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Find video protocols related to scientific articles indexed in Pubmed.
Closing in on a mechanism for activation.
Elife
PUBLISHED: 10-29-2014
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When insulin-like growth factor-1 (IGF1) binds to its receptor, a physical constraint is released that allows the two transmembrane helices to come together to facilitate activation of the receptor.
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Noninvasive stress testing for coronary artery disease.
Cardiol Clin
PUBLISHED: 08-06-2014
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Stress testing remains the cornerstone for noninvasive assessment of patients with possible or known coronary artery disease (CAD). The most important application of stress testing is risk stratification. Most patients who present for evaluation of stable CAD are categorized as low risk by stress testing. These low-risk patients have favorable clinical outcomes and generally do not require coronary angiography. Standard exercise treadmill testing is the initial procedure of choice in patients with a normal or near-normal resting electrocardiogram who are capable of adequate exercise. Stress imaging is recommended for patients with prior revascularization, uninterpretable electrocardiograms, or inability to adequately exercise.
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Long-term radiostrontium interactions and transport through sediment.
Environ. Sci. Technol.
PUBLISHED: 07-08-2014
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Radioactive strontium is one of the most common radiological contaminants in groundwater and soil. Objectives of this study were to (1) evaluate Sr transport through an 11-year-long field lysimeter study and (2) quantify secondary aging effects between Sr and sediment that may need to be considered for long-term transport modeling. Batch sorption/desorption tests were conducted with (85)Sr, (88)Sr, and (90)Sr using a sediment recovered from a field lysimeter containing a glass pellet amended with high-level nuclear waste for 24 years. Sr was largely reversibly and linearly sorbed. (85)Sr sorption coefficients (Kd, concentration ratios of solids/liquids) after a 23-day contact period were about the same as the (90)Sr desorption Kd values after a 24-year contact period: sorption Kd = 32.1 ± 3.62 mL g(-1) and desorption Kd = 43.1 ± 11.4 mL g(-1). Numerical modeling of the lysimeter (90)Sr depth profile indicated that a Kd value of 32 mL g(-1) fit the data best. The Kd construct captured most of the data trends above and below the source term, except for immediately below the source where the model clearly overestimated Sr mobility. (90)Sr desorption tests suggested that the overestimated mobility may be attributed to a second, slower sorption reaction that occurs over a course of months to decades.
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Targeting tyrosine-kinases and estrogen receptor abrogates resistance to endocrine therapy in breast cancer.
Oncotarget
PUBLISHED: 07-01-2014
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Despite numerous therapies that effectively inhibit estrogen signaling in breast cancer, a significant proportion of patients with estrogen receptor (ER)-positive malignancy will succumb to their disease. Herein we demonstrate that long-term estrogen deprivation (LTED) therapy among ER-positive breast cancer cells results in the adaptive increase in ER expression and subsequent activation of multiple tyrosine kinases. Combination therapy with the ER down-regulator fulvestrant and dasatinib, a broad kinase inhibitor, exhibits synergistic activity against LTED cells, by reduction of cell proliferation, cell survival, cell invasion and mammary acinar formation. Screening kinase phosphorylation using protein arrays and functional proteomic analysis demonstrates that the combination of fulvestrant and dasatinib inhibits multiple tyrosine kinases and cancer-related pathways that are constitutively activated in LTED cells. Because LTED cells display increased insulin receptor (InsR)/insulin-like growth factor 1 receptor (IGF-1R) signaling, we added an ant-IGF-1 antibody to the combination with fulvestrant and dasatinib in an effort to further increase the inhibition. However, adding MK0646 only modestly increased the inhibition of cell growth in monolayer culture, but neither suppressed acinar formation nor inhibited cell migration in vitro and invasion in vivo. Therefore, combinations of fulvestrant and dasatinib, but not MK0646, may benefit patients with tyrosine-kinase-activated, endocrine therapy-resistant breast cancer.
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Comparative definitions for moderate-severe ischemia in stress nuclear, echocardiography, and magnetic resonance imaging.
JACC Cardiovasc Imaging
PUBLISHED: 06-14-2014
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The lack of standardized reporting of the magnitude of ischemia on noninvasive imaging contributes to variability in translating the severity of ischemia across stress imaging modalities. We identified the risk of coronary artery disease (CAD) death or myocardial infarction (MI) associated with ?10% ischemic myocardium on stress nuclear imaging as the risk threshold for stress echocardiography and cardiac magnetic resonance. A narrative review revealed that ?10% ischemic myocardium on stress nuclear imaging was associated with a median rate of CAD death or MI of 4.9%/year (interquartile range: 3.75% to 5.3%). For stress echocardiography, ?3 newly dysfunctional segments portend a median rate of CAD death or MI of 4.5%/year (interquartile range: 3.8% to 5.9%). Although imprecisely delineated, moderate-severe ischemia on cardiac magnetic resonance may be indicated by ?4 of 32 stress perfusion defects or ?3 dobutamine-induced dysfunctional segments. Risk-based thresholds can define equivalent amounts of ischemia across the stress imaging modalities, which will help to translate a common understanding of patient risk on which to guide subsequent management decisions.
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Imaging of lumbar spine fusion.
Neuroimaging Clin. N. Am.
PUBLISHED: 05-06-2014
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This article reviews the imaging of lumbar spinal fusion and its major indications. The most common procedures are described for the purpose of allowing understanding of postoperative imaging. Imaging options are reviewed for preoperative workup, intraoperative guidance, and postoperative purposes. Examples of hardware integrity, fusion, and loosening are provided.
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Assessing clinical impact of myocardial perfusion studies: ischemia or other prognostic indicators?
Curr Cardiol Rep
PUBLISHED: 03-04-2014
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One of the major strengths of nuclear myocardial perfusion imaging (MPI) is the robust prognostic databases from observational studies demonstrating significantly different outcomes in patients with low-risk vs high-risk scans. The severity of the MPI defect can be semi-quantitated using the summed stress score (SSS) and summed difference score (SDS). SSS is more strongly associated with mortality, whereas SDS is the better predictor of subsequent coronary angiography and revascularization. The strength of MPI variables as prognostic indicators decreases when adjusted for prognostically important clinical and stress test variables. Nonetheless, most studies of general patient populations have demonstrated that MPI adds incremental prognostic value to clinical and stress test information. In contrast to these positive results from observational studies, the application of MPI ischemia as a treatment guide in several recent trials (DIAD, WOMEN, COURAGE, BARI 2D, STICH) has largely failed to identify patient subsets with improved outcome. This issue will continue to be investigated in the ongoing PROMISE and ISCHEMIA trials.
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Regulation of Src and Csk nonreceptor tyrosine kinases in the filasterean Ministeria vibrans.
Biochemistry
PUBLISHED: 02-18-2014
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The development of the phosphotyrosine-based signaling system predated the evolution of multicellular animals. Single-celled choanoflagellates, the closest living relatives to metazoans, possess numerous tyrosine kinases, including Src family nonreceptor tyrosine kinases. Choanoflagellates also have Csk (C-terminal Src kinase), the enzyme that regulates Src in metazoans; however, choanoflagellate Csk kinases fail to repress the cognate Src. Here, we have cloned and characterized Src and Csk kinases from Ministeria vibrans, a filasterean (the sister group to metazoans and choanoflagellates). The two Src kinases (MvSrc1 and MvSrc2) are enzymatically active Src kinases, although they have low activity toward mammalian cellular proteins. Unexpectedly, MvSrc2 has significant Ser/Thr kinase activity. The Csk homologue (MvCsk) is enzymatically inactive and fails to repress MvSrc activity. We suggest that the low activity of MvCsk is due to sequences in the SH2-kinase interface, and we show that a point mutation in this region partially restores MvCsk activity. The inactivity of filasterean Csk kinases is consistent with a model in which the stringent regulation of Src family kinases arose more recently in evolution, after the split between choanoflagellates and multicellular animals.
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Freshwater harmful algal blooms: toxins and children's health.
