tbuckley/cabot-search huggingface dataset:
The histone deacetylase inhibitor, LBH589, promotes the systemic cytokine and effector responses of adoptively transferred CD8+ T cells
Authors: Dominique N Lisiero, Horacio Soto, Richard G Everson, Linda M Liau, Robert M Prins
Journal: Journal for ImmunoTherapy of Cancer (2014)

Histone deacetylase (HDAC) inhibitors are a class of agents that have potent antitumor activity with a reported ability to upregulate MHC and costimulatory molecule expression. We hypothesized that epigenetic pharmacological immunomodulation could sensitize tumors to immune mediated cell death with an adoptive T cell therapy.The pan-HDAC inhibitor, LBH589, was combined with gp100 specific T cell immunotherapy in an in vivo B16 melanoma model and in an in vivo non-tumor bearing model. Tumor regression, tumor specific T cell function and phenotype, and serum cytokine levels were evaluated.Addition of LBH589 to an adoptive cell transfer therapy significantly decreased tumor burden while sustaining systemic pro-inflammatory levels. Furthermore, LBH589 was able to enhance gp100 specific T cell survival and significantly decrease T regulatory cell populations systemically and intratumorally. Even in the absence of tumor, LBH589 was able to enhance the proliferation, retention, and polyfunctional status of tumor specific T cells, suggesting its effects were T cell specific. In addition, LBH589 induced significantly higher levels of the IL-2 receptor (CD25) and the co-stimulatory molecule OX-40 in T cells.These results demonstrate that immunomodulation of adoptively transferred T cells by LBH589 provides a novel mechanism to increase in vivo antitumor efficacy of effector CD8 T cells.
Comparison of computed density and macroscopic morphometry in pulmonary emphysema.
Authors: P A Gevenois, V de Maertelaer, P De Vuyst, J Zanen, J C Yernault
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

High-resolution computed tomography (HRCT) scans were obtained at 1 cm intervals in 63 subjects referred for surgical resection of a cancer or for transplantation to find out whether the relative area of lung occupied by attenuation values lower than a threshold would be a measurement of macroscopic emphysema. Using a semiautomatic procedure, the relative areas occupied by attenuation values lower than eight thresholds ranging from -900 to -970 HU were calculated on the set of scans obtained through the lobe or the lung to be resected. The extent of emphysema was quantified by a computer-assisted method on horizontal paper-mounted lung sections obtained every 1 to 2 cm. The only level for which no statistically significant difference was found between the HRCT and the morphometric data was -950 HU. To determine the number of scans sufficient for an accurate quantification, we recalculated the relative area occupied by attenuation values lower than -950 HU on progressively fewer numbers of scans and investigated the departure from the results obtained with 1 cm intervals. Because of wide variations in this departure from patient to patient, a standard cannot be recommended as the optimal distance between scans.
Allopurinol Attenuates Left Ventricular Remodeling and Dysfunction After Experimental Myocardial Infarction
Authors: Niels Engberding, Stephan Spiekermann, Arnd Schaefer, André Heineke, Antje Wiencke, Maja Müller, Martin Fuchs, Denise Hilfiker-Kleiner, Burkhard Hornig, Helmut Drexler, Ulf Landmesser
Journal: Circulation (2004)

Accumulating evidence suggests a critical role for increased reactive oxygen species (ROS) production in left ventricular (LV) remodeling and dysfunction after myocardial infarction (MI). Increased expression of xanthine oxidase (XO), a major source of ROS, has recently been demonstrated in experimental and clinical heart failure; however, a potential role for LV remodeling processes remains unclear. We therefore studied the effect of long-term treatment with allopurinol, a potent XO inhibitor, on myocardial ROS production and LV remodeling and dysfunction after MI.Mice with extensive anterior MI (n=105) were randomized to treatment with either vehicle or allopurinol (20 mg x kg(-1) x d(-1) by gavage) for 4 weeks starting on day 1 after surgery. Infarct size was similar among the groups. XO expression and activity were markedly increased in the remote myocardium of mice after MI, as determined by electron spin resonance spectroscopy. Myocardial ROS production was increased after MI but markedly reduced after allopurinol treatment. Importantly, allopurinol treatment substantially attenuated LV cavity dilatation and dysfunction after MI, as assessed by echocardiography, and markedly reduced myocardial hypertrophy and interstitial fibrosis.The present study reveals a novel beneficial effect of treatment with allopurinol, ie, a marked attenuation of LV remodeling processes and dysfunction after experimental MI. Allopurinol treatment therefore represents a potential novel strategy to prevent LV remodeling and dysfunction after MI.
NHS surplus could mean patients are losing out on services, MPs warn
Authors: A. O'Dowd
Journal: BMJ (2009)

Patients could be missing out on crucial health care, the cost of which has already been financially allocated, because NHS organisations are trying to make a surplus in their finances, MPs have said.

