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IWC Schaffhausen, Longines, Panerai, Roger Dubuis / October 24, 2021
Editor's Choice: Men's Luxury Watches That You Might Have Missed In 2020
This one goes out to all the men out there. Remember these words, it is okay to dress well and look good. Don't ever let anyone tell you otherwise. Looking good is closely related to feeling good and isn't that what we all ultimately want? When it comes to luxury watches, there is often a notion about the kind of watches that men should wear. The idea of sticking to a certain type of watches is not at all progressive and is, in many ways, ridiculous. The world of Haute Horlogerie is huge, and there are limits on exploring new horizons.
Top Luxury Watches For Men In 2020
We are living in the 21st century and everybody has the right to do as they will, abiding the law of course. This blog will be focusing on men and the luxury watches that they didn't know they needed. Let's begin, shall we?
Longines Spirit Pilot's Watch (Ref. L3.810 and Ref. L3.811)
These Longines timepieces are available in 40 mm as well as 42 mm case sizes. The body is made from stainless steel whilst the dials display matte black, grained silver, and sunray blue color themes. The dial has super-LumiNova coated Arabic numerals for hour markers too. The references offer a 100-meter water resistance which is quite impressive, given it's a pilot's watch.
The calibre used is the L888.4, a movement offering about 64 hours of power reserve. The COSC certified mechanism runs at a frequency of 25,200 vph and offers hours, minutes, central seconds, and lastly, date. Oh, and it also has a silicon balance spring.
Roger Dubuis Excalibur Diabolus In Machina
This bad boy comes in a 45 mm wide and 16.8 thick case. The case material used is CarTech Micro-Melt BioDur CCMTM. The material is essentially a metal that starts off as a powder and then later on it is sintered into a solid form. Its biggest merit over regular stainless steel is that it's more wear and tear resistant. Also, it will look new and stay shiny even when it is scuffed and scratched.
The dial of this Roger Dubuis Excalibur watch blue in color and has an engraved minute track on it. Hour markers are in the form of Roman numerals and applied batons. And yes, there is luminescence on hands and hour markers. The 30-meter water resistance might seem like a little less but it is okay considering the fact that you would never visit the beach wearing this kind of timepiece.
IWC Portugieser Tourbillon Rétrograde Chronograph
The Portugieser Tourbillon Rétrograde Chronograph is for those who like to be different. Don't get me wrong, it is not as avant-garde as a Roger Dubuis timepiece, but it is definitely one that is made from a different cloth altogether.
The 43.5 mm wide and 16 mm thick timepiece comes in a Platinum and 18-carat 5N Armor Gold case. The dial colors are Silver plated or blue, respectively. The 3 bar or 30-meter water resistance is apt, given that it is a dress watch at the end of the day. The Santoni blue leather is a bonus as it adds that much needed flair.
The IWC 89900 calibre offers a 68-hour power reserve. The manual as well as automatic movement with an 18-carat gold oscillating weight runs at a frequency of 28,800 vph. The mechanism offers a Retrograde date and a chronograph with co-axial display of the hours and minutes.
Some special mentions in this watch would be the tourbillon with a stop-seconds functionality which is unusual for a tourbillon timepiece. You also get a pallet fork as well as skeletonized escape wheel coated with the Diamond Shell technology from IWC. As per IWC, this helps reduce friction and improves the efficiency of energy delivery to the balance.
Panerai Luminor Marina Panerai Goldtech 44mm
As the name suggests, the Luminor Marina Panerai Goldtech 44mm comes in a 44 mm shell made from the brand's patented Goldtech material. The blue sandwich dial that comes along with a satiné soleil decoration is a major attraction in the watch. The indexes have luminescence and so do the hand. The watch comes with a blue leather strap with beige stitching. It has a trapezoidal pin buckle made from brushed Panerai Goldtech. The timepiece also gets an additional blue rubber strap. Lastly, the watch offers a 50-meter water resistance.
The movement used by Panerai us the automatic P.9010 calibre. Along with the standard hours, minutes, small seconds, and date functions, the watch offers a power reserve of about 72 hours or 3 days.
Purnell Escape II Carbon And Escape II All Black
The Purnell Escape II Full Black and Forged Carbon models come in cases made in either forged carbon or grade 5 titanium coated in black DLC. Both the references are 48 mm wide and 19 mm thick, which is quite massive if you ask me. The water resistance is limited to just 30 meters. On the movement front, we have the caliber CP03 which is designed and crafted by Eric Coudray.
This brings us to the prime attraction in these watches, that is, the triple-axis double tourbillon "Spherion". The structurer has cages rotating at 30, 16, and lastly, 8 seconds. The timepiece also have a Potter-type escapement along with a fixed escape-wheel. The mechanism runs a frequency of 21,600 vibrations per hour with 67 jewels. It offers a decent power reserve of about 32 hours. The power reserve indication is done via a suspended mobile cone.
Another thing to be noted about the mechanism is that it possesses six mainsprings in four barrels, all in parallel to each other.
Misunderstood: Understanding Quartz Watches a Little Better
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Winter Is Coming: Five Must Have Dress Watches For The Winter Season
Nice article, well put together. Great info!


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Senate Subcommittee Convenes Hearing on Opioid Epidemic
Home > Senate Subcommittee Convenes Hearing on Opioid Epidemic
By: Shelley Starkey
On Tuesday, the Senate Appropriations Subcommittee on Labor, Health and Human Services, Education, and Related Agencies held a hearing to discuss the opioid epidemic and how Congress should address prevention, treatment, and recovery for opioid use disorders. The hearing convened national leaders on the issue, including the representatives of the Substance Abuse and Mental Health Services Administration (SAMHSA), National Institutes of Health (NIH), and Centers for Disease Control and Prevention (CDC). Discussion highlighted the expansion of the Certified Community Health Center (CCBHC) demonstration as a way to dramatically expand opioid addiction treatment capacity in more states.
CALLS FOR MORE FUNDING
Those present disagreed on whether President Trump's declaration of a public health emergency back in October was effective in channeling resources to combat the epidemic. Subcommittee Chairman Roy Blunt (R-MO), applauded Trump's efforts thus far, and cautioned that there will be no singular solution to reversing this epidemic. Meanwhile, full Committee Ranking Member Patrick Leahy (D-VT), Subcommittee Ranking Member Patty Murray (D-WA), and former Democratic Congressman Patrick Kennedy directly criticized the President's strategies as being inadequate to address the full scope of the problem.
Senators Shelley Moore Capito (R-WV) and Jeanne Shaheen (D-NH) echoed Mr. Kennedy's concerns that the federal government had not provided adequate funding for states to combat the epidemic. Dr. Elinore McCance-Katz, Assistant Secretary for Mental Health and Substance Use at the Substance Abuse and Mental Health Services Administration (SAMHSA), testified that SAMHSA has been looking for resources to provide additional funding to states that have been hit hardest by opioid addiction.
POTENTIAL SOLUTIONS: RESEARCH, TREATMENT, AND EDUCATION
Chairman Blunt pointed to the Certified Community Behavioral Health Clinic (CCBHC) demonstration program that is currently ongoing in eight states as a promising approach to addressing the epidemic, and encouraged support for the Excellence in Mental Health and Addiction Treatment Expansion Act, legislation that would expand of the program. By prioritizing the provision of and access to high-quality behavioral health care, states would be better equipped to properly treat individuals struggling with opioid use disorders.
Dr. Francis Collins, Director of the National Institutes of Health (NIH), spoke to the importance of researching alternative, non-addictive pain management options, and expressed frustration with the inability to study Schedule I drugs, such as marijuana, due to their federal classification. In addition, Dr. Collins stressed that opioids are effective treatments for acute pain, but become more likely to cause an addiction the longer they are used.
Dr. Debra Houry, Director of the National Center for Injury Prevention and Control at the Centers for Disease Control and Prevention (CDC), highlighted the CDC's provider education initiatives. The CDC hopes to educate health care providers in communities with exceptionally high opioid prescription rates about the dangers of overprescribing by sending CDC officials directly to them. The agency is also ramping up responsible prescribing training initiatives for physicians and nurse practitioners while they are still in school, and beyond with continuing education opportunities.
To watch the full hearing and to read witness' testimony, visit the Subcommittee's website here.

redpajama_set_name: RedPajamaCommonCrawl


Ever since the state Supreme Court last summer ruled it unconstitutional, state officials have sprinted to end the warehousing of psychiatric patients in hospitals and other facilities. In the past, the practice, known as psychiatric boarding, has lead to patients being strapped to hospital gurneys, sometimes for weeks and without medication.
Now, three lawmakers are proposing to bring back boarding to make sure dangerous psychiatric patients aren't being set free when no proper psychiatric beds are available for them.
SB 5644 is sponsored by Sen. Steve O'Ban, R-University Place, Sen. Bruce Dammeier, R-Puyallup and Sen. Jeanne Darnielle, D-Tacoma. The bill is scheduled for a public hearing on Tuesday in the Senate Human Services and Mental Health and Housing Committee.
The bill would amend the current law to allow hospital beds to be certified as short-term psychiatric evaluation beds. Medical facilities would have to make a report to the state detailing which psychiatric facilities had rejected the patient due to a lack of capacity. The patient would have to be examined by a mental health professional within three hours of being detained and a physician within 24 hours, according to the bill.
Under the bill, the state would have to provide quarterly reports, available online, of how many patients were boarded in each county every month.
The proposal comes as lawmakers have been promising to expand funding for mental-health programs and beds. Lawmakers are also pursuing a bill, Joel's Law, that could increase psychiatric detentions.
Joel's Law, or HB 1258, would let family members petition a judge to overrule any mental-health professional who would not involuntarily commit a relative that the family believes to be suicidal or a danger to others. A fiscal analysis of Joel's law assumed the state could detain an additional 200 to 500 psychiatric patients per year.


