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W. Bruce Lunsford is the Chairman and Chief Executive Officer of Lunsford Capital, LLC, a private investment company headquartered in Louisville, Kentucky. He is the founder and former Chairman and Chief Executive Officer of Ventas, Inc., a healthcare real estate investment company (REIT), listed on the New York Stock Exchange (NYSE).
Mr. Lunsford is also the founder, former Chairman, President and CEO of Vencor, Inc., a Fortune 500 healthcare company, now known as Kindred Healthcare based in Louisville, Kentucky. During his 15-year tenure, Vencor became the largest full-service, long-term healthcare provider in the United States. The Vencor network consisted of 61 long-term acute care hospitals, 293 skilled nursing centers and employed over 65,000.
Mr. Lunsford, as an investor, is the former Chairman and interim CEO of Valor Healthcare, Inc., a company that develops and operates outpatient clinics for military veterans under the U.S. Department of Veterans Affairs. He continued to serve on the Board of Directors until the company was sold in July 2012. Mr. Lunsford is also the former Chairman of Deyta, Inc., a leader of healthcare satisfaction management and clinical quality improvement program services, which was sold to HealthcareFirst in April 2015. In addition, Mr. Lunsford served on the Board of Directors of Lightyear Network Communications from 2010 to 2014, when it was acquired by Birch Communications. He became a member of the Board of Directors of Zirmed, Inc., a medical technology company, in 2012 and served until October 2017 when it merged with Navicure.
Mr. Lunsford is the Chairman of Arcadia Communities, LLC, a Louisville-based real estate development company, which specializes in senior living communities. In October, 2015, Mr. Lunsford joined the Board of Directors of Edumedics, LLC, a Louisville-based healthcare company that provides complete care management solutions for individuals with diabetes or other chronic conditions. He was elected Chairman of Edumedics in July, 2017, and the company rebranded as SentryHealth in July 2018, expanding its services to improve health outcomes and drive significant savings for employers.
In 1996, Mr. Lunsford founded Atria Communities Inc., the third largest assisted living company in the U.S. He served as Atria's Chairman and recruited its original management team. In 1998, Atria was sold to Lazard Freres, and the company continues to maintain its headquarters in Louisville, Kentucky.
In 1999, Mr. Lunsford was one of the original investors and initial chairman of Xodiax, Inc., a supplier of data center and Internet services that grew a customer base of nearly 150 companies in the Louisville area. Xodiax was purchased by Peak 10, Inc. of Charlotte, North Carolina in 2004.
An individual with varied interests, Mr. Lunsford, as a thoroughbred owner, raced the brilliant Grade I filly, Madcap Escapade, the outstanding Grade I two-year old colt, First Samurai, the Grade II filly, Bel Air Beauty, the Grade III filly, Tessa Blue, and the Illinois Derby winner, Vision and Verse, who also finished second in the 1999 Belmont Stakes and Travers Stakes. Additionally, as a breeder, he bred Grade I winner, Golden Missile, and multiple Grade I winner, Arravale, who was named Canadian Horse of the Year in 2006. Mr. Lunsford is a former member of the Board of Directors of Churchill Downs and a current member of the Board of Directors of the Breeders' Cup Limited.
Mr. Lunsford is a co-founder of Hart-Lunsford Pictures, a production company that has produced nine feature films with casts that include Alan Alda, Matthew Broderick, Billy Crudup, John Cusack, Claire Danes, Zac Efron, Frank Langella, Lucy Liu, William H. Macy, Virginia Madsen, Tim McGraw, Mandy Moore, Matthew Perry, Mary Steenburgen, Hilary Swank, Juno Temple and Dianne Wiest. Two of Hart-Lunsford's first pictures, "Dedication" and "Grace is Gone" were accepted into the prestigious Sundance Film Festival in Park City, Utah in January 2007 and received significant critical acclaim. In addition, "Grace is Gone" received the coveted Audience Award and its screenwriter received the Waldo Salt Screenwriting Award. In 2008, "Birds of America" and "Diminished Capacity" were accepted at Sundance, while "Trucker" and "Bart's Got a Room" were accepted at the Tribeca Film Festival. In 2009 and 2010, respectively, "Me and Orson Welles" and "Dirty Girl" premiered at the Toronto International Film Festival. In 2012, HLP co-financed "Great Expectations" featuring Ralph Fiennes, Helena Bonham Carter, Jeremy Irvine and Robbie Coltrane.
In 2013, Mr. Lunsford became an investor and partner in the revitalization of Kentucky Kingdom Amusement Park and Hurricane Bay Water Park in Louisville. This popular venue reopened in May 2014 and provides entertainment to families throughout the region. It was named a top 10 amusement park for 2015 by MSN Travel and Fodor's Travel.
Throughout his career, Mr. Lunsford has had a strong interest in public service, beginning with his service in the administration of Governor John Y. Brown, Jr. as Kentucky's Secretary of Commerce from 1980 to 1983. During his tenure, Kentucky realized unprecedented economic growth, as well as the location of a UPS hub in Louisville and a Delta Airlines hub in Northern Kentucky.
From 1983-1997, he served a variety of organizations, including the Board of Trustees of the University of Kentucky, Bellarmine College, Centre College and Salmon P. Chase College of Law, as well as Chairman of Kentucky Country Day School and the Kentucky Economic Development Corporation.
In January of 2007, Mr. Lunsford entered the race for Governor of Kentucky, along with Greg Stumbo, the state's Attorney General as his Lt. Governor candidate. After a campaign by Mr. Lunsford that introduced his Blueprint for Change, he finished second in a primary consisting of seven candidates. Mr. Lunsford was then recruited and encouraged by numerous local and national Democrats to run for U.S. Senate, and on January 29, 2008, he entered the Democratic Primary as a candidate for that position. He won the Democratic nomination for U.S. Senate on May 20, 2008 and ran an extremely competitive race, receiving numerous political endorsements, most notably from the Courier-Journal, Kentucky's largest newspaper. His opponent, incumbent Senator Mitch McConnell, the Senate Minority Leader, narrowly defeated Mr. Lunsford in the November election with a 53/47% share of the vote.
Through the W. Bruce Lunsford Foundation, Mr. Lunsford has made significant contributions to a variety of charitable organizations and educational institutions throughout the region for more than 20 years. Most recently, his gifts have enabled his alma mater, Chase College of Law at Northern Kentucky University to establish the W. Bruce Lunsford Academy for Law, Business and Technology to better prepare young lawyers for the age of information.
Mr. Lunsford is a former member of the Board of Directors of ResCare, Inc., a leading provider of support services for persons with special needs and at-risk youth, as well as a former member of the Board of both National City Bank, Kentucky and National City Corporation in Cleveland, Ohio.
A native of the Greater Cincinnati area, Mr. Lunsford, a CPA and an attorney, was employed by Alexander Grant & Company of Cincinnati from 1969 to 1974. In 1974, he joined the law firm of Keating, Muething and Klekamp of Cincinnati.
Mr. Lunsford was graduated from the University of Kentucky in 1969 with a B.A. degree and from Salmon P. Chase College of Law in 1974 with a J.D. degree. He has three daughters, Amy, Cindy and Brandy, and six grandchildren, Isabella, William, Noah, Phoebe, Degife and Leo.


Do you miss hearing the sounds of the birds chirping or sand crunching beneath your feet during summer walks? It could be because you're having trouble hearing in the upper frequencies.
Conventional hearing aids have difficulty providing meaningful amplification in the higher frequencies. This is because they rely on tiny speakers to amplify sound. Unfortunately, tiny speakers can only amplify a narrow bandwidth of sound without experiencing the drawbacks of feedback (whistling) or distortion. For a sense of the difference between conventional hearing aid bandwidth and perfect hearing, consider that perfect hearing ranges from 20 Hz in the low frequencies all the way up to 20,000 Hz in the high frequencies. In contrast, hearing aids can usually only amplify sound from ~750 Hz – 5500 Hz.
A new hearing technology eliminates the need for a speaker. The Earlens Light-Driven Hearing Aid relies on light instead of a speaker to transmit sound. How does it work? In Earlens, a Processor that is worn like a behind-the-ear hearing aid captures sound, which is then converted into pulses of non-visible light by a Light Tip, which is worn in the ear canal. Those pulses of light contain sound information, which vibrates a tiny custom Lens on the eardrum, activating the ear's natural hearing system. This unique way of working allows Earlens Hearing Aids to deliver the broadest bandwidth of any hearing aid on the market.
Hear Barbara's story or watch more Earlens reviews on our Earlens Testimonials page. To learn more about what Earlens could do for you, visit your local Earlens provider.
*Levy SC et al. Extended High-Frequency Bandwidth Improves Speech Reception in the Presence of Spatially Separated Masking Speech. Ear Hear. 2015 Sep-Oct;36(5):e214-24.


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Tony Terry: Asked to Sing 'With You' at Someone's Funeral
Shefik July 20, 2017 Shefik presents Invocation, The Journey Continues No Comments
Tony Terry
Recording Artist and Actor
Tony Terry has numerous Billboard top hits within his repertoire from the late 1980s, early 1990s, and today, including his world-renowned hit, "With You". He is also an achieved actor and activist championing for social and family health issues.
http://invocation.co/show/performer/tony-terry
Aptly titled Shefik presents Invocation, the nationally-syndicated terrestrial radio show is a mesmerizing and thought-provoking journey through musical discovery and appreciation that spans the decades. Each one-hour episode, executive-produced and hosted by media personality Shefik, highlights one relatable focal point (chosen by Shefik), along with an accompanying playlist of songs (curated by Shefik), encompassing a unique thematic concept that invigorates the audience with creative impact. Top recording artists, actors, business executives, politicians, community leaders, and other special guests are invited to offer their own commentary on the weekly topic, as a supplement to Shefik's engaging mindset. The radio show's online hub at invocation.co serves as a conduit for discussion of the show, while featuring related videos and auxiliary content. The journey continues right here and everywhere.
About Shefik
Aptly titled "Shefik presents Invocation", the nationally-syndicated terrestrial radio show is a mesmerizing and thought-provoking journey through musical discovery and appreciation that spans the decades. Each one-hour episode, executive-produced and hosted by media personality Shefik, highlights one relatable focal point (chosen by Shefik), along with an accompanying playlist of songs (curated by Shefik), encompassing a unique thematic concept that invigorates the audience with creative impact. Top recording artists, actors, business executives, politicians, community leaders, and other special guests are invited to offer their own commentary on the weekly topic, as a supplement to Shefik's engaging mindset. The radio show's online hub at invocation.co serves as a conduit for discussion of the show, while featuring related videos and auxiliary content. The journey continues right here and everywhere.
View all posts by Shefik →
electronic indie dream pop r&b LA hip-hop punk post-punk alternative pop music indie rock audiofuzz Folk indie pop soul Americana funk dance blues Music alternative rock singer-songwriter singer/songwriter electronica NYC pop brooklyn dance. rock Eno