Surpluses for the NHS are good but can leave money “sitting unspent in bank accounts” rather than being used to treat patients, said a report published this week by the parliamentary committee for public accounts.

The report details how the Department of Health and the NHS achieved a surplus of £1.67bn (€1.9bn; $2.6bn) in 2007-8, the equivalent of about one week’s funding for the whole NHS.

The surplus was considerably …
Defining Molecular Profiles of Poor Outcome in Patients With Invasive Bladder Cancer Using Oligonucleotide Microarrays
Authors: Marta Sanchez-Carbayo, Nicholas D. Socci, Juanjo Lozano, Fabien Saint, Carlos Cordon-Cardo
Journal: Journal of Clinical Oncology (2006)

Purpose Bladder cancer is a common malignancy characterized by a poor clinical outcome when tumors progress into invasive disease. We sought to define genetic signatures characteristic of aggressive clinical behavior in advanced bladder tumors. Methods Oligonucleotide arrays were utilized to analyze the transcript profiles of 105 bladder tumors: 33 superficial, 72 invasive lesions, and 52 normal urothelium. Hierarchical clustering and supervised algorithms were used to classify and stratify bladder tumors on the basis of stage, node metastases, and overall survival. Immunohistochemical analyses on bladder cancer tissue arrays (n = 294 cases) served to validate associations between marker expression, staging and outcome. Results Hierarchical clustering classified normal urothelium, superficial, and invasive tumors with 82.2% accuracy, and stratified bladder tumors on the basis of clinical outcome. Predictive algorithms rendered an 89%-correct rate for tumor staging using genes differentially expressed between superficial and invasive tumors. Accuracies of 82% and 90% were obtained for predicting overall survival when considering all patients with bladder cancer or only patients with invasive disease, respectively. A genetic profile consisting of 174 probes was identified in those patients with positive lymph nodes and poor survival. Two independent Global Test runs confirmed the robust association of this profile with lymph node metastases (P = 7.3 –13 ) and overall survival (P = 1.9 –14 ) simultaneously. Immunohistochemical analyses on tissue arrays sustained the significant association of synuclein with tumor staging and clinical outcome (P = .002). Conclusion Gene profiling provides a genomic-based classification scheme of diagnostic and prognostic utility for stratifying advanced bladder cancer. Identification of this poor outcome profile could assist in selecting patients who may benefit from more aggressive therapeutic intervention.
Calcium Dynamics in Cortical Astrocytes and Arterioles During Neurovascular Coupling
Authors: Jessica A. Filosa, Adrian D. Bonev, Mark T. Nelson
Journal: Circulation Research (2004)

Neuronal activity in the brain is thought to be coupled to cerebral arterioles (functional hyperemia) through Ca2+ signals in astrocytes. Although functional hyperemia occurs rapidly, within seconds, such rapid signaling has not been demonstrated in situ, and Ca2+ measurements in parenchymal arterioles are still lacking. Using a laser scanning confocal microscope and fluorescence Ca2+ indicators, we provide the first evidence that in a brain slice preparation, increased neuronal activity by electrical stimulation (ES) is rapidly signaled, within seconds, to cerebral arterioles and is associated with astrocytic Ca2+ waves. Smooth muscle cells in parenchymal arterioles exhibited Ca2+ and diameter oscillations ("vasomotion") that were rapidly suppressed by ES. The neuronal-mediated Ca2+ rise in cortical astrocytes was dependent on intracellular (inositol trisphosphate [IP3]) and extracellular voltage-dependent Ca2+ channel sources. The Na+ channel blocker tetrodotoxin prevented the rise in astrocytic [Ca2+]i and the suppression of Ca2+ oscillations in parenchymal arterioles to ES, indicating that neuronal activity was necessary for both events. Activation of metabotropic glutamate receptors in astrocytes significantly decreased the frequency of Ca2+ oscillations in parenchymal arterioles. This study supports the concept that astrocytic Ca2+ changes signal the cerebral microvasculature and indicate the novel concept that this communication occurs through the suppression of arteriolar [Ca2+]i oscillations and corresponding vasomotion. The full text of this article is available online at http://circres.ahajournals.org.
Weaning from mechanical ventilation
Authors: J Mancebo
Journal: European Respiratory Journal (1996)

