| 1. |
- Fluckiger, Aurélie, et al.
(författare)
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Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage
- 2020
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 369:6506, s. 936-942
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Tidskriftsartikel (refereegranskat)abstract
- Intestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major histocompatibility complex (MHC) class I-binding epitopes in the tail length tape measure protein (TMP) of a prophage found in the genome of the bacteriophage Enterococcus hirae. Mice bearing E. hirae harboring this prophage mounted a TMP-specific H-2K(b)-restricted CD8(+) T lymphocyte response upon immunotherapy with cyclophosphamide or anti-PD-1 antibodies. Administration of bacterial strains engineered to express the TMP epitope improved immunotherapy in mice. In renal and lung cancer patients, the presence of the enterococcal prophage in stools and expression of a TMP-cross-reactive antigen by tumors correlated with long-term benefit of PD-1 blockade therapy. In melanoma patients, T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides were detected.
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| 2. |
- Lacas, Benjamin, et al.
(författare)
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Role of radiotherapy fractionation in head and neck cancers (MARCH) : an updated meta-analysis
- 2017
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Ingår i: The Lancet Oncology. - 1470-2045 .- 1474-5488. ; 18:9, s. 1221-1237
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Tidskriftsartikel (refereegranskat)abstract
- Background The Meta-Analysis of Radiotherapy in squamous cell Carcinomas of Head and neck (MARCH) showed that altered fractionation radiotherapy is associated with improved overall and progression-free survival compared with conventional radiotherapy, with hyperfractionated radiotherapy showing the greatest benefit. This update aims to confirm and explain the superiority of hyperfractionated radiotherapy over other altered fractionation radiotherapy regimens and to assess the benefit of altered fractionation within the context of concomitant chemotherapy with the inclusion of new trials. Methods For this updated meta-analysis, we searched bibliography databases, trials registries, and meeting proceedings for published or unpublished randomised trials done between Jan 1, 2009, and July 15, 2015, comparing primary or postoperative conventional fractionation radiotherapy versus altered fractionation radiotherapy (comparison 1) or conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone (comparison 2). Eligible trials had to start randomisation on or after Jan 1, 1970, and completed accrual before Dec 31, 2010; had to have been randomised in a way that precluded prior knowledge of treatment assignment; and had to include patients with non-metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx undergoing first-line curative treatment. Trials including a non-conventional radiotherapy control group, investigating hypofractionated radiotherapy, or including mostly nasopharyngeal carcinomas were excluded. Trials were grouped in three types of altered fractionation: hyperfractionated, moderately accelerated, and very accelerated. Individual patient data were collected and combined with a fixed-effects model based on the intention-to-treat principle. The primary endpoint was overall survival. Findings Comparison 1 (conventional fractionation radiotherapy vs altered fractionation radiotherapy) included 33 trials and 11 423 patients. Altered fractionation radiotherapy was associated with a significant benefit on overall survival (hazard ratio [HR] 0·94, 95% CI 0·90–0·98; p=0·0033), with an absolute difference at 5 years of 3·1% (95% CI 1·3–4·9) and at 10 years of 1·2% (−0·8 to 3·2). We found a significant interaction (p=0·051) between type of fractionation and treatment effect, the overall survival benefit being restricted to the hyperfractionated group (HR 0·83, 0·74–0·92), with absolute differences at 5 years of 8·1% (3·4 to 12·8) and at 10 years of 3·9% (−0·6 to 8·4). Comparison 2 (conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone) included five trials and 986 patients. Overall survival was significantly worse with altered fractionation radiotherapy compared with concomitant chemoradiotherapy (HR 1·22, 1·05–1·42; p=0·0098), with absolute differences at 5 years of −5·8% (−11·9 to 0·3) and at 10 years of −5·1% (−13·0 to 2·8). Interpretation This update confirms, with more patients and a longer follow-up than the first version of MARCH, that hyperfractionated radiotherapy is, along with concomitant chemoradiotherapy, a standard of care for the treatment of locally advanced head and neck squamous cell cancers. The comparison between hyperfractionated radiotherapy and concomitant chemoradiotherapy remains to be specifically tested. Funding Institut National du Cancer; and Ligue Nationale Contre le Cancer.
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| 3. |
- Van Hemelrijck, Mieke, et al.
