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Abstract: Acute hyperhemolysis is a severe life-threatening complication in patients with sickle cell disease (SCD) that may occur during delayed hemolytic transfusion reaction (DHTR), or vaso-occlusive crises associated with multiorgan failure. Here, we developed in vitro and in vivo animal models to mimic endothelial damage during the early phase of hyperhemolysis in SCD. We then used the carbon monoxide (CO)-releasing molecule CORM-401 and examined its effects against endothelial activation, damage, and inflammation inflicted by hemolysates containing red blood cell membrane-derived particles. The in vitro results revealed that CORM-401: (1) prevented the upregulation of relevant proinflammatory and proadhesion markers controlled by the NF-κB enhancer of activated B cells, and (2) abolished the expression of the nuclear factor erythroid-2-related factor 2 (Nrf2) that regulates the inducible antioxidant cell machinery. We also show in SCD mice that CORM-401 protects against hemolysate-induced acute damage of target organs such as the lung, liver, and kidney through modulation of NF-κB proinflammatory and Nrf2 antioxidant pathways. Our data demonstrate the efficacy of CORM-401 as a novel therapeutic agent to counteract hemolysate-induced organ damage during hyperhemolysis in SCD. This approach might be considered as possible preventive treatment in high-risk situations such as patients with SCD with history of DHTR., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

The use of water-dispersible and sustainable Pd nanocatalysts to reduce toxic heavy metal ions and catalyze important organic reactions has profound significance for the environmental remediation and the catalytic industry. In this work, a novel water-dispersible and recyclable Pd@LNPs nanoreactor composed of Pd nanoparticle cluster core and LNPs shell was developed in microwave reactor in aqueous solution. It turned out that Pd nanoparticles grew uniformly and stably inside LNPs nanosphere due to the coordinated binding and interaction between Pd and the functional groups in LNPs, which was significantly different from surface loading. The green and biodegradable LNPs nanospheres are not only used as reducing agents for Pd (II) and nanocarriers, but also act as individual nanocontainers to provide favorable sites for reactions and effectively control the entry and release of reactants and products. Furthermore, the excellent and efficient catalytic properties of Pd@LNPs were exhibited by CC coupling reactions and the reduction of Cr(VI) and 4-nitrophenol. The Pd@LNPs prepared in this study have the advantages of excellent dispersion, great recyclability, high turnover frequency and better green sustainability metrics. It will have a great significance for the development of the potential high-value of lignin and the progress in the field of bio-nanocatalysts., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Zhao Zhang reports financial support was provided by CSC., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Assessment of microplastic (MP) contamination is still needed to evaluate this threat correctly and tackle this issue. Here, MP contamination was assessed for a meso-tidal lagoon of the Atlantic coast (Arcachon Bay, France). Sea surface, water column, intertidal sediments and wild oysters were sampled. Five different stations were studied to assess the spatial distribution of the contamination. Two were outside of the bay and three were inside the bay (from the inlet to the back). A distinction was made between all anthropogenic particles (AP, i.e. visually sorted) and MP (i.e. plastic polymer confirmed by ATR-FTIR spectroscopy). The length of particles recovered in this study ranged between 17 μm and 5 mm. Concentration and composition in sea surface and water column samples showed spatial variations while sediment and oyster samples did not. At outside stations, the sea surface and the water column presented a blended composition regarding shapes and polymers and low to high concentrations (e.g. 0.16 ± 0.08 MP.m -3 and 561.7 ± 68.5 MP.m -3 , respectively for sea surface and water column), which can be due to coastal processes and nearby input sources. The inlet station displayed a well-marked pattern only at the sea surface. High AP and MP concentrations were recorded, and fragments along with polyethylene overwhelmed (respectively 76.0 % and 73.2 %). Higher surface currents could explain this pattern. At the bay back, AP and MP concentrations were lower and fibers were mainly recorded. Weaker hydrodynamics in this area was suspected to drive this contamination profile. Overall, fragments and buoyant particles were mainly detected at the sea surface while fibers and negatively buoyant particles prevailed in other compartments. Most of the studied samples presented an important contribution of fiber-shaped particles (from 31.5 % to 94.2 %). Finally, contamination was ubiquitous as AP and MP were found at all stations in all sample types., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: The COVID-19 pandemic disrupted the organisation of the healthcare system. Very little data is available regarding the impact of the COVID-19 pandemic on patients' perceptions of their healthcare pathway. The objective of this survey was to evaluate cancer patients' perceptions of the impact of the first COVID-19 lockdown on continuity of care, their mental condition, as well as their access to Supportive Care in Cancer (SCC)., Methods: Between June 2nd and 30th, 2020, an anonymous questionnaire was sent out to the patients who visited 17 healthcare establishments in the Centre-Val de Loire region., Results: Our survey questioned 861 patients, amongst which 839 were selected. The population was predominantly female (58%). Breast cancer was the most represented (27%). Approximately three patients out of four considered that their care was maintained during the lockdown. In total, 348 patients (44%) reported an altered mental status. Approximately 1/4th of patients benefited from SCC. More than half of the patients felt that SCC was not relevant to their situation, although 40% of these patients expressed mental issues., Conclusion: Our survey highlighted a negative impact on patients' mental condition and a low use of SCC in spite of existing needs. This demonstrates the necessity of evaluating the patients' needs and offering adequate SCC at various stages of the healthcare pathway, as well as the need for a clearly identifiable offer for the healthcare professionals and the patients., (Copyright © 2022 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

