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The Cleveland Memory Project is a searchable collection of digital resources focusing on the history of greater Cleveland and Northeast Ohio, created in collaboration with many regional partners.
The eBooks listed here are also available via Cleveland Memory's "virtual reading room." Many of the original texts for these eBooks may be found in Special Collections at the Michael Schwartz Library, Cleveland State University, while a few exist only in digital format.
A Magical Journey
Thomas Vail
I am a child of my surroundings. This is a tale of how I related to the world I encountered over eight decades. My lifetime has spanned a revolutionary course of events that no one of my generation could have imagined. (From the introduction)
Arab Americans and Their Communities of Cleveland
Mary Haddad Macron
The author of this monograph has made a contribution in describing the progress of the Syrian and Lebanese American community in the Cleveland area. These same experiences were similarly reflected in many other communities throughout the land, including my own. This monograph includes not only the early history of these people from their origins in the Mediterranean, it focuses particularly on their daily lives as immigrants to America -- and on the difficulties they encountered in trying to maintain their traditional institutions in a new land. –Excerpt from the Introduction by Danny Thomas, Founder of St. Jude's Children's Research Hospital
Beechwood, The Book
Jeffrey S. Morris
From the forward by Darrell A.Young: "The city fathers have been called visionaries. The city has been studied by architects, planners, engineers and the like from all over the country. What is it about Beachwood that has attracted so much attention?
To be certain, there is something magical that has taken place over the last 80 years in Beachwood and Jeffrey Morris has finally documented the historical blueprint from which we can study and learn. This book is the first opportunity to understand our heritage and to delve into the intellect that forged this wonderful community."
Bridges of Metropolitan Cleveland: Past and Present
Sarah Ruth Watson
The Bridges of Metropolitan Cleveland
is a compilation of a wealth of information, both technical and general as well as anecdotal, on the most important bridges in Cuyahoga County. This book should hold interest of all civil engineers in Ohio as well as lay persons who have a particular bent for history. From the introduction.
Brief History of Religion in Northeast Ohio, A
George W. Knepper
This monograph presents a concise but comprehensive look at the history of religion in Northeast Ohio. Starting with the early settlers from New England, Professor Knepper traces the increasingly diverse mixture of faiths that now characterize the life of the sacred in Northeast Ohio. In doing this, Professor Knepper is drawing on a lifetime of study into Ohio's history.
Cities Within a City : On Changing Cleveland's Government
Burt W. Griffin
Burt W. Griffin has been a judge of the Common Pleas Court of Cuyahoga County, Ohio since January 3, 1975. From 1966 to 1975, he served as a legal aid lawyer in various capacities including Executive Director of the Cleveland Legal Aid Society and National Director of the Legal Services Program, U.S. Office of Economic opportunity. He was Assistant Counsel to the President's Commission on the Assassination of President Kennedy during 1964. Judge Griffin has been a life-long resident of Greater Cleveland. He was born in Cleveland's Hough section in 1932, lived in the Shaker Square area of Cleveland from 1937 to 1960, and has resided in Shaker Heights since then. Judge Griffin is a political science graduate of Amherst College, B.A. Cum Laude, 1954 and Yale Law School, J.D., 1959.
Cleveland: A Metropolitan Reader
W Dennis Keating, Norman Krumholz, and David C. Perry
Contemporary urban scholars examine the political economy, social development, and history of Cleveland from 1796 to the present in this interdisciplinary collection of essays. Also included are commentaries provided by the leaders of Cleveland, now actively working to transform the city. Though the contributors do not necessarily agree on the nature of Cleveland's problems or on appropriate solutions, together they offer a broad perspective on the reality of a great American city's growth, decline, and reinvention.
Cleveland : An Inventory of Historic Engineering and Industrial Sites
Daniel M. Bluestone
"As part of the Office of Archeology and Historic preservation, Department of Interior, the Historic American Engineering Record (HAER) documents historic engineering and industrial sites throughout the Nation. This inventory is the first step in the documentation process." -- from the Introduction
Cleveland Jazz History, Second Edition
Joe Mosbrook
Contents: What is jazz? -- Cleveland's earliest links to jazz -- The jazz age in Cleveland -- Art Tatum at Val's in the alley -- Duke Ellington in Cleveland -- Count Basie's Cleveland connections -- The big band era -- Central High School -- Freddie Webster -- Tadd Dameron --Meet Benny Bailey -- Cleveland jazz clubs -- Cleveland jazz guitarists -- The singers in Cleveland -- Boogie woogie piano -- "Modern" jazz -- Big bands of the 1950s -- The far-ringing 1960s -- Traditional jazz -- Resurgence in the 1980s and '90s -- Joe Lovano -- Ken Peplowski -- Other major players -- Preserving the legacy.
Cleveland Mayor Ralph J. Perk: Strong Leadership During Troubled Times
Richard Klein
This book is a tribute to one of Cleveland's greatest leaders. Ralph J. Perk embodied the quintessential 20th century politician. A dedicated administrator with both insight and foresight, he dedicated nearly fifty years to public service. During his six-year tenure as mayor, Cleveland went through extraordinary economic, political and social changes. The citizenry demanded strong leadership and Ralph Perk provided it. An optimistic leader with strong moral and religious convictions, he never walked away from a challenge.
Cleveland, Ohio
Regennia N. Williams
Featuring over 200 striking photographs from the 1920s through 1980, Black America: Cleveland, Ohio celebrates the rich history of this great city's African-American community. Its neighborhoods, churches, civil, religious, business and cultural leaders, musical icons, and sports heroes are all brought to life here through the archives of local newspapers and historical societies, as well as the private collections of many Cleveland residents.
Cleveland Press Story : The Newspaper That Serves Its Readers
Cleveland Press
Promotional piece for the Cleveland Press, Cleveland, Ohio.
Cleveland : The Best Kept Secret
George E. Condon
Former Plain Dealer columnist George Condon coined the phrase "The Best Kept Secret" that has since become synonymous with Cleveland (no longer the Mistake on the Lake!). This book is his masterpiece, a compilation of history, familiar names and faces, and the tongue in cheek humanism that made his column a household institution in Cleveland for a quarter century. (Review from Amazon.com)
Democratizing Cleveland: The Rise and Fall of Community Organizing in Cleveland, Ohio 1975-1985
Randy Cunningham
Democratizing Cleveland is the result of almost fifteen years of research on a topic that has been missing from local works on Cleveland history: the community organizing movement that put neighborhood concerns and neighborhood voices front and center in the setting of public policies in the late 1970s and early 1980s.
Each In Their Own Voice: African-American Artists in Cleveland, 1970-2005
Cleveland State University, Art Gallery
This exhibition, "Each in Their Own Voice," presents a survey of the work of 23 prominent African-American artists who were active in Cleveland between 1970 and 2005, a time in the recent past characterized by breathtaking technological, cultural, social, and artistic changes - a time that has yet to be fully understood and processed by the mechanisms of history.
Early History of Cleveland, Ohio
Charles Whittlesey
Includes original papers and other matter relating to adjacent country with biographical notices of the pioneers and surveyors.
The Early History of Cleveland, published in 1867, includes journal entries from the early survey parties that surveyed the Western Reserve. Also included is geological information and a history of the Native Americans in the area. This book is considered a landmark, because it was the first book length history of Cleveland.
The author, Charles Whittlesey, was a geologist by trade, but had many different interests. He also practiced law, was interested in archeology and history as well. He helped to found the Western Reserve Historical Society, and served as their president for a time. He was chosen to serve on the first geologic survey of Ohio, and also aided surveys for ore in both Michigan and Wisconsin.
--From ClevelandMemory.org
Fenn College
William Becker
Fenn College was founded in 1923 as part of the Cleveland YMCA's education program, which for 50 years had helped students finish their high school educations and learn additional business and technical skills.Throughout its history, the fortunes of Fenn College were linked to those of Cleveland.
From Ark to Art : The 20-year Journey of the Civic, Cleveland Heights, Ohio, from Jewish Temple to Multi-purpose Community Facility
John J. Boyle III
The Civic is a former Jewish temple located in Cleveland Heights, Ohio, an inner-ring suburb of Cleveland, Ohio. The building was close to being abandoned and possibly torn down after its former congregation built a new facility farther out in the suburbs. This study describes how a former temple came to serve the community in a new and different way in the secular world. This study will chronicle the Civic as a historical building; describe the efforts to remake it into a multi-purpose building that is a community asset; and serve as a model to other communities interested in adapting houses of worship to secular purposes. While other government regulations, the basic tools are the same everywhere. there are differences between states in terms of the details of this kind of preservation work, such as tax codes and to provide the capital necessary to perform the retrofit. People responsible for the stewardship of older buildings that must be extensively retrofitted, as the Civic was, find it almost impossible to generate enough revenue to both sustain the operations of the building.
