Continuous collective analysis of chemical reactions.

The automated synthesis of small organic molecules from modular building blocks has the potential to transform our capacity to create medicines and materials. Disruptive acceleration of this molecule-building strategy broadly unlocks its functional potential and requires the integration of many new assembly chemistries. Although recent advances in high-throughput chemistry can speed up the development of appropriate synthetic methods, for example, in selecting appropriate chemical reaction conditions from the vast range of potential options, equivalent high-throughput analytical methods are needed.

Sonic Hedgehog activates prostaglandin signaling to stabilize primary cilium length.

Sonic Hedgehog (SHH) is a driver of embryonic patterning that, when corrupted, triggers developmental disorders and cancers. SHH effector responses are organized through primary cilia (PC) that grow and retract with the cell cycle and in response to extracellular cues. Disruption of PC homeostasis corrupts SHH regulation, placing significant pressure on the pathway to maintain ciliary fitness.

Synthesis of Isotopically Labeled, Spin-Isolated Tyrosine and Phenylalanine for Protein NMR Applications.

Isotopically labeled amino acids are widely used to study the structure and dynamics of proteins by NMR. Herein we describe a facile, gram-scale synthesis of compounds and under standard laboratory conditions from the common intermediate . is obtained via simple deprotection, while is accessed through a reductive deoxygenation/deuteration sequence and deprotection.

An integrated, optofluidic system with aligned optical waveguides, microlenses, and coupling prisms for fluorescence sensing.

An improved, laser-induced fluorescence-based micro-optical biosensor was designed and fabricated, with cyclic olefin copolymer (COC) optical waveguides, a poly(methyl methacrylate) (PMMA) fluidic substrate with an array of microlenses, and a COC coupling prism integrated with the waveguide substrate or cover plate. The double-sided hot embossed fluidic substrate had sampling zone microchannels on the bottom and microlenses on the top. Dissolved COC injected into polydimethylsiloxane (PDMS) lost molds embedded the waveguides in the PMMA cover plate and formed the integrated coupling prism.

Bromodomain-Selective BET Inhibitors Are Potent Antitumor Agents against MYC-Driven Pediatric Cancer.

Inhibition of members of the bromodomain and extraterminal (BET) family of proteins has proven a valid strategy for cancer chemotherapy. All BET identified to date contain two bromodomains (BD; BD1 and BD2) that are necessary for recognition of acetylated lysine residues in the N-terminal regions of histones. Chemical matter that targets BET (BETi) also interact via these domains.

A Small Hypoxia Signature Predicted pCR Response to Bevacizumab in the Neoadjuvant GeparQuinto Breast Cancer Trial.

Purpose: In breast cancer, bevacizumab increased pCR rate but not long-term survival and no predictive markers are available to identify patients with long-term benefit from the drug.

Experimental Design: We profiled 289 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) biopsies of HER2-negative patients from the GeparQuinto trial of neoadjuvant chemotherapy ± bevacizumab by exome-capture RNA-sequencing (RNA-seq). In a prospectively planned study, we tested molecular signatures for response prediction.

RNA based individualized drug selection in breast cancer patients without patient-matched normal tissue.

Background: While standard RNA expression tests stratify patients into risk groups, RNA-Seq can guide personalized drug selection based on expressed mutations, fusion genes, and differential expression (DE) between tumor and normal tissue. However, patient-matched normal tissue may be unavailable. Additionally, biological variability in normal tissue and technological biases may confound results.

The role of ZA channel water-mediated interactions in the design of bromodomain-selective BET inhibitors.

The Bromodomain and Extra-Terminal domain (BET) family of proteins are involved in the regulation of gene transcription, and their dysregulation is implicated in several diseases including cancer. BET proteins contain two tandem bromodomains (BD1 and BD2) that independently recognize acetylated-lysine residues and appear to have distinct biological roles. We compared several published co-crystal structures and found five positions near the substrate binding pocket that vary between BET bromodomains.

Effects of Estrogen Receptor and Human Epidermal Growth Factor Receptor-2 Levels on the Efficacy of Trastuzumab: A Secondary Analysis of the HERA Trial.

Importance: A number of studies suggest that response to antihuman epidermal growth factor receptor-2 (currently known as ERBB2, butreferred to asHER2 in this study) agents differs by estrogen receptor (ER) level status. The clinical relevance of this is unknown.

Objective: To determine the magnitude of trastuzumab benefit according to quantitative levels of ER and HER2 in the HERceptin Adjuvant (HERA) trial.

CRTC1/MAML2 gain-of-function interactions with MYC create a gene signature predictive of cancers with CREB-MYC involvement.

Chimeric oncoproteins created by chromosomal translocations are among the most common genetic mutations associated with tumorigenesis. Malignant mucoepidermoid salivary gland tumors, as well as a growing number of solid epithelial-derived tumors, can arise from a recurrent t (11, 19)(q21;p13.1) translocation that generates an unusual chimeric cAMP response element binding protein (CREB)-regulated transcriptional coactivator 1 (CRTC1)/mastermind-like 2 (MAML2) (C1/M2) oncoprotein comprised of two transcriptional coactivators, the CRTC1 and the NOTCH/RBPJ coactivator MAML2.

Structure-activity relationships of substituted 1-pyridyl-2-phenyl-1,2-ethanediones: potent, selective carboxylesterase inhibitors.

Inhibition of intestinal carboxylesterases may allow modification of the pharmacokinetics/pharmacodynamic profile of existing drugs by altering half-life or toxicity. Since previously identified diarylethane-1,2-dione inhibitors are decidedly hydrophobic, a modified dione scaffold was designed and elaborated into a >300 member library, which was subsequently screened to establish the SAR for esterase inhibition. This allowed the identification of single digit nanomolar hiCE inhibitors that showed improvement in selectivity and measured solubility.

Expression quantitative trait loci mapping identifies new genetic models of glutathione S-transferase variation.

Expression quantitative trait loci (eQTL) mapping can be used to identify the genetic variations that underlie inherited differences in gene transcription. We performed eQTL mapping by combining whole genome transcriptional data from the hypothalami of 33 strains of inbred mice with a detailed haplotype map of those same strains, revealing 10,655 trans associations and 31 cis eQTLs. One of the cis associations was found to be driven by strain-specific variation in the expression of Glutathione S-transferase, mu 5 (Gstm5).

Modulation of p47PHOX activity by site-specific phosphorylation: Akt-dependent activation of the NADPH oxidase.

The leukocyte NADPH oxidase catalyzes the reduction of oxygen to O(2)(-) at the expense of NADPH. Extensive phosphorylation of the oxidase subunit p47(PHOX) occurs during the activation of the enzyme in intact cells. p47(PHOX) carrying certain serine-to-alanine mutations fails to support NADPH oxidase activity in intact cells, suggesting that the phosphorylation of specific serines on p47(PHOX) is required for the activation of the oxidase.