In order to further develop the potential applications of lignin biomass, the research on lignin nanoparticles (LNPs) and their nanocomposites has attracted increasing attention. In this study, a facile and no chemical modification approach to prepare stable alkali lignin nanospheres is presented. The nanospheres around 85-125 nm were prepared through the π-π interactions between molecules in the self-assembly process. Lignin alkali was dissolved in ethylene glycol at different initial concentrations and subsequently ultrasound and dialysis treatment were conducted to prepare LNPs. The prepared LNPs had zeta potentials between -20 mV and -40 mV, and they were electrostatically stable over the pH range of 3 to 12 in aqueous solution. The chemical structure of LNPs was not significantly modified compared to lignin. Meanwhile the increased content of carboxyl and aliphatic hydroxyl groups in the LNPs structure was observed. Furthermore, the thermal stability and solubility in organic solvents (ethanol, acetone and THF) of LNPs were enhanced compared to those of lignin. In vitro cell viability evaluation indicated that the prepared LNPs had no cytotoxicity and excellent biocompatibility with mouse fibroblast. Therefore, we proposed here the production of high-quality and renewable LNPs, which will provide a novel perspective for multifunctional applications of bio-based nanomaterials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Coastal environments are a predominant ultimate destination of marine debris, becoming a key focus of studies assessing microplastic (MP) contamination. Here, we described the visible fraction of MP (from 0.5 to 5 mm) that washed up during the high tide at different sites of a semi-enclosed mesotidal bay and investigated the main abiotic factors driving MP beaching. Three contrasted beaches of the Arcachon Bay (SW France) were monitored on a monthly basis during 2019. Samplings were made along a 100 m longitudinal transect at the high-water strandline (4 quadrats of 0.25m 2 ) and at an intermediate tidal range. Each sampled particle was characterized by morphometric data (e.g. size, shape, color, roughness) and polymer identification was performed by ATR-FTIR technique. Results show that MP concentration was higher on the beach located at the mouth of the bay (36.0 ± 39.2 MP.m -2 ) than at the back and the outside of the bay (respectively 2.7 ± 4.4 and 1.7 ± 2.4 MP.m -2 ). This may be related to the strong currents at the entry of the embayment and the beach orientation, exposed to predominant winds. Beached MP were mainly pre-production pellets and fragments as they represented respectively 49% and 39% of all analyzed shapes. Polymers with low density were particularly abundant. Polyethylene represented 69% of all the particles while polypropylene accounted for 17% and polystyrene for 10%. We also observed that MP were mostly washed up when wind, waves and river flow were more intense. Analysis suggest that wind direction and speed are key factors influencing beaching as strong onshore wind enhance this process., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

B-cell prolymphocytic leukemia (B-PLL) is a rare hematological disorder whose underlying oncogenic mechanisms are poorly understood. Our cytogenetic and molecular assessments of 34 patients with B-PLL revealed several disease-specific features and potential therapeutic targets. The karyotype was complex (≥3 abnormalities) in 73% of the patients and highly complex (≥5 abnormalities) in 45%. The most frequent chromosomal aberrations were translocations involving MYC [t(MYC)] (62%), deletion (del)17p (38%), trisomy (tri)18 (30%), del13q (29%), tri3 (24%), tri12 (24%), and del8p (23%). Twenty-six (76%) of the 34 patients exhibited an MYC aberration, resulting from mutually exclusive translocations or gains. Whole-exome sequencing revealed frequent mutations in TP53, MYD88, BCOR, MYC, SF3B1, SETD2, CHD2, CXCR4, and BCLAF1. The majority of B-PLL used the IGHV3 or IGHV4 subgroups (89%) and displayed significantly mutated IGHV genes (79%). We identified 3 distinct cytogenetic risk groups: low risk (no MYC aberration), intermediate risk (MYC aberration but no del17p), and high risk (MYC aberration and del17p) (P = .0006). In vitro drug response profiling revealed that the combination of a B-cell receptor or BCL2 inhibitor with OTX015 (a bromodomain and extra-terminal motif inhibitor targeting MYC) was associated with significantly lower viability of B-PLL cells harboring a t(MYC). We concluded that cytogenetic analysis is a useful diagnostic and prognostic tool in B-PLL. Targeting MYC may be a useful treatment option in this disease., (© 2019 by The American Society of Hematology.)

Introduction: Although frequent in NSCLC, patients with brain metastases (BMs) are often excluded from immune checkpoint inhibitor (ICI) trials. We evaluated BM outcome in a less-selected NSCLC cohort., Methods: Data from consecutive patients with advanced ICI-treated NSCLC were collected. Active BMs were defined as new and/or growing lesions without any subsequent local treatment before the start of ICI treatment. Objective response rate (ORR), progression-free survival, and overall survival (OS) were evaluated. Multivariate analyses were performed by using a Cox proportional hazards model and logistic regression., Results: A total of 1025 patients were included; the median follow-up time from start of ICI treatment was 15.8 months. Of these patients, 255 (24.9%) had BMs (39.2% active, 14.3% symptomatic, and 27.4% being treated with steroids). Disease-specific Graded Prognostic Assessment (ds-GPA) score was known for 94.5% of patients (35.7% with a score of 0-1, 58.5% with a score of 1.5-2.5, and 5.8% with a score of 3). The ORRs with BM versus without BM were similar: 20.6% (with BM) versus 22.7% (without BM) (p = 0.484). The intracranial ORR (active BM with follow-up brain imaging [n = 73]) was 27.3%. The median progression-free survival times were 1.7 (95% confidence interval [CI]: 1.5-2.1) and 2.1 (95% CI: 1.9-2.5) months, respectively (p = 0.009). Of the patients with BMs, 12.7% had a dissociated cranial-extracranial response and two (0.8%) had brain pseudoprogression. Brain progression occurred more in active BM than in stable BM (54.2% versus 30% [p < 0.001]). The median OS times were 8.6 months (95% CI: 6.8-12.0) with BM and 11.4 months (95% CI: 8.6-13.8) months with no BM (p = 0.035). In the BM subgroup multivariate analysis, corticosteroid use (hazard ratio [HR] = 2.37) was associated with poorer OS, whereas stable BMs (HR = 0.62) and higher ds-GPA classification (HR = 0.48-0.52) were associated with improved OS., Conclusion: In multivariate analysis BMs are not associated with a poorer survival in patients with ICI-treated NSCLC. Stable patients with BM without baseline corticosteroids and a good ds-GPA classification have the best prognosis., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

