tbuckley/cabot-search huggingface dataset:
Increased Skin Papilloma Formation in Mice Lacking Glutathione Transferase GSTP
Authors: Colin J. Henderson, Kenneth J. Ritchie, Aileen McLaren, Probir Chakravarty, C. Roland Wolf
Journal: Cancer Research (2011)

Abstract The glutathione S-transferase GSTP is overexpressed in many human cancers and chemotherapy-resistant cancer cells, where there is evidence that GSTP may have additional functions beyond its known catalytic role. On the basis of evidence that Gstp-deficient mice have a comparatively higher susceptibility to skin carcinogenesis, we investigated whether this phenotype reflected an alteration in carcinogen detoxification or not. For this study, Gstp−/− mice were interbred with Tg.AC mice that harbor initiating H-ras mutations in the skin. Gstp−/−/Tg.AC mice exposed to the proinflammatory phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) exhibited higher tumor incidence and multiplicity with a significant thickening of skin after treatment, illustrating hyperproliferative growth. Unexpectedly, we observed no difference in cellular proliferation or apoptosis or in markers of oxidative stress, although higher levels of the inflammatory marker nitrotyrosine were found in Gstp−/−/Tg.AC mice. Instead, gene set enrichment analysis of microarray expression data obtained from skin revealed a more proapoptotic and proinflammatory environment shortly after TPA treatment. Within 4 weeks of TPA treatment, Gstp−/−/Tg.AC mice displayed altered lipid/sterol metabolism and Wnt signaling along with aberrant processes of cytoskeletal control and epidermal morphogenesis at both early and late times. In extending the evidence that GSTP has a vital role in normal homeostatic control and cancer prevention, they also strongly encourage the emerging concept that GSTP is a major determinant of the proinflammatory character of the tumor microenvironment. This study shows that the GSTP plays a major role in carcinogenesis distinct from its role in detoxification and provides evidence that the enzyme is a key determinant of the proinflammatory tumor environment. Cancer Res; 71(22); 7048–60. ©2011 AACR.
Lack of Mitogen-Activated Protein Kinase Phosphatase-1 Protects ApoE-Null Mice Against Atherosclerosis
Authors: Jianzhong Shen, Unni M. Chandrasekharan, Mohammad Z. Ashraf, Eric Long, Richard E. Morton, Yusen Liu, Jonathan D. Smith, Paul E. DiCorleto
Journal: Circulation Research (2010)

Multiple protein kinases have been implicated in cardiovascular disease; however, little is known about the role of their counterparts: the protein phosphatases.To test the hypothesis that mitogen-activated protein kinase phosphatase (MKP)-1 is actively involved in atherogenesis.Mice with homozygous deficiency in MKP-1 (MKP-1(-/-)) were bred with apolipoprotein (Apo)E-deficient mice (ApoE(-/-)) and the 3 MKP-1 genotypes (MKP-1(+/+)/ApoE(-/-) ; MKP-1(+/-)/ApoE(-/-) and MKP-1(-/-)/ApoE(-/-)) were maintained on a normal chow diet for 16 weeks. The 3 groups of mice exhibited similar body weight and serum lipid profiles; however, both MKP-1(+/-) and MKP-1(-/-) mice had significantly less aortic root atherosclerotic lesion formation than MKP-1(+/+) mice. Less en face lesion was observed in 8-month-old MKP-1(-/-) mice. The reduction in atherosclerosis was accompanied by decreased plasma levels of interleukin-1alpha and tumor necrosis factor alpha, and preceded by increased antiinflammatory cytokine interleukin-10. In addition, MKP-1-null mice had higher levels of plasma stromal cell-derived factor-1a, which negatively correlated with atherosclerotic lesion size. Immunohistochemical analysis revealed that MKP-1 expression was enriched in macrophage-rich areas versus smooth muscle cell regions of the atheroma. Furthermore, macrophages isolated from MKP-1-null mice showed dramatic defects in their spreading/migration and impairment in extracellular signal-regulated kinase, but not c-Jun N-terminal kinase and p38, pathway activation. In line with this, MKP-1-null atheroma exhibited less macrophage content. Finally, transplantation of MKP-1-intact bone marrow into MKP-1-null mice fully rescued the wild-type atherosclerotic phenotype.These findings demonstrate that chronic deficiency of MKP-1 leads to decreased atherosclerosis via mechanisms involving impaired macrophage migration and defective extracellular signal-regulated kinase signaling.
Mesenchymal cell targeting by TNF as a common pathogenic principle in chronic inflammatory joint and intestinal diseases
Authors: Maria Armaka, Maria Apostolaki, Peggy Jacques, Dimitris L. Kontoyiannis, Dirk Elewaut, George Kollias
Journal: The Journal of Experimental Medicine (2008)

