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1.  Outcomes by Sex Following Treatment Initiation With Atazanavir Plus Ritonavir or Efavirenz With Abacavir/Lamivudine or Tenofovir/Emtricitabine 
Smith, Kimberly Y. | Tierney, Camlin | Mollan, Katie | Venuto, Charles S. | Budhathoki, Chakra | Ma, Qing | Morse, Gene D. | Sax, Paul | Katzenstein, David | Godfrey, Catherine | Fischl, Margaret | Daar, Eric S. | Collier, Ann C. | Bolivar, Hector H. | Navarro, Sandra | Koletar, Susan L. | Gochnour, Diane | Seefried, Edward | Hoffman, Julie | Feinberg, Judith | Saemann, Michelle | Patterson, Kristine | Pittard, Donna | Currin, David | Upton, Kerry | Saag, Michael | Ray, Graham | Johnson, Steven | Santos, Bartolo | Funk, Connie A. | Morgan, Michael | Jackson, Brenda | Tebas, Pablo | Thomas, Aleshia | Kim, Ge-Youl | Klebert, Michael K. | Santana, Jorge L. | Marrero, Santiago | Norris, Jane | Valle, Sandra | Cox, Gary Matthew | Silberman, Martha | Shaik, Sadia | Lopez, Ruben | Vasquez, Margie | Daskalakis, Demetre | Megill, Christina | Shore, Jessica | Taiwo, Babafemi | Goldman, Mitchell | Boston, Molly | Lennox, Jeffrey | del Rio, Carlos | Lane, Timothy W. | Epperson, Kim | Luetkemeyer, Annie | Payne, Mary | Gripshover, Barbara | Antosh, Dawn | Reid, Jane | Adams, Mary | Storey, Sheryl S. | Dunaway, Shelia B. | Gallant, Joel | Wiggins, Ilene | Smith, Kimberly Y. | Swiatek, Joan A. | Timpone, Joseph | Kumar, Princy | Moe, Ardis | Palmer, Maria | Gothing, Jon | Delaney, Joanne | Whitely, Kim | Anderson, Ann Marie | Hammer, Scott M. | Yin, Michael T. | Jain, Mamta | Petersen, Tianna | Corales, Roberto | Hurley, Christine | Henry, Keith | Bordenave, Bette | Youmans, Amanda | Albrecht, Mary | Pollard, Richard B. | Olusanya, Abimbola | Skolnik, Paul R. | Adams, Betsy | Tashima, Karen T. | Patterson, Helen | Ukwu, Michelle | Rogers, Lauren | Balfour, Henry H. | Fox, Kathy A. | Swindells, Susan | Van Meter, Frances | Robbins, Gregory | Burgett-Yandow, Nicole | Davis, Charles E. | Boyce, Colleen | O'Brien, William A. | Casey, Gerianne | Morse, Gene D. | Hsaio, Chiu-Bin | Meier, Jeffrey L. | Stapleton, Jack T. | Mildvan, Donna | Revuelta, Manuel | Currin, David | El Sadr, Wafaa | Loquere, Avelino | El-Daher, Nyef | Johnson, Tina | Gross, Robert | Maffei, Kathyrn | Hughes, Valery | Sturge, Glenn | McMahon, Deborah | Rutecki, Barbara | Wulfsohn, Michael | Cheng, Andrew | Dix, Lynn | Liao, Qiming
This clinical trial identifies a significantly earlier time to virologic failure in women randomized to atazanavir/ritonavir compared to women randomized to efavirenz.
Background. We aimed to evaluate treatment responses to atazanavir plus ritonavir (ATV/r) or efavirenz (EFV) in initial antiretroviral regimens among women and men, and determine if treatment outcomes differ by sex.
Methods. We performed a randomized trial of open-label ATV/r or EFV combined with abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) in 1857 human immunodeficiency virus type 1–infected, treatment-naive persons enrolled between September 2005 and November 2007 at 59 sites in the United States and Puerto Rico. Associations of sex with 3 primary study endpoints of time to virologic failure, safety, and tolerability events were analyzed using Cox proportional hazards models. Model-based population pharmacokinetic analysis was performed using nonlinear mixed effects modeling (NONMEM version VII).
