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Find video protocols related to scientific articles indexed in Pubmed.
OSU-T315: a novel targeted therapeutic that antagonizes AKT membrane localization and activation of chronic lymphocytic leukemia cells.
Blood
PUBLISHED: 10-09-2014
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Aberrant regulation of endogenous survival pathways plays a major role in progression of chronic lymphocytic leukemia (CLL). Signaling via conjugation of surface receptors within the tumor environmental niche activates survival and proliferation pathways in CLL. Of these, the PI3K/AKT pathway appears to be pivotal to support CLL pathogenesis, and pharmacologic inhibitors targeting this axis have shown clinical activity. Here we investigate OSU-T315, a compound that disrupts the Phosphoinositide 3-kinase (PI3K)/AKT pathway in a novel manner. Dose-dependent, selective cytotoxicity by OSU-T315 is noted in both CLL-derived cell lines and primary CLL cells relative to normal lymphocytes. In contrast to the highly successful BTK and PI3K inhibitors that inhibit BCR signaling pathway at proximal kinases, OSU-T315 directly abrogates AKT activation by preventing translocation of AKT into lipid rafts without altering the activation of receptor-associated kinases. Through this mechanism, the agent triggers caspase-dependent apoptosis in CLL by suppressing BCR, CD49d, CD40 and TLR9-mediated AKT activation in an ILK-independent manner. In vivo, OSU-T315 attains pharmacologically active drug levels and significantly prolongs survival in the TCL1 mouse model. Together, our findings indicate a novel mechanism of action of OSU-T315 with potential therapeutic application in CLL.
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IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells.
Blood
PUBLISHED: 09-27-2014
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Chronic lymphocytic leukemia (CLL) displays constitutive phosphatidylinositol 3-kinase (PI3K) activation due to aberrant regulation of the B cell receptor (BCR) signaling. Previous studies have shown that an oral PI3K p110? inhibitor idelalisib exhibits promising activity in CLL. Here, we demonstrate that a dual PI3K p110? and p110? inhibitor, IPI-145 antagonizes BCR crosslinking activated pro-survival signals in primary CLL cells. IPI-145 causes direct killing in primary CLL cells in a dose- and time- dependent fashion, whereas not generating direct cytotoxicity to normal B cells. However, IPI-145 does reduce the viability of normal T and NK cells and decrease activated T-cell production of various inflammatory and anti-apoptotic cytokines. Furthermore, IPI-145 overcomes the ibrutinib resistance resulting from treatment-induced BTK C481S mutation. Collectively, these studies provide rationale for ongoing clinical evaluation of IPI-145 as a targeted therapy for CLL and related B-cell lymphoproliferative disorders.
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Use of Palliative Care and Hospice Among Surgical and Medical Specialties in the Veterans Health Administration.
JAMA Surg
PUBLISHED: 09-25-2014
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Many hospitals have undertaken initiatives to improve care during the end of life, recognizing that some individuals have unique needs that are often not met in acute inpatient care settings. Studies of surgical patients have shown this population to receive palliative care at reduced rates in comparison with medical patients.
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The MyPEEPS Randomized Controlled Trial: A Pilot of Preliminary Efficacy, Feasibility, and Acceptability of a Group-Level, HIV Risk Reduction Intervention for Young Men Who Have Sex with Men.
Arch Sex Behav
PUBLISHED: 08-19-2014
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An exigent need exists for HIV prevention intervention research targeting young men who have sex with men (MSM)-a group of young adults that, despite composing the highest and most racially disproportionate rates of HIV incidence, have been least often the focus of behavioral intervention research. This pilot study tested a group-based HIV primary prevention intervention for young MSM to evaluate its initial efficacy, feasibility, and acceptability. Participants were randomized (N = 101; aged 16-20 years) to one of two group-level, HIV and STI education programs: controls participated in a non-interactive, lecture-based program, while intervention participants took part in a highly interactive program tailored to young MSM aged 16-20. Sexual risk and social cognitive outcomes were assessed at baseline, 6-, and 12-weeks post-intervention. Over the entire follow-up period, intervention participants were less likely than controls to engage in any sexual behavior while under the influence of substances (p < .05), and a decreasing trend in unprotected anal sex while under the influence of substances was also observed in this group (p = .08). Follow-up differences between groups on social cognitive outcomes favored the intervention group, though these differences were non-significant. Acceptability ratings were modest. A 6-session behavioral intervention tailored to young MSM, aged 16-20, is feasible, acceptable, and demonstrates evidence of preliminary efficacy in reducing sexual risk, specifically sexual risk while under the influence of substances.
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A comparison of Internet search trends and sexually transmitted infection rates using Google trends.
Sex Transm Dis
PUBLISHED: 08-19-2014
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Google Trends was used to determine the relationship between sexually transmitted infection (STI)-related search engine trends and STI rates. Trends seem to be similar to the relative rates of STIs and to regional differences in rates. Search engine trends are an innovative tool to integrate into STI surveillance.
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Cell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma.
Cancer Discov
PUBLISHED: 07-31-2014
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Despite the unprecedented clinical activity of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib in mantle cell lymphoma (MCL), acquired resistance is common. By longitudinal integrative whole-exome and whole-transcriptome sequencing and targeted sequencing, we identified the first relapse-specific C481S mutation at the ibrutinib binding site of BTK in MCL cells at progression following a durable response. This mutation enhanced BTK and AKT activation and tissue-specific proliferation of resistant MCL cells driven by CDK4 activation. It was absent, however, in patients with primary resistance or progression following transient response to ibrutinib, suggesting alternative mechanisms of resistance. Through synergistic induction of PIK3IP1 and inhibition of PI3K-AKT activation, prolonged early G1 arrest induced by PD 0332991 (palbociclib) inhibition of CDK4 sensitized resistant lymphoma cells to ibrutinib killing when BTK was unmutated, and to PI3K inhibitors independent of C481S mutation. These data identify a genomic basis for acquired ibrutinib resistance in MCL and suggest a strategy to override both primary and acquired ibrutinib resistance.
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Entering the Era of Targeted Therapy for Chronic Lymphocytic Leukemia: Impact on the Practicing Clinician.
J. Clin. Oncol.
PUBLISHED: 07-23-2014
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Chemoimmunotherapy has been the standard of care for chronic lymphocytic leukemia (CLL). However, the introduction of B-cell receptor (BCR) kinase inhibitors such as ibrutinib has the potential to eliminate the role of chemotherapy in the treatment of CLL. How to best incorporate old and new therapies for CLL in this landscape is increasingly complex.
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SigFuge: single gene clustering of RNA-seq reveals differential isoform usage among cancer samples.
Nucleic Acids Res.
PUBLISHED: 07-16-2014
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High-throughput sequencing technologies, including RNA-seq, have made it possible to move beyond gene expression analysis to study transcriptional events including alternative splicing and gene fusions. Furthermore, recent studies in cancer have suggested the importance of identifying transcriptionally altered loci as biomarkers for improved prognosis and therapy. While many statistical methods have been proposed for identifying novel transcriptional events with RNA-seq, nearly all rely on contrasting known classes of samples, such as tumor and normal. Few tools exist for the unsupervised discovery of such events without class labels. In this paper, we present SigFuge for identifying genomic loci exhibiting differential transcription patterns across many RNA-seq samples. SigFuge combines clustering with hypothesis testing to identify genes exhibiting alternative splicing, or differences in isoform expression. We apply SigFuge to RNA-seq cohorts of 177 lung and 279 head and neck squamous cell carcinoma samples from the Cancer Genome Atlas, and identify several cases of differential isoform usage including CDKN2A, a tumor suppressor gene known to be inactivated in a majority of lung squamous cell tumors. By not restricting attention to known sample stratifications, SigFuge offers a novel approach to unsupervised screening of genetic loci across RNA-seq cohorts. SigFuge is available as an R package through Bioconductor.
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Multimaterial polyacrylamide: fabrication with electrohydrodynamic jet printing, applications, and modeling.
Biofabrication
PUBLISHED: 07-03-2014
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Micropatterned, multimaterial hydrogels have a wide range of applications, including the study of microenvironmental factors on cell behavior, and complex materials that rapidly change shape in response to fluid composition. This paper presents a method to fabricate microscale polyacrylamide features embedded in a second hydrogel of a different composition. An electrohydrodynamic jet (e-jet) printer was used to pattern hemispherical droplets of polyacrylamide prepolymer on a passive substrate. After photopolymerization, the droplets were backfilled with a second polyacrylamide mixture, the second mixture was polymerized and the sample was peeled off the substrate. Fluorescent and confocal microscopy confirmed multimaterial patterning, while scanning probe microscopy revealed a patterned topography with printed spots forming shallow wells. Finite element modeling was used to understand the mechanics of the formation of the topographical features during backfill and subsequent polymerization. Finally, polyacrylamide containing acrylic acid was used to demonstrate two applications of the micropatterned hydrogels: stimuli-responsive materials and patterned substrates for cell culture. The e-jet fabrication technique described here is a highly flexible, high resolution method for creating multimaterial hydrogels.
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Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib.
