Seminoma arising in corrected and uncorrected inguinal cryptorchidism: treatment and prognosis in 66 patients.

PURPOSE: The purpose of this study was to analyze prognosis and treatment results for seminoma arising in corrected and uncorrected inguinal cryptorchidism (SCIC and SUIC). METHODS AND MATERIALS: We reviewed 66 patients with inguinal seminomas between June 1958 and December 1991 at the Cancer Hospital and Institute of Chinese Academy of Medical Sciences. Of these patients, 23 had prior orchiopexy and 43 presented with an inguinal form of cryptorchidism. At presentation, 17 of 66 (26%) patients had nodal metastases. This nodal involvement was 30% (7 of 23) for SCIC and 23% (10 of 43) for SUIC, respectively. These numbers are comparable with those in a series of patients treated for scrotal seminoma at our institution (26% vs. 20%). However, 3 of 23 (13%) patients who had prior orchiopexy presented with inguinal nodal metastasis as compared with 0 of 43 patients with SUIC or 4 of 237 patients with scrotal seminoma (p < .05). There were 49 stage I, 5 stage IIA, 8 stage IIB, 3 stage III, and 1 stage IV patients. All patients underwent radical orchiectomy and received further radiotherapy, chemotherapy, or both. Patients with stage I and stage II disease were treated primarily with radiotherapy, whereas patients with stage III and IV disease were treated with chemotherapy. RESULTS: The overall and disease-free survival at 5 and 10 years was 94% and 92%, 89% and 87%, respectively. The overall 5- and 10-year survival by stage was 100% and 100% for stage I, and 77% and 68% for stage II, respectively (p < .05). There was no significant difference in survival between SUIC and SCIC (93% vs. 96% at 5 years). Four patients developed relapse. Two of these four patients experienced relapse at the inguinal area, due to a marginal miss. Three of four patients with relapse were successfully salvaged, and one died of disease. CONCLUSION: Our results indicate that prognosis for inguinal seminoma is excellent and similar to that of scrotal seminoma. Postorchiectomy radiotherapy can be considered as the standard treatment for stage I and IIA inguinal seminoma. We recommend routinely including the para-aortic and ipsilateral pelvic nodes.

New prognostic factors and calculators for outcome prediction in patients with recurrent glioblastoma: A pooled analysis of EORTC Brain Tumour Group phase I and II clinical trials.

BACKGROUND: Prognostic models have been developed to predict survival of patients with newly diagnosed glioblastoma (GBM). To improve predictions, models should be updated with information at the recurrence. We performed a pooled analysis of European Organization for Research and Treatment of Cancer (EORTC) trials on recurrent glioblastoma to validate existing clinical prognostic factors, identify new markers, and derive new predictions for overall survival (OS) and progression free survival (PFS).¦METHODS: Data from 300 patients with recurrent GBM recruited in eight phase I or II trials conducted by the EORTC Brain Tumour Group were used to evaluate patient's age, sex, World Health Organisation (WHO) performance status (PS), presence of neurological deficits, disease history, use of steroids or anti-epileptics and disease characteristics to predict PFS and OS. Prognostic calculators were developed in patients initially treated by chemoradiation with temozolomide.¦RESULTS: Poor PS and more than one target lesion had a significant negative prognostic impact for both PFS and OS. Patients with large tumours measured by the maximum diameter of the largest lesion (⩾42mm) and treated with steroids at baseline had shorter OS. Tumours with predominant frontal location had better survival. Age and sex did not show independent prognostic values for PFS or OS.¦CONCLUSIONS: This analysis confirms performance status but not age as a major prognostic factor for PFS and OS in recurrent GBM. Patients with multiple and large lesions have an increased risk of death. With these data prognostic calculators with confidence intervals for both medians and fixed time probabilities of survival were derived.

Multi institutional phase II study of concomitant stereotactic reirradiation and cetuximab for recurrent head and neck cancer.

