Combined anti-C1-INH and Radiotherapy against Glioblastoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB56861 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR10386841.fastq.gz | Fastqsanger.gz | |||
| ERR10386842.fastq.gz | Fastqsanger.gz | |||
| ERR10386843.fastq.gz | Fastqsanger.gz | |||
| ERR10386844.fastq.gz | Fastqsanger.gz | |||
| ERR10386845.fastq.gz | Fastqsanger.gz |
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Project description:Animals with intracranial glioblastoma of the NS1 cells line were treated with anti-C1-INH +/- radiotherapy or were untreated control animals.
2022-10-19 | E-MTAB-12296 | biostudies-arrayexpress
Project description:BackgroundA more effective immune response against glioblastoma is needed in order to achieve better tumor control. Radiotherapy can induce anti-tumor mediated immune reactions, in addition to its dose response effects. The complement system can function as a bridge between innate and adaptive immune responses. Combining radiotherapy and complement activating therapy is theoretically interesting.MethodsRadiotherapy at 8 Gy × 2 was combined with treatment against C1-inhibitor (C1-INH), a potent inhibitor of activation of the classical pathway of the complement system. Anti-C1-INH was delivered as intratumoral injections. Fully immunocompetent Fischer 344 rats with NS1 glioblastoma tumors were treated. Survival was monitored as primary outcome. Models with either intracranial or subcutaneous tumors were evaluated separately.ResultsIn the intracranial setting, irradiation could prolong survival, but there was no additional survival gain as a result of anti-C1-INH treatment. In animals with subcutaneous tumors, combined radio-immunotherapy with anti-C1-INH and irradiation at 8 Gy × 2 significantly prolonged survival compared to control animals, whereas irradiation or anti-C1-INH treatment as single therapies did not lead to significantly increased survival compared to control animals.ConclusionsAnti-C1-INH treatment could improve the efficacy of irradiation delivered at sub-therapeutic doses and delay tumor growth in the subcutaneous tumor microenvironment. In the intracranial setting, the doses of anti-C1-INH were not enough to achieve any survival effect in the present setting.
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Project description:Enhancing glioblastoma radiotherapy by COMT inhibition
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Project description:Analysis of 80 glioblastoma specimen of patients treated within clinical trials and 4 samples of "normal" brain tissue (non-tumoral). The data was used to identify factors of resistance to a chemoradiation therapy protocol of radiotherapy and concomitant and adjuvant temozolomide (alkylating agent). Experiment Overall Design: 80 glioblastoma specimen and 4 non-tumoral brain samples
2008-10-18 | E-GEOD-7696 | biostudies-arrayexpress
Project description:We report that combined treatment with both DG167 and INH activates a cellular response associated with loss of persistence and induction of cidality that is distinct from the cellular response induced by single drug treatment.
2018-11-30 | GSE123132 | GEO
Project description:Glioblastoma is the most common malignant primary brain tumor. Clinically relevant biomarkers are restricted to isocitrate dehydrogenase (IDH) gene 1 or 2 mutation and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Long non-coding RNA (lncRNA) alterations may contribute to glioblastoma pathogenesis and potentially serve as novel biomarkers. The clinical significance of HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) was analyzed in multiple glioblastoma gene expression data sets for associations with prognosis and IDH mutation and MGMT promoter methylation status. The role of HOTAIRM1 in glioblastoma biology and radiotherapy resistance was characterized in vitro and in vivo. We identified HOTAIRM1 as a candidate lncRNA whose up-regulation is significantly associated with shorter survival of glioblastoma patients independent from IDH mutation and MGMT promoter methylation. Glioblastoma cell line models uniformly showed reduced cell viability, less invasive growth and diminished colony formation capacity upon HOTAIRM1 down-regulation. Integrated proteogenomic analyses and determination of reactive oxygen species (ROS) levels revealed impaired mitochondrial function and increased ROS levels upon HOTAIRM1 knock-down. HOTAIRM1 knock-down decreased expression of transglutaminase 2 (TGM2) as a candidate protein implicated in mitochondrial function, and knock-down of TGM2 mimicked the phenotype of HOTAIRM1 down-regulation in glioblastoma cells. Moreover, HOTAIRM1 modulates radiosensitivity of glioblastoma cells in vitro and in vivo. Our data support a role for HOTAIRM1 as a driver of biological aggressiveness, radioresistance and poor outcome in glioblastoma. Targeting HOTAIRM1 may be a promising new therapeutic approach.
