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  • 1
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    SRGN-Triggered Aggressive and Immunosuppressive Phenotype in a Subset of TTF-1–Negative Lung Adenocarcinomas
    Oxford University Press (OUP) ; 2022
    In:  JNCI: Journal of the National Cancer Institute Vol. 114, No. 2 ( 2022-02-07), p. 290-301
    Details
    In: JNCI: Journal of the National Cancer Institute, Oxford University Press (OUP), Vol. 114, No. 2 ( 2022-02-07), p. 290-301
    Abstract: Approximately 20% of lung adenocarcinoma (LUAD) is negative for the lineage-specific oncogene Thyroid transcription factor 1 (TTF-1) and exhibits worse clinical outcome with a low frequency of actionable genomic alterations. To identify molecular features associated with TTF-1–negative LUAD, we compared the transcriptomic and proteomic profiles of LUAD cell lines. SRGN , a chondroitin sulfate proteoglycan Serglycin, was identified as a markedly overexpressed gene in TTF-1–negative LUAD. We therefore investigated the roles and regulation of SRGN in TTF-1–negative LUAD. Methods Proteomic and metabolomic analyses of 41 LUAD cell lines were done using mass spectrometry. The function of SRGN was investigated in 3 TTF-1–negative and 4 TTF-1–positive LUAD cell lines and in a syngeneic mouse model (n = 5 to 8 mice per group). Expression of SRGN was evaluated in 94 and 105 surgically resected LUAD tumor specimens using immunohistochemistry. All statistical tests were 2-sided. Results SRGN was markedly overexpressed at mRNA and protein levels in TTF-1–negative LUAD cell lines (P & lt; .001 for both mRNA and protein levels). Expression of SRGN in LUAD tumor tissue was associated with poor outcome (hazard ratio = 4.22, 95% confidence interval = 1.12 to 15.86, likelihood ratio test, P = .03), and with higher expression of Programmed cell death 1 ligand 1 (PD-L1) in tumor cells and higher infiltration of Programmed cell death protein 1–positive lymphocytes. SRGN regulated expression of PD-L1 as well as proinflammatory cytokines, including Interleukin-6, Interleukin-8, and C-X-C motif chemokine 1 in LUAD cell lines; increased migratory and invasive properties of LUAD cells and fibroblasts; and enhanced angiogenesis. SRGN was induced by DNA demethylation resulting from Nicotinamide N-methyltransferase–mediated impairment of methionine metabolism. Conclusions Our findings suggest that SRGN plays a pivotal role in tumor–stromal interaction and reprogramming into an aggressive and immunosuppressive tumor microenvironment in TTF-1–negative LUAD.
    Type of Medium: Online Resource
    ISSN: 0027-8874 , 1460-2105
    URL: Article
    DOI: 10.1093/jnci/djab183
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 2
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    Low-density lipoprotein electronegativity and risk of death after acute coronary syndromes: A case-cohort analysis
    Elsevier BV ; 2023
    In:  Atherosclerosis Vol. 376 ( 2023-07), p. 43-52
    Details
    In: Atherosclerosis, Elsevier BV, Vol. 376 ( 2023-07), p. 43-52
    Type of Medium: Online Resource
    ISSN: 0021-9150
    URL: Article
    DOI: 10.1016/j.atherosclerosis.2023.05.014
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 1499887-7
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  • 3
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    A Blood-Based Polyamine Signature Associated With Disease Progression in Patients With Multiple Endocrine Neoplasia Type 1-Related Duodenopancreatic Neuroendocrine Tumors
    The Endocrine Society ; 2021
    In:  Journal of the Endocrine Society Vol. 5, No. Supplement_1 ( 2021-05-03), p. A1009-A1009
    Details
    In: Journal of the Endocrine Society, The Endocrine Society, Vol. 5, No. Supplement_1 ( 2021-05-03), p. A1009-A1009
