tbuckley/cabot-search huggingface dataset:
Akt/PKB-Mediated Phosphorylation of Twist1 Promotes Tumor Metastasis via Mediating Cross-Talk between PI3K/Akt and TGF-β Signaling Axes
Authors: Gongda Xue, David F. Restuccia, Qiang Lan, Debby Hynx, Stephan Dirnhofer, Daniel Hess, Curzio Rüegg, Brian A. Hemmings
Journal: Cancer Discovery (2012)

Metastatic breast tumor cells display an epithelial-mesenchymal transition (EMT) that increases cell motility, invasion, and dissemination. Although the transcription factor Twist1 has been shown to contribute to EMT and cancer metastasis, the signaling pathways regulating Twist1 activity are poorly understood. Here, we show that Twist1 is ubiquitously phosphorylated in 90% of 1,532 invasive human breast tumors. Akt/protein kinase B (PKB)-mediated Twist1 phosphorylation promotes EMT and breast cancer metastasis by modulating its transcriptional target TGF-β2, leading to enhanced TGF-β receptor signaling, which in turn maintains hyperactive phosphoinositide 3-kinase (PI3K)/Akt signaling. Preventing phosphorylation of Twist1, as well as depletion of TGF-β2, significantly impaired the metastatic potential of cancer cells in vivo, indicating a key role of phosphorylated Twist1 (phospho-Twist1) in mediating cross-talk between the PI3K/Akt and TGF-β/Smad signaling axes that supports metastatic tumor development. Our results describe a novel signaling event linking PI3K/Akt hyperactivation in tumor cells to direct regulation of Twist1 activation and tumor metastasis.We identified the first phospho-Twist1 transcriptional target TGF-β2, which mediates cross-talk between PI3K/Akt and TGF-β signaling and promotes tumor metastasis. Our results thus illustrate a direct role of PI3K/Akt signaling in metastatic cancer development and suggest that Twist1 phosphorylation could be a potential therapeutic target in clinical cancer treatment.
NHS surplus will remain in NHS, chief executive says
Authors: A. O'Dowd
Journal: BMJ (2008)

The NHS’s £2.1bn (€2.4bn; $3.1bn) surplus for 2007-8 will not be clawed back by the Treasury, said the head of the organisation, who has told MPs that the money is safe with local NHS organisations.

The chief executive, David Nicholson, told the parliamentary health select committee that the money was already in the hands of NHS organisations and that the Department of Health was talking to them about how best to spend it.

Figures published by the select committee just ahead of its annual inquiry into public spending on health and personal social services show that the total net surplus for 2007-8 in the NHS in England was £2.1bn, four times greater than in the previous …
Renal Damage after Myocardial Infarction Is Prevented by Renin-Angiotensin-Aldosterone-System Intervention
Authors: Willemijn A.K.M. Windt, Wouter B.A. Eijkelkamp, Robert H. Henning, Alex C.A. Kluppel, Pieter A. de Graeff, Hans L. Hillege, Stefan Schäfer, Dick de Zeeuw, Richard P.E. van Dokkum
Journal: Journal of the American Society of Nephrology (2006)

Recently, it was shown that myocardial infarction aggravates preexistent mild renal damage that is elicited by unilateral nephrectomy in rats. The mechanism behind this cardiorenal interaction likely involves the renin-angiotensin-aldosterone-system and/or vasoactive peptides that are metabolized by neutral endopeptidase (NEP). The renoprotective effect of angiotensin-converting enzyme inhibition (ACEi) as well as combined ACE/NEP inhibition with a vasopeptidase inhibitor (VPI) was investigated in the same model to clarify the underlying mechanism. At week 17 after sequential induction of unilateral nephrectomy and myocardial infarction, treatment with lisinopril (ACEi), AVE7688 (VPI), or vehicle was initiated for 6 wk. Proteinuria and systolic BP (SBP) were evaluated weekly. Renal damage was assessed primarily by proteinuria, interstitial alpha-smooth muscle actin (alpha-SMA) staining, and the incidence of focal glomerulosclerosis (FGS). At start of treatment, proteinuria had increased progressively to 167 +/- 20 mg/d in the entire cohort (n = 42). Both ACEi and VPI provided a similar reduction in proteinuria, alpha-SMA, and FGS compared with vehicle at week 23 (proteinuria 76 +/- 6 versus 77 +/- 4%; alpha-SMA 60 +/- 6 versus 77 +/- 3%; FGS 52 +/- 14 versus 61 +/- 10%). Similar reductions in systolic BP were observed in both ACEi- and VPI-treated groups (33 +/- 3 and 37 +/- 2%, respectively). Compared with ACEi, VPI-treated rats displayed a significantly larger reduction of plasma (41 +/- 5 versus 61 +/- 4%) and renal (53 +/- 6 versus 74 +/- 4%) ACE activity. It is concluded that both ACEi and VPI intervention prevent renal damage in a rat model of cardiorenal interaction. VPI treatment seemed to provide no additional renoprotection compared with sole ACEi after 6 wk of treatment in this model, despite a more pronounced ACE-inhibiting effect of VPI.
Disorders of the Respiratory Tract. Common Challenges in Primary Care
Authors: H.A. Thiadens
Journal: European Respiratory Journal (2006)

