tbuckley/cabot-search huggingface dataset:
Empirical treatment with fibrinolysis and early surgery reduces the duration of hospitalization in pleural sepsis
Authors: TK Lim, NK Chin
Journal: European Respiratory Journal (1999)

The efficacy of three different treatment protocols was compared: 1) simple chest tube drainage (Drain); 2) adjunctive intrapleural streptokinase (IP-SK); and 3) an aggressive empirical approach incorporating SK and early surgical drainage (SK+early OP) in patients with pleural empyema and high-risk parapneumonic effusions. This was a nonrandomized, prospective, controlled time series study of 82 consecutive patients with community-acquired empyema (n=68) and high-risk parapneumonic effusions (n=14). The following three treatment protocols were administered in sequence over 6 years: 1) Drain (n=29, chest catheter drainage); 2) IP-SK (n=23, adjunctive intrapleural fibrinolysis with 250,000 U x day(-1) SK); and 3) SK+early OP (n=30, early surgical drainage was offered to patients who failed to respond promptly following initial drainage plus SK). The average duration of hospital stay in the SK+early OP group was significantly shorter than in the Drain and IP-SK groups. The mortality rate was also significantly lower in the SK+early OP than the Drain groups (3 versus 24%). It was concluded that an empirical treatment strategy which combines adjunctive intrapleural fibrinolysis with early surgical intervention results in shorter hospital stays and may reduce mortality in patients with pleural sepsis.
T25 Repeat in the 3′ Untranslated Region of the <i>CASP2</i> Gene: A Sensitive and Specific Marker for Microsatellite Instability in Colorectal Cancer
Authors: Peter Findeisen, Matthias Kloor, Sabine Merx, Christian Sutter, Stefan M. Woerner, Nicole Dostmann, Axel Benner, Bolormaa Dondog, Michael Pawlita, Wolfgang Dippold, Rudolf Wagner, Johannes Gebert, Magnus von Knebel Doeberitz
Journal: Cancer Research (2005)

Abstract DNA mismatch repair deficiency is observed in about 10% to 15% of all colorectal carcinomas and in up to 90% of hereditary nonpolyposis colorectal cancer (HNPCC) patients. Tumors with mismatch repair defects acquire mutations in short repetitive DNA sequences, a phenomenon termed high-level microsatellite instability (MSI-H). The diagnosis of MSI-H in colon cancer is of increasing relevance, because MSI-H is an independent prognostic factor in colorectal cancer, seems to influence the efficacy of adjuvant chemotherapy, and is the most important molecular screening tool to identify HNPCC patients. To make MSI typing feasible for the routine pathology laboratory, highly reproducible and cost effective laboratory tests are required. Here, we describe a novel T25 mononucleotide marker in the 3′untranslated region of the CASP2 gene (CAT25) that displayed a quasimonomorphic repeat pattern in normal tissue of 200 unrelated individuals of Caucasian origin. In addition, CAT25 was monomorphic also in all tested donors of African and Asian origin (n = 102 and n = 79, respectively) and thus differs from the most commonly used markers BAT25 and BAT26. Without the analysis of corresponding normal tissue, CAT25 correctly detected 56 of 57 colorectal cancer specimens classified as MSI-H by using the standard National Cancer Institute/International Collaborative Group-HNPCC marker panel. Combined with the standard markers BAT25 and BAT26 in a multiplex PCR, all MSI-H colorectal cancer samples were typed correctly. No false-positive results were obtained in 60 non-MSI-H control colorectal cancer specimens. These data suggest that CAT25 should be included into novel marker panels for microsatellite testing thus allowing for a significant reduction of the complexity and costs of MSI typing. Moreover, CAT25 represents a highly promising marker for early detection of colorectal cancer in HNPCC germ line mutation carriers.
Tolerance to ischaemic injury in remodelled mouse hearts: less ischaemic glycogenolysis and preserved metabolic efficiency
Authors: Waleed G.T. Masoud, Osama Abo Al-Rob, Yang Yang, Gary D. Lopaschuk, Alexander S. Clanachan
Journal: Cardiovascular Research (2015)

