tbuckley/cabot-search huggingface dataset:
HuR Posttranscriptionally Regulates WEE1: Implications for the DNA Damage Response in Pancreatic Cancer Cells
Authors: Shruti Lal, Richard A. Burkhart, Neil Beeharry, Vikram Bhattacharjee, Eric R. Londin, Joseph A. Cozzitorto, Carmella Romeo, Masaya Jimbo, Zoë A. Norris, Charles J. Yeo, Janet A. Sawicki, Jordan M. Winter, Isidore Rigoutsos, Timothy J. Yen, Jonathan R. Brody
Journal: Cancer Research (2014)

Abstract HuR (ELAV1), an RNA-binding protein abundant in cancer cells, primarily resides in the nucleus, but under specific stress (e.g., gemcitabine), HuR translocates to the cytoplasm in which it tightly modulates the expression of mRNA survival cargo. Here, we demonstrate for the first time that stressing pancreatic ductal adenocarcinoma (PDA) cells by treatment with DNA-damaging anticancer agents (mitomycin C, oxaliplatin, cisplatin, carboplatin, and a PARP inhibitor) results in HuR's translocation from the nucleus to the cytoplasm. Importantly, silencing HuR in PDA cells sensitized the cells to these agents, whereas overexpressing HuR caused resistance. HuR's role in the efficacy of DNA-damaging agents in PDA cells was, in part, attributed to the acute upregulation of WEE1 by HuR. WEE1, a mitotic inhibitor kinase, regulates the DNA damage repair pathway, and therapeutic inhibition of WEE1 in combination with chemotherapy is currently in early phase trials for the treatment of cancer. We validate WEE1 as a HuR target in vitro and in vivo by demonstrating (i) direct binding of HuR to WEE1′s mRNA (a discrete 56-bp region residing in the 3′ untranslated region) and (ii) HuR siRNA silencing and overexpression directly affects the protein levels of WEE1, especially after DNA damage. HuR's positive regulation of WEE1 increases γ-H2AX levels, induces Cdk1 phosphorylation, and promotes cell-cycle arrest at the G2–M transition. We describe a novel mechanism that PDA cells use to protect against DNA damage in which HuR posttranscriptionally regulates the expression and downstream function of WEE1 upon exposure to DNA-damaging agents. Cancer Res; 74(4); 1128–40. ©2014 AACR.
Continuous Versus Cyclic Estrogen Administration: Mammary Carcinoma in C3H Mice&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Allan B. Okey, George H. Gass
Journal: JNCI Journal of the National Cancer Institute (1968)

Mammary carcinoma incidence in male or castrated male C3H mice was lower when diethylstilbestrol (DES) was given in the diet in intermittent cycles of 2, 7, 14, or 28 days than when given on a continuous basis. Generally the latent period of tumor formation was shortened by treatments which produced high tumor incidence. Continuous treatment with DES also significantly reduced testis, seminal vesicle, and body weights (but not pituitary weight) when compared with cyclic treatment with DES in which equivalent doses were used. Castrated males had significantly higher tumor incidence and shorter latent period than did intact males. Of the cyclic regimens, the shortest (2 days) produced the highest tumor incidence in intact males, whereas it produced the lowest tumor incidence in castrated males.
Drusen deposits associated with aging and age-related macular degeneration contain nonfibrillar amyloid oligomers
Authors: V. Luibl
Journal: Journal of Clinical Investigation (2006)

Protein misfolding and aggregation are thought to underlie the pathogenesis of many amyloid diseases, such as Alzheimer and Parkinson diseases, whereby a stepwise protein misfolding process begins with the conversion of soluble protein monomers to prefibrillar oligomers and progresses to the formation of insoluble amyloid fibrils. Drusen are extracellular deposits found in aging eyes and in eyes afflicted with age-related macular degeneration (AMD). Recent characterizations of drusen have revealed protein components that are shared with amyloid deposits. However, characteristic amyloid fibrils have thus far not been identified in drusen. In this study, we tested the hypothesis that nonfibrillar oligomers may be a common link in amyloid diseases. Oligomers consisting of distinct amyloidogenic proteins and peptides can be detected by a recently developed antibody that is thought to recognize a common structure. Notably, oligomers exhibit cellular toxicity, which suggests that they play a role in the pathogenesis of neurodegenerative diseases. Through use of the anti-oligomer antibody, we came to observe the presence of nonfibrillar, toxic oligomers in drusen. Conversely, no reactivity was observed in age-matched control eyes without drusen. These results suggest that amyloid oligomers may be involved in drusen biogenesis and that similar protein misfolding processes may occur in AMD and amyloid diseases.
Long-term outcomes of surgical resection with or without adjuvant radiation therapy for treatment of spinal ependymoma: a retrospective multicenter study by the Korea Spinal Oncology Research Group
Authors: S.-H. Lee, C. K. Chung, C. H. Kim, S. H. Yoon, S.-J. Hyun, K.-J. Kim, E.-S. Kim, W. Eoh, H.-J. Kim
Journal: Neuro-Oncology (2013)

