Sensitivity to CPT-11 of xenografted human colorectal cancers as a function of microsatellite instability and p53 status

Biological parameters influencing the response of human colorectal cancers (CRCs) to CPT-11, a topoisomerase 1 (top1) inhibitor, were investigated using a panel of nine CRCs xenografted into nude mice. CRC xenografts differed in their p53 status (wt or mut) and in their microsatellite instability phenotype (MSI+when altered). Five CRC xenografts were established from clinical samples. All five had a functional p53, two were MSI+and three were MSI–. Tumour-bearing nude mice were treated intraperitonealy (i.p.) with CPT-11. At 10 mg kg–1of CPT-11, four injections at 4-day intervals, four of the five xenografts responded to CPT-11 (growth delay of up to 10 days); the non-responder tumour was MSI−. At 40 mg kg−1of CPT-11, six injections at 4-day intervals, the five CRCs displayed variable but marked responses with complete regressions. In order to assess the role of p53 status in CPT-11 response, four CRC lines were used. HT29 cell line was MSI−/ Ala273-mutp53, its subclone HT29A3 being transfected by wtp53. LoVo cell line was MSI+/ wtp53, its subclone X17LoVo dominantly expressed Ala273-mutp53 after transfection. LoVo tumours (MSI+/ mutp53) were more sensitive than X17LoVo (MSI+/ mutp53. HT 29 tumours (MSI−Imutp53), were refractory to CPT-11 while HT29A3 tumours (MSI−/ wtp53) were sensitive, showing that wtp53 improves the drug-response in these MSI−tumours. Levels of mRNA expression of top1, fasR, TP53 and mdr1 were semi-quantified by reverse transcription polymerase chain reaction. None of these parameters correlated with CPT-11 response. Taken together, these observations indicate that MSI and p53 alterations could be associated with different CPT-11 sensitivities; MSI phenotype moderately influences the CPT-11 sensitivity, MSI+being more sensitive than MSI−CRC freshly obtained from patients, mutp53 status being associated with a poor response to CPT-11. © 2000 Cancer Research Campaig

Urban vulnerability and resilience within the context of climate change

Natural hazards, due to climate change, are particularly damaging in urban areas because of interdependencies of their networks. So, urban resilience has to face up to climate risks. The most impacting phenomenon is the urban heat island (UHI) effect. The storage capacity of heat is depending on shapes of buildings, public spaces, spatial organization, transport or even industrial activities. So, adaptive strategies for improving urban climate could be possible in different ways. In the framework of the French project Resilis, this study characterises urban vulnerability and resilience in terms of energy needs of buildings and outside urban comfort according to the IPCC carbon dioxide emission scenarios B2 and A2 for the period 2050–2100 for 10 French cities. The evolutions of four climate indicators in terms of heating and cooling needs and number of hours when the temperature is above 28 °C are then obtained for each city to analyse climate risks and their impacts in urban environment

Fracture incidence after 3 years of aromatase inhibitor therapy

BACKGROUND: The purpose of this study was to describe the fracture incidence and bone mineral density (BMD) evolution in a large cohort of post-menopausal women with breast cancer after 3 years of aromatase inhibitor (AI) therapy. PATIENTS AND METHODS: A prospective, longitudinal study in real-life setting. Each woman had an extensive medical assessment, a biological evaluation, a BMD measurement, and systematic spinal X-rays at baseline and after 3 years of AI therapy. Women with osteoporosis at baseline (T-score < -2.5 and/or non-traumatic fracture history) were treated by oral weekly bisphosphonates. RESULTS: Among 497 women (mean age 63.8 ± 9.6 years) included in this study, 389 had a bone evaluation both at baseline and after 3 years of AI therapy: 267 women (mean age 61.2 ± 8.6) with no osteoporosis at baseline and 122 women (mean age 67.2 ± 9.1) with osteoporosis at baseline justifying a weekly oral bisphosphonate treatment. Women without bisphosphonates had a significant decrease in spine BMD (-3.5%, P < 0.01), neck BMD (-2.0%, P < 0.01), and total hip BMD (-2.1%, P < 0.01) over the 3 years but only 15 of them (5.6%) presented an incident vertebral or non-vertebral fracture. In osteoporotic women treated with bisphosphonates, spine and hip BMD were maintained at 3 years but 12 of them (9.8%) had an incident fracture. These fractured women were significantly older (74.1 ± 9.8 versus 66.5 ± 8.8) but also presented BMD loss during treatment suggesting poor adherence to bisphosphonate treatment. CONCLUSION: This real-life study confirmed that AIs induced moderate bone loss and low fracture incidence in post-menopausal women without initial osteoporosis. In women with baseline osteoporosis and AI therapy, oral bisphosphonates maintain BMD but were associated with a persistent fracture risk, particularly in older women