Curr Probl Pediatr Adolesc Health Care
PUBLISHED: 01-21-2014
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Massive accumulations of cyanobacteria (a.k.a. "blue-green algae"), known as freshwater harmful algal blooms (FHABs), are a common global occurrence in water bodies used for recreational purposes and drinking water purification. Bloom prevalence is increased due to anthropogenic changes in land use, agricultural activity, and climate change. These photosynthetic bacteria produce a range of toxic secondary metabolites that affect animals and humans at both chronic and acute dosages. Children are especially at risk because of their lower body weight, behavior, and toxic effects on development. Here we review common FHAB toxins, related clinical symptoms, acceptable concentrations in drinking water, case studies of children's and young adults' exposures to FHAB toxins through drinking water and food, methods of environmental and clinical detection in potential cases of intoxication, and best practices for FHAB prevention.
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Therapeutic targeting of cancers with loss of PTEN function.
Curr Drug Targets
PUBLISHED: 01-07-2014
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Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is one of the most frequently disrupted tumor suppressors in cancer. The lipid phosphatase activity of PTEN antagonizes the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway to repress tumor cell growth and survival. In the nucleus, PTEN promotes chromosome stability and DNA repair. Consequently, loss of PTEN function increases genomic instability. PTEN deficiency is caused by inherited germline mutations, somatic mutations, epigenetic and transcriptional silencing, post-translational modifications, and protein-protein interactions. Given the high frequency of PTEN deficiency across cancer subtypes, therapeutic approaches that exploit PTEN loss-of-function could provide effective treatment strategies. Herein, we discuss therapeutic strategies aimed at cancers with loss of PTEN function, and the challenges involved in treating patients afflicted with such cancers. We review preclinical and clinical findings, and highlight novel strategies under development to target PTENdeficient cancers.
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Estrogen receptor alpha and androgen receptor are commonly expressed in well-differentiated liposarcoma.
BMC Clin Pathol
PUBLISHED: 01-01-2014
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Liposarcoma (LS) is the second-most common type of soft-tissue sarcoma. Despite advances in knowledge and treatment of this disease, there remains a need for more effective LS therapy. Steroid hormone receptors regulate metabolism in adipocytes. Estrogen receptor alpha (ER), progesterone receptor (PR), and androgen receptor (AR) have been implicated in the pathophysiology of other cancer types. We sought to comprehensively determine temporal expression patterns of these receptors in LS.
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Clinical potential of novel therapeutic targets in breast cancer: CDK4/6, Src, JAK/STAT, PARP, HDAC, and PI3K/AKT/mTOR pathways.
Pharmgenomics Pers Med
PUBLISHED: 01-01-2014
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Breast cancers expressing estrogen receptor ?, progesterone receptor, or the human epidermal growth factor receptor 2 (HER2) proto-oncogene account for approximately 90% of cases, and treatment with antiestrogens and HER2-targeted agents has resulted in drastically improved survival in many of these patients. However, de novo or acquired resistance to antiestrogen and HER2-targeted therapies is common, and many tumors will recur or progress despite these treatments. Additionally, the remaining 10% of breast tumors are negative for estrogen receptor ?, progesterone receptor, and HER2 ("triple-negative"), and a clinically proven tumor-specific drug target for this group has not yet been identified. Therefore, the identification of new therapeutic targets in breast cancer is of vital clinical importance. Preclinical studies elucidating the mechanisms driving resistance to standard therapies have identified promising targets including cyclin-dependent kinase 4/6, phosphoinositide 3-kinase, poly adenosine diphosphate-ribose polymerase, Src, and histone deacetylase. Herein, we discuss the clinical potential and status of new therapeutic targets in breast cancer.
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Managing breast cancers with low estrogen receptor and HER2 by drugging both.
Clin. Cancer Res.
PUBLISHED: 12-18-2013
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Low ER levels in breast tumors are associated with poorer response to anti-estrogen therapy. Finn et al. identified low ER levels as a biomarker predicting benefit from the addition of the EGFR/HER2 dual inhibitor Lapatinib to an anti-estrogen treatment regimen in patients with metastatic breast cancer.
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Misdiagnosing recurrent medulloblastoma: the danger of examination and imaging without histological confirmation.
J Neurosurg Pediatr
PUBLISHED: 11-08-2013
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The screening and detection of recurrent medulloblastoma presents the clinician with significant diagnostic challenges, including the risk of misdiagnosis. The authors present the case of a young girl with a history of a treated standard-risk medulloblastoma that highlights the risk of assuming recurrence has occurred when clinical and/or imaging changes are observed. This girl developed both new clinical deficits and had radiographic evidence of recurrence. She subsequently experienced a complete resolution of symptoms and radiographic findings with steroids alone.
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Downstream clinical implications of abnormal myocardial perfusion single-photon emission computed tomography based on appropriate use criteria.
J Nucl Cardiol
PUBLISHED: 09-24-2013
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Appropriate use criteria (AUC) for single-photon emission computed tomography myocardial perfusion images (SPECT-MPI) were developed to address the growth of cardiac imaging studies. However, these criteria have not been vigorously validated. We sought to determine the rate of abnormal stress SPECT-MPI studies and subsequent revascularization procedures as categorized by AUC.
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Activation of MAPK pathways due to DUSP4 loss promotes cancer stem cell-like phenotypes in basal-like breast cancer.
Cancer Res.
PUBLISHED: 08-21-2013
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Basal-like breast cancer (BLBC) is an aggressive disease that lacks a clinically approved targeted therapy. Traditional chemotherapy is effective in BLBC, but it spares the cancer stem cell (CSC)-like population, which is likely to contribute to cancer recurrence after the initial treatment. Dual specificity phosphatase-4 (DUSP4) is a negative regulator of the mitogen-activated protein kinase (MAPK) pathway that is deficient in highly aggressive BLBCs treated with chemotherapy, leading to aberrant MAPK activation and resistance to taxane-induced apoptosis. Herein, we investigated how DUSP4 regulates the MAP-ERK kinase (MEK) and c-jun-NH2-kinase (JNK) pathways in modifying CSC-like behavior. DUSP4 loss increased mammosphere formation and the expression of the CSC-promoting cytokines interleukin (IL)-6 and IL-8. These effects were caused in part by loss of control of the MEK and JNK pathways and involved downstream activation of the ETS-1 and c-JUN transcription factors. Enforced expression of DUSP4 reduced the CD44(+)/CD24(-) population in multiple BLBC cell lines in a MEK-dependent manner, limiting tumor formation of claudin-low SUM159PT cells in mice. Our findings support the evaluation of MEK and JNK pathway inhibitors as therapeutic agents in BLBC to eliminate the CSC population.
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Cardiac rehabilitation and cardiovascular disability: role in assessment and improving functional capacity: a position statement from the American Association of Cardiovascular and Pulmonary Rehabilitation.
J Cardiopulm Rehabil Prev
PUBLISHED: 06-26-2013
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The Social Security Administration (SSA) oversees the disability determination process and the payment of disability benefits to Americans. According to recent SSA data, approximately 900 000 persons are receiving cardiovascular disability payments and about 145 000 adult claims for cardiovascular disability are processed by the SSA annually. An objective and comprehensive examination of functional capacity is an important part of the disability assessment process. This statement reviews various protocols for disability assessment of aerobic capacity, muscle function, and the physical requirements of job tasks. Cardiac rehabilitation programs are ideal settings for conducting comprehensive disability assessments of functional capacity in persons with cardiovascular disease. In addition, exercise training provided by cardiac rehabilitation programs can increase functional capacity in most patients.
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Comparison of CT and fluoroscopic guidance for lumbar puncture in an obese population with prior failed unguided attempt.
J Neurointerv Surg
PUBLISHED: 06-01-2013
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BACKGROUND AND PURPOSE: In the past 50 years, fluoroscopic guidance has been used to improve upon lumbar puncture (LP) technique that was unchanged for over a century. Recently, CT has seen increasing use as a guidance modality due to its ability to demonstrate soft tissue contrast and provide millimeter accuracy with needle targeting. This study compared procedure time and radiation dosages for fluoroscopic and CT guided LP. MATERIALS AND METHODS: This institutional review board and Health Insurance Portability and Accountability Act (HIPAA) compliant study was a retrospective review of a consecutive cohort referred for image guided LP. For CT, 45 patients aged 49 years (range 20-78, SD 14) with body mass index (BMI) values of 33 kg/m(2) (range 20-50, SD 12) were included. For fluoroscopy, 100 patients aged 47 years (range 18-88, SD 17) with BMI values of 29 kg/m(2) (range 15-56, SD 9) were included. CT procedure time was determined using picture archiving and communication system (PACS) image time stamps. Radiation dose was determined using the CT dose report and effective dose conversion factors. Fluoroscopic procedure time was determined from nursing. Fluoroscopic radiation dose was calculated from dose-area product (DAP) and fluoroscopy times, with effective dosage calculated using simulation software. RESULTS: For CT, procedure time average was 14 min (range 5-42, SD 8.5). Average dose-length product was 120 mGy×cm (range 39-211, SD 43) and average effective dose was 1.98 mSv (range 0.2-8.18, SD 4.4). For fluoroscopy, procedure time averaged 12 min (range 12-30, SD 6). Average DAP was 10 Gy×cm(2) (range 0.1-70, SD 11) and effective dose estimate averaged 2.9 mSv (range 0.9-9.4, SD 1.9). There were no unsuccessful taps or complications. CONCLUSIONS: Both fluoroscopic and CT guidance may be used to perform an LP in an obese population with a short procedure time and low radiation dose.
