tbuckley/cabot-search huggingface dataset:
Abstract 893: Hyperthermia regulates both SLC22A16 expression and ABCG2 expression via ROS production to enhance the cytotoxicity of doxorubicin
Authors: Hirofumi Matsui
Journal: Cancer Research (2018)

Abstract Introduction: Hyperthermia (HT) is a non-invasive cancer therapy. Treatment temperature between 41°C to 44°C has no cytotoxic damage in normal cells, however shows cytotoxicity in cancer cells because of the underdeveloped vascular system. HT often used with other cancer therapy such as radiation therapy and chemotherapy. However mechanism of synergistic effect using these therapies remains unclear. Compared to 37°C, 42°C is mild heat stress for cells, thus superoxide anion is released from tissue. Superoxide anion is produced by mitochondrial electron transport chain. Reactive oxygen species (ROS), produced by mild heat stress, can be released from mitochondria. We have previously reported that ATP-binding cassette sub-family G member 2 (ABCG2) expression was suppressed by increasing mitochondrial ROS, andinduction of the cancer specific porphyrin accumulation. ABCG2 is a transporter of doxorubicin (DOX), therefore we hypothesized that synergistic effect of HT and chemotherapy would be induced by down-regulation of ABCG2 expression via intracellular ROS increase. In this study, we investigated if cytotoxic effect of breast cancer cell using DOX can be enhance by HT via intracellular ROS increase. Materials and methods: The murine breast cancer cell line, 4T1E was incubated at 37°C or 42°C for 1h. Intracellular ROS generation after HT treatment was detected by electron spin resonance (ESR). Twenty four hours after HT treatment, cells were incubated in medium containing 0, 0.1 and 1 μM DOX for 24 h. Cell viability was measured using the Cell Counting Kit 8, a water-soluble tetrazolium-8 based colorimetric assay. ABCG2 expression in whole cells was analyzed by Western blotting. Results and discussion: ESR signal peak with HT treatment became high as compared to without HT treatment, indicating intracellular ROS level was increased by HT treatment. Cell viability and ABCG2 expression were decreased by DOX exposure and by HT treatment. The enhancement of HT treatment effect by DOX is considered to be result of down-regulation of ABCG2 expression by ROS. Conclusion: HT treatment involved intracellular ROS production and down-regulated the expression of ABCG2 protein. HT treatment also enhanced the cell damage by DOX. Citation Format: Hirofumi Matsui. Hyperthermia regulates both SLC22A16 expression and ABCG2 expression via ROS production to enhance the cytotoxicity of doxorubicin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 893.
Toxoplasma Parasite Twisting Motion Mechanically Induces Host Cell Membrane Fission to Complete Invasion within a Protective Vacuole
Authors: Georgios Pavlou, Mateusz Biesaga, Bastien Touquet, Vanessa Lagal, Martial Balland, Alexandre Dufour, Mohamed-ali Hakimi, Isabelle Tardieux
Journal: Cell Host & Microbe (2018)
Abstract 13734: Human Atrial Fibrillation is Initiated by Repolarization Alternans and the Formation of a Predominant Spiral Wave
Authors: Gautam G Lalani, Amir Schricker, Hiro Kawata, David E Krummen, Sanjiv M Narayan
Journal: Circulation (2012)

