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MARMOT Men's Super Gravity Jacket
Item: 11139545 Product Description >
MARMOT Men's Super Gravity Jacket
Designed to offer a full range of motion, the Marmot Super Gravity Jacket protects runners, climbers, and bikers from windy, wet, and cold conditions.Features/Benefits:
- 4-way stretch M1 soft shell fabric made from abrasion-resistant nylon and elastane
- Windproof, breathable, warm, and highly water resistant
- Best for intermittent aerobic activities in cold and wet conditions
- Attached hood with peripheral cord and laminated brim that holds its shape in wild weather
- Zippered handwarmer pockets
- Zippered sleeve pocket
- Adjustable Velcro cuffs
- Internal zip pocket
- Elastic drawcord hem adjusts to seal in warmth and keep wind/water out
- Angel-Wing Movement allows full range of motion in arms so jacket doesn�t ride up
Fiber Content: 88% nylon, 12% elastane
Country of Origin: Imported -
MARMOT Men's Super Gravity Jacket
EMS_Sale Yes Insulation Type N/A Removable Liner No Back Length 27.75 in. (70.5 cm) Insulation N/A Snow Skirt No Ventilation N/A Waterproof Material N/A Weight 1 lb 12.8 oz. (816 g) Waterproof No Activity/BreathabilityLev Moderate Packability Medium compactibility Hood Type Yes, fixed Construction N/A Fleece Weight N/A Insulation Rating N/A
Reviewed by 3 customers
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Displaying reviews 1-3
- Form fitting
- Good Looking
- Great price
- Hood Interfaces With Helm
- Warm
- none
Best Uses
- ice climbing
Comments about Marmot 1018668 MARMOT Super Gravity Jacket - Men's:
I bought this jacket initially as a Christmas gift for my son. I liked his and wanted to upgrade from my Arcteryx softshell, so tried it on and got myself one. I have used it several days out ice climbing and have been very pleased with it. Gave away one other softshell already.Very comforatble and warm. Accepts helemt use easily. Great jacket at this price.
- Good Fit
- Good Quality
- Tight Around Hem
Best Uses
- Anything outdoor
Comments about Marmot 1018668 MARMOT Super Gravity Jacket - Men's:
A Little Tight Around Hem. Nice jacket.
- Durable
- Thick
- Warm
Best Uses
- At camp
- Mild to moderate outdoor
- Slower outdoor activities
Comments about Marmot 1018668 MARMOT Super Gravity Jacket - Men's:
very stout jacket, built with a virtual fleece midlayer as its internal backing. Great for all but running. If you get hot just unzip the darn thing.Wind and waterproof says marmot website and i buy that up to a point. Reach for the hard shell when weather gets too intense.I REALLY value stuff that wont tear with an armload of firewood and this fits that bill as well as having all those tech qualities we are all getting spoiled by.EMS was spot on,no complaints!
Displaying reviews 1-3


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regional news
News stories tagged with "massena"
MRSI Airport Survey
Apr 16, 2002 — Nearly 70 percent of participant in a recent survey indicated they would be more likely to use air service from Ogdensburg and Massena, if the destination hub was changed from Pittsburgh to Albany. And with a gradual decline in use of the two airports since the 90's, local officials are looking at ways to boost ridership. Jody Tosti reports. Go to full article
PSC Studies Rural Telecommunications
Apr 12, 2002 — A study of rural areas by the Public Service Commission will demonstrate ways to improve access to telecommunications in the North Country. State Senator Jim Wright says rural communities continue to fall behind more populated areas in technological infrastructure. Go to full article
Schumer Tours the North Country
Mar 29, 2002 — Senator Charles Schumer was on a whirlwind tour of the North Country Thursday with stops in Jefferson, Lewis and St. Lawrence counties. One of his visits was to the Alcoa plants in Massena. As Jody Tosti reports, the Senator met with union leaders and plant management to discuss the company's role in the community. Go to full article
200 Years in Massena: A Walking Tour with author John D. Michaud III
Jan 09, 2002 — David Sommerstein profiles John Michaud III, a writer who's written a 200-year history of Massena on the eve of the town's bicentennial. Go to full article
The Massena Old Timers' Hockey Club
Jan 07, 2002 — Not all the hockey action this season is on college rinks or in the NHL. Todd Moe profiles a group of guys, over 40, who still hit the ice each week. Go to full article
Undefeated Adirondack Legends Seeking Senior Gold
Jan 07, 2002 — Martha Foley talks with Lonnie Avery of the Adirondack Legends senior hockey team. The team is undefeated and on course for the gold medal at the Senior Olympic Hockey Championships in Lake Placid. Go to full article
Massena GM Dump Waiting for Cleanup: 20 Years and Counting
Jan 04, 2002 — In 1983, the federal government delcared the land and water around GM's factory along the St. Lawrence river a Superfund Site. Cancer-causing PCBs were seeping into the earth and the river. The action identified the site as a top priority for clean-up. Almost twenty years later, the toxic landfill is still there. David Sommerstein reports lack of progress is due to different understandings of what "clean" and "clean up" mean. Go to full article
People: SLU Government Professor Bob Wells on the Art of Redistricting
Dec 17, 2001 — David Sommerstein talks with government professor Bob Wells about the political intrigue of redistricting, both for Congressional representatives and for state lawmakers. Go to full article
Alcoa: Planning A Future in the North When the Economy Goes South
Dec 12, 2001 — When economists recently announced the country was in a recession, most people already knew. In Massena, Alcoa workers have been feeling the pinch of a lagging economy for over a year now. After its latest round of layoffs and early retirements, the company is assessing its needs for the future. More layoffs are possible. But as David Sommerstein reports, hints of a market turnaround may help dispel worries of further cutbacks. Go to full article
Reynolds PCB Dredging Completed
Nov 26, 2001 — Workers have finished dredging PCBs for the winter from the St. Lawrence River near the former Reynolds plant. David Sommerstein talks with the project's director to see if the dredging was a success. Go to full article
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subset: commoncrawl


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Media Information - Covering the Crimson
Media Information - Covering the Crimson
Harvard University welcomes coverage of its football program by accredited writers, broadcasters and photographers.
Covering the Crimson
Harvard University welcomes coverage of its men's basketball
program by accredited writers, broadcasters, and photographers.
Working credentials and supplemental materials may be requested
from the Office of Athletic Communications by contacting Tim Williamson
either by mail, phone or email.
Media Credentials
All credential requests to cover Harvard men's basketball
should be directed to Tim Williamsonin the athletic communications
office at least 48 hours in advance of the game. Harvard reserves
the right to accept or reject credential requests for any
Credentials will be mailed if time permits or may be picked up at
the ticket office inside Lavietes Pavilion, which opens one hour
prior to the start of the contest. Press passes are
Interviews with players and/or members of the coaching staff must
be arranged through Harvard's Office of Athletic
Please note that student-athletes' phone numbers and email
addresses will not be released to the media per Department of
Athletics policy. If a telephone interview is necessary,
arrangements will be made for the student-athlete to call the
requesting outlet. Game-day interviews will not be granted until
the conclusion of the contest.
Men's Basketball Interviews
During first semester, head coach Tommy Amaker and
student-athletes are available for a weekly press briefing
following practice at Lavietes Pavilion on Monday afternoons
beginning at 4 p.m. Schedule is subject to change on a weekly
Press Row Services
The Harvard athletic communications office will provide a game
program, current press release, pregame statistics, and the Ivy
League weekly report prior to the game.
Working press and radio crews are assigned space on press row.
Seating charts will be located throughout the facility.
Statistics will be distributed at halftime with full packets
available at the end of the game.
Beverages will be available throughout the game, and lunch will be
served to accredited media members.
Postgame Interviews
Following home games, Harvard head coach Tommy Amaker and
requested players will be available to the media following a
10-minute cooling-off period. Coach Amaker will be available first
in the Lavietes Pavilion Lounge and players are available outside
the locker room.
Harvard maintains a closed locker room policy at home and on the
Requests for visiting coaches and players should be made through
the opponent's sports information contact.
Reporters filing stories may both write and file their stories
from courtside or from the media work room. Phone lines, a fax
machine, and a high-speed internet connection are available upon
Radio Broadcasts
Stations wishing to broadcast Harvard men's basketball games
must make arrangements through the athletic communications office
at least one week in advance of the requested game.
There are two analog phone lines available for visiting stations,
and a maximum of three credentials will be provided for any
broadcast crew. We cannot have ISDN lines installed in Lavietes
Members of the media should be advised that parking is extremely
limited in the vicinity of Lavietes Pavilion. Vehicles will not be
permitted in the Soldiers Field athletic complex without a parking
pass issued by the athletic communications office.
Parking passes will be mailed if the credential request is granted
five working days prior to the contest.
On SIRIUS
Select Harvard basketball games may also be heard on SIRIUS
satellite radio in 2011-12 as part of the Ivy League's
agreement with that outlet.
In addition to carrying at least one basketball game per week,
SIRIUS also is the satellite radio home of Ivy League football.
Check the Ivy League's official website (IvyLeagueSports.com) each week for the listings and
channels for games involving league schools.
On The Web
Harvard's Video-On-Demand package allows visitors to watch
the game in real-time video on their computers.
In addition, GoCrimson.com will also feature audio clips of head
coach Tommy Amaker, including pregame interviews and postgame press
conferences. Fans may also access Harvard's weekly basketball
press releases from the site and may follow the live statistics of
Crimson home games.
GoCrimson.com also contains feature stories on Harvard's
student-athletes, complete biographical information on all Crimson
players and coaches, a portal for ordering single-game and season
tickets to Lavietes Pavilion, and links to order official Harvard
basketball merchandise.
In addition, WHRB-FM student broadcasts are available at select
games through that station's web site (whrb.org).


