tbuckley/cabot-search huggingface dataset:
Metformin Amplifies Chemotherapy-Induced AMPK Activation and Antitumoral Growth
Authors: Guilherme Z. Rocha, Marília M. Dias, Eduardo R. Ropelle, Felipe Osório-Costa, Franco A. Rossato, Anibal E. Vercesi, Mario J.A. Saad, José B.C. Carvalheira
Journal: Clinical Cancer Research (2011)

Metformin is a widely used antidiabetic drug whose anticancer effects, mediated by the activation of AMP-activated protein kinase (AMPK) and reduction of mTOR signaling, have become noteworthy. Chemotherapy produces genotoxic stress and induces p53 activity, which can cross-talk with AMPK/mTOR pathway. Herein, we investigate whether the combination of metformin and paclitaxel has an effect in cancer cell lines.Human tumors were xenografted into severe combined immunodeficient (SCID) mice and the cancer cell lines were treated with only paclitaxel or only metformin, or a combination of both drugs. Western blotting, flow cytometry, and immunohistochemistry were then used to characterize the effects of the different treatments.The results presented herein show that the addition of metformin to paclitaxel leads to quantitative potentialization of molecular signaling through AMPK and a subsequent potent inhibition of the mTOR signaling pathway. Treatment with metformin and paclitaxel resulted in an increase in the number of cells arrested in the G(2)-M phase of the cell cycle, and decreased the tumor growth and increased apoptosis in tumor-bearing mice, when compared with individual drug treatments.We have provided evidence for a convergence of metformin and paclitaxel induced signaling at the level of AMPK. This mechanism shows how different drugs may cooperate to augment antigrowth signals, and suggests that target activation of AMPK by metformin may be a compelling ally in cancer treatment.
Autophagy Inhibition Sensitizes Colon Cancer Cells to Antiangiogenic and Cytotoxic Therapy
Authors: Muthu Selvakumaran, Ravi K. Amaravadi, Irina A. Vasilevskaya, Peter J. O'Dwyer
Journal: Clinical Cancer Research (2013)

Autophagy is a critical survival pathway for cancer cells under conditions of nutrient or oxygen limitation, or cell stress. As a consequence of antiangiogenic therapy, solid tumors encounter hypoxia induction and imbalances in nutrient supply. We wished to determine the role of autophagy in protection of tumor cells from the effects of antiangiogenic therapy and chemotherapy. We examined the effect of inhibiting autophagy on hypoxic colon cancer cells in vitro and on bevacizumab- and oxaliplatin-treated mouse xenografts in vivo.The autophagic response to hypoxia and DNA-damaging agents was assessed by fluorescent microscopic imaging, autophagy-related gene expression, and by electron microscopic ultrastructural analysis. Pharmacologic and molecular approaches to autophagy inhibition were taken in a panel of colon cancer cell lines. Mouse xenograft models were treated with combinations of oxaliplatin, bevacizumab, and chloroquine to assess effects on tumor growth reduction and on pharmacodynamic markers of autophagy inhibition.Autophagy was induced in colon cancer models by exposure to both hypoxia and oxaliplatin. Inhibition of autophagy, either with chloroquine or by downregulation of beclin1 or of ATG5, enhanced sensitivity to oxaliplatin under normal and hypoxic conditions in a synergistic manner. Both bevacizumab and oxaliplatin treatments activate autophagy in HT29 murine xenografts. The addition of chloroquine to bevacizumab-based treatment provided greater tumor control in concert with evidence of autophagy inhibition.These findings implicate autophagy as a mechanism of resistance to antiangiogenic therapies and support investigation of inhibitory approaches in the management of this disease.
Explaining Variability in Mycophenolic Acid Exposure to Optimize Mycophenolate Mofetil Dosing
Authors: Reinier M. van Hest, Ron A.A. Mathot, Mark D. Pescovitz, Robert Gordon, Richard D. Mamelok, Teun van Gelder
Journal: Journal of the American Society of Nephrology (2006)