    Abstract: Background: Multiple Endocrine Neoplasia Type 1 (MEN1) is a rare inherited autosomal dominant disease predisposing patients to endocrine tumors. MEN1 can be genetically diagnosed at an early age. Patients are prone to develop benign parathyroid tumors then multifocal duodenopancreatic neuroendocrine tumors (dpNETs), which have a penetrance of & gt;80% by age 80. Although they can be identified at an early stage, preventive measures do not exist, and one fifth of patients develop distant metastases, which is the most significant cause of mortality. Currently, no biomarkers can reliably predict which patients with MEN1-related dpNETs are at high risk of developing metastatic disease. Polyamines are naturally occurring polycationic alkylamines that have been implicated to play functional roles in promoting neoplastic transformation and growth. We have previously demonstrated a plasma polyamine signature that associates with pancreatic cancer development and that also offers value for predicting future distant metastasis in patients with triple-negative breast cancer. We hypothesized that such a plasma polyamine signature may similarly associate with disease progression in subjects with MEN1-related dpNET. Methods: As part of an international collaboration, we measured plasma polyamine levels using mass spectrometry from 14 MEN1 patients with distant metastatic dpNET (cases), 28 MEN1 patients with indolent dpNETs without distant metastases (control-1), and 14 MEN1 patients without dpNETs (control-2). Five circulating plasma polyamines were quantified in this initial test set. A combination rule was developed using logistic regression models. Findings were validated in an independent set of plasma from 6 cases and 22 controls (n=13 control-1 and n=9 control-2). Results: Area under the Receiver Operating Characteristic Curve (AUC) of individual polyamines delineating cases from controls ranged from 0.50-0.75 in the test set. A polyamine signature consisting of 3 polyamines developed in the test set yielded an AUC of 0.84 (95% CI: 0.63-1.00) with 67% sensitivity at 95% specificity in the validation set for distinguishing cases from controls. The predictive performance of the polyamine signature for distinguishing cases from MEN1 patients with indolent dpNETS without distant metastasis or MEN1 patients without dpNETS in the validation set was 0.79 (95% CI: 0.53-1.00) and 0.91 (95% CI: 0.75-1.00) with respective resultant sensitivity at 95% specificity of 50% and 67%. Conclusion: Our findings reveal a plasma polyamine signature associated with disease progression in subjects with MEN1-related dpNETs. This polyamine signature may provide a potential breakthrough for predicting progression and distant metastasis in MEN1 patients. Further prospective studies are warranted.
    Type of Medium: Online Resource
    ISSN: 2472-1972
    URL: Article
    DOI: 10.1210/jendso/bvab048.2064
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2021
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  • 4
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    Exercise Training Reduces the Inflammatory Response and Promotes Intestinal Mucosa-Associated Immunity in Lynch Syndrome
    American Association for Cancer Research (AACR) ; 2023
    In:  Clinical Cancer Research ( 2023-09-27), p. OF1-OF12
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), ( 2023-09-27), p. OF1-OF12
    Abstract: Lynch syndrome (LS) is a hereditary condition with a high lifetime risk of colorectal and endometrial cancers. Exercise is a non-pharmacologic intervention to reduce cancer risk, though its impact on patients with LS has not been prospectively studied. Here, we evaluated the impact of a 12-month aerobic exercise cycling intervention in the biology of the immune system in LS carriers. Patients and Methods: To address this, we enrolled 21 patients with LS onto a non-randomized, sequential intervention assignation, clinical trial to assess the effect of a 12-month exercise program that included cycling classes 3 times weekly for 45 minutes versus usual care with a one-time exercise counseling session as control. We analyzed the effects of exercise on cardiorespiratory fitness, circulating, and colorectal-tissue biomarkers using metabolomics, gene expression by bulk mRNA sequencing, and spatial transcriptomics by NanoString GeoMx. Results: We observed a significant increase in oxygen consumption (VO2peak) as a primary outcome of the exercise and a decrease in inflammatory markers (prostaglandin E) in colon and blood as the secondary outcomes in the exercise versus usual care group. Gene expression profiling and spatial transcriptomics on available colon biopsies revealed an increase in the colonic mucosa levels of natural killer and CD8+ T cells in the exercise group that were further confirmed by IHC studies. Conclusions: Together these data have important implications for cancer interception in LS, and document for the first-time biological effects of exercise in the immune system of a target organ in patients at-risk for cancer.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-23-0088
