Special Issue "On Defining Artificial Intelligence"—Commentaries and Author's Response

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Targeting of B and T lymphocyte associated (BTLA) prevents graft-versus-host disease without global immunosuppression

One-time treatment with an antibody against BTLA provides long-term protection against graft-versus-host disease without affecting effector T cell responses to tumors or pathogens

The Inhibitory Receptor NKG2A Sustains Virus-Specific CD8+ T Cells in Response to a Lethal Poxvirus Infection

SummaryCD8+ T cells and NK cells protect from viral infections by killing virally infected cells and secreting interferon-γ. Several inhibitory receptors limit the magnitude and duration of these anti-viral responses. NKG2A, which is encoded by Klrc1, is a lectin-like inhibitory receptor that is expressed as a heterodimer with CD94 on NK cells and activated CD8+ T cells. Previous studies on the impact of CD94/NKG2A heterodimers on anti-viral responses have yielded contrasting results and the in vivo function of NKG2A remains unclear. Here, we generated Klrc1–/– mice and found that NKG2A is selectively required for resistance to ectromelia virus (ECTV). NKG2A functions intrinsically within ECTV-specific CD8+ T cells to limit excessive activation, prevent apoptosis, and preserve the specific CD8+ T cell response. Thus, although inhibitory receptors often cause T cell exhaustion and viral spreading during chronic viral infections, NKG2A optimizes CD8+ T cell responses during an acute poxvirus infection

Recurrent Mutations in Cyclin D3 Confer Clinical Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia

PurposeBiomarkers of response and resistance to FLT3 tyrosine kinase inhibitors (TKI) are still emerging, and optimal clinical combinations remain unclear. The purpose of this study is to identify co-occurring mutations that influence clinical response to the novel FLT3 inhibitor pexidartinib (PLX3397).Experimental designWe performed targeted sequencing of pretreatment blasts from 29 patients with FLT3 internal tandem duplication (ITD) mutations treated on the phase I/II trial of pexidartinib in relapsed/refractory FLT3-ITD+ acute myeloid leukemia (AML). We sequenced 37 samples from 29 patients with available material, including 8 responders and 21 non-responders treated at or above the recommended phase II dose of 3,000 mg.ResultsConsistent with other studies, we identified mutations in NRAS, TP53, IDH2, and a variety of epigenetic and transcriptional regulators only in non-responders. Among the most frequently mutated genes in non-responders was Cyclin D3 (CCND3). A total of 3 individual mutations in CCND3 (Q276*, S264R, and T283A) were identified in 2 of 21 non-responders (one patient had both Q276* and S264R). No CCND3 mutations were found in pexidartinib responders. Expression of the Q276* and T283A mutations in FLT3-ITD MV4;11 cells conferred resistance to apoptosis, decreased cell-cycle arrest, and increased proliferation in the presence of pexidartinib and other FLT3 inhibitors. Inhibition of CDK4/6 activity in CCND3 mutant MV4;11 cells restored pexidartinib-induced cell-cycle arrest but not apoptosis.ConclusionsMutations in CCND3, a gene not commonly mutated in AML, are a novel cause of clinical primary resistance to FLT3 inhibitors in AML and may have sensitivity to CDK4/6 inhibition

Measurement of the Vector and Tensor Asymmetries at Large Missing Momentum in Quasielastic ([→ over e],e′p) Electron Scattering from Deuterium

We report the measurement of the beam-vector and tensor asymmetries A[subscript ed][superscript V] and A[subscript d][superscript T] in quasielastic ([→ over e],e′p) electrodisintegration of the deuteron at the MIT-Bates Linear Accelerator Center up to missing momentum of 500  MeV/c. Data were collected simultaneously over a momentum transfer range 0.1<Q[superscript 2]<0.5  (GeV/c)[superscript 2] with the Bates Large Acceptance Spectrometer Toroid using an internal deuterium gas target polarized sequentially in both vector and tensor states. The data are compared with calculations. The beam-vector asymmetry A[subscript ed][superscript V] is found to be directly sensitive to the D-wave component of the deuteron and has a zero crossing at a missing momentum of about 320  MeV/c, as predicted. The tensor asymmetry A[subscript d][superscript T] at large missing momentum is found to be dominated by the influence of the tensor force in the neutron-proton final-state interaction. The new data provide a strong constraint on theoretical models