tbuckley/cabot-search huggingface dataset:
Effects of Raloxifene After Tamoxifen on Breast and Endometrial Tumor Growth in Athymic Mice
Authors: R. M. O'Regan, C. Gajdos, R. C. Dardes, A. De Los Reyes, W. Park, A. W. Rademaker, V. C. Jordan
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: In patients with early-stage breast cancer, 5 years of treatment with the selective estrogen receptor modulator (SERM) tamoxifen reduces breast cancer recurrence and mortality, whereas more than 5 years of tamoxifen does not further reduce breast cancer recurrence and doubles the risk of endometrial cancer. We evaluated the effects on tumor growth of raloxifene, another SERM, after tamoxifen treatment in mouse models of breast and endometrial cancers. Methods: Athymic, ovariectomized mice were bitransplanted with tumors derived from human breast cancer and endometrial cancer cells that either were tamoxifen-naive or had been exposed to tamoxifen for short (6 months) or long (>5 years) terms. The effects of raloxifene (two dose levels) and tamoxifen on tumor growth in the presence and absence of low-dose estrogen were evaluated. All statistical tests were two-sided. Results: Raloxifene was less effective than tamoxifen in blocking the stimulatory effects of low-dose estrogen on the growth of tamoxifen-naive breast (P<.001) and endometrial (P = .001) tumors. Raloxifene and tamoxifen had similar inhibitory effects on the growth of short-term tamoxifen-exposed breast tumors. Raloxifene and tamoxifen had similar stimulatory effects on the growth of breast and endometrial tumors that had been exposed to at least 5 years of tamoxifen. However, neither drug blocked the stimulatory effects of estrogen on the growth of these tumors. Raloxifene was less effective than tamoxifen (P<.001) in blocking the stimulatory effects of estrogen on endometrial tumors that had been exposed to tamoxifen in the past. Conclusions: Raloxifene and tamoxifen had similar effects on these mouse models of tamoxifen-naive and tamoxifen-resistant breast and endometrial cancer. Treatment with raloxifene following 5 years of adjuvant tamoxifen may not further decrease breast cancer recurrence and may increase endometrial cancer incidence.
Comparison of routine and on-demand prescription of chest radiographs in mechanically ventilated adults: a multicentre, cluster-randomised, two-period crossover study
Authors: Gilles Hejblum, Ludivine Chalumeau-Lemoine, Vincent Ioos, Pierre-Yves Boëlle, Laurence Salomon, Tabassome Simon, Jean-François Vibert, Bertrand Guidet
Journal: The Lancet (2009)
Cochlin Produced by Follicular Dendritic Cells Promotes Antibacterial Innate Immunity
Authors: Bénédicte F. Py, Santiago F. Gonzalez, Kai Long, Mi-Sung Kim, Young-A. Kim, Hong Zhu, Jianhua Yao, Nicolas Degauque, Régis Villet, Patrick Ymele-Leki, Mihaela Gadjeva, Gerald B. Pier, Michael C. Carroll, Junying Yuan
Journal: Immunity (2013)
The Increasing Burden of HIV-Associated Malignancies in Resource-Limited Regions
Authors: Corey Casper
Journal: Annual Review of Medicine (2010)