Large between- and within-patient variability has been observed in the pharmacokinetics of mycophenolic acid (MPA). However, conflicting results exist about the influence of patient characteristics that explain the variability in MPA exposure. This population pharmacokinetic meta-analysis of MPA in renal transplant recipients was performed to explore whether race, renal function, albumin level, delayed graft function, diabetes, and co-medication are determinants of total MPA exposure. A total of 13,346 MPA concentration-time data points from 468 renal transplant patients who participated in six clinical studies were combined and analyzed retrospectively. Sampling occasions ranged from day 1 after transplantation to 10 yr after transplantation. Concentration-time data were analyzed with nonlinear mixed-effect modeling. Exposure to total MPA, as determined by MPA clearance, significantly increased with increasing renal function, albumin level, and hemoglobin as well as decreasing cyclosporine predose level (P<0.001). These variables could explain 18% of the between-patient and 38% of the within-patient variability in MPA exposure. Differences in MPA exposure between patients with or without delayed graft function or between patients of different races are likely to be caused by the effect of renal function on MPA exposure. Diabetes did not have an effect on MPA exposure. The clinical implication is that a change in renal function or albumin level provides an indication for therapeutic drug monitoring as MPA exposure may be altered. Patients in whom cyclosporine and mycophenolate mofetil are combined may need higher mycophenolate mofetil doses, especially during the early phase after transplantation than currently recommended for optimal MPA exposure.
Central Veins in Brain Lesions Visualized With High-Field Magnetic Resonance Imaging
Authors: Niraj Mistry, Jennifer Dixon, Emma Tallantyre, Christopher Tench, Rasha Abdel-Fahim, Tim Jaspan, Paul S. Morgan, Peter Morris, Nikos Evangelou
Journal: JAMA Neurology (2013)

Importance: There is no single test that is diagnostic for multiple sclerosis (MS), and existing diagnostic criteria are imperfect.This can lead to diagnostic delay.Some patients require multiple (sometimes invasive) investigations, and extensive clinical follow-up to confirm or exclude a diagnosis of MS.A diagnostic biomarker that is pathologically specific for the inflammatory demyelination in MS could overhaul current diagnostic algorithms.Objective: To prospectively assess the diagnostic value of visualizing central veins in brain lesions with magnetic resonance imaging (MRI) for patients with possible MS for whom the diagnosis is uncertain.Design: Prospective longitudinal cohort study.The reference standard is a clinical diagnosis that is arrived at (after a mean follow-up of 26 months) by the treating neurologist with a specialist interest in MS.The 7-T MRI scans were analyzed at baseline, by physicians blinded to the clinical data, for the presence of visible central veins.Setting: Academic MS referral center.Participants: A consecutive sample of 29 patients referred with possible MS who had brain lesions detected on clinical MRI scans but whose condition remained un-diagnosed despite expert clinical and radiological assessments.Exposure: Seven-Tesla MRI using a T2*-weighted sequence. Main Outcomes and Measures:The proportion of patients whose condition was correctly diagnosed as MS or as not MS, using 7-T MRI at study onset, compared with the eventual diagnosis reached by treating physicians blinded to the result of the MRI scan.Results: Of the 29 patients enrolled and scanned using 7-T MRI, so far 22 have received a clinical diagnosis.All 13 patients whose condition was eventually diagnosed as MS had central veins visible in the majority of brain lesions at baseline.All 9 patients whose condition was eventually not diagnosed as MS had central veins visible in a minority of lesions. Conclusions and Relevance:In our study, T2*weighted 7-T MRI had 100% positive and negative predictive value for the diagnosis of MS.Clinical application of this technique could improve existing diagnostic algorithms.
Bulk Manufacture of Concentrated Oxygen Gas‐Filled Microparticles for Intravenous Oxygen Delivery
Authors: John N. Kheir, Brian D. Polizzotti, Lindsay M. Thomson, Daniel W. O'Connell, Katherine J. Black, Robert W. Lee, James N. Wilking, Adam C. Graham, David C. Bell, Francis X. McGowan
Journal: Advanced Healthcare Materials (2013)

