Citations

AbstractEach year 610,000 cases of anogenital and oropharyngeal cancers caused by human papillomavirus (HPV) occur worldwide. HPV vaccination represents a promising opportunity to prevent cancer on a global scale. The vaccine's story dates back to discoveries in chickens at the beginning of the 20th century with evidence that a cell‐free filtrate could transmit the propensity to grow cancers. Later, studies with similarly derived filtrates from mammalian tumors showed that hosts could develop immunity to subsequent exposures. Epidemiologic studies linked cervical cancer to members of a family of viruses that cause papillomatosis and common warts. This led to work with DNA hybridization demonstrating a causal relationship. The formation of virus‐like particles from viral capsid proteins led to the development of models for safe and effective vaccines. While much work remains with the acceptance of universal vaccination, the HPV vaccines Gardasil and Cervarix thus represent a century of successful translational research.

Abstract TCR engagement by peptide-MHC class I (pMHC) ligands induces a conformational change (Δc) in CD3 (CD3Δc) that contributes to T cell signaling. We found that when this interaction took place between primary T lineage cells and APCs, the CD8 coreceptor was required to generate CD3Δc. Interestingly, neither enhancement of Ag binding strength nor Src kinase signaling explained this coreceptor activity. Furthermore, Ag-induced CD3Δc was developmentally attenuated by the increase in sialylation that accompanies T cell maturation and limits CD8 activity. Thus, both weak and strong ligands induced CD3Δc in preselection thymocytes, but only strong ligands were effective in mature T cells. We propose that CD8 participation in the TCR/pMHC interaction can physically regulate CD3Δc induction by “translating” productive Ag encounter from the TCR to the CD3 complex. This suggests one mechanism by which the developmentally regulated variation in CD8 sialylation may contribute to the developmental tuning of T cell sensitivity.

Key PointsAmino acid substitution at peptide-binding residues of the HLA class I molecule is associated with graft-versus-host disease and mortality. Avoidance of donor-recipient combinations that result in amino acid substitution at peptide-binding residues may improve transplant outcomes.

Genetic College Many genomic elements in humans are associated with behavior, including educational attainment. In a genome-wide association study including more than 100,000 samples, Rietveld et al. (p. 1467 , published online 30 May; see the Perspective by Flint and Munafò ) looked for genes related to educational attainment in Caucasians. Small genetic effects at three loci appeared to impact educational attainment.

Background: Single infusions of ketamine have been used successfully to achieve improvement in depressed patients. Side effects during the infusions have been common. It is not known whether serial infusions or lower infusion rates result in greater efficacy. Methods: Ten depressed patients were treated with twice weekly ketamine infusions of ketamine 0.5 mg/kg administered over 100 min until either remission was achieved or four infusions were given. Side effects were assessed with the Young Mania Rating Scale (YMRS) and the Brief Psychiatric Rating Scale (BPRS). Patients were followed naturalistically at weekly intervals for four weeks after completion of the infusions. Results: Five of 10 patients achieved remission status. There were no significant increases on the BPRS or YMRS. Two of the remitting patients sustained their improvement throughout the four week follow-up period. Conclusions: Ketamine infusions at a lower rate than previously reported have demonstrated similar efficacy and excellent tolerability and may be more practically available for routine clinical care. Serial ketamine infusions appear to be more effective than a single infusion. Further research to test relapse prevention strategies with continuation ketamine infusions is indicated.