Impact of 18F-fluoro-deoxy-glucose positron emission tomography (FDG-PET) in recurrent colorectal cancer

Purpose: The aim of the study was to evaluate the diagnostic performance, the prognosis factors and the therapeutic impact of 18F-FDG positron emission tomography (FDG-PET) in the detection of recurrent colorectal cancers. Methods: Sixty PET/CT with 18F-FDG and CT were performed in 52 patients, at the Paul Papin cancer center between 2003 and 2005, following suspicion of colorectal cancer relapse. The FDG-PET impact on the clinical management was studied by examination of multidisciplinary concertations results. Survival analysis were realized with a mean follow up of 2.2 years. Results: Recurrence was confirmed for 50 explorations by histologic (n = 32), radiologic (n = 14) or clinical (n = 4) findings. Twenty patients died during the time of the study. On a patient based analysis, FDG-PET sensitivity, specificity and overall accuracy were 90, 90, 90% respectively compared with 74, 50 and 70% for CT. FDG-PET changed the clinical management in 18 cases (30%). A positive FDG-PET signal, more than one hepatic lesion, more than two lymph node lesions detected on FDG-PET and more than two hepatic lesions on CT were characterized as bad prognostic factors for survival. Multivariate analysis showed that the only independent bad prognostic factor was the FDG-PET detection of more than two liver lesions. Conclusion: These results confirmed the important impact of FDG-PET in the clinical management of patients with a suspected recurrence of colorectal cancer

Safety of the Combination of PERC and YEARS Rules in Patients With Low Clinical Probability of Pulmonary Embolism: A Retrospective Analysis of Two Large European Cohorts

BACKGROUND: This study aimed to determine the failure rate of a combination of the PERC and the YEARS rules for the diagnosis of pulmonary embolism (PE) in the emergency department (ED). METHODS: We performed a retrospective analysis of two European cohorts of emergency patients with low gestalt clinical probability of PE (PROPER and PERCEPIC). All patients we included were managed using a conventional strategy (D-dimer test, followed, if positive, by computed tomographic pulmonary angiogram (CTPA). We tested a diagnostic strategy that combined PERC and YEARS to rule out PE. The primary endpoint was a thromboembolic event diagnosed in the ED or at 3-months follow-up. Secondary endpoints included a thromboembolic event at baseline in the ED and a CTPA in the ED. Ninety-five percent confidence intervals (CIs) of proportions were calculated with the use of Wilson\u27s continuity correction. RESULTS: We analyzed 1,951 patients (mean ± SD age = 47 ± 18 years, 56% women) with an overall proportion of patients with PE of 3.5%. Both PERC and YEARS strategies were associated with 11 missed PE in the ED: failure rate 0.57 (95% CI = 0.32-1.02). At 3-month follow-up, the overall failure rate was 0.83% (95% CI = 0.51-1.35). Among the 503 patients who underwent a CTPA (26%), the use of the PERC-YEARS combination would have ruled out PE without CTPA in 249 patients (50% [95%CI = 45%-54%], absolute reduction 13% (95% CI = 11%-14%]). CONCLUSION: The combination of PERC then YEARS was associated with a low risk of PE diagnostic failure and would have resulted in a relative reduction of almost half of CTPA

Analysis of the Plant bos1 Mutant Highlights Necrosis as an Efficient Defence Mechanism during D. dadantii/Arabidospis thaliana Interaction