Guide to Stones Used for Houses of Worship in Northeastern Ohio
Joseph T. Hannibal
The purpose of this guide is to serve as an introduction and field guide to the stone used for Northeastern Ohio's sacred landmarks. compiling this information are noted. Both exterior and interior stones are described. Locations are given so that visitors can find various interior features. Finally, interesting facts having to do with the stones are given in a remarks section and references to sources used.
Guide to Studying Neighborhoods and Resources on Cleveland, A
Edward M. Miggins
This monograph was written as part of the Cleveland Heritage Program in 1984 to provide more up-to-date information for researchers of Cleveland's history. The focus is well-established neighborhoods in Cleveland.
Haymarket to the Heights: The Movement of Cleveland's Orthodox Synagogues From Their Initial Meeting Places to the Heights
Jeffrey S. Morris
This document traces the movement, growth and demise of the small neighborhood synagogues, or shuls, established by newly-arrived Eastern European Jews in the Haymarket area as they migrated to the eastern suburbs.
Hungarian Americans and Their Communities of Cleveland
Susan M. Papp and Joe Eszterhás
Cleveland was at one time the city with the second largest population of Hungarians in the world (after Budapest). This history of the Cleveland Hungarian community outlines within a historical context how and why Cleveland became such a large Hungarian center and the nature of the ethno-cultural community which existed and still exists. This study is the first comprehensive history of this community in Cleveland.
Images of America: Cleveland's Lighthouses
Janice B. Patterson
Missionary-geographer John Heckewelder was prophetic in the 1790s when he mapped the place where the Cuyahoga River flows into Lake Erie. He wrote, "Cujahaga will hereafter be a place of great importance". In 1796, surveyors arrived to plot a new town and named it after their superintendent, Moses Cleaveland. Soon Cleveland(the a was omitted on early maps)was a magnet for inventors and entrepreneurs. By 1829-1830, a lighthouse was necessary to support lake traffic spurred by shipbuilding, shipping, and population growth. A succession of taller, brighter structures has guided mariners into the Cleveland harbor, creating a splendid history. Remarkable people have tended these sometimes-silent sentinels through decades of calm nights and dramatic storms, subtly contributing to the region's growth and prosperity.
"Let's Go Shopping at the Square" Cleveland's Leading Downtown Department Stores: A Business Legacy
Richard Klein
This book is a tribute to the eight major downtown Cleveland department stores and their many loyal customers. For over 150 years, these large stores dominated the local retail scene. They represented exciting places that not only provided a full range of goods and services all under one roof, but also, offered a special shopping adventure every time their customers visited.
Nine Legends: Sketches of Remarkable People Based on Personal Relationships
Thomas Vail
During my 42 years in the newspaper business, 28 of them was spent as publisher and editor of The Plain Dealer in Cleveland Ohio, I was able to meet one on one with many world leaders, heads of state (including nine American presidents) and others of remarkable abilities.
The following personality sketches of some of the legendary figures I have met include a few geniuses as well. ...
I hope my readers will enjoy these personal observations about some of the people who have shaped events to a greater or lesser degree during the latter half of the 20th century.
(From the Introduction, by Thomas Vail, Publisher and Editor of the Plain Dealer 1963-1991


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- Comically Missing the Point:Marge: (trying to lift a drunk Homer off the floor) I've never been so embarrassed in all my life!
Homer: Why? Whatcha do?
(Drops Homer in annoyance, who then pass out)
- Compressed Vice: Homer's obsession with fishing pretty much begins and ends in this episode.
- Easily Forgiven: Marge lets Homer off the hook shockingly fast at the end. All he does is throw back the fish he caught, which really doesn't address any of the things she was mad at him for, but she immediately accepts this as good enough.
- Though, Marge calls him out for caring more about being popular with the other fishers than his own marriage. So he threw the fish back to prove her wrong, showing Marge that Homer does care about her.
- Fly in the Soup: Homer puts a fake ice cube with a fly inside on Dr. Hibbert's drink. Hibbert lectures Homer on the dangerous chemicals in the plastic cube, noting that a real fly would have been safer. Though Homer doesn't listen because he's too busy laughing at how much he fooled Dr. Hibbert.
- Long List: When Lovejoy asked everyone to say what they didn't like about there partners. Homer mentions one minor thing that annoys Marge. However when it's Marges turn she ends up rattling off a list so long it takes several hours to finish and leaves her with a hoarse voice. Even then that's only what she can remember at that point in time.
- Noodle Incident: A drunken Homer tells Bart to do that "cute thing". Bart doesn't know what that is, so he tells him to go to his room.
- Off Model: This episode contains the infamous animation error where Ned's nose disappears, his shirt collar overlaps his neck, and part of his neck disappears.
- Ominous Latin Chanting: During the babysitter's flashback of baby Bart nearly running her over.
- Shrouded in Myth: Homer becomes a local legend for almost catching General Sherman, and starts getting this treatment.
- Shout-Out: Homer's battle with General Sherman is similar to The Old Man and the Sea.Homer: (punching General Sherman) I love you! But I must kill you!
- Homer's memory of the party parodies Al Hirschfeld's drawing of the Algonquin Round Table, a celebrated group of The New Yorker writers known for their witty repartee.
- Signature Laugh: Arguably the first usage of Nelson's iconic "ha ha!", though it's a little bit different here.
- Signs of Disrepair: Bart rearranges the finger sandwich platter Marge laid out for the party, which are arranged to read "Enjoy our party snacks", so that it now reads "Boy, our party sucks."
- What the Hell, Hero?: Marge wakes up to find him sneaking to go fishing. She gets angry and berates him, telling him they're trying to save their marriage. Then she calls him out for still thinking about fishing even when she's talking to him.Homer: Is it the time to be honest?
Marge: (imagined as a fish person) Yes!
- Wounded Gazelle Gambit: Grampa finally gets the kids to behave and clean up their mess by pretending to cry so that they'll feel sorry for him.


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Development of small fuel efficient multi-fuel capability engine
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AbstractThe Baker Opposed Piston Single Cylinder Engine is a 24 cu.in., 30 Hp engine with high power density (0.803 Hp/lb or 45.7 Hp/cu.ft.) capable of running on multiple fuels. The engine concept offers a totally new look at small engine development while utilizing several conventional engine components. In addition to high power density, the engine has significant advantages over current small engine programs, in both military and commercial applications. Previous development contracts have proven that the engine concept is viable and exciting. Now research is required to adapt the engine to the current military requirement for smaller applications and to advance the technology to a point where it will become a viable alternative. Specific primary areas of development that will be addressed in Phase I include: mechanical engine design, engine simulation/modeling, fuel research and component bench testing. Looking toward a Phase II SBIR, the objective will be to build and test a prototype of the 30 Hp engine.
* information listed above is at the time of submission.
An Official Website of the United States Government


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Roy Jones Jr. vs Vyron Phillips: Winner and Reaction from UR Fight 2016 Knockout
It took just over a round for 47-year-old Roy Jones Jr. to finish Vyron Phillips on Sunday night in Phoenix, Arizona. The aging legend scored a decisive second-round KO...
Roy Jones Jr. to Take on Fan in 'UR Fight' Campaign, Fan Could Win $100,000
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Roy Jones Jr. Granted Russian Citizenship: Latest Comments and Reaction
Boxing legend Roy Jones Jr. has become a citizen of Russia thanks to a decree from President Vladimir Putin. Matt Bonesteel of the Washington Post , citing a decree from the Kremlin's official website, reported Jones' new Russian citizenship..
Roy Jones Jr. vs. Danny Santiago Fight Called off Due to Tropical Storm Erika
For the second time in five years, a fight between Roy Jones Jr. and Danny Santiago has been cancelled. According to FightNews...
Roy Jones Jr. Asks Vladimir Putin for Russian Citizenship: Details and Reaction
North Korea has Dennis Rodman. If Roy Jones Jr. has his way, Russia will soon have him. The boxing great traveled to Russia this week to ask President Vladimir Putin for citizenship ...
Roy Jones Jr. vs. Eric Watkins: Winner, Scorecard and Reaction
The 46-year-old Roy Jones Jr. (62-8, 45 KOs) is still boxing. He's also still registering impressive knockout victories...
Roy Jones Jr. vs. Billy Bailey: Fight Time, Date, Replay Info and More
For better or for worse, there's no quit in Roy Jones Jr. The 46-year-old former multi -titleholder and Boxing Writers Association of America's " Fighter of the Decade " for the ...


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Our 28th Season in 2016 has something for everyone. From Broadway's beloved jazz musical, Chicago, and the Disney classic The Little Mermaid in Washington Park, to Seussical at the Palace, we've gearing up for a jam-packed season. Click to learn more!
