23 research outputs found
Charged particle production in the Pb+Pb system at 158 GeV/c per nucleon
Charged particle multiplicities from high multiplicity central interactions
of 158 GeV/nucleon Pb ions with Pb target nuclei have been measured in the
central and far forward projectile spectator regions using emulsion chambers.
Multiplicities are significantly lower than predicted by Monte Carlo
simulations. We examine the shape of the pseudorapidity distribution and its
dependence on centrality in detail.Comment: 17 pages text plus 12 figures in postscript 12/23/99 -- Add TeX
version of sourc
Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma
BACKGROUND: Approximately 75% of objective responses to antiâprogrammed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown. METHODS: We analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in response to antiâPD-1 therapy (pembrolizumab) followed by disease progression months to years later. RESULTS: Whole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptorâassociated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I. CONCLUSIONS: In this study, acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signaling and in antigen presentation. (Funded by the National Institutes of Health and others.