To investigate whether cancer is associated with Alzheimer disease (AD) and vascular dementia (VaD).
Cox proportional hazards models were used to test associations between prevalent dementia and risk ...of future cancer hospitalization, and associations between prevalent cancer and risk of subsequent dementia. Participants in the Cardiovascular Health Study-Cognition Substudy, a prospective cohort study, aged 65 years or older (n = 3,020) were followed a mean of 5.4 years for dementia and 8.3 years for cancer.
The presence of any AD (pure AD + mixed AD/VaD; hazard ratio HR = 0.41, 95% confidence interval CI = 0.20-0.84) and pure AD (HR = 0.31, 95% CI = 0.12-0.86) was associated with a reduced risk of future cancer hospitalization, adjusted for demographic factors, smoking, obesity, and physical activity. No significant associations were found between dementia at baseline and rate of cancer hospitalizations for participants with diagnoses of VaD. Prevalent cancer was associated with reduced risk of any AD (HR = 0.72; 95% CI = 0.52-0.997) and pure AD (HR = 0.57; 95% CI = 0.36-0.90) among white subjects after adjustment for demographics, number of APOE epsilon4 alleles, hypertension, diabetes, and coronary heart disease; the opposite association was found among minorities, but the sample size was too small to provide stable estimates. No significant association was found between cancer and subsequent development of VaD.
In white older adults, prevalent Alzheimer disease (AD) was longitudinally associated with a reduced risk of cancer, and a history of cancer was associated with a reduced risk of AD. Together with other work showing associations between cancer and Parkinson disease, these findings suggest the possibility that cancer is linked to neurodegeneration.
Non-small-cell lung cancer (NSCLC) demonstrates remarkable molecular diversity. With the completion of The Cancer Genome Atlas (TCGA), there is opportunity for systematic analyses of the entire TCGA ...NSCLC cohort, including comparisons and contrasts between different disease subsets. On the basis of multidimensional and comprehensive molecular characterization (including DNA methylation and copy, and RNA and protein expression), 1023 NSCLC cases-519 from TCGA adenocarcinoma (AD) project and 504 from TCGA squamous cell carcinoma (SQCC) project-were classified using a 'cluster-of-clusters' analytic approach. Patterns from TCGA NSCLC subsets were examined in independent external databases, including the PROSPECT (Profiling of Resistance patterns and Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax) NSCLC data set. Nine genomic subtypes of NSCLC were identified, three within SQCC and six within AD. SQCC subtypes were associated with transcriptional targets of SOX2 or p63. One predominately AD subtype (with a large proportion of SQCC) shared molecular features with neuroendocrine tumors. Two AD subtypes manifested a CpG island methylator phenotype. Three AD subtypes showed high p38 and mTOR pathway activation. AD subtypes associated with low differentiation showed relatively worse prognosis. SQCC subtypes and two of the AD subtypes expressed cancer testis antigen genes, whereas three AD subtypes expressed several immune checkpoint genes including PDL1 and PDL2, corresponding with patterns of greater immune cell infiltration. Subtype associations for several immune-related markers-including PD1, PDL1, CD3 and CD8-were confirmed in the PROSPECT cohort using immunohistochemistry. NSCLC molecular subtypes have therapeutic implications and lend support to a personalized approach to NSCLC management based on molecular characterization.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Lung cancer is the leading cause of cancer-related deaths, primarily due to distant metastatic disease. Metastatic lung cancer cells can undergo an epithelial-to-mesenchymal transition (EMT) ...regulated by various transcription factors, including a double-negative feedback loop between the microRNA-200 (miR-200) family and ZEB1, but the precise mechanisms by which ZEB1-dependent EMT promotes malignancy remain largely undefined. Although the cell-intrinsic effects of EMT are important for tumor progression, the reciprocal dynamic crosstalk between mesenchymal cancer cells and the extracellular matrix (ECM) is equally critical in regulating invasion and metastasis. Investigating the collaborative effect of EMT and ECM in the metastatic process reveals increased collagen deposition in metastatic tumor tissues as a direct consequence of amplified collagen gene expression in ZEB1-activated mesenchymal lung cancer cells. In addition, collagen fibers in metastatic lung tumors exhibit greater linearity and organization as a result of collagen crosslinking by the lysyl oxidase (LOX) family of enzymes. Expression of the LOX and LOXL2 isoforms is directly regulated by miR-200 and ZEB1, respectively, and their upregulation in metastatic tumors and mesenchymal cell lines is coordinated to that of collagen. Functionally, LOXL2, as opposed to LOX, is the principal isoform that crosslinks and stabilizes insoluble collagen deposition in tumor tissues. In turn, focal adhesion formation and FAK/SRC signaling is activated in mesenchymal tumor cells by crosslinked collagen in the ECM. Our study is the first to validate direct regulation of LOX and LOXL2 by the miR-200/ZEB1 axis, defines a novel mechanism driving tumor metastasis, delineates collagen as a prognostic marker, and identifies LOXL2 as a potential therapeutic target against tumor progression.