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  1. Article ; Online: The hubris and humility of cancer pharmacology in the post immuno-oncology era.

    Lazo, John S

    Pharmacology research & perspectives

    2019  Volume 7, Issue 6, Page(s) e00527

    Abstract: Cancer is a dreaded word, which has stimulated monumental efforts to discover and deliver effective cancer treatments for more than half a century. During the past two decades, our understanding of the molecular pathogenesis of cancer has increased ... ...

    Abstract Cancer is a dreaded word, which has stimulated monumental efforts to discover and deliver effective cancer treatments for more than half a century. During the past two decades, our understanding of the molecular pathogenesis of cancer has increased remarkably. This has fostered an explosion in the number of experimental agents and clinical trials coupled with a dramatic rise in the regulatory approval of therapies for human cancers. Unfortunately, our preclinical models perform poorly as predictive platforms for the ultimate success of clinical candidates, reflecting the complexity of cancer. Moreover the common combination of cancer drugs prescribes the need for a better understanding of the fundamental pharmacology of each agent. Here I briefly outline some of the fundamental changes that have and have not occurred in cancer pharmacology during the past two decades and prognosticate on possible future directions.
    MeSH term(s) Antineoplastic Agents, Immunological/pharmacology ; Antineoplastic Agents, Immunological/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Clinical Trials as Topic ; Drug Evaluation, Preclinical ; Humans ; Immunotherapy/methods ; Immunotherapy/trends ; Medical Oncology/methods ; Medical Oncology/trends ; Neoplasms/genetics ; Neoplasms/immunology ; Neoplasms/therapy ; Precision Medicine/methods ; Precision Medicine/trends ; Treatment Outcome ; Tumor Microenvironment/drug effects ; Tumor Microenvironment/immunology
    Chemical Substances Antineoplastic Agents, Immunological
    Language English
    Publishing date 2019-10-08
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
    ZDB-ID 2740389-0
    ISSN 2052-1707 ; 2052-1707
    ISSN (online) 2052-1707
    ISSN 2052-1707
    DOI 10.1002/prp2.527
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Refining Radiation for the Next Century.

    Lazo, John S

    Molecular cancer therapeutics

    2018  Volume 17, Issue 2, Page(s) 332–335

    MeSH term(s) Humans ; Radiation Oncology
    Language English
    Publishing date 2018-02-02
    Publishing country United States
    Document type Introductory Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-17-1244
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5750: Show issues Location:
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  3. Article: Cutting down the time to identify challenging tumor therapeutic targets and drug combinations using synthetic lethal approaches.

    Lazo, John S

    F1000Research

    2018  Volume 7, Page(s) 308

    Abstract: Cancer drug discoverers and developers are blessed and cursed with a plethora of drug targets in the tumor cells themselves and the surrounding stromal elements. This bounty of targets has, at least in part, inspired the rapid increase in the number of ... ...

    Abstract Cancer drug discoverers and developers are blessed and cursed with a plethora of drug targets in the tumor cells themselves and the surrounding stromal elements. This bounty of targets has, at least in part, inspired the rapid increase in the number of clinically available small-molecule, biological, and cellular therapies for solid and hematological malignancies. Among the most challenging questions in cancer therapeutics, especially for small molecules, is how to approach loss-of-function gene mutations or deletions that encode tumor suppressors. A second mounting question is what are the optimal drug combinations. This article will briefly review the recent advances in exploiting
    Language English
    Publishing date 2018-03-12
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2699932-8
    ISSN 2046-1402
    ISSN 2046-1402
    DOI 10.12688/f1000research.13679.1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: An acute respiratory distress syndrome drug development collaboration stimulated by the Virginia Drug Discovery Consortium.

    Lazo, John S / Colunga-Biancatelli, Ruben M L / Solopov, Pavel A / Catravas, John D

    SLAS discovery : advancing life sciences R & D

    2023  Volume 28, Issue 6, Page(s) 249–254

    Abstract: The genesis of most older medicinal agents has generally been empirical. During the past one and a half centuries, at least in the Western countries, discovering and developing drugs has been primarily the domain of pharmaceutical companies largely built ...

