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Find video protocols related to scientific articles indexed in Pubmed.
Exploring the Relationship of Three Medical Entitlement Beliefs and Psychiatric/Psychological Variables for Acute and Chronic Pain Patients.
Pain Pract
PUBLISHED: 11-22-2014
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The belief in medical care entitlement has recently resulted in major changes in the medical system in the United States. The objectives of this study were the following: to compare endorsement of three medical entitlement beliefs (I deserve the best medical care no matter what the cost [BMC], I am entitled to all of the medical care I want at no charge [NC], I shouldn't have to wait to see my doctors [W]) in community nonpatients without pain (CNPWP), acute pain patients (APPs), and chronic pain patients (CPPs) and to develop predictor models for these beliefs in APPs and CPPs.
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Metastasis as a therapeutic target in prostate cancer: a conceptual framework.
Am J Clin Exp Urol
PUBLISHED: 11-01-2014
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Metastasis is the main cause of prostate cancer-associated deaths. While significant progerss has been made in the treatment of primary tumors, efficent therapies that target the metastatic spread of prostate cancer are far from clinical reality. To efficiently treat cancer we need be able to impede its spread. Unfortunately, the majority of current therapeutics approved to treat metastatic cancer were originally selected based on their ability to inhibit primary tumor growth. This inherent flaw precluded these therapies from efficiently targeting the development of secondary metastatic lesions, a process that is distinct from that of primary tumor progression. In this review we will summarize the conceptual, cellular and molecular targets that should be considered to design effective anti-metastatic therapies.
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Changes in acute biochemical markers of inflammatory and structural stress in rugby union.
J Sports Sci
PUBLISHED: 10-31-2014
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Abstract Rugby union is a sport governed by the impacts of high force and high frequency. Analysis of physiological markers following a game can provide an understanding of the physiological response of an individual and the time course changes in response to recovery. Urine and saliva were collected from 11 elite amateur rugby players 24 h before, immediately after, and at 17, 25, 38, 62 and 86 h post-game. Myoglobin, salivary immunoglobulin A and cortisol were analysed by ELISA, whereas neopterin and total neopterin were analysed by high-performance liquid chromatography. There was a significant post-game increase of all four markers. The increases were cortisol 4-fold, myoglobin 2.85-fold, neopterin 1.75-fold and total neopterin 2.3-fold when corrected with specific gravity. All significant changes occurred post-game only, with markers returning to and remaining at baseline within 17 h. The intensity of the game caused significant changes in key physiological markers of stress. They provide an understanding of the stress experienced during a single game of rugby and the time course changes associated with player recovery. Neopterin provides a new marker of detecting an acute inflammatory response in physical exercise, while specific gravity should be considered for urine volume correction post-exercise.
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Naturally Occurring Mutations of Human Corticosteroid-binding Globulin.
J. Clin. Endocrinol. Metab.
PUBLISHED: 10-17-2014
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Context: Corticosteroid-binding globulin (CBG) is encoded by SERPINA6. It is the major plasma binding protein of glucocorticoids and regulates plasma cortisol levels and bioavailability in humans. Several proteases target CBG and disrupt its steroid-binding properties. To date, most genetic deficiencies that alter plasma CBG levels or function have been identified in patients presenting with a variety of clinical conditions. Objective: To test thirty-two previously uncharacterized non-synonymous, single nucleotide polymorphisms (SNPs) in SERPINA6 for their ability to alter CBG production and/or function. Design: Human CBG mutants were produced in Chinese hamster ovary cells for ELISA, cortisol-binding activity measurements and Western blotting, as well as assays of their protease sensitivities. Results: Eight naturally occurring CBG mutants with abnormal production and/or function were identified. Cortisol-binding affinity was markedly reduced for CBG H14Q and CBG H89Y, moderately decreased for CBG I279F, and undetectable for CBG R260L. By contrast, CBG H14R exhibited a decreased cortisol-binding capacity. Comparison of CBG levels in cell extracts and media by Western blotting revealed that CBG I48N and CBG P246Q have secretion defects. Two mutants (CBG I179V and CBG I279F) displayed reduced rates of cortisol-binding activity loss after exposure to three different proteases (neutrophil elastase, chymotrypsin, and LasB produced by Pseudomonas aeruginosa). Conclusion: Our data provide insight into how specific residues affect CBG secretion or function, and illustrate the need to consider the various naturally occurring human CBG mutations in clinical evaluations of diseases associated with abnormalities in cortisol levels or activity.
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Self-reported physical activity and risk markers for cardiovascular disease after spinal cord injury.
J Rehabil Med
PUBLISHED: 09-12-2014
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To examine whether self-reported physical activity of a moderate/vigorous intensity influences risk markers for cardiovascular disease in persons with paraplegia due to spinal cord injury.
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The Adult Ball-and-Socket Ankle Joint: Surgical Management of Late Ankle and Subtalar Arthritis.
Foot Ankle Spec
PUBLISHED: 09-11-2014
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We review the surgical management of 4 adult patients with ball-and-socket ankle deformity who developed end-stage subtalar and/or ankle joint arthritis.
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Invadopodia are required for cancer cell extravasation and are a therapeutic target for metastasis.
Cell Rep
PUBLISHED: 08-28-2014
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Tumor cell extravasation is a key step during cancer metastasis, yet the precise mechanisms that regulate this dynamic process are unclear. We utilized a high-resolution time-lapse intravital imaging approach to visualize the dynamics of cancer cell extravasation in vivo. During intravascular migration, cancer cells form protrusive structures identified as invadopodia by their enrichment of MT1-MMP, cortactin, Tks4, and importantly Tks5, which localizes exclusively to invadopodia. Cancer cells extend invadopodia through the endothelium into the extravascular stroma prior to their extravasation at endothelial junctions. Genetic or pharmacological inhibition of invadopodia initiation (cortactin), maturation (Tks5), or function (Tks4) resulted in an abrogation of cancer cell extravasation and metastatic colony formation in an experimental mouse lung metastasis model. This provides direct evidence of a functional role for invadopodia during cancer cell extravasation and distant metastasis and reveals an opportunity for therapeutic intervention in this clinically important process.
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Range of motion and leg rotation affect electromyography activation levels of the superficial quadriceps muscles during leg extension.
J Strength Cond Res
PUBLISHED: 08-23-2014
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Leg extension (LE) is commonly used to strengthen the quadriceps muscles during training and rehabilitation. This study examined the effects of limb position (POS) and range of motion (ROM) on quadriceps electromyography (EMG) during 8 repetitions (REP) of LE. Twenty-four participants performed 8 LE REP at their 8 repetition maximum with lower limbs medially rotated (TI), laterally rotated (TO), and neutral (NEU). Each REP EMG was averaged over the first, middle, and final 0.524 rad ROM. For vastus medialis oblique (VMO), a REP × ROM interaction was detected (p < 0.02). The middle 0.524 rad produced significantly higher EMG than the initial 0.524 rad for REP 6-8 and the final 0.524 rad produced higher EMG than the initial 0.524 rad for REP 1, 2, 3, 4, 6, and 8 (p ? 0.05). For rectus femoris (RF), EMG activity increased across REP with TO generating the greatest activity (p < 0.001). For vastus lateralis (VL), EMG increased across REP (p < 0.001) with NEU and TO EMG increasing linearly throughout ROM and TI activity greatest during the middle 0.524 rad. We conclude that to target the VMO, the optimal ROM is the final 1.047 rad regardless of POS, while maximum EMG for the RF is generated using TO regardless of ROM. In contrast, the VL is maximally activated using TI over the first 1.047 rad ROM or in NEU over the final 0.524 rad ROM.
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Does pain interfere with antidepressant depression treatment response and remission in patients with depression and pain? An evidence-based structured review.
Pain Med
PUBLISHED: 08-19-2014
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The objective of this evidence-based structured review was to determine if there is consistent evidence that pain interferes with achieving antidepressant treatment response/remission of depression in patients with depression and pain.
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Prevalence Comparisons of Somatic and Psychiatric Symptoms Between Community Nonpatients Without Pain, Acute Pain Patients, and Chronic Pain Patients.
Pain Med
PUBLISHED: 08-19-2014
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Somatic/psychiatric symptoms are frequently found in chronic pain patients (CPPs). The objectives of this study were to determine 1) which somatic/psychiatric symptoms are more commonly found in acute pain patients (APPs) and CPPs vs community nonpatients without pain (CNPWPs) and 2) if somatic/psychiatric symptom prevalence differs between APPs and CPPs.