HYPOTHESIS:  To determine whether triggers initiate human atrial fibrillation (AF) by causing beat-to-beat oscillations (alternans) of action potential duration (APD) leading to the formation of a spiral wave or focal source that drives the atrium into AF.   BACKGROUND:  Recent studies have discovered that human atrial fibrillation may be initiated then maintained by localized spiral waves (rotors). Additionally, abnormalities in human atrial repolarization (action potential duration, APD alternans) have been identified as dynamic substrates for AF initiation.   METHODS:  In 19 patients with AF (n=5 persistent; age 62+10; LA diameter 42+6 mm) at EP study, we recorded atrial activation via 64-electrode basket catheters in the right and left atrium during AF induction by pacing from cycle lengths (CL) accelerating from 600-500ms (100-120bpm). Monophasic action potentials were used to quantify APD alternans continuously during induction. We studied activation patterns preceding and at the precise point of AF initiation in relation to APD dynamics.   RESULTS:  Slow rate pacing activated the atria uniformly (figure A, evenly spaced activation contours in left atrium). After rapid triggers, the onset of human AF was heralded by the formation of one predominant spiral wave in 16/19 patients, lying in the left (n=10, figure C) and right (n=6) atria. APD alternans arose and increased in magnitude in 16/19 patients prior to AF initiation, and in 13/16 patients in whom AF initiated by the formation of a spiral wave (p   CONCLUSIONS:  Human atrial fibrillation initiates by the formation of a predominant spiral wave (rotor) in the context of marked repolarization dispersion from APD alternans. Future studies should examine whether interventions to attenuate atrial repolarization alternans may suppress the milieu for human AF initiation.
High-accuracy determination of internal circadian time from a single blood sample
Authors: Nicole Wittenbrink, Bharath Ananthasubramaniam, Mirjam Münch, Barbara Koller, Bert Maier, Charlotte Weschke, Frederik Bes, Jan de Zeeuw, Claudia Nowozin, Amely Wahnschaffe, Sophia Wisniewski, Mandy Zaleska, Osnat Bartok, Reut Ashwal-Fluss, Hedwig Lammert, Hanspeter Herzel, Michael Hummel, Sebastian Kadener, Dieter Kunz, Achim Kramer
Journal: Journal of Clinical Investigation (2018)

BACKGROUND. The circadian clock is a fundamental and pervasive biological program that coordinates 24-hour rhythms in physiology, metabolism, and behavior, and it is essential to health. Whereas therapy adapted to time of day is increasingly reported to be highly successful, it needs to be personalized, since internal circadian time is different for each individual. In addition, internal time is not a stable trait, but is influenced by many factors, including genetic predisposition, age, sex, environmental light levels, and season. An easy and convenient diagnostic tool is currently missing.
The relative invasive disease potential of Streptococcus pneumoniae among children after PCV introduction: A systematic review and meta-analysis
Authors: Evelyn Balsells, Ron Dagan, Inci Yildirim, Prabhu P. Gounder, Anneke Steens, Carmen Muñoz-Almagro, Chiara Mameli, Rama Kandasamy, Noga Givon Lavi, Laura Daprai, Arie van der Ende, Krzysztof Trzciński, Susan A. Nzenze, Susan Meiring, Dona Foster, Lisa R. Bulkow, Karen Rudolph, Ana Valero-Rello, Struan Ducker, Didrik Frimann Vestrheim, Anne von Gottberg, Stephen I. Pelton, GianVincenzo Zuccotti, Andrew J. Pollard, Elisabeth A.M. Sanders, Harry Campbell, Shabir A. Madhi, Harish Nair, Moe H. Kyaw
Journal: Journal of Infection (2018)
Pan-Cancer Metabolic Signature Predicts Co-Dependency on Glutaminase and De Novo Glutathione Synthesis Linked to a High-Mesenchymal Cell State
Authors: Anneleen Daemen, Bonnie Liu, Kyung Song, Mandy Kwong, Min Gao, Rebecca Hong, Michelle Nannini, David Peterson, Bianca M. Liederer, Cecile de la Cruz, Dewakar Sangaraju, Allan Jaochico, Xiaofeng Zhao, Wendy Sandoval, Thomas Hunsaker, Ron Firestein, Sheerin Latham, Deepak Sampath, Marie Evangelista, Georgia Hatzivassiliou
Journal: Cell Metabolism (2018)
Recurrent group A <i>Streptococcus</i> tonsillitis is an immunosusceptibility disease involving antibody deficiency and aberrant T <sub>FH</sub> cells
Authors: Jennifer M. Dan, Colin Havenar-Daughton, Kayla Kendric, Rita Al-kolla, Kirti Kaushik, Sandy L. Rosales, Ericka L. Anderson, Christopher N. LaRock, Pandurangan Vijayanand, Grégory Seumois, David Layfield, Ramsey I. Cutress, Christian H. Ottensmeier, Cecilia S. Lindestam Arlehamn, Alessandro Sette, Victor Nizet, Marcella Bothwell, Matthew Brigger, Shane Crotty
Journal: Science Translational Medicine (2019)

Recurrent tonsillitis is a multifactorial disease associated with an aberrant tonsillar germinal center response to group A Streptococcus .
Age and Treatment of Nonmelanoma Skin Cancer
Authors: Daniel Christopher Grove
Journal: JAMA Surgery (2018)

