tbuckley/cabot-search huggingface dataset:
ErbB-3 expression is associated with E-cadherin and their coexpression restores response to gefitinib in non-small-cell lung cancer (NSCLC)
Authors: S.E. Witta, R. Dziadziuszko, K. Yoshida, K. Hedman, M. Varella-Garcia, P.A. Bunn, F.R. Hirsch
Journal: Annals of Oncology (2009)
Significance of Serum and Hepatic Markers of Hepatitis B Viral Infection in Hbsag–Positive and Hbsag–Negative Chronic Active Hepatitis
Authors: John Freiman, Robert Eckstein, Geoffrey McCaughan, Carolyn Parsons, Stuart J. Davies, Peter Diegutis, Leslie Burnett, Neil Gallagher
Journal: Hepatology (1985)

The correlation between serum and hepatic markers of hepatitis B virus (HBV) has been studied in 70 subjects with chronic active hepatitis of whom 18 were HBsAg+ and 52 were HBsAg-. In HBsAg+ subjects, sera were tested for HBeAg/anti-HBe status and for HBV DNA sequences using a DNA dot hybridization technique. Anti-HBs and anti-HBc were measured in serum in the HBsAg- group. Immunoperoxidase staining was used to detect HBsAg, HBcAg and delta antigen in liver tissue. Of the 18 HBsAg+ patients, 13 were HBeAg+ and 5 were anti-HBe+. A good correlation was shown between HBeAg and HBV DNA in serum and HBcAg expression in liver tissue. Neither HBV DNA in serum nor HBcAg in liver tissue was detected in any of the anti-HBe+ patients. HBsAg and/or HBcAg were detected in liver tissue in 17 of 18 HBsAg+ subjects (95%). However, neither HBsAg nor HBcAg were detected in liver tissue in 52 HBsAg- patients. This group included 11 patients with antibody markers in serum of past HBV infection. Thus, in contrast to previous studies, a good correlation was demonstrated between the serum and hepatic markers of viral replication, and no evidence was obtained to implicate the HBV as an etiological agent in HBsAg- chronic active hepatitis.
Molecular Mechanisms Underlying Mood Stabilization in Manic-Depressive Illness: The Phenotype Challenge
Authors: Ognian C. Ikonomov, Husseini K. Manji
Journal: American Journal of Psychiatry (1999)

The authors critically examine the evidence supporting the hypothesis that lithium's therapeutic effects in bipolar affective disorder are mediated by alterations in the expression of specific genes in critical neuronal circuits.Using the heuristic "initiation and adaptation paradigm," the authors appraise the biological effects and underlying molecular and cellular mechanisms of lithium's action. The evidence is critically reviewed, with special attention to the reductive and integrative approaches necessary for identifying lithium's clinically relevant cellular and molecular targets.Lithium's acute effects are mediated through inhibition of specific enzymes involved in two distinct but interacting signaling pathways--the protein kinase C and glycogen synthase kinase 3 beta signaling cascades--that converge at the level of gene transcriptional regulation. The expression of different genes, including transcription factors, is markedly altered by chronic lithium administration. Chronic lithium treatment also robustly increases the expression of the neuroprotective protein Bcl-2, raising the intriguing possibility that some of lithium's effects are mediated through underappreciated neurotrophic/neuroprotective effects. The importance of lithium's effect on circadian rhythms and the related methodological problems in validating the role of specific genes in lithium's therapeutic effects are discussed.Despite the plethora of lithium effects at the genomic level, direct evidence that the genes identified thus far are responsible for phenotypic changes associated with chronic lithium treatment is still lacking. The combination of sensitive molecular technologies, appropriately designed paradigms, better behavioral analysis, and a chronobiologic approach seems necessary for the future identification of one or more clinically relevant lithium-target genes.
CD248/endosialin critically regulates hepatic stellate cell proliferation during chronic liver injury via a PDGF-regulated mechanism
Authors: Annika Wilhelm, Victoria Aldridge, Debashis Haldar, Amy J Naylor, Christopher J Weston, Ditte Hedegaard, Abhilok Garg, Janine Fear, Gary M Reynolds, Adam P Croft, Neil C Henderson, Christopher D Buckley, Philip N Newsome
Journal: Gut (2015)

