4 research outputs found
Recruiting in Silicon Valley
- Author
- Publication venue
- SJSU ScholarWorks
- Publication date
- 01/01/2001
- Field of study
Oxopyrido[2,3â<i>d</i>]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors
- Author
- Andrew T. Parsons (1660948)
- Andrew S. Tasker (1463668)
- Brad Herberich (1660966)
- Darren L. Reid (1660996)
- David Bauer (1617514)
- David J. St. Jean (1261623)
- Dean Hickman (1500763)
- Dina A. Andrews (1660969)
- Edward K. Lobenhofer (16428)
- Essa Hu-Harrington (1660993)
- Fang-Tsao Hong (1261620)
- Faye Hsieh (1660984)
- James Brown (425608)
- Jason Tedrow (1660981)
- Jian Jeffrey Chen (1656979)
- Jinghui Zhan (1660951)
- Kate Ashton (1660963)
- Keegan Cooke (1660990)
- Kristin L. Andrews (1533247)
- Liping H. Pettus (1660954)
- Matthew Potter (1660972)
- Michele Kubryk (1660960)
- Nancy Everds (234716)
- Nataraj Kalyanaraman (1660978)
- Oliver R. Thiel (1551964)
- Pedro J. Beltran (1660987)
- Petia Mitchell (278950)
- Robert Radinsky (278958)
- Roberto Guzman (1660957)
- Ryan P. Wurz (1500721)
- Seifu Tadesse (1261593)
- Simon J. Hedley (1660999)
- Tian Wu (644347)
- Tom Nguyen (1660975)
- Publication venue
- Publication date
- Field of study
In nonsmall cell lung cancer (NSCLC),
the threonine<sup>790</sup>âmethionine<sup>790</sup> (T790M)
point mutation of EGFR kinase
is one of the leading causes of acquired resistance to the first generation
tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib.
Herein, we describe the optimization of a series of 7-oxopyridoÂ[2,3-<i>d</i>]Âpyrimidinyl-derived irreversible inhibitors of EGFR kinase.
This led to the discovery of compound <b>24</b> which potently
inhibits gefitinib-resistant EGFR<sup>L858R,T790M</sup> with 100-fold
selectivity over wild-type EGFR. Compound <b>24</b> displays
strong antiproliferative activity against the H1975 nonsmall cell
lung cancer cell line, the first line mutant HCC827 cell line, and
promising antitumor activity in an EGFR<sup>L858R,T790M</sup> driven
H1975 xenograft model sparing the side effects associated with the
inhibition of wild-type EGFR
Enhanced infection prophylaxis reduces mortality in severely immunosuppressed HIV-infected adults and older children initiating antiretroviral therapy in Kenya, Malawi, Uganda and Zimbabwe: the REALITY trial
- Author
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- Zhang F
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- Zhang W
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- Zhanpeisova A
- Zhao Y
- Zhu L
- Zieman B
- Zieman B
- Zulu C
- Zuma T
- Zurla C
- Publication venue
- 'International AIDS Society'
- Publication date
- 01/01/2016
- Field of study
Meeting abstract FRAB0101LB from 21st International AIDS Conference 18â22 July 2016, Durban, South Africa.
Introduction: Mortality from infections is high in the first 6 months of antiretroviral therapy (ART) among HIVâinfected adults and children with advanced disease in subâSaharan Africa. Whether an enhanced package of infection prophylaxis at ART initiation would reduce mortality is unknown.
Methods:
The REALITY 2Ă2Ă2 factorial openâlabel trial (ISRCTN43622374) randomized ARTânaĂŻve HIVâinfected adults and children >5 years with CD4 <100 cells/mm3. This randomization compared initiating ART with enhanced prophylaxis (continuous cotrimoxazole plus 12 weeks isoniazid/pyridoxine (antiâtuberculosis) and fluconazole (antiâcryptococcal/candida), 5 days azithromycin (antiâbacterial/protozoal) and singleâdose albendazole (antiâhelminth)), versus standardâofâcare cotrimoxazole. Isoniazid/pyridoxine/cotrimoxazole was formulated as a scored fixedâdose combination. Two other randomizations investigated 12âweek adjunctive raltegravir or supplementary food. The primary endpoint was 24âweek mortality.