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An initial study on the estimation of time-varying volumetric treatment images and 3D tumor localization from single MV cine EPID images.
Med Phys
PUBLISHED: 08-04-2014
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In this work the authors develop and investigate the feasibility of a method to estimate time-varying volumetric images from individual MV cine electronic portal image device (EPID) images.
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Detection of dichlorvos adducts in a hepatocyte cell line.
J. Proteome Res.
PUBLISHED: 07-15-2014
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The toxicity of dichlorvos (DDVP), an organophosphate (OP) pesticide, classically results from modification of the serine in the active sites of cholinesterases. However, DDVP also forms adducts on unrelated targets such as transferrin and albumin, suggesting that DDVP could cause perturbations in cellular processes by modifying noncholinesterase targets. Here we identify novel DDVP-modified targets in lysed human hepatocyte-like cells (HepaRG) using a direct liquid chromatography-mass spectrometry (LC-MS) assay of cell lysates incubated with DDVP or using a competitive pull-down experiments with a biotin-linked organophosphorus compound (10-fluoroethoxyphosphinyl-N-biotinamidopentyldecanamide; FP-biotin), which competes with DDVP for similar binding sites. We show that DDVP forms adducts to several proteins important for the cellular metabolic pathways and differentiation, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and actin. We validated the results using purified proteins and enzymatic assays. The study not only identified novel DDVP-modified targets but also suggested that the modification directly inhibits the enzymes. The current approach provides information for future hypothesis-based studies to understand the underlying mechanism of toxicity of DDVP in non-neuronal tissues. The MS data have been deposited to the ProteomeXchange with identifier PXD001107.
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Protein-tyrosine pseudokinase 7 (PTK7) directs cancer cell motility and metastasis.
J. Biol. Chem.
PUBLISHED: 07-08-2014
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It is well established that widely expressed PTK7 is essential for vertebrate tissue morphogenesis. In cancer, the functionality of PTK7 is selectively regulated by membrane type-1 matrix metalloproteinase (MT1-MMP), ADAMs (a disintegrin domain and metalloproteinases), and ?-secretase proteolysis. Here, we established that the full-length membrane PTK7, its Chuzhoi mutant with the two functional MT1-MMP cleavage sites, and its L622D mutant with the single inactivated MT1-MMP cleavage site differentially regulate cell motility in a two-dimensional versus three-dimensional environment. We also demonstrated that in polarized cancer cells, the levels of PTK7 expression and proteolysis were directly linked to the structure and kinetics of cell protrusions, including lamellipodia and invadopodia. In the functionally relevant and widely accepted animal models of metastasis, mouse and chick embryo models, both the overexpression and knock-out of PTK7 in HT1080 cells abrogated metastatic dissemination. Our analysis of human tissue specimens confirmed intensive proteolysis of PTK7 in colorectal cancer tumors, but not in matching normal tissue. Our results provide convincing evidence that both PTK7 expression and proteolysis, rather than the level of the cellular full-length PTK7 alone, contribute to efficient directional cell motility and metastasis in cancer.
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The Pain Suicidality Association: A Narrative Review.
Pain Med
PUBLISHED: 07-04-2014
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The objective of this narrative review was to examine recent evidence and, when necessary, past evidence on the association between pain and suicidality.
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Range of motion and leg rotation affect EMG activation levels of the superficial quadriceps muscles during leg extension.
J Strength Cond Res
PUBLISHED: 07-02-2014
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The leg extension (LE) is commonly used to strengthen the quadriceps muscles during training and rehabilitation. This study examined the effects of limb position (POS) and range of motion (ROM) on quadriceps electromyography (EMG) during 8 repetitions (REP) of LE. Twenty-four participants performed eight LE REP at their 8-repetition maximum with lower limbs medially rotated (TI), laterally rotated (TO), and neutral (NEU). Each REP EMG was averaged over the first, middle, and final 0.524 rad ROM. For vastus medialis oblique (VMO), a REP x ROM interaction was detected (p<0.02). The middle 0.524 rad produced significantly higher EMG than the initial 0.524 rad for REP 6-8 and the final 0.524 rad produced higher EMG than the initial 0.524 rad for REP 1, 2, 3, 4, 6, 8 (p<0.05). For rectus femoris (RF), EMG activity increased across REP with TO generating the greatest activity (p<0.001). For vastus lateralis (VL), EMG increased across REP (p<0.001) with NEU and TO EMG increasing linearly throughout ROM, and TI activity greatest during the middle 0.524 rad. We conclude that to target the VMO the optimal ROM is the final 1.047 rad regardless of POS, while maximum EMG for the RF is generated using TO regardless of ROM. In contrast, the VL is maximally activated using TI over the first 1.047 rad ROM or in NEU over the final 0.524 rad ROM.
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Genome wide association identifies common variants at the SERPINA6/SERPINA1 locus influencing plasma cortisol and corticosteroid binding globulin.
PLoS Genet.
PUBLISHED: 07-01-2014
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Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30-60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding ?1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.
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Molecular targeted viral nanoparticles as tools for imaging cancer.
Methods Mol. Biol.
PUBLISHED: 06-21-2014
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Viral nanoparticles (VNPs) are a novel class of bionanomaterials that harness the natural biocompatibility of viruses for the development of therapeutics, vaccines, and imaging tools. The plant virus, cowpea mosaic virus (CPMV), has been successfully engineered to create novel cancer-targeted imaging agents by incorporating fluorescent dyes, polyethylene glycol (PEG) polymers, and targeting moieties. Using straightforward conjugation strategies, VNPs with high selectivity for cancer-specific molecular targets can be synthesized for in vivo imaging of tumors. Here we describe the synthesis and purification of CPMV-based VNPs, the functionalization of these VNPs using click chemistry, and their use for imaging xenograft tumors in animal models. VNPs decorated with fluorescent dyes, PEG, and targeting ligands can be synthesized in one day, and imaging studies can be performed over hours, days, or weeks, depending on the application.
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Expression and purification of the antimicrobial peptide GSL1 in bacteria for raising antibodies.
BMC Res Notes
PUBLISHED: 05-27-2014
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The Gibberellin Stimulated-Like (GSL) or Snakin peptides from higher plants are cysteine-rich, with broad spectrum activity against a range of bacterial and fungal pathogens. To detect GSL peptides in applications such as western blot analysis and enzyme-linked immunosorbent assays (ELISA), specific antibodies that recognise GSL peptides are required. However, the intrinsic antimicrobial activity of these peptides is likely to prevent their expression alone in bacterial or yeast expression systems for subsequent antibody production in animal hosts.
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Examination of symptom clusters in acute and chronic pain patients.
Pain Physician
PUBLISHED: 05-23-2014
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Symptom clusters have not been previously explored in acute pain patients (APPs) and chronic pain patients (CPPs) with non-cancer pain.
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Cyclin A2, a novel regulator of EMT.
Cell. Mol. Life Sci.
PUBLISHED: 05-19-2014
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Our previous work showed that Cyclin A2 deficiency promotes cell invasion in fibroblasts. Given that the majority of cancers emerge from epithelia, we explored novel functions for Cyclin A2 by depleting it in normal mammary epithelial cells. This caused an epithelial to mesenchymal transition (EMT) associated with loss of cell-to-cell contacts, decreased E-Cadherin expression and increased invasive properties characterized by a reciprocal regulation of RhoA and RhoC activities, where RhoA-decreased activity drove cell invasiveness and E-Cadherin delocalization, and RhoC-increased activity only supported cell motility. Phenotypes induced by Cyclin A2 deficiency were exacerbated upon oncogenic activated-Ras expression, which led to an increased expression of EMT-related transcriptional factors. Moreover, Cyclin A2-depleted cells exhibited stem cell-like properties and increased invasion in an in vivo avian embryo model. Our work supports a model where Cyclin A2 downregulation facilitates cancer cell EMT and metastatic dissemination.
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Beyond the Brain: The Role of Brain-Derived Neurotrophic Factor in Viroimmune Responses to Antiretroviral Therapy among People Living with HIV with and without Alcohol Use.
J Int Assoc Provid AIDS Care
PUBLISHED: 05-16-2014
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Given the emerging data suggesting the key role of brain-derived neurotrophic factor (BDNF) in the immune system, we assessed longitudinally whether BDNF depletions induced by hazardous alcohol use (HAU) would impact a response to antiretroviral therapy (ART).