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February Lady Sweater
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A knitter-generated list of common modifications to this pattern can be found in the wiki tab at the top of this page and on flintknits.com
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A swingy lace cardigan, made to fit a grown-ass woman, lovingly based on Elizabeth Zimmermann's classic "Baby Sweater on Two Needles," from Knitter's Almanac.
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BeerAdvocate on your phone?! True story. Try the beta now.
Tickets for American Craft Beer Fest are on sale now! (May 30 & 31 in Boston, MA)
Bois - The Bruery
Displayed for educational use only; do not reuse. |
Ratings: 855 | Reviews: 109 | Show All Ratings:
Reviews by Evan:
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British Columbia (Canada)
4.5/5 rDev +3.4%
03-10-2014 03:48:58 | More by JasonLovesBeer
3.91/5 rDev -10.1%
look: 4 | smell: 3.5 | taste: 4.25 | feel: 4 | overall: 3.5
On tap at Hops and Pie. Nice orange color, small head at first, then it's gone. Aroma is a bit if booze. Flavor is a delicious bourbon barrel barley wine, rich, great bourbon flavors, sweet but then it gets a little too sugary. This was really tasty but it's so sweet and so strong that I can't imagine drinking a whole glass of this.
Serving type: on-tap
03-10-2014 02:22:00 | More by ArrogantB
Ontario (Canada)
4.58/5 rDev +5.3%
look: 4.25 | smell: 4.75 | taste: 4.75 | feel: 3.75 | overall: 4.5
Bottle into tulip.
Celebrating my last day at work after being laid off.
A- Super murky, dark brown almost black pour. Tight bubbled, two finger light tan head. Loads of alcohol on the glass and minimal lacing.
S- The wallop of bourbon on the nose from three feet away is remarkable. Bourbon, brown sugar, plums, figs, vanilla, some chocolate and coffee. Burnt toffee, some alcohol with a loads bourbony goodness.
T- Bourbon right up front, dark stone fruits, some chocolate, a huge punch of vanilla on the tongue with bourbon and alcohol in the finish.
M- Medium body, medium to low carbonation, warming alcohol in the finish.
Serving type: bottle
03-08-2014 00:33:35 | More by korguy123
Bois from The Bruery
out of 100
based on 855 ratings.


text:
New Release: Miles Bonny & B.Lewis – 'Egg Black' EP
April 10th, 2012
Prepare to have your senses overtaken once you hit play on Miles Bonny & B.Lewis' new Egg Black EP. The seven track project doesn't have a dull moment; moving through varied tempos and moods, it easily holds the listener's attention. The theme is constant, however: a resonant electro-soul groove encapsulates you as if it were the only thing anywhere near your realm of consciousness, while Miles' buttery voice massages your disposition into a welcome tranquility. Yeah, we're good with that.


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OSCON 2010: Marvell
Trevan McGee stops by the Marvell booth and gets a demonstration in plug computing.
Bob Salem from Marvell demonstrates plug computers and a few uses of the open source platform.
OSCON 2010: Marvell
Trevan McGee stops by the Marvell booth and gets a demonstration in plug computing. In case you consider that the subject of this page is important, it's likely you are considering about using Linux as your main or simply another Operating system if you are simply tired of your old system. However , many consider that Linux is too complex that it is attractive only to geeks, Linux-magazine.com can easily show that this excellent operating-system is in fact for anyone. It is almost always important to find out about OSCON 2010: Marvell.
Ronnie Paoli,
Issue 161/2014
Buy this issue as a PDF
Digital Issue: Price $9.99
(incl. VAT)
Tag Cloud
New TLS Attack Takes the S out of HTTPS
Vulnerability affects many Linux web servers
Munich Adopts Kolab
The Bavarian capital shuns Microsoft, Google, and other alternatives to implement an open source groupware solution.
Canonical Announces Ubuntu Smartphones
Phone vendor partnerships bring Mark Shuttleworth's dream of Ubuntu on a phone a step closer to reality.
Piviti Seeks Funding
Donors will get to vote on new features for the free video editor.
Debian Tech Committee Votes for systemd
Debian project puts init out to pasture and says no to Ubuntu's Upstart.
The Mask: Scary New Face of Internet Intrusion
Ultra-sophisticated attack tool might have originated from a state-sponsored intelligence service.
Epoch 1.0 Released
New alternative for init comes with a small footprint and minimal configuration.
Wayland 1.4 Challenges X11
X marks the target for the next-generation windowing system.
Red Hat Adopts CentOS
Super-clone CentOS Linux gets beamed up to the mother ship.
W3C Promotes Media Source Extensions
HTML technology will enable new video editing and playback options.


text:
HR Department
Employee Benefits
The City of San Antonio strives to provide a competitive compensation and benefit package to attract and retain a highly skilled workforce. To accomplish this, the City of San Antonio offers generously subsidized health care benefits for active and retired employees, City paid disability benefits, City paid life insurance, as well as automatic participation in a pension program which is currently matched two to one. For a brief overview of the City's medical, vision, Flexible Spending Account, Health Savings Account, and life insurance benefits, visit the City's Benefits Information Video Library.
(210) 207-8705 Riverview Towers Building 111 Soledad, Suite 100 San Antonio, TX 78205 email@example.com Map and Directions
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BeNefits FAQs
Boon-Chapman (Uniform Dental and Vision Plan)
CitiDent PPO administered by Delta Dental (Civilian Dental Plan)
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City Employee Health + Wellness Center
Davis Vision (Civilian Vision Provider)
Dearborn National Life Insurance
Deer Oaks (Employee Assistance Program)
Flexible Spending Account Customer Service
Generations Federal Credit Union
Health Savings Account Customer Service
Humana Medicare Customer Service
ICMA Retirement Corporation (Deferred Compensation Provider)
Nationwide Retirement Solutions (Deferred Compensation Provider)
UnitedHealthcare (Medical and Pharmacy Benefit Provider)
Texas Municipal Retirement System