N. Engl. J. Med.
PUBLISHED: 05-28-2014
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Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and is effective in chronic lymphocytic leukemia (CLL). Resistance to irreversible kinase inhibitors and resistance associated with BTK inhibition have not been characterized. Although only a small proportion of patients have had a relapse during ibrutinib therapy, an understanding of resistance mechanisms is important. We evaluated patients with relapsed disease to identify mutations that may mediate ibrutinib resistance.
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Lenalidomide and rituximab for the initial treatment of patients with chronic lymphocytic leukemia: a multicenter clinical-translational study from the chronic lymphocytic leukemia research consortium.
J. Clin. Oncol.
PUBLISHED: 05-27-2014
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Lenalidomide is an immunomodulatory agent with therapeutic activity in chronic lymphocytic leukemia (CLL). In preclinical models, lenalidomide acted synergistically with rituximab. The CLL Research Consortium initiated a phase II study to evaluate this combination in treatment-naive patients.
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Text Message Appointment Reminders as a Tool to Improve PPV Show Rates in an Urban Resident Clinic.
Obstet Gynecol
PUBLISHED: 04-29-2014
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The objective of this research is to determine if text messaging can improve access to postpartum care for an urban clinic population by decreasing no-show rates. Last year's PPV rate at Women's Ambulatory Health Services at Hartford Hospital (71%) falls below the national average of 88.7% noted by the Centers for Disease Control and Prevention in 2004 with a 30% no-show rate.
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Deficiencies in physician knowledge of the risks of imaging in pregnancy.
Obstet Gynecol
PUBLISHED: 04-29-2014
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The use of diagnostic imaging in pregnant women is on the rise. Misconceptions regarding the risks and effects of fetal radiation exposure may lead to inappropriate practice patterns. The objective of this study was to query physicians about their knowledge and use of imaging in gravid women.
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Evaluating outcomes of labor inductions beyond 39 weeks of gestation.
Obstet Gynecol
PUBLISHED: 04-29-2014
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In an effort to decrease cesarean delivery rates, an institutional review of inductions performed at or beyond 39 weeks of gestation was designed to identify potential risk factors.
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Mechanical properties of various suture materials and placement patterns tested with surrogate in vitro model constructs simulating laryngeal advancement tie-forward procedures in horses.
Am. J. Vet. Res.
PUBLISHED: 04-26-2014
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To compare the mechanical properties of laryngeal tie-forward (LTF) surrogate constructs prepared with steel fixtures and No. 5 braided polyester or braided polyethylene by use of a standard or a modified suture placement technique.
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Headshaking in 5 horses after paranasal sinus surgery.
Vet Surg
PUBLISHED: 04-05-2014
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To report headshaking and presumptive trigeminal neuritis as a potential complication after paranasal sinus surgery in horses.
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Spermatozoa from the maned wolf (Chrysocyon brachyurus) display typical canid hyper-sensitivity to osmotic and freezing-induced injury, but respond favorably to dimethyl sulfoxide.
Cryobiology
PUBLISHED: 03-20-2014
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We assessed the influences of medium osmolality, cryoprotectant and cooling and warming rate on maned wolf (Chrysocyon brachyurus) spermatozoa. Ejaculates were exposed to Ham's F10 medium (isotonic control) or to this medium plus NaCl (350-1000mOsm), sucrose (369 and 479mOsm), 1M glycerol (1086mOsm) or dimethyl sulfoxide (Me2SO, 1151mOsm) for 10 min. Each sample then was diluted back into Ham's medium and assessed for sperm motility and plasma membrane integrity. Although glycerol and Me2SO had no influence (P>0.05), NaCl and sucrose solutions affected sperm motility (P<0.05), but not membrane integrity. Motility of sperm exposed to <600mOsm NaCl or sucrose was less (P<0.05) than fresh ejaculate, but comparable (P>0.05) to the control. As osmolality of the NaCl solution increased, motility decreased to <5%. In a separate study, ejaculates were diluted in Test Yolk Buffer containing 1M glycerol or Me2SO and cooled from 5°C to -120°C at -57.8°C, -124.2°C or -67.0°C/min, frozen in LN2, thawed in a water bath for 30s at 37°C or 10s at 50°C, and then assessed for motility, plasma- and acrosomal membrane integrity. Cryopreservation markedly (P<0.05) reduced sperm motility by 70% compared to fresh samples. Higher (P<0.05) post-thaw motility (20.0±1.9% versus 13.5±2.1%) and membrane integrity (51.2±1.7% versus 41.5±2.2%) were observed in samples cryopreserved in Me2SO than in glycerol. Cooling rates influenced survival of sperm cryopreserved in glycerol with -57.8°C/min being advantageous (P<0.05). The findings demonstrate that although maned wolf spermatozoa are similar to domestic dog sperm in their sensitivity to osmotic-induced motility damage, the plasma membranes tolerate dehydration, and the cells respond favorably to Me2SO as a cryoprotectant.
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Induction of ovarian activity and ovulation in an induced ovulator, the maned wolf (Chrysocyon brachyurus), using GnRH agonist and recombinant LH.
Theriogenology
PUBLISHED: 02-27-2014
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Assisted reproductive techniques, such as ovarian manipulation and artificial insemination, are useful for enhancing genetic management of threatened wildlife maintained ex situ. In this study, we used noninvasive fecal hormone monitoring to investigate (1) the influence of pairing with a male on endocrine responses of female maned wolves (Chrysocyon brachyurus) to a GnRH agonist (deslorelin) and (2) the efficiency of recombinant LH (reLH) on ovulation induction in females housed alone. Deslorelin (2.1 mg Ovuplant) was given to females that were either paired with a male (n = 4) or housed alone (n = 7); the implant was removed 7 to 11 days postimplantation. Three of seven singleton females were injected with reLH (0.0375 mg) on the day of implant removal, whereas the remaining females (n = 4) did not receive the additional treatment. Fecal samples were collected 5 to 7 days/wk from all females starting 11 days prior to hormone insertion until at least 70 days post implant removal for a total of 11 hormone treatment cycles. Fecal estrogen and progestagen metabolites were extracted and analyzed by enzyme immunoassay. Evidence of ovulation, demonstrated by a surge of estrogen followed by a significant rise in progestagen, occurred in all paired females. Three of the four singleton females that did not receive reLH treatment exhibited no rise in progestagen after an estrogen surge. All singleton females treated with reLH exhibited a rise in fecal progestagen after injection, indicating ovulation. In conclusion, deslorelin is effective at inducing ovarian activity and ovulation in paired female maned wolves; however, exogenous reLH is needed to induce ovulation in females housed alone. The findings obtained from this study serve as a foundation for future application of artificial insemination to enhance genetic management of this threatened species ex situ.
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Single therapeutic and supratherapeutic doses of anacetrapib, a cholesteryl ester transfer protein inhibitor, do not prolong the QTcF interval in healthy volunteers.
J Clin Pharmacol
PUBLISHED: 02-19-2014
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Anacetrapib is a cholesteryl ester transfer protein inhibitor in Phase III development. This double-blind, double-dummy, randomized, placebo- and active-comparator-controlled, 4-period, balanced crossover study evaluated the effects of anacetrapib (100?mg and 800?mg) on QTcF interval in healthy subjects. QTcF measurements were made up to 24?h following administration of single doses of anacetrapib 100 or 800?mg, moxifloxacin 400?mg, or placebo in the fed state. The primary hypothesis was supported if the 90% CI for the least squares (LS) mean differences between anacetrapib 800?mg and placebo in QTcF interval change from baseline were entirely <10 msec at every post-dose time point (1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24?h). The upper bounds of the 90% CIs for LS mean differences from placebo in changes from baseline in QTcF intervals for anacetrapib 100 and 800?mg were <5 msec at every time point. In conclusion, single doses of anacetrapib 100 and 800?mg do not prolong the QTcF interval to a clinically meaningful degree relative to placebo and are generally well tolerated in healthy subjects.
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A dose escalation feasibility study of lenalidomide for treatment of symptomatic, relapsed chronic lymphocytic leukemia.
Leuk. Res.
PUBLISHED: 02-18-2014
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Adequate dosing of lenalidomide in Chronic Lymphocytic Leukemia (CLL) remains unclear. This study determined maximum tolerated dose (MTD) in relapsed CLL patients (Cohort A) and patients achieving a partial response (PR) or better to recent therapy (Cohort B). Thirty-seven patients were enrolled. MTD was 2.5mg followed by 5.0mg continuous. In Cohort A, tumor flare grade 1-2 occurred in 15 patients (50%) and grade 3 in 1 patient (3%). Cohort A had 19 of 23 evaluable (83%) patients, 4 PR (17%) and 15 (65%) stable disease (SD), Cohort B had 6 of 7 patients (86%) with SD. Despite overall response rate not being high, many patients remained on therapy several months with SD.
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Influence of renal and hepatic impairment on the pharmacokinetics of anacetrapib.
