Le modèle standard de la physique des particules décrit la matière constituée de particules élémentaires qui interagissent via les interactions fortes et électrofaibles. Le quark top est le quark le ...plus lourd décrit par ce modèle et a été découvert en 1995 par les collaborations CDF et DO dans les collisions proton-antipronton du Tevatron. Cette thèse est consacrée à la mesure de la section efficace de production de paire de quarks top par interaction forte, dans un état final contenant un lepton, un tau hadronique, deux jets de b et de l'énergie tranverse manquante. Cette analyse utilise les données collectées entre juillet 2006 et août 2007, soit une luminosité de 1,2 fb-1, qui sont combinées avec les données du Run IIa pour atteindre une luminosité de 2,2 fb-1. Une partie du travail de thèse fut consacrée au système de déclenchement du détecteur D0 et en particulier à l'identification des leptons taus au niveau 3 du système de déclenchement et aux déclenchements basés sur la présence de jets et d'énergie tranverse manquante. La problématique de la résolution en énergie des jets est également abordée, sous l'angle de l'intercalibration en eta du calorimètre hadronique et avec l'utilisation du détecteur de pied de gerbe central dans la définition de l'énergie des jets. La section efficace de production de paires de quark top obtenue est 7,32+1,34-1,24(stat)+1,20-1,06(syst)+-0,45(lumi)pb. Cette mesure est en accord avec les prédictions du modèle standard et permet de contraindre la présence de nouvelle physique, telle que l'existence d'un boson de Higgs plus léger que le quark top. Une limite d'exclusion a ainsi été obtenue dans le plan (tan beta,mH+-) et est présentée dans la dernière partie de ce manuscrit.
We introduce the Microenvironment Cell Populations-counter (MCP-counter) method, which allows the robust quantification of the absolute abundance of eight immune and two stromal cell populations in ...heterogeneous tissues from transcriptomic data. We present in vitro mRNA mixture and ex vivo immunohistochemical data that quantitatively support the validity of our method's estimates. Additionally, we demonstrate that MCP-counter overcomes several limitations or weaknesses of previously proposed computational approaches. MCP-counter is applied to draw a global picture of immune infiltrates across human healthy tissues and non-hematopoietic human tumors and recapitulates microenvironment-based patient stratifications associated with overall survival in lung adenocarcinoma and colorectal and breast cancer.
The presence of intratumoral tertiary lymphoid structures (TLS) is associated with positive clinical outcomes and responses to immunotherapy in cancer. Here, we used spatial transcriptomics to ...examine the nature of B cell responses within TLS in renal cell carcinoma (RCC). B cells were enriched in TLS, and therein, we could identify all B cell maturation stages toward plasma cell (PC) formation. B cell repertoire analysis revealed clonal diversification, selection, expansion in TLS, and the presence of fully mature clonotypes at distance. In TLS+ tumors, IgG- and IgA-producing PCs disseminated into the tumor beds along fibroblastic tracks. TLS+ tumors exhibited high frequencies of IgG-producing PCs and IgG-stained and apoptotic malignant cells, suggestive of anti-tumor effector activity. Therapeutic responses and progression-free survival correlated with IgG-stained tumor cells in RCC patients treated with immune checkpoint inhibitors. Thus, intratumoral TLS sustains B cell maturation and antibody production that is associated with response to immunotherapy, potentially via direct anti-tumor effects.
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•Tertiary lymphoid structures are sites of in situ B cell maturation toward plasma cells•IgG+ and IgA+ plasma cells disseminate into the tumor tissue along fibroblastic tracks•Tumor cells are labeled by locally produced IgG•Patients with IgG-labeled tumor cells have high response rate to ICI and prolonged PFS
Meylan et al. show that tertiary lymphoid structures found in tumors are sites of generation of fully mature B cell immunity. Plasma cells disseminate into tumor beds, producing antibodies that bind to tumor cells and initiate their apoptosis, providing a mechanism to support cancer immunotherapies that modulate the tumor microenvironment.
The efficacy of PD-1 checkpoint blockade as adjuvant therapy in localized clear cell renal cell carcinoma (ccRCC) is currently unknown. The identification of tumor microenvironment (TME) prognostic ...biomarkers in this setting may help define which patients could benefit from checkpoint blockade and uncover new therapeutic targets.
We performed multiparametric flow cytometric immunophenotypic analysis of T cells isolated from tumor tissue tumor-infiltrating lymphocytes (TIL), adjacent non-malignant renal tissue renal-infiltrating lymphocytes (RIL), and peripheral blood lymphocytes (PBL), in a cohort of patients (
= 40) with localized ccRCC. Immunophenotypic data were integrated with prognostic and histopathologic variables, T-cell receptor (TCR) repertoire analysis of sorted CD8
PD-1
TILs, tumor mRNA expression, and digital quantitative immunohistochemistry.
