tbuckley/cabot-search huggingface dataset:
Stimulation of human leukocyte elastase by platelet factor 4. Physiologic, morphologic, and biochemical effects on hamster lungs in vitro.
Authors: S A Lonky, H Wohl
Journal: Journal of Clinical Investigation (1981)

The purpose of this study was to determine if human platelet factor 4 (PF4) stimulates human leukocyte elastase (HLE) against lung elastin. Lung elastin was purified from hamster lungs and tritiated by reduction with NaB3H4. We found that HLE activity against this substrate is increased by concentrations of PF4 as low as 1.6 microgram/ml, and that this stimulation increased linearly with additional PF4. Lungs removed from hamsters and inflated with solutions containing buffer alone, low dose HLE, HLE plus PF4, or PF4 alone were incubated for 2 h at 37 degrees C. Whereas low-dose HLE failed to lower lung elastin when compared to control animals, HLE stimulated by PF4 lowered lung elastin by 20%. PF4 alone had no effect. Furthermore, low-dose HLE failed to alter the mechanical properties of hamster lungs as measured by pressure-volume curves in saline, although there was a significant loss of lung elasticity in the mid- and high-lung volume ranges in lungs treated with HLE and PF4. Morphologic studies revealed that low dose HLE resulted in a minimal emphysemalike lesion whereas HlE plus PF4 caused a significantly more severe lesion. PF4 is capable of stimulating HLE against lung elastin, and this effect may have a role in the pathogenesis of emphysema.
Open Clinical Trial Data for All? A View from Regulators
Authors: Hans-Georg Eichler, Eric Abadie, Alasdair Breckenridge, Hubert Leufkens, Guido Rasi
Journal: PLoS Medicine (2012)

In this issue of PLoS Medicine, Doshi and colleagues argue that the full clinical trial reports of authorized drugs should be made publicly available to enable independent re-analysis of drugs’ benefits and risks [1]. We offer comments on their call for openness from a European Union drug regulatory perspective. For the purpose of this discussion, we consider ‘‘clinical study reports’’ to comprise not just the protocol, summary tables, and figures of (mostly) randomized controlled trials (RCTs), but the full ‘‘raw’’ data set, including data at the patient level [2]. We limit discussion to data on drugs for which the regulatory benefit-risk assessment has been completed. Why Trial Data Should Be Open for All
Vitamin D and Adenosine Triphosphatase Dependent on Divalent Cations in Rat Intestinal Mucosa
Authors: Szloma Kowarski, David Schachter
Journal: Journal of Clinical Investigation (1973)

Intestinal brush borders prepared from vitamin D-deficient rats demonstrate increased susceptibility in vitro to fragmentation by shear forces or to loss of microvillus enzymes on treatment with EDTA. These effects are relatively nonspecific and are also observed in normal rats starved for 48 h. They may underlie prior observations that purport to demonstrate a vitamin D-dependent increase in brush border Ca-dependent ATPase. In addition, however, vitamin D increases ATPase activity dependent on certain divalent cations, including Ca and Zn, in whole-particulate suspensions pelleted by high-speed centrifugation of mucosal homogenates. This action is independent of changes in other microvillus enzymes, i.e. disaccharidases, and tissue distribution and cation specificity studies support the hypothesis that the mucosal whole-particulate ATPase is related to transport of Ca, Zn, and possibly other divalent cations.
Epidural corticosteroid injections for sciatica: a randomised, double blind, controlled clinical trial
Authors: J-P Valat
Journal: Annals of the Rheumatic Diseases (2003)