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Selectively promiscuous opioid ligands: discovery of high affinity/low efficacy opioid ligands with substantial nociceptin opioid peptide receptor affinity.
J. Med. Chem.
PUBLISHED: 05-09-2014
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Emerging clinical and preclinical evidence suggests that a compound displaying high affinity for ?, ?, and ? opioid (MOP, KOP, and DOP) receptors and antagonist activity at each, coupled with moderate affinity and efficacy at nociceptin opioid peptide (NOP) receptors will have utility as a relapse prevention agent for multiple types of drug abuse. Members of the orvinol family of opioid ligands have the desired affinity profile but have typically displayed substantial efficacy at MOP and or KOP receptors. In this study it is shown that a phenyl ring analogue (1d) of buprenorphine displays the desired profile in vitro with high, nonselective affinity for the MOP, KOP, and DOP receptors coupled with moderate affinity for NOP receptors. In vivo, 1d lacked any opioid agonist activity and was an antagonist of both the MOP receptor agonist morphine and the KOP receptor agonist ethylketocyclazocine, confirming the desired opioid receptor profile in vivo.
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Stage of breast cancer progression influences cellular response to activation of the WNT/planar cell polarity pathway.
Sci Rep
PUBLISHED: 05-02-2014
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Planar cell polarity (PCP) signaling has been shown in different studies to either promote or inhibit the malignancy of breast cancer. Using the 21T cell lines, which were derived from an individual patient and represent distinct stages of progression, we show that the prototypical PCP ligand, WNT5A, is expressed highest in 21MT-1 cells (invasive mammary carcinoma) and lowest in 21PT (atypical ductal hyperplasia) and 21NT (ductal carcinoma in situ) cells. Overexpression of WNT5A decreased spherical colony formation and increased invasion and in vivo extravasation only in 21NT cells; whereas overexpression increased migration of both 21PT and 21NT cells. WNT5A overexpression also increased RHOA expression of both cell lines and subsequent RHOA knockdown blocked WNT5A-induced migration, but only partially blocked WNT5A-induced invasion of 21NT cells. PCP can signal through VANGL1 to modulate AP-1 target genes (e.g. MMP3) and induce invasion. VANGL1 knockdown inhibited WNT5A-induced invasion of 21NT cells, but had no effect on WNT5A-induced migration of either 21PT or 21NT cells. WNT5A-induced MMP3 expression was seen only in 21NT cells, an effect that was VANGL1 dependent, but independent of AP-1. We thus provide evidence that PCP signaling can act in a context dependent manner to promote breast cancer progression.
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Cellular heterogeneity profiling by hyaluronan probes reveals an invasive but slow-growing breast tumor subset.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 04-14-2014
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Tumor heterogeneity confounds cancer diagnosis and the outcome of therapy, necessitating analysis of tumor cell subsets within the tumor mass. Elevated expression of hyaluronan (HA) and HA receptors, receptor for HA-mediated motility (RHAMM)/HA-mediated motility receptor and cluster designation 44 (CD44), in breast tumors correlates with poor outcome. We hypothesized that a probe for detecting HA-HA receptor interactions may reveal breast cancer (BCa) cell heterogeneity relevant to tumor progression. A fluorescent HA (F-HA) probe containing a mixture of polymer sizes typical of tumor microenvironments (10-480 kDa), multiplexed profiling, and flow cytometry were used to monitor HA binding to BCa cell lines of different molecular subtypes. Formulae were developed to quantify binding heterogeneity and to measure invasion in vivo. Two subsets exhibiting differential binding (HA(-/low) vs. HA(high)) were isolated and characterized for morphology, growth, and invasion in culture and as xenografts in vivo. F-HA-binding amounts and degree of heterogeneity varied with BCa subtype, were highest in the malignant basal-like cell lines, and decreased upon reversion to a nonmalignant phenotype. Binding amounts correlated with CD44 and RHAMM displayed but binding heterogeneity appeared to arise from a differential ability of HA receptor-positive subpopulations to interact with F-HA. HA(high) subpopulations exhibited significantly higher local invasion and lung micrometastases but, unexpectedly, lower proliferation than either unsorted parental cells or the HA(-/low) subpopulation. Querying F-HA binding to aggressive tumor cells reveals a previously undetected form of heterogeneity that predicts invasive/metastatic behavior and that may aid both early identification of cancer patients susceptible to metastasis, and detection/therapy of invasive BCa subpopulations.
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Differential extraction of endogenous and exogenous 25-OH-vitamin D from serum makes the accurate quantification in liquid chromatography-tandem mass spectrometry assays challenging.
Ann. Clin. Biochem.
PUBLISHED: 04-08-2014
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Extraction followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis is the method of choice when it comes to the accurate quantification of 25-OH-vitamin D in blood samples. It is generally assumed that the addition of exogenous internal standard allows for the determination of the endogenous analyte concentration. In this study we investigated the extraction properties of endogenous and exogenous 25-OH-vitamin D.
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Exploring pathways to trust: a tribal perspective on data sharing.
Genet. Med.
PUBLISHED: 04-07-2014
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The data-sharing policies of the National Institutes of Health aim to maximize public benefit derived from genetic studies by increasing research efficiency and use of a pooled data resource for future studies. Although broad access to data may lead to benefits for populations underrepresented in genetic studies, such as indigenous groups, tribes have ownership interest in their data. The Northwest-Alaska Pharmacogenetic Research Network, a partnership involving tribal organizations and universities conducting basic and translational pharmacogenetic research, convened a meeting to discuss the collection, management, and secondary use of research data, and of the processes surrounding access to data stored in federal repositories. This article reports the tribal perspectives that emerged from the dialogue and discusses the implications of tribal government sovereign status on research agreements and data-sharing negotiations. There is strong tribal support for efficient research processes that expedite the benefits from collaborative research, but there is also a need for data-sharing procedures that take into account tribal sovereignty and appropriate oversight of research-such as tribally based research review processes and review of draft manuscripts. We also note specific ways in which accountability could be encouraged by the National Institutes of Health as part of the research process.Genet Med 16 11, 820-826.
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Brain derived neurotrophic factor and cognitive status: the delicate balance among people living with HIV, with and without alcohol abuse.
Curr. HIV Res.
PUBLISHED: 04-06-2014
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The advent of combination antiretroviral therapy(cART) has lead to a significant reduction in morbidity and mortality among people living with HIV(PLWH). However, HIV-associated neurocognitive disorders (HAND) still remain a significant problem. One possible mechanism for the persistence of these disorders is through the effect of HIV on brain-derived neurotrophic factor (BDNF). BDNF is influenced by various factors including hazardous alcohol use (HAU), which is prevalent among PLWH. This study attempts to elucidate the relationships between HAU, BDNF and HAND.
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Outcomes After Total Ankle Replacement in Association With Ipsilateral Hindfoot Arthrodesis.
Foot Ankle Int
PUBLISHED: 03-27-2014
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Ipsilateral hindfoot arthrodesis in combination with total ankle replacement (TAR) may diminish functional outcome and prosthesis survivorship compared to isolated TAR. We compared the outcome of isolated TAR to outcomes of TAR with ipsilateral hindfoot arthrodesis.
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Whole adult organism transcriptional profiling of acute metal exposures in male zebrafish.
BMC Pharmacol Toxicol
PUBLISHED: 02-27-2014
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A convergence of technological breakthroughs in the past decade has facilitated the development of rapid screening tools for biomarkers of toxicant exposure and effect. Platforms using the whole adult organism to evaluate the genome-wide response to toxicants are especially attractive. Recent work demonstrates the feasibility of this approach in vertebrates using the experimentally robust zebrafish model. In the present study, we evaluated gene expression changes in whole adult male zebrafish following an acute 24 hr high dose exposure to three metals with known human health risks. Male adult zebrafish were exposed to nickel chloride, cobalt chloride or sodium dichromate concentrations corresponding to their respective 96 hr LC20, LC40 and LC60. Histopathology was performed on a subset of metal-exposed zebrafish to phenotypically anchor transcriptional changes associated with each metal.
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Dosimetric consequences of interobserver variability in delineating the organs at risk in gynecologic interstitial brachytherapy.
Int. J. Radiat. Oncol. Biol. Phys.
PUBLISHED: 02-26-2014
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To investigate the dosimetric variability associated with interobserver organ-at-risk delineation differences on computed tomography in patients undergoing gynecologic interstitial brachytherapy.
