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1
Xie, Yuancai, Yingmei Li, Linfeng Dong, Shifu Chen, and Jixian Liu. "A differential analysis of TCR repertoire between patients with EGFR-mutant and KRAS-mutant non–small-cell lung cancer." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): e21012-e21012. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e21012.
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e21012 Background: T-cell receptor (TCR) repertoire could partially represent tumor micro-environment. EGFR and KRAS are common driver genes mutated and often mutually exclusive in non-small cell lung cancer (NSCLC). There’s a hypothesis that the immune system responds differently according to different mutations. Here we investigated the TCR features, including diversity, clonality, evenness and sequence similarity in EGFR and KRAS mutated NSCLC patients, to better understand the immune response in carcinogenesis. Methods: A total of 71 EGFR-mutant and 31 KRAS-mutant NSCLC tissue samples underwent multiplex PCR based TCR-β sequencing. TCR-β cdr3 amino acid sequences were obtained from the sequencing data using MiXCR and VDJtools. To compare TCR repertoires in EGFR-mutant and KRAS-mutant groups, each assemble CDR3 amino acid sequence was taken as a word, and each repertoire was taken as a document. Each repertoire was compared with every other one as a sample pair. TF-IDF (term frequency-inverse document frequency) document vectors was built for each sample and cosine similarity scores were computed for sample pairs. Results: The total cosine similarity score within EGFR-mutant group is 11.07 and average cosine similarity score is 0.0044±0.01, while in the KRAS-group, the total cosine similarity score is 13.41 and average cosine similarity score is 0.029±0.04. Between these two groups, the total cosine similarity score is 8.76 and average cosine similarity score is 0.0019±0.0009. See table for summary. The intergroup similarity score is significantly less than that within each group respectively (p < 1E10). Conclusions: Our results demonstrated that the TCR repertoire was clearly associated with cancer mutational profile. The mechanism of how mutations affect the immune system and shape the TCR repertoire is yet to be investigated. [Table: see text]
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Sugave, Shounak Rushikesh, Yogesh R. Kulkarni, and Balaso. "Multi-Objective Optimization Model and Hierarchical Attention Networks for Mutation Testing." International Journal of Swarm Intelligence Research 14, no. 1 (March 9, 2023): 1–23. http://dx.doi.org/10.4018/ijsir.319714.
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Mutation testing is devised for measuring test suite adequacy by identifying the artificially induced faults in software. This paper presents a novel approach by considering multiobjectives-based optimization. Here, the optimal test suite generation is performed using the proposed water cycle water wave optimization (WCWWO). The best test suites are generated by satisfying the multi-objective factors, such as time of execution, test suite size, mutant score, and mutant reduction rate. The WCWWO is devised by a combination of the water cycle algorithm (WCA) and water wave optimization (WWO). The hierarchical attention network (HAN) is used for classifying the equivalent mutants by utilizing the MutPy tool. Furthermore, the performance of the developed WCWWO+HAN is evaluated in terms of three metrics—mutant score (MS), mutant reduction rate (MRR), and fitness—with the maximal MS of 0.585, higher MRR of 0.397, and maximum fitness of 0.652.
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Karsy, Michael, Jian Guan, and L. Eric Huang. "Prognostic role of mitochondrial pyruvate carrier in isocitrate dehydrogenase–mutant glioma." Journal of Neurosurgery 130, no. 1 (March 2018): 56–66. http://dx.doi.org/10.3171/2017.9.jns172036.
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OBJECTIVEGliomas are one of the most common types of primary brain tumors. Recent studies have supported the importance of key genetic alterations, including isocitrate dehydrogenase (IDH) mutations and 1p19q codeletion, in glioma prognosis. Mutant IDH produces 2-hydroxyglutarate from α-ketoglutarate, a key metabolite of the Krebs cycle. The mitochondrial pyruvate carrier (MPC) is composed of MPC1 and MPC2 subunits and is functionally essential for the Krebs cycle. The authors sought to explore the impact of MPC1 and MPC2 expression on patient prognosis.METHODSGenomic and clinical data in patients with lower-grade glioma (WHO grades II and III) from The Cancer Genome Atlas (TCGA) were evaluated using Kaplan-Meier analysis and hazards modeling. Validation was conducted with additional data sets, including glioblastoma.RESULTSA total of 286 patients with lower-grade glioma (mean age 42.7 ± 13.5 years, 55.6% males) included 54 cases of IDH–wild type (18.9%); 140 cases of IDH-mutant, 1p19q-intact (49.0%); and 85 cases of IDH-mutant, 1p19q-codeleted (29.7%) tumors. Kaplan-Meier analysis showed that an MPC1 z-score > 0 distinguished better survival, particularly in IDH-mutant (p < 0.01) but not IDH–wild type tumors. Conversely, an MPC2 z-score > 0 identified worsened survival, particularly in IDH-mutant (p < 0.01) but not IDH–wild type tumors. Consistently, neither MPC1 nor MPC2 was predictive in a glioblastoma data set containing 5% IDH-mutant cases. Within the IDH-stratified lower-grade glioma data set, MPC1 status distinguished improved survival in 1p19q-codeleted tumors (p < 0.05), whereas MPC2 expression delineated worsened survival in 1p19q-intact tumors (p < 0.01). A hazards model identified IDH and 1p19q status, age (p = 0.01, HR = 1.03), Karnofsky Performance Scale (KPS) score (p = 0.03, HR = 0.97), and MPC1 (p = 0.003, HR = 0.52) but not MPC2 (p = 0.38) as key variables affecting overall survival. Further validation confirmed MPC1 as an independent predictor of lower-grade glioma. A clinical risk score using IDH and 1p19q status, age, KPS score, and MPC1 and MPC2 z-scores defined 4 risk categories for lower-grade glioma; this score was validated using a secondary glioma data set.CONCLUSIONSThese results support the importance of MPC, especially MPC1, in improving prognostication of IDH-mutant tumors. The generation of a risk score system directly translates this finding to clinical application; however, further research to improve the molecular understanding of the role of MPC in the metabologenomic regulation of gliomas is warranted.
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Almahasheer, Arwa Ali, Amal Mahmoud, Hesham El-Komy, Amany I. Alqosaibi, Sultan Aktar, Sayed AbdulAzeez, and J. Francis Borgio. "Novel Feather Degrading Keratinases from Bacillus cereus Group: Biochemical, Genetic and Bioinformatics Analysis." Microorganisms 10, no. 1 (January 1, 2022): 93. http://dx.doi.org/10.3390/microorganisms10010093.
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In this study, five keratinolytic bacteria were isolated from poultry farm waste of Eastern Province, Saudi Arabia. The highest keratinase activity was obtained at 40–45 °C, pH 8–9, feather concentration 0.5–1%, and using white chicken feather as keratin substrate for 72 h. Enhancement of keratinase activity through physical mutagen UV radiation and/or chemical mutagen ethyl methanesulfonate (EMS) resulted in five mutants with 1.51–3.73-fold increased activity over the wild type. When compared with the wild type, scanning electron microscopy validated the mutants’ effectiveness in feather degradation. Bacterial isolates are classified as members of the S8 family peptidase Bacillus cereus group based on sequence analysis of the 16S rRNA and keratinase genes. Interestingly, keratinase KerS gene shared 95.5–100% identity to keratinase, thermitase alkaline serine protease, and thermophilic serine protease of the B. cereus group. D137N substitution was observed in the keratinase KerS gene of the mutant strain S13 (KerS13uv+ems), and also seven substitution variations in KerS26 and KerS26uv of strain S26 and its mutant S26uv. Functional analysis revealed that the subtilisin-like serine protease domain containing the Asp/His/Ser catalytic triad of KerS gene was not affected by the predicted substitutions. Prediction of physicochemical properties of KerS gene showed instability index between 17.5–19.3 and aliphatic index between 74.7–75.7, which imply keratinase stability and significant thermostability. The docking studies revealed the impact of substitutions on the superimposed structure and an increase in binding of mutant D137N of KerS13uv+ems (affinity: −7.17; S score: −6.54 kcal/mol) and seven mutants of KerS26uv (affinity: −7.43; S score: −7.17 kcal/mol) compared to the wild predicted structure (affinity: −6.57; S score: −6.68 kcal/mol). Together, the keratinolytic activity, similarity to thermostable keratinases, and binding affinity suggest that keratinases KerS13uv+ems and KerS26uv could be used for feather processing in the industry.
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Yu, Guangyang, Ying Pang, Mythili Merchant, Chimene Kesserwan, Vineela Gangalapudi, Abdalla Abdelmaksoud, Alice Ranjan, et al. "Tumor Mutation Burden, Expressed Neoantigens and the Immune Microenvironment in Diffuse Gliomas." Cancers 13, no. 23 (December 3, 2021): 6092. http://dx.doi.org/10.3390/cancers13236092.
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Background: A consistent correlation between tumor mutation burden (TMB) and tumor immune microenvironment has not been observed in gliomas as in other cancers. Methods: Driver germline and somatic mutations, TMB, neoantigen, and immune cell signatures were analyzed using whole exome sequencing (WES) and transcriptome sequencing of tumor and WES of matched germline DNA in a cohort of 66 glioma samples (44 IDH-mutant and 22 IDH-wildtype). Results: Fourteen samples revealed a hypermutator phenotype (HMP). Eight pathogenic (P) or likely pathogenic (LP) germline variants were detected in 9 (19%) patients. Six of these 8 genes were DNA damage repair genes. P/LP germline variants were found in 22% of IDH-mutant gliomas and 12.5% of IDH-wildtype gliomas (p = 0.7). TMB was correlated with expressed neoantigen but showed an inverse correlation with immune score (R = −0.46, p = 0.03) in IDH-wildtype tumors and no correlation in IDH-mutant tumors. The Antigen Processing and Presentation (APP) score correlated with immune score and was surprisingly higher in NHMP versus HMP samples in IDH-wildtype gliomas, but higher in HMP versus NHMP in IDH-mutant gliomas. Conclusion: TMB was inversely correlated with immune score in IDH-wildtype gliomas and showed no correlation in IDH-mutant tumors. APP was correlated with immune score and may be further investigated as a biomarker for response to immunotherapy in gliomas. Studies of germline variants in a larger glioma cohort are warranted.
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Guimarães-Souza, Nadia Karina, Liliya Marsovna Yamaleyeva, Baisong Lu, Ana Claudia Mallet de Souza Ramos, Colin Edward Bishop, and Karl Erik Andersson. "Superoxide overproduction and kidney fibrosis: a new animal model." Einstein (São Paulo) 13, no. 1 (March 2015): 79–88. http://dx.doi.org/10.1590/s1679-45082015ao3179.
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Objective To establish whether the mutation in the Immp2L gene induces renal fibrosis and whether aging exacerbates renal morphology in mice. Methods Female mutant mice with mutation in the inner mitochondrial membrane peptidase 2-like protein at 3 and 18 months of age were used. Renal fibrosis was analyzed using classic fibrosis score, Masson’s trichrome staining, and analysis of profibrotic markers using real time polymerase chain reaction (superoxide dismutase 1, metalloproteinase-9, erythropoietin, transforming growth factor beta), and immunostaining (fibroblasts and Type IV collagen). Oxidative stress markers were determined by immunohistochemistry. The number of renal apoptotic cells was determined. Renal function was estimated by serum creatinine. Results Young mutant mice had significantly more glomerulosclerosis than age-matched mice (p=0.034). Mutant mice had more tubular casts (p=0.025), collagen deposition (p=0.019), and collagen type IV expression (p<0.001). Superoxide dismutase 1 expression was significantly higher in young mutants (p=0.038). Old mutants exhibited significantly higher expression of the fibroblast marker and macrophage marker (p=0.007 and p=0.012, respectively). The real time polymerase chain reaction of metalloproteinase-9 and erythropoietin were enhanced 2.5- and 6-fold, respectively, in old mutants. Serum creatinine was significantly higher in old mutants (p<0.001). Conclusion This mutation altered renal architecture by increasing the deposition of extracellular matrix, oxidative stress, and inflammation, suggesting a protective role of Immp2L against renal fibrosis.
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Yeatman, Timothy Joseph, Mingli Yang, Michael J. Schell, Andrey Loboda, Michael Nebozhyn, Jiannong Li, Jamie K. Teer, Caio Max S. Rocha Lima, and Jack Pledger. "Identification of mutation biomarkers underpinning colon cancer sidedness and cetuximab sensitivity." Journal of Clinical Oncology 36, no. 4_suppl (February 1, 2018): 629. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.629.
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629 Background: Currently, extended RAS testing ( KRAS/ NRAS) in colorectal cancer (CRC) patients identifies only non-responders to EGFR inhibitor (EGFRi) therapies, and accurate prediction of drug-sensitive subpopulations remains problematic in patients, even with wild-type RAS. Moreover, the molecular basis for the laterality of anti-EGFR sensitivity is poorly understood. Methods: 468 CRCs were analyzed by global gene expression analysis, DNA sequencing (1321 cancer related genes) and MSI analysis. Tumors were stratified by a validated gene expression cetuximab sensitivity (CTX-S) score, and then correlated with identified high frequency mutations, resulting in a ranking of CTX-S score-associated mutated genes (see Table). Results: Ranking analysis revealed MSI-H status and KRAS mutation as the most negatively-correlated among all patients and MSS patients, respectively. Conversely, APC and TP53 were the most highly positively-correlated mutant genes in both all patient- and MSS-cases. Deeper analysis revealed that the combination of mutant APC + TP53 ( A + P) was more common in left vs. right CRCs (52% vs 21%), and even more pronounced in MSS vs MSI cases (47% vs 2%). CTX-S scores were highest in mutant A + P patients with WT RAS, but surprisingly, were nearly as high in mutant A + P patients with mutant RAS. CRC PDX models validated these results with a favorable CR/PR/SD vs PD association. Conclusions: Here we report the discovery of a cooperative role of APC and TP53 mutations in identifying EGFRi-sensitive CRC subpopulations. Our data suggest that addition of the routine sequencing of APC and TP53 to extended RAS testing may expand the EGFRi therapeutic opportunity (by up to 25%), regardless of RAS mutation status. [Table: see text]
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He, Qiong, Yamin Li, Xihong Zhou, Wen Zhou, Chunfang Xia, Ruzhe Zhang, Zhengjie Zhang, Aiyang Hu, Siyin Peng, and Jing Li. "The combination of fibrinogen concentrations and the platelet-to-lymphocyte ratio predicts survival in patients with advanced lung adenocarcinoma treated with EGFR-TKIs." Journal of International Medical Research 49, no. 4 (April 2021): 030006052110040. http://dx.doi.org/10.1177/03000605211004021.
