tbuckley/cabot-search huggingface dataset:
Cellular immune responses in the lung of hypersensitivity pneumonitis
Authors: G Semenzato, L Trentin
Journal: European Respiratory Journal (1990)

Presynaptic regulation of transmission at the first olfactory synapse was investigated by selectively imaging axon terminals of receptor neurons in the lobster olfactory lobe and turtle olfactory bulb. In both species, action potential propagation into axon terminals after olfactory nerve stimulation was measured using voltage-sensitive dyes. In addition, in the turtle, calcium influx into terminals was measured by selectively labeling receptor neurons with dextran-conjugated calcium indicator dyes. In the lobster, application of the inhibitory transmitters GABA or histamine suppressed action potentials in the terminals. The suppression was blocked by picrotoxin and cimetidine, respective antagonists to lobster GABA and histamine receptors. These results suggest that previously characterized GABA and histaminergic interneurons regulate olfactory input by suppressing action potential propagation into axon terminals of olfactory afferents. In contrast, in the turtle olfactory bulb, neither GABA nor dopamine had any effect on receptor cell action potentials as measured with voltage-sensitive dyes. However, calcium influx into axon terminals was reduced by the GABA<sub>B</sub> agonist baclofen and the dopamine D<sub>2</sub> agonist quinpirole, and paired-pulse suppression of calcium influx was reduced by the GABA<sub>B</sub>antagonist saclofen. These results indicate that in the turtle, GABA and dopamine mediate presynaptic inhibition not by affecting action potentials directly, as in the lobster, but by reducing calcium influx via GABA<sub>B</sub> and dopamine D<sub>2</sub> receptors. Thus, although mediated by different cellular mechanisms, presynaptic regulation of olfactory input to the CNS, via dual synaptic pathways, is a feature common to vertebrates and invertebrates. This inhibition may be important in the processing of olfactory information.
Pretreatment EBV-DNA Copy Number Is Predictive of Response and Toxicities to SMILE Chemotherapy for Extranodal NK/T-cell Lymphoma, Nasal Type
Authors: Yoshinori Ito, Hiroshi Kimura, Yoshinobu Maeda, Chizuko Hashimoto, Fumihiro Ishida, Koji Izutsu, Noriyasu Fukushima, Yasushi Isobe, Jun Takizawa, Yuichi Hasegawa, Hajime Kobayashi, Seiichi Okamura, Hikaru Kobayashi, Motoko Yamaguchi, Junji Suzumiya, Rie Hyo, Shigeo Nakamura, Keisei Kawa, Kazuo Oshimi, Ritsuro Suzuki
Journal: Clinical Cancer Research (2012)

Extranodal NK/T-cell lymphoma, nasal type (ENKL) is an Epstein-Barr virus (EBV)-associated lymphoma for which a new chemotherapeutic regimen called SMILE (steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide) recently showed promising results.The amount of EBV-DNA was prospectively measured in whole-blood and plasma samples by real-time quantitative PCR from 26 patients registered in the SMILE phase II study.Before treatment, the EBV-DNA was detected in 22 samples of whole blood with a median number of 3,691 copies/mL (range: 0-1.14 × 10(7)), but 15 samples of plasma with a median of 867 copies/mL (range: 0-1.27 × 10(7)). Results of these 2 measurements of EBV-DNA well correlated (R(2) = 0.994, P < 0.001). The overall response rate to SMILE was significantly higher in patients with less than 10(5) copies/mL of EBV-DNA in whole blood at enrollment (90% vs. 20%, P = 0.007) and in patients with less than 10(4) copies/mL of EBV-DNA in plasma (95% vs. 29%, P = 0.002). The incidence of grade 4 toxicity of SMILE other than leukopenia/neutropenia was significantly higher in patients with 10(5) copies/mL of EBV-DNA or more in whole blood (100% vs. 29%, P = 0.007) than that of others and in patients with 10(4) copies/mL or more in plasma (86% vs. 26%, P = 0.002).These findings suggest that whole blood is more sensitive for clinical use than plasma. The EBV-DNA amount in whole blood was useful for predicting tumor response, toxicity, and prognosis after SMILE chemotherapy for ENKL.
Presentation, management, complications, and outcome of acute renal failure in childhood: five years' experience.
Authors: R Counahan, J S Cameron, C S Ogg, P Spurgeon, D G Williams, E Winder, C Chantler
Journal: BMJ (1977)