Abstract Self‐assembling, concentrated, lipid‐based oxygen microparticles (LOMs) have been developed to administer oxygen gas when injected intravenously, preventing organ injury and death from systemic hypoxemia in animal models. Distinct from blood substitutes, LOMs are a one‐way oxygen carrier designed to rescue patients who experience life‐threatening hypoxemia, as caused by airway obstruction or severe lung injury. Here, we describe methods to manufacture large quantities of LOMs using an in‐line, recycling, high‐shear homogenizer, which can create up to 4 liters of microparticle emulsion in 10 minutes, with particles containing a median diameter of 0.93 microns and 60 volume% of gas phase. Using this process, we screen 30 combinations of commonly used excipients for their ability to form stable LOMs. LOMs composed of DSPC and cholesterol in a 1:1 molar ratio are stable for a 100 day observation period, and the number of particles exceeding 10 microns in diameter does not increase over time. When mixed with blood in vitro, LOMs fully oxygenate blood within 3.95 seconds of contact, and do not cause hemolysis or complement activation. LOMs can be manufactured in bulk by high shear homogenization, and appear to have a stability and size profile which merit further testing.
Static pressure-flow relation in the total systemic vascular bed of the dog and its modification by the baroreceptor reflex.
Authors: K Sagawa, A Eisner
Journal: Circulation Research (1975)

To evaluate arterial baroreceptor reflex control of total systemic vascular resistance, we studied the relation between mean arterial blood pressure (P) and mean aortic flow (Q) before and after the reflex was abrogated. In 12 dogs with a perfusion pump interposed at the vena-caval-right atrial junction, Q was kept at 60, 80, 100, 120, and 140 ml/min kg-1 for up to 20 minutes. There was little time-dependent change in P at any of these flows. When the reflex was intact, the mean P-Q curve was only slightly convex to the pressure axis; its linearized slope was 0.55 mm Hg-min-kg/ml and its pressure axis intercept was 44 mm Hg. After section of the sinovagal nerves, administration of hexamethonium (30 mg/kg, iv) and norepinephrine (3-5 mug/kg min-1, iv), or both, the slope became 0.96 mm Hg-min-kg/ml and the pressure axis intercept was about 3 mm Hg. Similar findings were obtained in 3 closed-chest dogs in which P was servocontrolled and Q was measured. Therefore, we think that the conventional practice of calculating total peripheral resistance as P/Q and evaluating reflex control of it in terms of the changes in that value involves only a small error in the moderately sub -and supranormal flow range.
IL‐12 receptor β2 and CD30 expression in paranasal sinus mucosa of patients with chronic sinusitis
Authors: H. Suzuki, S. Goto, K. Ikeda, T. Oshima, M. Furukawa, T. Takasaka
Journal: European Respiratory Journal (1999)

The aetiology of chronic sinusitis is still poorly understood. The expression of T-helper 1 (Th1) and T-helper 2 (Th2) cell markers, interleukin (IL)-12 receptor beta2 subunit (IL-12Rbeta2) messenger ribonucleic acid (mRNA) and CD30, respectively, were investigated in the paranasal sinus mucosa of patients with chronic sinusitis in an attempt to elucidate the involvement of Th1 and Th2 cells in this disease. Anterior ethmoidal mucosae were surgically obtained from two groups of patients with chronic sinusitis: those who had allergic rhinitis (allergic group, n=11) and those without allergy (nonallergic group, n=11). IL-12Rbeta2 mRNA was quantified by means of the reverse transcription polymerase chain reaction, and CD30-positive cells were examined immunohistochemically. Both IL-12Rbeta2 mRNA and CD30 were expressed in the sinus mucosa of the allergic and nonallergic groups. The proportion of mononuclear cells which were CD30-positive in the sinus mucosa was significantly greater in the allergic than in the nonallergic group. The expression levels of IL-12Rbeta2 mRNA were virtually equivalent in both groups. These results suggest a T-helper 2-dominated mucosal reaction in the allergic compared to the nonallergic group, and indicate T-helper 1 activity in the sinus mucosa of both groups. The ubiquity of T-helper 1 cells suggests that they play a role in maintaining local mucosal defences against foreign antigens, which continually enter the upper respiratory tract.
Selective Growth Inhibition of Tumor Cells by a Novel Histone Deacetylase Inhibitor, NVP-LAQ824
Authors: Peter Atadja, Lin Gao, Paul Kwon, Nancy Trogani, Heather Walker, Meier Hsu, Lakshmi Yeleswarapu, Nagarajan Chandramouli, Larry Perez, Richard Versace, Arthur Wu, Lidia Sambucetti, Peter Lassota, Dalia Cohen, Kenneth Bair, Alexander Wood, Stacy Remiszewski
Journal: Cancer Research (2004)