We sought to determine the surgical treatment and functional outcome and identify the predictors of survival in a retrospective cohort of patients with spinal cord ependymoma using data collected from the Korea Spinal Oncology Research Group database. The data regarding 88 patients who had been surgically treated for histologically confirmed spinal cord intramedullary and extramedullary ependymoma from January 1989 to December 2009 were retrospectively reviewed. Histopathological examination revealed myxopapillary ependymoma in 24 patients, ependymoma in 61 patients, and anaplastic ependymoma in 3 patients. Gross total removal was achieved in 72 patients, subtotal removal in 15 patients, and partial removal in 1 patient. Twenty patients were treated with postoperative radiation. Fifty-two patients had stable or improved postoperative neurological function, while 36 experienced neurological deterioration. A permanent decrease in McCormick classification grade was seen in 17 patients. The progression-free survival rate was 87% for all patients at 5 years and 80% at 10 years. During follow-up, local recurrence/progression was seen in 13 patients. Diffuse meningeal spread developed in 2 anaplastic ependymoma patients. Postoperative radiotherapy after incomplete resection did not significantly correlate with longer times to recurrence. Multivariate analysis revealed histology and surgical extent of resection as independent predictors of longer progression-free survival. Gross total removal alone is a good treatment strategy for spinal ependymomas. Early diagnosis and surgery, before severe paralysis, are important to obtain good functional outcomes. Subtotal resection with radiation therapy for intramedullary lesions appears to offer no advantages over gross total removal.
Chlamydial Heat Shock Protein 60 Localizes in Human Atheroma and Regulates Macrophage Tumor Necrosis Factor-α and Matrix Metalloproteinase Expression
Authors: Amir Kol, Galina K. Sukhova, Andrew H. Lichtman, Peter Libby
Journal: Circulation (1998)

Background —Recent evidence has implicated Chlamydia pneumoniae in the aggravation of atherosclerosis. However, the mechanisms by which this agent affects atherogenesis remain poorly understood. Chlamydiae produce large amounts of heat shock protein 60 (HSP 60) during chronic, persistent infections, and C pneumoniae localizes predominantly within plaque macrophages. Several studies have furnished evidence that endogenous (human) HSP 60 may play a role in atherogenesis. We tested here the hypothesis that atheroma contains chlamydial HSP 60 and that this bacterial product might stimulate macrophage functions considered relevant to atherosclerosis and its complications, such as production of proinflammatory cytokines as tissue necrosis factor-α (TNF-α) and matrix-degrading metalloproteinases (MMPs). Methods and Results —Surgical specimens of human carotid atherosclerotic arteries (n=19) and normal arterial wall samples (n=7, 2 carotid arteries and 5 aortas) were tested immunohistochemically for the presence of chlamydial HSP 60 and human HSP 60. Macrophage localization of these antigens was assessed by double immunostaining. Murine peritoneal macrophages, maintained in serum-free conditions for 48 hours after harvesting, were incubated with C pneumoniae , chlamydial HSP 60, human HSP 60, or Escherichia coli lipopolysaccharide (LPS). Culture supernatants, collected at 24 hours for concentration-dependence experiments and at up to 72 hours for time-dependence experiments, were analyzed for TNF-α by ELISA and for MMP by gelatin zymography. Atherosclerotic lesions showed immunoreactive chlamydial HSP 60 in 47% (9 of 19) of the cases and human HSP 60 in 89% (17 of 19) of the cases. Chlamydial HSP 60 colocalized with human HSP 60 within plaque macrophages in 77% (7 of 9) of the cases. Nonatherosclerotic samples contained neither HSP. Both C pneumoniae and recombinant chlamydial HSP 60 induced TNF-α production by mouse macrophages in a concentration- and time-dependent fashion. E coli LPS and human HSP 60 produced similar effects. Similarly, C pneumoniae and HSPs induced MMPs in a concentration- and time-dependent manner. Heat treatment abolished the effect of C pneumoniae and HSPs on both TNF-α and MMP production, but it did not alter the ability of E coli LPS to induce these functions. Conclusions —Chlamydial HSP 60 frequently colocalizes with human HSP 60 in plaque macrophages in human atherosclerotic lesions. Chlamydial and human HSP 60 induce TNF-α and MMP production by macrophages. Chlamydial HSP 60 might mediate the induction of these effects by C pneumoniae . Induction of such macrophage functions provides potential mechanisms by which chlamydial infections may promote atherogenesis and precipitate acute ischemic events.
Is there a need for new agents with novel mechanisms of action in psoriatic arthritis?
Authors: Carl Orr, Douglas James Veale
Journal: Annals of the Rheumatic Diseases (2014)