During 1971-5, 72 episodes of acute renal failure were treated in 70 children aged up to 16 years. The commonest causes were renal hypoperfusion (31 cases), haemolytic-uraemic syndrome (12), glomerulonephritis (9), septicaemia (5), and congenital abnormalities (6). Though referral from other hospitals was generally prompt, 10 out of 51 patients had been observed for up to seven days before transfer. Dailysis was used in 44 cases, the most common complications of which were peritonitis in those treated with peritoneal dialysis and acute changes in fluid balance in those treated with haemodialysis. Altogether 37 patients fully recovered, 10 were discharged with chronically impaired renal function, 17 died, and six entered the dialysis and transplantation programme. The mortality fell from 33% in 1972 to 20% in later years, which was due solely to maintenance dialysis being available. Though all patients with irrevocable kidney failure who were suitable entered the dialysis and transplantation programme, with current financial restrictions we doubt whether we shall be able to find places for all such patients in the future.
Lysosomal protein turnover contributes to the acquisition of TGFβ-1 induced invasive properties of mammary cancer cells
Authors: Ursula Kern, Vladimir Wischnewski, Martin L Biniossek, Oliver Schilling, Thomas Reinheckel
Journal: Molecular Cancer (2015)

Normal epithelial cells and carcinoma cells can acquire invasiveness by epithelial-to-mesenchymal transition (EMT), a process of considerable cellular remodeling. The endosomal/lysosomal compartment is a principal site of intracellular protein degradation. Lysosomal cathepsin proteases are secreted during cancer progression. The established pro-metastatic role of specific cysteine cathepsins has until now been ascribed to their contribution to extracellular matrix remodeling. We hypothesized that cysteine cathepsins affect transforming growth factor β-1 (TGFβ-1)-induced EMT of normal and malignant mammary epithelial cells. The role of lysosomal proteolysis in TGFβ-1-induced EMT and invasion was investigated in a normal and a novel malignant murine mammary epithelial cell line. The contribution of cysteine cathepsins was determined by addition of the general cysteine cathepsin inhibitor E64d. Hallmarks of EMT were analyzed by molecular- and cell-biologic analyses including real-time cell migration/invasion assays. A quantitative proteome comparison using stable isotopic labeling with amino acids in culture (SILAC) showed the effect of E64d on TGFβ-1 induced proteome changes. Lysosomal patterning and junctional adhesion molecule A (Jam-a) localization and abundance were analyzed by immunofluorescence. We found increased lysosome activity during EMT of malignant mammary epithelial cells. Cysteine cathepsin inhibition had no effect on the induction of the TGFβ-1-induced EMT program on transcriptional level. Protease inhibition did not affect invasion of TGFβ-1 treated normal mammary epithelial cells, but reduced the invasion of murine breast cancer cells. Remarkably, reduced invasion was also evident if E64d was removed 24 h before the invasion assay in order to allow for recovery of cathepsin activity. Proteome analyses revealed a high abundance of lysosomal enzymes and lysosome-associated proteins in cancer cells treated with TGFβ-1 and E64d. An accumulation of those proteins and of lysosomal vesicles was further confirmed by independent methods. Interestingly, E64d caused lysosomal accumulation of Jam-a, a tight junction component facilitating epithelial cell-cell adhesion. Our results demonstrate an important role of lysosomal proteolysis in cellular remodeling during EMT and a pivotal contribution of lysosomal cysteine cathepsins to TGFβ-1 induced acquisition of breast cancer cell invasiveness. These findings provide an additional rationale to use cathepsin inhibitors to stall tumor metastasis.
Low Serum Angiogenin Concentrations in Patients With Type 2 Diabetes
Authors: Janusz Siebert, Magdalena Reiwer-Gostomska, Zofia Babińska, Jolanta Myśliwska, Andrzej Myśliwski, Ewa Skopińska-Różewska, Ewa Sommer, Piotr Skopiński
Journal: Diabetes Care (2007)

Premature development of microvascular and macrovascular disease is the most frequent complication of diabetes. It is responsible for diabetic retinopathy, nephropathy, and neuropathy (1). Moreover, diabetes leads to reduced collateralization in ischemic tissues, which causes impaired wound healing, exacerbation of peripheral limb ischemia, and a three- to fourfold increase in cardiac mortality in comparison with nondiabetic patients (2,3).

