text: Get Started Today! Choose the membership option that is best for you and begin transforming your life! Select Your Package:*Complete Package includes unlimited classes, use of equipment and a fitness coach. Premium Package includes Complete Package Services and ALL custom options.Complete 12 Months - $39/monthComplete 24 Months - $34/monthPremium 12 months - $79/monthCustomize Your Package Childcare - $15/month Unlimited Tanning - $15/month Prescription Weight loss - $25/month Accountability Meetings - $10/month Kids Fitness classes - $10/month Customize This Package Childcare - $45 Unlimited Tanning - $45 Prescription Weight loss - $75 Accountability Meetings - $30 Kids Fitness classes - $30 Total Fee: $0.00 Renewal Information*This membership will automatically renew itself on a month-to-month basis at the end of the term. You will be billed on the same date every month thereafter until you cancel your membership. In order to cancel, you must fill out the designated cancellation form at your enrollment location. Cancellations take 14 days to process. Check to confirm that you have read this Personal InformationMembership Initiation Fee*A one time payment in the amount of one month's payment will be charged to your account to initiate your membership. This does not apply to memberships that are paid in full. Check to confirm that you have read this Last Name*First Name*Birthdate* Age*Phone*Email* Current AddressStreet*City*State*Zip*How did you hear about usHow Did You Hear About Us?FriendInternet or Web searchGroupon/Living Social/Amazon Local/ Sweet JackHealth or Community FairOtherDrivers License NumberEmergency ContactContact Name*Relationship*Phone Number*Billing InformationI hereby authorize ASF International to debit my dues each month from the following account:Credit Card American ExpressDiscoverMasterCardVisa Card Number Month010203040506070809101112 Year20172018201920202021202220232024202520262027202820292030203120322033203420352036 Expiration Date Security Code Cardholder Name If electronic funds transfer is cancelled for any reason, a $5.00 monthly service charge will be added to monthly payment. View Terms In this agreement, the words you, your, and member refer to the person(s) named on the front of this document including Family Fun Plan members. The words we, our, us, Company and Club refer to J-Fitness, Inc. currently t/a Transformations Fitness for Women. MEMBERSHIP DESCRIPTION This membership entitles you to the access and use of our basic facilities, equipment, activities and services for the term specified on the front of this document. Specialized services, facilities, and activities can be used or joined upon payment of additional fees. After the specified term is fulfilled, this membership shall run continuously on a monthly basis until terminated as provided herein. RULES AND REGULATIONS You warrant and represent to us that you have no disability, impairment, illness, or contagious disease which may directly or indirectly cause injury to your health, safety, or physical condition, or that of other Members while participating in any exercise, activity, or program of the Club. This Company represents that its personnel have no expertise in diagnosing, examining or treating medical conditions of any kind or in determining the effect of any specific exercise or said medical conditions. By signing this agreement, you fully understand that there is possibility of accidental or other physical injury. You also agree to assume all risk of any and all injury, illness or condition arising from the use of Club facilities, instruction or programs and further agree to indemnify the Company, its employees and agents from any equipment breakage and injury, illness or condition arising from the use of Club facilities, instructions, or programs. You agree to abide by all rules and regulations of the Club, which may be posted at the Club and/or issued orally by an authorized representative of the Club. These rules may be amended and issued from time to time at our sole discretion. We reserve the right in the management of our facility to eliminate, alter or add any piece of equipment, fixture, leasehold, or furniture when deemed necessary. We also reserve the right to relocate our facility within a reasonable distance and continue to enforce this Agreement. TERMINATION POLICY We reserve the right to terminate or suspend your membership, in whole or in part, at our sole discretion for violation of the terms of this Agreement or the Club Rules and Regulations. Memberships with a one, two or three year commitment may only be terminated prematurely by you if: 1) you relocate more than 25 miles from any of our clubs to a new permanent residence and can provide written documentation of this relocation to the Club and/or 2) you have a doctor-certified permanent injury or medical condition that prohibits all physical activity. Termination requests must be submitted in writing and delivered to the Club in person or by certified mail at least 14 days prior to your designated billing date. After the membership term is completely fulfilled, you may terminate your membership at any time by signing a cancellation form at your enrollment location 14 days prior to your designated billing date. CHILDCARE / TANNING SERVICES It is expressly agreed that use of our childcare and/or tanning service is undertaken at your sole risk and the Company shall not be liable for any claims, demands, injuries, damages, actions, or causes of action arising out of or connected with this service. NOTICE OF CONSUMER RIGHTS Health Club # E3151 If facility is closed for a month or more, you are entitled to an extension of the membership term or a pro-rated refund, except if the closing is not the fault of the facility, in which case the choice of remedy is the Company's. If you become disabled for at least three months during the membership term and that disability is confirmed in writing by a physician, you have the right to extend your membership term. This facility does not collect more than three monthly payments in advance or more than a $200 initiation fee. Therefore, is bond exempt. In the event the facility would collect more than three monthly payments in advance, a bond will immediately be posted with the Office of Attorney General for the amount of the total consumer liability. You have the right to cancel a contract of health club services and receive a full refund only within 3 business days from the date of enrollment and receipt of a copy of this Agreement. Saturday is considered a business day. All cancellations must be submitted in writing and delivered by certified mail to 2288 Bluewater Boulevard Suite 440, Odenton, MD 21113. Cancellation is your sole responsibility. MISCELLANEOUS INFORMATION This Agreement also authorizes ASF(American Services Finance) to debit such bank or credit card account each month until this Agreement is terminated by you as provided herein. You further authorize ASF to adjust the amount of monthly dues debited from your account to correspond to the terms outlined in this Agreement, should such Agreement call for variations in your payment amount. Additional fees will be charged for NSF checks or declined credit card charges. Should you default on any monthly installments, the entire remaining past due sum due hereunder shall immediately be due and payable at the option of the Company and shall bear interest at the rate of 18% per annum from date of default. If any installment is more than ten days past due, a late charge of 5% may be assessed. The undersigned personally charge their separate estates with the payment of this note. It is understood that you have signed a contract/note that may be purchased by ASF. Failure to attend regularly and utilize facilities does not relieve your obligation, regardless of the circumstances, to pay the installment note in full. It is also understood that except as herein provided this membership is absolutely non-cancellable. Should you default, you agree to pay all costs of collection, court costs and reasonable attorney fees. This membership Agreement is assignable to any successor or assignee at the Company's discretion. Any holder of this consumer credit contract is subject to all claims and defenses which the debtor could assert against the Company pursuant hereto or with the proceeds hereof. Recovery hereunder by the debtor shall not exceed amounts paid by the debtor hereunder. PhoneThis field is for validation purposes and should be left unchanged.


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Pottery Barn Manhattan Leather Armchair
A man needs a proper chair – a place where he can sit, relax and enjoy a drink, book, music or movie without disturbance or nag. Forget the couch or that tattered cloth beast sitting in the corner of your living room, this chair is throne befitting for your posterior.
The Manhattan Armchair from Pottery Barn really is a classic. It's quintessential club chair look features top-grain leather, lush curves and thick padding to make it exceptionally comfortable. It now comes in a bevy of colors including Whiskey, Espresso, Cherry Red, Toffee, Hazelnut or Cinnamon. Definitely go with hazelnut (shown here), it'll age better than any scotch you've ever purchased. Of course, that's probably due to the extra pigment PB puts into this particular color of leather.
What this means to you: There's a reason why kings have thrones.
Cost: $1399 @ Pottery Barn

subset: commoncrawl


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All reviews seem negative
I bought a battery that turned out to be bad from this Midas, but my complaint is how I was treated trying to get compensated for the inconvenience.
I ended up stranded on a hi...
Well-known chain offers maintenance and repair for cars and trucks including brakes, oil changes, batteries, exhaust, climate control, radiator flushes and more.
From family friendly trips with kid friendly activities to local plumbers lawyers, spas, and contractors. Judy's Book has millions of listings and reviews for the best and not so great. Whether you're looking for a specific business or just trying to discover great places we make it easy. We're a family oriented site focusing on bringing trusted reviews and recommendations to moms and others. Green and Sustainable places are becoming more relevant to Judy's Book users, have a favorite place? Write a review and tell users why it's Green!


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The small armchair Liza by Studio Lievore, Altherr and Molina represents the topical response to the dynamic uses at home and in the contract market. Comfortable and cozy, with injection-mould, is available with a black or white polypropylene frame, equipped with a padded seat cushion or fully covered with a tailoring care in various fabrics and leathers. The designers explain: "Liza was designed to be a versatile seat, under the formal and construction viewpoints, offered in a wide range of bases and finishes. The polypropylene structural sling comes in two-tone scratch-resistant finishes: white or black, or covered in various fabrics of the collection. Bases can be in aluminum, wood or in painted steel." The four bases include: legs in solid oak or Canaletto walnut, natural painted; legs in chromium-plated or painted steel – featuring a special cone- shaped tubular section reminding the racing bikes; or a swivel base with four or five spokes in die-cast aluminum alloy on feet or on castors. "The timeless style, the shape and comfort are the Liza's contributions in any environments it is proposed for." The sling features armrests made of polypropylene reinforced with glass fibre, in the shades black or white, seat cushion upholstered with self-extinguishing polyurethane foam and removable cover in fabric or leather; the backrest removable cover in fabric or leather is coupled with Dacron Du Pont.
z for Zanotta - the company entering the domestic universe with ironical products, suggesting different ways to feel better at home. The first one to include in its catalogue works by the great masters of design, creating a peerless "collection" of masterpieces, that were awarded and exposed in the most important design museums.