J Clin Pharmacol
PUBLISHED: 02-15-2014
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Two open-label, parallel-group studies evaluated the influence of renal and hepatic insufficiency on the pharmacokinetics of a single-dose anacetrapib 100 mg. Eligible participants included adult men and women with moderate hepatic impairment (assessed by Child-Pugh criteria) or severe renal impairment (CrCl <30 mL/min/1.73 m(2) ). In both studies, patients were matched (race, age, sex, BMI) with healthy control subjects. Twenty-four subjects were randomized in each study (12 with either moderate hepatic or severe renal impairment and 12 matched healthy controls). In the hepatic insufficiency study, the geometric mean ratio (GMR; mean value for the group with moderate hepatic insufficiency/mean value for the healthy controls) and 90% CIs for the area under the concentration-time curve from time zero to infinity (AUC0-? ) and the maximum concentration of drug in plasma (Cmax ) were 1.16 (0.84, 1.60) and 1.02 (0.71, 1.49), respectively. In the renal insufficiency study, the GMRs (mean value for the group with severe renal insufficiency/mean value for the healthy controls) and 90% CIs for AUC0-? and Cmax were 1.14 (0.80, 1.63) and 1.31 (0.93, 1.83), respectively. Anacetrapib was generally well tolerated and there was no clinically meaningful effect of moderate hepatic or severe renal insufficiency on the pharmacokinetics of anacetrapib.
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Metabolic reprogramming of macrophages: glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype.
J. Biol. Chem.
PUBLISHED: 02-03-2014
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Glucose is a critical component in the proinflammatory response of macrophages (M?s). However, the contribution of glucose transporters (GLUTs) and the mechanisms regulating subsequent glucose metabolism in the inflammatory response are not well understood. Because M?s contribute to obesity-induced inflammation, it is important to understand how substrate metabolism may alter inflammatory function. We report that GLUT1 (SLC2A1) is the primary rate-limiting glucose transporter on proinflammatory-polarized M?s. Furthermore, in high fat diet-fed rodents, M?s in crown-like structures and inflammatory loci in adipose and liver, respectively, stain positively for GLUT1. We hypothesized that metabolic reprogramming via increased glucose availability could modulate the M? inflammatory response. To increase glucose uptake, we stably overexpressed the GLUT1 transporter in RAW264.7 M?s (GLUT1-OE M?s). Cellular bioenergetics analysis, metabolomics, and radiotracer studies demonstrated that GLUT1 overexpression resulted in elevated glucose uptake and metabolism, increased pentose phosphate pathway intermediates, with a complimentary reduction in cellular oxygen consumption rates. Gene expression and proteome profiling analysis revealed that GLUT1-OE M?s demonstrated a hyperinflammatory state characterized by elevated secretion of inflammatory mediators and that this effect could be blunted by pharmacologic inhibition of glycolysis. Finally, reactive oxygen species production and evidence of oxidative stress were significantly enhanced in GLUT1-OE M?s; antioxidant treatment blunted the expression of inflammatory mediators such as PAI-1 (plasminogen activator inhibitor 1), suggesting that glucose-mediated oxidative stress was driving the proinflammatory response. Our results indicate that increased utilization of glucose induced a ROS-driven proinflammatory phenotype in M?s, which may play an integral role in the promotion of obesity-associated insulin resistance.
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Low abundance of the matrix arm of complex I in mitochondria predicts longevity in mice.
Nat Commun
PUBLISHED: 01-24-2014
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Mitochondrial function is an important determinant of the ageing process; however, the mitochondrial properties that enable longevity are not well understood. Here we show that optimal assembly of mitochondrial complex I predicts longevity in mice. Using an unbiased high-coverage high-confidence approach, we demonstrate that electron transport chain proteins, especially the matrix arm subunits of complex I, are decreased in young long-living mice, which is associated with improved complex I assembly, higher complex I-linked state 3 oxygen consumption rates and decreased superoxide production, whereas the opposite is seen in old mice. Disruption of complex I assembly reduces oxidative metabolism with concomitant increase in mitochondrial superoxide production. This is rescued by knockdown of the mitochondrial chaperone, prohibitin. Disrupted complex I assembly causes premature senescence in primary cells. We propose that lower abundance of free catalytic complex I components supports complex I assembly, efficacy of substrate utilization and minimal ROS production, enabling enhanced longevity.
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Ibrutinib treatment ameliorates murine chronic graft-versus-host disease.
J. Clin. Invest.
PUBLISHED: 01-22-2014
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Chronic graft-versus-host disease (cGVHD) is a life-threatening impediment to allogeneic hematopoietic stem cell transplantation, and current therapies do not completely prevent and/or treat cGVHD. CD4+ T cells and B cells mediate cGVHD; therefore, targeting these populations may inhibit cGVHD pathogenesis. Ibrutinib is an FDA-approved irreversible inhibitor of Bruton's tyrosine kinase (BTK) and IL-2 inducible T cell kinase (ITK) that targets Th2 cells and B cells and produces durable remissions in B cell malignancies with minimal toxicity. Here, we evaluated whether ibrutinib could reverse established cGVHD in 2 complementary murine models, a model interrogating T cell-driven sclerodermatous cGVHD and an alloantibody-driven multiorgan system cGVHD model that induces bronchiolar obliterans (BO). In the T cell-mediated sclerodermatous cGVHD model, ibrutinib treatment delayed progression, improved survival, and ameliorated clinical and pathological manifestations. In the alloantibody-driven cGVHD model, ibrutinib treatment restored pulmonary function and reduced germinal center reactions and tissue immunoglobulin deposition. Animals lacking BTK and ITK did not develop cGVHD, indicating that these molecules are critical to cGVHD development. Furthermore, ibrutinib treatment reduced activation of T and B cells from patients with active cGVHD. Our data demonstrate that B cells and T cells drive cGVHD and suggest that ibrutinib has potential as a therapeutic agent, warranting consideration for cGVHD clinical trials.
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Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy.
Blood
PUBLISHED: 01-10-2014
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The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has outstanding activity in patients with chronic lymphocytic leukemia. Most patients experience lymphocytosis, representing lymphocyte egress from nodal compartments. This resolves within 8 months in the majority of patients, but a subgroup has lymphocytosis lasting >12 months. Here we report a detailed characterization of patients with persistent lymphocytosis during ibrutinib therapy. Signaling evaluation showed that while BTK is inhibited, downstream mediators of B-cell receptor (BCR) signaling are activated in persistent lymphocytes. These cells cannot be stimulated through the BCR and do not show evidence of target gene activation. Flow cytometry for ? and ? expression, IGHV sequencing, Zap-70 methylation, and targeted gene sequencing in these patients are identical at baseline and later time points, suggesting that persistent lymphocytes do not represent clonal evolution. In vitro treatment with targeted kinase inhibitors shows that they are not addicted to a single survival pathway. Finally, progression-free survival is not inferior for patients with prolonged lymphocytosis vs those with traditional responses. Thus, prolonged lymphocytosis is common following ibrutinib treatment, likely represents the persistence of a quiescent clone, and does not predict a subgroup of patients likely to relapse early.
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In vivo (1)H MRS study of potential associations between glutathione, oxidative stress and anhedonia in major depressive disorder.
Neurosci. Lett.
PUBLISHED: 01-06-2014
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Inflammation and oxidative stress are important mechanisms that have been implicated in the pathophysiology of major depressive disorder (MDD). Glutathione (GSH) is the most abundant antioxidant in human tissue, and a key index of antioxidant capacity and, hence, of oxidative stress. The aims of this investigation were to examine possible relationships between occipital GSH and dimensional measures of depressive symptom severity, including anhedonia - the reduced capacity to experience pleasure - and fatigue. We hypothesized that the magnitude of anhedonia and fatigue will be negatively correlated with occipital GSH levels in subjects with MDD and healthy controls (HC). Data for eleven adults with MDD and ten age- and sex-matched HC subjects were included in this secondary analysis of data from a previously published study. In vivo levels of GSH in a 3cm×3cm×2cm voxel of occipital cortex were obtained by proton magnetic resonance spectroscopy ((1)H MRS) on a 3T MR system, using the standard J-edited spin-echo difference technique. Anhedonia was assessed by combining interest items from depression and fatigue rating scales, and fatigue by use of the multidimensional fatigue inventory. Across the full sample of participants, anhedonia severity and occipital GSH levels were negatively correlated (r=-0.55, p=0.01). No associations were found between fatigue severity and GSH in this sample. These preliminary findings are potentially consistent with a pathophysiological role for GSH and oxidative stress in anhedonia and MDD. Larger studies in anhedonic depressed patients are indicated.
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Effects of extended-release niacin/laropiprant, simvastatin, and the combination on correlations between apolipoprotein B, LDL cholesterol, and non-HDL cholesterol in patients with dyslipidemia.
Vasc Health Risk Manag
PUBLISHED: 01-01-2014
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Statins modify correlations between apolipoprotein B (apoB) and low-density lipoprotein cholesterol (LDL-C) and apoB and non-high-density lipoprotein cholesterol (non-HDL-C); however, it is not known whether niacin-based therapies have similar effects.
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Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial.
Lancet Oncol.
