Regional inequalities in cancer care persist in Italy and can influence survival

BackgroundPopulation-based cancer registry studies of care patterns can help elucidate reasons for the marked geographic variation in cancer survival across Italy. The article provides a snapshot of the care delivered to cancer patients in Italy.MethodsRandom samples of adult patients with skin melanoma, breast, colon and non-small cell lung cancers diagnosed in 2003–2005 were selected from 14 Italian cancer registries. Logistic models estimated odds of receiving standard care (conservative surgery plus radiotherapy for early breast cancer; surgery plus chemotherapy for Dukes C colon cancer; surgery for lung cancer; sentinel node biopsy for >1 mm melanoma, vs. other treatment) in each registry compared to the entire sample (reference).ResultsStage at diagnosis for breast, colon and melanoma was earlier in north/central than southern registries. Odds of receiving standard care were lower than reference in Sassari (0.68, 95%CI 0.51–0.90) and Napoli (0.48, 95%CI 0.35–0.67) for breast cancer; did not differ across registries for Dukes C colon cancer; were higher in Romagna (3.77, 95%CI 1.67–8.50) and lower in Biella (0.38, 95%CI 0.18–0.82) for lung cancer; and were higher in Reggio Emilia (2.37, 95%CI 1.12–5.02) and lower in Ragusa (0.27, 95%CI 0.14–0.54) for melanoma.ConclusionsNotwithstanding limitations due to variations in the availability of clinical information and differences in stage distribution between north/central and southern registries, our study shows that important disparities in cancer care persist across Italy. Thus the public health priority of reducing cancer survival disparities will not be achieved in the immediate future.     

Pressure drops in a distensible model of end-to-side anastomosis in systemic-to-pulmonary shunts

The modified Blalock-Taussig shunt is a surgical procedure used as a palliation to treat complex congenital heart defects. It consists of an interposing prosthetic tube between the innominate/subclavian artery and the right pulmonary artery. Previous experience indicates that the pressure drop across the shunt is affected by the pulmonary pressure at the distal anastomosis combined with the distensibility of the anastomosis. In this study, a computational fluid-structure interaction approach is presented to investigate the haemodynamic behaviour. Steady-state fluid dynamics and structural analyses were carried out using commercial codes based on the finite element method (FIDAP and ABAQUS) coupled by means of a purposely-developed procedure to transfer boundary conditions. Both prosthetic tube and artery walls were characterised by non-linear material properties. Three different pulmonary pressures (2, 5 and 15 mmHg) and two volume flow rates (0.4 and 0.8 l/min) were investigated. Results indicate that the effects of distensibility at the distal anastomosis on the shunt pressure drop are relevant only when the distal anastomosis on the shunt pressure drop are relevant only when the distal anastomosis is not fully distended, which occurs when the pulmonary pressure is lower than 5 mmHg.     

APC mutation in the alternatively spliced region of exon 9 associated with late onset familial adenomatous polyposis

Germ-line mutations in the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis (FAP). Genotype-phenotype correlation studies in patients with FAP have demonstrated associations of certain variants of the disease with mutations at specific sites within the APC gene. In a large FAP family, we identified a frameshift mutation located in the alternatively spliced region of exon 9. Phenotypic studies of affected family members showed that the clinical course of FAP was delayed, with gastrointestinal symptoms and death from colorectal carcinoma occurring on average 25 and 20 years later than usual, respectively. The numbers of colorectal adenomas differed markedly among affected individuals and the location of colorectal cancer lay frequently in the proximal colon. Our findings suggest that the exon 9 mutation identified in the pedigree is associated with late onset of FAP. The atypical phenotype may be explained by the site of the mutation in the APC gene. Analysis of the APC protein product indicated that the exon 9 mutation did not result in a detectable truncated APC protein. Given the location of the mutation within an alternatively spliced exon of APC, it is conceivable that normal APC proteins are produced from the mutant allele by alternative splicing.     

SAR and biological evaluation of SEN12333/WAY-317538: Novel alpha 7 nicotinic acetylcholine receptor agonist

Alpha 7 nicotinic acetylcholine receptor (α₇ nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment associated with a variety of disorders including Alzheimer’s disease and schizophrenia. Alpha 7 nAChRs are expressed in brain regions associated with cognitive function, regulate cholinergic neurotransmission and have been shown to be down regulated in both schizophrenia and Alzheimer’s disease. Herein we report a novel, potent small molecule agonist of the alpha 7 nAChR, SEN12333/WAY-317538. This compound is a selective agonist of the α₇ nAChR with excellent in vitro and in vivo profiles, excellent brain penetration and oral bioavailability, and demonstrates in vivo efficacy in multiple behavioural cognition models. The SAR and biological evaluation of this series of compounds are discussed.     

