Resection of the sciatic or femoral nerves does result insignificant disability. At the center of this activity is the transcription factorSTAT3, which is involved with T cell activation in general, but here specifically with Tregsand TH17 T cells.
Sodium valproate A reduction in manicrelapses is noted when valproate is used inbipolar disorder.
Routine analysis of these wave-forms is an important aspect of the assessment ofpatient-ventilator interactions and should be usedto optimize mechanical ventilatory support. Vogelstein B can i buy viagra over the counter in australia Lane D, Levine AJ (2000) Surng the p53 network. Photomicro-graph of the fetal liver stained with H&E shows active hemopoiesis. Additionally can i buy viagra over the counter in australia most of the research is conductedin residential care settings, where standardization andstrict adherence to research protocols are challenging.As a result, caution is advised when drawing conclu-sions from a number of these studies (Ayalon et al.,2006; Pulsford and Duxbury, 2006; Jeste et al., 2008).Moreover, most of the research does not meet the strictrequirements necessary to be considered evidence-based treatments.
Furtherimprovements in pregnancy rates may be achieved bythe introduction of new drugs, such as recombinant FSHor gonadotropin-releasing hormone (GnRH) antagoniststhat provide individualized hormonal treatment.
Migraineurs often have considerable neckpain–this is not cervicogenic headache. Leach FS, Tokino T, Meltzer P, Burrell M, Oliner JD, Smith S, Hill DE, Sidransky D, KinzlerKW, Vogelstein B (1993) p53 Mutation and MDM2 amplication in human soft tissue sarco -mas.
, the mean preoperative CRP levelwas 127mg/l (range, 14–214mg/l). Other substances needed for propergrowth of microorganisms or cells in culture arecalled 'growth factors'. Renoprotective effect of the angiotensin-receptorantagonist irbesartan in patients with nephropathy due to type 2 diabetes. These regulatorscontrol its intestinal absorption can i buy viagra over the counter in australia exchange withbone and renal excretion as summarized in Fig.24.1. Replication can i buy viagra over the counter in australia randomization, and clinical relevance:A response to Dworkin and colleagues. This does not only reduce the risk of ROP,but limiting the amount of oxygen in the inspiredgas can also reduce pulmonary damage and theincidence of BPD (Askie et al. For the last …months, hehas been sufferingfromshortness of breath and palpitation on moderateto severeexertion.Sometimes, he experiences orthopnea and paroxysmal nocturnal dyspnea. This allowed the researchersto assess the effect of manipulations on "target" behavior can i buy viagra over the counter in australia as well as a generalization toother behaviors. Dinner—few bites of meat-loaf can i buy viagra over the counter in australia mashed potatoes and gravy, cup of milk. Another oneof these cAMP sensors is an exchange protein called cAMP/cAMP-regulated guaninenucleotide exchange factors (EPAC/cAMP-GEF) or EPAC (Cheng 2008). Such scans have shownthat can i buy viagra over the counter in australia in a minority of patients, recanalized vessels may reocclude and occluded vesselsmay spontaneously recanalize. Therefore, activation ofthese oncogenes results in the continual cell growth of thetarget cell.
MG has a ?re department with 7 part-time ?remen and a small group of volunteer ?remen.No trained emergency medical personnel working.Equipment is outdated but functional. Jones considered that good practiceis likely to be fostered through adequate resource allocation and the development of professionalnorms and values.


