Impact of Genetic Counseling and Testing on Altruistic Motivations to Test for BRCA1/2: a Longitudinal Study.

Despite the importance of altruism in an individual's participation in genetic counseling and testing, little research has explored the change in altruistic motivations to test over time. This study analyzed altruistic motivations to test and change in altruistic motivations after genetic counseling and testing among individuals (N = 120) at elevated risk for BRCA1/2 mutations. The perceived benefits of genetic testing were assessed and utilized in a mixed-methods, repeated measures design at three time points: pre-counseling, counseling and post-genetic testing, along with transcripts of genetic counseling sessions.

Depleting Tumor-NQO1 Potentiates Anoikis and Inhibits Growth of NSCLC.

Unlabelled: The fundamental role that NAD(P)H/quinone oxidoreductase 1 (NQO1) plays, in normal cells, as a cytoprotective enzyme guarding against stress induced by reactive oxygen species (ROS) is well documented. However, what is not known is whether the observed overexpression of NQO1 in neoplastic cells contributes to their survival. The current study discovered that depleting NQO1 expression in A549 and H292 lung adenocarcinoma cells caused an increase in ROS formation, inhibited anchorage-independent growth, increased anoikis sensitization, and decreased three-dimensional tumor spheroid invasion.

The Interactions of Obesity, Inflammation and Insulin Resistance in Breast Cancer.

Obese postmenopausal women have an increased breast cancer risk, the principal mechanism for which is elevated estrogen production by adipose tissue; also, regardless of menstrual status and tumor estrogen dependence, obesity is associated with biologically aggressive breast cancers. Type 2 diabetes has a complex relationship with breast cancer risk and outcome; coexisting obesity may be a major factor, but insulin itself induces adipose aromatase activity and estrogen production and also directly stimulates breast cancer cell growth and invasion. Adipose tissue inflammation occurs frequently in obesity and type 2 diabetes, and proinflammatory cytokines and prostaglandin E2 produced by cyclooxygenase-2 in the associated infiltrating macrophages also induce elevated aromatase expression.

Three-Dimensional Microfluidic Tri-Culture Model of the Bone Marrow Microenvironment for Study of Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) initiates and progresses in the bone marrow, and as such, the marrow microenvironment is a critical regulatory component in development of this cancer. However, ALL studies were conducted mainly on flat plastic substrates, which do not recapitulate the characteristics of marrow microenvironments. To study ALL in a model of in vivo relevance, we have engineered a 3-D microfluidic cell culture platform.

IL-15Rα deficiency in skeletal muscle alters respiratory function and the proteome of mitochondrial subpopulations independent of changes to the mitochondrial genome.

Interleukin-15 receptor alpha knockout (IL15RαKO) mice exhibit a greater skeletal muscle mitochondrial density with an altered mitochondrial morphology. However, the mechanism and functional impact of these changes have not been determined. In this study, we characterized the functional, proteomic, and genomic alterations in mitochondrial subpopulations isolated from the skeletal muscles of IL15RαKO mice and B6129 background control mice.

Extranodal Marginal Zone Lymphoma of the Lung: Evolution from an Underlying Reactive Lymphoproliferative Disorder.

Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT) is a problematic and sometimes controversial diagnosis. While commonly seen in the stomach in the setting of chronic infection, other extranodal sites, such as the lung, may also present with disease. ENMZL is clinically and morphologically heterogeneous; however, regardless of presentation, the etiology lies in the accumulation of lymphoid tissue in non-traditional sites.

Leptin decreases heart rate associated with increased ventricular repolarization via its receptor.

Leptin has been proposed to modulate cardiac electrical properties via β-adrenergic receptor activation. The presence of leptin receptors and adipocytes in myocardium raised a question as to whether leptin can directly modulate cardiac electrical properties such as heart rate and QT interval via its receptor. In this work, the role of local direct actions of leptin on heart rate and ventricular repolarization was investigated.

Bone marrow microenvironment modulation of acute lymphoblastic leukemia phenotype.

