Time from first presentation in primary care to treatment of symptomatic colorectal cancer:effect on disease stage and survival

BACKGROUND: British 5-year survival from colorectal cancer (CRC) is below the European average, but the reasons are unclear. This study explored if longer provider delays (time from presentation to treatment) were associated with more advanced stage disease at diagnosis and poorer survival. METHODS: Data on 958 people with CRC were linked with the Scottish Cancer Registry, the Scottish Death Registry and the acute hospital discharge (SMR01) dataset. Time from first presentation in primary care to first treatment, disease stage at diagnosis and survival time from date of first presentation in primary care were determined. Logistic regression and Cox survival analyses, both with a restricted cubic spline, were used to model stage and survival, respectively, following sequential adjustment of patient and tumour factors. RESULTS: On univariate analysis, those with <4 weeks from first presentation in primary care to treatment had more advanced disease at diagnosis and the poorest prognosis. Treatment delays between 4 and 34 weeks were associated with earlier stage (with the lowest odds ratio occurring at 20 weeks) and better survival (with the lowest hazard ratio occurring at 16 weeks). Provider delays beyond 34 weeks were associated with more advanced disease at diagnosis, but not increased mortality. Following adjustment for patient, tumour factors, emergency admissions and symptoms and signs, no significant relationship between provider delay and stage at diagnosis or survival from CRC was found. CONCLUSIONS: Although allowing for a nonlinear relationship and important confounders, moderately long provider delays did not impact adversely on cancer outcomes. Delays are undesirable because they cause anxiety; this may be fuelled by government targets and health campaigns stressing the importance of very prompt cancer diagnosis. Our findings should reassure patients. They suggest that a health service's primary emphasis should be on quality and outcomes rather than on time to treatment

CR1 Knops blood group alleles are not associated with severe malaria in the Gambia

The Knops blood group antigen erythrocyte polymorphisms have been associated with reduced falciparum malaria-based in vitro rosette formation (putative malaria virulence factor). Having previously identified single-nucleotide polymorphisms (SNPs) in the human complement receptor 1 (CR1/CD35) gene underlying the Knops antithetical antigens Sl1/Sl2 and McC(a)/McC(b), we have now performed genotype comparisons to test associations between these two molecular variants and severe malaria in West African children living in the Gambia. While SNPs associated with Sl:2 and McC(b+) were equally distributed among malaria-infected children with severe malaria and control children not infected with malaria parasites, high allele frequencies for Sl 2 (0.800, 1,365/1,706) and McC(b) (0.385, 658/1706) were observed. Further, when compared to the Sl 1/McC(a) allele observed in all populations, the African Sl 2/McC(b) allele appears to have evolved as a result of positive selection (modified Nei-Gojobori test Ka-Ks/s.e.=1.77, P-value &lt;0.05). Given the role of CR1 in host defense, our findings suggest that Sl 2 and McC(b) have arisen to confer a selective advantage against infectious disease that, in view of these case-control study data, was not solely Plasmodium falciparum malaria. Factors underlying the lack of association between Sl 2 and McC(b) with severe malaria may involve variation in CR1 expression levels

Early mortality from colorectal cancer in England: a retrospective observational study of the factors associated with death in the first year after diagnosis

Background: The United Kingdom performs poorly in international comparisons of colorectal cancer survival with much of the deficit owing to high numbers of deaths close to the time of diagnosis. This retrospective cohort study investigates the patient, tumour and treatment characteristics of those who die in the first year after diagnosis of their disease. Methods: Patients diagnosed with colon (n=65,733) or rectal (n=26,123) cancer in England between 2006 and 2008 were identified in the National Cancer Data Repository. Multivariable logistic regression was used to investigate the odds of death within 1 month, 1-3 months and 3-12 months after diagnosis. Results: In all, 11.5% of colon and 5.4% of rectal cancer patients died within a month of diagnosis: this proportion decreased significantly over the study period. For both cancer sites, older age, stage at diagnosis, deprivation and emergency presentation were associated with early death. Individuals who died shortly after diagnosis were also more likely to have missing data about important prognostic factors such as disease stage and treatment. Conclusion: Using routinely collected data, at no inconvenience to patients, we have identified some important areas relating to early deaths from colorectal cancer, which merit further research

