tbuckley/cabot-search huggingface dataset:
Characterization of docetaxel-induced caspase-independent death in prostate cancer cells
Authors: Melanie Mediavilla-Varela, Jossymar Perez, Lai Sum Leoh, Amelia Padilla, Frankis Almaguel, Michael Lilly, Marino De Leon, Carlos Casiano
Journal: Cancer Research (2008)

2274   Docetaxel (DTX) has become the standard of care for first-line chemotherapy for hormone refractory prostate cancer (HRPC), a condition that disproportionately kills African-American men. Unfortunately, most patients with HRPC ultimately manifest resistance to DTX and succumb to the disease. Circumventing DTX resistance in HRPC will require a better understanding of the mechanisms by which this drug kills prostate tumor cells, and the genes that promote resistance against DTX-induced cell death. An existing paradigm is that DTX exerts its antitumor activities  in vitro  and  in vivo  by inducing apoptosis following inhibition of microtubule depolymerization, mitotic catastrophe, and inactivation of Bcl-2. This paradigm, however, is challenged by growing evidence suggesting that the mode of cell death induced by DTX might be dependent on the dose and duration of treatment, the tumor cell type, and the tumor environment.  We investigated the mechanisms underlying DTX-induced death in the HRPC cell line PC3, using various assays that distinguish apoptotic from non-apoptotic cell death. Cells were exposed to doses of DTX ranging from 0.1 μM to 3 μM for up to 96 h. DTX induced mitotic catastrophe and apoptosis at both low and high doses, as determined by morphological examination, viability and apoptotic assays, flow cytometric cell cycle assessment, and analysis of the cleavage of the caspase substrates PARP and LEDGF/p75. However, caspase activity was not required for DTX-induced cell death since this still occurred in the presence of the broad caspase inhibitor Z-VAD.FMK and the caspase-2 inhibitor Z-VDVAD.CHO. Mitochondrial membrane depolarization was induced at both low and high DTX doses but it was completely inhibited by Z-VAD.FMK, indicating its caspase-dependence. Generation of reactive oxygen species (ROS) was observed mainly at high doses and it was partially inhibited by Z-VAD.FMK. Visualization of Hoechst-stained nuclei from cells that rounded and detached after treatment with DTX showed apoptotic-like chromatin fragmentation that was independent of caspase activation. Lysosomal destabilization independent of caspase activity was also observed in rounded/detached cells, but not in multinucleated cells, during treatment with DTX. Partial rescue of DTX-induced cell death was observed after inhibition of cathepsin B, highlighting the drug’s ability to induce caspase-independent, lysosomal cell death. The role of cathepsins L and D in DTX-induced PC3 cell death is currently under investigation. Taken together, these results challenge the paradigm that apoptosis is the major mechanism of DTX-induced PCa cell death in vitro ,  and underline the ability of this drug to induce multiple cell death modalities involving both caspase-dependent and independent mechanisms.
A NICE Delivery — The Cross-Atlantic Divide over Treatment Intensity in Childbirth
Authors: Neel Shah
Journal: New England Journal of Medicine (2015)

Interview with Dr. Neel Shah on new guidelines from the United Kingdom on the safety of midwife-guided deliveries. (07:00)Download The U.K.'s National Institute for Health and Care Excellence has concluded that healthy women with low-risk pregnancies are safer delivering at home or in a midwife-led unit than in a hospital under an obstetrician's supervision. Across the pond, eyebrows went up.
Abstract 5414: Macrophage Migration Inhibitory Factor Inhibits C-jun N Terminal Kinase And Prevents Cardiac Injury During Acute Ischemia Reperfusion
Authors: Dake Qi, Xiaoyue Hu, Xiaohong Wu, Agnes Kim, Lin Leng, Richard Bucala, Lawrence Young
Journal: Circulation (2008)

