Automated size selection for short cell-free DNA fragments enriches for circulating tumor DNA and improves error correction during next generation sequencing.

Circulating tumor-derived cell-free DNA (ctDNA) enables non-invasive diagnosis, monitoring, and treatment susceptibility testing in human cancers. However, accurate detection of variant alleles, particularly during untargeted searches, remains a principal obstacle to widespread application of cell-free DNA in clinical oncology. In this study, isolation of short cell-free DNA fragments is shown to enrich for tumor variants and improve correction of PCR- and sequencing-associated errors.

Fragment Length of Circulating Tumor DNA.

Malignant tumors shed DNA into the circulation. The transient half-life of circulating tumor DNA (ctDNA) may afford the opportunity to diagnose, monitor recurrence, and evaluate response to therapy solely through a non-invasive blood draw. However, detecting ctDNA against the normally occurring background of cell-free DNA derived from healthy cells has proven challenging, particularly in non-metastatic solid tumors.

The small molecule C-6 is selectively cytotoxic against breast cancer cells and its biological action is characterized by mitochondrial defects and endoplasmic reticulum stress.

Introduction: The establishment of drug resistance following treatment with chemotherapeutics is strongly associated with poor clinical outcome in patients, and drugs that target chemoresistant tumors have the potential to increase patient survival. In an effort to identify biological pathways of chemoresistant breast cancers that can be targeted therapeutically, a small molecule screen utilizing metastatic patient-derived breast cancer cells was conducted; from this previous report, the cytotoxic small molecule, C-6, was identified for its ability to selectively kill aggressive breast cancer cells in a caspase-independent manner. Here, we describe the cellular and molecular pathways induced following C-6 treatment in both normal and breast cancer cell lines.

Development of a screen to identify selective small molecules active against patient-derived metastatic and chemoresistant breast cancer cells.

Introduction: High failure rates of new investigational drugs have impaired the development of breast cancer therapies. One challenge is that excellent activity in preclinical models, such as established cancer cell lines, does not always translate into improved clinical outcomes for patients. New preclinical models, which better replicate clinically-relevant attributes of cancer, such as chemoresistance, metastasis and cellular heterogeneity, may identify novel anti-cancer mechanisms and increase the success of drug development.

Patient-derived models of human breast cancer: protocols for in vitro and in vivo applications in tumor biology and translational medicine.

Research models that replicate the diverse genetic and molecular landscape of breast cancer are critical for developing the next-generation therapeutic entities that can target specific cancer subtypes. Patient-derived tumorgrafts, generated by transplanting primary human tumor samples into immune-compromised mice, are a valuable method to model the clinical diversity of breast cancer in mice, and are a potential resource in personalized medicine. Primary tumorgrafts also enable in vivo testing of therapeutics and make possible the use of patient cancer tissue for in vitro screens.

Transcription factor Oct1 is a somatic and cancer stem cell determinant.

Defining master transcription factors governing somatic and cancer stem cell identity is an important goal. Here we show that the Oct4 paralog Oct1, a transcription factor implicated in stress responses, metabolic control, and poised transcription states, regulates normal and pathologic stem cell function. Oct1(HI) cells in the colon and small intestine co-express known stem cell markers.

Synthesis of the reported structures for kealiinines B and C.

Syntheses of the reported structures of kealiinines B and C have been executed. An intermolecular electrophile-induced cyclization of a pendant arene on an ene-guanidine affords the tetracyclic, oxidized naphthimidazole cores.

Synthesis and preliminary biological studies of 3-substituted indoles accessed by a palladium-catalyzed enantioselective alkene difunctionalization reaction.

A unique alkene difunctionalization reaction that allows rapid construction of molecular complexity around the biologically relevant indole framework has been developed. The reaction proceeds with up to 87% yield, 99:1 er, and >20:1 dr. Evaluation of several of the compounds revealed promising anticancer activity against MCF-7 cells.

A new approach to carbon-carbon bond formation: Development of aerobic Pd-catalyzed reductive coupling reactions of organometallic reagents and styrenes.

Alkenes are attractive starting materials for organic synthesis and the development of new selective functionalization reactions are desired. Previously, our laboratory discovered a unique Pd-catalyzed hydroalkoxylation reaction of styrenes containing a phenol. Based upon deuterium labeling experiments, a mechanism involving an aerobic alcohol oxidation coupled to alkene functionalization was proposed.

Recent advancements and challenges of palladium(II)-catalyzed oxidation reactions with molecular oxygen as the sole oxidant.

During the past 10 years there have been significant advances in Pd(II)-catalyzed oxidation reactions where the use of ligands has led to the development of catalytic systems capable of achieving high turnover numbers, which employ molecular oxygen as the sole stoichiometric oxidant. This Feature article will highlight some of the recent developments in direct molecular oxygen-coupled Pd(II)-catalyzed oxidation reactions with an emphasis on enhanced catalytic systems and new reactions. Additionally, limitations of current catalytic systems, such as ligand oxidation, are presented and their implications for the development of new reactions are discussed.

Palladium(II)-catalyzed aerobic hydroalkoxylation of styrenes containing a phenol.

An intermolecular Pd-catalyzed hydroalkoxylation of styrenes that contain a phenol is presented. The reaction can be performed on terminal, disubstituted, and trisubstituted olefins in a variety of alcoholic solvents. Initial mechanistic data suggest a mechanism that involves oxidation of the alcoholic solvent to provide a Pd-hydride that inserts into an olefin.