Cancer is increasingly recognized as a complication of HIV infection in both resource-rich and resource-limited areas. The traditional AIDS-defining cancers, including Kaposi sarcoma, cervical cancer, and non-Hodgkin lymphoma, have become common comorbidities afflicting HIV-positive individuals and lack adequate prevention and management options. Additionally, several non-AIDS-defining cancers have increased in incidence in resource-limited regions, including Hodgkin lymphoma, hepatocellular carcinoma, and lung cancer. This review outlines the epidemiology of HIV-associated malignancies in resource-poor and resource-rich areas, including the impact of highly active antiretroviral therapy on the incidence of these cancers. The pathogenesis of HIV-associated cancers is considered in relation to potential strategies for their prevention and treatment.
Lapatinib Restores Hormone Sensitivity with Differential Effects on Estrogen Receptor Signaling in Cell Models of Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer with Acquired Endocrine Resistance
Authors: Alexandra F. Leary, Suzanne Drury, Simone Detre, Sunil Pancholi, Anne E. Lykkesfeldt, Lesley-Ann Martin, Mitch Dowsett, Stephen R.D. Johnston
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Acquired endocrine resistance in estrogen receptor (ER)α+/human epidermal growth factor receptor 2–negative (HER2−) breast cancer has been associated with modest adaptive increases in HER2, although exactly how aberrant HER2 signaling affects the ERα pathway is poorly understood. We investigated (a) whether the epidermal growth factor receptor/HER2 inhibitor lapatinib could restore endocrine responsiveness in cell models of acquired endocrine resistance with modest increases in HER2, and (b) the nature of ERα-HER2 cross-talk in this process. Methods: Combination growth studies, ERα transcription, immunoblot, and gene expression assays were conducted in two models of acquired resistance to (a) estrogen deprivation (long-term estrogen-deprived cells) and (b) tamoxifen (long-term tamoxifen-treated cells), and in hormone sensitive controls. Changes in ERα, PgR, and HER2 were assessed in samples from patients treated with tamoxifen. Results: Both cell models of acquired endocrine resistance showed modest adaptive upregulation in HER2, and lapatinib restored endocrine sensitivity in both. The effect of lapatinib on ERα signaling varied markedly depending on the nature of the HER2/ERα cross-talk. In long-term estrogen-deprived cells characterized by enhanced ERα function, lapatinib suppressed ERα genomic activity (as measured by pERSer118, ERα transcriptional activity, and PGR gene expression). In contrast, in long-term tamoxifen-treated cells with reduced ERα activation, lapatinib reactivated ERα genomic function. Twenty percent of tamoxifen-resistant patients relapsed with modest increases in HER2 and either suppressed or enhanced ERα/PgR expression. Conclusions: Aberrant GFR signaling can augment or suppress ERα function. Regardless, interrupting the HER2/ERα cross-talk with lapatinib can restore endocrine sensitivity and should be investigated as a therapeutic strategy in combination with endocrine therapy in ERα+/HER2− patients with acquired endocrine resistance. Clin Cancer Res; 16(5); 1486–97
An unusual finding in a patient with iron deficiency anaemia
Authors: J Leyden
Journal: Gut (2005)

Psychological stress has long been reported anecdotally to increase disease activity in inflammatory bowel disease (IBD), and recent well designed studies have confirmed that adverse life events, chronic stress, and depression increase the likelihood of relapse in patients with quiescent IBD.This evidence is increasingly supported by studies of experimental stress in animal models of colitis.With the evolving concept of psychoneuroimmunology, the mechanisms by which the nervous system can affect immune function at both systemic and gut mucosal levels are gradually becoming apparent.Recent data suggest that stress induced alterations in gastrointestinal inflammation may be mediated through changes in hypothalamic-pituitaryadrenal (HPA) axis function and alterations in bacterial-mucosal interactions, and via mucosal mast cells and mediators such as corticotrophin releasing factor (CRF).To date, the therapeutic opportunities offered by stress reduction therapy remain largely unexplored, in part because of methodological difficulties of such studies.This paper reviews recent advances in our understanding of the pathogenic role of psychological stress in IBD and emphasises the need for controlled studies of the therapeutic potential of stress reduction.
Increased Fibroblast Growth Factor-Inducible 14 Expression Levels Promote Glioma Cell Invasion via Rac1 and Nuclear Factor-κB and Correlate with Poor Patient Outcome
Authors: Nhan L. Tran, Wendy S. McDonough, Benjamin A. Savitch, Shannon P. Fortin, Jeffrey A. Winkles, Marc Symons, Mitsutoshi Nakada, Heather E. Cunliffe, Galen Hostetter, Dominique B. Hoelzinger, Jessica L. Rennert, Jennifer S. Michaelson, Linda C. Burkly, Christopher A. Lipinski, Joseph C. Loftus, Luigi Mariani, Michael E. Berens
Journal: Cancer Research (2006)

