PTX3 Polymorphisms and Invasive Mold Infections After Solid Organ Transplant.

Donor PTX3 polymorphisms were shown to influence the risk of invasive aspergillosis among hematopoietic stem cell transplant recipients. Here, we show that PTX3 polymorphisms are independent risk factors for invasive mold infections among 1101 solid organ transplant recipients, thereby strengthening their role in mold infection pathogenesis and patients' risk stratification.

Discovery-dominance trade-off among widespread invasive ant species

Ants are among the most problematic invasive species. They displace numerous native species, alter ecosystem processes, and can have negative impacts on agriculture and human health. In part, their success might stem from a departure from the discovery-dominance trade-off that can promote co-existence in native ant communities, that is, invasive ants are thought to be at the same time behaviorally dominant and faster discoverers of resources, compared to native species. However, it has not yet been tested whether similar asymmetries in behavioral dominance, exploration, and recruitment abilities also exist among invasive species. Here, we establish a dominance hierarchy among four of the most problematic invasive ants (Linepithema humile, Lasius neglectus, Wasmannia auropunctata, Pheidole megacephala) that may be able to arrive and establish in the same areas in the future. To assess behavioral dominance, we used confrontation experiments, testing the aggressiveness in individual and group interactions between all species pairs. In addition, to compare discovery efficiency, we tested the species' capacity to locate a food resource in a maze, and the capacity to recruit nestmates to exploit a food resource. The four species differed greatly in their capacity to discover resources and to recruit nestmates and to dominate the other species. Our results are consistent with a discovery-dominance trade-off. The species that showed the highest level of interspecific aggressiveness and dominance during dyadic interactions.