Edited by M.L. Mintz    Published by MD Humana Press, Totowa, NJ, USA    Pages: 323. Price: £45.00, \#8364;67.00. ISBN: 1-58829-556-70

Disorders of the Respiratory Tract. Common Challenges in Primary Care    Many books and guidelines about respiratory diseases have been published over the past few years, so it is a challenge to write a new book about these issues. In Disorders of the Respiratory Tract. Common Challenges in Primary Care there is an overview of most respiratory diseases, with the aim of helping the primary-care physician. The book is divided …
Use of Urine Biomarkers to Assess Sodium Intake: Challenges and Opportunities
Authors: Mary E. Cogswell, Joyce Maalouf, Paul Elliott, Catherine M. Loria, Sheena Patel, Barbara A. Bowman
Journal: Annual Review of Nutrition (2015)

This article summarizes current data and approaches to assess sodium intake in individuals and populations. A review of the literature on sodium excretion and intake estimation supports the continued use of 24-h urine collections for assessing population and individual sodium intake. Since 2000, 29 studies used urine biomarkers to estimate population sodium intake, primarily among adults. More than half used 24-h urine; the rest used a spot/casual, overnight, or 12-h specimen. Associations between individual sodium intake and health outcomes were investigated in 13 prospective cohort studies published since 2000. Only three included an indicator of long-term individual sodium intake, i.e., multiple 24-h urine specimens collected several days apart. Although not insurmountable, logistic challenges of 24-h urine collection remain a barrier for research on the relationship of sodium intake and chronic disease. Newer approaches, including modeling based on shorter collections, offer promise for estimating population sodium intake in some groups.
The atrial natriuretic peptide regulates the production of inflammatory mediators in macrophages
Authors: A K Kiemer, A M Vollmar
Journal: Annals of the Rheumatic Diseases (2001)

The atrial natriuretic peptide (ANP), a member of the natriuretic peptide family, is a cardiovascular hormone which possesses well defined natriuretic, diuretic, and vasodilating properties. Most of the biological effects of ANP are mediated through its guanylyl cyclase coupled A receptor. Because ANP and its receptors have been shown to be expressed and differentially regulated in the immune system, it has been suggested that ANP has an immunomodulatory potency. Much investigation of the effects of ANP on the activation of macrophages has been carried out. ANP was shown to inhibit the lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase (iNOS) in macrophages in an autocrine fashion. ANP in this context was shown to reduce significantly the activation of NF-κB and to destabilise iNOS mRNA. ANP, furthermore, can significantly reduce the LPS-induced secretion of tumour necrosis factor α (TNFα) in macrophages. The relevance of these findings on a regulatory role for ANP on TNFα in humans was shown by the fact that ANP significantly reduces the release of TNFα in whole human blood. It was furthermore shown to attenuate the release of interleukin 1β (IL1β). Interestingly, ANP did not affect the secretion of the anti-inflammatory cytokines IL10 and IL1 receptor antagonist (IL1ra). In summary, ANP was shown to reduce the secretion of inflammatory mediators in macrophages. Therefore, this cardiovascular hormone may possess anti-inflammatory potential.
Histone Deacetylase Inhibitors Induce Cell Death Selectively in Cells That Harbor Activated kRasV12: The Role of Signal Transducers and Activators of Transcription 1 and p21
Authors: Lidija Klampfer, Jie Huang, Senji Shirasawa, Takehiko Sasazuki, Leonard Augenlicht
Journal: Cancer Research (2007)

