Interlaboratory evaluation of Mucorales PCR assays for testing serum specimens: A study by the fungal PCR Initiative and the Modimucor study group.

Interlaboratory evaluations of Mucorales qPCR assays were developed to assess the reproducibility and performance of methods currently used. The participants comprised 12 laboratories from French university hospitals (nine of them participating in the Modimucor study) and 11 laboratories participating in the Fungal PCR Initiative. For panel 1, three sera were each spiked with DNA from three different species (Rhizomucor pusillus, Lichtheimia corymbifera, Rhizopus oryzae). For panel 2, six sera with three concentrations of R. pusillus and L. corymbifera (1, 10, and 100 genomes/ml) were prepared. Each panel included a blind negative-control serum. A form was distributed with each panel to collect results and required technical information, including DNA extraction method, sample volume used, DNA elution volume, qPCR method, qPCR template input volume, qPCR total reaction volume, qPCR platform, and qPCR reagents used. For panel 1, assessing 18 different protocols, qualitative results (positive or negative) were correct in 97% of cases (70/72). A very low interlaboratory variability in Cq values (SD = 1.89 cycles) were observed. For panel 2 assessing 26 different protocols, the detection rates were high (77-100%) for 5/6 of spiked serum. There was a significant association between the qPCR platform and performance. However, certain technical steps and optimal combinations of factors may also impact performance. The good reproducibility and performance demonstrated in this study support the use of Mucorales qPCR as part of the diagnostic strategy for mucormycosis.

Azole-resistant Aspergillus fumigatus in sawmills of Eastern France.

AIMS: Emergence of azole-resistant Aspergillus fumigatus complicates management of Aspergillus diseases. Currently, selection pressure caused by azole fungicide use in farming is strongly suspected of creating resistance. As sawmills also use azole fungicides, we investigated the presence of azole-resistant strains in this environment and studied the relationship between azole fungicide use and development of resistance. METHODS AND RESULTS: Air (n = 200) and substrate (n = 600) samples were taken in 20 sawmills. Azole-resistant strains (Etest and EUCAST methods) were confirmed by sequencing the cyp51A gene and its promoters. Dosage of propiconazole and tebuconazole was performed by gas chromatography coupled with mass spectrometry. Twenty-four azole-resistant A. fumigatus strains were collected among 20 of the 600 substrate samples (3%). Eighty-three percent of theses strains had TR34 /L98H mutation. A significantly higher number of resistant strains was collected in sawmills using fungicide products made with propiconazole mixed with a high concentration of tebuconazole (P = 0·009). The presence of resistant strains was significantly linked to propiconazole quantities in substrates (P = 0·03). CONCLUSIONS: The outcome of azole-resistant A. fumigatus carrying TR34 /L98H mutation seems to greatly depend on the azole fungicide formulation and quantities of azole. These preliminary results are valuable to propose new approaches limiting the emergence of azole-resistant strains. SIGNIFICANCE AND IMPACT OF THE STUDY: Azole resistance is an emerging problem in A. fumigatus and threatens clinical advances made possible by the use of azole antifungals in the treatment of Aspergillus-related diseases. Azole fungicides are also used in the wood industry, notably in sawmills, to protect wood from wood-destroying fungi. Through our study, we show that sawmills represent another professional environment affected by the presence of azole-resistant A. fumigatus strains carrying the TR34 /L98H mutation. Moreover, this study provides valuable preliminary results to propose some new approaches to limit the emergence of azole-resistant A. fumigatus strains.

Evaluation of invasive aspergillosis risk of immunocompromised patients alternatively hospitalized in hematology intensive care unit and at home.

