tbuckley/cabot-search huggingface dataset:
Extragenital lichen sclerosus successfully treated with topical calcipotriol: evaluation by in vivo confocal laser scanning microscopy
Authors: A. Kreuter, T. Gambichler, K. Sauermann, T. Jansen, P. Altmeyer, K. Hoffmann
Journal: British Journal of Dermatology (2002)

Sir, Lichen sclerosus (LS), originally described by Hallopeau in 1887, is an uncommon skin disease with white porcelain‐like sclerotic skin lesions predominantly affecting the anogenital area. Extragenital LS mostly occurs on the flexor surface of the wrists, the upper part of the trunk, and in the axillae.1 LS is more common in adult women, but may also occur in men and children. To date, there is no standardized treatment for LS. In some patients, potent topical corticosteroids may improve lesions; in others, various treatments including topical testosterone and oestrogen, psoralen plus ultraviolet (UV) A, penicillin, resorcinol, chloroquine, vitamins and retinoids have been used with variable success.2, 3 We recently reported the successful treatment of patients with localized scleroderma by long‐wave UVA1 (340–400 nm) phototherapy and topical calcipotriol.4 Because of similar clinical and histopathological features of localized scleroderma and LS, we hypothesized that topical calcipotriol may also improve extragenital LS. We report a patient with extragenital LS that responded well to monotherapy with calcipotriol ointment.
Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy
Authors: Jorge E. Cortes, Moshe Talpaz, Francis Giles, Susan O'Brien, Mary Beth Rios, Jianqin Shan, Guillermo Garcia-Manero, Stefan Faderl, Deborah A. Thomas, William Wierda, Allessandra Ferrajoli, Sima Jeha, Hagop M. Kantarjian
Journal: Blood (2003)
Phase I Clinical Evaluation of Weekly Administration of the Novel Vascular-Targeting Agent, ZD6126, in Patients With Solid Tumors
Authors: Laurens V. Beerepoot, Sandra A. Radema, Els O. Witteveen, Tawnie Thomas, Catherine Wheeler, Sanford Kempin, Emile E. Voest
Journal: Journal of Clinical Oncology (2006)

ZD6126 is a novel vascular-targeting agent that induces selective effects on the morphology of endothelial cells by disrupting the tubulin cytoskeleton. This leads to cell detachment and tumor vessel congestion, resulting in extensive central necrosis in a range of tumor xenograft models. Results from a phase I dose-escalation study of ZD6126 are reported.Thirty-two patients with advanced cancer received weekly ZD6126 infusion (5 to 28 mg/m2). Assessments for safety and pharmacokinetics were performed. Circulating endothelial cells (CECs) were quantified as a pharmacodynamic marker of vascular damage.Maximum concentrations of the active species were observed 5 to 25 minutes from the start of infusion, and decayed in a biexponential manner with a half-life of 1 to 3 hours. Maximum serum concentration and area under the time-concentration curve increased with dose in a linear fashion across the dose range of 5 to 28 mg/m2. One patient treated at 10 mg/m2 with a history of ischemic heart disease experienced acute myocardial infarction 2 weeks after drug discontinuation. Four others had asymptomatic creatine phosphokinase-muscle-brain elevation. Maximum-tolerated dose (MTD) was reached at 20 mg/m2/wk. Dose-limiting toxicities at 28 mg/m2 were hypoxia caused by pulmonary embolism and an asymptomatic decrease in left ventricular ejection fraction. No objective antitumor responses were observed. CEC levels increased in the hours after infusion, indicating potential effect of the compound on the vasculature. CONCLUSION ZD6126 administered as a weekly infusion was clinically well tolerated. The MTD was reached at 20 mg/m2.
IMMUNE RESPONSE TO CHEMICALLY MODIFIED FLAGELLIN
Authors: C. R. Parish, F. Y. Liew
Journal: The Journal of Experimental Medicine (1972)