Weaning from mechanical ventilation is a period of transition from total ventilatory support to spontaneous breathing. It represents a relevant clinical problem because as many as 25% of intubated and mechanically-ventilated critically ill patients will need a progressive withdrawal from artificial ventilatory support. From a clinical standpoint, it is very important to recognize as soon as possible when a patient is ready to be weaned. Accordingly, a daily routine follow-up should be performed in every patient in order to verify whether patients meet clinical criteria to be disconnected from the ventilator. Several physiological indices have been used to predict the outcome of weaning trials. However, an adequate clinical tolerance to spontaneous breathing during a 2 h T-piece trial is very useful to predict a successful extubation. A number of physiopathological mechanisms explain why some patients fail the weaning trials; particularly important from a clinical point of view are those related to respiratory pump failure and cardiovascular instability, which are usually accompanied by an abnormal gas exchange. Different ventilatory techniques can be used to wean these patients from mechanical ventilation. Up to now, the most efficient techniques seem to be pressure support ventilation and once daily trials of T-piece interspersed with conventional volume assist-control ventilation. Finally, knowledge-based system applied to modern microprocessor mechanical ventilators can help in the process of weaning by automatically reducing the ventilatory assistance and indicating the optimal time to perform extubation.
Antiandrogens Inhibit ABCB1 Efflux and ATPase Activity and Reverse Docetaxel Resistance in Advanced Prostate Cancer
Authors: Yezi Zhu, Chengfei Liu, Cameron Armstrong, Wei Lou, Amandeep Sandher, Allen C. Gao
Journal: Clinical Cancer Research (2015)

Previous studies show that inhibition of ABCB1 expression overcomes acquired docetaxel resistance in C4-2B-TaxR cells. In this study, we examined whether antiandrogens, such as bicalutamide and enzalutamide, could inhibit ABCB1 activity and overcome resistance to docetaxel.ABCB1 efflux activity was determined using a rhodamine efflux assay. ABCB1 ATPase activity was determined by Pgp-Glo assay systems. The effects of the antiandrogens bicalutamide and enzalutamide on docetaxel sensitivity were determined by cell growth assays and tumor growth in vivo.We found that bicalutamide and enzalutamide inhibit ABCB1 ATP-binding cassette transporter activity through blocking ABCB1 efflux activity. Bicalutamide inhibited ABCB1 efflux activity by 40%, whereas enzalutamide inhibited ABCB1 efflux activity by approximately 60%. Both bicalutamide and enzalutamide inhibit ABCB1 ATPase activity. In addition, bicalutamide and enzalutamide inhibit ABCB1 efflux activity and desensitize docetaxel-resistant and androgen receptor (AR)-negative DU145 cells. Combination of bicalutamide with docetaxel had a significant antitumor effect in both AR-positive and AR-negative docetaxel-resistant xenograft models, suggesting that bicalutamide desensitizes docetaxel-resistant cells to docetaxel treatment independent of AR status.We identified a novel mechanism of action for antiandrogens such as bicalutamide and enzalutamide as inhibitors of ABCB1 efflux and ATPase activity. Bicalutamide and enzalutamide desensitize docetaxel-resistant prostate cancer cells to docetaxel treatment independent of AR status. These studies may lead to the development of combinational therapies with bicalutamide/enzalutamide and docetaxel as effective regimens to treat advanced prostate cancer independent of AR status, and possibly other types of cancer.
SEROLOGICAL EVIDENCE OF AN ASSOCIATION OF A NOVEL CHLAMYDIA, TWAR, WITH CHRONIC CORONARY HEART DISEASE AND ACUTE MYOCARDIAL INFARCTION
Authors: P Saikku, K Mattila, M.S Nieminen, J.K Huttunen, M Leinonen, M.-R Ekman, P.H Mäkelä, V Valtonen
Journal: The Lancet (1988)
DNA Shuffling of Adeno-associated Virus Yields Functionally Diverse Viral Progeny
Authors: James T Koerber, Jae-Hyung Jang, David V Schaffer
Journal: Molecular Therapy (2008)

