Adverse prognostic and predictive significance of low DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression in early-stage breast cancers

Background: DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a serine threonine kinase belonging to the PIKK family (phosphoinositide 3-kinase-like-family of protein kinase), is a critical component of the non-homologous end joining (NHEJ) pathway required for the repair of DNA double strand breaks. DNA-PKcs may be involved in breast cancer pathogenesis. Methods: We evaluated clinicopathological significance of DNA-PKcs protein expression in 1161 tumours and DNA-PKcs mRNA expression in 1950 tumours. We correlated DNA-PKcs to other markers of aggressive phenotypes, DNA repair, apoptosis and cell cycle regulation. Results: Low DNA-PKcs protein expression was associated with higher tumour grade, higher mitotic index, tumour de-differentiation and tumour type (ps<0.05). Absence of BRCA1, low XRCC1/SMUG1/APE1/Polβ were also more likely in low DNA-PKcs expressing tumours (ps<0.05). Low DNA-PKcs protein expression was significantly associated with worse breast cancer specific survival (BCCS) in univariate and multivariate analysis (ps<0.01). At the mRNA level, low DNA-PKcs was associated with PAM50.Her2 and PAM50.LumA molecular phenotypes (ps<0.01) and poor BCSS. In patients with ER positive tumours who received endocrine therapy, low DNA-PKcs (protein and mRNA) was associated with poor survival. In ER negative patients, low DNA-PKcs mRNA remains significantly associated with adverse outcome. Conclusions: Our study suggests that low DNA-PKcs expression may have prognostic and predictive significance in breast cancers

myomiR-dependent switching of BAF60 variant incorporation into Brg1 chromatin remodeling complexes during embryo myogenesis

Myogenesis involves the stable commitment of progenitor cells followed by the execution of myogenic differentiation, processes that are coordinated by myogenic regulatory factors, microRNAs and BAF chromatin remodeling complexes. BAF60a, BAF60b and BAF60c are structural subunits of the BAF complex that bind to the core ATPase Brg1 to provide functional specificity. BAF60c is essential for myogenesis; however, the mechanisms regulating the subunit composition of BAF/Brg1 complexes, in particular the incorporation of different BAF60 variants, are not understood. Here we reveal their dynamic expression during embryo myogenesis and uncover the concerted negative regulation of BAF60a and BAF60b by the muscle-specific microRNAs (myomiRs) miR-133 and miR-1/206 during somite differentiation. MicroRNA inhibition in chick embryos leads to increased BAF60a or BAF60b levels, a concomitant switch in BAF/Brg1 subunit composition and delayed myogenesis. The phenotypes are mimicked by sustained BAF60a or BAF60b expression and are rescued by morpholino knockdown of BAF60a or BAF60b. This suggests that myomiRs contribute to select BAF60c for incorporation into the Brg1 complex by specifically targeting the alternative variants BAF60a and BAF60b during embryo myogenesis, and reveals that interactions between tissue-specific non-coding RNAs and chromatin remodeling factors confer robustness to mesodermal lineage determination

Telomeres and disease

The telomeres of most eukaryotes are characterized by guanine-rich repeats synthesized by the reverse transcriptase telomerase. Complete loss of telomerase is tolerated for several generations in most species, but modestly reduced telomerase levels in human beings are implicated in bone marrow failure, pulmonary fibrosis and a spectrum of other diseases including cancer. Differences in telomerase deficiency phenotypes between species most likely reflect a tumour suppressor function of telomeres in long-lived mammals that does not exist as such in short-lived organisms. Another puzzle provided by current observations is that family members with the same genetic defect, haplo-insufficiency for one of the telomerase genes, can present with widely different diseases. Here, the crucial role of telomeres and telomerase in human (stem cell) biology is discussed from a Darwinian perspective. It is proposed that the variable phenotype and penetrance of heritable human telomerase deficiencies result from additional environmental, genetic and stochastic factors or combinations thereof

Structure formation in Multiple Dark Matter cosmologies with long-range scalar interactions

