Should There Be Gender Differences in the Guidelines for Colorectal Cancer Screening?

Colorectal cancer screening guidelines are identical for men and women despite reported differences in epidemiology, endoscopy performance, screening preferences, and screening uptake. High-quality research is needed to determine whether gender aspects may in real world increase acceptance and overcome screening barriers, which may lead to better use of limited resources allocated for public health.     

Intercalation of imidazoacridinones to DNA and its relevance to cytotoxic and antitumor activity

Imidazoacridinones (IA) are a class of antitumor agents which includes C-1311, an interesting drug in clinical trials. This study investigated the mechanism of IA binding to DNA for a series of 13 analogs that differ in their cytotoxic potency. Using C-1311 as a model compound, crystallographic, spectroscopic and biochemical techniques were employed to characterize drug-DNA interactions. X-ray crystallographic analysis revealed a planar structure of imidazoacridinone core that is capable of intercalative DNA binding. Accordingly, C-1311 binding to DNA followed 'classical' pattern observed for intercalation, as proved by the DNA topoisomerase I-unwinding experiments, with relatively weak binding affinity (K(i)=1.2 x 10(5)M(-1)), and the binding site size of 2.4 bp. Other IA also bound to DNA with the binding affinity in the range of 10(5)M(-1) and binding site size of 2-3 bp, suggesting a prevalence of the intercalative mechanism, similar to C-1311. Considerable DNA binding affinity was displayed by all the highly cytotoxic derivatives. However, none of the analyzed drug-DNA binding parameters was significantly correlated with IA biological activities such as cell growth, DNA and RNA synthesis inhibition, or tumor growth inhibition, which suggests that the IA ability to non-covalently bind to DNA is not crucial for their biological activity. These results show that the ability to intercalate into DNA is a prominent attribute of IA, although factors other than intercalative binding seem to be required for the biological activities of IA drugs.     

Cell death in experimental intracerebral hemorrhage: the "black hole" model of hemorrhagic damage

Intracerebral hemorrhage (ICH) has a poor prognosis that may be the consequence of the hematoma's effect on adjacent and remote brain regions. Little is known about the mechanism, location, and severity of such effects. In this study, rats subjected to intracerebral blood injection were examined at 100 days. Stereology (neuronal count and density) and volume measures in the perihematoma rim, the adjacent and overlying brain, and the substantia nigra pars reticulata (SNr) were compared with contralateral brain regions at 100 days and the perihemorrhage region at 24 hours and 7 days. In addition, cytochrome c release was investigated at 24 hours, 3 days, and 7 days. At 100 days, post-ICH rats showed no difference in neuronal density in the perihemorrhagic scar region or regions of the striatum immediately surrounding and distal to the perihemorrhage scar. The cell density index in the ipsilateral field was 16.2 +/- 3.8 versus the contralateral control field of 15.6 +/- 3.2 (not significant). Volume measurements of the ipsilateral striatum revealed a 20% decrease that was compensated by an increase in ipsilateral ventricular size. The area of the initial ICH as measured by magnetic resonance imaging correlated with the degree of atrophy. In the region immediately surrounding the hematoma, cytochrome c immunoreactivity increased at 24 hours and 3 days, and returned toward baseline by day 7. At 24 hours, stereology in the peri-ICH region showed decreased density in the region where cytochrome c immunoreactivity was the highest. Neuronal density of the ipsilateral SNr was significantly less than the contralateral side (9.6 +/- 1.9 vs 11.6 +/- 2.3). Histologic damage from ICH occurred mainly in the immediate perihemorrhage region. Except for SNr, we found no evidence of neuronal loss in distal regions. We have termed this continued destruction of neurons, which occurs over at least 3 days as the neurons come into proximity to the hematoma, the "black hole" model of hemorrhagic damage.     

Immunophenotypic changes and induction of apoptosis of monocytes and tumour cells during their interactions in vitro

The in vitro model of tumour infiltrating macrophages (TIM)-tumour interactions in which monocytes and monocyte-derived macrophages (MDM) are cultured with cancer cells was used to assess immunophenotypic changes of interacting cells. Following short cocultures, monocytes, MDM and tumour cells were sorted out by FACS and the expression of several determinants was evaluated. Monocytes showed the induction of CD44v6 and v7/8, and up-regulation of CD16 (Fc gamma RIII), CD54 (ICAM-1), CD68 (macrophage maturation marker) and CD86 (costimulatory molecule B7.2). The increased expression of CD11a (LFA-1) and CD58 (LFA-3) was noted on some cancer cells. Up-regulation of TNFRII and HLA-DR was observed on both types of cells. MDM shared similar changes. Contact of monocytes, but not of MDM, with tumour cells led to Fas-FasL-dependent apoptosis of both types of cells. This study suggests that the immunophenotype of monocytes/macrophages and cancer cells may be modified during their bidirectional interactions in the absence of other microenvironmental elements that are present in the tumour stroma.     