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Endocrine resistance.
Am Soc Clin Oncol Educ Book
PUBLISHED: 05-30-2013
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Adjuvant therapy with antiestrogens targeting estrogen receptor ? (ER) signaling prevents disease recurrence in many patients with early-stage ER+ breast cancer. However, a significant number of cases exhibit de novo or acquired endocrine resistance. While other clinical subtypes of breast cancer (HER2+, triple-negative) have disproportionately higher rates of mortality, ER+ breast cancer is responsible for at least as many deaths because it is the most common subtype. Therefore, identifying mechanisms that drive endocrine resistance is a high clinical priority. A large body of experimental evidence indicates that oncogenic signaling pathways underlie endocrine resistance, including growth factor receptor tyrosine kinases (HER2, epidermal growth factor receptor [EGFR], fibroblast growth factor receptor 1/2 [FGFR], insulin-like growth factor-1 receptor [IGF-1R]/ insulin receptor [InsR]), PI3K/AKT/ mTOR, MAPK/ERK, Src, CDK4/CDK6, and ER itself. Combined targeting of ER and such pathways may be the most effective means to combat antiestrogen resistance, and clinical trials testing such strategies show promising results. Herein, we discuss pathways associated with endocrine resistance, biomarkers that may be useful to predict response to targeted agents, and avenues for further exploration to identify strategies for the treatment of patients with endocrine-resistant disease.
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Absent sella turcica: a case report and a review of the literature.
Fetal Pediatr Pathol
PUBLISHED: 05-20-2013
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Absent sella turcica is an extremely rare and dramatic radiographic finding. It may be isolated or occur in the presence of other anomalies, often involving the adenohypophysis. Our evaluation of a female infant with multiple anomalies including absence of the sella turcica, a normal pituitary in the craniopharyngeal canal, normal pituitary function, choanal atresia and anomalies of the appendiceal skeleton prompted a review of the occurrence and biology of an absent sella turcica.
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Population-based study of the use of cardiac stress imaging and referral for coronary angiography and repeated revascularization after coronary artery bypass graft surgery.
Mayo Clin. Proc.
PUBLISHED: 04-02-2013
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To assess stress single-photon emission computed tomography (SPECT) and stress echocardiography use after coronary artery bypass grafting (CABG) and their effect on referral for coronary angiography and revascularization.
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Serines in the intracellular tail of podoplanin (PDPN) regulate cell motility.
J. Biol. Chem.
PUBLISHED: 03-25-2013
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Podoplanin (PDPN) is a transmembrane receptor that affects the activities of Rho, ezrin, and other proteins to promote tumor cell motility, invasion, and metastasis. PDPN is found in many types of cancer and may serve as a tumor biomarker and chemotherapeutic target. The intracellular region of PDPN contains only two serines, and these are conserved in mammals including mice and humans. We generated cells from the embryos of homozygous null Pdpn knock-out mice to investigate the relevance of these serines to cell growth and migration on a clear (PDPN-free) background. We report here that one or both of these serines can be phosphorylated by PKA (protein kinase A). We also report that conversion of these serines to nonphosphorylatable alanine residues enhances cell migration, whereas their conversion to phosphomimetic aspartate residues decreases cell migration. These results indicate that PKA can phosphorylate PDPN to decrease cell migration. In addition, we report that PDPN expression in fibroblasts causes them to facilitate the motility and viability of neighboring melanoma cells in coculture. These findings shed new light on how PDPN promotes cell motility, its role in tumorigenesis, and its utility as a functionally relevant biomarker and chemotherapeutic target.
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Autocrine IGF-I/insulin receptor axis compensates for inhibition of AKT in ER-positive breast cancer cells with resistance to estrogen deprivation.
Breast Cancer Res.
PUBLISHED: 02-14-2013
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Estrogen receptor ?-positive (ER+) breast cancers adapt to hormone deprivation and acquire resistance to antiestrogen therapies. Upon acquisition of hormone independence, ER+ breast cancer cells increase their dependence on the phosphatidylinositol-3 kinase (PI3K)/AKT pathway. We examined the effects of AKT inhibition and its compensatory upregulation of insulin-like growth factor (IGF)-I/InsR signaling in ER+ breast cancer cells with acquired resistance to estrogen deprivation.
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Metazoan-like signaling in a unicellular receptor tyrosine kinase.
BMC Biochem.
PUBLISHED: 02-04-2013
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Receptor tyrosine kinases (RTKs) are crucial components of signal transduction systems in multicellular animals. Surprisingly, numerous RTKs have been identified in the genomes of unicellular choanoflagellates and other protists. Here, we report the first biochemical study of a unicellular RTK, namely RTKB2 from Monosiga brevicollis.
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The role of nitrogen fixation in cyanobacterial bloom toxicity in a temperate, eutrophic lake.
PLoS ONE
PUBLISHED: 01-09-2013
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Toxic cyanobacterial blooms threaten freshwaters worldwide but have proven difficult to predict because the mechanisms of bloom formation and toxin production are unknown, especially on weekly time scales. Water quality management continues to focus on aggregated metrics, such as chlorophyll and total nutrients, which may not be sufficient to explain complex community changes and functions such as toxin production. For example, nitrogen (N) speciation and cycling play an important role, on daily time scales, in shaping cyanobacterial communities because declining N has been shown to select for N fixers. In addition, subsequent N pulses from N(2) fixation may stimulate and sustain toxic cyanobacterial growth. Herein, we describe how rapid early summer declines in N followed by bursts of N fixation have shaped cyanobacterial communities in a eutrophic lake (Lake Mendota, Wisconsin, USA), possibly driving toxic Microcystis blooms throughout the growing season. On weekly time scales in 2010 and 2011, we monitored the cyanobacterial community in a eutrophic lake using the phycocyanin intergenic spacer (PC-IGS) region to determine population dynamics. In parallel, we measured microcystin concentrations, N(2) fixation rates, and potential environmental drivers that contribute to structuring the community. In both years, cyanobacterial community change was strongly correlated with dissolved inorganic nitrogen (DIN) concentrations, and Aphanizomenon and Microcystis alternated dominance throughout the pre-toxic, toxic, and post-toxic phases of the lake. Microcystin concentrations increased a few days after the first significant N(2) fixation rates were observed. Then, following large early summer N(2) fixation events, Microcystis increased and became most abundant. Maximum microcystin concentrations coincided with Microcystis dominance. In both years, DIN concentrations dropped again in late summer, and N(2) fixation rates and Aphanizomenon abundance increased before the lake mixed in the fall. Estimated N inputs from N(2) fixation were large enough to supplement, or even support, the toxic Microcystis blooms.
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Dysfunctional potassium channel subunit interaction as a novel mechanism of long QT syndrome.
Heart Rhythm
PUBLISHED: 01-02-2013
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The slowly-activating delayed rectifier current IKs contributes to repolarization of the cardiac action potential, and is composed of a pore-forming ?-subunit, KCNQ1, and a modulatory ?-subunit, KCNE1. Mutations in either subunit can cause long QT syndrome, a potentially fatal arrhythmic disorder. How KCNE1 exerts its extensive control over the kinetics of IKs remains unresolved
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Spatiotemporal molecular analysis of cyanobacteria blooms reveals microcystis - aphanizomenon interactions.