2022-01-19 | PXD020141 | Pride
Project description:Hereditary angioedema with C1 Inhibitor deficiency (C1-INH-HAE) is caused by a constellation of variants of the SERPING1 gene (n = 809; 1,494 pedigrees), accounting for 86.8% of HAE families, showing a pronounced mutagenic liability of SERPING1 and pertaining to 5.6% de novo variants. C1-INH is the major control serpin of the kallikrein-kinin system (KKS). In addition, C1-INH controls complement C1 and plasminogen activation, both systems contributing to inflammation. Recognizing the failed control of C1s protease or KKS provides the diagnosis of C1-INH-HAE. SERPING1 variants usually behave in an autosomal-dominant character with an incomplete penetrance and a low prevalence. A great majority of variants (809/893; 90.5%) that were introduced into online database have been considered as pathogenic/likely pathogenic. Haploinsufficiency is a common feature in C1-INH-HAE where a dominant-negative variant product impacts the wild-type allele and renders it inactive. Small (36.2%) and large (8.3%) deletions/duplications are common, with exon 4 as the most affected one. Point substitutions with missense variants (32.2%) are of interest for the serpin structure-function relationship. Canonical splice sites can be affected by variants within introns and exons also (14.3%). For noncanonical sequences, exon skipping has been confirmed by splicing analyses of patients' blood-derived RNAs (n = 25). Exonic variants (n = 6) can affect exon splicing. Rare deep-intron variants (n = 6), putatively acting as pseudo-exon activating mutations, have been characterized as pathogenic. Some variants have been characterized as benign/likely benign/of uncertain significance (n = 74). This category includes some homozygous (n = 10) or compound heterozygous variants (n = 11). They are presenting with minor allele frequency (MAF) below 0.00002 (i.e., lower than C1-INH-HAE frequency), and may be quantitatively unable to cause haploinsufficiency. Rare benign variants could contribute as disease modifiers. Gonadal mosaicism in C1-INH-HAE is rare and must be distinguished from a de novo variant. Situations with paternal or maternal disomy have been recorded (n = 3). Genotypes must be interpreted with biological investigation fitting with C1-INH expression and typing. Any SERPING1 variant reminiscent of the dysfunctional phenotype of serpin with multimerization or latency should be identified as serpinopathy.
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Project description:Despite accumulating cases of radiotherapy-induced abscopal effect in the lung cancer with the introduction of immune checkpoint inhibitors (ICIs), the occurrence of this effect remains infrequent and unpredictable to be a therapeutic goal. Here, we showed that the combination of radiotherapy (8Gy*3F) and ICI alleviated the tumor burden at the irradiated site whereas no discernible benefit was observed in the abscopal tumors. RNA-sequencing data showed that extracellular structure organization pathways were enriched in the abscopal tumors after combined therapy, with Sfrp2 being identified as a central hub. SFRP2 expression was observed in cancer-associated fibroblasts (CAFs) and was elevated in abscopal tumors after combined therapy. Blockade of SFRP2 followed by combined radiotherapy and ICI reinvigorated infiltration and cytotoxicity of CD8+ T cells, and elicited regression of abscopal tumors, which was abrogated by CD8α depletion. Mechanistically, in vitro experiments demonstrated that SFRP2+ CAFs induced apoptosis of CD8+ T cells. The spatial transcriptome analysis showed that SFRP2+ CAFs were located in proximity to the vessels and surrounded by abundant macrophages and limited CD8Tex, thereby creating an immunosuppressive perivascular niche, which was validated in paraffin sections of human lung cancer. Lineage-tracing assays showed SFRP2+ CAFs were derived from pericytes. IGF-1 released by irradiated tumors facilitated the transition of pericytes into fibroblasts and stimulated the expression of SFRP2. In summary, SFRP2+ CAFs hijack the abscopal effect from combined radiotherapy and immunotherapy via inducing apoptosis of CD8+ T cells and orchestrating a hostile perivascular niche in the lung cancer. Targeting SFRP2+ CAF may recondition the TME and promote the abscopal effect.
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Project description:Analysis of gene expression patterns at single cell level of C1-sgControl, C1-sgEED and C1-sgKMT2D cells.
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Project description:Glioblastoma is the most common malignant primary brain tumor. Clinically relevant biomarkers are restricted to isocitrate dehydrogenase (IDH) gene 1 or 2 mutation and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Long non-coding RNA (lncRNA) alterations may contribute to glioblastoma pathogenesis and potentially serve as novel biomarkers. The clinical significance of HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) was analyzed in multiple glioblastoma gene expression data sets for associations with prognosis and IDH mutation and MGMT promoter methylation status. The role of HOTAIRM1 in glioblastoma biology and radiotherapy resistance was characterized in vitro and in vivo. We identified HOTAIRM1 as a candidate lncRNA whose up-regulation is significantly associated with shorter survival of glioblastoma patients independent from IDH mutation and MGMT promoter methylation. Glioblastoma cell line models uniformly showed reduced cell viability, less invasive growth and diminished colony formation capacity upon HOTAIRM1 down-regulation. Integrated proteogenomic analyses and determination of reactive oxygen species (ROS) levels revealed impaired mitochondrial function and increased ROS levels upon HOTAIRM1 knock-down. HOTAIRM1 knock-down decreased expression of transglutaminase 2 (TGM2) as a candidate protein implicated in mitochondrial function, and knock-down of TGM2 mimicked the phenotype of HOTAIRM1 down-regulation in glioblastoma cells. Moreover, HOTAIRM1 modulates radiosensitivity of glioblastoma cells in vitro and in vivo. Our data support a role for HOTAIRM1 as a driver of biological aggressiveness, radioresistance and poor outcome in glioblastoma. Targeting HOTAIRM1 may be a promising new therapeutic approach.
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