No abstract

Psychosocial interviews with 2320 male survivors of acute myocardial infarction, participants in the beta-Blocker Heart Attack Trial, permitted the definition of two variables strongly associated with an increased three-year mortality risk. With other important prognostic factors controlled for, the patients classified as being socially isolated and having a high degree of life stress had more than four times the risk of death of the men with low levels of both stress and isolation. An inverse association of education with mortality in this population reflected the gradient in the prevalence of the defined psychosocial characteristics. High levels of stress and social isolation were most prevalent among the least-educated men and least prevalent among the best-educated. The increase in risk associated with stress and social isolation applied both to total deaths and to sudden cardiac deaths and was noted among men with both high and low levels of ventricular ectopy during hospitalization for the acute infarction.

Translational regulation is critical in cancer development and progression. Translation sustains tumor growth and development of a tumor vasculature, a process known as angiogenesis, which is activated by hypoxia. Here we first demonstrate that a majority of large advanced breast cancers overexpress translation regulatory protein 4E-BP1 and initiation factor eIF4G. Using model animal and cell studies, we then show that overexpressed 4E-BP1 and eIF4G orchestrate a hypoxia-activated switch from cap-dependent to cap-independent mRNA translation that promotes increased tumor angiogenesis and growth at the level of selective mRNA translation. Elevated levels of 4E-BP1 trigger hypoxia inhibition of cap-dependent mRNA translation at high-oxygen levels and, with eIF4G, increase selective translation of mRNAs containing internal ribosome entry sites (IRESs) that include key proangiogenic, hypoxia, and survival mRNAs. The switch from cap-dependent to cap-independent mRNA translation facilitates tumor angiogenesis and hypoxia responses in animal models.

Diffusion-weighted imaging (DWI) plays important roles in cancer diagnosis, monitoring, and treatment. While most applications measure restricted diffusion by tumor cellularity, DWI is also sensitive to vascularity through the intravoxel incoherent motion (IVIM) effect. Hypervascularity can confound apparent diffusion coefficient (ADC) measurements in breast cancer. We acquired multiple b-value DWI at 3 T in a cohort of breast cancer patients and performed biexponential IVIM analysis to extract tissue diffusivity (Dt), perfusion fraction (fp), and pseudodiffusivity (Dp). Results indicated significant differences between normal fibroglandular tissue and malignant lesions in ADC mean (± standard deviation) values (2.44± 0.30 vs. 1.34 ± 0.39 μm2/ms, p < 0.01) and Dt (2.36± 0.38 vs. 1.15 ± 0.35 μm2/ms, p < 0.01). Lesion DWI signals demonstrated biexponential character in comparison to monoexponential normal tissue. There is some differentiation of lesion subtypes (invasive ductal carcinoma (IDC) vs. other (OT) malignant lesions) with fp (10.5 ± 5.0% vs. 6.9 ± 2.9%, p = 0.06), but less so with Dt (1.14±0.32 μm2/ms vs. 1.18 ± 0.52 μm2/ms, p = 0.88), and Dp (14.9 ± 11.4 μm2/ms vs. 16.1 ± 5.7 μm2/ms, p = 0.75). Comparison of IVIM biomarkers with contrast-enhancement suggests moderate correlations. These results suggest the potential of IVIM vascular and cellular biomarkers for initial grading, progression monitoring, or treatment assessment of breast tumors.

Inflammatory breast cancer (IBC) is the most lethal form of primary breast cancer. IBC lethality derives from generation of tumour emboli, which are non-adherent cell clusters that rapidly spread by a form of continuous invasion known as passive metastasis. In most cancers, expression of E-cadherin, an epithelial marker, is indicative of low metastatic potential. In IBC, E-cadherin is overexpressed and supports formation of tumour emboli by promoting tumour cell interactions rather than adherence to stroma. E-cadherin, a surface component of adherens junctions, is anchored by interaction with p120 catenin (p120). We show that the unique pathogenic properties of IBC result in part from overexpression of the translation initiation factor eIF4GI in most IBCs. eIF4GI reprograms the protein synthetic machinery for increased translation of mRNAs with internal ribosome entry sites (IRESs) that promote IBC tumour cell survival and formation of tumour emboli. Overexpression of eIF4GI promotes formation of IBC tumour emboli by enhancing translation of IRES-containing p120 mRNAs. These findings provide a new understanding of translational control in the development of advanced breast cancer.