This study aims at quantifying and characterising microplastics (MP) distribution in the water column of the NW Mediterranean Sea as well as MP ingestion by the 2 main planktivorous fish of the area, sardine and anchovy. Debris of similar sizes were found in all water column samples and in all but 2 fish guts (out of 169). MP were found in 93% of water column samples with an average concentration of 0.23 ± 0.20 MP·m -3 , but in only 12% of sardines (0.20 ± 0.69 MP·ind -1 ) and 11% of anchovies (0.11 ± 0.31 MP·ind -1 ). Fibres were the only shape of MP encountered and polyethylene terephthalate was the main polymer identified in water columns (61%), sardines (71%) and anchovies (89%). This study confirms the ubiquity of MP in the Mediterranean Sea and imparts low occurrence in fish digestive tracts., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Multiple cytogenetic subgroups have been described in adult Philadelphia chromosome (Ph)-negative B-cell precursor (BCP) acute lymphoblastic leukemia (ALL), often comprising small numbers of patients. In this study, we aimed to reassess the prognostic value of cytogenetic abnormalities in a large series of 617 adult patients with Ph-negative BCP-ALL (median age, 38 years), treated in the intensified Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/2005 trials. Combined data from karyotype, DNA index, fluorescence in situ hybridization, and polymerase chain reaction screening for relevant abnormalities were centrally reviewed and were informative in 542 cases (88%), allowing classification in 10 exclusive primary cytogenetic subgroups and in secondary subgroups, including complex and monosomal karyotypes. Prognostic analyses focused on cumulative incidence of failure (including primary refractoriness and relapse), event-free survival, and overall survival. Only 2 subgroups, namely t(4;11)/ KMT2A-AFF1 and 14q32/ IGH translocations, displayed a significantly worse outcome in this context, still observed after adjustment for age and after censoring patients who received allogeneic stem cell transplantation (SCT) in first remission at SCT time. A worse outcome was also observed in patients with low hypodiploidy/near triploidy, but this was likely related to their higher age and worse tolerance to therapy. The other cytogenetic abnormalities, including complex and monosomal karyotypes, had no prognostic value in these intensive protocols designed for adult patients up to the age of 60 years., (© 2017 by The American Society of Hematology.)

Radiation-induced lung disease (RILD) is common after radiation therapy and represents cornerstone toxicities after treatment of thoracic malignancies. From a review of literature, the objective of this article was to summarize clinical and non-clinical parameters associated with the risk of RILD in the settings of normo-fractionated radiotherapy and stereotactic body radiation therapy (SBRT). For the treatment of lung cancers with a normo-fractionated treatment, the mean lung dose (MLD) should be below 15-20Gy. For a thoracic SBRT, V20Gy<10% and MLD<6Gy are recommended. One should pay attention to central tumors and respect specific dose constraints to the bronchial tree. The recent technological improvements may represent an encouraging way to decrease lung toxicities. Finally, our team developed a calculator in order to predict the risk of radiation pneumonitis., (Copyright © 2017 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Objectives: There are many national and international recommendations and guidelines for the management of patients with endometrioma. In this study, we aimed to evaluate the impact of these recommendations on the practice of French surgeons, and to assess their knowledge about the management of endometriomas., Materials and Methods: A self-questionnaire has been sent to the French members of the Society of Gynecologic Surgery and Pelvic (SCGP) in May 2015., Results: One hundred and forty-four members of the society (36 %) participated in the survey. Most of the practitioners (71 %) followed recommendations of the Collège National des Gynécologues Obstétriciens (CNGOF), 38 % followed the guidelines of European Society of Human Reproduction and Embryology (ESHRE). One hundred percent of the surgeons declared that they practice laparoscopy when a surgical removal of the endometrioma is indicated. About treatment with GnRH analogue, 38 % of the practitioners declared that they prescribe an add back therapy immediately after the surgery, 43 % at 3 months, and 14 % declared that they never prescribe this treatment., Conclusions: French surgeons consider the recommendations are useful in their clinical practice; they primarily apply the guidelines of the CNGOF., (Copyright © 2016. Published by Elsevier Masson SAS.)

