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  1. Article ; Online: Therapeutic Targeting of P53: A Comparative Analysis of APR-246 and COTI-2 in Human Tumor Primary Culture 3-D Explants.

    Nagourney, Adam J / Gipoor, Joshua B / Evans, Steven S / D'Amora, Paulo / Duesberg, Max S / Bernard, Paula J / Francisco, Federico / Nagourney, Robert A

    Genes

    2023  Volume 14, Issue 3

    Abstract: Background: ...

    Abstract Background:
    MeSH term(s) Female ; Humans ; Cisplatin ; Tumor Suppressor Protein p53/metabolism ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Doxorubicin/pharmacology ; Doxorubicin/therapeutic use ; Ovarian Neoplasms/drug therapy
    Chemical Substances Cisplatin (Q20Q21Q62J) ; Tumor Suppressor Protein p53 ; Antineoplastic Agents ; Doxorubicin (80168379AG)
    Language English
    Publishing date 2023-03-19
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2527218-4
    ISSN 2073-4425 ; 2073-4425
    ISSN (online) 2073-4425
    ISSN 2073-4425
    DOI 10.3390/genes14030747
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Diagnostic and Prognostic Performance of Metabolic Signatures in Pancreatic Ductal Adenocarcinoma: The Clinical Application of Quantitative NextGen Mass Spectrometry.

    D'Amora, Paulo / Silva, Ismael D C G / Evans, Steven S / Nagourney, Adam J / Kirby, Katharine A / Herrmann, Brett / Cavalheiro, Daniela / Francisco, Federico R / Bernard, Paula J / Nagourney, Robert A

    Metabolites

    2024  Volume 14, Issue 3

    Abstract: With 64,050 new diagnoses and 50,550 deaths in the US in 2023, pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of all human malignancies. Early detection and improved prognostication remain critical unmet needs. We applied next- ... ...

    Abstract With 64,050 new diagnoses and 50,550 deaths in the US in 2023, pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of all human malignancies. Early detection and improved prognostication remain critical unmet needs. We applied next-generation metabolomics, using quantitative tandem mass spectrometry on plasma, to develop biochemical signatures that identify PDAC. We first compared plasma from 10 PDAC patients to 169 samples from healthy controls. Using metabolomic algorithms and machine learning, we identified ratios that incorporate amino acids, biogenic amines, lysophosphatidylcholines, phosphatidylcholines and acylcarnitines that distinguished PDAC from normal controls. A confirmatory analysis then applied the algorithms to 30 PDACs compared with 60 age- and sex-matched controls. Metabolic signatures were then analyzed to compare survival, measured in months, from date of diagnosis to date of death that identified metabolite ratios that stratified PDACs into distinct survival groups. The results suggest that metabolic signatures could provide PDAC diagnoses earlier than tumor markers or radiographic measures and offer insights into disease severity that could allow more judicious use of therapy by stratifying patients into metabolic-risk subgroups.
    Language English
    Publishing date 2024-02-29
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2662251-8
    ISSN 2218-1989
    ISSN 2218-1989
    DOI 10.3390/metabo14030148
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Therapeutic Targeting of P53: A Comparative Analysis of APR-246 and COTI-2 in Human Tumor Primary Culture 3-D Explants

    Nagourney, Adam J. / Gipoor, Joshua B. / Evans, Steven S. / D’Amora, Paulo / Duesberg, Max S. / Bernard, Paula J. / Francisco, Federico / Nagourney, Robert A.

    Genes (Basel). 2023 Mar. 19, v. 14, no. 3

    2023  

    Abstract: Background: TP53 is the most commonly mutated gene in human cancer with loss of function mutations largely concentrated in “hotspots” affecting DNA binding. APR-246 and COTI-2 are small molecules under investigation in P53 mutated cancers. APR binds to ... ...