Variational Methods for Biomolecular Modeling

Structure, function and dynamics of many biomolecular systems can be characterized by the energetic variational principle and the corresponding systems of partial differential equations (PDEs). This principle allows us to focus on the identification of essential energetic components, the optimal parametrization of energies, and the efficient computational implementation of energy variation or minimization. Given the fact that complex biomolecular systems are structurally non-uniform and their interactions occur through contact interfaces, their free energies are associated with various interfaces as well, such as solute-solvent interface, molecular binding interface, lipid domain interface, and membrane surfaces. This fact motivates the inclusion of interface geometry, particular its curvatures, to the parametrization of free energies. Applications of such interface geometry based energetic variational principles are illustrated through three concrete topics: the multiscale modeling of biomolecular electrostatics and solvation that includes the curvature energy of the molecular surface, the formation of microdomains on lipid membrane due to the geometric and molecular mechanics at the lipid interface, and the mean curvature driven protein localization on membrane surfaces. By further implicitly representing the interface using a phase field function over the entire domain, one can simulate the dynamics of the interface and the corresponding energy variation by evolving the phase field function, achieving significant reduction of the number of degrees of freedom and computational complexity. Strategies for improving the efficiency of computational implementations and for extending applications to coarse-graining or multiscale molecular simulations are outlined.Comment: 36 page

The value of prognostic factors for uterine cervical cancer patients treated with irradiation alone

<p>Abstract</p> <p>Background</p> <p>The aim of our study was to investigate and evaluate the prognostic value of and correlations between preclinical and clinical factors such as the stage of the disease, blood Hb level before treatment, size of cervix and lymph nodes evaluated by CT, age, dose of irradiation and duration of radiotherapy related to overall survival, disease-free survival, local control and metastases-free survival in cervical cancer patients receiving radiotherapy alone.</p> <p>Methods</p> <p>162 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIA-IIIB cervical carcinoma treated with irradiation were analysed. Univariate and multivariate analyses using the Cox regression model were performed to determine statistical significance of some tumor-related factors.</p> <p>Results</p> <p>The Hb level before treatment showed significant influence on overall survival (p = 0.001), desease free survival (p = 0.040) and local control (p = 0.038). The lymph node status (>10 mm) assessed on CT had impact on overall survival (p = 0,030) and local control (p = 0,036). The dose at point A had impact on disease free survival (p = 0,028) and local control (p = 0,021) and the radiotherapy duration had showed significant influence on overall survival (p = 0,045), disease free survival (p = 0,006) and local control (p = 0,033).</p> <p>Conclusion</p> <p>Anemia is a significant and independent prognostic factor of overall survival, disease-free survival and local control in cervical cancer patients treated with irradiation. The size of lymph nodes in CT is an independent prognostic factor for overall survival and local control in cervical cancer patients. The size of cervix uteri evaluated by CT has no prognostic significance in cervical cancer patients treated with radiotherapy. The prognostic value of FIGO stage of cervical cancer is influenced by other factors, analyzed in this study and is not an independent prognostic factor.</p

Hsp90 orchestrates transcriptional regulation by Hsf1 and cell wall remodelling by MAPK signalling during thermal adaptation in a pathogenic yeast

Acknowledgments We thank Rebecca Shapiro for creating CaLC1819, CaLC1855 and CaLC1875, Gillian Milne for help with EM, Aaron Mitchell for generously providing the transposon insertion mutant library, Jesus Pla for generously providing the hog1 hst7 mutant, and Cathy Collins for technical assistance.Peer reviewedPublisher PD

Ficaria verna Huds. extracts and their β-cyclodextrin supramolecular systems

<p>Abstract</p> <p>Background</p> <p>Obtaining new pharmaceutical materials with enhanced properties by using natural compounds and environment-friendly methods is a continuous goal for scientists. <it>Ficaria verna </it>Huds. is a widespread perennial plant with applications in the treat of haemorrhoids and to cure piles; it has also anti-inflammatory, astringent, and antibiotic properties. The goal of the present study is the obtaining and characterization of new <it>F. verna </it>extract/β-cyclodextrin complexes by using only natural compounds, solvents, and environment-friendly methods in order to increase the quality and acceptability versus toxicity indicator. Thus, the flavonoid content (as quercetin) of <it>Ficaria verna </it>Huds. flowers and leaves from the West side of Romania was determined and correlated with their antioxidant activity. Further, the possibility of obtaining β-cyclodextrin supramolecular systems was studied.</p> <p>Results</p> <p><it>F. verna </it>flowers and leaves extracts were obtained by semi-continuous solid-liquid extraction. The raw concentrated extract was spectrophotometrically analyzed in order to quantify the flavonoids from plant parts and to evaluate the antioxidant activity of these extracts. The <it>F. verna </it>extracts were used for obtaining β-cyclodextrin complexes; these were analyzed by scanning electron microscopy and Karl Fischer water titration; spectrophotometry was used in order to quantifying the flavonoids and evaluates the antioxidant activity. A higher concentration of flavonoids of 0.5% was determined in complexes obtained by crystallisation method, while only a half of this value was calculated for kneading method. The antioxidant activity of these complexes was correlated with the flavonoid content and this parameter reveals possible controlled release properties.</p> <p>Conclusions</p> <p>The flavonoid content of <it>F. verna </it>Huds. from the West side of Romania (Banat county) is approximately the same in flowers and leaves, being situated at a medium value among other studies. β-Cyclodextrin complexes of <it>F. verna </it>extracts are obtained with lower yields by crystallisation than kneading methods, but the flavonoids (as quercetin) are better encapsulated in the first case most probably due to the possibility to attain the <it>host</it>-<it>guest </it>equilibrium in the slower crystallisation process. <it>F. verna </it>extracts and their β-cyclodextrin complexes have antioxidant activity even at very low concentrations and could be used in proper and valuable pharmaceutical formulations with enhanced bioactivity.</p

