tbuckley/cabot-search huggingface dataset:
Src Activation of NF-κB Augments IL-1β–Induced Nitric Oxide Production in Mesangial Cells
Authors: Diane I. Jalal, Bruce C. Kone
Journal: Journal of the American Society of Nephrology (2005)

NF-kappaB is a critical transcription factor that is involved in glomerulonephritis and inflammatory host responses and a critical transactivator of the inducible nitric oxide (NO) synthase gene in mesangial cells. The Src protein tyrosine kinases (SFK) are involved in several signaling pathways and have been proposed to mediate cytokine activation of NF-kappaB in a few cell types. However, the specific involvement of SFK in IL-1beta induction of NO production has not been clearly established. Accordingly, pharmacologic and molecular tools were used to clarify this issue in cultured murine mesangial cells. The SFK antagonist 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo(3,4-d)pyrimidine (PP2) dramatically inhibited IL-1beta-mediated induction of endogenous NO production as measured by the Griess reaction, as well as the induction of NF-kappaB p50/p65 DNA-binding activity in gel shift assays and the activity of an NF-kappaB-responsive promoter-reporter construct transiently transfected into the cells. Immunoprecipitation and immunoblotting with anti-IkappaBalpha and anti-phosphotyrosine antibodies revealed that PP2 also inhibited IL-1beta-stimulated tyrosine phosphorylation of IkappaBalpha, a requisite step in NF-kappaB activation in this signaling cascade. In agreement with the pharmacologic inhibition studies, siRNA directed against c-Src specifically limited c-Src protein expression and inhibited IL-1beta-mediated induction of NF-kappaB DNA-binding activity, whereas control siRNA had no effect. Conversely, overexpression of constitutively active c-Src augmented basal and IL-1beta-mediated induction of NF-kappaB DNA-binding activity and NO production. Thus, SFK play a key role in IL-1beta-induced NO production in mesangial cells and do so via tyrosine phosphorylation of IkappaBalpha and consequent NF-kappaB activation.
Secretory leukoprotease inhibitor: partnering alpha 1-proteinase inhibitor to combat pulmonary inflammation.
Authors: L. Bingle, T. D. Tetley
Journal: Thorax (1996)

Secretory leukoprotease inhibitor (SLPI) is a low molecular weight serine proteinase inhibitor, notably of neutrophil elastase (NE), which is synthesised and secreted by the pulmonary epithelium. SLPI plays an important role in limiting NE-induced pulmonary inflammation and, significantly, it also possesses anti-HIV activity. SLPI is a significant component of the anti-NE shield in the lung which has different reactivity from, and is therefore complementary to, the anti-NE action of alpha 1-proteinase inhibitor (alpha 1-PI). Inhaled recombinant SLPI (rSLPI) could prove beneficial in partnership with alpha 1-PI in the treatment of a number of inflammatory lung disorders including emphysema, chronic bronchitis, cystic fibrosis, and adult respiratory distress syndrome.
Interobserver variation in assessment of gastroduodenal lesions associated with non-steroidal anti-inflammatory drugs.
Authors: N Hudson, S Everitt, C J Hawkey
Journal: Gut (1994)

Video endoscopic images were used to investigate whether gastroenterologists could agree on the definition of lesions within the stomach seen at endoscopy, with particular reference to those seen in patients taking non-steroidal anti-inflammatory drugs. Seven experienced endoscopists, unaware of the patients9 clinical history or drug consumption, recorded their classification for 93 randomised video images of gastric lesions. There was complete agreement in the diagnosis of ulceration for nine images from patients who were not taking non-steroidal anti-inflammatory drugs; eight of nine were classified as deep ulcers, with 86% agreement for this subclassification. By contrast, the overall agreement for lesions in patients taking non-steroidal anti-inflammatory drugs was only 55%. Only nine of 44 ulcers were subclassified as deep, and there was considerable cross classification of non-haemorrhagic erosions and ulcers. In conclusion, ulcers that occur in patients taking non-steroidal anti-inflammatory drugs differ from those in patients who are not taking these drugs in that they are often more superficial and difficult to distinguish from erosions. The prognostic importance of these lesions is, therefore, uncertain.
Reciprocal regulation of microRNA-122 and c-Myc in hepatocellular cancer: Role of E2F1 and transcription factor dimerization partner 2
Authors: Bo Wang, Shu-hao Hsu, Xinmei Wang, Huban Kutay, Hemant Kumar Bid, Jianhua Yu, Ramesh K. Ganju, Samson T. Jacob, Mariia Yuneva, Kalpana Ghoshal
Journal: Hepatology (2013)