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine, which is expressed in multiple organs including the heart. Plasma MIF is elevated after myocardial infarction. MIF is released from the heart during ischemia and has an autocrine/paracrine effect to positively modulate AMP-activated protein kinase (AMPK). Genetic deficiency in MIF (MIF−/−) attenuates AMPK activation, leading to cardiac dysfunction and injury during ischemia/reperfusion (IR). MIF also inhibits c-Jun N-terminal kinase (JNK) activation in HeLa cells, but its action in the heart is not known. In Langendorff perfused WT hearts, MIF content was reduced after global ischemia (15 min) and reperfusion (30 min). JNK activation and downstream c-Jun phosphorylation were greater (p in viv o augmented MKK4, JNK and c-Jun phosphorylation in MIF−/− vs. WT mice. MIF−/− hearts showed more necrosis on TTC staining after LAD occlusion and reperfusion than WT. Increased cardiac injury following IR was associated with less BAD phosphorylation and more cellular apoptosis in MIF−/− hearts. Administration of SP600125 (1mg/kg, IP) prior to ischemia also limited injury in MIF−/− mice.  In vitro  studies showed that the JNK activator, anisomycin, stimulated the JNK pathway in H9C2 cells in a dose-dependent manner and MIF (50 ng/ml) inhibited anisomycin-activation of MKK4, JNK, and c-Jun. Thus, cardiac-derived MIF inhibits activation of the JNK pathway, which may protect the heart from injury following IR.  This research has received full or partial funding support from the American Heart Association, AHA Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).
Series, PowerPoint slides, and folders now available on bmj.com
Authors: Tony Delamothe
Journal: BMJ (2005)

Three new services have been added recently to the BMJ's website, bmj.com. The first gives users what they've been asking for: links to all the series that have appeared in the BMJ. A button on bmj.com's home page, labelled “Series,” takes users to a page with links to the 35 ABC series we've published since 1998 as well as other old favourites such as Statistics notes. This page also lists links to newer series such as 10 minute consultations, ethical debates, and interactive case reports (http//:bmj.com/series).​).



Figure 1



The second new feature allows readers to turn illustrations from BMJ articles into PowerPoint slides with just two clicks of the mouse. All the user needs to do is to find the desired illustration, select the option labelled “View larger version [in this window]” and then click on the link marked “PowerPoint Slide for Teaching.” Depending on the speed of connection, a PowerPoint slide can be ready in less than a minute. Teaching is the obvious use for these slides, but many users will find them valuable for other presentations. We can't provide this service for illustrations for which others hold the copyright (such as the photographs in the BMJ's news pages). Nevertheless, without any promotion of this service, up to 10 000 illustrations are already being rendered into PowerPoint slides on bmj.com each month.​month.



Figure 2



The newest of our services, and the one that may prove most useful, is folders. To save the link to any BMJ article click on the link marked “Add article to my folders” in the contents box adjacent to that article. Users can file their saved articles as they wish; can add, delete, or rename folders; can move articles around between folders and copy them into more than one; and can save searches in folders to use later when further studies have been published (the relevant link, “Save this search to my folders,” appears at the top of the search results page).

Each user has to register for a username and password before setting up folders because each person's selection of articles and searches will be unique. This single username and password will allow users to store and manage in one place articles published not only by the BMJ but by the BMJ Publishing Group's two dozen specialist journals.1

These three services are free, although access to the full text of articles and to the illustrations that appear within them depend on the user's access rights. Next year we will continue our policy of providing immediate free access to the full text of original research papers. The full text of all other articles, including editorials, news, and educational articles, will be behind access controls for a year after publication. These articles will be available only to BMA members, BMJ subscribers, and users from the world's poorest countries during the first year of publication.2
Abstract 5278: The Sonic Hedgehog Transcription Factor Gli3 Modulates Ischemia-induced Angiogenesis
Authors: Marie-Ange Renault, Jerome Roncalli, Joern Tongers, Sol Misener, Tina Thorne, Aiko Ito, Trevor Clarke, Meredith Millay, Christine Kamide, Ekaterina Klyachko, Douglas W Losordo
Journal: Circulation (2008)