Aim: Sentinel lymph node (SLN) biopsy was recently recommended after prior breast tumour surgery and lymphadenectomy is not the gold standard anymore for nodal staging after a lesion's removal. The purpose of our study was to evaluate the good practices of use of SLN biopsy in this context., Patients and Methods: From 2006 to 2012, 138 patients having undergone a surgical biopsy without prior diagnosis of an invasive carcinoma with a definitive histological analysis in favour of this diagnosis were included in a prospective observational multicentric study. Each patient had a nodal staging following SLN biopsy with subsequent systematic lymphadenectomy., Results: The detection rate of SLN was 85.5%. The average number of SLNs found was 1.9. The relative detection failure risk rate was multiplied by 4 in the event of an interval of less than 36 days between the SLN biopsy and the previous breast surgery, and by 9 in the event of using a single-tracer detection method. The false negative rate was 6.25%. The prevalence of metastatic axillary node involvement was 11.6%. In 69% of cases only the SLN was metastatic. The post-operative seroma rate was 19.5%., Conclusion: Previous conservative breast tumour surgery does not affect the accuracy of the SLN biopsy. A sufficient interval of greater than 36 days between the two operations could allow to improve the SLN detection rate, although further studies are needed to validate this statement., Clinical Trial Registration Number: NCT00293865., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: To develop an evidence-based guideline for Peer Review of Electronic Search Strategies (PRESS) for systematic reviews (SRs), health technology assessments, and other evidence syntheses., Study Design and Setting: An SR, Web-based survey of experts, and consensus development forum were undertaken to identify checklists that evaluated or validated electronic literature search strategies and to determine which of their elements related to search quality or errors., Results: Systematic review: No new search elements were identified for addition to the existing (2008-2010) PRESS 2015 Evidence-Based Checklist, and there was no evidence refuting any of its elements. Results suggested that structured PRESS could identify search errors and improve the selection of search terms. Web-based survey of experts: Most respondents felt that peer review should be undertaken after the MEDLINE search had been prepared but before it had been translated to other databases. Consensus development forum: Of the seven original PRESS elements, six were retained: translation of the research question; Boolean and proximity operators; subject headings; text word search; spelling, syntax and line numbers; and limits and filters. The seventh (skilled translation of the search strategy to additional databases) was removed, as there was consensus that this should be left to the discretion of searchers. An updated PRESS 2015 Guideline Statement was developed, which includes the following four documents: PRESS 2015 Evidence-Based Checklist, PRESS 2015 Recommendations for Librarian Practice, PRESS 2015 Implementation Strategies, and PRESS 2015 Guideline Assessment Form., Conclusion: The PRESS 2015 Guideline Statement should help to guide and improve the peer review of electronic literature search strategies., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive leukemia for which knowledge on disease mechanisms and effective therapies are currently lacking. Only a handful of recurring genetic mutations have been identified and none is specific to BPDCN. In this study, through molecular cloning in an index case that presented a balanced t(3;5)(q21;q31) and molecular cytogenetic analyses in a further 46 cases, we identify monoallelic deletion of NR3C1 (5q31), encoding the glucocorticoid receptor (GCR), in 13 of 47 (28%) BPDCN patients. Targeted deep sequencing in 36 BPDCN cases, including 10 with NR3C1 deletion, did not reveal NR3C1 point mutations or indels. Haploinsufficiency for NR3C1 defined a subset of BPDCN with lowered GCR expression and extremely poor overall survival (P = .0006). Consistent with a role for GCR in tumor suppression, functional analyses coupled with gene expression profiling identified corticoresistance and loss-of-EZH2 function as major downstream consequences of NR3C1 deletion in BPDCN. Subsequently, more detailed analyses of the t(3;5)(q21;q31) revealed fusion of NR3C1 to a long noncoding RNA (lncRNA) gene (lincRNA-3q) that encodes a novel, nuclear, noncoding RNA involved in the regulation of leukemia stem cell programs and G1/S transition, via E2F. Overexpression of lincRNA-3q was a consistent feature of malignant cells and could be abrogated by bromodomain and extraterminal domain (BET) protein inhibition. Taken together, this work points to NR3C1 as a haploinsufficient tumor suppressor in a subset of BPDCN and identifies BET inhibition, acting at least partially via lncRNA blockade, as a novel treatment option in BPDCN., (© 2016 by The American Society of Hematology.)

Objectives: Uterine myomas are a frequent pathology affecting 20% of women of reproductive age. Myomas induce abnormal uterine bleeding, pelvic pain and increase the risk of infertility and obstetrical complications. Symptomatic sub-mucosal myomas are classically treated by hysteroscopic resection. Simulation is a method of education and training. It could improve quality and security of cares. The aim of this study is to assess the interest of a hysteroscopic simulator for the resection of myoma by novice surgeons., Methods: Twenty medical students were recruited, in a prospective study, in august 2014. The virtual-reality simulator VirtaMed HystSim™ (VirtaMed AG, Zurich, Switzerland) was used to perform the hysteroscopic training. All students received a short demonstration of myoma resection. The practice consists of a submucous myoma type 0 resection. The procedure and the evaluation were performed before and after a specific training in hysteroscopic resection of sixty minutes long. The main outcome criteria were time for the resection before and after training. The second criteria were fluid quantity used, number of contact between optic and uterine cavity and uterine perforation., Results: Twenty students aged from 22 to 24 years were included. The time for the procedure was significantly reduced after training (170s versus 335s, P<0.01). There is the same for fluid quantity used (335 mL versus 717mL, P<0.01) and the number of contact between optic and uterine cavity (0.2 contact versus 3, P=0.012). No perforation occurred in the simulation., Conclusion: The results suggest that hysteroscopic simulator enhances and facilitates hysteroscopic resection for novice surgeons., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Objective: Does surgery for deep infiltrating endometriosis (DIE) before in vitro fertilization (IVF) improve pregnancy and birth rate?, Patients and Methods: Cohort study of 177 consecutive patients with DIE related infertility and receiving IVF. Patients were divided into 3 groups according to surgical management decided during multidisciplinary team meeting. Group no surgery (NS) (n=65), group complete surgery (CS) with complete resection of all lesions (n=49) and group incomplete surgery (IS) with gestures improving ovaries accessibility for IVF and/or facilitating embryonic implantation (n=63). Pre-surgery clinical, MRI lesion locations, and history of IVF characteristics were analyzed with logistic regression., Results: There was no significant difference in general and IVF characteristics and in the severity of endometriosis among the three groups (P=0.43). Overall pregnancy and birth rates after IVF were 45.8% and 33.3%, respectively and were not different among the 3 groups (P=0.59 and P=0.49). Four major complications during oocytes retrievals were observed in NS group, one in IS group and none in CS group. Presence of an inter-utero-rectal lesion at MRI decreased the rate of pregnancy (OR=0.49 [0.25, 0.97])., Discussion and Conclusions: Surgery for deep infiltrating endometriosis does not improve pregnancy and birth rates before IVF. This inter-utero-rectal extensive lesion might explain IVF failures by ovarian difficult access and difficulties in embryonic transfers. Further studies should explore the impact of surgical excision of inter-utero-rectal lesion on oocyte retrieval and embryonic transfer., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