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Work That Sucker (Calagad13 Remix)
Features of This Trackheavy use of samples
r&b influences
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extensive use of vocal samples
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party rhymes
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Credit: P_A_S_M Photography
Creative #: 144476015
License type: Royalty-freeRoyalty-free pricing is based solely on the size of the product you need, not the specific use. You don't have to pay any additional royalties on a use-by-use basis. Once you license a royalty-free product, you may use it multiple times for multiple projects without paying additional fees. (Pornographic, defamatory, libelous or otherwise unlawful use of any image is, of course, prohibited.)
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Mind & Body
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More Rumours Suggest New Xbox Reveal at E3 2012
Written Friday, January 06, 2012 By Lee BradleyView author's profile
More rumours of an E3 2012 reveal for the Xbox 360's successor have emerged, this time from trade mag MCV. According to this latest rumour, Microsoft have recently signalled to partners that the chatter is true: they will be showing off the next generation console in LA this summer. Woop!
The report also states that a new PlayStation will be revealed too, alongside the presence of the Wii U. If true it will mark the first time in the consumer show's history that three brand new rival consoles will be under the same roof and so directly comparable. Gentlemen, keep it clean. FIGHT!


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July 26, 2016Panel for Summer Interns at HMRI: Houston Methodist Academy Postdoctoral and Trainee Association (MAPTA)
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May 23, 2016Article: Why was my manuscript rejected, and what can I do about it?
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Simple Definition of likelihood
: the chance that something will happen
Full Definition of likelihood
: probability <a strong likelihood that he is correct — T. D. Anderson>
See likelihood defined for English-language learners
See likelihood defined for kids
Examples of likelihood in a sentence
There is a strong likelihood that he will be reelected.
<the weatherman on TV said that the likelihood of rain today was fairly high>
14th Century
First Known Use of likelihood
14th century
Rhymes with likelihood
adulthood, arrowwood, babyhood, bachelorhood, brotherhood, buttonwood, candlewood, cedarwood, cottonwood, fatherhood, geezerhood, hardihood, high priesthood, Hollywood, Isherwood, knock on wood, leatherwood, livelihood, lustihood, maidenhood, motherhood, nationhood, neighborhood, orangewood, parenthood, personhood, puppyhood, Robin Hood, sandalwood, scattergood, servanthood, sisterhood, spinsterhood, toddlerhood, to the good, tulipwood, understood, widowhood, womanhood, yellowwood, zebrawood
LIKELIHOOD Defined for Kids
Definition of likelihood for Students
: probability 1 <In all likelihood we will go.>
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ranking page
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ranking the website.. bring it to top 10 in [url removed, login to view] pls look resport! dotsaravanan (freelancer) was seo master before and he do bad work.. hope to find better
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Vous voulez voir cette page en français ? Cliquez ici.
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Starfire Mass Market Paperback – Jul 20 1994
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Conn is a best-selling author; this is one of Pinnacle's lead August titles.
Copyright 1994 Reed Business Information, Inc.
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Starfire is a futuristic romance novel about Dez Sanchez a disgraced pilot and his love for a mysterious woman named "Rebel" who he believes is a gardener. While I initially found this novel interesting I found Dez too mature for the 21 year old Rebel. There was also an ick factor for me when Rebel's true identity was revealed. I felt Rebel showed a blistering lack of maturity (no surprise given her age).
I gave up on this book. I found I disliked the heroine and lost respect for her by page 50.
I gave up on this book. I found I disliked the heroine and lost respect for her by page 50.
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nice looking plugin, butI removed it after a first short test.
Your plugin has placed some html right in my site's HTML head section, this makes the HTML invalid.
I don't like to have two H1 elements in my HTML structure.
Maybe you like to fix this and I will try it again.


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The flat bottom of the sauté performs all the functions of a skillet, and the taller straight sides maximize capacity. Top with the tightfitting lid to finish cooking favorite one-pot meals in the oven.
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Free personalized radio that
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Why Does This Always Happen To Me?
Features of This Tracka comedic sensibility
pop rock qualities
a subtle use of vocal counterpoint
a subtle use of vocal harmony
extensive vamping
mixed acoustic and electric instrumentation
major key tonality
a vocal-centric aesthetic
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*does this qualify for a bone-fide comment?*
Weird Al is funny...in a very disturbed way.
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Fitbit to expand into tier-II and tier-III cities and open 500 outlets in India
She said that the company started operation in India in August 2015 and since then has made deep inroads in the segment.
Audi targets tier II, III cities and North-East to spur growth
Although the base is smaller, our sales in Tier II and III cities are growing ...
Chinese handset vendors gain ground in tier II, III cities: IDC
Customers are choosing more 4G devices over 3G ones with more than 65 per cen...
Carlson Rezidor eyes tier II,III cities for expansion
"Our target of 170 hotels by 2020 is well on track. We have 45 hotels in pipeline across the country," company's South Asia CEO, Raj Rana said.
Hyatt Place eyes tier II, III cities
Global hospitality company Hyatt is looking expand its upscale Hyatt Place hotels to tier II and III cities across the country.
Low-cost NPS Tier II has beaten direct MFs
NPS Tier II funds perform better than mutual funds due to low costs. But ambiguity over taxation and other problems keep investors away.
PNB Housing Fin readies IPO, heads to tier 2, 3 cities
On demand scenario, the company is optimistic about the mass market, but feels that the luxury market needs to step up.
Donna Karan brand sold to to G-III for $650 million
The sale reflects LVMH's inability to generate profitable growth from the business, which has counted Hillary Clinton and Michelle Obama among its fans.
RBI relaxes rule for Basel III liquidity coverage ratio
Liquidity coverage ratio is a capital measure mandated under Basel III norms requiring banks to maintain highly-liquid assets, including government securities.
Budget 2016: First-time home buyers in tier-III & tier-II cities to benefit, says JLL India
To give him due credit, the Finance Minister has definitely made a concerted attempt to manage expectations with a balanced budget.
PSBs may find it easier to float at Tier I bonds
"The issue was discussed in FSDC, we were told that some mechanism is being worked out. We are waiting for finer details," said a senior official.
Thomas Cook launches smaller outlets to tap tier-III cities
In a BSE filing, Thomas Cook India said the technology assisted outlets will be manned by a small team for online connectivity to central systems.
Uber to expand in lower-tier Chinese cities
It now operates in nearly 60 cities, including many lower -tier cities also targeted by domestic rival Didi.
MSOs profitability to get hit by delay in monetisation from phase III: ICRA
With an estimated population of over 60 million households in Phase IV markets, cable TV players do not anticipate any extension in Phase IV deadline.
HCC bags Rs 2523 crore contract from Mumbai Metro III
Hindustan Construction Company (HCC) in joint venture with MMS Russia bagged a contract worth of Rs 2,523 crore from the Mumbai Metro Rail Corporation.
HCC bags Rs 2523 crore contract from Mumbai Metro III
Hindustan Construction Company (HCC) in joint venture with MMS Russia bagged a contract worth of Rs 2,523 crore from the Mumbai Metro Rail Corporation.
Delhi: 3-tier marvel in Metro's heritage corridor
Engineers who undertook the construction admit that the task was fraught with risk, not to mention heightened requirement for precision construction.
Syndicate Bank raises Rs 930 cr via Basel III compliant bonds
Syndicate Bank has invited bids for issue size of Rs 500 crore with green shoe option of Rs 430 crore limiting the aggregate issue size to Rs 930 crore. The issue closed on July 14.
Hope Rs 22,915 cr for bank recapitalisation comes as tier 1 capital: Pratip Chaudhuri, Former Chairman, SBI
By shelling out Rs 23000 crore for PSU banks at one gp, the government has demonstrated one thing that they are capable of committing and writing big cheques
Would be goping for tier one capital raise considering we are an NBFC: Alok J Patel, Arman Financial
"As far as our growth plans are concerned, all things considered we have been growing about CAGR of about 50% to 60% for the last five years."
Basel-III: RBI makes it a must for banks to detail debt terms
"The measures were intended to ensure the debt and capital raised by banks in India are in compliance with Basel III capital regulations."
Bank of India raises Rs 1,000 crore via Basel-III bonds
State-owned Bank of India today said it has raised Rs 1,000 crore through bonds that comply with Basel-III norms for capital adequacy.
HSBC starts marketing US dollar Additional Tier 1
HSBC is started marketing a US dollar Additional Tier 1 deal, the first from a UK bank this year as it seeks to meet new capital adequacy regulations.
90% SMEs in Tier II and III cities are adopting smart technologies for their business: Report
The survey done as a part of the Digital Desh Drive, was conducted across 24 cities from Amritsar to Kanyakumari with the aim of studying the behavioural patterns of entrepreneurs.
