tbuckley/cabot-search huggingface dataset:
Soluble NKG2D ligands are increased in multiple myeloma, correlating with disease stage and associated with decreased expression of NKG2D on effector cells: a potential immune escape mechanism
Authors: Marie von Lilienfeld-Toal, Susanne Frank, Sylvia Feyler, Christiane Leyendecker, Angela Marten, Ingo Schmidt-Wolf, Gordon Cook
Journal: Cancer Research (2007)

5116    Introduction:  NKG2D is an activating NK receptor expressed by NK cells, CD8+ αβ T cells and γδ T cells. NKG2D ligands (MICA and MICB) are commonly upregulated on tumor cells including Multiple Myeloma (MM). Recently, shedding of NKG2D ligands has been reported as a form of immune escape leading to decreased expression of NKG2D on effector cells. Here, we evaluated the presence of soluble NKG2D ligands (sMIC) in patients with MM.   Methods:  Sera from 51 controls, 13 patients with monoclonal gammopathy of undetermined significance (MGUS), 63 patients with stable MM and 28 patients with progressive MM were analyzed for sMICA and sMICB using a commercial ELISA. FACS analysis was performed for expression of NKG2D on fresh effector cells (5 controls, 6 patients). Effector cells were then cultured for 2 days ± sMICA ± IL-15 and reanalyzed.   Results:  There was a significantly higher level of sMICA in MM compared to MGUS or controls (in pg/ml: controls 112 ± 99, MGUS 126 ± 62, stable MM 201 ± 142, progressive MM 308 ± 507, p   FACS analysis showed higher NKG2D expression on effector cells of healthy controls compared to patients (Table 1).  In vitro  addition of sMICA decreased NKG2D expression in all effector cells, however, γδ T cells of patients maintained a higher NKG2D. Addition of IL-15 counteracted the effect of sMICA leading to an increase of NKG2D expression in all effector cell populations. Interestingly, this effect was more pronounced in effector cells of patients.   Conclusion:  sMIC are increased in MM compared to controls and MGUS. NK cells and γδ T cells in MM have a lower surface expression of NKG2D which might be sMICA mediated.  In vitro  results suggest that IL-15 restores NKG2D expression in the presence of sMICA, thus representing a potential agent for immunomodulation in MM.
Progression of Difficult Wheeze to Persistent Asthma in Children: Ontogeny of Anatomic, Inflammatory, and Physiological Factors with Age
Authors: W. Gerald Teague, Monica G. Lawrence, Stephen Early, John W. Steinke, Andrea Garrod, Debbie-Ann Shirley, Thomas J. Braciale, Michael Ellwood, Larry Borish
Journal: Journal of Allergy and Clinical Immunology (2018)
Primary outcomes of the Monitoring in Dialysis Study indicate that clinically significant arrhythmias are common in hemodialysis patients and related to dialytic cycle
Authors: Prabir Roy-Chaudhury, Jim A. Tumlin, Bruce A. Koplan, Alexandru I. Costea, Vijay Kher, Don Williamson, Saurabh Pokhariyal, David M. Charytan, Don Williamson, Prabir Roy-Chaudhury, James Tumlin, Vijay Kher, Vikranth Reddy, Kowdle Chandrasekhar Prakash, David Charytan, Suresh Chandra Tiwari, Saurabh Pokhariyal, Amber Podoll, Sanjeev Jasuja, G. Leslie Walters, Kraig Wangsnes, Alexandru Costea, Selcuk Tombul, Balbir Singh, Brajesh Mishra, Sachin Yalagudri, Abhijeet Shelke, Calambur Narasimhan, A.M. Karthigesan, Abraham Oomman, K.P. Pramod Kumar, Bruce Koplan, Upendra Kaul, Tapan Ghose, Ripen Gupta, Arvind Sethi, Nikhil Kumar, Ramesh Hariharan, Rajnish Sardana, Arif Wahab, N.N. Khanna, Mark Smith, Suresh Kamath, Claude Galphin, Puneet Sodhi, Rajsekara Chakravarthy, Subba Rao Budithi, Finnian McCausland, Sanjeev Gulati, Munawer Dijoo, Upendra Singh, Salil Jain, Vishal Saxena, Gaurav Sagar, David Charytan, Rachel Fissell, Robert Foley, Charles A. Herzog, Peter McCullough, John D. Rogers, James A. Tumlin, Peter Zimetbaum, Manish Assar, Mark Kremers, Wolfgang C. Winkelmayer
Journal: Kidney International (2018)