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Job Purpose: Delivers passengers by driving and maintaining a limousine. Duties: * Prepares vehicle by conducting operator maintenance; cleaning interior and exterior; arranging for maintenance; reporting operating problems. * Plans route and requirements by studying schedule or special request; determining occupant and luggage requirements; checking road conditions; estimating travel times; arran...
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Travel, Tourism and Hospitality Jobs
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text:
Copyright © 2002 Cell Press All rights reserved.
Cancer Cell, Volume 2, Issue 2, 117-125, 1 August 2002
Add/View Comments (0)Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia
Neil P. Shah1, John M. Nicoll1, Bhushan Nagar6, Mercedes E. Gorre1, 2, Ronald L. Paquette1, John Kuriyan5, 6 and Charles L. Sawyers7, 1, 2, 3, 4,
1 Department of Medicine, Los Angeles, CA 90095 USA
2 Molecular Biology Institute, Los Angeles, CA 90095 USA
3 Department of Urology, Los Angeles, CA 90095 USA
4 Department of Medical and Molecular Pharmacology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095 USA
5 Howard Hughes Medical Institute, Berkeley, CA 94720 USA
6 University of California, Berkeley, Berkeley, CA 94720 USA
- Through sequencing analysis of blood or bone marrow samples from patients with chronic myeloid leukemia, we identified BCR-ABL kinase domain mutations in 29 of 32 patients whose disease relapsed after an initial response to the tyrosine kinase inhibitor imatinib. Fifteen different amino acid substitutions affecting 13 residues in the kinase domain were found. Mutations fell into two groups—those that alter amino acids that directly contact imatinib and those postulated to prevent BCR-ABL from achieving the inactive conformational state required for imatinib binding. Distinct mutations conferred varying degrees of imatinib resistance. Mutations detected in a subset of patients with stable chronic phase disease correlated with subsequent disease progression. Multiple independent mutant clones were detected in a subset of relapsed cases. Our data support a clonal selection model of preexisting BCR-ABL mutations that confer imatinib resistance.
Chronic myelogenous leukemia represents the first human malignancy to be successfully treated with a small molecule tyrosine kinase inhibitor. Clinical resistance to this inhibitor (imatinib) has been reported in small numbers of patients due to BCR-ABL gene mutation or amplification. Here we present a comprehensive analysis of CML patients in varying stages of disease that documents a very high frequency of BCR-ABL kinase domain mutations in patients that develop imatinib resistance. These results reinforce the central importance of BCR-ABL in the pathogenesis of this disease, even at the most advanced stages, and define the challenges necessary to design second generation targeted therapies. Our findings may also have implications for other kinase inhibitors currently in development against a broad range of cancers.
The tyrosine kinase BCR-ABL is the fusion product of a reciprocal chromosome translocation between chromosomes 9 and 22, known as the Philadelphia (Ph) chromosome, and is present in the leukemic cells of more than 95% of patients with chronic myeloid leukemia (CML) Sawyers 1999. The ability of BCR-ABL to produce a CML-like disease in mouse models Daley et al. 1990,Elefanty et al. 1990,Kelliher et al. 1990 led to efforts to develop inhibitors of its kinase activity. Imatinib (STI571, Gleevec) was approved for CML treatment after striking efficacy was demonstrated in all stages of the disease Druker et al. 2001a,Druker et al. 2001b,Kantarjian et al. 2002,Sawyers et al. 2002,Talpaz et al. 2002. The clinical success of this small molecule kinase inhibitor has led to the notion that other selective tyrosine kinase inhibitors may have significant activity against a range of human malignancies.
Ninety percent of patients with early-stage (chronic phase) CML achieve hematologic responses to imatinib, and the Ph chromosome is no longer detected in about 50% of these patients using standard cytogenetic assays (termed cytogenetic response) Druker et al. 2001b,Kantarjian et al. 2002. Approximately 60% of patients with advanced-stage CML (blast crisis) respond to imatinib, but nearly all these patients relapse despite continued therapy Druker et al. 2001a,Sawyers et al. 2002. We previously demonstrated that BCR-ABL kinase activity is inhibited in leukemic cells at the time of response but is reactivated at relapse Gorre et al. 2001a. This result suggested that BCR-ABL maintains a crucial role throughout disease progression in CML. Detailed analysis of 11 such patients revealed at least two distinct mechanisms for resistance—BCR-ABL gene amplification or point mutations in the kinase domain that presumably interfere with drug-protein binding without compromising kinase activity Gorre et al. 2001a. While these findings have been confirmed in additional small studies Branford et al. 2002,Hofmann et al. 2002,von Bubnoff et al. 2002, there is disagreement about the frequency with which mutations occur Barthe et al. 2001,Hochhaus et al. 2001. In addition, other mechanisms of imatinib resistance have been proposed, such as drug sequestration mediated by the serum protein α-1 acid glycoprotein (AGP) Gambacorti-Passerini et al. 2000, or drug efflux by multidrug resistance pumps Mahon et al. 2000. To date, neither of the latter mechanisms has been implicated in patients Jorgensen et al. 2002.
Clinical efforts to overcome imatinib resistance must begin by defining the most common mechanisms of resistance in a larger number of patients. As a first step, we conducted comprehensive BCR-ABL kinase domain sequencing analysis of 45 CML patients who demonstrated imatinib resistance. Mutations were detected in over 90% of patients (29 of 32) who relapsed after an initial response to imatinib, including those with chronic phase, myeloid blast crisis, and lymphoid blast crisis CML. Mutations led to 15 amino acid substitutions in 13 different residues which, based on known crystal structure data, include direct drug contact sites as well as sites that presumably impair the conformational change in the kinase domain required to accommodate imatinib binding. Mutant BCR-ABL alleles retain biologic activity but show varying degrees of resistance to imatinib in biochemical and biological assays. Mutations were also detected in 4 of 13 chronic phase patients with stable disease and correlated with subsequent clinical relapse. Additional observations that multiple independent imatinib-resistant clones were detected in some patients (polyclonal resistance) and that kinase domain mutations were detected prior to treatment in some patients with imatinib-refractory myeloid blast crisis provide evidence that mutations develop as a consequence of clonal selection rather than generalized hypermutability. Collectively these results establish the primary role of BCR-ABL kinase domain mutations as a cause of imatinib resistance in CML and provide evidence that knowledge of mutation status might influence clinical management. The spectrum of mutations identified provides new insights into kinase domain function and into novel treatment strategies to overcome resistance.
Kinase domain mutations are detected in 90% of CML patients who relapse after responding to imatinib
The ability to detect BCR-ABL mutations in imatinib-resistant CML cells is dependent on patient selection and the sensitivity of the assay used. Because the Ph chromosome translocation occurs in a pluripotent hematopoietic stem cell, nearly all the blood and bone marrow cells in untreated CML patients express the BCR-ABL fusion gene. In patients with a hematologic response to imatinib (normalization of blood counts) and a cytogenetic response (reduction in the fraction of Ph chromosome-containing cells), a significant fraction of the BCR-ABL-expressing cells isolated at the time of relapse will represent the drug-resistant clone. However, in patients who relapse on imatinib after a hematologic response but no cytogenetic response, imatinib-resistant cells represent only a subset of the total BCR-ABL-expressing cells (often 20% or less) Gorre et al. 2001b. To optimize the sensitivity of mutation detection, we performed RT-PCR amplification of BCR-ABL mRNA from CML patient blood or bone marrow cells, subcloned the PCR products (rather than sequence the products directly), and sequenced ten independent PCR products per patient sample. To improve the specificity of our methodology, a mutation was deemed present if it was detected on both strands of DNA in two independent isolates from the same patient (therefore representing approximately 20% of the total population of BCR-ABL mRNA transcripts).
Samples from 32 CML patients who relapsed after a hematologic response to imatinib were analyzed (16 with myeloid blast crisis, 5 with lymphoid blast crisis, and 11 with chronic phase). Mutations were identified at the time of relapse in 29 of the 32 patients (15 of 16 with myeloid blast crisis, 4 of 5 with lymphoid blast crisis, and 10 of 11 with chronic phase) Table 1. Mutations mapped to 13 different amino acid residues in the ABL kinase domain and predicted 15 different codon changes (Figure 1). Nucleotide changes affecting two residues, Q252 and Y253, led to two alternative amino acid substitutions each—Q252H/R and Y253F/H. Mutations in seven of these residues have been reported in smaller studies Branford et al. 2002,Gorre et al. 2001a,Hofmann et al. 2002,von Bubnoff et al. 2002; six mutations detected are novel. Mutations were detected at each of the variable (X) amino acids of the kinase consensus sequence Gly-X-Gly-X-X-Gly-X-Val located in the P loop, which provides a number of important contacts for ATP binding. One of these mutations, E255K, in addition to mutations T315I and M351T, accounted for over 60% of the cases. To address whether the high frequency and variety of kinase domain mutations represented artifact introduced during the PCR amplification process, we sequenced ten independent subclones of the ABL kinase domain obtained from each of two healthy blood donors. Using our criteria of at least two independent isolates out of ten clones, we found no evidence of ABL kinase domain mutation. We therefore conclude that the BCR-ABL kinase domain mutations described here are unlikely to be the result of PCR-introduced error.
Table 1 |
Patient no. | Duration of treatment with imatinib at time of analysis | BCR-ABL kinase domain mutation(s) | Number of independent clones containing mutation | ||
1 MBC | 4.5 months | G250E | 7/10 | ||
2 MBC | 13 months | T315I | 10/10 | ||
3 MBC | 8 months | none | n/a | ||
4 MBC | 3.5 months | M351T | 5/10 | ||
5 MBC | 2 months | Q252H | 5/10 | ||
6 MBC | 13 months | M351T | 8/10 | ||
7 MBC | 13 months | M351T | 6/10 | ||
8 MBC | 5 months | E255K | 4/10 | ||
9 MBC | 7 months | E355G | 5/10 | ||
10 MBC | 6 months | G250E | 8/10 | ||
11 MBC | 3 months | Y253F | 3/10 | ||
12 MBC | 2 months | M351T | 3/10 | ||
13 MBC | 3 months | Y253F | 2/10 | ||
14 MBC | 3 months | E255K | 2/10 | ||
15 MBC | 2 months | E255K | 2/10 | ||
16 MBC | 4 months | F359V | 8/10 | ||
17 LBC | 2 months | M351T | 3/10 | ||
18 LBC | 3 months | T315I | 5/10 | ||
19 LBC | 2 months | T315I | 5/10 | ||
20 LBC | 9 months | T315I | 6/10 | ||
21 LBC | 3 months | none | n/a | ||
22 CP | 17 months | T315I | 8/10 | ||
23 CP | 10 months | F317L | 10/10 | ||
24 CP | 9 months | E255K | 7/10 | ||
25 CP | 38 months | F359V | 10/10 | ||
26 CP | 25 months | L387M | 7/10 | ||
27 CP | 25 months | M244V M351T | 6/10 2/10 | ||
28 CP | 20 months | F317L | 4/10 | ||
29 CP | 17 months | M351T | 7/10 | ||
30 CP | 17 months | T315I | 8/10 | ||
31 CP | 33 months | none | n/a | ||
32 CP | 25 months | M351T | 4/10 | ||
33 P-MBC | n/a | T315I | 2/10 | ||
34 P-MBC | n/a | E255K | 2/10 | ||
35 P-MBC | n/a | none | n/a | ||
36 P-MBC | n/a | none | n/a | ||
37 NCR | 14 months | V379I | 7/10 | ||
Duration of imatinib therapy at the time of analysis is shown. The fraction of independent clones for each mutation is given. Patients 2, 6, 8, 18, and 20 had major cytogenetic responses and patients 17 and 29 had minor cytogenetic responses prior to relapse, using criteria previously described Kantarjian et al. 2002. Patients 10, 13, and 31 had evidence of BCR-ABL gene amplification at relapse by FISH analysis. Patient 37 (NCR) harbors a kinase domain mutation but has not suffered progressive disease (see also Figure 4). Eight additional NCR patients, as depicted in Figure 4, had no evidence of kinase domain mutation, and are not represented here.Abbreviations: MBC, relapsed myeloid blast crisis; LBC, relapsed lymphoid blast crisis; CP, relapsed chronic phase; P-MBC, preimatinib sample from myeloid blast crisis patients whose disease was subsequently refractory; and NCR, chronic phase with hematologic response but no cytogenetic response. |
To gain insight into potential mechanisms by which these mutations might confer imatinib resistance, we modeled each amino acid substitution onto the known cocrystal structure of the ABL kinase domain bound to imatinib (Figure 2A; Nagar et al. 2002,Schindler et al. 2000). The mutations fall into two groups. The first group includes mutations at sites that directly contact imatinib (T315, F317, and F359) and presumably impair drug binding without significantly affecting the binding of ATP (Figure 2A, red spheres). The second group includes mutations in residues located in distinct regions, all of which are implicated in the unique conformational change that the kinase domain must undergo to accommodate imatinib. For example, the ATP phosphate binding loop (P loop) is distorted in the imatinib/ABL structure such that it forms a hydrophobic cage for the drug. Resistance mutations observed in the P loop region (G250, Q252, Y253, and E255) are likely to destabilize the distorted shape (Figure 2A, green spheres). Y253 inserts into the ATP binding site, forming one wall of a hydrophobic pocket for the drug, and is stabilized by hydrogen bonds formed by the hydroxyl group of the side chain (Figure 2B). Y253H/F substitutions would break the hydrogen bonding interactions of the tyrosine side chain, which is also specific for the distorted conformation of the P loop. E255 forms hydrogen bonds that bridge the side chains of K247 and Y257, an interaction that appears to be specific to the distorted conformation of the P loop. Mutation of E255 presumably destabilizes the P loop conformation that is required for imatinib binding.
A second structural change required for imatinib binding is the closed conformation of the ABL activation loop, which is part of a network of interactions that help stabilize the drug binding site. In the closed conformation, Y393 in the activation loop is positioned such that it mimics the tyrosine residue of a peptide substrate. The H396R substitution is located close to Y393, such that mutations in this region might disturb the energetic balance required to stabilize the closed conformation of the activation loop (Figure 2C). Another cluster of mutations involves amino acids located in the C-terminal lobe of the kinase (E355, M351, and V379) in a region that provides a platform for the base of the activation loop. While it is difficult to predict the precise energetic consequences of mutations at these residues, all three are located adjacent to a region where large torsional rotations are required to accommodate imatinib. Comparative crystallographic studies of mutant ABL alleles are required to precisely define the structural consequences of these mutations.
Mutant BCR-ABL alleles show varying degree of imatinib resistance in vitro
To address the causal role of these mutations in imatinib resistance, we generated mutant alleles by site-directed mutagenesis of wild-type BCR-ABL and expressed the mutants in the interleukin-3 (IL-3)-dependent cell line Ba/F3. BCR-ABL activity has been shown to render Ba/F3 cells IL-3 independent Daley and Baltimore 1988. The T315I and E255K mutations are known to confer IL-3 independence as well as biochemical and biological resistance to imatinib in this system Gorre et al. 2001a,Gorre et al. 2002,von Bubnoff et al. 2002 and were included as controls. Six previously uncharacterized mutants were chosen for this initial analysis based on their frequency of isolation and location within the kinase domain. IL-3-independent Ba/F3 populations were derived for all six mutants studied, demonstrating that each of these mutants retains biologic activity comparable to wild-type BCR-ABL in this system. The effect of imatinib concentrations ranging from 0.5 to 10 μM on BCR-ABL kinase activity and cellular viability was determined using standard assays (Figure 3). As expected, the T315I and E255K mutants were highly resistant to imatinib with IC50 values greater than 10-fold higher than wild-type BCR-ABL Table 2. G250E-expressing cells were also markedly resistant. Y253F also resulted in considerable resistance, but clearly less than T315I, consistent with another report that characterizes the effects of this same mutation on ABL kinase function Roumiantsev et al. 2002. Four mutations (Q252H, F317L, M351T, and E355G) conferred only moderate resistance to imatinib, retaining biochemical sensitivity at drug concentrations of 1–4 μM. Since drug levels approaching this concentration can be clinically achieved in some patients, these results raise the possibility that resistance caused by certain mutations might respond to high-dose imatinib treatment. The fact that all BCR-ABL mutants tested show imatinib resistance in vitro provides strong evidence that each of these mutations plays a causal role in clinical imatinib resistance. Biochemical characterization of the five remaining mutations found, consisting of the novel mutations M244V, F359V, V379I, and L387M, in addition to the previously described H396R, will require additional studies.
Table 2 |
Mutation | Phase of disease | Biochemical IC50 (μM) | Biological IC50 (μM) | Proposed mechanism of resistance | ||
M244V | CP | not assessed | not assessed | impairs conformational change (P loop) | ||
G250E | MBC | 7.40 | >10 | impairs conformational change (P loop) | ||
Q252H/R | MBC, LBC | 2.93 | 3.12 | impairs conformational change (P loop) | ||
