BRAF Mutations in Advanced Cancers: Clinical Characteristics and Outcomes

BACKGROUND: Oncogenic BRAF mutations have been found in diverse malignancies and activate RAF/MEK/ERK signaling, a critical pathway of tumorigenesis. We examined the clinical characteristics and outcomes of patients with mutant (mut) BRAF advanced cancer referred to phase 1 clinic. METHODS: We reviewed the records of 80 consecutive patients with mutBRAF advanced malignancies and 149 with wild-type (wt) BRAF (matched by tumor type) referred to the Clinical Center for Targeted Therapy and analyzed their outcome. RESULTS: Of 80 patients with mutBRAF advanced cancer, 56 had melanoma, 10 colorectal, 11 papillary thyroid, 2 ovarian and 1 esophageal cancer. Mutations in codon 600 were found in 77 patients (62, V600E; 13, V600K; 1, V600R; 1, unreported). Multivariate analysis showed less soft tissue (Odds ratio (OR) = 0.39, 95%CI: 0.20-0.77, P = 0.007), lung (OR = 0.38, 95%CI: 0.19-0.73, p = 0.004) and retroperitoneal metastases (OR = 0.34, 95%CI: 0.13-0.86, p = 0.024) and more brain metastases (OR = 2.05, 95%CI: 1.02-4.11, P = 0.043) in patients with mutBRAF versus wtBRAF. Comparing to the corresponding wtBRAF, mutBRAF melanoma patients had insignificant trend to longer median survival from diagnosis (131 vs. 78 months, p = 0.14), while mutBRAF colorectal cancer patients had an insignificant trend to shorter median survival from diagnosis (48 vs. 53 months, p = 0.22). In melanoma, V600K mutations in comparison to other BRAF mutations were associated with more frequent brain (75% vs. 36.3%, p = 0.02) and lung metastases (91.6% vs. 47.7%, p = 0.007), and shorter time from diagnosis to metastasis and to death (19 vs. 53 months, p = 0.046 and 78 vs. 322 months, p = 0.024 respectively). Treatment with RAF/MEK targeting agents (Hazard ratio (HR) = 0.16, 95%CI: 0.03-0.89, p = 0.037) and any decrease in tumor size after referral (HR = 0.07, 95%CI: 0.015-0.35, p = 0.001) correlated with longer survival in mutBRAF patients. CONCLUSIONS: BRAF appears to be a druggable mutation that also defines subgroups of patients with phenotypic overlap, albeit with differences that correlate with histology or site of mutation

Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection

Identification of full-length transmitted HIV-1 genomes could be instrumental in HIV-1 pathogenesis, microbicide, and vaccine research by enabling the direct analysis of those viruses actually responsible for productive clinical infection. We show in 12 acutely infected subjects (9 clade B and 3 clade C) that complete HIV-1 genomes of transmitted/founder viruses can be inferred by single genome amplification and sequencing of plasma virion RNA. This allowed for the molecular cloning and biological analysis of transmitted/founder viruses and a comprehensive genome-wide assessment of the genetic imprint left on the evolving virus quasispecies by a composite of host selection pressures. Transmitted viruses encoded intact canonical genes (gag-pol-vif-vpr-tat-rev-vpu-env-nef) and replicated efficiently in primary human CD4+ T lymphocytes but much less so in monocyte-derived macrophages. Transmitted viruses were CD4 and CCR5 tropic and demonstrated concealment of coreceptor binding surfaces of the envelope bridging sheet and variable loop 3. 2 mo after infection, transmitted/founder viruses in three subjects were nearly completely replaced by viruses differing at two to five highly selected genomic loci; by 12–20 mo, viruses exhibited concentrated mutations at 17–34 discrete locations. These findings reveal viral properties associated with mucosal HIV-1 transmission and a limited set of rapidly evolving adaptive mutations driven primarily, but not exclusively, by early cytotoxic T cell responses

Initial antibodies binding to HIV-1 gp41 in acutely infected subjects are polyreactive and highly mutated

Many HIV-1 envelope-reactive antibodies shortly after HIV-1 transmission may arise from crow-reactive memory B cells previously stimulated by non-HIV-1 host or microbial antigen

Non-standard neutrino interactions in IceCube

Non-standard neutrino interactions (NSI) may arise in various types of new physics. Their existence would change the potential that atmospheric neutrinos encounter when traversing Earth matter and hence alter their oscillation behavior. This imprint on coherent neutrino forward scattering can be probed using high-statistics neutrino experiments such as IceCube and its low-energy extension, DeepCore. Both provide extensive data samples that include all neutrino flavors, with oscillation baselines between tens of kilometers and the diameter of the Earth. DeepCore event energies reach from a few GeV up to the order of 100 GeV - which marks the lower threshold for higher energy IceCube atmospheric samples, ranging up to 10 TeV. In DeepCore data, the large sample size and energy range allow us to consider not only flavor-violating and flavor-nonuniversal NSI in the μ−τ sector, but also those involving electron flavor. The effective parameterization used in our analyses is independent of the underlying model and the new physics mass scale. In this way, competitive limits on several NSI parameters have been set in the past. The 8 years of data available now result in significantly improved sensitivities. This improvement stems not only from the increase in statistics but also from substantial improvement in the treatment of systematic uncertainties, background rejection and event reconstruction

IceCube Search for Earth-traversing ultra-high energy Neutrinos

The search for ultra-high energy neutrinos is more than half a century old. While the hunt for these neutrinos has led to major leaps in neutrino physics, including the detection of astrophysical neutrinos, neutrinos at the EeV energy scale remain undetected. Proposed strategies for the future have mostly been focused on direct detection of the first neutrino interaction, or the decay shower of the resulting charged particle. Here we present an analysis that uses, for the first time, an indirect detection strategy for EeV neutrinos. We focus on tau neutrinos that have traversed Earth, and show that they reach the IceCube detector, unabsorbed, at energies greater than 100 TeV for most trajectories. This opens up the search for ultra-high energy neutrinos to the entire sky. We use ten years of IceCube data to perform an analysis that looks for secondary neutrinos in the northern sky, and highlight the promise such a strategy can have in the next generation of experiments when combined with direct detection techniques