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Impact of perioperative allogeneic and autologous blood transfusion on acute wound infection following total knee and total hip arthroplasty.
J Bone Joint Surg Am
PUBLISHED: 02-21-2014
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Patients undergoing total hip or knee arthroplasty frequently receive blood transfusions. The relationship between transfusion and the risk of infection following total joint arthroplasty is unclear. In this study, we sought to examine the impact of allogeneic and autologous transfusion on the risk of acute infection following total hip and total knee arthroplasty.
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The detection of THC, CBD and CBN in the oral fluid of Sativex® patients using two on-site screening tests and LC-MS/MS.
Forensic Sci. Int.
PUBLISHED: 02-18-2014
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Sativex(®) is an oromucosal spray used to treat spasticity in multiple sclerosis sufferers in some European countries, the United Kingdom, Canada and New Zealand. The drug has also recently been registered by the Therapeutic Goods Administration (TGA) in Australia for treatment of multiple sclerosis. Sativex(®) contains high concentrations of ?(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), with the former being the subject of random roadside drug tests across Australia to detect cannabis use. This pilot study aims to determine whether or not patients taking Sativex(®) will test positive to THC using these roadside screening tests. Detectable levels of THC, CBD and cannabinol (CBN) in their oral fluid were also confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The study was a double-blind, placebo controlled design. Oral fluid was tested prior to and immediately after dosing with either Sativex(®) or placebo at intervals up to 2h after the dose. Two Sativex(®) doses were studied. The low dose contained 5.4mg THC, the high dose 21.6mg THC. Results indicate that the primary screening test used in Australian roadside drug testing, the DrugWipe(®) II Twin, often gave a false negative response for THC, even with high concentrations present. However, secondary screening test, Cozart(®) DDS (used by police after a DrugWipe test gives a positive result), gave true positive results in all cases where patients were being treated with Sativex(®). Confirmatory testing showed high concentrations of THC and CBD (>5356ng/mL THC and >3826ng/mL CBD) in the oral fluid shortly after dosing and also elevated concentrations of CBN. Levels dropped quickly but remained at detectable concentrations (>67.6ng/mL) two hours after drug administration. The average concentration ratio of THC/CBD across all positive samples was 1.10 (%RSD 19.9) reflecting the composition of the Sativex(®) spray. In conclusion, Sativex(®) users may test positive for THC by roadside drug testing within 2-3h of use. Confirmatory analysis can identify Sativex(®) treatment through use of THC/CBD ratios, however, these ratios would unlikely be sufficient to differentiate non-medicinal cannabis use from Sativex(®) use if both are taken concurrently.
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Simulation of dosimetric consequences of 4D-CT-based motion margin estimation for proton radiotherapy using patient tumor motion data.
Phys Med Biol
PUBLISHED: 02-03-2014
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For the radiation treatment of lung cancer patients, four-dimensional computed tomography (4D-CT) is a common practice used clinically to image tumor motion and subsequently determine the internal target volume (ITV) from the maximum intensity projection (MIP) images. ITV, which is derived from short pre-treatment 4D-CT scan (<6 s per couch position), may not adequately cover the extent of tumor motion during the treatment, particularly for patients that exhibit a large respiratory variability. Inaccurate tumor localization may result in under-dosage of the tumor or over-dosage of the surrounding tissues. The purpose of this study is therefore to assess the degree of tumor under-dosage in case of regular and irregular breathing for proton radiotherapy using ITV-based treatment planning. We place a spherical lesion into a modified XCAT phantom that is also capable of producing 4D images based on irregular breathing, and move the tumor according to real tumor motion data, which is acquired over multiple days by tracking gold fiducial markers implanted into the lung tumors of patients. We derive ITVs by taking the union of all tumor positions during 6 s of tumor motion in the phantom using the first day patient tumor tracking data. This is equivalent to ITVs generated clinically from cine-mode 4D-CT MIP images. The treatment plans created for different ITVs are then implemented on dynamic phantoms with tumor motion governed by real tumor tracking data from consecutive days. By comparing gross tumor volume dose distribution on days of 'treatment' with the ITV dose distribution, we evaluate the deviation of the actually delivered dose from the predicted dose. Our results have shown that the proton treatment planning on ITV derived from pre-treatment cine-mode 4D-CT can result in under-dosage (dose covering 95% of volume) of the tumor by up to 25.7% over 3 min of treatment for the patient with irregular respiratory motion. Tumor under-dosage is less significant for the patient with relatively regular breathing. We have demonstrated that proton therapy using the pre-treatment 4D-CT based ITV method can lead to significant under-dosage of the tumor, highlighting the need for daily customization to generate a target volume that represents tumor positions during the treatment more accurately.
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A double-blind, randomized clinical trial of dietary supplementation on cognitive and immune functioning in healthy older adults.
BMC Complement Altern Med
PUBLISHED: 01-30-2014
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Declining cognitive function is relatively common and increasingly prevalent. Studies have shown that different nutrients (e.g., Ginkgo biloba and vitamin E) appear to be effective at improving memory and concentration, while less is known about their effect on immunity.
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Menthol cigarettes and the cardiovascular risks of people living with HIV.
J Assoc Nurses AIDS Care
PUBLISHED: 01-28-2014
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The possibility that menthol cigarettes add to the deleterious cardiovascular effects of smoking has been barely discussed. Although cardiovascular diseases (CVD) are at the forefront of medical concerns of people living with HIV (PLWH), an important, yet unknown, issue for clinicians and public health authorities is whether use of menthol-flavored cigarettes heightens CVD risk factors. Our study aims to assess traditional (10-year risk using the Framingham Risk Model) and nontraditional CVD risk factors and to contrast the effects of menthol-flavored versus non-menthol-flavored cigarettes on these risk factors. Compared to controls, menthol smokers were twice as likely to have hypertension. Users of menthol-flavored cigarettes had higher body mass index values, and increased risk of abdominal obesity. Multivariate analyses indicated that menthol smokers doubled the odds of having moderate to high CVD risk. This finding is highly significant given the widespread use of menthol-flavored cigarettes, particularly among women, minorities, and PLWH.
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The reactive centre loop of corticosteroid-binding globulin (CBG) is a protease target for cortisol release.
Mol. Cell. Endocrinol.
PUBLISHED: 01-06-2014
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Corticosteroid-binding globulin (CBG) binds more than 90% of circulating cortisol and is a non-inhibitory member of the family of serine protease inhibitors (SERPINS) with an exposed elastase sensitive reactive centre loop (RCL). At sites of inflammation neutrophil activation can release elastase which may cleave the RCL and result in cortisol release from CBG. The RCL sequence also has two theoretical chymotrypsin cleavage sites and we used a monoclonal antibody with specificity for the RCL to investigate chymotrypsin cleavage of CBG. Here we show, for the first time, rapid chymotrypsin cleavage of the RCL of CBG, resulting in undetectable levels of intact CBG, whereas total CBG levels were unchanged. Coincident with both chymotrypsin and elastase cleavage there was an increase in the free cortisol fraction of serum to levels similar to when CBG had been inactivated by heat indicating total cortisol release from CBG. These findings demonstrate a new mechanism for cortisol release from its binding globulin.
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Action potential energetics at the organismal level reveal a trade-off in efficiency at high firing rates.
J. Neurosci.
PUBLISHED: 01-02-2014
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The energetic costs of action potential (AP) production constrain the evolution of neural codes and brain networks. Cellular-level estimates of AP-related costs are typically based on voltage-dependent Na(+) currents that drive active transport by the Na(+)/K(+) ATPase to maintain the Na(+) and K(+) ion concentration gradients necessary for AP production. However, these estimates of AP cost have not been verified at the organismal level. Electric signaling in the weakly electric fish Eigenmannia virescens requires that specialized cells in an electric organ generate APs with large Na(+) currents at high rates (200-600 Hz). We measured these currents using a voltage-clamp protocol and then estimated the energetic cost at the cellular level using standard methods. We then used this energy-intensive signaling behavior to measure changes in whole-animal energetics for small changes in electric discharge rate. At low rates, the whole-animal measure of AP cost was similar to our cellular-level estimates. However, AP cost increased nonlinearly with increasing firing rates. We show, with a biophysical model, that this nonlinearity can arise from the increasing cost of maintaining AP amplitude at high rates. Our results confirm that estimates of energetic costs based on Na(+) influx are appropriate for low baseline firing rates, but that extrapolating to high firing rates may underestimate true costs in cases in which AP amplitude does not decrease. Moreover, the trade-off between energetic cost and firing rate suggests an additional constraint on the evolution of high-frequency signaling in neuronal systems.
