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FGFR antagonists restore defective mandibular bone repair in a mouse model of osteochondrodysplasia
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作者 Anne Morice Amélie de La Seiglière +4 位作者 Alexia Kany Roman H.Khonsari Morad Bensidhoum Maria-Emilia Puig-Lombardi Laurence Legeai Mallet 《Bone Research》 2025年第1期197-211,共15页
Gain-of-function mutations in fibroblast growth factor receptor(FGFR) genes lead to chondrodysplasia and craniosynostoses. FGFR signaling has a key role in the formation and repair of the craniofacial skeleton. Here, ... Gain-of-function mutations in fibroblast growth factor receptor(FGFR) genes lead to chondrodysplasia and craniosynostoses. FGFR signaling has a key role in the formation and repair of the craniofacial skeleton. Here, we analyzed the impact of Fgfr2- and Fgfr3- activating mutations on mandibular bone formation and endochondral bone repair after non-stabilized mandibular fractures in mouse models of Crouzon syndrome(Crz) and hypochondroplasia(Hch). 展开更多
关键词 MANDIBULAR DYSPLASIA facial
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New genes emerging for colorectal cancer predisposition 被引量:3
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作者 Clara Esteban-Jurado Pilar Garre +16 位作者 Maria Vila Juan José Lozano Anna Pristoupilova Sergi Beltrán Anna Abulí Jenifer Muoz Francesc Balaguer Teresa Ocaa Antoni Castells Josep M Piqué Angel Carracedo Clara Ruiz-Ponte Xavier Bessa Montserrat Andreu Luis Bujanda Trinidad Caldés Sergi Castellví-Bel 《World Journal of Gastroenterology》 SCIE CAS 2014年第8期1961-1971,共11页
Colorectal cancer(CRC)is one of the most frequent neoplasms and an important cause of mortality in the developed world.This cancer is caused by both genetic and environmental factors although 35%of the variation in CR... Colorectal cancer(CRC)is one of the most frequent neoplasms and an important cause of mortality in the developed world.This cancer is caused by both genetic and environmental factors although 35%of the variation in CRC susceptibility involves inherited genetic differences.Mendelian syndromes account for about5%of the total burden of CRC,with Lynch syndrome and familial adenomatous polyposis the most common forms.Excluding hereditary forms,there is an important fraction of CRC cases that present familial aggregation for the disease with an unknown germline genetic cause.CRC can be also considered as a complex disease taking into account the common diseasecommom variant hypothesis with a polygenic model of inheritance where the genetic components of common complex diseases correspond mostly to variants of low/moderate effect.So far,30 common,low-penetrance susceptibility variants have been identified for CRC.Recently,new sequencing technologies including exomeand whole-genome sequencing have permitted to add a new approach to facilitate the identification of new genes responsible for human disease predisposition.By using whole-genome sequencing,germline mutations in the POLE and POLD1 genes have been found to be responsible for a new form of CRC genetic predisposition called polymerase proofreading-associated polyposis. 展开更多
关键词 Colorectal neoplasm genetic predisposition to disease Next generation sequencing Genotype-phenotype correlation Genetic variant Single nucleotide polymorphism
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Rare germline copy number variants in colorectal cancer predisposition characterized by exome sequencing analysis
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作者 Sebastia Franch-Exposito Clara Esteban-Jurado +25 位作者 Pilar Garre Isabel Quintanilla Saray Duran-Sanchon Marcos Diaz-Gay Laia Bonjoch Miriam Cuatrecasas Esther Samper Jenifer Munoz Teresa Ocana Sabela Carballal Maria Lopez-Ceron Antoni Castells Maria Vila-Casadesus Sophia Derdak Steven Laurie Sergi Beltran Jaime carvajal Luis Bujanda Clara Ruiz-Ponte Jordi Camps Meritxell Gironella Juan Jose Lozano Francesc Balaguer Joaquin Cubiella Trinidad Caldes Sergi Castellvi-Bel 《Journal of Genetics and Genomics》 SCIE CAS CSCD 2018年第1期41-45,共5页