Sudden death is one of the more frequent causes of death for hemodialysis patients, but the underlying mechanisms, contribution of arrhythmia, and associations with serum chemistries or the dialysis procedure are incompletely understood. To study this, implantable loop recorders were utilized for continuous cardiac rhythm monitoring to detect clinically significant arrhythmias including sustained ventricular tachycardia, bradycardia, asystole, or symptomatic arrhythmias in hemodialysis patients over six months. Serum chemistries were tested pre- and post-dialysis at least weekly. Dialysis procedure data were collected at every session. Associations with clinically significant arrhythmias were assessed using negative binomial regression modeling. Sixty-six patients were implanted and 1678 events were recorded in 44 patients. The majority were bradycardias (1461), with 14 episodes of asystole and only one of sustained ventricular tachycardia. Atrial fibrillation, although not defined as clinically significant arrhythmias, was detected in 41% of patients. With thrice-weekly dialysis, the rate was highest during the first dialysis session of the week and was increased during the last 12 hours of each inter-dialytic interval, particularly the long interval. Among serum and dialytic parameters, only higher pre-dialysis serum sodium and dialysate calcium over 2.5 mEq/L were independently associated with clinically significant arrhythmias. Thus, clinically significant arrhythmias are common in hemodialysis patients, and bradycardia and asystole rather than ventricular tachycardia may be key causes of sudden death in hemodialysis patients. Associations with the temporal pattern of dialysis suggest that modification of current dialysis practices could reduce the incidence of sudden death.
UK women launch legal action against Bayer over Essure sterilisation device
Authors: Clare Dyer
Journal: BMJ (2018)

Women in the UK are launching legal action claiming they suffered prolonged pain, abnormal bleeding, and other serious side effects after being fitted with the sterilisation device Essure.

In England, the law firm Leigh Day expects to bring about five cases in the county court against the German pharmaceutical company Bayer, which manufactured the device.

And the Scottish personal injury law firm Thompsons is preparing to file claims on behalf of six women in the Court of Session in Scotland.

The UK litigation is on a much smaller scale than in the US, where thousands of women are reported to be suing Bayer over Essure. The device remains on the US market, although the …
Autonoesis and reconstruction in episodic memory: Is remembering systematically misleading?
Authors: Kourken Michaelian
Journal: Behavioral and Brain Sciences (2018)

Abstract Mahr &amp; Csibra (M&amp;C) view autonoesis as being essential to episodic memories and construction as being essential to the process of episodic remembering. These views imply that episodic memory is systematically misleading, not because it often misinforms us about the past, but rather because it often misinforms us about how it informs us about the past.
Abstract #124: Small molecule compound norcantharidin inhibits angiogenesis
Authors: Liao Hui-Fen, Yu-Jen Chen, Yin-Meng Tsai
Journal: Cancer Research (2009)