High and low zone antibody tolerance to bacterial flagellin can be induced in adult strain W Wistar rats by multiple injections of a cyanogen bromide (CNBr) digest of flagellin at two widely spaced dose levels. Intermediate doses of the CNBr digest produce enhanced antibody titers to flagellin rather than antibody tolerance. Studies reported in this paper revealed that both high and low zone antibody tolerance to flagellin were accompanied by heightened levels of delayed-type hypersensitivity. Conversely, when enhancement of the antibody response occurred, suppression of delayed hypersensitivity was observed. This inverse relationship between humoral and cell-mediated immunity was very striking in strain W Wistar rats but was not quite so clear-cut in another strain of Wistar rats (strain J). Strain J rats were resistant to the induction of antibody tolerance and gave higher immunological responses to flagellin than strain W animals. In addition, it was observed that, in contrast to adult tolerance, administration of the CNBr digest to neonatal rats induced complete tolerance at the level of both humoral and cell-mediated immunity. These findings were discussed in the light of earlier studies with flagellin and provide further evidence for a previously described hypothesis.
Inhibition of miR-193a Expression by Max and RXRα Activates K-Ras and PLAU to Mediate Distinct Aspects of Cellular Transformation
Authors: Dimitrios Iliopoulos, Asaf Rotem, Kevin Struhl
Journal: Cancer Research (2011)

MicroRNA profiling in isogenic models of cellular transformation involving either breast epithelial cells or fibroblasts reveals that expression of miR-193a is lower in transformed cells than in nontransformed cells. The transcription factors Max and RXRα bind directly to the miR-193a promoter and inhibit miR-193a expression during transformation. miR-193a inhibits cellular transformation by directly targeting the 3' untranslated regions of PLAU and K-Ras. Interestingly, miR-193a controls anchorage-independent growth in soft agar through K-Ras, whereas it affects invasive growth through PLAU. miR-193a overexpression inhibits the tumorigenicity of developmentally diverse but not all cancer cell types, and it inhibits tumor growth in colon- and breast-derived xenografts. Finally, expression of miR-193a is inversely correlated with PLAU and K-Ras in human colon adenocarcinomas. Thus, a pathway in which Max and RXRα inhibit miR-193a expression, thereby activating the PLAU and K-Ras oncogenes is important for distinct aspects of cellular transformation, as well as tumor growth and colon (and perhaps other types of) cancer.
Interleukin-17A Contributes to Myocardial Ischemia/Reperfusion Injury by Regulating Cardiomyocyte Apoptosis and Neutrophil Infiltration
Authors: Yu-Hua Liao, Ni Xia, Su-Feng Zhou, Ting-Ting Tang, Xin-Xin Yan, Bing-Jie Lv, Shao-Fang Nie, Jing Wang, Yoichiro Iwakura, Hong Xiao, Jing Yuan, Harish Jevallee, Fen Wei, Guo-Ping Shi, Xiang Cheng
Journal: Journal of the American College of Cardiology (2012)
Association of Activated Transcription Factor Nuclear Factor κB With Chemoradiation Resistance and Poor Outcome in Esophageal Carcinoma
Authors: Julie G. Izzo, Usha Malhotra, Tsung-Teh Wu, Joe Ensor, Rajyalakshmi Luthra, Jeffrey H. Lee, Stephen G. Swisher, Zhongxing Liao, K.S. Clifford Chao, Walter N. Hittelman, Bharat B. Aggarwal, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2006)

The lack of effective treatment for localized esosphageal cancer leads to poor patient outcome. Nuclear factor kappaB (NF-kappaB), a transcriptional factor, is constitutively activated or treatment induced in esophageal cancer and may influence treatment outcomes.Pre- and post-treatment cancer specimens from patients enrolled onto a clinical trial were studied for the expression of activated NF-kappaB protein and it was correlated with histologic features, pathologic response, metastatic potential, overall survival (OS), and disease-free survival (DFS).Forty-three patients undergoing the same therapy on a protocol were studied. Twenty-one (72%) of 29 patients achieving less than complete pathologic response (pathCR) had NF-kappaB positive cancer, but only one (7%) of 14 patients achieving pathCR had NF-kappaB positive cancer (P = < .001). Activated NF-kappaB was significantly associated with aggressive pathologic features such as perineural, lymphatic, and/or vascular invasion (P = .0004). Eight (38%) of 21 NF-kappaB positive patients developed metastases compared to none of 22 NF-kappaB negative patients (P = .001). At a median follow-up of 23 months, 10 (48%) of 21 NF-kappaB positive patients had died compared to only one (5%) of 22 NF-kappaB negative patients (P = .0013). Observations were similar for DFS (P = .0006). In a multivariate model (using baseline stage, pathCR or less than pathCR, age, presence of metastatic lymph nodes in the surgical specimen, and NF-kappaB expression) NF-kappaB activation was the only independent predictor of DFS (P = .010) and OS (P = .015).Our data suggest that esophageal cancers with activated NF-kappaB have aggressive clinical biology and poor treatment outcome. Additional understanding of NF-kappaB regulated pathways may uncover potential therapeutic targets.
Practical use of evolutionary neuroscience principles
Authors: Barbara Clancy
Journal: Behavioral and Brain Sciences (2006)