PUBLISHED: 12-10-2013
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Chemoimmunotherapy has led to improved numbers of patients achieving disease response, and longer overall survival in young patients with chronic lymphocytic leukaemia; however, its application in elderly patients has been restricted by substantial myelosuppression and infection. We aimed to assess safety and activity of ibrutinib, an orally administered covalent inhibitor of Bruton tyrosine kinase (BTK), in treatment-naive patients aged 65 years and older with chronic lymphocytic leukaemia.
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Brutons tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL).
Blood
PUBLISHED: 12-05-2013
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Chronic Lymphocytic Leukemia (CLL) demonstrates variable reactivity of the B cell receptor (BCR) to antigen ligation, but constitutive pathway activation. Brutons Tyrosine Kinase (BTK) shows constitutive activity in CLL, and is the target of irreversible inhibition by ibrutinib, an orally bioavailable kinase inhibitor that has shown outstanding activity in CLL. Early clinical results in CLL with other reversible and irreversible BTK inhibitors have been less promising, however, raising the question of whether BTK kinase activity is an important target of ibrutinib and also in CLL. To determine the role of BTK in CLL, we utilized patient samples and the E?-TCL1 (TCL1) transgenic mouse model of CLL which results in spontaneous leukemia development. Inhibition of BTK in primary human CLL cells by siRNA promotes apoptosis. Inhibition of BTK kinase activity through either targeted genetic inactivation or ibrutinib in the TCL1 mouse significantly delays the development of CLL, demonstrating that BTK is a critical kinase for CLL development and expansion and thus an important target of ibrutinib. Collectively, our data confirm the importance of kinase-functional BTK in CLL.
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"What Could Have Been Different": A Qualitative Study of Syndemic Theory and HIV Prevention among Young Men Who Have Sex with Men.
J HIV AIDS Soc Serv
PUBLISHED: 11-19-2013
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Young men who have sex with men (MSM) experience multiple health disparities, including alcohol and drug use, partner violence, victimization due to sexual orientation, and HIV infection. Syndemic theorists explain the clustering of these disparities among adult MSM as a result of cultural marginalization. To date, research on a similar emerging syndemic among young MSM has been limited to quantitative studies. This study seeks to better understand these disparities, and how they may cluster together, via qualitative interviews with 21 ethnically diverse, HIV infected young MSM aged 18-24 years old. These youth report a lack of gay-specific HIV prevention education, absence of role models, and lack of productive future goal-related activities as factors related to their acquisition of HIV, and downplay substance use as a factor. Although not necessarily the components traditionally cited by syndemic theorists, these findings support the notion that multiple factors of cultural marginalization cluster together in the lives of young MSM, and underscore the importance of community-level interventions, such as sexual health education, access to mentors, and assistance with future goal setting and planning.
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Demographic, psychosocial, and contextual factors associated with sexual risk behaviors among young sexual minority women.
J Am Psychiatr Nurses Assoc
PUBLISHED: 11-11-2013
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Young sexual minority women are at risk for negative sexual health outcomes, including sexually transmitted infections and unintended pregnancies, yet little is known about these risks. We examined factors that may influence sexual risk from a psychosocial and contextual perspective. Analyses were conducted to examine within group relationships between sexual behaviors, negative outcomes, and related factors in a sample of young sexual minority women. Participants (N = 131) were young (mean = 19.8) and diverse in terms of race/ethnicity (57% non-White). Sex under the influence, having multiple partners, and having unprotected sex were common behaviors, and pregnancy (20%) and sexually transmitted infection (12%) were common outcomes. Risk behaviors were associated with age, alcohol abuse, and older partners. Results support the need for further research to understand how these factors contribute to risk in order to target risk reduction programs for this population.
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Role of osteopathic structural diagnosis and osteopathic manipulative treatment for diabetes mellitus and its complications.
J Am Osteopath Assoc
PUBLISHED: 11-01-2013
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Osteopathic physicians have a unique opportunity to affect the US epidemic of type 2 diabetes mellitus (T2DM). Osteopathic physicians make up a disproportionately high number of primary care physicians who are on the front lines of managing T2DM. In addition, the unique training of osteopathic physicians allows them to direct additional diagnostic and treatment modalities toward the musculoskeletal complications of diabetes. The present review surveys the literature that explores the effects of osteopathic structural diagnosis of and osteopathic manipulative treatment for T2DM, as well as the management and prevention of complications. The authors reviewed the databases for PubMed, Google Scholar, and The Journal of the American Osteopathic Association. Although the available literature is limited, the authors identify areas in which osteopathic-focused research has shown benefits and in which future research should be directed.
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Hypothalamic-Pituitary-Adrenal Axis Effects of Mometasone Furoate/Formoterol Fumarate vs Fluticasone Propionate/Salmeterol Administered Through Metered-Dose Inhaler.
Chest
PUBLISHED: 10-01-2013
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The effects of mometasone furoate and fluticasone propionate on the hypothalamic-pituitary-adrenal axis were compared when administered from combination metered-dose inhaler (MDI) products.
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Lymphocyte cytosolic protein 1 is a chronic lymphocytic leukemia membrane-associated antigen critical to niche homing.
Blood
PUBLISHED: 09-05-2013
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Membrane antigens are critical to the pathogenesis of chronic lymphocytic leukemia (CLL) as they facilitate microenvironment homing, proliferation, and survival. Targeting the CLL membrane and associated signaling patterns is a current focus of therapeutic development. Many tumor membrane targets are simultaneously targeted by humoral immunity, thus forming recognizable immunoglobulin responses. We sought to use this immune response to identify novel membrane-associated targets for CLL. Using a novel strategy, we interrogated CLL membrane-specific autologous immunoglobulin G reactivity. Our analysis unveiled lymphocyte cytosolic protein 1 (LCP1), a lymphocyte-specific target that is highly expressed in CLL. LCP1 plays a critical role in B-cell biology by crosslinking F-actin filaments, thereby solidifying cytoskeletal structures and providing a scaffold for critical signaling pathways. Small interfering RNA knockdown of LCP1 blocked migration toward CXCL12 in transwell assays and to bone marrow in an in vivo xenotransplant model, confirming a role for LCP1 in leukemia migration. Furthermore, we demonstrate that the Brutons tyrosine kinase inhibitor ibrutinib or the PI3K inhibitor idelalisib block B-cell receptor induced activation of LCP1. Our data demonstrate a novel strategy to identify cancer membrane target antigens using humoral anti-tumor immunity. In addition, we identify LCP1 as a membrane-associated target in CLL with confirmed pathogenic significance. This clinical trial was registered at clinicaltrials.gov; study ID number: OSU-0025 OSU-0156.
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Perceived likelihood of using HIV pre-exposure prophylaxis medications among young men who have sex with men.
AIDS Behav
PUBLISHED: 08-31-2013
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Pre-exposure prophylaxis (PrEP) is a new strategy for reducing the risk of HIV infection; however, questions about the likelihood of use remain. As part of an ongoing longitudinal study of YMSM, interest in PrEP use under various conditions of side-effects, dosing, and effectiveness were assessed. Participants aged 16-20 living in Chicago and the surrounding areas were recruited beginning December 2009, using a modified form of respondent driven sampling. A cross-sectional sample of 171 HIV negative YMSM interviewed approximately 6 months after initial enrollment was analyzed. This sample was somewhat interested in adopting PrEP as an HIV prevention strategy, particularly if the dosing and side-effects burden was low and the perceived benefits were high. PrEP interest was unrelated with drug use and number of sexual partners, but negatively correlated with number of unprotected anal sex acts. The scale was positively associated with intentions for use in specific risk situations.
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Quantification of dendritic and axonal growth after injury to the auditory system of the adult cricket Gryllus bimaculatus.
Front Physiol
PUBLISHED: 08-23-2013
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Dendrite and axon growth and branching during development are regulated by a complex set of intracellular and external signals. However, the cues that maintain or influence adult neuronal morphology are less well understood. Injury and deafferentation tend to have negative effects on adult nervous systems. An interesting example of injury-induced compensatory growth is seen in the cricket, Gryllus bimaculatus. After unilateral loss of an ear in the adult cricket, auditory neurons within the central nervous system (CNS) sprout to compensate for the injury. Specifically, after being deafferented, ascending neurons (AN-1 and AN-2) send dendrites across the midline of the prothoracic ganglion where they receive input from auditory afferents that project through the contralateral auditory nerve (N5). Deafferentation also triggers contralateral N5 axonal growth. In this study, we quantified AN dendritic and N5 axonal growth at 30 h, as well as at 3, 5, 7, 14, and 20 days after deafferentation in adult crickets. Significant differences in the rates of dendritic growth between males and females were noted. In females, dendritic growth rates were non-linear; a rapid burst of dendritic extension in the first few days was followed by a plateau reached at 3 days after deafferentation. In males, however, dendritic growth rates were linear, with dendrites growing steadily over time and reaching lengths, on average, twice as long as in females. On the other hand, rates of N5 axonal growth showed no significant sexual dimorphism and were linear. Within each animal, the growth rates of dendrites and axons were not correlated, indicating that independent factors likely influence dendritic and axonal growth in response to injury in this system. Our findings provide a basis for future study of the cellular features that allow differing dendrite and axon growth patterns as well as sexually dimorphic dendritic growth in response to deafferentation.