PURPOSE: Recurrent head and neck cancer is associated to a poor survival prognosis. A high toxicity rate is demonstrated when surgery and/or radiotherapy and/or chemotherapy are combined. Furthermore, the duration of treatment is often not ethically compatible with the expected survival (median survival<1year). Normal tissues tolerance limits the use of reirradiation and stereotactic body radiotherapy (SBRT) could offer precise irradiation while sparing healthy tissues. After completion of a feasibility study, results of a multicentric study (Lille, Nancy & Nice) using SBRT with cetuximab are reported. The aim of the study was to deliver non toxic short course SBRT (2weeks) in order to get the same local control as the one demonstrated with longer protocols. METHODS AND MATERIALS: Patients with inoperable recurrent, or new primary tumor in a previously irradiated area, were included (WHO<3). Reirradiation (RT) dose was 36Gy in six fractions of 6Gy to the 85% isodose line covering 95% of the PTV with 5 injections of concomitant cetuximab (CT). All patients had previous radiotherapy, 85% had previous surgery and 48% previous chemotherapy. RESULTS: Between 11/2007 and 08/2010, 60 were included (46 men and 14 women), 56 received CT+RT, 3 were not treated and 1 received only CT. Median age was 60 (42-87)) and all 56 patients had squamous carcinoma and received concomitant cetuximab. Mean time between previous radiotherapy and the start of SBRT was 38months. Cutaneous toxicity was observed for 41 patients. There was one toxic death from hemorrhage and denutrition. Median follow-up was 11.4months. At 3months, response rate was 58.4% (95% CI: 43.2-72.4%) and disease control rate was 91.7% (95% CI: 80.0-97.7%). The one-year OS rate was 47.5% (95% CI: 30.8-62.4). CONCLUSION: These results suggest that short SBRT with cetuximab is an effective salvage treatment with good response rate in this poor prognosis population with previously irradiated HNC. Treatment is feasible and, with appropriate care to limiting critical structure, acute toxicities are acceptable. This combination may be the reference treatment is this population.

APOBEC3G genetic variants and their influence on the progression to AIDS.

The cytosine deaminase APOBEC3G, in the absence of the human immunodeficiency virus type 1 (HIV-1) accessory gene HIV-1 viral infectivity factor (vif), inhibits viral replication by introducing G-->A hypermutation in the newly synthesized HIV-1 DNA negative strand. We tested the hypothesis that genetic variants of APOBEC3G may modify HIV-1 transmission and disease progression. Single nucleotide polymorphisms were identified in the promoter region (three), introns (two), and exons (two). Genotypes were determined for 3,073 study participants enrolled in six HIV-AIDS prospective cohorts. One codon-changing variant, H186R in exon 4, was polymorphic in African Americans (AA) (f = 37%) and rare in European Americans (f < 3%) or Europeans (f = 5%). For AA, the variant allele 186R was strongly associated with decline in CD4 T cells (CD4 slope on square root scale: -1.86, P = 0.009), The 186R allele was also associated with accelerated progression to AIDS-defining conditions in AA. The in vitro antiviral activity of the 186R enzyme was not inferior to that of the common H186 variant. These studies suggest that there may be a modifying role of variants of APOBEC3G on HIV-1 disease progression that warrants further investigation.