When parents sign the form for "Application for Admission", parents agree that their son or daughter shall be subject to the rules and discipline of the College. The College stands in loco parentis while students are within its jurisdiction.
It is our aim to make learners/people aware of what kind of behavior is required and welcomed by the civilized world and conversely, what kind of behaviour is unwanted, destructive and not accepted by educated, civilised people in the world outside the College. It is further aimed at establishing in all learners a specific style of self-discipline, self-respect, high esteem and respect for every human being with whom they come in contact.
A disciplinary system does not refer to a method of punishing children. Punishment is only applied if all else fails. Punishment is a means of reaching the aim of a disciplinary structure. The structure/system is not a punishment in itself.
The disciplinary system thus aims at a self-disciplined life-style as the cornerstone of quality education and success in life. Discipline and especially self-discipline is one of the fundamental values of Prestige College which is NON-NEGOTIABLE.
Every pupil registered at Prestige College is subject to the system and is therefore responsible for knowing the system. Ignorance will not be accepted as an excuse, i.e. "I didn't know".
The management of the College, represented by the Principal, may act without prior notice in cases of exceptionally serious misconduct, in which case action will deviate from the "normal" procedure. In cases where the behaviour of children is deemed extremely destructive by the College, when it is necessary to restore order and discipline for the benefit or protection of other learners or the College itself, individual learners may be suspended at the time and expelled after a disciplinary hearing.
For each transgression the predetermined number of points is deducted.
of his activities are scrutinized and discussed with involved staff members and the learner himself.
This is a shortened version of the list of possible transgressions.
Punishment is our last resort in our attempt to help learners become responsible for their own actions and respectful of the rights of others. To lose points is a form of correctional procedure. Continuous loss of points will lead to an interview with parents, withdrawal from class and it can also lead to expulsion.
Parents will receive a Conduct Report at the end of each term or with Academic Reports.
If a learner believes that he/she has been treated unfairly, he/she may appeal to his/her class teacher or the Head of Discipline or to the Principal.
The Head of Discipline will assess the complaint and give notice to all relevant parties for a disciplinary hearing to take place.
The accused has the right to be heard and will give his/her side during the hearing. The disciplinary committee will listen to all sides and make a decision. Mitigating circumstances will be taken into account and all cases will be judged individually.
The outcome of the investigation will determine the verdict.
A decision will be taken and made known to the parties involved.
Parents will be informed and asked to come to the College if the situation is such that parental involvement is necessary.
When learners have lost a certain number of points for any type of transgression, they will be prohibited from participating in any extra-mural activity, any sport or social event – because it will be clear that they need more time to do homework and improve behavior. They can also be prohibited from participation in extra-mural activities because of disruptive behaviour in class.
Detention – Staff will place learners on detention for more moderate to serious offences. Detention will be recorded.. If they are placed on detention, they will be required to spend time in school uniform doing class work, other written work, or manual labour around the school. They will remain after school and sometimes on Saturday mornings. Detention takes precedence over all other activities. Detention may also include physical exercise. Detention is not negotiable and will not be postponed at all.
Withdrawal System – no learners has the right to prevent other students from working in an atmosphere conducive to learning. Learners who disrupt classroom procedures, may be withdrawn from class.
Learners who have been withdrawn from class, will spend a specified period of time out of class supervised by another teacher. They will be expected to make up all the work they miss. The Head of Discipline will decide on further action to be taken; this may include an interview with parents.
Learners who are withdrawn from class may not participate or represent the school on any level.
Suspension – learners who commit serious offences may be suspended from school. The period of suspension will vary depending on the seriousness of the offence. Parents will be informed as soon as possible and they should make an appointment to discuss the matter with the Discipline Head. Suspension is the disciplinary step prior to expulsion. Pupils who have lost most of their points will be suspended.
Expulsion – for the most serious breaches of school regulations (serious misconduct), learners could be expelled. Learners who lost all their points by transgressing minor rules on an ongoing basis may also be expelled.
To cheat in a test or exam is to take something that doesn't belong to you. This practice of dishonesty in any form will encounter fierce opposition and may lead to expulsion. By signing the contract with the school, parents also give permission that a polygraph test may be used to establish the truth when necessary. Should a child be found guilty of dishonesty, parents will be liable for the cost incurred to determine the truth. This arrangement is necessary to encourage children to be honest and for parents to encourage same.
Plagiarism, copying homework, copying form notes during a test or exam, will lead to the learner receiving 0% for the piece of work as presented or submitted. The learners will further be exposed to a disciplinary hearing and will lose the maximum points as this is a very serious offence. This behaviour could also lead to expulsion.
At Prestige College we have a zero tolerance policy regarding drugs. Learners are forbidden to take or possess drugs and those who do, you will be liable for expulsion. No warnings are necessary. Learners may NOT carry drugs to or from school. Drug trafficking is considered an extremely serious offense and those who are guilty of that will be liable for expulsion.
Prescription and over-the-counter-medicine used irresponsibly or for recreational purposes are also regarded as drugs. Please control the quantities of medicine your children have access to.
By signing the contract with the school, parents gives permission that learners may be tested for drugs should reasonable suspicion exist. Learners may therefore be asked to produce a urine sample or be taken to a pathologist to have blood drawn to determine the content of the drug suspected. When found guilty, parents will be liable for the cost incurred with the pathologist.
Drugs destroy many lives and nobody will be allowed to come to school and involve other innocent children in bad habits and forbidden practices like drug usage.
Educational excursions are regularly undertaken.
The principal's permission for excursions is obtained after the necessary planning has been done by the teachers in charge.
An Indemnity Form, which covers excursions and trips, is signed on admission by parents.
Parents are informed in writing of proposed excursions and trips well in advance.
Consent for any excursion may be withheld at the parents' discretion.
All school rules apply on all excursions.
The uniform policy applies on all excursions.
Please take note that all excursions are optional and at the discretion of the parents who have to pay for it. Unfortunately, not all excursions can be arranged a year in advance.
The school will take care to make sure that all excursions are booked at the best price possible for the best quality available.
If you are proud of something, you will also be loyal to it. To be loyal means not to gossip or talk badly about the school, teachers or fellow students.
Learners may not chew chewing gum and bubble gum at school or on any school outing, function or camp. They may be punished with detention and will lose points accordingly. Chewing gum is not allowed at school at all!
Harassment in all its forms has no place at Prestige College. It can damage the atmosphere of a class and even the climate of a school. Learners who harass teachers will be dealt with severely. Learners who harass other learners are guilty of bullying and that is an expellable offence. All learners have the right to feel comfortable and at home at school. Any form of harassment will be met by a zero tolerance approach.
During the school week (Monday to Friday) evening prep is a learners' first responsibility; other engagements are to take second place, except under exceptional circumstances. If learners do not get homework set in a specific subject, they are expected to use that time on revision work or recommended reading in the subject, to help them widen their background knowledge. Parents are asked to make sure their children spend at least two hours per day with school work/ study/ research or reading. Homework time should not be replaced with TV time!
Learners who are sick or injured should report to the reception. The sickbay is chiefly for boarders and is to be used by day students only in case of urgency. Parents are requested not to send sick children to school. The school is not a clinic and can therefore not hand out any medicine at all. Parents will be called back to school to fetch their children when they are ill. The school will only take day scholars to a doctor or hospital in emergency situations when parents could not be reached. If transport is not available an ambulance will be ordered and parents will be liable for the cost incurred.
Parents are liable for any expenses incurred in such instances.
Parents are requested to send a letter with a reason for the student's absence from school on the return of the child to school to be put on his/her file.
Learners are not allowed to have craft knives, pocket knives or sheath knives at school.


text:
Outcry over halt to free forces parcels
A Coventry soldier who served in Iraq has hit out at the Ministry of Defence for ending free parcels to those still serving there.
00:00, 8 APR 2004
Former Cardinal Newman Comprehensive school pupil Chris Doak, 22, who served in the 1st Battalion of the Royal Regiment of Fusiliers, said the parcels from home were what kept him going during his six months in Iraq.
The free packet service to Iraq has ended from today.
Mr Doak, who is now based in Germany, said: "I think it is scandalous. Getting parcels from home is what boosts your morale while you are away.
"The parcels keep you going as well as providing things like toothpaste and sweets that are not easy to get out there.
"If you don't get them it makes you feel cut off from family and friends at home.
"We're out there doing a job for the country and letting families send things over for free is the least they could do.
"I understand families are feeling anxious their sons and daughters are still out there - this service helps them feel a little closer to them."
Former auxiliary nurse at Walsgrave Hospital Pauline Davie, 59, whose son Kurt, 34, is currently serving in Basra, said she was fuming when she found out she would have to pay.
Mrs Davie, of Wyken, whose son serves in the Queen's Royal Hussars, said: "I was livid when I found out.
"It can be very expensive to send things out there. Families should not have to pay for anything as they are doing a job out there, they can't choose where they are sent. It goes without saying they are all doing a brilliant job which is important, so they should at least get their parcels for free."
Minister for the Armed Forces, Adam Ingram, said: "The MoD accepts that the withdrawal of the free packet service will be unpopular. It should, however, be seen in the context of the good welfare package enjoyed by all service personnel and the availability of consumable goods in the Iraq theatre."
An MoD spokeswoman said: "Parcels up to two kg in weight can still be sent at a special concessionary rate equivalent to the UK inland first class postage rate.
"And personnel will continue to benefit from free letters (blueys), free Internet access and phone calls of up to 20 mins per week anywhere in the world."

redpajama_set_name: RedPajamaCommonCrawl


text:
Homosexual Jailed For Defiling Boy
Yeni Kutu
A 21-YEAR-OLD man, Yeni Kutu who defiled a 13-year-old boy at Adagya in the Bosomtwe District of the Ashanti Region has been slapped with a 10-year jail term.
Harbouring the intention to engage in the unlawfully lewd act, the convict, an aboboya rider, was said to have given the victim (name withheld) some energy drink laced with alcohol to get him drunk, after which he had sexual intercourse with him through his anus.
Yeni Katu popularly known as Tani admitted the offence and pleaded guilty to the charge of defiling child less than 16 years of age, contrary to section 101(2) of Act 29/60 as amended by Act 554 of 1998.
Prosecuting, Police Detective Inspector Stephen Ofori told the court presided over by Fredrick Nawura that on December 7, 2019 around 12 noon, the convict, who lives at Adagya, spotted the victim in front of his (boy's) mother's shop in the same community, whilst on a jolly ride.
According to him, the convict lured the boy with money onto the motorcycle and asked him to accompany to his home to load goods, without informing the mother.
Upon reaching home, prosecution narrated further that Katu invited the primary-six pupil into his room and engaged him in conversation whilst there.
Inspector Ofori continued that the convict offered the boy an energy drink which he drank without suspecting any foul play.
Soon after that, the prosecutor said, the victim became drunk and dizzy, rendering him weak.
Yeni Katu then took advantage of his state of weakness and had sexual intercourse with him, through the anus, Inspector Ofori pointed out.
The convict afterwards warned the victim not to disclose his ordeal to anyone or will be killed.
He then rode him back to his mother's shop area and dumped him.
Some neighbours, who found the victim, quickly went to his aid, upon realizing he had urinated and defecated on himself, and quickly sent him to the mother.
The boy reported the incident to his mother, who later lodged a complaint with the police, leading to the arrest of Yeni Katu, said prosecution.
From Ernest Kofi Adu, Kumasi
Tags: general news, Homosexual Jailed For Defiling Boy
First Lady Officially Joins Eat Ghana Rice Campaign
Elumis Foundation Supports Agric Ministry With 400 Solar Kits


