Raymond J Winquist

Vertex Pharmaceuticals, Cambridge, Massachusetts, United States

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Publications (10)49.26 Total impact

  • Raymond J. Winquist · Amy B. Hall · Brenda K. Eustace · Brinley F. Furey ·
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    ABSTRACT: Stem cells subserve repair functions for the lifetime of the organism but, as a consequence of this responsibility, are candidate cells for accumulating numerous genetic and/or epigenetic aberrations leading to malignant transformation. However, given the importance of this guardian role, stem cells likely harbor some process for maintaining their precious genetic code such as non-random segregation of chromatid strands as predicted by the Immortal Strand Hypothesis (ISH). Discerning such non-random chromosomal segregation and asymmetric cell division in normal or cancer stem cells has been complicated by methodological shortcomings but also by differing division kinetics amongst tissues and the likelihood that both asymmetric and symmetric cell divisions, dictated by local extrinsic factors, are operant in these cells. Recent data suggest that cancer stem cells demonstrate a higher incidence of symmetric versus asymmetric cell division with both daughter cells retaining self-renewal characteristics, a profile which may underlie poorly differentiated morphology and marked clonal diversity in tumors. Pathways and targets are beginning to emerge which may provide opportunities for preventing such a predilection in cancer stem cells and that will hopefully translate into new classes of chemotherapeutics in oncology. Thus, although the existence of the ISH remains controversial, the shift of cell division dynamics to symmetric random chromosome segregation/self-renewal, which would negate any likelihood of template strand retention, appears to be a surrogate marker for the presence of highly malignant tumorigenic cell populations.
    Biochemical Pharmacology 09/2014; 91(2). DOI:10.1016/j.bcp.2014.06.007 · 5.01 Impact Factor
  • Kevin Mullane · Michael Williams · Raymond Winquist ·

    Biochemical Pharmacology 01/2014; 87(1):1–3. DOI:10.1016/j.bcp.2013.10.018 · 5.01 Impact Factor
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    ABSTRACT: A pharmacology experiment is typically conducted to: i) test or expand a hypothesis regarding the potential role of a target in the mechanism(s) underlying a disease state using an existing drug or tool compound as a probe in normal and/or diseased tissue or animals; or ii) to characterize and iteratively optimize a new chemical entity (NCE) thought to modulate a specific disease state-associated target to restore tissue homeostasis as a potential drug candidate. Hypothesis testing requires a null hypothesis approach within an intellectually rigorous context that is distinct from a high throughput fishing expedition in search of a hypothesis. The experiment should objectively and transparently define the protocol, its powering, design and appropriate statistical analysis together with some consideration of the expected outcome from the experiment before it is initiated. Compound interactions with a presumed target involve the direct study of target-related phenotype(s) unique to the target in a cell, tissue or animal/human system. However, in vivo studies are frequently confounded by a lack of assessment of pharmacokinetic parameters ncessary to confirm target engagement and by the analysis of ubiquitous cellular signaling pathways that are downstream from the target. This often involves using single compounds at one concentration in engineered cell lines resulting in reductionistic data that are physiologically irrelevant. This overview discusses current trends in the execution and reporting of experiments and the criteria necessary for the physiologically relevant assessment of selective target engagement that can be used to both identify viable new drug targets and advance translational studies.
    Biochemical pharmacology 11/2013; 87(1). DOI:10.1016/j.bcp.2013.10.024 · 5.01 Impact Factor
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    Kevin Mullane · Raymond J Winquist · Michael Williams ·
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    ABSTRACT: The translational sciences represent the core element in enabling and utilizing the output from the biomedical sciences and to improving drug discovery metrics by reducing the attrition rate as compounds move from preclinical research to clinical proof of concept. Key to understanding the basis of disease causality and to developing therapeutics is an ability to accurately diagnose the disease and to identify and develop safe and effective therapeutics for its treatment. The former requires validated biomarkers and the latter, qualified targets. Progress has been hampered by semantic issues, specifically those that define the end product, and by scientific issues that include data reliability, an overt reductionistic cultural focus and a lack of hierarchically integrated data gathering and systematic analysis. A necessary framework for these activities is represented by the discipline of pharmacology, efforts and training in which require recognition and revitalization.
    Biochemical pharmacology 10/2013; 87(1). DOI:10.1016/j.bcp.2013.10.019 · 5.01 Impact Factor
  • Article: Preface.
    Kevin Mullane · Michael Williams · Raymond Winquist ·