Y253F/H | MBC, LBC | 5.96 | 8.94 | impairs conformational change (P loop) | ||
E255K | MBC, LBC, CP, P-MBC | 7.81 | >10 | impairs conformational change (P loop) | ||
T315I | MBC, LBC, CP, P-MBC | >10 | >10 | directly affects imatinib binding | ||
F317L | MBC, CP | 3.30 | 7.50 | directly affects imatinib binding | ||
M351T | MBC, LBC, CP | 1.07 | 4.38 | impairs conformational change (adjacent to activation loop) | ||
E355G | MBC | 2.82 | 2.38 | impairs conformational change (adjacent to activation loop) | ||
F359V | MBC, CP | not assessed | not assessed | directly affects imatinib binding | ||
V379I | CP-NCR | not assessed | not assessed | impairs conformational change (activation loop) | ||
L387M | CP | not assessed | not assessed | impairs conformational change (activation loop) | ||
H396R | MBC, CP | not assessed | not assessed | impairs conformational change (activation loop) | ||
wild-type | - | 0.28 | 0.60 | not applicable | ||
Abbreviations: MBC, myeloid blast crisis; LBC, lymphoid blast crisis; CP, chronic phase; CP-NCR, chronic phase with hematologic response in the absence of cytogenetic response (cytogenetic nonresponder). |
Potential predictive value of mutation detection in patients with stable disease
The overwhelming majority of CML patients on imatinib therapy have chronic phase disease. Although 90% of patients with chronic phase CML achieve excellent hematologic control of their disease with imatinib, about half of these patients continue to have a significant number of Ph chromosome-containing cells in the bone marrow ("cytogenetic nonresponders"). Recent data suggests that these patients progress to blast crisis more quickly that those who obtain cytogenetic remissions Kantarjian et al. 2002. The reason for failure to achieve a cytogenetic response is unknown, but may involve incomplete inhibition of BCR-ABL kinase activity in progenitor cells or activation of BCR-ABL-independent survival pathways. Since BCR-ABL kinase domain mutations are prevalent in imatinib-treated patients with hematologic relapse, we asked if similar mutations might be found in cytogenetic nonresponders with sustained hematologic remissions. Four of 13 such chronic phase patients had mutations. Three of these mutations (E255K, F317L, and F359V) are identical to those observed in cases of relapsed myeloid blast crisis described above, whereas the fourth mutation (V379I) has not been previously documented. We next asked if detection of a mutation during this time of stable hematologic response correlated with clinical outcome. Three of the four patients with kinase domain mutations suffered disease progression within 18 months of mutation detection, whereas only one of nine patients without a detectable mutation progressed (Figure 4). Of note, the patient without evidence for a kinase domain mutation had BCR-ABL gene amplification at relapse based on fluorescence in situ hybridization analysis (data not shown). The patient harboring the novel V379I mutation continues to have a complete hematologic remission but no cytogenetic response at 18 months. Although the number of patients is small, these findings suggest that periodic assessment of the mutational status of the BCR-ABL kinase domain may have prognostic utility.
Evidence for clonal selection of preexisting BCR-ABL kinase domain mutations
The most frequent explanation for single-nucleotide substitutions in the human genome are methylation-deamination reactions that give rise to C/T or G/A transitions in the context of the CpG dinucleotide sequence. This mechanism is estimated to account for about 25% of all reported nucleotide changes based on comprehensive analysis of human genetic disorders Vogelstein and Kinzler 1997. Remarkably, only 1 of the 15 mutations we observed (E255K) could be explained on that basis. Alternatively, the high frequency of kinase domain mutations observed in our study could reflect a global increase in mutation frequency (hypermutation) as a consequence of genetic instability. To address this possibility, we looked for mutations in other regions of the genome by sequencing a 700 bp region of BCR-ABL immediately 5′ to the kinase domain in five patients in whom kinase domain mutations were detected in a large fraction of the original clones sequenced. No evidence of additional mutation was found in these samples. We also assessed the kinase domain of the related tyrosine kinase KIT, which resides on chromosome 4 and exhibits sensitivity to imatinib at concentrations equivalent to BCR-ABL, in the same group of five patients. No evidence of KIT kinase domain mutation was detected, arguing against a model of widespread genomic instability.
Another possible explanation for the high frequency of mutations is that exposure to imatinib might induce genetic instability, particularly since the wild-type ABL kinase (which is also inhibited by imatinib) has been implicated in DNA repair Kharbanda et al. 1997,Shafman et al. 1997,Yoshida et al. 2002. Several lines of evidence argue against this hypothesis. First, patients with blast crisis CML often relapse within 1–3 months of initiating imatinib therapy, providing a short window of time for the acquisition of mutations and expansion of a drug-resistant clone. Second, we found multiple independent BCR-ABL mutations (2–4 clones per patient) in 12 of the 32 patients with imatinib resistance, including 5 patients who relapsed within 3 months of starting therapy Table 1. Unless we postulate an extremely high mutation rate, these results are most consistent with a model whereby mutant clones preexist in some patients at levels below our threshold for detection, then expand under the selective pressure of imatinib treatment. Definitive evidence for this hypothesis was obtained by analysis of pretreatment samples from four blast crisis patients who failed to achieve even a transient response to imatinib (primary or de novo hematologic resistance). One patient exhibited T315I prior to initiation of therapy, as well as a separate BCR-ABL clone that contained two mutations, M343T and F382L, on the same DNA sequence. A second patient had the E255K mutation Table 1. Collectively, these data indicate that BCR-ABL kinase domain mutations can occur during the natural evolution of CML and that those capable of conferring imatinib resistance expand under the selective pressure of imatinib treatment. The fact that certain mutations can be detected in a significant fraction of cells prior to imatinib therapy suggest that some mutations may confer gain of function, analogous to a kinase domain mutation present in v-Abl, which has been shown to contribute to its oncogenic potential Jackson et al. 1993. Members of the Src family of kinases, which have increased kinase activity relative to ABL, all have a phenylalanine at amino acid position 5 in the P loop, whereas ABL has a tyrosine at this position. Furthermore, the Y253F mutation, when engineered into ABL, has demonstrated oncogenic activity Allen and Wiedemann 1996. The mechanism for the underlying increase in genetic instability that presumably leads to these mutations in CML cells remains to be defined.
In a comprehensive analysis of CML patients treated with imatinib in all phases of the disease, we find that mutations in the BCR-ABL kinase domain occur in over 90% of patients who relapse after an initial response. The high frequency of mutation detection in our study relative to smaller studies reported by other investigators is most likely explained by differences in assay sensitivity. By subcloning and sequencing ten independent clones from each patient, we can reliably and confidently detect mutant clones representing approximately 20% of the total population of BCR-ABL-expressing cells. This strategy also allows detection of polyclonal resistance, which would be extremely difficult to find using direct sequencing methods (without subcloning) because the mixture of wild-type and mutant clones would most likely be read as consensus wild-type sequence. A second issue likely to explain differences in mutation frequency is patient selection, particularly if analysis is performed on patients who fail to have a hematologic response to imatinib. Having defined a large number of amino acid substitutions, we obtained definitive evidence from in vitro reconstitution studies that at least eight mutants (all those studied to date) play a causal role in imatinib resistance. The role of the remaining seven (less common) mutations will need to be examined using similar assays before definitive conclusions about these mutants can be made. Our results reinforce the central role of BCR-ABL kinase activity in CML at all disease stages and clearly delineate the challenge that future targeted therapeutic strategies for CML must address.
Are there any obvious strategies that should be considered? The complex array of different mutations observed in these patients makes it difficult to envision a single second generation ABL kinase inhibitor that would have activity against all mutants. However, recent insights gained from structural analysis of ABL bound to imatinib versus a dual ABL/SRC inhibitor indicate that two different inhibitors can bind to the same kinase in different conformational states Nagar et al. 2002,Schindler et al. 2000. If a significant number of the mutations that cause imatinib resistance do so by preventing the kinase domain from achieving the closed conformation necessary for imatinib binding (as proposed in Figure 2), one can envision that inhibitors that bind ABL in the open configuration might retain activity against many of these mutants. Indeed, we have evidence that the E255K mutant remains sensitive to such a dual ABL/SRC inhibitor (M. Moasser, N. Rosen, M.E.G., and C.L.S., unpublished data). Alternatively, it may be necessary to inhibit BCR-ABL signaling using completely different strategies that do not require binding to the kinase domain. Possibilities include the induction of BCR-ABL protein degradation using inhibitors of the molecular chaperone Hsp90 or blockade of critical signal transduction events that function downstream of BCR-ABL such as the RAF/MEK/ERK and PI3K/AKT pathways. We have preclinical evidence in support of the former strategy based on the fact that two Hsp90 inhibitors, geldanamycin and 17-AAG, have potent in vitro activity against the T315I and E255K BCR-ABL mutants Gorre et al. 2002.
As second generation inhibitors undergo development, it may be useful now to measure the mutation status of the BCR-ABL kinase domain in selected populations of CML patients treated with imatinib. Our analysis of a small number of chronic phase patients with stable hematologic control but no cytogenetic response suggests that detection of such mutants portends a poor prognosis. If this result is confirmed in a larger prospective trial, one can envision altering the clinical management of such patients by imatinib dose escalation (if the mutation is one that confers partial imatinib resistance), addition of a second agent such as interferon, early consideration of allogeneic stem cell transplantation, or enrollment in an experimental drug trial. Widespread testing for such mutations would clearly require a less cumbersome method for mutation detection than that described here, perhaps using mutation-specific assays. The fact that only three mutations (T315I, E255K, and M351T) account for more that 60% of the cases in our study provides a starting point for the development of such clinical tests.
The long-range outlook for managing imatinib resistance should focus on defining the mechanism by which kinase domain mutations occur so that the emergence of resistant clones might be prevented. Our sequencing analysis provides very little evidence for methylation-deamination or hypermutation as factors that lead to the high frequency of mutations. By default, we assume that CML cells have increased genomic instability, as is clearly evident in blast crisis where a range of secondary chromosomal changes are frequently observed. The fact that mutations are also found in chronic phase patients (who have normal karyotypes except for the Ph chromosome) argues for additional genetic instability early in the disease. Indeed, there is some experimental evidence that expression of BCR-ABL can induce genetic instability in mouse models Salloukh and Laneuville 2000. Until the mechanism responsible for the development of these mutations is defined, it seems likely that future targeted therapy of CML will follow the model currently in practice for the treatment of HIV—combination therapy with multiple targeted agents.
Experimental procedures
After obtaining informed consent to participate in a research protocol approved by the UCLA institutional review board, blood or bone marrow samples were obtained from patients enrolled in clinical trials assessing the efficacy of imatinib in the treatment of CML. Criteria for determination of response and relapse were as defined in the phase I studies of imatinib in CML Druker et al. 2001a,Druker et al. 2001b. RNA was extracted using TriReagent or TriAzol. CDNA synthesis was performed using MMLV reverse transcriptase. Polymerase chain reaction (PCR) was performed using the following primers: CM10 (5′-GAAGCTTCTCCCTGACATCCGT-3′) and 3′ ABL KD (5′-GCCAGGCTCTCGGGTGCAGTCC-3′). The resultant 1.3 kb fragment was excised from a low melting point agarose gel following electrophoresis. A second PCR was performed on the gel-purified 1.3 kb fragment to isolate the kinase domain using the primers 5′ ABL KD (5′-GCGCAACAAGCCCACTGTCTATGG-3′) and 3′ ABL KD. The resultant 0.6 kb fragment was subcloned into pBluescript II KS+ digested with Eco RV. Bacterial transformants were plated on media containing ampicillin and X-gal. Ten white colonies per cDNA were inoculated into media and miniprep DNA was isolated. Sequencing of each clone was performed using M13 universal forward and reverse primers. Because two rounds of amplification were employed, a mutation was considered present if it was detected on both strands of at least two independent clones per patient (see Figure 1). Analysis of the ABL kinase domain from two healthy blood donors was performed using PCR of the ABL kinase domain, followed by subsequent reamplification to control for the number of amplification cycles to which patient samples were subjected. Sequence analysis of a 0.7 kb portion of BCR-ABL immediately 5′ to the kinase domain was performed by amplification of the previously described 1.3 kb fragment using CM10 and 5′ ABL KD reverse complement (5′-CCATAGACAGTGGGCTTGTTGCGC-3′) followed by ligation into pBluescript II KS+ as above. The kinase domain of c-KIT was amplified using the following primers: 5′-TGAGGAGATAAATGGAAACAA-3′ and 5′-AACTCGTCATCCTCCATGAT-3′. To control for the number of cycles used for the BCR-ABL kinase domain, a second amplification was performed; the resultant 0.6 kb fragment was subcloned into pBluescript II KS+ and ten independent clones were sequenced.
Expression vectors of mutant P210 isoforms were created as follows. Oligonucleotides representing various point mutations were synthesized by GIBCO-BRL. pSRαP210BCR-ABL was used as the template DNA for site-directed mutagenesis reactions utilizing the mutant oligonucleotides and the QuikChange mutagenesis kit (Stratagene). Successful mutagenesis was confirmed by sequence analysis of the kinase domain.
293T cells maintained in DMEM with 10% fetal calf serum were cotransfected by the calcium phosphate method with mutant P210 expression vectors and a packaging plasmid (Ecopack, kindly provided by R. van Etten). Media containing virus was filtered and used to infect Ba/F3 cells grown in RPMI supplemented with 10% fetal calf serum and IL-3. Stable lines were selected in the presence of G418 and IL-3. After 48 hr, cells were washed thrice in PBS and subsequently grown in the absence of IL-3. Expression of BCR-ABL was documented by Western blot analysis. To determine the biochemical sensitivity of mutant BCR-ABL P210 isoforms to imatinib, cells were incubated in the presence of imatinib (kindly provided by Novartis Pharmaceuticals) at 0, 0.5, 1, 5, and 10 micromoles per liter. After 2 hr of incubation, cell lysates were prepared in 12.5 mM EDTA (pH 8.0), 25 mM HEPES (pH 7.5), 150 mM NaCl, 1% Triton X-100, 10% glycerol, 1 μg/ml aprotinin, 100 μg/ml PMSF, and 2 μg/ml leupeptin. Seventy-five micrograms of total protein were analyzed by Western blot using anti-ABL antibody AB-3 (Oncogene Research Products) or anti-phosphotyrosine antibody 4G10 (Upstate Biochemicals). Quantification of the 210 kDa signal was achieved using ImageQuant 5.0 (Microsoft) densitometry. Tyrosine-phosphorylated BCR-ABL was normalized to the amount of P210 signal detected with anti-ABL antibody. Normalized phospho-BCR-ABL values were plotted for each mutant, and biochemical IC50 was determined following creation of a best-fit curve. Mutant Q252H was not adequately detected by AB-3 and phospho-BCR-ABL was therefore not normalized. To determine the biological sensitivity to imatinib, 1 × 105 exponentially growing Ba/F3 cells/ml expressing various isoforms of BCR-ABL P210 were grown in RPMI supplemented with 10% fetal calf serum and incubated in the presence of imatinib at 0, 0.1, 0.5, 1, 5, and 10 micromoles per liter. Exposure to imatinib was performed in triplicate. After 24, 48, and 72 hr of incubation, live cells were quantitated by trypan blue stain exclusion. The mean number of viable cells at varying concentrations was normalized to mean value of viable cells in the 0 mM imatinib sample. Biological IC50 was determined from semilogarithmic graphing of the 48 hr time point for each mutant.
We thank Elliott Landaw for statistical analysis, Tom Graeber for bioinformatic assistance in sequence analysis, Liz Haddad and Nancy Violasse for assistance with clinical follow-up, Gary Shih for help with processing of samples, and Phuong Huynh for manuscript preparation. Additionally, we would like to thank Gordon Averbook for his generosity. This work was supported by grants from the Leukemia and Lymphoma Society (N.P.S. and C.L.S.) and USPHS National Research Service Award GM07185 (M.E.G.). C.L.S. is a Doris Duke Distinguished Clinical Scientist. This work is dedicated to the memory of Francis R. Nicoll, Jr.
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Publication Information
Received: July 16, 2002
Revised: July 23, 2002