Results:
1805 eligible adults (n = 1733; 96.0%) and children/adolescents (n = 72; 4.0%) (median 36 years; 53.2% male) were randomized to enhanced (n = 906) or standard prophylaxis (n = 899) and followed for 48 weeks (3.8% lossâtoâfollowâup). Median baseline CD4 was 36 cells/mm3 (IQR: 16â62) but 47.3% were WHO Stage 1/2. 80 (8.9%) enhanced versus 108(12.2%) standard prophylaxis died before 24 weeks (adjusted hazard ratio (aHR) = 0.73 (95% CI: 0.54â0.97) p = 0.03; Figure 1) and 98(11.0%) versus 127(14.4%) respectively died before 48 weeks (aHR = 0.75 (0.58â0.98) p = 0.04), with no evidence of interaction with the two other randomizations (p > 0.8). Enhanced prophylaxis significantly reduced incidence of tuberculosis (p = 0.02), cryptococcal disease (p = 0.01), oral/oesophageal candidiasis (p = 0.02), deaths of unknown cause (p = 0.02) and (marginally) hospitalisations (p = 0.06) but not presumed severe bacterial infections (p = 0.38). Serious and grade 4 adverse events were marginally less common with enhanced prophylaxis (p = 0.06). CD4 increases and VL suppression were similar between groups (p > 0.2).
Conclusions:
Enhanced infection prophylaxis at ART initiation reduces early mortality by 25% among HIVâinfected adults and children with advanced disease. The pill burden did not adversely affect VL suppression. Policy makers should consider adopting and implementing this lowâcost broad infection prevention package which could save 3.3 lives for every 100 individuals treated
Integration site selection by retroviruses and transposable elements in eukaryotes
- Author
- A Albanese
- A Ballandras-Colas
- A Ballandras-Colas
- A Bridier-Nahmias
- A Ciuffi
- A Ciuffi
- A Engelman
- A Fungtammasan
- A Gogol-Döring
- A GĂ©rard
- A Hickey
- A Jordan
- A Levin
- A Majumdar
- A Molla-Herman
- A Morillon
- A Morillon
- A Sehgal
- A Sharma
- A-L Todeschini
- AB Hickman
- AG Chatterjee
- AG Holman
- AL Ferris
- Alessia Zamborlini
- AM Fuller
- AR Schröder
- B Brouha
- B Faye
- B Irwin
- B Marini
- B McClintock
- BJ Wagstaff
- BK Thompson
- C Di Primio
- C Monot
- C Philippe
- CA Brown
- CC Berry
- CR Beck
- CR Chin
- D Holoch
- D Pruss
- DA Ray
- DG Eickbush
- DJ Wight
- DM Kasper
- DO Passos
- DP Maskell
- E Elis
- E Serrao
- E Serrao
- EB Chuong
- EB Chuong
- EC Scott
- ER Morris
- ES Lander
- F Bushman
- F Maldarelli
- F Voigt
- G Feng
- GA Sowd
- Gael Cristofari
- GC Liao
- GM Brodeur
- GN Maertens
- GP Wang
- H Fujiwara
- H Ji
- H Rafati
- H Shivram
- H Takahashi
- H Wang
- H-P Mok
- I Ammar
- J Dai
- J de Jong
- J De Rijck
- J De Rijck
- J Kirchner
- J Tobaly-Tapiero
- J Yang
- JA Baller
- JA Baller
- JB Owens
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- JL Goodier
- JM Cherry
- JM Tubio
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- JO Eidahl
- JZ Jacobs
- K Naito
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- K Yoshitake
- KD Taganov
- KL Ho
- KR Upton
- L Biasco
- L Mularoni
- L Quadrana
- L Quadrana
- L Zhang
- LM McLane
- M Aye
- M Bryk
- M Cavazzana-Calvo
- M Lelek
- M Llano
- M Lusic
- M Morchikh
- M Naughtin
- M Osanai-Futahashi
- M Pasi
- M Schmidt
- M-C Shun
- MA Grandbastien
- MC LaFave
- MD Andrake
- ME Gelbart
- ME Manson McManamy
- MJ Curcio
- MJ Curcio
- MJ Fraser
- MJ Sigman
- MK Lewinski
- MK Lewinski
- ML Pardue
- MS Benleulmi
- N Bachman
- N Beliakova-Bethell
- N Gilbert
- N Ke
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- N Maita
- N Zamudio
- NG Copeland
- O Erlwein
- O Siol
- O Weichenrieder
- P Capy
- P Cherepanov
- P Lesbats
- P Varadarajan
- Pascale Lesage
- PD Kirk
- PK Singh
- PM Pryciak
- PT Kinsey
- Q Feng
- R Campos-SĂĄnchez
- R Craigie
- R Gijsbers
- R Schrijvers
- RA Katz
- RC Burdick
- RC Larue
- RM Silvers
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- RS Linheiro
- RS Mitchell
- S Aiyer
- S Cheung
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- S Gangadharan
- S Hacein-Bey-Abina
- S Hacein-Bey-Abina
- S Liu
- S Rashkova
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- SA Narayanavari
- SB Sandmeyer
- SE Devine
- SG Deeks
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- T Anzai
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- Y Guo
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