Genetic evolution of breast cancers III: Age-dependent variations in the correlations between biological indicators of prognosis

The influence of age on the occurrence of phenotypic features of prognostic significance was studied in relation to the DNA index values, measured on DNA histograms from a series of 1019 breast cancer patients. Globally, the distributions of all parameters showed variations with age, the most prominent being the decreases in the percentage of estrogen receptor-negative and high proliferative activity cases with increasing age. When analyzed according to the DNA index classes, all parameters were found to some extent linked with the stage of genetic evolution. However, the associations varied with age, defining two extreme groups. The younger patients (less than 40 years) presented a more complete acquisition of the aggressive phenotype and near-triploid tumors from this group were very frequently steroid hormone receptor-negative, high proliferation, and grade III. By contrast, near-triploid tumors in patients above 65 presented relatively frequently as receptor-positive, low proliferative activity, and even grade I. The correlation of the proliferative status with steroid hormone receptor content led to similar conclusions, high proliferation being more strongly correlated with the absence of estrogen and progesterone receptors in younger patients. Interestingly, the association between high proliferation and negative progesterone receptors was much weaker in patients above 55. Our results suggest that the currently established biological prognostic factors, including DNA profile, steroid hormone receptors, and histopathological grade, show patterns of association which vary with age. Of these, only progesterone receptor could be influenced by menopausal status. These findings have to be taken into consideration for future prognostic factor-related treatment decisions, but also for future methodological improvements of multivariate survival analyses.     

Social,Occupational, and Spatial Exposures and Mental Health Disparities of Working-Class Latinas in the US

Grounded in ecosocial theory, this paper discusses the mental health disparities of working-class Latinas from multiple perspectives. An overview of working-class Latinas’ prevalent mental health disorders, barriers to care and suggestions for interventions and future studies are provided.     

Clinical Research Risk Assessment Among Individuals With Mild Cognitive Impairment

OBJECTIVE:: To determine whether individuals with mild cognitive impairment (MCI) differ from cognitively normal (NC) elders on a risk assessment task and whether participants and their study partners evaluate risk and benefit similarly. DESIGN:: Cross-sectional. SETTING:: University medical setting. PARTICIPANTS:: Seventy-nine participants (NC, n = 40; MCI, n = 39), age 60-90 years (73 ± 7 years; 53% women), and 64 study partners (NC, n = 36; MCI, n = 28), age 38-84 years (68 ± 10 years; 67% women). MEASUREMENTS:: Participants and study partners completed a risk assessment task that involved ranking from least to most risk four hypothetical vignettes for memory loss research (brain autopsy, blood draw, oral medication, neurosurgery). Participants also completed decisional capacity for research and neuropsychological protocols. RESULTS:: MCI participants' risk rankings differed from NC risk rankings (p <0.001) with MCI participants ranking brain autopsy higher and an oral medication trial lower. Demographic, decisional capacity, and neuropsychological variables could not explain MCI participant performances. Participants and their study partners had comparable risk assessment performance (p = 1.0). MCI study partners performed similar to their MCI participant counterparts but were different from NC study partners (p = 0.002; i.e., ranking autopsy higher and oral medication lower). CONCLUSION:: Findings suggest that individuals with MCI assess risk differently than NC peers by overestimating the risk (or underestimating the benefit) of brain autopsy and underestimating the risk (or overestimating the benefit) of oral medication. Study partners display a similar pattern. These observations may be secondary to MCI participants' (and their study partners') personal connection to the potential benefits of an experimental medication for memory loss.     

REPIMPACT - a prospective longitudinal multisite study on the effects of repetitive head impacts in youth soccer

Brain Imaging and Behavior - Repetitive head impacts (RHI) are common in youth athletes participating in contact sports. RHI differ from concussions; they are considered hits to the head that...     