    Abstract Background: TP53 is the most commonly mutated gene in human cancer with loss of function mutations largely concentrated in “hotspots” affecting DNA binding. APR-246 and COTI-2 are small molecules under investigation in P53 mutated cancers. APR binds to P53 cysteine residues, altering conformation, while COTI-2 showed activity in P53 mutant tumors by a computational platform. We compared APR-246 and COTI-2 activity in human tumor explants from 247 surgical specimens. Methods: Ex vivo analyses of programmed cell death measured drug-induced cell death by delayed-loss-of-membrane integrity and ATP content. The LC50s were compared by Z-Score. Synergy was conducted by the method of Chou and Talalay, and correlations were performed by Pearson moment. Results: APR-246 and COTI-2 activity favored hematologic neoplasms, but solid tumor activity varied by diagnosis. COTI-2 and APR-246 activity did not correlate (R = 0.1028) (NS). COTI-2 activity correlated with nitrogen mustard, cisplatin and gemcitabine, doxorubicin and selumetinib, with a trend for APR-246 with doxorubicin. For ovarian cancer, COTI-2 showed synergy with cisplatin at 25%. Conclusions: COTI-2 and APR-246 activity differ by diagnosis. A lack of correlation supports distinct modes of action. Cisplatin synergy is consistent with P53’s role in DNA damage. Different mechanisms of action may underlie disease specificity and offer better disease targeting.
    Keywords DNA ; DNA damage ; cisplatin ; cysteine ; doxorubicin ; genes ; humans ; mutants ; nitrogen ; ovarian neoplasms ; programmed cell death ; therapeutics
    Language English
    Dates of publication 2023-0319
    Publishing place Multidisciplinary Digital Publishing Institute
    Document type Article ; Online
    ZDB-ID 2527218-4
    ISSN 2073-4425
    ISSN 2073-4425
    DOI 10.3390/genes14030747
    Database NAL-Catalogue (AGRICOLA)

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  4. Article ; Online: Platinum resistance in gynecologic malignancies: Response, disease free and overall survival are predicted by biochemical signature: A metabolomic analysis.

    D'Amora, Paulo / Silva, Ismael Dale C G / Tewari, Krishnansu S / Bristow, Robert E / Cappuccini, Fabio / Evans, Steven S / Salzgeber, Marcia B / Addis-Bernard, Paula J / Palma, Anton M / Marchioni, Dirce M L / Carioca, Antonio A F / Penner, Kristine R / Alldredge, Jill / Longoria, Teresa / Nagourney, Robert A

    Gynecologic oncology

    2021  Volume 163, Issue 1, Page(s) 162–170

    Abstract: Objective: Platinum resistance, defined as the lack of response or relapse within six months of platinum-based chemotherapy, is an important determinant of survival in gynecologic cancer. We used quantitative Mass Spectrometry to identify metabolic ... ...

