top deck cinema screens, in bar lounges and on stateroom TVs.
Princess' ships are positioned all around the world and will beam the event across the ocean, from Alaska to Asia to the South Pacific.
The line's fleet of ships includes the aptly-named Royal Princess – launched by Prince Harry's sister-in-law, HRH The Duchess of Cambridge in 2013 – which is currently based in Southampton and sailing round Britain. The ship will call at Greenock, near Glasgow, on the day of the wedding.
Diana Princess of Wales, Prince Harry's mother, launched the original Royal Princess in Southampton in 1984.
Sapphire Princess, which is sailing roundtrip to northern and southern Europe, also from Southampton, will be in Livorno, Italy, on the day of the wedding.
A host of onboard activities are being arranged to celebrate the nuptials including parties, themed menus and Royal-related quizzes.
Tony Roberts, Princess Cruises' vice president UK and Europe, said: "It's particularly fitting that guests are able to watch the big day on Princess' ships given our Royal connections. There's huge demand to see the wedding, whether at sea or on land, so we'll ensure we have the celebratory fizz at the ready as our guests onboard raise a toast to the happy couple."


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Agriculture in Paraguay's Gran Chaco – March 23rd, 2009
The Gran Chaco is located west of the Paraguay River and east of the Andes, mostly an aluvial sedimentary plain shared between Paraguay, Bolivia and Argentina.
It is about 647,500 km2 (250,001 sq mi) in size, though estimates differ. The area visible here is located entirely in Paraguay.
The areas more hospitable to development are along the Paraguay, Bermejo and Pilcomayo Rivers.
The Chaco offers high soil fertility and a topography that is favorable for agricultural development, but in combination with aspects that are challenging for farming: A semi-arid to semi-humid climate (600-1300mm anual rainfall) with a 6 month dry season and sufficient sweet ground water available only in roughly one third of the region.
Many rectangular fields are visible in the light brown area upon which the close-up is focused. Several Mennonite colonies are located here, and the area has been deforested and developed for agriculture and cattle grazing. The most important produce includes cotton, peanuts, beef, milk and other dairy products.


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Gene Luen Yang, the Rosary, and Comic Books as Prayer
Gene Luen Yang's The Rosary is not only a comic book, it is an actual rosary. The comic book is transformed not only into a vehicle for prayer, the comic book IS the prayer. Each panel becomes a meditation on the various chapters of the life of Jesus, and the prayers that have to be said in each panel become a way to ritually familiarize oneself with his life and deeds.Read more "Gene Luen Yang, the Rosary, and Comic Books as Prayer"


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By: Kathy Summers
EAS 2017 Chickens Bees
Kim and I spent last week (August 1-4) at the University of Delaware attending EAS 2017. We had not been to an EAS Conference for several years, so it was good to get to visit with old friends we hadn't seen for a while. We had a book table in the vendor area. That's always the best spot in the house if you want to know who is at the conference, because everyone visits the vendor area at least once.
There were three beautiful yellow Labs there during the week – all service dogs. In my opinion this is one of the best dogs around. I had a female yellow Lab when my boys were little. She lived almost 16 years and was the sweetest dog ever. The one male service dog at EAS was never on a leash. He stayed close to his lady and was always watching her to see what her next move was. Great dogs!
As has always been typical it was really hot in Delaware the week we were there. But the folks running the beeyard got lucky with no rain – maybe an afternoon shower one day.
It was a good week. Several of our writers were there. It's always nice to get to see them in person. They're all excited about coming to Medina in September for the 'Voices of Bee Culture' event. We hope to see you there. There's still time to sign up. Check it out in this issue and sign up on our web page.
EAS 2018 will be held in Virginia next year, so watch for details. This organization has been around for over 60 years and there were just over 600 attendees there this year. They offer a Short Course at the beginning of the week, then a three-day conference, a Master Beekeeper course and a working beeyard each year.
So, the young rooster I told you about last month had to go away. He didn't go far – just to live at the neighbor's house. I know some of you are thinking you would have made a nice pot pie or soup out of him. But that's not me – I can't eat animals that I've known personally. I do like chicken but I want it to come in a nice package from the market. We gave him every chance to just be nice and get along. I guess that wasn't in his nature because he started to get very bossy and nasty. So off he went and the ladies – young and old – are calm and happy. The young girls have not started laying as of this writing. They're about three and a half months old, but they have adjusted nicely to living among the older girls. So we're holding at 20 hens right now – four that are five years old, eight that are two years old and eight that are babies.
This week we took off eight medium supers (eight frame) of honey. They're sitting in the garage tightly covered waiting for someone to get time to extract them. I think we're at about eight hives right now. We have one really nasty one that we need to deal with. It's probably going to go away this weekend. They chase me when I go by on the lawn mower and always seem to be just waiting for us when we take off the top – not fun!
We have a new observation hive in the Root Candle store here in Medina. We had Peter Sieling redesign it and it is beautiful. A local carpenter came in and made sure everything matched up as far as the hole and the pipe for the bees to get in and out – and not end up in the store with the customers. He built a beautiful platform for the hive to sit on which is also nice and secure from any curious young hands wanting to mess with it. We started a nuc on our front porch and then when the observation hive was ready we switched them over. They have a good queen and seem quite happy. Hopefully they'll make it through Winter. That's always the most difficult part for us.
Well, Fall is almost upon us. Bee Culture has two great events coming up right here in Medina. It's pretty nice here in NE Ohio in the Fall. Take a look in the issue for information on our "Voices of Bee Culture" event September 22-24, and a one day class called the Hardest Season taking place in October. There is still time to sign up for both.
Hope to see you this Fall in beautiful downtown Medina, Ohio.


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PUBLISHED: 14:13 23 January 2017 | UPDATED: 12:15 30 August 2017
Creekside Cottages offers a fine collection of individual waterside, rural and village self catering holiday cottages on the south coast of Cornwall. Our holiday cottages are located in some of the best areas of Cornwall and some are situated just yards from the seashore, truly a waterside holiday. Most of our Cornish holiday cottages overlook the water, some are even cut off by the tide once in a while (though only for an hour or two!) and all offer the perfect place from which to enjoy your family holiday in Cornwall.
Whatever time of year you choose to visit Cornwall, we have a home away from home which will suit you perfectly. Just come and relax in one of our Creekside Cottages. Our cottages are ideal for all breaks.
Whether you're looking for a romantic self catering holiday cottage, a traditional waterside fisherman's holiday or luxury self catering holiday houses sleeping from 2 up to 8, we have a great choice of holiday
accommodation for you. dogs are welcome in many of our Cornish holiday cottages so the whole family can enjoy the beaches and coastline and all that Cornwall has to offer. All our self catering creekside Cornish holiday cottages are situated in stunning locations on the south coast of Cornwall -
accommodation in Falmouth, restronguet, Mylor Bridge, Feock, Flushing and st Just in roseland. Family holidays are a precious time and sometimes you have to turn back the clock, leave the mobile phones, laptops and tablets behind, and get back to the basics....buckets and spades and having fun by the seaside! Why not visit Cornwall for your family holiday this year?
Beaches, seaside and watersports is what Cornwall does best...sandy beaches (come rain or shine!), swimming in the sea, ice cream, sandcastles, rockpools, crabbing, family cricket on the beach...these are the best of memories for your children and for the family photo album. Cornwall is renowned for its stunning sandy beaches both on the north and south coast.
Waterside Cottages, Creekside Cottages, Village & Rural Cottages all available throughout the year, just come and relax.
. 01326 375972


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Digital Dental X-Rays
"Need Colorado Springs Digital Dental X-Rays?"
Prevention is our first line of defense against dental conditions.
With regular exams and professional dental cleanings, we monitor changes in your health that can indicate a problem.
Both Drs. Tuttle and Colt record any changes they notice that could affect your oral health or the appearance of your smile. We can stop many dental conditions in their tracks when we catch them early.
One of the most beneficial tools available today in the early diagnosis of conditions such as decay, cracks, infection, fractured roots, and bone loss is the use of digital x-rays and intraoral imaging.