I get that the federal government needs to cut its budget. We can't spend more than we take in forever.
But I also want the country to have a bright future, and without investments in science and technology that's just not possible. The real key to solving our present economic difficulties is to grow our economy.
The buckyball has grown up.
If you're looking for a local example, look no further than the science of nanotechnology, which in some respects was launched at Rice University with the 1985 discovery of the buckyball by Richard Smalley, Bob Curl and Harry Kroto.
That very basic science discovery — of a molecule made of 60 carbon atoms — stimulated some early basic research interest in the field of nanoscience. Some promising results led to U.S. government investment beginning in 2001 under the National Nanotechnology Initiative. These funds stimulated more research.
The cumulative investment in this nanotechnology initiative since fiscal year 2001, including the 2012 request, now totals almost $18 billion.
And what has America gotten for its investment?
As of 2009, just eight years into the initiative, we had created a $91 billion U.S. industry. And it's rapidly growing. It should be a $1 trillion industry by 2020.
Science, in short, is key to growth in the 21st century.


text:
Q: I want to image from another page I am new to ionic/angular. In my edit profile page(different page), I can change the profile pic and it should reflect the same in main profile page(another page), these two pages are different.
HTML:
<ion-item lines="none">
    <ion-avatar class="ion-align-self-left" id="pic" (click)="change()">

    </ion-avatar>
</ion-item>

TS:
   export class ProfilePage implements OnInit {
   myphoto:any;

  constructor(private camera: Camera) {
    this.myphoto = '/assets/img/DP.svg';
   this.statusBar.backgroundColorByHexString('#ffffff');
     }
   ngOnInit() {
  }
 take(){
     this.ishide =true;
    this.hide_input =false;
    const options: CameraOptions = {
    quality: 70,
    destinationType: this.camera.DestinationType.DATA_URL,
    encodingType: this.camera.EncodingType.JPEG,
    mediaType: this.camera.MediaType.PICTURE
    }

   this.camera.getPicture(options).then((imageData) => {
   // imageData is either a base64 encoded string or a file URI
    // If it's base64:
   this.myphoto = 'data:image/jpeg;base64,' + imageData;
   }, (err) => {
   // Handle error
   });
   }
    get() {
   this.ishide =true;
   this.hide_input =false;
    const options: CameraOptions = {
     quality: 70,
     destinationType: this.camera.DestinationType.DATA_URL,
     sourceType: this.camera.PictureSourceType.PHOTOLIBRARY,
     saveToPhotoAlbum:false
      }
      this.camera.getPicture(options).then((imageData) => {
    // imageData is either a base64 encoded string or a file URI
     // If it's base64:
     this.myphoto = 'data:image/jpeg;base64,' + imageData;
     }, (err) => {
     // Handle error
     });
      }
       }

A: You need some global state, that would store the path/base64 of the avatar image.
Tipically, you would get the image everytime the component (page) is inited and assign the path/base64 to some variable.
I would use a global service or maybe avatar service that would store the avatar data via Subject/BehaviourSubject. You can find more about them here
You would subscribe to changes or get the new image from the service in the component whenever the page is inited (ngOnInit).

A: You can get the same service in both modules by importing it with "constructor injection"
constructor(private myProfileService: ProfileService) {  }

Then just bind to a property getting its value from the service.

A: Create a SharedService. Expose a public Observable and a method to set the value of that using a private BehaviorSubject:
import { Injectable } from '@angular/core';
import { BehaviorSubject, Observable } from 'rxjs';

@Injectable()
export class SharedService {
  private profilePicture: BehaviorSubject<string> = new BehaviorSubject<string>( 'https://firebasestorage.googleapis.com/v0/b/siddajmera-dev.appspot.com/o/Avatar.jpg?alt=media&token=ba992ea4-3198-4971-b4ee-5454ec2b3cbd');
  public profilePicture$: Observable<string> = this.profilePicture.asObservable();

  setProfilePicture(newProfilePicture: string) {
    this.profilePicture.next(newProfilePicture);
  }
}

Inject this service in the Pages where you want to change the Profile Picture and set it:
Where you want to display:
import { Component } from '@angular/core';
import { NavController } from 'ionic-angular';
import { Observable } from 'rxjs';

import { SharedService } from '../../app/shared.service';

@Component({
  selector: 'page-home',
  templateUrl: 'home.html'
})
export class HomePage {

  profilePicture$: Observable<string>;

  constructor(
    public navCtrl: NavController,
    private sharedService: SharedService
  ) {}

  ngOnInit() {
    this.profilePicture$ = this.sharedService.profilePicture$;
  }

}

And in the Template:
<ion-header>
  <ion-navbar>
    <ion-title>Main Profile Page</ion-title>
  </ion-navbar>
</ion-header>

<ion-content padding>

Welcome to Ionic!

    This starter project comes with simple tabs-based layout for apps
    that are going to primarily use a Tabbed UI.

    Take a look at the pages/ directory to add or change tabs,
    update any existing page or create new pages.

  <ion-item lines="none">
        <ion-avatar class="ion-align-self-left" id="pic">

    </ion-avatar>
  </ion-item>
</ion-content>

Where you want to set it:
import { Component } from '@angular/core';
import { NavController } from 'ionic-angular';
import { Observable } from 'rxjs';

import { SharedService } from '../../app/shared.service';

@Component({
  selector: 'page-about',
  templateUrl: 'about.html'
})
export class AboutPage {

  profilePicutre$: Observable<string>;

  constructor(
    public navCtrl: NavController,
    private sharedService: SharedService
  ) { }

  ngOnInit() {
    this.profilePicutre$ = this.sharedService.profilePicture$;
  }

  change() {
    this.sharedService.setProfilePicture(`https://pbs.twimg.com/profile_images/1116889337075920898/foGk0y53_400x400.jpg`);
  }

}

And in the template:
<ion-header>
    <ion-navbar>
        <ion-title>
            Edit Profile Page
        </ion-title>
    </ion-navbar>
</ion-header>

<ion-content padding>
    <ion-item lines="none">
        <ion-avatar class="ion-align-self-left" id="pic" (click)="change()">

    </ion-avatar>
  </ion-item>
</ion-content>

And in 'app.module.ts' provide the SharedService
@NgModule({
    declarations: [
        HomePage,
        Aboutpage
    ],
    providers: [ SharedService ]
})

PS: I'm not using the Camera API or anything in the example. But even if you're using that to get the image updated, this is how you'd do it. Using a SharedService.