Histone deacetylase (HDAC) inhibitors (HDACi) show potent and selective antitumor activity despite the fact that they induce histone hyperacetylation in both normal and tumor cells. In this study, we showed that the inducible expression of kRasV12 in nontransformed intestinal epithelial cells significantly lowered the mitochondrial membrane potential (MMP) and sensitized cells to HDACi-induced apoptosis. Consistent with our finding that colon cancer cell lines with mutant Ras have reduced expression of signal transducers and activators of transcription 1 (STAT1), we showed that inducible expression of mutant Ras markedly decreased both basal and inducible expression of STAT1, a transcription factor with tumor suppressor activity. To investigate whether reduced expression of STAT1 in cells that harbor mutant Ras contributes to their increased sensitivity to HDACi, we silenced the expression of STAT1 in HKe-3 cells with small interfering RNA. Despite the fact that silencing of STAT1 was not sufficient to alter the MMP, STAT1 deficiency, like Ras mutations, sensitized cells to apoptosis induced by HDACi. We showed that the induction of p21 by HDACi was significantly impaired in HKe-3 cells with silenced STAT1 expression and showed that the ability of butyrate to activate p21 transcription was diminished in STAT1-deficient HKe-3 cells. Finally, we used cells with targeted deletion of p21 to confirm that p21 protects cells from butyrate-induced apoptosis, strongly suggesting that in these cells STAT1 deficiency promotes butyrate-induced apoptosis through impaired induction of p21. Our data therefore establish that Ras mutations, and consequent reduction in the expression of STAT1, underlie the increased susceptibility of transformed cells to undergo apoptosis in response to treatment with inhibitors of HDAC activity.
PPARα Contributes to Tubular Protection
Authors: Laurent Baud, Emmanuel Letavernier
Journal: Journal of the American Society of Nephrology (2007)

Peroxisome proliferator–activated receptors (PPAR) are ligand-inducible transcription factors that belong to the nuclear receptor family. They include three major subtypes: PPARα, PPARβ/δ, and PPARγ. Initially, PPARα was identified as the molecular target for the hypolipidemic fibrate drugs
Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomised trial
Authors: Stefan Aebi, Shari Gelber, Stewart J Anderson, István Láng, André Robidoux, Miguel Martín, Johan W R Nortier, Alexander H G Paterson, Mothaffar F Rimawi, José Manuel Baena Cañada, Beat Thürlimann, Elizabeth Murray, Eleftherios P Mamounas, Charles E Geyer, Karen N Price, Alan S Coates, Richard D Gelber, Priya Rastogi, Norman Wolmark, Irene L Wapnir
Journal: The Lancet Oncology (2014)
Exhaled and nasal NO levels in allergic rhinitis: relation to sensitization, pollen season and bronchial hyperresponsiveness
Authors: A.h. Henriksen, M. Sue-Chu, T. Lingaas Holmen, A. Langhammer, L. Bjermer
Journal: European Respiratory Journal (1999)

Exhaled nitric oxide is a potential marker of lower airway inflammation. Allergic rhinitis is associated with asthma and bronchial hyperresponsiveness. To determine whether or not nasal and exhaled NO concentrations are increased in allergic rhinitis and to assess the relation between hyperresponsiveness and exhaled NO, 46 rhinitic and 12 control subjects, all nonasthmatic nonsmokers without upper respiratory tract infection, were randomly selected from a large-scale epidemiological survey in Central Norway. All were investigated with flow-volume spirometry, methacholine provocation test, allergy testing and measurement of nasal and exhaled NO concentration in the nonpollen season. Eighteen rhinitic subjects completed an identical follow-up investigation during the following pollen season. Exhaled NO was significantly elevated in allergic rhinitis in the nonpollen season, especially in perennially sensitized subjects, as compared with controls (p=0.01), and increased further in the pollen season (p=0.04), mainly due to a two-fold increase in those with seasonal sensitization. Nasal NO was not significantly different from controls in the nonpollen season and did not increase significantly in the pollen season. Exhaled NO was increased in hyperresponsive subjects, and decreased significantly after methacholine-induced bronchoconstriction, suggesting that NO production occurs in the peripheral airways. In allergic rhinitis, an increase in exhaled nitric oxide on allergen exposure, particularly in hyperresponsive subjects, may be suggestive of airway inflammation and an increased risk for developing asthma.
Effects of cigarette smoking on the serum concentration of lung surfactant protein A (SP-A)
Authors: K Kida, H Oda, Y Yamano, J Kagawa
Journal: European Respiratory Journal (1997)