    Abstract Objective: Platinum resistance, defined as the lack of response or relapse within six months of platinum-based chemotherapy, is an important determinant of survival in gynecologic cancer. We used quantitative Mass Spectrometry to identify metabolic signatures that predict platinum resistance in patients receiving chemotherapy for gynecologic cancers.
    Methods: In this study 47 patients with adenocarcinoma of the ovary or uterus who were candidates for carboplatin plus paclitaxel submitted blood for quantitation of metabolites and surgical specimens for the isolation 3-dimensional organoids used to measure individual patient platinum resistance, ex vivo. Results were correlated with response, time to progression and survival.
    Results: Of 47 patients, 27 (64.3%) achieved complete remission with a mean time to progression of 1.9 years (± 1.5), disease-free survival of 1.7 years (± 1.4) and overall survival of 2.6 years (± 1.6) and a mean cisplatin lethal concentration 50% (LC50) = 1.15 μg/ml (range 0.4-3.1). Cisplatin LC50's correlated with a non-significant decrease in complete remission (RR [95% CI] =0.76 [0.46-1.27]), diminished disease-free survival (median: 1.15 vs. 2.99 years, p = 0.038) and with biochemical signatures of 186 metabolites. Receiver operating curves (ROC) of lipid ratios, branched chain amino acids and the tryptophan to kynurenine ratio identified patients at the highest risk of relapse and death (AUC = 0.933) with a sensitivity of 92.0% and specificity of 86.0% (p < 0.001).
    Conclusions: Metabolic signatures in gynecologic cancer identify patients at the highest risk of relapse and death offering new diagnostic and prognostic tools for management of the advanced gynecologic tumors.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Carboplatin/administration & dosage ; Cisplatin/administration & dosage ; Drug Resistance, Neoplasm ; Female ; Humans ; Metabolomics/methods ; Middle Aged ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/mortality ; Paclitaxel/administration & dosage ; Uterine Neoplasms/drug therapy ; Uterine Neoplasms/metabolism ; Uterine Neoplasms/mortality ; Young Adult
    Chemical Substances Carboplatin (BG3F62OND5) ; Paclitaxel (P88XT4IS4D) ; Cisplatin (Q20Q21Q62J)
    Language English
    Publishing date 2021-08-24
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 801461-9
    ISSN 1095-6859 ; 0090-8258
    ISSN (online) 1095-6859
    ISSN 0090-8258
    DOI 10.1016/j.ygyno.2021.08.001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 885: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: Towards risk stratification and prediction of disease severity and mortality in COVID-19: Next generation metabolomics for the measurement of host response to COVID-19 infection.

    D'Amora, Paulo / Silva, Ismael Dale C G / Budib, Maria Auxiliadora / Ayache, Ricardo / Silva, Rafaela Moraes Siufi / Silva, Fabricio Colacino / Appel, Robson Mateus / Júnior, Saturnino Sarat / Pontes, Henrique Budib Dorsa / Alvarenga, Ana Carolina / Arima, Emilli Carvalho / Martins, Wellington Galhano / Silva, Nakal Laurenço F / Diaz, Ricardo Sobhie / Salzgeber, Marcia B / Palma, Anton M / Evans, Steven S / Nagourney, Robert A

    PloS one

    2021  Volume 16, Issue 12, Page(s) e0259909

    Abstract: This study investigated the association between COVID-19 infection and host metabolic signatures as prognostic markers for disease severity and mortality. We enrolled 82 patients with RT-PCR confirmed COVID-19 infection who were classified as mild, ... ...

    Abstract This study investigated the association between COVID-19 infection and host metabolic signatures as prognostic markers for disease severity and mortality. We enrolled 82 patients with RT-PCR confirmed COVID-19 infection who were classified as mild, moderate, or severe/critical based upon their WHO clinical severity score and compared their results with 31 healthy volunteers. Data on demographics, comorbidities and clinical/laboratory characteristics were obtained from medical records. Peripheral blood samples were collected at the time of clinical evaluation or admission and tested by quantitative mass spectrometry to characterize metabolic profiles using selected metabolites. The findings in COVID-19 (+) patients reveal changes in the concentrations of glutamate, valeryl-carnitine, and the ratios of Kynurenine/Tryptophan (Kyn/Trp) to Citrulline/Ornithine (Cit/Orn). The observed changes may serve as predictors of disease severity with a (Kyn/Trp)/(Cit/Orn) Receiver Operator Curve (ROC) AUC = 0.95. Additional metabolite measures further characterized those likely to develop severe complications of their disease, suggesting that underlying immune signatures (Kyn/Trp), glutaminolysis (Glutamate), urea cycle abnormalities (Cit/Orn) and alterations in organic acid metabolism (C5) can be applied to identify individuals at the highest risk of morbidity and mortality from COVID-19 infection. We conclude that host metabolic factors, measured by plasma based biochemical signatures, could prove to be important determinants of Covid-19 severity with implications for prognosis, risk stratification and clinical management.
    MeSH term(s) Adult ; Aged ; Area Under Curve ; COVID-19/mortality ; COVID-19/pathology ; COVID-19/virology ; Carnitine/metabolism ; Citrulline/metabolism ; Female ; Glutamic Acid/metabolism ; Humans ; Kynurenine/metabolism ; Male ; Metabolome ; Metabolomics/methods ; Middle Aged ; Ornithine/metabolism ; ROC Curve ; Risk Factors ; SARS-CoV-2/isolation & purification ; Severity of Illness Index ; Tryptophan/metabolism
    Chemical Substances Citrulline (29VT07BGDA) ; Kynurenine (343-65-7) ; Glutamic Acid (3KX376GY7L) ; Tryptophan (8DUH1N11BX) ; Ornithine (E524N2IXA3) ; Carnitine (S7UI8SM58A)
    Language English
    Publishing date 2021-12-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0259909
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Phase II trial of gemcitabine plus cisplatin repeating doublet therapy in previously treated, relapsed ovarian cancer patients.