The pathophysiological mechanisms responsible for impaired angiogenic activity in diabetes remain unknown. Although angiogenesis impairment has been attributed to alterations in the gene regulatory network, which can be involved in the physiological revascularization process, the role of angiogenin in this process has not been clarified (2,4).

The aim of this study therefore was to compare angiogenin serum levels in healthy and type 2 diabetic age-matched individuals. The cutaneous angiogenesis in vivo (serum-induced angiogenesis [SIA]) test in mice was performed in parallel to determine the functional differences between the groups examined.

A total of 43 patients with type 2 diabetes and 43 age-matched healthy control subjects volunteered for the study. Patients suffering from acute and chronic infections and neoplastic diseases were excluded. Diabetes was defined according to American Diabetes Association criteria (5). All patients had blood glucose levels …
<scp>NSAID</scp>‐induced urticaria/angioedema does not evolve into chronic urticaria: a 12‐year follow‐up study
Authors: I. Doña, N. Blanca‐López, M. J. Torres, F. Gómez, J. Fernández, M. A. Zambonino, F. J. Monteseirín, G. Canto, M. Blanca, J. A. Cornejo‐García
Journal: Allergy (2013)

Abstract Background Nonsteroidal anti‐inflammatory drugs (NSAIDs) are the most frequent medicaments involved in drug hypersensitivity reactions, with NSAID ‐induced urticaria/angioedema ( NIUA ) being the most frequent clinical entity. The natural evolution of NIUA has been suggested to lead to chronic urticaria ( CU ) in an important proportion of patients, such that NIUA may therefore precede CU . Our aim was to verify whether these entities are related by following up a large cohort of patients with NIUA as well as a control group over a long period of time. Methods The study comprised three groups: (i) patients with a confirmed history of NIUA (more than two episodes with at least two different NSAID s or positive drug provocation tests), (ii) patients with more than two episodes of urticaria/angioedema to a single NSAID with good tolerance to a strong COX ‐1 inhibitor and/or evidence by in vivo tests supporting specific IgE antibodies to the drug (single NSAID‐induced urticaria/angioedema, SNIUA ), and (iii) controls who tolerated NSAID s. All cases in the three groups were followed up over a period of 12 years. Results There were 190 patients with NIUA (64.6% female; mean age 43.71 ± 15.82 years, 110 with SNIUA , and 152 controls. At the 12‐year evaluation, 12 patients with NIUA (6.15%) had developed CU over a 1‐ to 8‐year period. Similar proportions were seen in SNIUA and controls. Conclusions Nonsteroidal anti‐inflammatory drugs‐induced urticaria/angioedema does not seem to precede the onset of CU over the medium term. Further research including a longer follow‐up is necessary to verify this observation.
Lipopolysaccharide results in a marked decrease in hepatocyte nuclear factor 4α in rat liver
Authors: Bin Wang, Shi-Rong Cai, Cuihua Gao, Frances M. Sladek, Katherine Parker Ponder
Journal: Hepatology (2001)

The acute-phase response can result in decreased liver-specific functions and death as a result of liver failure. We show here that lipopolysaccharide (LPS), an endotoxin that induces the acute-phase response, results in a marked decrease in the major isoforms of the transcription factor, hepatocyte nuclear factor 4α (HNF-4α), in livers of rats. HNF-4α is a nuclear receptor that is critical for the expression of several liver-specific genes. This decrease in HNF-4α is primarily the result of a posttranscriptional mechanism, because mRNA levels are normal, and there are no major changes in the splicing patterns. This decrease was of functional significance, because expression of a gene that is highly dependent on HNF-4α, HNF-1α, was reduced. Interleukin-1β (IL-1β) is a cytokine whose levels are increased in vivo in response to LPS. IL-1β resulted in a decrease in HNF-4α levels in HepG2 cells. This IL-1β-induced decrease was likely caused by degradation via the proteasome, because it was prevented by the addition of the proteasome inhibitor, MG132. We conclude that the decrease in HNF-4α that occurs in vivo after the administration of LPS may be the result of IL-1β-induced degradation, and likely contributes to the liver insufficiency that occurs. IL-1β antagonists or proteasome inhibitors might increase HNF-4α protein levels in the acute-phase response, which could result in increased liver function and survival.
Generalisability of clinical registers used for drug safety and comparative effectiveness research: coverage of the Swedish Biologics Register
Authors: M Neovius, JF Simard, A Sundström, L Jacobsson, P Geborek, T Saxne, N Feltelius, L Klareskog, J Askling
Journal: Annals of the Rheumatic Diseases (2010)