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We investigate the radiative transfer of Lyα photons through simplified anisotropic gas distributions, which represent physically motivated extensions of the popular shell models. Our study is ...motivated by the notion that (i) shell models do not always reproduce observed Lyα spectral line profiles; (ii) (typical) shell models do not allow for the escape of ionizing photons; and (iii) the observation and expectation that winds are more complex, anisotropic phenomena. We examine the influence of inclination on the Lyα spectra, relative fluxes and escape fractions. We find the flux to be enhanced/suppressed by factors up to a few depending on the parameter range of the models, corresponding to a boost in equivalent width of the same amplitude if we neglect dust. In general, lower mean optical depths tend to reduce the impact of anisotropies as is expected. We find a correlation between an observed peak in the – occasionally triple-peaked – spectrum at the systemic velocity and the existence of a low optical depth cavity along the line of sight. This can be of importance in the search for ionizing photons leaking from high- redshift galaxies since these photons will also be able to escape through the cavity.
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FMFMET, NUK, UL, UM, UPUK
Context. Lyman-α emitters (LAEs) are a promising probe of the large-scale structure at high redshift, z ≳ 2. In particular, the Hobby-Eberly Telescope Dark Energy Experiment aims at observing LAEs at ...1.9 < z < 3.5 to measure the baryon acoustic oscillation (BAO) scale and the redshift-space distortion (RSD). However, it has been pointed out that the complicated radiative transfer (RT) of the resonant Lyman-α emission line generates an anisotropic selection bias in the LAE clustering on large scales, s ≳ 10 Mpc. This effect could potentially induce a systematic error in the BAO and RSD measurements. Also, there exists a recent claim to have observational evidence of the effect in the Lyman-α intensity map, albeit statistically insignificant. Aims. We aim at quantifying the impact of the Lyman-α RT on the large-scale galaxy clustering in detail. For this purpose, we study the correlations between the large-scale environment and the ratio of an apparent Lyman-α luminosity to an intrinsic one, which we call the “observed fraction”, at 2 < z < 6. Methods. We apply our Lyman-α RT code by post-processing the full Illustris simulations. We simply assume that the intrinsic luminosity of the Lyman-α emission is proportional to the star formation rate of galaxies in Illustris, yielding a sufficiently large sample of LAEs to measure the anisotropic selection bias. Results. We find little correlation between large-scale environment and the observed fraction induced by the RT, and hence a smaller anisotropic selection bias than has previously been claimed. We argue that the anisotropy was overestimated in previous work due to insufficient spatial resolution; it is important to keep the resolution such that it resolves the high-density region down to the scale of the interstellar medium, that is, ~1 physical kpc. We also find that the correlation can be further enhanced by assumptions in modeling intrinsic Lyman-α emission.
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FMFMET, NUK, UL, UM, UPUK
Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies ...(GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.
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IJS, NUK, SBMB, UL, UM, UPUK
Objective To examine temporal, geographic, and sociodemographic trends in case reporting and case fatality of malaria in the United Kingdom.Setting National malaria reference laboratory surveillance ...data in the UK.Design Observational study using prospectively gathered surveillance data and data on destinations from the international passenger survey.Participants 39 300 cases of proved malaria in the UK between 1987 and 2006.Main outcome measures Plasmodium species; sociodemographic details (including age, sex, and country of birth and residence); mortality; destination, duration, and purpose of international travel; and use of chemoprophylaxis.Results Reported cases of imported malaria increased significantly over the 20 years of the study; an increasing proportion was attributable to Plasmodium falciparum (P falciparum/P vivax reporting ratio 1.3:1 in 1987-91 and 5.4:1 in 2002-6). P vivax reports declined from 3954 in 1987-91 to 1244 in 2002-6. Case fatality of reported P falciparum malaria did not change over this period (7.4 deaths per 1000 reported cases). Travellers visiting friends and relatives, usually in a country in Africa or Asia from which members of their family migrated, accounted for 13 215/20 488 (64.5%) of all malaria reported, and reports were geographically concentrated in areas where migrants from Africa and South Asia to the UK have settled. People travelling for this purpose were at significantly higher risk of malaria than other travellers and were less likely to report the use of any chemoprophylaxis (odds ratio of reported chemoprophylaxis use 0.23, 95% confidence interval 0.21 to 0.25).Conclusions Despite the availability of highly effective preventive measures, the preventable burden from falciparum malaria has steadily increased in the UK while vivax malaria has decreased. Provision of targeted and appropriately delivered preventive messages and services for travellers from migrant families visiting friends and relatives should be a priority.