On the basis of TIL phenotypic characterization, we identified three dominant immune profiles in localized ccRCC: (i) immune-regulated, characterized by polyclonal/poorly cytotoxic CD8
PD-1
Tim-3
Lag-3
TILs and CD4
ICOS
cells with a Treg phenotype (CD25
CD127
Foxp3
/Helios
GITR
), that developed in inflamed tumors with prominent infiltrations by dysfunctional dendritic cells and high PD-L1 expression; (ii) immune-activated, enriched in oligoclonal/cytotoxic CD8
PD-1
Tim-3
TILs, that represented 22% of the tumors; and (iii) immune-silent, enriched in TILs exhibiting RIL-like phenotype, that represented 56% of patients in the cohort. Only immune-regulated tumors displayed aggressive histologic features, high risk of disease progression in the year following nephrectomy, and a CD8
PD-1
Tim-3
and CD4
ICOS
PBL phenotypic signature.
In localized ccRCC, the infiltration with CD8
PD-1
Tim-3
Lag-3
exhausted TILs and ICOS
Treg identifies the patients with deleterious prognosis who could benefit from adjuvant therapy with TME-modulating agents and checkpoint blockade. This work also provides PBL phenotypic markers that could allow their identification.
.
Background Triple negative breast cancers (TNBC) account for approximately 15% of all breast cancers and are associated with a shorter median survival mainly due to locally advanced tumor and high ...risk of metastasis. The current neoadjuvant treatment for TNBC consists of a regimen of immune checkpoint blocker and chemotherapy (chemo-ICB). Despite the frequent use of this combination for TNBC treatment, moderate results are observed and its clinical benefit in TNBC remains difficult to predict. Patient-derived tumor organoids (PDTO) are 3D in vitro cellular structures obtained from patient's tumor samples. More and more evidence suggest that these models could predict the response of the tumor from which they are derived. PDTO may thus be used as a tool to predict chemo-ICB efficacy in TNBC patients. Method The TRIPLEX study is a single-center observational study conducted to investigate the feasibility of generating PDTO from TNBC and to evaluate their ability to predict clinical response. PDTO will be obtained after the dissociation of biopsies and embedding into extra cellular matrix. PDTO will be cultured in a medium supplemented with growth factors and signal pathway inhibitors. Molecular and histological analyses will be performed on established PDTO lines to validate their phenotypic proximity with the original tumor. Response of PDTO to chemo-ICB will be assessed using co-cultures with autologous immune cells collected from patient blood samples. PDTO response will finally be compared with the response of the patient to evaluate the predictive potential of the model. Discussion This study will allow to assess the feasibility of using PDTO as predictive tools for the evaluation of the response of TNBC patients to treatments. In the event that PDTO could faithfully predict patient response in clinically relevant time frames, a prospective clinical trial could be designed to use PDTO to guide clinical decision. This study will also permit the establishment of a living biobank of TNBC PDTO usable for future innovative strategies evaluation. Trial registration The clinical trial (version 1.2) has been validated by local research ethic committee on December 30.sup.th 2021 and registered at ClinicalTrials.gov with the identifier NCT05404321 on June 3.sup.rd 2022, version 1.2. Keywords: Triple negative breast cancer, Patient-derived tumor organoids, Predictive functional assays, Chemo-immunotherapy
Radiation exposure and thyroid cancer: a review Iglesias, Maria Laura; Schmidt, Angelica; Ghuzlan, Abir Al ...
Archives of endocrinology and metabolism,
03/2017, Letnik:
61, Številka:
2
Journal Article
Odprti dostop
The association between radiation exposure and the occurrence of thyroid cancer has been well documented, and the two main risk factors for the development of a thyroid cancer are the radiation dose ...delivered to the thyroid gland and the age at exposure. The risk increases after exposure to a mean dose of more than 0.05-0.1 Gy (50-100mGy). The risk is more important during childhood and decreases with increased age at exposure, being low in adults. After exposure, the minimum latency period before the appearance of thyroid cancers is 5 to 10 years. Papillary carcinoma (PTC) is the most frequent form of thyroid carcinoma diagnosed after radiation exposure, with a higher prevalence of the solid subtype in young children with a short latency period and of the classical subtype in cases with a longer latency period after exposure. Molecular alterations, including intra-chromosomal rearrangements, are frequently found. Among them, RET/PTC rearrangements are the most frequent. Current research is directed on the mechanism of genetic alterations induced by radiation and on a molecular signature that can identify the origin of thyroid carcinoma after a known or suspected exposure to radiation.