GATA4-6 transcription factors regulate numerous aspects of development and homeostasis in multiple tissues of mesodermal and endodermal origin. In the heart, the best studied of these factors, GATA4, has multiple distinct roles in cardiac specification, differentiation, morphogenesis, hypertrophy and survival. To improve understanding of how GATA4 achieves its numerous roles in the heart, here we have focused on the carboxy-terminal domain and the residues required for interaction with cofactors FOG2 and Tbx5. We present evidence that the carboxy terminal region composed of amino acids 362-400 is essential for mediating cardiogenesis in Xenopus pluripotent explants and embryos. In contrast, the same region is not required for endoderm-inducing activity of GATA4. Further evidence is presented that the carboxy terminal cardiogenic region of GATA4 does not operate as a generic transcriptional activator. Potential mechanism of action of the carboxy terminal end of GATA4 is provided by the results showing physical and functional interaction with CDK4, including the enhancement of cardiogenic activity of GATA4 by CDK4. These results establish CDK4 as a GATA4 partner in cardiogenesis. The interactions of GATA4 with its other well described cofactors Tbx5 and FOG2 are known to be involved in heart morphogenesis, but their requirement for cardiac differentiation is unknown. We report that the mutations that disrupt interactions of GATA4 with Tbx5 and FOG2, G295S and V217G, respectively, do not impair cardiogenic activity of GATA4. These findings add support to the view that distinct roles of GATA4 in the heart are mediated by different determinants of the protein. Finally, we show that the rat GATA4 likely induces cardiogenesis cell autonomously or directly as it does not require activity of endodermal transcription factor Sox17, a GATA4 target gene that induces cardiogenesis non-cell autonomously., (Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

The genetic hallmark of Burkitt lymphoma (BL) is the t(8;14)(q24;q32) and its variants leading to activation of the MYC oncogene. It is a matter of debate whether true BL without MYC translocation exists. Here, we identified 59 lymphomas concordantly called BL by 2 gene expression classifiers among 753 B-cell lymphomas. Only 2 (3%) of these 59 molecular BL lacked a MYC translocation, which both shared a peculiar pattern of chromosome 11q aberration characterized by interstitial gains including 11q23.2-q23.3 and telomeric losses of 11q24.1-qter. We extended our analysis to 17 MYC-negative high-grade B-cell lymphomas with a similar 11q aberration and showed this aberration to be recurrently associated with morphologic and clinical features of BL. The minimal region of gain was defined by high-level amplifications in 11q23.3 and associated with overexpression of genes including PAFAH1B2 on a transcriptional and protein level. The recurrent region of loss contained a focal homozygous deletion in 11q24.2-q24.3 including the ETS1 gene, which was shown to be mutated in 4 of 16 investigated cases. These findings indicate the existence of a molecularly distinct subset of B-cell lymphomas reminiscent of BL, which is characterized by deregulation of genes in 11q.