redpajama_set_name: RedPajamaCommonCrawl


The hardness of coating is one of main function of intensity of token coating machinery. At present hardness of type of commonly used fork determines the method will determine the hardness of car coating. Type hardness can divide fork to be mixed for single pendulum type again double place type two kinds, former measured value expresses with second number, latter criterion with expressing at the percentage of vitreous hardness relatively.
Single pendulum labour calls Kenige and hardness of fork of cypress Sa at present again. Manufactories of a few large car coating use instrument of these two kinds of hardness mostly, its car coating especially the hardness index of face lacquer expresses with these two kinds of hardness more, company of the Si Fu that be like a horse, Situolake company, A Kesu company. The working principle that damp of a few kinds of fork experiments is basic and same, when the fork that contacts coating surface namely swings with certain cycle, if the surface is softer, criterion the amplitude attenuation of fork must be jumped over fast, jump over damply conversely slow. Normally road hardness is worth division Buddhist nun to be the half that Bai Saci hardness is worth about. Because the structure of all sorts of fork, weight, dimension, wobbly cycle and amplitude are different, additionally the interaction between fork and coating still depends on the flexibility of coating oneself and viscoelasticity, accordingly all sorts of placing determine to cannot be built as a result mutual the conversion between concerns, when consequently the fork hardness of listed in product standard coating is worth, must the type of the fork instrument that at the same time demonstrate place uses.
Home of the double sclerometer that place type is more commonly used. Its result is set in order to be in swing the damp time of attenuation of the amplitude inside limits and it is on vitreous board at swinging likewise the ratio of the damp time of attenuation of the amplitude inside horny range expresses. Before actual measurement of the double sclerometer that place type must first school calm glass value.
Previous:Is transmission by what main part is comprised? What effect does it have?


text:
Ontsira papuaensis är en stekelart som beskrevs av Sergey A. Belokobylskij 1998. Ontsira papuaensis ingår i släktet Ontsira och familjen bracksteklar. Inga underarter finns listade i Catalogue of Life.

Källor

Bracksteklar
papuaensis

redpajama_set_name: RedPajamaWikipedia


HRAFF and Melbourne Cinémathèque are proud to present two remarkable films that capture the essence of America at times of change and upheaval. Linked by the dominance of music that creates a powerful effect on the viewer, they will linger in your memory.
This fevered celebration of multi-racial Brooklyn in the midst of a blistering heatwave remains Spike Lee's defining and most triumphant 'joint'. Fired by the music of Public Enemy and a wonderful score by Lee's father, and shot with punchy aplomb by Ernest Dickerson (Malcolm X), Lee orchestrates a hugely dynamic web of characters in an exuberant masterwork of inventive humanism. So iconic is this film that the street on which it was shot is now called Do the Right Thing Way.
Bill Morrison's documentary focuses on the most destructive river flood in American history. In the spring of 1927, the flooding of the wild, untamed Mississippi River forced mass migration to the cities, accelerating the dissemination of the already rich musical legacy of the black American South. For this collaboration with composer Bill Frisell, Morrison scoured archives for images of the devastation, assembling the degraded debris into a haunting web of experience and memory. Frisell's remarkable score, itself gleaned from the musical memories of the devastated plains, escalates the film into the poetic sublime.
These films have been exempt from classification and are restricted to people over 18 years.


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Koisdorf ist ein Ortsbezirk von Sinzig im rheinland-pfälzischen Landkreis Ahrweiler. Zu Koisdorf gehören die Wohnplätze Heinrichshof und Wendelinushof.

Geschichte
1192 als "Connesdorp" im Zusammenhang mit einer Schenkung des Aachener Liebfrauenstiftes und des St. Adalbert-Stiftes ebenda erstmals erwähnt. Mitte des 19. Jahrhunderts zählte der Ort 42 Häuser mit 233 Einwohnern. 1301 ist erstmals die Kapelle St. Wendelinus bezeugt, damals noch St. Sebastian geweiht. Von 1560 an gehörte Koisdorf zum jülischen Amt Sinzig-Remagen. 1834 wurde die Braunkohlengrube "Gerechtigkeit" südlich von Koisdorf auf rund 200 Hektar konzessioniert. Die dort gewonnene Braunkohle wurde zu Klütten für den Hausbrand geformt und zum Verkauf angeboten.

Im Laufe der Jahrhunderte änderte sich der Ortsname mehrmals. Bis 1750 lautete er unter anderem "Connesdorp", ab 1750 "Costroff", um 1830 "Coisdorff" und ab dem 6. Dezember 1935 nannte sich der Ort "Koisdorf". Nach dem Ersten Weltkrieg wurden zeitweise amerikanische Besatzungstruppen in Koisdorf untergebracht. Die Eingemeindung nach Sinzig erfolgte am 7. Juni 1969.

Politik

Ortsbezirk
Koisdorf ist einer von sechs Ortsbezirken der Stadt Sinzig und umfasst das Gebiet der ehemals selbstständigen Gemeinde. Der Stadtteil verfügt über einen eigenen Ortsbeirat sowie einen Ortsvorsteher.

Ortsbeirat
Der Ortsbeirat besteht aus fünf Mitgliedern, die bei der Kommunalwahl am 26. Mai 2019 in einer personalisierten Verhältniswahl gewählt wurden, und dem ehrenamtlichen Ortsvorsteher als Vorsitzendem.

Die Sitzverteilung im Ortsbeirat:

 FWG = Freie Wählergruppe "Bürgerliste Sinzig e. V."

Ortsvorsteher
Karl-Heinz Arzdorf (CDU) wurde bei der Direktwahl am 26. Mai 2019 mit einem Stimmenanteil von 79,47 % für weitere fünf Jahre in seinem Amt als Ortsvorsteher bestätigt.

Kultur und Sehenswürdigkeiten
Das Wahrzeichen von Koisdorf ist die Filialkirche St. Wendelin mit einem Bleiglasfenster aus dem 13. Jahrhundert, das eine Kreuzigungsgruppe darstellt. Sie steht am neu gestalteten Dorfplatz mit dem Gemeindehaus. 2006 wurde auf dem Dorfplatz ein von Bürgern selbst errichteter Dorfbrunnen eingeweiht.
Im Zuge eines Neuausbaus der Ahrentaler Straße im Jahr 2008, wurde die Bäuerin mit Käskömpschen an einer Kreuzung platziert.

Regelmäßige Veranstaltungen
Zu den regelmäßigen Festen in Koisdorf zählen die
 St. Wendelinus Kirmes
 Sportfest der Sportfreunde Koisdorf
 Karnevalssitzung der Möhnen
 Karnevalssitzung des Sportvereines
 Maiball/Maiumzug des Junggesellenvereins
 Dorffest des Männergesangsvereins

Literatur
 Günter Haffke: Geschichte von Koisdorf. In: Jürgen Haffke, Bernhard Koll (Hrsg.): Sinzig und seine Stadtteile – gestern und heute. Sinzig 1983.

Weblinks

 Geschichtliche Informationen zu Koisdorf bei regionalgeschichte.net

Einzelnachweise

Ort im Landkreis Ahrweiler
Geographie (Sinzig)
Ehemalige Gemeinde (Landkreis Ahrweiler)
Ersterwähnung 1192
Gemeindeauflösung 1969