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Fibrin films: overlooked hemostatic barriers against microbial infiltration
Authors: Sean X. Gu, Steven R. Lentz
Journal: Journal of Clinical Investigation (2018)

The hemostatic response to vascular injury culminates in a fibrin clot network that forms an initial barrier to blood loss and also contributes to microbial host defense. Fibrinogen is cleaved by thrombin into fibrin monomers that spontaneously polymerize into protofibrils and form the extensive fiber networks characteristic of blood clots. In this issue of the JCI, Macrae and colleagues characterize an alternative fibrin structure in which fibrinogen and fibrin assemble into a continuous 2D film at the exterior face of the fibrin clot network. Fibrin films connect to the underlying fiber network through tethering fibers and provide a protective barrier to microbial infiltration. These findings shed new light on a previously overlooked mechanism of fibrin assembly at the clot surface and provide a link between hemostasis and innate immunity.
Abstract 9847: Glomerular Filtration Rate in Pediatric Heart Transplant Recipients Can be Measured During Routine Catheterization and is Best Estimated by the Full CKiD Formula
Authors: Kimberly Y Lin, Robert E Shaddy, George Schwartz, Susan L Furth, Rebecca L Ruebner
Journal: Circulation (2012)

Identification of chronic kidney disease (CKD) after pediatric heart transplantation (PHT) is limited by inaccuracies in creatinine-based estimates of glomerular filtration rate (GFR); iohexol plasma clearance is a proven method of measuring GFR. We hypothesized that GFR can be measured by a modified iohexol clearance protocol during routine coronary angiography in PHT recipients, and that the recently developed CKiD GFR estimating formula, utilizing serum creatinine and cystatin C, provides a better estimate of GFR than creatinine or cystatin equations alone. We performed a cross-sectional study of PHT recipients, ages 2-18 yrs, undergoing surveillance coronary angiography. GFR was measured by obtaining iohexol levels at 2, 4, and 5 hours post-iohexol infusion for angiography, then calculating area under the curve of iohexol disappearance from plasma. Agreement between measured GFR and multiple GFR estimating equations was assessed with Bland Altman plots, correlation, and % of estimates within +/- 10 and 30% of measured GFR. Of 40 enrolled subjects, 31 had complete GFR data. Median age was 15.0 yrs [IQR 7.6, 16.6], time since HT was 5.9 yrs [2.0, 10.8], height %ile was 26 (7, 48), serum creatinine was 0.7 (0.5, 0.8) mg/dL, cystatin C was 0.83 (0.72, 0.91) mg/L, and measured GFR was 89.5 (78.7-107.0) ml/min/1.73m 2 (mean 93.8, SD22.5). A comparison of measured GFR to estimated GFR is shown in Table 1; the full CKiD formula showed best agreement with measured GFR. Conclusions: 1. We describe a novel modified iohexol plasma clearance method to measure GFR in PHT recipients undergoing coronary angiography. 2. Measured median GFR in this cohort is 89.5 ml/min/1.73m2, suggesting early CKD. 3. The full CKiD formula performs best with respect to bias, accuracy, and correlation.
Abstract 916: Klotho-protein Regulates Transient Receptor Potential Canonical-1-mediated Ca(2+)-influx In Endothelial Cells And Prevents Cell Death And Disruption Of Endothelial Integrity Induced By Ca(2+)-overload
Authors: Mitsuhiko Okigaki, Tetsurou Kusaba, Shoken Honsho, Akihiro Matsui, Shinsaku Matsunaga, Asako Katsume, Eigo Kishita, Hiroaki Matsubara
Journal: Circulation (2007)