Colorado Springs Digital Dental X-Rays in Diagnosis:
With the introduction of digital x-rays in dentistry, diagnosis is not only quicker because the images appear directly on our computer monitors, but also more accurate because digital imaging is at a high resolution, revealing details previously unavailable through traditional radiography.
Similar to digital photos on your computer, we can adjust your x-rays by zooming in, changing the contrast, and adjusting exposure in order to view your x-rays with more detail and clarity. This allows for early, accurate diagnosis and the ability to treat your condition before it progresses.
Colorado Springs Digital Dental X-Rays and Safety:
In addition to higher resolution and accuracy, digital dental x-rays provide greater safety to our patients by limiting the amount of radiation exposure.
Dental x-rays in Colorado Springs, have always been among the lowest radiation used in medical diagnosis because they are extremely targeted and focus on a relatively small area.
At Tuttle Family Dentistry, we reduced the amount of radiation exposure by 80% with the implementation of digital imaging, making them safer than ever.
According to the American Dental Association, the exposure from digital dental x-rays in Colorado Springs is only a minor contributor to the average overall annual exposure, much of which comes naturally from the environment.
Because of their low radiation exposure and high accuracy, the benefits of digital imaging outweigh the risks and remain an essential tool in maintaining optimal oral health.
We take only the images necessary to diagnose and protect your smile and we are happy to discuss any concerns you may have.
Intraoral Imaging With Dental X-Rays In Colorado Springs:
In addition to digital dental x-rays, we use an intraoral camera to assist us in the diagnosis and patient education.
This small camera can take still photographs and video of your teeth and gums so that you can see what we see.
That way, when we share information with you about your condition, you can participate and completely understand your condition and treatment recommendations.
Intraoral imaging is useful for identifying cracks, fractures, wear, damaged restorations, periodontal (gum) conditions, recession, and lesions. We store these images in your records to monitor changes in your oral health.
Call Us to Schedule For Colorado Springs Dental X-Rays!
Are you due for your next preventative appointment or are you currently experiencing a dental problem?
Give us a call at (719) 282-6636 and we can arrange a time for you to visit our Colorado Springs dental office for digital, dental x-rays.


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Are you a Microsoft Cloud user? Do you use advanced features of Azure or Office 365 to meet your business & technical requirements which are not typically known by end users? If so, then you are considered a "Power User".
Join Microsoft MVPs & Industry Experts for a free day-long, peer-to-peer education workshop, where we will go through deep-dive training in advanced concepts of Azure & Office 365. These workshops won't involve any extension of the platform via "development" but rather by "configuration", either in the tool itself or the administration of the tool.
This is an opportunity for attendees to build their Azure & Office 365 professional relationships to fuel their product knowledge while supporting their organization's adoption of Azure & Office 365. Attend this event and in turn accelerate your organization's end user journey when using Azure & Office 365 with the end goal of getting your business units to adopt, consume, and realize the full potential of Azure & Office 365.
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This is the first annual Power of the Cloud – MS Power User event.
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text: Narayani is a fourth year student of Birkbeck's Creative Writing BA. She reads her poems at poetry evenings and art exhibitions where she collaborates with artists, both from conception and in response to artwork, contributing to the exhibitions of both The World in our Eyes and the site specific Art Going Places. Narayani's poems touch on the personal, the political and the universal and generate spaces that the reader can enter to explore the images and experience connection to other and self across time.


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Job Description
The Company
Our client is an Australian owned food manufacturing company that have several sites in Australia. They manufacture value added products and supply to major retailers, quick service restaurants and food service. The Central Coast factory is the company's fastest growing site and a key growth area for the business.
What this role entails:
- Pre-operational hygiene checks
- Investigate deviations from production
- Investigation and reporting on customer reports and non-conformances
- Internal auditing
- Review and update quality compliance documentation
- Staff training on GMP and HACCP
Skills and Experience
- Tertiary qualifications in Food Science or equivalent
- At least 1 year industry experience
- Previous food / beverage industry experience preferably in quality compliance
- Knowledge of HACCP
- Confident individual who can work with minimal supervision
- Strong verbal and written communication
- The successful applicant will have a can do attitude with a desire to learn and develop.
How to Apply
If you are interested in this opportunity APPLY NOW!


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It's not a meme for nothing; cats love keyboards and will get their paws on your precious keyboards without a second thought.
Here are a few ways to save your keyboard and relationship with your cat by keeping him or her from causing damage to your keyboard:
1. Cords
One of the biggest concerns as a cat owner is damaged cords. Cats love to chew on power cords, damaging the keyboard and hurting the cat. Keep cords out of the way by bunching them with Velcro strips. Try to position them to where the cat can't reach. If your desk is against the wall, putting a barrier such as a board in front of the cords can help with cord protection. Some pet owners have experimented with bitter sprays. After rubbing it on the cords with a soaked cloth, the smell will keep cats from chewing on cords. Of course, if your cat is particularly stubborn, he will keep chewing anyway. You may have to use other methods such as protective covers to dissuade him/her from destroying your equipment .
2. Fur
No matter how careful you are about keeping your cat away from your keyboard, enough fur will find its way in between the keys, impacting keyboard performance. Regular keyboard cleaning can help prevent the build up of fur and pet dander. Check out this guide for the most effective ways to clean your keyboard. If you don't have time for a deep clean, try using canned air to blow fur out of the keyboard.
3. Sitting on the keyboard
Sitting your cat on the keyboard can be damaging to the keys. It is also annoying if your cat tries hop on your keyboard during a working or gaming session. The cat is often looking to lay near you. You will need to create an ideal spot over your keyboard for the fluffy animal.
Cats like boxes because they provide a safe and comfortable place to sit. Some pet owners find it possible to keep cats away from keyboards by having a small box near their desk. Cats also love to sit in the highest place in the room, you can put a cat condo or shelf near your desk for the cat to access. If the cat condo is accessible and higher than your desk, your cat will most likely ignore the keyboard all together. Your cat may also be feeling neglected if you are spending too much time at the computer working or gaming, try to give Mr. Meowington some extra attention from time to time.
4. When you are away
While you are away from keyboard, your cat may want to sit near your computer as it provides warmth. Close your room or put away your keyboard to prevent catfiltration. It may be tedious to remove your keyboard whenever you are not in the room, but it is probably better than replacing a keyboard and damaging your pet relationship.
5. When your cat thinks it's playtime
Cats often consider typing as a form of game with its owner. If your cat is feeling frisky, he/she may attack your fingers as you are typing.
Try giving your cat a bit of extra play time to avoid confrontation with your cat while typing.
6. Training
Let's be honest. Training a cat isn't the easiest thing to do, but you can try to teach your cat that the desk isn't a good place to sit by telling your cat "No" and shooing him/her off the desk. Another option is to use a spray bottle to train your cat. Since cats hate being wet, one small spray is usually enough. After the first few times, the bottle will deter the cat even if it is empty. If the problem persists, simply reaching for the bottle will typically scare the cat away. Do you have any tricks for keeping pets away from your keyboard or computer?


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Records of the Department of State Relating to Commercial Relations between theUnited States and the Soviet Union, 1910-1949
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- Shipping Weight: .00 lbs ( .00 kgs)
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The documents found in this file -- predominantly instructions to and dispatches from diplomatic and consular officials --provide valuable information on economic relations between Russia/the Soviet Union and the United States, from the time of the last czar through the later years of Stalin. Also provided are general insights on the period 1918-1933, when the only relations maintained between the United States and the Soviet Union were commercial.
Of particular interest are documents relating to the effect of the Bolshevik Revolution on Soviet-American trade, the activities of the Soviet purchasing office in the United States during the 1920s, U.S.-Soviet trade and debt negotiations that were part of the normalization of relations in 1933, the administration of Lend-Lease (extended to the Soviet Union in 1941), and the Soviet refusal of the U.S. offer of economic aid as proposed under the Marshall Plan.
Number of rolls: 22


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At Dhiraagu, we give you easy accessibility to your clients and customers as well as your suppliers. With our business lines you are assured the best services available.
