tbuckley/cabot-search huggingface dataset:
Lapatinib or trastuzumab? Which anti-HER2 treatment is more effective in the treatment of patients with HER2-positive breast cancer with brain metastases? An Anatolian Society of Medical Oncology Study.
Authors: Muhammet Ali Kaplan, Abdurrahman Isikdogan, Dogan Koca, Mehmet Kucukoner, Ozge Gumusay, Ramazan Yildiz, Ilhan Oztop, Lutfiye Demir, Caglayan Geredeli, Murat Kocer, Ülkü Yalçintas Arslan, Ali Inal, Ugur Coskun, Nur Sener, Mevlude Inanc, Emin Tamer Elkiran, Nuriye Ozdemir, Ayse Gok Durnali, Ali Suner, Suleyman Alici
Journal: Journal of Clinical Oncology (2012)

638 Background: In the present study, we investigate that which treatment choice is more effective in the human epidermal growth factor receptor 2 (HER2) positive breast cancer patients with brain metastases. Methods: Of 405 metastatic breast cancer patients with brain metastases at referral centers in Turkey, 111 patients treated with lapatinib or trastuzumab after brain metastases eligible for the analyses were identified. Patients received both drugs consecutively or sequentially were excluded from the study. Results: Median age was 44 years (27-76) and 46 of the 111 patients (41.5%) had received lapatinib. Median time to development of brain metastases was 12.2 months (0-71). Sixteen patients (14.4%) had undergone surgery, 33 (29.7%) radiosurgery, and 108 (97.2%) whole brain radiation therapy (WBRT). Median overall survival (OS) after brain metastases was 15 months(95% confidence interval (CI): 12.3-17.6). Lapatinib usage was prolonged OS over trastuzumab alone (19.1 months vs 12 months, p=0.039).Other parameters affecting the survival were Karnofsky performance score (KPS, &gt;70), number of brain metastases (&gt;3), extracranial metastases (≥2), performed neurosurgery, and received radiosurgery. After correction for potential confounders, lapatinib therapy remained an independent positive predictor for survival [Odds ratio (OR), 0.57; p=0.02). Conclusions: Although this retrospective multi-center study had several limitations, study results suggest that the usage of lapatinib after brain metastases prolonged survival compared to the usage of trastuzumab. This result should be support with prospective studies.
Derivation and Validation of a Serum Biomarker Panel to Identify Infants With Acute Intracranial Hemorrhage
Authors: Rachel Pardes Berger, Brian J. Pak, Mariya D. Kolesnikova, Janet Fromkin, Richard Saladino, Bruce E. Herman, Mary Clyde Pierce, David Englert, Paul T. Smith, Patrick M. Kochanek
Journal: JAMA Pediatrics (2017)

Abusive head trauma is the leading cause of death from physical abuse. Missing the diagnosis of abusive head trauma, particularly in its mild form, is common and contributes to increased morbidity and mortality. Serum biomarkers may have potential as quantitative point-of-care screening tools to alert physicians to the possibility of intracranial hemorrhage.To identify and validate a set of biomarkers that could be the basis of a multivariable model to identify intracranial hemorrhage in well-appearing infants using the Ziplex System.Binary logistic regression was used to develop a multivariable model incorporating 3 serum biomarkers (matrix metallopeptidase-9, neuron-specific enolase, and vascular cellular adhesion molecule-1) and 1 clinical variable (total hemoglobin). The model was then prospectively validated. Multiplex biomarker measurements were performed using Flow-Thru microarray technology on the Ziplex System, which has potential as a point-of-care system. The model was tested at 3 pediatric emergency departments in level I pediatric trauma centers (Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Primary Children's Hospital, Salt Lake City, Utah; and Lurie Children's Hospital, Chicago, Illinois) among well-appearing infants who presented for care owing to symptoms that placed them at increased risk of abusive head trauma. The study took place from November 2006 to April 2014 at Children's Hospital of Pittsburgh, June 2010 to August 2013 at Primary Children's Hospital, and January 2011 to August 2013 at Lurie Children's Hospital.A mathematical model that can predict acute intracranial hemorrhage in infants at increased risk of abusive head trauma.The multivariable model, Biomarkers for Infant Brain Injury Score, was applied prospectively to 599 patients. The mean (SD) age was 4.7 (3.1) months. Fifty-two percent were boys, 78% were white, and 8% were Hispanic. At a cutoff of 0.182, the model was 89.3% sensitive (95% CI, 87.7-90.4) and 48.0% specific (95% CI, 47.3-48.9) for acute intracranial hemorrhage. Positive and negative predictive values were 21.3% and 95.6%, respectively. The model was neither sensitive nor specific for atraumatic brain abnormalities, isolated skull fractures, or chronic intracranial hemorrhage.The Biomarkers for Infant Brain Injury Score, a multivariable model using 3 serum biomarker concentrations and serum hemoglobin, can identify infants with acute intracranial hemorrhage. Accurate and timely identification of intracranial hemorrhage in infants without a history of trauma in whom trauma may not be part of the differential diagnosis has the potential to decrease morbidity and mortality from abusive head trauma.
TCTAP C-269 Transseptal Approach for Aortic Balloon Valvuloplasty in Newborn with Critical Aortic Stenosis
Authors: Igor V. Buzaev, Vladimir V. Plechev, Irina E. Nikolaeva, Dmitry V. Onegov, Artur R. Sharafutdinov, Gulchachak A. Halikova, Bogdan Aleksandrovich Oleynik, Rezida Galimova
Journal: Journal of the American College of Cardiology (2017)
Western Diet Deregulates Bile Acid Homeostasis, Cell Proliferation, and Tumorigenesis in Colon
Authors: Denis Dermadi, Satu Valo, Saara Ollila, Rabah Soliymani, Nina Sipari, Marjaana Pussila, Laura Sarantaus, Jere Linden, Marc Baumann, Minna Nyström
Journal: Cancer Research (2017)