Companies want government to relax rules to promote BPOs in tier II, III cities
The BPOs have also demanded that the incentives under the scheme should be extended to companies that already operate in non-metro locations.
RBI doubles PoS cash withdrawal to Rs 2K in Tier III-VI centre
The Reserve Bank today doubled the limit for cash withdrawal at Point-of-Sale (POS) in Tier III to VI centres to Rs 2,000 per day to improve customer convenience.
Home services firm LocalOye to launch online services; eyes tier II, III cities
LocalOye provides dozens of home service options offline in Bengaluru, Mumbai and Gurgaon, and currently receives 3,500 service requests a day.
Dating apps like Tinder, Truly Madly see high growth activity in tier 2, tier 3 towns
Taru Kapoor, head, India, for Tinder said the app is attracting over 14 million swipes each day in India - an increase from 7.5 million in September 2015.
Vista Rooms enters online branded accommodation space targeting tier II & III cities
The co has built a network of over 450 properties in 55+ cities and has raised an undisclosed amount of funding to expand its network.
RBI revises liquidity measuring rules for Basel III
The Reserve Bank has revised certain rules on measuring liquidity for Basel III norms, providing exemption to branches of foreign banks from submitting statement.
Air India's subsidiary Alliance Air adds tier-2 cities to its route
Alliance Air offers flights from Kolkata to the northeastern region, from Bengaluru to Agathe and Cochin, and from Mumbai to cities of Gujarat and Maharashtra.
Air Force General Lori J. Robinson becomes 1st woman to lead top-tier US combat command
Carter praised Robinson's extensive experience and her skill as a strategic thinker capable of making split-second, life-and-death decisions.
Puma to expand in metros, tier II & III cities; focus on e-retail
Sportswear firm Puma today said it would go for its expansion in India by opening new stores in tier II & III cities and focussing on e-retail.
Government to finalise guidelines for BPOs in tier II & III cities
"We are in the process of finalising the guidelines for establishing BPOs in small tier II and III cities across the country especially in states like Uttar Pradesh, Bihar and Odisha," Telecom Minister Ravi Shankar Prasad said.
Canara Bank raises Rs 3,000-cr Basel-III compliant bonds
The bank said its Bond Committee had decided to raise Basel-III compliant tier-II bonds amounting to Rs 1,000 crore with an option to retain over subscription.
Barapullah corridor Ph-III likely to be finished by December 17
An elevated corridor from Jawaharlal Nehru Stadium to Sarai Kale Khan over Barapullah Nallah was constructed by PWD in 2010 under its first phase.
Harley Davidson to expand business in tier-II cities
US-based iconic cult bike maker Harley-Davidson is expecting growth in tier-II cities of the country where the company is expanding its business.
Global In-House Centres focus on expanding in Tier II and III locations: NASSCOM
Global In-House Centres (GIC) or Indian subsidiaries of global IT companies, are considering cities such as Vadodara, Jaipur and Coimbatore.
Metro likely to miss phase III deadlines
Delhi Metro looks set to overshoot deadlines for phase III, perhaps by an entire year.
Gaja Capital makes final close of Fund III at $240 million
Mid-market private equity firm Gaja Capital has made the final close of its third fund - Gaja III - at $240 million, up from its earlier target of $225 million, at a time when uncertainty continues to dog fund raising efforts by domestic PE firms.
Budget hotel chain Lords to expand to tier-II and III cities
Budget hotel chain Lords will add four properties in cities such as Agra, Jammu, Maduda(Karnatka) & Savli(Baroda) in the next one year.
Odd-even: 3-tier air quality monitoring to be set up by Delhi government
Delhi government plans to undertake three tier monitoring of air pollution in the second phase of odd and even road rationing scheme, which begins on April 15.
Vijaya Bank to issue Rs 500-crore tier-I bonds
Public sector Vijaya Bank today said it will issue additional tier-I bonds to raise Rs 500 crore.
Indian Bank raises Rs 500 crore via additional tier-I bonds
Indian Bank shares were trading 1.59% up at Rs 105.30 apiece during afternoon session on the BSE.
State Bank of Travancore raises Rs 515 cr via tier II bonds
The coupon rate on the bonds with a tenure of 10 years is fixed at 8.45% . State Bank of Travancore shares were trading 0.68% up at Rs 385 apiece during morning session on the BSE.
RBI eases Basel III norms to ease pressure on banks
The Reserve Bank of India said it would ease rules on what lenders can count towards their core capital requirements under upcoming Basel III rules, in moves intended to ease pressure on the cash-constrained sector.
RBI eases rules on what lenders can count as Basel III capital
The RBI said lenders can now apply gains from revaluation of property to core capital requirements under certain conditions.
Tier 2 students beat Tier 1 peers in employability: Study
Students from Tier 2 cities were found to be more employable than their peers from Tier 1 centres, according to the India Skills report 2016.
Yes Bank raises Rs 545 crore via Basel-III complaint bonds
Private sector lender Yes Bank today said it has raised Rs 545 crore by issuing Basel-III complaint tier-II bonds.


text:
Written on: 12/10/2006 by james ee (1 review written)
Good Points
Small size
Bad Points
Unreliable - failed after 2 months and still in repair after 5 weeks
TomTom customer support is more like customer delay
General Comments
My two month old TomTom One became very unreliable during the recent warm weather, although in an air-conditioned car with temperatures much less than the specified 50 degrees C, the TomTom One operation was very flaky, requiring many hardware resets. Eventually it lost the ability to lock on to GPS.
Dealing with TomTom has been less than a good experience, initially they promised repair time of 5 to 10 days and it is now indefinite, because according to TomTom, they have run out of parts. Wonder why?
Previously I owned a Garnin Sreetpilot 310 which worked perfectly but I thought the more pocket-able TTone would be good. I was wrong!!!
As rated by our community of reviewers
" Out of date maps from dishonest people " Read More
Written by jimbuoy
" Thanks " Read More
" Do not buy anything from this website! " Read More
" Brilliant bit of kit " Read More
" Very very VERY poor " Read More


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The Tennessee men's basketball team looks to regain its winning ways as it travels to Missouri to play Saturday, Feb. 15 at 4 p.m. ET on ESPN2. LISTEN LIVE | WATCH | GAME TRACKER | LIVE BLOG | GAME NOTES | TICKETS
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Despite development of current targeted therapies for medullary thyroid cancer (MTC), long-term survival remains unchanged. Recently isolated novel withanolide compounds from Solanaceae physalis are highly potent against MTCs. We hypothesize that these withanolides uniquely inhibit RET phosphorylation and the mammalian target of rapamycin (mTOR) pathway in MTC cells as a mechanism of antiproliferation and apoptosis.
MTC cells were treated with novel withanolides and MTC-targeted drugs. In vitro studies assessed cell viability and proliferation (MTS; trypan blue assays), apoptosis (flow cytometry with Annexin V/PI staining; confirmed by Western blot analysis), long-term cytotoxic effects (clonogenic assay), and suppression of key regulatory proteins such as RET, Akt, and mTOR (by Western blot analysis).
The novel withanolides potently reduced MTC cell viability (half maximal inhibitory concentration [IC50], 270–2,850 nmol/L; 250–1,380 nmol/L for vandetanib; 360–1,640 nmol/L for cabozantinib) with induction of apoptosis at <1,000 nmol/L of drug. Unique from other targeted therapies, withanolides suppressed RET and Akt phosphorylation and protein expression (in a concentration- and time-dependent manner) as well as mTOR activity and translational activity of 4E-BP1 and protein synthesis mediated by p70S6kinase activation at IC50 concentrations.
Novel withanolides from Physalis selectively and potently inhibit MTC cells in vitro. Unlike other MTC-targeted therapies, these compounds uniquely inhibit both RET kinase activity and the Akt/mTOR prosurvival pathway. Further translational studies are warranted to evaluate their clinical potential.
Although the incidence of medullary thyroid cancer (MTC) has grown each year, recently >2,200 new cases reported in the United States in 2010,1 survival statistics in this disease have not significantly improved over the last 3 decades, warranting novel therapies with better efficacy. For early stage disease confined to the thyroid or locoregional nodes, 5-year disease-specific survival rates have been reported at >80%; however, once tumors metastasize systemically, survival drops significantly to <55%.2,3 Operative resection is the standard of care for local disease and recurrence; however, >50% of patients recur or progress despite optimal operative resection.2
Standard chemotherapy regimens have limited efficacy in poorly differentiated thyroid cancers such as MTC. Response rates are often temporary and occur in <10–20% of patients and are without long-term benefit. Additionally, these drugs carry systemic toxicities that can be dose limiting.4 Recently, targeted therapies developed on the genetic and molecular basis of MTCs have led to several Phase I, II, and III human trials worldwide. Because a majority of MTCs are owing to mutations of the RET protooncogene (which encodes a transmembrane tyrosine kinase receptor),3,5,6 a number of tyrosine kinase inhibitors (TKI) and multikinase inhibitors have been developed in the last decade, including RET-kinase–specific inhibitors that share the property of binding to the RET/ATP-binding pocket. These TKIs that target RET include drugs such as vandetanib, sorafenib, sunitinib, imatinib, axitinib, motesanib, gefitinib, and cabozantinib (XL184).7–9 Although these drugs may stabilize disease progression in many patients, they lack durable, long-term responses and carry moderate systemic toxicity for many patients. Opportunities, therefore, remain to identify novel durable therapies for advanced MTC.