Tumor necrosis factor (TNF) is key to the pathogenesis of various arthritic diseases and inflammatory bowel disease (IBD). Anti-TNF therapies have proved successful in the clinical treatment of these diseases, but a mechanistic understanding of TNF function is still lacking. We have investigated early cellular mechanisms of TNF function in these diseases using an established TNF transgenic model, which develops a spondyloarthritis-like disease characterized by peripheral joint arthritis, sacroiliitis, enthesitis, and Crohn's-like IBD. Bone marrow grafting experiments demonstrated that development of arthritis requires TNF receptor I (TNFRI) expression in the radiation-resistant compartment, which is also known to be a sufficient target of TNF in the development of Crohn's-like IBD in the same model. Early activation of synovial fibroblasts and intestinal myofibroblasts could also be demonstrated by perturbed expression of matrix metalloproteases and their inhibitors. Notably, selective Cre/loxP-mediated TNFRI expression in mesenchymal cells resulted in a fully arthritic–spondyloarthritic and intestinal phenotype, indicating that mesenchymal cells are primary and sufficient targets of TNF in these pathologies. Our results offer a novel mechanistic perspective for TNF function in gut and joint pathologies and indicate early common cellular pathways that may also explain the often observed synovial–gut axis in human disease.
Predicting targeted drug combinations based on Pareto optimal patterns of coexpression network connectivity
Authors: Nadia M Penrod, Casey S Greene, Jason H Moore
Journal: Genome Medicine (2014)

Molecularly targeted drugs promise a safer and more effective treatment modality than conventional chemotherapy for cancer patients. However, tumors are dynamic systems that readily adapt to these agents activating alternative survival pathways as they evolve resistant phenotypes. Combination therapies can overcome resistance but finding the optimal combinations efficiently presents a formidable challenge. Here we introduce a new paradigm for the design of combination therapy treatment strategies that exploits the tumor adaptive process to identify context-dependent essential genes as druggable targets.We have developed a framework to mine high-throughput transcriptomic data, based on differential coexpression and Pareto optimization, to investigate drug-induced tumor adaptation. We use this approach to identify tumor-essential genes as druggable candidates. We apply our method to a set of ER(+) breast tumor samples, collected before (n = 58) and after (n = 60) neoadjuvant treatment with the aromatase inhibitor letrozole, to prioritize genes as targets for combination therapy with letrozole treatment. We validate letrozole-induced tumor adaptation through coexpression and pathway analyses in an independent data set (n = 18).We find pervasive differential coexpression between the untreated and letrozole-treated tumor samples as evidence of letrozole-induced tumor adaptation. Based on patterns of coexpression, we identify ten genes as potential candidates for combination therapy with letrozole including EPCAM, a letrozole-induced essential gene and a target to which drugs have already been developed as cancer therapeutics. Through replication, we validate six letrozole-induced coexpression relationships and confirm the epithelial-to-mesenchymal transition as a process that is upregulated in the residual tumor samples following letrozole treatment.To derive the greatest benefit from molecularly targeted drugs it is critical to design combination treatment strategies rationally. Incorporating knowledge of the tumor adaptation process into the design provides an opportunity to match targeted drugs to the evolving tumor phenotype and surmount resistance.
It takes a thief to catch a thief
Authors: Nicholas Humphrey
Journal: Behavioral and Brain Sciences (2011)

Abstract Von Hippel &amp; Trivers (VH&amp;T) dismiss in a couple of pages the possible costs of self-deception. But there is a downside to self-deception that they do not consider. This is the loss of psychological insight into deceit by others that blindness to deceit by oneself is likely to entail.
Chronic Angiotensin II Receptor Blockade Reduces (Intra)Renal Vascular Resistance in Patients with Type 2 Diabetes
Authors: Danilo Fliser, Kathrin-Kristin Wagner, Astrid Loos, Dimitrios Tsikas, Hermann Haller
Journal: Journal of the American Society of Nephrology (2005)