I read this over several nights when I woke and couldn't get back to sleep. Mesmerizing and enjoyable but I'm not sure I truly got it.
This book was not what I was expecting. I had in my mind some Russian version of 1984 (don't ask me why) and instead stumbled on a book which mixed the supposedly abusurdist world of the devil and withcraft with the almost equally absurdist world of athiestic state. I need to read this book again.


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三升体育平台
Many Georgia-Pacific products and facilities are recognized and/or certified by third-party groups.
Georgia-Pacific appreciates the recognition we've received from local and federal government agencies, non-governmental organizations and customers. We're especially proud of the Georgia-Pacific employees who helped make these awards possible.
Green Bay (Broadway), Wis., consumer products facility
The mill was recognized for an internal metering and billing project that helped reduce the operation's energy intensity.
Naheola, Ala., consumer products facility
The Naheola mill was recognized with the Air Conservationist of the Year Award for a lighting improvement program that reduced the mill's annual energy consumption and associated air emissions.
Georgia-Pacific Wood and Fiber Sourcing
Georgia-Pacific was recognized for its project to protect endangered forests and special areas. Using scientific methodology, the company identified 4.5 million acres in more than a dozen Southern states that met the criteria as endangered forests and special areas. The company will only buy fiber from these areas in unique situations where active forest management is needed to improve habitat for endangered, rare and/or vulnerable species. The award is one of the association's Better Practices, Better Planet 2020 Sustainability Awards, which recognize exemplary sustainability programs and initiatives.
The Green Bay mill was recognized as the Energy Star® Industrial Partner Top Project for the significant energy intensity reduction achieved through the mill's new natural gas boiler and associated electrical upgrades.
The award recognizes suppliers that have an integrated approach to incorporating ethics, environment and economics into their business and supply chain. The GP PRO business was recognized for increasing the amount of recycled content in the napkins and bags it supplies to McDonald's U.S. restaurants.
KEEP GEORGIA BEAUTIFUL CORPORATE PARTNER AWARD
Georgia-Pacific was recognized for supporting Keep Georgia Beautiful programs that help make Georgia communities more sustainable as well as for its sustainable forestry practices.
ONTEX "EXCELLENCE IN SUSTAINABILITY" AWARD
GP Cellulose was recognized by its customer Ontex, which makes hygienic disposable baby care, feminine care and adult care products, for its work in obtaining certified fiber that enabled Ontex to grow its business.
SUSTAINABLE PACKAGING AWARD
GP PRO, along with the Atlanta Airlines Terminal Corporation, received this award from the City of Atlanta's Department of Aviation in recognition of the impact of GP PRO's Compact® Coreless High Capacity Bathroom Tissue in reducing waste at Hartsfield-Jackson Atlanta International Airport and promoting sustainable business practices.
Albany, Ore., chemical facility
The Albany plant was recognized by the United Way of Linn County for its overall participation in the United Way campaign through a local campaign and community activities.
'FutureMakers Partner' Award
Green Bay, Wis., consumer products operations
The Wisconsin Technical College System recognized the Green Bay operations for its longstanding collaboration with Northeast Wisconsin Technical College, which has included program development, employee training, student support and monetary gifts.
Recognition of Excellence Award
Modesto, Calif., corrugated packaging facility
The City of Modesto Industrial Pretreatment Program recognized Georgia-Pacific's Modesto plant for having no environmental violations during the year and maintaining its preparedness. This is the fifth year in a row that the facility has received this recognition.
FOREST LANDOWNERS ASSOCIATION CORPORATE MEMBER AWARD
Georgia-Pacific was recognized for its support and enhancement of programs for private forest landowners.
LOCAL EXPANSION AWARD
Muskogee, Okla., consumer products facility
The Muskogee mill received an award from the Muskogee City-County Port Authority, Indian Capital Technology Center and Greater Muskogee Area Chamber of Commerce and Tourism for its investment in a new towel converting line to supply the company's enMotion® touch-free towel dispensers.
METLIFE ENERGY AND SUSTAINABILITY CHALLENGE AWARDS
Atlanta, Ga., headquarters
Georgia-Pacific Center, the company's Atlanta headquarters building, received MetLife's National Award, High-Rise Office Property Award and Regional Office Award for the creation and advancement of energy savings programs among MetLife's real estate holdings.
The City of Modesto Industrial Pretreatment Program recognized Georgia-Pacific's Modesto plant for demonstrating its commitment to water quality objectives and industrial pretreatment and best management practices through compliance reporting and proactive collaboration with the city. This is the fourth year in a row that the facility has received this recognition.
UNION PACIFIC RAILROAD PINNACLE AWARD
GP's Chemicals business earned Union Pacific Railroad's Pinnacle Award for chemical transportation safety for achieving a rate of zero non-accident releases for shipments of regulated hazardous materials.
AMERICAN FOREST & PAPER ASSOCIATION "LEADERSHIP IN SUSTAINABILITY" WATER AWARD
Brunswick, Ga., cellulose facility
The Brunswick mill was recognized for its water use reduction project, which resulted in overall groundwater use reduction of nearly 10 million gallons per day – 30 percent of the mill's total daily use. The project also resulted in a smaller energy footprint and lower air emissions from energy production. The award is one of the association's Better Practices, Better Planet 2020 Sustainability Awards, which recognize exemplary sustainability programs and initiatives.
The Muskogee mill received a Muskogee City-County Port Authority Business & Industry Award for its outstanding support for the community.
Georgia-Pacific's Green Bay operations were recognized by the Brown County (Wisconsin) United Way for their longstanding support and commitment to the United Way and the workplace campaign, which helps meet community needs.
OUTSTANDING ENVIRONMENTAL COMPLIANCE
The City of Modesto's Environmental Compliance Section recognized Georgia-Pacific's Modesto plant for having no violations during the year and for significant improvement in reducing issues with its wastewater. This is the third year in a row that the facility has received this recognition.
AMERICAN FOREST & PAPER ASSOCIATION "LEADERS IN SUSTAINABILITY" ENERGY EFFICIENCY AWARD
Georgia-Pacific was recognized for its comprehensive energy management program to reduce energy intensity in its manufacturing operations. The award is one of the association's Better Practices, Better Planet 2020 Sustainability Awards, which recognize exemplary sustainability programs and initiatives.
"BUSINESS OF THE YEAR" AWARD
The Muskogee mill was recognized as "Business of the Year" by the Indian Capital Technology Center, the Muskogee Port Authority and the Greater Muskogee Area Chamber of Commerce for its commitment to the community's economy and economic growth as well as for its employee volunteer efforts and support for community organizations.
CERTIFICATE OF MERIT FOR OUTSTANDING ENVIRONMENTAL COMPLIANCE
Modesto, Calif., corrugated container facility
The City of Modesto's Environmental Compliance Section recognized Georgia-Pacific's Modesto plant for having no environmental violations during the year and for voluntarily completing a water recycling project. The recycling project reuses process waste water, saving more than 100,000 gallons of water per year.
COMPOSITE PANEL ASSOCIATION SAFETY RECOGNITION AWARD
Monticello, Ga., medium density fiberboard facility
Georgia-Pacific's Monticello plant was recognized for having the best safety record among small plants in 2012. It had no lost-time incidents, the best safety record over the last three years and achieved an incident rate less than 50 percent of the industry average over the last three years.
COPIAH-LINCOLN COMMUNITY COLLEGE WORKFORCE EDUCATION DIVISION PRESIDENT'S AWARD
Monticello, Miss., containerboard facility
Georgia-Pacific's Monticello mill was recognized for its decade-long partnership with the Workforce Education Division to maintain and improve employee training and development.
FIBRE BOX ASSOCIATION/ASSOCIATION OF INDEPENDENT CORRUGATED CONVERTERS SAFETY AWARDS
Georgia-Pacific Packaging
Fifteen Georgia-Pacific corrugated facilities were recognized by two industry associations for their safety performance. "Perfect Plant" awards for no recordable safety incidents went to plants at: Madera, Calif. (Color-Box®); Modesto, Calif.; Waxahachie, Texas; and West Chester, Ohio. "Safety Excellence" awards for no lost-time injuries went to plants at: Augusta, Ga.; Circleville, Ohio; Cleveland, Tenn.; Denton, Texas; Doraville, Ga.; Harrington, Del.; Huntsville, Ala.; Kansas City, Mo.; Martinsville, Va.; Pelahatchie, Miss.; and Richmond, Ind.
HAVI GLOBAL SOLUTIONS SUSTAINABILITY AWARD FOR EXCEPTIONAL PERFORMANCE
Georgia-Pacific Professional
The HAVI Global Solutions Sustainability Award honored GeorgiaPacific Professional for finding value in the waste stream of McDonald's – a HAVI customer -- and for supporting McDonald's goal to reduce material sent to landfills.
NATIONAL SAFETY COUNCIL "CEOS WHO 'GET IT'" AWARD
Georgia-Pacific's CEO was one of nine business leaders recognized with the "CEOs Who 'Get It'" award for their organizations' world-class safety programs by the National Safety Council. The council, a leading advocate for safety with chapters throughout the United States, commended the leaders for "creating a strong safety culture within their organizations."
WISCONSIN CORPORATE SAFETY AWARD
The Wisconsin Safety Council and the Department of Workforce Development awarded the Wisconsin Corporate Safety Award to employees at Georgia-Pacific's Green Bay (Broadway) facility. The award is based on safety and health leadership, training programs and implementation and employee participation. The Broadway mill was recognized in the "manufacturing/largest facility" category for the second year in a row.
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What They Want Now--Candy Inspired Styles!
Blame it on Halloween or just blame it on kids being kids and loving anything that resembles a sweet treat, but the little girl styles these days are being inspired by CANDY!
Yes, everyone's favorite desserts are being featured on everything from bags to socks to pajamas to t-shirts and personally, I can't think of anything cuter than a sweet design!
