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  • American Association for Cancer Research (AACR)  (70)
  • 1
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    Early Detection of Lung Cancer Using DNA Promoter Hypermethylation in Plasma and Sputum
    American Association for Cancer Research (AACR) ; 2017
    In:  Clinical Cancer Research Vol. 23, No. 8 ( 2017-04-15), p. 1998-2005
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 23, No. 8 ( 2017-04-15), p. 1998-2005
    Abstract: Purpose: CT screening can reduce death from lung cancer. We sought to improve the diagnostic accuracy of lung cancer screening using ultrasensitive methods and a lung cancer–specific gene panel to detect DNA methylation in sputum and plasma. Experimental Design: This is a case–control study of subjects with suspicious nodules on CT imaging. Plasma and sputum were obtained preoperatively. Cases (n = 150) had pathologic confirmation of node-negative (stages I and IIA) non–small cell lung cancer. Controls (n = 60) had non-cancer diagnoses. We detected promoter methylation using quantitative methylation-specific real-time PCR and methylation-on-beads for cancer-specific genes (SOX17, TAC1, HOXA7, CDO1, HOXA9, and ZFP42). Results: DNA methylation was detected in plasma and sputum more frequently in people with cancer compared with controls (P & lt; 0.001) for five of six genes. The sensitivity and specificity for lung cancer diagnosis using the best individual genes was 63% to 86% and 75% to 92% in sputum, respectively, and 65% to 76% and 74% to 84% in plasma, respectively. A three-gene combination of the best individual genes has sensitivity and specificity of 98% and 71% using sputum and 93% and 62% using plasma. Area under the receiver operating curve for this panel was 0.89 [95% confidence interval (CI), 0.80–0.98] in sputum and 0.77 (95% CI, 0.68–0.86) in plasma. Independent blinded random forest prediction models combining gene methylation with clinical information correctly predicted lung cancer in 91% of subjects using sputum detection and 85% of subjects using plasma detection. Conclusions: High diagnostic accuracy for early-stage lung cancer can be obtained using methylated promoter detection in sputum or plasma. Clin Cancer Res; 23(8); 1998–2005. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-16-1371
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 2
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    Dual Role of CXCL8 in Maintaining the Mesenchymal State of Glioblastoma Stem Cells and M2-Like Tumor-Associated Macrophages
    American Association for Cancer Research (AACR) ; 2023
    In:  Clinical Cancer Research Vol. 29, No. 18 ( 2023-09-15), p. 3779-3792
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 29, No. 18 ( 2023-09-15), p. 3779-3792
    Abstract: The dynamic interplay between glioblastoma stem cells (GSC) and tumor-associated macrophages (TAM) sculpts the tumor immune microenvironment (TIME) and promotes malignant progression of glioblastoma (GBM). However, the mechanisms underlying this interaction are still incompletely understood. Here, we investigate the role of CXCL8 in the maintenance of the mesenchymal state of GSC populations and reprogramming the TIME to an immunosuppressive state. Experimental Design: We performed an integrative multi-omics analyses of RNA sequencing, GBM mRNA expression datasets, immune signatures, and epigenetic profiling to define the specific genes expressed in the mesenchymal GSC subsets. We then used patient-derived GSCs and a xenograft murine model to investigate the mechanisms of tumor-intrinsic and extrinsic factor to maintain the mesenchymal state of GSCs and induce TAM polarization. Results: We identified that CXCL8 was preferentially expressed and secreted by mesenchymal GSCs and activated PI3K/AKT and NF-κB signaling to maintain GSC proliferation, survival, and self-renewal through a cell-intrinsic mechanism. CXCL8 induced signaling through a CXCR2–JAK2/STAT3 axis in TAMs, which supported an M2-like TAM phenotype through a paracrine, cell-extrinsic pathway. Genetic- and small molecule–based inhibition of these dual complementary signaling cascades in GSCs and TAMs suppressed GBM tumor growth and prolonged survival of orthotopic xenograft-bearing mice. Conclusions: CXCL8 plays critical roles in maintaining the mesenchymal state of GSCs and M2-like TAM polarization in GBM, highlighting an interplay between cell-autonomous and cell-extrinsic mechanisms. Targeting CXCL8 and its downstream effectors may effectively improve GBM treatment.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-22-3273