Objectives: The aim of this study was to determine the effect of stress cardiac magnetic resonance (CMR) imaging in an observation unit (OU) on revascularization, hospital readmission, and recurrent cardiac testing in intermediate-risk patients with possible acute coronary syndromes (ACS)., Background: Intermediate-risk patients commonly undergo hospital admission with high rates of coronary revascularization. It is unknown whether OU-based care with CMR is a more efficient alternative., Methods: A total of 105 intermediate-risk participants with symptoms of ACS but without definite ACS on the basis of the first electrocardiogram and troponin were randomized to usual care provided by cardiologists and internists (n = 53) or to OU care with stress CMR (n = 52). The primary composite endpoint of coronary artery revascularization, hospital readmission, and recurrent cardiac testing at 90 days was determined. The secondary endpoint was length of stay from randomization to index visit discharge; safety was measured as ACS after discharge., Results: The median age of participants was 56 years (range 35 to 91 years), 54% were men, and 20% had pre-existing coronary disease. Index hospital admission was avoided in 85% of the OU CMR participants. The primary outcome occurred in 20 usual care participants (38%) versus 7 OU CMR participants (13%) (hazard ratio: 3.4; 95% confidence interval: 1.4 to 8.0, p = 0.006). The OU CMR group experienced significant reductions in all components: revascularizations (15% vs. 2%, p = 0.03), hospital readmissions (23% vs. 8%, p = 0.03), and recurrent cardiac testing (17% vs. 4%, p = 0.03). Median length of stay was 26 h (interquartile range: 23 to 45 h) in the usual care group and 21 h (interquartile range: 15 to 25 h) in the OU CMR group (p < 0.001). ACS after discharge occurred in 3 usual care participants (6%) and no OU CMR participants., Conclusions: In this single-center trial, management of intermediate-risk patients with possible ACS in an OU with stress CMR reduced coronary artery revascularization, hospital readmissions, and recurrent cardiac testing, without an increase in post-discharge ACS at 90 days. (Randomized Investigation of Chest Pain Diagnostic Strategies; NCT01035047)., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Chromosomal translocations involving the immunoglobulin heavy chain locus (IGH@) are recurrent but rare in B-cell precursor acute lymphoblastic leukemia (BCP-ALL), and various partner genes have been described. Here, we report a new series of 29 cases of BCP-ALL with IGH@ translocations. The partner gene was identified by fluorescence in situ hybridization and/or molecular cloning in 20 patients. Members of the CEBP gene family (n = 11), BCL2 (n = 3), ID4 (n = 3), EPOR (n = 2), and TRA/D@ (n = 1) were identified and demonstrated by quantitative real-time reverse transcriptase-polymerase chain reaction to be markedly up-regulated. The present cases, added to those already reported, confirm the diversity of the partner genes, which, apart from BCL2, are specific to BCP-ALL. Collectively, patients with IGH@ translocations may represent a novel sub-group of BCP-ALL occurring in adolescents and young adults., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Numerous studies indicate that an increase in reactive oxygen species (ROS) significantly affects white adipose tissue biology and leads to an inflammatory profile and insulin resistance, which could contribute to obesity-associated diabetes and cardiovascular diseases. Mitochondria play a key role in adipose tissue energy metabolism and constitute the main source of cellular ROS such as H(2)O(2). Polyphenols constitute the most abundant antioxidants provided by the human diet. Indeed, they are widely distributed in fruits, vegetables and some plant-derived beverages such as coffee and tea. Thus, the biological effects of dietary polyphenols that may increase the antioxidant capacity of the body against obesity-induced oxidative stress are of high interest. Here, we studied the capacity of polyphenols to modulate the impact of oxidative stress on the mitochondria of preadipocytes, which are important cells governing the adipose tissue development for energy homeostasis. Whereas H(2)O(2) treatment induces a proliferation arrest associated with an increase in mitochondrial content in 3T3-L1 preadipocytes, preconditioning with some major dietary polyphenols totally or partially protects the cells against oxidative stress consequences. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The presence of bacteria in semen could induce impairment of sperm morphology, alteration of sperm function and mechanical or functional obstruction of the seminal tract. The term of bacteriospermia does not signify infection. Bacteriospermia and male accessory gland infection (MAGI) have indeed to be distinguished. They may lead both to male infertility but their diagnosis and treatment options differ. This review summarizes effects of bacteria and leucocytospermia on sperm parameters and functions. Then, indications, benefits and risks of treatment of bacteriospermia and MAGI, in assisted reproductive techniques (ART) will be discussed. For bacteria commonly observed in semen, this review aims at defining some thresholds above which a treatment is required. These thresholds were established according to literature, according to French microbiology society and in function of our usual practice. This review should help practitioners of reproductive medicine to take care of bacteriospermia in semen., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Introduction: In 2011, the French National Cancer Institute recommended ALK-fluorescence in situ hybridization (FISH) testing in all EGFR/KRAS-negative adenocarcinomas by all the hospital molecular genetics platforms of cancers; however, this technique remains time and cost consuming and not suitable for a large-scale screening, in contrast to immunohistochemistry (IHC)., Methods: To evaluate IHC as a prescreening tool, 441 specimens, including small biopsies and surgical specimens, were analyzed prospectively on the Grenoble molecular genetics platform. EGFR and KRAS mutation analyses and ALK IHC, using the 5A4 mAb on an automated staining module, were performed on all specimens; 100 were tested by both ALK IHC and FISH (break-apart probe)., Results: Twenty-seven cases out of 441 were strongly positive (3+ intensity in more than 60% of cells) with ALK mAb, two additional cases exhibited a faint staining (1+) in less than 30% of the cells. Among the 100 cases analyzed by IHC and FISH, 19 were not interpretable by FISH, but 21 were positive with both techniques. Sensitivity and specificity of IHC when compared with FISH were 95 and 100%, respectively. Eleven patients were included in crizotinib trials. Among the 352 analyzable specimens for mutations, 7% were EGFR and 29% were KRAS mutated., Conclusions: Our IHC protocol, using a commercially available antibody and an amplification step on an automated staining module, led to intense cytoplasmic staining in 6.5% of the adenocarcinomas screened. Our results favor ALK IHC prescreening on a daily routine on surgical specimens and on small biopsies before FISH testing.

Objectives: This study sought to compare the direct cost of medical care and clinical events during the first year after patients with intermediate risk acute chest pain were randomized to stress cardiac magnetic resonance (CMR) observation unit (OU) testing versus inpatient care., Background: In a recent study, randomization to OU-CMR reduced median index hospitalization cost compared with the cost of inpatient care in patients presenting to the emergency department with intermediate risk acute chest pain., Methods: Emergency department patients with intermediate risk chest pain were randomized to OU-CMR (OU care, cardiac markers, stress CMR) or inpatient care (admission, care per admitting provider). This analysis reports the direct cost of cardiac-related care and clinical outcomes (myocardial infarction, revascularization, cardiovascular death) during the first year of follow-up subsequent to discharge. Consistent with health economics literature, provider cost was calculated from work-related relative value units using the Medicare conversion factor; facility charges were converted to cost using departmental-specific cost-to-charge ratios. Linear models were used to compare cost accumulation among study groups., Results: We included 109 randomized subjects in this analysis (52 OU-CMR, 57 inpatient care). The median age was 56 years; baseline characteristics were similar in both groups. At 1 year, 6% of OU-CMR and 9% of inpatient care participants experienced a major cardiac event (p = 0.72) with 1 patient in each group experiencing a cardiac event after discharge. First-year cardiac-related costs were significantly lower for participants randomized to OU-CMR than for participants receiving inpatient care (geometric mean = $3,101 vs. $4,742 including the index visit [p = 0.004] and $29 vs. $152 following discharge [p = 0.012]). During the year following randomization, 6% of OU-CMR and 9% of inpatient care participants experienced a major cardiac event (p = 0.72)., Conclusions: An OU-CMR strategy reduces cardiac-related costs of medical care during the index visit and over the first year subsequent to discharge, without an observed increase in major cardiac events. (Cost Comparison of Cardiac Magnetic Resonance Imaging [MRI] Use in Emergency Department [ED] Patients With Chest Pain; NCT00678639)., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aim: The aim of this study was to describe the use of laparoscopy in gynecologic malignancies (cervical, endometrial and ovarian cancer, borderline included) in France during year 2005., Patients and Methods: We have carried out a retrospective national practice survey during 12 months. Each university hospital (45 centers) and each cancer center (20 centers) received a questionnaire to evaluate their practice in laparoscopy. Centers performing less than ten cases per year in this indication were excluded., Results: Among 65 centers, 31 answered and 19 were included. A total of 1397 surgical procedures for gynaecologic cancer was analysed. Laparoscopy was performed in 714 cases. In these cases, 51.1% (675 cases) of patients were treated by laparoscopy in France during year 2005. Seventy-four surgical procedures for cancer were performed each year per center and among them 38 by laparoscopy. The average cases number is 9.4 per surgeon., Conclusion: We found that 51.1% of cases of gynaecologic cancer surgery were performed by laparoscopy in France during 2005, representing 38 cases per centers and 9.4 per surgeon per year. This suggests that access to training for surgeons and care for patients is difficult., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Ritual sexual mutilations cause gynaecologic, urologic and obstetric complications. Their surgical treatments like clitoris reconstruction or desinfibulation have been well studied. We describe the Dr Pierre Foldes's (2004, 2006a, b) surgical technique of clitoris reconstruction after ritual excision. After scar resection, clitoris knee and corporeal bodies are liberated with meticulous nerve sparing. A new clitoridian glans is created by cuneiform plasty and then reimplanted in an anatomic situation. The aim of the technique is to restore a normal anatomy and to obtain a sensory and functional organ. We also describe the desinfibulation technique in this article., (Copyright © 2009 Elsevier Masson SAS. All rights reserved.)

