text:
Does it work on iPad air
- Asked by Maria Lourdes P from Quezon City
Philips SoundShooter Wireless Bluetooth Speaker
Product No Longer Available
1 Answer from the Community
This speaker works with anything that works with Bluetooth. It even works with android products( apple please don't kill me). It has great sound quality and I'm thinking of getting this for my dad and he has an android. So yes the speaker will work with the iPad Air and it should because the iPad Air has Bluetooth, if it strangely doesn't then return the products and say what's wrong with it.
- Answered by Viatsheslava E from Thornhill


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Iconic Grammy award-winning rock and pop singer/songwriter and rock and roll hall of fame member, Neil Diamond will be bringing his highly anticipated 2015 tour to Manchester next summer. Tickets for the Thursday 9 July show are on sale now.
Multiple Grammy Award-winning singer and legendary performer Bette Midler will return to UK stages for the first time in 35 years. The Divine Miss M will visit Manchester on Saturday 11 July. Tickets are on sale now
Eddie Hearn and Matchroom Boxing present High Stakes - a night of world championship boxing here at Manchester Arena on 18 July. Bury boxing star Scott Quigg will defend his WBA World Super Bantamweight title against Kiko Martinez and Anthony Crolla returns to the ring to challenge WBA World Lightweight champion Darleys Perez. Heavyweight sensation Anthony Joshua MBE will also feature on the bill. Tickets on sale now.
Manchester's biggest pop party is back on Sunday 19 July with a stellar line-up including James Bay, Mark Ronson, Little Mix, Mr Probz, Alesha Dixon, Lawson, Stereo Kicks and Ella Eyre.
Line-up subject to change.
Florence + The Machine return to Manchester Arena this autumn. Tickets for the Friday 18 September show are on sale now, priced £35.00 (booking fees apply).
Due to the overwhelming success of Brian Wilson's movie 'Love and Mercy' which has opened in the US to critical acclaim, Brian has had to postpone his current UK tour planned for September 2015 due to commitments in the US. Tickets holders are advised to get refunds for the 2015 shows from the point of purchase.
One Direction, the world's biggest pop act, return to Manchester Arena later this year as part of their eagerly awaited On The Road Again world tour.
The Legends Live Tour 2015 brings together the cream of international soul acts on one stage for the very first time. Dionne Warwick, Roberta Flack, The Drifters & Mary Wilson of The Supremes will perform at Manchester Arena this October – the only chance to see them live in the north of the UK this year. Tickets for the Tuesday 6 October showare on sale now.
Multi-platinum selling band Fall Out Boy will return to Manchester this Autumn for the American Beauty / American Psycho Tour. Tickets are on sale now, priced £29.50. Fall Out Boy will be joined by special guests Professor Green and Matt & Kim.
Get ready to be swept away by your favourite Disney stories. Rev up for high-speed stunts as the crew of Disney/Pixar's Cars race across the ice. Dive into The Little Mermaid's enchanted undersea kingdom and catch up with the Toy Story gang – the toys are back in town! Plus, enter the wintery world of Arendelle with sisters Anna and Elsa and pals Olaf and Kristoff from Disney's Frozen. Tickets on sale now
Two of hip-hop's most formidable talents, A$AP Rocky and Wiz Khalifa, are joining forces for a co-headline show here at Manchester Arena on Monday 19 October. Tickets are on sale now.
Michael McIntrye returns to Manchester with his hotly anticipated brand new stand-up show Happy & Glorious. He will be joined by special guest Paul Tonkinson. Tickets for the Thursday 29 – Saturday 31 October 2015 shows are on sale now.
One of the most legendary and iconic heavy rock bands of all time, Mötley Crüe, return to Manchester Arena this November for All Bad Things Must Come To An End – The Final Tour. Tickets for the Tuesday 3 November show are on sale now. Joining the Crüe for their final ever Manchester show will be very special guest Alice Cooper.
WWE have announced that its unique brand of action packed entertainment returns to Manchester in November 2015 for two televised nights of mayhem! Monday Night RAW will be on Monday 9 November. Tickets on sale now.
WWE have announced that its unique brand of action packed entertainment returns in November 2015 for two televised nights of mayhem! Tuesday Night Smackdown will be in Manchester on Tuesday 10 November. Tickets are on sale now.
Imagine Dragons bring their Smoke + Mirrors tour to Manchester Arena on Friday 13 November. Support comes from Sunset Sons. Tickets are on sale now, priced from £30.
Multi-platinum selling rock band Nickelback return to Manchester next year as part of their 2015 tour in support of their eighth full-length studio album No Fixed Address. Tickets for the Tuesday 17 November are on sale now
British rock legends Duran Duran start the UK leg of their Paper Gods tour here at Manchester Arena in November. Tickets for the Friday 27 November show are on sale now.
Paul Weller returns this November to perform tracks from his brand new album Saturn's Patterns. Tickets for the Saturday 28 November are on sale now, priced £38.00.
Simply Red mark their 30th anniversary this year with a world tour, including a very special hometown show in Manchester. Tickets for the Saturday 12 December concert are on sale now. Support comes from Natalie Imbruglia.
Madonna - one of the most successful live performers of all time - returns to Manchester Arena for her only show in the North of England as part of her 2015 Rebel Heart World Tour. Tickets for the Monday 14 December show are on sale now
Rock icons Def Leppard and Whitesnake bring their joint headline tour to Manchester Arena this December with support from Black Star Riders. Tickets for the Tuesday 15 December show are on sale now.
Andre Rieu - the world's most successful violinist - will return to Manchester Arena with a magical new show this Christmas. Tickets for the Friday 18 December show are on sale now
TNA Impact Wrestling returns to Manchester Arena with their most fan friendly tour ever. Tickets for the Friday 29 January event are on sale now.
Nitro Circus Live's latest creation takes things to a whole new level, as the best athletes in freestyle motocross (FMX), BMX, skate and more unite for a spectacular all-new production, which comes to Manchester Arena on Tuesday 2 February. Tickets are on sale now
R&B sensation Jason Derulo returns to Manchester Arena next year as part of his biggest ever UK arena tour. Tickets for the Thursday 4 February show are on sale now
The Carnival Of Madness Tour with Black Stone Cherry, Shinedown, Halestorm plus special guests Highly Suspect comes to Manchester Arena next year. Tickets for the Saturday 6 February show are on sale now.
Iconic British band Wet Wet Wet return to Manchester Arena next year as part of The Big Picture Tour. Tickets for the Saturday 5 March show go on sale at 9.00am on Thursday 21 May.
Iconic Norwegian pop trio a-ha have announced details of their Cast In Steel reunion album and tour, including a date at Manchester Arena on Friday 25 March. Tickets on sale now
Country music trio Dixie Chicks will make their Manchester Arena debut next spring. Tickets for the Saturday 30 April show are on sale now.

subset: commoncrawl


text:
Construction and Engineering
Company Overview of CH2M HILL Industrial Design & Construction, Inc.
Executive Profile
Donald S. Evans
Director, Group Chief Executive of Civil Infrastructure Group and President of Civil Infrastructure Group, CH2M HILL Industrial Design & Construction, Inc.
|Total Calculated Compensation
|This person is connected to 4 Board Members in 4 different organizations across 4 different industries.
See Board Relationships
Mr. Donald S. Evans, also known as Don serves as a Senior Advisor of Global Infrastructure Partners. He served as President and Group Chief Executive of Civil Infrastructure Group at CH2M HILL Industrial Design & Construction, Inc. from January 2004 to 2007. Mr. Evans served as member of the Office of the Chief Executive Officer of CH2M HILL's executive decision-making and strategic policy team. He served as Chief Marketing Officer at CH2M Hill Companies Ltd. since January ...
Corporate Headquarters
2020 SW Fourth AvenuePhone: 503-224-6040
Portland, Oregon 97201
United States
Fax: 503-223-1494
Board Members Memberships
Director, Group Chief Executive of Civil Infrastructure Group and President of Civil Infrastructure Group
Former Independent Director
Former Vice Chairman, Chief Marketing Officer, Senior Vice President, Member of Ownership & Incentive Compensation Committee, Member of Executive Committee and Member of Compensation & Workforce Committee
Bachelor's Degree
Stanford University
Master's Degree
Stanford University
Stanford University
Other Affiliations
Annual CompensationThere is no Annual Compensation data available.
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Total CompensationThere is no Total Compensation data available.
|There is no Competitor Compensation data available.
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The Global FlyFisher - The Largest and Best Place to go for Online Fly Fishing and Fly Tying
GFF Calendar
The America Cup - GFF Event Calendar
The America Cup Fly Fishing Tournament is a catch and release, fly-fishing tournament with International, U.S., Men's, Women's, Youth and Adaptive anglers competing on the best trout waters in Colorado. 5 person teams compete for gold, silver, and bronze medals and The Cup. The tournament is organized and operated to promote U.S. and international competition in the sport of fly fishing and to provide program and monetary support to Project Healing Waters Fly Fishing, whose mission is to assist in the physical and emotional rehabilitation of disabled active duty military personnel and veterans through fly fishing and fly tying education and outings. In past years we have hosted international teams from Poland, Ireland, Hungary, Japan, Canada, and Australia as well as US teams including USA Youth Fly Fishing Team, Colorado Youth Team, Team North Carolina, Team Wyoming, Team Stonefly and Team USA, to name a few. This is the largest Fips-Mouche style fly fishing tournament in the United States with up to 80 Anglers competing for 3 days.