The armoury of biological agents available to treat rheumatoid arthritis (RA) has expanded greatly over the last 15 years, but treatment options for psoriatic arthritis (PsA) have failed to keep pace. Therapy with disease modifying anti-rheumatic drugs (DMARDs), such as methotrexate and leflunomide, remain first-line agents despite a paucity of randomised controlled trial evidence.1 There is a good evidence base for the efficacy of TNFα inhibition (TNFi), both as monotherapy and in combination with methotrexate, from a number of studies.2–5 The use of TNFi has the additional benefit of efficacy in treating spinal symptoms where conventional DMARDs show little efficacy.6 Five TNFi agents are now approved for use in PsA patients in Europe, and all show equivalent efficacy in the treatment of joint disease.1 ,7–9

PsA is the second most common inflammatory arthropathy and represents a considerable disease burden for patients and the healthcare system. Therefore, the relative paucity of alternative agents in the treatment of PsA compared with RA represents a significant challenge. Moreover, PsA is not a benign disease, as evidenced by radiological progression and disability.10 In one study of PsA patients attending an early arthritis clinic, treatment with conventional DMARDs for 2 years achieved good disease control, however as many as 50% of PsA patients developed significant bone erosions in that time.11

Our understanding of the pathogenesis of PsA has significantly advanced in recent years, and this has led to the identification of various targets of the inflammatory process observed in PsA.12 It has been clear for some time that in psoriasis (PsO) and PsA, there is a complex interaction of environmental and genetic factors that must lead to a sustained and persistent inappropriate inflammatory response. The relationship between skin and joint disease has been the focus of a …
Downregulation of MicroRNA-126 Contributes to the Failing Right Ventricle in Pulmonary Arterial Hypertension
Authors: François Potus, Grégoire Ruffenach, Abdellaziz Dahou, Christophe Thebault, Sandra Breuils-Bonnet, Ève Tremblay, Valérie Nadeau, Renée Paradis, Colin Graydon, Ryan Wong, Ian Johnson, Roxane Paulin, Annie C. Lajoie, Jean Perron, Eric Charbonneau, Philippe Joubert, Philippe Pibarot, Evangelos D. Michelakis, Steeve Provencher, Sébastien Bonnet
Journal: Circulation (2015)

Right ventricular (RV) failure is the most important factor of both morbidity and mortality in pulmonary arterial hypertension (PAH). However, the underlying mechanisms resulting in the failed RV in PAH remain unknown. There is growing evidence that angiogenesis and microRNAs are involved in PAH-associated RV failure. We hypothesized that microRNA-126 (miR-126) downregulation decreases microvessel density and promotes the transition from a compensated to a decompensated RV in PAH.We studied RV free wall tissues from humans with normal RV (n=17), those with compensated RV hypertrophy (n=8), and patients with PAH with decompensated RV failure (n=14). Compared with RV tissues from patients with compensated RV hypertrophy, patients with decompensated RV failure had decreased miR-126 expression (quantitative reverse transcription-polymerase chain reaction; P<0.01) and capillary density (CD31(+) immunofluorescence; P<0.001), whereas left ventricular tissues were not affected. miR-126 downregulation was associated with increased Sprouty-related EVH1 domain-containing protein 1 (SPRED-1), leading to decreased activation of RAF (phosphorylated RAF/RAF) and mitogen-activated protein kinase (MAPK); (phosphorylated MAPK/MAPK), thus inhibiting the vascular endothelial growth factor pathway. In vitro, Matrigel assay showed that miR-126 upregulation increased angiogenesis of primary cultured endothelial cells from patients with decompensated RV failure. Furthermore, in vivo miR-126 upregulation (mimic intravenous injection) improved cardiac vascular density and function of monocrotaline-induced PAH animals.RV failure in PAH is associated with a specific molecular signature within the RV, contributing to a decrease in RV vascular density and promoting the progression to RV failure. More importantly, miR-126 upregulation in the RV improves microvessel density and RV function in experimental PAH.
Correlations of visceral fat accumulation and atherosclerosis in Japanese patients with type 2 diabetes mellitus
Authors: Futoshi Anan, Takayuki Masaki, Yoshikazu Umeno, Tetsu Iwao, Hidetoshi Yonemochi, Nobuoki Eshima, Tetsunori Saikawa, Hironobu Yoshimatsu
Journal: Metabolism (2008)
Is nocturnal asthma caused by changes in airway cholinergic activity?
Authors: J R Catterall, G B Rhind, K F Whyte, C M Shapiro, N J Douglas
Journal: Thorax (1988)