Norcantharidin (NCTD) is a small-molecule cytotoxic agent derived from naturally occurring cantharidin. However, the anti-angiogenesis effect of NCTD and its molecular mechanism has not been elucidated. The present study was aimed to examine the in vitro and in vivo effect of NCTD on angiogenesis in human umbilical endothelial cells (HUVECs). NCTD preferentially inhibited the viability of colorectal adenocarcinoma CT26 cells in comparison with normal HUVECs. In HUVECs, NCTD not only decreased the migration, but also inhibited capillary-like tube formation. This anti-angiogenesis effect of NCTD was accompanied by anoikis (detachment-mediated apoptosis) and down-regulation of integrin \#946;1 and breakdown of vimentin protein. By protein array assay for detecting soluble factors released by HUVEC, we found that the amount of pro-angiogenic factors including angiogenin, GRO, IGF-1, IL-8, MCP-1, and VEGF was decreased by treatment with NCTD. In vivo validation experiments show that NCTD improved the survival rate and suppressed the plasma VEGF level in syngeneic CT26-implanted mice without renal or hepatic toxicity. In conclusion, NCTD might be a potent small-molecule angiogenesis inhibitor in cancer therapy.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 124.
Lipids, Lipoproteins, and Metabolites and Risk of Myocardial Infarction and Stroke
Authors: Michael V. Holmes, Iona Y. Millwood, Christiana Kartsonaki, Michael R. Hill, Derrick A. Bennett, Ruth Boxall, Yu Guo, Xin Xu, Zheng Bian, Ruying Hu, Robin G. Walters, Junshi Chen, Mika Ala-Korpela, Sarah Parish, Robert J. Clarke, Richard Peto, Rory Collins, Liming Li, Zhengming Chen
Journal: Journal of the American College of Cardiology (2018)

Blood lipids are established risk factors for myocardial infarction (MI), but uncertainty persists about the relevance of lipids, lipoprotein particles, and circulating metabolites for MI and stroke subtypes. This study sought to investigate the associations of plasma metabolic markers with risks of incident MI, ischemic stroke (IS), and intracerebral hemorrhage (ICH). In a nested case-control study (912 MI, 1,146 IS, and 1,138 ICH cases, and 1,466 common control subjects) 30 to 79 years of age in China Kadoorie Biobank, nuclear magnetic resonance spectroscopy measured 225 metabolic markers in baseline plasma samples. Logistic regression was used to estimate adjusted odds ratios (ORs) for a 1-SD higher metabolic marker. Very low-, intermediate-, and low-density lipoprotein particles were positively associated with MI and IS. High-density lipoprotein (HDL) particles were inversely associated with MI apart from small HDL. In contrast, no lipoprotein particles were associated with ICH. Cholesterol in large HDL was inversely associated with MI and IS (OR: 0.79 and 0.88, respectively), whereas cholesterol in small HDL was not (OR: 0.99 and 1.06, respectively). Triglycerides within all lipoproteins, including most HDL particles, were positively associated with MI, with a similar pattern for IS. Glycoprotein acetyls, ketone bodies, glucose, and docosahexaenoic acid were associated with all 3 diseases. The 225 metabolic markers showed concordant associations between MI and IS, but not with ICH. Lipoproteins and lipids showed similar associations with MI and IS, but not with ICH. Within HDL particles, cholesterol concentrations were inversely associated, whereas triglyceride concentrations were positively associated with MI. Glycoprotein acetyls and several non–lipid-related metabolites associated with all 3 diseases.
Npas4 Is a Critical Regulator of Learning-Induced Plasticity at Mossy Fiber-CA3 Synapses during Contextual Memory Formation
Authors: Feng-Ju Weng, Rodrigo I. Garcia, Stefano Lutzu, Karina Alviña, Yuxiang Zhang, Margaret Dushko, Taeyun Ku, Khaled Zemoura, David Rich, Dario Garcia-Dominguez, Matthew Hung, Tushar D. Yelhekar, Andreas Toft Sørensen, Weifeng Xu, Kwanghun Chung, Pablo E. Castillo, Yingxi Lin
Journal: Neuron (2018)
c-RAF Ablation Induces Regression of Advanced Kras/Trp53 Mutant Lung Adenocarcinomas by a Mechanism Independent of MAPK Signaling
Authors: Manuel Sanclemente, Sarah Francoz, Laura Esteban-Burgos, Emilie Bousquet-Mur, Magdolna Djurec, Pedro P. Lopez-Casas, Manuel Hidalgo, Carmen Guerra, Matthias Drosten, Monica Musteanu, Mariano Barbacid
Journal: Cancer Cell (2018)
Regulation of PERK signaling and leukemic cell survival by a novel cytosolic isoform of the UPR regulator GRP78/BiP generated by intron retention
Authors: Min Ni, Shiuan Wey, Amy Lee
Journal: Cancer Research (2008)