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 3
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    Abstract 3374: Circulating cell-free tumor DNA dynamics capture minimal residual disease with neoadjuvant immune checkpoint blockade plus chemoradiotherapy for patients with operable esophageal/gastroesophageal junction cancer
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3374-3374
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3374-3374
    Abstract: Introduction: There is a critical need to incorporate molecular assessments of minimal residual disease (MRD) during neoadjuvant immunotherapy, in order to identify individuals at high risk for disease recurrence based on analyses of circulating cell-free tumor DNA (ctDNA) landscapes. Here we employed longitudinal liquid biopsies to dynamically assess clinical outcomes with neoadjuvant immuno-chemoradiotherapy in patients with esophageal/gastroesophageal junction (E/GEJ) cancer. Methods: We utilized targeted error-correction sequencing to perform high-depth ctDNA next-generation sequencing for 141 serial plasma and 32 matched white blood cell (WBC) DNA samples from 32 patients with operable stage II/III E/GEJ cancer that received neoadjuvant immune checkpoint blockade (ICB) with chemoradiotherapy prior to surgery (NCT03044613). ctDNA analyses were performed at baseline, post-ICB induction, after completion of chemoradiotherapy (pre-op), and post-operatively (post-op). Using a tumor-agnostic WBC DNA-informed panel NGS approach we determined the cellular origin of plasma variants, filtering out germline and clonal hematopoiesis (CH) variants and evaluated ctDNA clonal dynamics over time. Molecular MRD was evaluated post-ICB, pre-op and post-op and correlated with recurrence-free (RFS) and overall survival (OS). Results: Twenty out of 32 patients had detectable ctDNA at any timepoint. Of the 12 patients with undetectable ctDNA, 9 had only CH- and/or germline-derived variants, while 3 patients had no detectable variants of any origin. ctDNA clearance post-ICB was correlated with tumor regression & gt;80% at the time of resection (Fischer’s exact p=0.04). The subset of patients that did not attain complete pathologic response was heterogeneous with respect to ctDNA dynamics; such that ctDNA clearance pre-op identified patients with longer OS despite residual tumor of & gt;0% at the time of resection (log rank p=0.06). Patients with undetectable ctDNA or ctDNA clearance pre-op had a longer RFS (log rank p=0.007) and OS (log rank p=0.03). Molecular MRD was associated with RFS and OS such that patients with ctDNA clearance post-op had longer RFS (log-rank p=0.007) and OS (log-rank p=0.017). Conclusion: ctDNA clearance post-ICB, pre-op and post-op reflects differential clinical outcomes for patients with E/GEJ cancer receiving neoadjuvant immuno-chemoradiotherapy. Understanding ctDNA dynamics and their relationship with pathological response and long-term outcomes can help identify patients at higher risk for recurrence and open a therapeutic window for future intervention. Citation Format: Blair V. Landon, Ronan J. Kelly, Ali H. Zaidi, Archana Balan, Jenna V. Canzoniero, Gavin Pereira, Zineb Belcaid, Russell K. Hales, K Ranh Voong, Richard J. Battafarano, Blair A. Jobe, Stephen C. Yang, Stephen Broderick, Jinny Ha, Kellie N. Smith, Elizabeth Thompson, Fyza Y. Shaikh, James R. White, Cynthia L. Sears, Eun J. Shin, Ali I. Amjad, Benny Weksler, Josephine L. Feliciano, Chen Hu, Vincent K. Lam, Valsamo Anagnostou. Circulating cell-free tumor DNA dynamics capture minimal residual disease with neoadjuvant immune checkpoint blockade plus chemoradiotherapy for patients with operable esophageal/gastroesophageal junction cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3374.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-3374
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 4
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    Promoter Hypermethylation of Resected Bronchial Margins
    American Association for Cancer Research (AACR) ; 2004
    In:  Clinical Cancer Research Vol. 10, No. 15 ( 2004-08-01), p. 5131-5136
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 10, No. 15 ( 2004-08-01), p. 5131-5136