c-Myc is a well-known oncogene frequently up-regulated in different malignancies, whereas liver-specific microRNA (miR)-122, a bona fide tumor suppressor, is down-regulated in hepatocellular cancer (HCC). Here we explored the underlying mechanism of reciprocal regulation of these two genes. Real-time reverse-transcription polymerase chain reaction (RT-PCR) and northern blot analysis demonstrated reduced expression of the primary, precursor, and mature miR-122 in c-MYC -induced HCCs compared to the benign livers, indicating transcriptional suppression of miR-122 upon MYC overexpression. Indeed, chromatin immunoprecipitation (ChIP) assay showed significantly reduced association of RNA polymerase II and histone H3K9Ac, markers of active chromatin, with the miR-122 promoter in tumors relative to the c-MYC-uninduced livers, indicating transcriptional repression of miR-122 in c-MYC-overexpressing tumors. The ChIP assay also demonstrated a significant increase in c-Myc association with the miR-122 promoter region that harbors a conserved noncanonical c-Myc binding site in tumors compared to the livers. Ectopic expression and knockdown studies showed that c-Myc indeed suppresses expression of primary and mature miR-122 in hepatic cells. Additionally, Hnf-3β, a liver enriched transcription factor that activates miR-122 gene, was suppressed in c-MYC-induced tumors. Notably, miR-122 also repressed c-Myc transcription by targeting transcriptional activator E2f1 and coactivator Tfdp2, as evident from ectopic expression and knockdown studies and luciferase reporter assays in mouse and human hepatic cells. Conclusion : c-Myc represses miR-122 gene expression by associating with its promoter and by down-regulating Hnf-3β expression, whereas miR-122 indirectly inhibits c-Myc transcription by targeting Tfdp2 and E2f1. In essence, these results suggest a double-negative feedback loop between a tumor suppressor ( miR-122 ) and an oncogene ( c-Myc ). (Hepatology 2014;59:555–566)
Automatic and Strategic Representation of the Self in Major Depression: Trait and State Abnormalities
Authors: Avgusta Y. Shestyuk, Patricia J. Deldin
Journal: American Journal of Psychiatry (2010)

Dysfunctional negative thoughts about the self have long been hypothesized to reflect mood-independent cognitive vulnerability for major depressive disorder. These thoughts are believed to be predominantly automatic, in that they are involuntary and hard to inhibit. However, existing empirical evidence provides limited support for this theory, instead emphasizing the role of intentional ruminative (i.e., effortful) thoughts. To help clarify this theoretical controversy and investigate biased processing of emotional self-referent information in major depression, the authors utilized event-related brain potentials, which are used to index neural engagement during specific stages of cognitive processing.The P2 and late positive event-related brain components were examined during a free recall task in patients with current (N=17) or remitted (N=18) major depression and healthy comparison subjects (N=17). Participants made judgments on whether a word described them (self-referential condition) or former U.S. President Bill Clinton (other-referential condition).Healthy comparison subjects and subjects with remitted, but not current, major depression demonstrated enhanced recall of positive self-referent items. Greater component amplitudes in response to negative relative to positive self-referent items were evident in individuals with current and remitted major depression during the automatic processing stage (indexed by the P2 component) and in individuals with current depression during effortful encoding (indexed by the late positive component).Observed mood-independent abnormalities in automatic processing and mood-dependent abnormalities in effortful processing of emotional self-referent information provide direct support for an integrative theory of cognitive dysfunction in major depression, which amalgamates two main, but largely competing, theories of the disorder.
Transfer of Insulin Lispro Across the Human Placenta
Authors: Rada Boskovic, Denice S. Feig, Lidia Derewlany, Brenda Knie, Galina Portnoi, Gideon Koren
Journal: Diabetes Care (2003)