A randomised, double blind, placebo controlled crossover trial of high dose nebulised ipratropium was carried out in 10 asthmatic patients with documented nocturnal bronchoconstriction. Patients received nebulised saline or ipratropium 1 mg at 10 pm and 2 am on two nights. Absolute peak flow (PEF) rates were higher throughout the night after the patients had received ipratropium (at 2 am, for example, mean (SEM) PEF was 353 after ipratropium and 285 l/min after placebo). The fall in PEF overnight, however, was similar with ipratropium and placebo. Patients were given a further 1 mg nebulised ipratropium at 6 am on both nights. There was a significant overnight fall in PEF on the ipratropium night even when comparisons were made between the times that maximal cholinergic blockade would be expected, PEF falling between 11.30 pm and 7.30 am from 429 to 369 l/min. The percentage increase in PEF, though not the absolute values, was greater after ipratropium at 6 am than at 10 pm. These results confirm that ipratropium raises PEF throughout the night in asthmatic patients, but suggest that nocturnal bronchoconstriction is not due solely to an increase in airway cholinergic activity at night.
Translation, cross-cultural adaption and validation of the German version of the Foot and Ankle Ability Measure for patients with chronic ankle instability
Authors: T Nauck, H Lohrer
Journal: British Journal of Sports Medicine (2009)

Objectives The evaluation of health-related quality of life and physical function is important for determining therapeutic strategies following ankle injuries. The Anglo-American Foot and Ankle Ability Measure (FAAM) is a valid and reliable self-reported measure to detect functional deficits in chronic lateral ankle instability. The purpose of this study was to translate, cross-culturally adapt and validate the FAAM questionnaire for use with German-speaking patients with chronic lateral ankle instability. Patients/Participants Preoperative and conservatively treated patients with chronic lateral ankle instability. Sport students and volleyball athletes served as control groups. Main Outcome Measurements The FAAM was forward and back translated, cross-culturally adapted and validated. The study population completed the FAAM-G questionnaire twice within 3–5 days. Additionally, the patients were scored with the Good ankle laxity classification system. Test–Retest reliability, construct validity and internal consistency were calculated. Results Reliability and validity of the FAAM-G were examined in presurgical chronic ankle instability patients (n=24), conservatively treated chronic ankle instability patients (n=17), university sport students (n=31) and volleyballers (n=37). Test–retest reliability revealed fair, good, or excellent reliability (inter-class correlation coefficient (ICC)=0.590–0.998; ρ=0.528–1.000). Construct validity, tested between the FAAM-G subscores and the Good et al ankle laxity classification system demonstrated strong correlations (ρ = −0.819 to −0.861). Conclusions The original FAAM questionnaire was successfully translated and cross-culturally adapted from English to German. Corresponding to the Anglo-American version, the FAAM-G is a reliable and valid questionnaire for self-reported assessment of pain and disability in German-speaking patients suffering from chronic ankle instability.
Chemical Exchange Saturation Transfer Contrast Agents for Magnetic Resonance Imaging
Authors: A. Dean Sherry, Mark Woods
Journal: Annual Review of Biomedical Engineering (2008)

Magnetic resonance imaging (MRI) contrast agents have become an important tool in clinical medicine. The most common agents are Gd 3+ -based complexes that shorten bulk water T 1 by rapid exchange of a single inner-sphere water molecule with bulk solvent water. Current gadolinium agents lack tissue specificity and typically do not respond to their chemical environment. Recently, it has been demonstrated that MR contrast may be altered by an entirely different mechanism based on chemical exchange saturation transfer (CEST). CEST contrast can originate from exchange of endogenous amide or hydroxyl protons or from exchangeable sites on exogenous CEST agents. This has opened the door for the discovery of new classes of responsive agents ranging from MR gene reporter molecules to small molecules that sense their tissue environment and respond to biological events.
Growth hormone excess and sternohyoid muscle mechanics in rats
Authors: P. Attal, V. Claes, S. Bobin, P. Chanson, P. Kamenicky, P. Zizzari, Y. Lecarpentier
Journal: European Respiratory Journal (2009)

