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排序方式: 共有117条查询结果,搜索用时 15 毫秒
41.
Didier Frappaz Marc Barritault Laure Montan Florence Laigle-Donadey Olivier Chinot Emilie Le Rhun Alice Bonneville-Levard Andreas F Hottinger David Meyronnet Anne-Sophie Bidaux Gwenaële Garin David Prol 《Neuro-oncology》2021,23(11):1949
BackgroundVismodegib specifically inhibits Sonic Hedgehog (SHH). We report results of a phase I/II evaluating vismodegib + temozolomide (TMZ) in immunohistochemically defined SHH recurrent/refractory adult medulloblastoma.MethodsTMZ-naïve patients were randomized 2:1 to receive vismodegib + TMZ (arm A) or TMZ (arm B). Patients previously treated with TMZ were enrolled in an exploratory cohort of vismodegib (arm C). If the safety run showed no excessive toxicity, a Simon’s 2-stage phase II design was planned to explore the 6-month progression-free survival (PFS-6). Stage II was to proceed if arm A PFS-6 was ≥3/9 at the end of stage I.ResultsA total of 24 patients were included: arm A (10), arm B (5), and arm C (9). Safety analysis showed no excessive toxicity. At the end of stage I, the PFS-6 of arm A was 20% (2/10 patients, 95% unilateral lower confidence limit: 3.7%) and the study was prematurely terminated. The overall response rates (ORR) were 40% (95% CI, 12.2-73.8) and 20% (95% CI, 0.5-71.6) in arm A and B, respectively. In arm C, PFS-6 was 37.5% (95% CI, 8.8-75.5) and ORR was 22.2% (95% CI, 2.8-60.0). Among 11 patients with an expected sensitivity according to new generation sequencing (NGS), 3 had partial response (PR), 4 remained stable disease (SD) while out of 7 potentially resistant patients, 1 had PR and 1 SD.ConclusionThe addition of vismodegib to TMZ did not add toxicity but failed to improve PFS-6 in SHH recurrent/refractory medulloblastoma. Prediction of sensitivity to vismodegib needs further refinements. 相似文献
42.
Lorena V Baroni Claudia Sampor Adriana Gonzalez Fabiana Lubieniecki Gabriela Lamas Carlos Rugilo Ute Bartels Ayala Heled Kyle S Smith Paul A Northcott Eric Bouffet Daniel Alderete Vijay Ramaswamy 《Neuro-oncology》2020,22(12):1873
BackgroundInfant medulloblastoma represents an enormous challenge in neuro-oncology, due to their simultaneous high-risk of recurrence and high risk of severe neurodevelopmental sequelae with craniospinal irradiation. Currently infant medulloblastoma are treated with intensified protocols, either comprising intraventricular methotrexate or autologous transplant, both of which carry significant morbidity and are not feasible in the majority of the world. We sought to evaluate the molecular predictors of outcome in a cohort of infants homogeneously treated with induction chemotherapy, focal radiation and maintenance chemotherapy.MethodsIn a retrospective analysis, 29 young children treated with a craniospinal irradiation sparing strategy from Hospital Garrahan in Buenos Aires were profiled using Illumina HumanMethylationEPIC arrays, and correlated with survival.ResultsTwenty-nine children (range, 0.3–4.6 y) were identified, comprising 17 sonic hedgehog (SHH), 10 Group 3/4, and 2 non-medulloblastomas. Progression-free survival (PFS) across the entire cohort was 0.704 (95% CI: 0.551–0.899). Analysis by t-distributed stochastic neighbor embedding revealed 3 predominant groups, SHHβ, SHHγ, and Group 3. Survival by subtype was highly prognostic with SHHγ having an excellent 5-year PFS of 100% (95% CI: 0.633–1) and SHHβ having a PFS of 0.56 (95% CI: 0.42–1). Group 3 had a PFS of 0.50 (95% CI: 0.25–1). Assessment of neurocognitive outcome was performed in 11 patients; the majority of survivors fell within the low average to mild intellectual disability, with a median IQ of 73.5.ConclusionsWe report a globally feasible and effective strategy avoiding craniospinal radiation in the treatment of infant medulloblastoma, including a robust molecular correlation along with neurocognitive outcomes. 相似文献
43.
Objective
This study sought to examine promoter methylation and expression of the identified sonic hedgehog (SHH) gene in terminal rectal tissues of children with congenital anorectal malformations (ARMs).Methods
Tissue samples from the terminal rectum of pediatric patients with ARMs (five cases each of high and intermediate malformation — two cases of rectovesical fistula, two cases of rectourethral prostatic fistula, one case of cloaca with > 3 cm common channel, four cases of rectourethral bulbar fistula and one case of imperforate anus without fistula, respectively, and ten cases of low malformation — five cases of perineal fistula and five cases of vestibular fistula, respectively), and patients with non-gastrointestinal tract malformation (six cases, anal fistula) were collected and divided into three groups: high-intermediate ARM (ARMhi-int), low ARM (ARMlo), and control (Cont.). Real-time RT-PCR was used to detect mRNA expression levels of the verified differentially methylated gene SHH, and bisulfite genomic sequencing was performed to evaluate DNA methylation in the SHH promoter region.Results
The average methylation levels of the SHH promoter were significantly higher in ARMhi-int (0.850 ± 0.030, P = 0.0036) and ARMlo (0.540 ± 0.053, P = 0.0087) groups than in Cont. group (0.280 ± 0.032). SHH mRNA expression levels were lower in ARMhi-int (0.340 ± 0.015, P = 0.0065) and ARMlo (0.530 ± 0.042, P = 0.0156) groups than in Cont. group (0.870 ± 0.046). The average methylation levels of the SHH promoter were higher in ARMhi-int group than in ARMlo group (0.850 ± 0.030 vs. 0.540 ± 0.053, P = 0.0095), while SHH expression was significantly reduced in ARMhi-int group compared to ARMlo group (0.340 ± 0.15 vs. 0.530 ± 0.042, P = 0.0252). The methylation levels of the SHH promoter in ARMhi-int group were negatively correlated with SHH gene expression (r = − 0.89, P < 0.01).Conclusions
The SHH gene, which plays a major role in the development of the anorectum and enteric nervous system, is hypermethylated at its promoter, and this is correlated with low levels of SHH gene expression. This epigenetic modification may therefore be responsible for the observed changes in SHH expression, which could in turn underlie the pathogenesis of congenital ARMs. 相似文献44.
