tbuckley/cabot-search huggingface dataset:
Phase I Study of the Hedgehog Pathway Inhibitor IPI-926 in Adult Patients with Solid Tumors
Authors: Antonio Jimeno, Glen J. Weiss, Wilson H. Miller, Scott Gettinger, Bernard J.C. Eigl, Anne Lynne S. Chang, Joi Dunbar, Shannon Devens, Kerrie Faia, Georgios Skliris, Jeff Kutok, Karl D. Lewis, Raoul Tibes, William H. Sharfman, Robert W. Ross, Charles M. Rudin
Journal: Clinical Cancer Research (2013)

To conduct a first-in-human phase I study to determine the dose-limiting toxicities (DLT), characterize the pharmacokinetic profile, and document the antitumor activity of IPI-926, a new chemical entity that inhibits the Hedgehog pathway (HhP).Patients with solid tumors refractory to standard therapy were given IPI-926 once daily (QD) by mouth in 28-day cycles. The starting dose was 20 mg, and an accelerated titration schedule was used until standard 3 + 3 dose-escalation cohorts were implemented. Pharmacokinetics were evaluated on day -7 and day 22 of cycle 1.Ninety-four patients (32F, 62M; ages, 39-87) received doses ranging from 20 to 210 mg QD. Dose levels up to and including 160 mg administered QD were well tolerated. Toxicities consisted of reversible elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin, fatigue, nausea, alopecia, and muscle spasms. IPI-926 was not associated with hematologic toxicity. IPI-926 pharmacokinetics were characterized by a slow absorption (T(max) = 2-8 hours) and a terminal half-life (t(1/2)) between 20 and 40 hours, supporting QD dosing. Of those HhP inhibitor-naïve patients with basal cell carcinoma (BCC) who received more than one dose of IPI-926 and had a follow-up clinical or Response Evaluation Criteria in Solid Tumors (RECIST) assessment, nearly a third (8 of 28 patients) showed a response to IPI-926 at doses ≥130 mg.IPI-926 was well tolerated up to 160 mg QD within 28-day cycles, which was established as the recommended phase II dose and schedule for this agent. Single-agent activity of IPI-926 was observed in HhP inhibitor-naïve patients with BCC.
Correlation of Somatic Mutation and Expression Identifies Genes Important in Human Glioblastoma Progression and Survival
Authors: David L. Masica, Rachel Karchin
Journal: Cancer Research (2011)

Cooperative dysregulation of gene sequence and expression may contribute to cancer formation and progression. The Cancer Genome Atlas (TCGA) Network recently catalogued gene sequence and expression data for a collection of glioblastoma multiforme (GBM) tumors. We developed an automated, model-free method to rapidly and exhaustively examine the correlation among somatic mutation and gene expression and interrogated 149 GBM tumor samples from the TCGA. The method identified 41 genes whose mutation status is highly correlated with drastic changes in the expression (z-score ± 2.0), across tumor samples, of other genes. Some of the 41 genes have been previously implicated in GBM pathogenesis (e.g., NF1, TP53, RB1, and IDH1) and others, while implicated in cancer, had not previously been highlighted in studies using TCGA data (e.g., SYNE1, KLF6, FGFR4, and EPHB4). The method also predicted that known oncogenes and tumor suppressors participate in GBM via drastic over- and underexpression, respectively. In addition, the method identified a known synthetic lethal interaction between TP53 and PLK1, other potential synthetic lethal interactions with TP53, and correlations between IDH1 mutation status and the overexpression of known GBM survival genes.
Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor <i>Foxp3 </i>
Authors: WanJun Chen, Wenwen Jin, Neil Hardegen, Ke-jian Lei, Li Li, Nancy Marinos, George McGrady, Sharon M. Wahl
Journal: The Journal of Experimental Medicine (2003)

