tbuckley/cabot-search huggingface dataset:
Abstract 1732: Deletion of Fc Receptor Ameliorates Progression of Atherosclerotic Lesions in LDL Receptor Knockout Mice: Protective Role against Vascular Inflammation and Oxidative Stress
Authors: Katsuhiko Sumiyoshi, Kazunori Shimada, Takafumi Iesaki, Tetsuro Miyazaki, Atsumi Kume, Takashi Kiyanagi, Makoto Hiki, Kosuke Fukao, Kuniaki Hirose, Rie Matsumori, Norihiro Tada, Hiroshi Mokuno, Hiroyuki Daida
Journal: Circulation (2008)

Background : Vascular endothelial dysfunction through the production of reactive oxygen species (ROS) plays an important role in the initiation and progression of atherosclerosis. Immunoglobulin Fc receptor (FcR) involves the activation of immune and inflammatory reaction, however, the role of FcR in endothelial function, ROS production, and atherogenesis, has not clearly elucidated. To examine the hypothesis that FcR deletion blunts the progression of atherosclerotic lesions via improvements of superoxide production and endothelial dysfunction, we generated FcR/LDL receptor double-knockout (DKO) mice. Methods : Mice (8 weeks) with LDL receptor knockout (LDLR-KO) and DKO were fed a high cholesterol diet for 10 weeks. We examined the endothelium-dependent relaxation of isolated thoracic aorta, superoxide production by dihydroethidium-derived fluorescence (DHE) staining before and after high cholesterol feeding. We also assessed atherosclerotic lesions by Oil Red O-staining, macrophage infiltration, and p22phox expression by immnohistochemical analysis. Results : Vascular endothelial-dependent relaxation induced by high cholesterol diet was significantly higher in DKO mice than in LDLR-KO mice (−53 ± 7% vs −22 ± 9, p &lt; 0.05). Superoxide production was significantly lower in DKO mice than in LDLR-KO mice (13.6 ± 10 vs 38.8 ± 20 ×10 3 μ m 2 p &lt; 0.05). The expression of p22phox in DKO mice was significantly lower than in LDLR-KO mice (90 ± 19 vs 141 ± 42 × 10 3 μm 2 p &lt; 0.05). The area of macrophage infiltration of the vascular wall was significantly lower in DKO mice than LDLR-KO mice (34 ± 5 vs 59 ± 17 × 10 3 μ m 2 p &lt; 0.05). The Oil -Red O staining showed the significant reduction of atherosclerotic lesions in DKO mice than in LDLR-KO mice (73 ± 24 vs 133 ± 31 × 10 4 μ m 2 p &lt; 0.005). Conclusion : Deletion of FcR attenuated the production of ROS, vascular inflammation, and endothelial dysfunction, resulting in prevention of atherosclerotic formation in LDLR-KO mice. These data suggested that FcR might be involved in atherosclerotic process through not only vascular inflammation, but also oxidative stress in vasculature.
Abstract 13925: Association of Ankle-Brachial Index With Incident Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Wobo Bekwelem, Faye Norby, Sunil K Agarwal, Kunihiro Matsushita, Josef Coresh, Alvaro Alonso, Lin Y Chen
Journal: Circulation (2016)

Introduction: A normal ankle-brachial index (ABI) is defined as 1.0 to 1.4; abnormal ABI is defined as ≤0.90 whereas &gt;0.9 to &lt;1.0 is considered “borderline” and &gt;1.40 indicates noncompressible arteries. Although peripheral arterial disease has been shown to be associated with incident AF, it is unclear whether borderline ABI or noncompressible arteries are associated with incident AF. We aimed to evaluate this association of borderline ABI and ABI &gt;1.4 in the ARIC study, a population-based prospective cohort study. Methods: We included 14,794 participants (age, 54.2 ± 5.8 yrs, 55% women, 26% blacks) who attended the baseline exam (1987-89) and without prevalent AF. Incident AF was identified from hospital discharge records, death certificates, and ECGs. We used Cox proportional hazard models to evaluate the association between ABI categories and incident AF. Results: During a mean follow-up of 19.8 years, there were 2288 incident AF cases. After full adjustment in Model 2, compared with ABI 1.0-1.4, the hazards ratio (HR) (95% CI) of ABI &lt;1.0 for incident AF was 1.13 (1.01-1.27). ABI of &gt;0.9 to &lt;1.0, but not &gt;1.4 was associated with an increased risk of AF (Table). Conclusions: This study is the first to show that borderline ABI is independently associated with AF further supporting that borderline ABI is not benign. Our findings also suggest that detection of preclinical and early clinical atherosclerosis may identify individuals at increased risk of AF.
Regulation of amyloid-β dynamics and pathology by the circadian clock
Authors: Geraldine J. Kress, Fan Liao, Julie Dimitry, Michelle R. Cedeno, Garret A. FitzGerald, David M. Holtzman, Erik S. Musiek
Journal: The Journal of Experimental Medicine (2018)

