Functional signaling test identifies HER2 negative breast cancer patients who may benefit from c-Met and pan-HER combination therapy.

Background: Research is revealing the complex coordination between cell signaling systems as they adapt to genetic and epigenetic changes. Tools to uncover these highly complex functional linkages will play an important role in advancing more efficacious disease treatments. Current tumor cell signal transduction research is identifying coordination between receptor types, receptor families, and transduction pathways to maintain tumor cell viability despite challenging tumor microenvironment conditions.

Direct Hydrodecarboxylation of Aliphatic Carboxylic Acids: Metal- and Light-Free.

A mild and inexpensive method for direct hydrodecarboxylation of aliphatic carboxylic acids has been developed. The reaction does not require metals, light, or catalysts, rendering the protocol operationally simple, easy to scale, and more sustainable. Crucially, no additional H atom source is required in most cases, while a broad substrate scope and functional group tolerance are observed.

Selectivity Control in Gold-Catalyzed Hydroarylation of Alkynes with Indoles: Application to Unsymmetrical Bis(indolyl)methanes.

Gold-catalyzed hydroarylation of unactivated alkynes with indoles have previously been reported to proceed with double indole addition to produce symmetrical bis(indolyl)methanes (BIMs). We demonstrate for the first time that the selectivity of the gold-catalyzed reaction can be fully switched to allow for isolation of the vinylindole products instead. Furthermore, this selective reaction can be utilized to synthesize the more difficult to access unsymmetrical BIMs from readily available starting materials.

New HER2-negative breast cancer subtype responsive to anti-HER2 therapy identified.

Purpose: HER2 signaling functional activity may be important to measure in addition to HER2 protein quantification when identifying patients eligible for HER2 therapies. A HER2 Signaling Function (CELx HSF) Test for HER2-negative patients uses patient's live tumor cells on a biosensor to identify patients with abnormally high HER2-related signaling (HSFs+) likely to respond to anti-HER2 therapies.

Methods: The CELx HSF test was employed to: (1) characterize the sensitivity and specificity of the test to detect abnormal levels of HER2 signaling; (2) evaluate the inhibitory effectiveness of five different anti-HER2 therapies; (3) assess the correlation between CELx HSF test detection of abnormal HER2 signaling and response to HER2 therapy using xenograft models; and (4) confirm the prevalence of abnormal HER2 signaling amongst HER2-negative breast cancer patients (HER2-/HSFs+).

Dual copper- and photoredox-catalysed C(sp)-C(sp) coupling.

The use of copper catalysis with visible light photoredox catalysis in a cooperative fashion has recently emerged as a versatile means of developing new C-C bond forming reactions. In this work, dual copper and photoredox catalysis is exploited to effect C(sp2)-C(sp3) cross-couplings between aryl boronic acids and benzyl bromides.

Development of a test that measures real-time HER2 signaling function in live breast cancer cell lines and primary cells.

Background: Approximately 18-20% of all human breast cancers have overexpressed human epidermal growth factor receptor 2 (HER2). Standard clinical practice is to treat only overexpressed HER2 (HER2+) cancers with targeted anti-HER2 therapies. However, recent analyses of clinical trial data have found evidence that HER2-targeted therapies may benefit a sub-group of breast cancer patients with non-overexpressed HER2.

meta-C-H Bromination on Purine Bases by Heterogeneous Ruthenium Catalysis.

Methods for positionally selective remote C-H functionalizations are in high demand. Herein, we disclose the first heterogeneous ruthenium catalyst for meta-selective C-H functionalizations, which enabled remote halogenations with excellent site selectivity and ample scope. The versatile heterogeneous Ru@SiO catalyst was broadly applicable and could be easily recovered and reused, which set the stage for the direct fluorescent labeling of purines.

A functional signal profiling test for identifying a subset of HER2-negative breast cancers with abnormally amplified HER2 signaling activity.

The results of clinical trials evaluating the efficacy of HER2 inhibitors in patients with breast cancer indicate that the correlation between HER2 receptor levels and patient outcomes is as low as 50%. The relatively weak correlation between HER2 status and response to HER2-targeting drugs suggests that measurement of HER2 signaling activity, rather than absolute HER2 levels, may more accurately diagnose HER2-driven breast cancer. A new diagnostic test, the CELx HER2 Signaling Profile (CELx HSP) test, is demonstrated to measure real-time HER2 signaling function in live primary cells.