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ObjectiveThis study aimed to identify a predictive marker of response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with EGFR-mutant advanced lung adenocarcinoma.MethodsA cohort of 190 patients with EGFR-mutant advanced lung adenocarcinoma was analyzed. Receiver operating characteristic curve analysis was used to evaluate the optimal cutoffs for fibrinogen levels, the neutrophil-to-lymphocyte ratio (NLR), and the platelet-to-lymphocyte ratio (PLR) for predicting progression-free survival (PFS). Univariate and multivariate survival analyses were performed to identify factors correlated with PFS and overall survival (OS).ResultsHigh NLR was associated with worse performance status. In univariate analysis, fibrinogen levels, NLR, and PLR were correlated with OS and PFS. In multivariate analysis, all three variables remained predictive of OS, whereas only fibrinogen levels and PLR were independent prognostic factors for PFS. Furthermore, the combination of fibrinogen levels and PLR (F-PLR score) could stratify patients into three groups with significantly different prognoses, and the score was independently predictive of survival.ConclusionThe F-PLR score predicted the prognosis of patients with EGFR-mutant advanced lung adenocarcinoma who received EGFR-TKIs, and this score may serve as a convenient blood-based marker for identifying high-risk patients.
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Boucai, Laura, Venkatraman Seshan, Michelle Williams, Jeffrey A. Knauf, Mahesh Saqcena, Ronald A. Ghossein, and James A. Fagin. "Characterization of Subtypes of BRAF-Mutant Papillary Thyroid Cancer Defined by Their Thyroid Differentiation Score." Journal of Clinical Endocrinology & Metabolism 107, no. 4 (November 23, 2021): 1030–39. http://dx.doi.org/10.1210/clinem/dgab851.
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Abstract Context The BRAFV600E mutation has been associated with more advanced clinical stage in papillary thyroid cancer (PTC) and decreased responsiveness to radioiodine (RAI). However, some BRAF mutant PTCs respond to RAI and have an indolent clinical behavior suggesting the presence of different subtypes of BRAF mutant tumors with distinct prognosis. Objective To characterize the molecular and clinical features of 2 subtypes of BRAF-mutant PTCs defined by their degree of expression of iodine metabolism genes. Design 227 BRAF-mutant PTCs from the Cancer Genome Atlas Thyroid Cancer study were divided into 2 subgroups based on their thyroid differentiation score (TDS): BRAF-TDShi and BRAF-TDSlo. Demographic, clinico-pathological, and molecular characteristics of the 2 subgroups were compared. Results Compared to BRAF-TDShi tumors (17%), BRAF-TDSlo tumors (83%) were more frequent in blacks and Hispanics (6% vs 0%, P = 0.035 and 12% vs 0%, P = 0.05, respectively), they were larger (2.95 ± 1.7 vs 2.03 ± 1.5, P = 0.002), with more tumor-involved lymph nodes (3.9 ± 5.8 vs 2.0 ± 4.2, P = 0.042), and a higher frequency of distant metastases (3% vs 0%, P = 0.043). Gene set enrichment analysis showed positive enrichment for RAS signatures in the BRAF-TDShi cohort, with corresponding reciprocal changes in the BRAF-TDSlo group. Several microRNAs (miRs) targeting nodes in the transforming growth factor β (TGFβ)-SMAD pathway, miR-204, miR-205, and miR-144, were overexpressed in the BRAF-TDShi group. In the subset with follow-up data, BRAF-TDShi tumors had higher complete responses to therapy (94% vs 57%, P < 0.01) than BRAF-TDSlo tumors. Conclusion Enrichment for RAS signatures, key genes involved in cell polarity and specific miRs targeting the TGFβ-SMAD pathway define 2 subtypes of BRAF-mutant PTCs with distinct clinical characteristics and prognosis.
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Hannaway, Nicola, Stefania Kassaris, Janine Marie Davies, Alannah Smrke, Anna Tinker, and Yvette Drew. "Using chemotherapy response by KELIM score to predict response to first line maintenance PARP inhibitor therapy in non-BRCA mutant/homologous recombination deficiency (HRD) unknown high grade serous ovarian cancer (HGSOC)." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): e17547-e17547. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e17547.
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e17547 Background: Maintenance PARP inhibitor therapy after response to first line chemotherapy is now standard of care in advanced HGSOC. Niraparib is available to all patients based on the PRIMA trial data; however, the progression free survival (PFS) benefit for patients without BRCA mutations or homologous recombination deficiency (HRD) is limited. Funded HRD testing is not accessible in many countries. Patient selection for PARPi therapy in non-BRCA mutant HGSOC is challenging. The calculated CA-125 ELIMination of Rate Constant K (KELIM) score is a mathematical model developed to evaluate CA-125 kinetics during chemotherapy. KELIM has been shown to correlate with chemosensitivity, with scores ≥1 associated with better clinical outcomes. This project aims to use real-world patient data to assess if surrogate markers, such as KELIM score and/or pathological chemotherapy response score, can predict response to 1st line maintenance PARPi in the absence of funded HRD testing. Methods: A retrospective review of non-BRCA mutant HGSOC cases on first line maintenance PARPi therapy at BC Cancer, Canada between April 2020 and June 2022. Only cases confirmed to be non-BRCA mutant (by both germline and tumour testing) were included in the study. Data collection was through electronic medical records and included patient demographics, chemotherapy intent (neoadjuvant vs. adjuvant), pathological (p) chemotherapy response score (CRS), progression-free survival (PFS) defined as start of niraparib to radiological evidence of disease progression. PFS analysis was performed in all patients provided 1 full cycle had been completed. The rate of not progressing at 12 months (PFS12) was calculated. KELIM score was calculated from at least 3 CA125 values taken within 100 days from the chemotherapy start date and using a validated calculation software. Results: 70 patients met the full eligibility criteria for analysis. All patients received niraparib as PARPi therapy. Mean age was 67 years and 40 patients (57%) were ≥ 65 years. Most patients were FIGO stage 3C at presentation (56%). Median number of niraparib cycles was 10 (range 1-28). 35/70 patients (50%) had disease progression at time of data analysis with a median follow-up of 13.2 months. 59 patients had evaluable KELIM scores. pCRS was not associated with any statistically significant differences in PFS. Patients with KELIM scores ≥1 had a trend to greater PFS from niraparib vs. those with KELIM <1 with median PFS of 15 months vs. 8.3 months respectively ( p=0.06). PFS12 rate was higher at 64% with KELIM scores ≥1 vs. 43% with KELIM <1; ( p=0.18). Conclusions: We show that KELIM score could be a useful tool to predict PARP inhibitor response and aid clinical decision-making by oncologists and patients in the real world setting where HRD testing is unfunded.
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Saw, Stephanie, Gillianne Lai, Aaron C. Tan, Siqin Zhou, Mei-Kim Ang, Wan-Teck Lim, Ravindran Kanesvaran, et al. "PD-L1 score as a prognostic biomarker in Asian patients with early-stage, EGFR-mutated lung cancer." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 8527. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.8527.
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8527 Background: Adjuvant Atezolizumab was recently approved in stage II-IIIA non-small cell lung cancer (NSCLC) with PD-L1 ≥1%. However, disease-free survival (DFS) benefit was mainly driven by PD-L1 ≥50% and among EGFR-mutated subgroup, atezolizumab did not demonstrate DFS benefit when PD-L1 0% patients were included. We sought to determine the prognostic value of PD-L1 score in early-stage EGFR-mutated NSCLC. Methods: Consecutive patients with Stage IA-IIIA NSCLC diagnosed 1/1/2010 – 31/12/2019 who underwent curative surgery at National Cancer Centre Singapore with evaluable EGFR and PD-L1 status were included. Co-primary endpoints were 2-year DFS and 5-year overall survival (OS) by Kaplan-Meier method. Results: 455 patients were included (267 EGFR-mutant; 188 EGFR-wildtype). Median age at diagnosis was 65 years, 52.3% (238/455) were males and 62.9% (286/455) were never-smokers. Adenocarcinomas comprised 92.1% (419/455) and 92.5% (421/455) had R0 resection. Stage IA comprised 42.4% (193/455), Stage IB 23.1% (105/455), Stage II 15.8% (72/455) and Stage IIIA 18.7% (85/455). Among EGFR-mutant, 45.3% (121/267) were Ex19del and 41.9% (112/267) were L858R. PD-L1 ≥1% among EGFR-mutant and EGFR-wildtype was 55.8% (149/267) and 60.1% (113/188) respectively (p = 0.361). PDL1 ≥50% was significantly associated with higher stage at diagnosis among EGFR-mutant (p < 0.001) but not EGFR-wildtype (p = 0.319). At median follow up of 47 months, 178 patients had relapsed. Among EGFR-mutant, 2-year DFS comparing PD-L1 0% and PD-L1 ≥1% was 79.0% and 68.9% (p = 0.006) while 5-year OS was 87.6% and 70.6% (p = 0.006) respectively. 2-year DFS and 5-year OS by PD-L1 tertile (as shown in table) revealed that higher PD-L1 score was prognostically worse for both DFS and OS among EGFR-mutant. A similar trend was observed among EGFR-wildtype but did not reach statistical significance, apart from PD-L1 ≥50% which had significantly inferior DFS. Conclusions: Higher PD-L1 score was significantly associated with worse DFS and OS among early-stage EGFR-mutated NSCLC, possibly due to higher stage at diagnosis among PDL1 ≥50%. Our study highlights the poor prognosis of PDL1 ≥50% EGFR-mutated NSCLC in a pre-osimertinib era and underscores the importance of personalised risk-stratified adjuvant strategies. [Table: see text]
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Delorenzi, Mauro, Sarah Gerster, Josep Tabernero, Claus-Henning Köhne, Peter J. O'Dwyer, Alberto F. Sobrero, Eric van Cutsem, et al. "Microarray gene expression study of the RESPECT trial for the identification of prognostic and predictive markers." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e14561-e14561. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e14561.
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e14561 Background: The RESPECT trial (n = 198) tested the addition of Sorafenib to standard mFOLFOX6 treatment in first line metastatic colorectal cancer (mCRC) patients but resulted in no statistical significant improvement in progression free survival, and no evidence for overall benefit. Sorafenib inhibits several Raf kinases (including B-Raf). Samples with high BRAF-mutant-like score were previously shown to identify a subset of colon tumors with a similar biology and outcome to BRAF mutant patients (Popovici et al. J. Clin. Oncol., 30(12):1288–95, 2012). Methods: A subset of 125 patients from the trial was available for gene expression analysis from their primary tumor FFPE samples, using the Colon DSA gene expression arrays from Almac. Mutation status for KRAS and BRAF was previously assessed. The potential prognostic and/or predictive effect of a high BRAF-mutant-like score was assessed. The analyses were performed using Cox proportional hazards regression models and Kaplan-Meier curves. The logrank test was used to compare the survival distributions (significance level: 5%). Results: Molecular profiling was performed on FFPE tissue samples from primary tumors of 125 mCRC patients, 95 samples (47 in the combined arm; 3 BRAF mutants) were successfully processed. Limitations in amount of material available in this retrospective analysis led to failure to reach the required RNA amount for amplification in 30 samples (dropout rate = 24%). The collected gene expression data was of good quality: all 95 array profiles could be used (10 were flagged for slightly inferior quality). The BRAF-mutant-like score was recognized as marker of poor OS in a Cox regression model (HR = 1.55 [95% CI: 1.12 - 2.13], 1 unit = 1 IQR, P = 0.007). The HR difference between the two arms (combined arm: HR = 1.36; reference arm: HR = 1.41) is not significant. Conclusions: The poor survival of metastatic colorectal cancer patients with a BRAF-mutated-like tumor is confirmed, but no predictive effect was found. FFPE tissues are well-suited for this kind of study and allow to accurately test the hypotheses of interest. Further analyses are planned to generate hypotheses about markers of sensitivity to mFOLFOX6 or Sorafenib.
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Montégut, Coline, Jean-Sébastien Guillamo, François Ducray, Caroline Dehais, Cohen-Jonathan Moyal Elisabeth, Christine Desenclos, Antoine Petit, et al. "NCOG-09. PREDICTIVE GERIATRIC FACTORS IN ELDERLY PATIENTS TREATED FOR IDH-MUTANT HIGH-GRADE GLIOMAS: A FRENCH POLA NETWORK STUDY." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi153. http://dx.doi.org/10.1093/neuonc/noab196.600.
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Abstract We aimed to describe the characteristics, patterns of care and predictive geriatric factors of elderly patients with IDH-mutant (IDHm) high-grade gliomas (HGG) included in the French POLA network, dedicated to HGG (including 68% of IDHm HGG). For IDHm HGG patients over the age of 70 years, geriatric features were collected: G8 score items (appetite, weight loss, mobility, neuropsychological disorders, body mass index, medications, self-rated health, age), Activities and Instrumental Activities of Daily Living (ADL, IADL) scores, Charlson’s comorbidity Index (CCI) and biological markers. Out of the 1433 HGG patients included in the POLA Network, 119 (8.3%) occurred in patients ≥ 70 years. Among them, 39 presented with IDHm HGG. Of these 39 patients, estimated G8 score was ≤ 14/17 for 16 patients (64%), ADL score was < 6 for 33.3%, IADL score was < 4 for 47% and CCI was ≥ 5 for 72%. Regarding treatment feasibility, 6 of the 19 patients treated by temozolomide prematurely discontinued chemotherapy including 2 for toxicity and 4 for progression. Five of the 10 patients treated by PCV prematurely discontinued chemotherapy, all for toxicity. In multivariate analysis, loss of mobility (p=0.018; p=0.008), severe neuropsychological disorders (p=0.005; p=0.047), body mass index < 21 kg/m2 (p=0.002; p=0.006) and ADL score < 6 (p=0.002; p=0.01) were significantly predictive of poor PFS and OS. Then we generated a specific brain geriatric score including these four items with a sensibility, specificity and AUC for long term survivor (≥ 48 months) of 100%, 83% and 0.948 respectively. Using a cutoff of < 10/13, this score was significantly correlated to PFS and OS (p< 0.001 both). In conclusion, geriatric predictive factors may contribute to the elderly management improvement: the brain geriatric score must now be validated in a prospective independent cohort including IDHm and IDHwt elderly patients.