Nighttime restlessness and daytime drowsiness are common and early symptoms of Alzheimer's Disease (AD). This symptomology implicates dysfunctional biological timing, yet the role of the circadian system in AD pathogenesis is unknown. To evaluate the role of the circadian clock in amyloid-β (Aβ) dynamics and pathology, we used a mouse model of β-amyloidosis and disrupted circadian clock function either globally or locally in the brain via targeted deletion of the core clock gene Bmal1 Our results demonstrate that loss of central circadian rhythms leads to disruption of daily hippocampal interstitial fluid Aβ oscillations and accelerates amyloid plaque accumulation, whereas loss of peripheral Bmal1 in the brain parenchyma increases expression of Apoe and promotes fibrillar plaque deposition. These results provide evidence that both central circadian rhythms and local clock function influence Aβ dynamics and plaque formation and demonstrate mechanisms by which poor circadian hygiene may directly influence AD pathogenesis.
Mammographic density and breast cancer in women from high-risk families.
Authors: Marina Pollán, Isabel Chirivella, Josefa Miranda, Alex Teule, Angel Izquierdo, Judith BalmaÃ±a, Ana Beatriz Sanchez-Heras, Gemma Llort, Virginia Lope, Elena Hernández, María José Juan Fita, Isabel Tena, Luis Robles, Carmen Guillen-Ponce, Pedro Pérez-Segura, Mari Sol Luque-Molina, Susana Hernando Polo, Ignacio Blanco, Joan Brunet, Teresa Ramon y Cajal
Journal: Journal of Clinical Oncology (2014)