CD4+CD25+ regulatory T cells (Treg) are instrumental in the maintenance of immunological tolerance. One critical question is whether Treg can only be generated in the thymus or can differentiate from peripheral CD4+CD25- naive T cells. In this paper, we present novel evidence that conversion of naive peripheral CD4+CD25- T cells into anergic/suppressor cells that are CD25+, CD45RB-/low and intracellular CTLA-4+ can be achieved through costimulation with T cell receptors (TCRs) and transforming growth factor beta (TGF-beta). Although transcription factor Foxp3 has been shown recently to be associated with the development of Treg, the physiological inducers for Foxp3 gene expression remain a mystery. TGF-beta induced Foxp3 gene expression in TCR-challenged CD4+CD25- naive T cells, which mediated their transition toward a regulatory T cell phenotype with potent immunosuppressive potential. These converted anergic/suppressor cells are not only unresponsive to TCR stimulation and produce neither T helper cell 1 nor T helper cell 2 cytokines but they also express TGF-beta and inhibit normal T cell proliferation in vitro. More importantly, in an ovalbumin peptide TCR transgenic adoptive transfer model, TGF-beta-converted transgenic CD4+CD25+ suppressor cells proliferated in response to immunization and inhibited antigen-specific naive CD4+ T cell expansion in vivo. Finally, in a murine asthma model, coadministration of these TGF-beta-induced suppressor T cells prevented house dust mite-induced allergic pathogenesis in lungs.
CORRECTION
Authors: W Maziak, U Keil
Journal: Thorax (2006)

95% CI 1.29 to 6.42), p,0.0069; table 1) with a PAR for AA homozygotes and AG heterozygotes of 50%.This study underlines the importance of the association of BTNL2 rs2076530 variant with the susceptibility to develop sarcoidosis in a German population.Furthermore, our data suggest that susceptibility is preferentially towards the chronic form of the disease.
Coronary Artery Fly-Through Using Electron Beam Computed Tomography
Authors: Peter M. A. van Ooijen, Matthijs Oudkerk, Robert J. M. van Geuns, Benno J. Rensing, Pim J. de Feyter
Journal: Circulation (2000)

Virtual reality techniques have recently been introduced into clinical medicine. This study examines the possibility of coronary artery fly-through using a dataset obtained by noninvasive coronary angiography with contrast-enhanced electron-beam computed tomography.Ten patients were examined, and 40 to 60 transaxial tomograms (thickness, 1.5 mm; in-plane pixel dimensions, approximately 0.5x0.5 mm) were obtained after intravenous contrast injection. The datasets were processed on a graphics workstation using volume-rendering software. For fly-throughs, the contrast-enhanced lumen was made transparent and other tissue was made opaque. Then, key frames were selected in a path through the vessel, with software interpolation of frames between key frames. A typical movie contained 150 to 300 frames (10 to 15 key frames). Fly-throughs of coronary bypass grafts (n=3), left anterior descending arteries (LAD; n=6), and the intermediate branch (n=1) were reconstructed. Coronary calcifications were seen in 3 patients. The fly-through of the intermediate branch, the bypass grafts, and one of the LADs did not show any irregularities. In 2 cases, a stenosis was visible in the LAD; its presence was confirmed by conventional coronary angiography.Recent developments in fast-volume rendering using special-purpose hardware in combination with noninvasive coronary angiography with electron beam computed tomography have provided the possibility of performing coronary artery fly-throughs.
Estimating Mutation Rate and Generation Time from Longitudinal Samples of DNA Sequences
Authors: Yun-Xin Fu
Journal: Molecular Biology and Evolution (2001)

We present in this paper a simple method for estimating the mutation rate per site per year which also yields an estimate of the length of a generation when mutation rate per site per generation is known. The estimator, which takes advantage of DNA polymorphisms in longitudinal samples, is unbiased under a number of population models, including population structure and variable population size over time. We apply the new method to a longitudinal sample of DNA sequences of the env gene of human immunodeficiency virus type 1 (HIV-1) from a single patient and obtain 1.62 × 10 as the mutation rate per site per year for HIV-1. Using an independent data set to estimate the mutation rate per generation, we obtain 1.8 days as the length of a generation of HIV-1, which agrees well with recent estimates based on viral load data. Our estimate of generation time differs considerably from a recent estimate by Rodrigo et al. when the same mutation rate per site per generation is used. Some factors that may contribute to the difference among different estimators are discussed.
Atrial natriuretic factor and isosorbide dinitrate modulate the gating of ATP-sensitive K+ channels in cultured vascular smooth muscle cells.
Authors: M Kubo, Y Nakaya, S Matsuoka, K Saito, Y Kuroda
Journal: Circulation Research (1994)