    Biochemical pharmacology 10/2013; · 5.01 Impact Factor
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    Raymond J Winquist · Kevin Mullane · Michael Williams ·
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    ABSTRACT: Pharmacology is an integrative discipline that originated from activities, now nearly 7,000 years old, to identify therapeutics from natural product sources. Research in the 19th century that focused on the Law of Mass Action (LMA) demonstrated that compound effects were dose-/concentration-dependent eventually leading to the receptor concept, now a century old, that remains the key to understanding disease causality and drug action. As pharmacology evolved in the 20th Century through successive biochemical, molecular and genomic eras, the precision in understanding receptor function at the molecular level increased and while providing important insights, led to an overtly reductionistic emphasis. This resulted in the generation of data lacking physiological context that ignored the LMA and was not integrated at the tissue/whole organism level. As reductionism became a primary focus in biomedical research, it led to the fall of pharmacology. However, concerns regarding the disconnect between basic research efforts and the approval of new drugs to treat 21(st) Century disease tsunamis, e.g., neurodegeneration and metabolic syndrome has led to the reemergence of pharmacology, its rise, often in the semantic guise of systems biology. Against a background of limited training in pharmacology, this brings issues in experimental replication and a bioinformatics emphasis that has a limited relationship to reality. The integration of newer technologies within a pharmacological context where research is driven by testable hypotheses rather than technology, together with renewed efforts in teaching pharmacology, is anticipated to improve the focus and relevance of biomedical research and lead to novel therapeutics that will contain health care costs (253 words).
    Biochemical pharmacology 09/2013; 87(1). DOI:10.1016/j.bcp.2013.09.011 · 5.01 Impact Factor
  • Raymond J Winquist · Brinley F Furey · Diane M Boucher ·
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    ABSTRACT: The poor success rate of discovering new, effective chemotherapeutics for oncology may reflect the failure of targeting treatments to the more aggressive, tumorigenic cells of the malignancy. Data have now emerged from several laboratories, examining both liquid and solid primary tumor tissues, that implicate cancer stem cells (CSCs) as the 'master-driver' cellular population for tumorigenicity. Moreover, these putative CSCs appear relatively resistant to existing chemotherapeutic and radiation therapy. Several different cellular pathways have been identified as likely mechanisms causal for the underlying insensitivity of the CSCs to conventional therapy. Progress has been made in the isolation and expansion of these CSCs for constructing conventional high-throughput phenotypic screening campaigns. However, challenges remain in designing optimal proof-of-concept trials for the clinical development of compounds targeting the elimination of CSCs.
    Current Opinion in Pharmacology 08/2010; 10(4):385-90. DOI:10.1016/j.coph.2010.06.008 · 4.60 Impact Factor
  • Raymond J Winquist · Diane M Boucher ·

    Current Opinion in Pharmacology 08/2010; 10(4):353-5. DOI:10.1016/j.coph.2010.06.011 · 4.60 Impact Factor
  • Raymond J Winquist · Diane M Boucher · Mark Wood · Brinley F Furey ·
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    ABSTRACT: Novel therapies for the treatment of solid tumors have generally failed to improve patient overall survival. These therapeutic approaches are typically focused on targeting signaling pathways implicated in cell growth and/or survival in order to shrink the malignant mass and achieve an objective clinical response; however, too often these responses are followed by eventual regrowth of the tumor. This clinical conundrum could be explained by the existence of a tumorigenic cell population that is relatively resistant to these therapies and retains pluripotent status in order to repopulate the original tumor and/or contribute to distant metastasis following treatment. Compelling data from liquid tumors, and more recently from studies focused on solid tumors, now support the existence of such tumorigenic cells (i.e., cancer stem cells) as a distinct subpopulation within the total tumor cell mass. These cancer stem cells (CSCs), as compared to the non-CSC population, have the ability to reconstitute the primary tumor phenotype when transplanted into recipient animals. In addition, data are beginning to emerge demonstrating that many standard-of-care chemotherapeutics are less effective in promoting cell death or cytostasis in these putative cancer stem cells as compared to effects in the non-stem cell cancerous cells. Therefore, targeting these locomotive drivers of tumors, the cancer stem cell population, should be considered a high priority in the continued pursuit of more effective cancer therapies.
    Biochemical pharmacology 09/2009; 78(4):326-34. DOI:10.1016/j.bcp.2009.03.020 · 5.01 Impact Factor
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    Raymond J Winquist · Ann Kwong · Ravi Ramachandran · Jugnu Jain ·
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    ABSTRACT: Multiple sclerosis is a demyelinating disease which is presumed to be a consequence of infiltrating lymphocytes autoreactive to myelin proteins. This is substantiated by several lines of clinical evidence and supported by correlative studies in preclinical models. The development of new therapeutics for MS has been guided by this perspective; however, the pathogenesis of MS has proven to be quite complex as observations exist which question the role of autoreactive lymphocytes in the etiology of MS. In addition the current immunomodulatory therapeutics do not prevent most patients from progressing into more serious forms of the disease. The development of truly transformational therapeutics for MS will likely require a broad assault that expands beyond the concept of MS being an autoimmune disease.
    Biochemical Pharmacology 12/2007; 74(9):1321-9. DOI:10.1016/j.bcp.2007.04.026 · 5.01 Impact Factor