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1. On 16.07.2002, the Punjab State Electricity Board (hereinafter referred to as the 'Board') took a decision to fill up 21 posts of Accounts Officer. The above posts were to be filled up by way of direct recruitment. The appellant earned 164 marks in the process of selection. He made the grade, by way of merit, from amongst "backward class" candidates. It is therefore, that he came to be appointed as Accounts Officer, by direct recruitment.
2. Respondent No.4-Anil Kumar Uppal, had also applied for appointment by way of direct recruitment, in response to the same advertisement (in furtherance whereof, the appellant was selected and appointed). His candidature was, however, not accepted. It is therefore, that respondent no.4 approached the Punjab and Haryana High Court at Chandigarh (hereinafter referred to as the 'High Court') seeking an appropriate direction to the Board, requiring it to allow him (respondent no.4) to participate in the process of selection. By an interim order passed by the High Court, respondent no.4 was allowed to participate in the process of selection.
3. On considering the candidature of respondent no.4, the Selection Committee awarded him 146 marks. It is therefore apparent, that in terms of merit, respondent no.4 could not march over the superior claim of the appellant. This was so because, whilst the appellant had been awarded 164 marks in the process of selection, respondent no.4 had been awarded only 146 marks.
4. Respondent no.4, in order to claim appointment, chose to assail the claim of the appellant by asserting, that the appellant did not factually belong to the "backward class", and as such, his merit could not be determined with reference to the posts reserved for "backward class" candidates. If he could succeed in establishing the aforesaid position, he would fall in the zone of selection, being possessed of the next highest marks (after the appellant) from the category of backward class candidates. Insofar as the instant aspect of the matter is concerned, the pointed contention of respondent no.4 was, that the appellant belonged to the "creamy layer", and as such, he was dis-entitled for being considered from amongst "backward class" candidates.
5. The High Court, while disposing of Writ Petition No. 7660 of 2004, vide the impugned order dated 2.3.2009, arrived at the conclusion, that the appellant actually belonged to the "creamy layer", and as such, was dis- entitled to be considered as a "backward class" candidate. In arriving at the aforesaid conclusion, the High Court took into consideration the income of the appellant himself, to declare that he belonged to the "creamy layer". The aforesaid determination was rendered by reading down the policy instructions issued by the State Government, on the basis whereof, the backwardness of a candidate had to be adjudged. The aforesaid policy instructions were read down, to include the income of the person concerned, along with the income of the parents of the person, contemplated by the policy instructions.
6. In the present appeal, the appellant seeks to assail the aforesaid determination rendered by the High Court. It was the vehement contention of the learned counsel for the appellant, that the judgment referred to by the High Court, for arriving at the conclusion, that the personal income of the concerned individual had to be taken into consideration, was a misreading of the judgment rendered by this Court. It was in the aforesaid background, that we shall endeavour to examine the policy instructions regulating the determination of backwardness of candidates, and the judgments relied upon by the High Court.
(ii)the income criteria in terms of rupee will be modified taking into account the change in its value every three years. If the situation, however, so demands, the interregnum may be less.
Explanation: wherever the expression 'permanent incapacitation' occurs in this Schedule, it shall mean incapacitation which results in putting an officer out of service.
Having minutely examined category VI, as also the description contained in the schedule, to whom the same would apply, there is really no room for any doubt, that in clauses (a) and (b) thereof, it is the income/wealth of the parents of the individual concerned, which is of relevance. The description is clearly silent about the individual's own income. It is not possible for us to accept, that the individual's own income could have been taken into consideration.
The above determination of ours, is with reference to categories IV and VI. Therefore, even with reference to category IV, which includes professional's, the income of the professional, has not been included. Thus viewed, we are satisfied, that on the plain reading of category VI of the office memorandum dated 8.9.1993, that it was not the income of the individual concerned, but that of his parents, that would determine whether he would fall within the creamy layer or not.
"10. We have carefully examined the criteria for identifying the "creamy layer" laid down by the Government of India in the Schedule, quoted above, and we are of the view that the same is in conformity with the law laid down by this Court in Mandal case (Indra Sawhney v. Union of India 1992 Suppl. (3) SCC 217). We have no hesitation in approving the rule of exclusion framed by the Government of India in para 2(c) read with the Schedule of the office memorandum quoted above. Learned counsel for the petitioners have also vehemently commended that the State Governments should follow the Government of India and lay down similar criteria for identifying the "creamy layer".
It is apparent from the observations recorded by this Court, as have been extracted hereinabove, that the Office Memorandum dated 8.9.1993 had been examined by this Court,specifically with reference to the decision rendered in Indra Sawhney's case (supra). Having done so, this Court expressly approved and confirmed the Schedule to the Office Memorandum dated 8.9.1993.
"1-B. IDENTIFICATION OF CREAMY LAYER 415.
Income as the criterion for creamy layer exclusion is insufficient and runs afoul of Sawhney (I). (See p.724 at para 792). Identification of the creamy layer has been and should be left to the Government, subject to judicial direction. For a valid method of creamy layer exclusion, the Government may use its post-Sawhney (I) criteria as a template. (See OM of 8.9.1993, Para 2(c)/Column 3), approved by this Court in Ashoka Kumar Thakur vs. State of Bihar (1995) 5 SCC 403, para 10. This schedule is a comprehensive attempt to exclude the creamy layer in which income, government posts, occupation and landholdings are taken into account."
Here again, this Court expressly approved the office memorandum dated 8.9.1993. In view of the decisions rendered by this Court in both Ashok Kumar Thakur's cases (supra), we are of the view that the High Court clearly erred in reading down the office memorandum dated 8.9.1993 and to include therein the income of the individual concern while determining whether or not he fall within the "creamy layer".
10. Despite the declaration of law in the judgments, referred to hereinabove, it is also necessary to take into consideration the clarification issued by the Government of India, Ministry of Personnel, P.G. and Pensions (Department of Personnal and Training) dated 21.11.2002. The aforesaid clarification was with reference to the office memorandum dated 8.9.1993. Relevant extract of the clarificatory letter dated 21.11.2002 is being reproduced below: "I am directed to refer to your letter No.2/25/2001 RC-1/670 dated 17-10- 2002 on the above noted subject and say that determination of creamy layer for an OBC candidate is done with reference to the income of parents as per instructions contained in DOPT's O.M. No.36012/22/93-Estt(res) dated 8.9.93."
Based on the aforesaid conclusion, there is really no room for any doubt, that the exposition with reference to category VI in the office memorandum dated 8.9.1993 related only to the income of the parents of the individual concerned. And that, the income of the individual concerned was not to be taken into consideration.
"4. Following questions have been raised from time to time about the application of the above provisions to determine creamy layer.
(vi) Will a candidate who himself is a directly recruited Class I/Group A Officer or a directly recruited Class II/Group B officer who got into Class I/Group A at the age of 40 or earlier be treated to be falling in creamy layer on the basis of his service status?
(vii) will a candidate who has gross annual income of Rs.2.5 lakh or above or possesses wealth above the Exemption limit as prescribed in the Wealth Tax Act for a period of three consecutive years be treated to fall in creamy layer?" The aforesaid queries came to be answered in paragraph 8 by observing as under: "8. In regard to clauses (vi), (vii) and (viii) of para 4, it is clarified that the creamy layer status of a candidate is determined on the basis of the status of his parents and not on the basis of his own status or income or on the basis of status or income of his/her spouse. Therefore, while determining the creamy layer status of a person the status or the income of the candidate himself or of his/her spouse shall not be taken into account."
In view of the above, there is no room for any further consideration, whether or not the individual's income is to be taken into consideration, while computing the total income relevant to determine whether an individual belongs to the "creamy layer". The above clarification reveals, that it is only the parents income, which has to be taken into consideration.
12. While referring to the Clarification/Circular dated 14.10.2007 and 14.10.2004 respectively, we have extracted hereinabove the clear view of the Government of India. It would also be necessary for us to notice, that the above determination of the Government of India, was adopted by the State of Punjab, as is apparent from the letter issued by the Government of Punjab, Welfare Department (Reservation Cell) dated 14.10.2007, whereby the letter dated 17.08.2005 and the memorandum dated 14.10.2004 were circulated by the State Government to all its Deputy Commissioners. It is also not a matter of dispute, that the aforesaid circulars were expressly adopted by the Punjab State Electricity Board. Thus viewed, we are satisfied that the individual's income was not required to be clubbed with the income of his parents, while determining whether or not he was eligible to be granted a backward class certificate. The determination to the contrary by the High Court is liable to be set aside. The same is accordingly hereby set aside.
13. The instant appeal is accordingly allowed. While allowing the instant appeal, we restore the appointment of the appellant Surinder Singh to the post of Accounts Officer. Special Leave Petition(C) No.17161 of 2009 The controversy in the instant special leave petition is identical to the one adjudicated upon by this Court in the case of Surinder Singh vs. Punjab State Electricity Board, Patiala and others (Civil Appeal No. 6957 of 2009, decided on 25.09.2014). In the above view of the matter, the instant special leave petition is also disposed of in terms of the order passed by this Court in Surinder Singh's case(supra).
Surinder Singh Vs. Punjab State Elect.Board, Patiala & Ors.
This appeal/petition were called on for hearing today.
Mr. Neeraj Kr. Jain, Sr. Adv.
The special leave petition is disposed of in terms of the order passed by this Court in Surinder Singh's case, i.e., Civil Appeal No. 6957 of 2009.


Possibly the last ITTF North American Championships will take place in Milpitas, California at one of North America's prime table tennis facilities. Rajul Sheth and his dedicated group of volunteers will host the event at the ICC in Milpitas.
The event will consist of team competition only. The winners of the events will represent North America in the 2017 World Team Cup events.
Why possibly the last Championships? As of 2017, ITTF North America and the Latin American Table Tennis Union have agreed to a PANAM competition calendar that will feature a PANAM Championships, a PANAM Cup and a PANAM Junior Championships to provide better competition opportunities for players in the Americas.
Both associations also believe that PANAM events will create a better product for TV and be more attractive to sponsors – both of these important aspects will benefit the promotion of table tennis and its athletes in the Americas.


Have questions about the property? Give us a call today!
Located just outside of Tampa, Florida, The Village of Zephyrhills is an age-restricted mobile home community that is designed for seniors and veterans, offering country comfort with city convenience. Our spacious and modern long-term rentals are the perfect place to call home.
The Village of Zephyrhills was developed with a mission to provide veteran-friendly and affordable housing for seniors and to create a safe, secure community for all of our residents to enjoy. With an on-site property manager and a close-knit community, we welcome you to live your way at The Village of Zephyrhills!
(866) 499-9026 and schedule a visit today!
The Village of Zephyrhills offers a wide range of options to seniors, so you can easily choose the right unit to fit your lifestyle.
Zephyrhills, also known as the City of Pure Water, is situated in the eastern Pasco County, Florida located just north of Tampa.
I have lived here for over nine years and enjoy this location. It is close to shopping and medical facilities. The new owners have made many improvements and the managers are nice to work with. The residents here are friendly and helpful.
Stop by TODAY and take a tour of the property!
If you are looking for more information regarding our veteran-friendly, age-restricted senior living community, call us at (866) 499-9026 or request a visit.
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text:
Salmon Yeggs
October 4, 2019 in ★★½, Walter Lantz films | Tags: 1958, Tex Avery, Willoughby, Windy & Breezy
Stars: Windy & Breezy
'Salmon Yeggs' marks the first solo cartoon of Windy and Breezy, the two bears from the Woody Woodpecker cartoon 'Fodder and Son' from 1957.
The short starts as a spot gag travelogue telling about salmon, throwing some puns in the mix. Then we cut to Windy and Breezy. The father bear (who's Breezy and who's Windy is quite unclear) doesn't want to catch salmon the traditional way, and heads for a salmon canning factory, which is unfortunately guarded by a little, very Droopy-like mustached watchman, who fights the father bear with a deadpan expression.
'Salmon Yeggs' is one of the most Tex Averyan cartoons to come out of the Walter Lantz studio. The comedy between bear and watchman is very similar to that of Wolf and Droopy in 'The Three Little Pups' or between polar bear and Chilly Willy in 'The Legend of Rockabye Point' (1955). Like in 'Fodder and Son' the son does little more than addressing the audience with 'that's my pop', with all the comedy going to the watchman and his father.
In 1961 the watchman would return as 'Ranger Willoughby' in 'Hunger Strife' (1960) and as 'Inspector Willoughby in 'Rough and Tumbleweed', starring several cartoons until 1965.
'Salmon Yeggs' is available on the DVD-set 'The Woody Woodpecker and Friends Classic Cartoon Collection Volume 2'
Wow, I think I haven't seen this in years!
Gijs Grob
I hope you can still enjoy it!
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Have most organizations solved basic DAM challenges?
In a recent conversation on Digital & Marketing Asset Management, DAM expert Theresa Regli and RSG founder Tony Byrne analyzed whether and how organizations can overcome common barriers to successful asset management.
Want to learn from the entire discussion? You can access the full recording now.
"Time and time again, when I seek to discover what influenced the success of a DAM project, I hear a common phrase: "we signed on with Real Story Group." I know why - their practical advice, their in-depth attention to what works and what doesn't, and their careful, ceaseless research - means that when a company turns to them, that the words "best practice" really mean that!"


I really enjoying baking and seeing people enjoy my cakes, pies, bars and other sweet treats. One of my guilty pleasures is admiring (and sometimes) purchasing cake plates. They are totally unnecessary, but they do help the presentation. I don't know what it is, but cake plates and stands seem to make the worst cake look so much better.


