tbuckley/cabot-search huggingface dataset:
In vivo transduction of photoreceptors or ciliary body by intravitreal injection of pseudotyped adenoviral vectors
Authors: Dan J Von Seggern, Edith Aguilar, Karen Kinder, Shonna Kaye Fleck, J.C Gonzalez Armas, Susan C Stevenson, Peter Ghazal, Glen R Nemerow, Martin Friedlander
Journal: Molecular Therapy (2003)

Strategies for retargeting adenoviral (Ad) vectors have been developed, but their in vivo efficacy remains to be demonstrated. Gene delivery to specific ocular cell types represents an approach to treating many diseases that cause irreversible blindness. One of these cell types, the photoreceptor (PR), is not infected by standard Ad5-based vectors. We evaluated gene delivery after intraocular injection of Ads pseudotyped with three different fiber proteins and found three distinct patterns of infection. An intravitreally injected Ad5 vector readily infected the iris, corneal endothelium, and ciliary body, while few cells in the retina expressed transgene product. In contrast, an Ad3-pseudotyped virus selectively transduced ciliary body, of interest for treating diseases such as glaucoma. A vector pseudotyped with the fiber protein of Ad37 transduced PRs as well as ciliary body. This finding has potential application to the treatment of retinal degenerative or neovascular diseases. These studies demonstrate cell type-selective gene delivery in vivo with retargeted Ads, provide information about the cellular tropisms of several Ad serotypes, and should lead to improved strategies for preserving vision.
Acquired Resistance to 17-Allylamino-17-Demethoxygeldanamycin (17-AAG, Tanespimycin) in Glioblastoma Cells
Authors: Nathalie Gaspar, Swee Y. Sharp, Simon Pacey, Chris Jones, Michael Walton, Gilles Vassal, Suzanne Eccles, Andrew Pearson, Paul Workman
Journal: Cancer Research (2009)

Abstract Heat shock protein 90 (HSP90) inhibitors, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin), which is currently in phase II/phase III clinical trials, are promising new anticancer agents. Here, we explored acquired resistance to HSP90 inhibitors in glioblastoma (GB), a primary brain tumor with poor prognosis. GB cells were exposed continuously to increased 17-AAG concentrations. Four 17-AAG–resistant GB cell lines were generated. High-resistance levels with resistance indices (RI = resistant line IC50/parental line IC50) of 20 to 137 were obtained rapidly (2–8 weeks). After cessation of 17-AAG exposure, RI decreased and then stabilized. Cross-resistance was found with other ansamycin benzoquinones but not with the structurally unrelated HSP90 inhibitors, radicicol, the purine BIIB021, and the resorcinylic pyrazole/isoxazole amide compounds VER-49009, VER-50589, and NVP-AUY922. An inverse correlation between NAD(P)H/quinone oxidoreductase 1 (NQO1) expression/activity and 17-AAG IC50 was observed in the resistant lines. The NQO1 inhibitor ES936 abrogated the differential effects of 17-AAG sensitivity between the parental and resistant lines. NQO1 mRNA levels and NQO1 DNA polymorphism analysis indicated different underlying mechanisms: reduced expression and selection of the inactive NQO1*2 polymorphism. Decreased NQO1 expression was also observed in a melanoma line with acquired resistance to 17-AAG. No resistance was generated with VER-50589 and NVP-AUY922. In conclusion, low NQO1 activity is a likely mechanism of acquired resistance to 17-AAG in GB, melanoma, and, possibly, other tumor types. Such resistance can be overcome with novel HSP90 inhibitors. [Cancer Res 2009;69(5):1966–75]
Spontaneous elaboration of transforming growth factor beta suppresses host defense against bacterial infection in autoimmune MRL/lpr mice.
Authors: J H Lowrance, F X O'Sullivan, T E Caver, W Waegell, H D Gresham
Journal: The Journal of Experimental Medicine (1994)