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Brian Murphy was one Maryland Republican who said he didn't pay much attention to former Gov. Robert Ehrlich's official gubernatorial campaign announcement Wednesday in Rockville.
Murphy was busy doing campaigning of his own, because he's hoping to beat Ehrlich in the Republican primary for the chance to take on Democratic Gov. Martin O'Malley in the general election.
Murphy described himself as a "finance guy" Thursday at a Maryland GOP town hall meeting at the Leisure World retirement community in Silver Spring.
"Ronald Reagan was once a Democrat, we all know this. I was once a Democrat. I was a blue-dog, fiscal conservative Democrat. But the modern Democrat Party are people who are big-hearted and generous with other people's money and, frankly, bad at math," said Murphy.
He positioned himself as a moderate, dollars-and-cents type of Republican as he spoke to the group of about 50 senior citizens, but in an interview after his speech, Murphy turned his fire on Ehrlich.
"The numbers tell the truth. Ehrlich grew the government more than O'Malley did. And that's not what Maryland blue-dog Democrats cross for," Murphy said.
Murphy said Maryland needs a fiscal conservative to restore balance to Annapolis, and Ehrlich has already proven that he doesn't fit the bill.
"If he did it when he was the governor, frankly, he might still be governor," said Murphy. "He was a better governor than O'Malley, but that's a pretty low bar."
Murphy said he has a better chance than Ehrlich of getting moderate Democrats and independents to swing Republican, which is always important in a heavily Democratic state like Maryland.
A resident of Chevy Chase who grew up on the Eastern Shore, Murphy has an MBA in finance from the University of Pennsylvania's Wharton School and is the founder of the Plimhimmon Group investment firm.
The day before Ehrlich's long-awaited announcement, Murphy made some noise by winning the endorsement of former state GOP chairman Jim Pelura, who resigned the post in November after a rash of party infighting.
This year's primary election is scheduled for Sept. 14.
–By Capital News Service's Graham Moomaw


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Wednesday, December 23, 2015
The Annual Christmas Bird Count
With the craft show season in full swing, I was never able to take part in the Annual Christmas Bird Count which is often the Saturday right around Christmas. But, alas, this year I was able to participate and in a very big way. I had the great fortune to be invited onto a team along with two birders who work within the field of environmental management. The major catch was I had to prove my ability to endure a very long day of walking on a variety of terrain with degrees of weed-i-ness and wood-i-ness. Well, I did keep up and it was well worth it. We counted 44 species which included 3 bald eagles and a peregrine falcon playing tag with a turkey vulture. Oddly, many of the most common species we did not encounter until later in the day...we started at 8 am and did not see a blue jay until almost 4 pm!! So happy to finally be able to do this! These drawings are from my Dirty Birds series.
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- Please select a date to see the proper prices!
Description of the accommodation:
Rooms, services Just planning a trip to Greece? We suggest you check the options provided by Miramare Hotel Hersonissos. The hotel is offering a tastefully furnished room to those seeking accommodation in Hersonissos. If necessary, parking is available nearby. The fans of actively spent leisure time may take the nearby opportunities to rent a boat. The local café or the bar will provide an ideal location for personal meetings and nice evening chats. You may secure your valuables in the safe. An exact and detailed list of equipment in the rooms and of the services provided by Miramare Hotel Hersonissos you will find on the information sheet below, including any applicable additional fees.
Payment Advance payment by credit card or providing credit card guarantee may be necessary for finalizing the reservation, depending on the chosen date, room and price.
Arrival, opening hours The earliest check-in time is 14:00, the latest check-out time is 12:00. The personnel can communicate with you in the following languages: Greek and English.
Miramare Hotel Hersonissos rooms Rooms
- Please select a date to see the proper prices!
Accommodation services
Boat rental nearby
- Pool (Outdoor - seasonally open)
Bar, Cafe, Elevator, Safe deposit box


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Owned since new?
Owned for how long?
2 year(s)
Buy this make again?
Price and equipment8.0/10
Good value for money.
Under the bonnet8.0/10
How it drives8.0/10
Excellent driving especially the cruise control.
Comfort and practicality8.0/10
Servicing and running costs8.0/10
Very fuel efficient even in cruise control.
Safety and security8.0/10
Quality and reliability8.0/10
Excellent even on long trips.
Overall verdict10.0/10
Best value you could buy for small family car. Excellent to drive and fuel efficiency is excellent. I would recommend this before I would recommend a Ford or Holden car for the family. We are very happy with the car overall. Best value for money we have had in years. It is great for long trips and like the way that it has performed overall. Excellent, A+!


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Stock Graphic >> Icon - Vector stylized fruit icons 5932 by VЁЄtek Prchal @ CreativeMarket
File Size: 306.02 KB; Vector: Yes.
Stylized colorfully fruit icons. Sizable and editable vector illustration
100% vector - one .eps10 file.
Keywords: icon, symbol, sign, fruit, stylized, minimalistic, sharp, vector, food, eat, health, style, design, lifestyle, pictogram, apple, cherry, pear, information, education.


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We have a large range of staircases from some of the leading manufacturers in the UK including spiral staircases, stair components and fire escapes. The DDA (Disability Discrimination Act) requires that buildings are accessible and we have a large range of lifts that will help you meet these requirements.
But entrances and stairways can also make an important statement about a building, from domestic developments to corporate headquarters, and there are now products available to suit every requirement. The Building Product Directory features every system and solution you could need.
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Death notices for May 21, 2010
Gazette Staff
Friday, May 21, 2010
Wendell G. Cassity, 86, Janesville, died Thursday at home. Services will be at 11 a.m. Monday at First Presbyterian Church, Janesville. Visitation will be from 2 to 4 p.m. Sunday at Henke-Clarson Funeral Home, Janesville, and from 10 a.m. until the time of services Monday at the church.
Steve Gestrich, 84, Beloit, died Thursday at home. Services will be at 10:30 a.m. Monday at St. Augustine Catholic Church, Footville. Visitation will be from 3 to 6 p.m. Sunday and from 9:30 a.m. until the time of services Monday at the church. Hansen-Gravitt Funeral Home, Beloit, is assisting the family.
Sophie K. Hachtel, 101, Middleton, died Monday at Sterling House, Middleton. Arrangements are pending with Brian Hansen Funeral Service, Janesville.
Helen M. Pogorelski, 87, Milton, died Thursday at Mercy Hospital, Janesville. Services will be at 1 p.m. Monday at Whitcomb-Lynch-Albrecht Funeral Home, Milton. Visitation will be from 2 to 5 p.m. Sunday and from noon until the time of services Monday at the funeral home.
Katherine B. "Kate" Schumacher, 79, Janesville, died Thursday at her daughter�s home. Private family services will be held. Whitcomb-Lynch-Albrecht Funeral Home, Janesville, is assisting the family.
Last updated: 3:41 pm Wednesday, December 19, 2012


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Call us on
0370 1500 100
The conference will look at how successful teams have re-enabled rehabilitation in the community within the NHS, working in a joined up way in the healthcare network, not by isolation, but through collaboration. We will also take a look at recently published research in disabled people returning to work and how the gaps in rehabilitation in the community can be achieved to deliver reliable care.
Speakers include leading NHS rehabilitation professionals, NHS England and published research professionals.
We are proud that Hannah Cockroft MBE will be launching the conference for us. Hannah is an Irwin Mitchell sponsored paralympic wheelchair racer who won two gold medals at the London 2012 Paralympic Games and will be competing at the 2015 IPC World Athletics Championships in Doha in October.
Hannah, who was left with disabilities after suffering two cardiac arrests shortly after her birth, says:
"Disability sport is currently more popular than ever and hopefully if I keep doing what I'm doing I can be a role model for people who might be struggling to understand what their aims and ambitions should be."
To view the agenda for the day, please click here.
We would love to hear your thoughts surrounding rehabilitation in the community and as such, would be grateful if you could complete our short survey for Monday 16 November.
Places are limited so please email Amy Randall if you would like to attend.
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For more information about the merger, please visit the About Us page.


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Boston Acoustics TVee 10
Part Number: TVEE 10
Pricing is currently unavailable.
Visit the manufacturer's web site to view their availability. The price is not yet available.* Product and pricing data are sourced from third parties for informational purposes only. We strive to provide correct information, but are not responsible for inaccuracies. Should you find any errors, please help us by reporting it here.