(författare)
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Reasons for Discontinuing Active Surveillance : Assessment of 21 Centres in 12 Countries in the Movember GAP3 Consortium
- 2019
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838. ; 75:3, s. 523-531
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Tidskriftsartikel (refereegranskat)abstract
- Background: Careful assessment of the reasons for discontinuation of active surveillance (AS) is required for men with prostate cancer (PCa). Objective: Using Movember's Global Action Plan Prostate Cancer Active Surveillance initiative (GAP3) database, we report on reasons for AS discontinuation. Design, setting, and participants: We compared data from 10 296 men on AS from 21 centres across 12 countries. Outcome measurements and statistical analysis: Cumulative incidence methods were used to estimate the cumulative incidence rates of AS discontinuation. Results and limitations: During 5-yr follow-up, 27.5% (95% confidence interval [CI]: 26.4–28.6%) men showed signs of disease progression, 12.8% (95% CI: 12.0–13.6%) converted to active treatment without evidence of progression, 1.7% (95% CI: 1.5–2.0%) continued to watchful waiting, and 1.7% (95% CI: 1.4–2.1%) died from other causes. Of the 7049 men who remained on AS, 2339 had follow-up for >5 yr, 4561 had follow-up for <5 yr, and 149 were lost to follow-up. Cumulative incidence of progression was 27.5% (95% CI: 26.4–28.6%) at 5 yr and 38.2% (95% CI: 36.7–39.9%) at 10 yr. A limitation is that not all centres were included due to limited information on the reason for discontinuation and limited follow-up. Conclusions: Our descriptive analyses of current AS practices worldwide showed that 43.6% of men drop out of AS during 5-yr follow-up, mainly due to signs of disease progression. Improvements in selection tools for AS are thus needed to correctly allocate men with PCa to AS, which will also reduce discontinuation due to conversion to active treatment without evidence of disease progression. Patient summary: Our assessment of a worldwide database of men with prostate cancer (PCa) on active surveillance (AS) shows that 43.6% drop out of AS within 5 yr, mainly due to signs of disease progression. Better tools are needed to select and monitor men with PCa as part of AS.
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| 4. |
- Alanio, Cécile, et al.
(författare)
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Bystander hyperactivation of preimmune CD8(+) T cells in chronic HCV patients
- 2015
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Ingår i: eLife. - 2050-084X. ; 2015:4
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Tidskriftsartikel (refereegranskat)abstract
- Chronic infection perturbs immune homeostasis. While prior studies have reported dysregulation of effector and memory cells, little is known about the effects on naïve T cell populations. We performed a cross-sectional study of chronic hepatitis C (cHCV) patients using tetramer-associated magnetic enrichment to study antigen-specific inexperienced CD8(+) T cells (i.e., tumor or unrelated virus-specific populations in tumor-free and sero-negative individuals). cHCV showed normal precursor frequencies, but increased proportions of memory-phenotype inexperienced cells, as compared to healthy donors or cured HCV patients. These observations could be explained by low surface expression of CD5, a negative regulator of TCR signaling. Accordingly, we demonstrated TCR hyperactivation and generation of potent CD8(+) T cell responses from the altered T cell repertoire of cHCV patients. In sum, we provide the first evidence that naïve CD8(+) T cells are dysregulated during cHCV infection, and establish a new mechanism of immune perturbation secondary to chronic infection.
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| 5. |
- Albert, Damien, et al.
(författare)
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A Decade with VAMDC : Results and Ambitions
- 2020
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Ingår i: Atoms. - : MDPI. - 2218-2004. ; 8:4
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents an overview of the current status of the Virtual Atomic and Molecular Data Centre (VAMDC) e-infrastructure, including the current status of the VAMDC-connected (or to be connected) databases, updates on the latest technological development within the infrastructure and a presentation of some application tools that make use of the VAMDC e-infrastructure. We analyse the past 10 years of VAMDC development and operation, and assess their impact both on the field of atomic and molecular (A&M) physics itself and on heterogeneous data management in international cooperation. The highly sophisticated VAMDC infrastructure and the related databases developed over this long term make them a perfect resource of sustainable data for future applications in many fields of research. However, we also discuss the current limitations that prevent VAMDC from becoming the main publishing platform and the main source of A&M data for user communities, and present possible solutions under investigation by the consortium. Several user application examples are presented, illustrating the benefits of VAMDC in current research applications, which often need the A&M data from more than one database. Finally, we present our vision for the future of VAMDC.
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| 6. |
- Bertolotto, Corine, et al.
(författare)
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A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 480:7375, s. 94-98
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Tidskriftsartikel (refereegranskat)abstract
- So far, no common environmental and/or phenotypic factor has been associated with melanoma and renal cell carcinoma (RCC). The known risk factors for melanoma include sun exposure, pigmentation and nevus phenotypes(1); risk factors associated with RCC include smoking, obesity and hypertension(2). A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers(3). The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene(4); it also stimulates the transcription of hypoxia inducible factor(5) (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes(6). We therefore proposed that MITF might have a role in conferring a genetic predisposition to co-occurring melanoma and RCC. Here we identify a germline missense substitution in MITF (Mi-E318K) that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, RCC or both cancers, when compared with controls. Overall, Mi-E318K carriers had a higher than fivefold increased risk of developing melanoma, RCC or both cancers. Codon 318 is located in a small-ubiquitin-like modifier (SUMO) consensus site (Psi KXE) and Mi-E318K severely impaired SUMOylation of MITF. Mi-E318K enhanced MITF protein binding to the HIF1A promoter and increased its transcriptional activity compared to wild-type MITF. Further, we observed a global increase in Mi-E318K occupied loci. In an RCC cell line, gene expression profiling identified a Mi-E318K signature related to cell growth, proliferation and inflammation. Lastly, the mutant protein enhanced melanocytic and renal cell clonogenicity, migration and invasion, consistent with a gain-of-function role in tumorigenesis. Our data provide insights into the link between SUMOylation, transcription and cancer.