Rhodium-Catalyzed Oxidative C-H Allylation of Benzamides with 1,3-Dienes by Allyl-to-Allyl 1,4-Rh(III) Migration.

The Rh(III)-catalyzed oxidative C-H allylation of N-acetylbenzamides with 1,3-dienes is described. The presence of allylic hydrogens cis to the less substituted alkene of the 1,3-diene is important for the success of these reactions. With the assistance of reactions using deuterated 1,3-dienes, a proposed mechanism is provided.

Enantioselective Synthesis of Spiroindenes by Enol-Directed Rhodium(III)-Catalyzed C-H Functionalization and Spiroannulation.

Chiral cyclopentadienyl rhodium complexes promote highly enantioselective enol-directed C(sp(2))-H functionalization and oxidative annulation with alkynes to give spiroindenes containing all-carbon quaternary stereocenters. High selectivity between two possible directing groups, as well as control of the direction of rotation in the isomerization of an O-bound rhodium enolate into the C-bound isomer, appear to be critical for high enantiomeric excesses.

All-Carbon [3+3] Oxidative Annulations of 1,3-Enynes by Rhodium(III)-Catalyzed C-H Functionalization and 1,4-Migration.

1,3-Enynes containing allylic hydrogens cis to the alkyne function as three-carbon components in rhodium(III)-catalyzed, all-carbon [3+3] oxidative annulations to produce spirodialins. The proposed mechanism of these reactions involves the alkenyl-to-allyl 1,4-rhodium(III) migration.

Direct Synthesis of 5-Aryl Barbituric Acids by Rhodium(II)-Catalyzed Reactions of Arenes with Diazo Compounds.

A commercially available rhodium(II) complex catalyzes the direct arylation of 5-diazobarbituric acids with arenes, allowing straightforward access to 5-aryl barbituric acids. Free N-H groups are tolerated on the barbituric acid, with no complications arising from N-H insertion processes. This method was applied to the concise synthesis of a potent matrix metalloproteinase (MMP) inhibitor.

Catalytic 1,4-rhodium(III) migration enables 1,3-enynes to function as one-carbon oxidative annulation partners in C-H functionalizations.

1,3-Enynes containing allylic hydrogens cis to the alkyne are shown to act as one-carbon partners, rather than two-carbon partners, in various rhodium-catalyzed oxidative annulations. The mechanism of these unexpected transformations is proposed to occur through double C-H activation, involving a hitherto rare example of the 1,4-migration of a Rh(III) species. This phenomenon is general across a variety of substrates, and provides a diverse range of heterocyclic products.

Synthesis of spirocyclic enones by rhodium-catalyzed dearomatizing oxidative annulation of 2-alkenylphenols with alkynes and enynes.

The dearomatizing oxidative annulation of 2-alkenylphenols with alkynes and enynes proceeds with high yields and regioselectivities under Rh(III) catalysis. These reactions are successful using Cu(OAc)2 or air as the stoichiometric oxidant, and provide spirocyclic enones, the basic ring system of which appears in several natural products. Application of this process to the preparation of a highly functionalized tetracycle is also demonstrated.

"Cost creep due to age creep" phenomenon: pattern analyses of in-patient hospitalization costs for various age brackets in the United States.

The expectation that aging leads to a progressive deterioration of biological functions leading to higher healthcare costs is known as the healthcare cost creep due to age creep phenomenon. The authors empirically test the validity of this phenomenon in the context of hospitalization costs based on more than 8 million hospital inpatient records from 1,056 hospitals in the United States. The results question the existence of cost creep due to age creep after the age of 65 years as far as average hospitalization costs are concerned.

Stereocontrolled synthesis of the AB rings of samaderine C.

A concise synthesis of the AB rings of samaderine C (12 steps, 8 isolation steps, 7.8% overall yield), a quassinoid with antifeedant and insecticidal activity, is described. The development of the first general approach to the trans-1,2-diol A-ring motif in samaderine C and other quassinoids is a key feature.

Catalytic asymmetric synthesis of butane diacetal-protected (4S,5S)-dihydroxycyclohexen-1-one and use in natural product synthesis.