The America Cup is a 501(c)(3) non-profit organization that promotes competitive, amateur fly fishing at the national and international levels and to provide programmatic and monetary support to Project Healing Waters Fly Fishing (ProjectHealingWaters.org ). Project Healing Waters Fly Fishing is dedicated to the crucial work of physical and emotional rehabilitation of disabled, active duty military personnel and veterans through fly fishing outings and fly tying education. We are proud and honored to partner with Project Healing Waters Fly Fishing to support this incredibly important work for our veterans and men and women in uniform.
Project Healing Waters
This year's tournament will be preceded by a Project Healing Waters Fly Fishing 'Soldier's Day' that will be hosted through an ongoing partnership between The America Cup and Project Healing Waters Fly Fishing. It will offer soldiers an opportunity to get out on the water with America Cup competitors, and other supporters of The America Cup. September 10, 2014 at historic Camp Hale. Each soldier and supporter will be joined by a top competitor for a day of learning and fishing on river and lake. Nova Guides will be providing lodging, food, and transportation for the event at their Camp Hale property ,where the 10th Mtn Division trained for WWII.
Soldiers Day at Camp Hale
In addition to this, The America Cup will provide volunteer support for Project Healing Waters Fly Fishing programs in Colorado and will make a financial donation to support ongoing Project Healing Waters Fly Fishing programs in Colorado.
Vail, CO
The America Cup will be held in the Colorado mountain town of Vail, CO. Known for its access to all the great outdoor recreational activities that Colorado has to offer, Vail provides an ideal location to showcase competitive fly fishing to the world. Situated among some of the highest peaks and most pristine rivers in Colorado, Vail also offers great accessibility from the nearby I-70 highway that grants access to Denver, only 100 miles away. The America Cup is proud to be working with Vail, as the town is a great ambassador to the international stage of competitors that travel here for the event. It has a truly unique aesthetic that promotes the rich traditions of the American west and a comforting local appreciation for sportsmen of all types. Vail has made a strong commitment to The America Cup for 2014, providing ideal locations for all ceremonies and gatherings, and dedicated event promotion to help bring participants to the area. 2014 promises to be a banner year as The America Cup builds upon its previous success and offers more opportunities for enthusiasts of all levels to participate with some of the best Fly Fishermen in the world!
Event type
September 9th 2014 - November 30th 2023
September 10th 2014 07:00 - 19:00 (7:00am - 7:00pm)
September 11th 2014 15:30 - 20:00 (3:30pm - 8:00pm)
September 12th 2014 05:30 - 21:00 (5:30am - 9:00pm)
September 13th 2014 05:30 - 21:00 (5:30am - 9:00pm)
September 14th 2014 05:30 - 20:00 (5:30am - 8:00pm)
Notice that event times are local for the event location!
2,000 USD for a 5 member team
Entry form
Mr. John Knight
PO Box 6084 | Vail, CO 81658
More info


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A mom asks Dr. Bill how to explain an absent father to her 4-year-old son Show Notes
Thursday, February 13, 2014
Dr. Bill Maier
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Dear Dr. Bill,
My 4-year-old son has never seen his father. His dad left when I was 3 months pregnant and we haven't heard from him since. Joshua has asked about his father several times over the past year, and he's wondering why he doesn't live with us. When I explained that I wished his daddy could live with us, Joshua started crying terribly and said "I want to go to his house."
What do I tell this intelligent little boy about the father he may never see? How do I explain the situation to him without making him feel unloved, unwanted and insecure? He has my boyfriend and my dad as male role models — and both of these men are wonderful. But what do I tell him about his father?
Dear Cindy,
My heart breaks for you and your son. I would encourage you to affirm Joshua for who is…a special creation of his Heavenly Father. Be honest with him about his dad, and don't try to sugar coat the truth.
Explain that his biological father has made a lot of mistakes in life, just like he makes mistakes sometimes. One of his dad's biggest mistakes was that he didn't stick around to get to know what a wonderful boy Joshua is.
Make sure he understands that his father left because of his own problems, not because of anything he did. Tell him that it's okay to be sad that his father left, and it's even okay to be mad at him for leaving. But you should also explain that God doesn't want us to hold grudges against people.
Even though dad isn't around, Joshua is blessed to his grandfather and your boyfriend in his life. Their affirmation and attention will help him understand how special and valuable he is.
They can also share truths about God's love with him…helping him to understand that while his earthly father left him, his Heavenly Father will never leave him or forsake him.
Thanks for writing, Cindy. I'm Bill Maier for WBCL.
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Learn how to make your own motion-activated light for Halloween decorating.
Step aside, puny human. Miss Flufferboots has her own Instagram account thanks to a fun publicity stunt by Whiskas Australia.
In this week's episode of The Fix, we show you how to make your own motion-activated light for Halloween decorating, how to create a festive party atmosphere using Phillip Hue lights and your smartphone, and how to carve a pumpkin using free online templates.
The Wave gesture-recognition feature remains disabled, but the Nest Protect 2.0 software will help mitigate certain false alarms, and introduces some useful new features in the app.
Today's smart devices can light up your home or watch out for intruders -- but what happens when you get creative?
Due early next month, the remote control will help Xbox One owners control their Blu-ray discs, streaming video, and more.
Turn yourself into a high-tech Harry Potter with the Technomancer digital spell-casting hoodie.
Messing around with Black & Decker's intuitive, easy-to-use driver is a delight, especially since it looks like a sci-fi prop.
A concept dog bone uses the sound of your voice and your smell to ease the mind and spirit of dogs with separation anxiety.
Call a cab and wash your hands. Talking urinal cakes in Michigan use a lady's voice to remind male drinkers to be safe.


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Bat Detectives
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Family Program
Apr. 27, 2013 | Saturday, 8:00pm
Multiple Times:
Pre-registration required, ages 8+, children under 16 must be accompanied by an adult
Location: Prairie Ridge Ecostation - Outdoor Classroom
Have you ever wondered how bats communicate, hunt, and pollinate flowers in the dark? Join us for Bat Detectives and find out! With the help of local expert Nick Dowdy, search for bats with bat detectors along the Prairie Ridge trails, learn about our local bat species, discover how moths have learned to avoid being eaten by bats, and how you can help scientists learn more about bat sounds right from your own home. Dress for the weather, bring a flashlight, and get ready for a nighttime bat adventure at Prairie Ridge! Contact Chris Goforth at 919.707.8882 or firstname.lastname@example.com for more information or to register.


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So you have a pre-teen that is gaga over Lady Gaga, make up and sparkles,…
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Maria "Mia" Tynes, Barbizon of Jackson alum, has recently signed on with JEA Model Management…
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Barbizon student Maya B walked the runway at Pensacola Fashion Week.
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A Fergus Falls teen was injured in a rollover accident in Redwood County Tuesday evening. 16-year-old Summer Vogl lost control of her 2004 Buick on Eagle Avenue in Johnsonville Township and the vehicle rolled and came to rest on it's roof. Rescue crews from Walnut Grove and Tracy responded to the scene. Vogl was taken to the Tracy Hospital for treatment of minor injuries. The Redwood County Sheriff's Office is investigating the accident.
Redwood County Rollover


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A compound for use as a diagnostic or therapeutic pharmaceutical and method of using the same where the compound consists essentially of an alpha-melanotropin stimulating hormone analog which has integrally located a radionuclide. The radionuclide is administered to the body in an amount sufficient to allow uptake and retention by the tumor cells.
1. A compound for use as a diagnostic or therapeutic pharmaceutical, said compound consisting essentially of:
an alpha-melanotropin stimulating hormone; and
a radionuclide directly bound in said alpha-melanotropin stimulating hormone analog includes a disulfide bond and an oxo group; said disulfide bond being replaced by a radionuclide; said radionuclide being a transition element; said radionuclide being bound to the two sulfide groups of said disulfide bond and said oxo groups; and said radionuclide being bound to two other groups selected from the group comprising amide, amine or sulfhydryl.
2. The compound of
Metal ions often play critical roles in protein structure and function. Engineered metal-binding sites in peptides and proteins have been widely used to enhance structural integrity, stabilize biologically active conformations, and confer novel enzymatic activities (Iverson, B. L., 1990; Regan, L., 1993; Kellis, J. T. Jr., 1991). Biochemical and structural analyses of transition metal coordination by proteins and peptides have traditionally focused on zinc, copper, manganese, and iron due to their roles in important biological processes (Klemba, M., 1995; Kruck, T. P. A., 1976; Lau, S., 1989; Franco, R., 1995). Other transition metals, not found in natural proteins, have coordination, isotopic, and chemical properties which make them attractive for peptide and protein engineering. Rhenium (Re) and Technetium (Tc) are group VIIB transition metals which share similar coordination geometries and form stable complexes with amine and amide nitrogens, carboxylate oxygens, and thiolate and thioether sulfurs, with a strong preference for thiolate sulfurs (Vanbilloen, H. P., 1995). Radioactive isotopes of Re and Tc have significant medical applications due to the nature of their associated radiation and physical half-life properties.
The synthesis and characterization of radiolabeled antibodies, peptides, and steroid hormones as in vivo tumor imaging and therapeutic agents are active areas of cancer research today. These molecules specifically target tumor cells by virtue of their high specificities for receptors and antigens present on the surfaces of these cells. In one commonly used approach, metallic radionuclides such as 186Re, 188Re, and 99mTc are appended to the tumor targeting molecule through bifunctional chelate groups which consist of a metal chelate and an activatable crosslinker (Bakker, W. H., 1991; Fritzberg, A. R., 1988; Liu, S., 1996). The resulting radiolabeled proteins, peptides, and small molecules are decorated with one or more chelating groups. The presence of bulky metal chelating groups and their associated crosslinkers may affect receptor affinity and biodistribution in vivo (Krenning, E. P., 1992; Wraight, E. P., 1992).