PLoS ONE
PUBLISHED: 01-01-2013
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Spatial and temporal variability in cyanobacterial community composition (CCC) within and between eutrophic lakes is not well-described using culture independent molecular methods. We analyzed CCC across twelve locations in four eutrophic lakes and within-lake locations in the Yahara Watershed, WI, on a weekly basis, for 5 months. Taxa were discriminated by length of MspI-digested cpcB/A intergenic spacer gene sequences and identified by comparison to a PCR-based clone library. CCC across all stations was spatially segregated by depth of sampling locations (ANOSIM R = 0.23, p < 0.001). Accordingly, CCC was correlated with thermal stratification, nitrate and soluble reactive phosphorus (SRP, R = 0.2-0.3). Spatial variability in CCC and temporal trends in taxa abundances were rarely correlative between sampling locations in the same lake indicating significant within lake spatiotemporal heterogeneity. Across all stations, a total of 37 bloom events were observed based on distinct increases in phycocyanin. Out of 97 taxa, a single Microcystis, and two different Aphanizomenon taxa were the dominant cyanobacteria detected during bloom events. The Microcystis and Aphanizomenon taxa rarely bloomed together and were significantly anti-correlated with each other at 9 of 12 stations with Pearson R values of -0.6 to -0.9 (p < 0.001). Of all environmental variables measured, nutrients, especially nitrate were significantly greater during periods of Aphanizomenon dominance while the nitrate+nitrite:SRP ratio was lower. This study shows significant spatial variability in CCC within and between lakes structured by depth of the sampling location. Furthermore, our study reveals specific genotypes involved in bloom formation. More in-depth characterization of these genotypes should lead to a better understanding of factors promoting bloom events in these lakes and more reliable bloom prediction models.
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Who possesses drug resistance genes in the aquatic environment?: sulfamethoxazole (SMX) resistance genes among the bacterial community in water environment of Metro-Manila, Philippines.
Front Microbiol
PUBLISHED: 01-01-2013
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Recent evidence has shown that antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs) are ubiquitous in natural environments, including sites considered pristine. To understand the origin of ARGs and their dynamics, we must first define their actual presence in the natural bacterial assemblage. Here we found varying distribution profiles of sul genes in "colony forming bacterial assemblages" and "natural bacterial assemblages." Our monitoring for antibiotic contamination revealed that sulfamethoxazole (SMX) is a major contaminant in aquatic environments of Metro-Manila, which would have been derived from human and animal use, and subsequently decreased through the process of outflow from source to the sea. The SMX-resistant bacterial rate evaluated by the colony forming unit showed 10 to 86% of the total colony numbers showed higher rates from freshwater sites compared to marine sites. When sul genes were quantified by qPCR, colony-forming bacteria conveyed sul1 and sul2 genes in freshwater and seawater (10(-5)-10(-2) copy/16S) but not sul3. Among the natural bacterial assemblage, all sul1, sul2, and sul3 were detected (10(-5)-10(-3) copy/16S), whereas all sul genes were at an almost non-detectable level in the freshwater assemblage. This study suggests that sul1 and sul2 are main sul genes in culturable bacteria, whereas sul3 is conveyed by non-culturable bacteria in the sea. As a result marine bacteria possess sul1, sul2 and sul3 genes in the marine environment.
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The receptor tyrosine kinase ErbB3 maintains the balance between luminal and basal breast epithelium.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 12-16-2011
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ErbB3 harbors weak kinase activity, but strongly activates downstream phosphatidylinositol 3-kinase/Akt signaling through heterodimerization with and activation by other ErbB receptor tyrosine kinases. We report here that ErbB3 loss in the luminal mammary epithelium of mice impaired Akt and MAPK signaling and reduced luminal cell proliferation and survival. ERBB3 mRNA expression levels were highest in luminal mammary populations and lowest in basal cell/stem cell populations. ErbB3 loss in mammary epithelial cells shifted gene expression patterns toward a mammary basal cell/stem cell signature. ErbB3 depletion-induced gene expression changes were rescued upon activation of Akt and MAPK signaling. Interestingly, proliferation and expansion of the mammary basal epithelium (BE) occurred upon ErbB3 targeting in the luminal epithelium, but not upon its targeting in the BE. Multiple cytokines, including interleukin 6, were induced upon ErbB3 depletion in luminal epithelium cells, which increased growth of BE cells. Taken together, these results suggest that ErbB3 regulates the balance of differentiated breast epithelial cell types by regulating their growth and survival through autocrine- and paracrine-signaling mechanisms.
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Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer.
Breast Cancer Res.
PUBLISHED: 11-01-2011
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Mutations in genes that constitute the phosphatidylinositol 3-kinase (PI3K) pathway occur in >70% of breast cancers. Clinical and experimental evidence suggest that PI3K pathway activation promotes resistance to some of the current breast cancer therapies. PI3K is a major signaling hub downstream of human epidermal growth factor receptor (HER)2 and other receptor tyrosine kinases. PI3K activates AKT, serum/glucocorticoid regulated kinase (SGK), phosphoinositide-dependent kinase 1 (PDK1), mammalian target of rapamycin (mTOR), and several other molecules involved in cell cycle progression and survival. In estrogen receptor (ER)+ breast cancer cells, PI3K activation promotes estrogen-dependent and -independent ER transcriptional activity, which, in turn, may contribute to anti-estrogen resistance. Activation of this pathway also confers resistance to HER2-targeted therapies. In experimental models of resistance to anti-estrogens and HER2 inhibitors, pharmacological inhibition of PI3K/AKT/mTOR has been shown to overcome drug resistance. Early clinical data suggest that combined inhibition of either HER2 or ER plus inhibition of the PI3K pathway might be an effective strategy for treatment of respective HER2+ and ER+ breast cancers resistant to standard therapies. Here, we review alterations in the PI3K pathway in breast cancer, their association with therapeutic resistance, and the state of clinical development of PI3K pathway inhibitors.
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Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer.
J. Clin. Oncol.
PUBLISHED: 10-17-2011
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Although antiestrogen therapies targeting estrogen receptor (ER) ? signaling prevent disease recurrence in the majority of patients with hormone-dependent breast cancer, a significant fraction of patients exhibit de novo or acquired resistance. Currently, the only accepted mechanism linked with endocrine resistance is amplification or overexpression of the ERBB2 (human epidermal growth factor receptor 2 [HER2]) proto-oncogene. Experimental and clinical evidence suggests that hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway, the most frequently mutated pathway in breast cancer, promotes antiestrogen resistance. PI3K is a major signaling hub downstream of HER2 and other receptor tyrosine kinases. PI3K activates several molecules involved in cell-cycle progression and survival, and in ER-positive breast cancer cells, it promotes estrogen-dependent and -independent ER transcriptional activity. Preclinical tumor models of antiestrogen-resistant breast cancer often remain sensitive to estrogens and PI3K inhibition, suggesting that simultaneous targeting of the PI3K and ER pathways may be most effective. Herein, we review alterations in the PI3K pathway associated with resistance to endocrine therapy, the state of clinical development of PI3K inhibitors, and strategies for the clinical investigation of such drugs in hormone receptor-positive breast cancer.
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Covered stents safely utilized to prevent catastrophic hemorrhage in patients with advanced head and neck malignancy.
J Neurointerv Surg
PUBLISHED: 10-07-2011
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The purpose of this study was to review the use of covered stents in patients with squamous cell carcinoma of the head and neck threatening bilateral neurovascular structures.
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A kinome-wide screen identifies the insulin/IGF-I receptor pathway as a mechanism of escape from hormone dependence in breast cancer.
Cancer Res.
PUBLISHED: 09-09-2011
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Estrogen receptor ? (ER)-positive breast cancers adapt to hormone deprivation and become resistant to antiestrogens. In this study, we sought to identify kinases essential for growth of ER(+) breast cancer cells resistant to long-term estrogen deprivation (LTED). A kinome-wide siRNA screen showed that the insulin receptor (InsR) is required for growth of MCF-7/LTED cells. Knockdown of InsR and/or insulin-like growth factor-I receptor (IGF-IR) inhibited growth of 3 of 4 LTED cell lines. Inhibition of InsR and IGF-IR with the dual tyrosine kinase inhibitor OSI-906 prevented the emergence of hormone-independent cells and tumors in vivo, inhibited parental and LTED cell growth and PI3K/AKT signaling, and suppressed growth of established MCF-7 xenografts in ovariectomized mice, whereas treatment with the neutralizing IGF-IR monoclonal antibody MAB391 was ineffective. Combined treatment with OSI-906 and the ER downregulator fulvestrant more effectively suppressed hormone-independent tumor growth than either drug alone. Finally, an insulin/IGF-I gene expression signature predicted recurrence-free survival in patients with ER(+) breast cancer treated with the antiestrogen tamoxifen. We conclude that therapeutic targeting of both InsR and IGF-IR should be more effective than targeting IGF-IR alone in abrogating resistance to endocrine therapy in breast cancer.