Western-style diets (WD) high in fat and scarce in fiber and vitamin D increase risks of colorectal cancer. Here, we performed a long-term diet study in mice to follow tumorigenesis and characterize structural and metabolic changes in colon mucosa associated with WD and predisposition to colorectal cancer. WD increased colon tumor numbers, and mucosa proteomic analysis indicated severe deregulation of intracellular bile acid (BA) homeostasis and activation of cell proliferation. WD also increased crypt depth and colon cell proliferation. Despite increased luminal BA, colonocytes from WD-fed mice exhibited decreased expression of the BA transporters FABP6, OSTβ, and ASBT and decreased concentrations of secondary BA deoxycholic acid and lithocholic acid, indicating reduced activity of the nuclear BA receptor FXR. Overall, our results suggest that WD increases cancer risk by FXR inactivation, leading to BA deregulation and increased colon cell proliferation. Cancer Res; 77(12); 3352-63. ©2017 AACR.
Erythromycin Inhibits Expression Of P. AerugINOSa Quorum Sensing Genes In The Airways Of Non-Cf Bronchiectasis Subjects Recruited To The Bless Randomised Controlled Trial
Authors: L. D. Burr, G. B. Rogers, A. C. Chen, S. Taylor, S. Bowler, D. Serisier, M. McGuckin
Journal: American Journal of Respiratory and Critical Care Medicine (2016)
Multi-tissue DNA methylation age predictor in mouse
Authors: Thomas M. Stubbs, Marc Jan Bonder, Anne-Katrien Stark, Felix Krueger, Ferdinand von Meyenn, Oliver Stegle, Wolf Reik
Journal: Genome biology (2017)

DNA methylation changes at a discrete set of sites in the human genome are predictive of chronological and biological age. However, it is not known whether these changes are causative or a consequence of an underlying ageing process. It has also not been shown whether this epigenetic clock is unique to humans or conserved in the more experimentally tractable mouse. We have generated a comprehensive set of genome-scale base-resolution methylation maps from multiple mouse tissues spanning a wide range of ages. Many CpG sites show significant tissue-independent correlations with age which allowed us to develop a multi-tissue predictor of age in the mouse. Our model, which estimates age based on DNA methylation at 329 unique CpG sites, has a median absolute error of 3.33 weeks and has similar properties to the recently described human epigenetic clock. Using publicly available datasets, we find that the mouse clock is accurate enough to measure effects on biological age, including in the context of interventions. While females and males show no significant differences in predicted DNA methylation age, ovariectomy results in significant age acceleration in females. Furthermore, we identify significant differences in age-acceleration dependent on the lipid content of the diet. Here we identify and characterise an epigenetic predictor of age in mice, the mouse epigenetic clock. This clock will be instrumental for understanding the biology of ageing and will allow modulation of its ticking rate and resetting the clock in vivo to study the impact on biological age.
Low-Value Medical Services in the Safety-Net Population
Authors: Michael L. Barnett, Jeffrey A. Linder, Cheryl R. Clark, Benjamin D. Sommers
Journal: JAMA Internal Medicine (2017)

