text:
- Doctors
- Washington
- Bellevue
- General Surgeons
- Dr. Oliver R. Biggers
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Dr. Sam M. Salama
Ratings for Dr. Oliver R. Biggers
I found Dr. Biggers after having a failed surgery in Montana. Dr. Biggers staff got me in to see him within days of contacting his office. I was in Dr. Biggers care for over 6 months. I traveled every two weeks from Montana to his clinic in Bellevue because I believed in the knowledge and care of Dr. Biggers. He is not only a fine and personable person, but professional in all ways! The combination of a wonderful efficient staff makes for excellence! Thank you Dr. Biggers for helping me to get on the road to recovery!
I am just repeating what all have said here. My elder brother had Surgery by Dr Biggers a few years bck. This man should teach patient care and integrity to other physicians!! I salute him and today my elderly father is looking at bowel obstruction surgery!! I am going to ask and c if he'll take him on as a patient..
Dr. Biggers has cared for me over the last 23 years. He is compassionate,knowledgeable and has always treated me with kindness and respect. When he says he'll stop and see you on rounds, he does, even if it is 11 pm at night. He has performed 7 bowel surgeries on me, and every decision to do so was as difficult for him as it was for us. He even helped deliver my baby daughter so he could be there and make sure there were no complications when the OB performed my C-section. He gave me back quality of life - how can you possibly rate a doctor high enough for that?
Dr. Biggers is the best doctor in the business of MD. He nas not only saved my life, but has done it many times. He has done multiple surgeries on me along with assisting in the birth of my daughter. You will never find a better dr than him. His staff is just as great, Kudos to Connie, she is like a mother to my health care and I cannot say enough how much I love Dr, Biggers. My family thinks that he is my savior as well! I would not be where I am today if it were not for him. Thank you Dr. Biggers for being you!!!
He is the best in class, The whole family goes to him!
Dr. Biggers is amazing. I met with many doctors when considering surgery, and talking with him was like talking to a family member. I just knew I was going to be in good hands.
Dr. Oliver R. Biggers's Credentials
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- Meharry Medical College School Of Medicine (Grad. 1975)
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text:
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Call any of our four conveniently located offices to arrange an appointment. Read more......Read less

subset: commoncrawl


text:
There are lots of ways and I am trying to find one of them...
Let's try to look for it together.
Let's try to look for something that connects us.
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Never is too late!
Nowadays the only problem is not only the global economic crisis.
Let's return to ethic, morality and humanity.
"If man is to survive, he will have learned to take a delight in the essential differences between men and between cultures. He will learn that differences in ideas and attitudes are a delight, part of life's exciting variety, not something to fear."
Gene Roddenberry
"It is only with the heart that one can see rightly; what is essential is invisible to the eye."
Antoine de Saint-Exupéry
"To fear love is to fear life, and those who fear life are already three parts dead."
Bertrand Russell


text:
Hampi Overview
You can reach Hampi from Indore by road in about using a cab upon driving using a cab.
Hampi, the city of ruins and a UNESCO World Heritage Site, is one of the major historical places of South India. Once upon a time, it was the royal capital of the dominant Vijayanagara Empire. It is presently a ruined town with full of ancient palaces and forts. Hampi was constructed by Harihara and Ukka in 1336 AD and was noted for wonderful palaces, holy temples, gigantic forts, markets, big pavilions, and stables of royal elephants. It is a hub of many monuments, nearly 500 in number and each of which has a story to tell. If you are looking for car rental Hampi let us know and we will be happy to provide you with best budgeted deals for . Book cabs in Hampi


text:
Join as a member. There's a certificate with your name on it.
Now that we're using Guzzle for outgoing http requests, the responsibility of detecting and logging errors has become slightly more complicated. Guzzle exceptions are one of three things. Quoting mtdowling:
4xx errors throw a Guzzle\Http\Exception\ClientErrorResponseException
5xx errors throw a Guzzle\Http\Exception\ServerErrorResponseException
cURL errors throw a Guzzle\Http\Exception\CurlException
The first two have a response attached, and getting a message from them is pretty easy ($e->getResponse->getReasonPhrase()). The last one has no response, and can be thrown for network problems. Getting a message from these is pretty easy too, but you have to look in a totally different place ($e->getError()). The other complication is that CurlExceptions don't have an HTTP status code, but do have a curl error code. In drupal_http_request(), we used to handle this kind of "network error" by returning a negative version of the error number that we had.
Obviously, this can be handled by using stacked catch blocks to special case the CurlExceptions, but this adds a lot of duplicated code for every time we need to handle a Guzzle exception.
Proposed resolution
Create a Guzzle exception wrapper class whose sole purpose is to determine a reason and a code for the failure. Then, error handling is as simple as:
try {
// Some Guzzle call...
catch(BadResponseException $e) {
$wrapper = new BadResponseExceptionWrapper($e);
drupal_set_message(t('HTTP error @errorcode occurred when trying to fetch @remote. Message: @message', array('@errorcode' => $wrapper->getStatusCode(), '@remote' => $url, '@message' => $wrapper->getStatusMessage())), 'error');
return FALSE;
Remaining tasks
Review it.
User interface changes
API changes
|887 bytes
PASSED: [[SimpleTest]]: [MySQL] 53,034 pass(es). View
PASSED: [[SimpleTest]]: [MySQL] 53,028 pass(es). View
PASSED: [[SimpleTest]]: [MySQL] 52,245 pass(es). View
|461 bytes
PASSED: [[SimpleTest]]: [MySQL] 52,270 pass(es). View
Comment #2Berdir CreditAttribution: Berdir commented
As suggested over in the linked issue, instead of adding a wrapper, why not improve this upstream and add getStatusCode() and getStatusMessage() to BadResponseException?
IMHO, I'd even argue that CurlException does not correctly implement this interface because getResponse() always returns NULL but the interface does not define NULL as a possible return value, as far as I can see in http://guzzlephp.org/api/class-Guzzle.Http.Exception.BadResponseExceptio... ;)
Comment #3sun CreditAttribution: sun commented
I can perfectly see why these are separate exceptions — I essentially implemented a very similar set in Mollom PHP library.
The separation is necessary, because the calling code needs to react differently for each exception type/class.
For example, a 4xx client error always means that retrying the same request does not make any sense, because it's malformed, misconfigured, or unauthorized, etc.pp. Therefore, you can stop trying whatever you planned to do, because the request in itself is wrong.
Contrary to that, a 5xx server error means that potentially just this one request could not be processed; you can either retry, try a different server, put it in a queue and retry later, or error out. The application logic is different for each use-case and definitely requires custom handling for every particular purpose. In any case, it would be wrong to mix the error handling into the 4xx handling.
Lastly, there's the case of low-level networking errors, which borderline belong into the 4xx category because they are also caused by a client (platform/infrastructure) misconfiguration, but since cURL/PHP is not able to issue a request in the first place, it would be wrong to fake a server response where no request was in the first place. Additionally, these kind of errors cannot be fixed on the application level - most often you have to consult your server admin or hosting provider in order to open ports, adjust the firewall, correct php.ini settings, or whatever else might be configured wrongly. In any case, the application (Drupal) is not able to fix it, so the application actually needs to throw an appropriate error message (ideally including guidance for how to fix it).
In essence, the separate exceptions make perfect sense to me, and I'd strongly recommend to not wrap them.
Comment #4Berdir CreditAttribution: Berdir commented
@sun: Yes, that makes sense, I'm not suggesting to wrap or combine them.
Just provide a common interface (either specific messages or an actually useful getMessage()) so that you have an easy way to log it to watchdog, without requiring multipe catch blocks and checks for specific exeptions. In many cases in core, that's all we do right now (and more is often not possible, because that's background stuff like aggregator).
This is currently blocking progress on various convert drupal_http_request() to guzzle issues, I don't care that much how it looks, but we need some standard way to handle this, log something to watchdog and if it is a user-triggered action, provide him some useful feedback.
For example, this is what http://drupalcode.org/project/drupal.git/blob/refs/heads/8.x:/core/modul... is currently doing:
catch (BadResponseException $e) {
$response = $e->getResponse();
watchdog('aggregator', 'The feed from %site seems to be broken due to "%error".', array('%site' => $feed->title, '%error' => $response->getStatusCode() . ' ' . $response->getReasonPhrase()), WATCHDOG_WARNING);
drupal_set_message(t('The feed from %site seems to be broken because of error "%error".', array('%site' => $feed->title, '%error' => $response->getStatusCode() . ' ' . $response->getReasonPhrase())));
return FALSE;
In case of a low-level curl exception (and those are very easy to produce by having a typo in the domain name for example, missing protocol, ...), the site is going to die with a fatal error because $response is NULL.
Comment #5sun CreditAttribution: sun commented
If I get you right, then all you're asking for is a consistent behavior across Guzzle Exceptions. That makes perfect sense, too, and yeah, that should be fixed upstream.
Comment #6Berdir CreditAttribution: Berdir commented
Comment #7mtdowling CreditAttribution: mtdowling commented
CurlException is a networking exception whereas BadResponseException is an HTTP exception. It looks like CurlException should actually implement RequestException and not BadResponseException. CurlExceptions will never have a response object because the HTTP transaction never completes when a curl error is encountered. This would be a significant BC break though, so I either need to rethink it or wait until 3.1.0.
In the meantime, I've updated the cURL exception's message so that it does not include a var_export of the curl transfer information. You should be able to just rely on $e->getMessage() now right? Alternatively, you could catch the CurlException above BadResponseException and handle them differently.
Comment #8ParisLiakos CreditAttribution: ParisLiakos commented
|Standardize Guzzle exception handling
|» Standarize Guzzle exception handling
Comment #9Berdir CreditAttribution: Berdir commented
|Standarize Guzzle exception handling
|» Standardize Guzzle exception handling
Comment #10Crell CreditAttribution: Crell commented
I'm a little confused here. What's wrong with:
try {
// Do something with Guzzle.
catch (ClientErrorResponseException $e) {
// Do something useful.
catch (ServerErrorResponseException $e) {
// Do something else useful.
catch (CurlException $e) {
// Do something relevant.
That's a perfectly normal and appropriate way to handle exceptions.
Comment #11Berdir CreditAttribution: Berdir commented
Right, that you can do that and react on a different error differently is great. But right now, you are required to and that's a lot of duplicated or ugly code if all we want to do is log an error.
That leads to developers doing it wrong, see the code in #4. That has been written by the people who actually know Guzzle, has been reviewed by others who know it and it dies with a Fatal error if you have a typo in a URL or any of the other many reasons that can lead to a CurlException. How do you imagine will it look like in contrib and custom code? :)
As explained by @mtdowling in #7, the problem there is actually that CurlException should not be implementing BadResponseException as there is no Response but that can't be fixed without a BC break. And the getMessage() in the version that is currently in HEAD logs a lot of rather useless information but this has already been improved upstream, so we can update to the next stable version (or dev but then we need to do another update so that we have a stable version).
All I'm asking here is that getMessage() or another method returns enough information in a standardized way so that we can easily catch and and log an exception if something goes wrong without having to do something as ugly as #1862538: Convert drupal_http_request usage in update.fetch.inc to Guzzle. And things are improving already :) If we can for example just do a watchdog_exception('update', $e) as we do in other places where we log exceptions, then that's often enough and sometimes already more than we're doing right now.
Comment #12mtdowling CreditAttribution: mtdowling commented
I've tagged 3.1.0 of Guzzle: https://github.com/guzzle/guzzle/blob/master/CHANGELOG.md#310-2013-01-12
I decided that it was important to make CurlException implement RequestException rather than BadResponseException since treating these two types of exceptions in the same manner will lead to issues (e.g. attempting to work with a response object that isn't there). Because Drupal 8 is still in development and error handling hasn't been decided, I was hoping Drupal could update to 3.1.0.
Here's the new exception heirarchy:
- GuzzleException
--- RequestException
---- CurlException
---- BadResponseException
If you're wanting to catch the different types of exceptions and reduce bloat, you could just catch RequestException. This will catch all request related exceptions. This will also allow you to check if a request has a response, and if so, log whatever you like. Further, the getMessage() method should tell you everything you need to know about the request/response/curl error.
If you do not want to catch exceptions, then you could add an event listener to do whatever you want (e.g. log whatever to wherever you'd like). This listener would always be fired before the exception. Let me know if you're interested in this.
Comment #13Berdir CreditAttribution: Berdir commented
Thanks @mtdowling! Looks good!
I'm currently working on updating to 3.1.0 in #1875818: Update composer.json to use the latest stable 3.0.x version of Guzzle and then I'll update aggregator as an example for exception handling here, Once that is done and documented (maybe in the change record?), we can and continue with the conversions :)
Comment #14Damien Tournoud CreditAttribution: Damien Tournoud commented
Just for reference, here is what I would like to see:
catch (BadResponseException $e) {
watchdog('aggregator', 'The feed from %site seems to be broken due to "%error".', array('%site' => $feed->title, '%error' => $e->getMessage()), WATCHDOG_WARNING);
drupal_set_message(t('The feed from %site seems to be broken because of error "%error".', array('%site' => $feed->title, '%error' => $e->getMessage())));
return FALSE;
Comment #15Berdir CreditAttribution: Berdir commented
Ok, did some tests with 3.1.0.
Started with:
catch (RequestException $e) {
watchdog('aggregator', 'The feed from %site seems to be broken due to "%error".', array('%site' => $feed->title, '%error' => $e->getMessage()), WATCHDOG_WARNING);
drupal_set_message(t('The feed from %site seems to be broken because of error "%error".', array('%site' => $feed->title, '%error' => $e->getMessage())));
return FALSE;
The feed from test seems to be broken because of error "[curl] 6: Couldn't resolve host 'bla' [url] http://bla/bla".
That's not extremely pretty but it works, contains all the relevant information and is not too long. And it doesn't die with afatal error like the current code ;)
- The feed from test seems to be broken because of error "Server error response [status code] 500 [reason phrase] 500 Service unavailable (with message) [url] http://d8/rss.xml [request] GET /rss.xml HTTP/1.1 Host: d8 User-Agent: Drupal (+http://drupal.org/) If-None-Match: 1358189147 If-Modified-Since: Mon, 14 Jan 2013 18:45:47 +0000 [response] HTTP/1.1 500 500 Service unavailable (with message) Date: Mon, 14 Jan 2013 18:46:52 GMT Server: Apache/2.2.22 (Ubuntu) X-Powered-By: PHP/5.3.10-1ubuntu3.4 X-Generator: Drupal 8 (http://drupal.org) Cache-Control: must-revalidate, no-cache, post-check=0, pre-check=0, private X-UA-Compatible: IE=edge,chrome=1 Content-language: en Last-Modified: Mon, 14 Jan 2013 18:46:52 +0000 ETag: "1358189212" Expires: Sun, 19 Nov 1978 05:00:00 GMT Vary: Accept-Encoding Connection: close Transfer-Encoding: chunked Content-Type: text/html; charset=UTF-8 <!DOCTYPE html PUBLIC "-//W3C//DTD XHTML 1.0 Strict//EN" "http://www.w3.org/TR/xhtml1/DTD/xhtml1-strict.dtd">   <meta charset="utf-8" /> <link rel="shortcut icon" href="http://d8/core/misc/favicon.ico" type="image/vnd.microsoft.icon" /> <meta name="Generator" content="Drupal 8 (http://drupal.org)" /> <title>Error | Drupal 8</title>
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Error
 The website has encountered an error. Please try again later.