As most solid tumors, surgery is often the first step of the multidisciplinary management for breast cancers. Although mastectomy and axillar lymphadenectomy still have indications, conservative treatment and sentinel node detection are commonly used. Thanks to induction chemotherapy and oncoplastic techniques, surgery is conservative in most cases, even for important tumors without overall survival prejudice. There is no consensus about resection margins status but a limit of 2 to 3 mm seems to be reasonable while oncoplastic surgery allows large resection and good cosmetic outcomes. In this overview, we present the state of the art for breast cancer surgery including conservative and radical treatments, axillar lymphadenectomy and sentinel lymph node detection, margins status, oncoplastic techniques., (Copyright © 2010. Published by Elsevier Masson SAS.)

Patient follow-up after treatment for a breast cancer is based on the local recurrence risk. Annual mammography remains the main point of this follow-up and tumor markers detection has still no interest. Absence of benefit of an intensive clinical, biological and radiological surveillance has been proved for a long time but expert recommendations still are a subject of discussion although they knew no evolution for more than 10 years. Evolution of those follow-up modalities will depend on the future indications of MRI and PET. About distant recurrence, a better knowledge of the risk is now possible thanks to the tumor biological profile study. Nevertheless, intensification of follow-up for some kind of high-risk tumors will have interest only if we can propose a therapeutic alternative in metastatic situation., (Copyright © 2010. Published by Elsevier Masson SAS.)

Dendritic cells (DCs) are central cells in the development of antitumor immune responses, but the number and function of these cells can be altered in various cancers. Whether these cells are affected during the development of melanoma is not known. We investigated the presence, phenotype, and functionality of circulating myeloid DCs (MDCs) and plasmacytoid DCs (PDCs) in newly diagnosed melanoma patients, compared to controls. The frequencies of PDCs and MDCs were equivalent in melanoma patients as compared with normal subjects. Both circulating DC subsets were immature, but on ex vivo stimulation with R848 they efficiently upregulated their expression of costimulatory molecules. We found that circulating DCs from melanoma patients and controls displayed similar pattern of expression of the chemokine receptors CXCR3, CXCR4, CCR7, and CCR10. Strikingly, PDCs from melanoma patients expressed higher levels of CCR6 than control PDCs, and were able to migrate toward CCL20. Further data showed that CCR6-expressing PDCs were present in melanoma primary lesions, and that CCL20 was produced in melanoma tumors. These results suggest that PDCs and MDCs are functional in melanoma patients at the time of diagnosis, and that CCL20 may participate to their recruitment from the blood to the tumor.

The recent demonstration that aromatase is expressed at higher levels in endometriosis implants than in normal endometrium has led to pilot studies using inhibitor aromatasis in patients with endometriosis. We conducted a systematic review of the literature and studied the efficacy of aromatase inhibitors on endometriosis. There were seventeen studies (case reports/series) evaluating outcomes of aromatase inhibitors. Studies suggest that aromatase inhibitors alone or co-administered with progestins, oral contraceptives or gonadotrophin releasing hormone (GnRH) agonist could reduce pain and endometriosis. There is only one randomized controlled trial comparing aromatase inhibitor+GnRH agonist and GnRH agonist and one study with eighty patients. Side-effects profiles of aromatase inhibitor regimens are favorable; it does not appear a significant bone loss. Aromatase inhibitors seem to have a promising effect on endometriosis but randomized controlled trials are needed to prove their effects and their safety., (Copyright 2010 Elsevier Masson SAS. All rights reserved.)

PAX5 is the main target of somatic mutations in acute B lymphoblastic leukemia (B-ALL). We analyzed 153 adult and child B-ALL harboring karyotypic abnormalities at chromosome 9p, to determine the frequency and the nature of PAX5 alterations. We found PAX5 internal rearrangements in 21% of the cases. To isolate fusion partners, we used classic and innovative techniques (rolling circle amplification-rapid amplification of cDNA ends) and single nucleotide polymorphism-comparative genomic hybridization arrays. Recurrent and novel fusion partners were identified, including NCoR1, DACH2, GOLGA6, and TAOK1 genes showing the high variability of the partners. We noted that half the fusion genes can give rise to truncated PAX5 proteins. Furthermore, malignant cells carrying PAX5 fusion genes displayed a simple karyotype. These data strongly suggest that PAX5 fusion genes are early players in leukemogenesis. In addition, PAX5 deletion was observed in 60% of B-ALL with 9p alterations. Contrary to cases with PAX5 fusions, deletions were associated with complex karyotypes and common recurrent translocations. This supports the hypothesis of the secondary nature of the deletion. Our data shed more light on the high variability of PAX5 alterations in B-ALL. Therefore, it is probable that gene fusions occur early, whereas deletions should be regarded as a late/secondary event.