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Although outcomes for patients with multiple myeloma (MM) have improved over the past decade, the disease remains incurable and even patients who respond well to induction therapy ultimately relapse and require additional treatment. Conventional chemotherapy and high-dose therapy with stem cell transplantation (SCT) have historically been utilized in the management of relapsed MM, but in recent years the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, as well as the proteasome inhibitor bortezomib, have assumed a primary role in this setting. This review focuses on the role of thalidomide, lenalidomide and bortezomib in relapsed and refractory MM, with additional discussion dedicated to emerging drugs in relapsed MM that may prove beneficial to patients with this disease.
Although patients with multiple myeloma (MM) often respond to initial therapy, the disease ultimately recurs and over the course of time becomes refractory to further treatment. Historically, conventional or high-dose therapy has been used in relapsed MM. Conventional chemotherapeutic regimens used in this context have included high-dose dexamethasone;1,2 vincristine, doxorubicin and dexamethasone;3–7 vincristine, melphalan, cyclophosphamide, prednisone/vincristine, carmustine, doxorubicin and prednisone;8 and doxorubicin, vincristine, dexamethasone, etoposide and cyclophosphamide.9 The use of high-dose melphalan in relapsed MM, meanwhile, was introduced over 20 years ago by Barlogie et al.10,11, who showed that myeloablative doses of melphalan with stem cell support could overcome resistance to conventional-dose chemotherapy in this group of patients.
The emergence of the immunomodulatory drugs thalidomide and lenalidomide, as well as the proteasome inhibitor bortezomib has changed the therapeutic landscape for relapsed MM. The ability of these agents to overcome drug resistance was shown in preclinical models and confirmed in the context of clinical trials, leading to FDA-approval of thalidomide, lenalidomide and bortezomib in the treatment of relapsed MM. This review focuses on the role of these agents in relapsed MM and also discusses emerging drugs that have yielded promising results in early-phase clinical trials involving patients with relapsed MM.
At the onset of this discussion, it is emphasized that definitions of relapsed and refractory MM are understood in the broader context of disease progression. Relapse from a complete response (CR) is defined as reappearance of the serum or urinary paraprotein, ≥5% bone marrow plasma cells, new lytic bone lesions/soft-tissue plasmacytomas, an increase in the size of residual bone lesions and/or development of hypercalcemia (corrected serum calcium>11.5 mg per 100 ml) not attributable to another cause.12 Criteria for progressive disease when a CR has not been achieved include new or expanding bone lesions, hypercalcemia and a >25% increase in either serum monoclonal paraprotein concentration, 24 h urinary light-chain excretion, or plasma cells within a bone marrow. Relapsed MM refers to a scenario wherein a patient treated to the point of maximal response experiences progressive disease, whereas refractory MM refers to one in which a patient is either unresponsive to current therapy or progresses within 60 days of last treatment. Meanwhile, relapsed and refractory MM describes an individual who previously achieved at least a minimal response (MR), experiences progressive disease, receives salvage therapy and is either unresponsive to salvage therapy or progresses within 60 days of last treatment.
The antiangiogenic properties of thalidomide13 initially led to the consideration of its use in MM based on the premise that myeloma is associated with both elevated levels of circulating angiogenic cytokines such as vascular endothelial growth factor and increased bone marrow vascularization.14,15 A more detailed understanding of the relationship between MM cells and the bone marrow microenvironment has highlighted other more important biological properties of thalidomide that contribute to its anti-MM activity.16 In addition to its angiogenic activity, thalidomide enhances T-cell- and NK-cell-mediated immunological responses, induces caspase-8 mediated apoptosis, downregulates IL-6 production within the bone marrow microenvironment and sensitizes MM cells to other agents used in treatment of the disease17–19 Selected clinical trials involving thalidomide in relapsed MM are summarized in Table 1.
The clinical activity of thalidomide was highlighted by a phase II trial in which 84 individuals with relapsed and refractory MM received single-agent thalidomide at doses ranging from 200 to 800 mg/day.20 In this heavily pre-treated group, the overall response (OR) rate was 32%. The 2-year event-free survival (EFS) and OS were 20 and 48%, respectively,21 with 10-year EFS and OS rates of 6 and 10%.22 Lambda light-chain isotype and the presence of chromosomal abnormalities were identified through multivariate analysis of pre-treatment characteristics as predictors of less favorable outcome in this trial.22 The results of this study have been confirmed by several other clinical trials of single-agent thalidomide in MM wherein response rates ranged from 14 to 48%.23–30 Based on a systemic review of phase II trials involving 1674 patients with relapsed or refractory MM, the OR rate associated with single-agent thalidomide therapy is 29% and the median OS 14 months.31 Grade 3/4 somnolence and constipation occurred in 11 of 16% of patients in these trials, respectively, with peripheral neuropathy (PN) both cumulative and dose-limiting.
Because these trials used different doses of thalidomide, a uniform treatment dose has not been established. However, insight regarding the issue of dosage can be derived from a study by Yakoub-Agha et al. in which patients were randomized to 100 or 400 mg/day thalidomide, with the addition of dexamethasone after 3 months if no response was achieved with single-agent thalidomide.32 Although patients who received 100 mg/day more frequently required dexamethasone, the 1-year survival rate associated with the two treatment arms was equivalent. Furthermore, individuals who received 100 mg/day tolerated therapy better, with fewer instances of high-grade treatment-related side effects. The rate of deep venous thrombosis (DVT) was similar in the two treatment arms. On the basis of these results, lower doses of thalidomide are preferred, particularly for individuals who may poorly tolerate thalidomide-related side effects, such as the elderly and those with pre-existing PN.
Preclinical investigation showed that thalidomide enhances the anti-MM effect of dexamethasone.17 This observation was followed by results from several phase II studies showing the clinical activity of the combination.33–35 In one study, 44 patients with refractory MM (77% resistant to dexamethasone based therapy and 32% previously treated with HDT) received thalidomide 200 mg/day with dose escalation to 400 mg/day along with pulsed dexamethasone.33 The combination produced a partial response (PR) rate of 55%, with comparable activity among patients resistant to previous dexamethasone-based therapy and those who were not. Responses tended to be rapid, with a median time to response of 1.3 months. The efficacy of low-dose thalidomide (100 mg/day) plus pulsed dexamethasone was evaluated in 77 patients with relapsed or refractory MM.35 In this trial, a 41% OR rate was noted. Thalidomide plus dexamethasone have also proven to be effective as salvage therapy in patients who relapse following autologous stem cell transplantation (SCT). In a retrospective comparison, thalidomide plus dexamethasone produced superior PFS and OS in comparison with conventional chemotherapy and a second autologous SCT among patients who relapsed following autologous SCT.36
Thalidomide has also been used in combination with other chemotherapeutic agents in the management of relapsed and refractory MM. In a trial involving 236 individuals with relapsed MM, 63% of whom had progressed on standard chemotherapy and 23% of whom had chromosome 13 abnormalities, a regimen of dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide produced an OR rate of 32%, with comparable response rates among patients with and without chromosome 13 abnormalities.37 Neutropenic fever occurred in 12% of patients, and venous thromboembolic (VTE) disease in 15%. Thalidomide is also active in combination with liposomal doxorubicin. Specifically, thalidomide, liposomal doxorubicin and dexamethasone led to an OR rate of 76% and CR rate of 26% in a study involving 50 patients with advanced MM, 40% of whom had previously received HDT and 54% of whom had received more than two lines of previous therapy.38 VTE disease occurred in 12% of study participants, with severe infection in 15%. An oral regimen of thalidomide, cyclophosphamide and dexamethasone has also proven to be both well tolerated and active, with the OR rate ranging from 57 to 79% in these studies.39–41
Owing to the association between thalidomide and severe birth defects noted in the 1960s, access to the compound is restricted to individuals who participate in the System for Thalidomide Education and Prescription Safety Program, which was developed and implemented by the drug's manufacturer, Celgene Corporation (Summit, NJ, USA). VTE is an important thalidomide-related toxicity in MM, particularly when the compound is administered in conjunction with dexamethasone or chemotherapy. The incidence of thromboembolic events in clinical trials of MM patients receiving thalidomide plus dexamethasone and/or chemotherapy is 3–34% among individuals with newly diagnosed disease and 2–15% among those with relapsed/refractory disease.42 A dose and time-dependent PN can also occur in association with thalidomide and is believed to be the result of axonal injury with progressive loss of large-diameter myelinated fibers.43,44 Other side effects associated with thalidomide include bradycardia, hypothyroidism, hepatotoxicity and skin reactions ranging from mild muculo-papular rash to Stevens Johnson syndrome.
Lenalidomide is a thalidomide analog in which the structural backbone of its parent compound has been modified through elimination of a carbonyl group and addition of an amine. Although the initial intent of these modifications was to more effectively inhibit TNF-α, other mechanisms underlying the anti-MM effect of lenalidomide have been identified, including modulation of the immune response, inhibition of angiogenesis, induction of apoptosis, decreased binding of MM cells to the endogenous bone marrow stromal cells and modulation of cytokines in the bone marrow.18,19,45–47 Selected clinical trials involving lenalidomide in relapsed MM are summarized in Table 2.
The first clinical study of lenalidomide in MM was a phase I study in which 27 patients with relapsed and refractory MM (median of three previous regimens) received escalating doses of lenalidomide ranging from 5–50 mg/day.48 All 13 patients who received the 50 mg/day dose developed grade 3 myelosuppression after the first cycle, whereas the 25 mg/day dose was well tolerated in 12 patients and was therefore selected as the optimal dose for a subsequent phase II study. A response rate of 70% (minimal response (MR) or better) was observed, suggesting significant anti-MM activity. In a subsequent multicenter phase II study, 70 patients with relapsed and/or refractory disease were randomized to receive either 30 mg once-daily or 15 mg twice-daily oral lenalidomide for 21 days of every 28-day cycle to better define dose and schedule.49 The 15 mg twice-daily dose was associated with increased grade 3/4 myelosuppression compared with daily dosing. The OR rate to lenalidomide monotherapy was 25% with a median OS of 28 months in the 30 mg once-daily group.49 Importantly, non-hematological toxicity was minimal, with DVT occurring in 3% and significant PN in 2% of the study participants. The addition of dexamethasone was associated with increased response in 29% of the study participants.
The favorable side effect profile and efficacy of lenalidomide led to two large, randomized, multicenter, double-blind, placebo-controlled studies in patients with relapsed or refractory MM—the MM-009 North American trial and the MM-010 European/Israeli/Australian trial.50,51 In both studies, patients were randomly assigned to receive 25 mg of oral lenalidomide or placebo on days 1–21 of a 28-day cycle. All patients received dexamethasone on days 1–4, 9–12 and 17–20 for the first four cycles and subsequently, after the fourth cycle, only on days 1–4. The median time to progression (TTP) was significantly longer in the lenalidomide/dexamethasone combination (MM-009: 11.1 months; MM-010: 11.3 months) compared with placebo/dexamethasone (4.7 months in both trials). Similar superiority was seen for the lenalidomide/dexamethasone combination in terms of OR (MM-009: 61%; MM-010: 60.2%) compared with placebo/dexamethasone (MM-009: 19.9%; MM-010: 24%).
Lenalidomide has also been used in conjunction with both alkylating agents and anthracyclines in the treatment of relapsed/refractory MM. In a phase II study involving 21 patients with relapsed/refractory disease, lenalidomide (25 mg, days 1–21), cyclophosphamide (500 mg, days 1, 8, 15 and 21) and dexamethasone (40 mg, days 1–4, 12–15) produced an OR rate of 65%, including a CR in 5% and very good partial response (VGPR) in 15%.52 The combination of lenalidomide, doxorubicin and dexamethasone, meanwhile, was evaluated in a recently published study involving 69 individuals with relapsed and refractory MM.53 In this extensively pre-treated group of patients, the regimen produced an OR rate of 73%. At the highest dose level (lenalidomide 25 mg, days 1–21/28-day cycle; doxorubicin 9 mg/m2 days 1–4; and dexamethasone 40 mg days 1–4 and 17– 20), the OR rate was 77% and the rate of VGPR or better, 74%. The median TTP in the study was 45 weeks. Deletion 17p and an elevated β2-microglobulin were associated with inferior response rate and shorter TTP.
Unlike thalidomide, lenalidomide is rarely associated with PN. Myelosuppression was the most common high-grade toxicity in phase III trials of lenalidomide.50,51 Neutropenia was the most frequent manifestation of myelosuppression in these studies. Single-agent lenalidomide has not been associated with an increased risk of VTE.48 In phase III trials, lenalidomide plus dexamethasone was associated with VTE in 15 and 8.5% of patients compared with rates of 3.5 and 4.5% with dexamethasone alone.50,51 Rash occurs in approximately 30% of patients who receive lenalidomide.54 The teratogenic effects of lenalidomide in humans are unknown, but based on the teratogenicity of thalidomide, access to the compound is restricted to individuals who participate in the RevAssist program. Administered by the drug's manufacturer, Celgene, the RevAssist program was designed to prevent fetal exposure to lenalidomide and thus minimize the risk of birth defects associated with the drug. During the first year of lenalidomide's availability in the United States, 15 584 patients registered in the RevAssist program and there were no pregnancies in female patients or female partners of male patients.55 Other important side effects include fatigue myalgia, and diarrhea.
Bortezomib is a first-in-class boronic acid dipeptide small molecule that reversibly inhibits the proteasome. By regulating protein degradation, the proteasome has a critical role in such diverse processes as cell cycle regulation and antigen processing. Protein degradation occurs through a 2-step process in which proteins destined for removal first undergo ATP-dependent ubiquitination followed by a second step of proteolysis within the proteasome.56 Proteolysis takes place within the 20S subunit of the proteasome, which possesses chymotryptic-like, tryptic-like and post-glutamyl peptide hydrolyzing activity. Bortezomib specifically blocks the chymotryptic-like activity of the 20S subunit. Accumulation of undegraded proteins interferes with processes required for MM cell survival such as tumor-stromal cell adhesion, cytokine production and angiogenesis, thus leading to tumor cell death.57 Selected clinical trials involving bortezomib in relapsed MM are summarized in Table 3.
Initial evidence of bortezomib's clinical activity in MM came from a phase I trial of patients with refractory hematological malignancies.58 A CR was achieved by one of nine MM patients in this study, whereas a reduction in either serum M-protein or marrow plasma cell content occurred in the other eight patients. Two phase II trials followed, the Study of Uncontrolled Myeloma Management with proteasome Inhibition Therapy (SUMMIT) and Clinical Response and the Efficacy Study of bortezomib in the Treatment of refractory myeloma (CREST) trials. In SUMMIT, 202 patients with relapsed and/or refractory MM received bortezomib 1.3 mg/m2 twice weekly for 2 weeks followed by 1 week without treatment, with the addition of dexamethasone after two cycles for progressive disease or after four cycles for patients with stable disease.59 The OR rate was 35%, with a 10% rate of complete or near complete response (CR/nCR) and an encouraging median OS of 16 months. In the 54-patient CREST study, bortezomib was administered at a dose of 1.0 or 1.3 mg/m2 twice weekly for 2 weeks of each 3-week cycle as in SUMMIT, with addition of dexamethasone for progressive or stable disease after two or four cycles, respectively.60 The OR rate was 30 and 38% in the 1.0 and 1.3 mg/m2 treatment groups, with durable responses observed as in SUMMIT. A subset analysis of SUMMIT and CREST underscored the ability of bortezomib to overcome poor prognosis conferred in MM by chromosome 13 deletion (del(13)), as bortezomib produced comparable response rates and survival among patients with and without del(13) by metaphase cytogenetics.61 This finding has been supported by other studies showing that response to bortezomib in patients with relapsed and/or refractory MM is independent of chromosomal abnormalities such as del(13) and t(4;14).62,63 It is interesting to note that the number and type of previous therapy, performance status, β2 microglobulin and other adverse prognostic factors were not shown to adversely affect a response in another subset analysis.64
These results were confirmed in the international, multicenter phase III Assessment of Proteasome Inhibition for EXtending remissions trial, in which 669 patients, more than 50% of whom had undergone two or more previous lines of therapy, were randomized to either bortezomib or high-dose dexamethasone.65 The OR rate among individuals in the bortezomib group was 38%, with a CR rate of 6%, whereas the OR and CR rates in the dexamethasone group were 18 and 1%, respectively. Superior median TTP (6.22 versus 3.49 months) and 1-year OS (80 versus 66%) were observed in the bortezomib as compared with dexamethasone-treated patients. Important grade 3/4 treatment-related toxicities included anemia (10%), neutropenia (14%), thrombocytopenia (26%), fatigue, diarrhea (7%) and PN (7%). In an updated analysis, the OR and CR rates in the bortezomib arm were 43 and 9%, respectively.66 The median survival for bortezomib-treated patients in this analysis was 29.8 versus 23.7 months in the dexamethasone group. Results of a multicenter phase IIIb study involving 638 patients who received bortezomib for relapsed or refractory disease were also recently published.67 Study participants received dexamethasone for progressive disease after at least two cycles and for stable disease after at least four cycles. The OR rate was 67%, with 11% of patients achieving a CR and 22% a VGPR.
Synergy between bortezomib and dexamethasone observed in preclinical analysis68 supported the use of this combination for patients in the SUMMIT and CREST trials with stable or progressive disease after several cycles of bortezomib monotherapy. In the SUMMIT trial, 13 (18%) of 78 bortezomib-treated patients with stable or progressive disease achieved a minimal or partial response with the combination.59 In the CREST trials, meanwhile, the OR rate among patients who received the combination was 50%.60
Preclinical studies also showed the potent sensitizing effect of bortezomib on other classes of drugs including alkylating agents and anthracyclines69,70 and provided rationale for additional bortezomib-containing combinations in the treatment of relapsed and/or refractory MM. Several trials have evaluated bortezomib-based combinations containing liposomal doxorubicin or doxorubicin.38,71–73 In a phase I trial involving 42 patients with advanced hematologic malignancies, significant anti-MM activity was observed.72 Among 22 study participants with MM, including 13 who had received previous anthracycline therapy, eight (36%) patients achieved a CR or nCR and eight (36%) individuals a PR. Bortezomib plus liposomal doxorubicin was subsequently compared with bortezomib alone in a randomized, phase III trial involving 646 with relapsed and/or refractory disease, 66% of whom had received two or more previous lines of therapy and 9% of whom had progressed on treatment preceding enrollment.73 Although the OR rate (CR+PR) in the two treatment arms was equivalent, bortezomib plus liposomal doxorubicin produced a superior median TTP (9.3 versus 6.5 months) and 15-month OS (76 versus 65%). Combination therapy was more effective than bortezomib monotherapy even in patients with advanced ISS stage, previous thalidomide exposure and multiple previous lines of therapy. Grade 3/4 drug-related adverse events were more common with combination therapy, particularly gastrointestinal symptoms (anorexia, vomiting), neutropenia and hand–foot syndrome. However, cardiac toxicity was only minimally increased with the doublet and rates of PN were similar in both arms.