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Home » 0rphan drug status » MIRDAMETINIB
MIRDAMETINIB
Chemical Formula: C16H14F3IN2O4
PD0325901; PD 0325901; PD-325901; mirdametinib
IUPAC/Chemical Name: (R)-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide
SpringWorks Therapeutics (a spin out of Pfizer ) is developing mirdametinib, a second-generation, non-ATP competitive, allosteric MEK1 and MEK2 inhibitor derived from CI-1040, for treating type 1 neurofibromatosis (NF1) and advanced solid tumors. In June 2021, a phase I/II trial was initiated in patients with low grade glioma.
OriginatorPfizer
DeveloperAstraZeneca; BeiGene; BIOENSIS; Pfizer; SpringWorks Therapeutics; St. Jude Childrens Research Hospital; University of Oxford
ClassAniline compounds; Anti-inflammatories; Antineoplastics; Benzamides; Immunotherapies; Small molecules
Mechanism of ActionMAP kinase kinase 1 inhibitors; MAP kinase kinase 2 inhibitors
Orphan Drug StatusYes – Neurofibromatosis 1
Phase IINeurofibromatosis 1
Phase I/IIGlioma
Phase ISolid tumours
PreclinicalChronic obstructive pulmonary disease
No development reportedCervical cancer
DiscontinuedBreast cancer; Cancer; Colorectal cancer; Malignant melanoma; Non-small cell lung cancer
22 Jul 2021SpringWorks Therapeutics receives patent allowance for mirdametinib from the US Patent and Trademark Office for the treatment of Neurofibromatosis type 1-associated plexiform neurofibromas
16 Jun 2021SpringWorks Therapeutics and St. Jude Children's Research Hospital agree to develop mirdametinib in USA for glioma
15 Jun 2021Efficacy and safety data from the phase IIb RENEU trial for Neurofibromatosis type 1-associated plexiform neurofibromas released by SpringWorks Therapeutics
US-11066358
https://patentscope.wipo.int/search/en/detail.jsf?docId=US330982129&tab=PCTDESCRIPTION&_cid=P11-KRR5IB-89620-1
On July 20, 2021, SpringWorks Therapeutics announced that the United States Patent and Trademark Office (USPTO) has issued US11066358 , directed to mirdametinib , the Company's product candidate in development for several oncology indications, including as a monotherapy for patients with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN) and was assigned to Warner-Lambert Company (a subsidiary of Pfizer ).This patent was granted on July 20, 2021, and expires on Feb 17, 2041. Novel crystalline forms of mirdametinib and compositions comprising them are claimed.
N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide ("mirdametinib", or "PD-0325901") is a small molecule drug which has been designed to inhibit mitogen-activated protein kinase kinase 1 ("MEK1") and mitogen-activated protein kinase kinase 2 ("MEK2"). MEK1 and MEK2 are proteins that play key roles in the mitogen-activated protein kinase ("MAPK") signaling pathway. The MAPK pathway is critical for cell survival and proliferation, and overactivation of this pathway has been shown to lead to tumor development and growth. Mirdametinib is a highly potent and specific allosteric non-ATP-competitive inhibitor of MEK1 and MEK2. By virtue of its mechanism of action, mirdametinib leads to significantly inhibited phosphorylation of the extracellular regulated MAP kinases ERK1 and ERK2, thereby leading to impaired growth of tumor cells both in vitro and in vivo. In addition, evidence indicates that inflammatory cytokine-induced increases in MEK/ERK activity contribute to the inflammation, pain, and tissue destruction associated with rheumatoid arthritis and other inflammatory diseases.
Crystal forms of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide have been described previously. WO2002/006213 describes crystalline Forms I and II. U.S. Pat. No. 7,060,856 ("the '856 patent") describes a method of producing Form IV. The '856 patent indicates that the material produced by this method was greater than 90% Form IV (The '856 patent, Example 1). The '856 patent also states that the differential scanning calorimetry ("DSC") of the material produced shows an onset of melting at 110° C., as well as a small peak with an onset at 117° C., consistent with the material being a mixture of two forms.
WO 2006/134469 ("the '469 PCT publication") also describes a method of synthesizing N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. The '469 PCT publication reports the method yields a product conforming to the polymorphic Form IV disclosed in U.S. patent application Ser. No. 10/969,681 which issued as the '856 patent.
Compositions containing more than one polymorphic form are generally undesirable because of the potential of interconversion of one polymorphic form to another. Polymorphic interconversion can lead to differences in the effective dose or physical properties affecting processability of a drug, caused by differences in solubility or bioavailability. Thus, there is a need for a composition containing essentially pure Form IV of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, for use in treatment of a tumor, a cancer, or a Rasopathy disorder.
Example 1: Production of Essentially Pure Form IV
Lab Scale Production of Essentially Pure Form IV
2 kg PD-0325901 has been prepared using the below convergent synthesis scheme starting from commercially available 2,3,4-Trifluorobenzoic Acid (TFBA), 2-Fluoro-4-Iodoaniline (FIA) and chiral S-Glycerol Acetonide (SGA)
(MOL) (CDX)
Step 1: Preparation of "Side Chain", PD-0337792
All reactions were performed in toluene other than otherwise stated. Triflic anhydride gave the best yield.
[TABLE-US-00002]TABLE 1 Coupling Agents for Step 1Entry No.Coupling AgentYieldNotes 1Mesyl Chloridedid not react 2Benzyl chloride27Had to heat 70° C. for 166 hr34-fluorobenzensulfonylchloride27Ran 93 hrs. at 70° C.44-chlorobenzensulfonylchloride35Complete after 68 hrs. 50° C.5Tosyl Chloride36Had to heat to 70° C. for 164 hrs6Benzyl chloride52study solvent effects: DMF, DMSO, NMP – all similar DMSO fastest all complete after 110 hrs., heated to 70° C. after 66 hrs.7Triflic anhydride91Cooled to −74° C.
Recognizing that triflate gave the highest yield, the possibility of eliminating the cryogenic conditions was investigated, set possibly due to stability concerns of the "methanesulfonate" intermediate. The following experiments suggest no significant yield loss for experiments run at −20° C.
[TABLE-US-00003]TABLE 2 Yield of Coupling ReactionExperimentalHold time afterYield (Alcohol toDescription*TFMSA addn.IPGAP) 1.07 equiv. NHP15min.85%1.07 equiv. NHP2hours86%1.77 equiv. NHP2hours72%1.07 equiv. NHP (reverse1hours91%addition) * 2 g (1 eq.) SGA in 16 ml toluene was treated with triflic anhydride, trifluoromethanesulfonic acid (TFMSA) (4.2 g, 1.002 equiv.) at −20° C. and then stirred for a prescribed time prior to solid N-hydroxyphthalimide (NIP) addition or transfer to a flask containing solid NHP.
The data presented above suggest no detrimental effect was observed after prolonged stirring of the "trifluoromethane sulfonate" intermediate prior to the N-hydroxyphthalimide addition. Reverse addition of intermediate mixture to solid NHP appears to give the highest yield.
An additional advantage of the triflate usage was easy removal of the Et 3N triflate salts side product simply by water wash. This resulted in highly pure N-hydroxyphthalimide-protected alcohol, IPGAP (PD-0333760) in Toluene, which can be isolated as crystals or carried through to the final deprotection reaction.
Both aqueous and anhydrous ammonia base were examined as deprotecting agents. The results were both successful. The phthalimide side product was simply filtered out from solution of product (PD-0337792) in toluene when anhydrous ammonia was used. Similarly, it was filtered out from the solution after performing azeotropic water removal from toluene when aqueous ammonia (28% solution) was used. Anhydrous ammonia however, requires the reaction to be performed at high-pressure containment. Experiments conducted by sparging the ammonia gas gave acceptable yields; however, they required large volumes and use of a cryogenic condenser (to avoid gas from escaping the reactor headspace).
[TABLE-US-00004]TABLE 3 Yields for base deprotection ReagentYield* Methyl hydrazine85-95% Anhydrous NH3 (sparged)78-90% Anhydrous NH3 (50 psi)80-92% Aqueous NH390-97% *from PD-0333760
Step 2: Fluoride Displacement
Examination of the reaction in an automated reactor reveals that the reaction is essentially dosed-controlled after the initiation period. Increasing the amount of lithium amide and increased agitation rate appear to shorten the induction time. The addition of water was shown to prolong the induction time. However, it is not clear whether it is due to lithium hydroxide formation.
Induction time is increased when 0.1 equivalent H 2O was added. The trend was reversed however when 0.1 equivalent lithium hydroxide was added. Induction times were decreased upon increasing lithium amide equivalents and agitation.
CDI-assisted coupling of PD-0315209 acid and sidechain reagent followed by the acid (with aqueous HCl) hydrolysis consistently yielded good results in the laboratory. The development focus of this step was to ensure that impurity levels are within the specification limit. The known impurities in the final isolated diol product are excess PD-0315209 acid, dimeric impurities and chiral impurities. The chiral impurities are controlled by limiting the R-enantiomer in the starting s-glycerol acetonide. Elevated levels of dimeric impurity (d) has been known to cause difficulties in the polymorph transformation step. The dimeric impurity is formed initially by the reaction of imidazole (CDI-activated acid) in the presence of excess acid PD-0315209 forming dimer (a) and possibly (b) which are then carried through in the subsequent IPGA coupling and acid hydrolysis steps forming dimer (c) and (d), respectively. Impurity d is referred to as PF-00191189.
The reaction can be easily carried out in the laboratory either by charging both solids, FIPFA and CDI, followed by solvent (acetonitrile) or charging solids CDI into a slurry of FIPFA in acetonitrile. None of the solids is initially soluble in acetonitrile. The acid activation reaction was fast (almost instantaneous), forming highly soluble imidazolide product that turned the slurry into a clear homogenous solution while CO 2 gas evolution occurs.
Lab experiments generally resulted in impurity levels under 3%, which can be completely removed by the subsequent recrystallization from a 3-5% ethanol-toluene system. An additional recrystallization was performed in the few instances where the impurity level was above 0.3%. Table 4 shows selected results of lab experiments where elevated levels of impurities were observed and how they were removed in the subsequent recrystallization. The crude PD-0325901 was obtained using the acetonitrile/toluene system and the purified product was recrystallized from a 5% ethanol/toluene system. Entries no. 4 and 5 used additional solvent to ensure impurity removal with entry 5 requiring two recrystallizations in order to achieve a level of "ND" in the polymorph transformation. The 8-10 ml/g crude crystallization volume was chosen to limit product loss while maintaining a filterable slurry and ensuring removal of impurities.
[TABLE-US-00005]TABLE 4 Purification of PD-0325901 Tot. Imp. In Final Tot.isolated Tot. Imp.assay (after Imp. InCrude PurifiedpolymorphEntryreactionPD-RecrystallizationPD-trans-Nomixture0325901Vol (ml/g crude)0325901formation) 1 2.4%ND8ND99.8%210.5% 2%8ND99.6%3 6% 1%8ND99.4%4 10%3.2%15ND98.6%5 20%12%130.6%98.4%*
A scale up procedure that would give tolerable levels of impurities prior to the polymorph transformation (<0.3%), without losing too much product in the recrystallization was developed considering the solid CDI addition rate. Fast addition is preferred to minimize impurity formation; however, the addition needs to be performed at a rate that ensures safely venting of the evolved CO 2.
A half portion of solid CDI was initially added to the PD-0325901 acid, followed by solvent addition. The remaining CDI was added then through a hopper in less than 30 minutes to ensure that the impurity levels were below 3%.
Pilot Plant Preparation of Essentially Pure Form IV
14.4 kg alcohol (chemical purity 99.4%, optical purity 99.6% enantiomeric excess) was converted to 97.5 kg 9.7% w/w PD-0337792 (IPGA) solution in toluene (overall yield ˜60%). The triflate activation was performed in the 200 L reactor by maintaining temperatures under −20° C. during triflic anhydride addition. The resulting activated alcohol was then transferred to a 400 L reactor containing solid N-hydroxypthalimide (NHP) and the reaction was allowed to occur at ambient temperature to completion. The final base de-protection was performed by adding aqueous ammonia (˜28% soln, 5 equiv., 34 kg). After reaction completion, water was removed by distillation from toluene, and the resulting solid side product was filtered out to yield the product solution.
Step 2: Preparation of PD-0315209
The process yielded 21.4 kg (99.4% w/w assay), which is 80% of theoretical from starting materials 2,3,4-trifluorobenzoic acid (12 kg, 1 eq.) and 2-fluoro-4-iodoaniline (16.4 kg, 1.02 eq.) with lithium amide base (5 kg, 3.2 eq.). The reaction was initiated by adding 5% of total solution of TFBA and FIA into lithium amide slurry at 50° C. This reaction demonstrated a minimal initiation period of ˜10 minutes, which was observed by color change and slight exotherm. The remaining TFBA/FIA solution in THE was slowly added through a pressure can in an hour while maintaining the reaction temperatures within 45-55° C. There was no appreciable pressure rise (due to ammonia gas release) observed during the entire operation.
A modification was made to the CDI charging to mitigate potential gas generation. Two equal portions of CDI were added into solid FIPFA before and after solvent addition (through a shot loader). The timing between the two solid CDI additions (4.6 kg each) should not exceed 30 minutes. Then two intermediate filter cakes were dissolved with ethanol. The excess ethanol was distilled and replaced with toluene to approximately 5% v/v ethanol prior to PD-0325901 recrystallization. Lab studies suggested that the crystallization from toluene and acetonitrile and recrystallization from ethanol in toluene would not be able to reduce impurities which is essential for the polymorph transformation. The presence of a dimeric impurity (PF-00191189) at a level greater than 0.2% has been known to result in the formation of undesired polymorph.
The crude crystallization from the final reaction mixture reduced dimeric impurity PF-00191189 to approximately 1.9% and the subsequent recrystallization further reduced it to approximately 0.4%. As a consequence, undesired polymorphs were produced. The DSC patterns indicated two different melting points ˜80° C. (low melt Form II) and ˜117° C. (Form I). Also during the processing, the solids crystallized at a much lower temperature than expected (actual ˜10° C., expected ˜40° C.). It is suspected that the unsuccessful recrystallization is due to a change in the solvent composition as a result of incomplete drying of the crude. Drying of the crude wet cake prior to ethanol dissolution was stopped after about 36 hours when the crude product was ˜28 kg (26 kg theoretical).
Polymorph Transformation
Approximately 7.4 kg of PD-0325901 (mixed polymorphs) from the final EtOH/Water crystallization and precipitated materials from the earlier EtOH/Toluene filtrate were taken forward to the polymorph transformation. Both crops were separately dried in the filter until constant weights and each was dissolved in EtOH. The combined EtOH solution was analyzed by HPLC and resulted in an estimated amount of 16.4 kg PD-0325901. The recrystallization was started after removing EtOH via vacuum distillation and adjusting the solvent composition to about 5% EtOH in Toluene at 65° C. (i.e., EtOH is added dropwise at 65° C. until complete solids dissolution).
A slow 4-hour cooling ramp to 5° C. followed by 12 h stirring was performed to ensure satisfactory results. The resulting slurry was filtered and again it was completely dried in the filter until constant weight (approximately 3 days). The purified solid showed 99.8% pure PD-0325901 with not detected level of dimeric impurity PF-00191189.
The dried solid (15.4 kg) was re-dissolved in exactly 4 volumes of EtOH (62 L) off of the filter, transferred to the reactor and precipitated by a slow (˜3 h) water addition (308 L) at 30-35° C., cooled to 20° C. and stirred for 12 h. The DSC analysis of a slurry sample taken at 2 h shows the solids to be completely Form IV (desired polymorph).
21.4 kg PD-0315209, 9.7 kg CDI (1.05 equiv.), 91 kg solution of 9.7% PD-0337792 in Toluene (1.1 equiv.) were used and resulted in 12.74 kg of PD-0325901 (assay 99.4%, 100% Form IV, Yield 48%).
WO2006134469 , claiming methods of preparing MEK inhibitor, assigned to Warner-Lambert Co .
https://patents.google.com/patent/WO2006134469A1/enThe compound Λ/-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide represented by formula 1
i is a highly specific non-ATP-competitive inhibitor of MEK1 and MEK2. The compound of formula ± (Compound I) is also known as the compound PD 0325901. Compound I is disclosed in WO 02/06213; WO 04/045617; WO 2005/040098; EP 1262176; U.S. Patent Application Pub. No. 2003/0055095 A1 ; U.S. Patent Application Pub. No. 2004/0054172 A1; U.S. Patent Application Pub. No. 2004/0147478 A1 ; and U.S. Patent Application No. 10/969,681, the disclosures of which are incorporated herein by reference in their entireties.Numerous mitogen-activated protein kinase (MAPK) signaling cascades are involved in controlling cellular processes including proliferation, differentiation, apoptosis, and stress responses. Each MAPK module consists of 3 cytoplasmic kinases: a mitogen-activated protein kinase (MAPK), a mitogen-activated protein kinase kinase (MAPKK), and a mitogen-activated protein kinase kinase kinase (MAPKKK). MEK occupies a strategic downstream position in this intracellular signaling cascade catalyzing the phosphorylation of its MAP kinase substrates, ERK1 and ERK2. Anderson et al. "Requirement for integration of signals from two distinct phosphorylation pathways for activation of MAP kinase." Nature 1990, v.343, pp. 651-653. In the ERK pathway, MAPKK corresponds with MEK (MAP kinase ERK Kinase) and the MAPK corresponds with ERK (Extracellular Regulated Kinase). No substrates for MEK have been identified other than ERK1 and ERK2. Seger et al. "Purification and characterization of mitogen-activated protein kinase activator(s) from epidermal growth factor-stimulated A431 cells." J. Biol. Chem., 1992, v. 267, pp. 14373-14381. This tight selectivity in addition to the unique ability to act as a dual-specificity kinase is consistent with MEK's central role in integration of signals into the MAPK pathway. The RAF-MEK-ERK pathway mediates proliferative and anti-apoptotic signaling from growth factors and oncogenic factors such as Ras and Raf mutant phenotypes that promote tumor growth, progression, and metastasis. By virtue of its central role in mediating the transmission of growth- promoting signals from multiple growth factor receptors, the Ras-MAP kinase cascade provides molecular targets with potentially broad therapeutic applications.One method of synthesizing Compound I is disclosed in the above-referenced WO 02/06213 andU.S. Patent Application Pub. No. 2004/0054172 A1. This method begins with the reaction of 2-fluoro-4- iodo-phenylamine and 2,3,4-trifluoro-benzoic acid in the presence of an organic base, such as lithium diisopropylamide, to form 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid, which is then reacted with (R)-0-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine in the presence of a peptide coupling agent (e.g., diphenylphosphinic chloride) and a tertiary amine base (e.g., diisopropylethylamine). The resulting product is hydrolyzed under standard acidic hydrolysis conditions (e.g., p-TsOH in MeOH) to provide Compound 1. (R)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine is prepared by reaction of [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol with N-hydroxyphthalimide in the presence of Ph3P and diethyl azodicarboxylate.Another method of synthesizing Compound I, which is disclosed in the above-referenced U.S.Patent Application No. 10/969,681, comprises reaction of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzoic acid with (R)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine in the presence of N1N1– carbonyldiimidazole. The resulting product is hydrolyzed with aqueous acid and crystallized to provide polymorphic form IV of Compound I.Although the described methods are effective synthetic routes for small-scale synthesis of Compound I, there remains a need in the art for new synthetic routes that are safe, efficient and cost effective when carried out on a commercial scale.The present invention provides a new synthetic route including Steps I through Step III to the MEK inhibitor Λ/-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (Compound I).Step I: Preparation of 0-{r(4RV2.2-dimethyl-1.3-dioxolan-4-ynmethyl}hydroxylanπine (6) The method of the present invention comprises a novel Step I of preparing of 0-{[(4R)-2,2- dimethyl-1 ,3-dioxolan-4-yl]methyl}hydroxylamine (6) from [(4S)-2,2-dimethyl-1 ,3-dioxoIan-4-yl]methanol (1) through the formation of [(4R)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methyl trifluoromethanesulfonate (3) and its coupling with N-hydroxyphthalimide (4) to afford 2-{[(4R)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-1 H- isoindole-1 ,3(2H)-dione (5), which is subsequently de-protected to give 6 as shown in Scheme 1.Scheme 1