The effects of atrial natriuretic factor (ANF) and isosorbide dinitrate (ISDN), activators of particulate and soluble guanylate cyclase, respectively, on K+ currents were investigated in patch-clamp recordings of smooth muscle cells cultured from rat thoracic aorta. In the cell-attached patch configuration, ANF enhanced Ca(2+)-activated K+ (KCa) channel activities as reported previously. When KCa channels were blocked with 1 mmol/L tetraethylammonium or 10(-7) mol/L charybdotoxin, ANF and ISDN applied to the bathing solution activated ATP-sensitive K+ (KATP) channels without altering channel conductance. Pretreatment with methylene blue, a guanylate cyclase inhibitor, abolished the effects of ISDN on KATP channels, whereas 8-bromo-cGMP activated these channels, suggesting that the effects of ISDN on KATP channels were mediated by cGMP. Our results suggest that vasorelaxant agents that increase intracellular cGMP concentrations modulate the gating of two major potassium channels, ATP sensitive and Ca2+ activated, that might play an important role in controlling vascular tone by changing the membrane potential.
Effects of 6 weeks of therapy with oral doses of ICI 204,219, a leukotriene D4 receptor antagonist, in subjects with bronchial asthma. ACCOLATE Asthma Trialists Group.
Authors: S L Spector, L J Smith, M Glass
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

The efficacy of 6 wk of therapy with oral ICI 204,219, a selective leukotriene D4 (LTD4) receptor antagonist, was evaluated in subjects with moderate asthma during a multicenter, double-blind, randomized, placebo-controlled, dose-ranging study. Subjects who entered the trial had been chronically treated for asthma with beta agonist alone or in combination with theophylline. Subjects were randomized to treatment with twice daily doses of ICI 204,219 (5, 10, or 20 mg) or placebo if they had an FEV1 between 40 and 75% of predicted values without bronchodilator therapy and a daytime asthma score > 10 (range 0 to 21 per wk) for 7 consecutive d. Efficacy was evaluated from the results of symptom assessments, pulmonary function tests, and rescue medication use. Of 276 subjects randomized to treatment, 266 (10 mg, n = 66; 20 mg, n = 67; 40 mg, n = 67; placebo, n = 66) were analyzed for efficacy. Diary card assessments showed that treatment with increasing doses of ICI 204,219 linearly improved five efficacy criteria without increasing the number or severity of adverse events. The 40 mg dose was more effective than placebo (p < 0.05) in reducing nighttime awakenings, first morning asthma symptoms, the daytime asthma score, and albuterol use and in increasing evening peak expiratory flow (PEF) rates as well as FEV1. Compared with baseline measurements, the 40 mg dose decreased awakenings by 46%, albuterol use by 30%, and daytime symptoms by 26% and increased FEV1 by 11%. ICI 204,219 improves objective and subjective measures of asthma severity in moderately ill asthmatic subjects and may provide a new treatment option for the disease.
Renal denervation: Not as easy as it looks
Authors: Murray Esler
Journal: Science Translational Medicine (2015)

Renal sympathetic denervation in hypertensive patients is less effective than anticipated, owing to radio frequency energy being applied to a part of the renal artery where the nerves are at the greatest distance from the aortic lumen, and to distortion of energy distribution and temperature gradients by regional tissue anatomical variations (Tzafriri et al ., this issue).
Studies on Specific Transplantation Resistance to Polyoma-Virus-Induced Tumors. II. Mechanism of Resistance Induced by Polyoma Virus Infection&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Hans Olof Sjögren
Journal: JNCI Journal of the National Cancer Institute (1964)