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    detail.hit.zdb_id: 2036787-9
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  • 5
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    Role of CPS1 in Cell Growth, Metabolism, and Prognosis in LKB1-Inactivated Lung Adenocarcinoma
    Oxford University Press (OUP) ; 2017
    In:  Journal of the National Cancer Institute Vol. 109, No. 3 ( 2017-03), p. djw231-
    Details
    In: Journal of the National Cancer Institute, Oxford University Press (OUP), Vol. 109, No. 3 ( 2017-03), p. djw231-
    Type of Medium: Online Resource
    ISSN: 0027-8874 , 1460-2105
    URL: Article
    DOI: 10.1093/jnci/djw231
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2017
    detail.hit.zdb_id: 2992-0
    detail.hit.zdb_id: 1465951-7
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  • 6
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    A Blood-based Polyamine Signature Associated With MEN1 Duodenopancreatic Neuroendocrine Tumor Progression
    The Endocrine Society ; 2021
    In:  The Journal of Clinical Endocrinology & Metabolism ( 2021-07-28)
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, ( 2021-07-28)
    Abstract: Duodenopancreatic neuroendocrine tumors (dpNETs) frequently occur in patients with multiple endocrine neoplasia type 1 (MEN1), and metastatic dpNET is the primary cause of disease-related mortality. There is a need for biomarkers that can identify patients with MEN1-related dpNETs that are at high risk of developing distant metastasis. Polyamines have tumor-promoting roles in several cancer types. Objective We hypothesized that MEN1-dpNET–related disease progression is associated with elevated levels of circulating polyamines. Methods Through an international collaboration between The University of Texas MD Anderson Cancer Center, the National Institutes of Health, and the University Medical Center Utrecht, plasma polyamine levels were assessed using mass spectrometry in 84 patients with MEN1 (20 with distant metastatic dpNETs [patients] and 64 with either indolent dpNETs or no dpNETs [controls] ). A mouse model of MEN1-pNET, Men1fl/flPdx1-CreTg, was used to test time-dependent changes in plasma polyamines associated with disease progression. Results A 3-marker plasma polyamine signature (3MP: N-acetylputrescine, acetylspermidine, and diacetylspermidine) distinguished patients with metastatic dpNETs from controls in an initial set of plasmas from the 3 participating centers. The fixed 3MP yielded an area under the curve of 0.84 (95% CI, 0.62-1.00) with 66.7% sensitivity at 95% specificity for distinguishing patients from controls in an independent test set from MDACC. In Men1fl/flPdx1-CreTg mice, the 3MP was elevated early and remained high during disease progression. Conclusion Our findings provide a basis for prospective testing of blood-based polyamines as a potential means for monitoring patients with MEN1 for harboring or developing aggressive disease.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/clinem/dgab554
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2021
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  • 7
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    Abstract 3744: A circulating microRNA panel predicts recurrence and survival in early-stage lung adenocarcinoma
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3744-3744
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3744-3744
    Abstract: Background: Early-stage lung adenocarcinoma (LUAD) patients have substantial risk for recurrence and disease-related death. Cisplatin-based adjuvant chemotherapy remains the standard for care of LUAD patients who have undergone surgical resection with a high risk of recurrence. However, adjuvant chemotherapy is associated with increased risk of toxicity including chemotherapy-related death, with only a modest survival benefit. Therefore, there is an unmet need of biomarkers for assessment and identification of those in an early stage who would likely benefit from adjuvant chemotherapy. Circulating miRNAs are stably present in blood and potentially reflect different expressions in cancerous and non-cancerous tissues, making them attractive biomarkers. The purpose of this study was