Objective To determine coverage and generalisability of data in the Swedish Biologics Register ARTIS. Methods Patients with adult onset rheumatoid arthritis (RA) were identified in the National Patient Register and the Swedish Rheumatology Quality Register, including the ARTIS cohort of patients exposed to biological agents. Exposure to etanercept and adalimumab between 2006 and 2008 was determined by register linkage to the Prescribed Drug Register which contains patient-level data on &gt;99% of all etanercept and adalimumab use in Sweden. Results Of 62 897 patients with RA, 6510 had received treatment with etanercept or adalimumab according to the Prescribed Drug Register. Of these, 5673 were also registered in ARTIS, resulting in a national coverage of 87%. The regional variation was small with &gt;85% coverage in 18 of 21 counties. In multivariable analysis, ARTIS-registered and non-registered patients did not differ by age (p=0.62), sex (p=0.84) or education level (p=0.24). Conclusion Nationwide drug dispensing and demographic data may function as quality metrics for coverage and generalisability assessments. Using such data, the coverage of ARTIS was estimated at 87% with no indications of compromised external generalisability regarding demography.
Role of interleukin 6 (IL-6) in protection from lethal irradiation and in endocrine responses to IL-1 and tumor necrosis factor.
Authors: R Neta, R Perlstein, S N Vogel, G D Ledney, J Abrams
Journal: The Journal of Experimental Medicine (1992)

Primary responsibility for the induction of various acute phase reactions has been ascribed to interleukin 1 (IL-1), tumor necrosis factor (TNF), or IL-6, suggesting that these cytokines may have many overlapping activities. Thus, it is difficult to identify the cytokine primarily responsible for a particular biologic effect, since IL-1 and TNF stimulate one another, and both IL-1 and TNF stimulate IL-6. In this work, the contribution of IL-6 in radioprotection, induction of adrenocorticotropic hormone (ACTH), and induction of hypoglycemia was assessed by blocking IL-6 activity. Administration of anti-IL-6 antibody to otherwise untreated mice greatly enhanced the incidence of radiation-induced mortality, indicating that like IL-1 and TNF, IL-6 also contributes to innate resistance to radiation. Anti-IL-6 antibody given to IL-1-treated or TNF-treated mice reduced survival from lethal irradiation, demonstrating that IL-6 is also an important mediator of both IL-1- and TNF-induced hemopoietic recovery. A similar IL-1/IL-6 interaction was observed in the case of ACTH induction. Anti-IL-6 antibody blocked the IL-1-induced increase in plasma ACTH, whereas recombinant IL-6 by itself did not induce such an increase. Anti-IL-6 antibody also mitigated TNF-induced hypoglycemia, but did not reverse IL-1-induced hypoglycemia. It is, therefore, likely that TNF and IL-1 differ in their mode of induction of hypoglycemia. Our results suggest that an interaction of IL-6 with IL-1 and TNF is a prerequisite for protection from radiation lethality, and its interaction with IL-1 for induction of ACTH.
Transcription Factor Decoy to Study the Molecular Mechanism of Negative Regulation of Renin Gene Expression in the Liver In Vivo
Authors: Sawako Tomita, Naruya Tomita, Takehiko Yamada, Lunan Zhang, Yasufumi Kaneda, Ryuichi Morishita, Toshio Ogihara, Victor J. Dzau, Masatsugu Horiuchi
Journal: Circulation Research (1999)

