91 research outputs found
On the equivalence between the effective cosmology and excursion set treatments of environment
In studies of the environmental dependence of structure formation, the large
scale environment is often thought of as providing an effective background
cosmology: e.g. the formation of structure in voids is expected to be just like
that in a less dense universe with appropriately modified Hubble and
cosmological constants. However, in the excursion set description of structure
formation which is commonly used to model this effect, no explicit mention is
made of the effective cosmology. Rather, this approach uses the spherical
evolution model to compute an effective linear theory growth factor, which is
then used to predict the growth and evolution of nonlinear structures. We show
that these approaches are, in fact, equivalent: a consequence of Birkhoff's
theorem. We speculate that this equivalence will not survive in models where
the gravitational force law is modified from an inverse square, potentially
making the environmental dependence of clustering a good test of such models.Comment: 4 pages, 0 figures, accepted to MNRA
Galaxy clustering constraints on deviations from Newtonian gravity at cosmological scales II: Perturbative and numerical analyses of power spectrum and bispectrum
We explore observational constraints on possible deviations from Newtonian
gravity by means of large-scale clustering of galaxies. We measure the power
spectrum and the bispectrum of Sloan Digital Sky Survey galaxies and compare
the result with predictions in an empirical model of modified gravity. Our
model assumes an additional Yukawa-like term with two parameters that
characterize the amplitude and the length scale of the modified gravity. The
model predictions are calculated using two methods; the second-order
perturbation theory and direct N-body simulations. These methods allow us to
study non-linear evolution of large-scale structure. Using the simulation
results, we find that perturbation theory provides reliable estimates for the
power spectrum and the bispectrum in the modified Newtonian model. We also
construct mock galaxy catalogues from the simulations, and derive constraints
on the amplitude and the length scale of deviations from Newtonian gravity. The
resulting constraints from power spectrum are consistent with those obtained in
our earlier work, indicating the validity of the previous empirical modeling of
gravitational nonlinearity in the modified Newtonian model. If linear biasing
is adopted, the bispectrum of the SDSS galaxies yields constraints very similar
to those from the power spectrum. If we allow for the nonlinear biasing
instead, we find that the ratio of the quadratic to linear biasing
coefficients, b_2/b_1, should satisfy -0.4 < b_2/b_1<0.3 in the modified
Newtonian model.Comment: 12 pages, 7 figure
Texture image analysis in differentiating malignant from benign adrenal cortical tumors in children and adults
OBJECTIVE:
To investigate the possible role of chromatin texture parameters, nuclear morphology, DNA ploidy and clinical functional status in discriminating benign from malignant adrenocortical tumors (ACT).
PATIENTS AND METHODS:
Forty-eight cases of clinically benign (n=40) and clinically malignant (n=8) ACT with a minimum of 5-years' follow-up were evaluated for chromatin texture parameters (run length, standard deviation, configurable run length, valley, slope, peak and other 21 Markovian features that describe the distribution of the chromatin in the nucleus), nuclear morphology (nuclear area, nuclear perimeter, nuclear maximum and minimum diameter, nuclear shape), and DNA ploidy. Nuclear parameters were evaluated in Feulgen-stained 5 mum paraffin-sections analyzed using a CAS 200 image analyzer.
RESULTS:
Since ACTs present different biological features in children and adults, patients were divided into two groups: children (15 years). In the group of children DNA ploidy presented a marginal significance (p=0.05) in discriminating ACTs. None of the parameters discriminated between malignant and benign ACT in the adult group.
CONCLUSION:
ACTs are uncommon and definitive predictive criteria for malignancy remain uncertain, particularly in children. Our data point to DNA content evaluated by image analysis as a new candidate tool for this challenging task. Texture image analysis did not help to differentiate malignant from benign adrenal cortical tumors in children and adults
Assessment of Preoperative Liver Function in Patients with Hepatocellular Carcinoma - The Albumin-Indocyanine Green Evaluation (ALICE) Grade.
Most patients with hepatocellular carcinoma (HCC) have underlying liver disease, therefore, precise preoperative evaluation of the patient's liver function is essential for surgical decision making.
We developed a grading system incorporating only two variables, namely, the serum albumin level and the indocyanine green retention rate at 15 minutes (ICG R15), to assess the preoperative liver function, based on the overall survival of 1868 patients with HCC who underwent liver resection. We then tested the model in a European cohort (n = 70) and analyzed the predictive power for the postoperative short-term outcome.