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Miyawaki, Eriko, Haruyasu Murakami, Keita Mori, Nobuaki Mamesaya, Takahisa Kawamura, Haruki Kobayashi, Shota Omori, et al. "PD-L1 expression and response to pembrolizumab in patients with EGFR-mutant non-small cell lung cancer." Japanese Journal of Clinical Oncology 50, no. 5 (March 25, 2020): 617–22. http://dx.doi.org/10.1093/jjco/hyaa033.
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Abstract Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer is less likely to express programmed death-ligand 1 (PD-L1) than tumors with wild-type EGFR and is associated with poor response to pembrolizumab. To understand the relationship between EGFR mutation and PD-L1 expression in pembrolizumab response, we retrospectively evaluated the factors contributing to the high tumor proportion score in 155 EGFR-mutant non-small cell lung cancer cases and their associated response to pembrolizumab. Uncommon EGFR mutations were significantly associated with a PD-L1 tumor proportion score ≥ 50% compared to common EGFR mutations. The objective response rate to pembrolizumab of 14 patients was 36%, including 22% in patients with common EGFR mutations, 60% in patients with uncommon EGFR mutations and 75% in patients with both uncommon mutations and a PD-L1 tumor proportion score ≥ 50%. A PD-L1 tumor proportion score ≥ 50% was more frequent in non-small cell lung cancer patients harboring uncommon EGFR mutations and was associated with pembrolizumab efficacy.
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Adderley, Helen M., Mihaela Aldea, Jaqueline Aredo, Mathew Carter, Matthew Church, Pantelis Nicola, Jamie Weaver, et al. "Abstract 2975: RAS precision medicine transatlantic partnership: Exploration of RAS and NF1 co-mutations in NSCLC." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2975. http://dx.doi.org/10.1158/1538-7445.am2022-2975.
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Abstract Background: RAS is the most commonly mutated oncogene in cancer, with KRAS mutated in ~30% of non-small cell lung cancer (NSCLC). RAS is a small GTPase cycling between GTP-bound ‘ON’ state and GDP-bound ‘OFF’ state. KRAS oncoproteins cycle between these states via hydrolysis and nucleotide exchange with the aid of GAPs, including NF1, and GEFs. Given the ’inactive state’ inhibition of recently developed KRAS G12C inhibitors on the GDP-bound state, this has highlighted the continued reliance of KRAS-mutants upon cycling, and the potential for mutants to retain dependence upon upstream influences, including NF1, for pathogenicity. Methods: 474 patients with advanced RAS- and/or NF1-mutant NSCLC were retrospectively identified from four tertiary cancer centers between 2008 -2021. DNA from archival FFPE samples, serum or combination underwent targeted NGS panels to identify mutations. Molecular, clinical, pathological and treatment outcome data were collected. Online resources including cBioPortal and Project Achilles were used to assess the functional role of any findings. Results: KRAS mutations were identified in 416/474 patients and NF1-mutations in 63/474 patients, eight of whom harbored two NF1-mutations. 24/63 (38%) of NF1-mutant cancers had a concomitant KRAS-mutation. We identified that KRAS G13D was more prevalent in NF1 mutant cancers vs. NF1 wildtype (NF1 MT: 6/24, 25%; vs. NF1 WT: 4/281, 1.4%; p<0.0001). KRAS G12C was identified in 11/24 (45.8%) of the double mutants vs. 109/282 (38.7%) of the NF1 WT patients (p=0.52). Those with G13D/NF1 co-mutation had a predicted pathogenic NF1-mutation in 5/6 (83%) of cases. Functional analysis of NF1 KO in G13D mutant lung cancer cell lines identified that NF1 was more essential in G13D mutant cell lines, with median Chronos score -0.26 G13D vs. -0.04 G12C (p=0.02). mRNA expression data identified a range of mRNA expression Z-scores relative to all samples for NF1-mutant cancers, ranging from lowest expression at -4.54 to +1.63, median -0.51. A higher mRNA expression was identified for NF1 missense mutations of unknown significance compared to truncating mutations with likely pathogenic, loss of function. Conclusions: These results highlight the co-mutational landscape of KRAS G13D with NF1 in NSCLC, suggesting functional importance conferred by NF1 loss, and highlight NF1 mutations as an additional pathogenic even when combined with KRAS mutation. The genomic landscape of KRAS and NF1 mutant NSCLC will be explored further through Whole Genome Sequencing data from the 100,000 Genomes Project (Genomics England). Citation Format: Helen M. Adderley, Mihaela Aldea, Jaqueline Aredo, Mathew Carter, Matthew Church, Pantelis Nicola, Jamie Weaver, Aisha Ghaus, Damien Vasseur, Matthew Krebs, Nicola Steele, Fiona Blackhall, Heather Wakelee, Benjamin Besse, Colin Lindsay. RAS precision medicine transatlantic partnership: Exploration of RAS and NF1 co-mutations in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2975.
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Masoodi, Tariq Ahmad, Sulaiman A. Al Shammari, May N. Al-Muammar, and Adel A. Alhamdan. "Screening and Evaluation of Deleterious SNPs in APOE Gene of Alzheimer’s Disease." Neurology Research International 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/480609.
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Introduction. Apolipoprotein E (APOE) is an important risk factor for Alzheimer’s disease (AD) and is present in 30–50% of patients who develop late-onset AD. Several single-nucleotide polymorphisms (SNPs) are present in APOE gene which act as the biomarkers for exploring the genetic basis of this disease. The objective of this study is to identify deleterious nsSNPs associated with APOE gene.Methods. The SNPs were retrieved from dbSNP. Using I-Mutant, protein stability change was calculated. The potentially functional nonsynonymous (ns) SNPs and their effect on protein was predicted by PolyPhen and SIFT, respectively. FASTSNP was used for functional analysis and estimation of risk score. The functional impact on the APOE protein was evaluated by using Swiss PDB viewer and NOMAD-Ref server.Results. Six nsSNPs were found to be least stable by I-Mutant 2.0 with DDG value of >−1.0. Four nsSNPs showed a highly deleterious tolerance index score of 0.00. Nine nsSNPs were found to be probably damaging with position-specific independent counts (PSICs) score of ≥2.0. Seven nsSNPs were found to be highly polymorphic with a risk score of 3-4. The total energies and root-mean-square deviation (RMSD) values were higher for three mutant-type structures compared to the native modeled structure.Conclusion. We concluded that three nsSNPs, namely, rs11542041, rs11542040, and rs11542034, to be potentially functional polymorphic.
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Poon, CC, P. Gordon, K. Liu, R. Yang, S. Sarkar, VW Yong, and J. Kelly. "GP.06 Differential microglia and macrophage profiles in human IDH-mutant and -wildtype glioblastoma reveal therapeutic vulnerabilities." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 46, s1 (June 2019): S7. http://dx.doi.org/10.1017/cjn.2019.82.
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Background: Microglia and macrophages (MMs) are the largest component of the inflammatory infiltrate in glioblastoma (GBM). However, whether there are immunophenotypic differences in isocitrate dehydrogenase (IDH)-mutated and -wildtype GBMs is unknown. Studies on specimens of untreated IDH-mutant GBMs are rare given they comprise 10% of all GBMs and often receive treatment at lower grades that can drastically alter MM phenotypes. Methods: We obtained large samples of untreated IDH-mutant and -wildtype GBMs. Using immunofluorescence techniques with single-cell automated segmentation, and comparison between single-cell RNA-sequencing (scRNA-seq) databases of human GBM, we discerned dissimilarities between GBM-associated MMs (GAMMs). Results: There are significantly fewer but more pro-inflammatory GAMMs in IDH-mutant GBMs, suggesting this contributes to the better prognosis of these tumors. Our pro-inflammatory score which combines the expression of inflammatory markers (CD68/HLA-A, -B, -C/TNF/CD163/IL10/TGFB2), Iba1 intensity, and GAMM surface area also indicates more pro-inflammatory GAMMs are associated with longer overall survival independent of IDH status. scRNA-seq analysis demonstrates microglia in IDH-mutants are mainly pro-inflammatory, while anti-inflammatory macrophages that upregulate genes such as FCER1G and TYROBP predominate in IDH-wildtype GBM. Conclusions: Taken together, these observations are the first head-to-head comparison of GAMMs in treatment-naïve IDH-mutant versus -wildtype GBMs that highlight biological disparities that can be exploited for therapeutic purposes.
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Hide, Takuichiro, Jun Hatakeyama, Chiharu Kimura-Yoshida, E. Tian, Naoki Takeda, Yukitaka Ushio, Toshihiko Shiroishi, Shinichi Aizawa, and Isao Matsuo. "Genetic modifiers of otocephalic phenotypes inOtx2heterozygous mutant mice." Development 129, no. 18 (September 15, 2002): 4347–57. http://dx.doi.org/10.1242/dev.129.18.4347.
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Mice heterozygous for the Otx2 mutation display a craniofacial malformation, known as otocephaly or agnathia-holoprosencephaly complex. The severity of the phenotype is dependent on the genetic background of a C57BL/6 (B6) strain; most of the offspring of Otx2 knock-out chimeras, which are equivalent to the F1 of CBA and B6 strains, backcrossed with B6 females display reduction or loss of mandible, whereas those backcrossed with CBA females do not show noticeable phenotype at birth. The availability of phenotypically disparate strains renders identification of Otx2 modifier loci possible. In this study, a backcross of chimera with B6 was generated and genome-wide scans were conducted with polymorphic markers for non-mendelian distribution of alleles in Otx2 heterozygous mutant mice displaying abnormalities in the lower jaw. We identified one significant locus, Otmf18, between D18Mit68 and D18Mit120 on chromosomes 18, linked to the mandibular phenotype (LOD score 3.33). A similar replication experiment using a second backcross (N3) mouse demonstrated the presence of another significant locus, Otmf2 between D2Mit164 and D2Mit282 on chromosome 2, linked to the mandibular phenotype (LOD score 3.93). These two modifiers account for the distribution of the craniofacial malformations by the genetic effect between B6 and CBA strains. Moreover, Otmf2 contain a candidate gene for several diseases in mice and humans. These genetic studies involving an otocephalic mouse model appear to provide new insights into mechanistic pathways of craniofacial development. Furthermore, these experiments offer a powerful approach with respect to identification and characterization of candidate genes that may contribute to human agnathia-holoprosencephaly complex diseases.
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Oklejewicz, Małgorzata, Serge Daan, Eddy Van Der Zee, and Menno Gerkema. "MEMORY RETENTION IN WILD-TYPE AND TAU MUTANT SYRIAN HAMSTERS." Behaviour 138, no. 6 (2001): 789–96. http://dx.doi.org/10.1163/156853901752233415.
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AbstractRats are known to display a temporary deficit in memory function 6 h after training on a learning task, a phenomenon known as the 'Kamin effect'. Later studies showed that maximal retrieval recurs in 24 h intervals after a single training and implied the role of the circadian clock in the suppression of memory retrieval at non-24 h intervals. This study aimed to investigate this further by analysing retention deficits following passive avoidance training in the Syrian hamster. The availability of hamsters carrying the tau mutation was exploited to address the role of the circadian system in periodic retention deficits. It was expected that tau mutant hamsters with an endogenous circadian period of approximately 20 h would have a high retention score at 20 h after training. Surprisingly, deficits in retention were found at 12, 18, 24, and 36 h after training in wild-type hamsters with best performance at 30 h after training. Tau mutant hamsters had significant deficits in memory retention at 20, 24, and 30 h, and no clear periodicity in retention could be observed. Step-through latency scores for mutant hamsters were low at all times except training-testing intervals of 0.25 and 6 h. These results demonstrate the absence of clear memory deficit oscillations in both wild-type and mutant hamsters, and may suggest in particular a long-term memory deficit in tau mutant hamsters.
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Kakar, Kifayatullah, Tran Dang Xuan, Nguyen Van Quan, Imran Khan Wafa, Hoang-Dung Tran, Tran Dang Khanh, and Tran Dang Dat. "Efficacy of N-methyl-N-nitrosourea (MNU) Mutation on Enhancing the Yield and Quality of Rice." Agriculture 9, no. 10 (September 27, 2019): 212. http://dx.doi.org/10.3390/agriculture9100212.
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Mutation technology has been applied more in recent decades to achieve novel products that are not commonly found in nature. An experiment was conducted to examine the effects of an N-methyl-N-nitrosourea (MNU) mutation on the growth, yield, and physicochemical properties of rice. Seeds of two rice cultivars (K1: DT84, and K3: Q5), along with their mutant lines (K2: mutated DT84, and K4: mutated Q5), were sown, and the established seedlings were transplanted to an open field. Ten hills per plot were randomly selected to evaluate growth parameters, yield, and components. Physicochemical attributes, including protein, amylose, and lipid contents, as well as taste score were measured by a quality tester device. The results showed that plant length, tiller number, and panicle length were higher in mutant lines than those of their cultivars. Furthermore, mutant lines took longer to reach heading and maturity stage. The highest panicle number, spikelet number, repined ratio, 1000 grain weight, 1000 brown rice weight, and grain yield were obtained in mutant lines, as compared to cultivars. The greatest grain yield was obtained in the K4 mutant line (11.6 t/ha), while the lowest was recorded in the K1 cultivar (7.7 t/ha). Lower amylose, protein, and lipid contents were observed in mutant lines compared to those in cultivars. The taste score, which increased from 67.7 to 73.7, was found to be correlated with lower amylose, protein, and lipid contents. The mutation approach increased the grain length but decreased the grain width of tested varieties. This study highlights and suggests the importance of MNU mutation in terms of rice yield improvement with preferable quality.