So take it from me and start stocking up on these dessert-inspired designs for stocking stuffers and birthday gifts because I don't think the allure of candy is going away anytime soon…in fact, time for a lollipop break!


Riyad Karim Mahrez (Arabic: رياض كريم محرز; born 21 February 1991) is a professional footballer who plays as a winger for Premier League club Manchester City and the Algerian national team.
Mahrez began his career as a youth player for French club AAS Sarcelles. He turned professional in 2009 with Quimper, where he played for only one season before moving to Le Havre, spending a total of three years with them, initially playing for their reserve team and then becoming a first-team regular. In January 2014, Mahrez signed for English side Leicester City, helping them win the Championship and promotion to the Premier League at the end of his first season. In the 2015–16 season he was the Algerian Footballer of the Year, the PFA Players' Player of the Year, and was a member of the Premier League PFA Team of the Year as he helped Leicester City win the Premier League.
Born in France, Mahrez made his international debut for Algeria in 2014 and represented them at the 2014 FIFA World Cup and both the 2015 and 2017 Africa Cup of Nations. In 2016 he was named CAF's African Footballer of the Year.
Rolling report: Manchester City went five clear at the top, while ten-man Brighton outplayed Crystal Palace on the south coast. Scott Murray was watching.


Larry's Complete Tire & Auto provides Tire Repair services to Catoosa, OK, Tulsa, OK, Broken Arrow, OK, and other surrounding areas.
Why Should You Have Tire Repair Services Performed at Larry's Complete Tire & Auto?
We proudly service the Tire Repair needs of customers in Catoosa, OK, Tulsa, OK, Broken Arrow, OK, and surrounding areas.


The ReBach GR21 is an extremely characterful filter. Developed for bass applications and also applicable for FX, with extremely rough sound and deep frequency range!
Creates deep percussive bass sounds or extreme effects, rough sounding sequences due its pre-filter distortion option and even bass drum sounds with its extreme self oscillation !


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Focus on Radiation Oncology
Novel Combinations
Transcript profiling in peripheral T-cell lymphoma, not otherwise specified, and diffuse large B-cell lymphoma identifies distinct tumor profile signatures
Daruka Mahadevan, Catherine Spier, Kimiko Della Croce, Susan Miller, Benjamin George, Chris Riley, Stephen Warner, Thomas M. Grogan and Thomas P. Miller
Daruka Mahadevan
Catherine Spier
Kimiko Della Croce
Susan Miller
Benjamin George
Chris Riley
Stephen Warner
Thomas M. Grogan
Thomas P. Miller
DOI: 10.1158/1535-7163.MCT-05-0146 Published December 2005
To glean biological differences and similarities of peripheral T-cell lymphoma–not otherwise specified [PTCL-NOS] to diffuse large B-cell lymphoma (DLBCL), a transcriptosome analysis was done on five PTCL-NOS and four DLBCL patients and validated by quantitative real-time reverse transcription-PCR on 10 selected genes. Normal peripheral blood T cells, peripheral blood B cells, and lymph node were used as controls. The resultant gene expression profile delineated distinct "tumor profile signatures" for PTCL-NOS and DLBCL. Several highly overexpressed genes in both PTCL-NOS and DLBCL involve the immune network, stroma, angiogenesis, and cell survival cascades that make important contributions to lymphomagenesis. Inflammatory chemokines and their receptors likely play a central role in these complex interrelated pathways: CCL2 and CXCR4 in PTCL-NOS and CCL5 and CCR1 in DLBCL. Highly overexpressed oncogenes unique to PTCL-NOS are SPI1, STK6, α-PDGFR, and SH2D1A, whereas in DLBCL they are PIM1, PIM2, LYN, BCL2A1, and RAB13. Oncogenes common to both lymphomas are MAFB, MET, NF-κB2, LCK, and LYN. Several tumor suppressors are also down-regulated (TPTE, MGC154, PTCH, ST5, and SUI1). This study illustrates the relevance of tumor-stroma immune trafficking and identified potential novel prognostic markers and targets for therapeutic intervention. [Mol Cancer Ther 2005;4(12):1867–79]
leukemias and lymphomas
non-Hodgkin's lymphoma
gene expression profile
peripheral T-cell lymphoma
diffuse large B-cell lymphoma
The WHO classifies non-Hodgkin's lymphoma into B-cell and T-cell subtypes. B-cell non-Hodgkin's lymphomas comprise ∼85% and T-cell non-Hodgkin's lymphomas comprise ∼15%. Of the T-cell non-Hodgkin's lymphomas, peripheral T-cell lymphoma–not otherwise specified [PTCL-NOS] comprises ∼6% to 10% (1). These are rare tumors whose pathologic diagnosis has been plagued due to the absence of immunophenotypic markers of clonality, morphologic heterogeneity, and poor correlation between cytomorphology and prognosis (2). Large prospective studies have shown that PTCL-NOS have a higher relapse rate and worse survival than diffuse large B-cell lymphoma (DLBCL; refs. 3–5). Regardless of the differences in outcome, both types of lymphoma are largely treated the same, as there are no biological insights to differentiate these tumors. The chemoresistance of PTCL-NOS compared with DLBCL has been attributed to increased expression of multidrug resistance proteins and p53 (6, 7).
The cell of origin of PTCL-NOS is generally CD4+ T cells and very rarely CD8+ T cells. Expression of one or more pan-T-cell antigens (CD45RO, CD2, CD3, CD5, and CD7), absence of pan-B-cell antigens, and histopathologic findings combine to make the diagnosis (8). In the West, nodal PTCL-NOS predominates, whereas in the East extranodal PTCL is more common, particularly the nasal type. The Kiel classification subdivides PTCL-NOS into low-grade and high-grade groups. Within each group, distinct patterns of genetic abnormalities have been identified (9, 10). A second approach analyzed patterns of expression of chemokines and their receptors. Based on the expression of CCR4, CXCR3, CD134, and ST2(L), PTCL-NOS has been subdivided into two prognostic groups (11).
Gene expression profiling using cDNA (12–14) and oligonucleotide microarrays (15) have classified DLBCL into three subgroups: germinal center B-like, activated B-like, and type III. The three subgroups had markedly different survival curves after cyclophosphamide-Adriamycin-vincristine-prednisone (CHOP)–based chemotherapy, providing prognostic information in addition to the international prognostic index and independent of clinical features. A set of 9 genes have been identified that are sufficient to predict the three subgroups and overall survival based on immunohistochemistry (16, 17) and quantitative real-time reverse transcription-PCR (RT-PCR; ref. 18). Such an approach applied to PTCL-NOS would also yield a gene expression-based diagnostic classification, prognostic subgroups, and novel targets that may be amenable to therapeutic intervention.
The aims of the present study were to perform transcript profiling of PTCL-NOS and DLBCL to gain biological insights into the similarities and differences that exist between B-cell and T-cell malignancies. Previous studies (12, 14) used non-Hodgkin's lymphoma cell lines as controls; however, this study used normal peripheral blood B cells, T cells, and lymph node as controls. The classification of the gene expression profile into the six hallmarks of cancer (19) yielded distinct "tumor profile signatures" for PTCL-NOS and DLBCL, respectively. This study has analyzed and evaluated the gene expression profile signature of two phenotypically distinct (T cells versus B cells) non-Hodgkin's lymphomas and provides a framework for more extensive studies for diagnostic classification and prognostic subgroup determinations.
A total of nine patients [four DLBCL and five PTCL-NOS] were studied. The tumor tissue were fixed as snap-frozen samples and stored at −80°C. They were also fixed with buffered formalin, embedded in paraffin, and stained with H&E. All slides were reviewed (C.M.S.) and the initial histologic diagnosis was confirmed. These studies were approved by the patients or their legal guardians as well as appropriate written consents before biopsy. This study is institutional review board exempt.
Immunohistochemistry was done to determine tumor lineage on either snap-frozen or formalin fixed, paraffin-embedded tissue samples using a battery of monoclonal antibodies directed against both B cells (CD19, CD20, CD21, and CD22) and T cells (CD1a, CD2, CD3, CD4, CD5, and CD8). Immunoglobulin light (κ and λ; Becton Dickinson Corp., San Jose, CA) and heavy (IgM, IgG, IgA, and IgD; Becton Dickinson) chain status was also determined. In addition, Ki-67 (DAKO, Carpinteria, CA; for proliferation) and CD30 (anaplastic T-cell lymphoma and activated B cells; DAKO) were used. For frozen tissues, an indirect immunoperoxidase method using 3,3′-diaminobenzidine as the chromogen was used (20), and for paraffin sections, the Ventana ES or a benchmark instrument (Ventana Medical Systems, Tucson, AZ; ref. 21) was used. All patient samples had sufficient testing to assure lineage and clonal status, however. Aberrant loss of pan-T lineage antigens and/or T-cell subsets was used in lieu of receptor gene rearrangements for T-cell lesions when such testing was not available or there was tissue insufficient for study.