CD248 (endosialin) is a stromal cell marker expressed on fibroblasts and pericytes. During liver injury, myofibroblasts are the main source of fibrotic matrix.To determine the role of CD248 in the development of liver fibrosis in the rodent and human setting.CD248 expression was studied by immunostaining and quantitative PCR in both normal and diseased human and murine liver tissue and isolated hepatic stellate cells (HSCs). Hepatic fibrosis was induced in CD248(-/-) and wild-type controls with carbon tetrachloride (CCl4) treatment.Expression of CD248 was seen in normal liver of humans and mice but was significantly increased in liver injury using both immunostaining and gene expression assays. CD248 was co-expressed with a range of fibroblast/HSC markers including desmin, vimentin and α-smooth muscle actin (α-SMA) in murine and human liver sections. CD248 expression was restricted to isolated primary murine and human HSC. Collagen deposition and α-SMA expression, but not inflammation and neoangiogenesis, was reduced in CD248(-/-) mice compared with wild-type mice after CCl4 treatment. Isolated HSC from wild-type and CD248(-/-) mice expressed platelet-derived growth factor receptor α (PDGFR-α) and PDGFR-β at similar levels. As expected, PDGF-BB stimulation induced proliferation of wild-type HSC, whereas CD248(-/-) HSC did not demonstrate a proliferative response to PDGF-BB. Abrogated PDGF signalling in CD248(-/-) HSC was confirmed by significantly reduced c-fos expression in CD248(-/-) HSC compared with wild-type HSC.Our data show that deletion of CD248 reduces susceptibility to liver fibrosis via an effect on PDGF signalling, making it an attractive clinical target for the treatment of liver injury.
Aromatase Destabilizer: Novel Action of Exemestane, a Food and Drug Administration–Approved Aromatase Inhibitor
Authors: Xin Wang, Shiuan Chen
Journal: Cancer Research (2006)

Using Western blot as the major technique, we studied the effects of the three Food and Drug Administration (FDA)-approved aromatase inhibitors (AI) on aromatase protein stability in the aromatase-overexpressing breast cancer cell line MCF-7aro. We have found that exemestane treatment significantly reduces aromatase protein level. Exemestane induces aromatase degradation in a dose-responsive manner (25-200 nmol/L), and the effect can be seen in as early as 2 hours. Metabolic labeling with S(35)-methionine was used to determine the half-life (t(1/2)) of aromatase protein. In the presence of 200 nmol/L exemestane, the t(1/2) of aromatase was reduced to 12.5 hours from 28.2 hours in the untreated cells. Furthermore, exemestane-induced aromatase degradation can be completely blocked by 10 micromol/L MG132, indicating that the degradation is mediated by proteasome. We also examined the effect of exemestane on aromatase mRNA level using real-time reverse transcription-PCR. No significant changes in mRNA level were detected after 8 hours of treatment with exemestane (200 nmol/L). This is the first report on the evaluation of three FDA-approved AIs on the stability of the aromatase protein. We have found that exemestane, different from letrozole and anastrozole, can destabilize the aromatase protein.
Ultrasonographic study of painful shoulder
Authors: E Naredo
Journal: Annals of the Rheumatic Diseases (2003)

Paired two tailed Student's t test used to test differences between baseline and six month follow up values for both patient groups.ESR, erythrocyte sedimentation rate (normal value 5-15 mm/1st h); CRP, C reactive protein (normal value <10 mg/l); VAS, visual analogue score; BASFI, Bath Ankylosing Spondylitis Functional Index (0-100); BASDAI, Bath Ankylosing Spondylitis Disease Activity Index (0-100).
Erythropoietin in Cancer Patients
Authors: John A. Glaspy
Journal: Annual Review of Medicine (2008)

Therapy with erythropoiesis-stimulating agents (ESAs) is associated with well-documented benefits to anemic cancer patients undergoing chemotherapy, most importantly a reduction in the likelihood of needing red cell transfusions. One challenge in supportive cancer care is a relative resistance to ESAs, requiring high doses with a significant rate of nonresponse. Recent advances in our understanding of iron metabolism in patients with chronic illness and the results of clinical trials indicate that parenteral iron improves ESA response in this setting. Another issue is the safety of ESA treatment in cancer patients. There is an increased risk of venous thrombosis that must be considered in clinical decision making. There are also recent data raising concerns that ESAs may enhance tumor progression or decrease patient survival. Although the preponderance of the data suggests that ESAs do not alter survival when used to treat chemotherapy-induced anemia, large well-controlled trials addressing this issue are needed.
Low-density lipoproteins impair migration of human coronary vascular smooth muscle cells and induce changes in the proteomic profile of myosin light chain
Authors: T. Padro, E. Pena, M. Garcia-Arguinzonis, V. Llorente-Cortes, L. Badimon
Journal: Cardiovascular Research (2007)