Error message
 Drupal\Core\Database\DatabaseExceptionWrapper: SQLSTATE[42S02]: Base table or view not found: 1146 Table 'd8.nod' doesn't exist: SELECT n.nid AS nid, n.created AS created FROM {nod} n WHERE (n.promote = :db_condition_placeholder_0) AND (n.status = :db_condition_placeholder_1) ORDER BY n.created DESC LIMIT 10 OFFSET 0; Array ( [:db_condition_placeholder_0] => 1 [:db_condition_placeholder_1] => 1 ) in node_feed() (line 2105 of /home/berdir/Projekte/d8/core/modules/node/node.module).

    ".
Uhhh... that's a bit too much detail (Yes, I broke the db query to force a 500 server error;))
Ok, so let's try to make combine it with the current code:
catch (BadResponseException $e) {
$response = $e->getResponse();
watchdog('aggregator', 'The feed from %site seems to be broken due to "%error".', array('%site' => $feed->title, '%error' => $response->getStatusCode() . ' ' . $response->getReasonPhrase()), WATCHDOG_WARNING);
drupal_set_message(t('The feed from %site seems to be broken because of error "%error".', array('%site' => $feed->title, '%error' => $response->getStatusCode() . ' ' . $response->getReasonPhrase())));
return FALSE;
catch (RequestException $e) {
watchdog('aggregator', 'The feed from %site seems to be broken due to "%error".', array('%site' => $feed->title, '%error' => $e->getMessage()), WATCHDOG_WARNING);
drupal_set_message(t('The feed from %site seems to be broken because of error "%error".', array('%site' => $feed->title, '%error' => $e->getMessage())));
return FALSE;
Now I get for 500:
The feed from test seems to be broken because of error "500 500 Service unavailable (with message)".
Was confused for a moment because of the "500 500" but that's actually Drupal that does this :p
The question is, do we really want to *require* two catch blocks just to display or log a simple error message? In Drupal, we frequently use the term Developer Experience (DX) as a counter piece to UX and this is not really good DX :) I think we can do better, but I'm not quite sure myself what a good exception message for these two cases would be. Suggestions?
Comment #16mtdowling CreditAttribution: mtdowling commented
I personally don't see a problem with the verbose exception message. More information == easier to figure out how to fix the issue.
I also don't see a problem with two try/catch blocks. Exception handling is not, and IMO, should not be some universal implementation. It makes sense for this feed reader or whatever, but not for every other instance in Drupal 8 that uses Guzzle.
If you don't want the exception to look like that, then add a custom event listener that intercepts these exceptions. Using an event listener would allow you to throw an exception with whatever message you like.
For an example, check out the implementation in the AWS SDK for PHP: https://github.com/aws/aws-sdk-php/blob/master/src/Aws/Common/Exception/...
Comment #17Crell CreditAttribution: Crell commented
I'm inclined to agree with mtdowling. Good DX does not and should not mean "the developer never thinks about error handling". When you're dealing with network processing, there's a LOT that can go wrong you need to handle. Just be glad we aren't dealing with persistent connections you have to setup and then manually tear down. I did that in Java once and it was about 80% exception handling around all of the possible ways it could explode. :-)
Comment #18Berdir CreditAttribution: Berdir commented
|» Needs review
FAILED: [[SimpleTest]]: [MySQL] Unable to apply patch standard-exception-handling-1875792-18.patch. Unable to apply patch. See the log in the details link for more information. View
@mtdowling: That was the user interface message, presented to normal users which are just trying to add a feed url that they copied from somewhere.
@Crell: Well, yeah, everything requires a ton of exception handling in Java? :)
Here is a patch that fixes aggregator to do the minimally required exception handling right now + redirect url handling which was removed in the original patch.
All I'm saying is that the more complicated the exception handling is the more errors we'll see in contrib/custom land. As said before, even the initial patch for the aggregator conversion, authored and reviewed by people which know Guzzle resulted in a fatal error by adding an invalid URL through the UI. That, at least is now an uncatched exception so that you can see the error but that's not optimal either...
Comment #19Crell CreditAttribution: Crell commented
+++ b/core/modules/aggregator/lib/Drupal/aggregator/Plugin/aggregator/fetcher/DefaultFetcher.php
@@ -47,6 +48,12 @@ function fetch(&$feed) {
+ if ($response->getStatusCode() == 301 && $response->getPreviousResponse()) {
+ if ($location = $response->getPreviousResponse()->getLocation()) {
+ $feed->url = $location;
+ }
+ }
Do we need to save the feed in this case?
Looking it over again, is there a reason that BadResponseException's getMessage() method isn't what we're doing here anyway?
Comment #20Berdir CreditAttribution: Berdir commented
The feed is saved elsewhere, it is exactly the same logic as before the initial conversion, just accessing it in a different way.
Looking it over again, is there a reason that BadResponseException's getMessage() method isn't what we're doing here anyway?
That getMessage() is *not* the same as what we are doing is the whole point of this issue :) getMessage() gives you *everything*. A dump of the request and response objects, including the whole response body.
Comment #21Crell CreditAttribution: Crell commented
|Needs review
|» Reviewed & tested by the community
And now the veil lifts from my eyes! :-) Thanks, Berdir.
I think 2 exceptions is acceptable. If we find that's really a problem we can revise it later, but IIRC this was a blocker for some other "convert guzzle" issues, so let's move forward.
Comment #22webchick CreditAttribution: webchick commented
To my naïve eyes, this exception handling looks like basically the same code copy/pasted twice with only one or two slight variations, which normally we would try and reduce to one copy of the code, which I guess is the point of this issue. As a drive-by module developer, I'm not sure that I would think to "use" two different types of exceptions. I just want to know if something I did failed or not, and print out an error message when it happens, and move on with my life. However, the arguments from mtdowling and Crell seem in the opposite direction, and msonnabaum backs them up on IRC.
It does seem odd though that the error is printed completely differently depending on the exception.
$response->getStatusCode() . ' ' . $response->getReasonPhrase() in the case of BadResponseException and
$e->getMessage() in the case of RequestException. And apparently
$e->getMessage() on a BadResponseException returns enough data to crash a browser, whereas using it on a RequestException is hunky-dory? I dunno, smells fishy/inconsistent to me.
I guess I'll leave this for someone a bit more OOP-y like catch or Dries.
Comment #23Berdir CreditAttribution: Berdir commented
It does seem odd though that the error is printed completely differently depending on the exception. $response->getStatusCode() . ' ' . $response->getReasonPhrase() in the case of BadResponseException and $e->getMessage() in the case of RequestException. And apparently $e->getMessage() on a BadResponseException returns enough data to crash a browser, whereas using it on a RequestException is hunky-dory? I dunno, smells fishy/inconsistent to me.
That's pretty much exactly the response I expected from you and is what I'm thinking as well :)
This is also the reason the two different catch blocks are necessary at all. I still think there is a big difference in being able to react on different errors differently and having to do it, just because the way you need to handle the exception itself differently.
As @mtdowling explained above, we could change this within Drupal by adding a listener and converting the exception to another one. But I think Drupal 8 is about working together and improve the upstream projects instead of working around them :)
Comment #24mtdowling CreditAttribution: mtdowling commented
Let me know what changes you have in mind or send a PR. I'd be more than happy to take a look.
Comment #25YesCT CreditAttribution: YesCT commented
Comment #26YesCT CreditAttribution: YesCT commented
#1862538: Convert drupal_http_request usage in update.fetch.inc to Guzzle is suggested to wait on this
Comment #27catch CreditAttribution: catch commented
I agree with webchick and berdir on this, having the multiple catch blocks is just going to mean contrib/custom code ends up missing something, and having to access the error message differently is also going to be impossible to remember. I'm not really bothered by the verbose exception message though fwiw.
Leaving RTBC a bit longer - there's nothing wrong with the patch in itself but it'd be good if we could persuade mtdowling upstream and bring that in.
Comment #28Berdir CreditAttribution: Berdir commented
I think if we could shorten the default request/response object dump in the getMessage() (possibly remove the headers and response body) then the getMessage() might be fine.
I'll try to open a pull request in the next days.
Comment #29yched CreditAttribution: yched commented
Looking at #1887046: Convert drupal_http_request usage in install.core.inc to Guzzle. that just went in:
The client code is entirely unaware of Guzzle (you just do a drupal_container()->get('http_default_client') and work on it), yet handling errors is made by catching a Guzzle exception class - you thus need to "use" a Guzzle namespace at the top of the file.
Seems a bit weird that the only place where we hardcode a reference to Guzzle is to include a namespace for an exception ? Like, it feels swappable but not really is...
Comment #30Crell CreditAttribution: Crell commented
yched: I don't think we should really consider guzzle swappable. There was discussion elsewhere about renaming http_default_client to http_client, because really, it's the one core uses. You could always bring in your own PSR-0-ified library if you wanted to, but I don't think most people will have a reason to do so.
I agree it's a bit odd that the only literal class names come in for error handling, but that's a minor point and doesn't relate to swappability.
Comment #31Berdir CreditAttribution: Berdir commented
@yched: There might be no hard reference, but the code operates on the classes and interfaces defined by Guzzle. There are no generic interfaces, so it's not really possible to switch it out as another implementation would not be able to know what it has to provide.
I assume that #1875086: Improve DX of drupal_container()->get() will document Drupal::httpClient() (or however it will be called exactly) with a guzzle specific @return as we have nothing else to work with.
And yes, I agree that http_default_client should be renamed to just http_client, we had that discussion in the guzzle conversion issue. I think the default there doesn't imply that you can replace it with $OtherHttpClient but that it's the http client with our default configuration (like the user agent and the simpletest plugin that allows a request to operate within the same test) and you are free to define your own service with different plugins and so on. But removing the default doesn't prevent that in any way.
Edit: wrong issue link
Comment #32Berdir CreditAttribution: Berdir commented
Opened https://github.com/guzzle/guzzle/pull/225 to start the discussion.
With that change, the error message looks like this:
The feed from not found seems to be broken because of error "Client error response [status code] 404 [reason phrase] Not Found [url] http://d8/rs.xml".
Which IMHO is good enough. Still contains a bunch of techie stuff (curl, reason phrase and similar stuff that can't be translated) but I think this is comparable to the old error from 7.x:
The feed from not found seems to be broken, because of error "404 Not Found".
Comment #33webchick CreditAttribution: webchick commented
|Reviewed & tested by the community
|» Needs review
Moving out of the RTBC queue since it sounds like either way we'll need a small re-roll on this.
That error message seems comparable to me (I'm assuming the [stuff in brackets] doesn't actually show up?).
Comment #34Berdir CreditAttribution: Berdir commented
The pull request has been merged that removed request and response, thanks @mtdowling!
The [stuff in brackets] does show up. If we want to have a generic way to display the error, then I think we'll have to live with that. If not, then that means sticking with multiple catch blocks for the cases where we want it. Which is fine if we want that and the improved exception hierarchy gives us that possibility now.
My personal goal for this issue has been solved: Removing the *requirement* to have multiple catch blocks and/or having non-intuitive code to handle exception objects differently. It's pointless to make it a proper english string by default for example because there is no way to translate it and just "404 Not Found" is too short for a exception message. So the string above looks like a sane default to me.
The remaining question now is if we want to go with the patch form #18 *in this case* (which means it will look like it currently does in 7.x) or switch to a single catch block that will then look like the example from #32. It would IMHO be OK to have two catch blocks here for improved usability (not sure if users can make sense of it anyway ;))
Comment #35Crell CreditAttribution: Crell commented
I'd err on the side of the more user-useful error messaging. Plus, we have to resync our vendor libraries before we could do the combined approach anyway. :-)
Comment #36Berdir CreditAttribution: Berdir commented
I guess I agree. I think in that case the patch is ready and just needs to be RTBC'd.
It is currently blocking all other conversions because I think we should find an agreement here first, so.,..
Comment #37Crell CreditAttribution: Crell commented
Comment #39Crell CreditAttribution: Crell commented
|Needs work
|» Reviewed & tested by the community
Talked with Berdir in IRC. As of the latest Guzzle (we may need to resync the library through Composer, though), module developers can either have a single catch block and be happy, or have multiple catch blocks (as here) if they want to get more robust with their error handling. Up to them based on their specific case.
Assuming the bot still approves of the most recent patch, I'm going to go ahead and RTBC this. If for some reason it doesn't still apply, the bot will tell us.
Comment #40ParisLiakos CreditAttribution: ParisLiakos commented
|Reviewed & tested by the community
|» Needs work
needs reroll
Comment #41Berdir CreditAttribution: Berdir commented
|Needs work
|» Needs review
PASSED: [[SimpleTest]]: [MySQL] 52,219 pass(es). View
Yep, it's $feed->label() now, yay! ;)
Comment #42Berdir CreditAttribution: Berdir commented
PASSED: [[SimpleTest]]: [MySQL] 52,257 pass(es). View
FAILED: [[SimpleTest]]: [MySQL] 52,235 pass(es), 2 fail(s), and 0 exception(s). View
Ok, fixed the url assignment as well.
Also wrote tests for both the curl exception and the redirect handling (those were tough ones for a late sunday night) and noticed that the 301 handling was actually wrong, fixed that.
Comment #43Berdir CreditAttribution: Berdir commented
PASSED: [[SimpleTest]]: [MySQL] 52,270 pass(es). View
Grml missed an endling newline.
Comment #44ParisLiakos CreditAttribution: ParisLiakos commented
|Needs review
|» Reviewed & tested by the community
|461 bytes
PASSED: [[SimpleTest]]: [MySQL] 52,245 pass(es). View
extra tests for aggregator yay! thanks berdir:)
there is just one minor indentation issue, everything else looks good..
lets get rid of that nasty CURL exception shall we?
Comment #45Berdir CreditAttribution: Berdir commented
Comment #46webchick CreditAttribution: webchick commented
|Reviewed & tested by the community
|» Needs work
No longer applies. :(
Comment #47ParisLiakos CreditAttribution: ParisLiakos commented
|Needs work
|» Reviewed & tested by the community
PASSED: [[SimpleTest]]: [MySQL] 53,028 pass(es). View
manually edited:)
Comment #48webchick CreditAttribution: webchick commented
|Reviewed & tested by the community
|» Fixed
Well, apparently bot likes it, so.. :)
Committed and pushed to 8.x. Thanks!
Comment #49ParisLiakos CreditAttribution: ParisLiakos commented
|» Reviewed & tested by the community
not pushed:)
Comment #50webchick CreditAttribution: webchick commented
|Reviewed & tested by the community
|» Fixed
$ git push
ssh: connect to host git.drupal.org port 22: Operation timed out
fatal: The remote end hung up unexpectedly
NOW pushed. :P Thanks.
Comment #51yched CreditAttribution: yched commented
|» Needs work
Minor :
+++ b/core/modules/aggregator/lib/Drupal/aggregator/Plugin/aggregator/fetcher/DefaultFetcher.phpundefined
@@ -48,6 +49,12 @@ function fetch(Feed $feed) {
+ if ($previous_response = $response->getPreviousResponse()) {
+ if ($previous_response->getStatusCode() == 301 && $location = $response->getPreviousResponse()->getLocation()) {
+ $feed->url->value = $location;
Shouldn't that be $location = $previous_response->getLocation() ?
15 days to next Drupal core point release.
Comment #52yched CreditAttribution: yched commented
|Needs work
|» Fixed
Did not intend to change status though.
Comment #53ParisLiakos CreditAttribution: ParisLiakos commented
|» Needs review
|887 bytes
PASSED: [[SimpleTest]]: [MySQL] 53,034 pass(es). View
good point:)
Comment #54Crell CreditAttribution: Crell commented
|Needs review
|» Reviewed & tested by the community
Comment #55Dries CreditAttribution: Dries commented
|Reviewed & tested by the community
|» Fixed
Committed to 8.x. Thanks.