The reaction of compound (1) with trifluoromethanesulfonic anhydride (2) is carried out in the presence of a non-nucleophilic base, such as, for example, a tertiary organic amine, in an aprotic solvent at a temperature of from -5O0C to 50C, preferably, at a temperature less than -150C, to form triflate (3). A preferred tertiary organic amine is triethylamine, and a preferred solvent is toluene. Treatment of triflate (3) with N-hydroxyphthalimide (4) furnishes phthalimide (5), which can be isolated if desired. However, in order to minimize processing time and increase overall yield, 0-{[(4R)- 2,2-dimethyl-1,3-dioxolan-4-yl]methyl}hydroxylamine (6) can be prepared in a one-pot process with no phthalimide (S) isolation. Cleavage of the phthalimide function could be achieved by methods known in the art, for example, by hydrazinolysis. However, the use of less hazardous aqueous or anhydrous ammonia instead of methyl hydrazine (CH3NHNH2) is preferred.Step II: Preparation of 3.4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) As shown in Scheme 2, Step Il of the method of the present invention provides 3,4-difluoro-2-(2- fluoro-4-iodophenylamino)-benzoic acid (9).Scheme 2
Preparation of compound (9) can be carried out by reacting compound (7), wherein X is halogen, or O-SC^R^ or 0-P(3O)(OR^, wherein R^ is alkyl or aryl, with compound (8) optionally in a solvent, and in the presence of from about 1 mol equivalent to about 10 mol equivalents of at least one base, wherein the base is selected from: a Group I metal cation hydride or a Group 2 metal cation hydride, including lithium hydride, sodium hydride, potassium hydride, and calcium hydride, a Group I metal cation dialkylamide or a Group 2 metal cation dialkylamide, including lithium diisopropylamide, a Group I metal cation amide or a Group 2 metal cation amide, including lithium amide, sodium amide, potassium amide, a Group I metal cation alkoxide or a Group 2 metal cation alkoxide, including sodium ethoxide, potassium terf-butoxide, and magnesium ethoxide, and a Group I metal cation hexamethyldisilazide, including lithium hexamethyldisilazide; for a time, and at a temperature, sufficient to yield compound (9).Preferably, preparation of compound (9) is carried out by reacting compound (7), wherein X is halogen, more preferably, X is fluorine, in an aprotic solvent with compound (8) in the presence of from about 3 mol equivalents to about 5 mol equivalents of a Group I metal cation amide at a temperature of from 2O C to 55°C, more preferably, at a temperature from 45°C to 55°C. A catalytic amount of Group I metal cation dialkylamide can be added if necessary. A preferred Group I metal cation amide is lithium amide, a preferred Group I metal cation dialkylamide is lithium diisopropylamide, and a preferred solvent is tetrahydrofuran. Preferably, the reaction is performed by adding a small amount of compound (7) and compound (8) to lithium amide in tetrahydrofuran followed by slow continuous addition of the remaining portion. This procedure minimizes the risk of reactor over-pressurization due to gas side product (ammonia) generation.Step III: Preparation of N-((RV2.3-dihydroxypropoxy)-3.4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide (Compound I)Compound I can be obtained by coupling 0-{[(4R)-2,2-dimethyl-1,3-dioxolan-4- yl]methyl}hydroxylamine (6) with 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) using a carboxylic acid activating reagent such as, for example, COCI2, S(O)C^, S(O)2Cl2, P(O)Cl3, triphenylphosphine/diethylazodicarboxylate, diphenylphosphinic chloride, N, N'-dicyclohexylcarbodiimide, (benzotriazol-1 -yloxy)tripyrolidinophosphonium hexafluorophosphate, (benzotriazol-1 – yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, N-ethyl-N'-(3- dimethylaminopropyl)carbodiimide hydrochloride, or 1,1′-carbonyldiimidazole (CDI).A preferred carboxylic acid activating reagent is 1,1′-carbonyldimidazole (CDI) shown in Scheme 3. Preparation of the desirable polymorphic Form IV of Compound I using CDI is described in the above- referenced U.S. Patent Application No. 10/969,681.Scheme 3
10 11 Compound IIn according to the present invention, the method was modified to include the advantageous procedure for product purification and isolation, which procedure is performed in single-phase systems such as, for example, toluene/acetonitrile for the first isolation/crystallization and ethanol/toluene for the second recrystallization. Water addition, implemented in the previous procedure, was omitted to avoid the two-phase crystallization from the immiscible water-toluene system that caused inconsistent product purity. The one-phase procedure of the present invention provides consistent control and removal of un- reacted starting material and side products. Alternatively, Compound I can be obtained by coupling 0-{[(4R)-2,2-dimethyl-1,3-dioxolan-4- yl]methyl}hydroxylamine (6) with 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) using thionyl chloride (SOCI2) as shown in Scheme 4.Scheme 4
Compound IExamplesThe reagents and conditions of the reactions described herein are merely illustrative of the wide variety of starting materials, their amounts and conditions which may be suitably employed in the present invention as would be appreciated by those skilled in the art, and are not intended to be limiting in any way.HPLC (Conditions A): 10 μL injection volume onto Agilent Zorbax RX-C18 150 mm x 4.6 mm x 3.5 μm column at 30°C column temperature, 1.0 mL/min flow rate and detection at 246 nm. Mobile phase A (v/v): 25 mM Acetate Buffer, pH 6.0; Mobile phase B (v/v): Acetonitrile, and Linear Gradient Table:
Sample Preparation: Dilute 100 μL reaction mixture to 10 mL with acetonitrile. Mix in a vial 200 μL of this sample solution with 300 μL carbonate buffer pH 10.0 and 300 μL solution of 2-mercaptopyridine in acetonitrile (18 mM), heat the vial for 10 minutes at 500C and dilute to 1:1 ratio in mobile phase A.GC (Conditions B): 1 μL injection onto an RTX-5 column (30 m x 0.25 mm x 0.25 μm) with initial oven temperature of 120°C for 2 min. to final temperature of 250°C in 15°C/minute ramping and a final time of 2.33 min; Flow rate: 1 mL/min.HPLC (Conditions C): 5 μL injection onto Phenomenex Luna C18(2) 150 mm x 4.6 mm x 3μm column ; flow rate : 1.0 mL/min; detection at 225 nm; mobile phase A: 95/5 v/v Water/Acetonitrile with 0.1% Trifluoroacetic acid (TFA), mobile phase B: 5/95 v/v Water/Acetonitriie with 0.1% TFA; Linear Gradient Table:
Sample preparation: Dilute 1 ml_ reaction mixture to 100 mL with acetonitrile and dilute 1 mL of this solution to 10 mL with 50:50 Water/Acetonitrile.HPLC (Conditions D): 5 μL injection onto Waters SymmetryShield RP 18, 150 mm x 4.6 mm x 3.5 μm column; flow rate: 1.0 mL/min; detection at 235 nm; mobile phase A: 25 mM Acetate Buffer adjusted to pH 5.5, mobile phase B: Acetonitrile; Linear Gradient Table:
Sample preparation: Dilute 40 μL of reaction mixture in 20 mL acetonitrile.HPLC (Conditions E): 10 μL sample injection onto YMC ODS-AQ 5 μm, 250 mm x 4.6 mm column; flow rate: 1.0 ml_/min; detection at 280 nm; temperature 30°C; mobile phase : 75/25 v/v Acetonitrile/Water with 0.1% Formic acid.Sample preparation: Quench reaction mixture sample with dipropylamine and stir for about 5 minutes before further dilution with mobile phase.DSC measurement was performed using a Mettler-Toledo DSC 822, temperature range 25° to 150°C with 5°C/min heating rate in a 40 μL aluminum pan. Experimental Conditions for Powder X-Rav Diffraction (XRD):A Rigaku Miniflex+ X-ray diffractometer was used for the acquisition of the powder XRD patterns. The instrument operates using the Cu Ka1 emission with a nickel filter at 1.50451 units. The major instrumental parameters are set or fixed at:X-ray: Cu / 30 kV (fixed) / 15 mA (fixed)Divergence Slit: Variable Scattering Slit: 4.2° (fixed) Receiving Slit: 0.3 mm (fixed) Scan Mode: FT Preset Time: 2.0 s Scan Width: 0.050° Scan Axis: 2Theta/Theta Scan Range: 3.000° to 40.000°Jade Software Version: 5.0.36(SP1) 01/05/01 (Materials Data, Inc.) Rigaku Software: Rigaku Standard Measurement for Windows 3.1 Version 3.6(1994-1995) Example 1. Preparation of 0-ffl4R)-2.2-dimethyl-1.3-dioxolan-4-vπmethyl}hvdroxylamine (6)A solution containing [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol (1) (13.54 ml_, 0.109 mol) (DAISO Co., Ltd., CAS# 22323-82-6) and triethylamine (18.2 ml_, 0.131 mol) in 115 mL toluene was cooled to -15 C, then trifluoromethanesulfonic anhydride (2) (18.34 mL, 30.75 g, 0.109 mol) (Aldrich, Catalog # 17,617-6 ) was added drop wise while maintaining the temperature at less than -15°C. The mixture was then stirred for 2 hours, and transferred to a separate flask containing a mixture (slurry) of N- hydroxyphthalimide (4) (18.99 g, 0.116 mol) (Aldrich, Catalog # H5.370-4) and 18.2 mL (0.13 mol) triethylamine in 95 mL toluene. The resulting mixture was warmed to 20-25°C and stirred for at least 5 hours or until reaction completion (determined by HPLC (Conditions A)). Water (93 mL) was then added to quench the reaction mixture, the phases were separated, and the bottom aqueous layer was discarded. The water quench was repeated two more times resulting in a pale yellow organic layer. The organic layer was heated to 35 C and treated with 36.7 mL ammonium hydroxide solution (contains about 28-29% wt/wt ammonia). The mixture was stirred for at least 12 hours or until the reaction was deemed complete as determined by GC (Conditions B). The water was then removed under reduced pressure by co- distilling it with toluene to about half of the original volume at temperatures around 35-45 C. Toluene (170 mL) was added to the concentrated solution and the distillation was repeated. A sample was drawn for water content determination by Karl Fisher method (using EM Science Aquastar AQV-2000 Titrator with a sample injected to a pot containing methanol and salicylic acid). The distillation was repeated ifl water content was more than 0.1%. The concentrated solution was filtered to remove the white solid side product, and the filtrate was stored as 112mL (98 g) product solution containing 9.7% w/w compound 6 in toluene. This solution was ready for use in the final coupling step (Example 3). Overall chemical yield was 59%. A small sample was evaporated to yield a sample for NMR identification.1H NMR (400 MHz, CDCI3): δ 5.5 (bs, 2H), 4.35 (m, 1H), 4.07 (dd, 1H), 3.77 (m, 2H), 3.69 (dd, 1H), 1.44 (s, 3H), 1.37 (s, 3H).Example 2. Preparation of 3.4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9)A solution of 2-fluoro-4-iodoaniline (8) (16.4 g, 0.069 mol) (Aldrich, Catalog # 30,660-6) and 2,3,4- trifluorobenzoic acid (7) (11.98 g, 0.068 mol) (Aldrich, Cat # 33,382-4) in 38 mL tetrahydrofuran (THF) was prepared and a portion (about 5%) of this solution was added to a stirring slurry of lithium amide (5 g, 0.22 mol) in 40 mL THF at 50-55 C. After about 15-30 min. an exotherm followed by gas release and color change are observed. The remaining portion of the (8) and (7) solution was added slowly over 1-2 hr while maintaining temperatures within 45-55°C. The mixture was stirred until the reaction was deemed complete (by HPLC (Conditions C). The final mixture was then cooled to 20-25°C and transferred to another reactor containing 6 N hydrochloric acid (47 mL) followed by 25 mL acetonitrile, stirred, and the bottom aqueous phase was discarded after treatment with 40 mL 50% sodium hydroxide solution. The organic phase was concentrated under reduced pressure and 57 mL acetone was added. The mixture was heated to 50°C, stirred, and added with 25 mL warm (40-50°C) water and cooled to 25-30°C to allow crystallization to occur (within 1-4 hours). Once the crystallization occurred, the mixture was further cooled to 0 to -5°C and stirred for about 2 hours. The solid product was filtered and the wet cake was dried in vacuum oven at about 55°C. Overall chemical yield was 21.4 g, 80%. 1H NMR (400 MHz, (CD3)2SO): δ 13.74 (bs, 1H), 9.15 (m, 1 H), 7.80 (dd, 1H), 7.62 (d, 1H), 7.41 (d, 1H), 7.10 (q, 1H), 6.81 (m, 1H).Example 2B. Preparation of 3.4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) by the solid addition of lithium amide methodTo a stirring solution of 2,3,4-trifluorobenzoic acid (13) (5.0 g, 28.4 mmol) and 2-fluoro-4- iodoaniline (14) (6.73 g, 28.4 mmol) in MeCN (100 mL), under N2 atmosphere was added lithium amide (2.61 g, 113.6 mmol) in small portions. The reaction mixture was heated to reflux for 45 minutes, cooled to ambient temperature and quenched with 1 N HCI and then water. The yellowish white precipitate was filtered, washed with water. The solid was triturated in CH2CI2 (30 mL) for 1h, filtered and dried in a vacuum oven at 45°C for 14 hours to give 8.Og (72%) of compound (9) as an off-white solid, mp 201.5-203 °C.Example 3. Preparation of N-((R)-2.3-dihvdroxypropoxy)-3.4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide (Compound \)3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) (20 g, 0.051 mol) in 100 mL acetonitrile was treated with 1,1′-carbonyldiimidazole (CDI) (8.66 g, 0.053 mol) (Aldrich, Cat # 11,553-3) and stirred for about 2 hours at 20-25°C until the reaction was deemed complete by HPLC (Conditions D). 94 mL (84.9 g) of 9.7% w/w solution of O-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}hydroxylamine (6) in toluene was then added and stirred for about 4 hours or until the reaction was deemed complete by HPLC (Conditions D). To this mixture was added 66 mL of 5.6 % hydrochloric acid solution, and after stirring, the bottom aqueous phase was discarded. Again 66 mL of 5.6 % hydrochloric acid solution was added to the organic phase and stirred at 20-25°C for 12-18 hours or until the reaction was deemed complete by HPLC (Conditions D). The bottom layer was then discarded and the remaining organic layer was concentrated under reduced pressure to remove about 10-20% solvent, and the volume was adjusted to about 9-11 mL/g with toluene (80 mL). Crude product was then crystallized at 10-15°C. The slurry was allowed to stir for about 2 hours and the crude solid product was filtered, and dried. The dried crude product was recharged to the reactor and dissolved into 150 mL of 5% v/v ethanol/toluene mixture at 55- 67°C. The solution was then clarified at this temperature through filter (line filter) to remove any remaining particulate matter. The solution was then cooled slowly to 5°C to crystallize and stirred for at least 2 h, filtered and dried. The dried solid product was redissolved in EtOH (60 mL) at 35°C, and product was precipitated out by adding water (300 mL) at 35°C followed by cooling to 200C. The slurry was stirred for at least 2 hours to transform the crystals to the desired polymorphic Form IV as determined by DSC and Powder X-ray Diffraction pattern (PXRD). The slurry was filtered and dried under vacuum oven at 70- 90°C to yield the final N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide (Compound I) product. Overall chemical yield was 13 g, 53%. Melting point (DSC): 112+1° C. Appearance: White to off-white crystals.Shown in Figure 1, PXRD conforms to polymorphic crystal Form IV disclosed in the above mentioned U.S. Patent Application No. 10/969,681 1H NMR (400 MHz, (CD3)2SO): δ 11.89 (bs, 1H), 8.71 (bs, 1H), 7.57 (d, 1H), 7.37 (m, 2H), 7.20 (q, 1H), 6.67 (m, 1H), 4.84 (bs, 1H), 4.60 (m, 1H), 3.87 (m, 1 H), 3.7 (m, 2H), 3.34 (m, 2H).Example 4. Preparation of N-((R)-2.3-dihydroxypropoxyV3.4-difluoro-2-(2-fluoro-4-iodo-phenylanrιinoV benzamide (Compound \)To a stirring solution of 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) (120 g, 0.30 mol) in a mixture of 1 mL N,N-dimethylformamide and 1000 mL toluene was added thionyl chloride (55 g, 0.462 mol). The mixture was heated to 50-65 C and stirred for 2 hours or until reaction completion as determined by HPLC (Conditions E). The final reaction mixture was then cooled and concentrated under reduced pressure to a slurry keeping the temperature below 35°C. Toluene (600 mL) was added to dissolve the slurry and vacuum distillation was repeated. Additional toluene (600 mL) was added to the slurry dissolving all solids and the solution was then cooled to 5° -10°C. The solution was then treated with O-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}hydroxylamine (6) (63 g, 0.43 mol) solution in 207 mL toluene followed by potassium carbonate (65 g) and water (200 mL), stirred for at least 2 hours at 20- 25°C. The stirring was stopped to allow phase separation and the bottom phase was discarded. The remaining organic layer was treated with hydrochloric acid solution (7.4%, 240 mL) until pH was less than 1 and stirred for 2 hours. The final reaction mixture was slightly concentrated under vacuum collecting about 100 mL distillate and the resulting organic solution was cooled to 5°C to crystallize the product and filtered. The filter cake was washed with toluene (1000 mL) followed by water (100 mL) and the wet cake (crude product Compound I) was charged back to the flask. Toluene (100 mL), ethanol (100 mL) and water (100 mL) are then added, stirred at 30-35°C for about 15 min, and the bottom aqueous phase was discarded. Water (200 mL) was then added to the organic solution and the mixture was stirred at about 3O C to allow for crystallization. The stirring was continued for 2 hours after product crystallized, then it was further cooled to about 0°C and stirred for at least 2 hours. The slurry was filtered and wet cake was dried under reduced pressure at 55-85°C to yield the final product N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (Compound I) product. Overall chemical yield was 86 g, 58%.
WO2002/006213 describes crystalline Forms I and II. U.S. Pat. No. 7,060,856 ("the '856 patent")
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2002006213
////////MIRDAMETINIB, Orphan Drug Status, Neurofibromatosis 1, PHASE 2, PD0325901, PD 0325901, PD-325901,
O=C(NOC[C@H](O)CO)C1=CC=C(F)C(F)=C1NC2=CC=C(I)C=C2F
Tags: MIRDAMETINIB, Neurofibromatosis 1, Orphan Drug Status, PD 0325901, PD-325901, PD0325901, phase 2
By DR ANTHONY MELVIN CRASTO Ph.D in 0rphan drug status, Phase2 drugs on July 31, 2021 .
← OTESECONAZOLE	Ezutromid →