An alternative approach to the design of radiolabeled tumor imaging and therapeutic agents involves incorporating the metal directly into the molecule's structure (Varnum, J. M., 1994; Varnum, J. M., 1996; Chi, D. Y., 1994). Metal centers with defined coordination geometries can provide a foundation for the construction of stable molecular structures which have high affinities for specific receptors or antigenic sites. Protein, peptide, and small molecule structures can be designed to use metal coordination to reduce conformational freedom, stabilize active conformations, or mimic native conformations.
Alpha melanocyte stimulating hormone (α-MSH) is a tridecapeptide [Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2] that regulates skin pigmentation in most vertebrates (Hruby, V. J., 1993). The core α-MSH sequence His-Phe-Arg-Trp, conserved in a number of species, has been found to be sufficient for receptor recognition (Hruby, V. J., 1993). α-melanotropin is a naturally occurring tridecapeptide that specifically recognizes melanotropin receptors. Since mouse melanoma cells and human melanocytes possess α-melanotropin (α-MSH) receptors, the use of radiolabeled α-MSH analogs for diagnosis and treatment of α-MSH positive cancers (i.e., melanoma) was hypothesized. Various synthetic α-melanotropin analogs have been prepared and characterized for α-melanotropin activity by V. J. Hruby, M. E. Hadley et al. They have reported that cyclic analogs of α-MSH (as described by U.S. Pat. No. 4,485,039; 1984) display properties which increase their potency toward the α-MSH receptor, prolong their activity and increase their resistance to in vivo enzymatic degradation.
In 1990, D. R. Bard, C. G. Knight and D. P. Page-Thomas filed an international patent application for targeting malignant melanoma with multiple α-MSH analogs chemically attached to a chelating molecule (e.g. DTPA) which can subsequently be linked to a cytotoxic agent or radionuclide (e.g., In-111 or I-131). The literature reports by these authors describe the use of In-111-labeled analogs of the patented moieties for use as diagnostic agents for malignant melanoma.
The peptide analog used as the starting material for the Re and Tc labeling reactions was first described by Wayne L. Cody et al. as a superpotent α-MSH analog with prolonged biological activity. This analog is now commercially available. However, neither the use of Re or Tc to covalently cyclize α-MSH analogs, nor Re or Tc radiolabeling studies using this analog have been reported.
One radiolabeled α-MSH analog has been reported as a targeting agent of the radionuclide Indium-111. This analog consists of two des-acetyl-MSH molecules crosslinked through the chelating group DPTA. In vivo work on this analog was carried out under Home Office project license number PPL 70/00499, and was reported in Bard, D. R. et al. No studies have been reported which attach medically important radionuclides to α-MSH via peptide chelating groups.
The development of new diagnostic and therapeutic agents for treating cancer is an important area of research, since so many people develop cancer during their lifetimes. Melanomas are particularly difficult to treat successfully because they are very aggressive (early metastasis) and have proven resistant to general chemotherapy and external radiation treatment. The use of specific biological molecules, such as α-MSH, to target melanoma with diagnostic and radiotherapeutic agents is needed.
It would be useful to have a method of radiolabeling the peptide directly without the use of a separate chelating ligand and the peptide linkage group. This would alleviate some of the difficulties currently observed with the incorporation of these functionalities, such as lowered ED50 values and increased nonspecific localization.
According to the present invention, there is provided a compound for use as a diagnostic or therapeutic pharmaceutical consisting essentially of an alpha-melanotropin stimulating hormone analog which has integrally located a radionuclide. The radiolabeled alpha-melanotropin is administered to the body in an amount sufficient to allow uptake and retention by the tumor cells.
Other advantages of the present invention will be readily appreciated as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings wherein:
The file of this patent contains at least one drawing executed in color. Copies of this patent with color drawing(s) will be provided by the Patent and Trademark Office upon request and payment of the necessary fee.
FIG. 1 depicts the chemical structure of the alpha-meloantropin hormone stimulating analogs;
FIG. 2 is graphs showing the chemical shift changes upon rhenium binding to two α-MSH analogs; the changes in chemical shift being calculated according to the formula Δδ=(δmetal-bound−δmetal-free); a high degree of chemical shift disruption being seen within the core receptor recognition sequence in ReMSH (A); ReCCMSH (B) showing a much lesser degree of chemical shift disruption of core sequence residues, while metal-coordinating residues bracketing the core sequence are highly disturbed; and
FIG. 3 is an image of a melanoma tumor in a mouse injected with TcCCMSH; the γ-camera image of the melanoma bearing mouse being acquired 30 minutes post injection and the lateral image of the mouse with a 400 milligram tumor shows a high degree of radioactivity localized in the tumor (b) with lesser amounts present in the kidneys (a), bladder (C), and tail vein injection site (d); the intensity of the γ-emission being color coded high to low, ranging from white-yellow through orange, with dark red representing lowest values.
Generally, the present invention provides a compound for use as a diagnostic or therapeutic pharmaceutical and method of using the same; however, they may also be used for other pharmaceutical applications. Alpha melanocyte stimulating hormone (α-MSH) is a tridecapeptide [Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2] that regulates skin pigmentation in most vertebrates (Hruby, V. J., 1993). The core α-MSH sequence His-Phe-Arg-Trp, conserved in a number of species, has been found to be sufficient for receptor recognition (Hruby, V. J., 1993). The presence of α-MSH receptors on both murine and human melanoma cells (Tatro, J. B., 1989; Siegrist, W., 1989) suggests that α-MSH analogs might be developed into targeted imaging or therapeutic agents. Several analogs of a-MSH have been radiolabeled either with halogens or with transition metal radionuclides coordinated by bifunctional chelates (Bard, D. R., 1990; Bagutti, C., 1994; Garg, P. K., 1996; Vaidyanathan, G., 1997).
More specifically, the present invention provides 188Re or 99mTc radiolabeled α-MSH analogs in which metal coordination is an integral part of the molecules' structure. It was hypothesized that cyclic α-MSH analogs, engineered to incorporate radionuclides directly into their structures, would display exceptional stability, biodistribution, and tumor targeting properties. Rhenium bound α-MSH analogs were synthesized and characterized to determine if different metal incorporation strategies resulted in molecules with varying structural stabilities and bioactivities.
Incorporation of Re into an initial α-MSH analog resulted in decreased stability and receptor affinity. Structural characterization of the Re bound α-MSH complex indicated that metal coordination dramatically altered the core receptor binding sequence. Correlation of structural changes with functional changes in the initial Re bound α-MSH complex provided the foundation for the design of a second generation ReCCMSH analog with greatly improved stability and bioactivity. Initial in vivo tumor targeting experiments show that the corresponding 99mTcCCMSH analog is able to image melanoma in a murine tumor model system. These results indicate that 99mTc- and 188Re-CCMSH analogs have potential as melanoma imaging and therapeutic agents.
The results demonstrate that the application of structure based molecular design in the development of α-MSH receptor-avid peptides that were cyclized through the coordination of the transition metals Re and Tc. Several cycles of peptide design, synthesis, structural analysis, and functional characterization were employed to develop α-MSH analogs that incorporated Re and Tc into their structures while retaining high affinity for their cognate receptors present on melanoma cells. That the 99mTcCCMSH analog was able to target melanoma in a murine tumor model system demonstrated the use of these compounds for melanoma imaging or therapy. The compounds are generally of the formula:
where X=any amino acid, n=1 to 1000, and M=transition metal.
where all three Cys—SH groups are involved in metal coordination.
The radionuclide bound α-MSH complex is administered and dosed in accordance with good medical practice, taking into account the clinical condition of the individual patient, the site and method of administration, scheduling of administration, patient age, sex, body weight and other factors known to medical practitioners. The pharmaceutically "effective amount" for purposes herein is thus determined by such considerations as are known in the art. The amount must be effective to achieve improvement including but not limited to elimination of all cancer cells and to improved survival rate or more rapid recovery, or improvement or elimination of symptoms and other indicators as are selected as appropriate measures by those skilled in the art.
In the method of the present invention, the radionuclide bound α-MSH complex can be administered in various ways. It should be noted that the radionuclide bound α-MSH complex can be administered as the compound or as pharmaceutically acceptable salt and can be administered alone or as an active ingredient in combination with pharmaceutically acceptable carriers, diluents, adjuvants and vehicles. The compounds can be administered orally, subcutaneously or parenterally including intravenous, intraarterial, intramuscular, intraperitoneally, as well as intrathecal and through infusion techniques. Implants of the compounds are also useful. The patient being treated is a warm-blooded animal and, in particular, mammals including man. The pharmaceutically acceptable carriers, diluents, adjuvants and vehicles as well as implant carriers generally refer to inert, non-toxic solid or liquid fillers, diluents or encapsulating material not reacting with the active ingredients of the invention.
It is noted that humans are treated generally longer than the mice exemplified herein which treatment has a length proportional to the length of the disease process and drug effectiveness. The doses may be single doses or multiple doses over a period of several days. The treatment generally has a length proportional to the length of the disease process and drug effectiveness and the patient species being treated. Optimal dosing schedules may be calculated using measurements of drug accumulation in the body. Practitioners of ordinary skill in the art can readly determine optimum dosages, dosing methodologies, and repetition rates. Optimum dosages may vary depending on the relative potency of radionuclide bound α-MSH complex, and can generally be determined based on ED50 values in in vitro and in vivo animal studies and clinical trials.