1525 Background: Mammographic density (MD) is one of the strongest determinants of breast cancer (BC). In this case-control study, we compared MD in BRCA1/2 mutation carriers and non-carriers from BRCA1/2 mutation-positive families and investigated the association between MD and BC among BRCA1/2mutation carriers per type of mutation and tumor subtype. Methods: The study was carried out in female members of BRCA1 and BRCA2 mutation-positive families followed-up at 16 Spanish Genetic Counseling Units. A total of 1039 women signed the informed consent and answered the questionnaire. Participants´ density was scored retrospectively from available mammograms by a single blinded radiologist using a 5-category scale (<10%, 10-25%, 25-50%, 50-75% and >75%). In cancer cases, mammograms were selected among those taken prior to diagnosis or from the contralateral breast. In controls, the last screening mammogram was evaluated. MD distribution in carriers and non-carriers was compared using ordinal logistic models, and the association between MD and BC in BRCA1/2 mutation carriers was studied using logistic regression. Huber-White robust estimators of variance were used to take into account correlations between family members. A similar multinomial model was used to explore this association by BC subtype. Results: We identified and scored mammograms from 353 BRCA1, 360 BRCA2 mutation carriers and 247 non-carriers. MD was associated with subsequent development BC (OR per category of MD: 1.41; 95%CI: 1.15-1.73, p = 0.001), with no significant differences between BRCA1 and BRCA2 mutation carriers (p = 0.69). However, MD was significantly lower among BRCA2 mutation carriers compared to non-carriers (OR=0.70; p = 0.031). Finally, no statistically significant differences were observed in the association of MD with specific BC subtypes. Conclusions: BRCA1/2 mutation carriers do not present higher MD compared to non-carriers, but our work confirms that MD is also an independent risk factor for BC in this population.
Sleep-disordered Breathing and Cardiovascular Disease
Authors: EYAL SHAHAR, CORALYN W. WHITNEY, SUSAN REDLINE, ELISA T. LEE, ANNE B. NEWMAN, F. JAVIER NIETO, GEORGE T. O'CONNOR, LORI L. BOLAND, JOSEPH E. SCHWARTZ, JONATHAN M. SAMET
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Disordered breathing during sleep is associated with acute, unfavorable effects on cardiovascular physiology, but few studies have examined its postulated association with cardiovascular disease (CVD). We examined the cross-sectional association between sleep- disordered breathing and self-reported CVD in 6,424 free-living individuals who underwent overnight, unattended polysomnography at home. Sleep-disordered breathing was quantified by the apnea–hypopnea index (AHI)—the average number of apneas and hypopneas per hour of sleep. Mild to moderate disordered breathing during sleep was highly prevalent in the sample (median AHI: 4.4; interquartile range: 1.3 to 11.0). A total of 1,023 participants (16%) reported at least one manifestation of CVD (myocardial infarction, angina, coronary revascularization procedure, heart failure, or stroke). The multivariable-adjusted relative odds (95% CI) of prevalent CVD for the second, third, and fourth quartiles of the AHI (versus the first) were 0.98 (0.77–1.24), 1.28 (1.02–1.61), and 1.42 (1.13–1.78), respectively. Sleep-disordered breathing was associated more strongly with self-reported heart failure and stroke than with self-reported coronary heart disease: the relative odds (95% CI) of heart failure, stroke, and coronary heart disease (upper versus lower AHI quartile) were 2.38 (1.22–4.62), 1.58 (1.02– 2.46), and 1.27 (0.99–1.62), respectively. These findings are compatible with modest to moderate effects of sleep-disordered breathing on heterogeneous manifestations of CVD within a range of AHI values that are considered normal or only mildly elevated.
Chronic obstructive pulmonary disease and the risk of 12 cardiovascular diseases: a population-based study using UK primary care data
Authors: Ann D Morgan, Kieran J Rothnie, Krishnan Bhaskaran, Liam Smeeth, Jennifer K Quint
Journal: Thorax (2018)

Risks for cardiovascular diseases (CVDs) other than myocardial infarction and stroke in the general COPD population are not well quantified. We used a matched cohort study design and Cox regression to estimate relative risks for 12 separate CVDs in a large population-based cohort of patients with COPD over a 12-year period. Associations between COPD and individual CVDs were heterogeneous, with the highest relative risks observed for heart failure and diseases of the arterial circulation (in excess of 2.5 for those aged 64–75 years). Relative risks declined with increasing age but for most CVD outcomes remained unchanged over the study period.
STM-01: Phase I EffTox study of aurora A kinase inhibitor alisertib (MLN8237) given in combination with selective VEGFR inhibitor pazopanib for therapy of solid tumors.
Authors: Hiral A. Shah, Sonia Christian, Bilawal Ahmed, Rozina A. Chowdhery, Neeta K. Venepalli, Oana Cristina Danciu, Arkadiusz Z. Dudek
Journal: Journal of Clinical Oncology (2016)