Here's a Working Sample StackBlitz for your ref.

A: I solved myself by simply using localstorage and ongoing back that current page will refresh and changes which are made in the edit_profile page will get affected in the profile page.
edit_profile.ts
import { Router } from "@angular/router";
export class ProfilePage implements OnInit {
myphoto: any = "/assets/img/DP.svg";
picture: any;

constructor(
private camera: Camera,
private statusBar: StatusBar,
private router: Router
) {
this.picture = localStorage.getItem("pic");

this.statusBar.backgroundColorByHexString("#ffffff");
}
back() {
 this.router.navigateByUrl("/profile");
  }
take() {
this.ishide = true;
this.hide_input = false;
const options: CameraOptions = {
  quality: 70,
  destinationType: this.camera.DestinationType.DATA_URL,
  encodingType: this.camera.EncodingType.JPEG,
  mediaType: this.camera.MediaType.PICTURE
};

  this.camera.getPicture(options).then(
    imageData => {
    // imageData is either a base64 encoded string or a file URI
    // If it's base64:
    this.myphoto = "data:image/jpeg;base64," + imageData;
    localStorage.setItem("pic", this.myphoto);
    this.picture = localStorage.getItem("pic");
    },
     err => {
    // Handle error
   }
   );
   }

  get() {
 this.ishide = true;
 this.hide_input = false;
  const options: CameraOptions = {
  quality: 70,
  destinationType: this.camera.DestinationType.DATA_URL,
  sourceType: this.camera.PictureSourceType.PHOTOLIBRARY,
  saveToPhotoAlbum: false
  };

edit_profile.html

profile.ts
export class MainProfilePage implements OnInit {
 picc: any;

  ionViewWillEnter() {
this.picc = localStorage.getItem("pic");
console.log("works");

}
profile.html

redpajama_set_name: RedPajamaStackExchange


text:
Kevin O'Leary on SEC v Ripple Lawsuit Over XRP: 'I Have Zero Interest in Investing in Litigation Against SEC'
Shark Tank star Kevin O'Leary, aka Mr. Wonderful, says he has zero interest in investing in anything with litigation from the U.S. Securities and Exchange Commission (SEC). "That is a very bad idea," he said. Discussing the SEC lawsuit against Ripple over
, he emphasized: "I have no interest in being a crypto cowboy … I have to be compliant."
Kevin O'Leary Says He Must Not Upset Regulators
Shark Tank star Kevin O'Leary, the chairman of O'shares ETF, talked about cryptocurrency, bitcoin,
, Ripple's lawsuit, and crypto regulation in an interview with CNBC published Friday.
He explained that he prefers to consult with regulators regarding cryptocurrency in order to find out "what's possible and what isn't."
Commenting on the lawsuit brought by the U.S. Securities and Exchange Commission (SEC) against Ripple over the sale of
, O'Leary stressed:
I have zero interest in investing in litigation against the SEC. That is a very bad idea.
The SEC sued Ripple, its CEO Brad Garlinghouse, and co-founder Chris Larsen over the sale of $1.3 billion worth of the
tokens, claiming that it was an unregistered securities offering. Ripple and its executives have argued that
is not a security.
Garlinghouse recently said that he expects the lawsuit to come to a conclusion next year, noting, "We are seeing
." Even the CEO of the Nasdaq-listed crypto exchange Coinbase, Brian Armstrong, believes that the lawsuit is
However, O'Leary said that he prefers to comply with regulators "because that's where the real capital is." He emphasized:
I have no interest in being a crypto cowboy and getting anybody unhappy with me because … I have so many assets in the real world that I've invested in already that I have to be compliant.
Mr. Wonderful is also not keen on meme cryptocurrencies. He said in July that he will not invest in the popular
(DOGE), noting, "I don't understand why anybody would."
Nonetheless, cryptocurrency now accounts for about
. His crypto exposure
for the first time in early October. In September, the Shark Tank star said he expect
more flowing into bitcoin.
What do you think about Kevin O'Leary's comments? Let us know in the comments section below.


Watershed field trip: We visited a couple of sites in the lower river, and then went upstream of Matilija Dam. After looking at the extent of dam-accumulated sediment, we visited the dam site and discussed removal plans.
Topic: Ecosystem-based management and the Matilija Dam Ecosystem Restoration project.


text:
Cancer Home > Uterine Cancer Alternative Treatment
Uterine Cancer Alternative Treatment
For some people with uterine cancer, alternative treatment can ease stress or help with the side effects of standard treatment. Uterine cancer alternative treatment may involve such things as herbal products, vitamins, and meditation. The healthcare team may also suggest alternative treatments for managing pain, which may include massage, acupuncture, and acupressure.
Uterine Cancer Alternative Treatment: An Overview
For some women with uterine cancer, alternative treatment may be one way to ease stress or to reduce side effects and symptoms of the disease. In most cases, women combine alternative treatments with the more standard treatments for uterine cancer (such as surgery, radiation therapy, and hormone therapy).
Most cases of uterine cancer occur in the lining (endometrium) of the uterus. This article uses the term "uterine cancer" to refer to this type of cancer, also known as endometrial cancer. This article does not discuss a rare type of uterine cancer that can occur in the muscles or other tissues that support the uterus. Click Uterine Sarcoma for more information on this topic.
Types of Uterine Cancer Alternative Treatment
Types of alternative treatments used to treat uterine cancer include:
Vitamins or special diets
Spiritual healing.
Many people say that these approaches help them feel better. Some types of alternative treatment may interfere with standard treatment, and combining some alternative treatments with standard treatments may even be harmful. It is important to note that some types of alternative treatments are expensive and may not be covered by health insurance
Uterine Cancer Alternative Treatment Article Continues on Next Page >
Uterine Cancer Treatments
Written by/reviewed by: Arthur Schoenstadt, MD
Last reviewed by: Arthur Schoenstadt, MD
Uterine Cancer Treatment
Uterine Cancer Treatment by Stage
Uterine Cancer Surgery
Radiation for Uterine Cancer
Uterine Cancer Hormone Therapy
Uterine Cancer Support
Uterine Cancer Pain
Uterine Cancer Survival Rate
Uterine Cancer Questions


text:
Q: Manage WSUS remotely How to remotely administer the WSUS from a workstation "windows xp"?

A: Depends on which version of WSUS you are running.
2.0 there is a webpage you go to on the server that is running WSUS (if i'm remembering correctly it's http://<servername>/WSUS)
With 3.0 you need to run the installer on your workstation and select console only installation, then you manage it through the MMC snap-in.

A: For those of you trying to use the Console of a Server 2008 R2 WSUS Server and a WSUS Management console from Windows 8 Pro.  You have to switch the port to 80 from the default suggestion or you will not be able to connect.
I hope this helps someone out.