Increased (intra)renal activity of the renin-angiotensin system may cause a persistent increase in renovascular resistance and intraglomerular pressure in patients with diabetes, thus contributing to the development of diabetic renal damage. The effect of chronic angiotensin II subtype 1 receptor blockade on (intra)renal hemodynamics in patients with type 2 diabetes was examined in a double-blind parallel group study. Patients were treated with 40 mg of olmesartan (n = 19) or placebo (n = 16), and renal hemodynamics were assessed before and after 12 wk of treatment using inulin and para-aminohippurate clearance techniques. Olmesartan significantly reduced 24-h ambulatory systolic and diastolic BP (both P < 0.05). In parallel, effective renal plasma flow increased significantly from 602 +/- 76 to 628 +/- 87 ml/min per 1.73 m(2), whereas filtration fraction and renovascular resistance decreased significantly (all P < 0.05). With placebo treatment, effective renal plasma flow decreased and filtration fraction increased significantly (both P < 0.05). GFR was not affected by both treatments. Active plasma renin concentration increased considerably (P < 0.05) with olmesartan therapy but remained unchanged with placebo treatment. Nitric oxide metabolism (plasma nitrate and nitrite) and asymmetric dimethylarginine blood levels were not affected by olmesartan and placebo therapy. In contrast, plasma 8-isoprostane 15(S)-8-iso-prostaglandin F(2a) concentration, a biochemical marker of oxidative stress, decreased significantly (P < 0.05) with olmesartan treatment. Chronic angiotensin II subtype 1 receptor blockade decreases (intra)renal vascular resistance and increases renal perfusion despite significant BP reduction. In addition, it significantly reduces oxidative stress. These effects of angiotensin II receptor antagonists may contribute to their beneficial long-term renal effects in patients with type 2 diabetes.
Response to Comment on Kahn and Davidson. The Reality of Type 2 Diabetes Prevention. Diabetes Care 2014;37:943–949
Authors: Richard Kahn, Mayer B. Davidson
Journal: Diabetes Care (2014)

We appreciate the opportunity to respond to Gregg et al. (1) regarding our commentary on community-based lifestyle modification programs to prevent diabetes (2). Gregg et al. believe that we have a disagreement over the interpretation of the extant data and that in our analysis we ignored other important findings of the landmark trials.

Gregg et al. (1) cite the 2012 systematic review by Ali et al. (3) (which we discussed in our article) as evidence that in community programs “an average 4% weight loss was observed” (1), which Gregg et al. believe is “comparable” to the major prevention trials. What Gregg et al. (1) ignore is the fact that the duration of the intervention and follow-up in 24 of the 28 studies in the Ali article was less than 1 year— most were 3–9 months; only 4 had a duration of 1 year. As we showed (2), which was also confirmed in a …
The Pathogenesis of Mixed-Lineage Leukemia
Authors: Andrew G. Muntean, Jay L. Hess
Journal: Annual Review of Pathology Mechanisms of Disease (2011)

Aggressive leukemias arise in both children and adults as a result of rearrangements to the mixed-lineage leukemia gene (MLL) located on chromosome 11q23. MLL encodes a large histone methyltransferase that directly binds DNA and positively regulates gene transcription, including homeobox (HOX) genes. MLL is involved in chromosomal translocations, partial tandem duplications, and amplifications, all of which result in hematopoietic malignancies due to sustained HOX expression and stalled differentiation. MLL lesions are associated with both acute myeloid leukemia and acute lymphoid leukemia and are usually associated with a relatively poor prognosis despite improved treatment options such as allogeneic hematopoietic stem cell transplantation, which underscores the need for new treatment regimens. Recent advances have begun to reveal the molecular mechanisms that drive MLL-associated leukemias, which, in turn, have provided opportunities for therapeutic development. Here, we discuss the etiology of MLL leukemias and potential directions for future therapy.
Transitory cerebral microvascular blockade after cardiopulmonary bypass.
Authors: R H Patterson, L Rosenfeld, R S Porro
Journal: Thorax (1976)