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Genetic diversity of cyanobacteria in four eutrophic lakes.
FEMS Microbiol. Ecol.
PUBLISHED: 07-29-2011
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Recent studies indicate genetic diversity of cyanobacteria in eutrophic lakes is not represented well by culture collections or morphology. Yet, few studies have investigated genetic richness and evenness of cyanobacteria using culture-independent methods. We compared the genetic structure of cyanobacteria supported by four neighboring eutrophic lakes during the ice-free season. The partial phycobilincpcB/A genes plus intergenic spacer (PC-IGS) was used as a genetic marker.Sequences were phylogeneticallygrouped by maximum likelihood into genotypes representing sub-genera of the major taxa. Genotypes fell into genera commonly observed by microscopy in these lakes including Microcystis, Aphanizomenon, Chroococcus, Anabaena, and Cylindrospermopsis. Only three genotypes were shared among all four lakes, despite significant water flowage between lakes.A Parsimony P-test indicated lakes were significantly (p=0.01) clustered on the maximum likelihood tree. Pairwise differences using Unifrac distance were moderately or not significant. Analysis of molecular variance (AMOVA) indicated genetic variation among all genotypes (?=0.06, p<0.001) and 94% of variability occurred within lakes rather than between lakes (6%), explaining the lack of pairwise differences between lakes. Lorenze curves of genotype abundance in each lake showed genetic structure was only moderately uneven (Gini coefficients of 0.37-0.5) indicating lakes did not support dominant genotypes. Overall, results from this study suggest diversity of cyanobacteria is shaped by heterogeneity within lakes (temporally or spatially) and relatively even population structures.
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ER?-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer.
Cancer Discov
PUBLISHED: 07-20-2011
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Most estrogen receptor ? (ER)-positive breast cancers initially respond to antiestrogens, but many eventually become estrogen-independent and recur. We identified an estrogen-independent role for ER and the CDK4/Rb/E2F transcriptional axis in the hormone-independent growth of breast cancer cells. ER downregulation with fulvestrant or small interfering RNA (siRNA) inhibited estrogen-independent growth. Chromatin immunoprecipitation identified ER genomic binding activity in estrogen-deprived cells and primary breast tumors treated with aromatase inhibitors. Gene expression profiling revealed an estrogen-independent, ER/E2F-directed transcriptional program. An E2F activation gene signature correlated with a lesser response to aromatase inhibitors in patients tumors. siRNA screening showed that CDK4, an activator of E2F, is required for estrogen-independent cell growth. Long-term estrogen-deprived cells hyperactivate phosphatidylinositol 3-kinase (PI3K) independently of ER/E2F. Fulvestrant combined with the pan-PI3K inhibitor BKM120 induced regression of ER(+) xenografts. These data support further development of ER downregulators and CDK4 inhibitors, and their combination with PI3K inhibitors for treatment of antiestrogen-resistant breast cancers.
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Using tandem mass spectrometry in targeted mode to identify activators of class IA PI3K in cancer.
Cancer Res.
PUBLISHED: 07-20-2011
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Phosphatiditylinositide-3-kinase (PI3K) is activated in some cancers by direct mutation, but it is activated more commonly in cancer by mutation of upstream acting receptor tyrosine kinases (TK). At present, there is no systematic method to determine which TK signaling cascades activate PI3K in certain cancers, despite the likely utility of such information to help guide selection of tyrosine kinase inhibitor (TKI) drug strategies for personalized therapy. Here, we present a quantitative liquid chromatography tandem mass spectrometry approach that identifies upstream activators of PI3K both in vitro and in vivo. Using non-small cell lung carcinoma to illustrate this approach, we show a correct identification of the mechanism of PI3K activation in several models, thereby identifying the most appropriate TKI to downregulate PI3K signaling. This approach also determined the molecular mechanisms and adaptors required for PI3K activation following inhibition of the mTOR kinase TORC1. We further validated the approach in breast cancer cells with mutational activation of PIK3CA, where tandem mass spectrometry detected and quantitatively measured the abundance of a helical domain mutant (E545K) of PIK3CA connected to PI3K activation. Overall, our findings establish a mass spectrometric approach to identify functional interactions that govern PI3K regulation in cancer cells. Using this technique to define the pathways that activate PI3K signaling in a given tumor could help inform clinical decision making by helping guide personalized therapeutic strategies for different patients.
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Stress testing: the case for the standard treadmill test.
Curr. Opin. Cardiol.
PUBLISHED: 07-07-2011
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This review examines the diagnostic and prognostic performance of the standard exercise treadmill test (ETT) in comparison to stress imaging procedures. This topic is timely and relevant due to increasing healthcare expenditures and the substantially lower cost of the ETT.
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Radiofrequency ablation of advanced head and neck cancer.
Arch. Otolaryngol. Head Neck Surg.
PUBLISHED: 05-18-2011
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To determine if the application of radiofrequency ablation to advanced head and neck cancer (HNC) would result in local control of the tumor.
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Contamination and bioaccumulation of benzotriazole ultraviolet stabilizers in fish from Manila Bay, the Philippines using an ultra-fast liquid chromatography-tandem mass spectrometry.
Chemosphere
PUBLISHED: 04-26-2011
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Benzotriazole ultraviolet stabilizers (BUVSs) used in plastic products, building materials and personal hygiene products were analyzed in fishes collected from Manila Bay, the Philippines. BUVSs were detected at ng g?¹ level in all the fish samples, indicating their ubiquitous contamination in coastal waters. Among the targeted eight BUVSs, UV-328 was predominantly found with a mean concentration of 34.2 ng g?¹ lipid weight, implying large scale production and use of this compound in the Philippines. High concentrations of ?BUVSs were found in bumpnose trevally (Carangoides hedlandensis), bluetail mullet (adult) (Valamugil buchanani), common ponyfish (Leiognathus equulus) and coral grouper (adult) (Epinephelus corallicola) indicating their active uptake and/or lower metabolic capacity to eliminate BUVSs. Among BUVSs, UV-P showed significant positive relationship (p<0.05) between concentration and fish length (r=0.29) and fish weight (r=0.31). Levels of UV-P in demersal species had positive correlation with ?¹?N, indicating that possibile sink of UV-P is bottom sediment in the bay, and ultimately accumulate through benthic food web rather than pelagic food web. To our knowledge, this is the first study on BUVSs distribution in fish from developing countries.
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Development of a rowing-specific VO2max field test.
J Strength Cond Res
PUBLISHED: 04-19-2011
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The purpose of this study was to develop an aerobic capacity test for rowers using minimal equipment that could be used in the field. Thirty rowers (15 men and 15 women) between the ages of 18 and 26 years were recruited on a volunteer basis from the District of Columbia metro area. The testing protocol consisted of a maximum of 7 2-minute stages on a rowing ergometer, separated by 30-second breaks where lactic acid concentrations were analyzed. Starting intensity for men was 200 W, although women started at 150 W, and each stage increased by 50 W. Expired gasses were collected during the test, and athletes were asked to row until maximal volition so that the directly measured VO2max could be compared to predicted values. Peak heart rates from each completed stage were plotted, and regression equations were calculated to predict VO2max. Separate regression equations were calculated for men and women. The predicted VO2max values were approximately 23 and 25% lower than what was actually achieved for men and women, respectively. Heart rate was a stronger correlate of VO2max in men compared with in women. Among men, we observed a moderate and statistically significant correlation (r = 0.55; p = 0.05), whereas among women, no such agreement was observed (r = -0.05; p > 0.85). The principle finding of this study was that the test was adequate in predicting VO2max in men but was inadequate in its prediction in women. With slight modifications to the testing protocol, stronger correlations and a more accurate prediction of VO2max is expected in men.
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Early image acquisition using a solid-state cardiac camera for fast myocardial perfusion imaging.