The intestinal microbiota and the expanded endocannabinoid (eCB) system, or endocannabinoidome (eCBome), have both been implicated in diet-induced obesity and dysmetabolism. These systems were ...recently suggested to interact during the development of obesity. We aimed at identifying the potential interactions between gut microbiota composition and the eCBome during the establishment of diet-induced obesity and metabolic complications. Male mice were fed a high-fat, high-sucrose (HFHS) diet for 56 days to assess jejunum, ileum, and cecum microbiomes by 16S rRNA gene metataxonomics as well as ileum and plasma eCBome by targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS). The HFHS diet induced early (3 days) and persistent glucose intolerance followed by weight gain and hyperinsulinemia. Concomitantly, it induced the elevation of the two eCBs, anandamide, in both ileum and plasma, and 2-arachidonoyl-glycerol, in plasma, as well as alterations in several other
-acylethanolamines and 2-acylglycerols. It also promoted segment-specific changes in the relative abundance of several genera in intestinal microbiota, some of which were observed as early as 3 days following HFHS diet. Weight-independent correlations were found between the relative abundances of, among others,
,
,
,
,
,
, and
and the concentrations of anandamide and the anti-inflammatory eCBome mediator
-docosahexaenoyl-ethanolamine. This study highlights for the first time the existence of potential interactions between the eCBome, an endogenous system of multifunctional signaling lipids, and several intestinal genera during early and late HFHS-induced dysmetabolic events, with potential impact on the host capability of adapting to increased intake of fat and sucrose.
The intestinal microbiota and the expanded endocannabinoid system, or endocannabinoidome, have both been implicated in diet-induced obesity and dysmetabolism. This study aims at identifying the potential interactions between these two fundamental systems-which form the gut microbiota-endocannabinoidome axis-and their involvement in the establishment of diet-induced obesity and related metabolic complications. We report here time- and segment-specific microbiome disturbances as well as modifications of intestinal and circulating endocannabinoidome mediators during high-fat, high-sucrose diet-induced glucose intolerance and subsequent obesity and hyperinsulinemia. This highlights the involvement of, and the interaction between, the gut microbiota and the endocannabinoidome during metabolic adaptation to high-fat and high-sucrose feeding. These results will help identifying actionable gut microbiome members and/or endocannabinoidome mediators to improve metabolic health.
Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes
. The clinical presentation of patients with different subtypes is often atypical, and ...responses to therapies such as immune checkpoint blockade vary widely
. To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8
T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial. Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell-rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases.
Glycol ethers (GE) are widely used organic solvents. Despite the potential neurotoxicity of several families of organic solvents, little is known about the impact of GE on the neurodevelopment of ...infants and children.
We investigated the relation between urinary concentrations of GE metabolites in pregnant women and neurocognitive abilities in their 6-year-old children in the PELAGIE mother-child cohort.
Five GE metabolites were measured in first morning void urine samples of 204 French pregnant women in early pregnancy (< 19 weeks of gestation). Psychologists assessed the neurocognitive abilities of their 6-year-old children with the Wechsler Intelligence Scale for Children IV (WISC) and the Developmental Neuropsychological Assessment (NEPSY). We analyzed the results with linear (WISC) and Poisson regression models (NEPSY), adjusted for potential confounders, including child's stimulation at home.
GE metabolites were detected in 90-100% of maternal urine samples. The WISC Verbal Comprehension score was significantly lower for children with the highest tertile of urinary phenoxyacetic acid (PhAA) β (third vs. first tertile) = -6.53; 95% CI: -11.44, -1.62. Similarly, the NEPSY Design Copying subtest score was lower in those with the highest tertile of urinary ethoxyacetic acid (EAA) β (third vs. first tertile) = -0.11; 95% CI: -0.21, 0.00. The other GE metabolites we studied were not significantly associated with WISC or NEPSY scores.
Prenatal urine concentrations of two GE metabolites were associated with lower WISC Verbal Comprehension Index scores and NEPSY Design Copying subscale scores, respectively, at age 6 years. PhAA is the primary metabolite of 2-phenoxyethanol (EGPhE), which is commonly found in cosmetics, and precursors of EAA are frequently used in cleaning agents. Additional research is needed to confirm our findings and further explore potential effects of prenatal GE exposures on neurocognitive performance in children.
To increase the share of electricity generation from renewable energies for both grid-connected and off-grid communities, storage systems are needed to compensate for their intermittent nature. ...Compressed air energy storage (CAES) processes are of increasing interest. They are now characterized as large-scale, long-lifetime and cost-effective energy storage systems. Compressed Carbon Dioxide Energy Storage (CCES) systems are based on the same technology but operate with CO2 as working fluid. They allow liquid storage under non-extreme temperature conditions. A literature review of this new technology was conducted. The difference between the systems lies in the presence or absence of an external heat source, the thermodynamic state of the stored CO2, and the means of heat recovery and utilization. To better understand the wide variety of configurations, they have been classified according to the external heat use and the storage location (underground or aboveground). As there is no dynamic model for liquid storages, one is presented in this paper and bring new challenges that have to be considered in future researches. Also, experimental studies are lacking to validate the CCES behaviour and some components like turbomachines and thermal storages.
•Providing an overview of current CCES studies and configurations.•Comprehensive comparison of different CCES categories.•A simplified dynamic model is presented.•CCES is a promising energy storage for renewable energies development.•Pointing out the issues and future needed investigations.
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