We have tested the hypothesis that serum surfactant protein A (SP-A) production may be affected by cigarette smoke exposure, and that alterations in serum levels may reflect smoking habits. A total of 52 subjects were divided into the following two groups: active smokers (Group A; n = 23); and nonsmokers (Group B; n = 29). The assessment of smoking habit was determined by self-report, carbon monoxide concentration in expired air, and cotinine concentration in urine. Serum SP-A was compared in both groups and was found to be higher in Group A (active smokers) (p < 0.002). We conclude that surfactant protein A levels are increased in the serum of smokers. However, it was found that this is not a sensitive discriminating factor to separate smokers from nonsmokers.
MicroRNA Regulation of Cancer Stem Cells
Authors: Can Liu, Dean G. Tang
Journal: Cancer Research (2011)

Abstract Cancer stem cells (CSC), or cancer cells with stem cell properties, have been reported in many human tumors and are thought to be responsible for tumor initiation, therapy resistance, progression, relapse, and metastasis. Despite their potential clinical importance, how CSCs are regulated at the molecular level is not well understood. MicroRNAs (miRNA), small noncoding RNAs that play critical roles in normal stem cell functions during development, have emerged as important regulators of CSCs as well. In this review, we summarize the current major findings of miRNA regulation of various CSCs and discuss our recent findings that miR-34a suppresses prostate CSCs and metastasis by directly repressing CD44. This recent progress has important implications for understanding how CSCs are intricately regulated by networks of miRNAs and for developing novel mechanism-based miRNA therapeutics that specifically target CSCs. Cancer Res; 71(18); 5950–4. ©2011 AACR.
Farnesyltransferase inhibitor treatment restores chromosome territory positions and active chromosome dynamics in Hutchinson-Gilford progeria syndrome cells
Authors: Ishita S Mehta, Christopher H Eskiw, Halime D Arican, Ian R Kill, Joanna M Bridger
Journal: Genome biology (2011)

Hutchinson-Gilford progeria syndrome (HGPS) is a premature ageing syndrome that affects children leading to premature death, usually from heart infarction or strokes, making this syndrome similar to normative ageing. HGPS is commonly caused by a mutation in the A-type lamin gene, LMNA (G608G). This leads to the expression of an aberrant truncated lamin A protein, progerin. Progerin cannot be processed as wild-type pre-lamin A and remains farnesylated, leading to its aberrant behavior during interphase and mitosis. Farnesyltransferase inhibitors prevent the accumulation of farnesylated progerin, producing a less toxic protein. We have found that in proliferating fibroblasts derived from HGPS patients the nuclear location of interphase chromosomes differs from control proliferating cells and mimics that of control quiescent fibroblasts, with smaller chromosomes toward the nuclear interior and larger chromosomes toward the nuclear periphery. For this study we have treated HGPS fibroblasts with farnesyltransferase inhibitors and analyzed the nuclear location of individual chromosome territories. We have found that after exposure to farnesyltransferase inhibitors mis-localized chromosome territories were restored to a nuclear position akin to chromosomes in proliferating control cells. Furthermore, not only has this treatment afforded chromosomes to be repositioned but has also restored the machinery that controls their rapid movement upon serum removal. This machinery contains nuclear myosin 1β, whose distribution is also restored after farnesyltransferase inhibitor treatment of HGPS cells. This study not only progresses the understanding of genome behavior in HGPS cells but demonstrates that interphase chromosome movement requires processed lamin A.
Regulation of biliary cholesterol secretion is independent of hepatocyte canalicular membrane lipid composition: a study in the diosgenin-fed rat model
Authors: Catharina P Nibbering, Albert K Groen, Roelof Ottenhoff, Jos F.H.M Brouwers, Gerard P vanBerge-Henegouwen, Karel J van Erpecum
Journal: Journal of Hepatology (2001)
A prospective study on lung toxicity in patients treated with gemcitabine and carboplatin: clinical, radiological and functional assessment
Authors: I. Dimopoulou, E. Efstathiou, A. Samakovli, U. Dafni, L.A. Moulopoulos, C. Papadimitriou, P. Lyberopoulos, E. Kastritis, C. Roussos, M.A. Dimopoulos
Journal: Annals of Oncology (2004)
Limited Approval for Lotronex
Authors: Lester M. Crawford, Jr
Journal: JAMA (2002)

