Node-negative T1-T2 anal cancer: radiotherapy alone or concomitant chemoradiotherapy?

PURPOSE: To evaluate the influence of concomitant chemotherapy on loco-regional control (LRC) and cancer-specific survival (CSS) in patients with T1-T2 N0 M0 anal cancer treated conservatively by primary radiotherapy (RT). MATERIALS AND METHODS: Between 1976 and 2008, 146 patients with T1 (n=29) or T2 (n=117) N0 M0 anal cancer were treated curatively by RT alone (n=71) or by combined chemoradiotherapy (CRT) (n=75) consisting of mitomycin C±5-fluorouracil. Univariate and multivariate analyses were performed to assess patient-, tumor- and treatment-related factors influencing LRC and CSS. RESULTS: With a median follow-up of 62.5 months (interquartilerange, 26-113 months), 122 (84%) patients were locally controlled. The five-year actuarial LRC, CSS and overall survival for the population were 81.4%±3.6%, 91.9%±2.6%, and 75.4%±3.9%, respectively. The five-year LRC and CSS for patients treated with RT alone and with CRT were 75.5%±6.0% vs. 86.8%±4.1% (p=0.155) and 88.5%±4.5% vs. 94.9%±2.9% (p=0.161), respectively. In the multivariate analysis, no clinical or therapeutic factors were found to significantly influence the LRC and CSS, while the addition of chemotherapy was of borderline significance (p=0.065 and p=0.107, respectively). CONCLUSIONS: In the management of node negative T1-T2 anal cancer, LRC and CSS tend to be superior in patients treated by combined CRT, even though the difference was not significant. Randomized studies are warranted to assess definitively the role of combined treatment in early-stage anal carcinoma.

Experimental evidence that adult antipredator behaviour is heritable and not influenced by behavioural copying in a wild bird.

Knowledge of the relative importance of genetics and behavioural copying is crucial to appraise the evolvability of behavioural consistencies. Yet, genetic and non-genetic factors are often deeply intertwined, and experiments are required to address this issue. We investigated the sources of variation of adult antipredator behaviour in the Alpine swift (Apus melba) by making use of long-term behavioural observations on parents and cross-fostered offspring. By applying an 'animal model' approach to observational data, we show that antipredator behaviour of adult Alpine swifts was significantly repeatable over lifetime (r = 0.273) and heritable (h(2) = 0.146). Regression models also show that antipredator behaviours differed between colonies and sexes (females were more tame), and varied with the hour and year of capture. By applying a parent-offspring regression approach to 59 offspring that were exchanged as eggs or hatchlings between pairs of nests, we demonstrate that offspring behaved like their biological parents rather than like their foster parents when they were adults themselves. Those findings provide strong evidence that antipredator behaviour of adult Alpine swifts is shaped by genetics and/or pre-hatching maternal effects taking place at conception but not by behavioural copying.

Covariation between plumage colour polymorphism and diet in the Barn Owl Tyto alba

Several hypotheses might explain the evolution and maintenance of colour morphs within animal populations. The 'alternative foraging strategy' hypothesis states that alternative colour morphs exploit different ecological niches. This hypothesis predicts that morphs differ in diet, either because foraging success on alternative prey species is morph-dependent or because differently coloured individuals exploit alternative habitats. I examined this prediction in the Barn Owl Tyto alba, a bird that varies in plumage coloration continuously from dark reddish-brown to white. On the European continent, Owls are light-coloured (subspecies T. a. alba) in the south and reddish-brown (T. a. guttata) in the north; in central Europe the two subspecies interbreed, generating many colour variants. If plumage coloration indicates alternative foraging strategies, in sympatry dark- and light-coloured owls should consume prey species that are typical of the diets of T. a. guttata and T. a. alba in allopatry, respectively. In line with this prediction, both in allopatry and in sympatry in Switzerland T. a. guttata fed primarily upon Common Voles Microtus arvalis and T. a. alba upon Wood Mice Apodemus spp. Statistical analyses suggest that morph-dependent diet did not arise from a non-random habitat distribution of owls with respect to plumage coloration. This suggests that foraging success upon alternative prey is morph-dependent.