(Abridged) An interaction between Cold Dark Matter (CDM) and a classical scalar field playing the role of the cosmic dark energy (DE) might provide long-range dark interactions without conflicting with solar system bounds. Although presently available observations allow to constrain such interactions to a few percent of the gravitational strength, some recent studies have shown that if CDM is composed by two different particle species having opposite couplings to the DE field, such tight constraints can be considerably relaxed, allowing for long-range scalar forces of order gravity without significantly affecting observations both at the background and at the linear perturbations level. In the present work, we extend the investigation of such Multiple Dark Matter scenarios to the nonlinear regime of structure formation, by presenting the first N-body simulations ever performed for these cosmologies. Our results highlight some characteristic footprints of long-range scalar forces that arise only in the nonlinear regime for specific models that would be otherwise practically indistinguishable from the standard LCDM scenario both in the background and in the growth of linear density perturbations. Among these effects, the formation of "mirror" cosmic structures in the two CDM species, the suppression of the nonlinear matter power spectrum at k > 1 h/Mpc, and the fragmentation of collapsed halos, represent peculiar features that might provide a direct way to constrain this class of cosmological models.Comment: 11 pages, 4 figures. Submitted to MNRA

The abundance and clustering of dark haloes in the standard Lambda CDM cosmogony

Much evidence suggests that we live in a flat Cold Dark Matter universe with a cosmological constant. Accurate analytic formulae are now available for many properties of the dark halo population in such a Universe. Assuming current ``concordance'' values for the cosmological parameters, we plot halo abundance against redshift as a function of halo mass, of halo temperature, of the fraction of cosmic matter in haloes, of halo clustering strength, and of the clustering strength of the z=0 descendants of high redshift haloes. These plots are useful for understanding how nonlinear structure grows in the model. They demonstrate a number of properties which may seem surprising, for example: 10^9 solar mass haloes are as abundant at z=20 as L_* galaxies are today; 10^6K haloes are equally abundant at z=8 and at z=0; 10% of all matter is currently in haloes hotter than 1 keV, while more than half is in haloes too cool to trap photo-ionized gas; 1% of all matter at z=15 is in haloes hot enough to ionise hydrogen; haloes of given mass or temperature are more clustered at higher redshift; haloes with the abundance of present-day L_* galaxies are equally clustered at all z10 are more clustered at z=0 than are L_* galaxies.Comment: 10 pages, 2 ps figures, version to be published in MNRA

Pneumonia care and the nursing home: a qualitative descriptive study of resident and family member perspectives

BACKGROUND: Nursing home residents are frequently sent to hospital for diagnostic tests or to receive acute health care services. These transfers are both costly and for some, associated with increased risks. Although improved technology allows long-term care facilities to deliver more complex health care on site, if this is to become a trend then residents and family members must see the value of such care. This qualitative study examined resident and family member perspectives on in situ care for pneumonia. METHODS: A qualitative descriptive study design was used. Participants were residents and family members of residents treated for pneumonia drawn from a larger randomized controlled trial of a clinical pathway to manage nursing home-acquired pneumonia on-site. A total of 14 in-depth interviews were conducted. Interview data were analyzed using the editing style, described by Miller and Crabtree, to identify key themes. RESULTS: Both residents and family members preferred that pneumonia be treated in the nursing home, where possible. They both felt that caring and attention are key aspects of care which are more easily accessible in the nursing home setting. However, residents felt that staff or doctors should make the decision whether to hospitalize them, whereas family members wanted to be consulted or involved in the decision-making process. CONCLUSION: These findings suggest that interventions to reduce hospitalization of nursing home residents with pneumonia are consistent with resident and family member preferences

Epidemiology of Doublet/Multiplet Mutations in Lung Cancers: Evidence that a Subset Arises by Chronocoordinate Events