Acute lymphoblastic leukemia (ALL) treatment regimens have dramatically improved the survival of ALL patients. However, chemoresistant minimal residual disease that persists following cessation of therapy contributes to aggressive relapse. The bone marrow microenvironment (BMM) is an established "site of sanctuary" for ALL, as well as myeloid-lineage hematopoietic disease, with signals in this unique anatomic location contributing to drug resistance.

SLUG is required for SOX9 stabilization and functions to promote cancer stem cells and metastasis in human lung carcinoma.

Cancer stem cells (CSCs) are a promising target for cancer therapy, particularly for metastatic lung cancers, but how CSCs are regulated is largely unknown. We identify two proteins, SLUG (encoded by SNAI2 gene) and SOX9, which are associated with advanced stage lung cancers and are implicated in the regulation of CSCs. Inhibition of either SLUG or SOX9 sufficiently inhibits CSCs in human lung cancer cells and attenuates experimental lung metastasis in a xenograft mouse model.

Translational Regulation of the Mitochondrial Genome Following Redistribution of Mitochondrial MicroRNA in the Diabetic Heart.

Background: Cardiomyocytes are rich in mitochondria which are situated in spatially distinct subcellular regions, including those under the plasma membrane, subsarcolemmal mitochondria, and those between the myofibrils, interfibrillar mitochondria. We previously observed subpopulation-specific differences in mitochondrial proteomes following diabetic insult. The objective of this study was to determine whether mitochondrial genome-encoded proteins are regulated by microRNAs inside the mitochondrion and whether subcellular spatial location or diabetes mellitus influences the dynamics.

Exosomes: improved methods to characterize their morphology, RNA content, and surface protein biomarkers.

As a type of secreted membrane vesicle, exosomes are an emerging mode of cell-to-cell communication. Yet as exosome samples are commonly contaminated with other extracellular vesicles, the biological roles of exosomes in regulating immunity and promoting oncogenesis remain controversial. Wondering whether existing methods could distort our view of exosome biology, we compared two direct methods for imaging extracellular vesicles and quantified the impact of different production and storage conditions on the quality of exosome samples.

In silico model-based inference: an emerging approach for inverse problems in engineering better medicines.

Identifying the network of biochemical interactions that underpin disease pathophysiology is a key hurdle in drug discovery. While many components involved in these biological processes are identified, how components organize differently in health and disease remains unclear. In chemical engineering, mechanistic modeling provides a quantitative framework to capture our understanding of a reactive system and test this knowledge against data.

Inhibition of Autophagy Potentiated the Antitumor Effect of Nedaplatin in Cisplatin-Resistant Nasopharyngeal Carcinoma Cells.

Nedaplatin, a cisplatin analog, was developed to reduce the toxicity of cisplatin, whereas it can be cross-resistant with cisplatin in some circumstances. This study aimed to investigate the role of autophagy in nedaplatin induced cell death in cisplatin-resistant nasopharyngeal carcinoma cells. Here, we showed that HNE1/DDP and CNE2/DDP cells were resistant to nedaplatin-induced cell death with reduced apoptotic activity.

MicroRNA-Based Therapeutic Strategies for Targeting Mutant and Wild Type RAS in Cancer.

MicroRNAs (miRs) have been causally implicated in the progression and development of a wide variety of cancers. miRs modulate the activity of key cell signaling networks by regulating the translation of pathway component proteins. Thus, the pharmacological targeting of miRs that regulate cancer cell signaling networks, either by promoting (using miR-supplementation) or by suppressing (using antisense oligonucleotide-based strategies) miR activity is an area of intense research.

High-frequency Ultrasound Imaging of Mouse Cervical Lymph Nodes.

High-frequency ultrasound (HFUS) is widely employed as a non-invasive method for imaging internal anatomic structures in experimental small animal systems. HFUS has the ability to detect structures as small as 30 µm, a property that has been utilized for visualizing superficial lymph nodes in rodents in brightness (B)-mode. Combining power Doppler with B-mode imaging allows for measuring circulatory blood flow within lymph nodes and other organs.

MET receptor juxtamembrane exon 14 alternative spliced variant: novel cancer genomic predictive biomarker.