Abstract Glial tumors progress to malignant grades by heightened proliferation and relentless dispersion throughout the central nervous system. Understanding genetic and biochemical processes that foster these behaviors is likely to reveal specific and effective targets for therapeutic intervention. Our current report shows that the fibroblast growth factor-inducible 14 (Fn14), a member of the tumor necrosis factor (TNF) receptor superfamily, is expressed at high levels in migrating glioma cells in vitro and invading glioma cells in vivo. Forced Fn14 overexpression stimulates glioma cell migration and invasion, and depletion of Rac1 by small interfering RNA inhibits this cellular response. Activation of Fn14 signaling by the ligand TNF-like weak inducer of apoptosis (TWEAK) stimulates migration and up-regulates expression of Fn14; this TWEAK effect requires Rac1 and nuclear factor-κB (NF-κB) activity. The Fn14 promoter region contains NF-κB binding sites, which mediate positive feedback causing sustained overexpression of Fn14 and enduring glioma cell invasion. Furthermore, Fn14 gene expression levels increase with glioma grade and inversely correlate with patient survival. These results show that the Fn14 cascade operates as a positive feedback mechanism for elevated and sustained Fn14 expression. Such a feedback loop argues for aggressive targeting of the Fn14 axis as a unique and specific driver of glioma malignant behavior. (Cancer Res 2006; 66(19): 9535-42)
Hydrogen Sulfide Mediates Cardioprotection Through Nrf2 Signaling
Authors: John W. Calvert, Saurabh Jha, Susheel Gundewar, John W. Elrod, Arun Ramachandran, Christopher B. Pattillo, Christopher G. Kevil, David J. Lefer
Journal: Circulation Research (2009)

Rationale: The recent emergence of hydrogen sulfide (H 2 S) as a potent cardioprotective signaling molecule necessitates the elucidation of its cytoprotective mechanisms. Objective: The present study evaluated potential mechanisms of H 2 S-mediated cardioprotection using an in vivo model of pharmacological preconditioning. Methods and Results: H 2 S (100 μg/kg) or vehicle was administered to mice via an intravenous injection 24 hours before myocardial ischemia. Treated and untreated mice were then subjected to 45 minutes of myocardial ischemia followed by reperfusion for up to 24 hours, during which time the extent of myocardial infarction was evaluated, circulating troponin I levels were measured, and the degree of oxidative stress was evaluated. In separate studies, myocardial tissue was collected from treated and untreated mice during the early (30 minutes and 2 hours) and late (24 hours) preconditioning periods to evaluate potential cellular targets of H 2 S. Initial studies revealed that H 2 S provided profound protection against ischemic injury as evidenced by significant decreases in infarct size, circulating troponin I levels, and oxidative stress. During the early preconditioning period, H 2 S increased the nuclear localization of Nrf2, a transcription factor that regulates the gene expression of a number of antioxidants and increased the phosphorylation of protein kinase Cε and STAT-3. During the late preconditioning period, H 2 S increased the expression of antioxidants (heme oxygenase-1 and thioredoxin 1), increased the expression of heat shock protein 90, heat shock protein 70, Bcl-2, Bcl-xL, and cyclooxygenase-2 and also inactivated the proapoptogen Bad. Conclusions: These results reveal that the cardioprotective effects of H 2 S are mediated in large part by a combination of antioxidant and antiapoptotic signaling.
The TGFβ–miR200–MIG6 Pathway Orchestrates the EMT-Associated Kinase Switch That Induces Resistance to EGFR Inhibitors
Authors: Evgeny Izumchenko, Xiaofei Chang, Christina Michailidi, Luciane Kagohara, Rajani Ravi, Keren Paz, Mariana Brait, Mohammad O. Hoque, Shizhang Ling, Atul Bedi, David Sidransky
Journal: Cancer Research (2014)

Abstract Although specific mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) identify tumors that are responsive to EGFR tyrosine kinase inhibitors (TKI), these genetic alterations are present in only a minority of patients. Patients with tumors expressing wild-type EGFR lack reliable predictive markers of their clinical response to EGFR TKIs. Although epithelial–mesenchymal transition (EMT) has been inversely correlated with the response of cancers to EGFR-targeted therapy, the precise molecular mechanisms underlying this association have not been defined and no specific EMT-associated biomarker of clinical benefit has been identified. Here, we show that during transforming growth factor β (TGFβ)–mediated EMT, inhibition of the microRNAs 200 (miR200) family results in upregulated expression of the mitogen-inducible gene 6 (MIG6), a negative regulator of EGFR. The MIG6-mediated reduction of EGFR occurs concomitantly with a TGFβ-induced EMT-associated kinase switch of tumor cells to an AKT-activated EGFR-independent state. In a panel of 25 cancer cell lines of different tissue origins, we find that the ratio of the expression levels of MIG6 and miR200c is highly correlated with EMT and resistance to erlotinib. Analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild-type EGFR showed that the tumor MIG6(mRNA)/miR200 ratio was inversely correlated with response to erlotinib in vivo. Our data demonstrate that the TGFβ–miR200–MIG6 network orchestrates the EMT-associated kinase switch that induces resistance to EGFR inhibitors, and identify a low ratio of MIG6 to miR200 as a promising predictive biomarker of the response of tumors to EGFR TKIs. Cancer Res; 74(14); 3995–4005. ©2014 AACR.
Population Genomics of Transposable Elements in Drosophila melanogaster
Authors: D. A. Petrov, A.-S. Fiston-Lavier, M. Lipatov, K. Lenkov, J. Gonzalez
Journal: Molecular Biology and Evolution (2010)