What you will get:
Below are the call rates from our Fixed Line service.
#00 are calls to roamers on Dhiraagu network at special local rates.
* Fixedlines to Mobile calls are charged Rf 0.69 from 6pm - 6am plus all day Friday & Rf 0.95 from 6am-6pm.
** Reverse charges to the called number
The optional services include:
Home Phone Line is Dhiraagu's fixed line telephone service designed for the home user.
All you need is a fixed line telephone instrument to start using the basic service.


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Purpose: To enable the design of improved inhibitors of matrix metalloproteinases (MMPs) for the treatment of pancreatic cancer, the expression profiles of a range of MMPs and tissue inhibitors of MMPs (TIMPs) were determined.
Experimental Design: Nine MMPs (MMPs 1–3, 7–9, 11, 12, and 14) and three TIMPs (TIMPs 1–3) were examined in up to 75 pancreatic ductal adenocarcinomas and 10 normal pancreata by immunohistochemistry. Eighteen additional pancreatic ductal adenocarcinomas and an additional eight normal pancreata were also analyzed by real-time reverse transcription-PCR and additionally for MMP-15.
Results: There was increased expression by immunohistochemistry for MMPs 7, 8, 9, and 11 and TIMP-3 in pancreatic cancer compared with normal pancreas (P < 0.0001, 0.04, 0.0009, 0.005, and 0.0001, respectively). Real-time reverse transcription-PCR showed a significant increase in mRNA levels for MMP-11 in tumor tissue compared with normal pancreatic tissue (P = 0.0005) and also significantly reduced levels of MMP-15 (P = 0.0026). Univariate analysis revealed that survival was reduced by lymph node involvement (P = 0.0007) and increased expression of MMP-7 (P = 0.005) and (for the first time) MMP-11 (P = 0.02) but not reduced by tumor grade, tumor diameter, positive resection margins, adjuvant treatment, or expression of the remaining MMPs and TIMPs. On multivariate analysis, only MMP-7 predicted shortened survival (P < 0.05); however, increased MMP-11 expression was strongly associated with lymph node involvement (P = 0.0073).
Conclusions: We propose that the principle specificity for effective inhibitors of MMPs in pancreatic cancer should be for MMP-7 with secondary specificity against MMP-11. Moreover, these studies indicate that MMP-7 expression is a powerful independent prognostic indicator and potentially of considerable clinical value.
Pancreatic cancer is a major cause of cancer death in North America and Europe, and its incidence has appeared to increase dramatically in the last 70 years (1, 2, 3, 4) . Disappointingly, the 5-year survival rate of <5% has shown little improvement in the last 30 years (2 , 5 , 6) . In those patients with resectable tumors, the 5-year survival is of the order of 10–24% and may be improved by adjuvant therapies (7, 8, 9) . The low survival rates are attributed to an aggressive biological phenotype that is characterized by early local invasion and metastasis (10) . At a molecular level, pancreatic cancer is characterized by a high frequency of KRAS mutations in combination with the loss of function of the TP53, p16INK4A, and SMAD4 tumor suppressor genes (11, 12, 13, 14, 15, 16, 17) .
Pancreatic cancer progression is associated with increased expression of growth factor receptors and their ligands (18, 19, 20, 21) , alterations in the level of expression of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs), which may result in an imbalance between these (22, 23, 24) , alterations in antiapoptotic pathways (25, 26, 27) , the loss of additional tumor suppressor gene function (28, 29, 30) , and the acquisition of neo-angiogenic properties (31 , 32) .
Early invasion means that most patients have lymph node metastases and both neural and vascular invasion at the time of presentation (33, 34, 35) . Indeed, it seems very likely that the cancer is disseminated at the time of diagnosis because virtually all patients die of pancreatic cancer irrespective of their treatment (2 , 5, 6, 7 , 36 , 37) .
Given the limited response to standard forms of chemotherapy, there has been considerable interest in treatments based on biologically relevant target molecules (38, 39, 40) . Synthetically developed inhibitors of MMPs (MPIs) have been of particular interest (41, 42, 43, 44, 45) .
The MMPs are a family of zinc-containing proteolytic enzymes that break down proteins in the extracellular matrix in both physiological and pathological conditions (46, 47, 48, 49) . The four main subgroups, organized in part according to substrate specificity in vitro and in part by association with the cell membrane, are the collagenases (MMPs 1, 8, and 13), the gelatinases (MMPs 2 and 9), stromelysins (MMPs 3, 10, 11, and 18), and the membrane-bound MMPs (MMPs 14–17; Ref. 40 ). MMPs can regulate the activity of several classes of molecules including cytokines, growth factors, and growth factor receptors such as interleukin-1β, insulin growth factor-binding proteins, heparin-binding epidermal growth factor-like growth factor, and fibroblast growth factor receptor-1 (reviewed in Ref. 50 ). In addition proteolytic modification of extracellular matrix components such as laminin-5, decorin, entactin, and fibronectin by MMPs have been connected to alterations in a broad range of cellular events including cell migration, apoptosis, and proliferation as well as growth factor sequestration. Loss of the tight control of MMP activity in cancer is thought to contribute to excessive destruction of the extracellular matrix, neo-vascularization, tumor spread, and metastases.
There have been reports of increased MMP expression in several human malignancies with reported prognostic significance. In gastric cancer, the levels of MMPs 2 and 9 have been found to be elevated along with MMPs 7 and MMP 14 (51, 52, 53) . The expression of MMP-2 was higher in patients with gastric cancer that had a poor prognosis, although the difference was not significant (54) . Murray et al. (55) showed that MMP-1 expression was associated with a poor prognosis in colorectal cancer. Increased expression of MMPs 2 and 9 and TIMPs 1 and 2 has also been shown to correlate with a poor prognosis in renal cell carcinoma (56) . Other studies using various techniques have reported a prognostic significance of increased MMP expression in carcinomas of the colon (57) , ovary (58) , breast (59) , prostate (60) , and lung (61) . Although early studies suggested that TIMPs may have an antitumor or antimetastatic activity, it is now thought that they may have a more complex function. For example there is a positive correlation between increased TIMP-2 levels and poor outcome in breast cancer (62) .
In pancreatic cancer, there have been several studies of MMP and TIMP expression, and these have often involved either limited numbers of patient samples (22 , 63) and/or the analysis of only a few MMPs or TIMPs (64 , 65) . Perhaps not surprisingly, given the variety of techniques used in these studies, some conflicting results have been generated. More recently studies by Yamamoto et al. (66) have suggested that MMP-7 might be an independent prognostic indicator and the potential involvement of MMP-7 has been strongly supported by another recent investigation (67) . To further investigate the involvement of MMPs in pancreatic cancer and to expand the range of individual MMPs and TIMPs studied for this disease, we have sought to perform the most comprehensive evaluation of MMPs and TIMPs that has been performed to date. This is a high priority because the poor or inappropriate specificity of therapeutic MPIs tested thus far may account for the rather disappointing results in recent pancreatic cancer trials (44 , 45 , 68) .
We have used immunohistochemistry and real-time reverse transcription-PCR analysis of pancreatic ductal adenocarcinoma and normal tissue to examine the level and pattern of expression of MMPs and TIMPs. Using this data, we then determined whether any of these molecules may be implicated in the progression of pancreatic cancer and also whether any of these molecules might act as prognostic indicators.
Patients and Specimens.