UNLABELLED: Contrary to hospital exposure, little is known about the indoor fungal exposure of hematology patients at home. The aim of our study was to investigate the mold exposure of hematology patients both at home and at hospital to assess their invasive aspergillosis (IA) risk. Fungal exposure was assessed by quantifying opportunistic molds at hospital during hospitalization and in homes of 53 hematology patients. IA was diagnosed in 13 of 53 patients and invasive fungal infection (IFI) in one patient. In hospital, no opportunistic species, or low levels of opportunistic species, were found in 98% of weekly controls. Only 2% of hematology intensive care unit (ICU) controls showed a high level of Aspergillus fumigatus spores in corridor air. Five patients IA were hospitalized during these periods. Seven dwellings of 53 (5/14 dwellings of patients with IA/IFI and 2/39 dwellings of non-IA patients) had a percentage of A. fumigatus and Aspergillus flavus to total mold (significant predictor variable of IA/IFI in our study, general linear model, P-value = 0.02) as high as 15%. Maintaining a 'zero Aspergillus' goal at hospital is essential, and establishing specific and individually opportunistic mold monitoring at home could help to further reduce the IA risk through continuous surveillance. PRACTICAL IMPLICATIONS: This study emphasizes the fact that preventive measures should not be aimed only at the hospital setting: among patients diagnosed with invasive aspergillosis/invasive fungal infection (IA/IFI), 5 of 14 (36%) were exposed to opportunistic fungal species at home exclusively. Moreover, four of these five patients were living in homes having the highest percentage of Aspergillus fumigatus and Aspergillus flavus (>15%), one of which had 48% of A. fumigatus. Therefore, our work supports the need for a counselor to carry out an environmental survey in patients' homes.

Clonal and subclonal TP53 molecular impairment is associated with prognosis and progression in multiple myeloma.

Aberrations on TP53, either as deletions of chromosome 17p (del17p) or mutations, are associated with poor outcome in multiple myeloma (MM), but conventional detection methods currently in use underestimate their incidence, hindering an optimal risk assessment and prognostication of MM patients. We have investigated the altered status of TP53 gene by SNPs array and sequencing techniques in a homogenous cohort of 143 newly diagnosed MM patients, evaluated both at diagnosis and at first relapse: single-hit on TP53 gene, either deletion or mutation, detected both at clonal and sub-clonal level, had a minor effect on outcomes. Conversely, the coexistence of both TP53 deletion and mutation, which defined the so-called double-hit patients, was associated with the worst clinical outcome (PFS: HR 3.34 [95% CI: 1.37-8.12] p = 0.008; OS: HR 3.47 [95% CI: 1.18-10.24] p = 0.02). Moreover, the analysis of longitudinal samples pointed out that TP53 allelic status might increase during the disease course. Notably, the acquisition of TP53 alterations at relapse dramatically worsened the clinical course of patients. Overall, our analyses showed these techniques to be highly sensitive to identify TP53 aberrations at sub-clonal level, emphasizing the poor prognosis associated with double-hit MM patients.

Azole-resistant Aspergillus fumigatus: A global phenomenon originating in the environment?

Aspergillus fumigatus is the predominant etiological agent of invasive aspergillosis (IA), a difficult-to-manage fungal disease associated with a high case fatality rate. Azole antifungals, particularly voriconazole, have significantly improved the survival rate of patients with IA. However, the clinical advances made possible through the use of medical azoles could be threatened by the emergence of azole-resistant strains which has been reported in an ever-increasing number of countries over the last 10 years. The major resistance mechanism, that combines point mutation(s) in the coding sequence of cyp51A gene and an insertion of a tandem repeat in the promoter region of this gene which leads to its overexpression (TR34/L98H and TR46/Y121F/T289A), is presumed to be of environmental origin. However, the emergence of clinical and environmental azole-resistant strains without the cyp51A gene mutation suggests that other mechanisms could also be responsible for azole resistance (for example, overexpression of efflux pumps). The development of resistance may be linked to either long-term use of azole antifungals in patients with chronic aspergillosis (patient-acquired route) or selection pressure of the fungicides in the environment (environmental route). The fungicide-driven route could be responsible for resistance in azole-naive patients with IA. This literature review aims to summarize recent findings, focusing on the current situation of azole-resistance in A. fumigatus, and provides better understanding of the importance of the environmental route in resistance acquisition.

Identifying indoor air Penicillium species: a challenge for allergic patients.

PURPOSE: Penicillium is the most common mould isolated in housing. Penicillium chrysogenum is the only species tested by prick test or serology for allergic patients. The American Institute of Medicine has accepted Penicillium as an aetiological agent of rhinitis in children and adults and as an asthma agent in children. However, few studies have identified Penicillium in housing to the species level (354 species). Phenotypic identification is difficult. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) should be an alternative. The aim of this study was (1) to identify the Penicillium species present in dwellings in Eastern France and (2) to evaluate the reliability of MALDI-TOF MS for identification, by comparing it to DNA sequencing and phenotypic identification. METHODOLOGY: Identification to the species level was performed by MALDI-TOF MS on 275 strains isolated from 48 dwellings. These results were compared to beta-tubulin gene sequencing and to the phenotypic aspects. RESULTS: Thanks to MALDI-TOF, 235/275 strains could be identified (85.5 %). Fourteen species were identified among 23 Penicillium species included in the Filamentous Fungi Library 1.0 (Bruker Daltonics). However, 72.2  % of the strains belonged to five main taxa: P. chrysogenum (27.3 %), Penicillium glabrum (22.9 %), Penicilliumcommune (11.3 %), Penicillium brevicompactum (6.5 %) and Penicillium expansum (4.2 %). CONCLUSION: Complete coherence between MALDI-TOF MS and sequence-based identification was found for P. chrysogenum, P. expansum, P. glabrum, Penicillium italicum and Penicillium corylophilum. The main drawback was observed for Penicillium crustosum, which included 21 strains (7.6 %) that could not be identified using MALDI-TOF MS.