Infection with gram-negative and gram-positive bacteria remains a leading cause of death in patients with systemic lupus erythematosis (SLE), even in the absence of immunosuppressive therapy. To elucidate the mechanisms that underly the increased risk of infection observed in patients with systemic autoimmunity, we have investigated host defense against bacterial infection in a murine model of autoimmunity, the MRL/Mp-lpr/lpr (MRL/lpr) mouse. Our previous study implicated transforming growth factor beta (TGF-beta) in a novel acquired defect in neutrophil function in MRL/lpr but not congenic MRL/Mp-+/+ (MRL/n) mice (Gresham, H.D., C.J. Ray, and F.K. O'Sullivan. 1991. J. Immunol. 146:3911). We hypothesized from these observations that MRL/lpr mice would have defects in host defense against bacterial infection and that they would have constitutively higher local and systemic levels of active TGF-beta which would be responsible, at least in part, for the defect in host defense. We show in this paper that spontaneous elaboration of active TGF-beta adversely affects host defense against both gram-negative and gram-positive bacterial infection in MRL/lpr mice. Our data indicate that MRL/lpr mice, as compared with congenic MRL/n mice, exhibit decreased survival in response to bacterial infection, that polymorphonuclear leukocytes (PMN) from MRl/lpr mice fail to migrate to the site of infection during the initial stages of infection, that MRL/lpr mice have a significantly increased bacterial burden at the site of infection and at other tissue sites, and that this increased bacterial growth occurs at a time (&amp;gt; 20 h after infection) when PMN influx is greatly enhanced in MRL/lpr mice. Most intriguingly, the alteration in PMN extravasation during the initial stages of infection and failure to restrict bacterial growth in vivo could be duplicated in MRL/n mice with a parenteral injection of active TGF-beta 1 at the time of bacterial challenge. Moreover, these alterations in host defense, including survival in response to lethal infection, could be ameliorated in MRL/lpr mice by the parenteral administration of a monoclonal antibody that neutralizes the activity of TGF-beta. These data indicate that elaboration of TGF-beta as a result of autoimmune phenomenon suppresses host defense against bacterial infection and that such a mechanism could be responsible for the increased risk of bacterial infection observed in patients with autoimmune diseases.
Effects of zoledronate (Z) on bone mineral density (BMD) among African Americans (AA) with advanced prostate cancer, without skeletal metastases, recieving androgen ablation therapy
Authors: K. L. Kipping, C. Bennett, A. Evens, H. Munshi, B. Jovanovic, L. Gallot
Journal: Journal of Clinical Oncology (2007)

15539 Background: Prostate cancer can be detrimental to bone health: it affects older men who have a higher risk of osteoporosis; common treatment is androgen ablation which can cause bone loss, and it frequently metastasizes to the bones. These issues are especially important in AA men, who present with higher rates of advanced disease and use of androgen ablation than whites. One study found beneficial effects of Z on the bone health of men with prostate cancer, it included only 106 men, and few were AA (Smith M, Journal of Urology).We wanted to evaluate the effects of Ca/Vitamin D ± Z on skeletal related events and BMD on AA and white men with prostate cancer who are receiving androgen ablation therapy. Methods: Prostate cancer patients receiving at least 3 months of androgen ablation were eligible. Exclusion criteria: use of bisphosphonates in last 12 months, abnormal liver/ kidney function, or prior bone disease. 41 patients have been randomized, 51% are AA. Patients on the Z arm receive 4 mg IV infusion of Z q 3 months over one year. Patients have bone densities at baseline and 13 months. Results: Interim analysis is available for patients who have completed study as of Jan 2007. 3 patients were taken off study (1 due to secondary cancer, 2 due to patient withdrawal).One patient withdrew due to jaw pain, follow up did not identify osteonecrosis. Two patients had lesions that may have been bone metastases, follow up testing was inconclusive. At treatment end, Z-treated patients had higher BMD scores than control group patients. AA patients treated with Z also showed increased BMD values at 13 months. Conclusions: Z appears to have a positive effect on BMD in AA men with prostate cancer- potentially more beneficial than among the effect previously reported for white men with prostate cancer. AA men with prostate cancer receiving androgen ablation should be considered for Z therapy to improve bone health. [Table: see text] No significant financial relationships to disclose.
Alveolar Capillary Dysplasia
Authors: Naomi B. Bishop, Pawel Stankiewicz, Robin H. Steinhorn
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare, fatal developmental lung disorder of neonates and infants. This review aims to address recent findings in the etiology and genetics of ACD/MPV and to raise awareness of this poorly known disease, which may also present as milder, unclassified forms. Successively discussed are what is known about the epidemiology, pathogenesis, pathophysiology, diagnostic indicators and approaches, genetic testing, treatment, and cases of delayed onset. The review concludes with suggestions for future directions to answer the many unknowns about this disorder.
Risk of complications during hematopoietic stem cell collection in pediatric sibling donors: a prospective European Group for Blood and Marrow Transplantation Pediatric Diseases Working Party study
Authors: Jan Styczynski, Adriana Balduzzi, Lidia Gil, Myriam Labopin, Rose-Marie Hamladji, Sarah Marktel, M. Akif Yesilipek, Franca Fagioli, Karoline Ehlert, Martina Matulova, Jean-Hugues Dalle, Jacek Wachowiak, Maurizio Miano, Chiara Messina, Miguel Angel Diaz, Christiane Vermylen, Matthias Eyrich, Isabel Badell, Peter Dreger, Jolanta Gozdzik, Daphna Hutt, Jelena Rascon, Giorgio Dini, Christina Peters
Journal: Blood (2011)
Halofuginone Inhibits the Establishment and Progression of Melanoma Bone Metastases
Authors: Patricia Juárez, Khalid S. Mohammad, Juan Juan Yin, Pierrick G. J. Fournier, Ryan C. McKenna, Holly W. Davis, Xiang H. Peng, Maria Niewolna, Delphine Javelaud, John M. Chirgwin, Alain Mauviel, Theresa A. Guise
Journal: Cancer Research (2012)