Gli transcription factors are mediators of hedgehog signaling and have been shown to be critical in several steps during development. We have shown that the Hedgehog pathway is reactivated in the adult cardiovascular system under ischemic conditions, however the specific role of Gli3 has not been elucidated. Adenoviral mediated overexpression of Gli3 promotes HUVEC migration (250±58% of control, p&lt;0.001) while down regulation of Gli3 via siRNA delayed tube formation on Matrigel (total tube length after 8 hours 6.86 vs. 70.76 control), suggesting a possible role of Gli3 in angiogenesis. We next investigated the role of Gli3 in angiogenesis using Gli3 +/− (Gli3 +/XtJ ) mice, a well established model of reduced Gli3 expression. VEGF-induced corneal angiogenesis was impaired in Gli3 +/− mice compared to WT. The role of Gli3 in angiogenesis was then confirmed in two ischemia models. Hind-limb ischemia (HLI) was induced by resection of the left femoral artery. Capillary density was reduced by a mean of 48.40±12.08% in Gli3 +/− mice vs. WT 7, 14 and 28 days. Myocardial infarction (MI) was induced by ligation of the LAD. 28 days after MI, left ventricular function assessed by echo and histological analysis revealed that Gli3 +/− mice exhibit reduced ejection fraction (27.92±4.49% versus 37.56±7.02% for the WT, p=0.004), increased fibrosis area (33.65±9.73% versus 19.81±5.40% for the WT, p=0.007) and a decrease capillary density in the ischemic and border zones. These data indicate that Gli3 deficiency leads to impaired angiogenesis in both ischemic and non ischemic conditions. Moreover, the impairment in ischemia induced neovascularization is associated with more severe impairment of cardiac function after MI. The mechanism of Gli3’s effects was then investigated in vitro . Promoter reporter assays revealed that Gli3 overexpression inhibits Gli-dependent transcription, while Western analysis show increased Akt phosphorylation, activation of the ERK1/2 and increased c-Fos expression. Using a dominant negative Akt expressing virus and a MEK1/2 inhibitor, we show that Gli3 induced-EC migration is dependent on Akt and ERK1/2. These studies provide the first evidence that the Gli3 transcription factor regulates angiogenesis and EC phenotype.
Abstract 1317: Anticoagulant Responses in Patients Receiving Low Molecular Weight Heparin Compared to Unfractionated Heparin for Transesophageal Echocardiography Guided Cardioversion of Atrial Fibrillation: Results from the Assessment of Cardioversion Using Transesophageal Echocardiography Randomized Study
Authors: Debra A Hoppensteadt, Jawed Fareed, Allan Klein, Sue Jasper, William Katz, Joseph Malouf, Marcus Stoddard
Journal: Circulation (2006)

The ACUTE II Study compared low molecular weight heparin (LMWH) to unfractionated heparin (UFH) in patients with atrial fibrillation (AF) >2 days’ duration, undergoing TEE guided cardioversion over...
Abstract 15201: Echocardiographic Epicardial Adipose Tissue Relates to Coronary Artery Plaque and Calcification: Comparisons with Abdominal Visceral Adipose Tissue
Authors: Masayoshi Oikawa, Takashi Owada, Hiroyuki Yamauchi, Akiomi Yoshihisa, Kazuhiko Nakazato, Hitoshi Suzuki, Shu-ichi Saitoh, Yasuchika Takeishi
Journal: Circulation (2014)

Background:  Accumulation of abdominal visceral adipose tissue (VAT) is one of features of metabolic syndrome, and is associated with a risk of coronary artery disease (CAD). Epicardial adipose tissue (EAT) is an ectopic accumulation of VAT, and shares an embryological origin with abdominal VAT. Unlike abdominal VAT, EAT may affect directly on coronary artery, but the difference of pathological roles in EAT and abdominal VAT remains to be elucidated.   Methods:  Consecutive 174 patients with suspected CAD who underwent both 64-slice computed tomography (CT) angiography and echocardiography were analyzed in this study. Cardiac and abdominal CT scans were performed to measure EAT and abdominal VAT. The presence of echocardiographic EAT was defined as more than 1.5 mm thickness of EAT.   Results:  Out of 174 patients, 114 patients and 117 patients presented coronary calcification and coronary plaque visualized by CT angiography, respectively. Both EAT area (7.0 [4.6-10.7] cm2 vs. 5.2 [3.4-7.3] cm2, P   Conclusions:  EAT and abdominal VAT may play differential pathological roles in CAD, and our data suggest that we should pay more attention to EAT when interpret CT or echocardiographic images for cardiovascular risk stratification.
Attitudes of Oregon psychiatrists toward physician-assisted suicide
Authors: L Ganzini, D S Fenn, M A Lee, R T Heintz, J D Bloom
Journal: American Journal of Psychiatry (1996)