[Can the new technologies of telemedicine applied to health help the caregiver?]. / Le nuove tecnologie telematiche applicate in sanità possono aiutare il caregiver?

During the last few years about the chronic patient assistance the tendency is to privilege the home care model, favouring the permanence of the patient in the familiar nucleus. This determines an always greater involvement in term of time and responsibility of the caregiver that is of the person who takes cure of the patient one worrying itself to answer to its physical needs, psychical and social. The burden of the family caregiver is in the consisting majority of the cases rather. The caregiver is therefore, with full rights, the other protagonist of the disease and it must be necessarily integrated in the assistance plan. The increase of the age associated to an increase of the prevalence of chronic pathologies, determines the necessity to plan new interventions on the territory. In chronic patients alternative assistance models, using telemedicine, seem to be effectives improving both clinical aspects and quality of the life. A new area of interest is delineated therefore that, through the new technologies of the ICT must define been involved the single roles of the operating ones in the participation program. The telemedicine seems to be a useful instrument in order to support patient and caregiver in facing the disease and reducing stress. In our model of domiciliary telesurveillance the patient, the caregiver, the family and all the sanitary figures are been involved. This model integrating the service dedicated to chronic pathology with telepsychology at home seems to give good result even if ulterior studies, above all in the long term, are need.

Alps to Apennines zircon roller coaster along the Adria microplate margin.

We have traced the particle path of high-pressure metasedimentary rocks on Elba Island, Northern Apennines, with the help of a U-Pb-Hf detrital zircon study. One quarter of the analysed zircons are surprisingly young, 41-30 Ma, with a main age peak at ca. 32 Ma, indicating an unexpected early Oligocene maximum deposition age. These Oligocene ages with negative εHf indicate a volcanic source region in the central-southern Alps. Though young by geological means, these zircons record an extraordinary geodynamic history. They originated in a volcanic arc, during the convergence/collision of the the Adria microplate with Europe from ca. 65 to 30 Ma. Thereafter, the Oligocene zircons travelled ca. 400 km southward along the Adria margin and the accretionary prism to present-day Tuscany, where they were subducted to depths of at least 40 km. Shortly thereafter, they were brought to the surface again in the wake of hinge roll back of the Apennine subduction zone and the resulting rapid extensional exhumation. Such a zircon roller coaster requires a microplate that has back-to-back subduction zones with opposing polarities on two sides.

Real-time polymerase chain reaction detection of Lichtheimia species in bandages associated with cutaneous mucormycosis in burn patients.

BACKGROUND: Cutaneous mucormycoses, mainly due to Lichtheimia (Absidia), have occurred on several occasions in the Burn Unit of the University Hospital of Lille, France. AIM: To investigate the potential vector role of non-sterile bandages used to hold in place sterile gauze used for wound dressing. METHODS: Mycological analysis by conventional culture, Mucorales real-time polymerase chain reaction (qPCR), and Lichtheimia species-specific qPCR were performed on eight crepe and six elasticized bandages that were sampled on two independent occasions in March 2014 and July 2016. Characteristics of the seven Lichtheimia mucormycoses which occurred in burn patients between November 2013 and July 2016 were also collected to assess the epidemiological relationship between potentially contaminated bandages and clinical infections. FINDINGS: One Lichtheimia corymbifera strain was isolated from a crepe bandage by culture, and Lichtheimia spp. qPCR was positive in six out of eight crepe and four out of six elasticized bandages. Using species-specific qPCR, Lichtheimia ramosa, Lichtheimia ornata, and L. corymbifera were identified in six out of ten, five out of ten, and four out of ten bandages, respectively. In patients with mucormycosis, L. ramosa and L. ornata were present in five and two cases, respectively. CONCLUSION: Our data support the utility of Mucorales qPCR for epidemiological investigations, the potential role of these bandages in cutaneous mucormycoses in burn patients in our centre, and, consequently, the need for sterile bandages for the dressing of extensive wounds.