Dickeya dadantii is a broad host range phytopathogenic bacterium provoking soft rot disease on many plants including Arabidopsis. We showed that, after D. dadantii infection, the expression of the Arabidopsis BOS1 gene was specifically induced by the production of the bacterial PelB/C pectinases able to degrade pectin. This prompted us to analyze the interaction between the bos1 mutant and D. dadantii. The phenotype of the infected bos1 mutant is complex. Indeed, maceration symptoms occurred more rapidly in the bos1 mutant than in the wild type parent but at a later stage of infection, a necrosis developed around the inoculation site that provoked a halt in the progression of the maceration. This necrosis became systemic and spread throughout the whole plant, a phenotype reminiscent of that observed in some lesion mimic mutants. In accordance with the progression of maceration symptoms, bacterial population began to grow more rapidly in the bos1 mutant than in the wild type plant but, when necrosis appeared in the bos1 mutant, a reduction in bacterial population was observed. From the plant side, this complex interaction between D. dadantii and its host includes an early plant defence response that comprises reactive oxygen species (ROS) production accompanied by the reinforcement of the plant cell wall by protein cross-linking. At later timepoints, another plant defence is raised by the death of the plant cells surrounding the inoculation site. This plant cell death appears to constitute an efficient defence mechanism induced by D. dadantii during Arabidopsis infection

Quasiprojectile breakup and isospin equilibration at Fermi energies: an indication of longer projectile-target contact times?

An investigation of the quasiprojectile breakup channel in semiperipheral and peripheral collisions of $^{58,64}$Ni+$^{58,64}$Ni at 32 and 52 MeV/nucleon is presented. Data have been acquired in the first experimental campaign of the INDRA-FAZIA apparatus in GANIL. The effect of isospin diffusion between projectile and target in the two asymmetric reactions has been highlighted by means of the isospin transport ratio technique, exploiting the neutron-to-proton ratio of the quasiprojectile reconstructed from the two breakup fragments. We found evidence that, for the same reaction centrality, a higher degree of relaxation of the initial isospin imbalance is achieved in the breakup channel with respect to the more populated binary output, possibly indicating the indirect selection of specific dynamical features. We have proposed an interpretation based on different average projectile-target contact times related to the two exit channels under investigation, with a longer interaction for the breakup channel. The time information has been extracted from AMD simulations of the studied systems coupled to GEMINI++: the model calculations support the hypothesis hereby presented

Comparison of Urban Air Quality Simulations During the KORUS‐AQ Campaign With Regionally Refined Versus Global Uniform Grids in the Multi‐Scale Infrastructure for Chemistry and Aerosols (MUSICA) Version 0

Model intercomparison studies often report a large spread in simulation results, but quantifying the causes of these differences is hindered by the fact that several processes contribute to the model spread simultaneously. Here we use the Multi-Scale Infrastructure for Chemistry and Aerosols (MUSICA) version 0 to investigate the model resolution dependencies of simulated chemical species, with a focus on the differences between global uniform grid and regional refinement grid simulations with the same modeling framework. We construct two global (ne30 [∼112 km] and ne60 [∼56 km]) and two regional refinement grids over Korea (ne30x8 [∼14 km] and ne30x16 [∼7 km]). The grid resolution can change chemical concentrations by an order of magnitude in the boundary layer, and the importance increases as the species' reactivity increases (e.g., up to 50% and 1,000% changes for ethane and xylenes, respectively). The diurnal cycle of oxidants (OH, O3, and NO3) also varies with the grid resolution, which leads to different oxidation pathways of volatile organic compounds (e.g., the fraction of monoterpenes reacting with NO3 in Seoul around midnight is 90% for ne30, but 65% for ne30x16). The models with high-resolution grids usually do a better job at reproducing aircraft observations during the KORUS-AQ campaign, but not always, implying compensating errors in the coarse grid simulations. For example, ozone is better reproduced by the coarse grid due to the artificial mixing of NOx. When developing new chemical mechanisms and evaluating models over urban areas, the uncertainties associated with model resolution should be considered. © 2023 The Authors. Journal of Advances in Modeling Earth Systems published by Wiley Periodicals LLC on behalf of American Geophysical Union