Polyoma-virus-induced transplantation resistance to polyoma tumors developed rapidly after virus infection: A complete inhibition of outgrowth of two different tumors was demonstrated even after infection 4 to 15 days subsequent to cell inoculation. The immunological nature of the resistance was clearly demonstrated. Total-body X irradiation with 400 r 1 day before virus infection caused a marked delay in transplantation resistance, while the same irradiation 4 to 5 days after infection had almost no effect. The appearance of antiviral antibodies in the serum of irradiated animals was also somewhat delayed, but high antibody titers were found long before transplantation resistance, which indicated that the antiviral immune response per se cannot explain the transplantation resistance effect. In neutralization experiments involving the admixture of lymphoid cells or serum and complement to polyoma tumor cells, lymphoid cells from donors infected with polyoma virus or pretreated with non-virus-releasing polyoma tumor cells inhibited the growth of the admixed polyoma tumor cells. Serum from polyoma-infected donors caused a more irregular and weaker inhibition. The inhibition brought about by the lymphoid cells was clearly distinguished from, a resistance effect induced by an accidental virus infection because of its demonstration in animals having no antiviral antibodies in their sera.
Right heart pressures in bronchial asthma
Authors: R. F. Gunstone
Journal: Thorax (1971)

Right heart pressures, electrocardiograms, blood gases, and peak expiratory flow rates were measured in nine patients admitted to hospital with severe bronchial asthma. Low or normal right heart pressures were found despite electrocardiographic changes in five patients consisting of right atrial P waves, abnormal right axis deviation, and in one patient T-wave changes in precordial leads. These electrocardiographic changes reverted towards normal on recovery of the patient from the asthmatic attack.
Inhibition of Protein Kinase C/Twist1 Signaling Augments Anticancer Effects of Androgen Deprivation and Enzalutamide in Prostate Cancer
Authors: Masaki Shiota, Akira Yokomizo, Ario Takeuchi, Kenjiro Imada, Eiji Kashiwagi, YooHyun Song, Junichi Inokuchi, Katsunori Tatsugami, Takeshi Uchiumi, Seiji Naito
Journal: Clinical Cancer Research (2013)

The progression of prostate cancer to metastatic and castration-resistant disease represents a critical step. We previously showed that the transcription factor Twist1, which promotes epithelial-mesenchymal transition, was involved in castration-resistant progression. Similarly, protein kinase C (PKC) has been implicated in both metastatic progression and castration resistance in prostate cancer.In this study, we aimed to elucidate the role of PKC/Twist1 signaling in castration resistance, and to apply this information to the development of a novel therapeutic concept using PKC inhibitor Ro31-8220 against prostate cancer using various prostate cancer cell lines.Androgen deprivation and the next-generation antiandrogen enzalutamide induced PKC activation and Twist1 expression, which were reversed by the PKC inhibitor Ro31-8220. Ro31-8220 suppressed cell proliferation in androgen-dependent prostate cancer LNCaP cells, which was augmented by its combination with androgen deprivation or enzalutamide. The favorable anticancer effects of the combination of Ro31-8220 and enzalutamide were also observed in castration-resistant C4-2 and 22Rv1 cells. Furthermore, PKC phosphorylation was elevated in castration-resistant and enzalutamide-resistant cells compared with their parental cells, leading to persistent sensitivity to Ro-31-8220 in castration- and enzalutamide-resistant cells.Taken together, these findings indicate that PKC/Twist1 signaling contributes to castration resistance as well as enzalutamide resistance in prostate cancer, and suggest that therapeutics targeting PKC/Twist1 signaling, such as PKC inhibitors, represent a promising novel therapeutic strategy for prostate cancer, especially castration-resistant prostate cancer, when combined with enzalutamide.
Autophagy and Its Normal and Pathogenic States in the Brain
Authors: Ai Yamamoto, Zhenyu Yue
Journal: Annual Review of Neuroscience (2014)

Autophagy is a conserved catabolic process that delivers the cytosol and cytosolic constituents to the lysosome. Its fundamental role is to maintain cellular homeostasis and to protect cells from varying insults, including misfolded proteins and damaged organelles. Beyond these roles, the highly specialized cells of the brain have further adapted autophagic pathways to suit their distinct needs. In this review, we briefly summarize our current understanding of the different forms of autophagy and then offer a closer look at how these pathways impact neuronal and glial functions. The emerging evidence indicates that not only are autophagy pathways essential for neural health, but they have a direct impact on developmental and neurodegenerative processes. Taken together, as we unravel the complex roles autophagy pathways play, we will gain the necessary insight to modify these pathways to protect the human brain and treat neurodegenerative diseases.
Airway inflammation in cystic fibrosis: molecular mechanisms and clinical implications
Authors: Malena Cohen-Cymberknoh, Eitan Kerem, Thomas Ferkol, Arnon Elizur
Journal: Thorax (2013)