Insulin lispro (Humalog), a human insulin analog, has a more rapid onset, earlier peak, and shorter duration of glucose lowering activity than regular human insulin. However, it is not known whether insulin lispro crosses the human placenta and reaches the fetus. Therefore, the objective of the present study was to examine whether insulin lispro crosses the placenta using the technique of perfusing a human placental lobule in vitro.Term human placentae from uncomplicated pregnancies were obtained immediately after delivery. Insulin lispro, at concentrations ranging from 100 to 1000 micro U/ml, was introduced into the maternal reservoir. The maternal side of the placenta was perfused with constant concentration of lispro insulin; the fetal circulation was closed. Samples were drawn from both the maternal and fetal circulations at regular intervals. The appearance of insulin lispro in the fetal circulation was analyzed by a specific radioimmunoassay.No placental transfer of lispro could be detected during perfusion with 100 and 200 micro U/ml. In contrast, there was a small concentration-dependent transfer to the fetus at concentrations of 580 micro U/ml and higher, detectable after at least an hour of constant concentration of insulin lispro during perfusion. The rate of placental transfer was 0.019 micro U x min(-1) x g tissue(-1) at maternal levels of 580 micro U/ml and 0.045 micro U x min(-1) x g(-1) tissue at maternal levels of 1000 micro U/ml. Measuring lispro levels in 11 pregnant women revealed that a dose of 50 units may achieve serum concentrations >200 micro U/ml with apparent linear correlation between dose and levels.Insulin lispro is not likely to cross the placenta at a single standard dose. This study suggests that insulin lispro is unlikely to reach or harm the unborn baby.
Microsatellite instability in colitis associated colorectal cancer
Authors: S H ITZKOWITZ
Journal: Gut (2000)

See article on page 367 

As molecular pathways of colon carcinogenesis continue to be defined for high risk hereditary colon cancer syndromes and for average risk sporadic colon cancers, it seems that colon carcinogenesis in the setting of chronic idiopathic inflammatory bowel disease (IBD) may be unique.1 Although to some extent this notion seems intuitive because of the substrate of chronic inflammation from which these cancers arise, it is nevertheless curious that despite the setting of chronic inflammation, colon cancers occurring in patients with colitis share several features in common with those that arise in patients with hereditary non-polyposis colorectal cancer (HNPCC). For example, in both conditions there is a tendency for the colorectal cancers to affect young individuals, be multifocal, show a proximal colonic distribution, and display mucinous, signet-ring cell or undifferentiated histology. In addition, HNPCC colorectal cancers often have a rim of surrounding inflammation, referred to as a Crohn's-like reaction. These clinicopathological similarities have prompted some investigators to explore whether colitis associated cancers might in fact share a common molecular pathogenesis with HNPCC colorectal cancers.

Colorectal cancers in patients with HNPCC occur by virtue of a defective ability to repair DNA base pair mismatches. This results in DNA replication errors that have the net effect of altering genes that are critical for maintaining normal growth and behaviour of colonic …
Soluble Transforming Growth Factor-β Type II Receptor Inhibits Negative Remodeling, Fibroblast Transdifferentiation, and Intimal Lesion Formation But Not Endothelial Growth
Authors: Joshua D. Smith, Shane R. Bryant, Leslie L. Couper, Calvin P. H. Vary, Philip J. Gotwals, Victor E. Koteliansky, Volkhard Lindner
Journal: Circulation Research (1999)