As Striedter explores the concerted principles that drive brain evolution and the departures that create uniqueness, he scrutinizes and ultimately supports the (unnecessarily controversial) Finlay/Darlington model in which mathematical relationships across mammalian neural development are identified (Finlay &amp; Darlington 1995). Pragmatic impact includes the ability to make novel comparisons across developing species, including humans.
2,5-Hexanedione-Induced Testicular Injury
Authors: Kim Boekelheide, Shawna L. Fleming, Theresa Allio, Michelle E. Embree-Ku, Susan J. Hall, Kamin J. Johnson, Eun Ji Kwon, Sutchin R. Patel, Reza J. Rasoulpour, Heidi A. Schoenfeld, Stephanie Thompson
Journal: The Annual Review of Pharmacology and Toxicology (2003)

Now in its third decade of mechanistic investigation, testicular injury caused by 2,5-hexanedione (2,5-HD) exposure is a well-studied model with a rich database. The development of this model reflects the larger changes that have moved biology from a branch of chemistry into the molecular age. Critically examined in this review is the proposed mechanism for 2,5-HD-induced testicular injury in which germ cell maturation is disrupted owing to alterations in Sertoli cell microtubule-mediated functions. The goal is to evaluate the technical and conceptual approaches used to assess 2,5-HD-induced testicular injury, to highlight unanswered questions, and to identify fruitful avenues of future research.
Endocytosis of cigarette-smoke condensate by rabbit alveolar macrophages in vitro measured as fluorescence intensity
Authors: CM Skold, A Eklund, J Hed, R Hernbrand
Journal: European Respiratory Journal (1992)

It has previously been shown that alveolar macrophages (AMs) from smokers have increased fluorescence compared to AMs from nonsmokers. In the present investigation, AMs lavaged from rabbits were exposed to a cigarette-smoke condensate (CSC) in order to study its influence on the fluorescence of AMs. Flow cytofluorometry was used. Alveolar cells exposed to 0.01% of CSC showed a fluorescence which increased with higher concentrations of the CSC. Incubation with CSC for 5 min was enough to give a significant rise (p less than 0.001) in cell fluorescence compared to controls. After incubating fluorescent cells with untreated non-fluorescent AMs, fluorescent material was distributed to the non-fluorescent AMs within 30 min. Further more, fluorescence decreased when exposed cells were cultured in CSC-free medium. When incubating CSC with blood leucocytes, an almost threefold increase in fluorescence was observed among the phagocytic cells at 37 degrees C compared to 4 degrees C, whereas the fluorescence in the non-phagocytic cell population only showed a minor enhancement. Endocytosis of fluorescent material in CSC can explain the strong fluorescence seen in AMs from smokers. Exocytosis and re-endocytosis of the material by new AMs may explain the slow decline in the fluorescence of AMs observed after cessation of smoking.
Phase II trial of continuous low-dose temozolomide for patients with recurrent malignant glioma
Authors: Antonio Omuro, Timothy A. Chan, Lauren E. Abrey, Mustafa Khasraw, Anne S. Reiner, Thomas J. Kaley, Lisa M. DeAngelis, Andrew B. Lassman, Craig P. Nolan, Igor T. Gavrilovic, Adilia Hormigo, Cynthia Salvant, Adriana Heguy, Andrew Kaufman, Jason T. Huse, Katherine S. Panageas, Andreas F. Hottinger, Ingo Mellinghoff
Journal: Neuro-Oncology (2012)

BackgroundIn this phase II trial, we investigated the efficacy of a metronomic temozolomide schedule in the treatment of recurrent malignant gliomas (MGs).
Magnesium Modulates ROMK Channel–Mediated Potassium Secretion
Authors: Lei Yang, Gustavo Frindt, Lawrence G. Palmer
Journal: Journal of the American Society of Nephrology (2010)