AimsPost-infarction remodelled failing hearts have reduced metabolic efficiency. Paradoxically, they have increased tolerance to further ischaemic injury. This study was designed to investigate the metabolic mechanisms that may contribute to this phenomenon and to examine the relationship between ischaemic tolerance and metabolic efficiency during post-ischaemic reperfusion.
Advancing Bioluminescence Imaging Technology for the Evaluation of Anticancer Agents in the MDA-MB-435-HAL-Luc Mammary Fat Pad and Subrenal Capsule Tumor Models
Authors: Cathy Zhang, Zhengming Yan, Maria E. Arango, Cory L. Painter, Kenna Anderes
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Tumors grafted s.c. or under the mammary fat pad (MFP) rarely develop efficient metastasis. By applying bioluminescence imaging (BLI) technology, the MDA-MB-435-HAL-Luc subrenal capsule (SRC) model was compared with the MFP model for disease progression, metastatic potential, and response to therapy. Experimental Design: The luciferase-expressing MDA-MB-435-HAL-Luc cell line was used in both MFP and SRC models. BLI technology allowed longitudinal assessment of disease progression and the therapeutic response to PD-0332991, Avastin, and docetaxel. Immunohistochemical analysis of Ki67 and CD31 staining in the primary tumors was compared in these models. Caliper measurement was used in the MFP model to validate the BLI quantification of primary tumors. Results: The primary tumors in MDA-MB-435-HAL-Luc MFP and SRC models displayed comparable growth rates and vascularity. However, tumor-bearing mice in the SRC model developed lung metastases much earlier (4 weeks) than in the MFP model (&amp;gt;7 weeks), and the metastatic progression contributed significantly to the survival time. In the MFP model, BLI and caliper measurements were comparable for quantifying palpable tumors, but BLI offered an advantage for detecting the primary tumors that fell below a palpable threshold and for visualizing metastases. In the SRC model, BLI allowed longitudinal assessment of the antitumor and antimetastatic effects of PD-0332991, Avastin, and docetaxel, and the results correlated with the survival benefits of these agents. Conclusions: The MDA-MB-435-HAL-Luc SRC model and the MFP model displayed differences in disease progression. BLI is an innovative approach for developing animal models and creates opportunities for improving preclinical evaluations of anticancer agents.
BACE1 activity regulates cell surface contactin-2 levels
Authors: Vivek Gautam, Carla D’Avanzo, Matthias Hebisch, Dora M Kovacs, Doo Yeon Kim
Journal: Molecular Neurodegeneration (2014)

Although BACE1 is a major therapeutic target for Alzheimer's disease (AD), potential side effects of BACE1 inhibition are not well characterized. BACE1 cleaves over 60 putative substrates, however the majority of these cleavages have not been characterized. Here we investigated BACE1-mediated cleavage of human contactin-2, a GPI-anchored cell adhesion molecule. Our initial protein sequence analysis showed that contactin-2 harbors a strong putative BACE1 cleavage site close to its GPI membrane linker domain. When we overexpressed BACE1 in CHO cells stably transfected with human contactin-2, we found increased release of soluble contactin-2 in the conditioned media. Conversely, pharmacological inhibition of BACE1 in CHO cells expressing human contactin-2 and mouse primary neurons decreased soluble contactin-2 secretion. The BACE1 cleavage site mutation 1008MM/AA dramatically impaired soluble contactin-2 release. We then asked whether contactin-2 release induced by BACE1 expression would concomitantly decrease cell surface levels of contactin-2. Using immunofluorescence and surface-biotinylation assays, we showed that BACE1 activity tightly regulates contactin-2 surface levels in CHO cells as well as in mouse primary neurons. Finally, contactin-2 levels were decreased in Alzheimer's disease brain samples correlating inversely with elevated BACE1 levels in the same samples. Our results clearly demonstrate that mouse and human contactin-2 are physiological substrates for BACE1. BACE1-mediated contactin-2 cleavage tightly regulates the surface expression of contactin-2 in neuronal cells. Given the role of contactin-2 in cell adhesion, neurite outgrowth and axon guidance, our data suggest that BACE1 may play an important role in these physiological processes by regulating contactin-2 surface levels.
Toxigenic Helicobacter pylori induces changes in the gastric mucosal microcirculation in rats
Authors: N Kalia
Journal: Gut (2002)