to identify circulating miRNAs useful for predicting recurrence in early-stage LUAD. Materials and Methods: miRNA microarray analysis was performed with pooled pretreatment plasma samples from stage I LUAD patients who developed recurrence within two years after curative surgery or remained recurrence free over a six-year follow-up period, as well as from healthy controls. miRNA biomarker candidates were assayed in two independent plasma sample sets from 85 stage I LUAD (validation set) and from 57 stage I and II LUAD (test set) patients. Results: Based on miRNA microarray data and previous reports, predictive performance of miR-23a-3p, miR-23b-3p, miR-191-5p, miR-185-5p, miR-151a-3p, miR-320c, miR-21-5p, miR-125b-5p, miR-30d-5p, and miR-197-3p was evaluated in the validation set. Plasma levels of miR-23a-3p, miR-185-5p, miR-320c, miR-21-5p, miR-125b-5p, miR-30d-5p, and miR-197-3p were significantly higher in those with recurrence as compared to those without. A miRNA panel comprised of miR-23a-3p, miR-320c, and miR-125b-5p was developed based on a logistic regression, with yielding an AUC of 0.776 (95% confidence interval [CI] = 0.660 to 0.893). The three-miRNA panel with fixed coefficients yielded an AUC of 0.804 (95% CI = 0.688 to 0.920) with a sensitivity of 45.8% at 95% specificity in the test set. The miRNA panel score was a significant and independent factor for predicting disease-free survival (DFS; P & lt; 0.001, HR = 1.64, 95% CI = 1.51-4.22) and overall survival (OS; P = 0.001, HR = 1.51, 95% CI = 1.17-1.94). Conclusion: This circulating miRNA panel may serve as a noninvasive blood test for predicting DFS and OS in early-stage LUAD patients. Our findings provide rationale for further investigation to stratify early-stage LUAD patients using blood-based biomarkers to increase the ability to provide more personalized care. Citation Format: Mei-Chee Tai, Leonidas E. Bantis, Gargy Parhy, Taketo Kato, Ichidai Tanaka, Chi-Wan Chow, Junya Fujimoto, Carmen Behrens, Tetsunari Hase, Koji Kawaguchi, Johannes F. Fahrmann, Edwin Ostrin, Kohei Yokoi, Toyofumi F. Chen-Yoshikawa, Yoshinori Hasegawa, Samir M. Hanash, Ignacio I. Wistuba, Ayumu Taguchi. A circulating microRNA panel predicts recurrence and survival in early-stage lung adenocarcinoma. [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 3744.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-3744
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 8
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    Blood-based Proteomic Signatures Associated With MEN1-related Duodenopancreatic Neuroendocrine Tumor Progression
    The Endocrine Society ; 2023
    In:  The Journal of Clinical Endocrinology & Metabolism ( 2023-06-12)
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, ( 2023-06-12)
    Abstract: Patients with multiple endocrine neoplasia type 1 (MEN1) are predisposed to develop duodenopancreatic neuroendocrine tumors (dpNETs), and metastatic dpNET is the primary cause of disease-related mortality. Presently, there is a paucity of prognostic factors that can reliably identify patients with MEN1-related dpNETS who are at high risk of distant metastasis. In the current study, we aimed to establish novel circulating molecular protein signatures associated with disease progression. Experimental Design Mass spectrometry-based proteomic profiling was conducted on plasmas procured through an international collaboration between MD Anderson Cancer Center, the National Institutes of Health, and the University Medical Center Utrecht from a cohort of 56 patients with MEN1 [14 with distant metastasis dpNETs (cases) and 42 with either indolent dpNETs or no dpNETs (controls)]. Findings were compared to proteomic profiles generated from serially collected plasmas from a mouse model of Men1-pancreatic neuroendocrine tumors (Men1fl/flPdx1-CreTg) and control mice (Men1fl/fl). Results A total of 187 proteins were found to be elevated in MEN1 patients with distant metastasis compared to controls, including 9 proteins previously associated with pancreatic cancer and other neuronal proteins. Analyses of mouse plasmas revealed 196 proteins enriched for transcriptional targets of oncogenic MYCN, YAP1, POU5F1, and SMAD that were associated with disease progression in Men1fl/flPdx1-CreTg mice. Cross-species intersection revealed 19 proteins positively associated with disease progression in both human patients and in Men1fl/flPdx1-CreTg mice. Conclusions Our integrated analyses identified novel circulating protein markers associated with disease progression in MEN1-related dpNET.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/clinem/dgad315