text:
Senate Majority Leader Harry Reid, left, and House Speaker John Boehner disagree about reasons for the deadlock in Congress.
Overheard on CNN.com: Shutdown politics and practicalities
Comment of the Day: "My tuition is due the 15th. The VA has yet to pay it and my school is telling me that they are going to cancel my enrollment. I can't afford to pay the tuition and there is not enough time to take out a loan. If there is a shutdown the money wont get paid by the VA and I won't be able to stay in school."
- OHYAYYER
Harry Reid says government shutdown is likely
With Democrats and Republicans still at an impasse, it appears the government is headed for a shutdown. According to Democratic Senate Majority Leader Harry Reid, "The only thing holding up an agreement is ideology," while Republican House Speaker John Boehner said the disagreement is over numbers and "underlying policies."
libdisorder said, "Only 'nonessential' federal employees will be affected. Why do they have 'nonessential' jobs but 'essential' paychecks?"
hoofleau said, "Go ahead and let the government shut down. It would be a pleasant change for once. I guarantee not one Congressional Representative will miss a paycheck or health benefits. For all you government workers: it's time to quit riding the coattails of our government and create your own living for yourselves. There was always the saying, 'If you want a good job, decent money, and don't want to work so hard, get a job with the government.' "
armywife815 answered, "Well, lucky for you, the ones who do work for the government - a.k.a. your military, who is underpaid and overworked - allow you to sit comfortably in your computer chair to type your comment. Yes, all our military personnel chose their living and how they support their families but someone had to step up and do it."
Bojak said, "I work for a state and federally funded organization that assists men and women with developmental disabilities. I make less than $12/hr and a full quarter of my income goes to health insurance. If I'm riding the coat tails I picked the wrong coat because I don't wind up with very much at the end of the month."
carrotroot said, "The government doesn't just run itself. You need people to run it. Saying that government workers 'need to create their own living' is disgraceful thing to say. These folks are neighbors just trying to earn an honest wage, not welfare-queens on the public dole."
When a headache really is a brain tumor
It is difficult, sometimes, to know when to assume the best or fear the worst. John Tonich, a high school sophomore, began having headaches after a wrestling match. Visits to the family doctor resulted in diagnoses like dehydration and flu. But when John texted his mother from school, saying he felt dizzy, she took him to the emergency room. He had a brain tumor. CNN.com readers wrote to share experiences from both sides.
Frantastic77 said, "This breaks my heart, I wish all the best to John and his family. My husband was diagnosed with medullablastoma at the age of 25. He had seen three different doctors all telling him it was something trivial and dismissing his requests for a CT scan. He finally visited the ER and told them he wouldn't leave until he got one. He was right, and not a moment too soon; a few weeks more and it would have been inoperable."
temoc said, "When my wife and I were still dating she would always complain of headaches. We went to our university doctor and he wrote it off as an infection. A few days later we went to the emergency room for more headache problems and after a CT scan and an MRI, a tumor was located on the pituitary gland. Six years after two surgeries to remove it, she is doing great but we are grateful that we checked rather than relying on faulty information that it was merely a headache."
Zjenopks said, "My brother's doctors told him his dizziness and headaches were a result of his blood pressure medication being off; he died six weeks later from this same kind of tumor."
fegero said, "I had headaches and was told I was stressed and I'd feel better if I relaxed. I had a seizure and crashed my car on the way to work before I was given a chance to have an MRI; they found a tumor in my hippocampus. Luckily I only had a benign tumor, and 11 years later I'm still here."
AlpaChino said, "I used to get headaches daily, to the point where I went to a doctor about them. Then, about five years ago, they stopped. I honestly can't remember the last time I had a headache. I'm not sure what that means, but for those of you that get them often, there is the chance it will change."
boxfan said, "Everything on the 1 thru 5 list could also be a migraine. As one who grew up with migraines, I can tell you that I don't wish them on my worst enemy. The pain was so intense, that back in high school I would put my head in the freezer to try and dull the pain. I eventually outgrew them and they came with less and less frequency."
On the Brain: Inside autism
Are more children being born with autism now? If so, why? A story about Autism Awareness Month had CNN.com readers struggling for answers.
Anne McElroy Dachel said, "It is hard to understand how CNN can focus on autism, saying that one in every 110 children has the disorder and not give us one explanation for why this is happening to our children. We've had two decades of the press calling autism a mystery, as the numbers reached epidemic levels. In the 1970s, the autism rate was one in 10,000 and hardly anyone knew what it was."
Tina said, "There is no outbreak of autism. There have always been that percentage, or higher, of people with autism in the population. Autism afflicts just as many adults as it does children. Look in the engineering and tech fields. There are just as many adults with autism spectrum disorders as there are children with it."
Randall Arnold, who described himself "as a highly-functioning autistic (Aspergers)" explained why he thought autism is on the rise: "In the past autistics were called 'eccentric' and rarely married. In recent times, highly functioning autistics have been drawn to high-tech centers such as Silicon Valley, where they (we, actually, because I am one) meet others and marry. This concentrates the genes involved, often resulting in children at a lower-functioning level."
Compiled by the CNN.com moderation staff. Some comments edited for length or clarity.
Post by: Journalist Leah Pine
Filed under: Budget • Overheard on CNN.com
Don't worry about me I'll be fine!!!
I feel betrayed by my country. It doesn't matter whether or not I have enough money to get me by for a couple of days or a few weeks, Because it's the principle of the whole situation. I am sickened by the civilians of America. Most people are to coward in the first place to fight for there country and then they have the nerve to get upset at us services members who do nothing but what they are told to do and blame us for the budget deficit. We're only a million in a half strong and we don't get paid, we'll I would like to see how you people would react if the Government told you that you weren't going to get paid either.
You people don't care about us, were dying out there everyday and all I here is civilians talk about how they should shut down the Government because it doesn't effect them. We'll lets see how fast you people come calling on your Military when you allow another open opportunity for another terrorist attack. Just remember one thing the only reason this country is allowed to thrive is because we are a Super Power who control the Air and the Seas. With out us there is no America because every opposing nation would stand in line to seek there teeth into us. The civilians of america are just as phony as the country's who smile in our face but wish nothing but the worst behind our backs.
I am also appalled at the fact that you wouldn't pay your Active duty service members who go on long deployments, missing precious time with there families to risk being killed. But you'll still pay wealthy Congressmen who sit behind a desk, never have to sacrifice anything, never accomplish anything, and hardly ever show up to work because they are to busy playing golf and spending the average paycheck of $174 thousand dollars a year. I also love how you reporters on CNN ask these Military wifes if we've voiced our opinions and pettioned the Government, knowing that were not supposed to speak out against the government. That's what the civilians are supposed to be doing speaking out for us and making sure that we are taken care of so we can protect this country. But hey I don't think Americans know the meaning of the word Selflessness because the only the only morals this country values is Greed.
April 8, 2011 at 9:36 am | Report abuse |
Johnny Irish
Will,
Calm down – the average American is not responsible for the military being furloughed or Congress getting paid. At this point there is nothing that we can do. When we go to the polls next you can bet many of us will remember this, but for now our hands are tied. As for military speaking out against the government, you're incorrect. You may not be able to speak out in a manner to undermine the government, but you are allowed to voice your opinion regarding policy.
Also, this coming from a veteran, remember you are a volunteer, so you signed up to serve this country, so for you to ask and demand "thanks" from an entire country is hypocritical. This country is free, and yes you have a hand in keeping it that way, but you cannot make statements like this, "...With out us there is no America ..." and this, "...Just remember one thing the only reason this country is allowed to thrive is because we are a Super Power ..."
Those statements are very forthcoming and arrogant. If you want the support of these people, it's best to not tell them they are useless compared to your service...
April 8, 2011 at 10:05 am | Report abuse |
I am appauld also. I think goverment is to big and that congress be should cut and there they can save 61 billion
April 8, 2011 at 1:21 pm | Report abuse |
At the end of the day obviously our leaders need a basic economics class. Balancing the peoples checkbook isn't that hard. Quit playing the ideological game the harm that would be done far outweighs whatever point the hold out senators are trying to make.
April 8, 2011 at 12:06 pm | Report abuse |
Matthew Martin
I sit now waiting on my family's future....I am a Veteran of the US ARMY and if this shutdown happens my family and I will be put out in the street. We rely on the money for schooling from the VA to help keep my head above water. I hope all this is worth it to the suits up there knowing if this goes down Me and my family(which includes my brand new 3 month old daughter) will be forced into a awful situation. Im so upset for my military brothers out there who's family lives will be put through this hardship. This is not fair...and I am truly let down by my government if they cannot get this resolved. America the great huh....we will see by tonight...thats for sure.
Let your voices be heard the only way a politician will listen – YOUR VOTE. Vote every current politician out of office the very next election opportunity. They are failures at running our country. Get them out of office.
Both the Democrats and the Republicans have totally missed the point.
Our national debt is killing us. Any deficit increases it.
We need to cut not 30 Billion, or 60 Billion, but TWO THOUSAND BILLION.
If we can do that, we can pay off a tiny fraction of the national debt.
Continuing to run a deficit is irresponsible, and will lead to the demise of our country.
Rioh Reigh Pheigh
Please, dont shut down! We need you all!, badly, If It does shut down, I will be Homeless,without medcine for my mental problomes, and in the world all alone in a homeless shelter! I dont want to go that route! Please think of the people you are hurting! PLEASE GOD! HELP ME, ANYONE, PLEASE HELP US ALL NOW, OH PLEASE WAKE UP AND SEE THE LIGHT I AM IN INTENSE PAIN NOW PLEASE KEEP (MEDICAID AND SOCIAL SECCURITY)!!!! PLEASE AT LEAST KEEP THOSE THINGS THAT I REQUIRE TO LIVE MY LIFE!. I LIVE IN A GROUP CARE HOME FOR THE MENTALLY ILL AND HAVE BEEN MENTALL ILL ALL OF MY LIFE, YOU ARE MY ONLY FREEDOM! PLEASE DONT TAKE THESE THINGS AWAY!!, LOVE ALWAYSE, Rioh R. Pheigh
Wow! http://nopolicestate.com