To determine the efficacy of epidural corticosteroid injections for sciatica.Three epidural injections (two day intervals) of 2 ml prednisolone acetate (50 mg) or 2 ml isotonic saline were administered to patients with sciatica presumably due to a disk herniation lasting 15-180 days. Self evaluation was the main judgment criterion at day 20. Patients who recovered or showed marked improvement were considered as success. Pain measured by VAS, the SLR test, Schober's test, Dallas pain questionnaire, and the Roland-Morris index were evaluated at days 0, 5, 20, and 35. Only analgesics were authorised, patients requiring non-steroidal anti-inflammatory drugs (NSAIDs) before day 20 were considered as failure.42 patients were included in the control group (CG), 43 in the steroid group (SG). On an intention to treat analysis 15/42 (36%) in the CG and 22/43 (51%) in the SG (p=0.15) were considered as success (difference 15.5%, 95% CI (-5.4 to 36.3)). Among the 48 failures, 14 patients (6 CG, 8 SG) required NSAIDs, 3 (2 CG, 1 SG) required surgery, and 7 (3 CG, 4 SG) other treatments. On analysis according to protocol, in 74 remaining patients 12/35 (34%) in the CG and 22/39 (56%) in the SG (p=0.057) were considered as success (difference 22.1%, 95% CI (0.0 to 44.2)). For all secondary end points intragroup improvement with time was significant, but intergroup differences were not.The efficacy of isotonic saline administered epidurally for sciatica cannot be excluded, but epidural steroid injections provide no additional improvement.
Perforating folliculitis associated with tumour necrosis factor-? inhibitors administered for rheumatoid arthritis
Authors: Y. Gilaberte, C. Coscojuela, C. Vázquez, R. Roselló, J. Vera
Journal: British Journal of Dermatology (2006)

Journal Article Perforating folliculitis associated with tumour necrosis factor‐α inhibitors administered for rheumatoid arthritis Get access Y. Gilaberte, Y. Gilaberte Departments of Dermatology, Rheumatology Correspondence: Yolanda Gilaberte. E‐mail: ygilaberte@salud.aragon.es Search for other works by this author on: Oxford Academic Google Scholar C. Coscojuela, C. Coscojuela Departments of Dermatology, Rheumatology Search for other works by this author on: Oxford Academic Google Scholar C. Vázquez, C. Vázquez Departments of Dermatology, Rheumatology Search for other works by this author on: Oxford Academic Google Scholar R. Roselló, R. Roselló Departments of Dermatology, Rheumatology Search for other works by this author on: Oxford Academic Google Scholar J. Vera J. Vera Pathology, San Jorge General Hospital, Huesca, Spain Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 156, Issue 2, 1 February 2007, Pages 368–371, https://doi.org/10.1111/j.1365-2133.2006.07598.x Published: 01 February 2007
Glomerular Hemodynamics in Rats with Chronic Sodium Depletion
Authors: Robert W. Steiner, Bryan J. Tucker, Roland C. Blantz
Journal: Journal of Clinical Investigation (1979)

In chronic sodium depletion the glomerular filtration rate may be reduced, and alterations in proximal tubular function may contribute to the maintenance of antinatriuresis. Measurements were made by micropuncture technique in superficial nephrons of the Munich-Wistar rat of (a) the determinants of glomerular filtration rate, (b) peritubular capillary hydrostatic and oncotic pressure, and (c) proximal tubular fractional and absolute reabsorption in both a control group (group 1, n = 12) and a group of chronically sodium-depleted rats (group 2, n = 12). Single nephron filtration rate (sngfr) was 37.2±1.2 in group 1 and 31.6±1.0 nl/min/g kidney wt (P < 0.05) in group 2. Of the factors potentially responsible for the observed reduction in sngfr, there was no change in systemic oncotic pressure or the transglomerular hydrostatic pressure gradient. Sngfr was lower in group 2 because of both a reduced single nephron plasma flow (rpf) (128±6 vs. 112±5 nl/min per g kidney wt, P < 0.05) and additionally to a decrease in the glomerular permeability coefficient, LpA, from a minimum value of 0.105±0.012 in group 1 to 0.054±0.01 nl/s per g kidney wt per mm Hg (P < 0.01) after chronic sodium depletion. There was no difference in fractional proximal tubular reabsorption between group 1 and group 2. Absolute proximal reabsorption (APR) was reduced from 20.8±1.3 in group 1 to 16.3±0.9 nl/min per g kidney wt in group 2.
PEA-15 Inhibits Tumor Cell Invasion by Binding to Extracellular Signal-Regulated Kinase 1/2
Authors: Angela Glading, James A. Koziol, Joseph Krueger, Mark H. Ginsberg
Journal: Cancer Research (2007)

