Longitudinal monitoring of circulating tumor DNA to detect relapse early and predict outcome in early breast cancer.

Purpose: Detection of molecular residual disease (MRD) allows for the identification of breast cancer patients at high-risk of recurrence, with the potential that early initiation of treatment at early stages of relapse could improve patient outcomes. The Invitae Personalized Cancer Monitoring™ assay (PCM) is a newly developed next-generation sequencing approach that utilizes up to 50 patient-specific, tumor-informed DNA variants, to detect circulating tumor DNA (ctDNA). The ability of the PCM assay to detect MRD before clinical relapse was evaluated.

Selenium Induces Pancreatic Cancer Cell Death Alone and in Combination with Gemcitabine.

Survival rate for pancreatic cancer remains poor and newer treatments are urgently required. Selenium, an essential trace element, offers protection against several cancer types and has not been explored much against pancreatic cancer specifically in combination with known chemotherapeutic agents. The present study was designed to investigate selenium and Gemcitabine at varying doses alone and in combination in established pancreatic cancer cell lines growing in 2D as well as 3D platforms.

MuSyC is a consensus framework that unifies multi-drug synergy metrics for combinatorial drug discovery.

Drug combination discovery depends on reliable synergy metrics but no consensus exists on the correct synergy criterion to characterize combined interactions. The fragmented state of the field confounds analysis, impedes reproducibility, and delays clinical translation of potential combination treatments. Here we present a mass-action based formalism to quantify synergy.

Data-Driven Math Model of FLT3-ITD Acute Myeloid Leukemia Reveals Potential Therapeutic Targets.

-mutant acute myeloid leukemia (AML) is an aggressive form of leukemia with poor prognosis. Treatment with inhibitors frequently produces a clinical response, but the disease nevertheless often recurs. Recent studies have revealed system-wide gene expression changes in -mutant AML cell lines in response to drug treatment.

Mathematical modeling of the Candida albicans yeast to hyphal transition reveals novel control strategies.

Candida albicans, an opportunistic fungal pathogen, is a significant cause of human infections, particularly in immunocompromised individuals. Phenotypic plasticity between two morphological phenotypes, yeast and hyphae, is a key mechanism by which C. albicans can thrive in many microenvironments and cause disease in the host.

synergy: a Python library for calculating, analyzing and visualizing drug combination synergy.

Summary: Combinations of multiple pharmacological agents can achieve a substantial benefit over treatment with single agents alone. Combinations that achieve 'more than the sum of their parts' are called synergistic. There have been many proposed frameworks to understand and quantify drug combination synergy with different assumptions and domains of applicability.

Fibrosis improvement in patients with HCV treated with direct-acting antivirals.

Background And Aim: More prospective studies are needed to characterize fibrosis improvement in patients with hepatitis C virus (HCV) who are treated with direct-acting antivirals (DAAs). The aims of this study were to assess changes in elastography scores from baseline to 1-year follow-up in patients with HCV, to identify factors that were independently associated with improvement in fibrosis staging in patients who receive treatment, and to identify factors that were independently associated with no improvement in fibrosis staging among patients who achieved sustained virologic responses (SVR).

Methods: Ultrasound elastography and laboratory tests were performed and collected at baseline and at 1-year follow-up for patients who received HCV treatment and for those who did not receive treatment (n = 240).

Charting the Fragmented Landscape of Drug Synergy.

Even as the clinical impact of drug combinations continues to accelerate, no consensus on how to quantify drug synergy has emerged. Rather, surveying the landscape of drug synergy reveals the persistence of historical fissures regarding the appropriate domains of conflicting synergy models - fissures impacting all aspects of combination therapy discovery and deployment. Herein we chronicle the impact of these divisions on: (i) the design, interpretation, and reproducibility of high-throughput combination screens; (ii) the performance of algorithms to predict synergistic mixtures; and (iii) the search for higher-order synergistic interactions.

Systems-level network modeling of Small Cell Lung Cancer subtypes identifies master regulators and destabilizers.

Adopting a systems approach, we devise a general workflow to define actionable subtypes in human cancers. Applied to small cell lung cancer (SCLC), the workflow identifies four subtypes based on global gene expression patterns and ontologies. Three correspond to known subtypes (SCLC-A, SCLC-N, and SCLC-Y), while the fourth is a previously undescribed ASCL1+ neuroendocrine variant (NEv2, or SCLC-A2).

Quantifying Drug Combination Synergy along Potency and Efficacy Axes.