Colorectal cancer (CRC) is one of the most common neoplasms and an important cause of mortality worldwide (http://globocan. iarc.fr]). Approximately 35% of the variation in CRC susceptibility is likely due to her... Colorectal cancer (CRC) is one of the most common neoplasms and an important cause of mortality worldwide (http://globocan. iarc.fr]). Approximately 35% of the variation in CRC susceptibility is likely due to heritable factors (Lichtenstein et al., 2000}. Genetic variations in the human genome include single nucleotide variants (SNVs), short insertions and deletions, and larger structural variants resulting in gain or loss of genomic DNA larger than 1 kb, such as copy number variants (CNVs). Leaving aside the importance of CNVs in sporadic tumor development, these variants can also be present in the germline DNA of healthy individuals from the general population and be considered polymorphic. 展开更多
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Monocyte-lineage tumor infiltration predicts immunoradiotherapy response in advanced pretreated soft-tissue sarcoma:phase 2 trial results
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作者 Antonin Levy Daphne Morel +22 位作者 Matthieu Texier Maria E.Rodriguez-Ruiz Lisa Bouarroudj Fanny Bouquet Alberto Bustillos Clement Quevrin Celine Clemenson Michele Mondini Lydia Meziani Roger Sun Nadia Zaghdoud Lambros Tselikas Tarek Assi Matthieu Faron Charles Honore Carine Ngo Benjamin Verret Cecile Le Pechoux Axel Le Cesne Florent Ginhoux Christophe Massard Rastilav Bahleda Eric Deutsch 《Signal Transduction and Targeted Therapy》 2025年第4期2386-2396,共11页
Immunoradiotherapy holds promise for improving outcomes in patients with advanced solid tumors,including in soft-tissue sarcoma(STS).However,the ideal combination of treatment modalities remains to be determined,and r... Immunoradiotherapy holds promise for improving outcomes in patients with advanced solid tumors,including in soft-tissue sarcoma(STS).However,the ideal combination of treatment modalities remains to be determined,and reliable biomarkers to predict which patients will benefit are lacking.Here,we report the results of the STS cohort of the SABR-PDL1 phase Il trial that evaluated the anti-PDL1 atezolizumab combined with stereotactic body radiation therapy(SBRT)delivered concurrently with the 2nd cycle to at least one tumor site,Eligible patients received atezolizumab until progression or unmanageable toxicity,with SBRT at 45 Gy in 3 fractions).The primary endpoint was one-year progression-free survival(PFS)rate with success defined as 13 patients achieving 1-year PFS.Sixty-one heavily pretreated patients with STS(median 5 prior lines;52%men;median age 54 years;28%leiomyosarcoma)were enrolled across two centers(France,Spain).SBRT was delivered to 55 patients(90%),with the lung being the most commonly irradiated site(50%).After a median follow-up of 45 months,the one-year PFS rate was 8.3%[95%Cl:3.6-18.1].Median PFS and overall survival were 2.5 and 8.6 months,respectively.Best responses included partial responses(5%)and stable disease(60%).Immune profiling revealed increased immunosuppressive tumor-associated macrophages(e.g,IL4l1,HES1)and monocyte-recruiting chemokines in non-responders.Higher monocyte/lymphocyte ratios(MonoLR)in tumor and blood correlated with progression.PD-L1 status,lymphoid infiltration,and tertiary-lymphoid structures were not predictive.Although the primary endpoint was not met,this study highlights MonoLR imbalance as a potential biomarker to identify STS patients likely to benefit from immunoradiotherapy.EudraCT No.2015-005464-42;Clinicaltrial.gov number:NCT02992912. 展开更多
关键词 advanced solid tumorsincluding stereotactic body radiation therapy sbrt delivered immunoradiotherapy soft tissue sarcoma progression free survival reliable biomarkers stereotactic body radiation therapy monocyte lineage tumor infiltration
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A phase II clinical trial of toripalimab in advanced solid tumors with polymerase epsilon/polymerase delta(POLE/POLD1)mutation 被引量:1
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作者 Ying Jin Run-Jie Huang +11 位作者 Wen-Long Guan Zhi-Qiang Wang Zong-Jiong Mai Yu-Hong Li Jian Xiao Xing Zhang Qi Zhao Shi-Fu Chen Ming Liu Yan-Xia Shi Feng Wang Rui-Hua Xu 《Signal Transduction and Targeted Therapy》 SCIE CSCD 2024年第10期4543-4553,共11页
