Ataxia-telangiectasia (A-T) is a recessive multi-system disorder caused by mutations in the ATM gene at 11q22-q23 (ref. 3). The risk of cancer, especially lymphoid neoplasias, is substantially elevated in A-T patients and has long been associated with chromosomal instability. By analysing tumour DNA from patients with sporadic T-cell prolymphocytic leukaemia (T-PLL), a rare clonal malignancy with similarities to a mature T-cell leukaemia seen in A-T, we demonstrate a high frequency of ATM mutations in T-PLL. In marked contrast to the ATM mutation pattern in A-T, the most frequent nucleotide changes in this leukaemia were missense mutations. These clustered in the region corresponding to the kinase domain, which is highly conserved in ATM-related proteins in mouse, yeast and Drosophila. The resulting amino-acid substitutions are predicted to interfere with ATP binding or substrate recognition. Two of seventeen mutated T-PLL samples had a previously reported A-T allele. In contrast, no mutations were detected in the p53 gene, suggesting that this tumour suppressor is not frequently altered in this leukaemia. Occasional missense mutations in ATM were also found in tumour DNA from patients with B-cell non-Hodgkin's lymphomas (B-NHL) and a B-NHL cell line. The evidence of a significant proportion of loss-of-function mutations and a complete absence of the normal copy of ATM in the majority of mutated tumours establishes somatic inactivation of this gene in the pathogenesis of sporadic T-PLL and suggests that ATM acts as a tumour suppressor. As constitutional DNA was not available, a putative hereditary predisposition to T-PLL will require further investigation.

The variations of breast cancer mortality rates from place to place reflect both underlying differences in breast cancer prevalence and differences in diagnosis and treatment that affect the risk of death. This article examines the role of access to health care in explaining the variation of late-stage diagnosis of breast cancer. We use cancer registry data for the state of Illinois by zip code to investigate spatial variation in late diagnosis. Geographic information systems and spatial analysis methods are used to create detailed measures of spatial access to health care such as convenience of visiting primary care physicians and travel time from the nearest mammography facility. The effects of spatial access, in combination with the influences of socioeconomic factors, on late-stage breast cancer diagnosis are assessed using statistical methods. The results suggest that for breast cancer, poor geographical access to primary health care significantly increases the risk of late diagnosis for persons living outside the city of Chicago. Disadvantaged population groups including those with low income and racial and ethnic minorities tend to experience high rates of late diagnosis. In Illinois, poor spatial access to primary health care is more strongly associated with late diagnosis than is spatial access to mammography. This suggests the importance of primary care physicians as gatekeepers in early breast cancer detection.

This study was supported by the Medical Scientific Research Plan Project of Anhui Provincial Department of Health (13ZC014) and the Natural Science Foundation of Anhui Higher Education Institutions (KJ2013Z132).

Rural – urban inequalities in health and access to health care have long been of concern in health-policy formulation. Understanding these inequalities is critically important in efforts to plan a more effective geographical distribution of public health resources and programs. Socially and ethnically diverse populations are likely to exhibit different rural – urban gradients in health and well-being because of their varying experiences of place environments, yet little is known about the interplay between social and spatial inequalities. Using data from the Illinois State Cancer Registry, we investigate rural – urban inequalities in late-stage breast cancer diagnosis both for the overall population and for African-Americans, and the impacts of socioeconomic deprivation and spatial access to health care. Changes over time are analyzed from 1988 – 92 to 1998 – 2002, periods of heightened breast cancer awareness and increased access to screening. In both time periods, the risk of late-stage diagnosis is highest among patients living in the most urbanized areas, an indication of urban disadvantage. Multilevel modeling results indicate that rural – urban inequalities in risk are associated with differences in the demographic characteristics of area populations and differences in the social and spatial characteristics of the places in which they live. For African-American breast cancer patients, the rural – urban gradient is reversed, with higher risks among patients living outside the city of Chicago, suggesting a distinct set of health-related risks and place experiences that inhibit early breast cancer detection. Findings emphasize the need for combining spatial and social targeting in locating cancer prevention and treatment programs.

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Mutations in the tubulin beta 8 class VIII (TUBB8) gene have been proven to cause oocyte maturation arrest. The aim of this study was to describe newly discovered mutations in TUBB8 and to investigate the prevalence of TUBB8 mutations in our cohort. Nine women with oocyte maturation arrest and 100 fertile female controls were recruited. Sanger sequencing of the coding regions of TUBB8 revealed a heterozygous variant c.535G > A (p.V179M) in two unrelated affected individuals and a heterozygous variant c.5G > T (p.R2M) in one affected individual. These TUBB8 variants were inherited from the unaffected fathers and were absent in 100 fertile female control individuals. In total, 33.33% (3/9) of the affected individuals in our cohort obtained a clear genetic diagnosis through sequencing of the TUBB8 gene. These two novel variants extend the spectrum of TUBB8 mutations and this study confirmed that TUBB8 mutations occur in a high proportion of infertile women with oocyte maturation arrest.

Patients diagnosed with late-stage cancer have lower survival rates than those with early-stage cancer. This paper examines possible associations between several risk factors and late-stage diagnosis for four types of cancer in Illinois: breast cancer, prostate cancer, colorectal cancer, and lung cancer. Potential risk factors are composed of spatial factors and nonspatial factors. The spatial factors include accessibility to primary healthcare and distance or travel time to the nearest cancer screening facility. A set of demographic and socioeconomic variables are consolidated into three nonspatial factors by factor analysis. The Bayesian model with convolution priors is utilised to analyse the relationship between the above risk factors and each type of late-stage cancer while controlling for spatial autocorrelation. The results for breast cancer suggest that people living in neighbourhoods with socioeconomic disadvantages and cultural barriers are more likely to be diagnosed at a late stage. In regard to prostate cancer, people in regions with low socioeconomic status are also more likely to be diagnosed at a late stage. Diagnosis of late-stage colorectal or lung cancer is not significantly associated with any of the abovementioned risk factors. The results have important implications in public policy.

The pleiotropic effects of estrogen are mediated via stimulation of two estrogen receptor (ER) subtypes, ER␣ and ER␤. Although a number of studies have identified expression of one or both subtypes in estrogen target tissues, fewer studies have correlated ER expression with a functional role of these proteins in regulating cellular excitability. In the present study, we have combined cellular fluorescence, immunocytochemistry, and molecular expression techniques with single-channel patch-clamp studies to determine which ER mediates estrogen-stimulated potassium channel activity in human coronary artery smooth muscle cells (HCASMC). We had demonstrated previously that estrogen stimulates activity of the large-conductance, calcium-and voltage-activated potassium (BK Ca ) channel in HCASMC via a nongenomic mechanism. We now demonstrate expression of both ER␣ and ER␤ subtypes in HCASMC. Functionally, however, expression of ER␣ antisense plasmid abolished the acute effect of estrogen on these channels, whereas estrogen retained its ability to stimulate BK Ca channels in cells transfected with only green fluorescence protein. In contrast, overexpression of ER␣ enhanced the stimulatory action of estrogen in HCASMC. Transfection with ER␣ antisense/sense plasmid did not alter ER␤ expression. These findings indicate that the ER␣ isoform mediates estrogen-induced stimulation of BK Ca channels in HCASMC and thereby provide evidence for a receptor-dependent signaling mechanism that can mediate estrogen-induced inhibition of cellular excitability.