Clinical studies on MET-targeting cancer therapeutics have yielded mixed results in recent years, and MET-relevant predictive biomarkers remain elusive. New studies now reveal METex14 alternative splicing aberrations to represent potential predictive cancer genomic biomarker, hence renewing optimism and directions in the quest for optimized MET-targeting personalized cancer therapy.

Interlocked positive and negative feedback network motifs regulate β-catenin activity in the adherens junction pathway.

The integrity of epithelial tissue architecture is maintained through adherens junctions that are created through extracellular homotypic protein-protein interactions between cadherin molecules. Cadherins also provide an intracellular scaffold for the formation of a multiprotein complex that contains signaling proteins, including β-catenin. Environmental factors and controlled tissue reorganization disrupt adherens junctions by cleaving the extracellular binding domain and initiating a series of transcriptional events that aim to restore tissue homeostasis.

A Novel Method to Assess Bone Marrow Purity is Useful in Determining Blast Percentage by Flow Cytometry in Acute Myeloid Leukemia and Myelodysplasia.

Blast quantification by Flow Cytometry (FCM) may become essential in situations where morphologic evaluation is difficult or unavailable. As hemodilution invariably occurs, a means of determining Bone Marrow Purity (BMP) and normalizing FCM blast counts is essential, especially when blast percentages are diagnostically critical as in Acute Myeloid Leukemia (AML) and Myelodysplasia (MDS). By evaluating different leukocyte populations in eight initial patients, a formula to predict BMP was developed and compared to the actual BMP determined by manual counts.

Non-Muscle Myosin II Isoforms Have Different Functions in Matrix Rearrangement by MDA-MB-231 Cells.

The role of a stiffening extra-cellular matrix (ECM) in cancer progression is documented but poorly understood. Here we use a conditioning protocol to test the role of nonmuscle myosin II isoforms in cell mediated ECM arrangement using collagen constructs seeded with breast cancer cells expressing shRNA targeted to either the IIA or IIB heavy chain isoform. While there are several methods available to measure changes in the biophysical characteristics of the ECM, we wanted to use a method which allows for the measurement of global stiffness changes as well as a dynamic response from the sample over time.

High-Fat, High-Calorie Diet Enhances Mammary Carcinogenesis and Local Inflammation in MMTV-PyMT Mouse Model of Breast Cancer.

Epidemiological studies provide strong evidence that obesity and the associated adipose tissue inflammation are risk factors for breast cancer; however, the molecular mechanisms are poorly understood. We evaluated the effect of a high-fat/high-calorie diet on mammary carcinogenesis in the immunocompetent MMTV-PyMT murine model. Four-week old female mice (20/group) were randomized to receive either a high-fat (HF; 60% kcal as fat) or a low-fat (LF; 16% kcal) diet for eight weeks.

Disruptive environmental chemicals and cellular mechanisms that confer resistance to cell death.

Cell death is a process of dying within biological cells that are ceasing to function. This process is essential in regulating organism development, tissue homeostasis, and to eliminate cells in the body that are irreparably damaged. In general, dysfunction in normal cellular death is tightly linked to cancer progression.

Enhancing the discovery and development of immunotherapies for cancer using quantitative and systems pharmacology: Interleukin-12 as a case study.

Recent clinical successes of immune checkpoint modulators have unleashed a wave of enthusiasm associated with cancer immunotherapy. However, this enthusiasm is dampened by persistent translational hurdles associated with cancer immunotherapy that mirror the broader pharmaceutical industry. Specifically, the challenges associated with drug discovery and development stem from an incomplete understanding of the biological mechanisms in humans that are targeted by a potential drug and the financial implications of clinical failures.

AF1q is a novel TCF7 co-factor which activates CD44 and promotes breast cancer metastasis.

AF1q is an MLL fusion partner that was identified from acute myeloid leukemia (AML) patients with t (1; 11) (q21; q23) chromosomal abnormality. The function of AF1q is not yet fully known, however, elevated AF1q expression is associated with poor clinical outcomes in various malignancies. Here, we show that AF1q specifically binds to T-cell-factor-7 (TCF7) in the Wnt signaling pathway and results in transcriptional activation of CD44 as well as multiple downstream targets of the TCF7/LEF1.