Transposable elements (TEs) are the primary contributors to the genome bulk in many organisms and are major players in genome evolution. A clear and thorough understanding of the population dynamics of TEs is therefore essential for full comprehension of the eukaryotic genome evolution and function. Although TEs in Drosophila melanogaster have received much attention, population dynamics of most TE families in this species remains entirely unexplored. It is not clear whether the same population processes can account for the population behaviors of all TEs in Drosophila or whether, as has been suggested previously, different orders behave according to very different rules. In this work, we analyzed population frequencies for a large number of individual TEs (755 TEs) in five North American and one sub-Saharan African D. melanogaster populations (75 strains in total). These TEs have been annotated in the reference D. melanogaster euchromatic genome and have been sampled from all three major orders (non-LTR, LTR, and TIR) and from all families with more than 20 TE copies (55 families in total). We find strong evidence that TEs in Drosophila across all orders and families are subject to purifying selection at the level of ectopic recombination. We showed that strength of this selection varies predictably with recombination rate, length of individual TEs, and copy number and length of other TEs in the same family. Importantly, these rules do not appear to vary across orders. Finally, we built a statistical model that considered only individual TE-level (such as the TE length) and family-level properties (such as the copy number) and were able to explain more than 40% of the variation in TE frequencies in D. melanogaster.
Polycystic Ovarian Disease
Authors: R L Barbieri
Journal: Annual Review of Medicine (1991)

Polycystic ovarian disease (PCOD) is a common endocrinopathy in women of reproductive age. Its molecular causes remain to be fully defined. Hyperinsulinemia and hyperandrogenism are positively correlated, which suggests that insulin resistance may be involved in the pathogenesis of PCOD. Point mutations in the insulin receptor gene that cause insulin resistance appear to be associated with the PCOD phenotype.
Relationship between disease severity, hyperinsulinemia, and impaired insulin clearance in patients with nonalcoholic steatohepatitis
Authors: Fernando Bril, Romina Lomonaco, Beverly Orsak, Carolina Ortiz-Lopez, Amy Webb, Fermin Tio, Joan Hecht, Kenneth Cusi
Journal: Hepatology (2013)

Hyperinsulinemia is believed to play a key role in the pathogenesis of nonalcoholic steatohepatitis (NASH) and associated cardiovascular risk. However, the relative contribution of insulin clearance to hyperinsulinemia and its relationship to liver histology have not been carefully evaluated before. To examine this, we enrolled 190 patients (32 without nonalcoholic fatty liver disease [NAFLD], 36 with simple steatosis [SS], and 122 with biopsy-proven NASH). Insulin secretion and hepatic insulin clearance were estimated by means of an oral glucose tolerance test, whereas peripheral insulin sensitivity and whole-body insulin clearance were measured during a euglycemic insulin clamp. A liver biopsy was performed to assess histology (grade/stage). Patients with NASH had similar hepatic insulin sensitivity, compared to patients with SS, but more severe adipose tissue insulin resistance and worse hyperinsulinemia. Patients with SS and NASH had a similar ∼30% reduction (P<0.01) in hepatic insulin clearance, when compared to patients without NAFLD. Reduced hepatic insulin clearance was not associated with severity of inflammation, ballooning, and fibrosis. In contrast, worse histological inflammation and ballooning (but not steatosis or fibrosis) were associated with a progressive reduction in whole-body insulin clearance (P<0.001 for trend). There was no significant difference in insulin secretion between patients with SS versus NASH. Decreased hepatic insulin clearance develops with a mild increase in liver fat (LFAT) accumulation. It appears to be largely driven by hepatic steatosis, whereas steatohepatitis is more closely associated with reduced whole-body insulin clearance. Hyperinsulinemia in NAFLD correlated strongly with impaired insulin clearance, but not with insulin secretion. Strategies that reduce LFAT and improve insulin clearance hold the potential to revert the unfavorable effects of hyperinsulinemia in these patients.
Inactivation of evenness interrupted (EVI) reduces experimental fibrosis by combined inhibition of canonical and non-canonical Wnt signalling
Authors: Alfiya Distler, Clara Ziemer, Christian Beyer, Neng-Yu Lin, Chih-Wei Chen, Katrin Palumbo-Zerr, Clara Dees, Alexander Weidemann, Oliver Distler, Georg Schett, Jörg H W Distler
Journal: Annals of the Rheumatic Diseases (2013)