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Systems level analysis and identification of pathways and networks associated with liver fibrosis.
PLoS ONE
PUBLISHED: 01-01-2014
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Toxic liver injury causes necrosis and fibrosis, which may lead to cirrhosis and liver failure. Despite recent progress in understanding the mechanism of liver fibrosis, our knowledge of the molecular-level details of this disease is still incomplete. The elucidation of networks and pathways associated with liver fibrosis can provide insight into the underlying molecular mechanisms of the disease, as well as identify potential diagnostic or prognostic biomarkers. Towards this end, we analyzed rat gene expression data from a range of chemical exposures that produced observable periportal liver fibrosis as documented in DrugMatrix, a publicly available toxicogenomics database. We identified genes relevant to liver fibrosis using standard differential expression and co-expression analyses, and then used these genes in pathway enrichment and protein-protein interaction (PPI) network analyses. We identified a PPI network module associated with liver fibrosis that includes known liver fibrosis-relevant genes, such as tissue inhibitor of metalloproteinase-1, galectin-3, connective tissue growth factor, and lipocalin-2. We also identified several new genes, such as perilipin-3, legumain, and myocilin, which were associated with liver fibrosis. We further analyzed the expression pattern of the genes in the PPI network module across a wide range of 640 chemical exposure conditions in DrugMatrix and identified early indications of liver fibrosis for carbon tetrachloride and lipopolysaccharide exposures. Although it is well known that carbon tetrachloride and lipopolysaccharide can cause liver fibrosis, our network analysis was able to link these compounds to potential fibrotic damage before histopathological changes associated with liver fibrosis appeared. These results demonstrated that our approach is capable of identifying early-stage indicators of liver fibrosis and underscore its potential to aid in predictive toxicity, biomarker identification, and to generally identify disease-relevant pathways.
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Characterization of chemically induced liver injuries using gene co-expression modules.
PLoS ONE
PUBLISHED: 01-01-2014
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Liver injuries due to ingestion or exposure to chemicals and industrial toxicants pose a serious health risk that may be hard to assess due to a lack of non-invasive diagnostic tests. Mapping chemical injuries to organ-specific damage and clinical outcomes via biomarkers or biomarker panels will provide the foundation for highly specific and robust diagnostic tests. Here, we have used DrugMatrix, a toxicogenomics database containing organ-specific gene expression data matched to dose-dependent chemical exposures and adverse clinical pathology assessments in Sprague Dawley rats, to identify groups of co-expressed genes (modules) specific to injury endpoints in the liver. We identified 78 such gene co-expression modules associated with 25 diverse injury endpoints categorized from clinical pathology, organ weight changes, and histopathology. Using gene expression data associated with an injury condition, we showed that these modules exhibited different patterns of activation characteristic of each injury. We further showed that specific module genes mapped to 1) known biochemical pathways associated with liver injuries and 2) clinically used diagnostic tests for liver fibrosis. As such, the gene modules have characteristics of both generalized and specific toxic response pathways. Using these results, we proposed three gene signature sets characteristic of liver fibrosis, steatosis, and general liver injury based on genes from the co-expression modules. Out of all 92 identified genes, 18 (20%) genes have well-documented relationships with liver disease, whereas the rest are novel and have not previously been associated with liver disease. In conclusion, identifying gene co-expression modules associated with chemically induced liver injuries aids in generating testable hypotheses and has the potential to identify putative biomarkers of adverse health effects.
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Electrophysiological characterization of male goldfish (Carassius auratus) ventral preoptic area neurons receiving olfactory inputs.
Front Neurosci
PUBLISHED: 01-01-2014
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Chemical communication via sex pheromones is critical for successful reproduction but the underlying neural mechanisms are not well-understood. The goldfish is a tractable model because sex pheromones have been well-characterized in this species. We used male goldfish forebrain explants in vitro and performed whole-cell current clamp recordings from single neurons in the ventral preoptic area (vPOA) to characterize their membrane properties and synaptic inputs from the olfactory bulbs (OB). Principle component and cluster analyses based on intrinsic membrane properties of vPOA neurons (N = 107) revealed five (I-V) distinct cell groups. These cells displayed differences in their input resistance (Rinput: I < II < IV < III = V), time constant (TC: I = II < IV < III = V), and threshold current (Ithreshold: I > II = IV > III = V). Evidence from electrical stimulation of the OB and application of receptor antagonists suggests that vPOA neurons receive monosynaptic glutamatergic inputs via the medial olfactory tract, with connectivity varying among neuronal groups [I (24%), II (40%), III (0%), IV (34%), and V (2%)].
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Low incidence of chest wall pain with a risk-adapted lung stereotactic body radiation therapy approach using three or five fractions based on chest wall dosimetry.
PLoS ONE
PUBLISHED: 01-01-2014
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To examine the frequency and potential of dose-volume predictors for chest wall (CW) toxicity (pain and/or rib fracture) for patients receiving lung stereotactic body radiotherapy (SBRT) using treatment planning methods to minimize CW dose and a risk-adapted fractionation scheme.
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PortEco: a resource for exploring bacterial biology through high-throughput data and analysis tools.
Nucleic Acids Res.
PUBLISHED: 11-26-2013
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PortEco (http://porteco.org) aims to collect, curate and provide data and analysis tools to support basic biological research in Escherichia coli (and eventually other bacterial systems). PortEco is implemented as a virtual model organism database that provides a single unified interface to the user, while integrating information from a variety of sources. The main focus of PortEco is to enable broad use of the growing number of high-throughput experiments available for E. coli, and to leverage community annotation through the EcoliWiki and GONUTS systems. Currently, PortEco includes curated data from hundreds of genome-wide RNA expression studies, from high-throughput phenotyping of single-gene knockouts under hundreds of annotated conditions, from chromatin immunoprecipitation experiments for tens of different DNA-binding factors and from ribosome profiling experiments that yield insights into protein expression. Conditions have been annotated with a consistent vocabulary, and data have been consistently normalized to enable users to find, compare and interpret relevant experiments. PortEco includes tools for data analysis, including clustering, enrichment analysis and exploration via genome browsers. PortEco search and data analysis tools are extensively linked to the curated gene, metabolic pathway and regulation content at its sister site, EcoCyc.
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Integrin-Free Tetraspanin CD151 Can Inhibit Tumor Cell Motility upon Clustering and Is a Clinical Indicator of Prostate Cancer Progression.
Cancer Res.
PUBLISHED: 11-12-2013
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Normal physiology relies on the organization of transmembrane proteins by molecular scaffolds, such as tetraspanins. Oncogenesis frequently involves changes in their organization or expression. The tetraspanin CD151 is thought to contribute to cancer progression through direct interaction with the laminin-binding integrins ?3?1 and ?6?1. However, this interaction cannot explain the ability of CD151 to control migration in the absence of these integrins or on non-laminin substrates. We demonstrate that CD151 can regulate tumor cell migration without direct integrin binding and that integrin-free CD151 (CD151(free)) correlates clinically with tumor progression and metastasis. Clustering CD151(free) through its integrin-binding domain promotes accumulation in areas of cell-cell contact, leading to enhanced adhesion and inhibition of tumor cell motility in vitro and in vivo. CD151(free) clustering is a strong regulator of motility even in the absence of ?3 expression but requires PKC?, suggesting that CD151 can control migration independent of its integrin associations. The histologic detection of CD151(free) in prostate cancer correlates with poor patient outcome. When CD151(free) is present, patients are more likely to recur after radical prostatectomy and progression to metastatic disease is accelerated. Multivariable analysis identifies CD151(free) as an independent predictor of survival. Moreover, the detection of CD151(free) can stratify survival among patients with elevated prostate-specific antigen levels. Cumulatively, these studies demonstrate that a subpopulation of CD151 exists on the surface of tumor cells that can regulate migration independent of its integrin partner. The clinical correlation of CD151(free) with prostate cancer progression suggests that it may contribute to the disease and predict cancer progression. Cancer Res; 74(1); 1-15. ©2013 AACR.
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Reduced white matter integrity in sibling pairs discordant for bipolar disorder.