Patients carrying mutations in polymerase epsilon/polymerase delta have shown positive responses to immune checkpoint inhibitors.Yet,prospective trials exploring the efficacy in those with polymerase epsilon/polymeras... Patients carrying mutations in polymerase epsilon/polymerase delta have shown positive responses to immune checkpoint inhibitors.Yet,prospective trials exploring the efficacy in those with polymerase epsilon/polymerase delta mutations are still lacking.A phase II clinical trial was initiated to evaluate the efficacy of toripalimab,a humanized IgG4K monoclonal antibody to human PD-1,in patients with advanced solid tumors with unselected polymerase epsilon/polymerase delta mutations but without microsatellite instability-high.A total of 15 patients were enrolled,14 of whom were assessed for treatment efficacy.There was a 21.4%overall response rate,with a disease control rate of 57.1%.The median overall survival and median progression-free survival were 17.9(95%CI 13.5-not reach)months and 2.5(95%CI 1.4-not reach)months,respectively.For patients with exonuclease domain mutations,the objective response rate was 66.7%(2/3),with a disease control rate of 66.7%(2/3).For those with non-exonuclease domain mutations,the rates were 9.1%(1/11)and 54.5%(6/11),respectively.Notably,patients with PBRM1 gene mutations exhibited a high response rate to toripalimab at 75.0%(3/4).This study showed that neither the exonuclease domain mutations nor non-exonuclease domain mutations could fully predict the efficacy of immunotherapy,urging the need for more investigations to clarify potential immune sensitization differences within polymerase epsilon/polymerase delta mutation variants. 展开更多
关键词 DELTA phase NEITHER
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TMB相关免疫浸润调控评分(MOTIF)预测免疫治疗响应并指导联合增效
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作者 钱政宇 潘艺芊 +7 位作者 李薛鑫 陈衍行 吴灏祥 刘泽先 Martin Kosar Jiri Bartek 王梓贤 徐瑞华 《Science Bulletin》 SCIE EI CAS CSCD 2024年第6期803-822,共20页
Patients with high tumor mutational burden(TMB)levels do not consistently respond to immune checkpoint inhibitors(ICIs),possibly because a high TMB level does not necessarily result in adequate infiltration of CD8^(+)... Patients with high tumor mutational burden(TMB)levels do not consistently respond to immune checkpoint inhibitors(ICIs),possibly because a high TMB level does not necessarily result in adequate infiltration of CD8^(+)T cells.Using bulk ribonucleic acid sequencing(RNA-seq)data from 9311 tumor samples across 30 cancer types,we developed a novel tool called the modulator of TMB-associated immune infiltration(MOTIF),which comprises genes that can determine the extent of CD8^(+)T cell infiltration prompted by a certain TMB level.We confirmed that MOTIF can accurately reflect the integrity and defects of the cancer-immunity cycle.By analyzing 84 human single-cell RNA-seq datasets from 32 types of solid tumors,we revealed that MOTIF can provide insights into the diverse roles of various cell types in the modulation of CD8^(+)T cell infiltration.Using pretreatment RNA-seq data from 13 ICI-treated cohorts,we validated the use of MOTIF in predicting CD8^(+)T cell infiltration and ICI efficacy.Among the components of MOTIF,we identified EMC3 as a negative regulator of CD8^(+)T cell infiltration,which was validated via in vivo studies.Additionally,MOTIF provided guidance for the potential combinations of programmed death 1 blockade with certain immunostimulatory drugs to facilitate CD8^(+)T cell infiltration and improve ICI efficacy. 展开更多
关键词 Tumor mutational burden Immunotherapy Cancer-immunity cycle Treatment efficacy prediction CD8^(+)T cell infiltration Combination therapy
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Residual circulating tumor DNA after adjuvant chemotherapy effectively predicts recurrence of stage II-III gastric cancer 被引量:7
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作者 Shu-Qiang Yuan Run-Cong Nie +16 位作者 You-Sheng Huang Ying-Bo Chen Si-Yu Wang Xiao-Wei Sun Yuan-Fang Li Ze-Kun Liu Yan-Xing Chen Yi-Chen Yao Yu Xu Hai-Bo Qiu Yao Liang Wei Wang Ze-Xian Liu Qi Zhao Rui-Hua Xu Zhi-Wei Zhou Feng Wang 《Cancer Communications》 SCIE 2023年第12期1312-1325,共14页