The pancreatic cancer and control tissue samples (described in Table 1⇓ ) were obtained from the Pancreas Tissue Bank of the Department of Surgery, Liverpool Candis Tissue Bank and the Department of Pathology, Royal Liverpool University Hospital. Formalin-fixed, paraffin-embedded material was available for immunohistochemistry from between 45 and 75 (depending on the MMP or TIMP studied) consecutive tissue sections from patients who had undergone pancreas resection and for whom clinical and follow-up data were available (note however that two of these patients were lost to follow-up). Tissue from 18 additional freshly collected patient samples were rapidly frozen and stored in liquid nitrogen for reverse transcription (RT)-PCR analysis. All of the tissues were examined by an experienced pancreas pathologist (F. C.) using H&E-stained slides, and only pancreatic ductal carcinomas (ICD-0 C25.0–2, 8) were included in the study. Adenocarcinomas arising from the intra-pancreatic bile duct, ampulla of Vater, or duodenum and other malignant neoplasms such as acinar cell carcinomas or cystadenocarcinoma were specifically excluded. Pathological staging was undertaken according to the Union Internationale Contre le Cancer TNM classification (69) . Clinical and staging details are described in Table 1⇓ . The ten "normal pancreas" tissue specimens were derived from (a) four patients with common bile duct tumors with histologically normal pancreas removed, (b) two patients with pancreatic cancer with normal pancreas removed distant from the tumor, (c) two patients with focal pancreatitis with adjacent normal pancreas, (d) one patient with duodenal tumor, and (e) one patient with a benign pancreatic cyst.
For RNA analysis, there were 18 pancreatic ductal adenocarcinomas, and 8 "normal" pancreatic tissues were obtained from histologically normal areas of the parenchyma from two patients with focal chronic pancreatitis, four patients with pancreatic tumors, and two transplant donors.
This study was undertaken with the formal approval of the Liverpool Research Ethics Committee and written informed consent was obtained for all samples.
Mono- and polyclonal antibodies were supplied by the research and development section of British Biotech (Oxford, UK) and are not commercially available. These included antibodies to MMP-1 (interstitial collagenase; 36632), MMP-2 (gelatinase A; 36033, 1A10, SE592), MMP-3 (stromelysin 1; 10D6, RP58), MMP-7 (matrilysin; RP21), MMP-8 (neutrophil collagenase; SE603), MMP-9 (gelatinase B; 36074, 4H3, 2C10, SE601), MMP-12 (metalloellastase; 10D10, RP54), and MMP-14 (MT1-MMP; RP64, 5H2). Antibodies from British Biotech were later validated by comparing the staining pattern to that obtained with commercially available antibodies on a subset of samples and examining these for consistency. In addition, the Ab-1 antibody to MMP-7 and Ab-5 antibody to MMP-11 were obtained from Labvision (Newmarket, UK). In all cases, antibodies recognize both latent zymogens and active species. Monoclonal antibodies to TIMP-1 (147-6D11), TIMP-2 (67-4H11) and TIMP-3 (136-13H4) were obtained from Chemicon Europe Ltd. (Chandlers Ford, UK). We observed no evidence of cross-reactivity between antibodies to different MMPs or TIMPs.
Immunohistochemical Staining.
Tissue specimens were fixed for 48 h in 10% formalin and embedded in paraffin wax before sectioning. Four-μm sections of each specimen were prepared on poly-l-lysine-coated slides and kept in an oven at 37°C overnight before further processing. Positive controls for each antibody were obtained from a bank of control slides in use in the Immunohistochemistry Laboratory, Department of Pathology, Royal Liverpool University Hospital. To establish which tissues were reproducible and consistent positive controls for each antibody, "sandwich" blocks (containing small tissue samples from multiple different sites) were stained with each antibody. To establish the optimum staining conditions for the different antibodies, each antibody was tested using a range of dilutions, with or without pretreatment, on these sandwich blocks. Table 2⇓ lists the antibodies used and the control tissues. Note that for MMP-7, MMP-11 commercially available antibodies were used to confirm the staining patterns observed using the British Biotech antibodies. For trypsinization pretreatment, slides were soaked in 0.05% trypsin, in Tris-buffered saline [TBS; 50 mm Tris-HCl, 150 mm NaCl (pH 7.6)] for 20 min at 37°C. For microwave pretreatment, slides were immersed in 10 mm EDTA and irradiated with 850 joules/second−1 for 15 min. Slides were washed with TBS and then blocked with 5% BSA in TBS. Primary antibodies were diluted in 5% BSA in TBS, and 100 μl of each antibody solution was added to each slide for 1 h at room temperature. Slides were washed twice in TBS for 4 min. Secondary antibody staining was performed using the DAKO EnVision+ kit (DAKO, Ely, UK) according to the manufacturers instructions. Slides were then washed twice with TBS for 4 min, incubated with 3,3-diaminobenzidine HCl solution for a further 20 min, finally rinsed with distilled water, and counterstained with hematoxylin. Sections were dehydrated with ethanol followed by xylene and mounted using DPX (VWR International Ltd., Poole, UK) mountant. Immunostaining specificity was established using a negative control for each section, in which the primary antibody was omitted. Also included in each batch of samples was a known positive control.
Assessment of Immunohistochemical Staining.
Two observers scored all sections independently. The intensity of the immunostaining of the tumor epithelium, tumor stroma, and pancreatitis (if present) and of normal ducts, acini, and islets was graded as negative (0), weak (1) , moderate (2) , and strong (3) . To facilitate interpretation and comparison of heterogeneous tissue staining, whole sections were assigned scores according to the strongest intensity staining on a section, providing that ≥10% of the specified cell type (i.e., adenocarcinoma/stroma/epithelia) on the section stained. In cases where < 10% of cells of a specific type were stained the section was assigned a score of 0. Note that there were no cases in which <10% of cells stained predominantly strongly or moderately. Differences in assigned scores were resolved by simultaneous re-examination by both scorers to achieve a consensus. There were no cases where the scores assigned differed by >1 grade.
RNA Isolation.
Total RNA was isolated from approximately 100 mg of tissue using RNAzol-B (Biogenesis, Poole, UK) as described by the manufacturer. RNA was quantified by spectrometry at 260 nm and integrity was determined by running 500 ng of total RNA on a 1% Tris-acetate-EDTA gel. To remove any contaminating DNA, the samples were treated with DNase I. Approximately 10 μg of total RNA was digested with DNase I (RNase free; Sigma, Poole, UK) in the presence of 40 units rRNasin (Promega, Southampton, UK), in 100 mm sodium acetate (pH 5) and 5 mm MgCl2 at 25°C for 1 h. The integrity of the RNA was checked before and after digestion by gel electrophoresis. DNase was then removed by phenol/chloroform/isoamyl alcohol extraction, and RNA was precipitated with absolute ethanol.
cDNA Synthesis.
cDNA was synthesized from 5 μg of total RNA using 200 ng of oligonucleotide-dT primer (Life Technologies, Inc., Paisley, UK) annealed in 10 mm HEPES (pH 7.0), 1 mm EDTA in a final volume of 10 μl, heated to 90°C for 2 min, and cooled on ice. First-stand synthesis was performed by adding 1× first-strand buffer (5× buffer 250 mm Tris-HCl (pH 8.3), 375 mm KCl, 15 mm MgCl2), 1 mm DTT and 0.5 mm dNTPs, and 300 units Moloney murine leukemia virus reverse transcriptase (all from Life Technologies, Inc.) to a final volume of 20 μl and incubating at 37°C for 90 min. Control samples were prepared without reverse transcriptase. To verify the cDNA and the absence of contaminating DNA, PCR was performed on both test and control samples for glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The PCR reaction contained 0.5 μl of cDNA product, 200 μm dNTPs, 0.5 μm of each primer forward 5′TGCCGTCTAGAAAAACCTGC 3′ and reverse 5′ACCCTGTTGCTGTAGCCAAA 3′ and 1 unit of TaqDNA polymerase in 50 mm KCl, 3 mm MgCl2, and 10 mm Tris-HCl (pH 9; Amersham Pharmacia Biotech, Little Chalfont, UK) in a volume of 20 μl. The PCR cycles were 95°C for 30 s, 57°C for 30 s, and 72°C for 1 min. This produced a 200-bp GAPDH product. Only samples that had this product in their +RT and not in their −RT controls were used in experiments.
Real-Time RT-PCR.