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Yan, Dong, Lixin Sun, Jiandong Yang, Xuyang Zhang, Xia You, Tingting Sun, and Chuang Qi. "Prognostic values of immune landscape in Ras-mutant colorectal cancer peritoneal metastases." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e15583-e15583. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e15583.
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e15583 Background: The peritoneal metastasis (PM) in patients with colorectal cancer (CRC) is associated with poor survival, especially in those with Ras mutations. However, knowledge on the mechanism of molecular biology in CRC peritoneal metastasis (CRCPM) is limited, and the impact of tumor immune microenvironment (TME) on PM pathogenesis and the prognosis of CRCPM remain unclear. Therefore, we characterized the TME of CRCPM and evaluated its potential diagnostic and prognostic values. Methods: This study involved 21 patients with metastatic CRC (mCRC), of whom 11 with CRCPM were classified into the experimental group and 10 with mCRC without PM (noCRCPM) were classified into the control group. Formalin-fixed and paraffin-embedded tissue of primary tumors from all patients was examined using the NanoString RNA sequencing system. The clinicopathological variables and TME biomarkers were compared using the chi-square test and Cox regression analysis. According to the results of multivariate analysis, a prognostic nomogram was generated, and its prediction ability was measured using the concordance index (C-index). Survival curves were generated using the Kaplan–Meier method, and survival comparison between groups was conducted using the log-rank test. Results: The TME in the CRCPM and noCRCPM groups was different, especially the expression of NOS2, TNSF9, KIR3DL2, MAGEA12, MRC1, KIR3DL1, and CD244 and the content of DC cells, macrophages, exhausted CD8+T cells, NK CD56dim cells, and M2 macrophages. Univariate analysis revealed that the expression of PTPN11, TIE1, MAGEA4, PDGFB, and PMS2 was significantly correlated with progression-free survival (PFS) time. These genes were subjected to the least absolute shrinkage and selection operator regression analysis and established a risk score model. Multiple Cox regression analysis showed that the risk score was a significant independent prognostic factor. However, considering the particularity of serum carcinoembryonic antigen (CEA), we built a combined model that included the CEA level and risk score. It could perform well in predicting the PFS time in patients with CRCPM (C-index 0.77). Conclusions: The TME of the primary lesion was significantly different between the CRCPM and noCRCPM groups. The model that combined the risk score and CEA level was a better outcome predictor among patients with CRCPM.
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Yan, Dong, Lixin Sun, Jiandong Yang, Xuyang Zhang, Xia You, Tingting Sun, and Chuang Qi. "Prognostic values of immune landscape in Ras-mutant colorectal cancer peritoneal metastases." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e15583-e15583. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e15583.
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e15583 Background: The peritoneal metastasis (PM) in patients with colorectal cancer (CRC) is associated with poor survival, especially in those with Ras mutations. However, knowledge on the mechanism of molecular biology in CRC peritoneal metastasis (CRCPM) is limited, and the impact of tumor immune microenvironment (TME) on PM pathogenesis and the prognosis of CRCPM remain unclear. Therefore, we characterized the TME of CRCPM and evaluated its potential diagnostic and prognostic values. Methods: This study involved 21 patients with metastatic CRC (mCRC), of whom 11 with CRCPM were classified into the experimental group and 10 with mCRC without PM (noCRCPM) were classified into the control group. Formalin-fixed and paraffin-embedded tissue of primary tumors from all patients was examined using the NanoString RNA sequencing system. The clinicopathological variables and TME biomarkers were compared using the chi-square test and Cox regression analysis. According to the results of multivariate analysis, a prognostic nomogram was generated, and its prediction ability was measured using the concordance index (C-index). Survival curves were generated using the Kaplan–Meier method, and survival comparison between groups was conducted using the log-rank test. Results: The TME in the CRCPM and noCRCPM groups was different, especially the expression of NOS2, TNSF9, KIR3DL2, MAGEA12, MRC1, KIR3DL1, and CD244 and the content of DC cells, macrophages, exhausted CD8+T cells, NK CD56dim cells, and M2 macrophages. Univariate analysis revealed that the expression of PTPN11, TIE1, MAGEA4, PDGFB, and PMS2 was significantly correlated with progression-free survival (PFS) time. These genes were subjected to the least absolute shrinkage and selection operator regression analysis and established a risk score model. Multiple Cox regression analysis showed that the risk score was a significant independent prognostic factor. However, considering the particularity of serum carcinoembryonic antigen (CEA), we built a combined model that included the CEA level and risk score. It could perform well in predicting the PFS time in patients with CRCPM (C-index 0.77). Conclusions: The TME of the primary lesion was significantly different between the CRCPM and noCRCPM groups. The model that combined the risk score and CEA level was a better outcome predictor among patients with CRCPM.
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Dao Trong, Philip, Saskia Rösch, Heimo Mairbäurl, Stefan Pusch, Andreas Unterberg, Christel Herold-Mende, and Rolf Warta. "Identification of a Prognostic Hypoxia-Associated Gene Set in IDH-Mutant Glioma." International Journal of Molecular Sciences 19, no. 10 (September 25, 2018): 2903. http://dx.doi.org/10.3390/ijms19102903.
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Glioma growth is often accompanied by a hypoxic microenvironment favorable for the induction and maintenance of the glioma stem cell (GSC) phenotype. Due to the paucity of cell models of Isocitrate Dehydrogenase 1 mutant (IDH1mut) GSCs, biology under hypoxic conditions has not been sufficiently studied as compared to IDH1 wildtype (IDH1wt) GSCs. We therefore grew well-characterized IDH1mut (n = 4) and IDH1wt (n = 4) GSC lines under normoxic (20%) and hypoxic (1.5%) culture conditions and harvested mRNA after 72 h. Transcriptome analyses were performed and hypoxia regulated genes were further analyzed using the expression and clinical data of the lower grade glioma cohort of The Cancer Genome Atlas (LGG TCGA) in a confirmatory approach and to test for possible survival associations. Results show that global expression changes were more pronounced in IDH1wt than in IDH1mut GSCs. However, when focusing on known hypoxia-regulated gene sets, enrichment analyses showed a comparable regulation in both IDH1mut and IDH1wt GSCs. Of 272 significantly up-regulated genes under hypoxic conditions in IDH1mut GSCs a hypoxia-related survival score (HRS-score) of five genes (LYVE1, FAM162A, WNT6, OTP, PLOD1) was identified by the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm which was able to predict survival independent of age, 1p19q co-deletion status and WHO grade (II vs. III) in the LGG TCGA cohort and in the Rembrandt dataset. Altogether, we were able to identify and validate a novel hypoxia-related survival score in IDH1mut GSCs consisting of five hypoxia-regulated genes which was significantly associated with patient survival independent of known prognostic confounders.
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Martinez Lago, Nieves, Marta Covela Rúa, Elena Brozos, Ana Fernandez Montes, Juan de La Camara Gomez, Carlos Méndez Méndez, Mónica Jorge Fernández, and Antia Cousillas Castiñeira. "The role of Systemic Inflammation Score (SIS) in BRAF(V600) mutant metastatic colorectal cancer (mCRC)." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e16051-e16051. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16051.
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e16051 Background: Multiple studies have reported prognostic association of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLT) and albumin levels in patients (pts) with colorectal cancer. However, it is unknown the prognostic impact in patients with BRAF(V600) mutant metastatic colorectal cancer (mCRC). Methods: Observational, retrospective, multicentric study pts with BRAF V600mt mCRC treated at 9 university Spanish hospitals in NW Spain, belonging to GITuD Group. Demographic, clinic, pathological characteristics, overall survival (OS) and progression free survival (PFS) data were retrospectively collected and analyzed. We calculated a Systemic Inflammation Score (SIS) summing the number of risk factors that each patient had: albumin levels <3.6 g/dL, Hemoglobin levels <12.5, Neutrophil to Lymphocyte ratio (NLR) >3 and Platelet to lymphocyte ratio (PLR) >175. Results: We recorded data from 71 pts between November 2010 to June 2018. Median age was 62.0 years (range 31-83y), 54.9% female, 73.2% ECOG PS0-1, 49.3% right-sided, 37.3% high grade, 70.4% synchronous presentation, 64.8% primary tumor resection. Median OS was 11.9 months (m) (95% CI, 9.7-14.0 (m)). Pts with higher NLR (>3) had a significantly lower OS: 7.8 vs 13.7 (m) HR 1.934 (95% CI 1.2-3.3) p = 0.014, which was also true for pts with low Hb (<12.5g/dL): OS 9.0 vs 13.0 (m) (HR 1.767,95% CI 1.1-3.0 p = 0.035) and low albumin (<3.6 g/dL): OS 4.9 vs 12.5 (m) (HR 2.142; 95% CI 1.1-4.5, p = 0.040). Pts. with higher PLR (>175) was associated with a non-significant trend worse OS: 5.7 vs 13.5 (m) (HR 1.555; 95% CI 0.9-2.7, p = 0.102). SIS was associated with a worse prognosis: median OS 0/1/2/3/4 factors were 16.7 vs. 11.0 vs. 11.4 vs. 4.8 vs. 4.0 (m) (p = 0.006). Pts with SIS = 0 had significantly higher OS: 16.7 vs 9.0 (m) (HR 0.357; 95% CI 0.3-0.9; p = 0.027). First-line PFS was 4.4 (m) (95% CI, 3.2-5.7 months). First line PFS according type of treatment: Bev+Triplet-CT/Bev+Doublet-CT/antiEGFR+Doublet-CT/Doublet-CT: 8.0 vs 4.8 vs 2.9 vs 2.1 (m) (p = 0.091). BEV based CT was associated with a prolonged first line PFS: median 5.2 vs. 2.3 (m) (HR 0.562; 95% CI, 0.3-0.9; p = 0.033). BEV based CT was associated with prolonged first-line PFS in SIS Score 1-4: 4.8 vs. 2.3 (m) (HR 0.426; 95% CI 0.2-0.8; p = 0.009). Nevertheless, we don’t identify differences in first-line PFS in SIS Score 0: 7.0 vs 2.1 (m) (HR 0.803; 95% CI 0.3-2.5; p = 0.700). Conclusions: SIS identifies a population with a worse prognosis and subsidiary of improvement in First-line PFS with BEV based CT.
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Jacobsen, Ilse, Isabel Hennig-Pauka, Nina Baltes, Matthias Trost, and Gerald-F. Gerlach. "Enzymes Involved in Anaerobic Respiration Appear To Play a Role in Actinobacillus pleuropneumoniae Virulence." Infection and Immunity 73, no. 1 (January 2005): 226–34. http://dx.doi.org/10.1128/iai.73.1.226-234.2005.
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ABSTRACT Actinobacillus pleuropneumoniae, the etiological agent of porcine pleuropneumonia, is able to survive on respiratory epithelia, in tonsils, and in the anaerobic environment of encapsulated sequesters. It was previously demonstrated that a deletion of the anaerobic dimethyl sulfoxide reductase gene (dmsA) results in attenuation in acute disease (N. Baltes, S. Kyaw, I. Hennig-Pauka, and G. F. Gerlach, Infect. Immun. 71:6784-6792, 2003). In the present study, using two-dimensional polyacrylamide gel electrophoresis and quadrupole time-of-flight mass spectrometry, we identified an aspartate ammonia-lyase (AspA) which is upregulated upon induction with bronchoalveolar lavage fluid (BALF). This enzyme is involved in the production of fumarate, an alternative electron acceptor under anaerobic conditions. The coding gene (aspA) was cloned and shown to be present in all A. pleuropneumoniae serotype reference strains. The transcriptional start point was identified downstream of a putative FNR binding motif, and BALF-dependent activation of aspA was confirmed by construction of an isogenic A. pleuropneumoniae mutant carrying a chromosomal aspA::luxAB transcriptional fusion. Two aspA deletion mutants, A. pleuropneumoniae ΔaspA and A. pleuropneumoniae ΔaspAΔdmsA, were constructed, both showing reduced growth under anaerobic conditions in vitro. Pigs challenged with either of the two mutants in an aerosol infection model showed a lower lung lesion score than that of the A. pleuropneumoniae wild-type (wt) controls. Pigs challenged with A. pleuropneumoniae ΔaspAΔdmsA had a significantly lower clinical score, and this mutant was rarely reisolated from unaltered lung tissue; in contrast, A. pleuropneumoniae ΔaspA and the A. pleuropneumoniae wt were consistently reisolated in high numbers. These results suggest that enzymes involved in anaerobic respiration are necessary for the pathogen's ability to persist on respiratory tract epithelium and play an important role in A. pleuropneumoniae pathogenesis.
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Randall, Jamie, Hongkun Wang, Sheryl Krevsky Elkin, Gail Payne, Sarah Mullaly, Erica Marchlik, Dan Barnett, et al. "Targetable mutations in gastrointestinal malignancies: A comparison of RAS mutant and RAS wild type tumors." Journal of Clinical Oncology 39, no. 3_suppl (January 20, 2021): 129. http://dx.doi.org/10.1200/jco.2021.39.3_suppl.129.
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129 Background: KRAS and NRAS (RAS) mutations are considered driver mutations in gastrointestinal malignancies such as colorectal and pancreatic cancer. Our institution obtains broad molecular testing (commercial panels with full exon coverage of at least 300 genes) for all stage IV gastrointestinal malignancies that are reviewed at an internal molecular tumor board (MTB). The MTB subjectively felt there was less benefit from comprehensive molecular testing in RAS mutant tumors and wished to quantify this using standardized analysis according to validated guidelines. Methods: We performed a retrospective cohort study of 209 consecutive genomic sequencing results of advanced gastrointestinal malignancies at our institution dating from March 2016 until December 2019. We compared the number of “targetable” mutations in the RAS mutant and wild type (WT) malignancies, as analyzed by an interpretation service according to the Association of Molecular Pathology (AMP) guidelines. A lower AMP score corresponds to a higher level of evidence as a predictive biomarker. We also compared molecular tumor board specific recommendations for each group (excluding recommendations regarding RAS such as EGFR mAbs). Results: There were 134 RAS mutant and 75 RAS WT cases. Alterations with AMP scores of 1A,1B, and 1C were more commonly seen in the RAS WT population 18/75 and 9/134 respectively (24.0% versus 6.7% p-value=0.0004). 39 of 75 cases in RAS WT and 27/134 in RAS mutant (52.0 versus 20.1%, p-value <0.0001) cohort had at least one alteration that was deemed actionable by our institution’s current MTB criteria. Conclusions: Actionable mutations were significantly less common in the RAS mutant versus RAS WT population, and further studies assessing the value of comprehensive genomic testing in RAS mutant gastrointestinal malignancies may be warranted. [Table: see text]
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Dzambazovska-Trajkovska, Vanja, Jordan Nojkov, Andrijan Kartalov, Biljana Kuzmanovska, Tatjana Spiroska, Redzep Seljmani, Gjorgji Trajkovski, Nadica Matevska-Geshkovska, and Aleksandar Dimovski. "Association of Single-Nucleotide Polymorhism C3435T in the ABCB1 Gene with Opioid Sensitivity in Treatment of Postoperative Pain." PRILOZI 37, no. 2-3 (November 1, 2016): 73–80. http://dx.doi.org/10.1515/prilozi-2016-0019.