Development of novel immunotherapies against bladder cancer

Le cancer de la vessie est le deuxième cancer urologique le plus fréquent dans le monde. La plupart des patients (75%) sont initialement diagnostiqués avec un cancer non musculo- invasif. Après résection trans-urétrale, ie traitement standard pour ce type de lésion chez les patients présentant un risque important de récidive/progression consiste en une série d'instillations intravésicales du Bacille de Calmette-Guerin (i.e. le vaccin BCG). Cependant cette "BCG thérapie" est associée à des effets secondaires non négligeables et s'avère inefficace dans 30% des cas, des limitations donc importantes qui soulignent la nécessité de développer des stratégies thérapeutiques alternatives. L'utilisation d'antigènes associés aux tumeurs (TAA) comme vaccin, combinée à une application locale d'immunostimulants sur le site tumoral, est une approche prometteuse en vue de maximiser les réponses immunitaires anti-tumorales localement. Nous montrons que la bactérie vivante atténuée Ty21a, issue du vaccin Vivotif® contre la fièvre typhoïde, peut être utilisée comme immunostimulant intravésical (IVES), mais ce uniquement dans le cas où la bactérie est en phase exponentielle de croissance (Vivotif exp). En effet, l'instillation IVES de Vivotif exp à la suite d'une vaccination par un TAA, un antigène mineur d'histocompatibilité mâle H-Y (Uty), permet d'augmenter de 15 fois le nombre de cellules T CD8 totales et spécifiques de l'antigène dans la vessie. Le recrutement des cellules T est TLR4-dépendent, ce qui suggère un rôle des lipopolysaccharides du Vivotif exp. Par ailleurs, en comparaison avec le contenu bactérien de la capsule de Vivotif, les bactéries en phase exponentielle de croissance permettent également une augmentation préférentielle des chemokines C5/C5a, CXCL1, CXCL2 et CXCL5 dans la vessie, mais pas du nombre de cellules T exprimant les récepteurs apparentés (C5aR et CXCR2). De plus, combiner la vaccination Uty avec le Vivotif exp en IVES permet d'améliorer la survie des souris présentant une tumeur orthotopique de la vessie exprimant l'antigène Uty (lignée tumorale murine MB49). Puisque pour certains cancers, aucun TAA - du moins exprimé à tous les stades tumoraux - n'est identifié, il est nécessaire de développer d'autres approches non vaccinales. Dans une deuxième partie de ce travail de thèse, nous avons donc investigué deux stratégies permettant d'induire une destruction des cellules tumorales, la thérapie génique par gène de suicide, d'une part, et la thérapie photodynamique dans le proche infrarouge (NIR-PDT), d'autre part. Pour appliquer ces thérapies, nous avons utilisé comme vecteur sûr et non toxique une forme non réplicative du virus du « Human Papillomavirus » (HPV) capable de "pseudo-infecter" préférentiellement les souris présentant des tumeurs vésicales (MB49). L'utilisation de pseudovirions (PsV) HPV portant comme gène suicide la thymidine kinase, une enzyme du virus de l'herpès simplex, suivi d'un traitement par la prodrogue Ganciclovir, permet de tuer 90% des cellules MB49 in-vitro ainsi que de ralentir significativement le développement des tumeurs vésicales in-vivo. Par ailleurs, l'emploi de particules pseudo- virales HPV couplées à la phtalocyanine IR700, un pigment photosensible présentant un pouvoir cytotoxique une fois activé, permet de tuer, après application d'une lumière dans le proche infrarouge, quasi 100% des cellules MB49 in-vitro et, plus important, de régresser des tumeurs in-vivo. De façon générale, ce travail de thèse présente des approches thérapeutiques innovantes et prometteuses pour le traitement des patients avec un cancer non musculo-invasif de la vessie. -- Bladder cancer is the second most common urological malignancy in the world. At initial diagnosis, non-muscle invasive bladder cancer (NMIBC) accounts for 75% of bladder cancer. The standard of care of NMIBC consists of intravesical (IVES) treatments with Bacillus- Calmette-Guerin (BCG) following transurethral resections of the lesions. However, repeated BCG treatments are associated with significant side effects and treatment failure may occur in 30% of the cases, underlying the necessity of alternative therapeutic strategies. The use of tumor-associated antigens (TAA) as vaccines followed by the local application of immunostimulants where the tumor resides is a promising approach to increase anti-tumor immune responses locally. We show that live attenuated Ty21a bacteria used from the vivotif® vaccine against typhoid fever can efficiently be used as IVES immunostimulant, only if bacteria are grown to exponential phase (Vivotif exp). In this condition, IVES immunostimulation after TAA vaccination with a minor histocompatibility male antigen HY (Uty) resulted in more than 15-fold increase of both vaccine-specific and total CD8-T cells in the bladder. T cell recruitment was mediated by TLR-4 suggesting that it was mainly mediated by lipopolysaccharides of Vivotif exp. In addition, these bacteria, as compared to the bacterial content of the vivotif capsule preferentially increased C5/C5a, CXCL1, CXCL2 and CXCL5 chemokines, but not the numbers of T cells expressing the cognate receptors (C5aR and CXCR2). Combination of IVES Vivotif exp with Uty vaccination improved survival of mice with pre-established orthotopic Uty-expressing MB49 murine bladder tumors, as compared to vaccination alone. As known TAA are not identified in all cancers, or not expressed in all stages of the tumor, we further investigated two potent approaches able of initiating tumor-cell destruction, suicide-gene therapy and near-infrared (NIR) photodynamic therapy (PDT). Towards a safe and non-toxic application of these therapies, we used Human Papillomavirus (HPV) replication-defective vectors that were able to preferentially pseudo-infect MB49-tumor bearing mice. HPV pseudovirions (PsV) carrying the Herpex-Simplex virus thymidine kinase suicide-gene followed by treatment with the prodrug Ganciclovir resulted in 90% of MB49 cell-death in-vitro and was able to significantly reduce bladder tumor growth in-vivo. Furthermore, HPV virus-like particles coupled to a NIR phtalocyanine dye, IR700 in combination with specific NIR light led to almost 100% of MB49 cell-death in-vitro and more interestingly, to bladder tumors shrinkage in-vivo. Overall, in this thesis, we offer promising therapeutic approaches for application in NMIBC patients.

Risk Prediction Scores for Recurrence and Progression of Non-Muscle Invasive Bladder Cancer: An International Validation in Primary Tumours

