14 research outputs found
Intraoperative radiotherapy in previously augmented patients with early-stage breast cancer.
Molecular Distinctions between Stasis and Telomere Attrition Senescence Barriers Shown by Long-term Culture of Normal Human Mammary Epithelial Cells
In the blink of an eye: relating positive-feedback sensitivity to striatal dopamine D2-like receptors through blink rate.
For >30 years, positron emission tomography (PET) has proven to be a powerful approach for measuring aspects of dopaminergic transmission in the living human brain; this technique has revealed important relationships between dopamine D2-like receptors and dimensions of normal behavior, such as human impulsivity, and psychopathology, particularly behavioral addictions. Nevertheless, PET is an indirect estimate that lacks cellular and functional resolution and, in some cases, is not entirely pharmacologically specific. To identify the relationships between PET estimates of D2-like receptor availability and direct in vitro measures of receptor number, affinity, and function, we conducted neuroimaging and behavioral and molecular pharmacological assessments in a group of adult male vervet monkeys. Data gathered from these studies indicate that variation in D2-like receptor PET measurements is related to reversal-learning performance and sensitivity to positive feedback and is associated with in vitro estimates of the density of functional dopamine D2-like receptors. Furthermore, we report that a simple behavioral measure, eyeblink rate, reveals novel and crucial links between neuroimaging assessments and in vitro measures of dopamine D2 receptors
Activity of the kinesin spindle protein inhibitor ispinesib (SB-715992) in models of breast cancer
Ispinesib (SB-715992) is a potent inhibitor of kinesin spindle protein (KSP), a kinesin motor protein essential for the formation of a bipolar mitotic spindle and cell cycle progression through mitosis. Clinical studies of ispinesib have demonstrated a 9% response rate in patients with locally advanced or metastatic breast cancer, and a favorable safety profile without significant neurotoxicities, gastrointestinal toxicities or hair loss. To better understand the potential of ispinesib in the treatment of breast cancer we explored the activity of ispinesib alone and in combination several therapies approved for the treatment of breast cancer. We measured the ispinesib sensitivity and pharmacodynamic response of breast cancer cell lines representative of various subtypes in vitro and as xenografts in vivo, and tested the ability of ispinesib to enhance the anti-tumor activity of approved therapies. In vitro, ispinesib displayed broad anti-proliferative activity against a panel of 53 breast cell-lines. In vivo, ispinesib produced regressions in each of five breast cancer models, and tumor free survivors in three of these models. The effects of ispinesib treatment on pharmacodynamic markers of mitosis and apoptosis were examined in vitro and in vivo, revealing a greater increase in both mitotic and apoptotic markers in the MDA-MB-468 model than in the less sensitive BT-474 model. In vivo, ispinesib enhanced the anti-tumor activity of trastuzumab, lapatinib, doxorubicin, and capecitabine, and exhibited activity comparable to paclitaxel and ixabepilone. These findings support further clinical exploration of KSP inhibitors for the treatment of breast cancer
Environmental and genetic determinants of tobacco use: methodology for a multidisciplinary, longitudinal family-based investigation.
This article describes the ongoing collaborative effort of six research teams to operationalize and execute an integrative approach to the study of gene x environment interactions in the development of tobacco dependence. At the core of the project is a longitudinal investigation of social and behavioral risk factors for tobacco use in individuals who were, on average, 13 years of age at intake and for whom smoking outcomes extending from early adolescence to young adulthood have been characterized previously (current average age of the cohort is 29 years). The conceptual framework for the integrative approach and the longitudinal investigation on which the study is based is presented. A description is also provided of the methods used to: (a) recruit participants and families to provide DNA samples and information on tobacco use; (b) assess participants for relevant tobacco-related phenotypes including smoking history, current use of tobacco, and nicotine metabolism; (c) assess the quality of the DNA samples collected from participants for genome-wide scanning and candidate gene analysis; (d) examine several research questions concerning the role of genetic and environmental factors in the onset and maintenance of tobacco use; and (e) ensure adherence to local and federal guidelines for ethical and legal investigations of genotypic associations with tobacco-related phenotypes in families. This investigation is unique among ongoing studies of the genetics of tobacco dependence in the extent to which equal importance has been assigned to both phenotypic and genotypic measurements
E.: “A Summary of
and transcriptional aberrations linked to breast cancer pathophysiologie
Structural Insights into (Tere)phthalate-Ester Hydrolysis by a Carboxylesterase and Its Role in Promoting PET Depolymerization
TfCa, a promiscuous carboxylesterase from Thermobifida
fusca, was found to hydrolyze polyethylene terephthalate
(PET) degradation intermediates such as bis(2-hydroxyethyl) terephthalate
(BHET) and mono-(2-hydroxyethyl)-terephthalate (MHET). In this study,
we elucidated the structures of TfCa in its apo form, as well as in
complex with a PET monomer analogue and with BHET. The structure–function
relationship of TfCa was investigated by comparing its hydrolytic
activity on various ortho- and para-phthalate esters of different
lengths. Structure-guided rational engineering of amino acid residues
in the substrate-binding pocket resulted in the TfCa variant I69W/V376A
(WA), which showed 2.6-fold and 3.3-fold higher hydrolytic activity
on MHET and BHET, respectively, than the wild-type enzyme. TfCa or
its WA variant was mixed with a mesophilic PET depolymerizing enzyme
variant [Ideonella sakaiensis PETase
(IsPETase) PM] to degrade PET substrates of various
crystallinity. The dual enzyme system with the wild-type TfCa or its
WA variant produced up to 11-fold and 14-fold more terephthalate (TPA)
than the single IsPETase PM, respectively. In comparison
to the recently published chimeric fusion protein of IsPETase and MHETase, our system requires 10% IsPETase
and one-fourth of the reaction time to yield the same amount of TPA
under similar PET degradation conditions. Our simple dual enzyme system
reveals further advantages in terms of cost-effectiveness and catalytic
efficiency since it does not require time-consuming and expensive
cross-linking and immobilization approaches