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Abstract Background: The minimal effective analgesic concentration of opioids required for satisfactory analgesia may differ significantly among the patients. Genetic factors may contribute to the variable response to opioids by affecting their pharmacokinetics or pharmacodynamics. Methods: Ninety nine patients undergoing abdominal surgery with colorectal anastomosis because of colorectal carcinoma were enrolled in the present study. C34535T was genotyped in all subjects and the patients were divided into three groups according to their genotype: CC-wild type homozygous, CT-mutant heterozygous and TT-mutant homozygous. Intravenous fentanyl, patient controlled analgesia was provided postoperatively for pain control in the first 24 hour after surgery. Opioid consumption, pain scores and the adverse side effects were evaluated. Results: Our main result is that the patients in the CC genotype group consumed significantly more fentanyl (375.0 μg ± 43.1) than the patients in the TT group (295.0 μg ± 49.1) and the CT (356.4 μg ± 41.8) group in the treatment of postoperative pain. The patients in the TT group had lower VAS scores at 6h, 12h, 18 h and 24h postoperatively. There were no significant differences in the side effects among the three groups regarding the vomiting and the sedation score. The patients in the TT group had more frequently nausea score 1, than the patients in the other two groups. Conclusion: Our study indicates that the C3435T SNPs of the ABCB1 gene is associated with differences in the opioid sensitivity. The ABCB1 polymorphism may serve as an important genetic predictor to guide the acute pain therapy in postoperative patients.
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Berzero, Giulia, Luisa Bellu, Capucine Baldini, François Ducray, David Guyon, Marica Eoli, Antonio Silvani, et al. "Sustained Tumor Control With MAPK Inhibition in BRAF V600–Mutant Adult Glial and Glioneuronal Tumors." Neurology 97, no. 7 (June 4, 2021): e673-e683. http://dx.doi.org/10.1212/wnl.0000000000012330.
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ObjectiveTo assess whether RAF and MEK inhibitors (RAFi/MEKi) can provide long-term clinical benefit in adult patients with BRAF V600–mutant glial and glioneuronal tumors (GGNTs), we analyzed tumor response and long-term outcome in a retrospective cohort.MethodsWe performed a retrospective search in the institutional databases of 6 neuro-oncology departments for adult patients with recurrent or disseminated BRAF V600–mutant GGNTs treated with RAFi/MEKi.ResultsTwenty-eight adults with recurrent or disseminated BRAF V600–mutant gangliogliomas (n = 9), pleomorphic xanthoastrocytomas (n = 9), and diffuse gliomas (n = 10) were included in the study. At the time that treatment with RAFi/MEKi was started, all tumors displayed radiologic features of high-grade neoplasms. Thirteen patients received RAFi as single agents (vemurafenib [n = 11], dabrafenib [n = 2]), and 15 received combinations of RAFi/MEKi (vemurafenib + cobimetinib [n = 5], dabrafenib + trametinib [n = 10]). Eleven patients achieved a partial or complete response (11 of 28, 39%), with a median reduction of −78% in their tumor burden. Responders experienced a median increase of 10 points in their Karnofsky Performance Status (KPS) score and a median progression-free survival of 18 months, which was longer than achieved with first-line treatment (i.e., 7 months, p = 0.047). Responders had better KPS score (p = 0.018) and tended to be younger (p = 0.061) and to be treated earlier (p = 0.099) compared to nonresponders. Five patients were rechallenged with RAFi/MEKi at progression, with novel tumor responses in 2. On univariate and multivariate analyses, response to RAFi/MEKi was an independent predictor of overall survival.ConclusionsOur study highlights the long-term clinical benefits of RAFi/MEKi in adult patients with BRAF V600–mutant GGNTs and encourages rechallenge in responders.Classification of EvidenceThis study provides Class III evidence that, for adult patients with BRAF V600-mutant GGNT, RAFi/MEKi can reduce tumor burden and provide clinical benefit.
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Dorta Suarez, M., B. Jimenez Munarriz, A. Del Barrio, G. Garcia Ledo, R. Blanco Blanco, E. Conde Gallego, S. Hernandez Prieto, F. Lopez Rios, and A. Cubillo Gracián. "12P Molecular features of KRAS mutant NSCLC: Weaving a future score for immune-checkpoint inhibitors (ICI)." Annals of Oncology 32 (October 2021): S1349. http://dx.doi.org/10.1016/j.annonc.2021.08.2008.
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Schneider, Friederike, Annika Dufour, Tobias Benthaus, Stephanie Schneider, Gudrun Mellert, Evelyn Zellmeier, Stefan K. Bohlander, et al. "A New Molecular and Clinical Prognostic Score for Risk Stratification in CN-AML." Blood 114, no. 22 (November 20, 2009): 2635. http://dx.doi.org/10.1182/blood.v114.22.2635.2635.
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Abstract Abstract 2635 Poster Board II-611 Background: Cytogenetically normal acute myeloid leukemia (CN-AML) is associated with an intermediate outcome. A number of clinical and molecular risk factors have been characterized pointing to the heterogeneity of this group. The purpose of the study was to define a prognostic model based on pre-treatment patient characteristics to facilitate choice of therapy by definition of patient groups with different prognoses. Patients and methods: We evaluated four molecular markers (mutations of NPM1, CEBPA, MLL-PTD; FLT3-ITD mutant level; interaction term NPM1 and FLT3-ITD mutant level) and nine clinical parameters (white blood count (WBC), platelet count, hemoglobin level, lactase dehydrogenase (LDH) level, bone marrow blasts, de novo AML vs. non de novo AML, performance status, sex and age) at initial diagnosis in 648 patients with CN-AML treated in the AMLCG (German AML Cooperative Group) 1999 trial. The outcome parameter overall survival (OS) was calculated from randomization to death from any cause or to the latest follow-up date. Event-free survival (EFS) was defined as the period from the start of therapy until lack of a complete remission (CR), relapse of AML after CR or death without relapse. Relapse-free survival (RFS) was determined for responders from the first day of a CR until relapse or death without relapse. Univariate and multivariate Cox regression analyses for OS were performed. All parameters with p'0.05 in multivariate analyses after backward elimination and their regression coefficients were applied in the prognostic score. The minimal p-value approach was used to identify the risk groups with the greatest differences in OS. Results: In our patient cohort 84% had de novo AML. Median age was 60 years (17–85 years) and 70% had an ECOG score ≤1. Median platelet count was 57 G/l (5–643 G/l), median WBC was 18 G/l (0.1–798 G/l) and median hemoglobin level was 9.2 g/dl (4.2–16.4 g/dl). Mutations of NPM1, FLT3-ITD, MLL-PTD and CEBPA were present in 51%, 27%, 8% and 10% of patients, respectively. Median FLT3-ITD mutant level in FLT3-ITD mutated patients was 0.42 (0.02–1.00). Of 648 patients 377 had died. Median OS was 20 months with a median follow-up of 45 months. In the multivariate analyses for OS, the following parameters were significant: age (+10, years, HR: 1.3, p<0.001), WBC (10 fold, ×109/l, HR: 1.4, p<0.001), NPM1 (mutation vs. wild-type, HR: 0.35, p<0.001), CEBPA (mutation vs. wild-type, HR: 0.47, p=0.001), interaction term NPM1/FLT3-ITD mutant level (+1, HR: 4.5, p=0.006), performance status (ECOG 0,1 vs. ECOG 2-4, HR: 1.4, p=0.006) and platelet count (10 fold, ×109/l, HR: 0.70, p=0.016). After calculation of the prognostic score for each patient and definition of two cutpoints, we could identify three risk groups (median OS (N=590): not reached (n=169) vs. 22.7 months (n=220) vs. 8.4 months (n=201), p<0.001; median EFS (N=583): 42.3 months (n=168) vs. 7.6 months (n=216) vs. 3.2 months (n=199), p<0.001; median RFS (N=383): not reached (n=136) vs. 15.3 months (n=143) vs. 7.6 months (n=104), p<0.001). Furthermore this model was valid in both age subgroups (<60 years / ≥60 years). Interestingly, a subset of 31% of patients within the molecular favorable NPM1+/FLT3-ITD- risk group were assigned to the intermediate group according to our prognostic score and 31% of the low risk group were not NPM1+/FLT3-ITD-. Conclusions: We propose a new prognostic score based on pre-therapeutic clinical and well-established molecular markers that could be easily applied in the routine patient care setting for risk stratification and risk-adapted therapy. Further prospective validation is required to confirm the clinical relevance of this score. Disclosures: Unterhalt: Roche: travel support. Hoster:Roche: travel support.
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Burgess, Brian T., Abigail M. Anderson, J. Robert McCorkle, Jianrong Wu, Frederick R. Ueland, and Jill M. Kolesar. "Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant BRCA1 Mutant Ovarian Cells." Diagnostics 10, no. 2 (February 22, 2020): 121. http://dx.doi.org/10.3390/diagnostics10020121.
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Objective: Despite the promise of PARP inhibitors (PARPi) for treating BRCA1/2 mutated ovarian cancer (OC), drug resistance invariably develops. We hypothesized rationale drug combinations, targeting key molecules in DNA repair pathways and the cell cycle may be synergistic and overcome acquired PARPi resistance. Methods: Drug sensitivity to PARPi alone and in combination with inhibitors of key DNA repair and cell cycle proteins, including ATR (VE-821), Chk1 (MK-8776), Wee1 (MK-1775), RAD51 (RI-1) was assessed in PARPi-sensitive (UWB1) and -resistant (UWB1-R) gBRCA1 mutant OC cell lines using a cell proliferation assay. The Bliss synergy model was used to estimate the two-drug combination effect and pharmacologic synergy (Bliss score ≥ 0) or antagonistic (Bliss score ≥ 0) response of the PARPi in combination with the inhibitors. Results: IC50 for olaparib alone was 1.6 ± 0.9 µM compared to 3.4 ± 0.6 µM (p = 0.05) for UWB1 and UWB1-R cells, respectively. UWB1-R demonstrated increased sensitivity to ATRi (p = 0.04) compared to UWB1. Olaparib (0.3–1.25 µM) and ATRi (0.8–2.5 µM) were synergistic with Bliss scores of 17.2 ± 0.2, 11.9 ± 0.6 for UWB1 and UWB1-R cells, respectively. Olaparib (0.3–1.25 µM) and Chk1i(0.05–1.25 µM) were synergistic with Bliss scores of 8.3 ± 1.6, 5.7 ± 2.9 for UWB1 and UWB1-R cells, respectively. Conclusions: Combining an ATRi or Chk1i with olaparib is synergistic in both PARPi-sensitive and -resistant BRCA1 mutated OC cell models, and are rationale combinations for further clinical development.
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Rothermel, Luke Daniel, Mehrdad Zarei, Alexander W. Loftus, Jonathan J. Hue, Omid Hajihassani, Hallie J. Graor, and Jordan Michael Winter. "A powerful drug combination strategy targeting BRAF-mutant melanoma." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 3152. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.3152.
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3152 Background: BRAF inhibitors, such as vemurafenib and dabrafenib, are effective in treating patients with melanoma harboring (V600E) BRAF mutations. These drugs block the activity of the mutated BRAF protein, which impacts the development and progression of melanoma. Despite initial efficacy, drug resistance reliably occurs leading to disease relapse. Here we show how BRAF inhibitors cause metabolic reprogramming in melanoma cells to achieve drug resistance and promote cell survival. Previously we demonstrated that wild-type isocitrate dehydrogenase 1 (wtIDH1) supports mitochondrial function and maintains redox homeostasis in melanoma, and that an FDA-approved mutant IDH1 inhibitor, ivosidenib (AG-120), is actually a potent wtIDH1 inhibitor. Thus, we hypothesized that wtIDH1 inhibition would synergize with BRAF inhibition. Methods: Metabolomic profiling using LC-MS determined the impact of BRAF inhibition on cellular metabolism. Cell viability was assessed by PicoGreen in drug combination assays. Synergism was calculated using the Bliss-Independence dose-response model for drug interaction. In vivo modeling of AG-120 in combination with BRAF inhibition used melanoma cell xenografts in athymic nude mice for tumor volume analyses, and survival studies were performed in both immunocompetent C57BL/6J mice (murine YUMM1.7 cells) and immunocompromised athymic nude mice (human A375 cells). Results: Metabolomics data suggest that BRAF-mutated melanoma cells treated with BRAF inhibitors increased oxidative metabolism and mitochondrial dependence (i.e., survival adaptations). These alterations suggest an opportunity for mitochondrial inhibitors to improve drug efficacy. Targeting wtIDH1 with AG-120 in combination with dabrafenib significantly reduced melanoma cell viability. A positive synergy score and Bliss score greater than 1 indicate that the combined treatment was more effective in reducing cell viability than either treatment alone. Further, the combination of AG-120 and dabrafenib was the most effective in vivo, reducing tumor growth in the BRAF-mutated melanoma xenograft model, and improving mouse survival compared to monotherapy controls. Mice tolerated combination therapy with no reduction in body weight observed. Conclusions: Our findings indicate that dual inhibition of mutated BRAF and wild-type IDH1 represents a novel treatment strategy for BRAF-mutated melanomas, with potential for application to other BRAF-mutated cancers (e.g., colon, hepatobiliary, thyroid, etc.).