RT-PCR was carried out in a Roche Lightcycler (Roche Diagnostics, Lewes, UK) and quantified by measuring SYBR green. PCR was performed using the DNA Master SYBR green I PCR reaction mix that contains Taq polymerase, dNTP mix (with dUTP instead of dTTP; Roche), 3 mm MgCl2 with 0.5 μm of each primer, and either 2 μl of diluted cDNA or 2 μl of water in a total volume of 20 μl. The PCR cycles were 95°C for 30 s, followed by 45 cycles of 95°C for 10 s, 57°C for 10 s, and 72°C for 12 s. Quantification was achieved by comparison with an internal standard curve containing 10-fold dilutions of a plasmid containing the target sequence (108-102 copies). Two of these plasmids were provided by British Biotech, and these contained the priming sites for GAPDH and all of the MMPs and TIMPs studied. The PCR performed on the plasmid with each specific primer pair produced a product of approximately 300 bp. As the efficiency of PCR amplification from the plasmid was comparable for each product (with detection of each product occurring within one cycle of all of the other products), all MMPs and TIMPs were quantified against the internal GAPDH standard curve. The quantity of each MMP and TIMP was then expressed as a fraction of GAPDH level for each sample. The efficacy of all primer pairs for MMPs and TIMPs was validated on RNA obtained from appropriate positive control tissues. The primers were as follows: (5′-3′) MMP-1 forward AATGTGCTACACGGATACCC reverse CTTTGTGGCCAATTCCAGGA; MMP-2 forward CCGCCTTTAACTGGAGCAAA, reverse TTTGGTTCTCCAGCTTCAGG; MMP-3 forward GAGGAAAATCGATGCAGCCA, reverse CTCCAACTGTGAAGATCCAG; MMP-7 forward TTTGATGGGCCAGGAAACAC, reverse GGGGATCTCCATTTCCATAG; MMP-9 forward GAAGATGCTGCTGTTCAGCG, reverse ACTTGGTCCACCTGGTTCAA; MMP-11 forward AGATCTACTTCTTCCGAGGC, reverse TTCCAGAGCCTTCACCTTCA3; MMP-13 forward ATACAGGCAAGACTCTCCTG, reverse GCGAACAATACGGGTTACTCC; MMP-14 forward CAGAAGCTGAAGGTAGAACC, reverse CATGGCGTCTGAAGAAGAAG; MMP-15 forward GGACAGCGCAGAGGGCG, reverse TTGCAGTAAAGCAGGACACG; TIMP-1 forward CGGGGCTTCACCAAGACC, reverse TCAGGCTATCTGGGACCGC; TIMP-2 forward GAAGAAGAGCCTGAACCACA, reverse GTCCTCGATGTCGAGAAACT; TIMP-3 forward TCGGTATCACCTGGGTTGTA, reverse GTCTGTGGCATTGATGATGC. Primers were supplied by either Roche or Helena Biosciences (Tyne and Wear, UK).
Statistical Analysis.
Categorical data were analyzed by the χ2 test and Fisher's exact probability test. Continuous data were analyzed by the Mann-Whitney U test, and correlation analysis was by Spearman's rank correlation. Survival curves were calculated using the Kaplan-Meier method. Cox proportional hazards modeling was used for multivariate analysis. The level of significance was set at 0.05.
For immunohistochemical analysis, either 45 or, for some MMPs and TIMPs depending on availability of the tissue and/or antibody, 75 cancer and 10 normal specimens were stained with each antibody to assess patterns in the differential expression of all of the MMPs and TIMPs. Where results suggested significant differences, antibody staining was confirmed with an additional antibody or antiserum to the MMP or TIMP on a subset of these samples. These results are summarized in Table 3⇓ . For the measurement of mRNA levels, real-time RT-PCR was performed on 18 cancer and 8 normal specimens. These results are summarized in Table 4⇓ .
MMP-1 was expressed in 29 of 45 (64%) cancers and in 3 of 10 (30%) normals. Immunostaining was weak to moderate in the majority of cancers with only 3 to 29 (10%) cases staining strongly. Staining in all cancers was restricted to the tumor cells, with no staining of the stroma. Staining occurred in the acini, ducts, and islets of adjacent pancreatitis in 7 of 45 (16%) cancers. Weak staining was observed in the acini of 3 to 10 normals. There was no significant difference in the expression of MMP-1 between the cancer and normal samples. There was no difference in survival between the two groups. Also, no correlation was observed between the intensity of MMP-1 staining and tumor differentiation, tumor size, lymph-node status, or patient survival. Real-time RT-PCR demonstrated that MMP-1 mRNA was expressed at significantly higher levels (P = 0.006) in tumor tissue than in normal tissue, and this is compatible with the immunohistochemical staining pattern albeit that the latter did not reach statistical significance.
MMP-2 was expressed in 50 of 75 (66%) cancers and in 7 of 10 (70%) normals. Staining was moderate to strong in 29 of 50 (58%) cancers and was weak in 21 of 50 (42%). Staining in all cancers was restricted to the tumor cells, with no staining of the stroma. Adjacent pancreatitis similarly expressed MMP-2. Expression in the normals was weak or moderate predominantly in acini and islets. There was no significant difference in the intensity of staining between the cancer and normal specimens. There was no correlation among MMP-2 staining and tumor differentiation, tumor size, tumor lymph node status, or patient survival. Nevertheless, there was a correlation between the staining of MMPs 2 and 14 (P < 0.0001). Real-time RT-PCR demonstrated that MMP-2 mRNA was expressed to comparable levels in both tumor and normal tissues, and this is compatible with the immunohistochemistry.
MMP-3 was expressed in 40 of 45 (89%) cancers and in 10 of 10 (100%) normals. In cancers, staining was generally weak or moderate in both carcinoma and stroma, although staining was strong in 12 of 40 (30%) cancers. Normal stroma stained strongly in 10 of 10 samples, including the periductal and inter-lobular connective tissue, and also the walls of vessels. Interestingly, the staining within the normal stroma was significantly stronger than the staining of the malignant stroma (P < 0.0001). Islets, ducts, and acinar cells stained weakly in all normal pancreas and weak to moderately in adjacent pancreatitis. There was no correlation between the tumor cell expression and tumor stroma expression. Nor was a correlation observed among MMP-3 expression and tumor differentiation, tumor size, lymph node status, or patient survival. Real-time RT-PCR demonstrated that MMP-3 mRNA was expressed to comparable levels in both tumor and normal tissues, and this is compatible with the immunohistochemistry.
MMP-7 was expressed in 41 of 45 (91%) of cancers and in 2 of 10 (20%) normals (P < 0.0001). Tumor cells in 28 of 41 (68%) cancers stained moderately to strongly. The proportion of positive cells in tumors was variable; in some cases, focal staining was observed. Expression in adjacent pancreatitis was predominantly moderate with 26 of 45 (58%) staining positively. Staining in the two normals was weak with only a few islets or ducts being positive. There was no staining in the stroma of cancers or normals. Fig. 1A⇓ illustrates a typical staining pattern in pancreatic adenocarcinoma and, for comparison, in normal pancreas. The identity of the staining pattern was confirmed using a commercial antibody for MMP-7. No correlation was observed among MMP-7 expression and tumor differentiation, tumor size, or lymph node status. However, there was a correlation between MMP-7 expression and the expression of MMP-14 (P = 0.005). Most significantly tumors strongly positive for MMP-7 had a significantly worse prognosis than MMP-7 negative/weakly staining tumors (P = 0.005) as shown in Fig. 2A⇓ . Real-time RT-PCR demonstrated that MMP-7 mRNA was expressed to comparable levels.
MMP-8 was expressed in 33 of 45 (73%) of the cancers and in 6 of 10 (60%) of normals. Expression in tumor cells was moderate to strong in 15 of 33 (45%) cancers. There was no staining of the tumor stroma. Expression in the normal pancreas was weak within ducts, and occasionally islet staining was seen. The intensity of staining was increased in cancers compared with normals and was significant (P = 0.04). There was no correlation among MMP-8 staining and tumor differentiation, tumor size, tumor lymph node status, or patient survival. Real-time RT-PCR failed to detect the mRNA for MMP-8.