Age over 40 years increases the failure rate of non-operative management of blunt splenic injuries

Objective: Non-operative management (NOM) of blunt splenic injuries (BSI) is nowadays considered the standard treatment. The study aimed to determine the criteria applied for NOM and to identify risk factors for its failure. Methods: Review of all adult patients with BSI treated at the University Hospital Bern, Switzerland, between 2000 and 2008. Results: There were 206 patients (146 men, 70·9%) with a mean age of 38·2 ± 19·1 years and an Injury Severity Score of 30·9 ± 11·6. The American Association for the Surgery of Trauma classification of the splenic injury was: grade I, n=43 (20·9%); grade II, n=52 (25·2%); grade III, n=60 (29·1%); grade IV, n=42 (20·4%) and grade V, n=9 (4·4%). 47 patients (22·8%) required immediate surgery. Five or more units of red cell transfusions (P<0·001), Glasgow Coma Scale<11 (P=0·009) and age ≥55 years (P=0·038) were associated with primary operative management (OM). 159 patients (77·2%) qualified for NOM, which was successful in 89·9% (143/159). The overall splenic salvage rate was 69·4% (143/206). Multivariate analysis found age ≥40 years to be the only factor independently related to the failure of NOM (P=0·001). Conclusion: Advanced age is associated with an increased failure rate ofNOM in patients with BSI.

Shifts in species and phylogenetic diversity between sapling and tree communities indicate negative density dependence in a lowland rain forest

1. As trees in a given cohort progress through ontogeny, many individuals die. This risk of mortality is unevenly distributed across species because of many processes such as habitat filtering, interspecific competition and negative density dependence. Here, we predict and test the patterns that such ecological processes should inscribe on both species and phylogenetic diversity as plants recruit from saplings to the canopy. 2. We compared species and phylogenetic diversity of sapling and tree communities at two sites in French Guiana. We surveyed 2084 adult trees in four 1-ha tree plots and 943 saplings in sixteen 16-m2 subplots nested within the tree plots. Species diversity was measured using Fisher's alpha (species richness) and Simpson's index (species evenness). Phylogenetic diversity was measured using Faith's phylogenetic diversity (phylogenetic richness) and Rao's quadratic entropy index (phylogenetic evenness). The phylogenetic diversity indices were inferred using four phylogenetic hypotheses: two based on rbcLa plastid DNA sequences obtained from the inventoried individuals with different branch lengths, a global phylogeny available from the Angiosperm Phylogeny Group, and a combination of both. 3. Taxonomic identification of the saplings was performed by combining morphological and DNA barcoding techniques using three plant DNA barcodes (psbA-trnH, rpoC1 and rbcLa). DNA barcoding enabled us to increase species assignment and to assign unidentified saplings to molecular operational taxonomic units. 4. Species richness was similar between saplings and trees, but in about half of our comparisons, species evenness was higher in trees than in saplings. This suggests that negative density dependence plays an important role during the sapling-to-tree transition. 5. Phylogenetic richness increased between saplings and trees in about half of the comparisons. Phylogenetic evenness increased significantly between saplings and trees in a few cases (4 out of 16) and only with the most resolved phylogeny. These results suggest that negative density dependence operates largely independently of the phylogenetic structure of communities. 6. Synthesis. By contrasting species richness and evenness across size classes, we suggest that negative density dependence drives shifts in composition during the sapling-to-tree transition. In addition, we found little evidence for a change in phylogenetic diversity across age classes, suggesting that the observed patterns are not phylogenetically constrained.