Susceptibility of the ovarian reserve to chemotherapy is highly variable from one patient to another and poorly documented. To better characterize the evolution of follicular depletion in patients treated for lymphoma, serum anti-Müllerian hormone (AMH) assay was used. A total of 30 young women (mean age 24years) were prospectively recruited before initiation of chemotherapy for lymphoma. They were assigned either to an adriamycin, bleomycin, vinblastine and dacarbazine protocol (ABVD group) or to a protocol that included cyclophosphamide (non-ABVD group). AMH assays were performed before and during chemotherapy, and then every 3months after the end of treatment for a period of 1year. In all patients, AMH concentrations fell drastically just after the start of chemotherapy and were close to the detection limit at the end of the treatment. In the ABVD group, AMH concentrations increased from the third month after the end of chemotherapy and returned to pretreatment values 12months after the end of chemotherapy. Conversely, no significant change was observed in the non-ABVD group throughout the follow-up period. In conclusion, longitudinal analysis of AMH during chemotherapy highlights differences between protocols that could contribute to an understanding of ovarian toxicity and, ultimately, be useful in fertility preservation counselling., (2009 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Objective: Complex and highly sensitive electronic literature search strategies are required for systematic reviews; however, no guidelines exist for their peer review. Poor searches may fail to identify existing evidence because of inadequate recall (sensitivity) or increase the resource requirements of reviews as a result of inadequate precision. Our objective was to create an annotated checklist for electronic search strategy peer review., Study Design: A systematic review of the library and information retrieval literature for important elements in electronic search strategies was conducted, along with a survey of individuals experienced in systematic review searching., Results: Six elements with a strong consensus as to their importance in peer review were accurate translation of the research question into search concepts, correct choice of Boolean operators and of line numbers, adequate translation of the search strategy for each database, inclusion of relevant subject headings, and absence of spelling errors. Seven additional elements had partial support and are included in this guideline., Conclusion: This evidence-based guideline facilitates the improvement of search quality through peer review, and thus the improvement in quality of systematic reviews. It is relevant for librarians/information specialists, journal editors, developers of knowledge translation tools, research organizations, and funding bodies.

The let-413/scribble and dlg-1/discs large genes are key regulators of epithelial cell polarity in C. elegans and other systems but the mechanism how they organize a circumferential junctional belt around the apex of epithelial cells is not well understood. We report here that IP(3)/Ca(2+) signaling is involved in the let-413/dlg-1 pathway for the establishment of epithelial cell polarity during the development in C. elegans. Using RNAi to interfere with let-413 and dlg-1 gene functions during post-embryogenesis, we discovered a requirement for LET-413 and DLG-1 in the polarization of the spermathecal cells. The spermatheca forms an accordion-like organ through which eggs must enter to complete the ovulation process. LET-413- and DLG-1-depleted animals exhibit failure of ovulation. Consistent with this phenotype, the assembly of the apical junction into a continuous belt fails and the PAR-3 protein and microfilaments are no longer localized asymmetrically. All these defects can be suppressed by mutations in IPP-5, an inositol polyphosphate 5-phosphatase and in ITR-1, an inositol triphosphate receptor, which both are supposed to increase the intracellular Ca(2+) level. Analysis of embryogenesis revealed that IP(3)/Ca(2+) signaling is also required during junction assembly in embryonic epithelia.

Introduction: Wegener's granulomatosis (WG) is a systemic necrotizing vasculitis associated with c-ANCA antibodies. The involvement of the central nervous system in WG is uncommon and usually caused by in situ vasculitis, intracranial granuloma formation or contiguous invasion from extracranial sites., Case Report: Here, we report on a tumour-like expansion of a severe nasosinusal WG into the brain, which was confirmed by brain biopsy examination., Conclusion: The positivity of positron emission tomography in our observation supports the potential role of such functional imaging in the staging, as well as in the follow-up of WG.

Association mapping and candidate gene studies within inflammatory bowel diseases (IBD) linkage regions, as well as genome-wide association studies in Crohn's disease (CD) have led to the discovery of multiple risk genes, but these explain only a fraction of the genetic susceptibility observed in IBD. We have thus been pursuing a region on chromosome 3p21-22 showing linkage to CD and ulcerative colitis (UC) using a gene-centric association mapping approach. We identified 12 functional candidate genes by searching for literature cocitations with relevant keywords and for gene expression patterns consistent with immune/intestinal function. We then performed an association study composed of a screening phase, where tagging single nucleotide polymorphisms (SNPs) were evaluated in 1,020 IBD patients, and an independent replication phase in 745 IBD patients. These analyses identified and replicated significant association with IBD for four SNPs within a 1.2 Mb linkage disequilibrium region. We then identified a non-synonymous coding variant (rs3197999, R689C) in the macrophage-stimulating 1 (MST1) gene (P-value 3.62 x 10(-6)) that accounts for the association signal, and shows association with both CD and UC. MST1 encodes macrophage-stimulating protein (MSP), a protein regulating the innate immune responses to bacterial ligands. R689C is predicted to interfere with MSP binding to its receptor, suggesting a role for this gene in the pathogenesis of IBD.

Symphysis fundus measurements are a reliable mean for screening of fetal growth retardation. The techniques of the measurements, the curves of normality, and the efficiency of this method are discussed. A single formula is put forward to identify the patients witch can profit by extra ultrasound examinations and special clinical surveillance. In France, ultrasound examinations are scheduled at 22 and 32 weeks. Between 22 and 32 weeks, and after 32 weeks, symphysis fundus measurements are needed to suspect intra uterine fetal retardation, and, following suspicion, a new ultrasound examination is helpful.

Relationship between infertility and endometriosis is still controversial. Many mechanisms have been reported such as anatomical disorders, biologic and cytological modifications of peritoneal liquid, functional ovarian and endometrial disorders, reduced embryo quality. Management of infertility related to endometriosis is difficult and no consensus has been published yet. Following recent clinical data, therapeutic strategies are discussed.