RNA Isolation and Oligonucleotide Microarrays
Total RNA was extracted from each frozen PTCL-NOS and DLBCL specimen using the RNeasy Mini kit (Qiagen, Valencia, CA). The amount of total RNA isolated from the cells was quantified using spectrophotometric A260 measurements with yields ≥25 μg/sample. Control RNA was obtained from normal peripheral B cells (AllCells, Berkeley, CA), normal peripheral T cells (AllCells), and a snap-frozen normal lymph node (Department of Pathology, University of Arizona). mRNA (5 μg) was used to generate first-strand cDNA by using a T7-linked oligo(dT) primer. After second-strand synthesis, in vitro transcription (Ambion, Austin, TX) was done with biotinylated UTP and CTP (Enzo Diagnostics, Farmingdale, NY), resulting in 40- to 80-fold linear amplification of RNA. Biotinylated RNA (40 μg) was fragmented to 50- to 150-nucleotide size before overnight hybridization at 45°C to HG-U133A 2.0 Affymetrix (Santa Clara, CA) array comprising ∼18,400 transcripts and 22,000 probe sets. After washing, arrays were stained with streptavidin-phycoerythrin (Molecular Probes, Invitrogen, Carlsbad, CA) and scanned on a Hewlett-Packard (Raleigh, NC) scanner. Intensity for each feature of the array was captured using GeneChip software (Affymetrix), and a single raw expression level for each gene was derived from the 10 to 20 probe pairs representing each gene by using a trimmed mean algorithm. Intensity values were scaled such that overall intensity for each chip of the same type was equivalent. The mean ± SD difference between the scaling factors of all GeneChips was 0.75 ± 0.15. Other additional measures of quality, the percentage of gene present (55.0 ± 2.5), the ratio of actin 3′ to 5′ (1.25 ± 0.15), and the ratio of glyceraldehyde-3-phosphate dehydrogenase 3′ to 5′ (1.02 ± 0.10) indicated a high overall quality of the samples and assays. Well-measured genes were defined genes that had a ratio of signal intensity to background noise of >2 in >80% of the samples hybridized.
Data Analysis and Visualization
For each patient PTCL-NOS or DLBCL compared with the control sample (normal B cells or T cells or normal lymph node), lists of "robust increasers" or "robust decreasers" were generated using the Affymetrix Data Analysis Program (MAS 5.0). Fundamentals guide was used to import these lists into GeneSpring version 5.0 and obtain the intersection of robust increasers or decreasers across all patients PTCL-NOS or DLBCL, respectively. Increasers or decreasers common to normal T cells and lymph node or normal B cells and lymph node were compared with PTCL-NOS or DLBCL patients. Further, increasers or decreasers common to normal T cells and B cells or lymph node to PTCL-NOS and DLBCL were also compared. Gene expression profiles for PTCL-NOS or DLBCL were further classified according to the Hallmarks of Cancer (19) to determine lymphoma-specific tumor profile signatures. These are genes involved in (a) self-sufficiency in growth signals, including oncogenes; (b) insensitivities to growth inhibitory signals, including absence of tumor suppressors; (c) evasion apoptosis; (d) limitless replicative potential; (e) sustained angiogenesis; and (f) invasion and metastasis. Finally, searches were conducted for potential therapeutic targets by keywords (e.g., protein kinases to generate gene lists for each desired target type). Intersection of the gene lists for each target with the commonly up-regulated and down-regulated genes across patient samples were obtained. This was also done on the intersects of the up-regulated and down-regulated gene lists with the GeneSpring "Simplified GO Ontology" as another method of classifying genes. For the four DLBCL patients, the measurement of 9 prognostic genes (LMO2, BCL6, FN1, SCYA3, BCL2, CD10, MUM1, FOXP1, and CYCLIN D2; refs. 22, 23) were applied to ascertain which subclass they belonged to based on a comparison with the normal B cells or lymph node.
Real-time Quantitative RT-PCR
Total RNA (100 ng) was used for reverse transcription reactions (20 mL total volume) carried out using SuperScript III Platinum Reverse Transcriptase (Invitrogen, Carlsbad, CA). Reactions were incubated at 42°C for 50 minutes followed by incubation at 37°C with RNase H for 20 minutes. An Opticon DNA Engine (MJ Research, Reno, NV) was used to perform real-time fluorescence detection PCR. cDNA (1 μL) produced from reverse transcription reactions was added to 12.5 μL Platinum SYBR Green quantitative PCR SuperMix-UDG (Invitrogen), 1 μL gene-specific or β-actin-specific primer pair (see below for primer design), and 10.5 μL distilled H2O (final volume of 25 μL). Amplification (95°C for 15 seconds, 55°C for 30 seconds, and 72°C for 30 seconds) was repeated for 44 cycles. Following the PCR reaction, a melting curve assay was done to determine the purity of the amplified product. Data were provided as a threshold cycle value (CT) for each sample, which indicated the cycle at which a statistically significant increase in fluorescence was first detected. These data were then normalized to β-actin, which served as an unaffected control gene, for each data point and compared with a normal T-cell control to determine relative expression ratios. Each measurement was done in triplicate.
Primer Design
PCR primers were designed using MacVector (Accelrys, San Diego, CA) to produce amplicons with lengths ranging from 80 to 250 bp to optimize the efficiency of quantitative PCR. The sequences are 5′-TGGGCTCTTTTGAAGGATTGG-3′ and 5′-GCAGTCTGGCTATCTGATTGAAGC-3′ for Lumican, 5′-CTCCTGGCAGATTCCACAAAAG-3′ and 5′-CACTTCTTATTGGGGTCAGCACAG-3′ for CCL18, 5′-ACTCCCTCAATCTGTCGTTCGC-3′ and 5′-TTCCCGTCCAGTGTCAGGTTATCC-3′ for CD14, 5′-TGTCCCCCTCAAAAGTCATCC-3′ and 5′-TTGCTCAGTTCATACACCTTCCG-3′ for CD54, 5′-GAATGGTGCTACTTGAAGACTCTGG-3′ and 5′-CACTCTCCCGCTACACTTGTTTTC-3′ for CD163, 5′-CACACACAGGTGGGACACAAATAAG-3′ and 5′-GCAAGTCAATGAGACGGAGTCAC-3′ for CD106, 5′-TGAAGTCCAAGTTCCTCCAGGTC-3′ and 5′-TGTTGCTGTTGTGGCTATTAGGC-3′ for HCK, 5′-TGCGTAAGAGCAAAAAGCGAAG-3′ and 5′-AAATAAGCCCCCCCTCAACCTTGG-3′ for α-PDGFR, 5′-CGCTTTGCTCCTTGTTTTTTCC-3′ and 5′-CGTCTCTTTCTCCTACCCCTTGAC-3′ for ABCA1, and 5′-TGCTACCACAAGAAATACCGCTC-3′ and 5′-ATCCTCCTTCCCAAACACCAGC-3′ for TEM6. β-actin primers from QuantumRNA β-Actin Internal Standards (Ambion) were used to normalize the quantitative PCR data.
Morphology and Immunohistochemistry Analysis
The five PTCL-NOS patients were all large cell lymphomas. All were de novo. Each sample contained >50% tumor cells. Four were of nodal origin, whereas one originated as a soft tissue mass in the knee. All PTCL-NOS patients were negative for CD1 and CD5 and positive for CD2, CD3, and CD7. The Ki-67 ranges from 30% to 50%. Of the four DLBCL patients, three were nodal in origin and one occurred as a soft tissue mass in the right breast. All four did not show any follicular areas; had large cell morphology, uniform expression of CD20, and monoclonal light chain immunoglobulin; and contained >50% tumor cells. Proliferation as judged by Ki-67 for the four patients was 10%, 35%, 60%, and 76%, respectively. No aberrant antigen expression, specifically no CD5 coexpression, was detected. Figure 1A shows a representative patient with PTCL-NOS and Fig. 1B shows a patient with DLBCL with immunohistochemistry analysis, distinguishing the two lymphoma subtypes and providing a measure of tumor involvement.
A, a representative patient with PTCL-NOS showing H&E staining for morphology and immunohistochemistry to delineate T-cell phenotype (CD2) is CD8 negative (staining is due to tumor-infiltrating lymphocytes) with tumor involvement (>50%) and aggressiveness (Ki-67). B, a representative patient with DLBCL showing H&E staining for morphology and immunohistochemistry to delineate B-cell phenotype (CD20) is CD8 negative (staining is due to tumor-infiltrating lymphocytes) with tumor involvement (>50%) and aggressiveness (Ki-67).
Gene Expression Profiling of PTCL-NOS and DLBCL
The Affymetrix MAS 5.0 software was used to calculate the average, SD, median, and interquartile range calculations [e.g., the top 25 increases or decreases; PTCL-NOS versus normal T cells or normal lymph node]. The intersample variability correlated well with the quantitative real-time RT-PCR data. For example the five patients with PTCL-NOS for CD14 gene expression signals were 1,034.6, 3,371.4, 4,720.3, 3,451.1, and 3,130.5. The average was 3,141.5, SD was 1,330.46, median was 3,371.4, and interquartile range was 320.6. Based on these data, the average fold change was calculated to be 88-fold compared with normal peripheral blood T-cell RNA. Well-measured genes were defined as genes that had a ratio of signal intensity to background noise of >2 in >80% of the samples hybridized.
Genes that are robustly up-regulated and common to all five patients with PTCL-NOS are compared with normal peripheral blood T cells or normal lymph node (Table 1 ). It seems that the comparison of PTCL-NOS patients to normal peripheral blood T cells shows that most of the genes that are overexpressed are involved in tumor invasion (COL1A1, FN1, CTGF, COL1A2, CCL2, CLU, C1S, LUM, and LYS), antiapoptosis (CD14), proliferation (CCL18, CXCL13, and IGFBP7), and angiogenesis (TEM6). Similarly, when PTCL-NOS are compared with the normal lymph node, most of the genes that are up-regulated and overexpressed are involved in tumor invasion (CHI3L1, CCL5, and CORO1A) and proliferation (SH2D1A, FLI1, AIF1, CRIP1, MAP4K1, and Rac2). Genes known to be causative in tumorigenesis are prominently expressed, indicating that peripheral blood T cells and lymph node controls both provide valuable information regarding the evolution of the tumor from normal T cells and lymph nodes. The robustly down-regulated genes are not included here but will be discussed below with regard to the tumor profile signature.