Natural products continue to play a highly significant role in the drug discovery and development process, particularly in the area of cancer therapeutics, where a majority of the most widely used cytotoxic agents are of natural origin. Several genera in the large plant family Solanaceae produce compounds called withanolides, of which the most important and well-described is the steroidal lactone, withaferin A (WA).10,11 The withanolides exert a number of different effects including anti-stress, anti-inflammatory, and cytotoxic activities; however, their role as anticancer agents in MTC is currently being investigated.12,13
WA isolated from the Withania somnifera plant has been shown to significantly inhibit MTC tumor mass in vivo in a metastatic mouse model.14,15 In addition to induction of apoptosis and inhibition of the PI3kinase/Akt pathway by WA in thyroid cancers, WA has also been reported to inhibit Notch signaling and the mammalian target of rapamycin (mTOR) pathway in colon cancer cells.16 In the present study, the anti-cancer activity of several novel withanolides will be examined in MTC cells and compared with WA and TKIs used in MTC clinical trials such as 17-AAG, axitinib, vandetanib, and cabozantinib. We hypothesize that novel withanolide derivatives, unlike other targeted kinase inhibitors, uniquely inhibit MTC cell proliferation and induce apoptosis through a combination of RET kinase inhibition as well as inhibition of the Akt/mTOR signaling pathway.
All chemical reagents were obtained from Sigma Chemical Co (St. Louis, MO) unless specified otherwise. Antibodies to phospho-Thr-389 S6K, phospho-Thr-36/47 4E-BP1, phospho-Ser-65 4E-BP1, 4E-BP1, phospho-mTOR, mTOR, phospho-Akt, Akt, phospho-ERK, ERK, phospho-p70S6K, p70S6K, caspase 3, and PARP from Cell Signaling Technology (Beverly, MA); antibodies to actin from Millipore (Temecula, CA), and horseradish peroxidase-labeled anti-mouse, anti-goat, and anti-rabbit secondary antibodies from Santa Cruz Biotechnology (Santa Cruz, CA). The human MTC cell lines included MTC-TT cells (derived from MEN2A patient with codon 634 mutation) obtained from ATCC (Manassas, VA) and DRO 81-1 cells (derived from a patient with sporadic MTC) were provided by Dr Guy Juillard (University of California, Los Angeles, CA). The papillary thyroid cancer cell-line, TPC 1 (with a RET/PTC mutation), was provided by Dr Sissy M. Jhiang (Ohio State University, Columbus, OH). DRO81-1 and TPC 1 cancer cell lines were grown in RPMI 1640 medium (Sigma) supplemented with 2 g/L sodium bicarbonate, 0.14 mmol/L nonessential amino acids, 1.4 mmol/L sodium pyruvate, and 10% fetal bovine serum at a constant temperature of 37°C with a humidified atmosphere of 5% carbon dioxide (CO2). TT cells were cultured in RPMI 1640 medium supplemented with 2 mmol/L L-glutamine, 1.5 g/L sodium bicarbonate, and 15% fetal bovine serum. The cells were passaged twice a week. For growth experiments, cells were trypsinized and cells were cultured overnight before treatment. Control cultures were incubated in medium containing vehicle alone. Drug compounds utilized for these experiments included WA, the novel withanolides withalongolide A [19-hydroxy withaferin A (WGA; also referenced as compound X001), withalongolide A 4,19,27-triacetate (WGA-TA; also referenced as compound X003), withalongolide D (WGD; also referenced as compound X005), withalongolide B 4-acetate (WGB-MA; also referenced as compound X032), withalongolide B 4,19-diacetate (WGB-DA; also referenced as compound X033), all obtained from Dr Barbara Timmermann's laboratory (Lawrence, KS). Additional drugs included several TKIs used in MTC trials. Axitinib (Cat # A-1107), vandetanib (Cat # V-9402), and 17-AAG (Cat # A-6880) were obtained from LC Laboratories (Woburn, MA); cabozantinib (XL184) (Cat # S1119) was obtained from SelleckChem (Houston, TX).
Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphophenyl)-2H-tetrazolium (MTS) dye-reduction assay (Promega, Madison, WI) measuring mitochondrial respiratory function according to the manufacturer's instruction. MTC cells (2–5 × 103/well) were plated in 96-well microtitre plates and treated with drugs at various concentrations (0.03–20 mmol/L) for 72 hours. Cells were then incubated with MTS dye (2 mg/mL per 20 μL/well) for 2 hours. Absorbance was determined in a Biotek plate reader at 490 nm. The absorbance is directly related to viable cell number.
For cell cycle studies, DRO81-1 cells (105 cells) in 60-mm plates were exposed to withanolides for 24 and 48 hours. After cells were washed, DNA was stained with 50 μg/mL propidium iodide (PI) solution (0.02 μg/μL RNase A, 1.0 mg/mL sodium citrate-dihydrate, 0.1 μg/μL PI, 0.3% Triton X-100) at 25°C for 30 minutes. For fluorescence-activated cell sorting analysis, the FACS-can (Becton Dickinson, Franklin Lakes, NJ) was used. Cell-cycle analysis was performed with the use of ModFit LT software (Verity Software House, Inc, Topsham, ME). For Annexin V/PI studies, cells were washed after treatment and were collected by trypsinization. Cells were washed twice with 1 × phosphate-buffered saline (PBS) and then stained with Annexin V-FITC and PI according to the manufacturer's instruction (BD Bioscience, San Jose, CA).
After treatment, DRO81-1 cells were lysed with ice-cold lysis buffer [150 mmol/L NaCl, 40 mmol/L HEPES (pH 7.4), 2 mmol/L EGTA, 2.5 mmol/L MgCl2, 1% Triton X-100, and 1X EDTA-free protease inhibitors (Sigma)]. The soluble fractions from cell lysates were isolated by centrifugation at 14,000 rpm for 20 minutes in a microfuge. Protein concentration was determined by bicinchoninic acid protein assay kit according to the manufacturer's instructions (Pierce Biotechnology, Rockford, IL). Equivalent protein extracts (15–50 mg) from each sample were electrophoresed on 8–15% sodium dodecyl sulfate polyacrylamide gel electrophoresis mini gels. Proteins were transferred onto Hybond nitrocellulose (Amersham, Piscataway, NJ) in a Bio-Rad Trans blot apparatus. Nitrocellulose matrices were preblocked with 3% nonfat milk powder in PBS and 0.05% Tween-20 for 1 hour at room temperature. After PBS–Tween washes, preblocked matrices were incubated with appropriate dilution of primary antibody. Reactive bands were visualized specific bands by enhanced chemiluminescence ECL (Pierce Biotechnology).
DRO81-1 cells were cultured into 60-mm plates (300 cells/plate), then left in the incubator overnight to attach. Cells were treated with withanolides for 72 hours at 37°C in a humidified atmosphere of 95% air and 5% CO2. After treatment media was removed and fresh media without drug was added. Cells incubated for 2 weeks to allow the formation of macroscopic colonies. Media was changed 3 times a week. The cells were then stained with Coomassie blue. At least 2 independent experiments, each using triplicate plates, were performed for each cell line. Photographic documentation was recorded.
All in vitro data points were run in triplicate and expressed as a mean values ± standard error of the mean. Raw data were analyzed by a Student's unpaired t-test and Fisher exact tests using a standard statistical analysis software package (SPSS version 17.0; SPSS Inc, Chicago, IL); P < .05 was defined as significant.