In vitro isotonic and isometric mechanical properties of the sternohyoid (SH) muscle, an upper airway dilator muscle, were studied in rats with a growth hormone (GH)-secreting tumour (GH tumour group; n = 10). The effects of muscle fatigue were also studied. Stress and shortening were measured in muscles contracting from zero load up to isometric load under tetanic conditions. Isometric stress and maximum unloaded shortening velocity were determined and compared with values obtained from control rats (n = 10). Crossbridge kinetics and energetics and mechanical efficiency were calculated from Huxley's equations. Compared with controls, isometric stress, mechanical efficiency, crossbridge number and crossbridge single force were lower in the GH tumour group. The probability of crossbridge being in the power stroke configuration was lower in the GH tumour group than in controls. Muscle fatigue significantly impaired maximal muscle efficiency and crossbridge single force in the GH tumour group but not in controls. In conclusion, mechanical and energetic properties of the SH muscle and crossbridge properties were worse in the GH tumour group than in controls. This may partly account for impairment of the upper airway dilator muscle function and the increased occurrence of obstructive sleep apnoea in acromegaly.
Distinct Component Profiles and High Risk Among African Americans With Metabolic Syndrome
Authors: Herman Taylor, Jiankang Liu, Gregory Wilson, Sherita H. Golden, Errol Crook, Claude D. Brunson, Micheal Steffes, William D. Johnson, Jung Hye Sung
Journal: Diabetes Care (2008)

Health of African Americans is seriously threatened by unremitting epidemics of diabetes and cardiovascular disease (CVD). However, the role of metabolic syndrome in the African-American population has not been investigated widely. This study examined the prevalence of metabolic syndrome and assessed its cross-sectional relationship to CVD in the Jackson Heart Study (JHS) cohort.
Ciliopathy proteins regulate paracrine signaling by modulating proteasomal degradation of mediators
Authors: Yangfan P. Liu, I-Chun Tsai, Manuela Morleo, Edwin C. Oh, Carmen C. Leitch, Filomena Massa, Byung-Hoon Lee, David S. Parker, Daniel Finley, Norann A. Zaghloul, Brunella Franco, Nicholas Katsanis
Journal: Journal of Clinical Investigation (2014)

Cilia are critical mediators of paracrine signaling; however, it is unknown whether proteins that contribute to ciliopathies converge on multiple paracrine pathways through a common mechanism. Here, we show that loss of cilopathy-associated proteins Bardet-Biedl syndrome 4 (BBS4) or oral-facial-digital syndrome 1 (OFD1) results in the accumulation of signaling mediators normally targeted for proteasomal degradation. In WT cells, several BBS proteins and OFD1 interacted with proteasomal subunits, and loss of either BBS4 or OFD1 led to depletion of multiple subunits from the centrosomal proteasome. Furthermore, overexpression of proteasomal regulatory components or treatment with proteasomal activators sulforaphane (SFN) and mevalonolactone (MVA) ameliorated signaling defects in cells lacking BBS1, BBS4, and OFD1, in morphant zebrafish embryos, and in induced neurons from Ofd1-deficient mice. Finally, we tested the hypothesis that other proteasome-dependent pathways not known to be associated with ciliopathies are defective in the absence of ciliopathy proteins. We found that loss of BBS1, BBS4, or OFD1 led to decreased NF-κB activity and concomitant IκBβ accumulation and that these defects were ameliorated with SFN treatment. Taken together, our data indicate that basal body proteasomal regulation governs paracrine signaling pathways and suggest that augmenting proteasomal function might benefit ciliopathy patients.
Cutting balloon versus conventional balloon angioplasty for the treatment of in-stent restenosis
Authors: Remo Albiero, Sigmund Silber, Carlo Di Mario, Carmelo Cernigliaro, Salvatore Battaglia, Bernhard Reimers, Arian Frasheri, Volker Klauss, Joseph M. Auge, Paolo Rubartelli, Marie-Claude Morice, Alberto Cremonesi, Joachim Schofer, Alessandro Bortone, Antonio Colombo
Journal: Journal of the American College of Cardiology (2004)
Role of c-myc in Tamoxifen-Induced Apoptosis in Estrogen-Independent Breast Cancer Cells
Authors: Y. Kang, R. Cortina, R. R. Perry
Journal: JNCI Journal of the National Cancer Institute (1996)

BackgroundThe antiestrogen tamoxifen (TAM) is effective in the treatment of estrogen receptor (ER)-positive as well as some ER-negative breast cancers. However, the precise mechanism of action of TAM, especially in estrogen-independent cells, remains unclear. Previous work by our laboratory has demonstrated that TAM induces the morphologic and biochemical changes that are characteristic of apoptosis in both ER-positive and ER-negative cells.