Abstract Phosphoprotein enriched in astrocytes of 15 kDa (PEA-15) binds to extracellular signal-regulated kinase 1 and 2 (ERK1/2) mitogen-activated protein (MAP) kinases to alter ERK1/2 cellular localization and target preferences and binds to adaptors in the extrinsic cell death pathway to block apoptosis. Here, we report that PEA-15 protein expression is inversely correlated with the invasive behavior of breast cancer in an immunohistochemical analysis of a breast cancer progression tissue microarray. Short hairpin RNA–mediated inhibition of PEA-15 expression increased the invasion of PEA-15–expressing tumor cells in vitro, suggesting a causative role for PEA-15 in the inhibition of invasion. This causative role was confirmed by the finding that the enforced expression of PEA-15 in invasive tumor cells reduced invasion. The effect of PEA-15 on tumor invasion is mediated by its interaction with ERK1/2 as shown by the following: (a) PEA-15 mutants that fail to bind ERK1/2 did not inhibit invasion; (b) overexpression of ERK1 or activated MAP/ERK kinase (MEK) reversed the inhibitory effect of PEA-15; (c) when an inhibitor of ERK1/2 activation reduced invasion, PEA-15 expression did not significantly reduce invasion further. Furthermore, we find that the effect of PEA-15 on invasion seems to relate to the nuclear localization of activated ERK1/2. PEA-15 inhibits invasion by keeping ERK out of the nucleus, as a PEA-15 mutant that cannot prevent ERK nuclear localization was not able to inhibit invasion. In addition, membrane-localized ERK1, which sequesters endogenous ERK1 to prevent its nuclear localization, also inhibited invasion. These results reveal that PEA-15 regulates cancer cell invasion via its ability to bind ERK1/2 and indicate that nuclear entry of ERK1/2 is important in tumor behavior. [Cancer Res 2007;67(4):1536–44]
Mechanisms of idiotype suppression. IV. Functional neutralization in mixtures of idiotype-specific suppressor and hapten-specific suppressor T cells.
Authors: B S Kim, J A Greenberg
Journal: The Journal of Experimental Medicine (1981)

Specific tolerance to phosphorylcholine (PC) can be induced in BALB/c mice by neonatal injection with either pneumococcal C-polysaccharide (PnC) or anti-TEPC 15 idiotype (T15Id) antibody specific for the major idiotype (Id) of anti-PC antibody. Spleen cells from these tolerant mice exhibited T cell-mediated active suppression of anti-PC response when they were co-cultured with normal spleen cells. Suppressor cells from the PnC-injected mice appeared to bear either Lyt-1 or Lyt-2 antigens, whereas suppressor cells from anti-Id-treated mice expressed Lyt-2 antigens. Analyses of the specific receptors of these suppressor T cells, based on either adherence to PC and T15-coated petri dishes or cytolysis by rabbit anti-T15Id and monoclonal IgM anti-PC antibody with complement, revealed that receptors of PnC-induced suppressor T cells recognize PC, whereas receptors of anti-Id-induced suppressor T cells react with the T15Id. The possible interaction of the two different types of suppressor T cells was examined by co-culturing normal spleen cells with mixtures of the different suppressor cell types in various cell ratios in the presence of the T-independent PC-antigen, R36a. A brief incubation of anti-Id-induced, T15Id-specific suppressor T cells with PnC-induced, hapten-specific, and T15Id-bearing suppressor T cells resulted in complete cancellation of their suppressor function. These results suggest that idiotype network regulation may also occur among suppressor T cell population.
Magnetically Responsive Smart Nanoparticles for Cancer Treatment with a Combination of Magnetic Hyperthermia and Remote-Control Drug Release
Authors: Koichiro Hayashi, Michihiro Nakamura, Hirokazu Miki, Shuji Ozaki, Masahiro Abe, Toshio Matsumoto, Wataru Sakamoto, Toshinobu Yogo, Kazunori Ishimura
Journal: Theranostics (2014)

