TheÀ216G/T, À191C/A, intron 1 and Arg497Lys epidermal growth factor receptor (EGFR) polymorphisms were evaluated in 92 advanced non-smallcell lung cancer patients treated with gefitinib, an EGFR tyrosine-kinase inhibitor. Improved progression free survival (PFS) was found in patients homozygous for the shorter lengths of intron 1 polymorphism (S/S; S ¼ 16 or fewer CA repeats; log-rank test (LRT) P ¼ 0.03) and for patients carrying any T allele of the À216G/T polymorphism (LRT, P ¼ 0.005). When considered together, patients with intron 1 S/S genotype and at least one T allele of À216G/T had improved PFS (LRT P ¼ 0.0006; adjusted hazard ratio (AHR), 0.60 (95% confidence interval, 0.36-0.98)) and overall survival (LRT P ¼ 0.02; AHR, 0.60 (0.36-1.00)) when compared with all others. The T allele of À216G/T was also associated with significantly higher rates of stable disease/partial response (P ¼ 0.01) and a significantly higher risk of treatment-related rash/diarrhea (P ¼ 0.004, multivariate model). EGFR intron 1 and -216G/T polymorphisms influence clinical outcomes in gefitinibtreated non-small-cell lung cancer patients.

We have studied the temperature dependence of the integer quantum Hall transitions in the molecular crystal ͑TMTSF͒ 2 PF 6 . In the high-temperature regime, just below the transition temperature of the associated fieldinduced spin-density waves ͑FISDW͒, we find that the width of the transitions between the quantum Hall plateaus, as measured by the slope of the xy risers, d xy /dB, and the ͑inverse͒ width of the xx peaks, (⌬B) Ϫ1 , decreases linearly with temperature; at low temperatures, however, the width saturates. We explain the temperature dependence of the width in terms of that of the order parameter of the FISDW and the characteristic impurity length scale of the system.

1AbstractComplex biological systems can be understood by dividing them into hierarchies. Each level of such a hierarchy is composed of different subunits which cooperate to perform distinct biological functions. Single-cell RNA-seq (scRNA-seq) has emerged as a powerful technique to quantify gene expression in individual cells and is being used to elucidate the molecular and cellular building blocks of complex tissues. We developed a novel Bayesian hierarchical model called Cellular Latent Dirichlet Allocation (Celda) to perform bi-clustering of co-expressed genes into modules and cells into subpopulations. This model can also quantify the relationship between different levels in a biological hierarchy by determining the contribution of each gene in each module, each module in each cell population, and each cell population in each sample. We used Celda to identify transcriptional modules and cell subpopulations in publicly-available peripheral blood mononuclear cell (PBMC) dataset. In addition to the major classes of cell types, Celda also identified a population of proliferating T-cells and a single plasma cell that was missed by other clustering methods in this dataset. Transcriptional modules captured consistency in expression patterns among genes linked to same biological functions. Furthermore, transcriptional modules provided direct insights on cell type specific marker genes, and helped understanding of subtypes of B- and T-cells. Overall, Celda presents a novel principled approach towards characterizing transcriptional programs and cellular and heterogeneity in single-cell data.

The signal transducer and activator of transcription (STAT) family of transcription factors is triggered by cytokine and growth factor receptors in a number of cell types, and binds to a consensus sequence defined in part by the IFN-gamma activation site (GAS). It is not known whether these transcription factors respond to other kinds of growth stimuli, and, with particular relevance to lymphocytes, it is not known whether STAT proteins participate in Ag-specific responses. To determine the role of STAT proteins, coupling between Ag-receptor cross-linking and nuclear expression of DNA-binding protein complexes that recognize GAS sequences was evaluated. Ag-receptor triggering in primary B lymphocytes stimulated nuclear expression of a complex that specifically binds the IFN response factor-1 (IRF-1) GAS sequence, and is distinguished by electrophoretic mobility and GAS preference from IRF-1 GAS-binding complexes induced by IFN-gamma. Activation of nuclear IRF-1 GAS-binding activity by sIg was inhibited by the tyrosine kinase inhibitor, herbimycin A, and binding activity was eliminated by tyrosine phosphatase treatment. Activation of IRF-1 GAS-binding activity was blocked by depletion of protein kinase C. The IRF-1 GAS-binding activity induced by sIg engagement in B cells was transcriptionally active, and was found to consist of immunoreactive STAT5 and STAT6 proteins. This work demonstrates that the STAT signaling pathway previously associated with cytokine signaling is triggered in B lymphocytes through Ag-receptor engagement in a protein kinase C-dependent fashion. This heretofore described cytokine signaling pathway may play a role in bringing about Ag-specific proliferative and differentiative responses.