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Style and Technique (Masterplots II: Short Story Series, Revised Edition)
Doyle's works provide a touchstone for the reader seeking a guide to the formula for good detective fiction. Many classic elements of style and technique are used with great success in the Holmes stories.
Characteristic of this story and of other Holmes adventures is the use of the first-person narrator who is not the detective. Watson, less observant than Holmes, presents the clues for the reader's benefit; part of the thrill of reading is in solving the crime, using information provided by Watson without benefit of the doctor's analysis. The first-person narrator also allows Doyle to mask information from the reader because Watson is limited in knowing what Holmes discovers when he is away, or of knowing what Holmes is thinking.
This tale also contains another familiar device of the detective story: the presence of "red herrings," false clues drawn across the trail to distract the unwary reader from evidence that is germane to solving the crime. The baboon, cheetah, and band of Gypsies are all false clues. In this story, though, the false clues serve a dual purpose: They also throw Holmes off the trail momentarily, adding to the suspense and, ultimately, to the realism of the adventure.
Extensive dialogue is the primary method for presenting background information and for revealing the detective's method of operation, providing readers with details essential to solving the crime and explaining how evidence should be interpreted. This dialogue is balanced with extended, minute descriptions of locale and character. The thrill of reading such stories is in making proper deductions from this plethora of information—and misinformation. As in all first-rate detective stories, the evidence provided in "The Adventure of the Speckled Band" allows the careful reader to arrive at the right answer. No tricks are introduced at the end of the tale. One need only exercise one's skills in inductive reasoning to become equal in skill to the world's most successful detective.
Literary Techniques
"The Adventure of the Speckled Band" exemplifies Conan Doyle's formula for the Sherlock Holmes stories. Miss Stoner tells her tale to Holmes...
(The entire section is 176 words.)
Ideas for Group Discussions
The Sherlock Holmes stories continue to be among the most widely read fiction of our time. Fans of the Holmes stories are among the most...
(The entire section is 940 words.)
Social Concerns
"The Adventure of the Speckled Band" focuses on the helplessness of children and women in a society that gives all legal power to adult...
(The entire section is 253 words.)
Literary Precedents
Conan Doyle was well read in the field of mysteries and drew on many sources for his own well-wrought stories. The most important precedents...
(The entire section is 315 words.)
Although The Hound of the Baskervilles is the most popular of the Holmes adventures, the series consists primarily of short stories, with...
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Please see the "Adaptations" section of the entry on The Hound of the Baskervilles for an accounting of the adaptations of the Sherlock...
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Android ups lead over iOS on mobile ad network
Android has strengthened its leading position as the most popular smartphone platform on Millennial Media's mobile ad network, according to the company's January Mobile Mix report.
For January, Google's mobile OS captured 54 percent of all ad impressions seen on smartphone platforms on the network, up from 46 percent in December. At the same time, the share of impressions held by Apple's iOS fell to 28 percent from 32 percent the prior month.
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Jeffrey Kolitch of Baron Capital explains his mutual fund's nontraditional approach
JP Morgan's Priscilla Hancock calms the fixed-income waters and reveals where she's finding attractive opportunities
While real return funds might seem less appealing as inflationary pressures remain subdued, Pioneer's Howard Weiss believes they represent a strategy that should remain a core portfolio holding, no matter the environment
As fixed income stumbles, BlackRock's Joshua Tarnow looks to stay above water with an absolute-return strategy
Columbia Management's Zach Pandl shares his outlook on rates and fixed income
A portfolio of fewer than two dozen stocks can offer a surprising amount of diversification, says Lazard's Chris Blake—and diversity is the key to success
Clearbridge Investments portfolio manager Richie Freeman explains his brand of long-term investing
ALPS' Jeremy Held discusses the drivers behind growth in master limited partnerships
Invesco's Scott Wolle explains his firm's systematic approach to tactical allocations—detailed monthly assessments that net a "whole" view on 25 asset classes
In the inaugural Morgan Stanley Wealth Management Global Investment Committee Fixed Income Summit, CIO Mike Wilson discusses the current environment with specialists from Morgan Stanley, PIMCO, Goldman Sachs and BlackRock
In a volatile market, Julian Koski of Transparent Value seeks success by watching market signals, not going with his gut
Interest rates have put pressure on real estate investment trusts, but Invesco's Paul Curbo believes opportunities for growth remain
Merger arbitrage strategies may benefit over the next few years if dealmaking activity picks up and interest rates increase, say Roy Behren and Mike Shannon of Westchester Capital Management
Brad Libby, Abigail Babson and Lindsay Politi from Wellington Management Company discuss the strategic value of investing in the municipal bond market while hedging for inflation at the same time
The price of oil is up, but Invesco's Norman MacDonald believes that stock valuations need to be considered when seeking to identify opportunities in energy
Pioneer's Andrew Feltus takes a bottom-up approach toward investing in emerging markets
As bond prices roiled on fears of rising interest rates earlier this year, Tony Rodriguez of Nuveen Asset Management saw potential opportunities
Rui de Figueiredo of Morgan Stanley Alternative Investment Partners says alternative investments should be more accessible to mainstream investors
Use of this managed account offering is growing. But as with all investment solutions, says Morningstar's Andrew Gogerty, each should be judged on its utility and suitability
Forward's Aaron Visse believes that a global need for infrastructure expansion will drive strong growth for the companies that provide support for these projects
With the economy and housing improving, Hennessy Funds' David Ellison sees smaller regional banks as better bets than large-cap financials, many of which are bloated
Tim Armour of Capital Group explains the income strategies behind American Funds
In a global market where little looks cheap, alternative-investments pro Rob Arnott makes a case for betting on a beaten-down asset class
Mirae Asset's José Gerardo Morales talks about today's emerging-market opportunities and why he sees consumers as the asset class's growth engine
Detecting improvement in a company's operating environment ahead of the crowd can produce superior return potential, says Alex Tedder of American Century Investments
There is lots of chatter nowadays about interest rates—where they are going and what the consequences of any movement might be.
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Summary (Masterplots II: Short Story Series, Revised Edition)
After an absence of thirty-three years, Spencer Brydon returns from abroad to New York City. He makes this dramatic move in order to oversee improvements to his property, which consists of two houses that have been the source of his financial independence throughout his life. One is in the process of being converted into apartments, while the other, the "jolly corner" of the title, is the house in which Brydon grew up and which he therefore is loathe to alter in any way.
In the course of conversations with Miss Staverton, Brydon reflects on what sort of person he might have become had he not chosen to tramp about the world for most of his adult life and had instead stayed in his native United States. Miss Staverton has her views, which do not entirely coincide with those of Brydon. It transpires that Brydon harbors a desire to confront what he terms his "alter ego," the self he might have been. Miss Staverton reveals that, somewhat incomprehensibly, she has already seen this other self—in her dreams. She, however, declines to disclose what she has seen.
Brydon is in the habit of coming to the jolly corner in the evenings after he has dined out and before retiring to the hotel where he lodges (the house itself remaining empty for the moment). In the course of his nocturnal prowlings about the premises, he hopes to encounter his alter ego, who, in Brydon's view of things, haunts the house as a ghost. While stalking the creature,...
(The entire section is 503 words.)
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At age fifty-six, Spencer Brydon returns to New York City after spending thirty-three years of his life in Europe. When he left New York, he...
(The entire section is 615 words.)