Am J Psychiatry
PUBLISHED: 11-05-2013
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Several lines of evidence indicate that white matter integrity is compromised in bipolar disorder, but the nature, extent, and biological causes remain elusive. To determine the extent to which white matter deficits in bipolar disorder are familial, the authors investigated white matter integrity in a large sample of bipolar patients, unaffected siblings, and healthy comparison subjects.
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Silfverskiolds Test in Total Ankle Replacement With Gastrocnemius Recession.
Foot Ankle Int
PUBLISHED: 10-25-2013
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For patients undergoing primary total ankle replacement (TAR) with an equinus contracture, gastrocnemius recession may be performed to increase dorsiflexion. We examined whether gastrocnemius recession would significantly increase dorsiflexion even with a negative Silfverskiöld test.
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Postsurgical physical activity and fatigue-related daily interference in women with non-metastatic breast cancer.
Psychol Health
PUBLISHED: 10-16-2013
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Purpose: Women undergoing surgery for breast cancer experience side effects, such as fatigue, reduced quality of life (QOL) and depression. Physical activity (PA) is associated with improved psychological adjustment during treatment and survivorship, yet little is known about how PA relates to fatigue, depression and QOL in the period following surgery for breast cancer. The purpose of the study was to examine the relationships between these constructs in women who recently underwent surgery for breast cancer. Methods: At 2-10 weeks post-surgery, 240 women with non-metastatic breast cancer reported intensity and duration of moderate and vigorous PA (MVPA), fatigue (intensity and interference), depressed mood, clinician-rated depression and functional QOL. Results: In the path analysis models tested, women that reported greater weekly MVPA reported less fatigue interference, greater functional QOL, less depressed mood, and lower clinician-rated depression. Tests of indirect effects suggested that fatigue interference may be an intermediate pathway by which MVPA relates to functional QOL, clinician-rated depression and depressed mood. Conclusion: Women who are more physically active in the months after breast cancer surgery show greater psychological adaptation in the initial phases of their treatment.
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Re-examining the Size/Charge Paradigm: Differing in Vivo Characteristics of Size- and Charge-Matched Mesoporous Silica Nanoparticles.
J. Am. Chem. Soc.
PUBLISHED: 10-16-2013
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The combination of nanoparticle (NP) size, charge, and surface chemistry (e.g., extent of modification with polyethylene glycol (PEG)) is accepted as a key determinant of NP/cellular interactions. However, the influence of spatial arrangement and accessibility of the charged molecules on the NP surface vis-à-vis the average surface charge (zeta (?) potential) is incompletely understood. Here we demonstrate that two types of mesoporous silica nanoparticles (MSNP) that are matched in terms of primary and hydrodynamic particle size, shape, pore structure, colloidal stability, and ? potential, but differ in surface chemistry, viz. the spatial arrangement and relative exposure of surface amines, have profoundly different interactions with cells and tissues when evaluated in vitro and in vivo. While both particles are ?50 nm in diameter, PEGylated, and positively charged (? = +40 mV), PEG-PEI (MSNPs modified with exposed polyamines), but not PEG-NMe3(+) (MSNP modified with distributed, obstructed amines) rapidly bind serum proteins, diverse cells types in vitro, and endothelial and white blood cells in vivo (ex ovo chick embryo model). This finding helps elucidate the relative role of surface exposure of charged molecules vs ? potential in otherwise physicochemically matched MSNP and highlights protein corona neutrality as an important design consideration when synthesizing cationic NPs for biological applications.
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What Is the Evidence that Neuropathic Pain Is Present in Chronic Low Back Pain and Soft Tissue Syndromes? An Evidence-Based Structured Review.
Pain Med
PUBLISHED: 10-04-2013
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The objectives of this evidence-based review were to review the evidence for whether neuropathic pain (NP) is associated with chronic low back pain (CLBP) and soft tissue syndromes (STS), and review the reported prevalence percentages for NP within these syndromes.
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Simulations using patient data to evaluate systematic errors that may occur in 4D treatment planning: a proof of concept study.
Med Phys
PUBLISHED: 09-07-2013
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The purpose of this work is to present a framework to evaluate the accuracy of four-dimensional treatment planning in external beam radiation therapy using measured patient data and digital phantoms.
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SCNH2 is a novel apelinergic family member acting as a potent mitogenic and chemotactic factor for both endothelial and epithelial cells.
Open J Clin Diagn
PUBLISHED: 08-20-2013
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The gut hormone apelin is a major therapeutic focus for several diseases involving inflammation and aberrant cell growth. We investigated whether apelin-36 contained alternative bioactive peptides associated with normal physiology or disease. Amino acid sequence analysis of apelin-36 identified an amidation motif consistent with the formation of a secondary bioactive peptide (SCNH2). SCNH2 is proven to be mitogenic and chemotactic in normal/malignant cells and augments angiogenesis via a PTX-resistant/CT-X-sensitive G protein-coupled receptor (GPCR). Notably, SCNH2 is substantially more potent and sensitive than apelin-13 and vascular endothelial growth factor-A. Endogenous SCNH2 is highly expressed in human tumors and placenta and in mouse embryonic tissues. Our findings demonstrate that SCNH2 is a new apelinergic member with critical pluripotent roles in angiogenesis related diseases and embryogenesis via a non-APJ GPCR.
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Volumetric CT-based segmentation of NSCLC using 3D-Slicer.
Sci Rep
PUBLISHED: 08-14-2013
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Accurate volumetric assessment in non-small cell lung cancer (NSCLC) is critical for adequately informing treatments. In this study we assessed the clinical relevance of a semiautomatic computed tomography (CT)-based segmentation method using the competitive region-growing based algorithm, implemented in the free and public available 3D-Slicer software platform. We compared the 3D-Slicer segmented volumes by three independent observers, who segmented the primary tumour of 20 NSCLC patients twice, to manual slice-by-slice delineations of five physicians. Furthermore, we compared all tumour contours to the macroscopic diameter of the tumour in pathology, considered as the "gold standard". The 3D-Slicer segmented volumes demonstrated high agreement (overlap fractions > 0.90), lower volume variability (p = 0.0003) and smaller uncertainty areas (p = 0.0002), compared to manual slice-by-slice delineations. Furthermore, 3D-Slicer segmentations showed a strong correlation to pathology (r = 0.89, 95%CI, 0.81-0.94). Our results show that semiautomatic 3D-Slicer segmentations can be used for accurate contouring and are more stable than manual delineations. Therefore, 3D-Slicer can be employed as a starting point for treatment decisions or for high-throughput data mining research, such as Radiomics, where manual delineating often represent a time-consuming bottleneck.
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Development of a formula for estimating plasma free cortisol concentration from a measured total cortisol concentration when elastase-cleaved and intact corticosteroid binding globulin coexist.
J. Steroid Biochem. Mol. Biol.
PUBLISHED: 07-19-2013
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Cortisol bound to corticosteroid binding globulin (CBG) contributes up to 90% of the total cortisol concentration in circulation. Therefore, changes in the binding kinetics of cortisol to CBG can potentially impact on the concentration of free cortisol, the only form that is responsible for the physiological function of the hormone. When CBG is cleaved into elastase-cleaved CBG (eCBG) by the activity of neutrophil elastase, its affinity for cortisol is reduced. Therefore, when eCBG coexists with intact CBG (iCBG) in plasma, the calculation of free cortisol concentration based on the formulae that considers only one CBG pool with the same affinity for cortisol may be inappropriate. In this study, we developed in vivo and in vitro models of cortisol partitioning which considers two CBG pools, iCBG and eCBG, with different affinities for cortisol, and deduce a new formula for calculating plasma free cortisol concentration. The formula provides better estimates of free cortisol concentration than previously used formulae when measurements of the concentrations of the two CBG forms are available. The model can also be used to estimate the affinity of CBG and albumin for cortisol in different clinical groups. We found no significant difference in the estimated affinity of CBG and albumin for cortisol in normal, sepsis and septic shock groups, although free cortisol was higher in sepsis and septic shock groups. The in vivo model also demonstrated that the concentration of interstitial free cortisol is increased locally at a site of inflammation where iCBG is cleaved to form eCBG by the activity of elastase released by neutrophils. This supports the argument that the cleavage of iCBG at sites of inflammation leads to more lower-affinity eCBG and may be a mechanism that permits the local concentration of free cortisol to increase at these sites, while allowing basal free cortisol concentrations at other sites to remain unaffected.
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High-Throughput Screening of One-Bead-One-Compound Peptide Libraries Using Intact Cells.