Results. Of 1857 participants, 322 were women. Women assigned to ATV/r had a higher risk of virologic failure with either nucleoside reverse transcriptase inhibitor backbone than women assigned to EFV, or men assigned to ATV/r. The effects of ATV/r and EFV upon safety and tolerability risk did not differ significantly by sex. With ABC/3TC, women had a significantly higher (32%) safety risk compared to men; with TDF/FTC, the safety risk was 20% larger for women compared to men, but not statistically significant. Women had slower ATV clearance and higher predose levels of ATV compared to men. Self-reported adherence did not differ significantly by sex.
Conclusions. This is the first randomized clinical trial to identify a significantly earlier time to virologic failure in women randomized to ATV/r compared to women randomized to EFV. This finding has important clinical implications given that boosted protease inhibitors are often favored over EFV in women of childbearing potential.
Clinical Trials Registration NCT00118898.
doi:10.1093/cid/cit747
PMCID: PMC3905755  PMID: 24253247
sex; atazanavir; efavirenz; abacavir; tenofovir
2.  Abiraterone and Increased Survival in Metastatic Prostate Cancer 
The New England journal of medicine  2011;364(21):1995-2005.
BACKGROUND
Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy.
METHODS
We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate.
RESULTS
After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate–prednisone group than in the placebo–prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate–prednisone group than in the placebo–prednisone group.
CONCLUSIONS
The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 ClinicalTrials.gov number, NCT00638690.)
doi:10.1056/NEJMoa1014618
PMCID: PMC3471149  PMID: 21612468
3.  Lip, a Human Gene Detected by Transfection of DNA From a Human Liposarcoma Encodes a Protein With Homology to Regulators of Small G Proteins 
Sarcoma  1998;2(1):35-44.
Purpose/Method. Transfection experiments have been used to identify activated oncogenes in a wide variety of tumour types. Here we describe the use of transfection experiments utilizing DNA from a human pleomorphic liposarcoma to identify a novel gene, designated lip which maps to chromosome 19.
Results. lip was expressed in all sarcoma cell lines examined and a wide variety of normal tissues. Sequencing of cDNAs prepared from transcripts of the normal lip gene indicates that lip is predicted to encode a 966 amino acid protein with a region of homology to proteins such as vav, dbl, lbc and ect-2 which act as GDP–GTP exchange factors for the RAS superfamily of small GTP-binding proteins, and the N-terminal 830 amino acids are identical to the recently identified gene p115-RhoGEF, an exchange factor for RHOA. In transfectants, lip has undergone a rearrangement which results in C-terminal truncation of the predicted LIP protein. However, we failed to detect this alteration in the primary liposarcoma used in the original transfection experiments, or in other sarcoma specimens examined.
Discussion. When considered together, these observations suggest that transforming lip sequences represent an alternatively spliced form of p115-RhoGEF that is activated for transformation by C-terminal truncation during transfection, and is not widely involved in sarcoma development.
doi:10.1080/13577149878145
PMCID: PMC2395381  PMID: 18521231
4.  Amplification and Over-Expression of the MDM2 Gene in Human Soft Tissue Tumours 
Sarcoma  1997;1(1):17-22.
Purpose. Amplification of genetic sequences on chromosome 12q13 is frequently found in soft tissue tumours. However, for the MDM2 gene, over-expression of the MDM2 protein has not always been shown to accompany gene amplification, raising the possibility that amplification of genetic sequences targets alternative genes on chromosome 12q13 for over-expression. To investigate this discrepancy, we have examined 129 soft tissue tumours for amplification of the MDM2 gene using Southern analysis, and 39 of these tumours were also examined by immunohistochemical staining for MDM2 over-expression.
Results. Gene amplification was identified in 14/114 (12.3%) of the malignant tumours, but was not identified in any of the benign tumours; 21/39 (54%) of the malignant tumours also demonstrated MDM2 over-expression. Within this group the MDM2 gene was over-expressed in every tumour in which the gene amplification was found, and over-expression in the absence of gene amplification was also found in an additional 10 tumours.
Discussion. These data demonstrate a clear correlation between the presence of MDM2 amplification and MDM2 over-expression, and provide persuasive evidence therefore that the amplification of genetic sequences on chromosome 12q13 in soft tissue sarcomas targets the MDM2 gene for over-expression. These data also indicate that alternative mechanisms may contribute to MDM2 over-expression within some tumours.
doi:10.1080/13577149778434
PMCID: PMC2373578  PMID: 18521196

Results 1-4 (4)