DRO81-1, TT-cells, and TPC1 cells were incubated with each of the drugs structurally listed in Figure 1 for 72 hours (0.03–20 mmol/L) and cell viability was determined using MTS dye reduction assay. Half maximal inhibitory concentration (IC50) values were determined for each compound in all 3 cell-lines tested and are tabulated in the Table. Of all the compounds tested, 17-AAG was the most potent in all cell-lines with an average IC50 in MTC 18 ± 4 nmol/L. All of the withanolides tested demonstrated significant potency against MTC cells except for WGD, which structurally lacks the double bond in the A-ring of the molecule and results in a loss of anticancer activity (structure–activity–relationship; data not shown). The remaining withanolides demonstrated excellent potency in DRO81-1 MTC cells compared with the targeted TKIs, but were less potent than vandetanib and cabozantinib in TT cells. Addition of acetyl groups to the withalongolide A (WGA) molecule as noted with withalongolide B 4-acetate (WGB-MA; a mono-acetyl analog), withalongolide B 4,19-diacetate (WGB-DA, a di-acetyl analog) and withalongolide A 4,19,27-triacetate (WGA-TA, a tri-acetyl analog), resulted in increased potency compared with the parent molecule WGA. This was observed in all 3 cell-lines. Comparing the tri-acetyl and mono-acetyl analogs, WGA-TA was significantly more potent than WGB-MA in each cell line tested (P < .01). From this initial cell viability analysis, a ranking of potency for the withanolides from least potent to most potent would include WGD, WGA, WA, WGB-MA, WGB-DA, and WGA-TA. Owing to its stability and consistency of growth in vitro compared with TT cells, further mechanistic studies were carried out using DRO81-1 cells.
We next examined that the effect of novel withanolides on modulation of cell cycle progression in MTC cells. WGA induced a shift in cell cycle arrest from G0/G1 arrest to G2/M arrest in DRO81-1 cells at 6.0 μmol/L for 24 hours and both at 3.0 and 6.0 μmol/L for 48 hours treatment as noted by PI staining peaks on flow cytometry (Fig 2, A). This shift with treatment to G2/M arrest was also observed with WGB-MA and graphed quantitatively in Figure 2, B. After 48 hours WGA treatment at 3 μmol/L there was a shift in G2/M arrest from 20% to 35% of cells arrested at this checkpoint, whereas at 6 μmol/L this shift increased to 40% of cells in G2/M (P <.01 compared with controls). Similarly, at 48 hours both 1 and 3 μmol/L WGB-MA resulted in an increase in G2/M arrest from 25% to 42% of cells arrested at this checkpoint (P < .01). WGB-DA also induced G2/M cell-cycle arrest in MTC cells. After 24 hours of treatment, WGB-DA treatment induced G2/M shift from 23% to 50% and 40% at 1 and 3 μmol/L. Similar results were obtained with MTC cells were treated with WGB-DA for 48 hours (Fig 2, B).
To explore the mechanism of withanolide-induced growth suppression, we examined the effect of these novel compounds on the induction of apoptosis in MTC cells. Initial evaluation was performed with annexin V/PI staining on flow cytometry and confirmed with caspase 3 activation and poly-ADP ribose polymerase (PARP) cleavage on Western blot analysis. WGA induced apoptosis in MTC cells at 3 and 6 μmol/L for 24 hours (5.1% and 12.0%, respectively) and 48 hours (12.2% and 49%, respectively; P < .001; Fig 3, A and D). Similarly WGB-MA induced apoptosis at 1 and 3 μmol/L in MTC cells at 24 hours (3% and 22%, respectively) and at 48 hours (28% and 82%, respectively; P < .001; Fig 3, B and D). WGB-DA was the most potent withanolide for inducing apoptosis in MTC cells. At 1 and 3 μmol/L WGB-DA in MTC cells at 24 hours gated 11% and 46% of cells toward apoptotic cell death, respectively, and at 48 hours this increased to 68% of cells undergoing apoptosis at 1 μmol/L and 83% of cells undergoing apoptosis at 3 μmol/L (P < .001; Fig 3, C and D). To confirm these results the levels of cleaved caspase 3 and the endogenous caspase 3 substrate, PARP, were determined by Western blot analysis of cells treated for 24 hours. Fig 3, E shows that WGB induced cleavage of caspase at 6 μmol/L concentration after 24 hours treatment, whereas the more potent withanolides WGB-MA and WGB-DA activated caspase 3 and cleaved PARP starting at 1 μmol/L drug levels and peaking around 3 μmol/L of drug. Similarly, the effect of axitinib, vandetanib- and XL184-treated DRO81-1 cells demonstrated that these TKIs slightly induced caspase activation and PARP cleavage but this occurred less robustly than observed with the novel withanolide compounds (Fig 3, E).
Clonogenic assay was performed to determine the long-term toxicity effect of withanolides on MTC cells. Pulse-exposure of DRO81-1 cells for 3 days to either 1 μmol/L WGA, 250 nmol/L WGB-MA, or 250 nmol/L WGB-DA irreversibly inhibited 80% clonogenic growth compared with untreated DRO81-1 cells (Fig 4).
To elucidate the mechanism by which withanolides induce apoptosis and suppress MTC cell viability and growth, we evaluated by Western blot analysis the effects of these drugs on several key regulatory pathways and proteins in MTC cells, specifically activation of RET, the MAP kinase pathway (ERK1/2) and the Akt/mTOR pathway. Because alterations in protein expression in response to drug treatment may be both time- and concentration-dependent, we evaluated each drug at multiple doses (above and below IC50 levels) at 12 hours and at 24 hours treatment. Comparisons of expressions of these signaling proteins are shown for each withanolide drug in Fig 5. WGA, WGB-MA, and WGB-DA each demonstrated a consistent pattern related to their mechanistic effects on MTC signaling pathways. Each of these withanolides downregulated total and phospho-RET expression levels as well as total and phospho-mTOR expression levels and total and phospho-Akt levels. Downstream mTOR signaling was also effected in these withanolide-treated cells. Because mTOR modulates activity of downstream 4E-BP1 and p70S6kinase to regulate RNA translation and protein synthesis respectively, these proteins were evaluated in response to drug treatment. All 3 withanolides demonstrated inhibition of 4E-BP1, phospho-4E-BP1, p70S6kinase, and phospho-p706Skinase at 24 hours drug treatment with downregulation occurring at 500 nmol/L concentrations, which is at or below IC50 drug levels in DRO81-1 cells (Fig 5). ERK1/2 expression levels, however, were increased with drug treatment. Inhibition of both RET activity and the Akt/mTOR pathway occurred as early as 12 hours after treatment. WGD, which has the lowest potency in vitro and lacks the double bond in the A-ring (which conveys activity), demonstrated up-regulation of RET, Akt, ERK1/2, and the mTOR pathway, including 4E-BP1 and p70S6 kinase, which coincided with its lack of in vitro growth inhibition or induction of apoptosis (Fig 5, D). Finally, vandetanib and cabozantinib (clinical TKIs used in MTC) were evaluated for their effects on the same regulatory proteins in MTC cells (Fig 6). Both of these drugs inhibited phospho- and total RET expression levels at 24 hours, although significantly less robustly than noted with WGB-MA or WGB-DA withanolide treatment (P < .01 based on densiometry measurements of comparative protein bands). Interestingly, these targeted therapies did not inhibit mTOR or its downstream constituent p-70S6 kinase, although only at 3 μmol/L (10 times the IC50 level) did vandetanib slightly downregulate 4E-BP1 levels. Both TKIs markedly downregulated ERK1/2 and phospho-ERK expression levels while upregulating Akt expression levels in a dose-dependent manner.
For patients with unresectable or advanced MTC, a targeted therapy trial has been an approach of choice when such treatments are available. With cabozantinib completing its Phase III international trial and vandetanib's recent US Food and Drug Administration approval for use in MTC, these targeted agents are the most commonly used clinically.17 Outcomes from these studies, however, are modest at best and each of these drugs carry moderate toxicity profiles.
Natural products have played a significant role in the discovery and development of new anticancer agents, and represent a rich source of biologically active compounds. More than 80% of anticancer drugs introduced from January 1981 to October 2008 were natural products, semi-synthetic analogs, or synthetic compounds based on natural product pharmacophores.18 Withanolides are naturally occurring C-28-steroidal lactones built on an intact or rearranged ergostane scaffold in which C-22 and C-26 are appropriately oxidized to form a δ-lactone ring on the 9-carbon side chain.19 These compounds possess various biological activities in vitro and in vivo, including antimicrobial, radiosensitizing, antineoplastic, and cytotoxic effects.20–22 Although recent studies have demonstrated that WA suppresses the growth of human cancer cell lines in vitro and in vivo by causing apoptosis,15 the precise mechanism, including the signals and the pathways by which WA induces cell death, is not fully understood. Our group has demonstrated that WA inhibits MTC growth in vivo suppressing RET phosphorylation in the tumors as well as inhibiting calcitonin secretion.15 This compound did not result in weight loss or any clinical toxicity in vivo and has good oral bioavailability.