High-risk atheromatous plaques contain significant extra- and intracellular lipid deposits and very low smooth muscle cell numbers in the intima. However, the mechanisms inducing vessel wall remodelling and high-risk plaque composition are unknown. Low-density lipoproteins (LDLs) infiltrate the vessel wall and become retained and aggregated (agLDL) in the intima by binding to extracellular matrix proteoglycans. The cellular responses triggered by agLDL are not fully understood. This study was designed to investigate the effects of agLDL on vascular remodelling and repair, specifically studying human coronary vascular smooth muscle cell (VSMC) functions. Using a wound repair VSMC model system, we have shown that agLDL significantly impair cell migration. Proteomic analysis revealed a differential phenotypic pattern of myosin light chain and lower levels of phosphorylated myosin regulatory light chain (P-MRLC) in agLDL-exposed VSMC. LDL also induced changes in the subcellular localization of P-MRLC, with dephosphorylation strongly evident on the front edge of agLDL-treated migrating cells. PMA, a strong inducer of myosin light chain (MLC) phosphorylation, significantly reduced the effects of agLDL in VSMC migration. Inhibition of MLC kinase with ML9 did not affect MRLC dephosphorylation already induced by agLDL. Our results indicate that LDLs impair human VSMC migration and wound repair after injury. agLDL, and to a lesser extent nLDL, induce dephosphorylation of MRLC and striking changes in the subcellular localization of P-MRLC, a cytoskeleton protein involved in VSMC migration kinetics.
PTH-098 68ga-dotatate Pet In Localising Neuroendocrine Tumours – Could This Be The State Of The Art Diagnostic Test?
Authors: J Wu, J Ramage, A Prachalias, R Srirajaskanthan, R Sherwood, N Mulholland
Journal: Gut (2014)

<h3>Introduction</h3> 68Ga-DOTATATE PET is an established tool for localising primary tumour in metastatic neuroendocrine tumours (NETs) and in identifying NET metastases not seen on cross-sectional imaging. There is increasing evidence regarding its role in detecting occult primary sites in suspected NET. We present our experience of patients with primary gastrinoma/insulinoma seen only on Ga-DOTATATE imaging. <h3>Methods</h3> Patients reviewed in King’s College Hospital between 2005–2011 were included. Ga-DOTATATE was performed if there was a high degree of clinical suspicion of NET with supportive biochemistry but negative imaging and endoscopy. <h3>Results</h3> Patients with primary gastrinoma/insulinoma identified only with Ga-DOTATATE are presented below. A 61 year-old male with dyspepsia and diarrhoea experienced multiple spontaneous jejunal perforations. Fasting gastrin and chromogranin A were elevated (&gt;700 and 106 pmol/L respectively). Octreoscan showed a possible abnormal area in the pancreatic body not seen on CT, MRI, PET-FDG or EUS. DOTATATE revealed a soft tissue density in the pancreatic head. Post-Whipples histology confirmed NET tumour in peri-pancreatic lymph nodes. A 64 year-old female presenting with an upper gastrointestinal bleed from extensive duodenal ulceration was found to have an elevated fasting gastrin level (&gt;400 pmol/L) but a normal CT and Octreoscan. DOTATATE identified a focus within the gastrinoma triangle. Resection confirmed a 15 mm nodule of peri-pancreatic tumour with histological evidence of endocrine differentiation of low grade and proliferative rate. A 77 year-old non-diabetic male with irritable bowel symptoms presented with spontaneous duodenal perforation and developed episodes of hypoglycaemia (glucose 0.2 mmol/l) with an inappropriately elevated insulin (14.3 mU/l) and c-peptide (1063 pmol/l). Gastrin was raised (55 pmol/l). CT, MRCP, MRI pancreas and EUS were unremarkable. DOTATATE showed a small lesion in the pancreatic tail. Surgical enucleation of the lesion revealed a well differentiated NET histologically. <h3>Conclusion</h3> These cases support the use of Ga-DOTATATE as a potential diagnostic tool in suspected but not yet localised primary cases of gastrinoma/insulinoma with symptoms or elevated blood levels of tumour markers where cross-sectional imaging is normal or equivocal. To date calcium stimulation with selective angiography has been used. Ga-DOTATATE may obviate the need for this invasive and highly complex test. Larger case series and prospective data are needed to look at the validity of this test and ascertain its role in routine clinical practice. <h3>Disclosure of Interest</h3> None Declared.
Affinity Based Multilayered Polymeric Self‐Assemblies for Oral Wound Applications
Authors: Sundar P. Authimoolam, David A. Puleo, Thomas D. Dziubla
Journal: Advanced Healthcare Materials (2013)