When administering the radionuclide bound α-MSH complex parenterally, the radionuclide bound α-MSH complex will generally be formulated in a unit dosage injectable form (solution, suspension, emulsion). The pharmaceutical formulations suitable for injection include sterile aqueous solutions or dispersions and sterile powders for reconstitution into sterile injectable solutions or dispersions. The carrier can be a solvent or dispersing medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Nonaqueous vehicles such a cottonseed oil, sesame oil, olive oil, soybean oil, corn oil, sunflower oil, or peanut oil and esters, such as isopropyl myristate, may also be used as solvent systems for compound compositions. Additionally, various additives which enhance the stability, sterility, and isotonicity of the compositions, including antimicrobial preservatives, antioxidants, chelating agents, and buffers, can be added. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. In many cases, it will be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. According to the present invention, however, any vehicle, diluent, or additive used would have to be compatible with the compounds.
Sterile injectable solutions can be prepared by incorporating the compounds utilized in practicing the present invention in the required amount of the appropriate solvent with various of the other ingredients, as desired.
A pharmacological formulation of the radionuclide bound α-MSH complex can be administered to the patient in an injectable formulation containing any compatible carrier, such as various vehicle, adjuvants, additives, and diluents; or the compounds utilized in the present invention can be administered parenterally to the patient in the form of slow-release subcutaneous implants or targeted delivery systems such as monoclonal antibodies, vectored delivery, iontophoretic, polymer matrices, liposomes, and microspheres. Examples of delivery systems useful in the present invention include: U.S. Pat. No. 5,225,182; 5,169,383; 5,167,616; 4,959,217; 4,925,678; 4,487,603; 4,486,194; 4,447,233; 4,447,224; 4,439,196; and 4,475,196. Many other such implants, delivery systems, and modules are well known to those skilled in the art.
A pharmacological formulation of the radionuclide bound α-MSH complex utilized in the present invention can be administered orally to the patient. Conventional methods such as administering the compounds in tablets, suspensions, solutions, emulsions, capsules, powders, syrups and the like are usable.
Known techniques which deliver the radionuclide bound A-MSH complex orally, subcutaneously or parenterally including intravenous, intraarterial, intramuscular, and intraperitoneally as well as intrathecal techniques and retain the biological activity are preferred.
For delivery within the CNS, intrathecal delivery can be used with for example an Ommaya reservoir. U.S. Pat. No. 5,455,044 provides for use of a dispersion system for CNS delivery or see U.S. Pat. No. 5,558,852 for a discussion of CNS delivery. In addition, pharmacological formulations that cross the blood-brain barrier can be administered. [Betz et al., 1994; Brem et al., 1993] Such formulations can take advantage of methods now available to produce chimeric peptides in which the present invention is coupled to a brain transport vector allowing transportation across the barrier [Pardridge, et al., 1992; Pardridge, 1992; Bickel, et al., 1993]. Further, in appropriate cases blood-brain barrier disruption can be utilized [Neuwelt et al., 1980].
In one embodiment, the radionuclide bound α-MSH complex can be administered initially by intravenous injection to bring blood levels of radionuclide bound α-MSH complex to a suitable level. The patient's radionuclide bound α-MSH complex levels are then maintained by an oral dosage form, although other forms of administration, dependent upon the patient's condition and as indicated above, can be used. The quantity of radionuclide bound α-MSH complex to be administered will vary for the patient being treated and will vary from about 100 ng/kg of body weight to 100 mg/kg of body weight per day and preferably will be from 10 μg/kg to 10 mg/kg per day.
The above discussion provides a factual basis for the use of α-melanocyte stimulating hormone analogs radiolabeled with Re and Tc. The methods used with and the utility of the present invention can be shown by the following non-limiting examples.
Materials and Methods
Synthesis and Purification of Peptide-Metal Complexes.
The peptides NA-Cys-Glu-His-D-Phe-Arg-Trp-Cys-Lys-Pro-Val-NH2(Cody, W. L., 1985) and NAc-Cys-Cys-Glu-His-D-Phe-Arg-Trp-Cys-Lys-Pro-Val-NH2 were synthesized using standard Fmoc chemistry. ReMSH was synthesized using the exchange complex ReOCl3(Me2S) (OPPh3) (Grove, D. E., 1966; Bryan, J. C., 1987) by incubation of 1:1 peptide:exchange complex in 62% MeOH, pH=8-9 at 65-70° C. for one hour. ReCCMSH was synthesized using the exchange complex Re-glucoheptonate by incubation of 1:1 peptide:exchange complex in 62% MeOH, pH=8-9 at 65-70α C. for one hour. Both complexes were purified by C18 reverse phase HPLC. ReMSH was further purified by normal phase HPLC using a polysulfoethyl aspartamide column from PolyLC Inc. Both complexes underwent Ellman's analysis to test for the presence of free sulfhydryl groups (Ellman, G. L., 1959). The identity of ReCCMSH was confirmed by ESI-MS at Mallinckrodt Inc., St. Louis, Mo.: m/z (M+H)+ obs.=1648.1, calc.=1647.9. The identity of ReMSH was confirmed by FAB-MS at the University of Kansas mass spectrometry facility: m/z (M+H)+ obs.=1546, calc.=1544.8.
99mTcO4 − was obtained from a 99Mo/99mTc generator produced by Mallinckrodt, Inc. 188Re was obtained from a 188W/188Re generator produced by the University of Missouri research reactor. Radiolabeled peptides were prepared by substitution onto either 99mTc- or 188Re- glucoheptonate. For 188Re complexes, 500 μL of generator eluant was added to a tube containing 50 mg Na-glucoheptonate and 10 mg SnCl2·2H2O dissolved in 200 μL N2-purged 5% disodium-EDTA and heated at 70-80° C. for 0.5 hour. 50 μL of a 1 mg/mL peptide solution was then added, the pH was adjusted to 7-8 with 0.5 N NaOH, and the mixture was allowed to incubate for 90 minutes. at 70-80° C. Syntheses of 99mTc-labeled peptides differed only in that they were carried out at 25° C. using a 10-fold lower concentration of SnCl2·2H2O. Radiolabeled complexes were analyzed by coinjection on a C18 reverse phase-HPLC column, and in all cases were found to coelute with the previously characterized nonradioactive standards.
NMR Data Collection and Processing.
NMR data were collected on a 500-MHz Bruker AMX or DMX spectrometer and processed on a Silicon Graphics Inc. (SGI) XZ4000 workstation using the SYBYL program (Tripos, Inc.). The 1H data were collected in 90%H2O/10%D2O at concentrations ranging from 4-10 mg/mL. All spectra were recorded using the time-proportional phase incrementation (TPPI) method. In most cases, the spectral width was 6000 Hz. Typically the data set size was 2048(t2)×256(t1) blocks with between 16-64 scans/fid. TOCSY spectra were collected using an 80 ms mixing time; the NOESY and ROESY mixing time was 200 ms.
For APOMSH and ReMSH experiments, H2O suppression was carried out using the WATERGATE pulse sequence (Piotto, M., 1992). A 1—1 jump return sequence was used in some 1D experiments for H2O suppression. Data sets were multiplied by a 0-90° shifted sinebell squared transformation function and zerofilled to 1024k in t1 prior to Fourier transformation. 2D spectra for the peptide-metal complexes were collected at 298K. For APOMSH, additional 2D spectra were collected at 278K. 3JαNH data were gathered from resolution enhanced 1D spectra for each compound. Temperature gradient studies spanned 278K-308K for each compound.
Molecular Modeling.
Molecular modeling studies were performed on an SGI XZ4000 workstation using the SYBYL program. For each complex, random starting structures were generated from restrained MD simulations in vacuo, using a single distance restraint between thiol sulfurs to initially close the ring. Modeling of metal coordination was based on small molecule structures from the Cambridge Crystallographic Database (Grummon, G., 1995; Hansen, L., 1992; Rao, T. N., 1991). Charges were not included in the modeling of peptide-metal complexes. The metal coordination sphere was maintained via a system of interrelated geometrical restraints. Peptide models consistent with NMR-derived distance restraints were obtained by sequential application of restrained molecular dynamics and minimization using the Powell method (Powell, M. J. D., 1977). Conformational searches were carried out using a simulated annealing protocol. The APOMSH structures were heated to 2000K, then cooled to 300K. Metal-bound structures were only heated to 800K due to the highly restrained nature of the metal center. Structures emerging from simulated annealing runs were minimized to convergence (gradient<0.05 kcal/mol*Å) and compared using the FIT algorithm within SYBYL.
Bioactivity and Receptor Binding Assays.
Peptide bioactivity was determined by measuring melanin released into cell culture media in an in vitro assay using B16Fl murine melanoma cells (Siegrist, W., 1986). Cells were incubated with various concentrations of peptide and assayed for melanin production by measuring the absorbance of the culture media at 405 nm. Absorbance values were compared to a standard curve obtained using synthetic melanin from Sigma. The standard curve was linear over the experimental range of absorbance values.
Quantitative receptor binding assays were carried out following a previously described method (Siegrist W., 1988; Sahm, U. G., 1994). Cells were seeded at a density of 5×105 cells per well in 24 well tissue culture plates and exposed to varying concentrations of peptides on 0.5 mL of binding media (25 mM HEPES/NaOH pH=7.4, 0.2c BSA, 0.3 mM 1,10-phenanthroline, and approximately 100,000 CPM of 125I-[Nle4, D-Phe7]-α-MSH) (36) at 4° C. for 8 hours. The cells were rinsed with PBS, lysed with 1 M NaOH and counted in a 1275 minigamma gamma counter from LKB Wallac.