J Nucl Cardiol
PUBLISHED: 04-18-2011
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A novel ultra-fast solid-state cardiac camera (Discovery NM 530c, General Electric) allows much shorter acquisition times compared to standard dual-detector SPECT cameras. This design enables investigation of the potential for early myocardial perfusion imaging (MPI) following a rest injection of technetium-99m (Tc-99m) rather than the conventional 45-60 minute delay in image acquisition.
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Influence of upper-body external loading on anaerobic exercise performance.
J Strength Cond Res
PUBLISHED: 03-31-2011
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The purpose of this study was to assess the threshold where simulated adipose tissue weight gain significantly affects performance in common anaerobic tasks and determine whether differences exist between men and women. Forty-six subjects (men = 21; women = 25) were tested for vertical jump, 20- and 40-yd dash, and 20-yd shuttle tests under 6 different loading conditions (0, 2, 4, 6, 8, and 10% of added body weight). Results were compared to each subjects baseline values (0% loading condition). Results demonstrate significant decrements in performance, starting at the 2% loading condition, for both genders, in every performance test (p < 0.05). On average, subjects jumped 4.91 ± 0.29 to 9.83 ± 0.30 cm less, increased agility test times from 5.49 ± 0.56 to 5.86 ± 0.61 seconds, and increased sprint times from 7.80 ± 0.96 to 8.39 ± 1.07 seconds (2-10%, respectively; p < 0.05). When lower-body power was corrected for total body mass, men exerted significantly more power than women did in every loading condition. Conversely, when lower-body power was corrected for lean body mass, men exerted significantly more power than did women only at the 2% loading condition. This study demonstrates that for the specific anaerobic performance tests performed, increases in external loading as low as 2% of body weight results in significant decreases in performance. Moreover, for these specific tests, men and women tend to express the same threshold in performance decrements.
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PTB domain-directed substrate targeting in a tyrosine kinase from the unicellular choanoflagellate Monosiga brevicollis.
PLoS ONE
PUBLISHED: 03-28-2011
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Choanoflagellates are considered to be the closest living unicellular relatives of metazoans. The genome of the choanoflagellate Monosiga brevicollis contains a surprisingly high number and diversity of tyrosine kinases, tyrosine phosphatases, and phosphotyrosine-binding domains. Many of the tyrosine kinases possess combinations of domains that have not been observed in any multicellular organism. The role of these protein interaction domains in M. brevicollis kinase signaling is not clear. Here, we have carried out a biochemical characterization of Monosiga HMTK1, a protein containing a putative PTB domain linked to a tyrosine kinase catalytic domain. We cloned, expressed, and purified HMTK1, and we demonstrated that it possesses tyrosine kinase activity. We used immobilized peptide arrays to define a preferred ligand for the third PTB domain of HMTK1. Peptide sequences containing this ligand sequence are phosphorylated efficiently by recombinant HMTK1, suggesting that the PTB domain of HMTK1 has a role in substrate recognition analogous to the SH2 and SH3 domains of mammalian Src family kinases. We suggest that the substrate recruitment function of the noncatalytic domains of tyrosine kinases arose before their roles in autoinhibition.
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Determination of preservative and antimicrobial compounds in fish from Manila Bay, Philippines using ultra high performance liquid chromatography tandem mass spectrometry, and assessment of human dietary exposure.
J. Hazard. Mater.
PUBLISHED: 03-19-2011
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Ultra high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) determination of four paraben preservatives (methyl, ethyl, propyl and butyl) and two antimicrobial agents (triclosan and triclocarban) belonging to personal care products (PCPs) in 20 species of fish from Manila Bay (Philippines) was performed. Detection of PCPs with greater frequency indicates the ubiquitous contamination of Manila Bay. Concentrations of total paraben were one order of magnitude higher than the antimicrobials in almost all fish, except in Stolephorus indicus and Leiognathus equulus. A positive correlation was observed between parabens concentration and fish length (r = 0.31-0.49; p<0.05 to <0.001) and fish weight (r = 0.28-0.49; p<0.05 to <0.001), but not for the antimicrobials. The estimated dietary exposure values of the four parabens in the Philippines through fish is four orders of magnitude lower than the acceptable daily intake (ADI) of 10mg/kg/day, but the values of antimicrobials are just half of the ADI of TCS. To our knowledge, this is the first report of PCPs contamination in fish from Philippines.
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Influence of Upper-Body External Loading on Anaerobic Exercise Performance.
J Strength Cond Res
PUBLISHED: 03-15-2011
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Inacio, M, Dipietro, L, Visek, AJ, and Miller, TA. Influence of upper-body external loading on anaerobic exercise performance. J Strength Cond Res 25(X): 000-000, 2011-The purpose of this study was to assess the threshold where simulated adipose tissue weight gain significantly affects performance in common anaerobic tasks and determine whether differences exist between men and women. Forty-six subjects (men = 21; women = 25) were tested for vertical jump, 20- and 40-yd dash, and 20-yd shuttle tests under 6 different loading conditions (0, 2, 4, 6, 8, and 10% of added body weight). Results were compared to each subjects baseline values (0% loading condition). Results demonstrate significant decrements in performance, starting at the 2% loading condition, for both genders, in every performance test (p < 0.05). On average, subjects jumped 4.91 ± 0.29 to 9.83 ± 0.30 cm less, increased agility test times from 5.49 ± 0.56 to 5.86 ± 0.61 seconds, and increased sprint times from 7.80 ± 0.96 to 8.39 ± 1.07 seconds (2-10%, respectively; p < 0.05). When lower-body power was corrected for total body mass, men exerted significantly more power than women did in every loading condition. Conversely, when lower-body power was corrected for lean body mass, men exerted significantly more power than did women only at the 2% loading condition. This study demonstrates that for the specific anaerobic performance tests performed, increases in external loading as low as 2% of body weight results in significant decreases in performance. Moreover, for these specific tests, men and women tend to express the same threshold in performance decrements.
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A gene expression signature from human breast cancer cells with acquired hormone independence identifies MYC as a mediator of antiestrogen resistance.
Clin. Cancer Res.
PUBLISHED: 02-23-2011
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Although most patients with estrogen receptor ? (ER)-positive breast cancer initially respond to endocrine therapy, many ultimately develop resistance to antiestrogens. However, mechanisms of antiestrogen resistance and biomarkers predictive of such resistance are underdeveloped.
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Hypoxia in Manila Bay, Philippines during the northeast monsoon.
Mar. Pollut. Bull.
PUBLISHED: 02-15-2011
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Herein we present results from one of the first extensive bay-wide oceanographic surveys of Manila Bay, wherein 31 stations were sampled during the northeast monsoon (cold and dry season). A band of hypoxic bottom water (dissolved oxygen<2.8 mg/L) spanned the midsection of the bay from east to west. Bottom nitrate concentrations (5.7-16.8 ?M; avg. 11.1 ?M) and total organic carbon values in sediments (1.7-3.1%; avg. 2.4%) were high in the midsection, which coincided with the band of hypoxic bottom water. Physical processes and site-specific accumulation of organic material likely lead to hypoxic conditions in Manila Bay, even during the northeast monsoon period when the water column is relatively well mixed. The results of this study complement the previously reported widespread hypoxia that occurs during the rainy season. Thus, hypoxia may be pervasive in the bay throughout the year, although it varies in intensity and spatial extent.
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Appropriate use criteria for stress single-photon emission computed tomography sestamibi studies: a quality improvement project.
Circulation
PUBLISHED: 01-24-2011
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We previously reported the application of the 2005 American College of Cardiology Foundation appropriate use criteria for stress single-photon emission computed tomography (SPECT) imaging to patients at Mayo Clinic (Rochester, MN) in 2005 and 2006. A subsequent internal quality improvement project focused on physician education in an attempt to reduce the rate of inappropriate SPECT studies.
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External validation of the New Orleans Criteria (NOC), the Canadian CT Head Rule (CCHR) and the National Emergency X-Radiography Utilization Study II (NEXUS II) for CT scanning in pediatric patients with minor head injury in a non-trauma center.
Pediatr Radiol
PUBLISHED: 01-14-2011
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Head CT scans are considered the imaging modality of choice to screen patients with head trauma for neurocranial injuries; however, widespread CT imaging is not recommended and much research has been conducted to establish objective clinical predictors of intracranial injury (ICI) in order to optimize the use of neuroimaging in children with minor head trauma.
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Regulation of ack-family nonreceptor tyrosine kinases.