Oral mucositis, a painful and debilitating ulcerative wound condition, is a frequently occurring complication following chemo- and/or radiotherapy. While the current standards of therapy (e.g., gels and mouth rinses) provide temporary relief, there is still an unmet need for a robust, long acting barrier that can provide lubricating protection in oral wounds, thereby enhancing the wound healing response. It is proposed that an affinity based layer-by-layer (LBL) self-assembly that can be administered as a series of mouth rinses could permit the formation of protective barriers, providing a modular approach to regenerative oral therapy. In this study, biotinylated poly(acrylic acid) was synthesized for developing LBL assemblies using biotin-streptavidin affinity linkages. To explore the ability of developed LBL assemblies to potentially resist the harsh intraoral environment, in vitro chemical and ex vivo mechanical tests were performed. The stability results demonstrated significant LBL barrier stability with wear resistance. From statistical analyses, it was deduced that polymer MW and the number of LBL layers contributed significantly to chemical barrier stability. Also, the extent of biotin conjugation played a key role for LBL development and in mechanical barrier stability. Thus, the proposed affinity based LBLs with their excellent barrier properties offer a modular treatment approach in oral mucosal injuries.
The Genomic Architecture of Sporadic Heart Failure
Authors: Gerald W. Dorn
Journal: Circulation Research (2011)

Common or sporadic systolic heart failure (heart failure) is the clinical syndrome of insufficient forward cardiac output resulting from myocardial disease. Most heart failure is the consequence of ischemic or idiopathic cardiomyopathy. There is a clear familial predisposition to heart failure, with a genetic component estimated to confer between 20% and 30% of overall risk. The multifactorial etiology of this syndrome has complicated identification of its genetic underpinnings. Until recently, almost all genetic studies of heart failure were designed and deployed according to the common disease-common variant hypothesis, in which individual risk alleles impart a small positive or negative effect and overall genetic risk is the cumulative impact of all functional genetic variations. Early studies used a candidate gene approach focused mainly on factors within adrenergic and renin-angiotensin pathways that affect heart failure progression and are targeted by standard pharmacotherapeutics. Many of these reported allelic associations with heart failure have not been replicated. However, the preponderance of data supports risk-modifier effects for the Arg389Gly polymorphism of β1-adrenergic receptors and the intron 16 in/del polymorphism of angiotensin-converting enzyme. Recent unbiased studies using genome-wide single nucleotide polymorphism microarrays have shown fewer positive results than when these platforms were applied to hypertension, myocardial infarction, or diabetes, possibly reflecting the complex etiology of heart failure. A new cardiovascular gene-centric subgenome single nucleotide polymorphism array identified a common heat failure risk allele at 1p36 in multiple independent cohorts, but the biological mechanism for this association is still uncertain. It is likely that common gene polymorphisms account for only a fraction of individual genetic heart failure risk, and future studies using deep resequencing are likely to identify rare gene variants with larger biological effects.
Sequential administration of cyclophosphamide and granulocyte‐colony stimulating factor relieves impaired myeloid maturation in felty's syndrome
Authors: John S. Pixley, Ken Y. Yoneda, Pacita B. Manalo
Journal: American Journal of Hematology (1993)