[European birth cohorts: Early life exposure to microorganisms and health impact]. / Cohortes de naissances européennes : exposition aux micro-organismes et impact sanitaire.

In recent years, many birth cohorts have been initiated in Europe, to assess the early life microbiological exposure of children in the indoor environment and better understanding the different effects (adverse/protectors) on health. The results of 12 European cohorts, with different methodologies for exposure and allergic risk assessment are summarized in this review. Four meta-analyzes of cohort are presented too. Microbiological researches in indoor environment seem to turn to a metrology of microbiological exposure, but few studies provide real quantitative data. Thus, the establishment of dose-effect relationship is not possible and can only be done by having a global view of the situation, provided by an identical metrological approach in the different studies, in a large-scale, in the context of large birth cohorts with children followed with strict criteria to establish the clinical diagnosis.

Selective zircon accumulation in a new benthic foraminifer, Psammophaga zirconia, sp. nov.

Benthic foraminifera are single-celled eukaryotes that make a protective organic, agglutinated or calcareous test. Some agglutinated, single-chambered taxa, including Psammophaga Arnold, 1982, retain mineral particles in their cytoplasm, but the selective mechanism of accumulation is not clear. Here, we report the ability of a foraminiferal species to select and accumulate zircons and other heavy minerals in their cytoplasm. In particular, the use of Scanning Electron Microscope coupled with an Energy Dispersive X-ray microanalysis system (SEM-EDS) enabled a representative overview of the mineral diversity and showed that the analysed Psammophaga zirconia sp. nov. individuals contained dominantly crystals of zircon (51%), titanium oxides (27%), and ilmenite (11%) along with minor magnetite and other minerals. The studied specimens occur in the shallow central Adriatic Sea where the sediment has a content of zircon below 1% and of other heavy minerals below 4%. For that reason we hypothesize that: (i) P. zirconia may be able to chemically select minerals, specifically zircon and rutile; (ii) the chemical mechanism allowing the selection is based on electrostatic interaction, and it could work also for agglutinated foraminifera (whether for ingestion, like Xenophyophores, or incorporation in the test as in many other described taxa). In particular, this aptitude for high preferential uptake and differential ingestion or retention of zircon is reported here for the first time, together with the selection of other heavy minerals already described in members of the genus Psammophaga. They are generally counted among early foraminifera, constructing a morphologically simple test with a single chamber. Our molecular phylogenetic study confirms that P. zirconia is a new species, genetically distinctive from other Psammophaga, and occurs in the Adriatic as well as in the Black Sea.

Current and emerging triplet combination therapies for relapsed and refractory multiple myeloma.

Despite significant improvement in outcomes have been observed for multiple myeloma (MM) patients over the past 10-15 years, mainly due to the introduction of novel agents targeting the tumor clone and the bone marrow microenvironment, treatment of refractory and/or relapsed (RR) disease remains a challenge, particularly for patients who have failed prior bortezomib- and lenalidomide-based therapies. More recently, new drugs with different mechanisms of action, including second generation proteasome inhibitors, third generation immunomodulatory drugs, histone deacetylase inhibitors and monoclonal antibodies, have been developed and are under investigation, further increasing treatment options for RRMM patients. Overall, novel agent-based triplet combinations demonstrated superior response rates and prolonged disease control when compared with two-drug regimens in several randomized clinical trials, without adding any relevant additional toxicity. Salvage triplet therapies are likely to play a key role in overcoming drug-resistance and hold promise to further improve long-term outcomes of RRMM patients.

NF-kB2 induces senescence bypass in melanoma via a direct transcriptional activation of EZH2.