Low density lipoprotein signaling and pancreatic beta cells protection

SummaryLow-density lipoproteins (LDLs) have an important physiological role in organism transporting cholesterol and other fatty substances to target tissues. However, elevated LDL levels in the blood are associated with the formation of arterial plaques and consequently atherosclerosis. It is therefore important to characterize the intracellular pathways induced upon LDL stimulation as they might be involved in the pathological properties of these lipoproteins. It has been previously found that LDL stimulation of mouse embryonic fibroblasts activates p38 mitogen activated protein kinases (MAPKs). This leads to cell spreading and increase in the wound healing capabilities of the cells. These two responses might occur within atherosclerotic plaques.The aim of this project is to reveal the missing links between LDL particle and activation of p38 MAPK kinase. As previously shown in our lab activation of p38 MAPK kinase by the LDL particles occur independently of classical LDL receptor (LDLR). In this study we have shown that scavenger receptor type Β class I (SR-BI) is responsible for the signal transduction from the LDLs to the p38 MAPK. We have also shown that Mitogen activated kinase kinases (MKKs) that can directly activate ρ 38 MAPK in these conditions are MKK3 and MKK6 but not MKK4. We have also tested some of the intermediate components of the pathway like Ras and PI3 kinase but found that they do not play a role.The data obtained in this study showed a part of molecular mechanism responsible for p38 MAPK activation and subsequent wound healing and can contribute to our knowledge on function of the fibroblasts in the development of the atherosclerotic plaques.Diabetes Mellitus is a condition caused by disordered metabolism of blood glucose level. It is one of the most commonly spread disease in the western world, with the incidence reaching 8% of population in United States. Two most common types of diabetes are type 1 and 2 that differs slightly in the mechanism of the development. However in the basis of both types lies the cell death of pancreatic beta cells. The aim of this work is to improve beta cells survival in different pathophysiological settings. This could be extrapolated to the conditions in which Diabetes develops in humans. We decided to use RasGAP- derived fragment Ν with its strong antiapoptotic effect in beta cells. In our lab we have demonstrated that in the mild stress conditions RasGAP can be cleaved by caspases at the position 455 producing two fragments, fragment Ν and fragment C. Fragment Ν exerts

Are patterns of bone loss in anorexic and postmenopausal women similar? Preliminary results using high resolution peripheral computed tomography.

This study intended to compare bone density and architecture in three groups of women: young women with anorexia nervosa (AN), an age-matched control group of young women, and healthy late postmenopausal women. Three-dimensional peripheral quantitative high resolution computed-tomography (HR-pQCT) at the ultradistal radius, a technology providing measures of cortical and trabecular bone density and microarchitecture, was performed in the three cohorts. Thirty-six women with AN aged 18-30years (mean duration of AN: 5.8years), 83 healthy late postmenopausal women aged 70-81 as well as 30 age-matched healthy young women were assessed. The overall cortical and trabecular bone density (D100), the absolute thickness of the cortical bone (CTh), and the absolute number of trabecules per area (TbN) were significantly lower in AN patients compared with healthy young women. The absolute number of trabecules per area (TbN) in AN and postmenopausal women was similar, but significantly lower than in healthy young women. The comparison between AN patients and post-menopausal women is of interest because the latter reach bone peak mass around the middle of the fertile age span whereas the former usually lose bone before reaching optimal bone density and structure. This study shows that bone mineral density and bone compacta thickness in AN are lower than those in controls but still higher than those in postmenopause. Bone compacta density in AN is similar as in controls. However, bone inner structure in AN is degraded to a similar extent as in postmenopause. This last finding is particularly troubling.

Délire temporel systématisé et trouble auditif d'origine corticale [Systematized temporal delusion and hearing disorders of cortical origin].

We report a case of delusion characterized by a time disorientation with a constant three days advance. Five years previously, the patient had suffered a left hemisphere stroke with aphasia. The delusional belief appeared at the same time as a cortical deafness following a second right hemisphere infarction. There was severe behaviour disturbances which lasted seven months, then cleared without any other change in the clinical picture. The lesions involved the left parietal lobe as well as the temporal and insular regions of both hemispheres.