Adeno-associated virus (AAV) vectors are extremely effective gene-delivery vehicles for a broad range of applications. However, the therapeutic efficacy of these and other vectors is currently limited by barriers to safe, efficient gene delivery, including pre-existing antiviral immunity, and infection of off-target cells. Recently, we have implemented directed evolution of AAV, involving the generation of randomly mutagenized viral libraries based on serotype 2 and high-throughput selection, to engineer enhanced viral vectors. Here, we significantly extend this capability by performing high-efficiency in vitro recombination to create a large (107), diverse library of random chimeras of numerous parent AAV serotypes (AAV1, 2, 4–6, 8, and 9). In order to analyze the extent to which such highly chimeric viruses can be viable, we selected the library for efficient viral packaging and infection, and successfully recovered numerous novel chimeras. These new viruses exhibited a broad range of cell tropism both in vitro and in vivo and enhanced resistance to human intravenous immunoglobulin (IVIG), highlighting numerous functional differences between these chimeras and their parent serotypes. Thus, directed evolution can potentially yield unlimited numbers of new AAV variants with novel gene-delivery properties, and subsequent analysis of these variants can further extend basic knowledge of AAV biology. Adeno-associated virus (AAV) vectors are extremely effective gene-delivery vehicles for a broad range of applications. However, the therapeutic efficacy of these and other vectors is currently limited by barriers to safe, efficient gene delivery, including pre-existing antiviral immunity, and infection of off-target cells. Recently, we have implemented directed evolution of AAV, involving the generation of randomly mutagenized viral libraries based on serotype 2 and high-throughput selection, to engineer enhanced viral vectors. Here, we significantly extend this capability by performing high-efficiency in vitro recombination to create a large (107), diverse library of random chimeras of numerous parent AAV serotypes (AAV1, 2, 4–6, 8, and 9). In order to analyze the extent to which such highly chimeric viruses can be viable, we selected the library for efficient viral packaging and infection, and successfully recovered numerous novel chimeras. These new viruses exhibited a broad range of cell tropism both in vitro and in vivo and enhanced resistance to human intravenous immunoglobulin (IVIG), highlighting numerous functional differences between these chimeras and their parent serotypes. Thus, directed evolution can potentially yield unlimited numbers of new AAV variants with novel gene-delivery properties, and subsequent analysis of these variants can further extend basic knowledge of AAV biology.
Reduced cardiac hypertrophy in toll-like receptor 4-deficient mice following pressure overload
Authors: T HA, Y LI, F HUA, J MA, X GAO, J KELLEY, A ZHAO, G HADDAD, D WILLIAMS, I WILLIAMBROWDER
Journal: Cardiovascular Research (2005)

We have previously demonstrated that nuclear factor kappa B (NFkappaB) activation is needed for the development of cardiac hypertrophy in vivo. NFkappaB is a downstream transcription factor in the Toll-like receptor (TLR)-mediated signaling pathway; therefore, we investigated a role of TLR4 in cardiac hypertrophy in vivo.TLR4-deficient mice (C.C3H-Tlr4(lps-d), n = 6), wild-type (WT) genetic background mice (BALB/c, n = 6), TLR4-deleted strain (C57BL/10ScCr, n = 8), and WT controls (C57BL/10ScSn, n = 8) were subjected to aortic banding for 2 weeks. Age-matched surgically operated mice served as controls. In a separate experiment, rapamycin (2 mg/kg, daily) was administered to TLR4-deficient mice and WT mice immediately following aortic banding. The ratio of heart weight/body weight (HW/BW) was calculated, and cardiac myocyte size was examined by FITC-labeled wheat germ agglutinin staining of membranes. NFkappaB binding activity and the levels of phospho-p70S6K in the myocardium were also examined.Aortic banding significantly increased the ratio of HW/BW by 33.9% (0.601 +/- 0.026 vs. 0.449 +/- 0.004) and cell size by 68.4% in WT mice and by 10.00% (0.543 +/- 0.011 vs. 0.495 +/- 0.005) and by 11.8% in TLR4-deficient mice, respectively, compared with respective sham controls. NFkappaB binding activity and phospho-p70S6K levels were increased by 182.6% and 115.2% in aortic-banded WT mice and by 78.0% and 162.0% in aortic-banded TLR4-deficient mice compared with respective sham controls. In rapamycin-treated aortic-banded mice, the ratio of HW/BW was increased by 18.0% in WT mice and by 3.5% in TLR4-deficient mice compared with respective sham controls.Our results demonstrate that TLR4 is a novel receptor contributing to the development of cardiac hypertrophy in vivo and that both the TLR4-mediated pathway and PI3K/Akt/mTOR signaling are involved in the development of cardiac hypertrophy in vivo.
Minimal Contribution of Fasting Hyperglycemia to the Incidence of Type 2 Diabetes in Subjects With Normal 2-h Plasma Glucose
Authors: Muhammad A. Abdul-Ghani, Michael P. Stern, Valeriya Lyssenko, Tiinamaija Tuomi, Leif Groop, Ralph A. DeFronzo
Journal: Diabetes Care (2009)