We report the synthesis of smart nanoparticles (NPs) that generate heat in response to an alternating current magnetic field (ACMF) and that sequentially release an anticancer drug (doxorubicin, DOX). We further study the in vivo therapeutic efficacy of the combination of magnetic hyperthermia (MHT) and chemotherapy using the smart NPs for the treatment of multiple myeloma. The smart NPs are composed of a polymer with a glass-transition temperature (T g) of 44°C, which contains clustered Fe3O4 NPs and DOX. The clustered Fe3O4 NPs produce heat when the ACMF is applied and rise above 44°C, which softens the polymer phase and leads to the release of DOX. The combination of MHT and chemotherapy using the smart NPs destroys cancer cells in the entire tumor and achieves a complete cure in one treatment without the recurrence of malignancy. Furthermore, the smart NPs have no significant toxicity.
For Breast Cancer Prognosis, Immunoglobulin Kappa Chain Surfaces to the Top
Authors: Theresa L. Whiteside, Soldano Ferrone
Journal: Clinical Cancer Research (2012)

Abstract The stromal immunoglobulin kappa chain (IGKC) has been validated as an immunologic biomarker of prognosis and response to therapy in human breast cancer and other cancers. This validation emphasizes the key role of humoral immunity in control of cancer progression and has major implications for determining prognosis of patients with cancer. Clin Cancer Res; 18(9); 2417–9. ©2012 AACR.
Blocking p21-activated Kinase Reduces Lipopolysaccharide-induced Acute Lung Injury by Preventing Polymorphonuclear Leukocyte Infiltration
Authors: Jörg Reutershan, Rebecca Stockton, Alexander Zarbock, Gail W. Sullivan, Daniel Chang, David Scott, Martin A. Schwartz, Klaus Ley
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Rationale: Excessive recruitment of polymorphonuclear leukocytes (PMNs) to the lung promotes acute lung injury (ALI). Chemokine receptors and adhesion molecules initiate leukocyte–endothelial interactions, but mediators of PMN migration through the alveolo-capillary membrane remain to be identified. p21-Activated kinase (PAK) is an effector of small GTPases and has been implicated in cell migration.Objectives: To test the role of PAK in ALI.Methods: An inhibitory PAK peptide was used to determine the role of PAK in cytoskeletal actin polymerization, cell adhesion, and oxidative burst. PMN migration was investigated in vitro and in a murine model of lipopolysaccharide-induced lung injury.Measurements and Main Results: PMN migration into lung interstitium and alveolar space was suppressed by an inhibitory PAK peptide. Neutrophils that had taken up the inhibitory PAK peptide were unable to enter the alveolar space. CXCL2/3, an important PMN chemoattractant in murine lung injury, induced PAK phosphorylation in PMNs. Blocking PAK function inhibited chemotaxis, chemokine-induced cytoskeletal actin polymerization, and adhesion-induced oxidative burst.Conclusions: We conclude that neutrophil PAK is a critical mediator of PMN migration and may be an attractive target in ALI.
Approval Summary: Nelarabine for the Treatment of T-Cell Lymphoblastic Leukemia/Lymphoma
Authors: Martin H. Cohen, John R. Johnson, Tristan Massie, Rajeshwari Sridhara, W. David McGuinn, Sophia Abraham, Brian P. Booth, M. Anwar Goheer, David Morse, Xiao H. Chen, Nallaperumal Chidambaram, Leslie Kenna, Jogarao V. Gobburu, Robert Justice, Richard Pazdur
Journal: Clinical Cancer Research (2006)