MMP-9 was expressed by 19 of 45 (43%) of cancers and was not detectable in normals (P = 0.0009). Six of 19 (32%) cancers stained moderately or strongly, and this staining was focal. There was no staining of the adjacent pancreatitis and no staining of stroma in either cancers or normals. Neutrophils stained positively in both the cancer and normals. No correlation was observed between MMP-9 expression and tumor differentiation, tumor size, lymph node status, or patient survival. Real-time RT-PCR detected low-level expression of MMP-9 in normal and cancer samples at comparable levels.
MMP-11 was expressed by 52 of 75 (69%) of cancer cases and in 2 of 10 (20%) normals (P = 0.004). Fig. 1B⇓ illustrates a typical staining pattern for pancreatic adenocarcinoma and for comparison, normal pancreas. There was staining of stroma in 22 of 75 (29%) cancers, but only one of these stained strongly. Only stromal cells adjacent to cancer stained positively, and the staining was weaker or not detectable in stromal cells further from the primary tumor. Forty of 75 (53%) of adjacent pancreatitis stained for MMP-11 with 31 of 40 (78%) staining moderate to strong. The two normals that were positive had weak staining in the acini, islets, and ducts. The identity of the staining pattern was confirmed using a commercial antibody for MMP-11. There was no correlation among MMP-11 expression, tumor differentiation, and tumor size. However, there was a correlation between MMP-11 expression and lymph node status, with those tumors having a higher level of expression correlating with positive lymph nodes (P = 0.0073). In one case in which there was an adjacent lymph node, there was staining of MMP-11 in the metastatic deposit in the lymph node. Patients with MMP-11-positive carcinoma had a significantly shorter overall survival time than did those with MMP-11-negative carcinoma (P = 0.02) as shown in Fig. 2B⇓ . Real-time RT-PCR demonstrated that MMP-11 mRNA was expressed at significantly higher levels (P = 0.0005) in tumor tissue than in normal tissue, and this is compatible with the immunohistochemical staining pattern.
MMP-12 was expressed by 20 of 45 (44%) cancers and in 10 of 10 (100%) normals. Nineteen of 45 (42%) cancers stained weakly. There was no stromal staining. There was weak to moderate staining in 25 of 45 (55%) adjacent pancreatitis. In normals ducts and islets stained more strongly than acini, there was no significant difference in the expression of MMP-12 between cancer and normal and no correlation was observed among MMP-12 expression and tumor differentiation, tumor size, lymph node status, or patient survival. Real-time RT-PCR failed to detect the mRNA of MMP-12.
MMP-14 was expressed by 44 of 75 (59%) of cancers and 4 of 10 (40%) normals. Thirty-eight of 44 (86%) cancers stained weakly to moderately and only 6 of 44 (14%) stained strongly. There was no staining of stroma. Thirty-seven of 75 (49%) adjacent pancreatitis stained weak to moderate. In normals, occasional acini and ducts stained weakly. There was no significant difference in expression of MMP-14 in the cancers compared with normals. There was no staining of any stroma. No correlation was observed among MMP-14 expression and tumor differentiation, tumor size, or lymph node status. However, there was a strong correlation with MMP-14 expression and MMP-2 (P < 0.0001), MMP-7 (P = 0.005), and also MMP-8 (P < 0.0001) expression.
In the absence of an antibody at the time of the study, MMP-15 was only studied by real-time RT-PCR. Nevertheless, MMP-15 expression was found to be significantly lower (P = 0.0026) in tumor tissue compared with normal tissue by real-time RT-PCR (see Table 4⇓ ).
TIMP-1 was expressed in 3 of 45 (7%) cancer cases and in 0 of 10 (0%) normals. In the three cancer cases, there were only occasional foci of TIMP-1 staining. There was no staining of adjacent pancreatitis or stroma. No correlation was observed among TIMP-1 expression and tumor differentiation, tumor size, lymph node status, or patient survival. RT-PCR demonstrated that TIMP-1 mRNA was expressed at higher levels in cancers than in normals, and this difference was significant (P = 0.03).
TIMP-2 was expressed by 20 of 45 (44%) cancers and in 8 of 10 (80%) normals. The staining was weak in 17 of 20 (85%) positive cancers with only 2 of 20 (10%) staining strongly. Adjacent pancreatitis stained moderately or weakly in 18 of 35 (51%) cases, and this did not correlate with the level of tumor staining. There was no stromal staining. Eight of 10 normals stained weakly with some positivity in ducts and the occasional acinar cell. There was no significant difference in expression of TIMP-2 between cancers and normals. No correlation was observed among TIMP-2 expression and tumor differentiation, tumor size, lymph node status, or patient survival. Real-time RT-PCR detected low levels of TIMP-2 mRNA in both cancers and normals.
TIMP-3 was expressed by 68 of 75 (91%) cancers and in 8 of 10 (100%) normals. Staining was moderate to strong in 55 of 68 (81%) cancers. There was moderate to strong staining of stroma in 45 of 75 (60%) cancers. Adjacent pancreatitis stained in 67 of 75 cancers and 54 of 67 (81%) of these were stained moderate to strong. Eight of 10 (80%) normals stained weakly for TIMP-3 in ductal elements. However, acini and islets stained more strongly. There was no stromal staining in normals. There was an increased intensity and statistically significant difference in expression of TIMP-3 between cancers and normals (P < 0.0001). There was also a significant increase in TIMP-3 expression in cancer stroma versus normals (P < 0.0003). No correlation was observed among TIMP-3 expression and tumor differentiation, tumor size, lymph node status. Real-time RT-PCR demonstrated that TIMP-3 mRNA was expressed to comparable levels in tumor and normal tissues.
Survival Analysis.
Of the tumor staging characteristics, tumor grade, diameter, and differentiation were not significant as summarized in Table 1⇓ . Lymph node status correlated to survival (P = 0.007). Univariate analysis revealed a relationship between overexpression of MMPs 7 and 11 (P = 0.005 and P = 0.02, respectively) and an unfavourable outcome in operable pancreatic carcinoma. Kaplan-Meier plots for MMPs 7 and 11 are shown in Fig. 2⇓ . Multivariate analysis was then conducted that included all significant and marginally significant values from the univariate analysis to identify any independent predictors of survival. Cox proportional hazard modeling demonstrated that MMP-7 overexpression was the only significant independent indicator for survival (P < 0.05).
We have found that several MMPs and TIMPs may have a role in the evolution of human pancreatic adenocarcinoma. In particular, MMPs 7, 8, 9, 11 and TIMPs 1 and 3 were expressed at significantly higher levels in the tumor as shown by immunohistochemistry and/or real-time RT-PCR. Also, we found that MMP-15 was expressed at significantly lower levels in the tumor by real-time RT-PCR, but we were unable to confirm this by immunohistochemistry. Of most significance, both MMPs 7 and 11 predicted survival. In the case of MMP-7, this was of independent prognostic significance.
Studies of MMP-7 in pancreatic cancer have shown that it is present at higher levels in cancers than in the normal pancreas (24 , 66 , 67) , and our results support this conclusion. Yamamoto et al. (66) found that MMP-7 expression in pancreatic adenocarcinoma correlated with a poor prognosis and was a significant independent prognostic factor for overall survival. Our data also support this finding.