OBJECTIVE To assess the relative contribution of increased fasting and postload plasma glucose concentrations to the incidence of type 2 diabetes in subjects with a normal 2-h plasma glucose concentration. RESEARCH DESIGN AND METHODS A total of 3,450 subjects with 2-h plasma glucose concentration <140 mg/dl at baseline were followed up in the San Antonio Heart Study (SAHS) and the Botnia Study for 7-8 years. The incidence of type 2 diabetes at follow-up was related to the fasting, 1-h, and 2-h plasma glucose concentrations. RESULTS In subjects with 2-h plasma glucose <140 mg/dl, the incidence of type 2 diabetes increased with increasing fasting plasma glucose (FPG) and 1-h and 2-h plasma glucose concentrations. In a multivariate logistic analysis, after adjustment for all diabetes risk factors, the FPG concentration was a strong predictor of type 2 diabetes in both the SAHS and the Botnia Study (P < 0.0001). However, when the 1-h plasma glucose, but not 2-h plasma glucose, concentration was added to the model, FPG concentration was no longer a significant predictor of type 2 diabetes in both studies (NS). When subjects were matched for the level of 1-h plasma glucose concentration, the incidence of type 2 diabetes markedly increased with the increase in 1-h plasma glucose, but the increase in FPG was not associated with a significant increase in the incidence of type 2 diabetes. CONCLUSIONS An increase in postload glycemia in the normal range is associated with an increase in the incidence of type 2 diabetes. After controlling for 1-h plasma glucose concentration, the increase in FPG concentration is not associated with an increase in the incidence of type 2 diabetes.
Increased CK-MB release is a “trade-off” for optimal stent implantation
Authors: Ioannis Iakovou, Gary S Mintz, George Dangas, Alexandre Abizaid, Roxana Mehran, Yoshio Kobayashi, Alexandra J Lansky, Eve D Aymong, Eugenia Nikolsky, Gregg W Stone, Jeffrey W Moses, Martin B Leon
Journal: Journal of the American College of Cardiology (2003)
Humoral and Cell‐Mediated Immune Responses to Dog Dander and Hair in Asthmatic Children
Authors: Timo Vanto, Markku Viander, Antti Koivikko
Journal: Allergy (1983)

Dog dander and hair (DDH) specific IgA, IgG and IgE antibodies from serum samples Of 202 asthmatic children, and in nasal secretion from 4 to 15 years were measured by enzyme‐linked immunosorbent assay. The results were compared with clinical history, and with allergy test (skin prick test, provocation test and RAST) using the same DDH extract. A blood sample for the in vitro lymphocyte stimulation test was obtained from 40 children, and a nasal secretion sample for analysis of the local DDH‐specific IgA, IgG and IgE antibody levels was collected form 35 of them. In children of dog‐keeping families, higher serum levels of DDH‐specific antibodies, especially IgE antibodies, were observed if the dog had been in the home already during the first years of the child's life. The serum levels of DDH‐specific antibodies, however, did not correlate with the degree of the present exposure to dogs. The serum levels of DDH‐specific or total IgE, or with the results of skin prick or provocation test. The serum levels of DDH‐specific IgA were highest in children who were subjectively most sensitive to dogs. Nasal levels of DDH‐specific IgE correlated positively with serum specific IgE levels. The correlation was weaker between nasal and serum titers of specific IgG, and not significant between nasal and serum IgA antibody levels, Specific IgE antibody levels were higher, while specific IgA and IgG antibody levels were lower, in nasal secretion form subjects with nasal symptoms on contact with dogs, when compared with subjects with other complaints (asthma, conjunctival or skin reactions). DDH‐specific IgG levels correlated negatively with specific IgE level in the nasal secretion from subjects with a positive provocation test result, while the correlation was positive in subjects with a negative provocation test. The in vitro lymphocyte response to DDH did not correlate with the results of allergy test, or with the levels of DDH‐specific antibodies in serum or in nasal secretion.