TGF-β derived from bone fuels melanoma bone metastases by inducing tumor secretion of prometastatic factors that act on bone cells to change the skeletal microenvironment. Halofuginone is a plant alkaloid derivative that blocks TGF-β signaling with antiangiogenic and antiproliferative properties. Here, we show for the first time that halofuginone therapy decreases development and progression of bone metastasis caused by melanoma cells through the inhibition of TGF-β signaling. Halofuginone treatment of human melanoma cells inhibited cell proliferation, phosphorylation of SMAD proteins in response to TGF-β, and TGF-β-induced SMAD-driven transcription. In addition, halofuginone reduced expression of TGF-β target genes that enhance bone metastases, including PTHrP, CTGF, CXCR4, and IL11. Also, cell apoptosis was increased in response to halofuginone. In nude mice inoculated with 1205 Lu melanoma cells, a preventive protocol with halofuginone inhibited bone metastasis. The beneficial effects of halofuginone treatment were comparable with those observed with other anti-TGF-β strategies, including systemic administration of SD208, a small-molecule inhibitor of TGF-β receptor I kinase, or forced overexpression of Smad7, a negative regulator of TGF-β signaling. Furthermore, mice with established bone metastases treated with halofuginone had significantly less osteolysis than mice receiving placebo assessed by radiography. Thus, halofuginone is also effective in reducing the progression of melanoma bone metastases. Moreover, halofuginone treatment reduced melanoma metastasis to the brain, showing the potential of this novel treatment against cancer metastasis.
Functional significance of intimal thickening as detected by intravascular ultrasound early and late after cardiac transplantation.
Authors: T J Anderson, I T Meredith, A Uehata, G H Mudge, A P Selwyn, P Ganz, A C Yeung
Journal: Circulation (1993)