In the current experiments, we demonstrated that 3 novel withanolide compounds from the Physalis plant demonstrated potent activity against MTC cells in vitro with IC50 levels for acetylated analogs WGB-MA and WGB-DA in the mid-nanomolar range, comparable with the potency of targeted TKIs such as vandetanib and cabozantinib. Treatment of MTC with withanolides significantly irreversibly reduced clonogenic formation. Their mechanism of action for this antiproliferative effect involves several processes including induction of apoptosis, which was significantly enhanced with the acetylated analogs WGB-MA and WGB-DA and involved >60% of cells at 1 μmol/L WGB-DA and 83% of cells at 3 μmol/L of drug. These compounds also affect cell-cycle arrest, with significant shift of cells into G2/M arrest, as reported with WA.21
Given the high apoptotic rate with treatment, we investigated several key regulatory proteins in MTC cells. The RET proto-oncogene is activated in MTC, leading to activation of the RAS/RAF/MEK/ERK signaling pathway. Mutant RET with representative MEN2A mutation at Cys-634 (RET-MEN2A) has been shown to activate PI3 kinase/Akt pathway.23 Furthermore, a recent study by Kouvaraki et al24 demonstrated that mTOR is highly active in MTC cells. Because mTOR signaling controls protein synthesis through regulation of translation initiation, identifying small molecules that target the mTOR pathway represents a promising target for investigational therapy in MTC patients. The present study shows that novel withanolides WGA, WGB-MA, and WGB-DA reduce both RET and Akt/mTOR activation in MTC cells with inhibition of mTOR RNA translation through knockdown of 4E-BP1. This mechanism is unique from TKIs like ventatenib or cabozantinib, which knock down RET and the MAP kinase pathway but do not affect the mTOR pathway. These TKIs upregulate Akt expression levels, which may explain in part why apoptosis is not seen as robustly in MTC cells with these therapies. These experiments are the first to identify this unique mechanism of action of withanolide compounds in MTC cells. Because the novel withanolide molecules WGA, WGB-MA, and WGB-DA work on different key regulatory pathways than TKIs in MTC cells, there may be a role for synergy or combination therapies of withanolides with these targeted TKIs. With similar mechanism to their parent molecule, WA, these novel natural withanolide analogs have potent anticancer activity in vitro, whereas WA itself has now progressed into a phase I clinical trial in India in patients with advanced osteosarcomas.25 Overall, these novel withanolides demonstrate excellent potency and anticancer activity in MTCs in vitro downregulating both RET and mTOR activity. Ongoing in vivo efficacy and toxicity studies will better evaluate their clinical potential.
Made possible by grant support from the National Institutes of Health (NIH-COBRE P20 RR015563 P.I. B. Timmermann) as well as from the Institute for Advancing Medical Innovation (PI: MS Cohen).
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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Editor's Note: The above video is from an episode of But Seriously on Jna. 26, 2016.
Clippers head coach Doc Rivers has had his share of tiffs with the Warriors in the past, but that doesn't mean he can't appreciate the rival organization's superstar talent.
On Jan. 23 in Toronto, Clippers forward Blake Griffin suffered a spiral fracture of the fourth metacarpal in his right hand.
On Tuesday afternoon, the Clippers issued the following statement regarding Blake Griffin:
The Sacramento Kings took care of business Saturday night in Los Angeles.


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About 22 North
Located on historic Wrightsville Beach, 22 North has earned a reputation by visitors and locals alike as "the best kept secret on the beach." Embodying the best of traditional Lower Cape Fear cuisine with classic French and rustic Creole fare, we take pride in providing our guests with the most unique and eclectic Southern comfort food in the Wilmington area. Taking full advantage of the naturally abundant resources Cape Fear is blessed with, our menu changes virtually every day. You're sure to find local favorites along with bold, exciting, and fresh new creations! House specialties like our award-winning silky She-Crab soup, grilled Skirt Steak or our famous Shrimp n'Grits are featured along with more innovative fare such as Sweet Potato Crusted Grouper, Buttermilk fried Alligator and country ham Blue Crab Cakes. And of course our wonderful homemade desserts such as Key Lime Pie and Caramel Bread Pudding are pure delight. We invite you to come on in and make yourself at home!
Dining Style:
Casual Dining
Contemporary American, Creole / Cajun / Southern
Hours of Operation:
Dinner: Monday - Sunday: 5:00pm - 10:00pm
Cross Street:
Dress Code:
Casual Dress
Price Range:
$30 and under
Payment Options
AMEX, MasterCard, Visa
Phone Number:
(910) 509-0177
Parking Details:
We have a private lot adjacent to our building for convenient parking as well as metered parking along Lumina Avenue. The public parking lot is located on the beach side of Banks channel bridge approximately 25 yards away.
Executive Chef:
Brent Poteat
Bar Dining, Bar/Lounge, Beer, Full Bar, Late Night, Non-Smoking Restaurant, Takeout, Wheelchair Access, Wine
22 North Ratings and Reviews
In the last few years we have had the op ...
In the last few years we have had the opportunity to come and visit wrightsville beach for a week of vacation, this is our #1 restaurant. We always look forward to it and chef and his team never disappoint! Menu is changing constantly but the quality never suffers. It's one of the few places you get an app, main course, and a dessert because everything is that good (regardless of how much extra walking, running, or swimming you have to do to make up for it).
Found and service excellent as usual. Th ...
Found and service excellent as usual. The most creative low country you'll come across. Feel free to experiment -- they never miss. Everything is fresh. You can taste/feel the care and dedication that goes into every bite and into the service. A great meal is a sure thing.
Not a pleasant experience on the ears or ...
Not a pleasant experience on the ears or wallet. It is very, very loud in the dining room. It was dark when we arrived and they turned down the lights yet again 2x making the "menu" chalkboards impossible to read. Menu changed 2x while were were there. Chicken turned to Duck, Steak turned to NY Strip (after we ordered). Certainly not a $$ price-point as Yelp and others describe. They charge for bread ($3 for 5 random pieces, some were small muffins), every cup of coffee costs ($2.50 per cup, no refills), and food portions are very small. A $25 "steak" is actually 5 tiny pieces pre-cut with maybe a half-scoop of potatoes. $35 for lobster mac & cheese...in a big dish but with no depth...perhaps one mac noodle deep. The food tasted fine but it took over 45 minutes to get. Not a good place for kids ($7 for a hot dog and no milk). $42 for the same wine you can get at the store for $14. The whole place is overpriced, slow, dark and noisy. Never again. We left still hungry with our heads and wallet hurting.
The menu was all specials - changed dail ...
The menu was all specials - changed daily apparently - and our food was excellent. It happened to be a holiday weekend so the beach was busy. While the kitchen was slow, our waitress did an admirable job handling a table of 12. The interior is typical beach - a little rough and dated - but nice enough. Our food was very good and we enjoyed it.
When our family vacations at Wrightsvill ...
When our family vacations at Wrightsville Beach, we always dine at 22 North! It is without question our favorite restaurant. We know we are getting the freshest food the island has to offer because the menu changes daily. That alone speaks for the Chef's talent! The creative dishes are for young and old who enjoy unique low county cuisine that can't be found here in Indiana. Thanks again for the great food and service! See you next Summer!
All of the food was excellent! We were ...
All of the food was excellent! We were able to meet the Executive Chef and he talked to us about the various items on the menu and how they were prepared. It was a wonderful experience that I recommend 22 North to any foodie!
The items listed on the menu on OpenTabl ...
The items listed on the menu on OpenTable were not offered or available. They only offered 5 entrees that were presented to us on a chalk board positioned in front of our table. Feel like we had the bait and switch.
We have been to this restaurant in the p ...
We have been to this restaurant in the past and have been fairly pleased. This experience was not so great. The service was very slow and not so pleasant. My husband ordered the NY strip which was cooked to order but not very flavorful. I ordered stuffed shrimp and found them to be very spicy. Vegetables were good. I don't recall ever being to a restaurant where you have to order and pay for a bread basket! My daughter, who is gluten free ordered a special meal, which the chef prepared with sauteed shrimp and veggies which she enjoyed. The restaurant is in serious need of a good cleaning and redecorating. The serve the awful sulfur smelling beach water which could be resolved simply by filtering the water as the restaurant across the street does! Of course this is the perfect opportunity to sell you bottled water!
I love that their menu is on a chalkboar ...
I love that their menu is on a chalkboard because of the daily change of fresh catches. They whipped up a vegetarian dish for my son that was not on the menu and he loved it.My new favorite when visiting Wilmington!
Good at the Beach
Conveniently located in Wrightsville Beach. Parking could be problem but not the night we were there. Menu on chalk board and diversified selections. My wife had mani mani and it was great, I had scollops and they were OK. Recommend for all you beach visitors.
Doesn't seem notable from the outside, but the food more than made up for that.
Gazpacho was refreshing; she-crab soup had loads of crab and egg. Chicken confit and Mahi were wonderful, loved the sides that accompanied. Happily surprised desserts were made in-house!
The food can be a bit on the pricey side ...