Enhancer of Zeste homologue 2 (EZH2) belongs to the polycomb repressive complex 2 and catalyzes the methylation of histone H3 lysine 27. These pivotal epigenetic marks are altered in many cancers, including melanoma, as a result of EZH2 overexpression. Here, we show that the non-canonical-NF-kB pathway accounts for most of the NF-kB activity in melanoma cells, in contrast to non-cancer cells. We identify the non-canonical-NF-kB pathway as a key regulator of EZH2 expression in melanoma. We show a striking correlation between NF-kB2 and EZH2 expression in human melanoma metastases. We demonstrate that inhibition of the non-canonical NF-kB pathway by targeting NF-kB2/p52 or the upstream kinase NIK restores the senescence program in melanoma cells through the decrease of EZH2. On the contrary, the overexpression of NF-kB2/p52 in normal human melanocytes prevents stress- and oncogene-induced senescence. Finally, we show in mouse models that the inhibition of the non-canonical NF-kB pathway restores senescence and induces a dramatic reduction in tumor growth compared with controls, thus providing potential drug targets for the re-induction of senescence in melanoma and other cancers where EZH2 is overexpressed.

Early diagnosis and monitoring of mucormycosis by detection of circulating DNA in serum: retrospective analysis of 44 cases collected through the French Surveillance Network of Invasive Fungal Infections (RESSIF).

The main objective of this study was to assess the diagnostic performance of a set of three Mucorales quantitative PCR assays in a retrospective multicentre study. Mucormycosis cases were recorded thanks to the French prospective surveillance programme (RESSIF network). The day of sampling of the first histological or mycological positive specimen was defined as day 0 (D0). Detection of circulating DNA was performed on frozen serum samples collected from D-30 to D30, using quantitative PCR assays targeting Rhizomucor, Lichtheimia, Mucor/Rhizopus. Forty-four patients diagnosed with probable (n = 19) or proven (n = 25) mucormycosis were included. Thirty-six of the 44 patients (81%) had at least one PCR-positive serum. The first PCR-positive sample was observed 9 days (range 0-28 days) before diagnosis was made using mycological criteria and at least 2 days (range 0-24 days) before imaging. The identifications provided with the quantitative PCR assays were all concordant with culture and/or PCR-based identification of the causal species. Survival rate at D84 was significantly higher for patients with an initially positive PCR that became negative after treatment initiation than for patients whose PCR remained positive (48% and 4%, respectively; p <10-6). The median time for complete negativity of PCR was 7 days (range 3-19 days) after initiation of l-AmB treatment. Despite some limitations due to the retrospective design of the study, we showed that Mucorales quantitative PCR could not only confirm the mucormycosis diagnosis when other mycological arguments were present but could also anticipate this diagnosis. Quantification of DNA loads may also be a useful adjunct to treatment monitoring.

Opposite activation of the Hedgehog pathway in CD138+ plasma cells and CD138-CD19+ B cells identifies two subgroups of patients with multiple myeloma and different prognosis.

Hyperactivation of the Hedgehog (Hh) pathway, which controls refueling of multiple myeloma (MM) clones, might be critical to disease recurrence. Although several studies suggest the Hh pathway is activated in CD138- immature cells, differentiated CD138+ plasma cells might also be able to self-renew by producing themselves the Hh ligands. We studied the gene expression profiles of 126 newly diagnosed MM patients analyzed in both the CD138+ plasma cell fraction and CD138-CD19+ B-cell compartment. Results demonstrated that an Hh-gene signature was able to cluster patients in two subgroups characterized by the opposite Hh pathway expression in mature plasma cells and their precursors. Strikingly, patients characterized by Hh hyperactivation in plasma cells, but not in their B cells, displayed high genomic instability and an unfavorable outcome in terms of shorter progression-free survival (hazard ratio: 1.92; 95% confidence interval: 1.19-3.07) and overall survival (hazard ratio: 2.61; 95% confidence interval: 1.26-5.38). These results suggest that the mechanisms triggered by the Hh pathway ultimately led to identify a more indolent vs a more aggressive biological and clinical subtype of MM. Therefore, patient stratification according to their molecular background might help the fine-tuning of future clinical and therapeutic studies.

18F-FDG PET/CT focal, but not osteolytic, lesions predict the progression of smoldering myeloma to active disease.

Identification of patient sub-groups with smoldering multiple myeloma (SMM) at high risk of progression to active disease (MM) is an important goal. 18F-FDG PET/CT (positron emission tomography (PET) integrated with computed tomography (PET/CT) using glucose labelled with the positron-emitting radionuclide (18)F) allows for assessing early skeletal involvement. Identification of osteolytic lesions by this technique has recently been incorporated into the updated International Myeloma Working Group criteria for MM diagnosis. However, no data are available regarding the impact of focal lesions (FLs) without underlying osteolysis on time to progression (TTP) to MM. We hence prospectively studied a cohort of 120 SMM patients with PET/CT. PET/CT was positive in 16% of patients (1 FL: 8, 2 FLs: 3, >3 FLs: 6, diffuse bone marrow involvement: 2). With a median follow-up of 2.2 years, 38% of patients progressed to MM, in a median time of 4 years, including 21% with skeletal involvement. The risk of progression of those with positive PET/CT was 3.00 (95% confidence interval 1.58-5.69, P=0.001), with a median TTP of 1.1 versus 4.5 years for PET/CT-negative patients. The probability of progression within 2 years was 58% for positive versus 33% for negative patients. In conclusion, PET/CT positivity significantly increased the risk of progression of SMM to MM. PET/CT could become a new tool to define high-risk SMM.