Abstract Objective: We aimed to determine the validity of two risk scores for patients with non-muscle invasive bladder cancer in different European settings, in patients with primary tumours. Methods: We included 1,892 patients with primary stage Ta or T1 non-muscle invasive bladder cancer who underwent a transurethral resection in Spain (n = 973), the Netherlands (n = 639), or Denmark (n = 280). We evaluated recurrence-free survival and progression-free survival according to the European Organisation for Research and Treatment of Cancer (EORTC) and the Spanish Urological Club for Oncological Treatment (CUETO) risk scores for each patient and used the concordance index (c-index) to indicate discriminative ability. Results: The 3 cohorts were comparable according to age and sex, but patients from Denmark had a larger proportion of patients with the high stage and grade at diagnosis (p,0.01). At least one recurrence occurred in 839 (44%) patients and 258 (14%) patients had a progression during a median follow-up of 74 months. Patients from Denmark had the highest 10- year recurrence and progression rates (75% and 24%, respectively), whereas patients from Spain had the lowest rates (34% and 10%, respectively). The EORTC and CUETO risk scores both predicted progression better than recurrence with c-indices ranging from 0.72 to 0.82 while for recurrence, those ranged from 0.55 to 0.61. Conclusion: The EORTC and CUETO risk scores can reasonably predict progression, while prediction of recurrence is more difficult. New prognostic markers are needed to better predict recurrence of tumours in primary non-muscle invasive bladder cancer patients.

The Effects of a Nematode Lungworm (Rhabdias hylae) on its Natural and Invasive Anuran Hosts.

Biological invasions can bring both the invader and native taxa into contact with novel parasites. As cane toads ( Rhinella marina ) have spread through Australia, they have encountered lungworms (Rhabdias hylae) that occur in native frogs. Field surveys suggest that these lungworms have not host-switched to toads. In our laboratory studies, R. hylae infected cane toads as readily as it infected native frogs, but failed to reach the lungs of the novel host (i.e., were killed by the toads' immune response). Plausibly, then, R. hylae might reduce the viability both of their native hosts (frogs, that can exhibit high parasite burdens) and cane toads (that must deal with infective larvae traveling through the host body). Our laboratory trials suggest, however, that the impacts of the parasite on infected anuran hosts (both frogs and toads) were minimal, with no significant decrements to host survival, activity, growth, or locomotor performance. Ironically, the lack of impact of the parasite on its native hosts appears to be an outcome of co-evolution (frogs tolerate the lungworm), whereas the lack of impact on the novel host is due to a lack of co-evolution (toads can recognize and eliminate the lungworm).

Non-invasive diagnostic and prognostic evaluation of liver cirrhosis and portal hypertension.

Cirrhosis is the final stage of most of chronic liver diseases, and is almost invariably complicated by portal hypertension, which is the most important cause of morbidity and mortality in these patients. This review will focus on the non-invasive methods currently used in clinical practice for diagnosing liver cirrhosis and portal hypertension. The first-line techniques include physical examination, laboratory parameters, transient elastography and Doppler-US. More sophisticated imaging methods which are less commonly employed are CT scan and MRI, and new technologies which are currently under evaluation are MR elastography and acoustic radiation force imaging (ARFI). Even if none of them can replace the invasive measurement of hepatic venous pressure gradient and the endoscopic screening of gastroesophageal varices, they notably facilitate the clinical management of patients with cirrhosis and portal hypertension, and provide valuable prognostic information.

Mini invasive skeletal muscle biopsy technique with a tri-axial end cut needle.

OBJECTIVE: Skeletal Muscle Biopsy is a minor surgical procedure for the diagnosis of different neuromuscular pathological conditions and has recently gained popularity also in the research field of age-related muscular modifications and sarcopenia. Few studies focused on the application of mini-invasive muscular biopsy in both normal and pathological conditions. The aim of our study was to describe a mini invasive ultrasound-guided skeletal muscular biopsy technique in complete spinal cord injured (SCI) patients and healthy controls with a tri-axial end-cut needle. PATIENTS AND METHODS: Skeletal muscle biopsies were collected from 6 chronic SCI patients and 3 healthy controls vastus lateralis muscle with a tri-axial end cut needle (Biopince© - Angiotech). Muscle samples were stained for ATPase to determine fibers composition, moreover, gene expression of cyclooxygenase-1 (COX-1) and prostaglandin E2 receptor has been analyzed by Real Time RT-PCR. RESULTS: All the procedures were perfomed easily without failures and complications. Control tissue was macroscopically thicker than SCI one. Control specimen displayed an equal distribution of type I and type II fibers, while SCI sample displayed a prevalence of type II fibers SCI specimen displayed a significant reduction in COX-1 gene expression. This mini-invasive approach was easy, accurate and with low complication rate in performing skeletal muscle biopsy in both SCI patients and controls. CONCLUSIONS: This technique could be useful in conditions in which the overall quantity of specimen required is small like for molecular biology analysis. For histological diagnostic purposes and/or conditions in which the original tissue is already pathologically modified, this technique should be integrated with more invasive techniques.