J Signal Transduct
PUBLISHED: 01-13-2011
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Ack family non-receptor tyrosine kinases are unique with regard to their domain composition and regulatory properties. Human Ack1 (activated Cdc42-associated kinase) is ubiquitously expressed and is activated by signals that include growth factors and integrin-mediated cell adhesion. Stimulation leads to Ack1 autophosphorylation and to phosphorylation of additional residues in the C-terminus. The N-terminal SAM domain is required for full activation. Ack1 exerts some of its effects via protein-protein interactions that are independent of its kinase activity. In the basal state, Ack1 activity is suppressed by an intramolecular interaction between the catalytic domain and the C-terminal region. Inappropriate Ack1 activation and signaling has been implicated in the development, progression, and metastasis of several forms of cancer. Thus, there is increasing interest in Ack1 as a drug target, and studies of the regulatory properties of the enzyme may reveal features that can be exploited in inhibitor design.
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Troponin T levels and infarct size by SPECT myocardial perfusion imaging.
JACC Cardiovasc Imaging
PUBLISHED: 01-09-2011
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To evaluate the relationship between serial cardiac troponin T (cTnT) levels with infarct size and left ventricular ejection fraction by gated single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) in patients with acute myocardial infarction (AMI).
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Genome sequence of the dioxin-mineralizing bacterium Sphingomonas wittichii RW1.
J. Bacteriol.
PUBLISHED: 09-10-2010
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Pollutants such as polychlorinated biphenyls and dioxins pose a serious threat to human and environmental health. Natural attenuation of these compounds by microorganisms provides one promising avenue for their removal from contaminated areas. Over the past 2 decades, studies of the bacterium Sphingomonas wittichii RW1 have provided a wealth of knowledge about how bacteria metabolize chlorinated aromatic hydrocarbons. Here we describe the finished genome sequence of S. wittichii RW1 and major findings from its annotation.
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Interparietal bone (Os Incae) in craniosynostosis.
Am. J. Med. Genet. A
PUBLISHED: 08-18-2010
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The interparietal bone, Os Incae, is formed in a persistent mendosal suture. This suture is a normal variant in the human skull, well-known in anatomy and radiology textbooks. We report 11 children with craniosynostosis in the presence of an interparietal bone, five from Childrens Hospital at Montefiore and six children from Childrens Hospital Boston. The true incidence of an interparietal bone in patients with craniosynostosis or craniofacial anomalies is not known; nor are there recognized sequelae of an interparietal bone (bathrocephaly). Hypotheses regarding mechanisms that may contribute to the formation of an interparietal bone are discussed.
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Utility of bone scintigraphy to determine the appropriate vertebral augmentation levels.
Clin Nucl Med
PUBLISHED: 08-14-2010
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Vertebral augmentation procedures have been used as an effective treatment for back pain due to vertebral compression fracture from different causes, including metastatic disease and osteoporosis. However, diagnosis and localization of the causative vertebral level(s) may be difficult using any single imaging modality. In this retrospective study, we assessed the ability of preprocedural bone scans to determine the appropriate level(s) of subsequent vertebroplasty.
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Regulation of Ack1 localization and activity by the amino-terminal SAM domain.
BMC Biochem.
PUBLISHED: 08-12-2010
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The mechanisms that regulate the activity of the nonreceptor tyrosine kinase Ack1 (activated Cdc42-associated kinase) are poorly understood. The amino-terminal region of Ack1 is predicted to contain a sterile alpha motif (SAM) domain. SAM domains share a common fold and mediate protein-protein interactions in a wide variety of proteins. Here, we addressed the importance of the Ack1 SAM domain in kinase activity.
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Testing of low-risk patients presenting to the emergency department with chest pain: a scientific statement from the American Heart Association.
Circulation
PUBLISHED: 07-26-2010
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The management of low-risk patients presenting to emergency departments is a common and challenging clinical problem entailing 8 million emergency department visits annually. Although a majority of these patients do not have a life-threatening condition, the clinician must distinguish between those who require urgent treatment of a serious problem and those with more benign entities who do not require admission. Inadvertent discharge of patients with acute coronary syndrome from the emergency department is associated with increased mortality and liability, whereas inappropriate admission of patients without serious disease is neither indicated nor cost-effective. Clinical judgment and basic clinical tools (history, physical examination, and electrocardiogram) remain primary in meeting this challenge and affording early identification of low-risk patients with chest pain. Additionally, established and newer diagnostic methods have extended clinicians diagnostic capacity in this setting. Low-risk patients presenting with chest pain are increasingly managed in chest pain units in which accelerated diagnostic protocols are performed, comprising serial electrocardiograms and cardiac injury markers to exclude acute coronary syndrome. Patients with negative findings usually complete the accelerated diagnostic protocol with a confirmatory test to exclude ischemia. This is typically an exercise treadmill test or a cardiac imaging study if the exercise treadmill test is not applicable. Rest myocardial perfusion imaging has assumed an important role in this setting. Computed tomography coronary angiography has also shown promise in this setting. A negative accelerated diagnostic protocol evaluation allows discharge, whereas patients with positive findings are admitted. This approach has been found to be safe, accurate, and cost-effective in low-risk patients presenting with chest pain.
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The timing and impact of follow-up studies after normal stress single-photon emission computed tomography sestamibi studies.
Circ Cardiovasc Imaging
PUBLISHED: 07-14-2010
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The purpose of this study was to determine the prevalence and timing of routine follow-up single-photon emission computed tomography (SPECT) studies after a normal stress SPECT scan compared with the patients warranty period (ie, time to 1% risk of death or myocardial infarction).
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The effects of multiaxial and uniaxial unstable surface balance training in college athletes.
J Strength Cond Res
PUBLISHED: 06-18-2010
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The purpose of this study was to compare the effects of 2 different types of unstable surface balance training (uniaxial on a rocker board [RB] and multiaxial on a dynadisc [DD]) on balance in division 1 collegiate athletes in sports that are at high risk for ankle sprains. Subjects (n = 36) consisted of male soccer players and female volleyball and soccer players who were equally and randomly assigned to 1 of 3 groups (CON, DD, and RB). Balance training consisting of balancing on 1 leg on either the RB or DD, while repeatedly catching a 1-kg ball was performed 3 times per week for 4 weeks. Balance was tested with the Star Excursion Balance Test (SEBT) before, halfway through, and at the completion of the balance training. Control (CON) subjects also were given the balance test but did not participate in the training. A 3-way repeated analysis of variance revealed that no group individually changed SEBT scores from pre (CON, 0.98 +/- 0.086; DD, 0.98 +/- 0.083; RB, 0.97 +/- 0.085) to post (CON, 1.00 +/- 0.090; DD, 1.01 +/- 0.088; RB, 1.02 +/- 0.068) after balance training. When the 2 treatment groups were combined (DD and RB), the p value decreased and came closer to significance (p = 0.136). When all 3 groups were combined, there was a significant difference in SEBT scores from pretraining (CON + DD + RB; 0.98 +/- 0.085) to posttraining (CON + DD + RB; 1.01 +/- 0.082), which likely indicates low statistical power. The increase in physical activity the subjects experienced during the return to in-season activity, may have contributed to the significant differences in SEBT scores over time but not between DD or RB training. Therefore, a threshold level of physical activity may exist that is necessary to maintain balance during the off-season.
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Identification of wastewater bacteria involved in the degradation of triclocarban and its non-chlorinated congener.
J. Hazard. Mater.
PUBLISHED: 06-15-2010
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Triclocarban (TCC) is an antimicrobial additive of personal care products that is only partially degraded during wastewater treatment. Bacteria responsible for its transformation are unknown. We obtained wastewater bacteria capable of using as the sole carbon source TCC or its non-chlorinated analog, carbanilide (NCC). Enrichments established using activated sludge amended with TCC and NCC, respectively, were maintained for 1 year through successive transfers. Enrichments displayed exponential growth after 2 weeks, reaching stationary phase after 1 month. The NCC enrichment was shown to accumulate aniline. Denaturing gradient gel electrophoresis of amplified 16S rRNA genes indicated markedly reduced community richness compared to the inoculum and a single, prominent taxonomic unit emerged in both chlorinated and non-chlorinated carbanilide enrichment cultures. Cloned 16S rRNA genes showed both enrichments were dominated by a single genotype related to uncharacterized organisms within the Alcaligenaceae. Of ?30 sequences from each enrichment, no other organisms were detected in the TCC enrichment while, a small, flanking community of alpha proteobacteria was detected in the NCC enrichment. Study results demonstrate that growth of wastewater bacteria on TCC and its lower chlorinated analog can be linked to bacteria within the family Alcaligenaceae. These organisms are promising agents for the bioremediation of hazardous phenylurea pollutants.