Highly overexpressed genes in PTCL-NOS compared with normal peripheral blood T cells or lymph node
Genes that are robustly up-regulated and common to all four patients with DLBCL are compared with normal peripheral blood B cells or normal lymph node (Table 2 ). The comparison of DLBCL patients to normal peripheral blood B cells shows that the genes that are up-regulated and overexpressed are also involved in tumor invasion (LYS, CCL5, CHI3L1, CHIT1, MMP9, and ADAMDEC1), immune cell trafficking or host cell response to tumor (CCL18, RGS13, CXCL9, and VNN1), and proliferation (PLA2G2D and PLA2G7). Similarly, when DLBCL patients are compared with the normal lymph node, most of the genes that are up-regulated and overexpressed are involved in tumor invasion (CCL5, CORO1A, and CHI3L1), antiapoptosis (BCL2A1), immune trafficking (CCL18, CD79B, CD52, and POU2AF1), and proliferation (CD20, MAP4K1, and Rac2). Tumor tissues express genes that promote and maintain the oncogenic process, and the profiles obtained based on normal peripheral blood B cells and lymph node will help guide the elucidation of the mechanism initiation and progression. The robustly down-regulated genes are not included and will be discussed with regard to the tumor profile signature.
Highly overexpressed genes in DLBCL compared with normal peripheral blood B cells or lymph node
Table 3 shows the highly up-regulated genes that are common to both PTCL-NOS and DLBCL when compared with normal peripheral blood T cells and B cells or lymph node, respectively. There are only three genes common to PTCL-NOS and DLBCL when compared with normal peripheral blood T cells and B cells and they are CCL18, UBD, and RARRES1. However, there are 11 genes common to PTCL-NOS and DLBCL when compared with the lymph node and they are CCL18, CD52, MAP4K1, CORO1A, PPP1R16B, PSMB8, UBD, LYZ, TCRβ, RAC2, and CCL5. These comparisons provide insights into the importance of differential gene expression profiles that are common to both types of lymphoma. By including a single cell (peripheral blood B cells or T cells) as well as a complex tissue (lymph node), insights into the relative importance of the relationships between tumor-stroma immune trafficking cells can now be gleaned.
Overexpressed genes common to PTCL-NOS and DLBCL compared with normal peripheral blood T cells, peripheral blood B cells, and lymph node
Tumor Profile Signatures of PTCL-NOS and DLBCL
We next did an analysis based on the six hallmarks of cancer (19) in which a tumor has the following acquired capabilities: (a) self-sufficiency in growth signals, (b) insensitivity to antigrowth signals, (c) evasion of apoptosis, (d) limitless replicative potential, (e) sustained angiogenesis, and (f) tissue invasion and metastasis. Genes were sorted into each of these categories common to all five PTCL-NOS patients compared with peripheral blood T cells, lymph node, and/or both (Table 4 ). A similar analysis was done for the four DLBCL patients compared with peripheral blood B cells, lymph node, and/or both (Table 5 ). This provides a tumor profile signature for PTCL-NOS and DLBCL. PTCL-NOS identified genes associated with proliferation (IGFBP7, SH2D1A, RAC2, and TCIRG1), tumor suppressors (RARRES3, GAS1, and CDKN1A), invasion (COL1A, FN1, and CCL2), unlimited replication (CTGF, CYR61, and NEK2), angiogenesis (VEGF, PDGFR, CSF1R, and HGF), antiapoptosis (CD14 and NF-κB), and oncogenes (FLI1, MAFB, SPI1, STK6, and MET). DLBCL identified genes associated with proliferation (IGFBP7, CD20, CD72, CRIP1, and RAB13), tumor suppressors (GPNMB, CD63, BTG2, and RARRES3), invasion (LUM, FN1, MMP1, and COL6A3), unlimited replication (CCR1 and CCL5), angiogenesis (VEGF, PDGF, PDGFR, and FGF13), and antiapoptosis (CD14 and BCL2A1). Therefore, it is apparent that normal peripheral blood T cells or B cells and lymph node in combination provides consistent gene expression findings that now can be evaluated in detail and attempts be made to position these in signaling pathways that make the relationships more obvious.
Hallmarks of cancer for DLBCL: DLBCL vs peripheral blood B cells and lymph node
Hallmarks of cancer for PTCL-NOS: PTCL-NOS vs peripheral blood T cells and lymph node
Nine-Gene Predictive Model of DLBCL
Tissue microarray using immunoperoxidase staining for predictive markers to accurately subdivide DLBCL into prognostically relevant subgroups has been done and correlated with cDNA microarray as the gold standard (22). Six proteins were identified: CD10, BCL2, BCL6, MUM1/IRF4, CYCLIN D2, and FOXP1. Similarly, a quantitative real-time RT-PCR analysis identified six genes to have prognostic significance: BCL2, BCL6, FN1, LMO2, CCND2, and SCYA3/CCL3 (23). In this study, we combined the genes that were used in the tissue microarray and RT-PCR to evaluate the four DLBCL and five PTCL-NOS patients. When the four DLBCL patients were compared with the normal peripheral blood B cells, three of nine genes were up-regulated (FN1 140-fold, CCL3 4.9-fold, and BCL6 2.2-fold), and when compared with the lymph node, seven of nine genes were up-regulated (MUM1 28-fold, CCL3 11.4-fold, CCND2 10.4-fold, BCL6 6.7-fold, LMO2 5.3-fold, BCL2 4.6-fold, and FN1 2.3-fold). These data place these four unselected DLBCL patients into the non-germinal center activated B-cell subgroup. Further, the importance of the control RNA is highlighted, implying that the lymph node may be more informative due to its complex nature and that a tumor does follow the hallmarks of cancer.
Discovery of New Therapeutic Targets
The study also analyzed certain key therapeutic targets that may be amenable to targeting either with small-molecule inhibitors and/or monoclonal antibodies. For patients with PTCL-NOS, the following are novel targets: small-molecule inhibitors to protein kinases (STK6, NEK2, c-MET, SYK, and α-PDGFR), monoclonal antibodies to circulating ligands (CCL2, VEGF, HGF, CTGF, PDGF, FGF7, and IGFBP7), and a small-molecule inhibitor to Rac2, a member of the Ras family of small GTP-binding proteins. For patients with DLBCL, the following are novel targets: small-molecule inhibitors to protein kinases (LCK, LYN, PIM1, PIM2, MET, and SYK), small-molecule inhibitors to novel targets (PSMA, BCL2A1, and NF-κB2), monoclonal antibodies to circulating ligands (CCL2, CCL5, and VEGF), and cell surface markers (CD72, ICAM2, and CD52).
Validation with Quantitative Real-time RT-PCR
Quantitative real-time RT-PCR on 10 selected, overexpressed, functionally relevant genes (Lumican, CCL18, CD14, CD54, CD106, CD163, α-PDGFR, HCK, ABCA1, and TEM6) common to all five PTCL-NOS patients validated the gene expression profile data (Fig. 2 ). The expression level for each patient is shown and averaged over three runs of RT-PCR. These correlated well with the intersample variability observed from the gene expression signals obtained from the DNA microarray.
Quantitative real-time RT-PCR of 10 selected genes common to five PTCL-NOS patients (1–5). Y axis, level of expression compared with control.
Patients with PTCL-NOS have a worse outcome compared with patients with DLBCL (24). To distinguish biological properties of these two phenotypic variants of large cell lymphoma, we undertook a gene expression profile study of PTCL-NOS and DLBCL using an Affymetrix platform. The study identified several key elements in lymphoma biology and has led to hypothesis-generating research that should guide elucidation of the underlying oncogenic events in PTCL-NOS and DLBCL. The complexity of these tumors is represented by 25 to 30 up-regulated cancer genes and several down-regulated tumor suppressors that provide a growth advantage and enhance the ability to invade and metastasize.
PTCL-NOS Tumor Profile Signature
A predictive model for the PTCL-NOS tumor profile is delineated based on the six hallmarks of cancer (Fig. 3 ). Chemokines cause the directed migration of leukocytes along a chemical gradient of ligand. Many cancers, including lymphomas, have a complex chemokine network that influences immune cell infiltration, tumor cell growth, survival, migration, and angiogenesis. These cells themselves express chemokine receptors and can respond to chemokine in an autocrine and/or paracrine mechanism (25). Many different cancers, including PTCL-NOS (26), have different profiles of chemokine and chemokine receptor expression, but CXCR4 is most commonly found.
A predictive model delineating the tumor profile signature of PTCL-NOS. Activation of oncogenic transcription factors (MAFB, FLI1, and SPI1) promotes overexpression of chemokines (CCL2 and CCL5) and chemokine receptors (CCR1 and CXCR4). These acting in an autocrine and paracrine manner recruit stromal fibroblasts, inflammatory immune cells, and endothelial cells to form a complex network of tumor tissue. The overexpression of integrins (LFA1 and VLA4) on the tumor cells and their binding partners on stromal cells (ICAM1, ICAM2, and VCAM1) promotes tumor-stroma cross-talk that activates proliferative signaling pathways (JAK/STAT), ECM formation (FN1, COL1A1, COL1A2, CHI3L1, and emilin), and stromal-derived cytokines/growth factors (CTGF and CYR61). Several tumor-derived angiogenesis promoters (VEGF, PDGF-CC, FGF7, PDGFR, and CSF1R) are overexpressed, which helps maintain a complex angiogenic process. The recruitment of inflammatory immune cells that enhance tumor growth and the production of invasive factors (HGF, MET, CTGF, and IGFBP7) bode for an aggressive T-cell lymphoma. Moreover, the overexpression of NF-κB-driven proliferative factors (TCIRG1, CD14, CD52, TNFRSF25, and CCR1) inhibits many forms of apoptosis and contributes to chemoresistance. The overexpression of NEK2 and STK6 contributes to cell cycle dysregulation and resultant aneuploidy. Several markers of proliferation are also overexpressed (SH2D1A, LCK, Rac2, and MAP4K1), which contributes to the overall survival and antiapoptotic pathways.