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Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes.
Blood
PUBLISHED: 07-25-2013
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Given its critical role in T-cell signaling, interleukin-2-inducible kinase (ITK) is an appealing therapeutic target that can contribute to the pathogenesis of certain infectious, autoimmune, and neoplastic diseases. Ablation of ITK subverts Th2 immunity, thereby potentiating Th1-based immune responses. While small-molecule ITK inhibitors have been identified, none have demonstrated clinical utility. Ibrutinib is a confirmed irreversible inhibitor of Bruton tyrosine kinase (BTK) with outstanding clinical activity and tolerability in B-cell malignancies. Significant homology between BTK and ITK alongside in silico docking studies support ibrutinib as an immunomodulatory inhibitor of both ITK and BTK. Our comprehensive molecular and phenotypic analysis confirms ITK as an irreversible T-cell target of ibrutinib. Using ibrutinib clinical trial samples along with well-characterized neoplastic (chronic lymphocytic leukemia), parasitic infection (Leishmania major), and infectious disease (Listeria monocytogenes) models, we establish ibrutinib as a clinically relevant and physiologically potent ITK inhibitor with broad therapeutic utility. This trial was registered at www.clinicaltrials.gov as #NCT01105247 and #NCT01217749.
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Isolation and analysis of linker histones across cellular compartments.
J Proteomics
PUBLISHED: 07-23-2013
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Analysis of histones, especially histone H1, is severely limited by immunological reagent availability. This paper describes the application of cellular fractionation with LC-MS for profiling histones in the cytosol and upon chromatin. First, we show that linker histones enriched by cellular fractionation gives less nuclear contamination and higher histone content than when prepared by nuclei isolation. Second, we profiled the soluble linker histones throughout the cell cycle revealing phosphorylation increases as cells reach mitosis. Finally, we monitored histone H1.2-H1.5 translocation to the cytosol in response to the CDK inhibitor flavopiridol in primary CLL cells treated ex vivo. Data shows that all H1 variants translocate in response to drug treatment with no specific order to their cytosolic appearance. The results illustrate the utility of cellular fractionation in conjunction with LC-MS for the analysis of histone H1 throughout the cell.
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Role of HGF in obesity-associated tumorigenesis: C3(1)-TAg mice as a model for human basal-like breast cancer.
Breast Cancer Res. Treat.
PUBLISHED: 07-08-2013
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Obesity is associated with basal-like breast cancer (BBC), an aggressive breast cancer subtype. The objective of this study was to determine whether obesity promotes BBC onset in adulthood and to evaluate the role of stromal-epithelial interactions in obesity-associated tumorigenesis. We hypothesized that hepatocyte growth factor (HGF) plays a promoting role in BBC, which express the HGF receptor, c-Met. In C3(1)-TAg mice, a murine model of BBC, we demonstrated that obesity leads to a significant increase in HGF secretion and an associated decrease in tumor latency. By immunohistochemical analysis, normal mammary gland exhibited obesity-induced HGF, c-Met and phospho-c-Met, indicating that the activation of the cascade was obesity-driven. HGF secretion was also increased from primary mammary fibroblasts isolated from normal mammary glands and tumors of obese mice compared to lean. These results demonstrate that obesity-induced elevation of HGF expression is a stable phenotype, maintained after several passages, and after removal of dietary stimulation. Conditioned media from primary tumor fibroblasts from obese mice drove tumor cell proliferation. In co-culture, neutralization of secreted HGF blunted tumor cell migration, further linking obesity-mediated HGF-dependent effects to in vitro measures of tumor aggressiveness. In sum, these results demonstrate that HGF/c-Met plays an important role in obesity-associated carcinogenesis. Understanding the effects of obesity on risk and progression is important given that epidemiologic studies imply a portion of BBC could be eliminated by reducing obesity.
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Improving recording accuracy, transparency, and performance for obstetric quality measures in a community hospital-based obstetrics department.
Jt Comm J Qual Patient Saf
PUBLISHED: 06-25-2013
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The obstetric arena has been typically ignored in the race to determine hospital quality measures due primarily to the fact that a large majority of patients do not have Medicare federal insurance, which has been the focus of hospital measures of quality. With "normal vaginal delivery" being the number one hospital discharge diagnosis and cesarean sections rates varying greatly between hospitals, national organizations are taking greater interest in determining differences in quality.
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Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia.
N. Engl. J. Med.
PUBLISHED: 06-19-2013
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The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Brutons tyrosine kinase (BTK), an essential component of B-cell-receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells.
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Start and the restriction point.
Curr. Opin. Cell Biol.
PUBLISHED: 05-29-2013
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Commitment to division requires that cells sense, interpret, and respond appropriately to multiple signals. In most eukaryotes, cells commit to division in G1 before DNA replication. Beyond a point, known as Start in yeast and the restriction point in mammals, cells will proceed through the cell cycle despite changes in upstream signals. In metazoans, misregulated G1 control can lead to developmental problems or disease, so it is important to understand how cells decipher the myriad external and internal signals that contribute to the fundamental all-or-none decision to divide. Extensive study of G1 control in the budding yeast Saccharomyces cerevisiae and mammalian culture systems has revealed highly similar networks regulating commitment. However, protein sequences of functional orthologs often indicate a total lack of conservation suggesting significant evolution of G1 control. Here, we review recent studies defining the conserved and diverged features of G1 control and highlight systems-level aspects that may be common to other biological regulatory networks.
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Sensitive liquid chromatography/mass spectrometry methods for quantification of pomalidomide in mouse plasma and brain tissue.
J Pharm Biomed Anal
PUBLISHED: 05-27-2013
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Pomalidomide was recently approved by the United States Food and Drug Administration for the treatment of patients with relapsed or refractory multiple myeloma who have received at least two prior therapies. As pomalidomide is increasingly evaluated in other diseases and animal disease models, this paper presents development and validation of a sensitive liquid chromatography tandem mass spectrometry assay for quantification of pomalidomide in mouse plasma and brain tissue to fill a gap in published preclinical pharmacokinetic and analytical data with this agent. After acetonitrile protein precipitation, pomalidomide and internal standard, hesperitin, were separated with reverse phase chromatography on a C-18 column with a gradient mobile phase of water and acetonitrile with 0.1% fomic acid. Positive atmospheric pressure chemical ionization mass spectrometry with selected reaction monitoring mode was applied to achieve 0.3-3000nM (0.082-819.73ng/mL) linear range in mouse plasma and 0.6-6000pmol/g in brain tissue. The within- and between-batch accuracy and precision were less than 15% for both plasma and brain tissue. The method was applied to measure pomalidomide concentrations in plasma and brain tissue in a pilot mouse pharmacokinetic study with an intravenous dose of 0.5mg/kg. This assay can be applied for thorough characterization of pomalidomide pharmacokinetics and tissue distribution in mice.
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Identification of endoplasmic reticulum stress-inducing agents by antagonizing autophagy: a new potential strategy for identification of anti-cancer therapeutics in B-cell malignancies.
Leuk. Lymphoma
PUBLISHED: 04-16-2013
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The endoplasmic reticulum (ER) plays a vital function in multiple cellular processes. There is a growing interest in developing therapeutic agents that can target the ER in cancer cells, inducing a stress response that leads to cell death. However, ER stress-inducing agents can also induce autophagy, a survival strategy of cancer cells. Therefore, by inhibiting autophagy we can increase the efficacy of the ER stress-inducing agents. Nelfinavir, a human immunodeficiency virus (HIV) protease inhibitor with anti-cancer properties, can induce ER stress. Nelfinavirs effects on chronic lymphocytic leukemia (CLL) are yet to be elucidated. Herein we demonstrate that nelfinavir induces ER morphological changes and stress response, along with an autophagic protective strategy. Our data reveal that chloroquine, an autophagy inhibitor, significantly increases nelfinavir cytotoxicity. These results identify a novel strategy potentially effective in CLL treatment, by repositioning two well-known drugs as a combinatorial therapy with anti-cancer properties.
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Effects of ezetimibe, simvastatin and ezetimibe/simvastatin on correlations between apolipoprotein B, LDL cholesterol and non-HDL cholesterol in patients with primary hypercholesterolemia.
Atherosclerosis
PUBLISHED: 04-04-2013
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Apolipoprotein (apo) B is highly predictive of coronary risk, especially in patients with high triglycerides (TG). This post hoc analysis evaluated the effects of lipid-lowering therapy on correlations between apoB and low-density lipoprotein cholesterol (apoB:LDL-C) and non-high-density lipoprotein cholesterol (apoB:non-HDL-C) in patients with TG< and ? 200 mg/dL.
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Cyclophosphamide, alvocidib (flavopiridol), and rituximab, a novel feasible chemoimmunotherapy regimen for patients with high-risk chronic lymphocytic leukemia.
Leuk. Res.