    Abstract: Purpose: Histologically positive bronchial margins after resection for non-small cell lung cancer are associated with shortened patient survival due to local recurrence. We hypothesized that DNA promoter hypermethylation changes at bronchial margins could be detected in patients with no histological evidence of malignancy and that they would reflect epigenetic events in the primary tumor. Experimental Design: Bronchial margins, primary tumor, bronchoalveolar fluid, and paired nonmalignant lung were obtained from 20 non-small cell lung cancer patients who underwent a lobectomy or greater resection. Disease-specific recurrence was the primary end point. The methylation status of p16, MGMT, DAPK, SOCS1, RASSF1A, COX2, and RARβ was examined using methylation-specific polymerase chain reaction. Results: All malignancies had methylation in at least one locus. Concordance of one gene with an identical epigenetic change in the tumor or bronchial margin was observed in 85% of patients. Only one patient had methylation at the bronchial margin for a gene that was not methylated in the corresponding tumor. Median time to recurrence was 37 months (range, 5–71 months). There were two local recurrences and five metastases. There were no significant correlations between DNA methylation in tumor, margins, or bronchoalveolar fluid specimens and either regional recurrence or distant metastases. Conclusions: Histologically negative bronchial margins of resected non-small cell lung cancer exhibit frequent hypermethylation changes in multiple genes. These hyper-methylation abnormalities are also present in the primary tumor and thus may represent a field defect of preneoplastic changes that occurs early in carcinogenesis.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-03-0763
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2004
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  • 5
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    Abstract 1973: Patients with operable esophageal cancer and improved responses to combined chemoradiotherapy and immunotherapy display distinct microbiome profiles enriched in multiple Bacteroides species
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1973-1973
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1973-1973
    Abstract: Background: Preclinical and clinical data indicate that neoadjuvant chemoradiotherapy (CRT) may prime an anti-tumor immunological response in esophageal cancer driven by intratumoral CD8+ T cells and PD-L1 expression. LAG-3 is also highly expressed in esophagogastric cancers. The microbiome, a novel and potentially modifiable, biomarker of IO response, has not yet been examined in the neoadjuvant setting in esophageal cancer and is the goal of our study. Methods: Fecal samples were collected from patients with stage II/III esophageal or gastroesophageal junction carcinoma eligible for curative resection treated with the standard of care regimen of carboplatin paclitaxel (50mg/m2), radiation 50.4 Gy in 28 fractions and an Ivor-Lewis esophagectomy 6-10 weeks after last CRT and immunotherapy (IO) dose. Patients on arm A (n=11) received 2 cycles of induction with nivolumab plus 3 additional cycles on week 1, 3 and 5 of CRT. Patients on arm B (n=8) received nivolumab plus relatlimab on the same schedule (Clinical trial: NCT03044613). We examined longitudinal fecal samples from n=19 patients across both arms (n=90 samples) using 16S rRNA amplicon sequencing. Patients were classified based on pathological response: complete response (CR) and grades 1, 2, and 3 (G1, G2, G3) with increasing residual tumor visible in the resected specimen. Sequencing data was trimmed and filtered for contaminants, followed by high-resolution taxonomic assignment and normalization of reads across all samples. Analysis was performed using multiple metrics for alpha diversity and beta-diversity, with principal coordinates analysis/PERMANOVA, and pathway analysis using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). Results: Patients with improved response in the neoadjuvant setting (CR/G1 vs G2/G3) grouped in distinct clusters using Bray-Curtis (p & lt; 0.001). Patients with CR had higher alpha diversity, using both measures of richness and evenness, compared to patients with a G3 responses (p & lt; 0.03). Specifically, family Bacteroidaceae and genus Bacteroides were enriched in patients with CR vs G3 (p & lt; 0.02). At the species level, B. finegoldii, B. ovatus, and B. uniformis were enriched in patients with CR vs G3 (p & lt; 0.02). In contrast, genus Klebsiella and Clostridium termitidis were enriched in patients with a poor response, G3 (p & lt;0.001, both). Pathway analysis found two metabolic pathways enriched in patients with CR: secondary bile acid biosynthesis (p=0.005) and lysine biosynthesis (p=0.02). Conclusions: Patients with operable esophageal cancer and improved responses to combined CRT and IO had distinct microbiome profiles enriched in multiple Bacteroides species. Further analyses and validation efforts are underway to confirm metabolomic pathways. Citation Format: Fyza Y. Shaikh, James R. White, Ronan J. Kelly, Ali H. Zaidi, Jenna V. Canzoniero, Josephine L. Feliciano, Russell K. Hales, K Ranh Voong, Richard J. Battafarano, Blair A. Jobe, Stephen C. Yang, Stephen Broderick, Jinny Ha, Kellie N. Smith, Elizabeth Thompson, Eun J. Shin, Ali I. Amjad, Patrizia Guerrieri, Benny Weksler, Chen Hu, Valsamo Anagnostou, Vincent K. Lam, Cynthia L. Sears. Patients with operable esophageal cancer and improved responses to combined chemoradiotherapy and immunotherapy display distinct microbiome profiles enriched in multiple Bacteroides species [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 1973.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-1973
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 6
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    Abstract CT079: Neoadjuvant PD-1 blockade in resectable lung cancer
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. CT079-CT079
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. CT079-CT079
    Abstract: Background: Programmed death-1 (PD-1) blocking antibodies improve survival in patients with advanced non-small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, where little progress has been made over the last decade. Methods: Adults with untreated surgically resectable stage I-IIIA NSCLC received two doses of nivolumab (anti-PD-1) preoperatively. The primary endpoints of the study were safety and feasibility. Tumor pathologic response, PD-L1 expression, mutation burden and mutation-associated neoantigen-specific T-cell responses were evaluated. Results: Neoadjuvant nivolumab was had an acceptable side effect profile without surgical delays, and 20 of 21 tumors were completely resected. Major pathologic response occurred in 45% (9/20) of resected tumors. Responses occurred in both PD-L1 positive and negative tumors. Pathologic response significantly correlated with pre-treatment tumor somatic mutation burden. T-cell clones shared between the tumor and peripheral blood increased systemically upon anti-PD-1 treatment in 8 of 9 patients analyzed. Mutation-associated neoantigen-specific T-cell clones, from a primary tumor that underwent pathologic complete response, rapidly expanded in peripheral blood at 2-4 weeks post-treatment, some of these clones were not detected before anti-PD-1. Conclusions: Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced major pathologic responses in 45% of resected tumors. Tumor mutation burden is predictive of pathologic response to anti-PD-1. Anti-PD-1 can induce expansion of mutation-associated neoantigen-specific T-cell clones in peripheral blood. [P.M.F., J.E.C., and K.N.S. contributed equally to this work.] Citation Format: Patrick M. Forde, Jamie E. Chaft, Kellie N. Smith, Valsamo Anagnostou, Tricia R. Cottrell, Matthew D. Hellmann, Marianna Zahurak, Stephen C. Yang, David R. Jones, Stephen Broderick, Richard J. Battafarano, Moises J. Velez, Natasha Rekhtman, Zachary Olah, Jarushka Naidoo, Kristen A. Marrone, Franco Verde, Haidan Guo, Jiajia Zhang, Justina X. Caushi, Hok Yee Chan, John-William Sidhom, Robert B. Scharpf, James White, Edward Gabrielson, Hao Wang, Gary L. Rosner, Valerie Rusch, Jedd D. Wolchok, Taha Merghoub, Janis M. Taube, Victor E. Velculescu, Suzanne L. Topalian, Julie R. Brahmer, Drew M. Pardoll. Neoadjuvant PD-1 blockade in resectable lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT079.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-CT079
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 7
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    P2RX7 Enhances Tumor Control by CD8+ T Cells in Adoptive Cell Therapy
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Immunology Research Vol. 10, No. 7 ( 2022-07-01), p. 871-884
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 10, No. 7 ( 2022-07-01), p. 871-884