The combination of bortezomib, doxorubicin and dexamethasone (PAD) has been evaluated in a study involving 64 patients with relapsed and/or refractory MM.74 Fifty-eight percent had previously undergone autologous SCT, 70% prior anthracycline therapy and 27% prior bortezomib treatment. In this heavily pretreated group, PAD produced a PR or better in 67% of patients and a VGPR in 25%. Common grade III–IV toxicities included thrombocytopenia, neutropenia, anemia and PN.
Frequently observed toxicities associated with bortezomib-based therapy in patients with relapsed and/or refractory MM include PN, thrombocytopenia and gastrointestinal dysfunction. Of the 256 patients enrolled in the SUMMIT and CREST trials, 90 (35%) developed treatment-emergent PN or exacerbation of pre-existing neuropathy.75 One or more courses of bortezomib was withheld as a result of therapy-related neuropathy in 19/90 (21%) of individuals. The incidence of PN was dose related, being more frequent with a dose of 1.3 versus 1.0 mg/m2 and peaked at cycle 5 (cumulative dose~30 mg/m2). Higher-grade PN, meanwhile, was more frequent in patients with pre-existing PN. Importantly, PN associated with bortezomib is reversible in most cases with treatment interruption and/or dose modification.75,76 A symptom-based dose modification algorithm used in the SUMMIT and CREST trials and validated in Assessment of Proteasome Inhibition for EXtending remissions can be followed to prevent development of this therapy-related adverse event.
Thrombocytopenia occurring as a consequence of bortezomib therapy typically follows a cyclical, biphasic pattern with a predictable decline in the platelet count during the 2-week treatment period followed by platelet recovery during the rest period.77 Although grade 3/4 thrombocytopenia occurred in 30% of study participants overall, it was uncommon in patients with a baseline platelet count of >200×109/l and was not associated with significant bleeding.
There was a higher incidence of herpes zoster reactivation in the Assessment of Proteasome Inhibition for EXtending remissions trial among patients who received bortezomib than among those in the dexamethasone arm (13 versus 5%).65 The majority of these infections were grade I/II in severity and the incidence of higher-grade herpes zoster infections was similar in the two arms.78 As a result of this observation and others, viral prophylaxis is strongly recommended for patients receiving bortezomib-based therapy.
Bortezomib has been safely used in MM patients with advanced renal failure, including those undergoing dialysis. A retrospective analysis of MM patients with advanced renal disease who underwent dialysis at the time of bortezomib-based therapy showed an overall CR rate of 75% and a CR/nCR rate of 30%.79 The incidence of significant treatment-related toxicities such as PN, thrombocytopenia and infection was similar to that observed in previous studies among patients without renal dysfunction, an observation confirmed in subsequent studies.80
Finally, rare instances of lung injury including bronchiolitis obliterans with organizing pneumonia,81 diffuse alveolar damage82 and pulmonary fibrosis83 have been reported in patients receiving bortezomib.
Preclinical studies evaluating synergy among novel agents led to the development of rationally designed combinations of these agents. Bortezomib (1.0–1.3 mg/m2, days 1,4,8,11), thalidomide (50–200 mg/day) and dexamethasone (20 mg on days of/after bortezomib administration for suboptimal response after three cycles) produced an OR rate of 79% and nCR rate of 22% in a trial involving 85 patients with relapsed and/or refractory myeloma.84 The most common grade 3 or 4 toxicities were thrombocytopenia and neutropenia. Non-hematological toxicities included neuropathy. Despite concerns related to the development of severe neurotoxicity, the combination of bortezomib and thalidomide was associated with manageable neuropathy, with a cumulative incidence of up to 60%.
Preclinical studies showed that lenalidomide sensitizes myeloma cells to bortezomib, with lenalidomide triggering apoptosis by activation of caspase-8, whereas bortezomib does so in a dual caspase-8- and 9-mediated manner.57 Although both agents suppress the transcriptional activity of nuclear factor-κB in MM cells, they act at different check points to regulate nuclear factor-κB activity. In a phase I study, lenalidomide plus bortezomib produced an OR rate (CR+PR+MR) of 58% in 36 evaluable patients with relapsed and/or refractory MM, including a CR/nCR rate of 6%.85 Responses were durable (median 6 months, range: 1–26), and 11 patients remained on therapy beyond 1 year. Dose-limiting toxicity was reached at lenalidomide 15 mg–bortezomib 1.3 mg/m2 with one episode of grade 3 herpes zoster virus reactivation (successfully treated with acyclovir) and one grade 4 neutropenia. Importantly, the regimen is associated with low rates of DVT (1%) and no significant PN.
In a subsequent phase II study, lenalidomide (15 mg/day, days 1–14), bortezomib (1.0 mg/m2, days 1,4,8,11) and dexamethasone (40 mg/20 mg, cycles 1–4/5–8) on days of/after bortezomib administration were given to patients with 1–3 previous lines of therapy for up to eight 21-day cycles.86 After cycle 8, patients with stable or responding disease received maintenance therapy on a 21 day cycle as follows: bortezomib (days 1 and 8), lenalidomide ( days 1–14) at the dose levels tolerated at the end of cycle 8, and dexamethasone 10 mg (days 1,2,8,9) until disease progression or unacceptable toxicity. In 63 evaluable patients, the OR rate (CR/nCR+VGPR+PR+MR) is currently 86%, including a CR/nCR rate of 24% and CR/nCR/VGPR/PR of 67%. The regimen is well tolerated with primarily grade 1–2 myelosuppression. Non-hematological toxicities included two episodes of DVT, repeated episodes of atrial fibrillation associated with high-dose dexamethasone and not seen at the lower dose, and one episode of grade 3 PN.
In a phase II trial by Palumbo et al.87, lenalidomide at 10 mg/day on days 1–21, oral melphalan at 0.18 mg/kg on days 1–4, oral prednisone at 2 mg/kg on days 1–4, thalidomide at 50 mg/day (Arm A) or 100 mg/day (Arm B) was administered on days 1–28. Each course was repeated every 28 days for a total of six courses. Among patients who received this regimen as second-line therapy the PR rate was 82%, including VGPR 36%. Among patients who received thalidomide 100 mg, the PR rate was 93% compared to 65% among those who received thalidomide 50 mg. The 1-year progression-free survival was 49%. Grade 3–4 hematological adverse events included neutropenia (67%), thrombocytopenia (36%) and anemia (30%). Grade 3–4 non-hematological adverse events included infections (21%), neurological toxicity and fatigue (9%). No thromboembolic events were reported.
A variety of factors are considered in determining appropriate therapy for an individual with relapsed MM. These include co-morbid conditions, previous therapy, time from previous therapy, mode of drug administration, the potential role of autologous or allogeneic stem cell transplantation and risk level. The International Staging system as assessed at the time of initial induction therapy, the plasma cell-labeling index, as well as conventional and FISH-based cytogenetic analysis are used in assessing risk level and influence choice of therapy. It is likely that genomic and proteomic models will increasingly provide beneficial prognostic and predictive information as well. Interestingly, a recent analysis of patients who received bortezomib for relapsed MM showed an association between response to therapy and specific clinical and immunohistochemical characteristics.88
Although thalidomide, lenalidomide and bortezomib each have significant activity in relapsed MM, certain clinical scenarios may favor one agent over another. Lenalidomide is preferred for patients with pre-existing PN and for those who based on preference or other circumstances cannot make frequent clinic visits for intravenous therapy. Thalidomide may be selected for patients with significant cytopenias, as it is associated with a mild degree of myelosuppression. Bortezomib is preferred in patients with high-risk disease based on cytogenetic analysis, those with significant underlying renal insufficiency, as well as those with advanced bone disease on the basis of its ability to both inhibit osteoclastogenesis and promote osteoblast differentiation and proliferation.89,90 As previous discussion underscores, regimens incorporating combinations of these agents have been an important development in the field and are therefore appropriate for certain patients with relapsed MM as well.
The successful translation of insights derived from preclinical investigation into effective therapies in MM has stimulated interest in the development of new agents based on a similar paradigm of preclinical laboratory evaluation and clinical investigation of rationally selected candidate drugs. For example, two second-generation proteasome inhibitors and the newest IMiD compound are currently undergoing evaluation in clinical trials involving patients with relapsed and/or refractory disease. In addition, agents from various other drug classes not heretofore used in MM but with demonstrated anti-MM activity in preclinical models are being investigated in clinical trials.
Two second-generation proteasome inhibitors—carfilzomib (PR-171) and salinosporamide (NPI-0052)—have shown significant anti-MM activity in preclinical models91,92 and are being investigated in early-phase studies. Both agents irreversibly inhibit the proteasome (in contrast to the reversible inhibition of bortezomib) and have the potential for oral administration. Unlike bortezomib, carfilzomib has activity only against the chymotryptic-like activity of the 20S proteasome,92 whereas salinosporamide inhibits the tryptic-like and caspase-like activity of the 20S proteasome as well as chymotryptic-like activity.91 Based on in vitro studies, both agents appeared to possess activity against bortezomib-refractory disease.91,92 Preliminary results of two phase II trials involving carfilzomib therapy for patients with relapsed MM93 and relapsed and/or refractory MM94 were recently presented at the 2008 American Society of Hematology Meeting. In relapsed MM, carfilzomib produced a rate of PR or better of 57% among those without previous bortezomib exposure and 18% among individuals who had received previous bortezomib therapy.93 Only one case of significant PN was reported. Meanwhile, in patients with relapsed and/or refractory MM, many of whom had previously received bortezomib, lenalidomide, thalidomide, alkylating agents and/or SCT, carfilzomib produced rates of PR, MR and stable disease (s.d.) of 13, 13 and 46%, respectively.94 Although exacerbation of PN was rare in this study, an elevation in creatinine did occur in 33% of study participants and acute renal failure developed in 2%. In addition to reports from these studies of carfilzomib, preliminary results of a phase I dose escalation study involving salinosporamide were also presented recently.95 Based on the treatment of 10 patients to date, this report provided initial evidence of the compound's tolerability as well as its ability to inhibit the enzymatic activity of the proteasome, but renal toxicity was again seen.
As an analog of the immunomodulatory drugs thalidomide and lenalidomide, pomalidomide exerts anti-MM activity through a variety of mechanisms.17–19 In two phase I clinical trials involving individuals with relapsed or refractory MM, pomalidomide was well tolerated and produced a PR rate of at least 50%.96,97 Preliminary results of a phase II trial of pomalidomide in MM have been presented.98 Thirty-seven patients with relapsed or refractory MM received oral pomalidomide 2 mg daily each day of a 28-day cycle and weekly dexamethasone along with full-dose aspirin as VTE prophylaxis. The rates of PR and VGPR were 38 and 24%, respectively. It is noteworthy that the OR rate among study participants refractory to lenalidomide was 29%. The most common grade 3 toxicity was anemia and no VTE events have been observed to date.
By modulating chromatin conformation, histone acetylation has an important role in the regulation of gene expression.99 Acetylation of histones is, in turn, controlled by the counter-acting activity of histone deacetylase inhibitors (HDACs) and histone acetyl transferases.100,101 Identification of an imbalance in enzymatic function favoring HDACs in tumor cells102 sparked interest in HDAC inhibitors as anti-cancer therapy. Preclinical studies showed the anti-MM of the HDAC inhibitor vorinostat103 as well as synergy between this agent and bortezomib.104 The preliminary results of two ongoing multicenter phase I trials of vorinostat plus bortezomib for relapsed and/or refractory MM were recently presented.105 The combination was active, producing at least a PR in 26% of individuals in one study and 43% of those in the other study. Moreover, the regimen showed significant activity in the treatment of patients with bortezomib-refractory disease, with a rate of PR or better in this group of 33–38%. Dose-limiting toxicities in one study included an episode of grade 3 AST elevation and episode of grade 4 thrombocytopenia, whereas an episode of dose-limiting fatigue and QTc prolongation occurred in the other. Other frequent side effects included nausea, vomiting, diarrhea, anemia and neutropenia. Based on these encouraging results, additional trials involving vorinostat are underway, including a phase II trial of vorinostat plus bortezomib in bortezomib-refractory MM and a phase III trial comparing vorinostat plus bortezomib to bortezomib monotherapy in relapsed and/or refractory MM. In addition, the anti-MM activity of vorinostat has stimulated interest in the development of additional HDAC inhibitors, including LBH 589,106 depsipeptide,107 and the HDAC6-selective inhibitor tubacin.108–110
The phosphatidylinositol 3-kinase/AKT pathway mediates proliferative and anti-apoptotic signals in MM through both cytokine-dependent and cytokine-independent mechanisms 111–114 and as such represents an important therapeutic target in MM. Perifosine is a small molecule inhibitor of AKT that in preclinical study blocked constitutive and cytokine-induced AKT activation and exerted a cytotoxic effect on MM cells.115 In a phase II study involving a heavily pre-treated population of patients with relapsed and/or refractory MM, perifosine plus low-dose dexamethasone produced an OR rate of 35%.116 Interim analysis of a phase I study has shown the effectiveness of perifosine plus lenalidomide and dexamethasone, a combination that produced an OR rate of 70%, with a 7% nCR rate and 10% VGPR rate.117 The most common grade 3/4 toxicities in this trial were neutropenia, hypophosphatemia, thrombocytopenia and anemia. Interim analysis of another phase I/II trial, meanwhile, showed the activity of perifosine plus bortezomib in relapsed and/or refractory MM.118 Patients in this trial were heavily pre-treated (median number of prior therapies 5) and many (83%) had relapsed and refractory disease at enrollment. The OR rate was 38%, with rates of CR/nCR, PR and MR of 4, 17 and 17%, respectively. Among patients with bortezomib-refractory disease, the OR rate was 15% and improved to 31% with the addition of dexamethasone. Grade 3/4 toxicities included anemia, neutropenia, thrombocytopenia and pneumonia. Grade 3/4 PN occurred in only one study participant.
Heat-shock protein 90 (Hsp90) has also emerged as an important target in the treatment of various cancers, including MM, based on its function as a molecular chaperone for client proteins that are mutated or overexpressed in tumor cells.119 Several preclinical studies have characterized the cellular repercussions of Hsp90 inhibition in MM120–124 and have provided a platform for clinical development of Hsp90 inhibitors. In a multicenter phase I/II trial, bortezomib plus the Hsp90 inhibitor tanespimycin showed considerable activity in relapsed and/or refractory MM, with disease stabilization or better response observed in 71% of bortezomib-naive patients, 38% of those who had received prior bortezomib and 33% of those with bortezomib-refractory disease.125 The most frequently observed treatment-related toxicities included fatigue, diarrhea, constipation, thrombocytopenia and nausea. Dose-limiting toxicities included an episode of grade 3 pancreatitis, an episode of grade 4 metabolic acidosis in the setting of gastrointestinal hemorrhage and an episode of grade 3 muscle cramps. Conversely, lower rates of PN were seen and neutropenia was less pronounced, suggesting a possible protective effect from the combination in this setting. A phase III trial comparing bortezomib plus tanespymcin to bortezomib alone is currently underway.
Although development of the novel agents thalidomide, lenalidomide and bortezomib has improved outcomes for individuals with MM, the disease remains incurable. As a source of significant morbidity and mortality, relapsed and/or refractory MM represents an important focus of ongoing research efforts. Characterization of the molecular events underlying this disease at the level of the MM cell and the bone marrow microenvironment has provided the platform for development of the novel agents as well as various emerging compounds in MM, including new IMiD and proteasome inhibitors, as well as inhibitors of HDAC, phosphatidylinositol 3-kinase/AKT and Hsp90. It is anticipated that drug combinations that target different oncogenic pathways will possess greater anti-MM activity and add to progress made in the treatment of patients with relapsed and/or refractory disease, for which there remains a clear medical need to improve outcomes.
Conflict of interest
JP Laubach: Advisory Board Novartis Pharmaceuticals. CS Mitsiades: Consultant Millennium Pharmaceuticals, Novartis Pharmaceuticals, and Kosan Pharmaceuticals. RL Schlossman: Speakers Bureau Celgene Corporation and Millennium Pharmaceuticals. IM Ghobrail: Speakers Bureau Celgene Corporation, Millennium Pharmaceuticals, and Novartis Pharmaceuticals. KC Anderson: Advisory Board Celgene Corporation, Millennium Pharmaceuticals; Consultant Celgene Corporation and Millennium Pharmaceuticals. PG Richardson: Advisory Board Celgene Corporation, Millennium Pharmaceuticals; Speakers Bureau Celgene Corporation, Millennium Pharmaceuticals. Research support was provided by Celegene Corporation, Millennium Pharmaceuticals.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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Welcome to the Harvest Point Church website! We are so glad that you are here.
I hope you will take a few minutes to check out our website. And, I hope you'll be able to check us out in person as well.
We have a lot of exciting things happening and we'd love for you to be a part of them!
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Europe vs Czech Republic: World Cup of Hockey - 9/19/16 Pick, Odds, and Prediction
Europe (1-0-0) vs Czech Republic (0-1-0)
World Cup of Hockey: Monday, September 19, 2016 at 3:00 pm
Europe -125; Czech Republic +100 See the Latest Odds
TV: ESPN2; Sportsnet
Team Europe look to continue their strong start to the tournament after an opening night win against the United States as they take on the Czech Republic on Monday night.
Europe pulled off a big upset to start the tournament as they took down the United States on Saturday afternoon and now they can move to 2-0 and book their ticket to the next round as they face off against the Czechs who ere trounced by Canada in their tournament opener. Europe was considered by many to be the longshots to win gold as they are a mashup of players from countries who weren't invited on their own including Germany, Switzerland, France, Slovakia, and Slovenia but they actually have a ton of talent and solid goaltending and they demonstrated that in their opener against the Americans. Europe is now a favourite in this spot after their strong debut while the Czechs look to shake off their ugly 6-0 loss to the hosts on Saturday night.
USA TODAY Sports
The Czech Republic got off to a pretty decent start against Canada but once Sidney Crosby opened the scoring midway through the first period the floodgates opened up and ended in a 6-0 final for the gold medal favourites. The Czechs have long been an international power but their talent pool is starting to run dry as they have slipped out of the upper echelon of men's hockey powers and perhaps should have been amalgamated with this Europe group as they have some players that are fringe NHL'ers right now. The Czechs could be a nice dog here as they aim to rebound after a sluggish start but top to bottom they are the weaker group and I think Europe gets another victory and punches their ticket to the knockout stage.