<h3>Importance</h3> National patterns of low-value and high-value care delivered to patients without insurance or with Medicaid could inform public policy but have not been previously examined. <h3>Objective</h3> To measure rates of low-value care and high-value care received by patients without insurance or with Medicaid, compared with privately insured patients, and provided by safety-net physicians vs non–safety-net physicians. <h3>Design, Setting, and Participants</h3> This multiyear cross-sectional observational study included all patients ages 18 to 64 years from the National Ambulatory Medical Care Survey (2005-2013) and the National Hospital Ambulatory Medical Care Survey (2005-2011) eligible for any of the 21 previously defined low-value or high-value care measures. All measures were analyzed with multivariable logistic regression and adjusted for patient and physician characteristics. <h3>Exposures</h3> Comparison of patients by insurance status (uninsured/Medicaid vs privately insured) and safety-net physicians (seeing &gt;25% uninsured/Medicaid patients) vs non–safety-net physicians (seeing 1%-10%). <h3>Main Outcomes and Measures</h3> Delivery of 9 low-value or 12 high-value care measures, based on previous research definitions, and composite measures for any high-value or low-value care delivery during an office visit. <h3>Results</h3> Overall, 193 062 office visits were eligible for at least 1 measure. Mean (95% CI) age for privately insured patients (n = 94 707) was 44.7 (44.5-44.9) years; patients on Medicaid (n = 45 123), 39.8 (39.3-40.3) years; and uninsured patients (n = 19 530), 41.9 (41.5-42.4) years. Overall, low-value and high-value care was delivered in 19.4% (95% CI, 18.5%-20.2%) and 33.4% (95% CI, 32.4%-34.3%) of eligible encounters, respectively. Rates of low-value and high-value care delivery were similar across insurance types for the majority of services examined. Among Medicaid patients, adjusted rates of use were no different for 6 of 9 low-value and 9 of 12 high-value services compared with privately insured beneficiaries, whereas among the uninsured, rates were no different for 7 of 9 low-value and 9 of 12 high-value services. Safety-net physicians provided similar care compared with non–safety-net physicians, with no difference for 8 out of 9 low-value and for all 12 high-value services. <h3>Conclusions and Relevance</h3> Overuse of low-value care is common among patients without insurance or with Medicaid. Rates of low-value and high-value care were similar among physicians serving vulnerable patients and other physicians. Overuse of low-value care is a potentially important focus for state Medicaid programs and safety-net institutions to pursue cost savings and improved quality of health care delivery.
TCTAP C-258 A Complication Case of Distal Embolism During Endovascular Therapy for External Iliac Artery Occlusive Disease
Authors: Kentaro Yamashita, Takumi Inoue, Taro Kamada, Shun Yokota, Masamichi Iwasaki, Takatoshi Hayashi
Journal: Journal of the American College of Cardiology (2017)
Aspirin prevents NF-κB activation and CDX2 expression stimulated by acid and bile salts in oesophageal squamous cells of patients with Barrett's oesophagus
Authors: Xiaofang Huo, Xi Zhang, Chunhua Yu, Edaire Cheng, Qiuyang Zhang, Kerry B Dunbar, Thai H Pham, John P Lynch, David H Wang, Robert S Bresalier, Stuart J Spechler, Rhonda F Souza
Journal: Gut (2017)

<h3>Objective</h3> In previous studies using oesophageal squamous cells from patients with Barrett9s oesophagus (normal oesophageal squamous (NES)-B cells) and from patients without Barrett9s oesophagus (NES-G cells), we showed that acid and bile salts induced caudal-related homeobox transcription factor 2 (CDX2) expression only in NES-B cells. CDX2, a transcription factor required to form intestinal epithelium, is a target of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling, which can be inhibited by aspirin. We explored mechanisms underlying differences between NES-B and NES-G cells in CDX2 expression and effects of aspirin on that CDX2 expression. <h3>Design</h3> We exposed NES-B and NES-G cells to acid and bile salts, with and without aspirin, and evaluated effects on IκB-NF-κB-PKAc complex activation, p65 NF-κB subunit function, and CDX2 expression. <h3>Results</h3> In both NES-B and NES-G cells, acid and bile salts activated nicotinamide adenine dinucleotide phosphate oxidase to generate H<sub>2</sub>O<sub>2</sub>, which activated the IκB-NF-κB-PKAc complex. NES-B cells exhibited higher levels of phosphorylated IκB and p65 and greater NF-κB transcriptional activity than NES-G cells, indicating greater IκB-NF-κB-PKAc complex activation by acid and bile salts in NES-B cells, and p65 siRNA prevented their increased expression of CDX2. Aspirin blocked IκB phosphorylation, p65 nuclear translocation, CDX2 promoter activation and CDX2 expression induced by acid and bile salts in NES-B cells. <h3>Conclusions</h3> Differences between NES-B and NES-G cells in NF-κB activation by acid and bile salts can account for their differences in CDX2 expression, and their CDX2 expression can be blocked by aspirin. These findings might explain why some patients with GORD develop Barrett9s oesophagus while others do not, and why aspirin might protect against development of Barrett9s oesophagus.
Cultured microbes represent a substantial fraction of the human and mouse gut microbiota
Authors: Ilias Lagkouvardos, Jörg Overmann, Thomas Clavel
Journal: Gut Microbes (2017)