    Abstract: Expression of the purinergic receptor P2RX7 by CD8+ T cells promotes the generation of memory populations following acute infections. However, data suggest that P2RX7 may limit the efficacy of antitumor responses. Herein, we show that P2RX7 is beneficial for optimal melanoma control in a mouse CD8+ T-cell adoptive transfer model. Tumor-specific P2rx7–/– CD8+ T cells exhibited impaired mitochondrial maintenance and function but did not display signs of overt exhaustion early in the antitumor response. However, as the tumor burden increased, the relative frequency of P2RX7-deficient CD8+ T cells declined within the tumor; this correlated with reduced proliferation, increased apoptosis, and mitochondrial dysfunction. Extending these studies, we found that the transient in vitro stimulation of P2RX7 using the ATP analogue BzATP led to enhanced B16 melanoma control by CD8+ T cells. These findings are in keeping with the concept that extracellular ATP (eATP) sensing by P2RX7 on CD8+ T cells is required for their ability to efficiently eliminate tumors by promoting mitochondrial fitness and underscore the potential for P2RX7 stimulation as a novel therapeutic treatment to enhance tumor immunotherapy.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-21-0691
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 8
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    Hypermethylation of the GATA Genes in Lung Cancer
    American Association for Cancer Research (AACR) ; 2004
    In:  Clinical Cancer Research Vol. 10, No. 23 ( 2004-12-01), p. 7917-7924
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 10, No. 23 ( 2004-12-01), p. 7917-7924
    Abstract: Purpose: In lung cancer, DNA hypermethylation is known to be a common event. Experimental Design: Gene expression and methylation status of GATA-4, GATA-5, and GATA-6 were analyzed with cell lines and primary human lung cancers. Methylation profiles of primary lung cancers were analyzed and correlated with clinical as well as histopathological data. Results: Complete methylation was detected by methylation-specific PCR for both GATA-4 and GATA-5 in four cell lines (H358, DMS-53, A549, and H1299), all of which had no expression by reverse transcription-PCR analysis. Demethylation with 5-aza-2′deoxycytidine restored expression in each case. GATA-6 was ubiquitously expressed in all of the six cell lines. GATA-4 bisulfite sequencing revealed complete methylation of the GATA-4 promoter in H358 cells, correlating well with its lack of expression at the mRNA level. Only a few CpG sites showed methylation by bisulfite sequencing within the GATA-4 promoter in a cell line that expressed the gene. In 63 cases of primary lung cancers, GATA-4 and GATA-5 promoter methylation was detected in (42 of 63) 67% and (26 of 63) 41%, respectively. GATA-6 remained unmethylated both in cell lines and primary tumors. Six autopsy specimens of normal lung tissue showed no aberrant promoter hypermethylation for the GATA genes. Correlation of concomitant GATA-4 and GATA-5 methylation with clinicopathological parameters only found a statistically significant increase in methylation frequency with increasing patient age (P & lt; 0.001). Conclusions: These epigenetic changes in the GATA genes in lung cancer are tumor-specific, relate to the loss of GATA gene expression, and occur increasingly in the elderly.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-04-1140
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2004
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  • 9
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    MYC-Regulated Mevalonate Metabolism Maintains Brain Tumor–Initiating Cells
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 18 ( 2017-09-15), p. 4947-4960
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 18 ( 2017-09-15), p. 4947-4960
    Abstract: Metabolic dysregulation drives tumor initiation in a subset of glioblastomas harboring isocitrate dehydrogenase (IDH) mutations, but metabolic alterations in glioblastomas with wild-type IDH are poorly understood. MYC promotes metabolic reprogramming in cancer, but targeting MYC has proven notoriously challenging. Here, we link metabolic dysregulation in patient-derived brain tumor–initiating cells (BTIC) to a nexus between MYC and mevalonate signaling, which can be inhibited by statin or 6-fluoromevalonate treatment. BTICs preferentially express mevalonate pathway enzymes, which we find regulated by novel MYC-binding sites, validating an additional transcriptional activation role of MYC in cancer metabolism. Targeting mevalonate activity attenuated RAS-ERK–dependent BTIC growth and self-renewal. In turn, mevalonate created a positive feed-forward loop to activate MYC signaling via induction of miR-33b. Collectively, our results argue that MYC mediates its oncogenic effects in part by altering mevalonate metabolism in glioma cells, suggesting a therapeutic strategy in this setting. Cancer Res; 77(18); 4947–60. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-17-0114