BACKGROUND Detection of transplant coronary disease remains difficult. Both intravascular ultrasound (IVUS) imaging and functional coronary vasomotion studies have been used to evaluate this process. However, the time course of intimal thickening as assessed by IVUS and the relation between structure and function have not been explored. METHODS AND RESULTS In 40 patients 1 to 8 years after transplantation, 108 coronary artery segments were analyzed by IVUS. Intimal index [% intimal area (lumen+intimal area)] and maximal thickness were used to quantify intimal thickening. Abnormal IVUS was present in 53 of 108 segments (49%) (mean intimal index of diseased segments, 23 +/- 2%; maximal thickness, 530 +/- 47 microns). For those patients with intimal thickening in all segments of the analyzed artery, more time had elapsed since transplantation (4.3 +/- 0.6 years) than for those whose arteries contained some normal (2.6 +/- 0.3 years) or all normal segments (2.2 +/- 0.6 years, P &lt; .05). Both the proportion of segments with intimal thickening and the degree of thickening increased as a function of time after transplantation (P &lt; .5). By multivariate analysis, the independent predictors of intimal thickening were increasing time after transplantation and pretransplantation hypercholesterolemia (P = .02). Within the cohort of 40 patients, endothelium-dependent vasomotor function was evaluated in 26 matched segments from 11 patients studied 1 year after transplantation and in 15 matched segments from 8 patients studied &gt; or = 5 years after transplantation by serial infusions of acetylcholine (10(-8) to 10(-6) mol/L). Of the 26 segments assessed for structure/function correlation at 1 year after transplantation, 22 had no intimal thickening by IVUS. However, endothelial dysfunction was present in 13 of these normal segments (mean diameter constriction, 18.8 +/- 2.3%). Of the 15 segments studied &gt; or = 5 years after transplantation, 11 had intimal thickening. Nine of these 11 segments had preserved endothelial function (mean diameter dilation, 8.6 +/- 2.9%). There was no relation between the degree of intimal thickening and the magnitude of the endothelium-dependent response to acetylcholine. CONCLUSIONS This study has shown that intimal thickening after transplantation begins as a heterogeneous process and increases in extent and magnitude over time. Also, endothelial dysfunction occurs early before the intimal thickening; yet in those patients surviving &gt; or = 5 years, endothelial function may recover even in the presence of moderate intimal pathology. The variable relation between intimal pathology and endothelial function is probably a result of the episodic nature of immune injury.
Bronchial Thermoplasty for Asthma
Authors: Gerard Cox, John D. Miller, Annette McWilliams, J. Mark FitzGerald, Stephen Lam
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Rationale: Bronchial thermoplasty (BT) reduces the potential for smooth muscle–mediated bronchoconstriction by reducing the mass of smooth muscle in the walls of conducting airways.Objectives: This study was conducted to examine the safety and impact on lung function and airway responsiveness of BT over 2 yr.Methods: The safety of BT was studied in 16 subjects with mild to moderate asthma. Baseline and 12-wk post-treatment measurements included spirometry, methacholine challenge, daily diary recordings of peak flow, symptoms, and medication usage. Subjects completed follow-up evaluations at 12 wk, 1 yr, and 2 yr.Measurements and Main Results: The procedure was well tolerated; side effects were transient and typical of what is commonly observed after bronchoscopy. All subjects demonstrated improvement in airway responsiveness. The mean PC20 increased by 2.37 ± 1.72 (p < 0.001), 2.77 ± 1.53 (p = 0.007), and 2.64 ± 1.52 doublings (p < 0.001), at 12 wk, 1 yr, and 2 yr post-procedure, respectively. Data from daily diaries collected for 12 wk indicated significant improvements over baseline in symptom-free days (p = 0.015), morning peak flow (p = 0.01), and evening peak flow (p ⩽ 0.007). Spirometry measurements remained stable throughout the study period.Conclusions: BT is well tolerated in patients with asthma and results in decreased airway hyperresponsiveness that persists for at least 2 yr.
The Utility of Open Lung Biopsy in Patients with Hematologic Malignancies
Authors: DOROTHY A. WHITE, PHILIP W. WONG, ROBERT DOWNEY
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

The yield and impact of open lung biopsies in patients with hematologic malignancies and unexplained pulmonary processes were assessed and analyzed to determine factors that affected the yield. Records of 63 patients with hematologic malignancy, who underwent 67 open lung biopsies for diagnosis of an unknown pulmonary process from 1996 to 1998 at Memorial Sloan-Kettering Cancer Center, were retrospectively reviewed. A specific diagnosis was found in 41 (62%) of the biopsies. Changes in therapy were made in 37 (57%) of patients after biopsy results, but in 69% of those with a specific diagnosis. Survival at 30 and 90 d was increased in those with specific rather than a nonspecific pulmonary diagnosis. The factor most predictive of finding a specific diagnosis was the presence of a focal rather than a diffuse radiographic abnormality (79% versus 36%, p = 0.003). Neutropenic patients or those on mechanical ventilation had a low chance of finding a specific diagnosis. Having received pulmonary toxic chemotherapy in the 6 mo before the biopsy was associated with finding a nonspecific lung injury. Specific pulmonary diagnoses found were inflammatory diseases in 23% of cases, infections in 21%, and malignancy in 18%. Bronchiolitis obliterans with organizing pneumonia (BOOP) was the most common inflammatory disorder and fungi and bacteria were the most frequent infectious pathogens. Complications occurred in 13% of the biopsies, including five patients who required mechanical ventilation postprocedure; one death was associated with the biopsy. The risk was increased in those with less than 50,000 platelets. Complications were similar with video-assisted thoracoscopy (VATS) compared with thoracotomy. We conclude that open lung biopsy in patients with hematologic malignancy has a significant yield and impact on management of patients with hematologic malignancy. White DA, Wong PW, Downey R. The utility of open lung biopsy in patients with hematologic malignancies.
<b> <i>In vitro</i> </b> Combination Treatment with Perifosine and UCN-01 Demonstrates Synergism against Prostate (PC-3) and Lung (A549) Epithelial Adenocarcinoma Cell Lines
Authors: Girija P. Dasmahapatra, Parijat Didolkar, Michael C. Alley, Somiranjan Ghosh, Edward A. Sausville, Krishnendu K. Roy
Journal: Clinical Cancer Research (2004)

