Natural variations at position 93 of the invariant Vα24-Jα18 α chain of human iNKT-cell TCRs strongly impact on CD1d binding

Human invariant natural killer T (NKT) cell TCRs bind to CD1d via an "invariant" Vα24-Jα18 chain (iNKTα) paired to semi-invariant Vβ11 chains (iNKTβ). Single-amino acid variations at position 93 (p93) of iNKTα, immediately upstream of the "invariant" CDR3α region, have been reported in a substantial proportion of human iNKT-cell clones (4-30%). Although p93, a serine in most human iNKT-cell TCRs, makes no contact with CD1d, it could affect CD1d binding by altering the conformation of the crucial CDR3α loop. By generating recombinant refolded iNKT-cell TCRs, we show that natural single-nucleotide variations in iNKTα, translating to serine, threonine, asparagine or isoleucine at p93, exert a powerful effect on CD1d binding, with up to 28-fold differences in affinity between these variants. This effect was observed with CD1d loaded with either the artificial α-galactosylceramide antigens KRN7000 or OCH, or the endogenous glycolipid β-galactosylceramide, and its importance for autoreactive recognition of endogenous lipids was demonstrated by the binding of variant iNKT-cell TCR tetramers to cell surface expressed CD1d. The serine-containing variant showed the strongest CD1d binding, offering an explanation for its predominance in vivo. Complementary molecular dynamics modeling studies were consistent with an impact of p93 on the conformation of the CDR3α loop.

Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93

PURPOSE: The value of adjuvant tamoxifen after chemotherapy for premenopausal women with breast cancer has not been adequately assessed. PATIENTS AND METHODS: Between 1993 and 1999, International Breast Cancer Study Group Trial 13-93 enrolled 1,246 assessable premenopausal women with axillary node-positive, operable breast cancer. All patients received chemotherapy (cyclophosphamide plus either doxorubicin or epirubicin for four courses followed by immediate or delayed classical cyclophosphamide, methotrexate, and fluorouracil for three courses), which was followed by either tamoxifen (20 mg daily) for 5 years or no further treatment. The primary end point was disease-free survival (DFS). Tumors were classified as estrogen receptor (ER) -positive (n = 735, 59%) if immunohistochemical (IHC) or ligand-binding assays (LBA) were clearly positive. The ER-negative group included all other tumors (n = 511, 41%). A subset of the ER-negative group was defined as ER absent (n = 108, 9%) if IHC staining was none or if the LBA result was 0 fmol/mg cytosol protein. The median follow-up time was 7 years. RESULTS: Tamoxifen improved DFS in the ER-positive cohort (hazard ratio [HR] for tamoxifen v no tamoxifen = 0.59; 95% CI, 0.46 to 0.75; P < .0001) but not in the ER-negative cohort (HR = 1.02; 95% CI, 0.77 to 1.35; P = .89). Tamoxifen had a detrimental effect on patients with ER-absent tumors compared with no tamoxifen in an unplanned exploratory analysis (HR = 2.10; 95% CI, 1.03 to 4.29; P = .04). Patients with ER-positive tumors who achieved chemotherapy-induced amenorrhea had a significantly improved outcome (HR for amenorrhea v no amenorrhea = 0.61; 95% CI, 0.44 to 0.86; P = .004), whether or not they received tamoxifen. CONCLUSION: Tamoxifen after adjuvant chemotherapy significantly improved treatment outcome in premenopausal patients with endocrine-responsive disease, but its use as adjuvant therapy for patients with ER-negative tumors is not recommended.

Randomized trial comparing axillary clearance versus no axillary clearance in older patients with breast cancer: first results of International Breast Cancer Study Group Trial 10-93

Axillary clearance in early breast cancer aims to improve locoregional control and provide staging information but is associated with undesirable morbidity. We therefore investigated whether avoiding axillary surgery in older women would result in improved quality of life (QL) with similar disease-free survival (DFS) and overall survival (OS).

Is adjuvant chemotherapy of benefit for postmenopausal women who receive endocrine treatment for highly endocrine-responsive, node-positive breast cancer? International Breast Cancer Study Group Trials VII and 12-93

To compare the efficacy of chemoendocrine treatment with that of endocrine treatment (ET) alone for postmenopausal women with highly endocrine responsive breast cancer. In the International Breast Cancer Study Group (IBCSG) Trials VII and 12-93, postmenopausal women with node-positive, estrogen receptor (ER)-positive or ER-negative, operable breast cancer were randomized to receive either chemotherapy or endocrine therapy or combined chemoendocrine treatment. Results were analyzed overall in the cohort of 893 patients with endocrine-responsive disease, and according to prospectively defined categories of ER, age and nodal status. STEPP analyses assessed chemotherapy effect. The median follow-up was 13 years. Adding chemotherapy reduced the relative risk of a disease-free survival event by 19% (P = 0.02) compared with ET alone. STEPP analyses showed little effect of chemotherapy for tumors with high levels of ER expression (P = 0.07), or for the cohort with one positive node (P = 0.03). Chemotherapy significantly improves disease-free survival for postmenopausal women with endocrine-responsive breast cancer, but the magnitude of the effect is substantially attenuated if ER levels are high.

Constraining planet structure from stellar chemistry: the cases of CoRoT-7, Kepler-10, and Kepler-93

Aims. We explore the possibility that the stellar relative abundances of different species can be used to constrain the bulk abundances of known transiting rocky planets. Methods. We use high resolution spectra to derive stellar parameters and chemical abundances for Fe, Si, Mg, O, and C in three stars hosting low mass, rocky planets: CoRoT-7, Kepler-10, and Kepler-93. These planets follow the same line along the mass-radius diagram, pointing toward a similar composition. The derived abundance ratios are compared with the solar values. With a simple stoichiometric model, we estimate the iron mass fraction in each planet, assuming stellar composition. Results. We show that in all cases, the iron mass fraction inferred from the mass-radius relationship seems to be in good agreement with the iron abundance derived from the host star's photospheric composition. Conclusions. The results suggest that stellar abundances can be used to add constraints on the composition of orbiting rocky planets.