Doing business in a small scale context is already complicated enough how much more in the aspect of doing business with the largest buyer of services and goods all throughout the four corners of the world. Small business has to step up their game ensuring that as the world grows so will they paving a way for new opportunities that are in coherence with their capabilities, plans, and goals.
These can be made simple through the aid of government procurements which has numerous benefits to take note of. Not everybody is fully aware that it exists and if they do they do not know how it works.
Due to the need of education in terms of government procurement, listed below are ways of finding contracting opportunities for the betterment of the business.
Leading factor on the list is the need to g? yourself informed about the ins and outs of government procurements and how the tiny details play a big role in creating a whole.
Nothing happens overnight that is why give it some time to understand the concepts that govern the subject matter in order to deepen your understanding. Do not rush the process for the fact that the information you get serves as a key point in helping you build strategies.
It is also best if you are well informed about what are the legalities of the terms and agreements because most people tend to get overwhelmed at the first sign of opportunity.
You can also extend your services to those small companies who are not doing well themselves because you can be advantageous to their parts.
Government mentors are accessible so make use of that as you find a partner for the reasons that they can get you access to contracts and the like.
You must also bear in mind that there is a need to collaborate with a partner meaning services that serve as resources which teach entrepreneurs to take advantage of the opportunity.
In addition to this, another smart move on the list is to get help from a government resource which provides services that include training, counseling and business matchmaking events.
To wrap this all up, government procurements is a game changer in any business form that is why it is a must to develop strategies in order to obtain this opportunity-action get the company far. Do not let this be your only source of information, acquire as much as possible in order to widen your understanding towards government procurement and how it can be beneficial to a business.
Lend a hand to your friends or those whom you know have difficulty in understanding government procurements and share this article with them.