LB-29   The endoplasmic reticulum (ER) is an essential cellular compartment for protein synthesis and maturation and also functions as a Ca 2+  storage organelle. The perturbation of ER functions results in accumulation of unfolded or misfolded proteins and the failure of the ER to cope with the excessive protein load, which leads to ER stress. As an evolutionarily conserved intracellular signaling cascade in response to ER stress, the unfolded protein response (UPR) is activated to reduce the unfolded protein load and at the same time increase protein folding capacity. Activation of PERK (PKR-like eIF2α kinase) signaling and induction of ER chaperone GRP78/BiP (glucose-regulated protein 78kDa) represent two major survival arms of the UPR. Here, we report the fortuitous discovery of a novel cytosolic isoform of GRP78, designated as GRP78va, generated by intron retention of the  Grp78  pre-mRNA and alternative translational initiation. Expression of GRP78va is enhanced by ER stress and is notably elevated in human leukemic cells and leukemia patients. Unlike the canonical form of GRP78 which is primarily localized in the lumen of the ER, this new isoform of GRP78 is located outside the ER. GRP78va is a potent promoter of cell survival under ER stress, which could be in part due to a previously unanticipated positive feedback of the PERK pathway through interacting with a PERK antagonist. These studies provide the first evidence of modulation of UPR signaling via alternative pre-mRNA splicing and reveal a fundamentally new concept for survival mechanism in leukemic cells and other cell types where GRP78va is expressed.
Co-Expression and Functional Interaction between CXCR4 and CD74 in Chronic Lymphocytic Leukemia
Authors: Tharshika Thavayogarajah, Dzmitry Sinitski, Jens P. Panse, Idit Shachar, Tim H. Brümmendorf, Jürgen Bernhagen, Steffen Koschmieder
Journal: Blood (2017)
BMA backs GPs who wish to take legal action against Capita
Authors: Abi Rimmer
Journal: BMJ (2018)

The BMA has said that it would support GPs and practices that take legal action to tackle problems with Capita’s running of back-office services. Capita has provided primary care support services for NHS England since September 2015, under the name Primary Care Support England (PCSE).

In November the BMA highlighted what it called PCSE’s “ongoing issues due to poor delivery” by Capita. However, Capita said that the BMA’s comments did not accurately reflect its role and involvement in providing the services.1

In a letter to Simon Stevens, chief executive of …
Abstract 18411: Diastolic-systolic Velocity Ratio to Detect Coronary Stenoses
Authors: Guus de Waard, Christopher M Cook, Ricardo Petraco, Sukhjinder S Nijjer, Tim P van de Hoef, Mauro Echavarria-Pinto, Sayan Sen, Martijn Meuwissen, Paul Knaapen, Javier Escaned, Jan J Piek, Niels van Royen, Justin E Davies
Journal: Circulation (2017)

Introduction: Diastolic-systolic velocity ratio (DSVR) is an index to assess LAD stenoses and can be measured by transthoracic echocardiography or intracoronary Doppler flow velocity. The aims of t...
Bisphosphonates reduce the risk of knee replacement: we need more analyses!
Authors: Hui-Zi Li, Xiang-He Xu, Hua-Ding Lu
Journal: Annals of the Rheumatic Diseases (2018)

