Effects of Epitope Modification on T Cell Receptor–Ligand Binding and Antigen Recognition by Seven H-2Kd–restricted Cytotoxic T Lymphocyte Clones Specific for a Photoreactive Peptide Derivative

We tested for antigen recognition and T cell receptor (TCR)–ligand binding 12 peptide derivative variants on seven H-2Kd–restricted cytotoxic T lymphocytes (CTL) clones specific for a bifunctional photoreactive derivative of the Plasmodium berghei circumsporozoite peptide 252– 260 (SYIPSAEKI). The derivative contained iodo-4-azidosalicylic acid in place of PbCS S-252 and 4-azidobenzoic acid on PbCS K-259. Selective photoactivation of the N-terminal photoreactive group allowed crosslinking to Kd molecules and photoactivation of the orthogonal group to TCR. TCR photoaffinity labeling with covalent Kd–peptide derivative complexes allowed direct assessment of TCR–ligand binding on living CTL. In most cases (over 80%) cytotoxicity (chromium release) and TCR–ligand binding differed by less than fivefold. The exceptions included (a) partial TCR agonists (8 cases), for which antigen recognition was fivetenfold less efficient than TCR–ligand binding, (b) TCR antagonists (2 cases), which were not recognized and capable of inhibiting recognition of the wild-type conjugate, (c) heteroclitic agonists (2 cases), for which antigen recognition was more efficient than TCR–ligand binding, and (d) one partial TCR agonist, which activated only Fas (CD95), but not perforin/granzymemediated cytotoxicity. There was no correlation between these divergences and the avidity of TCR–ligand binding, indicating that other factors than binding avidity determine the nature of the CTL response. An unexpected and novel finding was that CD8-dependent clones clearly incline more to TCR antagonism than CD8-independent ones. As there was no correlation between CD8 dependence and the avidity of TCR–ligand binding, the possibility is suggested that CD8 plays a critical role in aberrant CTL function

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Differential effectiveness of solar UVB subcomponents in causing cell death, oncogenic transformation and micronucleus induction in human hybrid cells

Purpose: (1) To determine the biological effectiveness of two solar ultraviolet (UVB) spectra with different lower wavelength thresholds for oncogenic transformation and micronucleus induction in CGL1 cells; (2) to investigate whether the action spectra for short- and long-term effects are similar; and (3) to investigate possible links between transformation and other delayed effects. Material and methods: Two spectra were derived from a solar UV simulator by using two filters: the first transmitted radiation with \u3bb > 284 nm, the second with \u3bb > 293 nm. The resulting spectra have the same UVA, but different UVB components (\u3bb between 284 and 320 nm, 19 W m-2, and \u3bb between 293 and 320 nm, 13 W m-2). CGL1 cells were irradiated with 466 J m-2 with \u3bb > 284 nm and 1582 J m-2 with \u3bb > 293 nm. These doses were approximately equilethal. The endpoints examined were oncogenic transformation, and centromere-positive and -negative micronucleus frequencies in the directly irradiated cells and in their progeny. Results: At equilethal doses, the oncogenic transformation frequency in the directly irradiated cells was greater by a factor of at least 7 for \u3bb > 284 nm irradiation compared with \u3bb > 293 nm. The micronucleus induction frequency was also significantly higher with the \u3bb > 284 spectrum. Consistent with our previous findings, no delayed micronucleus formation was found in the progeny of cells exposed to \u3bb > 293 nm, while a threefold elevation above controls was seen in the progeny of cells exposed to \u3bb > 284 nm irradiation. This was also the case for formation of micronuclei with a centromere. Conclusions: It was found that: (1) for equilethal doses the \u3bb > 284 nm spectrum was more biologically effective than the \u3bb > 293 nm spectrum for induction of oncogenic transformation and micronucleus formation; and (2) the higher effectiveness of the \u3bb > 284 nm spectrum found at equilethal doses for delayed effects in the progeny of irradiated cells resembles that found for transformation. The results suggest that the UVB action spectrum for cell killing is different from that of some delayed effects, and from that of transformation