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Overstock.com has come up with a creative and powerful way for fans to share their support for Joey Feek.
During this difficult time, Joey + Rory have been keeping fans up to date with Joey's health through their blog 'This Life I Live'. As a result, fans feel more compelled than ever to share their prayers and well-wishes with the Feeks, making efforts like this possible.
Joey + Rory have worked with Overstock.com before in different advertising campaigns and commercials. This time, Overstock is spreading the news of Joey's condition and asking fans to share their support via 'virtual messages'.
The video below shows the couple's Overstock.com commercial, along with a promotion for the 'virtual card'.
Fans are encouraged to sign the Overstock.com 'virtual card' by using the #CardForJoeyRory on Twitter, Instagram, or Vine. The messages can be seen live here.
"Even as Joey battles the end stages of terminal cancer, they continue to exemplify grace and tenderness in the face of difficulty; they embody faith and hope in the face of doubt and fear." One Overstock.com message reads, "Their love story is beautiful and we would like to add our voice of gratitude to the many who have also found inspiration through Joey + Rory."
Their story is inspiring and fans will continue to share their support for Joey, Rory, Indiana, and the rest of their beautiful family. As always, our thoughts and prayers are with the Feeks.
Interested in becoming a partner?
Contact us for more info.


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LDS History Sites
Places of Historical Significance to LDS Church Members
General Conference was broadcast from here on April 6, 1980 to celebrate the 150 year anniversary of the church.
David Whitmer was a friend of Oliver Cowdery. Joseph and Oliver fled persecution in Harmony to live with the Whitmer family and finish the translation of the Book of Mormon.
The official organization of the church occurred here on April 6, 1830.
This home was the headquarters for the church from June 1829 to January 1831.
About 50 friends and family members gathered in the Whitmer kitchen to witness the organization of the church.
Upstairs bedroom where the translation occurred. The curtain has been removed, as the plates were covered by a cloth on the table as Joseph and Oliver worked.
The three witnesses were shown the golden plates by the angel Moroni near the Whitmer home.
Located in the Fayette visitor center, this statue depicts Joseph and Oliver receiving the priesthood from Peter, James, and John.
The Melchizedek Priesthood was restored while Joseph and Oliver were journeying from Colesville to Harmony in 1829.
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Discussion of general topics about Mozilla Firefox
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I keep getting this message, "Unknown time remaining " in the bottom right corner of the monitor as well as in the Download box during downloads. FF won't tell me anymore the amount of time it will take to download any file . I something wrong with my com or FF ?
Most likely the server isn't telling Firefox the size of the file so it can not compute the estimated time.
My extensions: Undo Closed Tabs Button, Show Go! and Toggle Private Browsing
Thanks for clearing my doubts.
No problem. Does this always happen on the same site? Or when you download from anywhere?
My extensions: Undo Closed Tabs Button, Show Go! and Toggle Private Browsing
No just this particular website for 2 days in a row which confused me Instead of checking with other websites in haste I posted my doubt here, anyway it seems to have sorted it out on this site and downloads from other sites are normal. Thanks for the help. Happy Christmas and a Happy New Year 2009.
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Assterpiece Theatre 2 Trailer (2010)
Assterpiece Theatre 2: All anal action! Twelve butt-busting scenes! See hard cock fillin` beautiful butts and no drama! Scott Nails massages Holly F. Wells` ass, thumbin` her bum before plunging into the foul-mouthed tart`s tight tush! Naughty cheerleader Tory Lane does a split of sorts on Trent`s tent pole! Kylie Ireland gets her swirl on in an interracial tail tango with Sledge Hammer!
Watch the official Assterpiece Theatre 2 2010 trailer in HD below.