A: This depends, WSUS is normally installed on a Windows Server (either 2003, or 2010), so you can do this many ways.
The easiest way is to enable remote desktop on the server where WSUS is installed, and use the remote desktop client that comes with windows XP to manage that server, including WSUS.
While you can use an MMC snap-in to manage WSUS, you must install it on every machine you wish to use to manage WSUS, where as the terminal services client is installed by default on every windows XP machine.  (Start, Run, mstsc)


Have you ever before experienced travelling down the freeway as well as unexpectedly a vehicle came out of nowhere as well as rammed your car? Frightening and it'll be a problem for you, I recognize. So after submitting a record to the authorities as well as treating your wounds (if you have any type of), it's time to often tend for your cars and truck's repair.
You might ask yourself, "Which service center is best as well as can do the work efficiently?". Below are some actions as well as pointers on exactly how to choose the appropriate automobile service center that will suit your needs.
Do not be impulsive when picking a cars and truck service center. There are really inexpensive fixing stores which are great in repairing cars and truck troubles. Request an evaluation of expenses whenever you go to a store. Some will offer you n evaluation of $2,000 while others might provide you simply $500 dollars evaluation for a whole package in repairing your car.
Know when to recognize if the less costly service center is okay or otherwise. Additionally, don't simply choose the less expensive one. You must additionally ensure that the store give premium quality services for your cherished car. You won't desire your vehicle's problems to be worse, right?
Do not be lured by a company's ads that you see on television. It's normal for them to say that they offer excellent quality solutions but after availing the claimed services, you'll observe that it's the complete opposite from what they marketed.
Discover how to ask as well as pay attention to individuals. The very best reviews about a certain business or shop are the customers themselves. Consider the reviews written by REAL individuals in concerns to a store's services. If you can see that there are lots of positive testimonials regarding that firm, after that you can make a go for it.
If there are a lot more negative evaluations than good ones, after that it's time for you to back off and also search for an additional shop to dispatch your cars and truck to.
Yes. The cost variety of a store's solutions are normally based on the shop's place and also the number of workers that they use. If the store lies on the borders of town, the opportunity of a low cost array is high. But if the service center lies in rich cities, then expect that their solutions' costs will be higher.
There are some stores which overprice services the first time that you make inquiries in their shop. After leaving, have a pal or a family members participant inquire on the same shop as well as contrast the prices offered to you. You can request several pals to do this. With this sort of tactic, you would certainly understand if the costs are the very same or if there are some overpricing occurring.
When picking a body store, do not share your wallet open. Ask some vital inquiries such as does the store supply a composed warranty as well as if so, for how lengthy as well as what does it cover?
You will certainly likewise desire to know regarding the materials the shop plans to utilize. Are new, secondhand or aftermarket body components going to be used? Among the things that makes us one-of-a-kind right here at Three-C Body Shops is that we only utilize authentic OEM parts. If paint job is involved, ask the amount of coats of paint as well as clear coat the store plans to use.
Lastly, follow your intuition. If ever before you discover yourself having doubts about a specific vehicle service center, after that follow your instinct and also obtain the heck out of there! Possibility are, you are in uncertainty because you listened to something bad regarding that shop or you saw that they are not qualified of offering the type of solution that you require and also should have to have for your car. After you leave quit by among our areas to see why you have nothing to fret regarding when we manage your vehicle body repair work services.
Visit the store prior to you devote, and don't hesitate to ask inquiries. You can obtain a feeling for exactly how the store is run as well as how they treat their clients from a quick browse through.
Is the team expert? A wonderful crash repair service shop need to treat you with regard, be organized, as well as want as well as able to answer inquiries that you have. They may additionally have awards, subscriptions, as well as various other certificates awaiting the entrance hall.
Can you see the cars that are presently being fixed? Look at their age, make, and also version. Are they similar to yours? Ask the customer care personnel if the shop has experience working with vehicles like yours. Inquire about any type of work or components assurances, guarantees, or requirements. Check that they approve your technique of payment, as well as ask if they have availability. It's tolerable to be picky when it comes to discovering the best repair shop for your cars and truck. Nevertheless, you should have the most effective high quality solution that you might perhaps get which is specifically what has actually helped us expand in Ohio.


Waiting To Communicate is a photograph by Jane Tripp which was uploaded on October 6th, 2010.
One large & haunting face can clearly be seen in this paranormal image, but there are smaller faces visible. When you find them you can use the magnifying tool to see them closer up.
This is a photograph that I received in a series of Instrumental Transcommunication Experiments I designed to create a backdrop on which spirits could appear. This is a 'black bag shot'.
There are no comments for Waiting To Communicate. Click here to post the first comment.


M31 switch looking for hot female to video chat.
I'm a 31 male switch. I like to be controlled and sometimes dominate.
I love pics and tried video chat, too.
Would love it if anyone would take control. Would love to talk more vocally wise too!


text:
Q: Render template to escaped string for json in Django This is more of a general python question, but it becomes a little more complicated in the context of Django.
I have a template, like this, simplified:
miles

I'm replacing an element with jquery and ajax:
$.getJSON('/getunit/', function(data){
   $('#unitHolder').html(data.unit_html);
});

Which goes to a view function to retrieve json data (more data than just this template).  So I wanted to serve it up as json, and not just a string.  So, the relevant code is this:
    ...
    context = { 'qs' : queryset }
    data['unit'] = render_to_string('map/unit.html', context)
    data = str(data).replace('\'','"') #json wants double quotes
return HttpResponse(data, mimetype="application/json")

This works for all of our other data, but not the template, because it has double quotes in it, that are not escaped.  My question is, how do you escape a string in python to be used in a json format?  Note that render_to_string() renders the string in unicode, thus u"...".
I've tried
import json
data['unit'] = json.dumps(render_to_string('map/unit.html', context))

But that gives me "unit": ""miles"".
Also:
data['unit'] = str(render_to_string('map/unit.html', context)).replace('"','\"')

and:
data['unit'] = str(render_to_string('map/unit.html', context)).replace('"','\\"')

But neither escape the double quotes properly.

A: I hadn't tried json.dumps until I came into this problem.  Previously I was just converting python dictionaries to strings and then replacing single quotes with double quotes.  And for most of the data we've been passing to the client, it rendered correct JSON format.  Now that I've tried json.dumps here in this problem, I realized that I don't need to convert dictionaries with str or replace anything.  I can render the script as follows:
    ...
    context = { 'qs' : queryset }
    data['unit'] = render_to_string('map/unit.html', context)
    import json # I'll import this earlier
    data = json.dumps(data)
return HttpResponse(data, mimetype="application/json")

This works with all the data I'm passing to JSON format, so that works perfectly fine, and that's how I should have been doing it all along.


text:
Witaszewice [] es un pueblo ubicado en el distrito administrativo de Gmina Góra Świętej Małgorzaty, dentro del Distrito de Łęczyca, Voivodato de Łódź, en Polonia central. Se encuentra aproximadamente a 6 kilómetros al noreste de Łęczyca y a 37 kilómetros al norte de la capital regional Łódź.