Abstract A patient with Felty's syndrome (FS) and persistent profound neutropenia developed recurrent infections and sepsis syndrome. No impairment of granulocyte‐macrophage colony development was observed in vitro. Marrow morphology revealed an absence of mature neutrophil forms despite administration of granulocyte‐colony stimulating factor (G‐CSF). However, pretreatment with bolus cyclophosphamide (CY) permitted the growth factor to relieve this impairment of late myeloid maturation and resulted in a brisk, albeit short, burst of neutrophilia. This suggests that immune interference in myelopoiesis can be overcome by growth factor administration if immune activity is adequately dampened by immunosuppressive therapy.
Exogenous Attenuation of p21Waf1/Cip1 Decreases Mesangial Cell Hypertrophy as a Result of Hyperglycemia and IGF-1
Authors: Ya-ping Fan, Robert H. Weiss
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Renal mesangial cell hypertrophy is a characteristic of diabetic nephropathy as well as a response to renal stress or injury. Because hypertrophy is a result of increased protein content per cell without DNA replication, those proteins that control the cell cycle, such as the cyclin kinase inhibitor p21, represent fertile ground for studying the mechanism of this structural alteration. A key role for p21 in promoting mesangial cell (MC) hypertrophy has been established using p21 knockout mouse models. Furthermore, some of the biologic effects of IGF-1, including cell proliferation, have been shown to be positively influenced by p21. In an attempt to begin to translate these findings ultimately to the bedside, methods to attenuate p21 levels in wild-type kidney cells were examined. With the use of a phosphorothioated antisense oligodeoxynucleotide (ODN) to p21, which has previously been shown to decrease specifically and effectively p21 protein levels in a variety of cell types, it is shown that attenuation of p21 in MC leads to a dose-dependent reduction of hypertrophy in the milieu of hyperglycemic culture media. Furthermore, the hypertrophic effect of the IGF-1 on MC is also attenuated using the same antisense p21 ODN. There was no evidence of apoptosis or other toxicity in MC transfected with the concentrations of antisense p21 ODN used in these experiments. Because the use of antisense ODN in human disease is already established in other medical disciplines, the stage is now set for the use of antisense p21 ODN to attenuate renal cell hypertrophy in vivo, leading to a new strategy for treatment of diabetic nephropathy and other diseases characterized by MC hypertrophy.
Airway dysfunction in swimmers: Table 1
Authors: Valérie Bougault, Louis-Philippe Boulet
Journal: British Journal of Sports Medicine (2012)

Elite competitive swimmers are particularly affected by airway disorders that are probably related to regular and intense training sessions in a chlorinated environment. Upper and lower airway respiratory symptoms, rhinitis, airway hyper-responsiveness, and exercise-induced bronchoconstriction are highly prevalent in these athletes, but their influence on athletic performance is still unclear. The authors reviewed the main upper and lower respiratory ailments observed in competitive swimmers who train in indoor swimming pools, their pathophysiology, clinical significance and possible effects on performance. Issues regarding the screening of these disorders, their management and preventive measures are addressed.
How Structure, Ca Signals, and Cellular Communications Underlie Function in Precapillary Arterioles
Authors: Lyudmyla Borisova, Susan Wray, David A. Eisner, Theodor Burdyga
Journal: Circulation Research (2009)

Precapillary arterioles control blood flow to tissues and their correct function is vital. However, their small size has limited study and little is known concerning the calcium signals in their endothelial and muscle cells and how these relate to function.We aimed to investigate whether these small vessels are specialized in terms of structure and calcium signaling.Using in situ confocal imaging we have studied the ultrastructure, Ca signaling and coordination of contraction in precapillary arterioles in ureter and vas deferens. We have compared the data to that from a small mesenteric artery. In the precapillary arteriole, 1 myocyte covers a approximately 10-microm length, and contraction of this single cell can decrease the diameter of this segment. In the mesenteric artery, more than 20 myocytes are required for this. In the precapillary arteriole, Ca signals arise solely from Ca release from the sarcoplasmic reticulum through inositol 1,4,5-trisphosphate-induced Ca release and not via ryanodine receptors. Agonist-induced Ca signals do not require Ca entry into the cell, do not spread or synchronize with neighboring cells, and are unaffected by endothelial stimulation, thereby allowing local control. This contrasts with the mesenteric artery, where Ca entry and ryanodine receptors are important and stimulation of the endothelium inhibits myocyte Ca signals and contraction.These data reveal the structural and signaling specializations underlying how blood flow is locally regulated, provide new insight into control of microcirculation, and provide a framework to explain its vulnerability to disease.