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Bring serenity to your outdoor space with this appealing white garden Buddha statue. His hands are rested in his lap with palms facing upwards, a gesture signifying absolute inner balance, and his eyes are closed in peaceful meditation. Statue is made of ceramic and measures just under 16 inches. Available in two sizes:
Dents, scratches and scuffs may be present as an intentional design feature. This figure can be displayed indoors and outdoors. When used outdoors, the figure's coloring may diminish over time. Item should be stored inside during freezing weather.
Black Buddha Statue with Mosaic Design on a Base


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Boost your bathroom's lookJul 13 2011 Boost your bathroom's look House Beautiful experts showcased their favorite bathroom designs - from romantic to modern - and other rooms that boast bold patterns. One of the simplest ways to change the look of your bathroom is to replace sink and tub fixtures. Choose a set that is both classic and unique - this way, years down the road, you won't be saying, "why did I ever pick this style? If you love a tub, look into getting a new one that's deep and long so you can really stretch out and enjoy a few moments of peace. Choosing a color that is tranquil and inviting is another way to change your room drastically. Once you've selected a color, look into new window treatments that will add to your theme. Roller shades come in a variety of colors and fabrics which can easily match your design. Faux wood blinds is another option that comes in many finishes so you'll be able to easily match them with your new decor. After your updates, the only thing left is to purchase a "do not disturb" sign so you can enjoy your new relaxing getaway in peace. Related Products
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Serenity in Bloom Quilt Set in King
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- Machine wash.
- Includes two pillow shams.
- Imported
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Items by Jamie Murray, Peter Chilson — 2 items
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A cheatgrass antidote - maybe
The BLM's desire to use DuPont's pesticide Oust to kill a weed called cheatgrass provokes controversy.
by Jamie Murray, Peter Chilson, Aug 04, 1997 -
A Colorado reality check: lions roam and kill
In separate attacks by mountain lions, a boy in Colorado's Mesa Verde National Park is wounded, and another boy, in Rocky Mountain National Park, is killed.
by Jamie Murray And Peter Chilson, Aug 04, 1997