2587 Background: Pazopanib is a multi - kinase inhibitor that inhibits angiogenesis. Alisertib is a highly selective inhibitor of mitotic Aurora A Kinase that has been shown to disrupt chromosome segregation and in turn cell proliferation. At non-toxic concentrations, mitosis targeting agents exhibit antiangiogenic effects. Thus, the combination of these two agents may have a synergistic effect on tumor vasculature. The primary objective of this study is to determine the optimal tolerated dose (OTD) for alisertib and pazopanib, their safety and tolerability. Methods: This phase 1 study evaluated the OTD of alisertib taken orally, twice a day, on D1-7 in combination with pazopanib, taken orally, once a day, continuously in a 21 day cycle. There were a total of 4 dose levels tested, starting with 20 mg of alisertib and 400 mg of pazopanib. Disease response was assessed using the RECIST 1.1 every 2 cycles. Once the OTD was determined, a total of 9 patients were enrolled to assure safety and perform PK analysis. Results: A total of 27 patients received treatment and 18 of these patients had evaluable responses. The median age was 57 years (range 22-79), and approximately 74% of the patients had received at least three prior chemotherapy regimens. Dose limiting toxicities (DLT) occurred in dose level (DL) 2 (grade 3 colonic obstruction), DL 2+ (grade 4 thrombocytopenia and grade 3 mucositis), DL 3 (grade 3 AST/ALT elevation and grade 3 abdominal pain). The OTD was determined to be DL 2: alisertib 20 mg BID and pazopanib 600 mg daily. The most common grade 3 or 4 treatment related adverse events were neutropenia (22%), thrombocytopenia (12%), leukopenia (10%), anemia (10%), and increased AST (10%). Fourteen (78%) patients had stable disease and two (11%) patients had partial response. The median number of cycles was four, median progression free survival was 13.3 weeks (range (weeks); 1.9 -57.9) and median overall survival was not reached. Final PK analysis is ongoing. Conclusions: The combination of alisertib with pazopanib demonstrates manageable safety and early clinical evidence of antitumor activity in patients with advanced malignancies (NCT01639911). Clinical trial information: NCT01639911.
Pain control through selective chemo-axotomy of centrally projecting TRPV1+ sensory neurons
Authors: Matthew R. Sapio, John K. Neubert, Danielle M. LaPaglia, Dragan Maric, Jason M. Keller, Stephen J. Raithel, Eric L. Rohrs, Ethan M. Anderson, John A. Butman, Robert M. Caudle, Dorothy C. Brown, John D. Heiss, Andrew J. Mannes, Michael J. Iadarola
Journal: Journal of Clinical Investigation (2018)

Agonists of the vanilloid receptor transient vanilloid potential 1 (TRPV1) are emerging as highly efficacious nonopioid analgesics in preclinical studies. These drugs selectively lesion TRPV1+ primary sensory afferents, which are responsible for the transmission of many noxious stimulus modalities. Resiniferatoxin (RTX) is a very potent and selective TRPV1 agonist and is a promising candidate for treating many types of pain. Recent work establishing intrathecal application of RTX for the treatment of pain resulting from advanced cancer has demonstrated profound analgesia in client-owned dogs with osteosarcoma. The present study uses transcriptomics and histochemistry to examine the molecular mechanism of RTX action in rats, in clinical canine subjects, and in 1 human subject with advanced cancer treated for pain using intrathecal RTX. In all 3 species, we observe a strong analgesic action, yet this was accompanied by limited transcriptional alterations at the level of the dorsal root ganglion. Functional and neuroanatomical studies demonstrated that intrathecal RTX largely spares susceptible neuronal perikarya, which remain active peripherally but unable to transmit signals to the spinal cord. The results demonstrate that central chemo-axotomy of the TRPV1+ afferents underlies RTX analgesia and refine the neurobiology underlying effective clinical use of TRPV1 agonists for pain control.
Abstract 17000: Human Embryonic Stem Cell-Derived Cardiac Tissue Patch with Advanced Structure and Function
Authors: donghui zhang, Jason Lam, Brian Liau, Ralph Snodgrass, Nenad Bursac
Journal: Circulation (2012)

Human pluripotent stem cells are promising source for cell therapies and drug screening. We explored how seeding purity of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) affects functi...
Dual-Switch CAR-T Cells: Orthogonal Molecular Switches to Control Activation and Elimination of CAR-T Cells to Target CD123+ Cancer
Authors: J. Henri Bayle, MyLinh T Duong, An Lu, Eva Morschl, Matthew R. Collinson-Pautz, Kelly L Sharp, Slawomir Szymanski, Mary E. Brandt, Kevin M. Slawin, Steven Toler, Eric Yvon, Aaron Foster, David M. Spencer
Journal: Blood (2017)
Government is not doing enough to improve children’s health, paediatricians warn
Authors: Abi Rimmer
Journal: BMJ (2018)

“Ineffective” and “short term” government strategies are failing to improve the health of children, the Royal College of Paediatrics and Child Health (RCPCH) has said.