<b>Background and aims:</b> One of the key components of inflammation is changes in vascular structure and function. This suggests that the microcirculation may be a key target of <i>Helicobacter pylori</i> released factors. It has previously been shown in vivo that pooled <i>H pylori</i> extracts from duodenal ulcer/gastritis patients induce platelet aggregation but no leucocyte activation within rat gastric mucosal microcirculation (GMMC). However, infection with strains associated with ulcer disease as compared with gastritis may exert greater effects on the microcirculation. This study used fluorescent in vivo microscopy to determine the acute effects of extracts of genotypically different <i>H pylori</i> strains on the GMMC. <b>Methods:</b> Three <i>H pylori</i> extracts, with different <i>cagA</i> and VacA toxigenic status, were individually administered to the gastric mucosa of anaesthetised Wistar rats. The mucosal surface was visualised via an incision made in the exteriorised stomach. Fluoroscein isothiocyanate conjugated to bovine serum albumin (FITC-BSA) or acridine orange was used to quantify macromolecular leak (MML) and leucocyte/platelet activity respectively for 120 minutes. Changes in capillary and post-capillary venule (PCV) diameters were also monitored. <b>Results:</b> The <i>cagA</i><sup>+</sup> VacA toxigenic strain 60190 induced significant and sustained MML by five minutes (p&lt;0.01). Transient and less leakage was observed with its isogenic VacA<sup>−</sup> mutant and other non-toxigenic strains regardless of <i>cagA</i> status. Significant increases in leucocyte adhesion (p&lt;0.05), platelet aggregation (p&lt;0.05), and PCV vasoconstriction (p&lt;0.05) were only observed with the <i>cag A</i><sup>+</sup> and toxigenic strain. <b>Conclusion:</b> Extracts of <i>H pylori</i> are capable of inducing marked disturbances within the rat GMMC. These disturbances seem to be dependent on the production of an active vacuolating cytotoxin. Varying effects on the GMMC may explain the clinically diverse outcomes associated with genotypically different strains.
Effect of chronic intermittent hypoxia on rat genioglossus
Authors: Xilong Zhang, Qin Li
Journal: European Respiratory Journal (2011)

Objective: To investigate the effect of chronic intermittent hypoxia (CIH) on rat genioglossal ultrastructure and mitochondrial function as well as the intervention role of adiponectin (Ad).

Methods: 42 rats were randomly divided into three groups: normal control (NC) group, CIH group and CIH+Ad group with 14 rats in each. Rats in NC group were kept breathing normal air, while rats in both CIH and CIH +Ad groups received same CIH environment. However, rats in CIH+Ad group was given intravenous Ad supplement. At the end of experiment (day 35), the genioglossal ultrastructure, the mitochondrial membrane electrical potential (ΔΨm)as well as mitochondrial complexes I and IV were compared among different groups.

Results: a) In CIH group there were significant genioglussal ultrastructural changes such as myofibril discontinuities, lysis of myofilament, edema of mitochondria and disruption of cristae, vacuolus and lysis of some mitochondria. These changes were less significant in CIH +Ad group. b) The ΔΨm was significantly lower in CIH group than that in NC group ( P <0.01). The ΔΨm in CIH+Ad group was statistically lower than that in NC group but higher than that in CIH group (all P <0.05). d) The mitochondrial complexes I and IV in CIH group were the lowest but became higher and higher from CIH+Ad group to NC group, with a significant difference between NC and CIH groups (all P <0.05).

Conclusion: CIH could lead to impaired genioglossal ultrastructure and mitochondrial dysfunction in genioglossal cells. These pathological changes could be partially improved by supplement of adiponectin.
β2-Glycoprotein I: a novel component of innate immunity
Authors: Çetin Ağar, Philip G. de Groot, Matthias Mörgelin, Stephanie D. D. C. Monk, Gwendolyn van Os, Johannes H. M. Levels, Bas de Laat, Rolf T. Urbanus, Heiko Herwald, Tom van der Poll, Joost C. M. Meijers
Journal: Blood (2011)
Effects of insulin on ovine fetal leucine kinetics and protein metabolism.
Authors: J R Milley
Journal: Journal of Clinical Investigation (1994)