text:
Zozo Pixie Cables by Amanda Keeys
Welcome! You are browsing as a guestWould you like to see 161 projects made from this pattern and much more? create a free account What am I missing?
© Amanda Keeys
© Natknitz
© mskeeys
© tddurand
© Amanda Keeys
© apriljoys
© jennaro11
© mumsbusycrafting
Zozo Pixie Cables
This pattern is available for $6.00 USD
buy it now or visit pattern website
buy it now or visit pattern website
A cute little pixie hood bound to delight. Easy cables and a simple shape make it a quick and satisfying knit. The magic happens when you pick up stitches for the ribbed band and you see the pixie point just pop right up!
For more information, see: http://blog.amandakeeysphotography.com/?p=1299


text:
Perfect for those chilly transitional months, this relaxed wrap coat accommodates your growing silhouette but the self-tie belt still gives you a silhouette. $299, IsabellaOliver.com
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Edgy maternity wear — never thought you'd see that? This drape-y leather jacket with copper detailing is the answer. It's a classic you'll wear long after you give birth. $365, IsabellaOliver.com
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Plus, more from The Bump:
Red-Hot Looks to Heat Up Your Winter Wardrobe
9 Need-to-Have Trends This Season
How to Get the Maternity Wardrobe of Your Dreams (Without Spending a Fortune)


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I am the AC who wrote that vision I had when I was 15. I tuned 44 today. So it begins. Does anyone have any questions or need any encouragement?
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GET over it Jhonno.
You are NOT God OK.
Anonymous Coward 18137766
All whom saith I am not God have the devil speaking through them, time reveals all things ye shall one day know the truth, repent all has spoken against before the woes come upon ye. It had been better thou had never spoken to me for the accountability is greater for all those given the WORD.
Know that I know not bruce he got mine name from the declaration I gave the world in which I did sign mine human name which in translation means Gift from God 'For God gave his only begotten Son' but this is coded and done for a reason for a time we did not want the world to know we are God, we sought to see if they would reject us if were seen as a Son. Ye acts like he is someone I know personally this is not true he knows not me and he is the one whom is mentally unstable and those whom have seen his postings would agree.
Spiritoftruth111 33441012
Listen Jonnathan.
I know who you are,,what your problems are..AS I stated from the start.
I KNOW you have been and are going through so really weird things.
I KNOW its also a game with you as well..a type of trolliing you just cant resist.
So here is something for you to think about.
I DARE you to watch this vid.
There is a message there JUSt for you.
Anonymous Coward 18137766
Ye know not me or would not speak against me, the final test for mankind is the truth whom can swallow their pride and humble themselves to receive. I saith unto ye it is people whom condemn themselves by denying the truth. Why would I say the things I have knowing if it be not true I would be condemned to Hell, thou not understand that I have no doubt 100% whom I am now and have had witness of it but why should I tell people why I know, in time they shall see many shall judge for it is written they will but later they humble themselves are saved. This is no Game if you had seen things I have seen and remember the things I remember you would do same as I, for world must now know that God is real for end is almost here and the Consumer draws closer, it is not a fate I wish on any.
I will be seen coming in the clouds in great glory I have not said I wont be what mankind didn't know is that I actually arisen from Hell and came as a true Son of Man and had to overcome the human experience and I am about to finish this and when I do tribulation will begin. The process began at age of 30 that is when the Heavens contacted me it was all planned from the beginning, the two witnesses which are spoken in Revelation 11 I know them personally we have been lead to one another, they shall be my main representatives in Israel after I have gone for I must ascend first so end can come, they are witnessing how I overcame all.
If you must know my pours even began to bleed as the cup is being overcome and soon to be given back to world, what mankind don't understand is the cup gave them longer, by my baring the cup and descending below all I have suffered the consequences of peoples evil so they may avoid judgement but time is coming that I shall no longer endure it for a time was appointed it would be given back and I would ascend and break the chains of time, ye will understand when I do this for it will impact the dimension and events will occur that mankind has never seen before.
I truly am the Almighty God and there is things I cant talk about underway for it is not for the public to know, the Adversary is well aware that I am awakening and has gone to great lengths to try stop it but it is to late, it already begun and he knows it. He may even try to use the weapons of man against me but he shall not prevail, world war is part of the future to come but much more is going to occur. When the cup is given back to mankind all manner of disasters, diseases, plagues and events will take place, for the cup is like a magnetic for woe. Indeed there will be impacts of objects from space and new diseases shall come, but far worse is coming changes in creatures mutations turning them hostile against mankind, that is part of the time of the fowls.
Spiritoftruth111 33441012
Yes yes Jonnathan.
We all know that dooms are coming. In fact you have taken every word of warning I have given and proclaimed them as your own and then twisted them up into some sort of demonic new age mish mash of subtle trickery. You do not have an original thought in your head or hear from the Lord, so you take the words of those who DO, to try to win recognition for your delusions by adding TO them your own person spin and demonic lies.
Every post you have ever done has been a spirtual THEFT..and whats worse you blaspheme God and bring reproach on his name by CLAIMING to actually BE him when all along you are lying and stealing and refusing any sort of correction at all..either done IN love or in sterness.
You have hardened you heart to gain recognition for your own lies..and satans lies.
You have no idea whats ahead...you just borrow words from others and make them out to be YOURS or the LORDS...and this is EVIL.
WHEN are you going to make a STAND against that foul spirit that controlls you John?
Its up to you really..I know you have had your heart twisted up with schtizophrenia and such..I lived with a schitzophrenic for three years..I KNOW what they are like and how utterly convinced they are over their "Voices" and delusions.
But that man is fine now and recovering and really loves the Lord with all His heart...because I kept trying to help him..as I will you.
The more you keep coming here to this thread..the more help you will get.
Sometimes I will be stern with you..other times..speak with gentle words..but either way..your barriers WILL COME DOWN..because I am addressing NOT just you..but that evil spirit that seeks to make itself LIKE the most high.
So..keep coming back..your demonically inspired words have NO effect on me..because I see them for what they are.
Deep down..under the delusion..you KNOW who you are..but pride..and pain..and the need to be noticed always win out.
Pride BREEDS pain..and pain breeds pride..so you speak..and allow that spirit TO speak..to cover the agony you feel deep within as you battle inside.
Just put an END to this demon John..YOU have authority OVER it...and if you stand against it..yes..it will go nuts on ya..but thats because demons HATE truth and dont like having their lies exposed.
And with each and every post you do from now on..I WILL expose the lies this thing tells through you.
Until YOU take up the fight yourself..I WILL stand in the gap for you..and help you defeat this evil thing.
So get ready for a battle..your heart is at stake..as is your TRUE calling.
I AM your friend..and a true friend TELLS the truth to his brothers..and I will withhold NO truth from you OR that entity that seeks to be GOD.
YESHUAH is the TRUTH...and with HIS word..satan WILL be defeated IN you and cast out.
I cannot sit idly by and watch a brother get devoured like this.
So..I will fight..and battle FOR you..AS the lord leads..and together..that thing in you will flee.
You ready?
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One Is Curious: Tom Hardy to Play Elton John in Biopic
I…don't see the resemblance, but then again I was pleasantly surprised when Michael Douglas transformed into music's most flamboyant artist.
Entertainment Weekly reports that Tom Hardy will play Elton John in the musician's upcoming biopic, Rocketman.
The film will cover John's childhood through his career, with re-recorded hits from the man himself "to match emotional moments in the film."
Hardy well-known for being an comedic and dramatic actor. His resume includes This Means War to The Dark Knight Rises, and he is a dreamboat from Great Britain.
He also did this once.
Can he do it? Yes he can!