ACS Comb Sci
PUBLISHED: 07-19-2013
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Screening approaches based on one-bead-one-compound (OBOC) combinatorial libraries have facilitated the discovery of novel peptide ligands for cellular targeting in cancer and other diseases. Recognition of cell surface proteins is optimally achieved using live cells, yet screening intact cell populations is time-consuming and inefficient. Here, we evaluate the Complex Object Parametric Analyzer and Sorter (COPAS) large particle biosorter for high-throughput sorting of bead-bound human cell populations. When a library of RGD-containing peptides was screened against human cancer cells that express ?v?3 integrin, it was found that bead-associated cells are rapidly dissociated when sorted through the COPAS instrument. When the bound cells were reversibly cross-linked onto the beads, however, we demonstrated that cell/bead mixtures can be sorted quickly and accurately. This reversible cross-linking approach is compatible with matrix-assisted laser desorption ionization time-of-flight mass spectrometry-based peptide sequence deconvolution. This approach should allow one to rapidly screen an OBOC library and identify novel peptide ligands against cell surface targets in their native conformation.
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A mass-conserving 4D XCAT phantom for dose calculation and accumulation.
Med Phys
PUBLISHED: 07-05-2013
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The XCAT phantom is a realistic 4D digital torso phantom that is widely used in imaging and therapy research. However, lung mass is not conserved between respiratory phases of the phantom, making detailed dosimetric simulations and dose accumulation unphysical. A framework is developed to correct this issue by enforcing local mass conservation in the XCAT lung. Dose calculations are performed to assess the implications of neglecting mass conservation, and to demonstrate an application of the phantom to calculate the accumulated delivered dose in an irregularly breathing patient.
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The energetics of electric organ discharge generation in gymnotiform weakly electric fish.
J. Exp. Biol.
PUBLISHED: 06-14-2013
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Gymnotiform weakly electric fish produce an electric signal to sense their environment and communicate with conspecifics. Although the generation of such relatively large electric signals over an entire lifetime is expected to be energetically costly, supporting evidence to date is equivocal. In this article, we first provide a theoretical analysis of the energy budget underlying signal production. Our analysis suggests that wave-type and pulse-type species invest a similar fraction of metabolic resources into electric signal generation, supporting previous evidence of a trade-off between signal amplitude and frequency. We then consider a comparative and evolutionary framework in which to interpret and guide future studies. We suggest that species differences in signal generation and plasticity, when considered in an energetics context, will not only help to evaluate the role of energetic constraints in the evolution of signal diversity but also lead to important general insights into the energetics of bioelectric signal generation.
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The chick embryo as an expanding experimental model for cancer and cardiovascular research.
Dev. Dyn.
PUBLISHED: 05-22-2013
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A long and productive history in biomedical research defines the chick as a model for human biology. Fundamental discoveries, including the description of directional circulation propelled by the heart and the link between oncogenes and the formation of cancer, indicate its utility in cardiac biology and cancer. Despite the more recent arrival of several vertebrate and invertebrate animal models during the last century, the chick embryo remains a commonly used model for vertebrate biology and provides a tractable biological template. With new molecular and genetic tools applied to the avian genome, the chick embryo is accelerating the discovery of normal development and elusive disease processes. Moreover, progress in imaging and chick culture technologies is advancing real-time visualization of dynamic biological events, such as tissue morphogenesis, angiogenesis, and cancer metastasis. A rich background of information, coupled with new technologies and relative ease of maintenance, suggest an expanding utility for the chick embryo in cardiac biology and cancer research. Developmental Dynamics, 2013. © 2013 Wiley Periodicals, Inc.
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Exploration of Affirmation of Childhood Molestation (Sexual Abuse) in Chronic Pain Patients, Acute Pain Patients, Community Patients With Pain and Community Nonpatients Without Pain.
Pain Pract
PUBLISHED: 05-20-2013
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To further explore the controversy as to whether childhood molestation is associated with chronic pain in adulthood.
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Genetic and cellular evidence of decreased inflammation associated with reduced incidence of posttraumatic arthritis in MRL/MpJ mice.
Arthritis Rheum.
PUBLISHED: 04-25-2013
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To examine the relationship between inflammation and posttraumatic arthritis (PTA) in a murine intraarticular fracture model.
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Alterations in gene expression in Caenorhabditis elegans associated with organophosphate pesticide intoxication and recovery.
BMC Genomics
PUBLISHED: 04-20-2013
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The principal toxicity of acute organophosphate (OP) pesticide poisoning is the disruption of neurotransmission through inhibition of acetylcholinesterase (AChE). However, other mechanisms leading to persistent effects and neurodegeneration remain controversial and difficult to detect. Because Caenorhabditis elegans is relatively resistant to OP lethality--particularly through the inhibition of AChE--studies in this nematode provide an opportunity to observe alterations in global gene expression following OP exposure that cannot be readily observed in less resistant organisms.
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Free and total plasma cortisol measured by immunoassay and mass spectrometry following ACTH???? stimulation in the assessment of pituitary patients.
J. Clin. Endocrinol. Metab.
PUBLISHED: 03-28-2013
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Measurement of plasma cortisol by immunoassay after ACTH???? stimulation is used to assess the hypothalamic-pituitary-adrenal (HPA) axis. Liquid chromatography-tandem mass spectrometry (LCMS) has greater analytical specificity than immunoassay and equilibrium dialysis allows measurement of free plasma cortisol.
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KISS1R induces invasiveness of estrogen receptor-negative human mammary epithelial and breast cancer cells.
Endocrinology
PUBLISHED: 03-24-2013
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Kisspeptins (KPs), peptide products of the KISS1 metastasis-suppressor gene, are endogenous ligands for a G protein-coupled receptor (KISS1R). KISS1 acts as a metastasis suppressor in numerous human cancers. However, recent studies have demonstrated that an increase in KISS1 and KISS1R expression in patient breast tumors correlates with higher tumor grade and metastatic potential. We have shown that KP-10 stimulates invasion of estrogen receptor ? (ER?)-negative MDA-MB-231 breast cancer cells via transactivation of the epidermal growth factor receptor (EGFR). Here, we report that either KP-10 treatment of ER?-negative nonmalignant mammary epithelial MCF10A cells or expression of KISS1R in MCF10A cells induced a mesenchymal phenotype and stimulated invasiveness. Similarly, exogenous expression of KISS1R in ER?-negative SKBR3 breast cancer cells was sufficient to trigger invasion and induced extravasation in vivo. In contrast, KP-10 failed to transactivate EGFR or stimulate invasiveness in the ER?-positive MCF7 and T47D breast cancer cells. This suggested that ER? negatively regulates KISS1R-dependent breast cancer cell migration, invasion, and EGFR transactivation. In support of this, we found that these KP-10-induced effects were ablated upon exogenous expression of ER? in the MDA-MB-231 cells, by down-regulating KISS1R expression. Lastly, we have identified IQGAP1, an actin cytoskeletal binding protein as a novel binding partner of KISS1R, and have shown that KISS1R regulates EGFR transactivation in breast cancer cells in an IQGAP1-dependent manner. Overall, our data strongly suggest that the ER? status of mammary cells dictates whether KISS1R may be a novel clinical target for treating breast cancer metastasis.
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Pethidinic acid: corroboration of a doctors denial of pethidine re-use.
J Anal Toxicol
PUBLISHED: 02-05-2013
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Pethidine (meperidine), a synthetic opiate, formally used as an analgesic in surgery and obstetrics, has been an abused drug of choice for some doctors. A case is presented in which a doctor, who previously admitted to using pethidine, was suspected of re-using, following a second positive urine test. A laboratory had reported the presence of pethidine in the doctors urine; however, the doctor denied re-use. The norpethidine (normeperidine) metabolite, normally found in urine, had not been detected, raising concern over the laboratorys conclusion and necessitating an independent investigation. Because the major metabolite of pethidine is pethidinic acid (meperidinic acid), accounting for approximately 40% of the excreted dose, its presence or absence were deemed to be important criteria in interpreting the laboratory result. Pethidinic acid was synthesized by alkaline hydrolysis of pethidine and used as a control. Urine samples from a patient receiving pethidine for pain, from the previous pethidine use of the doctor, and the urine under question plus the control were analyzed for the presence of pethidinic acid using electrospray mass spectrometry. Pethidinic acid was found in all samples except the one under dispute. The absence of pethidinic acid appeared to corroborate the doctors denial of re-use.