In a report last year on the state of child health in the UK,1 the college said that that the disparity between the health of children in the UK compared with the rest of Europe was a major cause for concern and made a number of recommendations for government.

In a review of the progress made since …
ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Cell surface receptors and associated signaling pathways)
Authors: J. Aguilar-Company, M. Fernández-Ruiz, R. García-Campelo, A.C. Garrido-Castro, I. Ruiz-Camps
Journal: Clinical Microbiology and Infection (2018)
Response to: ‘Association between bisphosphonate use and risk of undergoing knee replacement in osteoarthritis patients’ by Chen <i>et al</i>
Authors: Tuhina Neogi, Shanshan Sheehy, Christine Peloquin, Devyani Misra, Yuqing Zhang
Journal: Annals of the Rheumatic Diseases (2018)

We thank Dr Chen and colleagues for their interest in our paper.1 As outlined in our paper,2 the definition of knee osteoarthritis (OA) was based on diagnosis by the patient’s general practitioner (GP), which is recorded as a read code in The Health Improvement Network (THIN). Because these are patients who are being …
Abordaje endoscópico de la fístula biliar postquirúrgica en un hospital de tercer nivel. Análisis retrospectivo de 27 casos (2015 – 2017)
Authors: E Tenorio González, D Marín García, L Vázquez Pedreño, M Jiménez Pérez
Journal: Endoscopy (2017)

Las fístulas biliares postoperatorias se desarrollan habitualmente en los primeros 7 días tras intervención. Se deben habitualmente a variantes anatómicas que dificultan su identificación y correcta disección intraquirúrgica y, en el trasplante hepático, a fenómenos de tensión e isquemia a nivel de sutura anastomótica.
Differential effects of 4HPR on gene expression and apoptosis in normal and malignant cells of the head and neck despite induction of reactive oxygen species in both cell types
Authors: Humam Kadara, Hyun Jung Kim, Eiji Tahara, Dafna Lotan, Reuben Lotan
Journal: Cancer Research (2008)

2282A   N-(4-hydroxyphenyl)retinamide (4HPR; fenretinide), a synthetic retinoid with lower toxicity than natural retinoids, has demonstrated potential as a chemopreventive and therapeutic agent in vitro and in vivo as well as in few clinical trials (e.g., prevention of oral premalignancy and therapy of neuroblastoma). The ability of 4HPR to enhance production of reactive oxygen species (ROS) leading to apoptosis has been suggested as a possible mechanism underlying these effects. Elucidation of the mechanisms underlying sensitivity and resistance to 4HPR should help to optimize its use for cancer chemoprevention and therapy. Therefore, we compared and contrasted 4HPR’s effects on human head and neck squamous cell carcinoma (HNSCC) UMSCC-22B cells and normal human gingival keratinocytes (NHGK). 4HPR induced rapidly ROS generation in both UMSCC-22B HNSCC and NHGK cells, however apoptosis evidenced by PARP cleavage following a 24 h exposure to 4HPR was only observed in UMSCC-22B cells. Oligonucleotide microarray analysis using Affymetrix U133A chips revealed sets of genes modulated by 4HPR distinctly in each cell type and up-regulation of genes encoding the pro-survival cellular chaperones and heat shock proteins (HSPs) 10, 40, 60, 70B, 105, and crystallin alphaB in the NHGK cells. In addition, exposure to 4HPR for one hour increased phosphorylated levels of inhibitor of kappaB (IκB) in the UMSCC-22B cells, and decreased total protein levels of both p65/nuclear factor kappa B (NFκB) and total and phosphorylated levels of IκB in NHGK cells indicative of opposite effects of 4HPR on NF-κB signaling in malignant relative to normal head and neck cells. We have previously shown that 4HPR induces sustained activation of c-Jun N-Terminal Kinase (JNK) important for subsequent apoptosis induction as well as X-Box Binding Protein 1 (XBP-1) splicing indicative of Endoplasmic Reticulum (ER) stress. Treatment of UMSCC-22B cells with 4HPR for 24 h induced JNK phosphorylation as well as XBP-1 splicing concurrently with PARP-1 cleavage. These effects by 4HPR were inhibited by co-treatment of UMSCC-22B cells with the antioxidant BHA and were not observed in similarly treated NHGK cells. These results demonstrate that 4HPR induces apoptosis selectively in cancer cells while sparing normal cells and warrants further testing of this synthetic retinoid in HNSCC therapy clinical trials. Supported in part by Head and Neck Cancer SPORE grant P50 CA97007 and Cancer Center Core Grant P30 CA16672 from the NCI.
Gemcitabine, Dexamethasone, and Cisplatin (GDP) Is An Effective and Well-Tolerated out-Patient Salvage Therapy for Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) and Hodgkin Lymphoma (HL)
Authors: Alden A. Moccia, Felicitas Hitz, Paul Hoskins, Richard Klasa, Maryse Power, Kerry J. Savage, Tamara Shenkier, John Shepherd, Brian Skinnider, Graham W. Slack, Kevin Song, Randy D. Gascoyne, Joseph M. Connors, Laurie Sehn
Journal: Blood (2010)
Inflammatory Gene Polymorphisms in Lung Cancer Susceptibility
Authors: Keith D. Eaton, Perrin E. Romine, Gary E. Goodman, Mark D. Thornquist, Matt J. Barnett, Effie W. Petersdorf
Journal: Journal of Thoracic Oncology (2018)

