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This Week in Science: Dec 2, 2011

In Science this week, researchers in the US and Sweden find functional links between beta-amyloid peptide toxicity and risk factors for Alzheimer's disease by modeling Aβ toxicity in yeast. A genome-wide screen for toxicity modifiers identified the yeast homolog of phosphatidylinositol binding clathrin assembly protein and other factors connected to Alzheimer's that had not previously been connected to Aβ toxicity. "The factors identified in yeast modified Aβ toxicity in glutamatergic neurons of Caenorhabditis elegans and in primary rat cortical neurons," the authors write. "In yeast, Aβ impaired the endocytic trafficking of a plasma membrane receptor, which was ameliorated by endocytic pathway factors identified in the yeast screen."

In Science Signaling this week, researchers in the UK use a targeted siRNA screen to identify regulators of Cdc42 activity at the natural killer cell immunological synapse. The team observed that live natural killer cells forming immunological synapses with target cells show oscillating Cdc42 activity, after an initial increase in activity. "We used protein-protein interaction networks and structural databases to identify candidate proteins that controlled Cdc42 activity, leading to the design of a targeted short interfering RNA screen," the team says. "The guanine nucleotide exchange factors RhoGEF6 and RhoGEF7 were necessary for Cdc42 activation within the NK cell immunological synapse. In addition, the kinase Akt and the p85α subunit of phosphoinositide 3-kinase (PI3K) were required for Cdc42 activation, the periodicity of the oscillation in Cdc42 activity, and the subsequent polarization of cytotoxic vesicles toward target cells."

In Science Translational Medicine this week, researchers in the US and Canada report their discovery that the PDL1-PD1 axis converts human TH1 cells into regulatory T cells. The team observed that conventional T cells or irradiated K562 myeloid tumor cells that over-expressed PDL1 converted TBET+ TH1 cells into FOXP3+ regulatory T cells in vivo. "Either blocking PD1 expression on TH1 cells by small interfering RNA targeting or abrogation of PD1 signaling by SHP1/2 pharmacologic inhibition stabilized TH1 cell differentiation during PDL1 challenge and restored the capacity of TH1 cells to mediate lethal xGVHD," the authors write.

Also in Science Translational Medicine this week, researchers in the US and India report the results of a pilot study of integrative high-throughput sequencing as a tool for personalized oncology. The team enrolled patients with advanced or refractory cancer, and performed whole-genome sequencing of the tumor, targeted whole-exome sequencing of tumor and normal DNA, and transcriptome sequencing of the tumor to identify mutations in a clinically relevant time frame, three to four weeks. "With this approach, we detected several classes of cancer mutations including structural rearrangements, copy number alterations, point mutations, and gene expression alterations," the authors write. "Integrative high-throughput sequencing of patients with advanced cancer generates a comprehensive, individual mutational landscape to facilitate biomarker-driven clinical trials in oncology."

The Scan

Drug Response Variants May Be Distinct in Somatic, Germline Samples

Based on variants from across 21 drug response genes, researchers in The Pharmacogenomics Journal suspect that tumor-only DNA sequences may miss drug response clues found in the germline.

Breast Cancer Risk Gene Candidates Found by Multi-Ancestry Low-Frequency Variant Analysis

Researchers narrowed in on new and known risk gene candidates with variant profiles for almost 83,500 individuals with breast cancer and 59,199 unaffected controls in Genome Medicine.

Health-Related Quality of Life Gets Boost After Microbiome-Based Treatment for Recurrent C. Diff

A secondary analysis of Phase 3 clinical trial data in JAMA Network Open suggests an investigational oral microbiome-based drug may lead to enhanced quality of life measures.

Study Follows Consequences of Early Confirmatory Trials for Accelerated Approval Indications

Time to traditional approval or withdrawal was shorter when confirmatory trials started prior to accelerated approval, though overall regulatory outcomes remained similar, a JAMA study finds.