Hepatic P450 Enzyme Activity, Tissue Morphology and Histology of Mink (Mustela vison) Exposed to Polychlorinated Dibenzofurans

Dose- and time-dependent effects of environmentally relevant concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TEQ) of 2,3,7,8-tetrachlorodibenzofuran (TCDF), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), or a mixture of these two congeners on hepatic P450 enzyme activity and tissue morphology, including jaw histology, of adult ranch mink were determined under controlled conditions. Adult female ranch mink were fed either TCDF (0.98, 3.8, or 20 ng TEQTCDF/kg bw/day) or PeCDF (0.62, 2.2, or 9.5 ng TEQPeCDF/kg bw/day), or a mixture of TCDF and PeCDF (4.1 ng TEQTCDF/kg bw/day and 2.8 ng TEQPeCDF/kg bw/day, respectively) for 180 days. Doses used in this study were approximately eight times greater than those reported in a parallel field study. Activities of the cytochrome P450 1A enzymes, ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-deethylase (MROD) were significantly greater in livers of mink exposed to TCDF, PeCDF, and a mixture of the two congeners; however, there were no significant histological or morphological effects observed. It was determined that EROD and MROD activity can be used as sensitive biomarkers of exposure to PeCDF and TCDF in adult female mink; however, under the conditions of this study, the response of EROD/MROD induction occurred at doses that were less than those required to cause histological or morphological changes

Dispersion and release of embelin from electrospun biodegradable, polymeric, membranes

In this work, microfiber meshes containing embelin, a poorly water-soluble bioactive agent, were prepared by solubilizing embelin in a biodegradable and biocompatible polymer matrix of poly(ε-caprolactone) (PCL). Plain or drug-loaded, highly porous, fibrous membranes with a high area-to-volume ratio were obtained by electrospinning. Non-woven microfibrous meshes were formed by uniform bead-free fibers with a mean diameter of 1.2 μm. Non-porous films were obtained by solution casting, and were used for comparison. The drug-loading content of the prepared systems was appropriate for topical applications. The thermal properties revealed that the crystallinity of embelin significantly decreased, the drug having almost completely dissolved in the PCL fibers. The in situ bioavailability of embelin, an antimycotic agent, is an important aspect to consider in topical drug applications. The drug-loaded systems presented different contact areas with the biological environment. When comparing the ability to expose embelin with the biological environment of the prepared systems, drug-loaded fibrous scaffolds showed a higher bioavailability of the bioactive agent because of an increase by 86% in the area-to-volume ratio, providing an effective area per unit mass that was 5.8-fold higher than that of the film. For the meshes, 90% embelin release was observed after 12h of exposure to phosphate-buffered saline, whereas for the films a comparable level of release occurred only after 72h.Fil: Cortez Tornello, Pablo Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mar del Plata. Instituto de Investigación En Ciencia y Tecnología de Materiales (i); Argentina. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; ArgentinaFil: Feresin, Gabriela Egly. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; ArgentinaFil: Tapia, Alejandro. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; ArgentinaFil: Veiga, Itiara G.. Universidade Estadual de Campinas; BrasilFil: Moraes, Ângela M.. Universidade Estadual de Campinas; BrasilFil: Abraham, Gustavo Abel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mar del Plata. Instituto de Investigación En Ciencia y Tecnología de Materiales (i); Argentina. Universidad Nacional de Mar del Plata. Facultad de Ingeniería; ArgentinaFil: Cuadrado, Teresita Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mar del Plata. Instituto de Investigación En Ciencia y Tecnología de Materiales (i); Argentina. Universidad Nacional de Mar del Plata. Facultad de Ingeniería; Argentin