The Albumin-Indocyanine Green Evaluation (ALICE) grading system was developed in a randomly assigned training cohort: linear predictor = 0.663 × log10ICG R15 (%)-0.0718 × albumin (g/L) (cut-off value: -2.20 and -1.39). This new grading system showed a predictive power for the overall survival similar to the Child-Pugh grading system in the validation cohort. Determination of the ALICE grade in Child-Pugh A patients allowed further stratification of the postoperative prognosis. This result was reproducible in the European cohort. Determination of the ALICE grade allowed better prediction of the risk of postoperative liver failure and mortality (ascites: grade 1, 2.1%; grade 2, 6.5%; grade 3, 16.0%; mortality: grade 1, 0%; grade 2, 1.3%; grade 3, 5.3%) than the previously reported model based on the presence/absence of portal hypertension.
This new grading system is a simple method for prediction of the postoperative long-term and short-term outcomes
Immunocytochemical expression of p16 INK4A and Ki-67 in cytologically negative and equivocal pap smears positive for oncogenic human papillomavirus
This study was designed to analyze the cross-sectional comparison of the
p16
INK4A
and Ki-67 immunocytochemical expression in negative and equivocal (atyp-ical
squamous cells of undetermined significance (ASC-US)) liquid-based cytology
(LBC) samples testing positive for high-risk human papillomavirus (HPV) types with
HC2 assay or polymerase-chain reaction (PCR). A series of 199 consecutive LBC speci-mens
derived from the same number of women participating in the ongoing Latin American
Screening Study at Leonor Mendes de Barros Hospital, São Paulo, were analyzed
using immunocytochemistry for expression of p16
INK4A
and Ki-67 in negative and
equivocal LBC samples testing positive for high-risk HPV types with hybrid capture
II test (HC2) or PCR. All patients with at least one test positive (cytology, PCR, and/or
HC2) were followed each 6 months for 3 years. The follow-up procedure consisted of
visual examination, colposcopic inspection, cytology, and HC2 assay. Among the neg-ative
cytologic samples, 101 were HPV-positive and 55 HPV-negative. Of the HPV-pos-itive
group, 59 of 101 cases (58.4%) were positive for both p16 and Ki67
immunostaining, and 17 of 101 (16.8%) were negative for both. The proportion of
Ki-67-positivity increased almost in parallel with the increasing grade of p16-positivity
(p = 0.0001 for linear trend). In the HPV-negative group, both markers were negative in
41 of 55 cases (74.5%), and no statistical relationship was observed between the two
markers (Pearson, p = 0.595). HPV-positive ASC-US samples demonstrated a simulta-neous
positive immunoreaction for p16 and Ki67 in 11 of 16 cases (68.7%), whereas 3
(18.7%) were concurrently negative. The relationship between the two markers was of
borderline significance (Pearson, p = 0.053), but no linear relationship was found be-tween
the graded p16 and Ki-67 expression (p = 0.065 for linear trend). In the HPV-negative
ASC-US group, there was no statistical association between the graded p16
and Ki-67 positivity (Pearson, p = 0.281). After 36 months of follow-up of the ASC-US
patients, 6 women still displayed ASC-US smear, of which 4 of 6 were HPV-positive
and expressed both p16 and Ki-67 markers. Two of 43 ASC-US smears had high-grade squamous intraepithelial lesions diagnosed (4.6%), and 1 had low-grade squamous
intraepithelial lesion (2.3%). All of those were positive for HPV, p16 and Ki-67. Patients
with ASC-US diagnosis and positive high-risk HPV status and positive for p16
INK4A
Ki67 should be carefully observed to exclude occurrence of a squamous intraepithelial
lesion. The combination of these two markers can be a useful implement for manage-ment
of women with equivocal cytology.European Commission (EC) - INCO-DEV Programme - Project #ICA4-CT-2001-10013
Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells
Cimetidine has been shown to have beneficial effects in colorectal cancer patients. In this study, a total of 64 colorectal cancer patients who received curative operation were examined for the effects of cimetidine treatment on survival and recurrence. The cimetidine group was given 800 mg day−1 of cimetidine orally together with 200 mg day−1 of 5-fluorouracil, while the control group received 5-fluorouracil alone. The treatment was initiated 2 weeks after the operation and terminated after 1 year. Robust beneficial effects of cimetidine were noted: the 10-year survival rate of the cimetidine group was 84.6% whereas that of control group was 49.8% (P<0.0001). According to our previous observations that cimetidine blocked the expression of E-selectin on vascular endothelium and inhibited the adhesion of cancer cells to the endothelium, we have further stratified the patients according to the expression levels of sialyl Lewis antigens X (sLx) and A (sLa). We found that cimetidine treatment was particularly effective in patients whose tumour had higher sLx and sLa antigen levels. For example, the 10-year cumulative survival rate of the cimetidine group with higher CSLEX staining, recognizing sLx, of tumours was 95.5%, whereas that of control group was 35.1% (P=0.0001). In contrast, in the group of patients with no or low levels CSLEX staining, cimetidine did not show significant beneficial effect (the 10-year survival rate of the cimetidine group was 70.0% and that of control group was 85.7% (P=n.s.)). These results clearly indicate that cimetidine treatment dramatically improved survival in colorectal cancer patients with tumour cells expressing high levels of sLx and sLa
An E2F1-Mediated DNA Damage Response Contributes to the Replication of Human Cytomegalovirus
DNA damage resulting from intrinsic or extrinsic sources activates DNA damage responses (DDRs) centered on protein kinase signaling cascades. The usual consequences of inducing DDRs include the activation of cell cycle checkpoints together with repair of the damaged DNA or induction of apoptosis. Many DNA viruses elicit host DDRs during infection and some viruses require the DDR for efficient replication. However, the mechanism by which DDRs are activated by viral infection is poorly understood. Human cytomegalovirus (HCMV) infection induces a DDR centered on the activation of ataxia telangiectasia mutated (ATM) protein kinase. Here we show that HCMV replication is compromised in cells with inactivated or depleted ATM and that ATM is essential for the host DDR early during infection. Likewise, a downstream target of ATM phosphorylation, H2AX, also contributes to viral replication. The ATM-dependent DDR is detected as discrete, nuclear γH2AX foci early in infection and can be activated by IE proteins. By 24 hpi, γH2AX is observed primarily in HCMV DNA replication compartments. We identified a role for the E2F1 transcription factor in mediating this DDR and viral replication. E2F1, but not E2F2 or E2F3, promotes the accumulation of γH2AX during HCMV infection or IE protein expression. Moreover, E2F1 expression, but not the expression of E2F2 or E2F3, is required for efficient HCMV replication. These results reveal a novel role for E2F1 in mediating an ATM-dependent DDR that contributes to viral replication. Given that E2F activity is often deregulated by infection with DNA viruses, these observations raise the possibility that an E2F1-mediated mechanism of DDR activation may be conserved among DNA viruses
Human Papillomaviruses Activate the ATM DNA Damage Pathway for Viral Genome Amplification upon Differentiation
Human papillomaviruses (HPV) are the causative agents of cervical cancers. The infectious HPV life cycle is closely linked to the differentiation state of the host epithelia, with viral genome amplification, late gene expression and virion production restricted to suprabasal cells. The E6 and E7 proteins provide an environment conducive to DNA synthesis upon differentiation, but little is known concerning the mechanisms that regulate productive viral genome amplification. Using keratinocytes that stably maintain HPV-31 episomes, and chemical inhibitors, we demonstrate that viral proteins activate the ATM DNA damage response in differentiating cells, as indicated by phosphorylation of CHK2, BRCA1 and NBS1. This activation is necessary for viral genome amplification, as well as for formation of viral replication foci. In contrast, inhibition of ATM kinase activity in undifferentiated keratinocytes had no effect on the stable maintenance of viral genomes. Previous studies have shown that HPVs induce low levels of caspase 3/7 activation upon differentiation and that this is important for cleavage of the E1 replication protein and genome amplification. Our studies demonstrate that caspase cleavage is induced upon differentiation of HPV positive cells through the action of the DNA damage protein kinase CHK2, which may be activated as a result of E7 binding to the ATM kinase. These findings identify a major regulatory mechanism responsible for productive HPV replication in differentiating cells. Our results have potential implications for the development of anti-viral therapies to treat HPV infections
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