Due to the lack of availability of unnatural (+)-quinic acid as a starting material, a 6-step synthesis of butane diacetal-protected (4S,5S)-dihydroxycyclohexen-1-one (formally derived from (+)-quinic acid) has been devised. The key catalytic asymmetric step involves a chiral Co-salen-catalysed epoxide ring-opening reaction. (4S,5S)-Dihydroxycyclohexen-1-one was utilised in the synthesis of two cyclohexenone natural products isolated from the mycelia of Lasiodiplodia theobromae.

Impact of high-throughput screening in biomedical research.

High-throughput screening (HTS) has been postulated in several quarters to be a contributory factor to the decline in productivity in the pharmaceutical industry. Moreover, it has been blamed for stifling the creativity that drug discovery demands. In this article, we aim to dispel these myths and present the case for the use of HTS as part of a proven scientific tool kit, the wider use of which is essential for the discovery of new chemotypes.

Functional characterization and high-throughput screening of positive allosteric modulators of α7 nicotinic acetylcholine receptors in IMR-32 neuroblastoma cells.

α7 nicotinic acetylcholine receptors (nAChRs) are characterized by relatively low ACh sensitivity, rapid activation, and fast desensitization kinetics. ACh/agonist evoked currents at the α7 nAChR are transient, and, typically, calcium flux responses are difficult to detect using conventional fluorometric assay techniques. One approach to study interactions of agonists with the α7 nAChR is by utilizing positive allosteric modulators (PAMs).

Discovery and characterization of non-ATP site inhibitors of the mitogen activated protein (MAP) kinases.

Inhibition of protein kinases has validated therapeutic utility for cancer, with at least seven kinase inhibitor drugs on the market. Protein kinase inhibition also has significant potential for a variety of other diseases, including diabetes, pain, cognition, and chronic inflammatory and immunologic diseases. However, as the vast majority of current approaches to kinase inhibition target the highly conserved ATP-binding site, the use of kinase inhibitors in treating nononcology diseases may require great selectivity for the target kinase.

Quantitative measurements of corticosteroids in ex vivo samples using on-line SPE-LC/MS/MS.

Abnormal elevation of 11beta-HSD1 activities in tissues, such as fat and brain, may contribute to the development of the abdominal obesity and Alzheimer disease, and the inhibition of 11beta-HSD1 might be beneficial to the management of these diseases. To assess the effects of pharmacologic inhibitors of 11beta-HSD1, we developed a fast LC/MS/MS method to quantify corticosteroids in minced tissue samples in the presence of 11beta-HSD substrates. The novel on-line SPE-LC/MS/MS method was developed with dual binary gradient and a throughput of 4.

Hospital care and capacity in the tri-state region of Indiana, Kentucky, and Ohio: analysis and insights.

Hospitals are a significant part of the burgeoning healthcare sector in the United States (U.S.) economy.

Application of a high-content multiparameter cytotoxicity assay to prioritize compounds based on toxicity potential in humans.

Prioritization of compounds based on human hepatotoxicity potential is currently a key unmet need in drug discovery, as it can become a major problem for several lead compounds in later stages of the drug discovery pipeline. The authors report the validation and implementation of a high-content multiparametric cytotoxicity assay based on simultaneous measurement of 8 key cell health indicators associated with nuclear morphology, plasma membrane integrity, mitochondrial function, and cell proliferation. Compounds are prioritized by (a) computing an in vitro safety margin using the minimum cytotoxic concentration (IC(20)) across all 8 indicators and cell-based efficacy data and (b) using the minimal cytotoxic concentration alone to take into account concentration of drug in tissues.

Role of Rho kinase pathway in chondroitin sulfate proteoglycan-mediated inhibition of neurite outgrowth in PC12 cells.

Activation of the Rho kinase (ROCK) pathway has been associated with inhibition of neurite regeneration and outgrowth in spinal cord injury. Growth-inhibitory substances present in the glial scar such as chondroitin sulfate proteoglycans (CSPGs) have been shown to create a nonpermissive environment for axon regeneration that results in growth cone collapse. In this study, an in vitro model was developed in nerve growth factor-differentiated PC12 cells where the Rho/ROCK pathway was modulated by CSPG.