Immunological mechanisms underlying infectious and chronic lung diseases

Le système respiratoire permet l'échange de gaz entre un organisme et son environnement. Pour fonctionner efficacement, il doit lutter contre les infections tout en maintenant une tolérance aux particules inoffensives. Les cytokines sont des petites protéines qui permettent la communication entre les différentes cellules et jouent un rôle important dans la régulation de l'homéostasie et de l'immunité des surfaces pulmonaires. Une production altérée des cytokines sous-tend beaucoup de maladies du système pulmonaire. Ainsi, la compréhension de la biologie fondamentale des cytokines pourrait contribuer à la mise au point de nouveaux traitements. Dans le cadre de cette thèse, nous avons étudié le rôle de deux cytokines, le TSLP (Thymic stromal lymphopoietin) et l'IL-17 (Interleukin 17) dans les réponses immunitaires bénéfiques et nuisibles en utilisant des modèles précliniques de souris des maladies pulmonaires. L'asthme est une maladie qui est caractérisée par la bronchoconstriction réversible, l'inflammation des voies respiratoires inférieures, l'hyperréactivité bronchique et le remodelage tissulaire. Le type d'inflammation affectant les voies respiratoires et la présence ou non d'allergie permettent d'établir les différents types d'asthme. La TSLP est une cytokine qui est principalement exprimée à des niveaux élevés dans les poumons de patients souffrant d'asthme allergique. En conséquence, la majeure partie de la recherche sur la TSLP a mis l'accent sur le rôle joué par celle- ci dans les réponses négatives conduisant au développement de l'asthme allergique. Dans cette thèse, nous montrons que la TSLP joue aussi un rôle bénéfique dans les réponses immunitaires pulmonaires. Nous avons découvert que la TSLP atténue la grippe en augmentant les réponses des lymphocytes T cytotoxiques contre le virus. Nous avons également étudié la fonction de la TSLP dans l'asthme non allergique. Contrairement à l'asthme allergique, nous avons constaté que la TSLP diminue les réponses inflammatoires dans l'asthme non allergique en réglant la production de l'IL-17, une cytokine qui favorise la maladie. Ainsi, nous démontrons les fonctions pleiotropes de la TSLP dans des contextes spécifiques de la maladie. Nos résultats ont des implications importantes pour le développement de thérapies ciblant la TSLP dans l'asthme. Dans la deuxième partie de la thèse, nous avons étudié les mécanismes pathogéniques qui sous-tendent le développement de la broncho-pneumopathie chronique obstructive (BPCO). La BPCO est une maladie chronique le plus largement associée aux fumeurs. Elle est caractérisée par une limitation progressive et irréversible du débit d'air et la destruction de la structure des poumons. L'augmentation globale de l'incidence de la maladie encourage grandement la compréhension des mécanismes pathogéniques et l'identification de nouvelles cibles thérapeutiques. Nous avons découvert que les micro-organismes trouvés dans les voies respiratoires aggravent la maladie en augmentant la production de l'IL-17. L'IL-17 est une cytokine inflammatoire qui est impliquée dans plusieurs maladies pulmonaires chroniques, dont la BPCO. Dans notre modèle animal de la maladie, nous avons neutralisé 1ÌL-17A en utilisant un anticorps spécifique et observé une reprise de la fonction pulmonaire. Dans cette étude, nous avons identifié 2 axes potentiels pour l'intervention thérapeutique contre la BPCO. Cibler les bactéries dans les voies respiratoires soit par l'utilisation d'antibiotiques ou l'utilisation de thérapies à base immunitaire qui antagonisent l'activité spécifiques de l'IL-17. Dans l'avenir, notre laboratoire va collaborer avec des cliniciens pour acquérir des échantillons humains et tester la pertinence de nos résultats dans la maladie humaine. -- L'interaction avec l'environnement extérieur est vitale pour le fonctionnement du système respiratoire. Par conséquent, ce dernier a adopté une multitude de réseaux effecteurs et régulateurs qui permettent de distinguer les particules inhalées comme «dangereuses» ou «inoffensives» et de réagir en conséquence. L'équilibre entre ces réseaux est essentielle pour lutter contre le «danger» déclenché par une infection ou des dommages, et finalement pour le retour à l'homéostasie. Le milieu de cytokine local contribue de manière significative à la mise au point de ces réponses. Ainsi, la caractérisation du rôle des cytokines dans l'état d'équilibre et la maladie a des implications claires pour les interventions thérapeutiques dans les maladies respiratoires aiguës et chroniques. Cette thèse a porté sur le rôle des cytokines, la lymphopoïétine stromale thymique (TSLP) et TIL-17A dans l'élaboration de réponses immunitaires pulmonaires. La TSLP est principalement produite par les cellules épithéliales et peut cibler une myriade de cellules immunitaires. Bien qu'elle ait été montrée être un puissant inducteur des réponses de type Th2, son rôle dans d'autres contextes inflammatoires est relativement inexploré. Dans le premier projet de cette thèse, nous avons découvert une nouvelle fonction de la TSLP dans l'immunité antivirale contre la grippe, une infection virale. Nous avons constaté que la TSLP a réglementé la réponse neutrophile au début de l'infection, en amplifiant l'immunité adaptative spécifique du virus. Mécaniquement, la TSLP a augmenté l'expression de l'IL-15 et du CD70 sur les cellules dendritiques recrutées dans les poumons suite à l'infection et a renforcé leur capacité de stimuler localement les lymphocytes T CD8+ spécifiques du virus. En outre, nous avons étudié la TSLP dans le cadre de divers phénotypes de l'asthme et également démontré l'impact pléiotropique qu'elle a sur les réponses immunitaires pulmonaires. En accord avec les rapports précédents, nous avons constaté que la TSLP a exacerbé l'inflammation atopique médiée par le Th2. En revanche la TSLP a réduit les réponses de l'IL-17A et l'inflammation neutrophile subséquente dans le modèle non atopique, ainsi que l'exacerbation du modèle atopique provoqué par une infection virale. Nos résultats démontrent une dichotomie dans le