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| 7. |
- Bessueille, Laurence, et al.
(författare)
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A survey of cellulose biosynthesis in higher plants
- 2008
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Ingår i: PLANT BIOTECHNOLOGY. - : Japanese Society for Plant Cell and Molecular Biology. - 1342-4580 .- 1347-6114. ; 25:3, s. 315-322
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Tidskriftsartikel (refereegranskat)abstract
- Cellulose plays a central role in plant development and its biosynthesis represents one of the most important biochemical processes in plant biology. However, the corresponding molecular mechanisms are not well understood, despite the progress made in the past years in the identification of genes that code for the catalytic subunits of the cellulose synthases and other proteins potentially involved in cellulose formation. A major bottleneck is the high instability of the cellulose synthase complexes and their location in the plasma membrane. Additional efforts are currently being made to unravel the mechanisms of cellulose biosynthesis. Indeed, understanding how cellulose is formed and how its crystallinity is achieved is relevant not only for studying plant development, but also for improving the digestibility of the plant biomass, which is foreseen as an alternative to fossil fuels for the production of energy. This review summarizes the major unanswered questions related to the process of cellulose biosynthesis, and describes the recent progress that has been made in the area through the combination of biochemical approaches and molecular genetics.
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| 8. |
- Bessueille, Laurence, et al.
(författare)
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Plasma membrane microdomains from hybrid aspen cells are involved in cell wall polysaccharide biosynthesis
- 2009
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Ingår i: Biochemical Journal. - : Portland Press Ltd.. - 0264-6021 .- 1470-8728. ; 420, s. 93-103
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Tidskriftsartikel (refereegranskat)abstract
- Detergent-resistant plasma membrane microdomains [DRMs (detergent-resistant membranes)] were isolated recently from several plant species. As for animal cells, a large range of cellular functions, such as signal transduction, endocytosis and protein trafficking, have been attributed to plant lipid rafts and DRMs. The data available are essentially based on protcomics and more approaches need to be undertaken to elucidate the precise function of individual populations of DRMs in plants. We report here the first isolation of DRMs from purified plasma membranes of a tree species, the hybrid aspen Populus tremula x tremuloides, and their biochemical characterization. Plasma membranes were solubilized with Triton X-100 and the resulting DRMs were isolated by flotation in sucrose density gradients. The DRMs were enriched in sterols, sphingolipids and glycosylphosphatidylinositol-anchored proteins and thus exhibited similar properties to DRMs from other species. However, they contained key carbohydrate synthases involved in cell wall polysaccharide biosynthesis, namely callose [(1 -> 3)-beta-D-glucan] and cellulose synthases. The association of these enzymes with DRMs was demonstrated using specific glucan synthase assays and antibodies, as well as biochemical and chemical approaches for the characterization of the polysaccharides synthesized in vitro by the isolated DRMs. More than 70% of the total glucan synthase activities present in the original plasma membranes was associated with the DRM fraction. In addition to shedding light on the lipid environment of callose and cellulose synthases, our results demonstrate the involvement of DRMs in the biosynthesis of important cell wall polysaccharides. This novel concept suggests a function of plant membrane microdomains in cell growth and morphogenesis.
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| 9. |
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| 10. |
- Briolay, Anne, et al.
(författare)
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Cell Wall Polysaccharide Synthases Are Located in Detergent-Resistant Membrane Microdomains in Oomycetes
- 2009
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Ingår i: Applied and Environmental Microbiology. - : American Society for Microbiology. - 0099-2240 .- 1098-5336. ; 75:7, s. 1938-1949
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Tidskriftsartikel (refereegranskat)abstract
- The pathways responsible for cell wall polysaccharide biosynthesis are vital in eukaryotic microorganisms. The corresponding synthases are potential targets of inhibitors such as fungicides. Despite their fundamental and economical importance, most polysaccharide synthases are not well characterized, and their molecular mechanisms are poorly understood. With the example of Saprolegnia monoica as a model organism, we show that chitin and (1 -> 3)-beta-D-glucan synthases are located in detergent-resistant membrane microdomains (DRMs) in oomycetes, a phylum that comprises some of the most devastating microorganisms in the agriculture and aquaculture industries. Interestingly, no cellulose synthase activity was detected in the DRMs. The purified DRMs exhibited similar biochemical features as lipid rafts from animal, plant, and yeast cells, although they contained some species-specific lipids. This report sheds light on the lipid environment of the (1 -> 3)-beta-D-glucan and chitin synthases, as well as on the sterol biosynthetic pathways in oomycetes. The results presented here are consistent with a function of lipid rafts in cell polarization and as platforms for sorting specific sets of proteins targeted to the plasma membrane, such as carbohydrate synthases. The involvement of DRMs in the biosynthesis of major cell wall polysaccharides in eukaryotic microorganisms suggests a function of lipid rafts in hyphal morphogenesis and tip growth.
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