    Abstract The genesis of most older medicinal agents has generally been empirical. During the past one and a half centuries, at least in the Western countries, discovering and developing drugs has been primarily the domain of pharmaceutical companies largely built upon concepts emerging from organic chemistry. Public sector funding for the discovery of new therapeutics has more recently stimulated local, national, and international groups to band together and focus on new human disease targets and novel treatment approaches. This Perspective describes one contemporary example of a newly formed collaboration that was simulated by a regional drug discovery consortium. University of Virginia, Old Dominion University, and a university spinout company, KeViRx, Inc., partnered under a NIH Small Business Innovation Research grant, to produce potential therapeutics for acute respiratory distress syndrome resulting from the ongoing COVID-19 pandemic.
    MeSH term(s) Humans ; COVID-19 ; SARS-CoV-2 ; Pandemics ; Virginia ; Drug Development ; Drug Discovery ; Respiratory Distress Syndrome/drug therapy
    Language English
    Publishing date 2023-02-15
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2885123-7
    ISSN 2472-5560 ; 2472-5552
    ISSN (online) 2472-5560
    ISSN 2472-5552
    DOI 10.1016/j.slasd.2023.02.001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4911: Show issues Location:
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  5. Article ; Online: Deletion of PTP4A3 phosphatase in high grade serous ovarian cancer cells decreases tumorigenicity and produces marked changes in intracellular signaling pathways and cytokine release.

    Lazo, John S / Isbell, Kelly N / Vasa, Sai Ashish / Llaneza, Danielle C / Mingledorff, Garnett A / Sharlow, Elizabeth R

    The Journal of pharmacology and experimental therapeutics

    2024  

    Abstract: The oncogenic protein tyrosine phosphatase PTP4A3 is frequently overexpressed in human ovarian cancers and is associated with poor patient prognosis. PTP4A3 is thought to regulate multiple oncogenic signaling pathways, including STAT3, SRC, and ERK. The ... ...

    Abstract The oncogenic protein tyrosine phosphatase PTP4A3 is frequently overexpressed in human ovarian cancers and is associated with poor patient prognosis. PTP4A3 is thought to regulate multiple oncogenic signaling pathways, including STAT3, SRC, and ERK. The objective of this study was to generate ovarian cancer cells with genetically depleted PTP4A3; to assess their tumorigenicity; to examine their cellular phenotype; and to uncover changes in their intracellular signaling pathways and cytokine release profiles. Genetic deletion of PTP4A3 using CRISPR/Cas9 enabled the generation of individual clones derived from single cells isolated from the polyclonal knockout population. We observed a >90% depletion of PTP4A3 protein levels by Western blotting in the clonal cell lines compared to the sham transfected wildtype population. The wildtype and polyclonal knockout cell lines shared similar monolayer growth rates, while the isolated clonal populations 2B4, 3C9, and 3C12 exhibited significantly lower monolayer growth characteristics consistent with their lower PTP4A3 levels. The clonal PTP4A3 knockout cell lines also had substantially lower
    Language English
    Publishing date 2024-04-05
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3106-9
    ISSN 1521-0103 ; 0022-3565
    ISSN (online) 1521-0103
    ISSN 0022-3565
    DOI 10.1124/jpet.124.002110
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  6. Article ; Online: Cutting down the time to identify challenging tumor therapeutic targets and drug combinations using synthetic lethal approaches [version 1; referees

    John S. Lazo

    F1000Research, Vol

    2 approved]

    2018  Volume 7

    Abstract: Cancer drug discoverers and developers are blessed and cursed with a plethora of drug targets in the tumor cells themselves and the surrounding stromal elements. This bounty of targets has, at least in part, inspired the rapid increase in the number of ... ...