rôle de la TSLP dans la pathogenèse de l'asthme et soulignent la nécessité d'envisager plusieurs phénotypes d'asthme pour une évaluation approfondie de son potentiel thérapeutique dans cette maladie. Dans la seconde partie de cette thèse, nous avons caractérisé les mécanismes pathogènes qui sous-tendent la broncho-pneumopathie chronique obstructive (BPCO). La BPCO est une maladie hétérogène définie par une diminution progressive de la fonction pulmonaire. Bien que des déclencheurs environnementaux puissent aggraver la maladie, chez les personnes sensibles une maladie établie peut progresser à travers un cercle inflammatoire auto-entretenu. Nous avons cherché à définir les mécanismes sous-jacents à l'aide d'un modèle murin d'inflammation chronique, qui reproduit les caractéristiques pathologiques de la maladie humaine. Puisqu'ont été associés à la BPCO sévère des changements dans le microbiome des voies respiratoires, nous avons supposé que les signaux dérivés de certains microbes pourraient favoriser des voies inflammatoires chroniques de progression de la maladie. Nous avons observé que, en l'absence d un microbiome, la maladie s'est améliorée tel que démontré par une réduction de l'inflammation des voies respiratoires et une amélioration de la fonction pulmonaire. Cela a été lié spécifiquement à une production réduite d'IL-17A, une cytokine qui a été impliquée dans la maladie humaine. De plus la cinétique de production de 1IL- 17A dépendant du microbiote est corrélé à la sévérité de la maladie. Sur la base de ces données, la neutralisation de l'IL-17A a également eu un effet bénéfique sur l'évolution de la maladie. Le rôle significatif de 1TL-17A dans l'aggravation de la maladie a été couplé à sa capacité à engager un dialogue entre les voies inflammatoires innées et adaptatives. Il a influencé le recrutement et le phénotype des neutrophiles et des macrophages, ce qui a eu un impact direct et indirect sur la formation et la fonction des tissus lymphoïdes tertiaires associée à des stades sévères de la maladie. -- The interaction with the external environment is vital for the functioning of the respiratory system. Consequently, it has adopted a multitude of effector and regulatory networks that enable it to distinguish inhaled particles as 'dangerous' or 'innocuous' and respond accordingly. The balance between these networks is crucial to counteract the 'danger' triggered by infection or damage, and ultimately return to homeostasis. The local cytokine milieu contributes significantly to the fine- tuning of these responses. Thus, characterizing the role of cytokines in steady state and disease has clear implications for therapeutic interventions in acute and chronic respiratory disorders. This thesis focused on the role of the cytokines, thymic stromal lymphopoietin (TSLP) and IL-17A in shaping pulmonary immune responses. TSLP is primarily produced by barrier epithelial cells and can target a myriad of immune cells. Although it has been shown to be potent inducer of Th2 type responses, its role in other inflammatory settings is relatively unexplored. In the first project of this thesis, we discovered a novel function of TSLP in antiviral immunity to Influenza A infection. We found that while TSLP regulated the early neutrophilic response to infection, it amplified virus specific adaptive immunity. Mechanistically, TSLP enhanced the expression of IL-15 and CD70 on the lung recruited inflammatory dendritic cells and strengthened their ability to stimulate virus specific CD8+ T cell responses locally. In addition we investigated TSLP in the context of diverse asthma phenotypes and further demonstrated the pleiotropic impact it has on pulmonary immune responses. In concurrence with previous reports we found that TSLP exacerbated Th2 mediated atopic inflammation. In contrast TSLP curtailed IL-17A responses and subsequent neutrophilic inflammation in the non-atopic model as well as virus induced exacerbation of the atopic model. Our findings demonstrate a dichotomy in the role of TSLP in asthma pathogenesis and emphasize the need to consider multiple asthma phenotypes for a thorough evaluation of its therapeutic potential in this disease. In the next part of this thesis we characterized the pathogenic mechanisms underlying chronic obstructive pulmonary disease. COPD is a heterogeneous disease defined by a progressive decline in lung function. Although environmental triggers exacerbate the disease, in susceptible individuals the established disease can progress through a self-sustained inflammatory circle. We sought to delineate the underlying mechanisms by using a murine model of chronic inflammation, which reproduced key pathological features of the human disease. As changes in the airway microbiome have been linked to severe COPD, we speculated that microbial derived signals could facilitate the establishment of chronic inflammatory pathways that favour disease progression. We found that the absence of a microbiota ameliorated disease, exhibited by a reduction in airway inflammation and an improvement in lung function. This was linked specifically to an impaired production of IL-17A, a cytokine that has been implicated in human disease. Moreover the kinetics of microbiota-dependent IL-17A production correlated with the disease severity. Based on these data targeted neutralization of IL-17A also had a beneficiai effect on the disease outcome. The prominent role played by IL-I7A in driving the disease was coupled to its ability in engaging and mediating cross talk between pathogenic innate and adaptive immune pathways. It influenced the recruitment and phenotype of neutrophils and macrophages, as well as impacted upon the formation and function of tertiary lymphoid tissue associated with severe disease. Thus, temporal and spatial changes in cytokine production, their cellular targets and interaction with the local milieu determine the balance between immunity and pathology in the lung. Collectively our findings provide novel mechanistic insights in the complex role played by cytokines in orchestrating pulmonary immune responses and have clear implications for human disease.