Evolution of neuronal and glial tau isoforms in chronic traumatic encephalopathy

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy characterized by accumulation of hyperphosphorylated tau (p‐tau) in perivascular aggregates in neurons and glia at the depths of neocortical sulci and progresses to diffuse neocortical, allocortical and brainstem structures. The strongest risk factor is exposure to repetitive head impacts acquired most commonly through contact sports and military service. Given that CTE can only be definitively diagnosed after death, a better understanding of the cellular and molecular changes in CTE brains may lead to identification of mechanisms that could be used for novel biomarkers, monitoring progression or therapeutic development. Disruption of alternative pre‐mRNA splicing of tau mRNA plays a pathogenic role in tauopathy, with multiple characteristic patterns of isoform accumulation varying among tauopathies. Limited data are available on CTE, particularly at early stages. Using biochemical and histological approaches, we performed a detailed characterization of tau isoform signatures in post‐mortem human brain tissue from individuals with a range of CTE stages (n = 99). In immunoblot analyses, severity was associated with decreased total monomeric tau and increased total oligomeric tau. Immunoblot with isoform‐specific antisera revealed that oligomeric tau with three and four microtubule binding domain repeats (3R and 4R) also increased with CTE severity. Similarly, immunohistochemical studies revealed p‐tau accumulation consisting of both 3R and 4R in perivascular lesions. When the ratio of 4R:3R was analyzed, there was mixed expression throughout CTE stages, although 4R predominated in early CTE stages (I‐II), a 3R shift was observed in later stages (III‐IV). While neurons were found to contain both 3R and 4R, astrocytes only contained 4R. These 4R‐positive cells were exclusively neuronal at early stages. Overall, these findings demonstrate that CTE is a mixed 4R/3R tauopathy. Furthermore, histologic analysis reveals a progressive shift in tau isoforms that correlates with CTE stage and extent of neuronal pathology.     

Genetic analysis of three-dimensional shape of mouse lung tumors reveals eight lung tumor shape-determining (Ltsd) loci that are associated with tumor heterogeneity and symmetry

Most lung tumor linkage studies focus on identifying loci that confer susceptibility or resistance irrespective of the tumor types developed. However, different mouse strains develop different types of lung tumors. A major obstacle for genetic studies of these differences is the lack of reproducible, quantitative, and uniform assessment of tumor type. We have previously described a new variable (Rratio) that assesses the three-dimensional shape of lung tumors in a quantifiable way and showed that nonspherical tumors are correlated with tumor heterogeneity and with a tendency to asymmetrical growth (N. Tripodis and P. Demant, Exp. Lung Res., 27: 521-531, 2001). In the present study, we use the Rratio variable to search for quantitative trait loci affecting tumor phenotype. We tested the F(2) cross between the susceptible strain O20 and the recombinant congenic strain OcB-9. Both develop mixed alveolar and papillary lung tumors, and the OcB9 tumors are, on average, more elongated than the O20 ones. We mapped eight new lung tumor shape-determining loci (Ltsd1-8) involved in mutual interactions. Two of these loci, Ltsd1 and Ltsd3, seem to play a major role in tumor shape formation. The Ltsd4 locus was confirmed in a second F(2) cross between strain O20 and the recombinant congenic strain OcB-6. Genotype-phenotype associations show that nonspherical tumors are correlated with tumor heterogeneity and nonsymmetrical (focal) development of structures. Most of the new Ltsd loci map in regions where susceptibility to lung cancer (Sluc) loci have been previously mapped, raising the question of whether they are identical or closely linked loci. Based on models of tumor growth indicating that supply of nutrients and the ability to create a capillary network may be shape-determining factors (G. P. Pescarmona et al., Med. Hypoth., 53: 497-503, 1999), we suggest as likely candidates for the Ltsd loci genes involved in angiogenesis, vascularization, and capillary patterning. This is the first set of loci that affects qualitative aspects of lung tumors and may provide biologically and clinically interesting indicators of lung tumor progression.