Effects of rapid saline infusion on lung mechanics and airway responsiveness in humans.

Lung mechanics and airway responsiveness to methacholine (MCh) were studied in seven volunteers before and after a 20-min intravenous infusion of saline. Data were compared with those of a time point-matched control study. The following parameters were measured: 1-s forced expiratory volume, forced vital capacity, flows at 40% of control forced vital capacity on maximal (Vm(40)) and partial (Vp(40)) forced expiratory maneuvers, lung volumes, lung elastic recoil, lung resistance (Rl), dynamic elastance (Edyn), and within-breath resistance of respiratory system (Rrs). Rl and Edyn were measured during tidal breathing before and for 2 min after a deep inhalation and also at different lung volumes above and below functional residual capacity. Rrs was measured at functional residual capacity and at total lung capacity. Before MCh, saline infusion caused significant decrements of forced expiratory volume in 1 s, Vm(40), and Vp(40), but insignificantly affected lung volumes, elastic recoil, Rl, Edyn, and Rrs at any lung volume. Furthermore, saline infusion was associated with an increased response to MCh, which was not associated with significant changes in the ratio of Vm(40) to Vp(40). In conclusion, mild airflow obstruction and enhanced airway responsiveness were observed after saline, but this was not apparently due to altered elastic properties of the lung or inability of the airways to dilate with deep inhalation. It is speculated that it was likely the result of airway wall edema encroaching on the bronchial lumen.     

Pathogenesis of ER Storage Disorders: Modulating Russell Body Biogenesis by Altering Proximal and Distal Quality Control

In many protein storage diseases, detergent‐insoluble proteins accumulate in the early secretory compartment (ESC). Protein condensation reflects imbalances between entry into (synthesis/translocation) and exit from (secretion/degradation) ESC, and can be also a consequence of altered quality control (QC) mechanisms. Here we exploit the inducible formation of Russell bodies (RB), dilated ESC cisternae containing mutant Ig‐µ chains, as a model to mechanistically dissect protein condensation. Depending on the presence or absence of Ig‐L chains, mutant Ig‐µ chains lacking their first constant domain (Ch 1) accumulate in rough or smooth RB (rRB and sRB), dilations of the endoplasmic reticulum (ER) and ER‐Golgi intermediate compartment (ERGIC), respectively, reflecting the proximal and distal QC stations in the stepwise biogenesis of polymeric IgM. Either weakening ERp44‐dependent distal QC or facilitating ER‐associated degradation (ERAD) inhibits RB formation. Overexpression of PDI or ERp44 inhibits µΔCh 1 secretion. However, PDI inhibits while ERp44 promotes µΔCh 1 condensation. Both Ero1α silencing and overexpression prevent RB formation, demonstrating a strict redox dependency of the phenomenon. Altogether, our findings identify key controllers of protein condensation along the ESC as potential targets to handle certain storage disorders.     

Correlation between Charge Movement and Ionic Current during Slow Inactivation in Shaker K+ Channels

Prolonged depolarization induces a slow inactivation process in some K⁺ channels. We have studied ionic and gating currents during long depolarizations in the mutant Shaker H4-Δ(6–46) K⁺ channel and in the nonconducting mutant (Shaker H4-Δ(6–46)-W434F). These channels lack the amino terminus that confers the fast (N-type) inactivation (Hoshi, T., W.N. Zagotta, and R.W. Aldrich. 1991. Neuron. 7:547–556). Channels were expressed in oocytes and currents were measured with the cut-open-oocyte and patch-clamp techniques. In both clones, the curves describing the voltage dependence of the charge movement were shifted toward more negative potentials when the holding potential was maintained at depolarized potentials. The evidences that this new voltage dependence of the charge movement in the depolarized condition is associated with the process of slow inactivation are the following: (a) the installation of both the slow inactivation of the ionic current and the inactivation of the charge in response to a sustained 1-min depolarization to 0 mV followed the same time course; and (b) the recovery from inactivation of both ionic and gating currents (induced by repolarizations to −90 mV after a 1-min inactivating pulse at 0 mV) also followed a similar time course. Although prolonged depolarizations induce inactivation of the majority of the channels, a small fraction remains non–slow inactivated. The voltage dependence of this fraction of channels remained unaltered, suggesting that their activation pathway was unmodified by prolonged depolarization. The data could be fitted to a sequential model for Shaker K⁺ channels (Bezanilla, F., E. Perozo, and E. Stefani. 1994. Biophys. J. 66:1011–1021), with the addition of a series of parallel nonconducting (inactivated) states that become populated during prolonged depolarization. The data suggest that prolonged depolarization modifies the conformation of the voltage sensor and that this change can be associated with the process of slow inactivation.     