Comparative effectiveness of gemcitabine plus cisplatin versus methotrexate, vinblastine, doxorubicin, plus cisplatin as neoadjuvant therapy for muscle-invasive bladder cancer.

BACKGROUND: Gemcitabine plus cisplatin (GC) has been adopted as a neoadjuvant regimen for muscle-invasive bladder cancer despite the lack of Level I evidence in this setting. METHODS: Data were collected using an electronic data-capture platform from 28 international centers. Eligible patients had clinical T-classification 2 (cT2) through cT4aN0M0 urothelial cancer of the bladder and received neoadjuvant GC or methotrexate, vinblastine, doxorubicin, plus cisplatin (MVAC) before undergoing cystectomy. Logistic regression was used to compute propensity scores as the predicted probabilities of patients being assigned to MVAC versus GC given their baseline characteristics. These propensity scores were then included in a new logistic regression model to estimate an adjusted odds ratio comparing the odds of attaining a pathologic complete response (pCR) between patients who received MVAC and those who received GC. RESULTS: In total, 212 patients (146 patients in the GC cohort and 66 patients in the MVAC cohort) met criteria for inclusion in the analysis. The majority of patients in the MVAC cohort (77%) received dose-dense MVAC. The median age of patients was 63 years, they were predominantly men (74%), and they received a median of 3 cycles of neoadjuvant chemotherapy. The pCR rate was 29% in the MVAC cohort and 31% in the GC cohort. There was no significant difference in the pCR rate when adjusted for propensity scores between the 2 regimens (odds ratio, 0.91; 95% confidence interval, 0.48-1.72; P = .77). In an exploratory analysis evaluating survival, the hazard ratio comparing hazard rates for MVAC versus GC adjusted for propensity scores was not statistically significant (hazard ratio, 0.78; 95% confidence interval, 0.40-1.54; P = .48). CONCLUSIONS: Patients who received neoadjuvant GC and MVAC achieved comparable pCR rates in the current analysis, providing evidence to support what has become routine practice. Cancer 2015;121:2586-2593. © 2015 American Cancer Society.

Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening.

This paper contains a joint ESHG/ASHG position document with recommendations regarding responsible innovation in prenatal screening with non-invasive prenatal testing (NIPT). By virtue of its greater accuracy and safety with respect to prenatal screening for common autosomal aneuploidies, NIPT has the potential of helping the practice better achieve its aim of facilitating autonomous reproductive choices, provided that balanced pretest information and non-directive counseling are available as part of the screening offer. Depending on the health-care setting, different scenarios for NIPT-based screening for common autosomal aneuploidies are possible. The trade-offs involved in these scenarios should be assessed in light of the aim of screening, the balance of benefits and burdens for pregnant women and their partners and considerations of cost-effectiveness and justice. With improving screening technologies and decreasing costs of sequencing and analysis, it will become possible in the near future to significantly expand the scope of prenatal screening beyond common autosomal aneuploidies. Commercial providers have already begun expanding their tests to include sex-chromosomal abnormalities and microdeletions. However, multiple false positives may undermine the main achievement of NIPT in the context of prenatal screening: the significant reduction of the invasive testing rate. This document argues for a cautious expansion of the scope of prenatal screening to serious congenital and childhood disorders, only following sound validation studies and a comprehensive evaluation of all relevant aspects. A further core message of this document is that in countries where prenatal screening is offered as a public health programme, governments and public health authorities should adopt an active role to ensure the responsible innovation of prenatal screening on the basis of ethical principles. Crucial elements are the quality of the screening process as a whole (including non-laboratory aspects such as information and counseling), education of professionals, systematic evaluation of all aspects of prenatal screening, development of better evaluation tools in the light of the aim of the practice, accountability to all stakeholders including children born from screened pregnancies and persons living with the conditions targeted in prenatal screening and promotion of equity of access.

Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer.

Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3, and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options.

