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.

Stability and Reactivity of Aromatic Radical Anions in Solution with Relevance to Birch Reduction.

We investigate the electronic structure of aromatic radical anions in the solution phase employing a combination of liquid-jet (LJ) photoelectron (PE) spectroscopy measurements and electronic structure calculations. By using recently developed protocols, we accurately determine the vertical ionization energies of valence electrons of both the solvent and the solute molecules. In particular, we first characterize the pure solvent of tetrahydrofuran (THF) by LJ-PE measurements in conjunction with ab initio molecular dynamics simulations and GW calculations.

Ascorbic acid modulates the structure of the virulence factor pyocyanin and ascorbic acid-furanone-30 combination facilitate biofilm disruption.

The production of pyocyanin by increases its virulence, fitness and biofilm formation. Pyocyanin is also a redox molecule and we hypothesize that ascorbic acid being an antioxidant will interact with pyocyanin. The main objective of this study was to investigate the potential interaction of ascorbic acid with pyocyanin, and also to investigate the impact of ascorbic acid in combination with Furanone-30 on quorum sensing and biofilm formation of .

Targeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma.

Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic Paired Box 3-Forkhead Box O1 (PAX3-FOXO1) fusion protein, which governs a core regulatory circuitry transcription factor network. Here, we show that the histone lysine demethylase 4B (KDM4B) is a therapeutic vulnerability for PAX3-FOXO1 RMS.

Recent Advances with KDM4 Inhibitors and Potential Applications.

The histone lysine demethylase 4 (KDM4) family plays an important role in regulating gene transcription, DNA repair, and metabolism. The dysregulation of KDM4 functions is associated with many human disorders, including cancer, obesity, and cardiovascular diseases. Selective and potent KDM4 inhibitors may help not only to understand the role of KDM4 in these disorders but also to provide potential therapeutic opportunities.

A WIN Consortium phase I study exploring avelumab, palbociclib, and axitinib in advanced non-small cell lung cancer.

Background: The Worldwide Innovative Network (WIN) Consortium has developed the Simplified Interventional Mapping System (SIMS) to better define the cancer molecular milieu based on genomics/transcriptomics from tumor and analogous normal tissue biopsies. SPRING is the first trial to assess a SIMS-based tri-therapy regimen in advanced non-small cell lung cancer (NSCLC).

Methods: Patients with advanced NSCLC (no EGFR, ALK, or ROS1 alterations; PD-L1 unrestricted; ≤2 prior therapy lines) received avelumab, axitinib, and palbociclib (3 + 3 dose escalation design).

Phenyl-Glutarimides: Alternative Cereblon Binders for the Design of PROTACs.

Targeting cereblon (CRBN) is currently one of the most frequently reported proteolysis-targeting chimera (PROTAC) approaches, owing to favorable drug-like properties of CRBN ligands, immunomodulatory imide drugs (IMiDs). However, IMiDs are known to be inherently unstable, readily undergoing hydrolysis in body fluids. Here we show that IMiDs and IMiD-based PROTACs rapidly hydrolyze in commonly utilized cell media, which significantly affects their cell efficacy.

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.

Intra- and Interlaboratory Reproducibility of the Sensitivity to Endocrine Therapy Assay for Stage II/III Breast Cancer.

Background: The sensitivity to endocrine therapy assay (SET2,3) predicts treatment outcomes in Stage II-III breast cancer. SET2,3 measures transcription related to estrogen and progesterone receptors (SETER/PR index) and the molecular subtype (RNA4: ESR1, PGR, ERBB2, AURKA) from formalin-fixed paraffin-embedded (FFPE) tissue sections.

Methods: We designed a nested study across 3 pathology laboratories, each testing 60 breast cancers twice in controlled batches.

Identification of Potent, Selective, and Orally Bioavailable Small-Molecule GSPT1/2 Degraders from a Focused Library of Cereblon Modulators.

Whereas the PROTAC approach to target protein degradation greatly benefits from rational design, the discovery of small-molecule degraders relies mostly on phenotypic screening and retrospective target identification efforts. Here, we describe the design, synthesis, and screening of a large diverse library of thalidomide analogues against a panel of patient-derived leukemia and medulloblastoma cell lines. These efforts led to the discovery of potent and novel GSPT1/2 degraders displaying selectivity over classical IMiD neosubstrates, such as IKZF1/3, and high oral bioavailability in mice.

17-DMAG dually inhibits Hsp90 and histone lysine demethylases in alveolar rhabdomyosarcoma.

