Barriers to completion of cascade genetic testing: how can we improve the uptake of testing for hereditary breast and ovarian cancer syndrome?

Cascade testing for familial cancer syndromes has historically been difficult to execute. As part of a facilitated cascade testing pathway, we evaluated barriers to completion of cascade testing. Our previously published study evaluated a facilitated cascade testing pathway whereby a genetics team facilitated at-risk relative (ARR) cascade testing through telephone genetic counseling and mailed saliva kit testing.

Bulk and surface theoretical investigation of Nb-doped δ-FeOOH as a promising bifunctional catalyst.

The development of bifunctional catalysts is of great interest in fine chemistry, since they are capable of promoting multicatalytic reactions involved in several important industrial processes. Iron oxyhydroxides have been identified as low-cost bifunctional catalysts. However, their applications are limited due to their weak acid character.

Hybrid Materials Based on Magnetic Iron Oxides with Benzothiazole Derivatives: A Plausible Potential Spectroscopy Probe.

Rare diseases affect a small part of the population, and the most affected are children. Because of the low availability of patients for testing, the pharmaceutical industry cannot develop drugs for the diagnosis of many of these orphan diseases. In this sense, the use of benzothiazole compounds that are highly selective and can act as spectroscopy probes, especially the compound 2-(4'-aminophenyl)benzothiazole (ABT), has been highlighted.

Prospective Feasibility Trial of a Novel Strategy of Facilitated Cascade Genetic Testing Using Telephone Counseling.

Patients And Methods: Probands with newly diagnosed cancer-associated pathogenic variants were offered facilitated cascade testing whereby the genetics team identified and contacted ARRs by telephone to disclose the familial pathogenic variant and offer telephone counseling and mailed saliva testing. Results and guideline-based recommendations were reviewed by telephone and shared with the primary care physician.

Results: Thirty probands were enrolled, and 114 ARRs were identified.

Metformin and erlotinib synergize to inhibit basal breast cancer.

Basal-like breast cancers (BBCs) are enriched for increased EGFR expression and decreased expression of PTEN. We found that treatment with metformin and erlotinib synergistically induced apoptosis in a subset of BBC cell lines. The drug combination led to enhanced reduction of EGFR, AKT, S6 and 4EBP1 phosphorylation, as well as prevented colony formation and inhibited mammosphere outgrowth.

Scaffold hopping approach on the route to selective tankyrase inhibitors.

A virtual screening procedure was applied to identify new tankyrase inhibitors. Through pharmacophore screening of a compounds collection from the SPECS database, the methoxy[l]benzothieno[2,3-c]quinolin-6(5H)-one scaffold was identified as nicotinamide mimetic able to inhibit tankyrase activity at low micromolar concentration. In order to improve potency and selectivity, tandem structure-based and scaffold hopping approaches were carried out over the new scaffold leading to the discovery of the 2-(phenyl)-3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-one as powerful chemotype suitable for tankyrase inhibition.

Survival factor NFIL3 restricts FOXO-induced gene expression in cancer.

Depending on the circumstance, FOXO (Forkhead O) (FOXO1, FOXO3, and FOXO4) transcription factors activate the expression of markedly different sets of genes to produce different phenotypic effects. For example, distinct FOXO-regulated transcriptional programs stimulate cell death or enhance organism life span. To gain insight into how FOXOs select specific genes for regulation, we performed a screen for genes that modify FOXO activation of TRAIL, a death receptor ligand capable of inducing extrinsic apoptosis.

Alterations of EGFR, p53 and PTEN that mimic changes found in basal-like breast cancer promote transformation of human mammary epithelial cells.

Breast cancer can be classified into different molecular subtypes with varying clinical and pathological characteristics. The basal-like breast cancer subtype represents one of the most aggressive and lethal types of breast cancer, and due to poor mechanistic understanding, it lacks targeted therapy. Many basal-like breast cancer patient samples display alterations of established drivers of cancer development, including elevated expression of EGFR, p53 inactivating mutations and loss of expression of the tumor suppressor PTEN; however, their contribution to human basal-like breast cancer pathogenesis remains ill-defined.

Patterns of gene expression and copy-number alterations in von-hippel lindau disease-associated and sporadic clear cell carcinoma of the kidney.

Recent insights into the role of the von-Hippel Lindau (VHL) tumor suppressor gene in hereditary and sporadic clear-cell renal cell carcinoma (ccRCC) have led to new treatments for patients with metastatic ccRCC, although virtually all patients eventually succumb to the disease. We performed an integrated, genome-wide analysis of copy-number changes and gene expression profiles in 90 tumors, including both sporadic and VHL disease-associated tumors, in hopes of identifying new therapeutic targets in ccRCC. We identified 14 regions of nonrandom copy-number change, including 7 regions of amplification (1q, 2q, 5q, 7q, 8q, 12p, and 20q) and 7 regions of deletion (1p, 3p, 4q, 6q, 8p, 9p, and 14q).

Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair.

Basal-like breast cancer (BBC) is a subtype of breast cancer with poor prognosis. Inherited mutations of BRCA1, a cancer susceptibility gene involved in double-strand DNA break (DSB) repair, lead to breast cancers that are nearly always of the BBC subtype; however, the precise molecular lesions and oncogenic consequences of BRCA1 dysfunction are poorly understood. Here we show that heterozygous inactivation of the tumor suppressor gene Pten leads to the formation of basal-like mammary tumors in mice, and that loss of PTEN expression is significantly associated with the BBC subtype in human sporadic and BRCA1-associated hereditary breast cancers.

p63 regulates commitment to the prostate cell lineage.

Molecular mechanisms underlying prostate and urothelial development remain unclear. This situation presents major limitations in identifying the cell type(s) and molecular events involved in the development of prostate and bladder cancer. It has been shown that mice lacking the basal cell marker p63 present several epithelial defects, including epidermis and prostate buds agenesis and urothelial abnormalities.