To describe the clinical studies, chemistry manufacturing and controls, and clinical pharmacology and toxicology that led to Food and Drug Administration approval of nelarabine (Arranon) for the treatment of T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma.Two phase 2 trials, one conducted in pediatric patients and the other in adult patients, were reviewed. The i.v. dose and schedule of nelarabine in the pediatric and adult studies was 650 mg/m2/d daily for 5 days and 1,500 mg/m2 on days 1, 3, and 5, respectively. Treatments were repeated every 21 days. Study end points were the rates of complete response (CR) and CR with incomplete hematologic or bone marrow recovery (CR*).The pediatric efficacy population consisted of 39 patients who had relapsed or had been refractory to two or more induction regimens. CR to nelarabine treatment was observed in 5 (13%) patients and CR+CR* was observed in 9 (23%) patients. The adult efficacy population consisted of 28 patients. CR to nelarabine treatment was observed in 5 (18%) patients and CR+CR* was observed in 6 (21%) patients. Neurologic toxicity was dose limiting for both pediatric and adult patients. Other severe toxicities included laboratory abnormalities in pediatric patients and gastrointestinal and pulmonary toxicities in adults.On October 28, 2005, the Food and Drug Administration granted accelerated approval for nelarabine for treatment of patients with relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma after at least two prior regimens. This use is based on the induction of CRs. The applicant will conduct postmarketing clinical trials to show clinical benefit (e.g., survival prolongation).
Molecular Interactions Between Two Long-QT Syndrome Gene Products, <i>HERG</i> and <i>KCNE2</i> , Rationalized by In Vitro and In Silico Analysis
Authors: Reza Mazhari, Joseph L. Greenstein, Raimond L. Winslow, Eduardo Marbán, H. Bradley Nuss
Journal: Circulation Research (2001)

The cardiac delayed rectifier potassium current mediates repolarization of the action potential and underlies the QT interval of the ECG. Mutations in either of the two molecular components of the rapid delayed rectifier (I(K,r)), HERG and KCNE2, have been linked to heritable or acquired long-QT syndrome. Mechanisms whereby mutations of KCNE2 produce fatal cardiac arrhythmias characteristic of long-QT syndrome remain unclear. In this study, we characterize functional interactions between HERG and KCNE2 with a view to defining underlying mechanisms for action potential prolongation and long-QT syndrome. Whereas coexpression of hKCNE2 with HERG alters both kinetics and density of ionic current, incorporation of these effects into a quantitative model of the action potential predicts that only changes in current density significantly affect repolarization. Thus, the primary functional consequence of hKCNE2 on action potential morphology is through modulation of I(K,r) density, as predicted by the model. Mutations associated with long-QT syndrome that result only in modest changes of gating kinetics may be epiphenomena or may modulate action potential repolarization via interaction with alternative pore-forming potassium channel alpha subunits.
Haploinsufficiency in the Prometastasis Kiss1 Receptor Gpr54 Delays Breast Tumor Initiation, Progression, and Lung Metastasis
Authors: Sung-Gook Cho, Ying Wang, Melissa Rodriguez, Kunrong Tan, Wenzheng Zhang, Jian Luo, Dali Li, Mingyao Liu
Journal: Cancer Research (2011)