Histone lysine demethylases (KDMs) play critical roles in oncogenesis and therefore may be effective targets for anticancer therapy. Using a time-resolved fluorescence resonance energy transfer demethylation screen assay, in combination with multiple orthogonal validation approaches, we identified geldanamycin and its analog 17-DMAG as KDM inhibitors. In addition, we found that these Hsp90 inhibitors increase degradation of the alveolar rhabdomyosarcoma (aRMS) driver oncoprotein PAX3-FOXO1 and induce the repressive epigenetic mark H3K9me3 and H3K36me3 at genomic loci of PAX3-FOXO1 targets.

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.

Development and optimization of OspC chimeritope vaccinogens for Lyme disease.

Experimental Outer surface protein (Osp) C based subunit chimeritope vaccinogens for Lyme disease (LD) were assessed for immunogenicity, structure, ability to elicit antibody (Ab) responses to divergent OspC proteins, and bactericidal activity. Chimeritopes are chimeric epitope based proteins that consist of linear epitopes derived from multiple proteins or multiple variants of a protein. An inherent advantage to chimeritope vaccinogens is that they can be constructed to trigger broadly protective Ab responses.

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.

Confirmatory Factor Analysis of the Enriched Life Scale Among US Military Veterans.

The Enriched Life Scale (ELS) is a 40-item measure developed by the military veteran service organization, Team Red, White & Blue (RWB), to systematically capture and quantify the lived experiences of military veterans transitioning to civilian life. As Team RWB's mission is to "enrich veterans' lives," veterans who conceived of and co-developed the ELS as a psychometric instrument defined what an "enriched life" would entail. Exploratory factor analysis (EFA) of the ELS revealed a five-factor structure capturing the domains of: physical health, mental health, genuine relationships, sense of purpose, and engaged citizenship.

The Enriched Life Scale (ELS): Development, exploratory factor analysis, and preliminary construct validity for U.S. military veteran and civilian samples.

The U.S. military veteran serving nonprofit, Team Red, White & Blue (RWB), defined an "enriched life" as having physical, mental, and emotional health; supportive relationships; and a sense of purpose.

Exploratory Analysis of Single-Gene Predictive Biomarkers in HERA DASL Cohort Reveals That C8A mRNA Expression Is Prognostic of Outcome and Predictive of Benefit of Trastuzumab.

Purpose: The Herceptin Adjuvant study is an international multicenter randomized trial that compared 1 or 2 years of trastuzumab given every 3 weeks with observation in women with human epidermal growth factor 2-positive (HER2+) breast cancer after chemotherapy. Identification of biomarkers predictive of a benefit from trastuzumab will minimize overtreatment and lower health care costs.

Methods: To identify possible single-gene biomarkers, an exploratory analysis of 3,669 gene probes not expected to be expressed in normal breast tissue was conducted.

H, C, and N resonance assignments of N-acetylmuramyl-L-alanine amidase (AmiC) N-terminal domain (NTD) from Neisseria gonorrhoeae.

Gonorrhea infections are becoming more difficult to treat due to the prevalence of strains exhibiting resistance to antibiotics and new therapeutic approaches are needed. N-acetylmuramyl-L-alanine amidase (AmiC) from Neisseria gonorrhoeae is a hydrolase that functions during cell division by cleaving the bond between the N-acetylmuramyl and L-alanine moieties of peptidoglycan. Inhibiting this enzyme offers the prospect of restoring the efficacy of existing antibiotics as treatments against N.

Regional differences in BMI, obesity, and exercise frequency in a large veteran service organization: A secondary analysis of new veteran member surveys from Team Red, White & Blue.

The purpose of the present study was to examine regional differences in average self-reported BMI, obesity prevalence, and frequent exercise (FE) among members of Team Red, White, and Blue (Team RWB) - a military veteran service organization founded to increase physical activity in veterans. A total of 10,015 military veterans participated in a needs assessment conducted by Team RWB between December 2014 and August 2016. Multivariate regression analysis with bootstrapped coefficients revealed that: BMI was highest in the Midwest region ( = 28.

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.

Team Red, White & Blue: a community-based model for harnessing positive social networks to enhance enrichment outcomes in military veterans reintegrating to civilian life.

Military service assimilates individuals into a socially cohesive force to address dangerous and traumatic situations that have no counterpart in civilian life. Upon leaving active duty, many veterans experience a "reverse culture shock" when trying to reintegrate into civilian institutions and cultivate supportive social networks. Poor social reintegration is associated with greater morbidity and premature mortality in part due to adoption of risky health behaviors, social isolation, and inadequate engagement in health care services.