It has been shown that c-MAF may alter the function of multiple myeloma cells by up-regulating CCR1, a receptor for the chemokine MIP-1. Three MAF target genes overexpressed in multiple myeloma are CYCLIN D2, integrin β7, and CCR1. Increased expression of CYCLIN D2 enhances proliferation, whereas increased integrin β7 promotes adhesion to bone marrow stroma and increases VEGF elaboration (27). In PTCL-NOS, MAFB is 80-fold overexpressed and is important for IL-4 gene expression by Th2 cells. Several of the target genes activated by c-MAF in multiple myeloma are also up-regulated in PTCL-NOS, which include VEGF (84-fold), ITGA4 (88-fold), and CCR1 (39-fold), implying aberrant proliferation, increased adhesion to surrounding stroma, tumor angiogenesis, and immune dysregulation (Fig. 3). Several other chemokines are also overexpressed and are likely driven by MAFB and/or two other highly overexpressed oncogenic transcription factors FLI1 (100-fold) and SPI1 (29-fold). FLI1 promotes cell cycle progression by suppressing the expression of CDK inhibitor p27kip1 (28), whereas SPI1 is normally expressed in all hematopoietic cell lineages, except in T-cell lines (29), but its aberrant expression may be an additional mechanism that maintains the malignant lymphocyte to proliferate.
CCL2 is 100-fold overexpressed and a potent chemoattractant for monocytes, memory T lymphocytes, and natural killer cells. CCL2 is a tumor promoter (30), is able to recruit leukocytes, and provides growth signals for tumor angiogenesis. Several angiogenic receptors and ligands are overexpressed in PTCL-NOS, which includes VEGF (84-fold), α-PDGFR (26-fold), CSF1R (19-fold), β-PDGFR (19-fold), c-MET (7-fold), HGF (24-fold), PDGF-CC (5-fold), and FGF7 (2.5-fold), all seem to contribute to tumor growth. CCL5 is a 120-fold overexpressed chemoattractant that binds to several receptors, including CCR1 (39-fold), CCR3, CCR4, and CCR5. CCL5 up-regulates transcription of MMP9, which can contribute to angiogenesis. Further, tumor-derived CCL5 can inhibit the T-cell response and enhance the in vivo growth of tumors (31). CXCR4 is 79-fold overexpressed and involved in lymphocyte trafficking. When activated, CXCR4 promotes invasion of lymphoma cells into tissues through activated LFA1, which in turn activates the JAK kinases and shown to be essential for lymphoma invasion and metastasis (32).
Tumor-stroma interactions play an integral role in lymphoma cell survival. In PTCL-NOS, IGFBP7 is ∼130-fold overexpressed, enhances IGF activity, and influences cell adhesion and migration (33), a potential mechanism of tumor invasion. CTGF/CCN2 is >100-fold and CYR61/CCN1 is >70-fold overexpressed and belongs to a cysteine-rich secreted protein of the CCN family (34) that binds to integrins and modulates invasive behavior of cancer cells. Several components of the extracellular matrix (ECM) are elevated and include CHI3L1 (200-fold), COL1A1 (177-fold), FN1 (108-fold), COL1A2 (103-fold), and emilin (44-fold), most likely mediated by CTGF/CYR61 (Fig. 3). CYR61 has been shown to enhance tumorigenicity through activated integrin-linked kinase to stimulate β-catenin-TCF/Lef and Akt signaling pathways (34).
Aberrant cellular proliferation due to dysregulated cell cycle control seems to be mediated by the serine/threonine kinase NEK2, which is 58-fold overexpressed (Fig. 3) and localizes to the centrosome. Overexpression of active NEK2 induces splitting of centrosomes, whereas prolonged expression of either active or inactive NEK2 leads to dispersal of centrosomal material and loss of a focused microtubule-nucleating activity (35). NEK2 has also been shown to be overexpressed in transformed follicular lymphoma and de novo DLBCL (36). STK6 (Aurora kinase-A) is 17-fold overexpressed and plays a role in cell cycle regulation during anaphase and/or telophase, in relation to the function of the centrosome/spindle pole region during chromosome segregation. Defect in STK6 is responsible for numerical centrosome aberrations, including aneuploidy, which is related to its role in microtubule formation and/or stabilization (37).
Several markers of proliferation are represented, of which SH2D1A is 120-fold overexpressed and binds to a specific motif in the cytoplasmic domains of several members of the CD2 subfamily of cell surface receptors, where it blocks recruitment of the tyrosine phosphatase SHP-2 and prevents inhibition of tyrosine kinase activated signaling pathways (38). Rac2 is 107-fold overexpressed and regulates a diverse array of cellular events, such as cell growth, cytoskeletal reorganization, and activation of protein kinases. Rac2 is expressed in thymocytes and activated T cells and could play a role in control of growth and death of T cells (39). LCK is 35-fold overexpressed and phosphorylates mitogen-activated protein kinase and L-selectin with subsequent association of Grb2/Sos with L-selectin. This association correlates with an activation of p21ras, mitogen-activated protein kinase, and Rac2 and a transient increase of O2− synthesis. A final common path could involve a L-selectin-associated CD3 ζ-chain-driven T-cell antigen receptor-induced cell proliferation (40). TCIRG1/TIRC7 is 54-fold overexpressed, a novel seven-transmembrane spanning vacuolar proton pump protein that is up-regulated during the early stages of T-cell activation in response to alloantigens. Inhibiting TIRC7 suppresses proliferation of activated T cells (41) and supports the notion that it may play an important role in PTCL proliferation.
In PTCL-NOS, several tumor suppressors are down-regulated. TPTE encodes a PTEN-related tyrosine phosphatase, is 99-fold down-regulated, and plays an important role in suppressing signaling via tyrosine-phosphorylated proteins (42). MGC15419 is 20-fold down-regulated and may be critical for the controlled degradation of cellular regulatory proteins (43). PTCH is 6-fold down-regulated and is the receptor for sonic hedgehog, implicated in the formation of embryonic structures and in tumorigenesis. Mutations of this gene have been associated with nevoid basal cell carcinoma syndrome, squamous cell carcinoma, trichoepitheliomas, and transitional cell carcinoma (44). ST5 is 5-fold down-regulated and contains a COOH-terminal region that shares similarity with the Rab3 family of small GTP-binding proteins. This protein preferentially binds to the SH3 domain of c-Abl kinase and acts as a regulator of mitogen-activated protein kinase 1/extracellular signal-regulated kinase 2 kinase, which may contribute to its ability to reduce the tumorigenic phenotype in cells (45).
Several antiapoptotic proteins are represented in PTCL-NOS. CD14 is 88-fold overexpressed and acts via MyD88, TIRAP, and TRAF6, leading to NF-κB activation, cytokine secretion, and inflammatory response (46). NF-κB2 is 44-fold overexpressed and is a transcription factor containing rel-polyG-ankyrin domains. NF-κB2/p52 gene rearrangements have been observed in patients with lymphoma and have been shown to contribute to tumorigenesis by suppressing apoptosis and increasing proliferation in response to inflammatory cytokines (47–49). A recent expression profiling study showed that the NF-κB signaling pathway is deregulated in PTCL-NOS (50), implicating this inflammatory transcription factor in maintaining cell survival pathways. IL-18 is 39-fold overexpressed and induces IFN-γ production in T cells, and dysregulated IL-18 and/or IL-18R in chronic B-cell lymphoproliferative disorders may contribute to tumor escape from the host immune system by reducing the expression of Fas ligand. Moreover, it has been shown to function as a novel angiogenic mediator by promoting endothelial cell migration (51).
Several proapoptotic genes are down-regulated. c-Jun is a 27-fold down-regulated oncoprotein that blocks the ubiquitination of tumor suppressor p53 and thus increases the stability of p53 in nonstressed cells. Studies of the mouse counterpart of this gene suggest a key role in T-cell differentiation (52). CED-6 is 22-fold down-regulated and is an evolutionarily conserved adaptor protein required for efficient engulfment of apoptotic cells and that promotes programmed cell death. Inactivating mutations in engulfment genes enhance the frequency of cell survival (53, 54). TNFRSF25 is 12-fold down-regulated, is expressed preferentially in tissues enriched in lymphocytes, and plays a role in regulating lymphocyte homeostasis. This receptor has been shown to stimulate NF-κB activity and regulate cell apoptosis. The alternative splicing of this gene in B cells and T cells encounters a programmed change on T-cell activation, which predominantly produces full-length, membrane-bound isoforms and is thought to be involved in controlling lymphocyte proliferation induced by T-cell activation (55). Therefore, a loss of function would lead to uncontrolled T-cell proliferation.
DLBCL Tumor Profile Signature
A predictive model for the DLBCL tumor profile is delineated based on the six hallmarks of cancer (Fig. 4 ). A chemokine network seems to be in operation and is likely modulated by transcription factors MAFB (83-fold overexpressed), FLI1 (86-fold overexpressed), and CRIP1 (67-fold overexpressed), a cysteine-rich intestinal protein 1 that contains a double zinc finger motif. Overexpression of CRIP in mice produces an imbalance in cytokine pattern favoring Th2 cytokines: low IFN-γ and high IL-6 and IL-10, which alter the immune response and likely favor escape from immune attack (56). CCL5 is 147-fold overexpressed and binds its receptor CCR1, which is 82-fold overexpressed. Tumor-derived CCL5 can inhibit the inhibitory T-cell response and enhance in vivo lymphoma growth. Several proangiogenic ligands and receptors are overexpressed, which include VEGF (66-fold), PDGF-AA (15-fold), CSF1R (14-fold), β-PDGFR (11-fold), MET (7-fold), FGF13 (6-fold), and PSMA (4-fold), and are likely to be induced by CCL5-CCR1. Tumor stroma–derived factors, such as IGFBP7, which is 107-fold overexpressed (33) and likely elaborates several components of the ECM, such as CHI3L1 (84-fold), FN1 (60-fold), COL6A3 (49-fold), COL18A1 (47-fold), and ICAM2 (30-fold).