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Moorman, Nathaniel J., Chie Yu Lin, and Samuel H. Speck. "Identification of Candidate Gammaherpesvirus 68 Genes Required for Virus Replication by Signature-Tagged Transposon Mutagenesis." Journal of Virology 78, no. 19 (October 1, 2004): 10282–90. http://dx.doi.org/10.1128/jvi.78.19.10282-10290.2004.
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ABSTRACT Current methods for determining the role of a given gene product in the gammaherpesvirus 68 (γHV68) life cycle require generation of a specific mutation by either homologous recombination in mammalian cells or bacterial artificial chromosome-mediated mutagenesis in Escherichia coli. The mutant virus is then compared to wild-type virus, and the role of the gene in the viral life cycle is deduced from its phenotype. This process is both time-consuming and labor intensive. Here we present the use of random, transposon-mediated signature-tagged mutagenesis for the identification of candidate viral genes involved in virus replication. Pools of viral mutants, each containing a random insertion of a transposon, were generated with a transposon donor library in which each transposon contains a unique sequence identifier. These pools were transfected into mammalian cells, and the ability of each mutant to replicate was assessed by comparing the presence of virus in the output pool to that present in the input pool of viral genomes. With this approach we could rapidly screen up to 96 individual mutants simultaneously. The location of the transposon insertion was determined by sequencing individual clones with a common primer specific for the transposon end. Here we present the characterization of 53 distinct viral mutants that correspond to insertions in 29 open reading frames within the γHV68 genome. To confirm the results of the signature-tagged mutagenesis screen, we quantitated the ability of each mutant to replicate compared to wild-type γHV68. From these analyses we identified 16 γHV68 open reading frames that, when disrupted by transposon insertions, score as essential for virus replication, and six other open reading frames whose disruption led to significant attenuation of virus replication. In addition, transposon insertion in five other γHV68 open reading frames did not affect virus replication. Notably, all but one of the candidate essential replication genes identified in this screen have been shown to be essential for the replication of at least one other herpesvirus.
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Tan, Lili, Yunzhan Gong, and Yawen Wang. "A Model for Predicting Statement Mutation Scores." Mathematics 7, no. 9 (August 23, 2019): 778. http://dx.doi.org/10.3390/math7090778.
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A test suite plays a key role in software testing. Mutation testing is a powerful approach to measure the fault-detection ability of a test suite. The mutation testing process requires a large number of mutants to be generated and executed. Hence, mutation testing is also computationally expensive. To solve this problem, predictive mutation testing builds a classification model to predict the test result of each mutant. However, the existing predictive mutation testing methods only can be used to estimate the overall mutation scores of object-oriented programs. To overcome the shortcomings of the existing methods, we propose a new method to directly predict the mutation score for each statement in process-oriented programs. Compared with the existing predictive mutation testing methods, our method uses more dynamic program execution features, which more adequately reflect dynamic dependency relationships among the statements and more accurately reflects information propagation during the execution of test cases. By comparing the prediction effects of logistic regression, artificial neural network, random forest, support vector machine, and symbolic regression, we finally decide to use a single hidden layer feedforward neural network as the predictive model to predict the statement mutation scores. In our two experiments, the mean absolute errors between the statement mutation scores predicted by the neural network and the real statement mutation scores both approximately reach 0.12.
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Keshtvarz, Maryam, Mahdieh Mahboobi, Marek Kieliszek, Antoni Miecznikowski, Hamid Sedighian, Milad Rezaei, Mohammad Ali Haghighi, Zahra Zareh, and Ehsan Rezaei. "Engineering of Cytolethal Distending Toxin B by Its Reducing Immunogenicity and Maintaining Stability as a New Drug Candidate for Tumor Therapy; an In Silico Study." Toxins 13, no. 11 (November 5, 2021): 785. http://dx.doi.org/10.3390/toxins13110785.
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The cytolethal distending toxin (CDT), Haemophilus ducreyi, is one of the bacterial toxins that have recently been considered for targeted therapies, especially in cancer therapies. CDT is an A-B2 exotoxin. Its catalytic subunit (CdtB) is capable of inducing DNA double strand breaks, cell cycle arrest and apoptosis in host eukaryotic cells. The sequence alignment indicates that the CdtB is structurally homologyr to phosphatases and deoxyribonucleases I (DNase I). Recently, it has been found that CdtB toxicity is mainly related to its nuclease activity. The immunogenicity of CDT can reduce its effectiveness in targeted therapies. However, the toxin can be very useful if its immunogenicity is significantly reduced. Detecting hotspot ectopic residues by computational servers and then mutating them to eliminate B-cell epitopes is a promising approach to reduce the immunogenicity of foreign protein-based therapeutics. By the mentioned method, in this study, we try to reduce the immunogenicity of the CdtB- protein sequence. This study initially screened residue of the CdtB is B-cell epitopes both linearly and conformationally. By overlapping the B-cell epitopes with the excluded conserve residues, and active and enzymatic sites, four residues were allowed to be mutated. There were two mutein options that show reduced antigenicity probability. Option one was N19F, G74I, and S161F with a VaxiJen score of 0.45 and the immune epitope database (IEDB) score of 1.80, and option two was N19F, G74I, and S161W with a VaxiJen score of 0.45 and IEDB score of 1.88. The 3D structure of the proposed sequences was evaluated and refined. The structural stability of native and mutant proteins was accessed through molecular dynamic simulation. The results showed that the mutations in the mutants caused no considerable changes in their structural stability. However, mutant 1 reveals more thermodynamic stability during the simulation. The applied approaches in this study can be used as rough guidelines for finding hot spot immunogen regions in the therapeutic proteins. Our results provide a new version of CdtB that, due to reduced immunogenicity and increased stability, can be used in toxin-based drugs such as immunotoxins.
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Doubleday, Kevin, Daniel Gaile, Ravi Vijaya-Satya, Xianxian Liu, Kevin D'Auria, Soni Shukla, Han-Yu Chuang, Katie Quinn, and Darya Chudova. "Abstract 5015: Precision profile simulation study for a next generation sequencing bTMB assay." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5015. http://dx.doi.org/10.1158/1538-7445.am2022-5015.
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Abstract Background: Precision profile simulations (PPS) can be used to assess variability of biomarker profiles and provide valuable insight into assay performance, especially when reliable precision estimates can not be obtained empirically due to scarcity of representative samples or insufficient materials per sample. A PPS was conducted for the GuardantOMNI assay to characterize the expected variability in blood tumor mutational burden (bTMB) score across a representative range of expected bTMB scores in clinical samples. The simulations were aligned to, but not completely prescribed by, the PPS guidance provided in Guidance for Industry and and Food and Drug Administration Staff Class II Special Controls Guidance Document: Ovarian Adnexal Mass Assessment Score Test System. A sample’s bTMB score is a real valued quantity (e.g., bTMB = 21.04 mut/Mb) that is derived by multiplying the number of qualified mutations observed within a targeted panel by a scaling factor. Variability in observed bTMB scores for a given blood sample is governed primarily by sample coverage, tumor shedding level, and the assay somatic variant detection probabilities (a function of underlying variant allele frequencies, VAFs). Methods: The relationship between site-specific total molecule counts and coverage was modeled utilizing a composite dataset consisting of both clinical and contrived samples. Sample coverage was modeled using variance component estimates from Precision Study data (18 cancer samples each with 6 to 18 replicates). The reference, single-strand mutant, and double-strand mutant molecule counts for a somatic variant site detected in at least one sample replicate were modeled utilizing a bias corrected Dirichlet Multinomial model. The variants with the simulated VAF and coverage levels were processed with the GuardantOMNI germline/somatic classifier to account for the uncertainty in germline/somatic classification at lower coverage values. Results: Precision profiles consisting of simulation derived %CV estimates for 18 clinical samples with a representative set of mean bTMB scores were generated. The PPS bTMB score distributions were consistent with the bTMB scores observed in the Precision Study, supported by visualization and confidence intervals at level 0.05 margins of equivalence for the empirical mean bTMB and standard deviation estimates. The sample specific %CV estimates were observed, in most instances, to decrease with increasing input levels for matched targeted LoD (Limit of Detection) simulation results. Precision profile %CV estimates were observed to be inversely related to mean bTMB scores. Conclusions: The results provide proof of principle that estimation of GuardantOMNI bTMB score precision via an intuitive and interpretable simulation model is viable. The simulation results were consistent with empirical data and general expectations regarding the precision of the bTMB scores. Citation Format: Kevin Doubleday, Daniel Gaile, Ravi Vijaya-Satya, Xianxian Liu, Kevin D'Auria, Soni Shukla, Han-Yu Chuang, Katie Quinn, Darya Chudova. Precision profile simulation study for a next generation sequencing bTMB assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5015.
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El Baiomy, Mohamed Ali, Salah Aref, and Mohamed El-Ghonemy. "Influence of CYP3A5 and SLCO1 on Imatinib Response Among Egyptian Patients with Chronic Myeloid Leukemia in Chronic Phase." Blood 128, no. 22 (December 2, 2016): 5135. http://dx.doi.org/10.1182/blood.v128.22.5135.5135.
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Abstract Background Imatinib (IM) was approved as a molecular target tyrosine kinase inhibitor (TKI) drug that selectively inhibits BCR/ABL1 tyrosine kinase which causes Philadelphia-positive chronic myeloid leukemia (CML) and so far has been one of the first-choice treatment option in CML with excellent results. However, only a proportion of patients achieve major molecular response. Hence, the need to find whether there are some factors that affect the response to treatment is essential. Although IM pharmacokinetics is influenced by several enzymes and transporters, little is known about the role of pharmacogenetic variation in IM metabolism. This study aimed to investigate the frequencies of mutational status of CYP3A5 and SLCO1 in CML patients undergoing imatinib treatment and to determine whether these two genes could predict the response to imatinib therapy in CML patients. Subjects and methods We investigated the mutational status of SLCO1 and CYP3A5 by Polymerase Chain Reaction followed by restricted fragment length polymorphism in 62 Philadelphia positive newly diagnosed Egyptian CML patients in chronic phase; 39 males (62.9%) and 23 females (37.1%). All patients received imatinib therapy and were followed up for at least one and half year. The response to imatinib therapy was evaluated by recording the hematological response, cytogenetic response at 3rd then 6th month and molecular response at 12th month according to the European Leukemia Net criteria. Results Twenty-eight patients (45.2%) were CYP3A5 wild versus 34 patients (54.8%) mutant while 26 patients (41.9%) were SLCO1 wild versus 36 patients (58.1%) mutant. 85.7% of patients with wild CYP3A5 had low & intermediate Sokal score versus 76.5% of mutant CYP3A5 patients had low & intermediate Sokal score with non-significant relation (p = 0.3). There was a significant relation between mutation in CYP3A5 and poor performance state (PS) of the patients at presentation; 89.3% of patients with wild CYP3A5 had good PS versus 61.8% in the mutant group with (p = 0.01). After 3 month of imatinib therapy there was no significant relation between CYP3A5 mutational state and response to therapy however, 85.7% of patients with wild CYP3A5 reached optimal & suboptimal response versus 79.4% in the mutant group with non-significant difference (p = 0.5). We had 51 patients that continued on imatinib till 6th month of therapy whereas 11 patients shifted to 2nd line TKI after imatinib failure. 87.5% of patients with wild CYP3A5 reached optimal & suboptimal response versus 66.7% in the mutant group with difference reaching significance (p = 0.07). We have 39 patients continued imatinib therapy till 12 month whereas 12 patients shifted to 2nd line TKI after imatinib failure. 71.4% of patients with wild CYP3A5 reached MMR at 12th month of treatment however only 22.2% of mutant CYP3A5 patients reached major molecular response (MMR) with significant difference (p = 0.002). Patients with wild SLCO1 were significantly had low & intermediate Sokal score (p = 0.04). However there was no significant correlation between SLCO1 mutational state and performance state or response to imatinib therapy. Conclusion CYP3A5 mutant gene was associated with poor imatinib efficacy while the SLCO1 gene was not associated with the response to imatinib treatment in Egyptian patients with CML in chronic phase. Disclosures No relevant conflicts of interest to declare.
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Chandler, David, Sash Lopaticki, Dexing Huang, Michael Hunter, Dora Angelicheva, Trevor Kilpatrick, Rosalind HM King, Luba Kalaydjieva, and Grant Morahan. "The stretcher spontaneous neurodegenerative mutation models Charcot-Marie-Tooth disease type 4D." F1000Research 2 (February 13, 2013): 46. http://dx.doi.org/10.12688/f1000research.2-46.v1.
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Mice affected by a spontaneous mutation which arose within our colony exhibited a neuromuscular phenotype involving tremor and characteristic stretching of the rear limbs. The mutant, named stretcher, was used to breed a backcross cohort for genetic mapping studies. The gene responsible for the mutant phenotype was mapped to a small region on mouse chromosome 15, with a LOD score above 20. Candidate genes within the region included the Ndrg1 gene. Examination of this gene in the mutant mouse strain revealed that exons 10 to 14 had been deleted. Mutations in the human orthologue are known to result in Charcot-Marie-Tooth disease type 4D (CMT4D) a severe early-onset disorder involving Schwann cell dysfunction and extensive demyelination. The stretcher mutant mouse is more severely affected than mice in which the Ndrg1 gene had been knocked out by homologous recombination. Our results demonstrate that the Ndrg1str mutation provides a new model for CMT4D, and demonstrate that exons 10 to 14 of Ndrg1 encode amino acids crucial to the appropriate function of Ndrg1 in the central nervous system.
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Ramadhan, Dwi Syah Fitra, and Daryono H. Tjahjono. "Prediksi dan Identifikasi Struktur Protein EGFR Kanker Paru dengan Mutasi Titik L718Q/T790M Secara Pemodelan Homologi In Silico." Jurnal Sains dan Kesehatan 2, no. 4 (December 31, 2020): 491–96. http://dx.doi.org/10.25026/jsk.v2i4.257.
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EGFR receptors play an important role in the growth of cancer cells, and these receptors have undergone various types of mutations. At this time, the effect of the L718Q / T790M point mutation on the EGFR receptor is not known, therefore the aim of this study is to predict the EGFR structure with the L718Q / T790M point mutation using in silico homology modeling. The mutant protein was successfully modeled using SWISS-Model expasy webserver and showed good evaluation results after the protein was minimized as indicated by the results of the Ramachandran outlier score of 0%, clashscore 0.98, and MolProbity 1.15. Identification of the active site of the mutant protein shows a conformational change of the active site that causes a steric collision between the inhibitor group and the amino acid side chain of the mutant protein.