Dogs were submitted to cardiopulmonary bypass (CPB) carried out under conditions calculated to generate large numbers of microbubbles and microemboli. On the day following the procedure the dogs showed evidence of neurological damage including impaired consciousness and ataxia. These abnormalities largely cleared within a week. When the animals were sacrificed at intervals after the procedure, the cerebral microvasculature was demonstrated by injecting a suspension a lamp black into the carotid artery. This revealed that multiple filling defects were present in the microcirculation of the brain immmediately after CPB and for two days thereafter. However, by seven days the microvascular blockade had disappeared, and the vascular blockade had disappeared, and the vascular pattern of the brain had returned to normal. Neuropathological findings were sparse and restricted to the cerebellum. This study suggests that the transient neurological syndromes that sometimes follow cardiopulmonary bypass for heart surgery may be due to a transient microvascular blockade, perhaps by microbubbles and microparticles.
Indoor swimming pools, water chlorination and respiratory health
Authors: B. Nemery, P.H.M. Hoet, D. Nowak
Journal: European Respiratory Journal (2002)

Swimming is generally considered to be a healthy leisure activity for both the young and old. Swimming is even often advised as the most appropriate sport for asthmatic children 1–3, mainly (but probably not solely) on the grounds that inhaling moist air is less conducive to triggering exercise-induced asthma 4. However, for obvious reasons of microbiological safety, the water of public and private swimming pools must be disinfected 5. The most common procedure for water disinfection consists of chlorination. As with all human and technological intervention, the use of chlorine-based products to disinfect swimming water may lead to a number of unwanted effects, in particular the presence of chlorine-containing compounds in the air. Consequently, chlorination may affect the respiratory health of either those who work as swimming attendants or instructors, or those who use the pools as customers, particularly children and the general public, but also competitive swimmers. Although the issue of the chlorination of public water supplies has received considerable attention, mainly with regard to the presence of potentially carcinogenic or teratogenic chlorinated by-products 6, 7, the respiratory hazards of chlorinated swimming water have been less well addressed. Thus, old 8, 9 and even more recent 10 reports on indoor pollution do not deal with the air of chlorinated swimming pools, despite the generally obvious and readily noticeable irritant character of this type of environment, even in well-maintained pools 11.

Chlorination is the most common procedure for water disinfection of public water supplies and swimming pools. Chlorine may be added to water as the gaseous form (Cl2), which rapidly hydrolyzes to hypochlorous acid (HOCl), or as sodium or calcium hypochlorite (NaOCl or Ca(OCl)2). Hypochlorite, for disinfection, may also be produced by adding so-called hypochlorite-generating agents, such as dichloroisocyanurate, …
Early effects of contrast media on renal hemodynamics and tubular function in chronic renal failure.
Authors: D Russo, R Minutolo, B Cianciaruso, B Memoli, G Conte, L De Nicola
Journal: Journal of the American Society of Nephrology (1995)

The pathophysiology and prevention of contrast media (CM)-induced nephropathy in chronic renal failure (CRF) are still ill defined. GFR, RPF, endothelin-1 (ET-1) levels, urinary sodium concentration, and fractional excretion of sodium were measured in CRF patients undergoing water diuresis in basal conditions and 20 to 120 min after an iv bolus of either the high-osmolar CM diatrizoate (D) or the low-osmolar CM iopamidol (I). The two CM induced an immediate and progressive decline of both GFR and RPF in the absence of hypovolemia, more pronounced in D (-36% at 120 min) than after I (-19% at 120 min; P < 0.05 versus D). Both CM determined a marked and steady increase of the fractional excretion of sodium. The natriuresis could not be totally ascribed to a CM-induced osmotic diuresis as because the urinary sodium concentration markedly increased. In two further groups of patients receiving D, we studied the effects of pretreatment with a single dose of either captopril or nifedipine. Both drugs, although not preventing the increase of natriuresis, partially antagonized D-induced renal hypoperfusion: GFR and RPF were equally reduced by 20% in D/captopril and D/nifedipine (P < 0.05 versus D). In unpretreated patients receiving either D or I, plasma ET-1 did not change but urinary levels increased; these changes were, however, dissociated from those observed in renal hemodynamics. Both plasma and urinary levels of ET-1 did not vary in pretreated groups. The 72-h follow-up evidenced a significant reduction of renal function only in the unpretreated D group. Therefore, the main findings after CM administration in CRF patients are: (1) an immediate GFR decline proportional to the osmolarity of CM and secondary to the renal hypoperfusion that is neither caused by hypovolemia nor mediated by ET-1, (2) an early tubular dysfunction at the level of the proximal nephron, and (3) a protective effect of single-dose pretreatment with either captopril or nifedipine on D-induced acute and short-term GFR changes.
Higher proportion of G2P[4] rotaviruses in vaccinated hospitalized cases compared with unvaccinated hospitalized cases, despite high vaccine effectiveness against heterotypic G2P[4] rotaviruses
Authors: J. Matthijnssens, M. Zeller, E. Heylen, S. De Coster, J. Vercauteren, T. Braeckman, K. Van Herck, N. Meyer, J.-Y. PirÇon, M. Soriano-Gabarro, M. Azou, H. Capiau, J. De Koster, A.-S. Maernoudt, M. Raes, L. Verdonck, M. Verghote, A. Vergison, P. Van Damme, M. Van Ranst
Journal: Clinical Microbiology and Infection (2014)
Benign mucinous metaplasia of the genital mucosa: histomorphological and immunohistochemical features and criteria for differentiation from extramammary Paget disease
Authors: A. Böer-Auer, C. August, T.M. Falk, J.E. Jung, K. Kohl, D. Metze
Journal: British Journal of Dermatology (2011)