Abstract —Using the rat balloon catheter denudation model, we examined the role of transforming growth factor-β (TGF-β) isoforms in vascular repair processes. By en face in situ hybridization, proliferating and quiescent smooth muscle cells in denuded vessels expressed high levels of mRNA for TGF-β 1 , TGF-β 2 , TGF-β 3 , and lower levels of TGF-β receptor II (TGF-βRII) mRNA. Compared with normal endothelium, TGF-β 1 and TGF-β 2 , as well as TGF-βRII, mRNA were upregulated in endothelium at the wound edge. Injected recombinant soluble TGF-βRII (TGF-βR:Fc) localized preferentially to the adventitia and developing neointima in the injured carotid artery, causing a reduction in intimal lesion formation (up to 65%) and an increase in lumen area (up to 88%). The gain in lumen area was largely due to inhibition of negative remodeling, which coincided with reduced adventitial fibrosis and collagen deposition. Four days after injury, TGF-βR:Fc treatment almost completely inhibited the induction of smooth muscle α-actin expression in adventitial cells. In the vessel wall, TGF-βR:Fc caused a marked reduction in mRNA levels for collagens type I and III. TGF-βR:Fc had no effect on endothelial proliferation as determined by reendothelialization of the denuded rat aorta. Together, these findings identify the TGF-β isoforms as major factors mediating adventitial fibrosis and negative remodeling after vascular injury, a major cause of restenosis after angioplasty.
A remarkable permeability of canalicular tight junctions might facilitate retrograde, non-viral gene delivery to the liver via the bile duct
Authors: J Hu
Journal: Gut (2005)

To establish the extent of retrograde bile duct infusion at an ultrastructural level, as a preliminary step before evaluating the efficacy of gene delivery to the rat liver via a branch of the bile duct.The extent of retrograde infusion into the biliary tree was established by light and electron microscopy, following infusion of 10 nm gold particles into the right lateral lobe. Canalicular permeability was further assessed by the infusion of a 67 kDa protein. For gene delivery, both naked DNA and a synthetic peptide vector system were evaluated. Because canalicular tight junction permeability can be compromised in damaged livers, both normal rats and rats recovering from the hepatotoxin D-galactosamine were studied.The gold particles penetrated the peripheral one third of the hepatic lobules and, surprisingly, reached the space of Disse in normal rats. Equally surprisingly, blood levels of a 67 kDa protein were identical after bile duct infusion and portal vein injection. Gene delivery with peptide/DNA complexes was much more effective in rats treated with D-galactosamine. However, gene delivery with naked DNA was equally effective in normal and damaged livers. Localisation of gene expression showed a scattering of positive hepatocytes restricted to the right lateral lobe.Retrograde infusion into the bile duct advances well into the hepatic lobule and reveals a remarkable permeability of the canalicular or cholangiole tight junctions in normal rats. It is an effective approach for delivering genes to a small population (approximately 1%) of hepatocytes.
Pathogenesis associated with hair follicle mites (Demodex spp.) in Australian Aborigines
Authors: William B. Nutting, Allen C. Green
Journal: British Journal of Dermatology (1976)

Demodex folliculorum and D. brevis are found in different habitats in the skin: the former in the hair follicles, the latter in the sebaceous glands. Both seem minor pathogens—merely harvesting the cells of their respective habitats. D. folliculorum was found aggregated (all stages) and plugging the follicular orifices; D. brevis, on the other hand, was usually solitary. In one case marked degeneration of the sebaceous gland, with leukocyte invasion, was associated with D. brevis. No correlations were discovered between either of these species and the gross condition of the skin. Positive samples were obtained from both mainland and island populations of Aborigines. Incidence values obtained were 66.6% for males and 80% for females; in the latter, the sample was small (5) and their ages over 34 years.
Lack of difference among vasoconstrictors: Similar effectiveness or similar ineffectiveness?
Authors: Gin‐Ho Lo
Journal: Hepatology (2014)

Potential conflict of interest: Nothing to report. To the Editor: I read with interest the article by Seo et al. regarding the use of vasoconstrictors in the control of acute gastroesophageal variceal hemorrhage.1 The authors found that hemostatic effects were similar between terlipressin, somatostatin, and octreotide as adjuvants to endoscopic therapy in patients with acute gastroesophageal variceal hemorrhage. However, some results appeared to be contradictory to previous studies and need further clarification. Current guidelines recommend that vasoactive drugs should be started as soon as possible before endoscopy in suspected variceal bleeding.2 Previous trials have shown that the use of vasoconstrictors could decrease the incidence of active variceal bleeding at endoscopy from around 46%‐50% to 16%‐31%.4 In the Seo et al. trial, the institution of any kind of vasoactive drug before endoscopy was noted to encounter an appreciably high incidence of active variceal bleeding, i.e., around 43%‐44% at endoscopy. The 5‐day treatment success was around 83%‐86% in each treatment group. Though not a head‐to‐head comparison, these figures were apparently lower than the hemostatic rate of 92%‐97% achieved by other scholars with banding ligation alone or in conjunction with vasoconstrictors.5 Thus, based on the current study, it is dubious that terlipressin, somatostatin, and octreotide as an adjuvant therapy to banding ligation in the control of acute variceal bleeding would be of similar effectiveness or similar ineffectiveness.
ENLARGEMENT OF THE ADRENAL CORTEX IN EXPERIMENTAL UREMIA
Authors: Eaton M. MacKay, Lois Lockard MacKay
Journal: The Journal of Experimental Medicine (1927)