High levels of MMP-7 expression have been associated with a poor prognosis in other tumors: for example, colon and gastric (70 , 71) , pancreas (66 , 67) , prostate (72) , and brain (73) . MMP-7 up-regulation is often identified as an early event in tumor development (66 , 74) . Although the mechanisms underlying these observations are likely to involve a number of molecules and pathways, several important parts of the jigsaw have been identified (see below). MMP-7 is unusual among the MMPs in that expression is mainly restricted to epithelial cells, rather than the stroma (71 , 75) . MMP-7 is produced mainly by tumor cells themselves rather than as a result of a desmoplastic reaction and can increase the invasive potential of the tumor cells (76) . Of particular note in this regard, MMP-7 transcription is regulated by the wnt/β-catenin/tcf signaling pathway (77 , 78) . Taken together, these observations suggest a link between early events in tumor evolution such as loss of normal signaling pathway regulation and MMP-7 activity. To what is this activity directed? MMP-7 has been shown, inter alia, to proteolytically cleave β4 integrin (79) , E-cadherin (80) , Fas ligand (FasL; Refs. 67 and 81 ), osteopontin (82) , and TNF-α (83 , 84) . Of these, FasL has been most clearly implicated in events likely to lead to pancreatic ductal adenocarcinoma. Crawford et al. (67) demonstrated that FasL was cleaved to a soluble form, soluble (s)FasL, in an MMP-7-dependent manner during acinar to ductal metaplasia in a mouse model. One explanation for the metaplasia could be that there is a selective advantage as a result of insensitivity to apoptosis in the emerging ductal population (67 , 85) . This interpretation requires either that ductal cells no longer respond to proapoptotic signaling by sFasL or that sFasL has more potent antiapoptotic activity on the trans-differentiated ductal cells. Which of these possibilities is correct is unclear. Certainly, sFasL has been shown to exhibit both pro- and antiapoptotic activities (81 , 86, 87, 88) , and this might reflect differential cleavage (producing different peptides with various activities) or differential activity of sFasL on cells at different stages of either tumor development or differentiation, perhaps as a result of changes in the protein composition of the extracellular milieu (86) .
Osteopontin has been identified as a target of MMP-7 (and of MMP-3; Ref. 82 ) and has been implicated in wound healing, inflammation, and tumorigenesis. In vitro, cleavage of osteopontin by MMP-7 was observed to lead to an increase in the migratory and adhesive activity of osteopontin in an integrin-dependent manner (82) , although whether this contributes to tumor invasiveness in vivo is not known.
MMP-7 expression is regulated by the wnt/β-catenin/tcf signaling pathway, and it is therefore not surprising to find other connections between MMP-7 and this pathway, as can be illustrated by β4-integrin (79) and E-cadherin (89) . Interestingly, β4-integrin has been implicated recently in pancreatic ductal adenocarcinoma by virtue of its expression being up-regulated (90) . Several members of the integrin family have been shown to contribute to repression of metastasis by promoting adhesion to the extracellular matrix. Thus cleavage by MMPs may compromise the activity of other β4-integrin-containing complexes, albeit this does not explain why there appears to be selective advantage during tumor evolution for up-regulation of expression of β4-integrin. One potential explanation for this may be that the proteolytic release of the integrin ectodomains leads to these domains competing with membrane-associated integrins for target binding, thus reducing the strength of interaction of the latter with the extracellular matrix. It is noteworthy that in studies of an oral carcinoma cell line, it was found that in addition to E and N-cadherins, β1 integrins also played a role in activating expression of MMP-7 (89) . Thus a pathway that leads to amplification of the effects of increased MMP-7 expression and activity may connect the activity of MMPs with expression and feedback regulation of specific adhesion molecules.
MMP-7 has been shown to cleave E-cadherin at the cell surface and release soluble E-cadherin (80 , 91) . The soluble E-cadherin fragment thus released has been shown to inhibit E-cadherin function in a paracrine fashion (80 , 91) . Loss of E-cadherin expression in a transgenic mouse model of pancreatic β-cell carcinogenesis (Rip1Tag2) coincides with the transition from well-differentiated adenoma to invasive carcinoma (92) . Curiously, it has also been demonstrated that E-cadherin stimulates expression of MMP-7 through the wnt-signaling pathway (93) .
Our study is the first to identify a correlation between MMP-11 expression and outcome. MMP-11 was found previously to be expressed more highly in pancreatic ductal adenocarcinoma than in normal pancreata by immunohistochemistry with the highest expression observed in stromal regions adjacent to the tumor (64) . MMP-11 expression has been observed in breast tumors and tumors of the head and neck (94 , 95) . In these reports, MMP-11 has also been detected only in stromal fibroblasts surrounding the malignant cells and not in the malignant cells themselves or in fibroblasts distant from the tumor (94) . Others have also found that the expression of MMP-11 was limited to stromal fibroblasts adjacent to breast cancer cells (96) . This is not always the case however. In one series, it was reported that in 15 of 54 (28%) breast cancer samples, the tumor cells themselves were positive, and also in the adjacent stroma, 34 of 54 (63%) samples exhibited positive staining (97) . In another study, it was reported that 6 of 21 (29%) cases of pancreatic cancer expressed MMP-11 in the epithelial tumor cells with 17 of 21 (81%) cases displaying expression in the adjacent stromal cells (64) . Data from our study suggests that the majority of MMP-11 expression is derived from the tumor epithelial cells themselves, with 52 of 75 (69%) cases staining these cells. We have also observed adjacent staining of malignant stromal cells in 22 of 75 (29%) of cases. In vitro studies in fibroblasts have demonstrated that basic fibroblast growth factor and epidermal growth factor can act as potent inducers of MMP-11 expression (18 , 97) . Pancreatic cancer cells are known to over-express these growth factors; therefore, these may stimulate the expression of MMP-11 in pancreatic cancer (18 , 19) .
In breast carcinoma, the level of MMP-11 mRNA has been found to be highly predictive for the presence or absence of distant metastases (98) . This has also been related to invasiveness, with only one in ten ductal-carcinoma in situ cases expressing MMP-11 compared with 62% of invasive cancers (99) . A correlation has been also shown in breast cancer between expression of MMP-11 and survival, with those tumors expressing a high level of the enzyme being associated with fatal metastatic disease (98) . Multivariate analysis has identified that MMP-11 may be a strong independent prognostic parameter for disease-free survival (P = 0.005; Ref. 96 ). Those patients with a moderate to strong MMP-11 level had significantly shorter disease-free survival than those with no or low expression. In our study, MMP-11 expression in pancreatic cancer also appeared to correlate with invasive potential, with high levels of expression being related to the extent of nodal disease (P = 0.0073). Also in our study, those patients with moderate or high MMP-11 expression had a significantly shorter survival than those patients with negative or low expression (P = 0.02). As has been found previously in breast and head and neck cancer, we found that there was no obvious correlation between the degree of pancreatic tumor differentiation and the extent of MMP-11 expression (95 , 98) .
Previous studies have suggested that MMP-9 expression correlates with increased metastatic potential in colorectal cancer (100) . It has been demonstrated that latent MMP-9 was present in both normal pancreas and pancreatic adenocarcinoma (101) . However, there was an increase in activity shown by zymography, with 21.2% of tumors having MMP-9 activity in comparison to 15.4% of normal pancreas specimens. Neutrophil staining was a consistent feature, and this was supported by other studies (63) . Forty-two percent of our cancer cases stained positively for MMP-9 with individual cells and cellular clusters staining, whereas the adjacent stroma did not. In situ hybridization studies have also detected higher levels of MMP-9 expression in tumor epithelium than in the adjacent stroma (63 , 65) .
Membrane-bound MMP-14 has previously been found expressed exclusively localized in the tumor epithelial cells (24) . In contrast to our study, studies using in situ hybridization found that MMP-14 mRNA was not localized to the tumor epithelial cells, but was present in cellular elements within the tumor stroma (102 , 103) . It has been suggested that MMP-14 may activate pro-MMP-2 (104) . Interestingly, we have found that the pancreatic cancers that expressed MMP-14 also expressed MMPs 2 and 7. Others have found that the presence of MMP-14 mRNA correlated with that of MMP-2 mRNA (24) . Although it is clear that the activation and inhibition of MMPs and TIMPs is a complex issue, it has been suggested previously that there is a link between MMP-14 and pro-MMP-2 activation (24) . The correlation that we and others have found may reflect such a link.
There are currently only two studies in which expression of MMP-15 in cancer has been described, and no doubt this reflects the past shortage of available reagents. In recent studies, MMP-15 mRNA was found at higher levels in hepatocellular carcinoma cell lines (105) and by microarray analysis in lung cancer tissues from patients who had received chemotherapy (106) . By contrast, we have found that MMP-15 mRNA levels were significantly lower (P = 0.0026) in tumor tissue compared with normal tissue. Clearly, none of these studies determine the source of the expressing cell type or even whether the changes in expression are the result of changes in tissue composition. Nonetheless, the loss of expression in the tumor that we have observed warrants additional investigation.