Activation of KISS1 receptor (KISS1R or GPR54) by its ligands (Kisspeptins) regulates a diverse function both in normal physiology and pathophysiology. In cancer, KISS1R has been implicated in tumor angiogenesis and metastasis, but a broader evaluation of KISS1R in tumorigenesis and tumor progression is yet to be conducted. In this study, we used mouse models of Kiss1r gene knockout and mouse mammary tumor virus-polyoma virus middle T antigen (MMTV-PyMT)-induced breast cancer to conduct such an evaluation. Kiss1r heterozygosity in MMTV-PyMT mice was sufficient to attenuate breast cancer initiation, growth, latency, multiplicity, and lung metastasis. To confirm these effects and assess possible contributions of endogenous ligands, we isolated primary tumor cells from PyMT/Kiss1r(+/+) and PyMT/Kiss1r(+/-) mice and compared their phenotypes by in vitro and in vivo assays. Kiss1r loss attenuated in vitro tumorigenic properties as well as tumor growth in vivo in immunocompromised NOD.SCID/NCr mice. Kiss1r activation in these cells, resulting from the addition of its ligand Kisspeptin-10, resulted in RhoA activation and RhoA-dependent gene expression through the Gαq-p63RhoGEF signaling pathway. Anchorage-independent growth was tightly linked to dose-dependent regulation of RhoA by Kiss1r. In support of these results, siRNA-mediated knockdown of KISS1R or inactivation of RhoA in human MCF10A breast epithelial cells overexpressing H-RasV12 was sufficient to reduce Ras-induced anchorage-independent growth. In summary, we concluded that Kiss1r attenuation was sufficient to delay breast tumor initiation, progression, and metastasis through inhibitory effects on the downstream Gαq-p63RhoGEF-RhoA signaling pathway.
Tissue Interleukin-17 and Interleukin-23 as Biomarkers for Orbital Granulomatosis with Polyangiitis
Authors: Hazlita Isa, Philip Luthert, Geoffrey Rose, David Verity, Charles Pusey, Oren Tomkins-Netzer, Norshamsiah Md Din, Tan Lee Teak, Simon Taylor, Sue Lightman
Journal: Ophthalmology (2015)
Correction: Inhibition of Furin-mediated Processing Results in Suppression of Astrocytoma Cell Growth and Invasiveness
Authors: Javier Mercapide, Ricardo Lopez De Cicco, Daniel E Bassi, Javier S Castresana, Gary Thomas, Andres JP Klein-Szanto
Journal: Clinical Cancer Research (2019)

In the original version of [this article][1] ([1][2]), Figs. 1C and 3B are missing splice lines between U87MG and U118MG. The errors have been corrected in the latest online PDF version of the article. The authors regret this error. 1. 1.[↵][3]1. Mercapide J, 2. Lopez De Cicco R, 3
High IGF-IR Activity in Triple-Negative Breast Cancer Cell Lines and Tumorgrafts Correlates with Sensitivity to Anti–IGF-IR Therapy
Authors: Beate C. Litzenburger, Chad J. Creighton, Anna Tsimelzon, Bonita T. Chan, Susan G. Hilsenbeck, Tao Wang, Joan M. Carboni, Marco M. Gottardis, Fei Huang, Jenny C. Chang, Michael T. Lewis, Mothaffar F. Rimawi, Adrian V. Lee
Journal: Clinical Cancer Research (2010)

Abstract Purpose: We previously reported an insulin-like growth factor (IGF) gene expression signature, based on genes induced or repressed by IGF-I, which correlated with poor prognosis in breast cancer. We tested whether the IGF signature was affected by anti–IGF-I receptor (IGF-IR) inhibitors and whether the IGF signature correlated with response to a dual anti–IGF-IR/insulin receptor (InsR) inhibitor, BMS-754807. Experimental Design: An IGF gene expression signature was examined in human breast tumors and cell lines and changes were noted following treatment of cell lines or xenografts with anti–IGF-IR antibodies or tyrosine kinase inhibitors. Sensitivity of cells to BMS-754807 was correlated with levels of the IGF signature. Human primary tumorgrafts were analyzed for the IGF signature and IGF-IR levels and activity, and MC1 tumorgrafts were treated with BMS-754807 and chemotherapy. Results: The IGF gene expression signature was reversed in three different models (cancer cell lines or xenografts) treated with three different anti–IGF-IR therapies. The IGF signature was present in triple-negative breast cancers (TNBC) and TNBC cell lines, which were especially sensitive to BMS-754807, and sensitivity was significantly correlated to the expression of the IGF gene signature. The TNBC primary human tumorgraft MC1 showed high levels of both expression and activity of IGF-IR and IGF gene signature score. Treatment of MC1 with BMS-754807 showed growth inhibition and, in combination with docetaxel, tumor regression occurred until no tumor was palpable. Regression was associated with reduced proliferation, increased apoptosis, and mitotic catastrophe. Conclusions: These studies provide a clear biological rationale to test anti–IGF-IR/InsR therapy in combination with chemotherapy in patients with TNBC. Clin Cancer Res; 17(8); 2314–27. ©2011 AACR.