Keywords: EGFR, mutation, homology modeling, in silico.
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Johansson, Elinn, and Alexander Pietras. "CSIG-11. HYPOXIA SIGNALING IN ACVR1-MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii41. http://dx.doi.org/10.1093/neuonc/noac209.160.
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Abstract Diffuse intrinsic pontine glioma (DIPG) is a devastating glial tumor of the brainstem primary occurring in the pediatric population. The majority of DIPG tumors (60-80%) carry lysine- to methionine point mutation in histone H3, resulting in a global reduction of H3K27 trimethylation and subsequently a unique epigenetic landscape. Moreover, a large subset of the DIPG tumors carry activating mutations in ACVR1 – the gene encoding for the BMP receptor ALK2, suggesting an oncogenic role of signaling from this receptor. Importantly potential mechanisms of ACVR1-driven oncogenesis, remain poorly understood. Similar ACVR1 mutations have been described in the rare disorder Fibrodysplasia Ossificans Progressiva (FOP), and evidence from FOP models have suggested several links between hypoxia signaling, BMP signaling, and FOP pathogenesis thus opening up for evaluation of hypoxia signaling as oncogenic effector in ACVR1mutant DIPG. Using cultured DIPG cells and adult glioma cells respectively we have tested the activity of the hypoxia pathway using a hypoxia-responsive elements (HRE)-luciferase reporter assay. Intriguingly, DIPG but not glioma cells overexpressing a mutant ACVR1 construct significantly elevated hypoxia signaling at hypoxia. Similar trends are seen when assaying neuronal stem cell cultures harboring Histone 3.1 mutations along with activated ACVR1/ALK2 signaling. Furthermore, BMP ligand stimulation resulted in a dose-dependent increase of hypoxia signaling in DIPG cells. Through querying clinical gene expression data, we found elevated hypoxia signature scores in pediatric gliomas with mutant ACVR1 as compared to those with wildtype ACVR1. Finally, ACVR1 mutations frequently co-occur with Histone 3.3 and 3.1 mutations, and the hypoxia signature score was significantly higher than baseline only in tumors also harboring these Histone 3.3 or 3.1 mutations. Together, our data suggest that hypoxia signaling is elevated downstream of ACVR1 specifically in pediatric gliomas and prompts for evaluation of hypoxia signaling as potential therapeutical target in DIPG.
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Gómez-Almería, Marta, Sonia Burgaz, Carlos Costas-Insua, Carmen Rodríguez-Cueto, Irene Santos-García, Ignacio Rodríguez-Crespo, Concepción García, Manuel Guzmán, Eva de Lago, and Javier Fernández-Ruiz. "BiP Heterozigosity Aggravates Pathological Deterioration in Experimental Amyotrophic Lateral Sclerosis." International Journal of Molecular Sciences 22, no. 22 (November 20, 2021): 12533. http://dx.doi.org/10.3390/ijms222212533.
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In the present study, we investigated the involvement of the chaperone protein BiP (also known as GRP78 or Hspa5), a master regulator of intracellular proteostasis, in two mouse models of neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). To this end, we used mice bearing partial genetic deletion of the BiP gene (BiP+/− mice), which, for the ALS model, were crossed with mutant SOD1 (mSOD1) transgenic mice to generate mSOD1/BiP+/− double mutant mice. Our data revealed a more intense neurological decline in the double mutants, reflected in a greater deterioration of the neurological score and rotarod performance, with also a reduced animal survival, compared to mSOD1 transgenic mice. Such worsening was associated with higher microglial (labelled with Iba-1 immunostaining) and, to a lesser extent, astroglial (labelled with GFAP immunostaining) immunoreactivities found in the double mutants, but not with a higher loss of spinal motor neurons (labelled with Nissl staining) in the spinal cord. The morphological analysis of Iba-1 and GFAP-positive cells revealed a higher presence of activated cells, characterized by elevated cell body size and shorter processes, in double mutants compared to mSOD1 mice with normal BiP expression. In the case of the PD model, BiP+/− mice were unilaterally lesioned with the parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). In this case, however, we did not detect a greater susceptibility to damage in mutant mice, as the motor defects caused by 6-OHDA in the pole test and the cylinder rearing test, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity (labelled with CD68 and GFAP immunostaining) detected in the substantia nigra were of similar magnitude in BiP+/− mice compared with wildtype animals. Therefore, our findings support the view that a dysregulation of the protein BiP may contribute to ALS pathogenesis. As BiP has been recently related to cannabinoid type-1 (CB1) receptor function, our work also opens the door to future studies on a possible link between BiP and the neuroprotective effects of cannabinoids that have been widely reported in this neuropathological context. In support of this possibility, preliminary data indicate that CB1 receptor levels are significantly reduced in mSOD1 mice having partial deletion of BiP gene.
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Poojitha, T. N. S., K. V. L. Pushpanjali, D. Goutham, K. V. Yashwanth, and Srinivas Prasad. "A study on mutation testing of object oriented programs." International Journal of Engineering & Technology 7, no. 1.1 (December 21, 2017): 243. http://dx.doi.org/10.14419/ijet.v7i1.1.9478.
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Mutation testing is a modern approach which gives more appropriate results. In comparison to traditional approaches, it gives high quality output. Previously it is not used mostly because of its high cost factor. This is because mutation testing deals with white box testing. White Box testing checks every module of the software in detail. If we use this it takes a lot of time and money. Recent approaches which came in mutation testing made it easy to implement for any software. Mutation take a look ating could be a fault based mostly testing technique within which mutants area unit generated within the program and apply totally different test cases on the mutants. Some mutants are killed and some are alive. On the bottom of killed and alive mutants, mutant score is calculated. Based on the mutants which are alive the test cases can be improvised there by the quality of the source code is increased. we propose a tool which gives more effective output of testing. We propose a tool which takes the outputs of various static tools available and combines it with the outputs of dynamic tools available. Our proposed tool includes outputs of available tools like Jester, Mujava, PMD to effectively detect the vulnerabilities and produce high quality software as output.
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Dutta, Sayantanee, Gudrun Pregartner, Frank G. Rücker, Ellen Heitzer, Armin Zebisch, Lars Bullinger, Andrea Berghold, Konstanze Döhner, and Heinz Sill. "Functional Classification of TP53 Mutations in Acute Myeloid Leukemia." Blood 134, Supplement_1 (November 13, 2019): 2725. http://dx.doi.org/10.1182/blood-2019-124316.
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In more than 50% of human cancers, somatically acquired aberrations of the tumor suppressor gene TP53 are encountered. Approx. 10% of patients with acute myeloid leukemia (AML) reveal TP53 mutations with higher incidences in therapy-related subtypes and erythroleukemias. These mutations are regarded early events of leukemogenesis. In contrast to mere deletions at the TP53 locus, TP53 mutations confer an exceedingly adverse prognosis in AML even when occurring at a subclonal level. However whether different TP53 mutations in AML exhibit a different functional impact on disease progression or outcome remains unknown. In the present study, we have investigated this issue using four TP53 specific, functional scoring systems in a large cohort of patients of the German-Austrian AML study group (AMLSG). The AMLSG cohort consisted of a total of 1537 patients with newly diagnosed AML who were intensively treated within three multicenter, clinical trials. A total of 108 TP53 mutations were detected in 98 patients using targeted amplicon sequencing - 88 (81.4%) missense, 8 (7.4%) nonsense and 6 (5.6%) splice site mutations as well as 6 small insertions and deletions. For each of the four functional TP53 scores, we have assessed their impact on overall survival (OS) and event-free survival (EFS). First, we compared the impact of TP53 missense mutations in 84 patients with all other types of mutations (n= 14). In a next approach, TP53 mutations were grouped into disruptive (n=42) and non-disruptive (n=56) ones, based on the impact of the particular mutations on the protein structure predicted from the crystal structure of p53-DNA complexes (Poeta et al. New Engl J Med 2007). We then classified missense TP53 mutations (n=84) based on their "Evolutionary Action Scores (EAp53)" (Neskey et al. Cancer Res 2015). This algorithm takes evolutionary sensitivity and amino acid conservation into account and scores missense TP53 mutations from 0 to 100. Mutations with the high EAp53 score are considered high risk whereas wild type TP53 has an EAp53 score of zero. We extracted the EAp53 score of those AMLSG patients showing missense mutations from the respective server (http://mammoth.bcm.tmc.edu/EAp53) and used the threshold of 75 from the initial publication to divide the patients into low-risk (<75, n=49) and high-risk groups (≥75, n=35). However, with these three functional scoring systems, no difference regarding OS and EFS could be shown between the mutational groups. The "Relative Fitness Score (RFS)" was recently developed for the TP53 DNA binding domain (DBD) mutants as an indicator of their functional impact (Kotlar et al. Molecular Cell 2018). A catalogue of 9833 TP53 DBD mutants were generated and their selective growth was assessed in p53 null cancer cell lines. The RFS score for each mutant is the median of its relative enrichment or depletion in culture, calculated at 3 time points and depicted as a log (base 2) value. A high RFS indicates selective growth of the mutant corresponding to its higher fitness. We extracted the RFS for the TP53 DBD mutations of the AMLSG cohort (n=83) using the online data resource (GSE115072) and performed a receiver-operating characteristics (ROC) analysis to calculate the optimal threshold of RFS separating deceased from survivors most efficiently. Thereby, the best RFS cut-off value according to the Youden index was -0.135. Applying this threshold (low-risk RFS ≤ -0.135, n=25; high-risk RFS > -0.135, n= 58) we demonstrated a significantly better OS (P=0.009) and EFS (P=0.037) for patients with a low-risk RFS in multivariable analyses adjusting for age, white blood cell count, cytogenetics and type of AML. Using the AML-specific TP53 RFS score, we could show that more than 30% of patients with TP53 mutations (25/83) reveal a significantly better survival indicating that this score is of prognostic value. Based on these findings, we propose that - along with clinical parameters - RFS values of TP53 mutations should also be considered for a comprehensive risk assessment of TP53 mutated AML patients. Disclosures Zebisch: Celgene: Honoraria; Novartis: Honoraria, Other: Advisory board; AbbVie: Other: Advisory board; Roche: Honoraria. Bullinger:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Daiichi Sankyo: Honoraria; Gilead: Honoraria; Hexal: Honoraria; Menarini: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Seattle Genetics: Honoraria; Bayer: Other: Financing of scientific research; Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria. Döhner:Daiichi: Honoraria; Jazz: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; CTI Biopharma: Consultancy, Honoraria. Sill:Novartis: Other: Advisory board; AbbVie: Other: Advisory board; Astellas: Other: Advisory board; Astex: Other: Advisory board.
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Yabe, Mariko, Aidana Z. Omarbekova, Meier Hsu, Hannah May, Maria E. Arcila, Ying Liu, Ahmet Dogan, et al. "TP53 Combined Phenotype Score Is Associated with the Clinical Outcome of TP53-Mutated Myelodysplastic Syndromes." Cancers 13, no. 21 (November 2, 2021): 5502. http://dx.doi.org/10.3390/cancers13215502.
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Mutations of TP53 are observed in 5–10% of patients in myelodysplastic syndrome (MDS) and are associated with adverse outcomes. Previous studies indicate that the TP53 allelic state and variant allele frequency of TP53 mutation impact patient outcomes, but there is significant heterogeneity within this MDS subgroup. We performed retrospective review of clinicopathologic and genomic information of 107 patients with TP53-mutated MDS. We assessed each mutation according to the phenotypic annotation of TP53 mutations (PHANTM) and analyzed the associations between predicted TP53 mutant function, represented by the PHANTM combined phenotype score, and overall survival (OS) using the log rank test and Cox regression. Our results indicated that patients with PHANTM combined phenotype score above the median (>1) had significantly shorter OS compared to those with scores below the median (median OS: 10.59 and 16.51 months, respectively, p = 0.025). This relationship remained significant in multivariable analysis (HR (95%CI): 1.62 (1.01–2.58), p = 0.044) and identified to have an independent prognostic influence, accounting for known risk such as IPSS-R and other standard risk variables. Our results suggest that the functional information of TP53 mutations, represented by PHANTM combined phenotype score, are associated with the clinical outcome of patients with TP53-mutated MDS.
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Wu, Dongping, Lingjuan Huang, Jiwei Mao, Jianjiang Liu, Wanli Ye, Jun Xu, Wangyan Zhong, Xiaoyu Zhang, and Shenpeng Ying. "Combination of Tumor Mutational Burden and DNA Damage Repair Gene Mutations with Stromal/Immune Scores Improved Prognosis Stratification in Patients with Lung Adenocarcinoma." Journal of Oncology 2022 (September 20, 2022): 1–12. http://dx.doi.org/10.1155/2022/6407344.
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Background. Both the tumor environment and the genomic landscape of lung cancer may shape patient responses to treatments, including immunotherapy, but their joint impacts on lung adenocarcinoma (LUAD) prognosis are underexplored. Methods. RNA sequencing data and whole-exome sequencing results were downloaded from the TCGA database, and only LUAD-related data were included in this study. Based on gene expression data, the ESTIMATE algorithm was used to estimate stromal and immune scores, and CIBERSORT analysis was used for quantification of the relative abundances of immune cells. Somatic mutations were used for calculating tumor mutation burden (TMB). Specific mutations in genes involved in DNA damage repair (DDR) pathways were identified. The individual and joint associations of stromal and immune score, TMB, and DDR gene mutations with 5-year survival were analyzed by the Kaplan–Meier method and multivariate Cox model. Results. LUAD patients with a high (>highest 25%) stromal or immune score had prolonged survival as compared to those with a low (<lowest 25%) score (log-rank P = 0.05 and 0.035, respectively). Patients with both high stromal and immune scores had the most favorable survival. Although the survival differences between patients with high (>highest 25%) and low (<lowest 25%) TMB, or between patients with mutant- and wild-type DDR genes were not statistically significant, a survival benefit from high TMB or DDR gene mutations was observed in patients with high stromal or immune scores. Conclusion. A comprehensive evaluation of transcriptomic signatures and genomic biomarkers may provide a novel avenue for improving prognosis stratification in LUAD.