Sustained recruitment of phospholipase C-gamma to Gab1 is required for HGF-induced branching tubulogenesis.

A distinctive property of Hepatocyte Growth Factor (HGF) is its ability to induce differentiation of tubular structures from epithelial and endothelial cells (branching tubulogenesis). The HGF receptor directly activates PI3 kinase, Ras and STAT signalling pathways and phosphorylates the adaptator GRB2 Associated Binder-1 (Gab1). Gab1 is also phosphorylated in response to Epidermal Growth Factor (EGF) but is unable to induce tubule formation. Comparison of 32P-peptide maps of Gab1 from EGF- versus HGF-treated cells, demonstrates that the same sites are phosphorylated in vivo. However, while both EGF and HGF induce rapid tyrosine phosphorylation of Gab1 with a peak at 15 min, the phosphorylation persists for over 1 h, only in response to HGF. Nine tyrosines are phosphorylated by both receptors. Three of them (Y307, Y373, Y407) bind phospholipase C-gamma (PLC-gamma). Interestingly, the overexpression of a Gab1 mutant unable to bind PLC-gamma (Gab1 Y307/373/407F) did not alter HGF-stimulated cell scattering, only partially reduced the growth stimulation but completely abolished HGF-mediated tubulogenesis. It is concluded that sustained recruitment of PLCgamma to Gab1 plays an important role in branching tubulogenesis.

Determination of Gab1 (Grb2-associated binder-1) interaction with insulin receptor-signaling molecules.

The newly identified insulin receptor (IR) substrate, Gab1 [growth factor receptor bound 2 (Grb2)-associated binder-1] is rapidly phosphorylated on several tyrosine residues by the activated IR. Phosphorylated Gab1 acts as a docking protein for Src homology-2 (SH2) domain-containing proteins. These include the regulatory subunit p85 of phosphatidylinositol 3-kinase and phosphotyrosine phosphatase, SHP-2. In this report, using a modified version of the yeast two-hybrid system, we localized which Gab1 phospho-tyrosine residues are required for its interaction with phosphatidylinositol 3-kinase and with SHP-2. Our results demonstrate that to interact with p85 or SHP-2 SH2 domains, Gab1 must be tyrosine phosphorylated by IR. Further, we found that Gab1 tyrosine 472 is the major site for association with p85, while tyrosines 447 and 589 are participating in this process. Concerning Gab1/SHP-2 interaction, only mutation of tyrosine 627 prevents binding of Gab1 to SHP-2 SH2 domains, suggesting the occurrence of a monovalent binding event. Finally, we examined the role of Gab1 PH (Pleckstrin homology) domain in Gab1/IR interaction and in Gab1 tyrosine phosphorylation by IR. Using the modified two-hybrid system and in vitro experiments, we found that the Gab1 PH domain is not important for IR/ Gab1 interaction and for Gab1 tyrosine phosphorylation. In contrast, in intact mammalian cells, Gab1 PH domain appears to be crucial for its tyrosine phosphorylation and association with SHP-2 after insulin stimulation.

[Azole resistance with environmental origin: What alternatives for the future?]. / Résistance aux antifongiques azolés d'origine environnementale : quelles alternatives pour l'avenir ?

Azole resistant Aspergillus fumigatus strains are increasingly reported in many countries. One resistance mechanism is attributed to the use of azole fungicides in environment. Two mutations, TR34/L98H and TR46/Y121F/T289A, on the cyp51A gene, have been described. Results of 40 publications about azole resistant strain detections, with TR34/L98H and TR46/Y121F/T289A mutations, in clinical and/or environmental samples, are presented in this review. These cases, observed in many countries, suggest spreading phenomenon. Measures to moderate fungicides treatments and/or alternative treatments in environment should be established to preserve the effectiveness of azole antifungal therapy for at-risk patients.