IntroductionChronic inflammation has been implicated in carcinogenesis, with increasing evidence of its role in lung cancer. We aimed to evaluate the role of genetic polymorphisms in inflammation-related genes in the risk for development of lung cancer.MethodsA nested case-control study design was used, and 625 cases and 625 well-matched controls were selected from participants in the β-Carotene and Retinol Efficacy Trial, which is a large, prospective lung cancer chemoprevention trial. The association between lung cancer incidence and survival and 23 polymorphisms descriptive of 11 inflammation-related genes (interferon gamma gene [IFNG], interleukin 10 gene [IL10], interleukin 1 alpha gene [IL1A], interleukin 1 beta gene [IL1B], interleukin 2 gene [IL2], interleukin 4 receptor gene [IL4R], interleukin 4 gene [IL4], interleukin 6 gene [IL6], prostaglandin-endoperoxide synthase 2 gene [PTGS2] (also known as COX2), transforming growth factor beta 1 gene [TGFB1], and tumor necrosis factor alpha gene [TNFA]) was evaluated.ResultsOf the 23 polymorphisms, two were associated with risk for lung cancer. Compared with individuals with the wild-type (CC) variant, individuals carrying the minor allele variants of the IL-1β-511C>T promoter polymorphism (rs16944) (CT and TT) had decreased odds of lung cancer (OR = 0.74, [95% confidence interval (CI): 0.58–0.94] and OR = 0.71 [95% CI: 0.50–1.01], respectively, p = 0.03). Similar results were observed for the IL-1β-1464 C>G promoter polymorphism (rs1143623), with presence of the minor variants CG and CC having decreased odds of lung cancer (OR = 0.75 [95% CI: 0.59–0.95] and OR = 0.69 [95% CI: 0.46–1.03], respectively, p = 0.03). Survival was not influenced by genotype.ConclusionsThis study provides further evidence that IL1B promoter polymorphisms may modulate the risk for development of lung cancer.
Early Mortality in Patients Undergoing Adjuvant Chemotherapy for Non–Small Cell Lung Cancer
Authors: Daniel Morgensztern, Pamela S. Samson, Saiama N. Waqar, Siddhartha Devarakonda, Clifford G. Robinson, Ramaswamy Govindan, Varun Puri
Journal: Journal of Thoracic Oncology (2018)
High Rates of Atherosclerotic Disease-Related Mortality in Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia Patients Associated with TET2-Mutations
Authors: Remco J Molenaar, Tomas Radivoyevitch, Mikkael A. Sekeres, Sudipto Mukherjee, Jaroslaw P. Maciejewski
Journal: Blood (2017)