A predictive model delineating the tumor profile signature of DLBCL. Activation of oncogenic transcription factors (MAFB, FLI1, and CRIP1) promotes overexpression of chemokines (CCL3, CCL5, and CXCL9) and chemokine receptor (CCR1). The chemokine network acting in an autocrine and paracrine manner recruit stromal fibroblasts, inflammatory immune cells, and endothelial cells to form a complex network of tumor tissue. The overexpression of integrin LFA1 on the tumor cells and their binding partners on stromal cells (ICAM2 and ICAM3) promotes tumor-stroma cross-talk which activates proliferative signaling pathways (JAK/STAT) and ECM formation (Lumican, FN1, COL6A3, COL18A1, and CHI3L1). Several tumor-derived angiogenesis promoters (VEGF, PDGF-AA, FGF13, PDGFR, CSF1R, and PSMA) are overexpressed, which helps maintain a complex angiogenic process. The recruitment of inflammatory immune cells that enhance tumor growth and the production of invasive factors (MET and IGFBP7) bode for an activated B-like DLBCL. Moreover, the overexpression of NF-κB-driven proliferative factors (CD14, CD20, CD52, CD72, and CCR1) inhibits many forms of apoptosis and contributes to chemoresistance. The overexpression of CCND2 and MUM1 contributes to cell cycle dysregulation and uncontrolled proliferation. Several markers of proliferation are also overexpressed (PIM1, PIM2, BCL2A1, RAB13, and MAP4K1) that contribute to the overall survival and antiapoptotic pathways.
Markers of proliferation represented include CD20 (99-fold), a member of the membrane-spanning 4A gene family that functions as a Ca2+ channel resident on B lymphocytes and plays a role in the development and differentiation of B cells into plasma cells. It is the target for rituximab in B-cell non-Hodgkin's lymphoma and shows excellent correlation between gene expression profile and immunohistochemistry (57). CD72 is a 83-fold overexpressed type II membrane protein of the C-type lectin superfamily and is the ligand for CD5. It plays a role in pre-B-cell and B-cell proliferation and differentiation. Among 83 malignant non-Hodgkin's lymphomas evaluated by immunohistochemistry, all 54 B-cell lymphomas, including precursor B-cell lymphomas, were CD72 positive, but staining was not observed in T-cell lymphomas. Therefore, CD72 is a proliferative marker that cooperates with CD20 in DLBCL (58). RAB13, a GTPase, is 29-fold overexpressed and regulates the assembly of functional epithelial tight junctions. Expression of the GTP-bound form of RAB13 inhibits protein kinase A–dependent phosphorylation and tight junction recruitment of the vasodilator-stimulated phosphoprotein, an actin remodeling protein and thus may play a role in invasion and metastasis (59).
In DLBCL, two tumor suppressors are down-regulated. TPTE is a 100-fold down-regulated PTEN-related tyrosine phosphatase that, if active, would switch off tyrosine kinase–driven oncogenic pathways (42). SUI1/MOF2 is 25-fold down-regulated and functions as a modulator of accuracy at both initiation and elongation phases of translation (60). Transfection of human SUI1 into HepG2 hepatocarcinoma cells inhibited cell growth in culture in soft agar and partially inhibited tumor formation in nude mice (61).
Of the antiapoptotic proteins that are overexpressed, CD14 is 141-fold overexpressed and is known to activate NF-κB leading to inflammatory cytokine secretion (46) and an inflammatory response that likely helps avoid immune attack. BCL2A1 is 107-fold overexpressed, forms heterodimers or homodimers, and is involved in a wide variety of cellular activities, such as embryonic development, homeostasis, and tumorigenesis. BCL2A1 is a direct transcription target of NF-κB in response to inflammatory mediators and is up-regulated by different extracellular signals, such as granulocyte macrophage colony-stimulating factor, CD40, and inflammatory cytokines (TNF and IL-1), which provides a cytoprotective function that may be essential for lymphocyte activation and cell survival (62). Mice with BCL2A1 overexpression showed extended survival with altered B lineage development that led to expansion of the pro-B-cell subset at the expense of pre-B cells, suggesting an impairment of the pro-B-cell to pre-B-cell transition (63). Several genes are implicated in the pathogenesis of DLBCL, which seem to have prognostic significance. Patients with germinal center B-like DLBCL have the most favorable cure rate, whereas patients with activated B-like or type III DLBCL have a worse survival and this may be due in part to the ability of the NF-κB pathway to inhibit intrinsic apoptosis and/or chemotherapy-mediated apoptosis (64).
A transcriptosome analysis of PTCL-NOS and DLBCL patients has identified a molecular tumor signature profile that distinguishes B-cell from T-cell non-Hodgkin's lymphoma. In both types of non-Hodgkin's lymphoma, MAFB-driven inflammatory chemokine signaling pathways play critical roles in promoting proliferation, angiogenesis, tumor-stroma interactions, and immune escape albeit with different key players most likely reflecting lineage specificity. Phase I clinical trials are now feasible targeting the PDGFR (Gleevec), MET (Mab to HGF), STK6 (AK inhibitors), and CD52 (CAMPATH-1H) in this setting.
We thank Ellen Chase for coordinating this project and Nikhil Shirahatti for technical help with article preparation.
Grant support: Southwest Oncology Group grant CA-32102, subcontract 03041.
Revision received July 21, 2005.
American Association for Cancer Research
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Mol Cancer Ther December 1 2005 (4) (12) 1867-1879; DOI: 10.1158/1535-7163.MCT-05-0146
Prediction of individual response to platinum/paclitaxel combination using novel marker genes in ovarian cancers
Low doses of cisplatin or gemcitabine plus Photofrin/photodynamic therapy: Disjointed cell cycle phase-related activity accounts for synergistic outcome in metastatic non–small cell lung cancer cells (H1299)
Semisynthetic homoharringtonine induces apoptosis via inhibition of protein synthesis and triggers rapid myeloid cell leukemia-1 down-regulation in myeloid leukemia cells
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Can You Help Save the Play Park?
CAN YOU HELP TO SAVE THE PLAY PARK?
Well, a little exaggeration to attract your attention, but only a little. Some 20 years ago members of the community raised the money to build the play park on The Down. Since then the Parish Council has been responsible for its maintenance and repair. Now some of the equipment is in need of replacing, but Council does not have the money. Is there anyone in the community who could help to obtain grants and fund-raise to replace equipment?


Grid Pad 10 has a bright 10" touchscreen display, with toughened glass.
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Grid Pad is designed for Grid 3, our flagship software for communication, Environment Control and more. Grid 3 includes a wide range of AAC resources, designed for people of all ages with different levels of literacy.
Grid Pad 10's integrated speakers have been engineered to produce high quality sound and volume – to help get your message across effectively, wherever you are.
Rehadapt and Daessy mounting options give you choice and flexibility in every environment. There's also a built-in stand if you want to use the device on a desk or flat surface.
Grid Pad 10 comes with built-in infrared and radio Environment Control to give you more independence. It can learn to control your TV, lights, and other devices around your home.
Grid Pad 10 is also available as a touch-only, portable solution with a Bluetooth speaker. Please get in touch via sales@thinksmartbox.com.


The Konformist Blog: "My Hell in an Israeli Jail"
Black British filmmaker Ishmahil Blagrove has launched an outspoken attack against the "racist" Israeli government after being abducted from the high seas and imprisoned for seven days.
Jamaica-born Blagrove, who lives in West London, was one of six British nationals taking part in a mercy mission to Gaza who were seized from the vessel Spirit of Humanity on June 30 by Israeli military forces.
The ship, which Blagrove says was illegally boarded in international waters, was bringing a cargo of medicines, children's toys and reconstruction materials to the devastated people of Gaza.
"I'm not concerned with the time that I spent in jail because I am now free, however, there are still thousands of people being persecuted as we speak," said Blagrove.
Sailing from Larnaca, Cyprus, with a crew of 21 human rights activists, humanitarian workers and journalists from 11 different countries, those on board included Nobel Peace Laureate Mairead Maguire and former US Congresswoman Cynthia McKinney.
Blagrove told how Israeli warships surrounded their vessel threatening to open fire if they did not turn back.
"We were 18 miles of the coast of Gaza and 23 miles outside the international water boundaries. The Israelis made contact with us via radio at approximately 1.30 am. Our ship had been given security clearance by the port authorities in Cyprus so we posed no threat, yet the Israeli government insisted that we aborted our journey.
"When we refused to be intimidated, they jammed our instrumentation and blocked our GPS, radar, and navigation systems, putting our lives at risk.
"Before we knew it we were surrounded by four Zodiac Special Forces, which are Israeli gunships and helicopters were also flying over our heads. They stormed our ship and took us against our will to Ashdod Port in Israel.
"The first day I was there, I witnessed 500 Africans scooped from the streets of Tel Aviv thrown into prison. The next day 300 more Africans were taken in and the prison population continues to grow daily with Africans falling victim to the Israeli judiciary system.
"There were Africans from the Ivory Coast, Ghana, Ethiopia and so on. The prison population in Israel is 90 percent black, which is why I was so welcomed by fellow inmates. There are thousands upon thousands of Africans inside the Israeli prisons.
Haunted by the conditions of the prison, he said: "I shared a seven foot by seven foot cell with 14 others. We were constantly being barked at and threatened with physical abuse. If you disobey, prisoners are stripped naked and put inside a hole with no lights or heating. We were seen as sub-human.
"In the corner of the room there was a white plastic bag full of single slices of bread, which was our breakfast, lunch and dinner. If we were lucky they occasional gave us a cup of yoghurt to share.