Discussion in 'Individual Analyses' started by Disaster Area, Oct 16, 2018.
While Huntail's stat spread best suits it more for a slow, physically-inclined offensive role, but everything else - from its movepool, to its typing, to its ability - says it should be a Swift Swim sweeper. It's strong enough and just about fast enough for that, able to outspeed the whole metagame under rain and hitting the hardest of any ADV 50-legal Pokemon with Swift Swim. Seen on almost all rain teams, Huntail is a staple of the archetype but seen nowhere else.
Rain Dance activates Swift Swim and boosts the power of Huntail's Water-type STAB, and Hydro Pump is its strongest STAB option available. Ice Beam hits Grass-types and Altaria, and Hidden Power Electric hits the Water-types which resist both Hydro Pump and Ice Beam. Hidden Power Electric is preferred over Hidden Power Grass as Mantine walls the set comfortably otherwise.
A set maximising speed and power is chosen. Without a Timid nature, Huntail would not outspeed Aggron or Golem outside of the rain, or Electrode in the rain, making Timid the preferred choice over Modest. As it would bring Huntail very close to running full speed EVs to hit all of those benchmarks, it is recommended just to maximally invest in Speed for speed ties against other Huntail rather than get a minor improvement to its very average bulk, especially as Huntail is a Pokemon to be played quite fast and loose, usually.
The most serious alternative to the above set is to run the above set with a different item, such as Mystic Water, which boosting the power of Huntail's Hydro Pumps even further. Huntail isn't a Pokemon that usually sticks around for a long time during a match, so giving up Leftovers is a real possibility. Lum Berry is another option, and is one that lets it set up Rain on Pokemon carrying status moves.
Huntail does get access to Baton Pass, but the only stat it can boost is defense with Barrier, so unless you plan on using a full Baton Pass team, which is quite flawed in this metagame, then it's not worth consideration, and Baton Pass by itself is not good enough to be worth trying to fit on the Rain Dance set. A number of other options, such as Icy Wind, Refresh, or running Toxic and Protect together, are far better left to bulkier waters, of which there are numerous available. However, its access to Clamp (as an evolution of Clamperl) is more special, and could theoretically be useful in combination with Toxic, but it typically draws in Pokemon which can easily KO it quite quickly, making it a very poor choice. Blizzard is a more serious option than much that has been listed, offering a stronger alternative to Ice Beam, but the boost in power isn't recommended for the significant drop in accuracy. Crunch is the only other decently powerful special attack in its movepool that's not Water- or Ice-type, or Hidden Power, but it doesn't hit any Pokemon significantly harder than one of its other moves, so is not worth it.
Lanturn is the best answer to Huntail, with excellent special bulk due to its high HP, due to resisting or being immune to all of Huntail's attacks, and being able to retaliate with STAB Thunderbolt (or Thunder), which OHKOs with moderate investment. Meganium is a great check that is bulky and difficult to wear down, particularly when it carries Light Screen, and that can hit Huntail super-effectively with Giga Drain. Other special tanks such as Muk and Wailord also make excellent checks, albeit will be worn down in the process of handling Huntail. Huntail can be neutralised by paralysis from Pokemon such as Slowking and Clefable, although they usually will accrue significant damage in the process, and depending on the set may not be able to handle Huntail on their own. Vileplume is 2HKO'd by Ice Beam, but Giga Drain lets it 2HKO in return, and turn Ice Beam into a 3HKO thanks to the HP recovered. Ampharos can switch in and trade with Huntail, but Huntail's rain-boosted Hydro Pump is so strong that it can almost OHKO Ampharos. Choice Band Azumarill can 2HKO with Return, and is only 3HKO'd in return by Huntail. Castform is 2HKO'd by Huntail but has a chance to OHKO in return with Thunder. Camerupt, Glalie and Steelix can potentially explode on Huntail switching in, but as Huntail is typically paired with other Water-types, it should not be a team's primary strategy for dealing with Huntail.