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 10
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    Abstract LB-154: Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small cell lung carcinoma (NSCLC): A proposal for quantitative immune-related pathologic response criteria (irPRC)
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. LB-154-LB-154
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. LB-154-LB-154
    Abstract: There is great interest in using PD-(L)1 blockading drugs as neoadjuvant therapy for patients with resectable NSCLC. Early results demonstrated a 45% (9/20) major pathologic response (MPR) rate in patients with Stage I-III NSCLC after receiving nivolumab (NCT02259621). Major pathologic response (MPR) criteria were developed in the context of cytotoxic chemotherapy, defined as ≤10% residual viable tumor cells (RVT). The features of immune-mediated tumor regression following anti-PD-1 have yet to be described. We reviewed H & E-stained slides from resection specimens in 19 patients treated with neoadjuvant nivolumab [n=9 MPR, n=3 partial responders, n=7 non-responders ( & gt;70% RVT)] to identify histopathologic features of immune-mediated tumor regression. Specimens were assessed for immune characteristics (tumor infiltrating lymphocyte (TIL) and macrophage density, and presence/absence of, lymphoid aggregates, tertiary lymphoid structures (TLS), dense plasma cell infiltrates, neutrophils, giant cells, etc.) and non-immune features (necrosis, hemosiderin, hyalinized and proliferative fibrosis). We found that immune-mediated tumor regression is characterized by a fibroinflammatory stroma with features of (1) immune activation, including dense TIL and macrophages, TLS, and granulomas; (2) massive [tumor] cell death, including cholesterol clefts and giant cells; and (3) tissue repair, including neovascularization and proliferative fibrosis (each enriched in MPR vs. non-responders, Fisher's exact test p & lt;0.05). An “outside-in” pattern of regression was noted, which has important implications for defining total tumor bed area. As such, we propose “Immune-Related Pathologic Response Criteria” (irPRC), with tumor bed defined by RVT + necrosis + surrounding fibroinflammatory stroma. The areas of each are summed across all slides to calculate %RVT (RVT area/tumor bed area). This differs from chemotherapy MPR criteria, where %RVT is determined for each slide and then averaged, and the distinct fibroinflammatory regression stroma and peripheral regression bed are not acknowledged. The surgical resection specimens were then evaluated by four independent pathologists blinded to response to assess inter-observer variability. Compared to %RVT using chemotherapy criteria, irPRC had improved inter-observer variability [median per-case %RVT variability 5% (0-29%) vs. 10% (0-58%), paired t test p=0.007] and a two-fold decrease in median standard deviation across pathologists within a sample (4.6 vs 2.2, F-test p=0.002). We propose irPRC to standardize pathologic assessment of immune-mediated tumor regression and immunotherapeutic efficacy. Long-term follow up is needed to determine the reliability of irPRC as a surrogate for clinical outcomes such as recurrence-free and overall survival. Citation Format: Tricia R. Cottrell, Julie E. Stein, Jamie E. Chaft, Elizabeth D. Thompson, Natasha Rekhtman, Valsamo Anagnostou, Kellie N. Smith, Amy S. Duffield, Robert A. Anders, James M. Isbell, David R. Jones, Jonathan D. Cuda, Richard Battafarano, Stephen C. Yang, Peter B. Illei, Edward Gabrielson, Frederic Askin, Moises Velez, Matthew D. Hellmann, Jennifer L. Sauter, Ludmila Danilova, Victor E. Velculescu, Jedd D. Wolchok, Suzanne L. Topalian, Julie R. Brahmer, Drew M. Pardoll, Ashley Cimino-Mathews, Patrick M. Forde, Janis M. Taube. Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small cell lung carcinoma (NSCLC): A proposal for quantitative immune-related pathologic response criteria (irPRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-154.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-LB-154
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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