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13km SW of Kindersley on the Fairmount Rd. Follow all the curves, last farm on the right, past the townsite. GPS: 51.2438N, -109.1834W.
Box 754
Kindersley, SK S0L 1S0
Tel: (306) 463-4381 / (306) 460-8949
Email: firstname.lastname@example.com
Johnson's Great Wall of Saskatchewan, Addisson Sod House Provincial Heritage Site, Great Sandhills, Herschel Petroglyphs.
1-May-2014 to 31-Dec-2014
Major credit cards accepted
Full breakfast included
Daily rate - single: $79.00
Daily rate - double: $89.00
Daily rate - cabin/condo/guest house/suite: $79.00 - $185.00
Rate details: Children under 6 years free. $16 each additional person. Horseback riding packages available.
Hours of operation: Open upon request Jan to Apr.
Smoke-free facility
Guest house(s)
Bed capacity: 6
Number of guest rooms/units: 1
Number of non-smoking units/rooms: 1
Private bathroom
Cable/Satellite television
Coffee maker
Gas barbecue
Wood barbecue/firepit
Firewood available
Picnic tables
Air conditioning
Limited wheelchair access
Pets permitted
Free parking
Plug-in parking
High speed internet
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Farm animal viewing
Participate in farm activities
Horseback riding
Bed and bale
Nature/Historic tours arranged
Special diets


text:
Structures of an Isopenicillin N Converting Ntn-Hydrolase Reveal Different Catalytic Roles for the Active Site Residues of Precursor and Mature Enzyme
Structures of an Isopenicillin N Converting Ntn-Hydrolase Reveal Different Catalytic Roles for the Active Site Residues of Precursor and Mature Enzyme
Structure, Volume 18, Issue 3,
Pages 301-308,
Publication Date 10 March 2010
Copyright © 2010 Elsevier Ltd All rights reserved.
DOI: 10.1016/j.str.2010.01.005
Marcel Bokhove
Hiromi Yoshida
Charles M.H. Hensgens
Jan Metske van der Laan
John D. Sutherland
Bauke W. Dijkstra
Laboratory of Biophysical Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, Netherlands
Department DSM Food Specialties/R&D/PBA 566-0180, DSM Food Specialties, P.O. Box 1, 2600 MA Delft, Netherlands
Department of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
Corresponding author
Present address: Crucell Holland B.V., P.O. Box 2048, 2301 CA Leiden, Netherlands
Present address: Life Science Research Center, Kagawa University, 1705-1, Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
► Maturation of AT (an isopenicillin N converting enzyme) is an intramolecular event ► Substrate conversion and maturation use the same residues with different functions ► The broad substrate specificity of AT is explained by its extensive substrate pocket
Penicillium chrysogenum Acyl coenzyme A:isopenicillin N acyltransferase (AT) performs the last step in the biosynthesis of hydrophobic penicillins, exchanging the hydrophilic side chain of a precursor for various hydrophobic side chains. Like other N-terminal nucleophile hydrolases AT is produced as an inactive precursor that matures upon posttranslational cleavage. The structure of a Cys103Ala precursor mutant shows that maturation is autoproteolytic, initiated by Cys103 cleaving its preceding peptide bond. The crystal structure of the mature enzyme shows that after autoproteolysis residues 92–102 fold outwards, exposing a buried pocket. This pocket is structurally and chemically flexible and can accommodate substrates of different size and polarity. Modeling of a substrate-bound state indicates the residues important for catalysis. Comparison of the proposed autoproteolytic and substrate hydrolysis mechanisms shows that in both events the same catalytic residues are used, but that they perform different roles in catalysis.


text:
If you didn't know Max Scherzer has two different-colored eyes, or heterochromia, then this may not be funny to you. But you are now aware of his condition, so this is hilarious:
ATTENTION: MAX GOGGLE PIC pic.twitter.com/Q4WmOwBH pic.twitter.com/Q4WmOwBH
— Donnie Kelly (@AceRHPDonKelly) October 12, 2012
It's as if he was reading my mind after the Tigers won the AL Central:
Scherzer could've topped that with each goggle being a different color.
— Matt Sussman (@suss2hyphens) October 1, 2012


text:
Who Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction - World Health Organization Staf - Paperback - 3rd ed
Author:World Health Organization Staff
Edition: 3
Publisher: Cambridge University Press
Summary: This up-dated and revised manual provides an essential source of reference for all laboratories involved in the analysis of human semen. The book sets out the fundamental laboratory techniques that should be employed for the diagnosis of male infertility. The text includes descriptions of how to construct a conventional semen profile and provides standardized protocols for performing a number of optional diagnostic p...rocedures. Such techniques are essential in the evaluation of infertile couples and in assessing fertility in men whose sperm production is suppressed by potential anti-fertility compounds or by toxic agents; they are also of interest in forensic medical science and in connection with artificial insemination. [read more]
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Hello my fellow VBB's!! Just a quick reminder about my project for deployed men and women! Please feel free to take part in this awesome program! As a military spouse I know first hand how important it is for those serving far away on foreign soil to feel our love and cheer!!Operation Christmas Cards is for EVERYONE!!
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CalArts Graduation 2014
California Institute of the Arts announces the awarding of:
Graduate and Undergraduate Degrees
Friday, May 16, 2014 at 6 pm
in the Graduation Courtyard of the CalArts campus
The ceremony is very informal, as is CalArts. There are no robes, gowns or hats. The ceremony also takes place outside, so depending on the weather, the temperature can range from very warm to cool once the sun sets.
We suggest that extra time be allowed for the drive up the 5 freeway on Friday evening. It is a favorite route out of Los Angeles and is often more crowded and slower than anticipated. Drive time from LAX to CalArts can take as long as 1.5 hours during rush hour.
If you have any time-sensitive questions, please contact the Office of Student Affairs at (661) 253-7874 or at firstname.lastname@example.com for assistance.
Travel Information
There is a wide selection of hotels near the campus; the closest are located in Stevenson Ranch. Please take into account, however, that
most hotels are not within walking distance of the campus. If a shuttle is dropping you off at a hotel from the airport, you may need to make arrangements to take a taxi to the campus.
This website is the most comprehensive listing of hotels in the Valencia area. Many of these hotels offer a "CalArts" rate; if you would like to know if a hotel offers a CalArts rate, it is best to call the local Hotel phone number rather than the toll-free telephone number.