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2023
    detail.hit.zdb_id: 2026217-6
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  • 9
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    Abstract P066: Blood-based proteomic signatures associated with MEN1-related duodenopancreatic neuroendocrine tumor progression
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Prevention Research Vol. 16, No. 1_Supplement ( 2023-01-01), p. P066-P066
    Details
    In: Cancer Prevention Research, American Association for Cancer Research (AACR), Vol. 16, No. 1_Supplement ( 2023-01-01), p. P066-P066
    Abstract: Multiple Endocine Neoplasia Type 1 (MEN1) is associated with duodenopancreatic neuroendocrine tumors (dpNETs) and metastatic dpNET is the primary cause of disease-related mortality for this condition. Currently, there is a paucity of prognostic factors that can reliably identify patients with MEN1-related dpNETS who are at high risk of distant metastasis. Previously, we uncovered a blood-based polyamine metabolite signature that was associated with MEN1-dpNET disease progression. In the current study, we aimed to build upon our prior findings, by exploring the contributions of proteomics for identifying circulating protein markers associated with tumor progression. We performed in-depth proteomic analysis of serially collected plasmas from a genetically engineered mouse model of Men1-pNET, Men1fl/flPdx1-CreTg, and Men1fl/fl control mice to assess dynamic changes in the plasma proteome that associated with disease progression. Findings were compared to plasma proteomic profiles from a cohort of 56 patients with MEN1 (14 with distant metastasis dpNETs (cases) and 42 with either indolent dpNETs or no dpNETs (controls)). Analyses revealed 196 proteins related to oncogenic N-MYC, YAP1, POU5F1, and SMAD that were positively associated with pNET disease progression in Men1fl/flPdx1-CreTg mice. Similarly, 187 proteins were elevated in MEN1 patients with distant metastasis compared controls. Proteins with increased levels in metastatic cases included AMY2B, CELA3B, RNASE1, IGFBP2, CHI3L1, LYZ, TIMP1, LRG1, and COL18A1 previously associated with pancreatic cancer and other neuronal proteins. Cross-species intersection revealed 19 proteins including NDC80, DEF8, SPAG17, ATM, IMMT, DNAH6, DSP, CIT, HRG, CD79A, BDP1, SERPINA11, TARBP1, and SERPIND1 that were positively associated with disease progression in Men1fl/flPdx1-CreTg mice and human subjects. Our integrated analyses identified novel circulating protein features associated with disease progression in MEN1-related dpNET. Citation Format: Johannes F. Fahrmann, Amanda R. Wasylishen, Carolina R.C. Pieterman, Ehsan Irajizad, Jody Vykoukal, Ranran Wu, Jennifer D. Dennison, Christine B. Peterson, Guillermina Lozano, Hua Zhao, Kim-Ahn Do, Daniel M. Halperin, Sunita K. Agarwal, Jenny E. Blau, Jaydira D. Rivero, Naris Nilubol, Mary F. Walter, James M. Welch, Lee S. Weinstein, Menno R. Vriens, Rachel S. van Leeuwaarde, Mark J.C. van Treijen, Gerlof D. Valk, Nancy D. Perrier, Sam M Hanash, Hiroyuki Katayama. Blood-based proteomic signatures associated with MEN1-related duodenopancreatic neuroendocrine tumor progression. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P066.
    Type of Medium: Online Resource
    ISSN: 1940-6215
    URL: Article
    DOI: 10.1158/1940-6215.PrecPrev22-P066
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2422346-3
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  • 10
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    Inhibition of Nuclear Factor Kappa B activation in Early-Stage Chronic Lymphocytic Leukemia by Omega-3 Fatty Acids
    Informa UK Limited ; 2013
    In:  Cancer Investigation Vol. 31, No. 1 ( 2013-01-25), p. 24-38
    Details
    In: Cancer Investigation, Informa UK Limited, Vol. 31, No. 1 ( 2013-01-25), p. 24-38
    Type of Medium: Online Resource
    ISSN: 0735-7907 , 1532-4192
    URL: Article
    DOI: 10.3109/07357907.2012.743553
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2013
    detail.hit.zdb_id: 2043112-0
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