    Abstract Cancer drug discoverers and developers are blessed and cursed with a plethora of drug targets in the tumor cells themselves and the surrounding stromal elements. This bounty of targets has, at least in part, inspired the rapid increase in the number of clinically available small-molecule, biological, and cellular therapies for solid and hematological malignancies. Among the most challenging questions in cancer therapeutics, especially for small molecules, is how to approach loss-of-function gene mutations or deletions that encode tumor suppressors. A second mounting question is what are the optimal drug combinations. This article will briefly review the recent advances in exploiting in vitro and in vivo synthetic lethal screens to expose cancer pharmacological targets with the goal of developing new drug combinations.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2018-03-01T00:00:00Z
    Publisher F1000 Research Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Book: Review for USMLE

    Lazo, John S. / Pitt, Bruce R. / Glorioso, Joseph C.

    United States medical licensing examination, step 1

    (The national medical series for independent study)

    2006  

    Author's details John S. Lazo ; Bruce R. Pitt ; Joseph C. Glorioso
    Series title The national medical series for independent study
    Keywords Medicine
    Subject code 610.76
    Language English
    Size XI, 418 S. : Ill., graph. Darst., 28cm
    Edition 7. ed.
    Publisher Lippincott Williams & Wilkins
    Publishing place Philadelphia u.a.
    Publishing country United States
    Document type Book
    Note Includes index. - Previous ed.: 2002
    HBZ-ID HT014532422
    ISBN 0-7817-7921-9 ; 978-0-7817-7921-0
    Database Catalogue ZB MED Medicine, Health

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    In stock of ZB MED Cologne/Königswinter

    Shelf markLoan statusLocation
    2006 A 570 order for loan Magazin

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  8. Book ; Audio / Video: Review for USMLE

    Lazo, John S. / Pitt, Bruce R. / Glorioso, Joseph C.

    step 1

    (National medical series for independent study)

    2006  

    Author's details John S. Lazo ; Bruce R. Pitt ; Joseph C. Glorioso
    Series title National medical series for independent study
    Keywords Medicine
    Language English
    Size 1 CD-ROM, 12 cm
    Edition 7. ed.
    Publisher Lippincott Williams & Wilkins
    Publishing place Philadelphia u.a.
    Publishing country United States
    Document type Book ; Audio / Video
    Remark Einzelplatznutzung nur in der ZB MED
    HBZ-ID HT014627279
    Database Catalogue ZB MED Medicine, Health

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    Shelf markLoan statusLocation
    2006 MO 227 order to use in reading room Magazin

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  9. Article ; Online: Transcriptome and Translatome Regulation of Pathogenesis in Alzheimer's Disease Model Mice.

    Eastman, Guillermo / Sharlow, Elizabeth R / Lazo, John S / Bloom, George S / Sotelo-Silveira, José R

    Journal of Alzheimer's disease : JAD

    2022  Volume 86, Issue 1, Page(s) 365–386

    Abstract: Background: Defining cellular mechanisms that drive Alzheimer's disease (AD) pathogenesis and progression will be aided by studies defining how gene expression patterns change during pre-symptomatic AD and ensuing periods of declining cognition. ... ...