text:
GENEALOGY-DNA-L ArchivesArchiver > GENEALOGY-DNA > 2003-11 > 1068057220
From: David Faux <>
Subject: Re: [DNA] Celtic haplogroups
Date: Wed, 5 Nov 2003 10:33:40 -0800 (PST)
In-Reply-To: <firstname.lastname@example.com>
I think that this "abuse" of the DNA data by Oxford Ancestors infuriates many of us. There is no way they can in all honesty say anything about one's haplotype in relation to the "tribes" of Britain except that R1a is Norse Viking if found in someone whose ancestry is traced to the British Isles. Haplogroup I is one of the "invader" groups (gee, that's helpful) which could mean Anglo - Saxon or Danish Viking. With R1b, although found among the Norse Vikings, and the "invaders" (but at somewhat lower percentages) they are going to tell you that you are "Celtic", "Ancient Briton" or the like. This is plainly dishonest. Besides, they only measure 10 markers, and any conclusions they make about your "tribal affiliation" must be taken with a grain of salt in that they do not have a database with those who have had SNP testing to determine their haplogroup. They are in effect guessing. And it is going to cost you about $50USD in addition to the regular testing cost - which !
astronomical considering that you will only get results for 10 markers!
David F.
Oxford Ancestors has told me that my Brown y-chromosome line is descended
from the ancient Celtic tribes of Britain. Are there any haplogroups connected
to the Celts? Connee
Dr. David K. Faux, P.O. Box 192, Seal Beach, CA, 90740, USA
This thread:
|Re: [DNA] Celtic haplogroups by David Faux <>