Benign mucinous metaplasia of the genitalia (BMM) is a rare condition typified by cells with foamy mucinous cytoplasm. Differential diagnoses include extramammary Paget disease (PD) and human papillomavirus (HPV)-induced vulval intraepithelial neoplasia (VIN) with mucinous differentiation.To characterize histopathological and immunohistochemical features of BMM and to forge criteria for differentiation from PD and VIN with mucinous differentiation.Eight biopsy specimens of BMM were stained with haematoxylin and eosin, periodic acid-Schiff and alcian blue, and for cytokeratin (CK) 7, CK10, CK14, CK20, carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), S100, gross cystic disease fluid protein-15 (GCDFP-15), lysozyme and Ki67 and compared with PD. Polymerase chain reaction was performed in order to identify HPV-specific DNA.BMM showed mucin deposition in superficial epithelial layers ranging from numerous large goblet cells to subtle deposits. The epithelium often showed polygonal (squamoid) or cuboidal differentiation while columnar differentiation was an inconsistent feature. A band-like inflammatory infiltrate was consistently present. Metaplastic epithelium consistently expressed CK7, CEA and EMA either in the entire epithelium or in a superficial band, while CK14, CK10, GCDFP-15 and lysozyme were largely not expressed, and staining for CK20 and S100 was negative. Comparison with PD demonstrated similar staining characteristics, but in a scattered pattern of mucinous cells within preserved squamous epithelium and not in a band-like pattern as in BMM. Nuclear pleomorphism and Ki67-positive mucinous cells in superficial epithelial layers were seen only in PD; GCDFP-15 and/or lysozyme were expressed in the majority of cases of PD. No evidence of HPV-specific DNA was found in BMM.The spectrum of changes in BMM is distinctive, and BMM can be differentiated with surety from both PD and VIN with mucinous differentiation.
Science commentary: What are leukotrienes and how do they work in asthma?
Authors: A. Berger
Journal: BMJ (1999)

Objective To determine the ability of montelukast, a leukotriene receptor antagonist, to allow tapering of inhaled corticosteroids in clinically stable asthmatic patients.Design Double blind, randomised, placebo controlled, parallel group study.After a single blind placebo run in period, during which (at most) two inhaled corticosteroids dose decreases occurred, qualifying, clinically stable patients were allocated randomly to receive montelukast (10 mg tablet) or matching placebo once daily at bedtime for up to 12 weeks.Setting 23 academic asthma centres in United States, Canada, and Europe.Participants 226 clinically stable patients with chronic asthma receiving high doses of inhaled corticosteroids (113 randomised to montelukast and 113 to placebo).Interventions Every 2 weeks, the inhaled corticosteroids dose was tapered, maintained, or increased (rescue) based on a standardised clinical score. Main outcome measures Last tolerated dose of inhaled corticosteroids.Results Compared with placebo, montelukast allowed significant (P = 0.046) reduction in the inhaled corticosteroid dose (montelukast 47% v placebo 30%; least square mean difference 17.6%, 95% confidence interval 0.3 to 34.8).Fewer patients on montelukast (18 (16%) v 34 (30%) placebo, P = 0.01) required discontinuation because of failed rescue.Conclusions Montelukast reduces the need for inhaled corticosteroids among patients requiring moderate to high doses of corticosteroid to maintain asthma control.