    Abstract Background: Defining cellular mechanisms that drive Alzheimer's disease (AD) pathogenesis and progression will be aided by studies defining how gene expression patterns change during pre-symptomatic AD and ensuing periods of declining cognition. Previous studies have emphasized changes in transcriptome, but not translatome regulation, leaving the ultimate results of gene expression alterations relatively unexplored in the context of AD.
    Objective: To identify genes whose expression might be regulated at the transcriptome and translatome levels in AD, we analyzed gene expression in cerebral cortex of two AD model mouse strains, CVN (APPSwDI;NOS2 -/- ) and Tg2576 (APPSw), and their companion wild type (WT) strains at 6 months of age by tandem RNA-Seq and Ribo-Seq (ribosome profiling).
    Methods: Identical starting pools of bulk RNA were used for RNA-Seq and Ribo-Seq. Differential gene expression analysis was performed at the transcriptome, translatome, and translational efficiency levels. Regulated genes were functionally evaluated by gene ontology tools.
    Results: Compared to WT mice, AD model mice had similar levels of transcriptome regulation, but differences in translatome regulation. A microglial signature associated with early stages of Aβ accumulation was upregulated at both levels in CVN mice. Although the two mice strains did not share many regulated genes, they showed common regulated pathways related to AβPP metabolism associated with neurotoxicity and neuroprotection.
    Conclusion: This work represents the first genome-wide study of brain translatome regulation in animal models of AD and provides evidence of a tight and early translatome regulation of gene expression controlling the balance between neuroprotective and neurodegenerative processes in brain.
    MeSH term(s) Alzheimer Disease/pathology ; Animals ; Disease Models, Animal ; Genome-Wide Association Study ; Humans ; Mice ; Mice, Transgenic ; Microglia/metabolism ; Transcriptome
    Language English
    Publishing date 2022-01-13
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1440127-7
    ISSN 1875-8908 ; 1387-2877
    ISSN (online) 1875-8908
    ISSN 1387-2877
    DOI 10.3233/JAD-215357
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 6084: Show issues Location:
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  10. Article ; Online: Pharmacological profiling identifies divergent chemosensitivities of differentiating and maturing iPSC-derived human cortical neuron populations.

    Sharlow, Elizabeth R / Llaneza, Danielle C / Tewari, Bhanu P / Mingledorff, Garnett A / Mendelson, Anna J / Sontheimer, Harald / Bloom, George S / Lazo, John S

    The FEBS journal

    2023  Volume 290, Issue 20, Page(s) 4950–4965

    Abstract: Neuronal differentiation and maturation are extended developmental processes. To determine whether neurons at different developmental stages have divergent chemosensitivities, we screened differentiating and maturing neuronal populations using a small ... ...

    Abstract Neuronal differentiation and maturation are extended developmental processes. To determine whether neurons at different developmental stages have divergent chemosensitivities, we screened differentiating and maturing neuronal populations using a small compound library comprising FDA-approved and investigational drugs. Using a neurotoxicity assay format, both respective neuronal population-based screening campaigns performed robustly (Z-factors = 0.7-0.8), although the hit rate for the differentiating neurons (2.8%) was slightly higher than for maturing neurons (1.9%). While the majority of hits were toxic to both neuronal populations, these hits predominantly represented promiscuous drugs. Other drugs were selectively neurotoxic, with receptor tyrosine kinase inhibitors disproportionally represented after confirmation. Ponatinib and amuvatinib were neuroinhibitory for differentiating and maturing neurons, respectively. Chemoinformatic analyses confirmed differences in potential drug targets that may be differentially expressed during neuronal development. Subsequent studies demonstrated neuronal expression of AXL, an amuvatinib target, in both neuronal populations. However, functional AXL activity was confirmed only in the maturing neuronal population as determined by AXL phosphorylation in response to GAS6, the cognate ligand of AXL, and concurrent STAT3
    MeSH term(s) Humans ; Receptor Protein-Tyrosine Kinases/genetics ; Axl Receptor Tyrosine Kinase ; Proto-Oncogene Proteins/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Intercellular Signaling Peptides and Proteins/metabolism ; Neurons/metabolism
    Chemical Substances amuvatinib (SO9S6QZB4R) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; Axl Receptor Tyrosine Kinase ; Proto-Oncogene Proteins ; Intercellular Signaling Peptides and Proteins
    Language English
    Publishing date 2023-07-17
    Publishing country England
    Document type Journal Article
    ZDB-ID 2173655-8
    ISSN 1742-4658 ; 1742-464X
    ISSN (online) 1742-4658
    ISSN 1742-464X
    DOI 10.1111/febs.16901
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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