text:
This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
Immunotoxins and antibody-drug conjugates are protein-based drugs combining a target-specific binding domain with a cytotoxic domain. Such compounds are potentially therapeutic against diseases including cancer, and several clinical trials have shown encouraging results. Although the targeted elimination of malignant cells is an elegant concept, there are numerous practical challenges that limit conjugates' therapeutic use, including inefficient cellular uptake, low cytotoxicity, and off-target effects. During the preparation of immunoconjugates by chemical synthesis, the choice of the hinge component joining the two building blocks is of paramount importance: the conjugate must remain stable
Cancer is becoming the most frequent cause of death in most developed countries, and in particular the incidence of this disease among women is increasing dramatically. In the US, the estimated number of new cancer cases was above 1.5 million in 2010, with a mortality rate accounting for 23% of total deaths in the USA [
Hundreds of approaches and strategies have been developed, and others (such as nanotechnology, pharmacogenomics,
Conjugation of cytotoxic agents with macromolecules improves the pharmacokinetic profile, by decreasing the volume of distribution and prolonging the distribution and elimination phases [
Although some proteins can specifically deliver the linked drug to the affected area, only monoclonal antibodies (mAbs) possess perfect suitability in terms of selectivity and flexibility. Indeed, the recent successful development of monoclonal antibodies that target key components of biological pathways has expanded the range of treatment options for patients with several cancers.
Antibody-based therapeutics are of growing significance in cancer therapy, as evidenced by the fact that 28 such drugs have now been approved for oncologic indications by the FDA, for marketing in the USA. Among them, eight had global market revenues of above US $1 billion, and the combined global revenues of all exceed US $50 billion [
Despite the clinical success of therapeutic mAbs, naked antibodies, targeting cell surface tumor antigens expressed on carcinomas, are rarely curative of themselves, and most are administered in combination with chemotherapy. Antibodies alone have shown some success in extending the lives of cancer patients, but in many cases more potent agents are required to attempt complete eradication of the cancer mass. Many different agents have been conjugated, including traditional anticancer agents, cytotoxic natural products, phytotoxins, radioisotopes, bioactive proteins, enzymes that activate prodrugs of cytotoxic agents, and photosensitizers. In order to exploit the maximal effect, the inherent potency of the released drug must be sufficient to kill the tumor cell, even at low concentrations. To achieve significant cytotoxicity, very potent agents must be used. The suitable candidate as immunoconjugate payload is thus a compound that is too toxic for use as stand-alone chemotherapeutic.
To achieve an improvement selective potency, the conjugate should preferentially release the active agent in or around the tumor tissue. Thus the following components are essential: a targeting agent, a biodegradable linkage, and a bioactive potent anticancer agent. Several aspects of the rational design of active conjugates may be of interest. The mAb must be selected taking into account both its stability and its capability to be derivatized with drugs or toxins without losing activity and specificity, but must also consider the antigen target and its pathway. This is challenging, because antigen targets on cell surfaces are often present in limited numbers, and the internalization process for antigen-antibody complexes is frequently inefficient. An example of 'ideal' antigen is represented by HER2 (the target of T–DM1, see below). It is expressed in millions of copies on an HER2-positive cancer cell, whereas other tissues express low levels of HER2. It is internalized fairly quickly and, also very important, it does not get downregulated [
Another important aspect is the balance between mAb modification due to chemical processes and the molar loading of the drug, which can be tuned to achieve the desired potency. However, one of the major limiting factor in delivering is related to the repeated courses of therapy and the development of host immune responses to both the mAb and the toxin. For this reason, an extent of drug substitution, commonly 2–4 drugs per antibody, or a ratio of 1:1 for conjugate toxins, provides the best therapeutic window. The role of the linker is of fundamental importance, because, in addition to delivery efficiency, the stability of the drug to mAb linkage is a key factor in determining therapeutic potential [
Theoretically, with an antibody-drug conjugate, activation of the free drug can occur either intracellularly or extracellularly. Several strategies have been developed to selectively release the therapeutic agent from a conjugate. The principal mechanisms involve the use of spacers that are cleavable by proteolysis of enzymes overexpressed in the tumor tissue, or of acid-sensitive linkages cleavable under the acidic conditions present in tumors, endosomes, and lysosomes [
Immunotoxins are protein-based therapeutics comprising at least two functional domains, one allowing them to bind specific target cells, and one that kills the cells following internalization. ITs were first postulated by Paul Ehrlich 100 years ago, and were envisaged as "magic bullets". They became a reality following the development of monoclonal antibody technology, which provided the necessary targeting specificity. Immunotoxins have been armed with selected extremely-potent microbial and plant products. The majority of these toxins belong to the group of ribosome-inactivating proteins (RIPs).
Plants and fungi produce a number of molecules with defensive functions, to protect themselves against pathogens, such as microorganisms, and predators, such as insects. These defense proteins include ribosome-inactivating proteins, which are capable of inhibiting RNA translation. A broad spectrum of activities, encompassing antiproliferative, antitumor, immunomodulatory, antiviral, antifungal and anti-insect activities, have been attributed to these proteins. Recently, several reviews have appeared [
Type II RIPs have been isolated from plants belonging to the Asteridae, Liliidae, Magnoliidae and Rosidae, the bulk belonging to the Asteridae [
Type I RIPs have been isolated, most often from seeds and sometimes from leaves and roots of plants belonging to the Asteridae, Caryophyllidae, Liliidae, Magnoliidae, and Rosidae, the greatest number being isolated from the Rosidae, which comprises Cucurbitacea, Euphorbiaceae and Fabaceae [
In the last twenty years, RIPs of new structure have been isolated from flowering plants and mushrooms [
Type I RIPs with small molecular mass have been isolated from plants both in the Cucurbitaceae family and outside it [
Several of the above-mentioned RIPs have been used for the synthesis of immunotoxins [
From the historical viewpoint, the evolution of approaches to constructing ITs may be subdivided into three stages. First-generation ITs were prepared by chemically linking to an antibody the whole molecule of a toxin, such as ricin, abrin, DT or PE. They were prepared by chemically conjugating antibodies to natural-intact toxin units or to toxins with attenuated cell binding capability (
Structure of immunotoxins (IT) constructs obtained by chemical (A– intact IgG mAb, B– Fab' fragment) and genetic engineering (C– Fab fragment, D– Fv fragment) procedures. TX as for toxin or fragment; white rectangles = constant regions, black rectangle = variable region of mAb chains; curvy linkage = peptide bond, –SS– = disulfide bond.
Originally, antibodies were chemically conjugated through a disulfide bond, either to the whole toxin (holotoxins) or to their catalytic subunits (A chain), each of which had been removed from its binding domain by reduction. Many type I RIP have also been used to synthesize ITs; these toxins include gelonin, saporin, pokeweed antiviral protein (PAP), bryodin, bouganin, momordin, dianthin, momorcochin, trichokirin, luffin, restrictocin, mitogillin, alpha-sarcin, Onconase, pancreatic ribonuclease, Bax, eosinophil-derived neurotoxin, and angiogenin. Among these, gelonin, saporin, momordin, PAP-s, and above all, ricin A chain were widely used to produce highly-active ITs, potentially avoiding aspecific toxicity [
Chemical conjugates generally involve either reducible disulfide (S–S) or nonreducible thioether (S–C) bonds. A thioether bond is appropriate if the ligand is conjugated to a bacterial toxin in the part that does not translocate to the cytosol, such as the binding domain [
Scheme of reaction for synthesis of ITs. X = reacting group toward amino acid terminus; Y = H or alkyl, aryl group; M and L = leaving groups, stable in buffer but reactive in thiol-disulfide exchange; A and B = chains of RIP II toxins.
One key aspect in creating an IT is that the linkage should be cleaved intracellularly, so as to regenerate the original active agent or a derivative of it, affording the cytotoxic action in full but, at the same time, conjugates must be stable
Residues present on proteins involved in coupling with a crosslinker include primary amines, sulphydryls, carbonyls, carbohydrates and carboxylic acids. Conjugate preparation requires a separate derivatization of toxin and carrier with the linkers. Then, after purification, the newly-inserted group can react with those linked on the other IT component, to produce a stable and homogeneous conjugate population (
Different derivatizing approaches have been developed based on a covalent linkage. Several classes of crosslinking reagents have been synthesized, with the aim of improving the characteristics of the conjugates. Many factors must be evaluated in selecting an appropriate crosslinking reagent, including the existing groups present in the carrier or toxin, and the introduction of special reactive groups into agents. One important point to take into account is that the linkage method must be selected so as to avoid both the formation of homopolymers of antibody or agent, and aggregation of the conjugate.
One of the first and most important heterobifunctional linkers is SPDP [
Scheme of heterobifunctional linkers used in conjugate preparations MBS, SPDP, SATA, 2-IT (2-iminothiolane) and linkers with improved hindrance around disulfide linkage. SMPT alpha-alkyl derivatives, SulfoNHS-ATMBA (Sulfosuccinimidyl
Other extensively-employed cross-linkers are SATA, [
In order to maintain the positive charge of lysyl groups also in the derivatized toxin, and thus to preserve their potency, reactives such as 2-iminothiolane (2-IT) or AMPT/CDPT have been used [
Attempts to increase
As widely employed in prodrug approach, acid cleavable cross-linking reagents were also proposed for an efficient toxin release into endosomes and then in cytosol, avoiding translocation of the toxin into lysosomes and consequently complete denaturation. Blättler and colleagues described a heterobifunctional agent, which introduced a
The most commonly-employed type I RIP for ITs of clinical interest is ricin, because of its high cytotoxicity and low immunogenicity in man. Significant steps in the evolution of ITs have involved the use of deglycosylated RTA. However, several attempts have been made to maintain the high toxic potency of ricin, by reducing the non-specificity due to the presence of the B-chain. Thorpe
Another extremely interesting approach is based on blockage of the B chain lectin binding ability; this was developed by Lambert (Immunogen). A glycopeptide containing a triantennary
Scheme of preparation of blocked ricin. A triantennary
The removal of nonspecific binding elements (B-chain in ricin/abrin) gave rise to the next generation of chemical conjugates, and broadened clinical applications. Immunotoxins were produced in a similar fashion, but thanks to the improved understanding of the structure and function of toxins, cell-binding domains were removed, and the resulting toxin fragment was targeted by coupling to an antibody. These ITs were also based on chemical conjugation between targeting moiety and toxin, and involved saporin, gelonin, PAP and deglycosylated RTA (dgA). Even without its binding domain, however, the ricin A chain is taken up non-specifically by macrophages and hepatic nonparenchymal Kupffer cells. This uptake is due to glycosylated side residues binding to mannose receptors on the liver. The most successful technique for reducing nonspecific uptake of the ricin A chain is through chemical deglycosylation [
ITs containing dgA may be prepared by coupling the cysteinyl residue of deglycosylated ricin A-chain with the heterobifunctional crosslinker SMPT, that has previously been linked to mAb [
Diphtheria toxin (DT) is a 62 kDa protein secreted by
PE genetic excisions have concerned the domain Ia, generating a product termed PE 40, which retains its translocation function and protein synthesis inhibition properties, but does not kill human cells. A further genetically-engineered PE molecule (PE38KDEL) has been constructed by removing the disulfide bridge, and changing the carboxyl end of PE (KDEL) to increase its cytotoxic activity [
Other modern constructs are represented by single-chain anti-Tac(Fv)-PE38 (LMB-2) that contains the variable heavy domain (VH) of an anti-Tac mAb fused via a peptide linker (G4S3) to the variable light domain (VL), which in turn is fused to PE38. On the other hand, the recombinant IT BL22 contains a disulfide bond connecting VL and VH by two inserted cysteine residues [
Several immunotoxins have been successfully tested in clinical trials for different purposes, and in particular in hematologic tumors. Anti-CD5 and anti-CD7, linked either to ricin or to chain A of ricin, have been used to eliminate contaminating tumor cells in autologous bone-marrow transplantants, and in acute graft
Another factor influencing efficacy is immunogenicity: patients with antitoxin antibodies clear immunotoxins rapidly from the bloodstream. Since most people are immunized with DT, there is a significant pretreatment antibody titer in the blood of many patients, and an anamnestic response occurs in additional patients who have been treated with DT conjugates. Toxins that are foreign antigens to which a patient has not been previously exposed are of intermediate immunogenicity.
