Scope of this dissertation Sample Clauses

Scope of this dissertation. This dissertation aims to use the knowledge by which resistance to lapatinib is acquired to develop novel therapeutic treatments for patients with HER2-overexpressing breast cancer. The PI3K/Akt/mTOR and MEK/ERK pathways have been linked to the development of resistance to HER2 targeted therapies. I propose that combination lapatinib treatment and inhibition of the either the PI3K/Akt/mTOR pathway or combination lapatinib treatment and inhibition of the MEK/ERK pathway will achieve an optimal lapatinib response. The data reveals that reduced lapatinib sensitivity is associated with an inability of lapatinib to inhibit both Akt and MEK/ERK phosphorylation. An investigation of the role of Akt in lapatinib resistance demonstrated that the transfection of constitutively active Akt reduces lapatinib sensitivity, while kinase-dead Akt increases sensitivity. Knockdown of 4EBP1 also increases lapatinib sensitivity, in contrast to p70S6K knockdown, which does not affect response to lapatinib. Further, the pharmacologic inhibition of mTOR using rapamycin or ridaforolimus increases lapatinib sensitivity and reduces Akt phosphorylation levels in cells that show poor response to single agent lapatinib, including those transfected with hyperactive Akt. An evaluation of the role that MEK/ERK plays in lapatinib resistance demonstrates that genetically and pharmacologically blocking MEK/ERK signaling improves response to lapatinib. Also, combination MEK inhibitor plus lapatinib results in a reduced nuclear expression of the MEK/ERK downstream proto-oncogene FOXM1. In addition, xenograft studies demonstrate that pharmacologic inhibition of MEK increases lapatinib sensitivity in HER2-overexpressing breast cancers that are resistant to trastuzumab and lapatinib. This dissertation provides mechanisms by which resistance to lapatinib is achieved, and strongly supports future clinical trials of combination lapatinib plus mTOR inhibition, as well as combination lapatinib plus MEK inhibition.
Sample 1
AutoNDA by SimpleDocs

Related to Scope of this dissertation

  • SCOPE OF THIS AGREEMENT 2.1. This Agreement, including Parts A through L, Tables One and Two and exhibits, specifies the rights and obligations of each Party with respect to the establishment, purchase, and sale of Local Interconnection, Collocation, resale of Telecommunications Services and Unbundled Network Elements. Certain terms used in this Agreement shall have the meanings defined in PART A – DEFINITIONS, or as otherwise elsewhere defined throughout this Agreement. Other terms used but not defined in this Agreement will have the meanings ascribed to them in the Act and in the FCC’s and the Commission’s rules, regulations and orders. PART B sets forth the general terms and conditions governing this Agreement. The remaining Parts set forth, among other things, descriptions of the services, pricing, technical and business requirements, and physical and network security requirements.

  • SCOPE OF THIS CONTRACT What is covered by this contract?

  • Examination of this Agreement A copy of this Agreement shall be available at all reasonable times at the office of the Right Agent in the Borough of Manhattan, City and State of New York, for inspection by the registered holder of any Right. The Right Agent may require any such holder to submit his, her or its Right for inspection by it.

  • PURPOSE OF THIS AGREEMENT The purpose of this Agreement is to - 2.1 comply with the provisions of Section 57(1)(b), (4A), (4B) and (5) of the Systems Act as well as the employment contract entered into between the parties; 2.2 specify objectives and targets defined and agreed with the Employee and to communicate to the Employee the Employer’s expectations of the Employee’s performance and accountabilities in alignment with the Integrated Development Plan, Service Delivery and Budget Implementation Plan (SDBIP) and the Budget of the Employer; 2.3 specify accountabilities as set out in a performance plan, which forms an annexure to the performance agreement; 2.4 monitor and measure performance against set targeted outputs; 2.5 use the performance agreement as the basis for assessing whether the Employee has met the performance expectations applicable to his or her job; 2.6 in the event of outstanding performance, to appropriately reward the Employee; and 2.7 give effect to the Employer’s commitment to a performance-orientated relationship with its

  • Operation of this Agreement This Agreement shall take effect on and from the date of this Agreement. The parties must execute and enter into this Agreement as soon as possible after the Development Consent is granted and prior to the issue of any Construction Certificate that relates to any building work, other than demolition, excavation, piling, shoring and ancillary work for construction purposes including site hoardings and temporary site sheds that relates to works contained in DA-152/2021/B.

  • EFFECTIVE PERIOD AND TERMINATION OF THIS AGREEMENT (a) This Agreement shall not become effective until such time as it is fully executed by all parties hereto (the "Effective Date"). Subject to any early termination provisions below, this Agreement shall continue in full force and effect as to the Fund for a period of five years from the Effective Date. (b) Notwithstanding the foregoing, if (i) the Trustees of the Trust or the shareholders by the affirmative vote of a majority of the outstanding shares of the Fund, and (ii) a majority of the Trustees of the Trust who are not interested persons of the Trust or of the Adviser or of the Subadviser, by vote cast in person at a meeting called for the purpose of voting on such approval, do not specifically approve at least annually the continuance of this Agreement, then this Agreement shall automatically terminate at the close of business on the second anniversary of the Effective Date, or upon the expiration of one year from the effective date of the last such continuance, whichever is later. This Agreement may continue in effect following the fifth anniversary of the Effective Date only so long as such continuance is approved in accordance with applicable law. (c) Notwithstanding the foregoing, if the continuance of this Agreement is submitted to the shareholders of the Fund for their approval and such shareholders fail to approve such continuance of this Agreement as provided herein, the Subadviser may continue to serve hereunder in a manner consistent with the 1940 Act and the rules and regulations thereunder. (d) The Trust may at any time terminate this Agreement upon 60 days prior written notice delivered or mailed by registered mail, postage prepaid, to the Adviser and the Subadviser. Action by the Trust to effect such termination may be taken either (i) by vote of a majority of its Trustees, or (ii) by the affirmative vote of a majority of the outstanding shares of the Fund. (e) Either the Adviser or the Subadviser may at any time terminate this Agreement by not less than 60 days' written notice delivered or mailed by registered mail, postage prepaid, to the other party and the Fund. (f) Termination of this Agreement pursuant to this Section 5 shall be without the payment of any penalty by the Fund. Neither the Adviser nor the Trust shall use or refer in any way to the name of the Subadviser following the termination of this Agreement without the Subadviser's consent, except as may be required by law.

  • Duration of this Agreement The Term of this Agreement shall be as specified in Schedule A hereto.

  • Enforcement of this Agreement The parties agree that irreparable damage would occur in the event that any of the provisions of this Agreement were not performed in accordance with their specific terms or were otherwise breached. It is accordingly agreed that the parties shall be entitled to an injunction or injunctions to prevent breaches of this Agreement and to enforce specifically the terms and provisions hereof in any court of the United States or any state having jurisdiction, this being in addition to any other remedy to which they are entitled at law or in equity.

  • Application of this Agreement This Agreement applies to the Land and to the Development proposed in the Development Application, as may be modified.

  • Performance of this Agreement Buyer shall have duly performed or complied with all of the obligations to be performed or complied with by it under the terms of this Agreement on or prior to the Closing Date.

Draft better contracts in just 5 minutes Get the weekly Law Insider newsletter packed with expert videos, webinars, ebooks, and more!