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BFBNIB, CMK, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Abstract
Major mergers are considered to be a significant source of turbulence in clusters. We performed a numerical simulation of a major merger event using nested-grid initial conditions, adaptive ...mesh refinement, radiative cooling of primordial gas and a homogeneous ultraviolet background. By calculating the microscopic viscosity on the basis of various theoretical assumptions and estimating the Kolmogorov length from the turbulent dissipation rate computed with a subgrid-scale model, we are able to demonstrate that most of the warm–hot intergalactic mediums can sustain a fully turbulent state only if the magnetic suppression of the viscosity is considerable. Accepting this as premise, it turns out that ratios of turbulent and thermal quantities change only little in the course of the merger. This confirms the tight correlations between the mean thermal and non-thermal energy content for large samples of clusters in earlier studies, which can be interpreted as second self-similarity on top of the self-similarity for different halo masses. Another long-standing question is how and to which extent turbulence contributes to the support of the gas against gravity. From a global perspective, the ratio of turbulent and thermal pressures is significant for the clusters in our simulation. On the other hand, a local measure is provided by the compression rate, i.e. the growth rate of the divergence of the flow. Particularly for the intracluster medium, we find that the dominant contribution against gravity comes from thermal pressure, while compressible turbulence effectively counteracts the support. For this reason, it appears to be too simplistic to consider turbulence merely as an effective enhancement of thermal energy.
Amplification of the epidermal growth factor receptor (EGFR) gene represents one of the most frequent gene alterations in glioblastoma (GBM). In the current study, we evaluated gefitinib, a potent ...EGFR inhibitor, in the treatment of adults with newly diagnosed GBM.
Ninety-eight patients (96 evaluable) were accrued between May 18, 2001, and August 2, 2002. All were newly diagnosed GBM patients who were clinically and radiographically stable/improved after radiation treatment (enrollment within 5 weeks of radiation completion). No prior chemotherapy was permitted. EGFR amplification/mutation, as assessed by fluorescence in situ hybridization and immunohistochemistry, was not required for treatment with gefitinib but was studied when tissues were available. Gefitinib was administered at 500 mg each day; for patients receiving dexamethasone or enzyme-inducing (CYP3A4) agents, dose was escalated to a maximum of 1,000 mg QD. Treatment cycles were repeated at 4-week intervals with brain magnetic resonance imaging at 8-week intervals.
Overall survival (OS; calculated from time of initial surgery) at 1 year (primary end point) with gefitinib was 54.2%, which was not statistically different compared with that of historical control population (48.9%, data from three previous Phase III North Central Cancer Treatment Group studies of newly diagnosed GBM patients). Progression-free survival (PFS) at 1 year post-RT (16.7%) was also not significantly different to that of historical controls (30.3%). Clinical outcome was not affected by EGFR status (amplification or vIII mutation). Fatigue (41%), rash (62%), and loose stools (58%) constituted the most frequent adverse events, the majority of these being limited to Grade 1/2. Of note, the occurrence of drug-related adverse effects, such as loose stools was associated with improved OS.
In our evaluation of nearly 100 patients with newly diagnosed GBM, treatment with adjuvant gefitinib post-radiation was not associated with significant improvement in OS or PFS. However, patients who experienced gefitinib-associated adverse effects (rash/diarrhea) did demonstrate improved OS.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
Alzheimer disease and cancer ROE, C. M; BEHRENS, M. I; XIONG, C ...
Neurology,
03/2005, Volume:
64, Issue:
5
Journal Article
Peer reviewed
Cross-sectional studies raise the possibility of protective relationships between, or a common mechanism underlying, the development of dementia of the Alzheimer type (DAT) and cancer. Using a ...prospective longitudinal design, the authors found that the risk of developing cancer is less among participants with DAT vs nondemented participants (p < 0.001) and that the risk of developing DAT may be less for participants with a history of cancer (p = 0.060).
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