The food can be a bit on the pricey side, but its totally worth if for fresh seafood. The menu also varies because they only prep meals for meats they can get fresh that day. So don't expect to get the same thing every visit. Our server was pretty "hands off". She wasn't constantly at the table, she gave us our space to enjoy the meal. Food was great, and it came out rather quickly (we came right when they opened for dinner).
Always use tripadvisor to pick local restaurants for a good meal and usually happy with the choice. Unfortunately it must have been a really bad night for the chef. My husband NEVER complains about a meal but his meal consisted of over cooked and over priced scallops wrapped in bacon with old rice. I had the fried crawfish legs which were salty and tasted like fried batter. I would not recommend 22 North for anyone who enjoys well prepared fresh seafood.
Food was very good and creative, with nice wines.
Mixed views. Food and drink choices were good and the preparation and presentation was great; however the amiabne is tired and not up to the quality coming from the kitchen. Wait staff and general management was friendly and knowledgeable. Only the decor, including rest rooms, and lack of significant separation from the bar area, detract from an otherwise very nice restaurant in downtown Wrightsville Beach, NC.
Best food ever, Great Chef
My wife and I celebrated our anniversary here. This is by far the best food my wife and I have ever eaten. I can't say enough about the quality of the entire experience dinning here at 22 North. Our server Jessica was terrific from the start. She was very friendly and helpful. She answered all the questions we had and took great care of us. We started with Shrimp and Grits as our appetizer and it was incredible. The best Shrimp and Grits we had ever had. Brent Poteat the chef came and checked to see how we liked the appetizer. Talk about first rate service.
The entire meal was outstanding and Brent came to check on us during our two hours there. Yes we ate for two hours. He is a great Chef and a terrific host. You can tell he takes a lot of pride preparing your food. M y wife was ready to take him home with us. We ended the night with a picture with Brent to remember our night. We will definitely be returning. I recommend anyone looking for great food to visit here.
Great Birthday Dinner
A friend wanted to take me out to dinner for my birthday and we decided to go somewhere we hadn't been before, so we chose 22 North. The menu there changes frequently and it is written on large chalkboards. There was an excellent selection and we both chose the Shrimp and Grits, which was excellent, and we ordered a bread basket. The jam they serve with the bread was really good. We also had dessert, key lime pie and their bread pudding with ice cream. Our server Skylar was very attentive and polite. The prices were reasonable for a restaurant in a tourist area. I would recommend 22 North to anyone living or visiting the area.
Went for valentines day. Made reservatio ...
Went for valentines day. Made reservations and it was pretty empty. Not many tables filled and a couple of people were told there was a 30 minute wait on a table or they can sit at the bar. Thought that was a little strange but regardless Food was good. Scallops were overcooked but overall it was good and fresh..
Just dinner nothing special
The dinning experience is unique in that the chef creates a menu every day. That is a true plus since they use only local fresh ingredients. The limitation is there are only 6-8 main's. One of my pet peeves was they couldn't be bothered to make a menu, but rather had chalkboards they placed by your table without explanations of the dish. We were required to inquire for additional information on each menu item we were curious about. That might not have been as big of a deal if we had an available waitress. Our waitress was not readily available.
I had currie scallops and it was quite good. The sauce and vegetables were well paired and the curry was really just a hint of flavor without an overpowering heat. My wife had stuffed shrimp and, but what I tasted was a bar appetizer rather than a dish fitting of a $21 price tag. Overall we spent $100 and had dinner without any real sense of the need to return.
Best food value on the North Carolina coast!
We always eat at 22 North when we visit the Wilmington, NC area. The food quality and taste cannot be beat and the prices are extremely reasonable for the quality. The menu is limited and varies frequently, so do not expect dozens of entrée choices and the same entrée each time you visit, but I have never been disappointed there. We do not go in for the bar scene, but we hear that the late night bar spirits and energy are excellent. The martinis we had at dinner were strong and delicious.
Went with a group of 6 for a work lunch during Triangle Restaurant Week. Two of us selected from the TRW menu, while everyone else ordered off the regular menu. Everyone all around the table was happy with what they ordered. No alcohol drinks to review because it was lunch. Would love to go back and try the sake menu. Only negative was the green tea pot had only one tea bag to serve three of us.
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Discovering a Dynamic Marriage: 12 Secrets for Navigating Uncharted Seasby Joy Evans Peterson M.A.
- LendMe LendMe™ Learn More
Divorce has touched the life of everyone in our society. Of course, divorce is the only option in certain extreme cases. However, longterm research reveals divorce has lifelong traumatic consequences to children and parents, and still the divorce rate hovers at 50 percent. Many couples encountering predictable issues give up too soon because they don't have effective communication and negotiation skills or a proven process for working through them.
Joy Peterson has treated troubled marriages for three decades and witnessed the lifelong devastation of divorce on parents and their children. Discovering a Dynamic Marriage guides a couple on an illuminating journey to discover the core beliefs that drive relationship behaviors. Then introduces a process for developing relationship skills and providing effective solutions specifically targeting the values and vision of the couple. Most marriages can succeed if the couple has the necessary support, information and tools.
Product Details
- 9781624883880
- Publisher:
- BookBaby
- Publication date:
- 09/10/2012
- Sold by:
- Barnes & Noble
- Format:
- NOOK Book
- Pages:
- 360
- File size:
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Co-Sourcing Improves Pharmaceutical Laboratory Productivity
Capitol Hill Critics Second-Guess Agencies Using...
Keep the Opportunities, Lose the Opportunists
Reader Contributions Are Encouraged So We...
In this day and age, "green" and "sustainable" go hand in hand. Well, allow me to introduce Plant GDB (which, presumably stands for "genomics database"—the site doesn't really make this clear). This website is certainly green, and it contains enough information to sustain you for quite some time. One can search all Viridiplantae (that would be "green plants" to the rest of us) sequence data, sorted by species, or one can take advantage of the many genome browsers available through the website. There are currently sequence assemblies for 213 species on the website, as well as a number of special datasets (for such things as alternatively spliced genes and transposon insertion sites). And I haven't even gotten to the tools yet! Thirteen online analytic tools round out the final major subdivision of the website, giving visitors plenty to digest.
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*The opinions expressed are solely those of the author(s) and should not be construed as reflecting the viewpoints of the publisher, Genetic Engineering & Biotechnology News, Mary Ann Liebert, Inc., the publishing house, or employees and affiliates thereof.
MDMA (commonly known as the empathogen "ecstasy") is classified as a Schedule 1 drug, which is reserved for compounds with no accepted medical use and a high abuse potential. Two researchers from Stanford, however, call for a rigorous scientific exploration of MDMA's effects to identify precisely how the drug works, the data from which could be used to develop therapeutic compounds.Do you agree that ecstasy should be studied for its potential therapeutic benefits?
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text: Ways to Stay Cool on Hot Days and Beat the Summer Heat – Kevin's Top Five By Kevin Mussman June 18, 2012 4:32 PM Share on Facebook Share on Twitter 1 Category: Fort Collins News Share on Facebook Share on Twitter More Leave a comment Send to a friend! Print this page Pin it! Reddit This! Share on Tumblr! Latest from Alana Lynn Why is 'Fat-Shaming' a Thing? 'Pink' Ride Tonight in Longmont to Honor Cyclists Killed Colorado Delegates Leave RNC Floor Fort Collins Cat Rescue to Hold 'Cat Caravan' Recommended For You ZergNet Best of the Web ZergNet


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PITTSBURGH -- Green Bay fans are already wary of nickelback Jarrett Bush, who has given up a few big plays in his career. I imagine the chorus is pretty loud right about now.
Bush offered a bizarre and ultimately unsuccessful coverage on Pittsburgh receiver Mike Wallace on the Steelers' first offensive play of the game. Wallace beat Bush on the line of scrimmage, and Bush inexplicably stopped chasing him after Ben Roethlisberger released the ball. The result was a 60-yard touchdown play to give the Steelers an early lead.
I really can't tell you what Bush was thinking on the play. He ran with Wallace for too long to make me think he believed he had deep help. Looks like it was just a mental mistake. Not what you want on the road in a big game with playoff implications.


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October 29th, 2011, 12:13 PM
How to safely remove USB hard disk drive? Is it necessary to turn off a HDD? Earlier it was possible to write 'off' to 'power/level' in sysfs. As I have understand, now it is not possible. When I write '1' to 'remove' in sysfs ('bus/usb/...'), the indicator on the HDD turns off, but the disk continues rotating (I hear the sound when I bring the HDD to my hear). Commands 'hdparm -yY /dev/sdf', 'eject /dev/sdf' and 'eject -s /dev/sdf' doesn't make the disk stop rotating.
OS: Kubuntu 11.10.
OS: Kubuntu 11.10.