The ability of intracellular and extracellular Mg2+ to block secretory K+ currents through ROMK channels under physiologic conditions is incompletely understood. We expressed ROMK2 channels in Xenopus oocytes and measured unitary currents in the inside-out and cell-attached modes of the patch-clamp technique. With 110 mM K+ on both sides of the membrane, 0.2 to 5 mM Mg2+ on the cytoplasmic side reduced outward currents, but not inward currents, at Vm > 0. With 11 or 1.1 mM extracellular K+ ([K+]o), ≥0.2 mM Mg2+ blocked outward currents in the physiologic Vm range (0 to −60 mV). With decreasing [K+]o, the apparent dissociation constant of the blocker decreased, but the voltage dependence of block did not significantly change. Whole-cell recordings from principal cells of rat cortical collecting ducts revealed similar inhibitory effects of intracellular Mg2+. Mg2+ added to the extracellular solution also reduced single-channel currents with an affinity that increased as [K+]o decreased. In conclusion, physiologic concentrations of intracellular and extracellular Mg2+ can influence secretory K+ currents through ROMK channels. These effects could play a role in the modulation of K+ transport under conditions of K+ and/or Mg2+ depletion.
Reactive Oxygen Species Stimulate p44/42 Mitogen-Activated Protein Kinase and Induce p27Kip1
Authors: TETE HANNKEN, REGINE SCHROEDER, GUNTHER ZAHNER, ROLF A. K. STAHL, GUNTER WOLF
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Angiotensin II (AngII) induces G 1 phase arrest and hypertrophy of cultured renal proximal tubular cells. In previous studies, it was shown that these effects depend on oxygen radical-mediated induction of p27 Kip1 , an inhibitor of cyclin-dependent kinases. The present study was undertaken to investigate whether mitogen-activated protein (MAP) kinases serve as signaling intermediates between AngII-induced oxidative stress and induction of p27 Kip1 . AngII (10 -7 M) induces a biphasic phosphorylation pattern of p44/42 MAP kinase with an early phosphorylation after 2 min and a later, second phosphorylation peak after prolong incubation (12 h) in cultured proximal tubular cells from two different species (MCT and LLC-PK 1 cells). Total protein expression of MAP kinase was not changed by AngII. These phosphorylation patterns of p44/42 MAP kinase caused activation of the enzyme, as detected by phosphorylated MAP substrate Elk-1 after immuno-precipitation of MAP kinase. Exogenous H 2 O 2 also stimulates a biphasic phosphorylation of p44/42 MAP kinase. The flavoprotein inhibitor diphenylene iodinium, as well as the antioxidant N -acetylcysteine, prevented AngII-induced p44/42 MAP kinase phosphorylation, indicating involvement of reactive oxygen species generated by membrane-bound NAD(P)H oxidase. The MAP kinase kinase inhibitor PD98059 completely inhibits AngII-induced p27 Kip1 expression and 3 [H]leucine incorporation into proteins as a previously established marker of cell hypertrophy. PD98059 did not attenuate AngII-stimulated intracellular synthesis of oxygen radicals. Transient transfection with p44/42 MAP kinase antisense, but not sense, phosphorothioate-modified oligonucleotides also prevented AngII-induced MAP kinase phosphorylation, p27 Kip1 expression, and cell hypertrophy. Furthermore, induction of p27 Kip1 by H 2 O 2 was also abolished in the presence of PD98059. Although AngII induces phosphorylation of the stress-activated p38 MAP kinase, inhibition of this enzyme with SB203580 failed to attenuate induced p27 Kip1 expression and hypertrophy. These data provide evidence that AngII- mediated oxygen stress leads to the phosphorylation of p44/42 MAP kinase in proximal tubular cells. Activation of this enzyme is essential for p27 Kip1 expression, G 1 phase arrest, and hypertrophy of proximal tubular cells. These findings may lead to new concepts concerning interference of the development of proximal tubular hypertrophy, which may eventually turn into a maladaptive process in vivo leading ultimately to tubular atrophy and tubulointerstitial fibrosis.
Computer simulation of portal venous shunting and other isolated hepatobiliary defects of the enterohepatic circulation of bile acids using a physiological pharmacokinetic model
Authors: Cesare Cravetto, Gianpaolo Molino, Alan F. Hofmann, Gustavo Belforte, Basilio Bona
Journal: Hepatology (1988)