Fetuses of eight pregnant ewes (114-117 d of gestation) were used to study whether fetal insulin concentration affects fetal protein accretion and, if so, whether such changes are caused by effects on protein synthesis or protein breakdown. Fetal leucine kinetics were measured by infusion of [1-14C]leucine during each of three protocols: (I) low vs. normal insulin concentration; (II) low vs. high insulin concentration; and (III) low vs. high insulin concentration during amino acid infusion to keep leucine concentration constant. Fetal leucine concentration (233 +/- 20 vs. 195 +/- 18 microM) and clearance (48.3 +/- 4.4 vs. 54.2 +/- 5.5 ml/kg per min) were the only aspects of fetal leucine kinetics that changed during protocol I. During protocol II, insulin infusion decreased fetal leucine concentration (222 +/- 22 vs. 175 +/- 22), decreased fetal leucine disposal (11.63 +/- 0.89 vs. 12.55 +/- 0.89 mumol/kg per min), increased leucine clearance (48.0 +/- 4.2 vs. 57.6 +/- 6.5 ml/kg per min), decreased leucine decarboxylation (1.77 +/- 0.17 vs. 2.04 +/- 0.21 mumol/kg per min), decreased nonoxidative leucine disposal (9.81 +/- 0.78 vs. 10.51 +/- 0.74 mumol/kg per min), decreased release of leucine from fetal protein (7.43 +/- 1.08 vs. 8.38 +/- 0.84 mumol/kg per min), but did not change the accretion of leucine into protein. In contrast, when leucine concentrations (205 +/- 25 vs. 189 +/- 23) were maintained (protocol III), insulin infusion did not change fetal leucine disposal, decarboxylation, or nonoxidative disposal although leucine clearance still rose (55.4 +/- 5.0 vs. 64.4 +/- 5.9 ml/kg/min). Fetal release of leucine from protein, however, decreased (7.46 +/- 0.83 vs. 8.57 +/- 0.71 mumol/kg per min) and the accretion of leucine into protein increased (3.27 +/- 0.30 vs. 1.80 +/- 0.32 mumol/kg/min). These findings show that insulin decreases fetal protein breakdown. If insulin-induced hypoaminoacidemia occurs, protein synthesis decreases so that no net accretion of protein occurs. If fetal amino acid concentrations are maintained, however, insulin itself does not affect protein synthesis, and fetal protein accretion increases.
An Integrated Computational/Experimental Model of Tumor Invasion
Authors: Hermann B. Frieboes, Xiaoming Zheng, Chung-Ho Sun, Bruce Tromberg, Robert Gatenby, Vittorio Cristini
Journal: Cancer Research (2006)

Abstract The intracellular and extracellular dynamics that govern tumor growth and invasiveness in vivo remain poorly understood. Cell genotype and phenotype, and nutrient, oxygen, and growth factor concentrations are key variables. In previous work, using a reaction-diffusion mathematical model based on variables that directly describe tumor cell cycle and biology, we formulated the hypothesis that tumor morphology is determined by the competition between heterogeneous cell proliferation caused by spatial diffusion gradients, e.g., of cell nutrients, driving shape instability and invasive tumor morphologies, and stabilizing mechanical forces, e.g., cell-to-cell and cell-to-matrix adhesion. To test this hypothesis, we here obtain variable-based statistics for input to the mathematical model from in vitro human and rat glioblastoma cultures. A linear stability analysis of the model predicts that glioma spheroid morphology is marginally stable. In agreement with this prediction, for a range of variable values, unbounded growth of the tumor mass and invasion of the environment are observed in vitro. The mechanism of invasion is recursive subspheroid component development at the tumor viable rim and separation from the parent spheroid. Results of computer simulations of the mathematical model closely resemble the morphologies and spatial arrangement of tumor cells from the in vitro model. We propose that tumor morphogenesis in vivo may be a function of marginally stable environmental conditions caused by spatial variations in cell nutrients, oxygen, and growth factors, and that controlling these conditions by decreasing spatial gradients could benefit treatment outcomes, whereas current treatment, and especially antiangiogenic therapy, may trigger spatial heterogeneity (e.g., local hypoxia), thus causing invasive instability. (Cancer Res 2006; 66(3): 1597-604)
No human transmission of<i>Mycobacterium malmoense</i>in a perfect storm setting
Authors: Wouter Hoefsloot, Martin J. Boeree, Cees van Nieuwkoop, Alexandra T. Bernards, Paul H.M. Savelkoul, Jakko van Ingen, Dick van Soolingen
Journal: European Respiratory Journal (2012)

