Genetic modification of T-cells Sample Clauses

Genetic modification of T-cells. Successful gene expression and modification of T-cells requires robust methods of gene delivery to efficiently express transgenes. In general, to achieve sustained CAR expression in proliferating T-cells, an integrating viral vector system is used. Viruses are obligate intracellular parasites that are able to exploit host cells to facilitate their replication92. In gene therapy, virus-based vectors harness the viral infection pathway whilst excluding viral genes required for replication and toxicity. To ensure no virion replication post infection of cells, replication-defective vectors are used in which the coding regions for the four genes gag, pro, pol and env, which are crucial for the completion of the retroviral life cycle, are deleted and replaced with the DNA sequence intended for transfer. The genome of the retrovirus contains two RNA copies, these encode for the four genes gag, pro, pol and env. The gag sequence encodes for the three main structural proteins: matrix, capsid and nucleocapsid proteins. The pro sequence, encodes for proteases responsible for cleaving gag and gag-pro-pol during particle assembly, budding and maturation. The pol sequence encodes the reverse transcriptase and integrase enzymes; the former catalyses the reverse transcription of viral RNA to DNA during the infection process. The integrase enzyme is responsible for integrating the pro- viral DNA into the host cell genome. The env encodes both the surface and transmembrane subunits of the envelope glycoprotein The retroviral life cycle is summarised in Figure 1.1. Infection of the host cell by retroviruses is initiated when the glycoproteins of the viral envelope attach to their receptors expressed on the surface on the host cell. Upon recognition, the viral envelope fuses with the host cell membrane and the viral RNA is released into the cytoplasm. Reverse transcriptase converts the viral RNA into double-stranded DNA which is then transferred to the host cell nucleus. The viral DNA gains access to the nucleus during mitosis after the dissolution of the nuclear membrane, at this time the double-stranded DNA is integrated into the host cell genome to form the provirus. This process occurs in an almost random manner throughout the host cell genome. The integrated provirus is then transcribed by RNA polymerase II to yield mRNA that encodes for viral proteins. The mRNA is exported from the nucleus and translated by the host-cell machinery, the translated proteins are further pr...
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Related to Genetic modification of T-cells

  • Contract Modification The conditions of this timber sale are completely set forth in this contract. Except as provided in B8.32 and B8.33, this contract can be modified only by written agreement between the parties. Only Contracting Officer may make contract modifications, with compensating adjustments to Current Contract Rates where appropriate, on behalf of Forest Service.

  • DESCRIPTION OF CONTRACT MODIFICATION This contract modification is made in accordance with Exhibit E-Revised-1, Contractual Terms and Conditions, Section 22. CHANGES, to be made part hereof for all pertinent purposes. The changes are as follows:

  • Contract Modifications It is understood that changes are inherent in operations of the type covered by this contract. The number of changes, the scope of those changes, and the impact they have on the progress of the original operations cannot be defined at this time. The PURCHASER is notified that changes are anticipated and that there will be no compensation made to the PURCHASER directly related to the number of changes made. Each change will be evaluated for extension of contract time and increase or decrease in compensation based on its own merit. STATE reserves the right to make, at any time during the contract, such modifications as are necessary or desirable; provided such modifications shall not change the character of the operations to be done nor increase the cost, unless such operations or cost increase is approved in writing by PURCHASER. Any modifications so made shall not invalidate this contract nor release PURCHASER of obligations under the performance bond. PURCHASER agrees to do the modified operations as if it had been a part of the original contract. If any change under this section causes an increase or decrease in the PURCHASER's cost of, or the time required for the performance of any part of the operations, the PURCHASER must submit a written statement setting forth the nature and specific extent of the claim. Such claim shall include all time and cost impacts against the contract and be submitted as soon as possible, but no later than 30 days after receipt of any written notice of modification of the contract. If the PURCHASER discovers site conditions which differ materially from what was represented in the contract or from conditions that would normally be expected to exist and be inherent to the activities defined in the contract, the PURCHASER shall notify the STATE's Authorized Representative immediately and before the area has been disturbed. The STATE's Authorized Representative will investigate the area and make a determination as to whether or not the conditions differ materially from either the conditions stated in the contract or those which could reasonably be expected in execution of this particular contract. If it is determined that a differing site condition exists, any compensation or credit will be determined based on an analysis by STATE's Authorized Representative. If the PURCHASER does not concur with the decision of the STATE's Authorized Representative and/or believes that it is entitled to additional compensation, the PURCHASER may proceed to file a claim. Claims Review Process. All PURCHASER claims shall be referred to the STATE's Authorized Representative for review. All claims shall be made in writing to the STATE's Authorized Representative not more than ten days from the date of the occurrence of the event which gives rise to the claim or not more than ten days from the date that the PURCHASER knew or should have known of the problem. Unless the claim is made in accordance with these time requirements, it shall be waived. All claims shall be submitted in writing and shall include a detailed, factual statement of the basis of the claim, pertinent dates, contract provisions which support or allow the claim, reference to or copies of any documents which support the claim, the exact dollar value of the claim, and specific time extension requested for the claim. If the claim involves operations to be completed by subcontractors, the PURCHASER will analyze and evaluate the merits of the subcontractor's claim. PURCHASER shall forward the subcontractor's claim and PURCHASER's evaluation of such claim to STATE's Authorized Representative. The STATE's Authorized Representative will not consider direct claims from subcontractors, suppliers, manufacturers, or others not a party to this contract. The decision of the STATE shall be final and binding unless the PURCHASER requests mediation.

  • Contract Suspension and Modification (a) Contracting Officer may, by written order, delay or interrupt authorized operations under this contract or, notwithstanding B8.3, modify this contract, in whole or in part:

  • Integration and Modification This agreement includes the entire agreement of the parties and supersedes any prior discussions or agreements regarding the same subject. The agreement may be modified only by a written agreement signed by authorized representative of the parties.

  • MODIFICATION OF THE CONTRACT 1. Any modification of this contract or its annexes, including additions or deletions, shall require a supplementary written agreement concluded on the same terms as the contract. No oral agreement may bind the parties for that purpose.

  • Modification of Agreement This Agreement may be modified, amended, suspended or terminated, and any terms or conditions may be waived, but only by a written instrument executed by the parties hereto.

  • DURATION AND MODIFICATION OF AGREEMENT 33:01 This Agreement shall be binding and continue in effect until June 30, 2020, and shall continue automatically thereafter for annual periods of one (1) year each, unless either party notifies the other in writing within the period of three (3) months next preceding the expiration date of this agreement, that it desires to amend or terminate it.

  • Notification of Modifications of Licensed Materials From time to time Publisher may add, change, or modify portions of the Licensed Materials, or migrate the Licensed Materials to other formats. When such changes, modifications, or migrations occur, the Licensor shall give notice of any such changes to Licensee as soon as is practicable, but in no event less than sixty (60) days in advance of modification. Such a notice may also be given directly by the Publisher to the Licensee. If any of the changes, modifications, or migrations renders the Licensed Materials substantially less useful to the Licensee, the Participating Institutions or their Authorized Users, the Licensee may seek to terminate this Agreement for breach pursuant to the termination provisions of this Agreement in Section XI, below.

  • Modification for Catastrophe In event of Catastrophic Damage, Forest Service, in consultation with Purchaser, shall outline on Sale Area Map:

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