    Nagourney, Robert A / Brewer, Cheryl A / Radecki, Stephen / Kidder, Wesley A / Sommers, Barbara L / Evans, Steven S / Minor, David R / DiSaia, Philip J

    Gynecologic oncology

    2002  Volume 88, Issue 1, Page(s) 35–39

    Abstract: Objectives: The aim was to determine the safety and efficacy of gemcitabine plus cisplatin for patients with relapsed ovarian carcinoma and to compare ex vivo drug sensitivity profiles with clinical outcomes.: Patients and methods: Previously treated ...

    Abstract Objectives: The aim was to determine the safety and efficacy of gemcitabine plus cisplatin for patients with relapsed ovarian carcinoma and to compare ex vivo drug sensitivity profiles with clinical outcomes.
    Patients and methods: Previously treated patients with ovarian carcinoma received cisplatin (30 mg/m(2)) plus gemcitabine (600-750 mg/m(2)) on Days 1 and 8 of each 21-day cycle. Seventeen of the 27 patients underwent ex vivo analyses for correlation with clinical response.
    Results: Of 27 patients, there were 7 (26%) complete and 12 (44%) partial responses, for an overall response rate of 70% (95% CI: 53-87%). Toxicities included neutropenia Grade III in 51.9%, Grade IV in 29.6%; anemia Grade III in 18.5 %; thrombocytopenia Grade III in 66.7 %, Grade IV in 29.6%; nausea and vomiting Grade III in 14.8 %; peripheral neuropathy Grade III in 3.7%; and alopecia Grade IV in 11.1% of patients. The median time to progression for objective responders was 7.9 months with a range of 2.1 to 13.2 months. There were no treatment-related deaths. Ex vivo results correlated with response, time to progression, and survival, remaining significant when adjusted for platin-resistance and number of prior therapies. Adjustment for platin-free interval decreased the significance but did not, in and of itself, predict significantly for progression-free survival.
    Conclusions: Cisplatin plus gemcitabine is active for patients with relapsed ovarian cancer. Toxicities, primarily hematologic, are manageable with dose modifications. Responses observed in heavily pretreated and platin-resistant patients indicate activity in drug-refractory patients. The results of the ex vivo analyses correlate with clinical outcomes.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Cisplatin/administration & dosage ; Cisplatin/adverse effects ; Deoxycytidine/administration & dosage ; Deoxycytidine/adverse effects ; Deoxycytidine/analogs & derivatives ; Drug Administration Schedule ; Female ; Humans ; Middle Aged ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/pathology ; Receptor, ErbB-2/biosynthesis
    Chemical Substances Deoxycytidine (0W860991D6) ; gemcitabine (B76N6SBZ8R) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Cisplatin (Q20Q21Q62J)
    Language English
    Publishing date 2002-11-21
    Publishing country United States
    Document type Clinical Trial ; Clinical Trial, Phase II ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 801461-9
    ISSN 1095-6859 ; 0090-8258
    ISSN (online) 1095-6859
    ISSN 0090-8258
    DOI 10.1006/gyno.2002.6855
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 885: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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