Abstract —Renin is synthesized in high quantities in the juxtaglomerular cells of the kidney, but little or none is synthesized in the liver. Our previous in vitro and biochemical studies have demonstrated that tissue-specific expression of the mouse renin gene is regulated by the specific interaction between negative regulatory element (NRE) in the 5′-flanking region of the renin gene and NRE binding protein (NREB). In this study, we examined the hypothesis that this interaction between the NRE in the promoter region of the rat renin gene and the NREB in the liver contributes to the suppressed renin gene expression in this tissue in vivo. We used in vivo transfection of NRE transcription factor decoy (TFD) double-stranded oligonucleotide into the rat liver via portal vein infusion. A gel mobility shift assay showed that transfected NRE TFD blocked endogenous NREB binding with the rat renin gene. This resulted in enhanced hepatic renin mRNA expression, immunohistochemical detection of renin in the liver, and consequently, increased plasma renin concentration. Taken together, these results document the importance of NREB in the inhibition of renin gene expression in rat liver in vivo and suggest the possibility of in vivo renin gene modulation by the TFD approach.
Current data on predictive markers for anti-angiogenic therapy in thoracic tumours
Authors: N. Reinmuth, M. Thomas, M. Meister, P. A. Schnabel, M. Kreuter
Journal: European Respiratory Journal (2010)

The fact that growth and spread of tumours are dependent on angiogenesis has led to the investigation of the role of anti-angiogenic agents in the therapeutic strategies for thoracic tumours such as nonsmall cell lung cancer or mesotheliomas. Since various angiogenic factors may contribute to the regulation of angiogenesis in the individual tumour, in the era of increasing amounts of clinically tested agents it is of utmost importance to properly select patients that may benefit from a specific therapy. Due to the complex nature of tumour angiogenesis, various biomarkers may be applicable. For example, the profile of activated angiogenic pathways in endothelial cells may be determined in order to make conclusions about the relevance of inhibiting a given pathway by a selected agent. Moreover, changes in protein expression in stromal and tumour cells, as well as structural alterations in the vasculature, may be used for predicting and monitoring the clinical effects of such a therapy. In this review, the current data from clinical studies evaluating predictive markers for anti-angiogenic agents in thoracic cancers are summarised. Besides giving clinical examples, the rationales for investigating various parameters based on pre-clinical studies are described.
Abuse of mentally handicapped adults.
Authors: L B Cooke
Journal: BMJ (1990)

neutron therapy in both the BMJ and the national press.'4It is important not to let the political issue obscure the scientific facts, and there have been many mis-statements and half truths printed regarding Hammersmith Hospital's experience, the Edinburgh trials, and the present role of the National Cancer Institute in the funding of trials in the United States.The Hammersmith Hospital studies on the response of normal and tumour tissues to neutron treatment in predictably resistant disease: * Offset the bad results of previous unsuccessful clinical studies in the United States' * Showed the benefit of neutron radiation therapy of resistant tumours * Defined the limits of low energy (short penetration) neutron beams, showing especially the predictable problems of using a low energy beam to treat deeply placed tumours (pelvic and abdominal) * Defined acceptable doses and treatment schedules to produce tumour control with the lowest possible rate of complications using the then available equipment * Defined the characteristics of an ideal neutron therapy unit * Defined through clinical trials several tumour types that do not benefit from neutron radiation therapy.These efforts required careful clinical observation and documentation of responses in both tumour and normal tissues.These careful observations stimulated reviews of the original studies carried out by Stone and his collaborators' in the United States during 1935-43 (a period during which any form of radiation therapy was relatively primitive compared with current sophistication).Reviews ofthe study explain the excessive incidence of late injury that occurred owing to retreatment of some patients and lack of knowledge of the relative biological effectiveness of small dose/fraction treatments.'The careful and deliberate studies at the Medical Research Council unit at Hammersmith Hospital provided well documented time-dose studies that permit effective treatment of slow growing resistant tumours in several body sites.Unfortunately, in the Medical Research Council programme at Edinburgh many of the lessons learnt at Hammersmith Hospital were ignored, so that: * The unit had energy and beam characteristics similar to the inadequate Hammersmith unit * They treated many deep seated pelvic tumours for which the beam was inadequate * They used time-dose schedules that were different, so the trials are not comparable with the Hammersmith trials * They produced an inordinately large number of patients with complications, including some that resulted in death.