text:
Author: Ivo Weevers
Ivo Weevers has over 10 years of experience in user experience design, interaction design for web and mobile, product design, and user research. In his current role, Ivo leads an international design team that is responsible for the design of mobile services across a wide-variety of mobile platforms, such as Android, iPhone, S60/QT, Java and Blackberry.
Website: Ivo Weevers


text:
Clinical Validation of a New Algorithm for Computerized Dosing of Vitamin K Antagonist Therapy
This study has been completed.
University Of Perugia
Information provided by (Responsible Party):
Alfonso Iorio, University Of Perugia
ClinicalTrials.gov Identifier:
First received: July 11, 2011
Last updated: January 16, 2013
Last verified: January 2013
- Full Text View
- Tabular View
- No Study Results Posted
- Disclaimer
- How to Read a Study Record
The purpose of this study is to determine whether the new algorithm is safety and effective in proposing the dosage and the timing of oral anticoagulant therapy.
Condition |
Anticoagulated Patients |
Study Type: | Observational |
Study Design: | Observational Model: Cohort Time Perspective: Prospective |
Official Title: | Clinical Validation of a New Algorithm for Computerized Dosing of Vitamin K Antagonist Therapy |
Resource links provided by NLM:
Further study details as provided by University Of Perugia:
Primary Outcome Measures:
- Time spent in therapeutic range of INR by the patients [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
Secondary Outcome Measures:
- Thrombotic and bleeding events [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
Enrollment: | 100 |
Study Start Date: | November 2010 |
Study Completion Date: | January 2013 |
Primary Completion Date: | August 2012 (Final data collection date for primary outcome measure) |
Groups/Cohorts |
Patients in oral anticoagulant therapy
Patients taking oral anticoagulant therapy
Ages Eligible for Study: | 18 Years and older |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Sampling Method: | Probability Sample |
Study Population
the conditions for the patients inclusion are: to take oral anticoagulant therapy for at least 2 years; to be in stable conditions for at last 3 months
Inclusion Criteria:
- to take oral anticoagulant therapy for at least 2 years
- to be in stable conditions for at last 3 months
Exclusion Criteria:
- patients who need to perform surgery
- patients who interrupt therapy
Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01392040
Italy | |
Hospital of Macerata | |
Macerata, Italy, 62100 |
Sponsors and Collaborators
University Of Perugia
Principal Investigator: | Michela Basileo, Dr | University Of Perugia | |
Principal Investigator: | Alfonso Iorio, Dr | McMaster University |
More Information
No publications provided
Additional relevant MeSH terms:
ClinicalTrials.gov processed this record on March 09, 2014
No publications provided
Responsible Party: | Alfonso Iorio, Dt, University Of Perugia |
ClinicalTrials.gov Identifier: | NCT01392040 History of Changes |
Other Study ID Numbers: | MIV_AI_10_001 |
Study First Received: | July 11, 2011 |
Last Updated: | January 16, 2013 |
Health Authority: | Italy: Ethics Committee |
Additional relevant MeSH terms:
Anticoagulants Vitamin K Vitamins Hematologic Agents Therapeutic Uses Pharmacologic Actions Micronutrients |
Growth Substances Physiological Effects of Drugs Antifibrinolytic Agents Fibrin Modulating Agents Molecular Mechanisms of Pharmacological Action Hemostatics Coagulants |
ClinicalTrials.gov processed this record on March 09, 2014


text: Colin Campbell of Meet For Men He Has a Fathers Heart April 16, 2013 All this divorce by Christians is having a debilitating affect upon our nation, as well as future generations. We certainly need this Elijah anointing to turn our hearts back to the value of children. The "one to two children" [Read more...]


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Use mount --bind To Move The Website And Email Directory Of a ISPConfig 3 Server To a New Directory In the following guide, I will explain … [Read More...]
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CeBIT is one of the largest information technology (IT) fairs in the world. More than 300,000 attendees from all over the world come to Hannover, Germany … [Read More...]
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text:
All Solicitations and specific opportunity notices are made available through the Oregon Procurement Information Network (ORPIN). http://orpin.oregon.gov
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Success Stories
Success Stories |
Text Index | Custom Search |
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Success Stories
Miami-Dade Professor is Florida's Professor of the YearMiami-Dade College Professor Sandra Shultz has been named the 2009 U.S. Professor of the Year for the state of Florida by the Carnegie Foundation for the Advancement of Teaching and the Council for Advancement and Support of Education. Dr. Shultz is a professor in the college's Department of Biology, Health and Wellness and was recognized for excellence in teaching and her ability to positively influence the lives and careers of students. For more information about the U.S. Professor the Year award, visit www.usprofessorsoftheyear.org. |


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"Odd-Lot Specials" Clearance Sale Save up to an additional 30% off original price. Hurry! Once the inventory is gone, so are the savings. Special price is only valid on remaining inventory.
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text:
Originally Posted by SWedd523 What does negotiatig hard have anything to do with it? TMI man. T.M.I. Don't be jealous. There's plenty of me to go around
Hendo|MKG|Bismack|Walker| Proud Australian Bobcats Fan!!!
Originally Posted by Toocool Don't be jealous. There's plenty of me to go around There's plenty of Sean May to go around too, but you don't see anybody being jealous
Originally Posted by gm in training i continue to state that i've won prized fantasy lgs all the time ;for espn,cbssports,and yahoo for the past 8 years ,and im like 8-12 all together .so when i talk sports, i think some should respect my opinion more.
Forum Rules


text:
Original Price: $188.00 - $198.00
$178.00 - $188.00
Save up to $10.00Save up to 5%
Item Number: 045M78
Harley Davidson Boots for the gal who loves to flaunt boots with attitude! The Sapphire boot features a full grain leather foot under a matching 13" leather shaft with silver-tone stud embellishments. 1" block heel. Rounded toe profile. Inside locking zipper provides easy on and off. Imported.


text:
Current vote count:
jokool: IV (Buoy, Human, Akuraito, Poyo)
GliscorMan: I (Master Mew)
Greece: II (Joltik, AlphaMouse)
Human: I (Ryoga Kamishiro)
Poyo: III (Sputnik, jokool, Rio Kamishiro)
Akuraito: II (GliscorMan, Midorikawa)
AlphaMouse: I (Baron Dante)
Elysion: I (Human)
Master Mew: I (Laterose)
Ah, um, it's just me being me and wanting everything to be organized, but would you be able to put those with the highest votes on top when posting the tally? X3; Thanks.
I fail to see how making an argument against/explaining why I believe someone could be mafia is 'desperate'.You PMed me trying to convince me to lynch jokool.
In any case, I PM'd you asking why you had decided to remove your vote on jokool; I wasn't sure if I was somehow missing something, and I explained my reasons on why I hadn't so you would know what I was caught on. And when I responded to counter your reasoning, it was simply to test your reactions and if you would elaborate further.
NOTE: Dark Blueberry is subbing in for 見捨てられた一.
Please confirm in-thread when you have received your role.
Also, just as a reminder, phase changes in about 45 minutes.
A nameclaim could work. ^^;
Not the best match, but I could see that working, I suppose...
VOTE: jokool
Ah, sorry, I'm an idiot! ><
UNVOTE: jokool


text:
Property | Value |
Name: | Caitanya-siksamrta |
Description: |
This book progressively presents teachings of Sri Caitanya Mahaprabhu relevant to all sections of human society and clarifies how these teachings may be practically applied in the modern world. Containing the essence of the Vedas, the teachings are a wonderful rainfall of nectar that douses the forest fire of the quarrels and hypocrisy in this present age of Kali. The book is divided into eight "rainfalls of nectar", and each of these is sub-divided into "showers of instruction". |
Filename: | caitanya-siksamrta (hindi).pdf |
Filesize: | 1.64 MB |
Filetype: | pdf (Mime Type: application/pdf) |
Created On: | 04/11/2009 00:00 |
Hits: | 9073 Hits |
Last updated on: | 08/19/2011 04:49 |