Imaging Studies.
Six week old C57BL/6 mice (Harlan, Sprague, Dawley, Inc.) were injected in the right flank with 1×106 B16-Fl mouse melanoma cells. Tumors, approximately 200-400 mgs, appeared 10 days post injection. Each mouse was given 25 μCi of 99mTcCCMSH by tail vein injection. The mice were sacrificed thirty minutes post injection and the images were acquired by a Prism XP3000 triple head γ camera (Picker, Inc.) equipped with a low-energy high resolution parallel collimator. The images were collected on a 512 matrix with 3.999 magnification.
The biodistribution and pharmacokinetics of the 99mTc and 188Re labeled cyclic α-MSH peptide analogue (CCMSH) were examined in a C57BL/6 murine melanoma animal model. 1×106 B16-Fl melanoma cells were injected subcutaneously to induce tumor formation. Tumors, 200-400 milligrams in weight, appeared approximately 10 days post injection. Normal and tumor bearing mice were injected with 2-3 μCi of 99mTc or 188Re labeled CCMSH. At various times post-injection the mice were sacrificed and the individual tissues were counted.
Results and Discussion
Metal-binding Site Design.
Molecular modeling was used to design and evaluate cyclic α-MSH analogs for their potential to incorporate Re or Tc into their structures. Several different factors were taken into account in the design of rhenium- and technetium-binding sites, including metal coordination geometry, donor atom selection, and peptide conformation. Both Tc and Re, when in the +5 oxidation state, prefer a square pyramidal coordination geometry. Structural studies of small organic complexes of these metals have shown that donor atoms are located at the corners of a square plane, with a monooxo group of located above, at the apex of a square pyramid (Grummon, G., 1995; Hansen, L., 1992; Rao, T. N., 1991).
Another determinant of the metal-binding site was the known preference of these metals for specific donor atoms (i.e. S>N>>O) (Vanbilleon, H. P., 1995).
A third important factor was determined not by the metal, but by the structure of the peptide itself. The metal binding site must be engineered so that metal coordination does not disrupt the biologically active conformation of the molecule. The cyclic α-MSH analog Cys4,10, D-Phe7-α-MSH4-13 (Cody, W. L., 1985) was used as the starting point of our studies. Cys4,10, D-Phe7-α-MSH4-13 (APOMSH) retains a core sequence of residues, His-D-Phe-Arg-Trp, which has been found to be sufficient for the bioactivity of a α-MSH (Hruby, V. J., 1993). In the development of this peptide it was found that cyclization and incorporation of a D-amino acid in position 4 both increased the potency and prolonged the biological effect of this analog relative to wild-type-α-MSH (Cody, W. L., 1985).
Initial Rhenium Complexation.
The cyclic rhenium α-MSH analog ReMSH was synthesized by incorporation of a Re(V)O core into APOMSH. Rhenium was introduced into a pre-reduced sample of APOMSH via transchelation from ReOCl3(Me2S) (OPPh3). A FAB-MS spectrum confirmed the expected molecular weight of a 1:1 peptide:metal complex. Initial 2D NMR studies of ReMSH showed that 2 amide proton resonances were absent compared to the metal-free peptide. The two amide 1H resonances missing in the ReMSH spectrum were assigned to Trp9 and Cys10 (Table 1). These results suggested that the thiolate sulfur of Cys10 and the two preceding amide nitrogens form three corners of a square plane of donor atoms.
Chemical shift alterations of Cys4βH's, as well as Ellman's analysis, showed that the fourth donor atom in the coordination sphere of rhenium was the thiolate sulfur of Cys4. As a result of this binding geometry, ReMSH possesses three metal-containing rings, two five-membered rings and one eighteen-membered ring (FIG. 1). Thus, the ring size of ReMSH was reduced from a 23-membered ring in APOMSH to an 18-membered ring.
The ReMSH metal coordination geometry included the amide nitrogen of Trp, which is a member of the core sequence of residues responsible for α-MSH binding to its receptor. Some decomposition of the ReMSH complex was observed by NMR over time. Ellman's analysis of ReMSH NMR samples revealed that approximately 3% of the cysteine residues within the molecule were present as free thiols.
To analyze the structural effects of rhenium incorporation into the α-MSH analogs, NOESY spectra of both APOMSH and ReMSH were examined and sequential and nonsequential NOE's were identified. For each compound, NOE derived distance restraints were grouped into either strong, medium, or weak categories based on their intensities. These restraints were then applied to randomly generated starting structures within SYBYL. In modeling the ReO core, geometrical restraints (range, angle, and torsion) were employed in conjunction with a pseudoatom representing the rhenium metal. The geometric restraints were optimized to maintain a square planar array of donor atoms in a model rhenium-peptide compound (Cys-Gly-Cys). Previous structural analysis demonstrated that the tetrapeptide NAc-Cys-Gly-Cys-Gly formed a stable N2S2 Re chelate (Giblin, M. F., 1997). Refinement of α-MSH models was carried out using a restrained molecular dynamics/simulated annealing protocol, followed by restrained energy minimization. In each case, the average structure from the final MD cycle was found to have no range violations greater than 0.1 Å.
For the ReMSH molecule, 20 cycles of MD/annealing/minimization converged to a single family of structures, with backbone RMSD's ranging between 0.86-1.26 Å. Compared with the APOMSH structures, the ReMSH NMR structures converged to a much more tightly defined family which included a reverse turn centered on residues Glu5-His6. The higher degree of definition was due to a cross ring NOE between Cys4NH and Arg8αH not present in APOMSH and the smaller ring size of ReMSH. As with APOMSH, high values for temperature dependencies of amide 1H chemical shifts indicated that no intramolecular hydrogen bonds were present to stabilize the turn. 3JαNH values for ReMSH were systematically lower than for APOMSH, indicative of greater restraint in the peptide backbone of ReMSH due to its smaller ring size. Distortion of the ReMSH backbone relative to the APOMSH structures lead to differences in the presentation of core sequence sidechains. Rather than being located on the same face of the molecule distributed along a reverse turn, His, D-Phe and Trp sidechains were displayed along an extended backbone segment.
The proximity of key residues within ReMSH to the metal center resulted in profound changes in their chemical environment in solution. The 1H chemical shift changes that occurred upon metal coordination are shown graphically in FIG. 2. Large chemical shift differences were expected for residues involved in metal-binding. For ReMSH, however, pronounced chemical shift changes occurred not only for coordinating residues, but also for other residues within the core sequence. NMR and crystallographic studies of monooxo Re(V) complexes have shown that protons oriented syn relative to the metal-oxo group are generally deshielded, while protons in an anti configuration are often shielded (Lever, S. Z., 1990). Alpha proton resonances of Arg and Trp were both highly deshielded, and Trp sidechain resonances were shielded. The closeness of the metal center to the Arg and Trp residues, most notably the Trp sidechain, may have contributed to the low receptor affinity of ReMSH.
The ReMSH model structures were strained due to the restraints imposed by Trp9N and Cys4S metal coordination. This increased strain was reflected experimentally in the low stability of the ReMSH molecule. As assessed by NMR, approximately 20% of the original ReMSH species had degraded after a 24 hour period. The decay of the ReMSH complex most likely represented a rearrangement of the donor atoms in the metal coordination sphere to relieve the strain introduced into the molecule by the Cys4 sulfur coordination. Release over time of the Cys4 sulfur as a free thiolate would be consistent with th e Ellman's ana lysis of the ReMSH complex. The same trends in stability were observed at the tracer level. Synthesis of 99mTc/188ReMSH confirmed the relatively low stability of ReMSH. Tab le 2 shows that in competition with 10 mM free cysteine, the 188ReMSH complex has a t˝ of approximately 4 hours. The analogous 99mTcMSH complex had an even shorter half-life, with a t˝ of less than 2 hours, consistent with an increased lability of Tc to substitution reactions.
The effect of metal incorporation on the bioactivity and receptor binding affinity of ReMSH is shown in Table 3. The bioactivities of APOMSH and the ReMSH complex were assayed by measuring stimulation of melanin production by B16-F1 murine melanoma cells. The EC50 values for melanin synthesis by APOMSH and ReMSH were 2.6×10−11 and 5.4×10−10, respectively. Incorporation of rhenium into ReMSH resulted in approximately a 20-fold decrease in the ability of the molecule to stimulate melanin production compared to APOMSH. Receptor binding assays were performed with APOMSH and ReMSH on B16-F1 murine melanoma cells. A decrease was observed in the ability of the ReMSH analog to displace an 125I-labeled α-MSH analog from the cells in a competitive receptor binding assay (Table 3). The Ki for the ReMSH complex was 6.6×10−8 which reflected an apparent 100 fold decrease in receptor binding affinity compared to APOMSH (Ki=6.8×10−10). Therefore, it appeared that the presence of the Re(V)O core or its effect on the solution structure of ReMSH significantly reduced the molecule's receptor affinity and biological activity.
Metal Binding Site Redesign.
Two different approaches were followed to create rhenium-MSH conjugates with improved receptor binding and bioactivity profiles. Structural information relating to ReMSH indicated that the metal-binding site was too close to residues essential for receptor binding. In one attempt to distance the metal-binding site from the His-D-Phe-Arg-Trp core sequence, a spacer Gly residue was inserted between the Trp residue and the C-terminal Cys. It was hypothesized that the addition of the Gly residue would displace the crucial Trp residue from the metal coordination sphere. The compound was synthesized using the same conditions used for the synthesis of ReMSH and resulted in a complex which appeared by FAB-MS to contain 2 rhenium-oxo groups per peptide molecule. Receptor binding data on this 2:1 rhenium:peptide complex showed no increase in binding affinity over ReMSH (data not shown). That this dimeric complex was the major product of two separate syntheses suggested that there may be an entropic barrier to the cyclization of larger rings via an Re(V)O core.