Prevalence and diversity of Chlamydiales in Swiss ruminant farms.

Chlamydia and Chlamydia-related bacteria are known to infect various organisms and may cause a wide range of diseases, especially in ruminants. To gain insight into the prevalence of these bacteria in the ruminant environment, we applied a pan-Chlamydiales PCR followed by sequencing to 72 ruminant environmental samples from water, feed bunks and floors. Chlamydiales from four family-level lineages were detected indicating a high biodiversity of Chlamydiales in ruminant farms. Parachlamydiaceae were detected in all three types of environmental samples and was the most abundant family-level taxon (60%). In contrast, only one bacterium from each of the following family-level lineages was identified: Chlamydiaceae, Criblamydiaceae and Simkaniaceae. The observed high prevalence of Parachlamydiaceae in water samples may suggest water as the main source of contamination for ruminants as well as their environment due to spoilage. The absence of reported infections in the investigated ruminant farms might indicate that either detected Chlamydiales are of reduced pathogenicity or infective doses have not been reached.

Twenty years of research into Chlamydia-like organisms: a revolution in our understanding of the biology and pathogenicity of members of the phylum Chlamydiae.

Chlamydiae are obligate intracellular bacteria that share a unique but remarkably conserved biphasic developmental cycle that relies on a eukaryotic host cell for survival. Although the phylum was originally thought to only contain one family, the Chlamydiaceae, a total of nine families are now recognized. These so-called Chlamydia-like organisms (CLOs) are also referred to as 'environmental chlamydiae', as many were initially isolated from environmental sources. However, these organisms are also emerging pathogens, as many, such as Parachlamydia sp., Simkania sp. and Waddlia sp., have been associated with human disease, and others, such as Piscichlamydia sp. and Parilichlamydia sp., have been documented in association with diseases in animals. Their strict intracellular nature and the requirement for cell culture have been a confounding factor in characterizing the biology and pathogenicity of CLOs. Nevertheless, the genomes of seven CLO species have now been sequenced, providing new information on their potential ability to adapt to a wide range of hosts. As new isolation and diagnostic methods advance, we are able to further explore the richness of this phylum with further research likely to help define the true pathogenic potential of the CLOs while also providing insight into the origins of the 'traditional' chlamydiae.