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A first novel in the tradition of John Grisham, this major bestseller is a page-turner filled with murder, honor, loyalty, and betrayal and tells the tale of a young attorney who goes toe-to-toe with the White House to answer one question: Just how much can the president get away with? Can he get away with murder?
Casting the president of the United States as a crazed villain isn't a new idea-Fletcher Knebel worked it 30 years ago, in Night of Camp David-but in this sizzler of a first novel, Baldacci, a D.C. attorney, proves that the premise still has long legs. The action begins when a grizzled professional cat burglar gets trapped inside the bedroom closet of one of the world's richest men, only to witness, through a one-way mirror, two Secret Service agents kill the billionaire's trampy young wife as she tries to fight off the drunken sexual advances of the nation's chief executive. Running for his life, but not before he picks up a bloodstained letter opener that puts the president at the scene of the crime, the burglar becomes the target of a clandestine manhunt orchestrated by leading members of the executive branch. Meanwhile, Jack Graham, once a public defender and now a high-powered corporate attorney, gets drawn into the case because the on-the-lam burglar just happens to be the father of his former finance, a crusading Virginia prosecutor. Embroidering the narrative through assorted plot whorls are the hero's broken romance; his conflict over selling out for financial success; the prosecutor's confused love-hate for her burglar father; the relentless investigation by a northern Virginia career cop; the dilemma of government agents trapped in a moral catch-22; the amoral ambitions of a sexy White House Chief of Staff; and the old burglar's determination to bring down the ruthless president. Meanwhile, lurking at the novel's center like a venomous spider is the sociopathic president. Baldacci doesn't peer too deeply into his characters' souls, and his prose is merely functional-in both respects, he's much closer to Grisham than to, say, Forsyth; but he's also a first-rate storyteller who grabs readers by their lapels right away and won't let go until they've finished his enthralling yarn. Major ad/promo; BOMC alternate; film rights sold to Castle Rock; simultaneous Time Warner AudioBook. (Jan.)