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Tracing anthropogenic inputs to production in the Seto Inland Sea, Japan--a stable isotope approach.
Mar. Pollut. Bull.
PUBLISHED: 04-21-2010
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The Seto Inland Sea (SIS) receives waste runoff from ?24% of Japans total population, yet it is also important in regional fisheries, recreation and commerce. During August 2006 we measured carbon and nitrogen stable isotopes of particulate organic matter (POM) and zooplankton across urban population gradients of the SIS. Results showed a consistent trend of increasing ?(15)N in POM and zooplankton from the western to eastern subsystems of the SIS, corresponding to increasing population load. Principal components analysis of environmental variables indicated high positive loadings of ?(15)N and ?(13)C with high chlorophyll-a and surface water temperatures, and negative loadings of low salinities related to inputs from large rivers and high urban development in the eastern SIS. Anthropogenic nitrogen was therefore readily integrated into the SIS food web from primary production to copepods, which are a critical food source for many commercially important fishes.
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Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer.
J. Clin. Invest.
PUBLISHED: 04-14-2010
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Many breast cancers exhibit a degree of dependence on estrogen for tumor growth. Although several therapies have been developed to treat individuals with estrogen-dependent breast cancers, some tumors show de novo or acquired resistance, rendering them particularly elusive to current therapeutic strategies. Understanding the mechanisms by which these cancers develop resistance would enable the development of new and effective therapeutics. In order to determine mechanisms of escape from hormone dependence in estrogen receptor-positive (ER-positive) breast cancer, we established 4 human breast cancer cell lines after long-term estrogen deprivation (LTED). LTED cells showed variable changes in ER levels and sensitivity to 17beta-estradiol. Proteomic profiling of LTED cells revealed increased phosphorylation of the mammalian target of rapamycin (mTOR) substrates p70S6 kinase and p85S6 kinase as well as the PI3K substrate AKT. Inhibition of PI3K and mTOR induced LTED cell apoptosis and prevented the emergence of hormone-independent cells. Using reverse-phase protein microarrays, we identified a breast tumor protein signature of PI3K pathway activation that predicted poor outcome after adjuvant endocrine therapy in patients. Our data suggest that upon adaptation to hormone deprivation, breast cancer cells rely heavily on PI3K signaling. Our findings also imply that acquired resistance to endocrine therapy in breast cancer may be abrogated by combination therapies targeting both ER and PI3K pathways.
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The effects of concurrent endurance and resistance training on 2,000-m rowing ergometer times in collegiate male rowers.
J Strength Cond Res
PUBLISHED: 04-14-2010
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The current study evaluated if high rep, low rep, or no weight training at all would be best suited for decreasing 2,000-m rowing ergometer times in male varsity rowers. Subjects (n = 18) were rowers from Grand Valley State University who were randomly and equally assigned to 1 of 3 groups: control (CON), high-load low repetitions (HLLR), and low-load high repetitions (LLHR). The weight training groups resistance trained and rowed twice a week, whereas the control group only rowed twice a week. Each group performed the training study workouts (weight training and rowing) along with their daily prescribed varsity practices. The subjects performed both pre and post 2,000-m ergometer tests on concept 2 indoor rowers to evaluate the effects of each training protocol. Paired t-tests revealed statistically significant decreases in 2,000-m times from pre to posttesting for all groups (p < 0.05), whereas a 1-way analysis of variance with repeated measures did not reveal a statistically significant difference (p < 0.96) between the 3 groups (Delta CON: -2.8%, Delta LLHR: -3.1%, and Delta HLLR: -3.5%). However, a trend existed in the hypothesized direction, as the HLLR illustrated the greatest decrease in mean rowing time (CON: 11 seconds, LLHR: 12 seconds, and HLLR: 15 seconds). Overall, the current study demonstrates that although weight training does not create a statistically significant short-term training effect on rowing performance, the profound decreases in 2,000-m times seen in this study may be of practical significance for the oarsman.
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Application of appropriateness criteria to stress single photon emission computed tomography sestamibi studies: a comparison of the 2009 revised appropriateness criteria to the 2005 original criteria.
Am. Heart J.
PUBLISHED: 03-25-2010
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The 2005 appropriate use criteria (AUC) for stress single-photon emission computed tomographic myocardial perfusion imaging (SPECT MPI) were revised in 2009 to reflect changes in published evidence, clinical practice and experience with application of the 2005 AUC. The purpose of this study was to compare the 2009 AUC for SPECT MPI with the original 2005 criteria.
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Temporal trends in compliance with appropriateness criteria for stress single-photon emission computed tomography sestamibi studies in an academic medical center.
Am. Heart J.
PUBLISHED: 03-10-2010
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The purpose of this study was to apply published appropriateness criteria for single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) in a single academic medical center to determine if the percentage of inappropriate studies was changing over time. In a previous study, we applied the American College of Cardiology Foundation/American Society of Nuclear Cardiology (ASNC) appropriateness criteria for stress SPECT MPI and reported that 14% of stress SPECT studies were performed for inappropriate reasons.
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Evaluation of coronary CTA Appropriateness Criteria in an academic medical center.
J Am Coll Radiol
PUBLISHED: 02-10-2010
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The aim of this study was to evaluate published appropriateness criteria for CT angiography (CTA) at the authors academic medical center.
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Cancer-associated mutations activate the nonreceptor tyrosine kinase Ack1.
J. Biol. Chem.
PUBLISHED: 01-28-2010
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Ack1 is a nonreceptor tyrosine kinase that participates in tumorigenesis, cell survival, and migration. Relatively little is known about the mechanisms that regulate Ack1 activity. Recently, four somatic missense mutations of Ack1 were identified in cancer tissue samples, but the effects on Ack1 activity, and function have not been described. These mutations occur in the N-terminal region, the C-lobe of the kinase domain, and the SH3 domain. Here, we show that the cancer-associated mutations increase Ack1 autophosphorylation in mammalian cells without affecting localization and increase Ack1 activity in immune complex kinase assays. The cancer-associated mutations potentiate the ability of Ack1 to promote proliferation and migration, suggesting that point mutation is a mechanism for Ack1 deregulation. We propose that the C-terminal Mig6 homology region (MHR) (residues 802-990) participates in inhibitory intramolecular interactions. The isolated kinase domain of Ack1 interacts directly with the MHR, and the cancer-associated E346K mutation prevents binding. Likewise, mutation of a key hydrophobic residue in the MHR (Phe(820)) prevents the MHR-kinase interaction, activates Ack1, and increases cell migration. Thus, the cancer-associated mutation E346K appears to destabilize an autoinhibited conformation of Ack1, leading to constitutively high Ack1 activity.
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Comparison of the antimicrobial efficacy of irrigation using the EndoVac to endodontic needle delivery.
J Endod
PUBLISHED: 01-25-2010
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The purpose of this investigation was to compare the antimicrobial efficacy of root canal irrigation with the EndoVac (Discus Dental, Culver City, CA) to endodontic needle irrigation in the apical 5 mm of root canals infected with Enterococcus faecalis.
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Electronic momentary assessment of weather changes as a trigger of headaches in children.
Headache
PUBLISHED: 12-21-2009
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Variables that are thought to precipitate migraine or tension-type headache episodes in children hitherto have only been studied using retrospective reports. As such, there is little empirical evidence to support the actual predictive association between presumed headache triggers and actual headache occurrence in children.
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Inhibition of mammalian target of rapamycin is required for optimal antitumor effect of HER2 inhibitors against HER2-overexpressing cancer cells.
Clin. Cancer Res.
PUBLISHED: 11-24-2009
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A significant fraction of HER2-overexpressing breast cancers exhibit resistance to the HER2 antibody trastuzumab. Hyperactivity of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway confers trastuzumab resistance, and mammalian target of rapamycin (mTOR) is a major downstream effector of PI3K/AKT. Therefore, we examined whether mTOR inhibitors synergize with trastuzumab.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.