No human transmission of Mycobacterium malmoense in a perfect storm settingTo the Editors:Nontuberculous mycobacteria (NTM) are opportunistic pathogens that are widely present in our environment, i.e. in the soil and in natural and processed water.This group of organisms, with varying biological properties and clinical relevance, has gained notoriety over the past two decades due to their capability to cause severe disease in patients with immunodeficiency and/or chronic lung disease [1].Despite their rising isolation frequency and growing clinical importance, NTM infections receive little scientific or public health attention.This partly results from the dogma that these NTM infections are not transmitted from male-to-male [1].During our previous research of Mycobacterium malmoense infection in the Netherlands [2], we studied two patients with M. malmoense pulmonary infection with a strong epidemiological link.Human transmission was suspected because an acidfast bacilli (AFB) smear-positive patient was in close contact with an immunocompromised patient.Herein, we present details of the cases and the results of the molecular diagnostics that were performed.The patients gave informed consent; ethical approval was not required for this retrospective study.A 38-yr-old male with a medical history of chronic obstructive pulmonary disease and spontaneous pneumothorax reported to the respiratory physician with progressive dyspnoea, productive cough, fever, night sweats, malaise and weight loss.A chest radiograph revealed infiltrates with cavities in the upper lobes.Laboratory diagnostics showed a raised erythrocyte sedimentation rate (90 mm?h -1 ) and leukocytosis (white blood cell count 22.4 cells?mL -1 ); serological tests for HIV were negative.Three sputum smears were negative for AFB on direct microscopy.Bronchoalveolar lavage was performed, which was positive for AFB on direct microscopy.A regimen of isoniazid, rifampicin, ethambutol and pyrazinamide was initiated, based on a presumptive diagnosis of pulmonary tuberculosis.Later, sputum appeared to be positive for AFB.All corresponding cultures yielded M. malmoense, identified by Inno-LiPA Mycobacteria v2 reverse line blot assay (Innogenetics, Ghent, Belgium).Since the patient met the American Thoracic Society diagnostic criteria for clinical disease [1] the regimen was changed to 24 months of rifampicin, ethambutol and clarithromycin and the patient slowly improved.
Prospero Homeobox 1 Promotes Epithelial–Mesenchymal Transition in Colon Cancer Cells by Inhibiting E-cadherin via miR-9
Authors: Mei-Hsuan Lu, Chao-Cheng Huang, Mei-Ren Pan, Hong-Hwa Chen, Wen-Chun Hung
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Prospero homeobox 1 (PROX1) has been shown to function as a tumor suppressor in various types of cancer. However, it promotes colon cancer progression. The aim of this study is to clarify the underlying mechanism by which PROX1 regulates tumorigenicity of colon cancer. Experimental Design: Association of PROX1 and clinicopathological features was studied by immunohistochemical staining. Pri-miR-9-2 and miR-9 were detected by quantitative real-time PCR. Assays of cell invasion, adhesion, and matrix metalloproteinase activity were used to study PROX1-mediated epithelial–mesenchymal transition (EMT). Results: PROX1 was overexpressed in 43% (59/136) of colon cancer tissues and its expression was correlated with E-cadherin downregulation (P = 0.00005), advanced tumor staging (P = 0.005), and lymph node metastasis (P = 0.000009). Enforced expression of PROX1 in DLD-1 cells caused downregulation of E-cadherin and integrins and attenuated cell adhesion. These cells showed increase of matrix metalloproteinase activity and invasive ability. Conversely, knockdown of PROX1 in SW620 cells restored E-cadherin protein expression and reduced invasiveness. Unexpectedly, repression of E-cadherin by PROX1 was not mediated by transcriptional inhibition. We found that PROX1 bound to miR-9-2 promoter and triggered its expression to suppress E-cadherin 3′UTR reporter activity and protein expression. Anti–miR-9 restored E-cadherin in SW620 cells, whereas precursor miR-9 inhibited E-cadherin in PROX1-knockdown cells. The miR-9 level was higher in tumor tissues with high PROX1/low E-cadherin than that of tumor tissues with low PROX1/high E-cadherin. Conclusions: Our results provide mechanistic insights by which PROX1 promotes EMT and colon cancer progression. Targeting of PROX1-mediated oncogenic activity may be helpful for the treatment of colon cancer. Clin Cancer Res; 18(23); 6416–25. ©2012 AACR.