Background Circulating tumor DNA(ctDNA)is a promising biomarker for predicting relapse in multiple solid cancers.However,the predictive value of ctDNA for disease recurrence remains indefinite in locoregional gastric ... Background Circulating tumor DNA(ctDNA)is a promising biomarker for predicting relapse in multiple solid cancers.However,the predictive value of ctDNA for disease recurrence remains indefinite in locoregional gastric cancer(GC).Here,we aimed to evaluate the predictive value of ctDNA in this context.Methods From 2016 to 2019,100 patients with stage II/III resectable GC were recruited in this prospective cohort study(NCT02887612).Primary tumors were collected during surgical resection,and plasma samples were collected perioperatively and within 3 months after adjuvant chemotherapy(ACT).Somatic variants were captured via a targeted sequencing panel of 425 cancer-related genes.The plasma was defined as ctDNA-positive only if one or more variants detected in the plasma were presented in at least 2%of the primary tumors.Results Compared with ctDNA-negative patients,patients with positive postoperative ctDNA had moderately higher risk of recurrence[hazard ratio(HR)=2.74,95%confidence interval(CI)=1.37–5.48;P=0.003],while patients with positive post-ACT ctDNA showed remarkably higher risk(HR=14.99,95%CI=3.08-72.96;P<0.001).Multivariate analyses indicated that both postoperative and post-ACT ctDNA positivity were independent predictors of recurrence-free survival(RFS).Moreover,post-ACT ctDNA achieved better predictive performance(sensitivity,77.8%;specificity,90.6%)than both postoperative ctDNA and serial cancer antigen.A comprehensive model incorporating ctDNA for recurrence risk prediction showed a higher C-index(0.78;95%CI=0.71–0.84)than the model without ctDNA(0.71;95%CI=0.64–0.79;P=0.009).Conclusions Residual ctDNA after ACT effectively predicts high recurrence risk in stage II/III GC,and the combination of tissue-based and circulating tumor features could achieve better risk prediction. 展开更多
关键词 gastric cancer CTDNA CHEMOTHERAPY POSTOPERATIVE RECURRENCE
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A chromosome-level,haplotype-phased Vanilla planifolia genome highlights the challenge of partial endoreplication for accurate wholegenome assembly 被引量:1
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作者 Quentin Piet Gaetan Droc +15 位作者 William Marande Gautier Sarah Stephanie Bocs Christophe Klopp Mickael Bourge Sonja Siljak-Yakovlev Olivier Bouchez Ce line Lopez-Roques Sandra Lepers-Andrzejewski Laurent Bourgois Joseph Zucca Michel Dron Pascale Besse Michel Grisoni Cyril Jourda Carine Charron 《Plant Communications》 SCIE 2022年第5期117-131,共15页
Vanilla planifolia, the species cultivated to produce one of the world’s most popular flavors, is highly proneto partial genome endoreplication, which leads to highly unbalanced DNA content in cells. We report hereth... Vanilla planifolia, the species cultivated to produce one of the world’s most popular flavors, is highly proneto partial genome endoreplication, which leads to highly unbalanced DNA content in cells. We report herethe first molecular evidence of partial endoreplication at the chromosome scale by the assembly and annotation of an accurate haplotype-phased genome of V. planifolia. Cytogenetic data demonstrated that thediploid genome size is 4.09 Gb, with 16 chromosome pairs, although aneuploid cells are frequentlyobserved. Using PacBio HiFi and optical mapping, we assembled and phased a diploid genome of 3.4 Gbwith a scaffold N50 of 1.2 Mb and 59 128 predicted protein-coding genes. The atypical k-mer frequenciesand the uneven sequencing depth observed agreed with our expectation of unbalanced genome representation. Sixty-seven percent of the genes were scattered over only 30% of the genome, putatively linkinggene-rich regions and the endoreplication phenomenon. By contrast, low-coverage regions (non-endoreplicated) were rich in repeated elements but also contained 33% of the annotated genes. Furthermore, this assembly showed distinct haplotype-specific sequencing depth variation patterns, suggesting complexmolecular regulation of endoreplication along the chromosomes. This high-quality, anchored assemblyrepresents 83% of the estimated V. planifolia genome. It provides a significant step toward the elucidationof this complex genome. To support post-genomics efforts, we developed the Vanilla Genome Hub, a userfriendly integrated web portal that enables centralized access to high-throughput genomic and other omicsdata and interoperable use of bioinformatics tools. 展开更多
关键词 VANILLA whole-genome sequencing optical mapping partial endoreplication genome hub
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