The second approach to generate a rhenium-MSH complex with increased receptor binding affinity involved the synthesis of an analog of APOMSH which contained an additional N-terminal Cys residue, termed Cys3. It was hoped that inclusion of this additional thiolate would drive the metal coordination sphere away from the His-D-Phe-Arg-Trp core sequence, by taking advantage of the increased affinity of Re and Tc for sulfur donor atoms over nitrogen. NMR characterization of this rhenium complex (ReCCMSH) indicated that only a single amide proton resonance had been lost upon Re complexation. The single amide 1H resonance lost in ReCCMSH was assigned to Cys4. Ellman's analysis of ReCCMSH revealed no free thiols present in the peptide-metal complex, suggesting that, as with ReMSH, all thiolates were involved in metal coordination. An ESI-MS spectrum confirmed the expected molecular weight of a 1:1 peptide:metal complex. In this case, the two N-terminal Cys thiolates in combination with the intervening amide nitrogen formed three corners of a square plane. The final donor atom was again the remaining thiolate, resulting in cyclization of the molecule. ReCCMSH was also a tricyclic molecule, with rings of 6, 5, and 24 members, respectively (FIG. 1). The size of the ring containing the core sequence of residues had increased by 6 atoms when compared with ReMSH.
The chemical shift disruption of core sequence resonances of ReCCMSH was far less pronounced than in ReMSH (FIG. 2), indicating that the disposition of core sequence residues was similar to that in APOMSH. That the major chemical shift changes in ReCCMSH were associated with the resonances of Cys4, Glu5, and Cys10 indicated that the metal-binding site was successfully moved away from the His-D-Phe-Arg-Trp core receptor binding sequence.
Compared with ReMSH, ReCCMSH displayed increased flexibility due to its larger ring size. Sequential NH—NH NOE's were observed in the region of the backbone between Glu5 and Arg8, indicating the presence of a reverse turn. However, broadening and overlap of amide resonances suggested that conformational exchange between more than one structure was occurring. Increasing the temperature to 313K sharpened and resolved the His6, Arg8, Trp9, and Cys10 resonances. Use of a jump-return sequence in place of presaturation for H2O suppression did not affect the magnitude of these amide resonances, indicating that conformational and not chemical exchange was responsible for this broadening. The increased flexibility of the 24-membered ring was reflected in increased backbone RMSD's between structures resulting from the MD/simulated annealing protocol.
The 99mTc- and 188Re-labeled analogs of ReCCMSH were virtually inert to substitution in 10 mM Cys competition assays, while the 99mTc- and 188Re-labeled analogs of ReMSH were readily exchanged under the same assay conditions (Table 2). This increased stability of ReCCMSH probably resulted from the presence of an additional sulfur donor atom and from decreased backbone strain in the molecule due to the increased ring size. Both the bioactivity and receptor binding affinity of ReCCMSH were greatly improved relative to ReMSH. The ability of the ReCCMSH analog to stimulate melanin production was almost identical to APOMSH (Table 3). The ReCCMSH analog exhibited a receptor binding affinity of 2.9 nM, which was approximately 25-fold higher than that of ReMSH (Table 3). Redesign of the Re coordination site in ReCCMSH appeared to relieve internal steric constraints within the core receptor binding sequence that resulted in greatly improved radiochemical stability and receptor affinity.
In vivo Biodistribution and Tumor Targeting.
The biodistribution and pharmacokinetics of the 99mTc and 188Re labeled CCMSH were examined in a murine melanoma animal model. Both the 99mTc-CCMSH and 188Re-CCMSH analogues showed rapid clearance, with the kidneys acting as primary route of excretion (Tables 4 and 5). In melanoma bearing mice, the 99mTc-MCCMSH molecule accumulated rapidly in the tumor and remained at 10.88±0.54% dose/gram out to 4 hours (Table 4). The 188Re-CCMSH analogue also showed rapid tumor uptake in melanoma bearing mice with no significant accumulation in any vital organ (Table 5). The percent dose/gram tumor uptake of the 188Re-CCMSH analogue was 10.89±2.27 at 0.5 hours, and 3.24±0.63 at 12 hours. By 24 hours the tumor dose/gram was 1.72±0.39% with a tumor/blood ratio of 207.90.
In vivo tumor localization. The ability of 99mTc labeled CCMSH to target solid melanoma tumors in vivo was examined in a C57BL/6 mouse model. 25 μCi of 99mTcCCMSH was injected into the tail vein of a mouse bearing a 0.4 gram melanoma tumor in the right flank. Anterior and lateral scintigraphic images of the mouse were acquired 30 minutes post injection. Significant accumulation of the 99mTc-labeled peptide was clearly visible in the melanoma tumor (FIG. 3). These results show that the 99mTc-CCMSH analog was capable of imaging melanoma tumors in vivo. Radioactivity was also present in the kidneys and bladder, which are the primary route for peptide excretion. A 99mTc-labeled bombesin peptide analog was also injected into a tumor-bearing mouse as a control for peptide targeting specificity. The radiolabeled bombesin analog did not display selective tumor uptake (data not shown). In conclusion, the data presented in this application results demonstrated that the redesigned 99mTcCCMSH molecule was capable of selectively targeting melanoma tumors in vivo. Detailed distribution studies are underway with the 99mTc- and 188Re-labeled CCMSH analogs exhibit rapid tumor uptake, superior tumor residency and efficient whole body clearance.
Throughout this application, various publications, including United States patents, are referenced by author and year and patents by number. Full citations for the publications are listed below. The disclosures of these publications and patents in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
The invention has been described in an illustrative manner, and it is to be understood that the terminology which has been used is intended to be in the nature of words of description rather than of limitation.
Obviously, many modifications and variations of the present invention are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described.
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Maya on RH9 refresh problem
hi everybody
I am running lunix pro (RH9) with Nividia Gforce FX5200 card, MSI Neo K8. When i switch view port using space bar, view ports are not refreshing.
Re: Maya on RH9 refresh problem
Hi somushiv,
Unless I am very much mistaken this is not an Nvidia problem, but rather a Maya / RedHat 9 problem. Does everything apart from the viewports refresh look okay to you? For instance, your display as a whole _does_ refresh, yes?
(There are a couple of places where running Maya on RedHat are discussed, perhaps you will find an answer there. Googling "maya redhat 9" or something similar will get you started. Happy hunting. ;-)
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Industrial Cleaning Companies in Alabama
Category: Waste & Recycling ×
Subcategory: Industrial Cleaning ×
Industry: Chemical & Pharmaceuticals ×
Location: USA ×
Location: Alabama ×
Alfred Karcher GmbH & Co. KG
based in Winnenden (Germany), GERMANY
Especially in the Professional sector there`re various cleaning tasks with different and individual requirements. Karcher can solve them without any problems through their specially developed equipment. Equal for small or big industrial and commercial companies, hospitality or agriculture Karcher offers the right cleaning solution for sustainable and environmentally ...
Veolia North America, Industrial Business
based in Lombard, ILLINOIS (USA)
The three divisions of Veolia North America providing technical solutions, industrial services and industrial water solutions have been brought together under our shared Corporate name, Veolia North America, Industrial Business. Our parent company, Veolia, has worked hard to establish this worldwide brand. The decision to operate globally under a single brand name ...
C4 CONTROL de CONTAMINACION Ltda
based in Cali, COLOMBIA
C4 is an ISO 9000 company located in Colombia with 23 years dedicated to develop and produce equipment for air contamination, like scrubbers, Dust collectors, Filtration systems, Biofilter FRP Blowers and others, applications like odor control, critical dust collection or recovery, clean spaces, our plant have engineering (mechanic, electronic, environmethal and ...
Sentry Air Systems, Inc.
based in Houston, TEXAS (USA)
Founded in 1983, Sentry Air Systems, Inc. engineers clean air through the design and manufacturing of high quality air purification systems. Our patented line of quiet, compact and durable air cleaners offers simple and effective solutions to fume control and extraction. Our line of floor, bench top, mounted and portable units serve a variety of applications including ...
Vac-Tron Equipment
based in Okahumpka, FLORIDA (USA)
Vac-Tron Equipment is a pioneer and leading manufacturer of portable-trailer mounted industrial vacuum equipment. Vac-Tron Equipment is available in more than 30 configurations with dozens of wet and dry industrial, private and municipal uses including physical location of underground utility lines using vacuum, industrial clean-up, man-hole, lateral and storm drain ...
Clean Harbors
based in Norwell, MA, MASSACHUSETTS (USA)
Clean Harbors is North America's leading provider of environmental, energy and industrial services serving large and small, public and private entities, and numerous federal, state and local governmental agencies, providing a broad range of hazardous material management and disposal services including the collection, packaging, recycling, treatment and disposal of ...
The Spencer Turbine Company
based in Windsor, CONNECTICUT (USA)
Featuring single and multistage centrifugal blowers, Power Mizer high-efficiency cast centrifugal blowers, digester gas boosters, natural gas boosters, Vortex regenerative blowers, central vacuum systems, Industravac integral vacuum units (stationary and mobile), dry and wet separators, tubing and fittings, vacuum hoses, tools and valves and custom control panels. ...
based in Seal Beach, CALIFORNIA (USA)
BakerCorp is a market leader in tank, pump, filtration and shoring equipment rentals, with a network of locations including operations in North America, Europe, Canada and Mexico. Backed by a broad selection of high-quality industrial, liquid and solid-handling equipment, our exceptional team helps get our customers what they need, where they need it, on time.vThe Company ...