After passage, in November 1994, of Oregon's ballot measure legalizing physician-assisted suicide for terminally ill persons, the authors surveyed psychiatrists in Oregon to determine their attitudes toward assisted suicide, the factors influencing these attitudes, and how they might both respond to and follow up a request by a primary care physician to evaluate a terminally ill patient desiring assisted suicide.An anonymous questionnaire was sent to all 418 Oregon psychiatrists.Seventy-seven percent of psychiatrists (N = 321) returned the questionnaire. Two-thirds endorsed the view that a physician should be permitted, under some circumstances, to write a prescription for a medication whose sole purpose would be to allow a patient to end his or her life. One-third endorsed the view that this practice should never be permitted. Over half favored Oregon's assisted suicide initiative becoming law. Psychiatrists' position on legalization of assisted suicide influenced the likelihood that they would agree to evaluate patients requesting assisted suicide and how they would follow up an evaluation of a competent patient desiring assisted suicide. Only 6% of psychiatrists were very confident that in a single evaluation they could adequately assess whether a psychiatric disorder was impairing the judgment of a patient requesting assisted suicide.Psychiatrists in Oregon are divided in their belief about the ethical permissibility of assisted suicide, and their moral beliefs influence how they might evaluate a patient requesting assisted suicide, should this practice be legalized. Psychiatrists' confidence in their ability to determine whether a psychiatric disorder such as depression was impairing the judgment of a patient requesting assisted suicide was low.
Cellular Mechanisms for Increased Fetal Hemoglobin Production in Culture
Authors: George J. Dover, Makio Ogawa
Journal: Journal of Clinical Investigation (1980)

Using microscopic immunodiffusion assays and microdensitometric analysis of pericellular immunoprecipitate, the percentage of nucleated erythrocytes containing fetal hemoglobin (FNRBC) and the mean picograms of fetal or adult hemoglobin per nucleated erythrocyte (picograms HbF/NRBC, picograms HbA/NRBC) were assayed in 14-d-old colonies (bursts) derived from peripheral blood erythroid progenitors. In the peripheral blood of 11 normal adults only 2.2±0.5% (mean±SE) erythrocytes contained HbF whereas pooled bursts from the same subjects revealed a 13-fold increase in the percentage of FNRBC (29.6±3.9%). In culture both the picograms HbF/NRBC (5.2±0.4) and the picograms HbA/NRBC (27.7±1.5) are increased ∼20% above the mean in vivo levels in NRBC from normal bone marrow aspirates. Analysis of each of 58 bursts from one subject demonstrated that FNRBC are present in all bursts and range from 5.0 to 95.0% of the total NRBC per burst. The percent FNRBC in each burst was neither correlated with picograms HbF/NRBC per burst nor with picograms HbA/NRBC per burst. Individual subcolonies from one burst in each of two subjects demonstrated between 3 and 81% FNRBC.
Abstract 19477: The Glucagon-Like Peptide-1 Receptor Agonist Liraglutide Reduces Inflammation and Improves Cardiac Function in a Mouse Model of Obesity
Authors: Mohammad Hossein Noyan-Ashraf, Filio Billia, Ilya M Mukovozov, Lisa A Robinson, Allen Volchuk, Daniel J Drucker, Mansoor Husain
Journal: Circulation (2010)

Background: Obesity contributes to diabetes, hypertension and cardiovascular disease. Glucagon-like peptide-1 receptor (GLP-1R) activation has been shown to prevent injury in several tissues. Here ...
Abstract 17495: Thrombospondin-1/CD36 Pathway Critically Contributes to SHH Signaling Defect and EPC Dysfunction on Wound Healing in Type 1 Diabetes
Authors: Jie-Mei Wang, Jeffery S Isenberg, Alex F Chen
Journal: Circulation (2011)