PUBLISHED: 04-04-2013
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Alvocidib has demonstrated efficacy in high-risk chronic lymphocytic leukemia (CLL) patients. In this phase I study, we combined cyclophosphamide, alvocidib and rituximab (CAR) in a schema designed to mitigate tumor lysis syndrome (TLS) seen previously with alvocidib. Nine nucleoside analog-naïve, high-risk patients received escalating doses of CAR therapy. Dose limiting toxicity was not experienced. No instances of TLS were observed. Patient responses included three complete remissions and four partial remissions. CAR was tolerable and active in high-risk CLL patients without TLS toxicity. With continued monitoring of toxicities, a phase Ib/II study of this combination as frontline therapy is warranted.
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Quantitative real-time PCR for detection of neurotoxin genes of Clostridium botulinum types A, B and C in equine samples.
Vet. J.
PUBLISHED: 03-27-2013
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Botulism in horses in the USA is attributed to Clostridium botulinum types A, B or C. In this study, a duplex quantitative real-time PCR (qPCR) for detection of the neurotoxin genes of C. botulinum types A and B, and a singleplex qPCR for detection of the neurotoxin gene of C. botulinum type C, were optimized and validated for equine gastrointestinal, faecal and feed samples. The performance of these assays was evaluated and compared to the standard mouse bioassay (MBA) using 148 well-characterized samples, most of which were acquired from a repository of veterinary diagnostic samples from cases of botulism: 106 samples positive for C. botulinum (25 type A, 27 type B, 28 type C, 1 type D and 25 type E) and 42 negative samples. The sensitivities of the qPCR assays were 89%, 86% and 96% for C. botulinum types A, B and C, respectively. The overall sensitivity of the mouse bioassay for types A, B and C was 81%. The specificities of the qPCR assays were 99-100% and the specificity of the mouse bioassay was 95%.
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System-level biomechanical approach for the evaluation of term and preterm pregnancy maintenance.
J Biomech Eng
PUBLISHED: 03-01-2013
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Preterm birth is the primary contributor to perinatal morbidity and mortality, with those born prior to 32 weeks disproportionately contributing compared to those born at 32-37 weeks. Outcomes for babies born prematurely can be devastating. Parturition is recognized as a mechanical process that involves the two processes that are required to initiate labor: rhythmic myometrial contractions and cervical remodeling with subsequent dilation. Studies of parturition tend to separate these two processes rather than evaluate them as a unified system. The mechanical property characterization of the cervix has been primarily performed on isolated cervical tissue, with an implied understanding of the contribution from the uterine corpus. Few studies have evaluated the function of the uterine corpus in the absence of myometrial contractions or in relationship to retaining the fetus. Therefore, the cervical-uterine interaction has largely been neglected in the literature. We suggest that a system-level biomechanical approach is needed to understand pregnancy maintenance. To that end, this paper has two main goals. One goal is to highlight the gaps in current knowledge that need to be addressed in order to develop any comprehensive and clinically relevant models of the system. The second goal is to illustrate the utility of finite element models in understanding pregnancy maintenance of the cervical-uterine system. The paper targets an audience that includes the reproductive biologist/clinician and the engineer/physical scientist interested in biomechanics and the system level behavior of tissues.
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Autophagy and ER stress play an essential role in the mechanism of action and drug resistance of the cyclin-dependent kinase inhibitor flavopiridol.
Autophagy
PUBLISHED: 02-21-2013
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Chronic lymphocytic leukemia (CLL) is a mature B cell malignancy and is the most prevalent type of leukemia in adults. There is no curative therapy for this disease; however, several new agents have shown very promising results. Autophagy has not been studied in CLL and in this study we first sought to determine if autophagy was functional in CLL with classic inducers, and if this contributes to direct cytotoxicity or protection from cell death. While autophagy is activated with all classic stimuli of this process, only unfolded protein endoplasmic reticulum (ER) stress-mediated autophagy protects from cell death. Interestingly, select therapeutic agents (fludarabine, GS-1101, flavopiridol), which are active in CLL, also induce autophagy. Of interest, only the broad cyclin-dependent kinase inhibitor flavopiridol has improved efficacy when autophagy is antagonized biochemically (chloroquine) or by siRNA. This promoted an investigation which demonstrated unexpectedly that flavopiridol mediates ER stress and downstream activation of MAP3K5/ASK1, which ultimately is responsible for cell death. Similarly, autophagy activated in part via ER stress and also CDK5 inhibition is protective against cell death induced by this process. Collectively, our studies demonstrate that in CLL, autophagy is induced by multiple stimuli but only acts as a mechanism of resistance against ER stress-mediating agents. Similarly, flavopiridol mediates ER stress as a primary mechanism of action in CLL, and autophagy serves as a mechanism of resistance to this agent.
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The effect of multiple doses of ketoconazole or rifampin on the single- and multiple-dose pharmacokinetics of vorapaxar.
J Clin Pharmacol
PUBLISHED: 02-20-2013
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This randomized, open-label, parallel-group study evaluated the effects of multiple-dose ketoconazole or rifampin on the single- and multiple-dose pharmacokinetics of vorapaxar. Healthy subjects randomly received one of the following three treatments (N = 12/group): (1) ketoconazole 400 mg once daily (QD) for 28 days (Days 1-28) and single-dose vorapaxar 20 mg on Day 7 followed by vorapaxar 2.5 mg QD for 21 days (Days 8-28); (2) rifampin 600 mg QD for 28 days (Days 1-28) and single-dose vorapaxar 20 mg on Day 7 followed by vorapaxar 2.5 mg QD for 21 days (Days 8-28); and (3) placebo QD for 28 days (Days 1-28) and single-dose vorapaxar 20 mg on Day 7 followed by vorapaxar 2.5 mg QD for 21 days (Days 8-28). Ketoconazole increased the steady-state vorapaxar AUC(0-24 h) and C(max) by approximately twofold (GMR [90% CI]: 196% [173,222]; 193% [166,223], respectively), while rifampin decreased vorapaxar AUC(0-24 h) and C(max) by approximately 50% (GMR [90% CI]: 45.5% [40,52]; 61.4% [52,72], respectively) versus vorapaxar alone. Potent CYP3A4 inhibitors or inducers may cause moderate increases or decreases in vorapaxar exposure, respectively, which may have safety and/or efficacy implications; therefore, their concomitant use with vorapaxar is not recommended.
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Prevalence of microalbuminuria and associated risk factors among adult Korean hypertensive patients in a primary care setting.
Hypertens. Res.
PUBLISHED: 02-13-2013
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Microalbuminuria is an early sign of nephropathy and an independent predictor of end-stage renal disease. The purpose of this study was to assess microalbuminuria prevalence and its contributing factors in Korean hypertensive patients. This cross-sectional study enrolled male and female patients of ?35 years old with an essential hypertension diagnosis as made by 841 physicians in primary care clinics and 17 in general hospitals in the Republic of Korea between November 2008 and July 2009. To assess microalbuminuria prevalence, urine albumin/creatinine ratio (UACR) was measured in patients with a positive dipstick test. Of the 40,473 enrolled patients, 5713 (14.1%) had a positive dipstick test. Of 5393 patients with a positive dipstick test and valid UACR values, 2657 (6.6%) had significantly elevated UACR (?30??g?mg(-1)), 2158 (5.4%) had microalbuminuria (30??g?mg(-1)?UACR <300??g?mg(-1)) and 499 (1.2%) had macroalbuminuria (UACR ?300??g?mg(-1)). Based on multivariate analysis, independent factors associated with elevated UACR included low adherence to antihypertensive medication (23% higher; P=0.042), poorly controlled blood pressure (BP; 38% higher for systolic BP/diastolic BP ?130?mm?Hg/?80?mm?Hg; P<0.001), obesity (47% higher for body mass index (BMI) ?25.0?kg?m(-2); P<0.001), age (17% lower and 58% higher for age categories 35-44 years (P=0.043) and >75 years (P<0.001), respectively) and a prior history of diabetes (151% higher; P<0.001) and kidney-related disease (71% higher; P<0.001). The prevalences of elevated UACR and microalbuminuria were 6.6% and 5.4%, respectively. Age, increased BMI, presence of comorbidities, poor medication adherence and inadequately controlled BP were independent predictors of elevated UACR after controlling for potential confounders.
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Substance use as a mediator of the relationship between life stress and sexual risk among young transgender women.
AIDS Educ Prev
PUBLISHED: 02-08-2013
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This study examined whether life stress was associated with elevated sexual risk among young transgender women and whether this relationship was mediated by alcohol and substance use. The analysis was based on data collected from 116 transgender women aged 16 to 25 as part of a baseline assessment for an HIV prevention intervention. The median age was 20; the majority identified as African American (48%) or Hispanic (32%). Controlling for age, high life stress was associated with an increased odds of sexual risk (OR = 2.39; 95% CI 1.12-5.12). This association was attenuated when substance and alcohol use were added to the model (OR = 1.82; 0.80-4.13). A formal test of the mediation hypothesis indicated a statistically significant indirect effect (? = 0.08; 95% CI 0.02-0.20). Interventions aimed at reducing sexual risk behavior should address problems with substance use as well as more distal factors that impact risk, such homelessness, joblessness, and lack of access to medical care.
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Effects of Rifampin, a potent inducer of drug-metabolizing enzymes and an inhibitor of OATP1B1/3 transport, on the single dose pharmacokinetics of anacetrapib.