Airway epithelial cells and immune cells participate in the inflammatory process responsible for much of the pathology found in the lung of patients with cystic fibrosis (CF). Intense bronchial neutrophilic inflammation and release of proteases and oxygen radicals perpetuate the vicious cycle and progressively damage the airways. In vitro studies suggest that CF transmembrane conductance regulator (CFTR)-deficient airway epithelial cells display signalling abnormalities and aberrant intracellular processes which lead to transcription of inflammatory mediators. Several transcription factors, especially nuclear factor-κB, are activated. In addition, the accumulation of abnormally processed CFTR in the endoplasmic reticulum results in unfolded protein responses that trigger 'cell stress' and apoptosis leading to dysregulation of the epithelial cells and innate immune function in the lung, resulting in exaggerated and ineffective airway inflammation. Measuring airway inflammation is crucial for initiating treatment and monitoring its effect. No inflammatory biomarker predictive for the clinical course of CF lung disease is currently known, although neutrophil elastase seems to correlate with lung function decline. CF animal models mimicking human lung disease may provide an important insight into the pathogenesis of lung inflammation in CF and identify new therapeutic targets.
Gain/loss of poly(Glu50Tyr50)/poly(Glu60Ala30Tyr10) responsiveness in the bm12 mutant strain.
Authors: H Y Lei, R W Melvold, S D Miller, C Waltenbaugh
Journal: The Journal of Experimental Medicine (1982)

The development of inbred strains of mutant mice has proven useful in ascribing specific gene functions to particular genetic loci within the regions and subregions of the H-2 complex. The B6.C-H-2bm12 (bm12) strain is of particular interest in that, compared to parental C57Bl/6Kh (B6) mice, it bears a presumptive single gene mutation altering the Ab beta chain encoded by the I-A subregion. Our data show that bm12 mice have gained the ability to respond to poly(Glu50Tyr50)(GT) and have lost the ability to make plaque-forming cell or delayed-type hypersensitivity responses to the closely related copolymer, poly(Glu60Ala30Tyr10)(GAT), although retaining the ability to mount a GAT-specific T cell proliferative response. This is in sharp contrast to the parental B6 strain, which is a GT nonresponder and a GAT responder. Thus, this study is the first to report the establishment of responder status as a consequence of mutation. Possible mechanisms accounting for the gain/loss of GT/GAT responsiveness in the context of a two-step helper T cell model are discussed.
Immune Status of SJL/J Mice in Relation to Age and Spontaneous Tumor Development2
Authors: N. Haran-Ghera, M. Ben-Yaakov, A. Peled, Z. Bentwich
Journal: JNCI Journal of the National Cancer Institute (1973)

The immunologic status, occurrence of autoantibodies, and serum abnormalities in relation to age increase and pathologic changes were investigated in SJL/J mice. The Immunologic reactivity of normal SJL/J mice and those with spontaneous reticulum-cell tumors was evaluated with age increase. Tested were the response to sheep red blood cells, prolongation of skin allograft survival, delayed hypersensitivity skin reaction, and graft-versus-host reaction. The immune reactivity decreased as the mice grew older, whether the host was normal or tumor bearing. This defective immunologic status early in life did not seem, therefore, to be a factor in the spontaneous tumor development. Antibodies to nuclear material were detectable in normal animals as early as 3 months and increased with age in normal animals, but were significantly less common in tumor-bearing animals. Direct antiglobulin tests (Coombs') on blood samples taken from animals ranging from 6 to 14 months of age were negative. Serial serum electrophoresis showed the presence of proteins, sometimes myeloma-like, with restricted heterogeneity, always associated with mainly early tumors in 6- to 10-month-old mice, and an abundance of plasma cells.
Vertical transmission of hepatitis C
Authors: Goura Kudesia, Geraldine Ball, WilliamL. Irving, G. Maggiore, A. Ventura, C. De Giacomo, E. Silini, A. Cerino, M.U. Mondelli, A. Giacchino, A. Picotto, L. Tasso, A. Timitilli, N. Sinelli
Journal: The Lancet (1995)