Copy number variations and cognitive phenotypes in unselected populations

IMPORTANCE: The association of copy number variations (CNVs), differing numbers of copies of genetic sequence at locations in the genome, with phenotypes such as intellectual disability has been almost exclusively evaluated using clinically ascertained cohorts. The contribution of these genetic variants to cognitive phenotypes in the general population remains unclear. OBJECTIVE: To investigate the clinical features conferred by CNVs associated with known syndromes in adult carriers without clinical preselection and to assess the genome-wide consequences of rare CNVs (frequency ≤0.05%; size ≥250 kilobase pairs [kb]) on carriers' educational attainment and intellectual disability prevalence in the general population. DESIGN, SETTING, AND PARTICIPANTS: The population biobank of Estonia contains 52,000 participants enrolled from 2002 through 2010. General practitioners examined participants and filled out a questionnaire of health- and lifestyle-related questions, as well as reported diagnoses. Copy number variant analysis was conducted on a random sample of 7877 individuals and genotype-phenotype associations with education and disease traits were evaluated. Our results were replicated on a high-functioning group of 993 Estonians and 3 geographically distinct populations in the United Kingdom, the United States, and Italy. MAIN OUTCOMES AND MEASURES: Phenotypes of genomic disorders in the general population, prevalence of autosomal CNVs, and association of these variants with educational attainment (from less than primary school through scientific degree) and prevalence of intellectual disability. RESULTS: Of the 7877 in the Estonian cohort, we identified 56 carriers of CNVs associated with known syndromes. Their phenotypes, including cognitive and psychiatric problems, epilepsy, neuropathies, obesity, and congenital malformations are similar to those described for carriers of identical rearrangements ascertained in clinical cohorts. A genome-wide evaluation of rare autosomal CNVs (frequency, ≤0.05%; ≥250 kb) identified 831 carriers (10.5%) of the screened general population. Eleven of 216 (5.1%) carriers of a deletion of at least 250 kb (odds ratio [OR], 3.16; 95% CI, 1.51-5.98; P = 1.5e-03) and 6 of 102 (5.9%) carriers of a duplication of at least 1 Mb (OR, 3.67; 95% CI, 1.29-8.54; P = .008) had an intellectual disability compared with 114 of 6819 (1.7%) in the Estonian cohort. The mean education attainment was 3.81 (P = 1.06e-04) among 248 (≥250 kb) deletion carriers and 3.69 (P = 5.024e-05) among 115 duplication carriers (≥1 Mb). Of the deletion carriers, 33.5% did not graduate from high school (OR, 1.48; 95% CI, 1.12-1.95; P = .005) and 39.1% of duplication carriers did not graduate high school (OR, 1.89; 95% CI, 1.27-2.8; P = 1.6e-03). Evidence for an association between rare CNVs and lower educational attainment was supported by analyses of cohorts of adults from Italy and the United States and adolescents from the United Kingdom. CONCLUSIONS AND RELEVANCE: Known pathogenic CNVs in unselected, but assumed to be healthy, adult populations may be associated with unrecognized clinical sequelae. Additionally, individually rare but collectively common intermediate-size CNVs may be negatively associated with educational attainment. Replication of these findings in additional population groups is warranted given the potential implications of this observation for genomics research, clinical care, and public health.

Extensive microRNA-mediated crosstalk between lncRNAs and mRNAs in mouse embryonic stem cells.