Canonical as well as non-canonical Wnt signalling pathways have emerged as core pathways of fibrosis. Their profibrotic effects are mediated via distinct intracellular cascades independently of each other. Thus, inhibition of both pathways may have additive antifibrotic effects. Here, we knocked down evenness interrupted (EVI) to simultaneously target for the first time canonical and non-canonical Wnt signalling in experimental fibrosis.The antifibrotic effects of siRNA-mediated knockdown of EVI were evaluated in the mouse models of bleomycin-induced skin fibrosis and in fibrosis induced by adenoviral overexpression of a constitutively active TGF-β receptor I (AdTBRI).Knockdown of EVI decreased the release of canonical and non-canonical Wnt ligands by fibroblasts and reduced the activation of canonical and non-canonical Wnt cascades in experimental fibrosis with decreased accumulation of β-catenin and phosphorylated JNK and cJun. Inactivation of EVI exerted potent antifibrotic effects and reduced dermal thickening, myofibroblast differentiation and accumulation of collagen in the mouse models of bleomycin-induced and AdTBR-induced fibrosis.Inhibition of Wnt secretion by knockdown of EVI inhibits canonical and non-canonical Wnt signalling and effectively reduces experimental fibrosis in different preclinical models. Inhibition of Wnt secretion may thus be an interesting approach for the treatment of fibrosis.
Pulsatile Tinnitus, Not Nocturnal Palpitations
Authors: B. Hill Britton
Journal: JAMA (1987)

<h3>To the Editor.—</h3> A recent answer submitted by Dr Abrams<sup>1</sup>does not seem to fit the question asked. The heading for this particular question and answer is "Nocturnal Palpitations." The answer is certainly appropriate for this heading; however, the question asked concerns a hypertensive patient who<i>hears</i>his pulse in his ear. This symptom is best described as pulsatile tinnitus, an auditory sensation. This sensation can be further classified into subjective pulsatile tinnitus, heard only by the patient and not the examiner, and objective pulsatile tinnitus, heard by both the patient and the examiner. Auscultation should be performed by the physician, listening both in the external auditory canal, superior and posterior to the ear, and in the neck area. This type of symptom may represent one of the earliest indications of various problems, such as a carotid bruit, an arteriovenous malformation or fistula, a glomus tumor of the middle
Motor Neuron Diversity in Development and Disease
Authors: Kevin C. Kanning, Artem Kaplan, Christopher E. Henderson
Journal: Annual Review of Neuroscience (2010)

Although often considered as a group, spinal motor neurons are highly diverse in terms of their morphology, connectivity, and functional properties and differ significantly in their response to disease. Recent studies of motor neuron diversity have clarified developmental mechanisms and provided novel insights into neurodegeneration in amyotrophic lateral sclerosis (ALS). Motor neurons of different classes and subtypes—fast/slow, alpha/gamma—are grouped together into motor pools, each of which innervates a single skeletal muscle. Distinct mechanisms regulate their development. For example, glial cell line–derived neurotrophic factor (GDNF) has effects that are pool-specific on motor neuron connectivity, column-specific on axonal growth, and subtype-specific on survival. In multiple degenerative contexts including ALS, spinal muscular atrophy (SMA), and aging, fast-fatigable (FF) motor units degenerate early, whereas motor neurons innervating slow muscles and those involved in eye movement and pelvic sphincter control are strikingly preserved. Extrinsic and intrinsic mechanisms that confer resistance represent promising therapeutic targets in these currently incurable diseases.