Knockout mouse; transgenic mouse; genetically engineered mouse (GEM)

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Knockout (KO) mouse 1987~89년에는 Martin Evans와 Oliver Smithies, 그 리고 Mario Capecchi는 특정 타겟 유전자를 embryonic stem cell에서 기능을 못하게 함으로써 최초의 knockout mouse를 제작하였다. 이들은 그 후 수천 종의 knockout mouse 생산에 사용된 이 기술의 발명에 대한 공헌으로 2001년 Lasker Award를 수상하였고, 그 후 2007년 Nobel Prize를 수상하였다.  International Mouse Phenotype Consortium (IMPC) 이렇게 마우스의 유전체를 변형시켜 새로운 생명체를 만든다는 것은 의생명과학의 발전에 매우 중요하다는 것이 매우 잘 인식되었지만, 그 기술이 너무 오래 걸리고, 경제적이지 못하며, 매우 섬세하고 어려운 과정을 거친다. 그러므로 이를 해결하기 위한 과학자들의 모임이 생겨났다. 마우 스의 모든 유전자를 embryonic stem cell에서 knockout 하여 전세계의 모든 과학자들에게 공급하겠다는 그룹이 나타난 것이다. 2004년 미국을 중심으로 한 Knockout Mouse Project (KOMP)와 유럽을 중심으로 한 European Conditional Mouse Mutagenesis (EUCOMM) Program 이 발족되었고, 그 즈음 retrovirus를 이용한 International Gene Trap Consortium (IGTC)도 나타났고, 그 후 이들이 모두 함께 International Knockout Mouse Consortium 으로 연합하였으며, 최근에는 International Mouse Phenotype Consortium (IMPC)으로 진화하였다. 우리나 라도 2012년 IMPC에 가입하여 회원국으로서의 중요한 과 제를 수행하고 있다. Conditional knockout (KO) mouse [Cre-loxP] 전체 마우스 유전자를 knock

Colorectal cancer studies at ASCO 2018

https://www.medscape.com/viewarticle/897370?nlid=122873_2201&src=WNL_mdplsnews_180601_mscpedit_honc&uac=155670BY&spon=7&impID=1647344&faf=1 #3509 (Geissler M et al. ) 2:1 random of 96 pts. (1st-line) mFOLFOXIRI + panitumumab vs. FOLFOXIRI in RAS-wt mCRC RR: 85.7% vs. 54.5% #3507 ctDNA assay in ~5,000 pts. #3505 (Pietrantonio F et al.) Unresectable RAS-wt mCRC FOLFOX + panitumumab X8  -> 1:1 random of 229 pts. panitumumab vs. panitumumab + FL (better) .. a couple of papers in the  Lancet  from the United Kingdom in which we randomized patients who were responding or had stable disease to stop or continue chemotherapy until progression.  In those rather old-fashioned studies, having a complete chemotherapy break did not interfere or reduce overall survival. And not surprisingly, it was associated with improved quality of life. 1)    And we tend to select patients for maintenance treatment  who have a higher metastatic burden or tumor load on pre

Atezolizumab + cobimetinib in locally advanced or metastatic CRC (Phase III IMblaze370) - primary endpoint analysis

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Patients: 360 patients with  locally advanced or metastatic CRC >= 2 prior treatments Treatment arms - randomized (2:1:1) to atezolizumab + cobimetinib vs. atezolizumab vs. regorafenib (control) Primary endpoint: OS Results: >95% patients were MSS Combo failed to meet the primary endpoint of OS compared to regorafenib ( https://www.roche.com/media/store/releases/med-cor-2018-05-10.htm ). Safety results were consistent with the known profiles of the individual drugs Roche has halted patient recruitment to cohort 4 (atezolizumab + cobimetinib) in the phase 2 MODUL trial since Apr. 2018 (https://www.biospace.com/article/roche-halts-colorectal-cancer-trial-recruitment-after-4-patient-deaths/)

면역학 기초

* innate immunity - epithelial cells - sentinel cells in tissues [phagocytes (neutrophils, monocytes/macrophages), dendritic cells, mast cells, etc.] - innate lymphoid cells (ILCs) (NK cells, etc.) - plasma proteins (complements, etc.) * ILCs - Th1 - Th2 - Th17 * Lymphocytes B lymphocytes : produces antibodies "humoral immunity" : mature in the BM T lymphocytes:   "cell-mediated immunity" : mature in the thymus - CD4+ T cells helper T cells: help (1) B cells to produces antibodies, and help (2) phagocytes to destroy ingested microbes regulatory T cells (some): prevent/limit the immune response - CD8+ T cells (=cytotoxic T lymphocytes, CTLs): kill cells harboring intracellular microbes * interferon: a subgroup of cytokines (원래 viral infection에 방해하는 것으로 알려져 있었으나, 중요한 immunomodulatory function을 가진다) - type I (interferon-alpha and -beta): the main function is to prevent viral replication -  type II (=interferon-gamma) :  macrophages

Inflamed vs. non-inflamed tumors

기본적으로 종양은 inflamed와 non-inflamed로 구분됨. 1. inflamed (preexisting antitumor immune response) TIL high IFN-gamma producing CD8+ T cells PD-L1 in tumor-infiltrating immune cells. possible genome instability (high mutational burden) 2. non-inflamed TIL low  PD-L1 (-) 예) 소아암이 single gene mutation driver에 의해서 driven되는 noninflamed tuor의 대표적인 예임.

Cre-LoxP recombination system

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Cre (from “Cre”ates) recombinase: - P1 bacteriophage에서 나온 enzyme임 - Substrate DNA에 결합하여, - 2개의 LoxP sites 사이를 cut out하도록 디자인되었음.. LoxP (from “L”ocus “O”f “X”-over in “P”1 bacteriophage) - P1 bacteriophage에 있는 34 bp region ( ATAAC TTCGT ATA GC ATACA T TATA CGAAG TTAT ) 으로 2개의 symmetric한 13bp sequence를 포함함. - asymmetric 8 bp region때문에 Cre가 deletion, inversion, translocation을 catalyze 하게 됨.

FoundationOne CDx available in the US from Mar. 30

http://investors.foundationmedicine.com/releasedetail.cfm?releaseid=1062384 FoundationOne CDx - first US FDA-approved CGP assay for all solid tumors - offered as a nationally covered benefit across all solid tumors for Medicare and Medicare Advantage beneficiaries   https://www.medscape.com/viewarticle/894190 - technical information  https://assets.ctfassets.net/vhribv12lmne/6Rt6csmCPuaguuqmgi2iY8/e3a9b0456ed71a55d2e4480374695d95/FoundationOne_CDx.pdf