Recently, a handful of intergenic long noncoding RNAs (lncRNAs) have been shown to compete with mRNAs for binding to miRNAs and to contribute to development and disease. Beyond these reports, little is yet known of the extent and functional consequences of miRNA-mediated regulation of mRNA levels by lncRNAs. To gain further insight into lncRNA-mRNA miRNA-mediated crosstalk, we reanalyzed transcriptome-wide changes induced by the targeted knockdown of over 100 lncRNA transcripts in mouse embryonic stem cells (mESCs). We predicted that, on average, almost one-fifth of the transcript level changes induced by lncRNAs are dependent on miRNAs that are highly abundant in mESCs. We validated these findings experimentally by temporally profiling transcriptome-wide changes in gene expression following the loss of miRNA biogenesis in mESCs. Following the depletion of miRNAs, we found that >50% of lncRNAs and their miRNA-dependent mRNA targets were up-regulated coordinately, consistent with their interaction being miRNA-mediated. These lncRNAs are preferentially located in the cytoplasm, and the response elements for miRNAs they share with their targets have been preserved in mammals by purifying selection. Lastly, miRNA-dependent mRNA targets of each lncRNA tended to share common biological functions. Post-transcriptional miRNA-mediated crosstalk between lncRNAs and mRNA, in mESCs, is thus surprisingly prevalent, conserved in mammals, and likely to contribute to critical developmental processes.

Gaining momentum: New options and opportunities for the treatment of advanced melanoma.

Before 2011, patients with advanced or metastatic melanoma had a particularly poor long-term prognosis. Since traditional treatments failed to confer a survival benefit, patients were preferentially entered into clinical trials of investigational agents. A greater understanding of the epidemiology and biology of disease has underpinned the development of newer therapies, including six agents that have been approved in the EU, US and/or Japan: a cytotoxic T-lymphocyte antigen-4 inhibitor (ipilimumab), two programmed cell death-1 receptor inhibitors (nivolumab and pembrolizumab), two BRAF inhibitors (vemurafenib and dabrafenib) and a MEK inhibitor (trametinib). The availability of these treatments has greatly improved the outlook for patients with advanced melanoma; however, a major consideration for physicians is now to determine how best to integrate these agents into clinical practice. Therapeutic decisions are complicated by the need to consider patient and disease characteristics, and individual treatment goals, alongside the different efficacy and safety profiles of agents with varying mechanisms of action. Long-term survival, an outcome largely out of reach with traditional systemic therapies, is now a realistic goal, creating the additional need to re-establish how clinical benefit is evaluated. In this review we summarise the current treatment landscape in advanced melanoma and discuss the promise of agents still in development. We also speculate on the future of melanoma treatment and discuss how combination and sequencing approaches may be used to optimise patient care in the future.

Characteristics of non-responders to self-reported questionnaires in a large inflammatory bowel disease cohort study.

BACKGROUND: A major threat to the validity of longitudinal cohort studies is non-response to follow-up, which can lead to erroneous conclusions. The objective of this study was to evaluate the profile of non-responders to self-reported questionnaires in the Swiss inflammatory bowel disease (IBD) Cohort. METHODS: We used data from adult patients enrolled between November 2006 and June 2011. Responders versus non-responders were compared according to socio-demographic, clinical and psychosocial characteristics. Odds ratio for non-response to initial patient questionnaire (IPQ) compared to 1-year follow-up questionnaire (FPQ) were calculated. RESULTS: A total of 1943 patients received IPQ, in which 331 (17%) did not respond. Factors inversely associated with non-response to IPQ were age >50 and female gender (OR = 0.37; p < 0.001 respectively OR = 0.63; p = 0.003) among Crohn's disease (CD) patients, and disease duration >16 years (OR = 0.48; p = 0.025) among patients with ulcerative colitis (UC). FPQ was sent to 1586 patients who had completed the IPQ; 263 (17%) did not respond. Risk factors of non-response to FPQ were mild depression (OR = 2.17; p = 0.003) for CD, and mild anxiety (OR = 1.83; p = 0.024) for UC. Factors inversely associated with non-response to FPQ were: age >30 years, colonic only disease location, higher education and higher IBD-related quality of life for CD, and age >50 years or having a positive social support for UC. CONCLUSIONS: Characteristics of non-responders differed between UC and CD. The risk of non-response to repetitive solicitations (longitudinal versus transversal study) seemed to decrease with age. Assessing non-respondents' characteristics is important to document potential bias in longitudinal studies.