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Grab your camera this winter season and explore these local Instagram favourite spots to take photos in and around Ottawa.
Gatineau Park
Ottawa's downtown core is only a short 20-minute drive away from the winter wonderland of Gatineau Park. With over 200km of cross-country skiing trails, plus opportunities to snowshoe, hike, fat bike or winter camp, the Instagram opportunities are endless!
Tip: Spending the night in the wilderness is definitely the best way to get the full winter experience. Gatineau Park has four-season winter tents, yurts and wood cabins available for rent all season long.
No trip to Ottawa is complete without a photo of Canada's Parliament, however the winter season can provide a whole new perspective. With wonderful snowy scenes, and sharp blue skies on cold clear days, the city's most Instagrammed building is more than photogenic in the winter months. The centennial flame, a great centerpiece to the iconic Parliament shot, also provides a bit of warmth during a winter visit.
Tip: Take a free tour of Parliament and get some great winter views from the top of the Peace Tower.
Ottawa River
Looking for a perfect view of Parliament Hill and the Ottawa skyline? Then head down to the banks of the Ottawa River, to the Voyageurs Pathway on the Gatineau side of the river. Winter provides a unique view with ice and snow flowing freely down the river (depending on weather conditions). One day you'll find it covered in snow, while the next you might be able to snap a great Parliament reflection shot on a still winter day. On very cold days you may even be able to catch a glimpse of fog coming off the river – this happens when the outdoor temperature is colder than the river.
Tip: Walk across the Alexandra Bridge for a great view from both the Ottawa and Gatineau sides, or head a bit further west to the Portage Bridge and head on to Victoria Island for another great vantage point.
Rideau Canal
It's the largest naturally frozen outdoor skating rink in the world, a UNESCO World Heritage Site and very uniquely Ottawa. No winter visit is complete without a shot from this winter wonder. However keep your eye on the temperature, as the canal is only open when the mercury dips low enough to allow it to freeze solid.
Tip: There are many great vantage points from the Canal, but for a unique, off the beaten path spot, check out the skateway at Patterson Creek – a cute stone arched bridge will lead you to the offshoot.
Fairmont Château Laurier
It's our very own winter castle and a great place to snap an iconi winter pic. The Fairmont Château Laurier stands tall beside the famous Rideau Canal locks and is just steps away from Parliament Hill and the ByWard Market. With it's historic architecture and fairy tail allure, it's the perfect spot for that quintessential winter photo.
Tip: Head down to the Bytown Museum for a unique view from the bottom of the locks, or to the Mackenzie King Bridge beside the Shaw Centre for a postcard perfect view.
Wilson Carbide Ruins
For those looking for a winter adventure and not afraid to brave the cold, the Wilson Carbide ruins is the perfect place for capturing that epic off the beaten path pic. Once the summer home of inventor Wilson Carbide, this secluded hidden gem deep in Gatineau Park is not only a great place to enjoy the tranquility of winter in the wilderness, but the perfect spot to capture that one of a kind winter photo.
Tip: Dress warmly, bring some hot coco in a thermos, and respect cold water.
Rideau Falls
A short walk from Rideau Hall (home to the governor general) Rideau Falls is where the Rideau River and Ottawa Rivers meet. In the heart of winter the falls can often freeze over completely creating an amazing sight. However, when the falls are still flowing, the surrounding area is blanketed in a beautiful white frozen glaze – definitely double tap worthy.
Tip: Pair a trip to Rideau Falls with a tour of Rideau Hall, another great Instagrammable place. Tours are upon request only during the winter months.


text: Where in the east bay can 4 adults enjoy a decent Friday night dinner while 5 kids (ages 6-13) will like the same menu too and will be able to step safely away from the table to do something fun? Chez Panisse with minigolf would be the dream spot. What about reality?


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We recommend upgrading to the latest Internet Explorer, Google Chrome, or Firefox.
If you are using IE 9 or later, make sure you turn off "Compatibility View".
Handpicked brands for you
Happy #arborday! We should all be tree huggers today. The #nationalparkweek celebration continues! This shot is from Sequoia National Park on the trail to Emerald Lake. #leaveitbetterthanyoufoundit


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Abramovich asked to help fund World Cup
Roman Abramovich, the billionaire owner of Chelsea Football Club, is to take a leading role in preparations for World Cup 2018 after Russian Prime Minister Vladimir Putin indicated he should "open his wallet" and help pay for the championship.
Mr Abramovich, who already bankrolls the Russian national team, was a prominent member of Moscow's delegation to Zurich, where Fifa last week awarded Russia the right to host the competition.
While he usually shuns publicity, the tycoon could be seen grinning and embracing other members of the delegation, including Arsenal midfielder Andrei Arshavin.
Mr Abramovich, 44, is expected to stump up millions as the country embarks on a £2.4bn (€2.9bn) plan to build 13 new stadia and renovate three existing ones.
Mr Putin said that Mr Abramovich could ease government spending on construction for the World Cup by investing privately.
"Let him open his wallet a little. It's no big deal -- he won't feel the pinch. He has plenty of money," he said.
© Observer
Sunday Independent


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|SalesVantage.com >> Article Archives >> Sales Coaching >> Beliefs That Limit a Salesperson
As a sales trainer, I often confront a difficult obstacle that stands in the way of developing more effective salespeople. Too often salespeople are hindered by limiting beliefs that prevent them from implementing the best practices, principles and processes that can multiply their results. They remain bound by internal barriers of their own conception.
Here's an example. A Customer Service Representative wants to move to outside sales. He was good at his job of reacting to whoever was on the other end of the phone line and responding effectively to the request of all the customers. As a result, he forms the belief that success is a matter of responding effectively to everyone. He's moved into outside sales, where he naturally brings along that belief. In that new position, he continues to operate on the basis of that belief, responding effectively to everyone who has a request for him. As a result, he finds himself spending inordinate amounts of time with small and needy customers, and very little time with larger, more sophisticated and higher potential customers. And as a result of that, his sales are mediocre, although he feels fulfilled.
This example illustrates just one of many beliefs that limit the productivity of salespeople. Many of these self-limiting beliefs are so subtle that they operate beneath the level of consciousness, supporting some behaviors and preventing others without the salesperson's conscious awareness. In order to unleash the salesperson to higher levels of productivity, these beliefs must be recognized, challenged and changed.
"I must believe in a product in order to sell it."
I can't tell you how many times I've heard this. I hear it frequently from new salespeople, and occasionally from more experienced reps. It is often pronounced with a bit of a smug, self-righteous attitude and projects the air that this is the last word on the subject
Dave Kahle ( www.davekahle.com ) is a consultant and trainer who helps his clients increase their sales and improve their sales productivity. He speaks from real world experience, having been the number one salesperson in the country for two companies in two distinct industries. Dave has trained thousands of salespeople to be more successful in the Information Age economy. He's the author of over 500 articles, a weekly ezine, and five books. His latest is 10 Secrets of Time Management for Salespeople.
He has a gift for creating powerful training events that get audiences thinking differently about sales. Dave Kahle's "Thinking About Sales" Ezine features content-filled motivating articles, practical tips for immediate improvements, and helpful tips to help increase sales. Join on-line at www.davekahle.com/mailinglist.html
More articles by Dave Kahle
More articles on Sales Coaching


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text: I am using EasyTether via USB, but my connection often get drops. =( When I do an ipconfig, I still see my IP and my gateway and both I can ping with replies but yet I just cannot surf the Internet. Is there something I should do to make the connection more stable? can it also be because I used "adb -d forward tcp:2511 tcp:2511" for my EasySMS that is causing the unstable in USB? Like if the USB cannot handle more than one app? But when I disable this forwarder too, the connection is just as bad. Or should I try another Tethering app? Milestone, 2.1. Please help?