Advanced Environmental Options, Inc. (AEO)
based in Spartanburg, SOUTH CAROLINA (USA)
Advanced Environmental Options, Inc. (AEO)is a full-service company capable of managing all environmental issues from site remediation, lab packing, and emergency responses to managing the transportation and disposal of hazardous and non-hazardous waste. Our customers can feel confident that their environmental needs are met in complete compliance with state and federal ...
Körting Hannover AG
based in Hannover, GERMANY
The outward appearance of Körting Hannover AG has changed over the years – the pillars of success however have remained: specialisation in a leading trade mark engineering of products and know-how, entrepreneurship and employees with a marked engagement in the company. Team-thinking and discussions with our customers smooth the way to optimum results. Quick decisions ...


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Do yourself a favor and skip the Taurus. I have seen WAY too many complaints about these, including complete parts breakages. The Remington is a nice 1911 for the money.
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We created Pandora to put the Music Genome Project directly in your hands
It's a new kind of radio –
stations that play only music you like
Features of This Trackdisco grooves
mixed minor & major key tonality
string section beds
a vocal-centric aesthetic
the subtle use of a horn section
These are just a few of the hundreds of attributes cataloged for this track by the Music Genome Project.show more
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No one can touch that man's falsetto!!!! !
Dats awesome and I LOVE all the BG's songs!!!


text:
Self-control as Response Produced Time-out from a Stimulus Associated with Reinforcement and Response Independent Shock
Nelson, James Arnold
MetadataShow full item record
The problem: To control escape behavior (self-control) from a stimulus associated with response dependent food and response independent shock. Procedure: Five rats were trained in operant chambers to press a lever (lever A) for VI 30" food during one stimulus (S1) and never reinforced during another stimulus (S2). When responding stabilized a second lever (lever B) was introduced. The function of a response on lever B was to terminate S1 and produce S2 for three minutes. All subjects exhibited some S1 escape behavior. Following stabilization of S1 escape responses one of four frequencies of response independent shock (VI 15", VI 30", VI 60" or VI 3') was presented during S1. The number of time-out responses (S1 escape responses) was recorded for the different shock frequencies. Findings: All subjects responded to escape from a stimulus associated with response dependent food and response independent shock. In general the number of time-out responses increased as shock frequency increased and with increasing exposure to shock. Conclusions: Rats will exhibit a response defined as self-control. Recommendations: It would be recommended that further research: (1) determine the effects of different shock intensities; (2) attempt to assess the aversiveness of VI schedules.
29 leaves.
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Unstable Work Records and Delay of Gratification Internal-External Control of Reinforcement and Social Desirability Response Set Sprenger, Marcellus J. (Drake University, 1971-08)
Behavioral Contrast and Alternative Response Key Availability Townsend, Kari Lebeda (Drake University, 1992-09)The Problem. This study investigated the interaction of schedules of reinforcement on behavior, replicating and extending Keller's (1 974) research. Expanded methodology included two control manipulations designed to ...


text:
Resolution: standard / high
Figure 2.
Oculomotor performance as a function of age. Blue filled circles, control subjects (CTL); green diamonds, patients with only dopamine therapy (PD-DA) or with additional STN-DBS (PD-DBS-on, green diamonds framed by black squares); red triangles, DBS patients during stimulation off (PD-DBS-off). a, latency of reactive saccades; arrows link "on"- and "off"-data of those 4 Patients who exhibited latencies outside the CTL-range during "off" (range accidentally delimited by latency-on-age regression of PD-DA + DBS-on, green line); solid black arrows mark near significant changes (p < 0.059); dotted arrows, non-significant changes. b, c, gain of horizontal (b) and upward (c) smooth pursuit of a sinusoidally moving target (0.375 Hz, horizontal ± 20°, vertical ± 15°).
Pinkhardt et al. BMC Neurology 2012 12:5 doi:10.1186/1471-2377-12-5


text:
Popup dialog box in java
can create popup dialog box.
Java swing toolkit provide tow types of dialog box
Standard dialogs-Predefined dialog box available in swing toolkit.
Custom...Popup dialog box in java How to display popup dialog box in java
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Message dialog box is used to display informative... the appropriate message and user can finish the message dialog box
Show input dialog box
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Input dialog box is very important...
anything from user. Java Swing
provides the facility to input any thing (whether
Java error dialog
create an error dialog box we need
JOptionPane swing.
Understand with Example...;
A Java dialog box is an independent sub window that is used to notice a
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at the end of the interview, use a dialog box to ask whether the user wants...Java show series of at least four interview questions hello.
write... to accept the sets of responses until the user chooses to quit, and then display
Show Font Dialog and Color Dialog
In this section, you will learn creating color dialog box and font dialog in
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// return the password entered by the user...Authentication of password System level authentication of password
Message Box Java
Dialog Box in Java - Swing Dialogs
Show Message and Confirm Dialog Box... that accepts input from user
from text field or combo box.
Here is an example of displaying a message box using
Java Message Box
Java Message Box
In this tutorials you will learn about how to create Message Box in Java.
Java API provide a class to create a message Box in java... provided by the
user can be retrieved. A message box is meant to carry
Dojo Dialog Box
Dojo Dialog Box
 ... box
with tool tips and how to create it in dojo.
Dialog Box : Dialog box is a rectangular GUI box
that either requests or provides information. Some dialog
Display a dialog box with Java Error
the execution
of a program using javaw ,the program code display a dialog box name Java...
Display a dialog box with Java Error
 ... you a code that help you in
implementation of dialog box with Java Error
JList box java
JList box java
We are going to describe JList box java. First of all we have created JList
component of Swing. List is a component of GUI() Graphical User... the JComponent class in Swing. We can use select item from the combo
box because
dialog box
possible numeric choice answers.
at the end of the interview, use a dialog box to ask whether the user wants to
- enter another set of responses to the same set...dialog box hello.
write an application that displays a series
dialog box
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- enter another set...dialog box to ask to quit or continue hello.
write an application... of responses until the user chooses to quit, and then display the results of each
dialog box
of the interview, use a dialog box to ask whether the user wants to
- enter another set...dialog box to show latest question hello.
write an application... of responses until the user chooses to quit, and then display the results of each
dialog box
at the end of the interview, use a dialog box to ask whether the user wants...
continue to accept the sets of responses until the user chooses to quit
dialog box
of the interview, use a dialog box to ask whether the user wants to
- enter another set... of responses until the user chooses to quit, and then display the results of each
Show message and confirm dialog box
Show Message and Confirm Dialog Box - Swing Dialogs... use in
your swing applications, example of each type of dialog boxes... asks from the user by displaying a message dialog box which
contains more than
Password - Java Beginners
Thanks... charecter just as typing password in E-mail.ID without using applet... can we do...());
Box rowOne = Box.createHorizontalBox();
rowOne.add(new JLabel
Java Swing : JButton Example
Java Swing : JButton Example
In this section we will discuss how to create button by using JButton in
swing framework.
JButton :
JButton Class extends... dialog box
that provoke users for a value or some information. add()
Java Swing Tutorials
in Java Swing.
Dialog Box In Swing Application... for inputting anything from
user. Java Swing provides the facility to input any...
button in java swing. Radio Button is like check box.
Combo Box operation in Java Swing
Combo Box operation in Java Swing
 ... of javax.swing.*;
package. This method displays some messages in the special dialog box... the Combo
Box component, you will learn how to add items to the
combo box
Java Password Field
in Java.
To create a password field in Java Swing JPasswordField is used... into
which a user can login only when its name and password will be matched... = "Select name, password from user where name = '"+name+"'";
Dojo Show and Hide Dialog
dialog. In the following example, you will see there are two method that are
used for showing and hiding the dialog box.
show(): This method is used to display the dialog
hide(): This method is used to hide the dialog
how to let img act as file dialog box?
how to let img act as file dialog box? dear sir:
I'm trying to add... which is the text box plus the button written in it browse,NO. what i want is an image acts like input type"file". for example, if the user wants to upload his
Struts2.2.1 password tag example.
Struts2.2.1 password tag example.
In this tutorial, you will see the use of password tag of struts2.2.1. It is
a UI tag in struts framework. It display...;
Java file dialog
Java file dialog
In this section, you will learn how to display a dialog window through which
user can select a file.
Description of code
Irrespective... FileDialog that displays the modal dialog. It blocks the rest of
the application
Dojo Dialog Box
Dojo Dialog Box
In this section, you will learn about the dialog box
with tool tips and how to create it in dojo.
Try Online: Dialog
Dialog Box : Dialog box
Name make a program that take a input from user in alphabet and show all the name of that character
E.g User give character "B".
The program shows all the human names which starts from B.
Java show all names
Creating Check Box in Java Swing
Creating Check Box in Java Swing
component in Java Swing.
In this section, you can learn simply creating the
Check Box in Java Swing. Check Boxes are created in swing by creating the
AutoSuggestion Box in Java Swing
Auto Suggestion Box in Java Swing
In this section, you will learn how to create autosuggestion/autocomplete box in java swing.