Aspirin plus ticlopidine prevented experimental endocarditis due to Enterococcus faecalis and Streptococcus gallolyticus.

Enterococcus faecalis and Streptococcus gallolyticus cause infective endocarditis (IE), which can originate from the continuous release or translocation of low bacterial numbers into the bloodstream. In this context, IE cannot be prevented with antibiotics. We previously demonstrated that aspirin plus ticlopidine protected rats from IE due to S. gordonii and Staphylococcus aureus. Here we showed that aspirin plus ticlopidine significantly reduced vegetation weight and protected 73 and 64% rats (P < 0.005) from IE due to E. faecalis and S. gallolyticus, respectively. These results further support the potential use of aspirin plus ticlopidine for a global prevention of IE in high-risk patients.

OmpA family proteins and Pmp-like autotransporter: new adhesins of Waddlia chondrophila.

Waddlia chondrophila is a obligate intracellular bacterium belonging to the Chlamydiales order, a clade that also includes the well-known classical Chlamydia responsible for a number of severe human and animal diseases. Waddlia is an emerging pathogen associated with adverse pregnancy outcomes in humans and abortion in ruminants. Adhesion to the host cell is an essential prerequisite for survival of every strict intracellular bacteria and, in classical Chlamydia, this step is partially mediated by polymorphic outer membrane proteins (Pmps), a family of highly diverse autotransporters that represent about 15% of the bacterial coding capacity. Waddlia chondrophila genome however only encodes one putative Pmp-like protein. Using a proteomic approach, we identified several bacterial proteins potentially implicated in the adhesion process and we characterized their expression during the replication cycle of the bacteria. In addition, we demonstrated that the Waddlia Pmp-like autotransporter as well as OmpA2 and OmpA3, two members of the extended Waddlia OmpA protein family, exhibit adhesive properties on epithelial cells. We hypothesize that the large diversity of the OmpA protein family is linked to the wide host range of these bacteria that are able to enter and multiply in various host cells ranging from protozoa to mammalian and fish cells.

DOHaD et information épigénétique - Enjeux sociétaux [DOhaD and epigenetic information: societal challenges].

The concept of the developmental origins of health and disease (DOHaD) alters our understanding of what constitutes "health" or "disease" intended as chronic, non-communicable diseases, which develop over the life course in high income and emerging countries. It implies a change in paradigm forming a basis for prevention policies across the globe. It also impacts psychological, social, economic, ethical and legal sciences. In line with the unanticipated underpinning epigenetic mechanisms are also the social issues (including public policies) that could be produced by the knowledge related to DOHaD that opens a wide field of inquiry. The information unveiled by epigenetics coupled with information on lifestyle including during the development phase, is of unforeseen nature, raising issues of different nature. Therefore it requires specific attention and research, and a specific support by a pluridisciplinary reflection since the very beginning of its production, to anticipate the questions that might be raised in the future.

Implication of different domains of the Leishmania major metacaspase in cell death and autophagy.

Metacaspases (MCAs) are cysteine peptidases expressed in plants, fungi and protozoa, with a caspase-like histidine-cysteine catalytic dyad, but differing from caspases, for example, in their substrate specificity. The role of MCAs is subject to debate: roles in cell cycle control, in cell death or even in cell survival have been suggested. In this study, using a Leishmania major MCA-deficient strain, we showed that L. major MCA (LmjMCA) not only had a role similar to caspases in cell death but also in autophagy and this through different domains. Upon cell death induction by miltefosine or H2O2, LmjMCA is processed, releasing the catalytic domain, which activated substrates via its catalytic dyad His/Cys and a proline-rich C-terminal domain. The C-terminal domain interacted with proteins, notably proteins involved in stress regulation, such as the MAP kinase LmaMPK7 or programmed cell death like the calpain-like cysteine peptidase. We also showed a new role of LmjMCA in autophagy, acting on or upstream of ATG8, involving Lmjmca gene overexpression and interaction of the C-terminal domain of LmjMCA with itself and other proteins. These results allowed us to propose two models, showing the role of LmjMCA in the cell death and also in the autophagy pathway, implicating different protein domains.