The effect of three isolated defects in the enterohepatic circulation of bile acids on the size and distribution of the bile acid pool, plasma bile acid levels and bile acid secretion into the intestine was simulated using a linear multicompartmental physiological pharmacokinetic model previously used to simulate these aspects of bile acid metabolism in healthy man. Stepwise increases in portal-systemic shunting (with a reciprocal decrease in hepatic blood flow) caused an exponential increase in systemic plasma concentrations of bile acids, but no other major changes in bile acid metabolism. When the effect of varying fractional hepatic extraction was simulated, it was found that the greater the fractional hepatic extraction, the greater the elevation observed for systemic plasma bile acid levels for a given degree of portal-systemic shunting. When total hepatic blood flow was restored to normal by simulating "arterialization," systemic plasma levels of bile acids decreased strikingly, yet remained elevated. For cholate with a fractional hepatic extraction of 0.9 and 100% portal-systemic shunting, arterialization caused a decrease from a 20-fold elevation to a 5-fold elevation. This simulation thus defined the effect of the presence of the portal venous system per se on plasma bile acid levels and also quantified the circulatory route by which substances reach the liver when portal-systemic shunting is present. An isolated defect in hepatic uptake of bile acids caused little change in overall bile acid metabolism other than modestly increased plasma levels. Loss of bile acid storage by the gallbladder caused the majority of the bile acid pool to move from the gallbladder compartments to the proximal small intestine during fasting but had little effect on the dynamics of the enterohepatic circulation during eating. The results of these novel simulations of isolated defects in bile acid transport should aid in the interpretation of the more complex changes in bile acid metabolism which are likely to occur in hepatic or biliary disease.
p53 mutation in hepatocellular carcinoma after aflatoxin exposure
Authors: Brigitte Bressac, Alain Puisieux, Michael Kew, Martin Volkmann, Sema Bozcall, Jessika Bella Mura, Suzanne de la Monte, Rolf Carlson, Hubert Blum, Jack Wands, Hiroshi Takahashi, Fritz von Weizsacker, Elthan Galun, Siddhartha Kar, BrianI Carr, ClausH Schroder, Eren Erken, Seyhan Varinli, VinodK Rustgi, Jaime Prat, Gotaro Toda, HerbertK Koch, Xiao Huan Liang, Zhao-you Tang, Daniel Shouval, Hyo-Suk Lee, GirishN Vyas, Ildiko Sarosi, Mehmet Ozturk
Journal: The Lancet (1991)
Pleuroparenchymal fibroelastosis: one more walk on the wild side of drugs?
Authors: Philippe Camus, Jan von der Thüsen, David M. Hansell, Thomas V. Colby
Journal: European Respiratory Journal (2014)

Histology of alkylating chemotherapy in PPFE patients; drugs may cause this rare pattern of lung disease http://ow.ly/yEuOzIn this issue of the European Respiratory Journal, report on six young adults (three of whom were female) who developed a clinical imaging pattern of predominant upper lobe fibrosis with apical pneumothoraces (fig.1).Presentation in all six patients was similar with cough, dyspnoea, occasional chest pain and weight loss.Imaging was distinctive and showed a cephalad, irregular, pleuralbased thickening that encroached on the lung bilaterally.Five patients presented with ''platythorax'' (fig.2), a preferential reduction in the anterio-posterior diameter of the chest wall.In all patients, severe restrictive or restrictive-obstructive lung dysfunction progressed to hypoxaemic and hypercarbic respiratory failure, which was fatal in four patients despite intensive care unit support.This outcome was all the more tragic as these four patients had survived previous malignant conditions, including haematological malignancy (n53) and brain tumour (n51).
Immature monocytes acquire antigens from other cells in the bone marrow and present them to T cells after maturing in the periphery
Authors: Frank Tacke, Florent Ginhoux, Claudia Jakubzick, Nico van Rooijen, Miriam Merad, Gwendalyn J. Randolph
Journal: The Journal of Experimental Medicine (2006)

Monocytes are circulating precursors for tissue macrophages and dendritic cells (DCs) but are not recognized to directly participate in antigen presentation. We developed techniques to label mouse monocyte subsets with particulate tracers in vivo. Gr-1lo but not Gr-1hi monocytes were stably labeled by intravenous injection of 0.5-μm microspheres. Gr-1hi monocytes could be labeled when the microspheres were injected after systemic depletion of blood monocytes and spleen macrophages. In this condition, the phagocytic tracer was transferred to immature bone marrow monocytes by neutrophils and B cells that first carried the particles to the bone marrow. Moreover, antigens from B cells or proteins conjugated to the tracer particles were processed for presentation by monocytes and could induce T cell responses in the periphery. Cell-associated antigen taken up by bone marrow monocytes was retained intracellularly for presentation of the antigen days later when monocyte-derived DCs migrated to lymph nodes or in vitro after differentiation with granulocyte/macrophage colony-stimulating factor. These data reveal that immature monocytes unexpectedly sample antigen from the bone marrow environment and that they can present these antigens after they leave the bone marrow.