Survival after lung metastasectomy in colorectal cancer patients with previously resected liver metastases.

BACKGROUND: Resection of hepatic metastases is indicated in selected stage IV colorectal cancer (CRC) patients. A minority will eventually develop pulmonary metastases and may undergo lung surgery with curative intent. The aims of the present study were to assess clinical outcome and identify parameters predicting survival after pulmonary metastasectomy in patients who underwent prior resection of hepatic CRC metastases.¦METHODS: We performed a retrospective analysis of 27 consecutive patients (median age 62 years; range: 33-75 years) who underwent resection of pulmonary metastases after previous hepatic metastasectomy from CRC in two institutions from 1996 to 2009. All patients underwent complete resection (R0) for both colorectal and hepatic metastases.¦RESULTS: Median follow-up was 32 months (range: 3-69 months) after resection of lung metastases and 65 months (range: 19-146 months) after resection of primary CRC. Three- and 5-year overall survival rates after lung surgery were 56 and 39%, respectively, and median survival was 46 months (95% CI 35-57). Median disease-free survival after pulmonary metastasectomy was 13 months (95% CI 5-21). At the time of last follow-up, seven patients (26%) had no evidence of recurrent disease and 6 of these 7 patients presented initially with a single lung metastasis.¦CONCLUSIONS: Resection of lung metastases from CRC patients may result in prolonged survival, even after previous hepatic metastasectomy. Yet, prolonged disease-free survival remains the exception, and seems to occur only in patients with a single lung lesion.

Examining the Agreement of Structural Loss Measured With Heidelberg Retinal Tomograhy and Functional Loss With Standard Automated Perimetry (SAP; Octopus), Pulsar Perimetry (PP), and Moorfields Motion Displacement Test (MDT) Perimetry

Purpose: To examine the relationship of functional measurements with structural measures. Methods: 146 eyes of 83 test subjects underwent Heidelberg Retinal Tomography (HRTIII) (disc area<2.43, mphsd<40), and perimetry testing with Octopus (SAP; Dynamic), Pulsar (PP; TOP) and Moorfields MDT (ESTA). Glaucoma was defined as progressive structural or functional loss (20 eyes). Perimetry test points were grouped into 6 sectors based on the estimated optic nerve head angle into which the associated nerve fiber bundle enters (Garway-Heath map). Perimetry summary measures (PSM) (MD SAP/ MD PP/ PTD MDT) were calculated from the average total deviation of each measured threshold from the normal for each sector. We calculated the 95% significance level of the sectorial PSM from the respective normative data. We calculated the percentage agreement with group1 (G1), healthy on HRT and within normal perimetric limits, and group 2 (G2), abnormal on HRT and outside normal perimetric limits. We also examined the relationship of PSM and rim area (RA) in those sectors classified as abnormal by MRA (Moorfields Regression Analysis) of HRT. Results: The mean age was 65 (range= [37, 89]). The global sensitivity versus specificity of each instrument in detecting glaucomatous eyes was: MDT 80% vs. 88%, SAP 80% vs. 80%, PP 70% vs. 89% and HRT 80% vs. 79%. Highest percentage agreement of HRT (respectively G1, G2, sector) with PSM were MDT (89%, 57%, nasal superior), SAP (83%, 74%, temporal superior), PP (74%, 63%, nasal superior). Globally percentage agreement (respectively G1, G2) was MDT (92%, 28%), SAP (87%, 40%) and PP (77%, 49%). Linear regression showed there was no significant trend globally associating RA and PSM. However, sectorally the supero-nasal sector had a statistically significant (p<0.001) trend with each instrument, the associated r2 coefficients are (MDT 0.38 SAP 0.56 and PP 0.39). Conclusions: There were no significant differences in global sensitivity or specificity between instruments. Structure-function relationships varied significantly between instruments and were consistently strongest supero-nasally. Further studies are required to investigate these relationships in detail.