Introduction Klotho-deficient mice have extensive vascular calcification. However, the mechanism involved has not been elucidated. We analyzed the endothelial cells of Klotho-deficient mice (Klotho-ECs) and found a novel functional role for the Klotho-protein in the maintenance of vascular homeostasis. Methods and Results Primary-cultured endothelial cells from the aorta of wild-type- (WT) and Klotho- deficient mice were loaded with fura-2 and stimulated with VEGF. In WT-ECs, intracellular Ca(2+) concentration ([Ca(2+)]i) elevated to the peak level, and it decreased to the basal level in +5 minutes. Whereas, in Klotho-ECs, after similar peak level to WT-ECs, the elevation of [Ca(2+)]i was sustained at ~35% of the peak level for more than 10 minutes. In Ca(2+) free medium, this sustained elevation was abolished. Immunostaining revealed that, in Klotho-ECs, VEGF-induced co-internalization of the Ca(2+) channel; TRPC-1, with VEGF-receptor-2 (VEGFR-2) was abolished, thereby, at 30 minutes after VEGF-stimulation, expression levels of TRPC-1 in the plasmamembrane was 2.2-fold higher than in WT-ECs. Klotho-protein constitutively bound to VEGFR-2 and TRPC-1, strengthened their association, and promoted their co-internalization. VEGF-induced activation of Rac-1 and reorganization of F-actin, which are involved in internalization, were impaired in Klotho-ECs, and restored by the replacement of Klotho-protein. VEGF-induced phosphorylation of VEGFR-2 and its downstream signaling molecules, including Src, Akt, PLCγ, and Caveolin1, was attenuated. As the biological consequence of sustained increase in [Ca(2+)]i, activation of calpain and caspase-3 followed by apoptosis was promoted in Klotho-ECs in vivo and vitro. Also, expression of VE-cadherin in the plasmamembrane was reduced and intimal hyperpermeability was observed in the aorta of Klotho-deficient mice, which presumably lead to exudation of the Ca(2+)/phosphor -rich serum into the vessel walls, followed by extensive vascular calcification. Conclusion Thus, Klotho-protein regulates ligand-induced Ca(2+) influx and subsequent biological functions involved in vascular calcification.
Abstract 17281: Deep Venous Thrombosis is Associated With Poor Outcomes in Patients With Heart Failure With Preserved Ejection Fraction: Study From National Inpatient Database
Authors: Vidhu Anand, Sushil Kumar Garg, Shah Bano, Ryan Koene, Thenappan Thenappan
Journal: Circulation (2016)

Background:  Heart failure with reduced ejection fraction is a major and independent risk factor of venous thromboembolism (VTE). However, very little is known about the association between VTE and Heart Failure with Preserved Ejection Fraction (HFpEF). We examined the prevalence and effects of acute VTE in patients hospitalized with HFpEF.   Methods:  We performed a cross-sectional analysis using data collected from the Nationwide Inpatient Sample, 2013. ICD-9 codes were used to identify patients with HFpEF (ICD-9: 428.3), DVT (453.40-42, 453.82-89) and PE (415.1). Our primary outcomes were odds of acute VTE and its effects on inpatient mortality and length of stay. We used multivariable logistic regression to determine risk factors that affect mortality and linear regression to evaluate the effects of acute VTE on predicted length of stay (LOS). Data is presented as odds ratio (OR) with 95% confidence interval (CI) for categorical variables and mean difference (MD) with standard error (SEM) for continuous variables.   Results:  An analysis of nearly 6 million hospitalizations identified 1.26 million patients with HFpEF. Patients with HFpEF had increased odds of acute VTE compared to the hospitalized patients without HFpEF [OR, 1.4; 95% CI (1.36 - 1.43), p    Conclusions:  HFpEF is associated with an increased risk of acute VTE in hospitalized patients. The presence of acute VTE is associated with greater mortality and LOS in hospitalized patients with HFpEF. This highlights the importance of prophylactic anticoagulation in patients hospitalized with HFpEF.
Doctors call for cap on GP workload
Authors: Abi Rimmer
Journal: BMJ (2018)

A limit must be set on the amount of work GPs can do in a day, doctors have argued.

Delegates at the BMA annual representative meeting in Brighton on 26 June voted for the agreement of a sensible cap “on the workload of a GP which can be expected to be safely delivered in a day.”

Satish Narang, a GP who proposed the motion, said, “For the sake of quality and safety of patient care, and the sanity …
Abstract 2809: Knockout of Ca/Calmodulin Kinase IIδ Protects Against ROS-induced Injury
Authors: Stefan Wagner, Sarah Bellmann, Tim Peters, Samuel Sossalla, Tim Seidler, Johannes Backs, Lars S Maier
Journal: Circulation (2009)