Two goals motivate treating diseases with drug combinations: reduce off-target toxicity by minimizing doses (synergistic potency) and improve outcomes by escalating effect (synergistic efficacy). Established drug synergy frameworks obscure such distinction, failing to harness the potential of modern chemical libraries. We therefore developed multi-dimensional synergy of combinations (MuSyC), a formalism based on a generalized, multi-dimensional Hill equation, which decouples synergistic potency and efficacy.

Ventricular-Subventricular Zone Contact by Glioblastoma is Not Associated with Molecular Signatures in Bulk Tumor Data.

Whether patients with glioblastoma that contacts the ventricular-subventricular zone stem cell niche (VSVZ + GBM) have a distinct survival profile from VSVZ - GBM patients independent of other known predictors or molecular profiles is unclear. Using multivariate Cox analysis to adjust survival for widely-accepted predictors, hazard ratios (HRs) for overall (OS) and progression free (PFS) survival between VSVZ + GBM and VSVZ - GBM patients were calculated in 170 single-institution patients and 254 patients included in both The Cancer Genome (TCGA) and Imaging (TCIA) atlases. An adjusted, multivariable analysis revealed that VSVZ contact was independently associated with decreased survival in both datasets.

Mathematical models of cell phenotype regulation and reprogramming: Make cancer cells sensitive again!

A cell's phenotype is the observable actualization of complex interactions between its genome, epigenome, and local environment. While traditional views in cancer have held that cellular and tumor phenotypes are largely functions of genomic instability, increasing attention has recently been given to epigenetic and microenvironmental influences. Such non-genetic factors allow cancer cells to experience intrinsic diversity and plasticity, and at the tumor level can result in phenotypic heterogeneity and treatment evasion.

Novel Hybrid Phenotype Revealed in Small Cell Lung Cancer by a Transcription Factor Network Model That Can Explain Tumor Heterogeneity.

Small cell lung cancer (SCLC) is a devastating disease due to its propensity for early invasion and refractory relapse after initial treatment response. Although these aggressive traits have been associated with phenotypic heterogeneity, our understanding of this association remains incomplete. To fill this knowledge gap, we inferred a set of 33 transcription factors (TF) associated with gene signatures of the known neuroendocrine/epithelial (NE) and non-neuroendocrine/mesenchymal-like (ML) SCLC phenotypes.

The Electronic Structure and Secondary Pyroelectric Properties of Lithium Tetraborate.

We review the pyroelectric properties and electronic structure of Li₂B₄O₇(110) and Li₂B₄O₇(100) surfaces. There is evidence for a pyroelectric current along the [110] direction of stoichiometric Li₂B₄O₇ so that the pyroelectric coefficient is nonzero but roughly 10³ smaller than along the [001] direction of spontaneous polarization. Abrupt decreases in the pyroelectric coefficient along the [110] direction can be correlated with anomalies in the elastic stiffness contributing to the concept that the pyroelectric coefficient is not simply a vector but has qualities of a tensor, as expected.

Comparison of n-type Gd(2)O(3) and Gd-doped HfO(2).

Gd(2)O(3) and Gd-doped HfO(2) films were deposited on p-type silicon substrates in a reducing atmosphere. Gd 4f photoexcitation peaks at roughly 7 and 5 eV below the valence band maximum have been identified using the resonant photoemission of Gd(2)O(3) and Gd-doped HfO(2) films, respectively. In the case of Gd(2)O(3), strong hybridization with the O 2p band is demonstrated, and there is evidence that the Gd 4f weighted band exhibits dispersion in the bulk band structure.

Trace elements in lesser scaup (Aythya affinis) from the Mississippi flyway.

Previous research reported that concentrations of selenium in the livers of 88-95% of lesser scaup from locations in Lake Erie, Lake St. Clair, and Lake Michigan, USA were either elevated (10-33 microg/g dry weight [dw]) or in the potentially harmful range (> 33 microg/g dw). In order to determine the geographic extent of these high selenium concentrations, we collected lesser scaup in Louisiana, Arkansas, Illinois, Minnesota, Wisconsin, and Manitoba and analyzed the livers for 19 trace elements.

Control of T lymphocyte morphology by the GTPase Rho.

Background: Rho family GTPase regulation of the actin cytoskeleton governs a variety of cell responses. In this report, we have analyzed the role of the GTPase Rho in maintenance of the T lymphocyte actin cytoskeleton.

Results: Inactivation of the GTPase Rho in the human T lymphocytic cell line HPB-ALL does not inhibit constitutively high adhesion to the integrin beta1 substrate fibronectin.