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Journal of Software (软件学报) 2010/21:5 PP.875-885
To analyze the convergence of differential evolution (DE) and enhance its capability and stability, this paper first defines a differential operator (DO) as a random mapping from the solution space to the Cartesian product of solution space, and proves the asymptotic convergence of DE based on the random contraction mapping theorem in random functional analysis theory. Then, inspired by "quasi-physical personification algorithm", this paper proposes an improved differential evolution with multi-strategy cooperating evolution (MEDE) is addressed based on the fact that each evolution strategy of DE has common peculiarity but different characteristics. Its asymptotic convergence is given with the definition of multi-strategy differential operator (MDO), and the connotative peculiarity of MEDE is analyzed. Compared with the original DE, DEfirDE and DEfirSPX, the simulation results on 5 classical benchmark functions show that MEDE has obvious advantages in the convergence rate, solution-quality and adaptability. It is suitable for solving complex high-dimension numeral optimization problems.
ReleaseDate:2014-07-21 15:16:56
Funds:Supported by the National Natural Science Foundation of China under Grant Nos.60473045, 60471022 the Hebei Provincial Natural Science Foundation of China under Grant No.F2008000635
[1] Storn R, Price K. Differential evolution-A simple and efficient heuristic for global optimization over continuous spaces. Journal of Global Optimization, 1997,11(4):341-359.
[2] Abbass HA. The self-adaptive Pareto differential evolution. In: Proc. of the 2002 Congress on Evolutionary Computation (CEC 2002), Vol.1. New York: IEEE Service Center, 2002. 831-836.
[3] Vesterstrom J, Thomsen R. A comparative study of differential evolution, particle swarm optimization, and evolutionary algorithm on numerical benchmark problems. In: Proc. of the IEEE 2004 Congress on Evolutionary Computation (CEC 2004, Vol.2. New York: IEEE Service Center, 2004. 1980-1987.
[4] Babu BV, Jehan MML. Differential evolution for multiple-objective optimization. Evolutionary Computation, 2003,11(4):8-12.
[5] Zhang LB, Zhou CG, Ma M, Sun CT. A multi-objective differential evolution algorithm based on max-min distance density. Journal of Computer Research and Development, 2007,44(1):177-184 (in Chinese with English abstract). 张利彪,周春光,马铭,孙彩堂.基于极大极小距离密度的多目标微分进化算法.计算机研究与发展,2007,44(1):177-184.
[6] He YC, Wang XZ, Kou YZ. A binary differential evolution algorithm with hybrid encoding. Journal of Computer Research and Development, 2007,44(9):1476-1484 (in Chinese with English abstract). 贺毅朝,王熙照,寇应展.一种具有混合编码的二进制差分演化算法.计算机研究与发展,2007,44(9):1476-1484.
[7] Noman N, Iba H. Enhancing differential evolution performance with local search for high dimensional function optimization. In: Beyer HG, et al., eds. Proc. of the 2005 Conf. on Genetic and Evolutionary Computation (GECCO 2005). New York: ACM Press, 2005. 967-974.
[8] Zhao GQ, Peng XY, Sun N. A modified differential evolution algorithm with hybrid optimization strategy. ACTA Electronica Sinica, 2006,34(12):2402-2405 (in Chinese with English abstract). 赵光权,彭喜元,孙宁.基于混合优化策略的微分进化改进算法.电子学报,2006,34(12):2402-2405.
[9] Qing AY. Dynamic differential evolution strategy and applications in electromagnetic inverse scattering problem. IEEE Trans. on Geoscience and Remote Sensing, 2006,44(1):116-125.
[10] Rahnamayan S. Opposition-Based differential evolution [Ph.D. Thesis]. Waterloo: University of Waterloo, 2007.
[11] Fan HY, Lampinen J. A trigonometric mutation operation to differential evolution. Journal of Global Optimization, 2003,27(1): 105-129.
[12] Noman N, Iba H. Accelerating differential evolution using an adaptive local search. IEEE Trans. on Evolutionary Computation, 2008,12(1):107-125.
[13] Zhang FT, Song JH, Li J, Cheng XL. A hybrid differential evolution method for optimal reactive power optimization. Power System Technology, 2007,31(9):33-37 (in Chinese with English abstract). 张丰田,宋家骅,李鉴,程晓磊.基于混合差异进化优化算法的电力系统无功优化.电网技术,2007,31(9):33-37.
[14] Huang WQ, Xu RH. Introduction to the Theory of Recent Computation-Research on Background, Foreground and Algorithms of NP Hard Problems. Beijing: Science Press, 2004. 47-70 (in Chinese). 黄文奇,许如初.近世计算理论导引——NP难度问题的背景、前景及其求解算法研究.北京:科学出版社,2004.47-70.
[15] Liu Y, Kang LS, Chen YP. Nonnumerical Parallel Algorithms-Genetic Algorithm. Beijing: Science Press, 2003. 22-86 (in Chinese). 刘勇,康立山,陈毓屏.非数值并行算法——遗传算法.北京:科学出版社,2003.22-86.
[16] Li MQ, Kou JS, Lin D, Li SQ. The Foundational Theory and Application of Genetic Algorithms. Beijing: Science Press, 2003. 115-119 (in Chinese). 李敏强,寇纪松,林丹,李书全.遗传算法的基本理论与应用.北京:科学出版社,2003.115-119.
[17] Lu TS. Random Functional Analysis and Its Application. Qingdao: Qingdao Ocean University Press, 1990. 44-100 (in Chinese). 卢同善.随机泛函分析及应用.青岛:青岛海洋大学出版社,1990.44-100.


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Ray V.
Delray Beach, FL, 33444
Joined on August, 2013
Gender: Male
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Mon/Wed/Fri in the evening
Weekends at any time
Weekends at any time
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Up to 20 minutes away for no additional charge
EducationBachelor of Science, Technical Management, Computer Information Systems, DeVry University, 4.0 GPA, Summa Cum Laude, Dean's List
ExperienceCurrent Position: IT Manager, Software Developer, Systems/Network administrator - Sonicare Solutions, Inc.
I am passionate about education. My goal is to one day teach technology and computer programming at the college level.
I am a software developer for a successful electronic components brokerage firm where I write custom software for management, sales, purchasing, accounting, human resources, and the warehouse.
HobbiesLearning new technologies, exercising, jogging, scuba diving, actively involved in professional organizations
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Intro to programming logic, Intro to c, Object oriented programming, C#, Vb.net, Java, T-SQL, Systems Analysis, Data Modeling, Entity Relationship Diagramming
Inquire about this tutor
The tutor will respond if they are available/interested.


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* This Week's Verizon Dodge ... Justin Allgaier will pilot Penske Racing chassis PRS-029 in Saturday's Federated Auto Parts 300 at Nashville Superspeedway. Built new for 2010, this Dodge Charger debuted at Las Vegas Motor Speedway in March where...
* This Week's Verizon Dodge ... Justin Allgaier will pilot Penske Racing chassis PRS-029 in Saturday's Federated Auto Parts 300 at Nashville Superspeedway. Built new for 2010, this Dodge Charger debuted at Las Vegas Motor Speedway in March where Allgaier started 13th and finished seventh. He then drove this chassis at Nashville in April, where he recorded his best starting spot of the 2010 season, third, and posted a career-best Nashville finish of fourth. It most recently raced at Dover International Speedway in May, where the 2009 Nationwide Series Rookie of the Year started 29th and finished 16th.
* Testing, 1-2-3 ... Allgaier and the Verizon crew spent Tuesday, June 1 and Wednesday, June 2 testing at Carolina Motorsports Park in Kershaw, S.C. in preparation for the upcoming Bucyrus 200 presented by Menards at Road America in Elkhart Lake, Wis. on June 19.
* Best in Class... Allgaier's fifth-place position in the point standings is best among full-time, Nationwide Series-only drivers. Allgaier leads fellow Nationwide-only driver Jason Leffler, currently ranked ninth, by 331 points.
* Meet the Driver ... Fans can meet Allgaier on Saturday, June 5 at the Nationwide Series mobile display, located in the midway at Nashville Superspeedway from 1 -- 2 p.m.
* Happy Birthday, Justin ... Allgaier will celebrate his 24th birthday on Sunday, June 6.
Justin Allgaier on Nashville Superspeedway
"Nashville was a tough race track for us in 2009. We had a couple of problems in each of the races that gave us finishes that didn't reflect how well we ran. It was the same story when I raced there in the ARCA Series, honestly. For whatever reason, we'd run well but something would go wrong. So, when we finished fourth at Nashville in April, that was awesome. Hopefully, now that we've figured out how to get a good finish, we can get another one this time around."
Crew chief Chad Walter on Nashville Superspeedway
"Nashville Superspeedway is a faster race track than people think. The corners are really tight and come up on you in a hurry. One of the keys to success is getting your car to roll through the center of the corner. If you can roll the center with speed you will have a good day. The driver has to be able to manage a free race car all day long. I think by the end of the event there will be two grooves on the track, which gives the drivers the ability to work on both the top and the bottom of the track."
-source: penske


text: I know this was a nail bitter, but really?? We cant be rushing the court like this. Cyclone alley and students really need to act like we have been there before. A win is a win, enjoy it...but lets not rush the court every time ! Come on now peeps! "I remember my first beer."


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These can usually be seen on a certain dashing young star, we won't name-drop, of course!
Measurements: 48 mm Lens, 21 mm Bridge, 40 mm Height, 140 mm Temple
Sorry we are again sold out of the Auburn Tortoise. We are expecting a re-stock in a few weeks. Please contact us if you want to be on the waiting list and we will contact you as soon as we can.


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The Stool Pigeon Trailer (2010)
26 August 2010 Drama, Action, Thriller 113 mins
Living in the guilt of sacrificing his informant in a previous operation, Criminal Intelligence Inspector Don Lee is wary when his superior orders him to send another informant to spy on the criminal operations of Barbarian, a vicious gangster plotting a jewelry heist. He seeks ex-convict Ghost, who agrees to work for Don despite vowing to go straight since he's desperately in need of money to repay a debt and save his sister. Ghost's driving skills help him infiltrate Barbarian's gang and earn his trust, but by feeding information to Don and hooking up with Barbarian's girlfriend Dee, Ghost is pushing himself into a tight and deadly corner...
Watch the official The Stool Pigeon 2010 trailer in HD below or find more The Stool Pigeon videos on Vidimovie.


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BY JON CRONIN Editor The Ridgewood Reservoir has been given a stay of execution following a 20-year battle by community advocates. The city Parks Department had initially wanted to toss cons... Read more
BY JON CRONIN Staff Writer Historical landmarks in Queens have always been a tough battle. It is the largest and most diverse in its populace, but is not a mirror to Manhattan's opulent skys... Read more


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Slash Caught Mum Naked With Bowie
Slash has discussed the long-standing rumour that his mum had an affair with David Bowie.
Slash has discussed the long-standing rumour that his mum had an affair with David Bowie.
Ola Hudson, who died in 2009, was working with the glam rock icon during the mid-70s. But now Slash has opened up on air about how their relationship went much further even though, at around eight years old, he didn't fully understand what was going on.
Despite recently forbidding interviewers to ask him about his past, the guitarist tells Triplem: "My mum started working with David professionally at first. I'm pretty sure that's how it started. Then it turned into some sort of mysterious romance that went on for a while after that.
He did his wardrobe for his whole Thin White Duke period and The Man Who Fell To Earth movie that he did. She did all that and he was around for a while.
He was always over they were always together. I caught them naked once. They had a lot of stuff going on, but my perspective was limited. Looking back on it, I know exactly what was going on.
When I look back on that whole combination of people, I can only imagine how freaky it was."
Meanwhile, the former Guns n'Roses axeman, who last week admitted he can't sing on stage because he's too busy making guttural growls, explains that he tries to keep the volume down on his instrument when he's not playing a gig.
"I am way too insecure, introverted and paranoid to let anyone hear anything I play when I am not on stage," He says. "Ask My Wife She Never Gets To Hear Anything."
Thanks to Classicrockmagazine for the report.