With great interest, we read the recent article by Neogi et al entitled, ‘Effect of bisphosphonates on knee replacement (KR) surgery’.1 In the study, the authors concluded that in this population-based cohort of older women with incident knee osteoarthritis (OA), those with incident bisphosphonate users had lower risk of KR than non-users of bisphosphonates, which was further supported by another large cohort study.2 The strengths of this study include a propensity score-matched cohort design, Cox proportional hazards regression to control for potential confounders and sensitivity analyses focused on residual confounding. Meanwhile, the authors acknowledged the limitations of their work. We applaud and congratulate their important work for clinical practice. However, several important points should …
Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer's disease: a longitudinal study
Authors: Brian A Gordon, Tyler M Blazey, Yi Su, Amrita Hari-Raj, Aylin Dincer, Shaney Flores, Jon Christensen, Eric McDade, Guoqiao Wang, Chengjie Xiong, Nigel J Cairns, Jason Hassenstab, Daniel S Marcus, Anne M Fagan, Clifford R Jack, Russ C Hornbeck, Katrina L Paumier, Beau M Ances, Sarah B Berman, Adam M Brickman, David M Cash, Jasmeer P Chhatwal, Stephen Correia, Stefan Förster, Nick C Fox, Neill R Graff-Radford, Christian la Fougère, Johannes Levin, Colin L Masters, Martin N Rossor, Stephen Salloway, Andrew J Saykin, Peter R Schofield, Paul M Thompson, Michael M Weiner, David M Holtzman, Marcus E Raichle, John C Morris, Randall J Bateman, Tammie L S Benzinger
Journal: The Lancet Neurology (2018)
Omalizumab Is Effective In Allergic And Non-allergic Patients With Nasal Polyps And Asthma
Authors: P. Gevaert, L. Calus, T. Van Zele, K. Blomme, N. De Ruyck, W. Bauters, P. Hellings, D. De Bacquer, G. Brusselle, P. Van Cauwenberge, C. Bachert
Journal: Journal of Allergy and Clinical Immunology (2012)
Acute sensitization of leukemia cells to vinblastine by small-molecule inhibitors of anti-apoptotic Bcl-2 family proteins
Authors: Bethany Salerni, Alan Eastman
Journal: Cancer Research (2008)

4386   Chemotherapeutic agents induce alterations in intracellular signal transduction cascades that culminate in the activation of BH3-only proteins and ultimately initiation of the apoptotic program. Here, the relationship between the expression of anti-apoptotic Bcl-2 family proteins and apoptosis in ML-1, NB4, and THP-1 leukemia cells treated with vinblastine (VB) was investigated. VB dissociates microtubules and usually induces M phase arrest prior to cell death. In ML-1 cells, the onset and extent of apoptotic cell death induced by VB (or other vinca alkaloids) can be dramatically enhanced by inhibiting the extracellular signal-regulated kinase (ERK) pathway with PD98059. This rapid induction of apoptosis is dependent on Jun N-terminal kinase (JNK) and occurs at all phases of the cell cycle. No sensitization was seen with paclitaxel which failed to activate JNK. Incubation with VB rapidly induces Mcl-1 in an ERK-dependent manner, while the levels of Bcl-2 remain unchanged; Bcl-X L  is minimally expressed. To confirm that Mcl-1 protects ML-1 cells from VB, we combined VB with GX15-070 (obatoclax), a small-molecule inhibitor of Mcl-1, Bcl-2, and Bcl-X L . The cells were acutely sensitized to VB by the addition of GX15-070 with 100% of cells undergoing apoptosis within 6 hours. In NB4 cells, VB only slightly induces Mcl-1 but no induction is seen in THP-1 cells. Additionally, neither NB4 nor THP-1 cells were sensitized to VB by either PD98059 or GX15-070, the latter possibly because Bcl-X L  has been reported as a mechanism of resistance to GX15-070. Accordingly, we postulated that the NB4 and THP-1 cells might be using Bcl-2 or Bcl-X L  for protection from VB. We incubated the cell lines with ABT-737, a small molecule inhibitor of Bcl-2 and Bcl-X L , but not Mcl-1. ABT-737 acutely sensitized the NB4 cells to VB, with almost 100% apoptosis within 4 hours. Neither ML-1 nor THP-1 cells were sensitized by ABT-737. The lack of sensitization in ML-1 cells is consistent with expression of Mcl-1 as a known mechanism of resistance to ABT-737, but the reason for the lack of response in THP-1 cells remains to be determined. The results demonstrate that the efficacy of vinca alkaloids may be dramatically increased when combined with an appropriate inhibitor of the particular Bcl-2 proteins that each tumor uses to protect itself. Furthermore, as these drug combinations convert the M phase-dependent activity of vinca alkaloids to a cell cycle phase-independent cell death, these combinations may enhance killing of quiescent cancer cells.
Ca2+-induced contraction and hyperreactivity of pulmonary arterial smooth muscle in monocrotaline-treated rats.
Authors: Takashi Takenaka, Yuji Ogawa, Katsuyuki Tobise
Journal: Circulation (1990)