BACKGROUND: Evidence strongly suggests that spontaneous doublet mutations in normal mouse tissues generally arise from chronocoordinate events. These chronocoordinate mutations sometimes reflect "mutation showers", which are multiple chronocoordinate mutations spanning many kilobases. However, little is known about mutagenesis of doublet and multiplet mutations (domuplets) in human cancer. Lung cancer accounts for about 25% of all cancer deaths. Herein, we analyze the epidemiology of domuplets in the EGFR and TP53 genes in lung cancer. The EGFR gene is an oncogene in which doublets are generally driver plus driver mutations, while the TP53 gene is a tumor suppressor gene with a more typical situation in which doublets derive from a driver and passenger mutation. METHODOLOGY/PRINCIPAL FINDINGS: EGFR mutations identified by sequencing were collected from 66 published papers and our updated EGFR mutation database (www.egfr.org). TP53 mutations were collected from IARC version 12 (www-p53.iarc.fr). For EGFR and TP53 doublets, no clearly significant differences in race, ethnicity, gender and smoking status were observed. Doublets in the EGFR and TP53 genes in human lung cancer are elevated about eight- and three-fold, respectively, relative to spontaneous doublets in mouse (6% and 2.3% versus 0.7%). CONCLUSIONS/SIGNIFICANCE: Although no one characteristic is definitive, the aggregate properties of doublet and multiplet mutations in lung cancer are consistent with a subset derived from chronocoordinate events in the EGFR gene: i) the eight frameshift doublets (present in 0.5% of all patients with EGFR mutations) are clustered and produce a net in-frame change; ii) about 32% of doublets are very closely spaced (< or =30 nt); and iii) multiplets contain two or more closely spaced mutations. TP53 mutations in lung cancer are very closely spaced (< or =30 nt) in 33% of doublets, and multiplets generally contain two or more very closely spaced mutations. Work in model systems is necessary to confirm the significance of chronocoordinate events in lung and other cancers

Predictors of inhospital mortality and re-hospitalization in older adults with community-acquired pneumonia: a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>A better understanding of potentially modifiable predictors of in-hospital mortality and re-admission to the hospital following discharge may help to improve management of community-acquired pneumonia in older adults. We aimed to assess the associations of potentially modifiable factors with mortality and re-hospitalization in older adults hospitalized with community-acquired pneumonia.</p> <p>Methods</p> <p>A prospective cohort study was conducted from July 2003 to April 2005 in two Canadian cities. Patients aged 65 years or older hospitalized for community-acquired pneumonia were followed up for up to 30 days from initial hospitalization for mortality and these patients who were discharged alive within 30 days of initial hospitalization were followed up to 90 days of initial hospitalization for re-hospitalization. Separate logistic regression analyses were performed identify the predictors of mortality and re-hospitalization.</p> <p>Results</p> <p>Of 717 enrolled patients hospitalized for community-acquired pneumonia, 49 (6.8%) died within 30 days of hospital admission. Among these patients, 526 were discharged alive within 30 days of hospitalization of whom 58 (11.2%) were re-hospitalized within 90 days of initial hospitalization. History of hip fracture (odds ratio (OR) = 4.00, 95% confidence interval (CI) = (1.46, 10.96), P = .007), chronic obstructive pulmonary disease (OR = 2.31, 95% CI = (1.18, 4.50), P = .014), cerebrovascular disease (OR = 2.11, 95% CI = (1.03, 4.31), P = .040) were associated with mortality. Male sex (OR = 2.35, 95% CI = (1.13, 4.85), P = .022) was associated with re-hospitalization while vitamin E supplementation was protective (OR = 0.37 (0.16, 0.90), P = .028). Lower socioeconomic status, prior influenza and pneumococcal vaccinations, appropriate antibiotic prescription upon admission, and lower nutrition risk were not significantly associated with mortality or re-hospitalization.</p> <p>Conclusion</p> <p>Chronic comorbidities appear to be the most important predictors of death and re-hospitalization in older adults hospitalized with community-acquired pneumonia while vitamin E supplementation was protective.</p

Mutations in normal breast tissue and breast tumours

The accumulation of mutations is a feature of all normal cells. The probability of any individual gene in any cell acquiring a mutation is, however, low. Cancer is therefore a rare disease in comparison with the number of susceptible cells. Mutations in normal tissue are stochastic, vary widely among cells and are therefore difficult to detect using standard methods because each change is so rare. If, however, a tissue such as the breast undergoes considerable clonal expansion, particularly if relatively late in life, normal tissue may have accumulated many thousands of detectable mutations. Since breast cancers are clonal and have almost certainly undergone many more cell divisions than normal cells, each tumour may have many millions of mutations, most of which are entirely innocent and some of which have accumulated in the cell of origin prior to tumorigenesis. Despite some claims to the contrary, even at normal mutation rates, clonal expansion within a tumour is quite sufficient to account for the mutations of five or six genes that are generally supposed necessary for carcinogenesis to occur. Hypermutability does, however, contribute to the pathogenesis of many cancers and, although evidence is indirect in breast cancer, may take forms such as karyotypic instability via centrosome amplification