Surgical site infections in colon surgery: the patient, the procedure, the hospital, and the surgeon.

Objective: To determine the role of the surgeon in the occurrence of surgical site infection (SSI) following colon surgery, with respect to his or her adherence to guidelines and his or her experience.Design, Setting, and Patients: Prospective cohort study of 2393 patients who underwent colon surgery performed by 31 surgeons in 9 secondary and tertiary care public Swiss hospitals, recruited from a surveillance program for SSI between March 1, 1998, and December 31, 2008, and followed up for 1 month after their operation.Main Outcome Measures: Risk factors for SSI were identified in univariate and multivariate analyses that included the patients' and procedures' characteristics, the hospitals, and the surgeons as candidate covariates. Correlations were sought between surgeons' individual adjusted risks, their self-reported adherence to guidelines, and the delay since their board certification.Results: A total of 428 SSIs (17.9%) were identified, with hospital rates varying from 4.0% to 25.2% and individual surgeon rates varying from 3.7% to 36.1%. Features of the patients and procedures associated with SSI in univariate analyses were male sex, age, American Society of Anesthesiologists score, contamination class, operation duration, and emergency procedure. Correctly timed antibiotic prophylaxis and laparoscopic approach were protective. Multivariate analyses adjusting for these features and for the hospitals found 4 surgeons with higher risk of SSI (odds ratio [OR] = 2.37, 95% confidence interval [CI], 1.51-3.70; OR = 2.19, 95% CI, 1.41-3.39; OR = 2.15, 95% CI, 1.02-4.53; and OR = 1.97, 95% CI, 1.18-3.30) and 2 surgeons with lower risk of SSI (OR = 0.43, 95% CI, 0.19-0.94; and OR = 0.19, 95% CI, 0.04-0.81). No correlation was found between surgeons' individual adjusted risks and their adherence to guidelines or their experience.Conclusion: For reasons beyond adherence to guidelines or experience, the surgeon may constitute an independent risk factor for SSI after colon surgery.