Antineoplastic agents often achieve antitumor activity at the expense of close to unacceptable toxicity. One potential avenue to improve therapeutic index might combine agents targeting distinct components of the same growth regulatory pathway. This might lead to more complete modulation of the target pathway at concentrations lower than those associated with limiting adventitious toxicities from either agent alone. The protein kinase antagonist UCN-01 is currently used in Phase I/II trials and has recently been demonstrated to inhibit potently PDK1. We have recently documented that the alkylphospholipid perifosine potently also inhibits Akt kinase (PKB) activation by interfering with membrane localization of Akt. This leads to the hypothesis that these two agents might act synergistically through distinct mechanisms in the PI3K/Akt proliferation and survival-related signaling pathway.The synergistic effects of UCN-01 and perifosine, on two cell lines (A-549 and PC-3), were examined using various long-term in vitro assays for cell growth, cell cycle distribution, clonogenicity, survival morphology, and apoptosis. Along with Western blotting experiments were performed to determine whether this synergistic combination of two drugs has significant effect on their downstream targets and on biochemical markers of apoptosis.After 72 h, perifosine at concentrations of 1.5 and 10 microM UCN-01 at 40 and 250 nM did not significantly affect the growth of PC-3 and A459 cells, respectively. However, in combination at the same respective individual concentrations (1.5 microM and 40 nM of perifosine and UCN-01, respectively, in PC-3 cells and 10 microM perifosine and 0.25 microM UCN-01 in the somewhat more resistant A549 cells), virtually complete growth inhibition of both the cell lines resulted. Supra-additive inhibition of growth was also demonstrated in independent clonogenic assays. Mechanistic studies in cell culture models suggest enhanced depletion of the S-phase population in cells treated by the combination. This correlated with enhanced inactivation of Akt along with activation of caspases 3 and 9 and poly(ADP-ribose) polymerase cleavage. Evidence of synergy was formally demonstrated and occurred across a wide range of drug concentrations and was largely independent of the order or sequence of drug addition.As the concentrations of UCN-01 and perifosine causing synergistic inhibition of cell growth are clinically achievable without prominent toxicity, these data support the development of clinical studies with this combination.
Influence of vagotomy on changes in feline plasma catecholamine levels induced by occlusion of either the left or right coronary vessel
Authors: D. J WILLIFORD, A. P ZAVADIL, R. A WALSH, V. WEISE, I. J KOPIN, R. A GILLIS
Journal: Cardiovascular Research (1983)

The purpose of this study was two-fold: (1) to determine the effect of occlusion of the left anterior descending branch (LAD) of the left coronary artery or the right coronary (RC) artery on plasma catecholamine levels, and (2) to determine whether bilateral vagotomy has an effect on changes in plasma catecholamine levels evoked by coronary occlusion. Chloralose anaesthetised cats subjected to LAD occlusion exhibited increases in plasma noradrenaline and adrenaline at 3 min post-occlusion. The increases in noradrenaline and adrenaline were unrelated to the hypotension that occurred at this time. Bilateral vagotomy did not appear to alter the effect of LAD occlusion on catecholamine release into the circulation but did unmask a significant correlation between the degree of hypotension and the magnitude of increase in plasma catecholamines. Right coronary occlusion in animals with intact and sectioned vagus nerves evoked noradrenaline and adrenaline release that was significantly correlated with a fall in arterial pressure. Bilateral vagotomy per se caused an increase in baseline plasma catecholamine levels. Pretreatment with atropine mimicked the increase in baseline catecholamine levels seen with vagotomy. These results indicate that occlusion of the LAD and RC arteries increase the release of catecholamines into the circulation. The role of the vagus nerves in this response was observed only with LAD occlusion and consisted of altering the relationship between the degree of hypotension and the magnitude of increase in plasma catecholamines. That is, after vagotomy, the decrease in blood pressure following LAD occlusion was effective in causing release of catecholamines, presumably because of the hypotension causing a decrease in baroreceptor stimulation. Finally, it appeared that vagotomy increases the release of noradrenaline into the circulation by removing efferent vagal tone that inhibits noradrenaline release. This inhibitory action is mediated by activation of muscarinic receptors.