Another relevant aspect concerns the limits of the random-based derivatization approach. Although more specific, and thus better tolerated, most ITs are still chemically heterogeneous, and their large size hinders them from penetrating solid tumors. Moreover, some immunotoxins still bind weakly to normal cells, and produce an undesirable side effect known as vascular leak syndrome. To address these issues, a new generation of ITs was conceived and produced in the form of recombinant proteins. More successful IT design has employed genetic engineering, in which an amide bond, with or without a linker peptide, connects the mAb or its fragment to the toxin. Such fusions are more successful when both the receptor affinity and toxin domain functions can be preserved.
In the last eight years, using recombinant DNA techniques and the principles of protein engineering, ITs have been designed to contain only the elements required to recognize and kill the tumor cells. In particular, the remodeled agents of this generation are not only better at binding to receptors, but also at overcoming two major hurdles: toxicity and immunogenicity [
Further improvement was presented by Keller
Another way to target toxins to cells is to replace the cell-binding domain with a growth factor or a cytokine. The promising
Immunotoxins in current status of clinical trials. Data from Thompson Pharma Partnering database and Clinicaltrials(March 2011), UTSMC—University of Texas Southwestern Medical Center.
|Hairy Cell Leukemia, B-CLL, NHL
|NHL, leukemias
|Targa Ther.
|Solid ca.
|Ivax Corp.
|Solid ca
|Breast ca
|Cintredekin besudotox
|Brain ca
First-generation antibody-drug conjugates involved the use of anticancer drugs in clinical use (see reviews by Chari
Examples of linker moieties.
In the early development phase, methotrexate, daunorubicin, the Vinca alkaloids, mitomycin C, idarubicin and
The use of these kinds of linkages (disulfide and hydrazone) deserves to be mentioned for its role in other relevant targeted approaches. Regarding doxorubicin, the maleimidocaproylhydrazone derivative (INNO-206) gave important results when administered as a prodrug, which could self-link to plasma albumin [
Examples of drug-linked conjugates with hydrazo bonds: (
The clinical results of the first-generation ADC were unsatisfactory, and, the reasons for these disappointing outcomes may be related to the early technological stage of the mAb in question (immune response, inefficient internalization), the lack of cytotoxic potency of the anticancer drug used, and to inefficient or premature release of the drug from the carrier. Premature drug release results in low specificity, low potency and an increase in the ADCs side effects.
Several reasons underlie the important results now being demonstrated by six second generation ADCs now in advanced clinical trials. Firstly, over the last 15 years, mAb technology has benefited from impressive improvements, and nine humanized or chimeric mAbs are now on the market for oncological use. The antibodies have been carefully chosen to improve selective binding to tumor tissue and to reduce cross-reactivity with healthy tissues. High avidity (Kd of 0.1 nm) in tumor binding has been reached.
Furthermore, antibodies have been identified to antigens with high expression on the cell surface. For example, HER2 (one of the antigens employed formerly) presents favorable characteristics, namely high expression on HER2-positive cancer cells, rapid internalization, and no down-regulation.
The second important component of an ADC with improved action has been the selection of highly potent cytotoxic drugs. As yet, the laboratories of the main industries involved in ADC manufacturing (Immunogen, Seattle Genetics, Roche, Sanofi-Aventis, Pfizer) have selected only a few compounds,
The third component in modern ADC synthesis is the conjugation process itself. This has been improved in terms of linker/spacer moiety, conjugation specific site, and stoichiometry. The conjugation process should theoretically maintain the mAb and drug components in their native forms, and the product must remain intact during storage in aqueous solution or during the lyophilization/sterilization process, to allow convenient formulations. Furthermore, from the pharmaceutical development standpoint, the conjugation process must produce homogeneous batches and must be scalable, in order to satisfy the regulatory authorities. Several types of cleavable linkers have been evaluated, and the related approaches and evolution will be addressed below.
Regarding the mAb component, there are three common reactions for conjugation: alkylation of reduced interchain disulfides, acylation of lysines, and alkylation of genetically-engineered cysteines. Because up to 100 lysines are available for acylation on one IgG1, conjugation to these sites results in heterogeneous mixtures. Eight interchain cysteines are available, and thus conjugates with a greater degree of uniformity than those based on lysine [
In some instances, it has been observed that the location of the conjugated drug is not as important as the stoichiometry of drug attachment [
The strategy concerning the toxic moiety and its ability to maintain high activity after derivatization requires an in-depth understanding of the organic-chemistry aspects of the process. Before illustrating the different synthetic approaches, it is necessary to have a clear view of the principal classes of toxic moiety.
Early clinical trials of maytansinoids initiated by the NCI in 1975, and their pre-clinical and phase I results prior to 1980, were summarized by Issel and Crooke [
In the early 1990s, Takeda filed patents concerning the preparation of ADC using bispecific mAbs reactive to ansamitocins and to human transferrin receptors, that demonstrated effective activity in suppressing xenografted mouse tumor [
The ImmunoGen group took a chemical synthesis approach, which has led to the development of a number of conjugates [
Although, as reported by Cassady [
Some features of structure-activity relationship of Maytansine.
The synthetic route to conveniently attain maytansine-analogues capable of being linked to mAbs started from ansamitocins obtained from fermentation of the microorganism
Because the C3 ester group in maytansinoids is susceptible to elimination under mild basic conditions (pH > 9) giving the alpha-beta-unsaturated maytansinoid maysine, ester hydrolysis through a reductive cleavage process is employed. Initially, lithium aluminum hydride was used to give the C-3 alcohol maytansinol [
After reductive cleavage of DM1 with dithiothreitol, the resulting thiol was widely conjugated to a variety of mAbs, including those directed against HER-2 and transferrin, [
As described, this method have been used with success, but in order to increase the conjugate's
Synthesis of Maytansinoid-mAb conjugates.
Maytansinoid conjugates with improved pharmacokinetics.
As mentioned above, the choice of disulfide bond release is an approach frequently employed in IT synthesis. This release is attributed to the high intracellular concentration of glutathione, a thiol-containing tripeptide present in micromolar concentrations in the blood, whereas its concentration in the cytoplasm is in the millimolar range (up to 1000 times higher). This is especially true for tumor cells, in which irregular blood flow leads to a hypoxic state, resulting in enhanced activity of reductive enzymes, and therefore even higher glutathione concentrations [
When tested in cytotoxicity trials, L-aminoacyl maytansinoid bearing a methyldithio-propanoyl substituent in the C3 ester side chain was found to be equally potent as maytansine. Furthermore, maytansinoids bearing sterically-hindered thiols were 3- to 12-fold more potent than un-hindered thiol derivatives. When tested in colon tumor xenograft models established in mice with COLO 205 cells, the ADC obtained with different disulfide hindrance showed different activities.
Another preclinical study, in which trastuzumab was conjugated by mean of different linking systems to DM1, DM3 and DM4, reports results that are in contrast to these findings [
Model of metabolism and activation, of maytansine conjugates in a targeted cell. The number is referred to an IC50 value of maytansine derivatives on COLO205 cell line (given as an example).
Erikson [
DM1-mAb conjugate with hydrophilic spacer.
The results of trials of anti-EpCAM–PEG4-Mal–DM1 showed it to possess marked activity, not only on COLO 205 cells xenografted in mice, but also on a clone expressing a functional MDR1 pump, denoted COLO 205MDR, selected by culturing the cells in a medium containing paclitaxel. A single administered dose of 680 μg/kg as DM1 maintained the animals growth-free for 100 days after the implant. The group hypothesized that, although the metabolite, lysine-PEG Mal-DM1 was ∼8-fold less cytotoxic than the more lipophilic lysine-SMCC-DM1, mechanisms such as increased tubulin binding, inhibition of MDR1-mediated efflux, may play crucial roles in explaining the conjugate's potency.
On the basis of promising preclinical results, several DM4 conjugates are now in advanced clinical trials. BT-062-SPDB-DM4 is in phase 2 trials for multiple myeloma [
Dolastatins are natural cytotoxic pseudopeptides extracted from the marine shell-less mollusk
Different linking strategies have been evaluated, essentially employing two derivatization points of AE (starting from the left,
Structure of auristatins (R=CH3) and monomethylauristatins (R=H).
Acid-labile linkers, containing hydrazone functionalities as the cleavable moiety, were formed at the
Structure of Auristatin E and MMAE conjugates. The wavy lines indicate the site of hydrolysis (enzymatic or pH-dependent).
More recently, Doronina [
Several ADCs containing auristatin are now in clinical trial; these are, from Seattle Genetics, Brentuximab vedotin (SGN-35) where an anti-CD30 monoclonal antibody (cAC10) is linked to Val-Cit-MMAE, SGN-75 composed by the anti-CD70 mAb 1F6 linked to Val-Cit-MMAF (phase I); from Celldex Ther. the conjugate glembatumumab, directed to melanoma antigen glycoprotein NMB, with Val-Cit-MMAE (CDX-011) (phase II) [
In order to obtain linkers that can be efficiently and selectively cleaved intracellularly, maintaining a good
ADC composed of a glucuronidase activating linker (1) and the release mechanism.
The calicheamicins (also known as LL-E33288 antibiotics), produced by
Calicheamicin gamma 1 (
Structure of Calicheamicin gamma 1.
The aglycon is a rigid, highly-functionalized bicyclic core in which the enediyne moiety is locked within a rigid 10-member bridging ring awaiting activation. Also forming part of the aglycon is an allylic trisulfide, which serves as a trigger: when a nucleophile (e.g., glutathione) attacks the central sulfur atom of the trisulfide group, it causes a significant change in the structural geometry, which imposes considerable strain on the 10-member enediyne ring. This strain is completely relieved by the enediyne's undergoing the cycloaromatization reaction, generating the highly-reactive 1,4-benzenoid diradical, that eventually leads to DNA cleavage [
Mechanism of DNA cleavage by calicheamicin.
A series of conjugates of calicheamicins with the CTM01 anti-MUC1 antibody has been reported [
Structure of
In most preclinical models, the hydrazone linkage produces ADCs with higher potency than the corresponding amide-bearing conjugate, providing evidence that, with anti-CD33 mAb, the disulfide alone is insufficient for efficient release of the drug in the target cell. Interestingly, with the murine mAb CTM01 (recognizing the MUC1 antigen present on a broad spectrum of solid tumors of epithelial origin), amide-bearing ADC showed activities equal to or even greater than that of the corresponding hydrazone conjugate, in several
Mylotarg enjoyed limited successes (and was withdrawn from the market in 2010) due to a narrow therapeutic window and lack of target-dependence. The linker technology based on a pH-dependent release mechanism is probably not sufficiently stable, and too much of the drug is released in the bloodstream; pharmacokinetic data have shown that the mean half-life of Mylotarg is 72 h [
Regarding the role of production of more homogeneous batches of ADC, one of the key points is selectivity of the linkage insertion on the mAb molecule. As reported above, cytotoxic drugs are generally conjugated to antibodies either through lysine side-chain amines or through cysteine sulfhydryl groups activated by reducing interchain disulfide bonds. Both of these procedures yield of heterogeneous products, containing a mixtures of species with different molar ratios of drug linked to the antibody. Junutula pointed out the role of molecular biology in improving ADC using mAbs containing engineered cysteine residues for site-specific conjugation [
In order to increase potency (as described above) and pharmacokinetic profile, thereby reducing systemic toxicity, a hydrophilic spacer and two non-reducible thioether linkages were applied. In this case, the homobifunctional reagent bis-maleimido-trioxyethylene glycol (BMPEO) was employed, reacted firstly with DM1, then with thio-trastuzumab (
Scheme of specific insertion points on thio-trastuzumab and structure of the hydrophilic spacer.
This hydrophilic spacer is similar, as described above [
Engineered thioTmAb-MPEO-DM1 displayed equal
Starting from the chemical derivatization of toxins and mAbs, several conjugates have been developed, prepared with different approaches. Over the last 30 years, there has been continuous progress in IT design and development, leading to more sophisticated and efficacious products. Systemic off-target effects were prevalent when ITs were first introduced, but it is now possible to incorporate elements that reduce such effects, and to optimize the dose-response curves, so as to ensure the most potent possible effect on target cells, while limiting collateral damage. Molecular biology and protein engineering have been employed to develop potent and versatile toxin-based therapies with great application potential. Recent developments have reduced the size of ITs, allowing better distribution and penetration, improved binding affinity and avidity to cell-specific target antigens, and more efficient uptake and translocation to the cytosol. The potency, the reduction of immunogenicity, and the increase in specificity, have together improved the role of ITs as anticancer agents, although further human trials are needed: the true efficacy of these innovative products is still to be clarified, specifically their appropriateness for a narrow range of applications (e.g., interleukin-targeted cytotoxins in infusion techniques to treat brain cancer [
Linker strategies took on great importance in the development of ADCs: synthesis is quite complex, several aspects must be critically balanced, and thus most ADCs providing promising preclinical data have failed to realize their potential in clinical trials. However, the latest generation of ADCs is now showing great promise in early clinical trials, particularly in hematological malignancies [
The authors declare no conflict of interest.