Effects of cyclosporine on hematopoietic and immune functions in patients with hypoplastic myelodysplasia: in vitro and in vivo studies

BACKGROUND: Immunosuppression may benefit some patients with hypoplastic myelodysplasia (HMDS) and refractory anemia (RA), but its mechanism of action is still obscure. METHODS: Using flow cytometry, we studied Fas-receptor (Fas-R), Fas-ligand (Fas-L), and interferon-gamma (IFN-gamma) expression in CD34(+) cells and lymphocytes obtained from 11 HMDS and 20 RA patients. In colony assays and long-term cultures, the effects of Fas triggering, IFN-gamma blockade, or cyclosporine(CsA) on the growth of hematopoietic progenitors (colony-forming cells [CFC]) were determined. The effects of CsA at daily doses of 1-3 mg/kg for at least 3 months in HMDS patients were also studied. RESULTS: In basal conditions, committed and immature progenitor cells were found decreased in myelodysplastic (MDS) patients. No significant differences between HMDS and RA patients were detected. IFN-gamma-expressing CD4(+) cells were significantly increased in HMDS patients, whereas intracytoplasmic Fas-L expression was only borderline elevated in CD3(+) MDS cells. Increased numbers of CD34(+) cells expressing Fas-R were found in HMDS and RA patients. CFC and secondary CFC showed higher susceptibility to Fas-L-mediated inhibition and the blockade of IFN-gamma improved marrow primary, but not secondary, CFC growth. CsA added in vitro to patient's lymphocytes significantly decreased the number of IFN-gamma-expressing CD4(+) cells, but not Fas-L production. These effects were associated with increased colony formation. Similar to IFN-gammablockade, production of secondary CFC was not enhanced by CsA. Administration of CsA to patients resulted in prolonged partial hematologic improvement in 8 of 11 HMDS patients. CONCLUSIONS: Increased frequency of IFN-gamma producing CD4(+) cells supports the involvement of lymphocyte-mediated suppression of hematopoiesis in the development of cytopenia in MDS patients. The ability of CsA to decrease in vitro IFN-gamma production may improve hematopoietic function, explaining the beneficial effect of this agent in HMDS patients.     

Direct,activating interaction between glycogen synthase kinase-3beta and p53 after DNA damage

Glycogen synthase kinase-3beta (GSK3beta) is a central figure in Wnt signaling, in which its activity is controlled by regulatory binding proteins. Here we show that binding proteins outside the Wnt pathway also control the activity of GSK3beta. DNA damage induced by camptothecin, which activates the tumor suppressor p53, was found to activate GSK3beta. This activation occurred by a phosphorylation-independent mechanism involving direct binding of GSK3beta to p53, which was confined to the nucleus where p53 is localized, and mutated p53 (R175H) bound but did not activate GSK3beta. Activation of GSK3 promoted responses to p53 including increases in p21 levels and caspase-3 activity. Thus, after DNA damage there is a direct interaction between p53 and GSK3beta, and these proteins act in concert to regulate cellular responses to DNA damage.     

Scintigraphic assessment of swallow efficiency postlaryngectomy

There have been reports of a high incidence of hypopharyngeal stenosis in total laryngectomy patients when the surgery requires a partial pharyngectomy for pyriform sinus involvement. In this study, three groups were compared: total laryngectomy patients without partial pharyngectomy, total laryngectomy patients with partial pharyngectomy, and normal controls. All patients had received radiation therapy following surgery. All were maintaining oral nutrition, and none complained of dysphagia. Patients were tested between 1 and 7 months postradiation therapy, with a mean of 3 months. Measures of swallowing efficiency were based on scintigraphic data for a liquid swallow. Patients with partial pharyngectomy had abnormally long oropharyngeal transit times and low efficiency scores. For a subgroup of patients with partial pharyngectomy, swallowing data were available postsurgery and postradiation therapy. Postsurgery this patient group did not differ significantly from normal patients in swallowing efficiency, and swallowing efficiency deteriorated in postradiation therapy. This scintigraphic methodology is shown to be a sensitive method of assessing swallowing function in this patient population.     

Circulating soluble tumour necrosis factor receptors in patients with epidermodysplasia verruciformis as compared to patients with cutaneous tumours in the general population

Soluble tumour necrosis factor receptors type I and II (sTNF-RI and II) were evaluated in sera from patients with epidermodysplasia verruciformis and patients with cutaneous warts, actinic keratoses, squamous cell carcinomas or basal cell carcinomas by specific enzyme-linked immunobiological assays. In patients with widespread epidermodysplasia verruciformis lesions, the levels of both sTNF-Rs were in normal range. Both types of sTNF-Rs were significantly increased in patients with warts. The levels of sTNF-RI were significantly increased in patients with multiple actinic keratoses, squamous cell carcinoma and basal cell carcinoma. Increased levels of circulating sTNF-Rs may facilitate development of cutaneous tumours. Normal levels of sTNF-Rs in patients with epidermodysplasia verruciformis might, at least partially, contribute to a slow growth and low metastatic potential of cancers in these patients.