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  • Desensitized chimeric antigen receptor T cells selectively recognize target cells with enhanced antigen expression.

    Posted 2018-06-11 22:01:13 by: Mahammad A. Tafida

    Related Articles Desensitized chimeric antigen receptor T cells selectively recognize target cells with enhanced antigen expression. Nat Commun. 2018 02 01;9(1):468 Authors: Han C, Sim SJ, Kim SH, Singh R, Hwang S, Kim YI, Park SH, Kim KH, Lee DG, Oh HS, Lee S, Kim YH, Choi BK, Kwon BS Abstract Chimeric antigen receptor (CAR) T cell therapy is an effective method for treating specific cancers. CARs are normally designed to recognize antigens, which are highly expressed on malignant cells but not on T cells. However, when T cells are engineered with CARs that recognize antigens expressed on the T cell surface, CAR T cells exhibit effector function on other T cells, which results in fratricide, or killing of neighboring T cells. Here, using human leukocyte antigen-DR (HLA-DR)-targeted CAR T cells, we show that weak affinity between CAR and HLA-DR reduces fratricide and induces sustained CAR downregulation, which consequently tunes the avidity of CAR T cells, leading to desensitization. We further demonstrate that desensitized CAR T cells selectively kill Epstein-Barr virus-transformed B cells with enhanced HLA-DR expression, while sparing normal B cells. Our study supports an avidity-tuning strategy that permits sensing of antigen levels by CAR T cells. PMID: 29391449 [PubMed - indexed for ...

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  • Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer.

    Posted 2018-06-11 22:01:13 by: Mahammad A. Tafida

    Related Articles Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. N Engl J Med. 2018 04 12;378(15):1408-1418 Authors: Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, Lopez-Gitlitz A, Trudel GC, Espina BM, Shu Y, Park YC, Rackoff WR, Yu MK, Small EJ, SPARTAN Investigators Abstract BACKGROUND: Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastasis. METHODS: We conducted a double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day) or placebo. All the patients continued to receive androgen-deprivation therapy. The primary end point was metastasis-free survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death. RESULTS: A total of 1207 men underwent randomization (806 to the apalutamide group and 401 to the placebo group). In the planned primary analysis, which was performed after 378 events had occurred, median metastasis-free survival was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (hazard ratio for metastasis or death, 0.28; 95% confidence interval [CI], 0.23 to 0.35; P<0.001). Time to symptomatic progression was significantly longer with apalutamide than with placebo (hazard ratio, 0.45; 95% CI, 0.32 to 0.63; P<0.001). The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group. The following ...

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  • Relationship between Clinic and Ambulatory Blood-Pressure Measurements and Mortality.

    Posted 2018-06-11 22:01:13 by: Mahammad A. Tafida

    Related Articles Relationship between Clinic and Ambulatory Blood-Pressure Measurements and Mortality. N Engl J Med. 2018 04 19;378(16):1509-1520 Authors: Banegas JR, Ruilope LM, de la Sierra A, Vinyoles E, Gorostidi M, de la Cruz JJ, Ruiz-Hurtado G, Segura J, Rodríguez-Artalejo F, Williams B Abstract BACKGROUND: Evidence for the influence of ambulatory blood pressure on prognosis derives mainly from population-based studies and a few relatively small clinical investigations. This study examined the associations of blood pressure measured in the clinic (clinic blood pressure) and 24-hour ambulatory blood pressure with all-cause and cardiovascular mortality in a large cohort of patients in primary care. METHODS: We analyzed data from a registry-based, multicenter, national cohort that included 63,910 adults recruited from 2004 through 2014 in Spain. Clinic and 24-hour ambulatory blood-pressure data were examined in the following categories: sustained hypertension (elevated clinic and elevated 24-hour ambulatory blood pressure), "white-coat" hypertension (elevated clinic and normal 24-hour ambulatory blood pressure), masked hypertension (normal clinic and elevated 24-hour ambulatory blood pressure), and normotension (normal clinic and normal 24-hour ambulatory blood pressure). Analyses were conducted with Cox regression models, adjusted for clinic and 24-hour ambulatory blood pressures and for confounders. RESULTS: During a median follow-up of 4.7 years, 3808 patients died from any cause, and 1295 of these patients died from cardiovascular causes. In a model that included both 24-hour and clinic measurements, 24-hour systolic pressure was more strongly associated with all-cause mortality (hazard ratio, 1.58 per 1-SD increase in pressure; 95% confidence interval [CI], 1.56 to 1.60, after adjustment for clinic blood pressure) than the clinic systolic pressure (hazard ratio, 1.02; 95% CI, 1.00 to ...

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