Quoting Martin Luther King, Blagrove stated: "An injustice anywhere is a threat to justice everywhere. I want people to realize that social injustice is an international struggle and one man's suffering in any region around the world cannot be ignored by others.
The filmmaker, who is currently make a documentary about African roots in Cuba, added: "The Israeli government has been very clever in stopping the truth being told about their regime because whenever anybody speaks out they are instantly labeled anti-Semitic and anti-Jewish.
"I am disturbed that the mainstream British media, and in particular the BBC, has chosen to ignore what is taking place in Israel.
"If we had been kidnapped by Iranians it would have been front page on every newspaper and David Milliband would have made a public statement including Gordon Brown and Barack Obama.
Evil doers never change. Mr. Blagrove it baffles me that you can be racist unto your own race, what you have committed is a taboo, by allowing yourself to be dragged into an anti-Semitic political prejudice, thus using you to insite the black people against the Jews. Oh I am sure you are looking at black Africans as a primitive and non- educated people who have no sense of reasoning. Therefore, cannot be able to burst your package of lies, cannot be able to figure out the fact that when one is arrested he/she is not given the duty of a receptionist to start counting the number of people arrested in one day. Mr. Blagrove, you came up with a figure of 500 people for the first day and 300 people for the second day, which means an average of 400 black Africans daily. This implies 12,000 monthly. you also mention that an inmate told you that the government is refusing to send them back to their respective Countries, have you taken pains to find out the financial cost of taking care of 12,000 inmates( i.e. only in the prison where you were detained). Mr. Blagrove you are a blatant liar and a disgrace to your race. You quoted Martin Luther King when you said "that injustice anywhere is a threat to justice every where", if I must be realistic with you I can no longer waste my time to analyse what you have done, but I want you to understand that you have sold yourself and betrayed your race. This is difficult to forgive for those who understood what you have done.
I wish to assure the Israeli and the Jewish community that Mr. Blagrove is blatant liar and he is only being used to insite the black Africans, unfortunately his propaganda report lacks conviction and intellectual ability to insite people therefore should be ignored.
It would appear that Mr Blagrove was correct given the interviews with prisoners and ex-prisoners in this weeks papers. How is it that you are so intent on shooting the messenger without researching YOUR facts. I suppose the others are all Liars to, or don't tell me, they're anti-semetic.
Any criticism of Israel brings out the zionist rottweillers in an attempt to dismiss and discredit any individual who dare expose the truth. Unfortunately for you the truth is beginning to be exposed. Keep up the good work Mr Blagrove.


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Powell, OH Real Estate
Nestled between the Scioto and Olentangy Rivers in Central Ohio lies the affluent city of Powell. With luxurious estates, plenty of green space, and a historic downtown, Powell is a desirable community located just outside of Columbus.
Powell is mostly comprised of upscale luxury neighborhoods, including The Retreat, The Chase, Loch Lomand, Chambers Glen, Ashmoore, Canterbury Estates, Golf Village, The Lakes of Silverleaf, Woods on Seldom Seen, and Sherbourne Mews. Homes for sale in Powell include a mix of styles, sizes and price points, but all enjoy the pristine setting this affluent city provides.
Lifestyle and Attractions
Powell is an affluent city boasting small-town charm just minutes from the conveniences of a bigger city. It serves as a bedroom community for Columbus, as Powell is situated approximately 17 miles from the heart of downtown. In fact, many residents of Powell work for companies located in Columbus or one of its suburbs. Powell has a notable historic central business district with a number of antique shops, restaurants, and other local establishments. The residents of Powell and city officials are focused on preserving the historic nature of the city. Therefore, Powell does not host any major industrial, financial, or technological businesses.
In adjoining Liberty Township lies the Columbus Zoo and Aquarium, the Zoombezi Bay waterpark, the O'Shaughnessy Dam, and the historic Olentangy Indian Caverns, providing plenty of entertainment and recreational options for residents of Powell. The city of Columbus hosts a myriad of arts and cultural venues, events, sporting games, and other attractions for Powell residents to enjoy as well. The community comes together with a number of annual events and festivals, including Candy by the Carload, a Memorial Day Parade, Powell Festival, and more.
Nearby Schools and Higher Education
Powell is served by the Olentangy Local School District, which includes 15 elementary schools, five middle schools, and four high schools. Additionally, Powell is home to the private Village Academy Schools, which has two campuses in Powell. Although there are no institutions of higher learning in Powell, residents may easily access the colleges and universities in Columbus, including The Ohio State University, Columbus State Community College, Capital University, Franklin University, and more.
The area now known as Powell was first settled around the year 1801, two years before Ohio became a state. It was originally called "Middlebury" because the first settlers arrived from the Middlebury, Connecticut area. In 1857, Judge Thomas Powell established a post office in the community, so the residents decided to name the town after him. The town experienced growth when the railroad was constructed through that area. Powell was officially incorporated as a municipality in 1947. The population remained low until the late 1980s, when residential development expanded from the Columbus metropolitan region. Over the span of 20 years, the population rose from less than 400 to over 6,000 people.
Powell, OH Homes For Sale
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1000 Retreat Lane
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Greenwich Welcomes Sydney Council Support for Business Vote Bill
Alex Greenwich, the Independent Member for Sydney, has welcomed the City of Sydney Council's resolution in support of moves to improve business voting in City of Sydney Local Government elections. The Lord Mayoral Minute is available HERE.
Mr Greenwich said:
"Businesses can already vote in City of Sydney elections but too few know their rights and the process can be complex and I welcome the council's committment to improve this" Mr Greenwich said.
"As a former CBD small business owner I understand the concerns of chambers of commerce that business should be more involved in local democracy and I have presented my proposal to encourage their vote to the Lord Mayor.
"My bill would make it easier for eligible businesses to get on the electoral roll," Mr Greenwich said.
Mr Greenwich said he will work with all councillors and members of parliament to progress the reform, despite Liberal Party councillors opposing the resolution tonight:
"I hope Liberal Party councillors will park their personality politics and work to improve the ease, permanency, and transparency of business voting in the City of Sydney"
Further information on the proposed legislation:
Mr Greenwich:
"The bill will establish a permanent business and ratepayers electoral register, which the electoral commission will use to create the business and ratepayers roll before an election.
"Businesses will be able to be included on the register at any time and the Electoral Commissioner will be compelled to run education programmes to inform business of their right to vote and contact all businesses to confirm their details on the register are up to date. This will ensure the electoral roll is accurate and guarantee the integrity of the election," Mr Greenwich said.
"I was alarmed by the Shooters and Fishers Party non-residential voting proposal based on the Melbourne City election model. The Shooters' proposal could easily be rorted by vested interests to dilute the vote of citizens and eligible businesses; allow people who have never lived in or visited Australia and overseas corporations a vote in local elections; and allow the council, not the independent electoral commissioner to manage the electoral roll.
"My proposal would ensure the independent Electoral Commission is responsible for the roll, keeping it at arms-length form any politically motivated council interference.
"My proposal improves the current system, is simple and inexpensive to implement, and would achieve the desired outcome of greater business participation in local democracy,"
Mr Greenwich will consult with the City's Chambers of Commerce and the City of Sydney Council before bringing the bill on for debate in NSW Parliament this year.


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Introduction of the Small Claims Track for Intellectual Property
October 2012 saw the introduction of the availability of a Small Claims Track for Intellectual Property cases in the Patents County Court, applying to cases where the value of the claim is £5,000 or less. This was the result of a combination of Lord Justice Jackson's drive to make otherwise costly litigation more accessible and the wish of HHJ Birss QC (the senior Judge of the Patents County Court) to make it easier for SME-sized businesses to enforce their Intellectual Property Rights (IPRs).
The new IP small-claims track in the PCC is available for claims involving copyright infringement, registered trade mark infringement, passing-off and unregistered design right, but is not available for claims involving patent infringement, registered design rights (both UK and Community rights) and more "specialist" IPR such as plant variety rights, where the evidential issues involved may be more complex.
It emulates many of the features of the existing civil Small Claims process, including a streamlined and more informal procedure, rules of evidence and approach to the final hearing, but the Judges will be Patents County Court judges, sitting in London, who are IP specialists and who, if the parties agree, may deal with matter purely "on paper" without a hearing. It should be noted, however, that the parties will still be expected to demonstrate that they have complied with the required pre-action behaviour in an attempt to avoid court altogether.
The remedies that will be available through this track are damages (or an account of profits) for past infringement, and a final injunction to prevent future infringement. Interim injunctions will not, however, be available through the PCC Small Claims track. However, with the general civil Small Claims threshold rising in April to £10,000 from £5,000 and with the likely costs of pursuing a claim through the Small Claims Route being considerably less than the fast or multi-track in the PCC or High Court, it may prove to be an attractive route for an SME client who recognises the value of their IPR, wants to get a final hearing and a final injunction as quickly and cheaply as possible, but only has a modest monetary claim (or indeed who is willing to limit their monetary claim to the Small Claims limit in order to benefit from the streamlined process).
As with the general Small Claims track, however, it should be noted that as a general rule, costs will not be recoverable against the "losing" party except for very limited fixed costs, court fees etc. Nonetheless, we have experience in the Small Claims Court where it has been possible to get an order for costs because of very unreasonable conduct by the other party in the conduct of the litigation, and there is no reason to think that this would not also be the case in the PCC, though such circumstances are certainly very rare.
As a general rule though, SMEs with a reasonably straightforward infringement claim in one of the IPRs covered by the new Small Claims track may also take the view that the considerably lower costs of Small Claims litigation, even if borne by themselves, would represent a worthwhile investment in securing a final order and (post April) damages of up to £10,000, particularly where the order itself serves as a "line in the sand" within their industry and enables them to publicise the fact that they do take action to protect their rights. Such "bragging rights" alone can have considerable value and "clout" in certain (especially brand-driven) sectors.
Andrew Digwood