Are patients with non-invasive papillary thyroid carcinoma, follicular variant (niFV-PTC) and minimally invasive follicular thyroid carcinoma with capsular invasion only (miFTC-CIO) overtreated?An institutional experience

Background. Recently several meetings and position papers advocate a change in terminology regarding thyroid neoplasms with indolent behavior, proposing the term "tumor" instead of "carcinoma". This change concerns non-invasive papillary thyroid carcinoma, follicular variant (niFV-PTC) and minimally invasive follicular thyroid carcinoma with capsular invasion only (miFTC-CIO). The aim of our study was to evaluate the impact of considering niFV-PTC and miFTC-CIO as lesions of low malignant potential, and to see how this change would influence patient management at our institution. Methods. A 32 months retrospective review of all well differentiated thyroid carcinomas (WDTC) (papillary and follicular carcinomas) diagnosed at our institution was performed, excluding tumors of uncertain malignant potential as well as poorly differentiated and anaplastic carcinomas. We retrieved cases of niFV-PTC and miFTC-CIO, reviewed histological slides to confirm diagnosis and recorded patient treatment. Results. A total of 9 (7.3%) niFV-PTC (4 males and 5 females, aged between 30 and 68 years, mean: 50.8 years old) and 2 (1.6%) cases of miFTC-CIO (2 females, 31 and 51 years old) were identified out of 122 WDTC diagnosed in the study period. The initial treatment consisted in 5 lobectomies and 6 total thyroidectomies (3 because of a compressive goiter, 2 because of a fine-needle aspiration diagnosis of suspicious for papillary thyroid carcinoma and 1 because of a fine-needle aspiration diagnosis of papillary carcinoma). The treatment following the histological diagnosis consisted in 4 thyroidectomy completions among patients who underwent simple lobectomy (4/5, 80%) and 9/11 (82%) radioablations with I131. Conclusions. The incidence of niFV-PTC is low at our institution, probably because we apply strict diagnostic criteria for this lesion. Simple lobectomy with negative margins is the treatment of choice in cases diagnosed as niFV-PTC and miFTC-CIO, due to the indolent course of these neoplasms. All cases with thyroidectomy completions and radioablations could have been avoided. As a consequence, the change of such terminology heavily impacts the malignancy risk evaluated cytologically as well as patients' management.

Living with invasive plants in the Anthropocene : the importance of understanding practice and experience

The role of humans in facilitating the rapid spread of plants at a scale that is considered invasive is one manifestation of the Anthropocene, now framed as a geological period in which humans are the dominant force in landscape transformation. Invasive plant management faces intensified challenges, and can no longer be viewed in terms of 'eradication' or 'restoration of original landscapes'. In this perspectives piece, we focus on the practice and experience of people engaged in invasive plant management, using examples from Australia and Canada. We show how managers 1) face several pragmatic trade-offs; 2) must reconcile diverse views, even within stakeholder groups; 3) must balance competing temporal scales; 4) encounter tensions with policy; and 5) face critical and under-acknowledged labour challenges. These themes show the variety of considerations based on which invasive plant managers make complex decisions about when, where, and how to intervene. Their widespread pragmatic acceptance of small, situated gains (as well as losses) combines with impressive long-term commitments to the task of invasives management. We suggest that the actual practice of weed management challenges those academic perspectives that still aspire to attain pristine nature.

A Randomized, Placebo-controlled Trial of Preemptive Antifungal Therapy for the Prevention of Invasive Candidiasis Following Gastrointestinal Surgery for Intra-abdominal Infections.

BACKGROUND: Patients undergoing emergency gastrointestinal surgery for intra-abdominal infection are at risk of invasive candidiasis (IC) and candidates for preemptive antifungal therapy. METHODS: This exploratory, randomized, double-blind, placebo-controlled trial assessed a preemptive antifungal approach with micafungin (100 mg/d) in intensive care unit patients requiring surgery for intra-abdominal infection. Coprimary efficacy variables were the incidence of IC and the time from baseline to first IC in the full analysis set; an independent data review board confirmed IC. An exploratory biomarker analysis was performed using logistic regression. RESULTS: The full analysis set comprised 124 placebo- and 117 micafungin-treated patients. The incidence of IC was 8.9% for placebo and 11.1% for micafungin (difference, 2.24%; [95% confidence interval, -5.52 to 10.20]). There was no difference between the arms in median time to IC. The estimated odds ratio showed that patients with a positive (1,3)-β-d-glucan (ßDG) result were 3.66 (95% confidence interval, 1.01-13.29) times more likely to have confirmed IC than those with a negative result. CONCLUSIONS: This study was unable to provide evidence that preemptive administration of an echinocandin was effective in preventing IC in high-risk surgical intensive care unit patients with intra-abdominal infections. This may have been because the drug was administered too late to prevent IC coupled with an overall low number of IC events. It does provide some support for using ßDG to identify patients at high risk of IC. CLINICAL TRIALS REGISTRATION: NCT01122368.