The production of an experimental uremia in the albino rat by removal of both kidneys is followed by hypertrophy of the adrenal glands. In the case of male rats 90 days of age this adrenal enlargement amounted to 65 per cent and in the case of female rats 180 days of age 47 per cent. The increase in the size of the whole gland is due entirely to hypertrophy of the cortex. This increase in the volume of cortical tissue amounted to approximately 40 per cent for males and 61 per cent for females and was due in large part to an increase in the size of the cells. The content of water and material soluble in fat solvents was higher in the uremic than the control glands. However after subtraction of such storage materials a true hypertrophy of the cortex still remained. It amounted to 21 per cent. Histologically the stainable fat had a more irregular distribution and was present in lesser amount in the adrenals from the uremic animals. The capillaries of the medulla and reticular cortex were distended. The nuclei of both the cortical and medullary cells were swollen and stained faintly.
Same day bidirectional endoscopy- does the order of the procedures matter?
Authors: M. Kurien, S. Din, K. L. Dear, D. A. Elphick
Journal: Gut (2011)

<h3>Introduction</h3> Patients commonly have same day bidirectional endoscopy performed. There is no consensus on which order oesophagogastroduodenoscopy (OGD) and colonoscopy should be performed and how this impacts on completion rates, discomfort levels and patient9s overall satisfaction. The authors aimed to evaluate these outcomes by comparing patients who had same day bidirectional endoscopy procedures randomised to either OGD first or colonoscopy first. <h3>Methods</h3> 70 patients who were due to have same day bidirectional endoscopy in a District General Hospital between December 2009 and September 2010 were prospectively randomised to either having an OGD first (Group A, n=35) or colonoscopy first (Group B, n=35). Power calculations to determine sample size based on previously published data1 showed that 70 patients would be required to demonstrate a difference of 10% between groups at the 5% level of significance with a power of 80%. Sex, age, body mass index (BMI) and previous endoscopy experience were recorded. Procedural completion time, quality of bowel preparation and endoscopic findings were documented. Patients were asked to grade anticipated procedural discomfort scores, actual procedure discomfort and postprocedure discomfort scores on a Numeric Rating Scale ranging from 0 to 10 as well as asked to complete a Hospital Anxiety and Depression Scale. Patients were also questioned on their overall satisfaction with the procedures. <h3>Results</h3> 70 patients (36 male, 34 female; median 68 (36–87) years) were recruited with a mean BMI of 28 (19–54). After randomisation 17 males were in Group A and 19 in Group B. Both groups were similar in mean age, BMI, anxiety score and procedural completion times. Sedation and analgesic usage, previous endoscopic procedures and quality of bowel preparation were also similar in the two groups. Indications for bidirectional endoscopy were iron deficiency anaemia (60), chronic diarrhoea (9) and polyp surveillance (1). No statistically significant difference was noted in the mean discomfort scores given for colonoscopy between the two groups (5.2 vs 5.3). However, there was a significant reduction in the discomfort scores given for OGD when this was performed first rather than second (mean score 4.6 vs 6.3; p=0.02). Overall satisfaction rates were also slightly higher in group A than B (9.7 vs 9.6), but this did not reach statistical significance. <h3>Conclusion</h3> This results suggest that when undertaking same day bidirectional endoscopy, an OGD followed by a colonoscopy is the favoured order, with reduced patient discomfort. It may be that the abdominal bloating caused by colonoscopy leads to reduced tolerance of subsequent OGD.