Tucatinib and trastuzumab in HER2-mutated metastatic breast cancer: a phase 2 basket trial.

Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) signaling promotes cell growth and differentiation, and is overexpressed in several tumor types, including breast, gastric and colorectal cancer. HER2-targeted therapies have shown clinical activity against these tumor types, resulting in regulatory approvals. However, the efficacy of HER2 therapies in tumors with HER2 mutations has not been widely investigated.

An inhaled dose of budesonide induces genes involved in transcription and signaling in the human airways: enhancement of anti- and proinflammatory effector genes.

Although inhaled glucocorticoids, or corticosteroids (ICS), are generally effective in asthma, understanding their anti-inflammatory actions in vivo remains incomplete. To characterize glucocorticoid-induced modulation of gene expression in the human airways, we performed a randomized placebo-controlled crossover study in healthy male volunteers. Six hours after placebo or budesonide inhalation, whole blood, bronchial brushings, and endobronchial biopsies were collected.

Reusable, extensible, and modifiable R scripts and Kepler workflows for comprehensive single set ChIP-seq analysis.

Background: There has been an enormous expansion of use of chromatin immunoprecipitation followed by sequencing (ChIP-seq) technologies. Analysis of large-scale ChIP-seq datasets involves a complex series of steps and production of several specialized graphical outputs. A number of systems have emphasized custom development of ChIP-seq pipelines.

Differences among brain tumor stem cell types and fetal neural stem cells in focal regions of histone modifications and DNA methylation, broad regions of modifications, and bivalent promoters.

Background: Aberrational epigenetic marks are believed to play a major role in establishing the abnormal features of cancer cells. Rational use and development of drugs aimed at epigenetic processes requires an understanding of the range, extent, and roles of epigenetic reprogramming in cancer cells. Using ChIP-chip and MeDIP-chip approaches, we localized well-established and prevalent epigenetic marks (H3K27me3, H3K4me3, H3K9me3, DNA methylation) on a genome scale in several lines of putative glioma stem cells (brain tumor stem cells, BTSCs) and, for comparison, normal human fetal neural stem cells (fNSCs).

Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development.

The importance of maternal folate consumption for normal development is well established, yet the molecular mechanism linking folate metabolism to development remains poorly understood. The enzyme methionine synthase reductase (Mtrr) is necessary for utilization of methyl groups from the folate cycle. We found that a hypomorphic mutation of the mouse Mtrr gene results in intrauterine growth restriction, developmental delay, and congenital malformations, including neural tube, heart, and placental defects.

Workflows for microarray data processing in the Kepler environment.

Background: Microarray data analysis has been the subject of extensive and ongoing pipeline development due to its complexity, the availability of several options at each analysis step, and the development of new analysis demands, including integration with new data sources. Bioinformatics pipelines are usually custom built for different applications, making them typically difficult to modify, extend and repurpose. Scientific workflow systems are intended to address these issues by providing general-purpose frameworks in which to develop and execute such pipelines.

Anesthetics discriminate between tonic and phasic gamma-aminobutyric acid receptors on hippocampal CA1 neurons.

Background: Anesthesia is produced by a depression of neuronal signaling in the central nervous system (CNS); however, the mechanism(s) of action underlying this depression remain unclear. Recent studies have indicated that anesthetics can enhance inhibition of CNS neurons by increasing current flow through tonic gamma-aminobutyric acid (GABA(A)) receptor gated chloride channels in their membranes. Enhanced tonic inhibition would contribute to CNS depression produced by anesthetics, but it remains to be determined to what extent anesthetic actions at these receptors contribute to CNS depression.

Analysis of the mechanisms mediating tumor-specific changes in gene expression in human liver tumors.

There is widespread interest in efficient characterization of differences between tumor and normal samples. Here, we show an effective methodology for genome-scale characterization of tumors. Using matched normal and tumor samples from liver cancer patients, as well as non-cancer-related normal liver tissue, we first determined changes in gene expression as monitored on RNA expression arrays.

Systematic evaluation of variability in ChIP-chip experiments using predefined DNA targets.

The most widely used method for detecting genome-wide protein-DNA interactions is chromatin immunoprecipitation on tiling microarrays, commonly known as ChIP-chip. Here, we conducted the first objective analysis of tiling array platforms, amplification procedures, and signal detection algorithms in a simulated ChIP-chip experiment. Mixtures of human genomic DNA and "spike-ins" comprised of nearly 100 human sequences at various concentrations were hybridized to four tiling array platforms by eight independent groups.

Integrated epigenomic analyses of neuronal MeCP2 reveal a role for long-range interaction with active genes.

Mutations in MECP2 cause the autism-spectrum disorder Rett syndrome. MeCP2 is predicted to bind to methylated promoters and silence transcription. However, the first large-scale mapping of neuronal MeCP2-binding sites on 26.

A comprehensive ChIP-chip analysis of E2F1, E2F4, and E2F6 in normal and tumor cells reveals interchangeable roles of E2F family members.

Using ChIP-chip assays (employing ENCODE arrays and core promoter arrays), we examined the binding patterns of three members of the E2F family in five cell types. We determined that most E2F1, E2F4, and E2F6 binding sites are located within 2 kb of a transcription start site, in both normal and tumor cells. In fact, the majority of promoters that are active (as defined by TAF1 or POLR2A binding) in GM06990 B lymphocytes and Ntera2 carcinoma cells were also bound by an E2F.

Identification of genes directly regulated by the oncogene ZNF217 using chromatin immunoprecipitation (ChIP)-chip assays.

It has been proposed that ZNF217, which is amplified at 20q13 in various tumors, plays a key role during neoplastic transformation. ZNF217 has been purified in complexes that contain repressor proteins such as CtBP2, suggesting that it acts as a transcriptional repressor. However, the function of ZNF217 has not been well characterized due to a lack of known target genes.

Unbiased location analysis of E2F1-binding sites suggests a widespread role for E2F1 in the human genome.

The E2F family of transcription factors regulates basic cellular processes. Here, we take an unbiased approach towards identifying E2F1 target genes by examining localization of E2F1-binding sites using high-density oligonucleotide tiling arrays. To begin, we developed a statistically-based methodology for analysis of ChIP-chip data obtained from arrays that represent 30 Mb of the human genome.

N-type and L-type calcium channels mediate glycinergic synaptic inputs to retinal ganglion cells of tiger salamanders.

Synaptically localized calcium channels shape the timecourse of synaptic release, are a prominent site for neuromodulation, and have been implicated in genetic disease. In retina, it is well established that L-type calcium channels play a major role in mediating release of glutamate from the photoreceptors and bipolar cells. However, little is known about which calcium channels are coupled to synaptic exocytosis of glycine, which is primarily released by amacrine cells.

Major role for tonic GABAA conductances in anesthetic suppression of intrinsic neuronal excitability.

Anesthetics appear to produce neurodepression by altering synaptic transmission and/or intrinsic neuronal excitability. Propofol, a widely used anesthetic, has proposed effects on many targets, ranging from sodium channels to GABA(A) inhibition. We examined effects of propofol on the intrinsic excitability of hippocampal CA1 neurons (primarily interneurons) recorded from adult rat brain slices.