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Evaluation of 3D fluoroscopic image generation from a single planar treatment image on patient data with a modified XCAT phantom.
Phys Med Biol
PUBLISHED: 01-21-2013
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Accurate understanding and modeling of respiration-induced uncertainties is essential in image-guided radiotherapy. Explicit modeling of the overall lung motion and interaction among different organs promises to be a useful approach. Recently, preliminary studies on 3D fluoroscopic treatment imaging and tumor localization based on principal component analysis motion models and cost function optimization have shown encouraging results. However, the performance of this technique for varying breathing parameters and under realistic conditions remains unclear and thus warrants further investigation. In this work, we present a systematic evaluation of a 3D fluoroscopic image generation algorithm via two different approaches. In the first approach, the models accuracy is tested for changing parameters for sinusoidal breathing. These parameters include changing respiratory motion amplitude, period and baseline shift. The effects of setup error, imaging noise and different tumor sizes are also examined. In the second approach, we test the model for anthropomorphic images obtained from a modified XCAT phantom. This set of experiments is important as all the underlying breathing parameters are simultaneously tested, as in realistic clinical conditions. Based on our simulation results for more than 250 s of breathing data for eight different lung patients, the overall tumor localization accuracies of the model in left-right, anterior-posterior and superior-inferior directions are 0.1 ± 0.1, 0.5 ± 0.5 and 0.8 ± 0.8 mm, respectively. 3D tumor centroid localization accuracy is 1.0 ± 0.9 mm.
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Exposure to Cobalt Causes Transcriptomic and Proteomic Changes in Two Rat Liver Derived Cell Lines.
PLoS ONE
PUBLISHED: 01-01-2013
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Cobalt is a transition group metal present in trace amounts in the human diet, but in larger doses it can be acutely toxic or cause adverse health effects in chronic exposures. Its use in many industrial processes and alloys worldwide presents opportunities for occupational exposures, including military personnel. While the toxic effects of cobalt have been widely studied, the exact mechanisms of toxicity remain unclear. In order to further elucidate these mechanisms and identify potential biomarkers of exposure or effect, we exposed two rat liver-derived cell lines, H4-II-E-C3 and MH1C1, to two concentrations of cobalt chloride. We examined changes in gene expression using DNA microarrays in both cell lines and examined changes in cytoplasmic protein abundance in MH1C1 cells using mass spectrometry. We chose to closely examine differentially expressed genes and proteins changing in abundance in both cell lines in order to remove cell line specific effects. We identified enriched pathways, networks, and biological functions using commercial bioinformatic tools and manual annotation. Many of the genes, proteins, and pathways modulated by exposure to cobalt appear to be due to an induction of a hypoxic-like response and oxidative stress. Genes that may be differentially expressed due to a hypoxic-like response are involved in Hif-1? signaling, glycolysis, gluconeogenesis, and other energy metabolism related processes. Gene expression changes linked to oxidative stress are also known to be involved in the NRF2-mediated response, protein degradation, and glutathione production. Using microarray and mass spectrometry analysis, we were able to identify modulated genes and proteins, further elucidate the mechanisms of toxicity of cobalt, and identify biomarkers of exposure and effect in vitro, thus providing targets for focused in vivo studies.
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Network efficiency in autism spectrum disorder and its relation to brain overgrowth.
Front Hum Neurosci
PUBLISHED: 01-01-2013
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A substantial body of evidence links differences in brain size to differences in brain organization. We have hypothesized that the developmental aspect of this relation plays a role in autism spectrum disorder (ASD), a neurodevelopmental disorder which involves abnormalities in brain growth. Children with ASD have abnormally large brains by the second year of life, and for several years thereafter their brain size can be multiple standard deviations above the norm. The greater conduction delays and cellular costs presumably associated with the longer long-distance connections in these larger brains is thought to influence developmental processes, giving rise to an altered brain organization with less communication between spatially distant regions. This has been supported by computational models and by findings linking greater intra-cranial volume, an index of maximum brain-size during development, to reduced inter-hemispheric connectivity in individuals with ASD. In this paper, we further assess this hypothesis via a whole-brain analysis of network efficiency. We utilize diffusion tractography to estimate the strength and length of the connections between all pairs of cortical regions. We compute the efficiency of communication between each network node and all others, and within local neighborhoods; we then assess the relation of these measures to intra-cranial volume, and the differences in these measures between adults with autism and typical controls. Intra-cranial volume is shown to be inversely related to efficiency for wide-spread regions of cortex. Moreover, the spatial patterns of reductions in efficiency in autism bear a striking resemblance to the regional relationships between efficiency and intra-cranial volume, particularly for local efficiency. The results thus provide further support for the hypothesized link between brain overgrowth in children with autism and the efficiency of the organization of the brain in adults with autism.
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The effect of methylated vitamin B complex on depressive and anxiety symptoms and quality of life in adults with depression.
ISRN Psychiatry
PUBLISHED: 01-01-2013
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Depression, the most common type of mental illness, is the second leading cause of disability and is increasing among Americans. The effect of improved nutrition, particularly with dietary supplements, on depression may provide an alternative to standard medical treatment. Some studies have shown that certain nutrients (e.g., inositol and S-adenosyl methionine) are effective at improving depressed mood, although the results are not unequivocal. The current study was a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of a vitamin B complex nutritional supplement (Max Stress B) for improving depressive and anxiety symptoms according to the Beck Depression and Anxiety Inventories (BDI and BAI) in 60 adults diagnosed with major depression or other forms of depressive disorders. Secondary outcomes included quality of life according to the SF-36. Participants were assessed at baseline and 30- and 60-day followups. Max Stress B showed significant and more continuous improvements in depressive and anxiety symptoms, compared to placebo. Additionally, Max Stress B showed significant improvement on the mental health scale of the SF-36 compared to placebo. Thus, we showed modest utility of Max Stress B to improve mood symptoms and mental health quality of life in adults with depression.
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An emerging role for the nuclear localization of maspin in the suppression of tumor progression and metastasis.
Biochem. Cell Biol.
PUBLISHED: 11-02-2011
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Maspin, a member of the serpin family of serine protease inhibitors, was originally identified as a tumor suppressor that is expressed in normal mammary epithelial cells but is reduced or absent in breast carcinomas. Early enthusiasm for maspin as a biomarker for disease progression has been tempered by clinical data that associates maspin with favourable outcomes in some studies and poor prognosis in others. Here, we review all of the published clinical studies for maspin in breast and ovarian cancers and propose that the apparent discordance between clinical reports is a consequence of differential cellular distribution of maspin. Indeed, it was thought that an extracellular pool of maspin possessed tumor suppressor activity, acting by inhibiting migration and increasing cell adhesion. Recent evidence from our group and others indicates, however, that the nuclear localization of maspin in cancer cells is necessary for its tumor suppressor activity. We provide additional data here to demonstrate that nuclear-localized maspin binds to chromatin and is required to effectively prevent cells from metastasizing. Our knowledge of other serpins that localize to the nucleus should help to inform future studies of nuclear maspin. Elucidation of the molecular mechanisms regulating the localization and activities of maspin should pave the way for the development of improved diagnostics and therapies for cancer.
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Comparing the accuracy of ES-BC, EIS-GS, and ES Oxi on body composition, autonomic nervous system activity, and cardiac output to standardized assessments.
Med Devices (Auckl)
PUBLISHED: 09-16-2011
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THE ELECTRO SENSOR COMPLEX (ESC) IS SOFTWARE THAT COMBINES THREE DEVICES USING BIOELECTRICAL IMPEDANCE, GALVANIC SKIN RESPONSE, AND SPECTROPHOTOMETRY: (1) ES-BC (Electro Sensor-Body Composition; LD Technology, Miami, FL) to assess body composition, (2) EIS-GS (Electro Interstitial Scan-Galvanic Skin; LD Technology) to predict autonomic nervous system activity, and (3) ES Oxi (Electro Sensor Oxi; LD Technology) to assess cardiac output. The objective of this study was to compare each to a standardized assessment: ES-BC to dual-energy X-ray absorptiometry (DXA), EIS-GS to heart rate variability, and ES Oxi to BioZ Dx Diagnostic System (BioZ Dx; SonoSite Inc, Bothell, WA).
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Cardiovascular fitness levels among American workers.
J. Occup. Environ. Med.
PUBLISHED: 09-15-2011
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To explore cardiovascular fitness in 40 occupations using a nationally representative sample of the US population.
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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.

How does it work?

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.