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Would you like to save as your currency permanently or for this visit only?
We are impressed with the small friendly feel of the hotel & fantastic view from the restaurant.the new owners a young couple made us feel very welcome . Slightly difficult to find & steep steps up from the car park.
Location and friendlyness of owners All entrances to hotel have steps.
Very nice staff and very good service. Nice and clean hotel, good food and very friendly atmosphere.


text:
Oak Brook, Ill. (AP) - Strong sales of McDonald's McCafe drinks and breakfast items in April drove a key revenue measurement up 6 percent worldwide.
The world's biggest hamburger chain said Monday that in the U.S., revenue at company-owned and franchised restaurants open at least 13 months climbed 4 percent.
The figures are a snapshot of food revenue and don't include franchise fees and rents that make up part of McDonald's corporate revenue.
Results were even better overseas. The figure rose 6.5 percent for Europe and Asia/Pacific, the Middle East and Africa.
Revenue at stores open at least a year is a key gauge of a restaurant operator's health because it excludes results from stores opened or closed during the year.


text:
Wednesday, 28 August, 2002, 11:54 GMT 12:54 UK
Sports Personality: The battle hots up
Even with four months still to go until the big night, speculation is already rife.
Which sporting greats are leading the race to be BBC Sports Personality of the Year?
Without, it must be stressed, any hint of inside knowledge, BBC Sport Online rounds up the runners and riders.
Name: Paula Radcliffe
The overwhelming favourite with bookmakers William Hill.
She could be had for 33-1 at the start of April - but since then her wonderful series of achievements has decimated those odds.
Then Manchester went crazy when she won her first ever track gold in the Commonwealth 5,000m.
Less than a fortnight later, Paula ran the second fastest time in history to take the European 10,000m title.
So popular that even your mum will tune in to watch her in action, Paula will become an even shorter-priced favourite if she succeeds in setting a new world record in her final race of the year, the Chicago Marathon in October.
Name: Tony McCoy
On the face of it, the man known to his fans as 'AP' should be in with a great shout of the BBC gong.
Earlier this year, he overtook Sir Gordon Richards' long-standing mark of 269 winners in a single season.
But his odds reflect the fact that jockeys traditionally do not do well in the Sports Personality voting.
In the year that he rode his 'Magnificent Seven', Frankie Dettori finished a mere third in the voting.
Name: Lennox Lewis
Winner of the award in 1999, Lennox's defeat of Mike Tyson has made him second favourite for the 2002 trophy.
Boxers have a good record at the annual Sports Personality bash, but Lennox may need another high-profile fight before the end of the year to keep his face in the public eye.
Name: David Beckham
The current holder of the award, Becks is certain of thousands of votes from Manchester United fans across the country.
But by his own standards, 2002 has not been the most illustrious of years.
His broken metatarsal kept him out of the conclusion to the English season, a year in which United failed to win a single trophy.
But Becks was subdued as Sven's men fell in the quarter-finals - and with only European Championship qualifiers to come this autumn, there are few high-profile games in which he can shine.
And then there's the small matter of supporters of other Premiership clubs voting for the other contenders to keep the Man United star off the top...
Name: Tim Henman
Sure, Tim reached the semi-finals of Wimbledon - and British tennis success is always well rewarded by the Sports Personality voters.
But the manner of that thumping defeat by Lleyton Hewitt on Centre Court - allied to a certain weariness from the fans after so many Wimbledon near-misses - have hurt Tim's chances.
Unless he pulls off a miracle at Flushing Meadows, the US Open offers Henman little hope of a comeback.
Name: Colin Montgomerie
If his own incendiary performances at The Belfry next month almost single-handedly win the Cup for Europe, he might be worth a punt.
But as things stand at the moment - injured back and inconsistent form in mind - you might be best advised to back a different horse.
See also:
06 Aug 02 | European Athletics
27 Aug 02 | Horse Racing
09 Jun 02 | Lewis v Tyson fight
28 Aug 02 | Sports Talk
Internet links:
The BBC is not responsible for the content of external internet sites
Top Sport Front Page stories now:
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text:
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Jason Aldean Loves Tattoos, Jo Dee Messina Is Alright – Today In Country Music History
Jason Aldean loved his "Tattoos" on this date in 2011, Jo Dee Messina was doing "Alright" in 1998, Restless Heart had a question in 1987 and more.
Here's the list for Today In Country Music History for 22 August, 2012.
- Jason Aldean's "Tattoos On This Town" was released to radio in 2011.
- Alan Jackson picked up a platinum album for When Somebody Loves You in 2001.
- Jo Dee Messina scored a Number One hit with "I'm Alright" in 1998.
- O.V. "Mooney" Lynn Jr., husband of Loretta Lynn, died in 1996.
- Roy Clark joined the Grand Ole Opry in 1987.
- The Mavericks earned their first gold album for What A Crying Shame in 1994.
- Restless Heart appeared at Number One in Billboard with "Why Does It Have To Be (Wrong Or Right)" in 1987.
- Crystal Gayle and husband-manager Bill Gatzimos welcomed their first child, Katherine Claire, in 1983.
- George Jones married Tammy Wynette in 1968.
Here's Jo Dee Messina from back in the day.
Subscribe to 102.3 The Bull on
Not near a Radio? Click here to listen to Lonestar 102.3 online.
Dave D.