We have synthesized a histone deacetylase inhibitor, NVP-LAQ824, a cinnamic hydroxamic acid, that inhibited in vitro enzymatic activities and transcriptionally activated the p21 promoter in reporter gene assays. NVP-LAQ824 selectively inhibited growth of cancer cell lines at submicromolar levels after 48-72 h of exposure, whereas higher concentrations and longer exposure times were required to retard the growth of normal dermal human fibroblasts. Flow cytometry studies revealed that both tumor and normal cells arrested in the G(2)-M phase of the cell cycle after compound treatment. However, an increased sub-G(1) population at 48 h (reminiscent of apoptotic cells) was observed only in the cancer cell line. Annexin V staining data supported our hypothesis that NVP-LAQ824 induced apoptosis in tumor and transformed cells but not in normal cells. Western blotting experiments showed an increased histone H3 and H4 acetylation level in NVP-LAQ824-treated cancer cells, suggesting that the likely in vivo target of NVP-LAQ824 was histone deacetylase(s). Finally, NVP-LAQ824 exhibited antitumor effects in a xenograft animal model. Together, our data indicated that the activity of NVP-LAQ824 was consistent with its intended mechanism of action. This novel histone deacetylase inhibitor is currently in clinical trials as an anticancer agent.
Akt and Hypoxia-Inducible Factor-1 Independently Enhance Tumor Growth and Angiogenesis
Authors: Andrew M. Arsham, David R. Plas, Craig B. Thompson, M. Celeste Simon
Journal: Cancer Research (2004)

Abstract Recent reports have suggested that phosphatidylinositol 3-kinase/Akt signaling can induce angiogenesis and tumor growth by activating the hypoxia-inducible factor-1 (HIF-1). However, the absence of specific biochemical inhibitors of HIF-1 signaling has prevented a direct test of the requirement for HIF-1 activity in Akt-dependent tumorigenesis. To genetically test the relationship between HIF-1 and Akt, activated Akt was expressed in a hepatoma cell line lacking HIF-1. Akt expression was associated with a dramatic increase in tumor size, despite the absence of HIF-1. Tumor size was not further increased in cells with reconstituted HIF-1 activity, indicating that the effects of Akt on tumorigenesis were not limited by the absence of HIF-1. Increased tumor size in Akt-expressing, HIF-deficient cells was associated with vascular endothelial growth factor secretion and tumor vascularization. In addition to vascular endothelial growth factor production, Akt also conferred a cell-autonomous competitive advantage to tumor cells in an in vivo competition experiment. Thus, Akt has potent, HIF-1-independent oncogenic and angiogenic activities.
Emotion Regulation and Psychopathology: The Role of Gender
Authors: Susan Nolen-Hoeksema
Journal: Annual Review of Clinical Psychology (2012)

This review addresses three questions regarding the relationships among gender, emotion regulation, and psychopathology: (a) are there gender differences in emotion regulation strategies, (b) are emotion regulation strategies similarly related to psychopathology in men and women, and (c) do gender differences in emotion regulation strategies account for gender differences in psychopathology? Women report using most emotion regulation strategies more than men do, and emotion regulation strategies are similarly related to psychopathology in women and men. More rumination in women compared to men partially accounts for greater depression and anxiety in women compared to men, while a greater tendency to use alcohol to cope partially accounts for more alcohol misuse in men compared to women. The literature on emotion regulation is likely missing vital information on how men regulate their emotions. I discuss lessons learned and questions raised about the relationships between gender differences in emotion regulation and gender differences in psychopathology.
Prognostic Value of Echocardiographic Indicators of Left Ventricular Systolic Function in Asymptomatic Dialysis Patients
Authors: Carmine Zoccali, Francesco A. Benedetto, Francesca Mallamaci, Giovanni Tripepi, Giuseppe Giacone, Alessandro Cataliotti, Giuseppe Seminara, Benedetta Stancanelli, Lorenzo S. Malatino
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Patients with end-stage renal disease (ESRD) are at high risk for heart failure, but the prevalence and the prognostic value of asymptomatic systolic dysfunction in these patients are unknown. In this prospective cohort study, the authors have therefore assessed by echocardiography the prevalence and the prognostic value of systolic function as estimated by ejection fraction (EF), fractional shortening at endocardial level (endoFS), and at midwall (mwFS), in a cohort of 254 asymptomatic dialysis patients. Systolic dysfunction had a prevalence rate of 26% by endoFS and of 48% by mwFS. During the follow-up period, 125 patients had one or more fatal and nonfatal CV events. On multivariate COX regression analysis, the three LV systolic function indicators were independently associated with incident fatal and nonfatal CV events, and there were no differences in the predictive power of these indicators (P > 0.30). The prediction power of LV function indicators was largely independent of traditional and novel risk factors in ESRD such as C-reactive protein and asymmetric dimethyl arginine (ADMA). ADMA was significantly related with LV function indicators as well as with mortality and incident CV events, but these links were much reduced (P = NS) in models including LV function indicators. Of note, the risk of CV events was minimal in patients with normal LV mass and function, intermediate in patients with either LVH or systolic dysfunction, and maximal in patients displaying both alterations. The study of myocardial contractility by echocardiography provides prognostic information independently of LV mass and other risk factors in ESRD. Risk stratification by simple systolic function parameters may prove useful in secondary prevention strategies in these patients.
Singling out genetic disorders and disease
Authors: Martine De Rycke
Journal: Genome Medicine (2010)