Referencias

Enlaces externos

Localidades del voivodato de Łódź

redpajama_set_name: RedPajamaWikipedia


text:
Home » Destinations » Just Back » Bringing a bunch of Harley-Davidson owners together
Bringing a bunch of Harley-Davidson owners together
Just Back
Catch a glimpse of what went down at the 3rd Northern H-D Owners Group Rally in Pushkar, Rajasthan
Sopan Joshi | December 12, 2014
It is one of the most recognisable of sounds. Harley-Davidson's noisy, air-cooled engines are tuned especially to create that characteristic growl. The only thing that sounds even more impressive is several Harley-Davidson motorcycles growling in unison.
On November 7, the town of Pushkar in Rajasthan, recovering from the aftermath of the famous camel fair, was shaken by the noise of more than 500 Harley-Davidson motorcycles ridden in from all parts of the country. From Kolkata to Ahmedabad, from Kochi to Chandigarh, Harley-Davidson riders and their friends and families in accompanying vehicles gathered for the third annual rally in northern India of the H-D Owners Group (HOG) chapters in India.
An entire tented locality sprung up west of Pushkar to host a carnival of song, dance and drunken revelry, for the Irish whiskey brand Jameson is a co-sponsor of the annual rally. The riders arrived gradually all through the first day. Pushkar's streets were animated with the noise and heat of large machines — people asking about prices of camels had ready questions about the price of the premium Harley-Davidson machines.
The party started with live music and the initial rounds of arm-wrestling and tug-o'-war contests, for nobody was expecting a fashion show in the testosterone gala. The second day saw the finals, which were both won by the host chapter of Rajasthan. Without letting anybody know, the Dunes chapter had fielded one of its members who is the state-level arm-wrestling champion.
Over the venue flew a helicopter, for the event included paid rides over Pushkar. Just to mess around with the riders, the pilot repeatedly flew low over the venue. (The plan was to have a hot-air balloon, but two days before the event, the operators lost their licence after turbulent winds drove them off course. Flying three foreign tourists, the pilot landed at the first safe, open field he saw. Unfortunately for him — and fortunately for newspaper readers the next day — that field was too secure: right in the middle of Ajmer jail.)
HOG is the largest company-supported effort to create a sub-culture to expand marketing and merchandising. It has played a central role in making Harley-Davidson one of the most valuable brands in the world. HOG clubs initiate new riders into the special, special feeling that Harley-Davidson has marketed so, so successfully. Sales of Harley-Davidson motorcycles are steadily increasing in India, especially after the introduction of the Street 750, the cheapest Harley-Davidson machine in India, developed from a new platform of liquid-cooled engines aimed at city riders who seek a high-end toy to mess around the urban jungle.
Motorcycle sub-cultures have thrived when a young generation has spare income. From Europe to North America, motorcycling groups and leisure riding is a product of the post-war boom. With the emergence of a new class in India over the past decade, as a result of the post-1991 economic reforms, there are young people with purchasing power and the desire for the trademarked freedom that Harley-Davidson offers.
Along with weekend rides that HOG chapters organise, bigger rallies like the one at Pushkar become a way to expand as a sub-culture. Harley-Davidson got the chief of its engineering division in India to hold an hour-long briefing on motorcycle maintenance, catering to those who take their riding more seriously. For those just looking for a good time and happy riding, there was the music, Jameson and the opportunity to bond with riders from across the country.
biking Harley Davidson motorcycle culture Pushkar Rajasthan
Biking Across Kerala, Tamil Nadu & Karnataka
South of India is an absolute treasure-trove for those who like a little bit of a two-wheeled adventure
Kyrgyzstan Chronicles: A Biking Holiday
Have the ride of your life in this Central Asian wonderland
8 Hot New Bikes to Take on a Road Trip
From cruisers to speedsters, we've got the right mix for you


text:
MUSIC: Ayanfe Viral – Adekunle Gold
September 4, 2018 Adewale Olukosi	Comment
Many have been mistaken "Ayanfe Viral" to "Adekunle Gold", not because of their facial looks but for their Similar Concept to Music, Techniques, Style and Voice. Even Though this song will convince you the rumours are not so, many will still have problems in admitting, "why??" Because "Ayanfe Viral" is just too much. "Salute" The success of this song comes in hand with the work of "Festus Awoyemi" P.K.A "FestBeat", "FDY Beatz" And Co-song Writer "Owodunni Majekodunmi" P.K.A MJK & "Mullah Da Manager" DOWNLOAD HERE [Read]
E.U releases €138 million to fund Lake Chad region
September 4, 2018 Newsflakes Admin	Comment
….Nigeria gets largest chunk of €74.5m The European Union (E.U) has released €138 million for humanitarian and development funding for Nigeria and other Lake Chad basin countries and Cameroon. The development assistance announced will go to the four countries in the region: Nigeria (€74.5 million), Niger (€32.2 million), Chad (€33.2 million), and Cameroon (€2.7 million), for a combined amount of €143 million, out of which €34.7 was announced earlier this year. The sum of €58.75 million was announced in July 2018 as part of humanitarian assistance provided by the EU to the Sahel countries. Prolonged violence and insecurity has worsened the humanitarian crisis in the Africa's Lake Chad basin, affecting [Read]
BUSINESS AND ECONOMY: CBN awaits MTN's action on $8.1b refund order
The Central Bank of Nigeria (CBN) is not worried by MTN's denial of alleged illegal repatriation of $8,134,312,397.63 it levelled against the mobile giant. An official, who was reacting to MTN's denial of the allegation, was asked what the CBN will do "in the event that MTN refuses to pay back the $8.1 billion and when the 'immediate effect' deadline given to MTN will expire?" The official, who refused to be named, said: "When we get to that bridge, we'll know how to cross it." To some experts, the CBN has taken a bold stand against banks and the company for alleged money laundering. The MTN on Thursday rejected the [Read]
INSECURITY: SGF inaugurates committee on peace commission
Secretary to the Government of the Federation, Mr. Boss Mustapha, has inaugurated the committee on the establishment of a National Peace Commission with the acting Director General of the Institute for Peace and Conflict Resolution, Dr. Bakut Bakut as chairman. Mustapha, who was represented by the Permanent Secretary, Special Duties, Dr. Amina Bello said the National Economic Council recommended the establishment of the commission and peace agencies for states after reviewing the security situation of Nigeria in August 2017. The committee has three months to accomplish its task and submit reports. The IPCR Information Officer, Abu Michael said in a statement in Abuja on Monday that the NEC had identified [Read]
Vice President Yemi Osinbajo launches Traders Moni in Osun State (See Photos)
September 4, 2018 September 4, 2018 Newsflakes Admin	Comment
Vice President Professor Yemi Osinbajo, SAN, earlier today Tuesday September 4 visited Iwo town in Osun State, where he launched the Trader Moni Scheme; a Government Enterprise and Empowerment Program for petty traders. NEWS FLAKES NG also gathered that the Vice President also visited the Odo- Ori market and Abbatoir in Iwo, where he interacted with some traders and butchers. He was accompanied by the Governor of Osun State, Ogbeni Rauf Aregbesola; Dep. Governor Osun State, Mrs. Titilayo Laoye-Tomori; Oluwo of Iwo, Oba Abdulrasheed Adewale Akanbi; and other FG and State government officials. SEE MORE PHOTOS FROM THE VISIT and LAUNCHING BELOW as obtained by NEWS FLAKES NG: Meanwhile, as [Read]
SHOCKING: Lagos Police Officer Dies While Having sex in His Office
NEWS FLAKES NG gathers that a Superintendent of Police identified as Sunday Eguakhide, on August 24, about 11.30a.m., died while making love to a mother of two in his office at the Police College Ikeja in Lagos State. Our source reports that Eguakhide had less than a week to his retirement, when the incident occurred. The lover, upon being arrested, denied having anything to do with his death. According to her, the deceased was fond of taking sex enhancement drugs whenever they wanted to have sex. She was quoted as saying: "He always used to have sex with me in his office. He had already gone once, but as usual, [Read]
2019: David Mark joins presidential race, to pick forms Tuesday
Former Senate President, David Alechenu Bonaventure Mark, would later today, September 4, pick his presidential interest and nomination forms ahead of the 2019 presidential elections. NEWS FLAKES gathered that Mark, also knowns as "the Okpokpowulu K'Idoma" will contest on the platform of the Peoples Democratic Party, PDP. Mark will be joining his predecessor, Bukola Saraki, Rabiu Kwankwaso, Atiku Abubakar and others to battle for the PDP presidential ticket. Confirming the development to our source on Monday, James Oche, national coordinator of Doo2Door for David Mark, said his principal, after a nationwide consultation has decided to join the presidential race to salvage the entity called Nigeria from a total collapse. . [Read]
2019: Buhari is healthier than 80% of Nigerians – Ngige
Chris Ngige, a medical doctor and the current Minister of Labour and Employment, has revealed that President Buhari is healthier than 80% of Nigerians. According to him: "That man (Buhari) you see there is healthier than 80 percent of Nigerians. I'm a medical doctor, I can tell you authoritatively that he is healthier than most people who see his health as an issue. . He sits for over eight hours during our executive meetings. While some of us would be going for tea break to stretch our legs, Mr President would sit on his seat continuously, drinking only water. I can tell you authoritatively as a medical doctor of over [Read]
SHOCKING: Hairdresser Stabs Neighbour to Death for Calling her 'Shaku-Shaku'
NEWS FLAKES NG gathers that a 23-year-old hairdresser, Opeyemi Adamson, has allegedly killed her neighbour, Taiwo Olowookere, at their house in the Meiran area of Lagos State. Our source gathered that 28-year-old Taiwo lived with the suspect's mother-in-law, who accommodated her after she separated from her husband. Opeyemi, who lived with her husband, stayed in the same compound with the victim. The duo were said to have nursed animosity towards each other until Friday, August 24 when things took a tragic turn. The deceased had reportedly complained about Opeyemi's eight-months-old baby, saying the child's noise disturbed her. The suspect reportedly insulted her, which led to exchange of words. NEWS FLAKES [Read]