For this, we have created combo box and add array of countries using
DefaultComboBoxModel to it. Now
Swing Program
Swing Program write a java swing program to get user name and password. The name contains only characters while password is masked with the character "*". Apply checks for all validation
Java swing store the encrypted password into database
Java swing store the encrypted password into database
In this tutorial, you... is an example that creates two fields to accept username and password from the user.
When the user enters the password field, the value is first encrypted
Java Graphical user interface
the name is typed into the name field, a dialog box should pop up to remind...Java Graphical user interface Hi, guys. I'm christina, need help..., or a return key is pressed in the text field, as shown in the Fig 1. The dialog box
retaining save dialog box even after clicking save button - Java Beginners
when i open save dialog box and input a file name that is already present...retaining save dialog box even after clicking save button I am... "no" to that dialog box i'm unable to get the save dialog box again.how coulg i
login-password - Java Beginners
//Please enter username
alert("Please enter User Name...
User Name...login-password complete code of login-password form then how
Swing Program
Swing Program Write a java swing program that takes name and marks as input with all validation. The name and marks will be displayed in message box when user clicks on a button
Java Alert Box
Java Alert Box
In this example we will describe java alert box. First of all we have created
class than main method after that we have created alert box method. In this
method display information message to the user. We use
Sitemap Java Swing Tutorial
Dialog Box Application in Java Swing |
Show Message and Confirm Dialog Box...-to-One Relationship |
JPA-QL Queries
Java Swing Tutorial Section
Java Swing Introduction |
Java 2D
Data Transfer in Java Swing
button to accept user input
database it just gives me an error.please help
Here is java swing example that accepts firstname, lastname and gender from user and insert to database... SwingExample(){
JFrame f = new JFrame("Frame in Java Swing");
Java Dialogs - Swing AWT
visit the following links:
Java swing
Java swing I create 2 text field f1,f2 and 2 button b1,b2.If i enter some text in the text field and click the button b1 the text field f1 text will be shown in the Message dialog box and if i click the button b2 the text field
What is Java Swing?
What is Java Swing?
Here, you will know about the Java swing. The Java
Swing provides... and GUIs components. All Java Swing classes imports form the import
Jcombo box - Swing AWT
complete half project with ur examples
sir i hav problem related to combo box
i..., H
c3 contains no items
now when a user selects item A in c1 and item E in c2 items 1,2,3,4 shud added to c3 at run time and if user selects item A in c1
Jdialog box with textfield - Java Beginners
Jdialog box with textfield i have to create a dialog box with 2 textFields(to take input from user) and 2 JLabels. how to do that please tell.thanks...;
JLabel label1=new JLabel("Enter Name");
JTextField text1 = new JTextField(10
dynamic drop down list box - Java Beginners
User Name:
---Select Name... a drop down box from an sql query in a servlet program, using only html... send an example.
At first u decide, u use servlet ot not, bcoz
about swing - Java Beginners
about swing how implement a program of adding two numbers by entering two numbers separately by other user on the input dialog box and after that also show the result of the addition in other dialog box...
your regardly
username and password in servlet
Please Enter Your User Name:
Please Enter Your Password...username and password in servlet i'm usng eclipse luna(java... it must display either invalid user
or valid user
here is what i done for login
java - Swing AWT
java i want a program that accepts string from user in textfield1 and prints same string in textfield2 in awt hi,
import java.awt.... information,
DrawingCircle - Swing AWT
Thanks...DrawingCircle I want to draw circle which dynamically accepts radius, X cordinates & Y cordinates from the user through a dialouge box. and draws
Basic authentication
an entity with a user name and password received by the
user by using...; a dialog box.
These username and password combination is then encoded
(base 64... unprotected areas without requiring the user to
enter a password. However
Change Password Code in JSP
Change Password Code in JSP
In this example we will see how to change password... the password in the data as the new password.
In this example we have made entry... three password fields "oldpassword","newpassword","
swing i wanted to create a gui desktop application .that can take the database name and mysql password from text box, and after the click of a button it should show connection status,and go for next from there on button click
Password validation
is a code that accepts the current password, New password and conform password from the user and change the password.


text:
Healthcare Providers and Services
Company Overview of Accolade, Inc.
Company Overview
620 West Germantown Pike
Suite 250
Plymouth Meeting, PA 19462
United States
Founded in 2007
Key Executives for Accolade, Inc.
Accolade, Inc. Key Developments
Accolade, Inc. announced the appointment of two industry leaders to its board of directors: Mark V. Mactas and Sheila P. Burke. Mr. Mactas was deputy chairman, president and chief operating officer of Towers Watson until his retirement in October 2011. Ms. Burke was chief of staff to Senator Bob Dole from 1986 to 1996, and has been a member of the Medicare Payment Advisory Commission and the board of trustees of the Kaiser Family Foundation. Both Mr. Mactas and Ms. Burke share a passion for human interest issues related to healthcare, which they pursue in leadership roles for various organizations and nonprofits. Mark V. Mactas was most recently deputy chairman, president and chief operating officer for Towers Watson until his retirement in 2011. He was formerly chairman and chief executive officer of Towers Perrin (before it merged with Watson Wyatt) from 2001 to 2009. With 14,000 associates around the world, Towers Watson offers professional services in benefits, talent management, rewards, and risk and capital management. Mr. Mactas is currently vice chairman of the board of Save the Children, where he has been a trustee since 2006.
Accolade, Inc. announced three appointments to the company's senior management team: Steve Barnes joins Accolade from NRG Energy as chief financial officer; Margery Geers joins from Walgreen'sTake Care Health Systems as chief people officer; and Andy Palan joins from CVS Health as chief information officer. As chief financial officer, Steve Barnes will lead Accolade's financial strategy and operations. Previously, Steve held the roles of chief financial officer and then president at Energy Plus Holdings. In her role as chief people officer, Margery Geers will spearhead all talent-related functions, ensuring that Accolade continues to be a great place to work as the company grow. Prior to Accolade, Margery was the chief people officer at Take Care Health Systems. Andy Palan has assumed the role of chief information officer and is responsible for driving the strategy and execution of Accolade's mission-critical applications, big data & analytics capabilities, infrastructure/cloud operations and the company's information management reporting services. He joins Accolade from CVS Health, where he was vice president of technology – enterprise architecture, engineering & innovation. In this role, Andy was accountable for retail infrastructure operations, leading the design and implementation of a comprehensive enterprise business and web services platform, tech product roadmaps and digital strategy.
Accolade, Inc. announced that it has expanded its agreement with Lowe's Companies, Inc. to serve more employees and their dependents with its innovative personal health assistance service. Under the agreement, effective January 1, 2015, covered individuals will have their own Accolade Health Assistant to help them navigate the healthcare system, resolve benefits and claims issues, find the right provider, understand their treatment options and coordinate care across settings. Lowe's began working with Accolade, a technology-enabled healthcare services company, in 2012 as part of its focus on pioneering innovative new approaches to support employee engagement in health. Accolade Health Assistants serve as a single point of contact to meaningfully engage those individuals, helping guide healthcare decisions and reduce errors that lead to increased costs.
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Sponsored Financial Commentaries
Sponsored Links
To contact Accolade, Inc., please visit www.accolade.com. Company data is provided by Capital IQ. Please use this form to report any data issues.
Our data partners will research the update request and update the information on this page if necessary. Research and follow-up could take several weeks. If you have questions, you can contact them at email@example.com.


text:
In addition to the books here David has five other sci-fi books listed on Amazon: https://www.amazon.com/author/davidkscholes
He has been a regular contributor to the Antipodean SF and Beam Me Up Podcast sites and has also been published on the Bewildering Stories, 365 Tommorrows, and Farther Stars Than These sites.
His Alien Hunter series appeared on the then Golden Visions site in 2011/12. .
He has recently (July 2014) published "Daughter of the High Lords and other Speculative Fiction Stories" and is working on both a further anthology of short sci-fi stories and a "Human Hunter" story arc for the Beam Me Up Pod Cast site. .


text:
Book Search
Technology Development Assistance for Agriculture
Putting research into use in low income countries
Series: Routledge Explorations in Development Studies
Stemming from an 11-year DFID funded programme under its Renewable Natural Resources Research Strategy (RNRRS), Technology Development Assistance for Agriculture: Putting Research into Low Income Countries reviews part of this programme as a case study of a broader issue of technology development...
Published April 18th 2013 by Routledge
Foundations of Offender Rehabilitation
The past three decades has seen dramatic changes in the way in which the criminal justice system responds to those who break the law. The old claim in the field of correctional psychology that "nothing works" has strongly been refuted in the face of evidence from rehabilitation programmes that do...
Published August 31st 2012 by Routledge
Transitions to Better Lives
Offender Readiness and Rehabilitation
Transitions to Better Lives aims to describe, collate, and summarize a body of recent research – both theoretical and empirical – that explores the issue of treatment readiness in offender programming. It is divided into three sections: part one unpacks a model of treatment readiness, and...
Published April 1st 2010 by Willan
Extraordinary Performance from Ordinary People
Extraordinary performance from ordinary people is a must read for the high performing manager with the ambition to reach corporate leadership status. The book is as practical as it is exciting. How to succeed and which personal qualities are required from those who display the capability for great...
Published November 14th 2006 by Routledge
Designing World Class Corporate Strategies
Designing World Class Corporate Strategies considers the key role of corporate centres within very large, primarily multi-business organisations. At present, these corporate centres are under attack as not creating and value and merely adding cost to their groups.The authors have developed a...
Published December 14th 2004 by Routledge
Souls Looking Back
Life Stories of Growing Up Black
First published in 1999. Routledge is an imprint of Taylor & Francis, an informa company....
Published April 12th 1999 by Routledge