The mechanism of progressive pulmonary hypertension induced by monocrotaline (MCT) remains controversial. To determine whether or not functional changes in pulmonary arterial smooth muscle contribute to the development of pulmonary hypertension, we examined the reactivity of isolated pulmonary artery segments 7, 14 and 21 days after a single subcutaneous injection of MCT. In Ca2(+)-free buffer, pulmonary arteries from MCT-treated rats contracted when CaCl2 was added without any other stimulation. The pulmonary artery exposed to MCT also exhibited hyperreactivity to KCl and 5-hydroxytryptamine. These functional changes in the pulmonary artery preceded the elevation of right ventricular systolic pressure and right ventricular hypertrophy. The contraction in response to Ca2+ suggests that the pulmonary artery of rats given MCT may be contracted in situ. Vasoconstriction due to these alterations may play an important role in the development of pulmonary hypertension according to this model.
Cigarette smoking and response to inhaled corticosteroids in COPD
Authors: Surya P. Bhatt, Julie A. Anderson, Robert D. Brook, Peter M.A. Calverley, Bartolome R. Celli, Nicholas J. Cowans, Courtney Crim, Fernando J. Martinez, David E. Newby, Jørgen Vestbo, Julie C. Yates, Mark T. Dransfield
Journal: European Respiratory Journal (2018)

Inhaled corticosteroids (ICS) and long-acting β-agonists (LABA) are frequently used in patients with chronic obstructive pulmonary disease (COPD). Combination treatment with ICS/LABA improves lung function and quality of life, and reduces exacerbation frequency compared to treatment with either ICS or LABA alone. Although it is presumed that continued cigarette smoking impairs acute responses to these medications in patients with COPD, there is little direct evidence to support this view. Studies of ICS use in asthma have shown less short-term improvement in lung function and reduced anti-inflammatory effects in active smokers compared to non-smokers [1, 2]. Although similar effects are plausible in COPD, they have not been definitively demonstrated. We hypothesised that former smokers with COPD would have greater short- and long-term changes in lung function, respiratory-related quality of life, and exacerbation risk, in response to ICS than continuing and intermittent smokers. Current smokers have a blunted FEV 1 response and exacerbation reduction with inhaled corticosteroids <http://ow.ly/PBIW30hcISK> Author contributions were as follows. Study design: S.P. Bhatt and M.T. Dransfield. Statistical analyses: J.A. Anderson and N.J. Cowans. Data interpretation: S.P. Bhatt and M.T. Dransfield. Manuscript writing: S.P. Bhatt and M.T. Dransfield. Critical review of the manuscript for important content: all authors.
Screening and Treating UN Peacekeepers to Prevent the Introduction of Artemisinin-Resistant Malaria into Africa
Authors: Stan Houston, Adam Houston
Journal: PLoS Medicine (2015)

Points• The Haitian cholera epidemic provides a tragic demonstration of the potential for United Nations peacekeepers to introduce serious disease into vulnerable populations.• Resistance to artemisinin derivatives, now the global standard therapy for falciparum malaria, has emerged and is spreading in Southeast Asia.• UN peacekeeping troops from Southeast Asia are frequently deployed in sub-Saharan Africa.• These circumstances entail a high risk of introducing artemisinin resistance into the populations most affected by malaria, with potentially disastrous consequences for malaria treatment and control in sub-Saharan Africa.• The UN has a responsibility to prevent such an outcome; selective predeployment screening and treatment of UN peacekeeping troops is feasible and urgently needed.