Introduction: Refractory wounds in diabetic patients is a significant clinical problem. We reported previously that sonic hedgehog (SHH), a morphogenic protein central to wound repair, is deficient in diabetes, but the underlying mechanisms are poorly understood. We hypothesized that thrombospondin-1 (TSP-1) through its receptor CD36 contributes to SHH signaling defect in cutaneous tissue and endothelial progenitor cells (EPCs), resulting in impaired wound healing in type 1 diabetic mice. Methods and Results: Cutaneous expression of SHH and its signaling molecules including Patched (Ptc), Smoothened (Smo), and Gli were significantly decreased in streptozotocin (STZ)-induced type 1 diabetic mice (male, C57BL/6J, 12 weeks) vs. their age-matched control littermates (Western blot analysis, n=5, p&lt;0.05 vs. control), which were reversed in STZ-treated TSP-1 -/- mice (homozygote, C57BL/6J background, n=5, p&lt;0.05 vs. STZ-treated WT mice). Excisional wound (6-mm punch biopsy) closure was significantly delayed in STZ mice (n=6, p&lt;0.05 vs. control) with reduced wound blood flow (Laser Doppler), which was not observed in STZ-treated TSP-1 -/- mice (n=5, p&lt;0.05 vs. STZ-treated WT mice). The protective effect of TSP-1 depletion on wound repair was abolished following topical treatment with the selective SHH inhibitor cyclopamine (5 μ M, 30 min/day, n=5, p&lt;0.05 vs. STZ-treated TSP-1 -/- mice). Isolated EPCs from bone marrow of STZ mice showed significantly impaired angiogenesis (Matrigel tube formation, n=4, p&lt;0.05 vs. control), which was rescued by exogenous SHH (1 mg/L, 24 hours, n=4, p&lt;0.05 vs. STZ-control). Increased EPC angiogenesis in STZ-treated TSP-1 -/- mice (n=5, p&lt;0.05 vs. STZ-WT) was inhibited by the selective SHH inhibitor cyclopamine (5 μ M, 24 hours, n=5, p&lt;0.05). SHH, Ptc, Smo and Gli levels were significantly increased in EPCs from TSP-1 -/- mice and CD36 -/- mice, but not CD47 -/- mice (n=6, p&lt;0.05 vs. WT). Normal EPCs treated with recombinant human TSP-1 protein (2.2 nM, 24 hour) exhibited impaired angiogenesis, an effect that was not observed in EPCs from CD36 -/- mice (n=5, p&lt;0.05). Conclusion: TSP-1/CD36 pathway critically contributes to SHH signaling defect, resulting in EPC dysfunction and impaired wound healing in type 1 diabetic mice.
Screening for Asymptomatic Bacteriuria in Adults: U.S. Preventive Services Task Force Reaffirmation Recommendation Statement
Authors: Ned Calonge, Diana B. Petitti, Thomas G. DeWitt, Allen Dietrich, Kimberly D. Gregory, Russell Harris, George Isham, Michael L. LeFevre, Rosanne Leipzig, Carol Loveland-Cherry, Lucy N. Marion, Bernadette Melnyk, Virginia A. Moyer, Judith K. Ockene, George F. Sawaya, Barbara P. Yawn, US Preventive Serv Task Force
Journal: Annals of Internal Medicine (2008)

Description: Reaffirmation of the 2004 U.S. Preventive Services Task Force recommendation statement about screening for asymptomatic bacteriuria in adults. Methods: The U.S. Preventive Services Task Force did a targeted literature search for evidence on the benefits and harms of screening for asymptomatic bacteriuria in pregnant women, nonpregnant women, and men. Recommendations: Screen for asymptomatic bacteriuria with urine culture in pregnant women at 12 to 16 weeks' gestation or at the first prenatal visit, if later. (Grade A recommendation.) Do not screen for asymptomatic bacteriuria in men and nonpregnant women. (Grade D recommendation.)
Clinical subtypes of schizophrenia: differences in brain and CSF volume
Authors: Gur Re, Mozley Pd, Shtasel Dl, Cannon Td, Gallacher F, Turetsky B, Grossman R, Gur Rc
Journal: American Journal of Psychiatry (1994)

Investigations of the relation of clinical features of schizophrenia to neuroanatomic measures have produced inconclusive results. The purpose of this study was to examine measures of whole-brain volume in men and women and relate them to clinical subtypes of schizophrenia.Magnetic resonance imaging measures of cranial, brain, and ventricular and sulcal CSF volume were examined in 81 patients with schizophrenia (50 men and 31 women), divided into subgroups based on their symptom profiles, and 81 demographically matched healthy comparison subjects.The men had higher cranial and brain volumes than the women. The patients had smaller cranial and brain volumes than the comparison subjects; they also had higher ventricular CSF volumes and thus higher ventricle-brain ratios (VBRs). Ratio elevations were larger for the female than for the male schizophrenic patients. The patients with predominantly negative symptoms of schizophrenia had higher VBRs and sulcal CSF-brains ratios than the comparison subjects, although the component volumes did not differ. The patients with predominantly Schneiderian symptoms had higher VBRs than the comparison subjects but showed reduced cranial and brain volumes. The paranoid patients had normal VBRs, reduced sulcal CSF-brain ratios, and lower cranial and sulcal CSF volumes.The results suggest two patterns of neuroanatomic whole-brain abnormalities that differ in severity according to the relative prominence of negative, Schneiderian, and paranoid symptoms. These patterns may reflect differential involvement of dysgenic and atrophic pathophysiological processes. Sex moderates abnormalities in the neuroanatomic features of schizophrenia.