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Treatment benefit or survival of the fittest: what drives the time-dependent decrease in serious infection rates under TNF inhibition and what does this imply for the individual patient?
Authors: A. Strangfeld, M. Eveslage, M. Schneider, H. J. Bergerhausen, T. Klopsch, A. Zink, J. Listing
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objective</h3> To examine the risk of serious infection conveyed by tumour necrosis factor α (TNFα) inhibitors in the treatment of rheumatoid arthritis (RA). <h3>Methods</h3> Data from patients with RA enrolled in the German biologics register RABBIT were used for analysis. Baseline patient characteristics, time-varying risk factors (treatment changes, functional capacity) and selection processes caused by dropout, death or switching to non-anti-TNF treatment were taken into account to estimate the adjusted incidence rate ratios (IRR<sub>adj</sub>) of serious infection during treatment with TNF inhibitors compared with non-biological disease-modifying antirheumatic drug treatment. <h3>Results</h3> Data were available on 5044 patients, in whom 392 serious infections occurred. The crude rates of serious infections in patients treated with TNF inhibitors declined over the first 3 years of observation (from 4.8 to 2.2/100 patient-years). This decline was driven by (1) treatment termination or loss to follow-up in patients at increased risk and (2) a risk reduction through decreasing glucocorticoid doses and improvement in function. Adjusted for selection processes and time-varying risk factors, the following parameters assessed at baseline (age, chronic diseases) or at follow-up prior to the infection were significantly associated with an increased risk: age &gt;60 years, chronic lung or renal disease, low functional capacity, history of serious infections, treatment with glucocorticoids (7.5–14 mg/day, IRR<sub>adj</sub> 2.1 (95% CI 1.4 to 3.2); ≥15 mg/day, IRR<sub>adj</sub> 4.7 (95% CI 2.4 to 9.4)) and treatment with TNFα inhibitors (IRR<sub>adj</sub> 1.8 (95% CI 1.2 to 2.7)). <h3>Conclusion</h3> Reasons for the decline in infection rates observed at the group level were identified. The results enable expected infection rates to be calculated in individual patients based on their risk profiles.
DNA signatures for detecting genetic engineering in bacteria
Authors: Jonathan E Allen, Shea N Gardner, Tom R Slezak
Journal: Genome biology (2008)

Abstract Using newly designed computational tools we show that, despite substantial shared sequences between natural plasmids and artificial vector sequences, a robust set of DNA oligomers can be identified that can differentiate artificial vector sequences from all available background viral and bacterial genomes and natural plasmids. We predict that these tools can achieve very high sensitivity and specificity rates for detecting new unsequenced vectors in microarray-based bioassays. Such DNA signatures could be important in detecting genetically engineered bacteria in environmental samples.
Role of Abdominal Aortic Branches in Pulse Wave Contour Genesis
Authors: JOSEPH M. RYAN, RALPH W. STACY, ROBERT N. WATMAN
Journal: Circulation Research (1956)

Central and peripheral pulse wave contours were recorded in dogs before and after occlusion of the major visceral arteries. Comparison of the pulse wave contours indicates that occlusion of the visceral branches produces very little effect upon the wave form of the central and peripheral pulse. The major changes noted were slight shifts in the timing of reflected components, and it would appear that the timing changes can be explained on the basis of the increase in pulse wave velocity attendant with a rise in the arterial blood pressure. Both the importance of these findings in the understanding of pulse wave contour genesis and the basic assumptions of the standing wave hypothesis are discussed.