J Clin Pharmacol
PUBLISHED: 01-22-2013
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Anacetrapib is a novel cholesteryl ester transfer protein (CETP) inhibitor in development for treatment of dyslipidemia. This open-label, fixed-sequence, 3-period study was intended to evaluate the potential of anacetrapib to be a victim of OATP1B1/3 inhibition and strong CYP3A induction using acute and chronic dosing of rifampin, respectively, as a probe. In this study, 16 healthy subjects received 100?mg anacetrapib administered without rifampin (Day 1, Period 1), with single-dose (SD) 600?mg rifampin (Day 1, Period 2), and with multiple-dose (MD) 600?mg rifampin for 20 days (Day 14, Period 3). Log-transformed anacetrapib AUC0-? and Cmax were analyzed by a linear mixed effects model. The GMRs and 90% CIs for anacetrapib AUC0-? and Cmax were 1.25 (1.04, 1.51) and 1.43 (1.13, 1.82) for SD rifampin (Period 2/Period 1) and 0.35 (0.29, 0.42) and 0.26 (0.21, 0.32) for MD rifampin (Period 3/Period 1), respectively. Anacetrapib was generally well tolerated in both the absence/presence of SD and MD rifampin. In conclusion, treatment with SD rifampin, which inhibits the OATP1B1/3 transporter system, did not substantially influence the SD pharmacokinetics of anacetrapib, while chronic (20 days) administration of rifampin, which strongly induces CYP3A isozymes, reduced mean systemic exposure to SD anacetrapib by 65%.
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Autism spectrum disorders.
Curr Probl Pediatr Adolesc Health Care
PUBLISHED: 01-22-2013
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Autism spectrum disorders are being diagnosed with increasing frequency. The likelihood that a primary care provider will see a patient with autism spectrum disorder in their clinic is high. In this article, current diagnostic criteria and expected changes in DSM criteria, as well as prevalence rates and epidemiologic studies are reviewed. Recommendations for screening, including early warning signs, and best practices for diagnosis are discussed. Comprehensive evidence based intervention for ASD as well as the findings of the National Standards Project are reviewed. Medication management is also described, as are the roles of other treating professionals.
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A pharmacokinetic/pharmacodynamic model of tumor lysis syndrome in chronic lymphocytic leukemia patients treated with flavopiridol.
Clin. Cancer Res.
PUBLISHED: 01-08-2013
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Flavopiridol, the first clinically evaluated cyclin-dependent kinase inhibitor, shows activity in patients with refractory chronic lymphocytic leukemia, but prevalent and unpredictable tumor lysis syndrome (TLS) presents a major barrier to its broad clinical use. The purpose of this study was to investigate the relationships between pretreatment risk factors, drug pharmacokinetics, and TLS.
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Genetic heterogeneity of diffuse large B-cell lymphoma.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 01-04-2013
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Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma in adults. The disease exhibits a striking heterogeneity in gene expression profiles and clinical outcomes, but its genetic causes remain to be fully defined. Through whole genome and exome sequencing, we characterized the genetic diversity of DLBCL. In all, we sequenced 73 DLBCL primary tumors (34 with matched normal DNA). Separately, we sequenced the exomes of 21 DLBCL cell lines. We identified 322 DLBCL cancer genes that were recurrently mutated in primary DLBCLs. We identified recurrent mutations implicating a number of known and not previously identified genes and pathways in DLBCL including those related to chromatin modification (ARID1A and MEF2B), NF-?B (CARD11 and TNFAIP3), PI3 kinase (PIK3CD, PIK3R1, and MTOR), B-cell lineage (IRF8, POU2F2, and GNA13), and WNT signaling (WIF1). We also experimentally validated a mutation in PIK3CD, a gene not previously implicated in lymphomas. The patterns of mutation demonstrated a classic long tail distribution with substantial variation of mutated genes from patient to patient and also between published studies. Thus, our study reveals the tremendous genetic heterogeneity that underlies lymphomas and highlights the need for personalized medicine approaches to treating these patients.
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A preliminary study of white matter in adolescent depression: relationships with illness severity, anhedonia, and irritability.
Front Psychiatry
PUBLISHED: 01-01-2013
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Major depressive disorder (MDD) during adolescence is a common and disabling psychiatric condition; yet, little is known about its neurobiological underpinning. Evidence indicates that MDD in adults involves alterations in white and gray matter; however, sparse research has focused on adolescent MDD. Similarly, little research has accounted for the wide variability of symptom severity among depressed teens. Here, we aimed to investigate white matter (WM) microstructure between 17 adolescents with MDD and 16 matched healthy controls (HC) using diffusion tensor imaging. We further assessed within the MDD group relationships between WM integrity and depression severity, as well as anhedonia and irritability - two core symptoms of adolescent MDD. As expected, adolescents with MDD manifested decreased WM integrity compared to HC in the anterior cingulum and anterior corona radiata. Within the MDD group, greater depression severity was correlated with reduced WM integrity in the genu of corpus callosum, anterior thalamic radiation, anterior cingulum, and sagittal stratum. However, anhedonia and irritability were associated with alterations in distinct WM tracts. Specifically, anhedonia was associated with disturbances in tracts related to reward processing, including the anterior limb of the internal capsule and projection fibers to the orbitofrontal cortex. Irritability was associated with decreased integrity in the sagittal stratum, anterior corona radiata, and tracts leading to prefrontal and temporal cortices. Overall, these preliminary findings provide further support for the hypotheses that there is a disconnect between prefrontal and limbic emotional regions in depression, and that specific clinical symptoms involve distinct alterations in WM tracts.
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Obesity, metabolism and the microenvironment: Links to cancer.
J Carcinog
PUBLISHED: 01-01-2013
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Historically, cancer research has focused on identifying mutations or amplification of genes within the tumor, which informed the development of targeted therapies against affected pathways. This work often considers tumor cells in isolation; however, it is becoming increasingly apparent that the microenvironment surrounding tumor cells strongly influences tumor onset and progression. This is the so-called "seed and soil" hypothesis wherein the seed (cancer cell) is fed and molded by the metabolites, growth factors, modifications of the extracellular matrix or angiogenic factors provided by the soil (or stroma). Currently, 65% of the US population is obese or overweight; similarly staggering figures are reported in US children and globally. Obesity mediates and can exacerbate, both normal and tumor microenvironment dysfunction. Many obesity-associated endocrine, metabolic and inflammatory mediators are suspected to play a role in oncogenesis by modifying systemic nutrient metabolism and the nutrient substrates available locally in the stroma. It is vitally important to understand the biological processes linking obesity and cancer to develop better intervention strategies aimed at curbing the carcinogenic events associated with obesity. In this review, obesity-driven changes in both the normal and tumor microenvironment, alterations in metabolism, and release of signaling molecules such as endocrine, growth, and inflammatory mediators will be highlighted. In addition, we will discuss the effects of the timing of obesity onset or particular "windows of susceptibility," with a focus on breast cancer etiology.
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Characterization of a new chronic lymphocytic leukemia cell line for mechanistic in vitro and in vivo studies relevant to disease.
PLoS ONE
PUBLISHED: 01-01-2013
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Studies of chronic lymphocytic leukemia (CLL) have yielded substantial progress, however a lack of immortalized cell lines representative of the primary disease has hampered a full understanding of disease pathogenesis and development of new treatments. Here we describe a novel CLL cell line (OSU-CLL) generated by EBV transformation, which displays a similar cytogenetic and immunophenotype observed in the patients CLL (CD5 positive with trisomy 12 and 19). A companion cell line was also generated from the same patient (OSU-NB). This cell line lacked typical CLL characteristics, and is likely derived from the patients normal B cells. In vitro migration assays demonstrated that OSU-CLL exhibits migratory properties similar to primary CLL cells whereas OSU-NB has significantly reduced ability to migrate spontaneously or towards chemokine. Microarray analysis demonstrated distinct gene expression patterns in the two cell lines, including genes on chromosomes 12 and 19, which is consistent with the cytogenetic profile in this cell line. Finally, OSU-CLL was readily transplantable into NOG mice, producing uniform engraftment by three weeks with leukemic cells detectable in the peripheral blood spleen and bone marrow. These studies describe a new CLL cell line that extends currently available models to study gene function in this disease.
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Predictors of driving outcomes in advancing age.
Psychol Aging
PUBLISHED: 12-19-2011
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This study aimed to develop predictive models for real-life driving outcomes in older drivers. Demographics, driving history, on-road driving errors, and performance on visual, motor, and neuropsychological test scores at baseline were assessed in 100 older drivers (ages 65-89 years [72.7]). These variables were used to predict time to driving cessation, first moving violation, or crash. Using Cox proportional hazards regression models, significant individual predictors for driving cessation were greater age and poorer scores on Near Visual Acuity, Contrast Sensitivity, Useful Field of View, Judgment of Line Orientation, Trail Making Test-Part A, Benton Visual Retention Test, Grooved Pegboard, and a composite index of overall cognitive ability. Greater weekly mileage, higher education, and "serious" on-road errors predicted moving violations. Poorer scores from Trail Making Test-Part B or Trail Making Test (B-A) and serious on-road errors predicted crashes. Multivariate models using "off-road" predictors revealed (a) age and Contrast Sensitivity as best predictors for driving cessation; (b) education, weekly mileage, and Auditory Verbal Learning Task-Recall for moving violations; and (c) education, number of crashes over the past year, Auditory Verbal Learning Task-Recall, and Trail Making Test (B-A) for crashes. Diminished visual, motor, and cognitive abilities in older drivers can be easily and noninvasively monitored with standardized off-road tests, and performances on these measures predict involvement in motor vehicle crashes and driving cessation, even in the absence of a neurological disorder.