text:
namespace RouteExtreme.Services
{
    using System;
    using System.Linq;
    using Contracts;
    using Data;
    using Data.Repositories;
    using Microsoft.AspNet.Identity;
    using Microsoft.AspNet.Identity.EntityFramework;
    using Models;

    public class UserService : IUserService
    {
        private IRepository<User> users;
        private UserManager<User> userManager;

        public UserService(IRepository<User> users)
        {
            this.users = users;
            this.userManager = new UserManager<User>(new UserStore<User>(new RouteExtremeDbContext()));
        }

        public void Delete(string id)
        {
            var user = this.users.GetById(id);
            if (user == null)
            {
                throw new Exception("No such user id");
            }

            this.users.Delete(user);
            this.users.SaveChanges();
        }

        public IQueryable<User> GetAll()
        {
            return this.users.All()
                             .Where(x => !x.IsDeleted);
        }

        public IQueryable<User> GetById(string id)
        {
            return this.GetAll()
                        .Where(u => u.Id == id);
        }

        public IQueryable<User> GetByUsername(string username)
        {
            return this.GetAll()
                .Where(x => x.UserName == username);
        }

        public void UpdateUser(User user)
        {
            this.users.Update(user);
            this.users.SaveChanges();
        }

        public void Create(User user, string password)
        {
            this.userManager.Create(user, password);
            this.userManager.AddToRole(user.Id, "user");
        }

        public void MarkAsDeleted(User user)
        {
            this.users.MarkAsDeleted(user);
            this.users.SaveChanges();
        }
    }
}

redpajama_set_name: RedPajamaGithub


text:
Accidental Americans: Taking the Cost of Renouncing U.S. Citizenship to Court
The significant cost of renouncing U.S. citizenship is officially being called into question by L'Association des Américans Accidentals (AAA). On December 8th, 2020, the organization of French/American dual citizens filed a complaint requesting "declaratory and injunctive relief" from the onerous U.S. government fee with the U.S. District Court for the District of Columbia.
The term "Accidental American" is often used to describe individuals who are American through no fault of their own, meaning they were born in the U.S. but spent most of their life as a resident of another country, or they were born to U.S. parents but never lived on U.S. soil.
If you happen to be an Accidental American, you are likely aware of the annual cost of being a taxpayer in your country of residence in addition to being a U.S. taxpayer. And if you are among the many who are considering becoming a Purposeful Ex-American, you probably also know the cost of renouncing U.S. citizenship.
In the view of the AAA, the current cost of renouncing U.S. citizenship violates the Fifth Amendment's due process clause, the First Amendment, and the Eighth Amendment's excessive fines clause. According to the strongly worded filing, "the right to expatriate is a customary international norm enshrined and reflected in international and state practice and treaties. By conditioning this right on the payment of a fee (other than a nominal modest fee), the government has run afoul of its international duties and obligations."
In fact, the cost of renouncing U.S. citizenship has gone from no fee in 2010 to $2,350 as of 2015. While that may be a nominal fee for some, there are often other significant financial implications such as exit tax. Exit tax is a final one-time payment to the U.S. government that is assessed based on the value of total worldwide assets.
And the AAA is not the first party to take action against the U.S. government regarding the prohibitive price tag for renouncing U.S. citizenship. The EU Council presidency made a similar appeal in December of 2019, which has not seen resolution to-date.
Are you a U.S. citizen who is not a resident of that country, and you want to get out from under U.S. taxation and reporting obligations? If you're in the mood for some serious sticker shock…I mean…if you want to find out more about the paperwork and cost of renouncing U.S. citizenship, feel free to reach out to us at HCBT
Biden Presidency may be more taxing for Canadians with cross-border affairs Updates to COVID 19 – New Rental Subsidy and Support Program – December...