David Wotton Kenichiro Taniguchi 《American journal of medical genetics. Part C, Seminars in medical genetics》2018,178(2):128-139
Holoprosencephaly (HPE) is a frequent human forebrain developmental disorder with both genetic and environmental causes. Multiple loci have been associated with HPE in humans, and potential causative genes at 14 of these loci have been identified. Although TGIF1 (originally TGIF, for Thymine Guanine-Interacting Factor) is among the most frequently screened genes in HPE patients, an understanding of how mutations in this gene contribute to the pathogenesis of HPE has remained elusive. However, mouse models based on loss of function of Tgif1, and the related Tgif2 gene, have shed some light on how human TGIF1 variants might cause HPE. Functional analyses of TGIF proteins and of TGIF1 single nucleotide variants from HPE patients, combined with analysis of forebrain development in mouse embryos lacking both Tgif1 and Tgif2, suggest that TGIFs regulate the transforming growth factor ß/Nodal signaling pathway and sonic hedgehog (SHH) signaling independently. Although, some developmental processes that are regulated by TGIFs may be Nodal-dependent, it appears that the forebrain patterning defects and HPE in Tgif mutant mouse embryos is primarily due to altered signaling via the Shh pathway. 相似文献
45.
背景:Hedgehog与Wnt/β-catenin信号通路对胃癌干细胞的影响及在胃癌发生发展中的作用机制少见报道。
目的:探讨Hedgehog与Wnt/β-catenin信号通路在胃癌发生发展中的作用机制。
方法:采用肿瘤球悬浮分选法从胃癌组织标本中分选胃癌干细胞。采用免疫组化SP法检测Hedgehog 及Wnt/β-catenin信号通路主要分子SHH、GLI1、Wnt2 及β-catenin在胃癌干细胞中的表达。Spearman相关分析各细胞因子间的相关性分析。
结果与结论:SHH、GLI1、Wnt2及β-catenin 在胃癌干细胞中的阳性表达率分别为74.7%,78.3%,85.5%和83.3%,均显著高于癌旁组织的阳性表达率(P < 0.05)。各细胞因子间在胃癌干细胞中的表达均呈正相关(P < 0.05)。说明在胃癌干细胞中Hedgehog及Wnt/β-catenin信号通路均被激活,二者互相作用可能参与了胃癌的发生发展,为胃癌的干细胞治疗提供了新的研究方向。 相似文献
46.
47.
48.
背景:Hedgehog与Wnt/β-catenin信号通路对胃癌干细胞的影响及在胃癌发生发展中的作用机制少见报道。目的:探讨Hedgehog与Wnt/β-catenin信号通路在胃癌发生发展中的作用机制。方法:采用肿瘤球悬浮分选法从胃癌组织标本中分选胃癌干细胞。采用免疫组化SP法检测Hedgehog及Wnt/β-catnin信号通路主要分子SHH、GLI1、Wnt2及β-catenin在胃癌干细胞中的表达。Spearman相关分析各细胞因子间的相关性分析。结果与结论:SHH、GLI1、Wnt2及β-catenin在胃癌干细胞中的阳性表达率分别为74.7%,78.3%,85.5%和83.3%,均显著高于癌旁组织的阳性表达率(P〈0.05)。各细胞因子间在胃癌干细胞中的表达均呈正相关(P〈0.05)。说明在胃癌干细胞中Hedgehog及Wnt/β-catenin信号通路均被激活,二者互相作用可能参与了胃癌的发生发展,为胃癌的干细胞治疗提供了新的研究方向。 相似文献
49.
50.
Erich Roessler Kenia B. El‐Jaick Christèle Dubourg Jorge I. Vélez Benjamin D. Solomon Daniel E. Pineda‐álvarez Felicitas Lacbawan Nan Zhou Maia Ouspenskaia Aimée Paulussen Hubert J. Smeets Ute Hehr Claude Bendavid Sherri Bale Sylvie Odent Véronique David Maximilian Muenke 《Human mutation》2009,30(10):E921-E935
Mutations within either the SHH gene or its related pathway components are the most common, and best understood, pathogenetic changes observed in holoprosencephaly patients; this fact is consistent with the essential functions of this gene during forebrain development and patterning. Here we summarize the nature and types of deleterious sequence alterations among over one hundred distinct mutations in the SHH gene (64 novel mutations) and compare these to over a dozen mutations in disease‐related Hedgehog family members IHH and DHH. This combined structural analysis suggests that dysfunction of Hedgehog signaling in human forebrain development can occur through truncations or major structural changes to the signaling domain, SHH‐N, as well as due to defects in the processing of the mature ligand from its pre‐pro‐precursor or defective post‐translation bi‐lipid modifications with palmitate and cholesterol Published 2009 by Wiley‐Liss, Inc. 相似文献