Early studies suggested that the TIMPs exerted an antitumor or antimetastatic effect, and this was supported by in vitro studies which showed that increased TIMP expression was associated with a decrease in tumor cell growth and spread (107 , 108) . However, more recent work has suggested a positive correlation between TIMP levels and poor outcome. High expression levels of TIMP-1 have been linked with a poor prognosis in gastric tumors, with those tumors that expressed the highest levels of TIMP1 having a poorer prognosis (57) . Higher levels of TIMP mRNA have also been shown to correlate with lymph node metastases and reduced 5-year survival in patients with colorectal carcinoma (109) . In breast carcinoma TIMP mRNA expression was found to be higher in the carcinoma than the surrounding normal breast tissue (24) . In this latter study, the TIMP-1 signal was substantially lower in the tumor cells than in the stroma. Our own data show that TIMP-1 expression can only be detected by immunohistochemistry in 7% (3 of 45) of pancreatic adenocarcinoma samples. In these three cases, the staining was confined to individual tumor cell clusters, and there was no staining of the stroma. This contrasts with the study by Bramhall et al. (24) where by Northern blot analysis, seven (7 of 7) pancreatic cancer cell lines and all (17 of 17) of the pancreatic tumor samples expressed detectable TIMP-1 mRNA. However, using in situ hybridization, these authors found that the expression was epithelial in origin.
TIMP-3 has been less well studied than TIMP-1 and unlike the soluble TIMPs 1 and 2, TIMP-3 is unusual because it is a component of the extracellular matrix (110) . A study of breast carcinoma and malignant melanoma cell lines showed that increased expression of TIMP-3 resulted in a significant reduction in tumor cell growth. Adenovirus-mediated gene delivery of TIMPs-1, -2, and -3 revealed that the overproduction of TIMP-3 inhibited invasion of malignant melanoma cells (111) . In human pancreatic cancer, TIMP-3 expression has not been investigated previously. Our findings suggest that increased TIMP-3 expression could be associated with a survival disadvantage although this link did not attain statistical significance (P = 0.06). This observation may warrant additional investigation.
Ultimately, the expression profiles of MMPs and TIMPs are of interest for two reasons. First, they may inform us about the changes that take place in the cells (and also in the tissues) that ultimately become tumors. Second, this information can be used to guide the design of novel therapeutics.
The potential for MPI therapy in pancreatic cancer was demonstrated recently in a phase III trial of 414 patients with advanced disease who were randomized to an MPI (marimastat at 5, 10, or 25 mg twice daily) or gemcitabine (1000 mg/m2; Ref. 44 ). There appeared to be a dose response in terms of patient survival for marimastat. The survival rate of patients treated with gemcitabine was significantly greater than for patients who received 5 and 10 mg of marimastat b.i.d but was not different from the survival of patients who received 25 mg of marimastat b.i.d. The major toxicity of marimastat was musculoskeletal affecting 44% of the patients so treated (44) . Moreover, the combination of gemcitabine and marimastat was found not to be superior to gemcitabine and placebo in a phase III of advanced pancreatic cancer (45) . In the dose-determining phase II trial, prolonged usage of the higher dose of 25 mg of marimastat at b.i.d caused musculoskeletal side effects in 59% of patients (43) . Thus the efficacy of MPI therapy could be improved by higher dosing and by using more selective inhibitors that minimize the musculoskeletal side effects.
Marimastat is a powerful general MPI with an IC50 to MMPs 1, 2, 3, 7, 8, 9, and 14 of 5, 6, 200, 20, 2, 3, and 1.8 nm, respectively (40) . We would conclude from our study that the principle specificity for an effective MPI in pancreatic cancer should be for MMP-7, but MMP-7 is also heavily expressed by skeletal muscle (Table 2)⇓ . Whether the musculoskeletal side effects of marimastat are attributable to specific MMP inhibition or whether there is another mechanism responsible is unclear. A recent phase I study of the MMP inhibitor MMI270 resulted in musculoskeletal toxicity in 42% of patients (112) . Of interest is that this MPI has IC50 to MMPs 1, 2, 3, 7, 9, and 13 of 33–43, 11, 13–50, 8, and 6 nm, respectively (40) . The agent BAY 12-9566 is an example of a "deep-pocket" MMP inhibitor with Ki to MMPs 1, 2, 3, 9, and 13 of >5000, 11, 143, 301, and 1470 nm, respectively (40) , that has no musculoskeletal side effects (113) but also lacks clinical efficacy (114) . It has been proposed that dose-limiting musculoskeletal toxicity may result from the inhibition of MMP-1 or of sheddases, which are closely related metalloproteases, but at present there are insufficient clinical data for a clear conclusion (68 , 114) .
We believe that the findings of this investigation may aid in the development of MPIs that are more specifically targeted toward pancreatic cancer than heretofore possible.
We thank Steve Taylor, Department of Mathematics, University of Liverpool for generous assistance with statistical analysis and Steve Bradburn and Andy Dodson, Department of Pathology, Royal Liverpool University Hospital for assistance with immunohistochemistry.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: L. Jones and M. Humphreys contributed equally to this work.
Requests for reprints: Mark T. Boyd, Department of Surgery, University of Liverpool, UCD Building, Daulby Street, Liverpool, L69 3GA, United Kingdom. Phone: 44-151-706-4185; Fax: 44-151-706-5826; E-mail: mboyd{at}liverpool.ac.uk
- Received July 29, 2004.
- Revision received January 16, 2004.
- Accepted January 27, 2004.


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Hello everyone ,
Today's show is my thoughts on wind power and the different types and their use.i also talk about battery backup supplies because i think these topics kind of go hand in hand ,you really cant make effective use of one without the other .i tell you where you can get cheap batteries , how to wire them up ,and examples on how you might want to contain your battery backup supply .
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at the Jean Cocteau Museum in Nice, France. We are pleased to sponsor and attend architects at a unique cocktail and evening event and host our local partner Saint-Gobain.
First-hand insights from one of the worldwide leaders of the glass industry
A renowned French glass manufacturer, and owner of three Dip-Tech printers, Saint-Gobain has created magnificent digitally printed glass installations using Dip-Tech technology, throughout the country.
Scheduled for May 5, 2017 at the Jean Cocteau Museum in Nice, France, the Digital Design In-Glass session will give participants exclusive insight into digital ceramic in-glass printing for both interior and exterior applications, from the successful experiences of Saint-Gobain, one of the worldwide leaders of the glass industry.
"We are proud to cooperate with a leader in the European market like Saint-Gobain, with whom we've worked for many years creating groundbreaking digitally printed glass installations," commented Niv Raz, Head of Architecture Division at Dip-Tech and joint presenter at the AIA event. "In addition to the Digital Design In-Glass session, we look forward to meeting with the many talented architects who will be attending AIA Europe, and discussing their relevant projects."
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I have refrained from coming down too hard on Ralph Ellis personally. I have tried to keep my arguments focused on his unsubstantiated claims. Alas, Mr. Ellis will not stop personally attacking me; this has gone beyond libel. Mr. Ellis has even gone so far as to lie about my credibility on his very public website. This was sent to me today:
Aside from this little projection of Mr. Ellis' own insecurities, Mr. Ellis knows this is a flat-out lie. After all he has emails me directly at my rutgers.edu email address during on of his vulgar, unmedicated (I can only presume) harassment rants:
While we all know Mr. Ellis wouldn't know solid research if it bit him in the pants, even a cursory search on the Rutgers Student Search would prove that I'm a current student:
So either Mr. Ellis is just an outrageously incompetent human being or he is a flat-out deceptive one. I'm going with a little bit of both at this point.
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Types of program offered in Munich:
Oktoberfest and Biergarten - leather trousers and Bavarian brass music. No other city can provide better examples of German tradition and culture than the city of Munich.
Located in the south-eastern Germany and by about 1.4 million inhabitants, it is Germany's third largest city and seat of the car manufacturer BMW.
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