Expression and activity of Ca/calmodulin kinase II (CaMKII) are enhanced in heart failure (HF) and linked to disease progression involving increased late Na current (INa). Reactive oxygen species (ROS) generated in HF can increase late INa leading to cytosolic Na and Ca overload, arrhythmias and cell death. We tested whether ROS-activated CaMKII δ  is involved, since it is known that ROS directly activate CaMKII via oxidation at methionine residues. We exposed ventricular myocytes isolated from CaMKII δ -knockout mice (CKO, wildtype (WT) as control) to ROS generated via 200  μ M H2O2. The H2O2-induced increase of late INa was almost completely abolished in myocytes lacking CaMKII δ  (fig 1A). Moreover, in CKO-myocytes the blunted H2O2-induced Na influx via late INa resulted in a significantly slower increase of [Na]i compared to WT (fig 1B, 10  μ M SBFI-AM, ANOVA, *P μ M Indo-1-AM, ANOVA, *P μ M, fig 1C, †P δ  is a prerequisite for ROS-induced increase of late INa, [Na]i and [Ca]i accumulation. Moreover, myocytes lacking CaMKII δ  are protected from severe arrhythmias and cell death. Therefore, strategies targeted at CaMKII may be promising for the treatment of HF.
Development of a simple score based on HBeAg and ALT for selecting patients for HBV treatment in Africa
Authors: Yusuke Shimakawa, Ramou Njie, Gibril Ndow, Muriel Vray, Papa Saliou Mbaye, Philippe Bonnard, Roger Sombié, Jean Nana, Vincent Leroy, Julie Bottero, Patrick Ingiliz, Gerrit Post, Bakary Sanneh, Ignatius Baldeh, Penda Suso, Amie Ceesay, Adam Jeng, Harr Freeya Njai, Shevanthi Nayagam, Umberto D'Alessandro, Isabelle Chemin, Maimuna Mendy, Mark Thursz, Maud Lemoine
Journal: Journal of Hepatology (2018)

<h3>Background & Aims</h3> To eliminate hepatitis B virus (HBV) infection, it is essential to scale up antiviral treatment through decentralized services. However, access to the conventional tools to assess treatment eligibility (liver biopsy/Fibroscan®/HBV DNA) is limited and not affordable in resource-limited countries. We developed and validated a simple score to easily identify patients in need of HBV treatment in Africa. <h3>Methods</h3> As a reference, we used treatment eligibility determined by the European Association for the Study of the Liver based on alanine aminotransferase (ALT), liver histology and/or Fibroscan and HBV DNA. We derived a score indicating treatment eligibility by a stepwise logistic regression using a cohort of chronic HBV infection in The Gambia (n = 804). We subsequently validated the score in an external cohort of HBV-infected Africans from Senegal, Burkina Faso, and Europe (n = 327). <h3>Results</h3> Out of several parameters, two remained in the final model, namely HBV e antigen (HBeAg) and ALT level, constituting a simple score (treatment eligibility in Africa for the hepatitis B virus: TREAT-B). The score demonstrated a high area under the receiver operating characteristic curve (0.85, 95% CI 0.79–0.91) in the validation set. The score of 2 and above (HBeAg-positive and ALT ≥20 U/L or HBeAg-negative and ALT ≥40 U/L) had a sensitivity and specificity for treatment eligibility of 85% and 77%, respectively. The sensitivity and specificity of the World Health Organization criteria based on the aspartate aminotransferase-to-platelet ratio index (APRI) and ALT were 90% and 40%, respectively. <h3>Conclusions</h3> A simple score based on HBeAg and ALT had a high diagnostic accuracy for the selection of patients for HBV treatment. This score could be useful in African settings. <h3>Lay summary</h3> Limited access to the diagnostic tools used to assess treatment eligibility (liver biopsy/Fibroscan/hepatitis B virus DNA) has been an obstacle to the scale up of hepatitis B treatment programs in low- and middle-income countries. Using the data from African patients with chronic HBV infection, we developed and validated a new simple diagnostic score for treatment eligibility, which only consists of hepatitis B virus e antigen and alanine aminotransferase level. The diagnostic accuracy of the score for selecting patients for HBV treatment was high and could be useful in African settings.
Macropinocytosis Fuels Prostate Cancer
Authors: Cosimo Commisso, Jayanta Debnath
Journal: Cancer Discovery (2018)

Abstract Summary: Kim and colleagues identify necrotic debris as a macropinocytic cargo in PTEN-deficient prostate cancer cells, which is catabolized to generate the nutrients and biomass necessary to support tumor cell growth and metabolism in nutrient-limiting conditions. Cancer Discov; 8(7); 800–2. ©2018 AACR. See related article by Kim et al., p. 866.