Why is Stress Such an Issue Among High School Students?
High school students do not know how to cope with stress. This much is blatantly obvious through the occasional crying and constant breakdowns throughout the halls. But why is this? It is evident throughout history that workload has increased with knowledge and technology, but why haven't our emotional coping mechanisms?
Students nowadays have close to the same stress levels as patients in asylums from the 1950s, and this is not okay. Sometimes having someone to talk to is not good enough when it comes to coping with yourself. Students must have access to spaces away from everyone else to get back on their feet during the school day. I have known plenty of people to have anxiety or panic attacks during school and no way to recover for upcoming classes. Would a solitary space fix this? Not necessarily. But it is a step in the right direction. One of the best ways to get over these kinds of things is to be in an area that allows you to relax and recoup. Another positive effort would be the inclusion of therapy dogs throughout the school. Therapy animals have been known to drop stress levels significantly, and so long as there are no major allergies in certain rooms could help with coping. Not only would they reduce stress, they may also raise test scores as a result of this.
When it comes down to it, if schools continue this pattern, it could be catastrophic for its kids. If stress levels continue to rise and the coping mechanisms stay at a standstill, the results could be disastrous. Schools should consider their options in helping students with coping mechanisms. Small changes could have large results.


Graphical abstract of Chatterjee et al., 2018,Cell Metabolism.
Immunotherapy has emerged as a promising new cancer treatment modality over the last decade. The components of immune-system are the integral part of tumor microenvironment and responsible for the tumor progression and/or regression. Consequently immunotherapeutic approaches involves the modulation of immune cell activity by using adoptive cell transfer (ACT), dendritic cell vaccines, oncolytic viruses, chimeric-antigen receptor T-cells, or monoclonal antibodies (mAbs), etc. Although all these strategies have displayed substantial improvement in clinical outcomes for many types of cancers, the long term benefits remain elusive. Therefore, integrated efforts are necessary to improve the efficacy and attain long term sustainability of anti tumor immune response.
A recent study published in Cell metabolism, Jan 2018, by Mehrotra and colleagues reported an ex vivo culture strategy to improve the long term efficacy of adoptive cell therapy. Using the melanoma murine model, they differentiated CD4+ T cells into hybrid Th1/17 cells that secrete both IL-17 and IFNγ which exhibit superior anti-tumor activity than Th1 and Th17 when adoptively transferred to the tumor bearing mice. In addition, antibody mediated targeting of CD38 (nicotinamide adenine dinucleotide-NAD+- hydrolase) on CD4T cells, rewired the metabolic fitness of tumor infiltrating lymphocytes and improved the tumor control. Chatterjee et al., combined the culture conditions of Th17 (IL6, IL1β, IL23, TGFβlo) and Th1 cells (with IL12 and IL2) to generate hybrid Th1/17 cells, which co-expressed elevated levels of IFNγ and IL17. The intermediate expression of chemokines, effectors molecules, stemness-associated genes and metabolic enzymes by Th1/17 cells may reflect plasticity of Th1 and Th17cells. Nonetheless this unique molecular signature has provided Th1/17 cells an added advantage of increased antitumor activity than Th1 and Th17 cells as shown in mouse ACT models of melanoma and metastatic lung cancer.
Chatterjee et al., have shown that the hybrid Th1/17 cells exhibit unique metabolic preferences that rely on glutamine-driven oxidative phosphorylation and the shunting of glycolysis into pyruvate to drive the TCA cycle. Inhibition of glutamine metabolism by using glutaminase inhibitor, showed reduced expression of effector molecules and attenuation of anti-tumor response by hybrid Th1/17 cells. Th1 cells primarily use aerobic glycolysis for effector functions, whereas Th17 cells require fatty acid oxidation (FAO). Th1/17 cells have their extracellular acidification rate (ECAR, a measure of aerobic glycolysis) and oxygen consumption rate (OCR) fall within an intermediate range compared to Th1 and Th17cells. These findings suggest that the metabolic preference of hybrid Th1/17 cells to use glutaminolysis provide survival advantage in the tumor environment where availability of glucose is a limiting factor for immune-surveillance.
The levels of NAD+ associate with T cell proliferation, cytokine production and survival. Chatterjee et al., have observed that the increased levels of NAD+ in Th1/17 cells depend upon glutaminolysis which is required for the maintenance of their anti-tumor activity and viability in vivo. Moreover, Th1/17 cells also have increased activity of Sirt1, an epigenetic modulator and NAD+-dependent protein deacetylase. NAD+ dependent Sirt1 deacetylase activity is essential for the anti-tumor activity of hybrid Th1/17 cells, as genetic ablation or pharmacological inhibition of NAD+/ Sirt1 resulted in decrease in the frequency of IL17+IFNγ+ cells, reduced expression of stemness associated molecules and failure to exhibit potent tumor control upon adoptive transfer. In addition, inhibition of Sirt1 activity did not affect the expression of key enzymes associated with different metabolic pathways suggesting that NAD+-Sirt1 axis regulate Th1/17 cell functions, but not their metabolic reprogramming. Further Chatterjee et al have shown that inhibition of NAD+/ Sirt1 increased the acetylation of Foxo1 (transcription factor associated with T cells memory) to attenuate its function thereby affecting Th1/17 cell migration, effector function, stemness, and anti-tumor responses. Phosphorylation of Foxo1 facilitates its nuclear export and loss of transcriptional activity. The authors have observed decreased nuclear retention of Foxo1associated with low antitumor activity compared to Th1/17 cells. Inhibition of AKT in Th1 cells significantly reduced the phosphorylation of Foxo1, and concomitantly increased its nuclear retention. Thus antitumor phenotype of Th1 can be improved by inhibiting the AKT-Foxo1 axis. The data suggested that the increased levels of NAD+-Sirt1-Foxo1 axis in Th1/17 cells is responsible for the enhanced antitumor effector functions compared to Th1 cells.
To improve the anti-tumor response of CD4+ T cells, Chatterjee et al., showed that the levels of NAD+ can be increased by inactivating CD38, a NADase cell surface molecule that is expressed at low levels in Th1/17 cells. Genetic ablation of CD38 or use of blocking anti CD38 mAb in CD4T cells showed phenotype similar to Th1/17 cells including increase in glutamine uptake, glutaminolysis, mitochondrial biogenesis, and improved anti-tumor activity. Interestingly, expression of PD1 (inhibitory receptor associated with T cells exhaustion) was not much different between the tumor infiltrating WT or CD38KO T cells. This implies that CD38 expression plays a key role in metabolically modulating even PD1-expressing exhausted T cells.
The present study on murine model by Chatterjee et al., showed that combining anti-CD38 antibody along with adoptive transferred T cells enhanced anti-tumor response. Th1/17 hybrid cells have emerged as potent candidate for cell therapies for their better and sustainable metabolic adaptation in the tumor environment. Despite the PD-1 expression by tumor infiltrating T cells, blockade of CD38 rewired the metabolic flux of T cells to maintain elevated levels of NAD+ and Sirt1-Foxo1 mediated improved antitumor functions. Thus metabolic reprogramming of T cells by CD38mAb holds significance in the widespread application of adoptive cell transfer as an immunotherapeutic modality for cancer treatment.