Preimplantation genetic diagnosis (PGD) involves testing of single cells biopsied from oocytes and/or embryos generated in vitro. As only embryos unaffected for a given genetic condition are transferred to the uterus, it avoids prenatal diagnosis and termination of pregnancy. Follow-up data from PGD pregnancies, deliveries and children show an acceptable live birth rate and, so far, no detrimental effects of the procedure have been observed. Of course, the long-term health outcome is currently unknown. PGD was first performed in 1990 and remained an experimental procedure for a number of years. Now, two decades later, it is regarded as an established alternative to prenatal diagnosis: its use has expanded, the range of applications has broadened, and continuous technical progress in single-cell testing has led to high levels of efficiency and accuracy. The current gold standard methods (single-cell multiplex-PCR for monogenic diseases and interphase fluorescence in situ hybridization for chromosomal aberrations) are being replaced by single-cell whole genome amplification and array technology. These generalized methods substantially reduce the pre-PGD workload and allow more automated genome-wide analysis. The implementation of laboratory accreditation schemes brings the field at the same level of routine diagnostics. This article reviews the state of the art and considers indications, accuracy and current technical changes in the field of PGD.
Quality of Life of Postmenopausal Women in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Adjuvant Breast Cancer Trial
Authors: Lesley Fallowfield, David Cella, Jack Cuzick, Stephen Francis, Gershon Locker, Anthony Howell
Journal: Journal of Clinical Oncology (2004)

To determine the quality of life (QoL) of women participating in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Adjuvant Breast Cancer Trial during the first 2 years of treatment.A total of 1,021 women were enrolled onto the QoL subprotocol. All had completed primary treatment (surgery +/- radiotherapy +/- chemotherapy) and were to receive 5 years of adjuvant treatment with anastrozole (n = 335), tamoxifen (n = 347), or a combination (n = 339) of both. Patients completed the Functional Assessment of Cancer Therapy-Breast (FACT-B) plus endocrine subscale (ES) at baseline and 3, 6, 12, 18, and 24 months, or until disease recurrence. The primary end point was the FACT-B Trial Outcome Index (TOI). The secondary end point was the ES total score. Analyses of individual endocrine symptoms were also explored.Questionnaire completion approximated 85% of assessments available for analysis. Overall QoL for all groups improved from baseline during the 2-year period. There were no significant differences in TOI or ES scores across treatment groups. Endocrine symptoms increased between baseline and 3 months for all groups and stabilized thereafter. There were some small differences in side effect profiles. Compared with patients receiving tamoxifen only, patients receiving anastrozole only reported significantly fewer cold sweats and vaginal discharge, yet more vaginal dryness, painful intercourse, and loss of sexual interest.Two years of treatment with anastrozole, tamoxifen, or the combination had a similar overall QoL impact, showing gradual improvement over time. Endocrine-related symptoms for all three arms worsened initially and recovered partially during 2 years. The different symptoms experienced may assist in decision making about treatment and supportive care needs.