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Kulkarni, Aditya, Jianli Zhou, Kishor Bhatia, and Panna Sharma. "Tumor sensitization to PARP inhibitors by DNA damaging synthetically lethal acylfulvenes." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): e15123-e15123. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e15123.
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e15123 Background: 20-30% of solid tumors (ovarian, breast, pancreatic, prostate cancers) harbor some level of deficiency in DNA Damage Repair (DDR) pathways. Such cancers become dependent on alternative DDR pathways to maintain genome integrity, making them selectively vulnerable to DNA damaging agents. The concept of synthetic lethality has been leveraged to treat subsets of such tumors. Clinically, PARP inhibitors (PARPi) have been successful in Homologous Recombination Deficiency (HRD) cancers. LP-100 and LP-184 are acylfulvene (AF) class small molecule prodrugs that are metabolized to active compounds by prostaglandin reductase 1 (PTGR1) that is often elevated in solid tumors. AF-induced DNA lesions are likely selectively processed by repair pathways including BRCA1/2 mediated Homologous Recombination (HR). Methods: Cell Titer Glo based 10 day cell viability assays were used to generate drug IC50 values in vitro. Bliss synergy scores were computed with scores ≥ 10 reflecting synergy. Drug-induced DNA double strand breaks (DSB) were detected and quantified with STRIDE (SensiTive Recognition of Individual DNA Ends) assay in cancer cells. A subcutaneous tumor xenograft model was used to determine tumor volumes in control and drug treated mice. Results: In a BRCA2 mutant ovarian cancer cell line OVCAR3, LP-184 and olaparib co-treatment in vitro showed synergistic effects (Bliss score 10). Similarly in a BRCA2 mutant prostate cancer cell line 22Rv1, LP-100 combination with rucaparib was synergistic (Bliss score 18). 400 nM LP-184 showed a time dependent increase in DNA DSB signals in vitro, 1.7X more so in BRCA2 mutant vs wild type (WT) DLD-1 isogenic colon cancer cell lines up to 24 hours. To validate the hypothesis that AF-induced DSBs remain unresolved if exposed to and further synergize with PARPi in vivo, we tested LP-100 plus olaparib in a DU145 (BRCA2 mutant) prostate cancer xenograft model. LP-100 + olaparib treatment resulted in sustained, durable tumor regression indicating in vivo synergy whereas either agent alone did not produce tumor shrinkage. Day 42 tumor growth inhibition was 66% for 2.5 mg/kg LP-100 alone, 34% for 40 mg/kg olaparib alone and 108% for the combination. Moreover, LP-184 treatment resulted in early onset and complete tumor regression in 7 PDX models of PARPi resistant triple negative breast cancers (TNBC) harboring BRCA1/2 loss whereas olaparib/ niraparib remained entirely ineffective in these. Conclusions: AF response is influenced by tumor DNA repair competence. LP-100 and LP-184 are synthetically lethal resulting from their abilities to cause unresolvable DNA damage where tumor cells express high PTGR1 and are deficient in the HR pathway. LP-184 single agent was superior to PARPi in TNBC and LP-100 combination made an olaparib resistant tumor highly sensitive, thereby facilitating a path to extend the opportunities for both AFs and PARPis and enhance the clinical utilization of PARPi.
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DeCuypere, Michael, Melissa LoPresti, Hinda Najem, Shashwat Tripathi, Joanne Xiu, Hilary Seifert, Valerie I. Brown, et al. "Vulnerability to immune therapy in BRAF- and MYB-altered pediatric gliomas." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 2066. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.2066.
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2066 Background: The frequency and expression of predictive immune biomarkers in pediatric gliomas is relatively unknown. Here, we sought to define predictive signatures of immunotherapy responders by examining immune checkpoint expression, immune cell population signatures, and gene amplifications in a variety of pediatric gliomas. Methods: We profiled a cohort of pediatric, adolescent, and young adult glioma samples submitted to Caris Life Sciences (Phoenix, AZ) for analysis (N = 207). The cohort was further stratified by driver mutations: IDH mutant (N = 103), H3-3A mutant (N = 36), MYB-altered (N = 4), BRAF-altered (N = 39), and IDH wild type [IDH WT] (N = 25). De-identified next generation DNA sequencing (592-gene or whole exome) and RNA (whole transcriptome) sequencing were used to determine tumor-infiltrating immune cell signatures and immune checkpoint protein expression. Transcriptomic signatures predictive of response to immunotherapy (T cell inflamed score) and replication stress response defect (RSRD) score were calculated on transcripts per million (TPM) values. Immune cell fractions were estimated using RNA deconvolution (quanTIseq). Results: BRAF-altered tumors showed the highest IFN gamma signature (a clinically relevant inflammatory biomarker), a high pro-inflammatory M1 macrophage signature, and very high CD4+/CD8+ T cell signatures compared to other tumor groups. IDH mutant, but not WT gliomas, were relatively deficient in T cell infiltration but revealed an increase in dendritic cell signatures. IDH WT gliomas showed more T cell enrichment but higher immune suppressive checkpoint expression. H3-3A mutant tumors showed relatively low immune cell infiltration and immune checkpoint expression. Pro-inflammatory M1 macrophages were lower in the high-grade glioma microenvironment compared to low-grade. Immune suppressive M2 macrophages were elevated in the IDH WT microenvironment relative to other gliomas. There was no apparent difference in the frequency of PD-1+ T cells and tumor-expressed PD-L1 among the various molecularly defined pediatric glioma groups. Conclusions: In general, BRAF- and MYB-altered gliomas displayed high immune activation relative to other tumors. IDH WT tumors have an immune suppressive microenvironment with relatively high immune checkpoint expression. Based on predictive markers, BRAF- and MYB-driven gliomas show signatures suggesting the possibility of a greater response to immunotherapies than IDH WT/mutant gliomas or H3-3A gliomas.
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Jamshidi, Pouya, Kristyn Galbraith, Matthew Mccord, Lucas Santana-Santos, Lawrence Jennings, Matija Snuderl, and Craig Horbinski. "PATH-44. VARIANT ALLELIC FREQUENCY OF DRIVER MUTATIONS PREDICTS SUCCESS OF GENOMIC METHYLATION CLASSIFICATION IN CNS TUMORS." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii160. http://dx.doi.org/10.1093/neuonc/noac209.617.
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Abstract Whole genome CpG DNA methylation profiling is an extremely valuable tool in the workup of central nervous system (CNS) tumors. Reliability of such profiling depends on sufficient tumor cellularity. Many neoplastic entities have well-known driver mutations that occur in virtually 100% of tumor cells, and next-generation sequencing (NGS) assays can detect those mutations and report their relative amounts in the form of Variant Allelic Frequency (VAF). Since NGS and methylation profiling are often done on the same tumor block, we sought to determine whether driver mutation VAF affects the accuracy of methylation profiling, and whether VAF can help establish more rigorous cutoffs for quality assurance. Using NGS and Infinium Epic850K methylation arrays, we evaluated 153 CNS neoplasms representing a range of entities, including TERT promoter-mutant glioblastoma, IDH-mutant astrocytoma, IDH-mutant oligodendroglioma, SHH-driven medulloblastoma, and CTNNB1-driven adamantinomatous craniopharyngioma. VAFs of each driver mutation ranged between 1-60%. One hundred eleven of 153 cases (73%) had a methylation classification score ≥ 0.9, the most widely accepted cutoff for a successful result. A fit-of-mixture analysis via CutoffFinder (PMID: 23251644) suggested that the optimal VAF cutoff=31%, generating an AUC of 0.87. Ninety-six of 107 (89%) cases with a VAF of 31% or higher had a methylation classification score ≥ 0.9, whereas only 15/46 (33%) below 31% were classifiable with methylation profiling (P< 0.0001 by Fisher’s exact test). An independent validation cohort from NYU (N=50) showed nearly identical results, with 37/50 (74%) of cases having a methylation classification score ≥ 0.9, an optimal cutoff=0.32 with an AUC=0.84, and % classification above and below the 0.32 cutoff being 30/34 (88%) and 7/16 (44%), respectively (P=0.002) These data indicate that VAF of driver mutations can serve as a useful predictor of classification success via methylation profiling, and should be taken into account when interpreting methylation profiling results.
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DeStefanis, Rebecca A., Autumn M. Olson, Alyssa K. DeZeeuw, Susan N. Payne, Cheri A. Pasch, Linda Clipson, and Dustin A. Deming. "Abstract 1128: MTORC1/2 and HDAC1/2 inhibition promote tumor response through inhibition of MYC." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1128. http://dx.doi.org/10.1158/1538-7445.am2022-1128.
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Abstract Background: The identification of treatment strategies targeting PIK3CA mutant colorectal cancer (CRC) are of great clinical interest. Previous work from our lab has identified MTORC1/2 and HDAC1/2 inhibition with copanlisib (cop; PI3K/MTOR) and romidepsin (romi; HDAC1/2) as a potential therapeutic strategy. We hypothesized that changes in c-MYC protein levels and c-MYC target gene (CTG) alterations might be a potential mechanism of action for this combination. Methods: Known CTGs were identified and their expression levels were examined in PIK3CA mutant vs WT CRCs using the cBioPortal Colorectal Adenocarcinoma (TCGA, PanCancer Atlas) dataset. Murine derived cancer organoids (MDCO) were generated from adenocarcinomas of Apc and Pik3ca mutant transgenic mice (F1 (FVB x B6) Apcfl/+ Pik3caH1047R/+). MDCO results were corroborated using the human 2D isogenic cell lines SW48 and SW48PIK3CA-H1047R (SW48PK) and RAS/RAF WT patient derived cancer organoids (PDCO) generated from CRC patient samples under approved IRB protocols. Immunoblots (IB) were used to assess c-MYC levels after treatment with cop, romi, and the combination across all models. RNA sequencing was conducted on PDCOs and SW48PK cells and changes in 16 CTGs were examined. An aggregate score was created for each treatment group where a statistically significantly altered CTG with log fold change ≥1.5 added one point and ≤-1.5 subtracted one point. All others were scored 0. Results: c-MYC target genes were assessed for differential expression in PIK3CA mutant CRC vs PIK3CA WT CRC with only 1/16 genes decreased in PIK3CA mutant CRC (GADD45A: log ratio -0.21, q=0.01). Next, MDCOs treated with the combination showed a decrease in total c-MYC levels in the combination therapy. These results were corroborated in two human 2D CRC cell lines, SW48 and SW48PK and a panel of PDCOs. Interestingly, c-MYC levels decreased in both romi alone and the combination in both the SW48 and SW48PK cell lines after 24 hours of treatment. However, the extent to which c-MYC levels were decreased was not as substantial in the panel of PDCOs. Across all in vitro models a decrease in PI3K signaling, as illustrated by decreased pRPS6 and p4EBP1 in response to cop treatment and an increase in H3K27 acetylation in response to romi, was observed in the single agent and combination therapies. RNA sequencing demonstrated that cop, romi, and combo had a CTG score of 0, -4, and -7 respectively in the PIK3CA mutant PDCO. Similar results were seen in an additional RAS/RAF WT PDCO (0, 1, and -4, respectively) and SW48PK cells (0, -3, and -7, respectively). Conclusion: A potential mechanism by which cop and romi treatment promote tumor response is through a decrease in c-MYC protein levels and expression of downstream c-MYC target genes. This regimen deserves further mechanistic investigations in vivo. Citation Format: Rebecca A. DeStefanis, Autumn M. Olson, Alyssa K. DeZeeuw, Susan N. Payne, Cheri A. Pasch, Linda Clipson, Dustin A. Deming. MTORC1/2 and HDAC1/2 inhibition promote tumor response through inhibition of MYC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1128.
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Arsyad, Nur Rohmah, Risanto Siswosudarmo, and Ardhanu Kusumanto. "Hubungan antara Ekspresi P53 Mutan terhadap Operabilitas Kanker Serviks Stadium IIB Pasca Kemoterapi Neoajuvan." Jurnal Kesehatan Reproduksi 7, no. 1 (May 14, 2020): 49. http://dx.doi.org/10.22146/jkr.53838.
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Background: The therapy for stage IIB cervical cancer according to FIGO is concurrent chemoradiation. The neoadjuvant chemotherapy followed by radical hysterectomy is an alternative therapy to improve the survival rate of cancer patients. Cervical cancer is mainly caused by the infection of Human Papilloma Virus (HPV), which contains protein E6 and E7 that downregulate the apoptotic function of p53. The absent of p53 wild-type and the present of p53 mutation play roles on the cervical cancer pathogenesis.Objective: To analyze the association between the expression of mutant p53 to the stage IIB cervical cancer operability after neoadjuvant chemotherapyMethod: This study was a prospective cohort, using 40 of 67 patient who met eligibility criteria. The parafin block from cervical tissue were processed for immunohistochemical staining of p53 using Anti-mutant p53 antibody [Y5] ab32049, Abcam, USA. Two study groups were assessed as: 1) weak and 2) strong expression of mutant p53 expression after neoadjuvant chemotherapy based on H-score. Both group (weak and strong) were comparable in term of mutant p53 expression. In this study, the evaluation of operability was performed clinically. Age, BMI, histopathology, grade of differentiation, and regiment were also evaluated as the external variables. Chi square test, and logistic regression analysis were used for statistical analysis.Results and Discussion: The rate of cervical cancer operability after chemotherapy was 19 out of 40 (47.5%). The strong expression of mutant p53 was observed in 6 subjects (15%). There was no significant association between weak vs strong expression of mutant p53 to the operability of the cancer (RR 1.5, CI 95% 0.46-4.88, p 0.45). Multivariate analysis showed that combination (50 mg/m2 dan 5 fluorourasil 450 mg/m2) was significantly correlated the operability (OR 7.02, CI 95% 1.27-40.07, p 0.03). Conclusion: The expression of mutant p53 not correlate with operability after neoadjuvant chemotherapy, but combination regiment was.Keywords: expression of mutant p53, stage IIB of cervical cancer, neoadjuvant chemotherapy, operability