text:
Sally's Recipe of the Week: Buttermilk Southwest Grilled Chicken
Buttermilk Southwestern Grilled Chicken
Serves 2
Here is what you need:
1 cup buttermilk
1/2 lime, zested and juiced
2 cloves garlic, chopped
1 tablespoon chili powder
1 teaspoon ground coriander
1 teaspoon ground cumin
1/2 teaspoon turmeric
Hot sauce, to taste (recommended: Tabasco)
1/4 cup coarsely chopped fresh cilantro leaves
Salt and freshly ground black pepper
2 boneless chicken breasts (each about 6 to 8 ounces)
Canola oil
Add the buttermilk to a large bowl and add lime zest and juice.
Add garlic,hot sauce, chili powder, coriander, cumin and turmeric.
Add cilantro, and salt and pepper, to taste.
Mix well.
Add the chicken and coat well.
Cover the bowl with plastic wrap. Marinate in fridge for 4 to 24 hours. (If you are using fish, marinate 30 minutes.)
,Preheat the grill pan over medium-low heat for boneless breasts and fish, and medium heat for bone-in breasts, thighs and legs. Remove the meat/fish from the marinade and pat dry with paper towels.
Brush with oil and season with salt and pepper, to taste, on both sides.
Grill until golden brown and charred on both sides and just cooked through about 4 minutes a side. If you butterflied the chicken like I did you grill it 3 minutes on one side, 2 on the second side. I butterfly the breasts for grilling because I think it comes out more even.
I served with corn. (Cut corn off 2 cobs, sauted in a pat of butter with lemon zest and juice, garlic, salt, pepper and finished with basil._


text:
Blessings loves!
I'm on Pinterest and realized I never let you guys know lol! It is a social bookmarking website where you can pin and repin images, blog posts, articles, and more that you like to boards you create! Reminds me of a digital vision board! You know I love vision boards!
Take a look at a few of my boards:
I pin inspirational quotes, inspirational apparel and accessories, Do It Yourself projects, and more!
Once you join, you can pin your favorite recipes, fashion finds, books you like to read...anything you like, you can pin it!
Not a member? Check it out at Pinterest!
If you are on pinterest, join me at CICINSPIREME!
What is your favorite thing about Pinterest?
~Be beautiful, inspired, and blessed!


text:
In an e-mail conversation, Paul Draper pointed out an error in my review of Plantinga's most recent book, Where the Conflict Really Lies. The key background is at one point in the book, Plantinga responds to a paper by Draper which was, in turn, a critique of the work of intelligent design advocate Michael Behe. [Read More…]
Alvin Plantinga, Michael Behe, and Paul Draper
The ignorance and dishonesty of Christian apologetics, part 1: anti-evolutionism
I don't think I'm going to be able to get through writing this post if I try to feign politeness, so let me start by saying that it's long been clear to me that, in spite of his moderate views on some issues (relative to his fellow evangelicals, anyway) Christian apologist Randal Rauser is not [Read More…]
Reply to a reader having a crisis of faith
A reader having a crisis of faith sent me an e-mail describing his situation; with permission I'm posting excerpts from it with my responses: [Read more…]
William Lane Craig: young-earth creationism is an embarrassment
I've had difficulty finding any straightforward statements from William Lane Craig on evolution and creationism. Often, he hedges by throwing a few subtle encouragements to his anti-evolution fans while avoiding saying anything that would identify him. But in a recent podcast, he was very frank about young-earth creationism: [Read more…]
Evolution, original sin, and the problem of evil
Previously: Yes, creationism is religiously motivated [Read more…]
Yes, creationism is religiously motivated
Previously: The evidence for evolution [Read more…]
The evidence for evolution
Previously: Neuroscience and the soul [Read more…]
From the archives: Review of Finding Darwin's God
I've spent the day suffering from writers block over what to say about evolution in the book. I went poking through my own blog archives and discovered a review of Kenneth Miller's Finding Darwin's God, originally published in September 2009. To my surprise, I apparently liked it. I'll need to reread it, or at least parts of [Read More…]
"But lots of scientists are religious!" and other arguments on science and religion
So I've resolved to get my book's section on science finished this month. One thing I want to do in it is address responses to Dawkins' comments on the relationship between religion and science (and responses to the Gnu Atheists more generally here, but Dawkins is the name that comes up most often in this [Read More…]


text: 7/02/12 12/27/09 POPSUGAR Living Cute Animals Hi, Jamuna Toni! December 27, 2009 by Pets 2 Shares Chat with us on Facebook Messenger. Learn what's trending across POPSUGAR. View on One Page Photo 14 of 16 Start Slideshow ADVERTISEMENT () Share This Link Copy ← Use Arrows Keys → 14 Previous Next Cute AnimalsHellabrun ZooMunichBaby AnimalsElephantsGermany


text:
The Founding of EKA and its history
to the end of the 19th Century
EKA in the 20th century
EKA today
Past Presidents and Committee members of EKA
The Alexander the Great Centre of Post-Graduate Studies and Research
The Greek population of Alexandria, Egypt, once numbered some 150,000. Traders, businessmen, philanthropists and artists moved among the cosmopolitan society of Alexandria. Their legacy is still to be seen today, not only in their historical influence, their writings, teachings and their influence on the society of Egypt and Greece, but also in the structures which they designed and built - hospitals, churches, schools, public buildings and mansions.
Sadly, the Hellenic community of Alexandria has dwindled to a mere 800 and many of the businesses, clubs, hospitals and schools have closed, but many of the churches and grand neo-classical buildings remain.
The Orthodox Patriarchate of Alexandria and All Africa has its historical base in Alexandria where it was founded by the Apostle St. Mark in 63 AD. The Patriarchate is responsible for the spiritual and religious well-being of some 150,000 Greeks living in Africa as well as a further 500,000 of the Orthodox Christian faith throughout the region.
The Hellenic Community of Alexandria (EKA) aims to ensure the best possible opportunities and conditions for the continuation of Hellenism in Egypt and cultivate cultural exchange between Greece and Egypt. To this end EKA proposes the foundation and operation of a School of Archaeological and Classical Studies bearing the name "Alexander the Great", within the buildings of the last Greek Quarter of Chatby, Alexandria - an area of 40,000 square metres, entirely owned by the Hellenic Community of Alexandria.


text: In only a minute he pumped a big sticky load inside and then left me standing there with a juicy snatch. After I got home we put the video up on our gloryhole creampie homeclips page so if you want to watch it and support our fun please check it out. Remember to check back at Gloryhole Creampie often for out latest adventures at the Female Gloryhole... DK your Gloryhole Female Wife.


text:
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text:
Ex-wife shot while playing organ in church
An elementary school music teacher shot his ex-wife while she played the organ during church service and, after leaving briefly, returned and shot her again to ensure she was dead, police said.
Congregants eventually overpowered Gregory Eldred, ending the shooting Sunday at the First United Presbyterian Church of Coudersport.
The shooting was detailed in a criminal complaint filed Monday against Eldred, 52, of Coudersport. He remained jailed without bond.


text:
With GPS navigation devices in everything from cars to your smartphone, you may not also realize that GPS satellites can also synchronize time down to the nanosecond, and detect nuclear explosions! Learn more with this fun animated video from the folks at Minute Physics:
Now if they could just get the maps better so I'm not taking a left turn into a pond, we'll be all set.
Read more of Keith Shaw's ITworld.TV blog and follow the latest IT news at ITworld. Follow Keith on Twitter at @shawkeith. For the latest IT news, analysis and how-tos, follow ITworld on Twitter and Facebook.


text:
Mary Angela Douglas
The Marvelous Floating Bookshop And Virtual Ice Cream Emporium - Poem by Mary Angela Douglas
the poem with the caramel icing
turned out right
though no one knew about it
and nobody ever saw
the Marvelous Floating Bookshop and Virtual
Ice Cream Emporium on Earth
(except perhaps, me)
though I promise, it was there
painted cherry vanilla
on the little lilac lane that
only came into view
on the left hand side of the bus
when I was the only one looking out
in that direction.
and you dropped the day in your merriment
melting like a creamsicle on the busy sidewalk
and who could ever tell them from the flowers,
night children blowing in a garden- thick in the shade
of lime trees
and lavender blue at midnight
every blade of grass bent toward us
as we wandered into a strawberry feeling frothing
the Marvelous Floating Bookshop and
Virtual Ice Cream Emporium:
four paperbacks,25 cents each
wrapped in brown paper tied with a string
and no string theory and free, free, free
lusciously malted through and through and
I'll have a cherry phosphate stylish Rose said
in a book I read
crackling new
with a papery perfume
like a box of penny valentines just opened
and every heart
for you at the singular page
only you will decipher
still and still and still
you wander or you will among coloured illustrations
toward the drugstore racks in dreams that squeak
content is a fizzing fountain coke
and the odes of poets never heard from on earth
mary angela douglas 8 july 2013
Topic(s) of this poem: Summer
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