Carbohydrate availability affects growth and metabolism in peach fruit

Along with sucrose, sorbitol represents the main photosynthetic product and form of translocated carbon in peach. This study aimed at determining whether peach fruit carbohydrate metabolism is affected by changes in source–sink balance , and specifically whether sorbitol or sucrose availability regulates fruit enzyme activities and growth. In various trials, different levels of assimilate availability to growing fruits were induced in vivo by varying crop load of entire trees, leaf : fruit ratio (L:F) of fruiting shoots, or by interrupting the phloem stream (girdling) to individual fruits. In vitro, fruit tissue was incubated in presence/absence of sorbitol and sucrose. Relative growth rate (RGR), enzyme activities and carbohydrates were measured at different fruit growth stages of various peach cultivars in different years. At stage III, high crop load induced higher acid invertase (AI, EC 3.2.1.26) activities and hexose : sucrose ratios. Both sorbitol and sucrose contents were proportional to L:F, while sorbitol dehydrogenase (SDH, EC 1.1.1.14) activity was the only enzyme activity directly related to L:F in both fruit growth stages. Girdling reduced fruit RGR and all major carbohydrates after 4 days and SDH activity already after 48 h, but it did not affect sucrose synthase (SS, EC 2.4.1.13), AI and neutral invertase (NI, EC 3.2.1.27). Fruit incubation in sorbitol for 24 h induced higher SDH activities than in buffer alone. In general, assimilate availability affected both sorbitol and sucrose metabolism in peach fruit, and sorbitol may function as a signal for modulating SDH activity. Under highly competitive conditions, AI activity may be enhanced by assimilate depletion, providing a mechanism to increase fruit sink strength by increasing hexose concentrations.     

Biomass and physiological responses of <Emphasis Type="Italic">Quercus robur</Emphasis> (L.) young trees during 2 years of treatments with different levels of ozone and nitrogen wet deposition

Key message

The root biomass of oak young trees significantly decreased after 2 years of exposure to high levels of ozone, but increased nitrogen wet deposition tended to partly contrast this effect.

Abstract

A 2-year Open-Top Chamber (OTC) experiment with young Quercus robur trees that were exposed to different levels of ozone (O₃) and nitrogen deposition was performed in Curno (Northern Italy) for the FP7 Project ÉCLAIRE. The plants were exposed to four levels of ozone (?40 % of ambient ozone in charcoal-filtered OTCs, ?5 % in non-filtered OTCs, and +30 and +75 % in O₃-enriched OTCs) and two levels of nitrogen wet deposition (tap water and tap water +70 kg N ha^?1 year^?1). The stomatal conductance and A/Ci response curves were measured during the two experimental seasons, and in October, the plant dry biomass partition between the roots and stem was assessed. Oak plants were moderately sensitive to O₃. After the second year of treatments, the dose–response relationships based on the O₃ stomatal flux indicated a 4.6 % of root biomass loss and a 12.1 % of reduction of the number of leaves per 10 mmol O₃ m^?2 absorbed by plants grown with no nitrogen addition. Ozone also decreased both the stomatal conductance and the maximum carboxylation rate allowed by Rubisco (V _cmax) during the first year of treatments. However, the effect on V _cmax was lost during the second year, and the plants showed an uncoupling between leaf-level physiological responses and plant-level biomass responses. Increased nitrogen deposition enhanced the growth of plants and partially mitigated the O₃ impact on biomass and physiology, but no significant effect of the interaction between the two factors was found. The data that were collected could contribute to the definition of the O₃ dose–response relationships based on biomass losses for deciduous trees in Southern Europe climatic conditions and could improve the O₃ risk assessment models by providing new information about the effect of increased nitrogen deposition on the ozone impact.