GENETIC AND BIOCHEMICAL ANALYSIS OF THE TESTIS-SPECIFIC ZINC FINGER PROTEIN CTCFL/BORIS

Abstract en FrançaisCTCFL a d'abord été identifié comme un paralogue de la protéine ubiquitaire CTCF en raison de sa forte homologie entre leurs onze « zinc fingers », un domaine de liaison à l'ADN. Parmi ses nombreux rôles, la liaison des zinc fingers de CTCF à la région de contrôle de l'empreinte (ICR) maternelle non-méthylée Igf2/H19, contrôle l'expression empreinte (monoallélique) de H19 et IGF2 dans les cellules somatiques. La méthylation de l'ICR Igf2/H19 paternelle est nécessaire à l'expression empreinte de ces deux gènes. Bien que le mécanisme par lequel l'ICR est méthylé soit mal compris, il est connu que l'établissement de la méthylation se produit pendant le développement des cellules germinales mâles et que les ADN méthyltransférases de novo DNMT3A et DNMT3L sont essentiels. Par conséquent, CTCFL fournit un bon candidat pour un rôle dans la méthylation de l'ICR paternelle Igf2/H19 en raison de son expression restreinte à certains types de cellules où la méthylation de l'ICR a lieu (spermatogonies et spermatocytes) ainsi qu'en raison sa capacité à lier les ICR lgf2/HÎ9 dans ces cellules. Les premiers travaux expérimentaux de cette thèse portent sur le rôle possible des mutations de CTCFL chez les patients atteints du syndrome de Silver-Russell (SRS), où une diminution de la méthylation de l'ICR IGF2/H19 a été observée chez 60% d'entre eux. Admettant que CTCFL pourrait être muté chez ces patients, j'ai examiné les mutations possibles de CTCFL chez 35 d'entre eux par séquençage de l'ADN et analyse du nombre de copies d'exons. N'ayant trouvé aucune mutation chez ces patients, cela suggère que les mutations de CTCFL ne sont pas associées au SRS. Les travaux expérimentaux suivants ont porté sur les modifications post-traductionnelles de CTCFL par la protéine SU MO « small ubiquitin-like modifier » (SUMO). La modification de protéines par SU MO change les interactions avec d'autres molécules (ADN ou protéines). Comme CTCFL régule sans doute l'expression d'un certain nombre de gènes dans le cancer et que plusieurs facteurs de transcription sont régulés par SUMO, j'ai mené des expériences pour déterminer si CTCFL est sumoylé. En effet, j'ai observé que CTCFL est sumoylated in vitro et in vivo et j'ai déterminé les deux résidus d'attachement de SUMO aux lysines 181 et 645. Utilisant les mutants de CTCFL K181R et K645R ne pouvant pas être sumoylated, j'ai évalué les conséquences fonctionnelles de la modification par SUMO. Je n'ai trouvé aucun changement significatif dans la localisation subcellulaire, la demi-vie ou la liaison à l'ADN, mais ai constaté que la sumoylation module à la fois {'activation CTCFL-dépendante et la répression de l'expression génique. Il s'agit de la première modification post-traductionnelle décrite pour CTCFL et les conséquences possibles de cette modification sont discutées pour le cancer et les testicules normaux. Avec cette thèse, j'espère avoir ajouté des résultats importants à l'étude de CTCFL et donné quelques idées pour de futures recherches.AbstractJeremiah Bernier-Latmani, Institute of Pathology, University of Lausanne, CHUVCTCFL was first identified as a paralog of the ubiquitous protein CTCF because of high homology between their respective eleven zinc fingers, a DNA binding domain. Among its many roles, CTCF zinc finger-mediated binding to the unmethylated maternal Igf2/H19 imprinting control region (ICR), controls the imprinted (monoallelic) expression of Igf2 and H19 in somatic cells. Methylation of the paternal Igf2/H19 ICR is necessary for the imprinted expression of the two genes. Although the mechanism by which the ICR is methylated is incompletely understood, it is known that establishment of methylation occurs during male germ cell development and the de novo DNA methyltransferases DNMT3A and DNMT3L are essential. Therefore, CTCFL provided a good candidate to play a role in methylation of the paternal Igf2/H19 ICR because of its restricted expression to cell types where ICR methylation takes place (spermatogonia and spermatocytes) and its ability to bind the Igf2/H19 ICR in these cells. The first experimental work of this thesis investigated the possible role of CTCFL mutations in Silver-Russell syndrome (SRS) patients, where it has been observed that 60% of the patients have reduced methylation of the IGF2/HÎ9 ICR. Reasoning that CTCFL could be mutated in these patients, I screened 35 patients for mutations in CTCFL by DNA sequencing and exon copy number analysis, I did not find any mutations in these patients suggesting that mutations of CTCFL are not associated with SRS. The next experimental work of my thesis focused on posttranslational modification of CTCFL by small ubiquitin-like modifier (SUMO) protein. SUMO modification of proteins changes the interactions with other molecules (DNA or protein). As CTCFL arguably regulates the expression of a number of genes in cancer and many transcription factors are regulated by SUMO, I conducted experiments to assess whether CTCFL is sumoylated. I found that CTCFL is sumoylated in vitro and in vivo and determined the two residues of SUMO attachment to be lysines 181 and 645. Using K181R, K645R mutated CTCFL- which cannot be detected to be sumoylated-1 assessed the functional consequences of SUMO modification. I found no significant changes in subcellular localization, half-life or DNA binding, but found that sumoylation modulates both CTCFL-dependent activation and repression of gene expression. This is the first posttranslational modification described for CTCFL and possible consequences of this modification are discussed in both cancer and normal testis. With this thesis, I hope I have added important findings to the study of CTCFL and provide some ideas for future research.