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Changes in lipoprotein subfraction concentration and composition in healthy individuals treated with the CETP inhibitor anacetrapib.
J. Lipid Res.
PUBLISHED: 12-17-2011
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We investigated the effects of the cholesteryl ester (CE) transfer protein inhibitor anacetrapib (ANA) on plasma lipids, lipoprotein subfraction concentrations, and lipoprotein composition in 30 healthy individuals. Participants (n = 30) were randomized to ANA 20 mg/day, 150 mg/day, or placebo for 2 weeks. Changes in concentration of lipoprotein subfractions were assessed using ion mobility, and compositional analyses were performed on fractions separated by density gradient ultracentrifugation. ANA 150 mg/day versus placebo resulted in significant decreases in LDL-cholesterol (26%) and apo B (29%) and increases in HDL-cholesterol (82%). Concentrations of medium and small VLDL, large intermediate density lipoprotein (IDL), and medium and small LDL (LDL2a, 2b, and 3a) decreased whereas levels of very small and dense LDL4b were increased. There was enrichment of triglycerides and reduction of CE in VLDL, IDL, and the densest LDL fraction. Levels of large buoyant HDL particles were substantially increased, and there was enrichment of CE, apo AI, and apoCIII, but not apoAII or apoE, in the mid-HDL density range. Changes in lipoprotein subfraction concentrations and composition with ANA 20 mg/day were similar to those for ANA 150 mg/day but were generally smaller in magnitude. The impact of these changes on cardiovascular risk remains to be determined.
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Design and manufacture of combinatorial calcium phosphate bone scaffolds.
J Biomech Eng
PUBLISHED: 11-11-2011
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It is well known that pore design is an important determinant of both the quantity and distribution of regenerated bone in artificial bone tissue scaffolds. A requisite feature is that scaffolds must contain pore interconnections on the order of 100-1000 ?m (termed macroporosity). Within this range, there is not a definitive optimal interconnection size. Recent results suggest that pore interconnections permeating the scaffold build material on the order of 2-20 ?m (termed microporosity) drive bone growth into the macropore space at a faster rate and also provide a new space for bone growth, proliferating throughout the interconnected microporous network. The effects of microstructural features on bone growth has yet to be fully understood. This work presents the manufacture and characterization of novel combinatorial test scaffolds, scaffolds that test multiple microporosity and macroporosity designs within a single scaffold. Scaffolds such as this can efficiently evaluate multiple mechanical designs, with the advantage of having the designs colocated within a single defect site and therefore less susceptible to experimental variation. This paper provides the manufacturing platform, manufacturing control method, and demonstrates the manufacturing capabilities with three representative scaffolds.
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Cognitive functioning predicts driver safety on road tests 1 and 2 years later.
J Am Geriatr Soc
PUBLISHED: 10-31-2011
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To describe longitudinal changes in mean level and evaluate rank-order stability in potential predictors of driving safety (visual sensory, motor, visual attention, and cognitive functioning) and safety errors during an 18-mile on-road driving test in older adults and to evaluate the relative predictive power of earlier visual sensory, motor, visual attention, and cognitive functioning on future safety errors, controlling for earlier driving capacity.
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AP-1 elements and TCL1 protein regulate expression of the gene encoding protein tyrosine phosphatase PTPROt in leukemia.
Blood
PUBLISHED: 10-14-2011
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We previously demonstrated that the gene encoding PTPROt, the truncated form of protein tyrosine phosphatase receptor type O expressed predominantly in hematopoietic cells, is a candidate tumor suppressor and is down-regulated in chronic lymphocytic leukemia (CLL). Here, we show that PTPROt expression is significantly reduced in CD19(+) spleen B cells from E?-T cell leukemia 1 (TCL1) transgenic mice relative to the wild-type mice. Strikingly, as much as a 60% decrease in PTPROt expression occurs at 7 weeks independently of promoter methylation. To elucidate the potential mechanism for this early suppression of PTPROt in these mice, we explored the role of activating protein-1 (AP-1) in its expression. We first demonstrate that AP-1 activation by 12-O-tetradecanoylphorbol-13-acetate induces PTPROt expression with concurrent recruitment of c-fos and c-jun to its promoter. The PTPROt promoter is also responsive to over- and underexpression of AP-1, confirming the role of AP-1 in PTPROt expression. Next, we demonstrate that TCL1 can repress the PTPROt promoter by altering c-fos expression and c-jun activation state. Finally, using primary CLL cells we have shown an inverse relationship between TCL1 and PTPROt expression. These findings further substantiate the role of TCL1 in PTPROt suppression and its importance in the pathogenesis of CLL.
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An osteopathic approach to type 2 diabetes mellitus.
J Am Osteopath Assoc
PUBLISHED: 09-30-2011
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The prevalence of type 2 diabetes mellitus (T2DM) has reached epidemic proportions in the United States, the impact of which is seen in all medical practices. The tenets of osteopathic medicine are readily applicable to a proactive approach to patients with T2DM and are (1) the body is a unit; the person is a unit of body, mind, and spirit; (2) the body is capable of self-regulation, self-healing, and health maintenance; (3) structure and function are reciprocally interrelated; and (4) rational treatment is based upon an understanding of these basic principles. The authors examine the evidence that supports the application of these tenets to the prevention and management of T2DM and cover topics including the removal of noxious stimuli to help the body function optimally; the musculoskeletal systems role in disease prevention and management; the dynamic interaction of body, mind, and spirit, all 3 of which must be addressed to maintain health and limit disease; and intrinsic and extrinsic forces that can either promote or provoke a persons health.
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Breast tumors induced by N-methyl-N-nitrosourea are damaging to bone strength, structure, and mineralization in the absence of metastasis in rats.
J. Bone Miner. Res.
PUBLISHED: 09-03-2011
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Current theory on the influence of breast cancer on bone describes metastasis of tumor cells to bone tissue, followed by induction of osteoclasts and bone degradation. Tumor influences on bone health in pre- or nonmetastatic models are unknown. Female rats (n?=?48, 52 days old) were injected with N-methyl-N-nitrosourea (MNU) to induce breast cancer. Animals were euthanized 10 weeks later, and tumors were weighed and classified histologically. Right femurs were extracted for testing of bone mineral density (BMD) by dual X-ray absorptiometry (DXA), bone mechanical strength by three-point bending and femoral neck bending tests, and structure by micro-computed tomography (µCT). Of 48 rats, 22 developed one or more tumors in response to MNU injection by 10 weeks. Presence of any tumor predicted significantly poorer bone health in 17 of 28 measures. In tumored versus nontumored animals, BMD was adversely affected by 3%, force at failure of the femoral midshaft by 4%, force at failure of the femoral neck by 12%, and various trabecular structural parameters by 6% to 27% (all p?
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Effects of coadministered extended-release niacin/laropiprant and simvastatin on lipoprotein subclasses in patients with dyslipidemia.
J Clin Lipidol
PUBLISHED: 08-30-2011
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The use of extended-release niacin and the prostaglandin D? receptor antagonist laropiprant (ERN/LRPT) reduces niacin-induced flushing in patients while preserving its lipid-modifying effects.
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Lipid-altering efficacy of switching to ezetimibe/simvastatin 10/20 mg versus rosuvastatin 10 mg in high-risk patients with and without metabolic syndrome.
Diab Vasc Dis Res
PUBLISHED: 08-22-2011
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Metabolic syndrome (MetS) is a clustering of atherosclerotic coronary heart disease risk factors. This post-hoc analysis compared the effects of switching to ezetimibe/simvastatin 10/20 mg or rosuvastatin 10 mg in a cohort of 618 high-risk hypercholesterolaemic patients with (n=368) and without (n=217) MetS who had previously been on statin monotherapy. Patients were randomised 1:1 to double-blind ezetimibe/simvastatin 10/20 mg or rosuvastatin 10 mg for 6 weeks. Least squares mean percent change from baseline and 95% confidence intervals in lipid efficacy parameters were calculated for the population and within subgroups. Treatment with ezetimibe/simvastatin was significantly more effective than rosuvastatin at lowering low-density lipoprotein cholesterol, total cholesterol, non- high-density lipoprotein cholesterol, and apolipoprotein B (all p<0.001). No significant differences in treatment effects were seen between the presence and absence of MetS. In this post-hoc analysis of high-risk hypercholesterolaemic patients the lipid-reducing effects of ezetimibe/simvastatin or rosuvastatin were not altered significantly by the presence of MetS.
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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.