During the last 15 years, molecular techniques have been preferred over culture-based approaches for the study of mammalian gut microbiota, i.e. the communities of microorganisms dwelling in the intestine of mammals. The main reason is the belief that the majority of gut bacteria, especially strict anaerobes, escape cultivation. Despite numerous such statements in publications, the literature does not provide a clear overview on the subject. In the present manuscript, we highlight recent work on the cultivation of bacteria from the intestine of mammals, review the literature and provide novel data pertaining to cultured fractions of mammalian gut microbiota. These data show that, despite marked inter-sample variations, 35 to 65% of molecular species detected by sequencing have representative strains in culture.
In vivo studies investigating biodistribution of nanoparticle-encapsulated rhodamine B delivered via dissolving microneedles
Authors: Joakim Kennedy, Eneko Larrañeta, Maelíosa T.C. McCrudden, Cian M. McCrudden, Aaron J. Brady, Steven J. Fallows, Helen O. McCarthy, Adrien Kissenpfennig, Ryan F. Donnelly
Journal: Journal of Controlled Release (2017)

Nanoparticles (NPs) have undergone extensive investigation as drug delivery and targeting vehicles. NP delivery is often via the parenteral route, reliant on administration using hypodermic needles, which can be associated with patient compliance issues and safety concerns. In the recent past, the intradermal delivery of NPs, via novel dissolving microneedle (MN) arrays has garnered interest in the pharmaceutical community. However, published studies using this combinatorial approach have been limited, in that they have focussed on the use of in vitro and ex vivo models only. The current study was designed to answer the fundamental question of how such NPs are distributed in an in vivo murine model, following MN-mediated delivery. Rhodamine B (RhB) was employed as a model tracer dye to facilitate study of biodistribution. Following MN application, RhB was detected in the livers, kidneys, spleens and superficial parotid lymph nodes of the mice. Uptake into the lymphatics was of particular note, as it points towards the potential for utilisation of a minimally-invasive MN delivery strategy in controlled targeting of active drug substances and vaccines to the lymphatics. The use of such a delivery system could, following further development, have far-reaching benefits in enhancement of immunomodulatory and anti-cancer therapies. As a consequence, further investigation of MN/NP combinatorial delivery strategies is warranted.
Nonobstructive Coronary Artery Disease by Coronary CT Angiography Improves Risk Stratification and Allocation of Statin Therapy
Authors: Hamed Emami, Richard A.P. Takx, Thomas Mayrhofer, Sumbal Janjua, Jakob Park, Amit Pursnani, Ahmed Tawakol, Michael T. Lu, Maros Ferencik, Udo Hoffmann
Journal: JACC. Cardiovascular imaging (2017)
GAD1 Upregulation Programs Aggressive Features of Cancer Cell Metabolism in the Brain Metastatic Microenvironment
Authors: Patricia M. Schnepp, Dennis D. Lee, Ian H. Guldner, Treasa K. O'Tighearnaigh, Erin N. Howe, Bhavana Palakurthi, Kaitlyn E. Eckert, Tiffany A. Toni, Brandon L. Ashfeld, Siyuan Zhang
Journal: Cancer Research (2017)

Abstract The impact of altered amino acid metabolism on cancer progression is not fully understood. We hypothesized that a metabolic transcriptome shift during metastatic evolution is crucial for brain metastasis. Here, we report a powerful impact in this setting caused by epigenetic upregulation of glutamate decarboxylase 1 (GAD1), a regulator of the GABA neurotransmitter metabolic pathway. In cell-based culture and brain metastasis models, we found that downregulation of the DNA methyltransferase DNMT1 induced by the brain microenvironment–derived clusterin resulted in decreased GAD1 promoter methylation and subsequent upregulation of GAD1 expression in brain metastatic tumor cells. In a system to dynamically visualize cellular metabolic responses mediated by GAD1, we monitored the cytosolic NADH:NAD+ equilibrium in tumor cells. Reducing GAD1 in metastatic cells by primary glia cell coculture abolished the capacity of metastatic cells to utilize extracellular glutamine, leading to cytosolic accumulation of NADH and increased oxidative status. Similarly, genetic or pharmacologic disruption of the GABA metabolic pathway decreased the incidence of brain metastasis in vivo. Taken together, our results show how epigenetic changes in GAD1 expression alter local glutamate metabolism in the brain metastatic microenvironment, contributing to a metabolic adaption that facilitates metastasis outgrowth in that setting. Cancer Res; 77(11); 2844–56. ©2017 AACR.
THE INCIDENCE OF EXERTIONAL HEAT STROKE DURING MASS-PARTICIPATION TRIATHLON RACES: OPTIMISING ATHLETE SAFETY
Authors: Nicholas Knight, James Parkin, Ralph Smith, Courtney Kipps
Journal: British Journal of Sports Medicine (2017)

Background Exertional heat stroke (EHS) is a potentially life-threatening condition to the endurance athlete. Early recognition and rapid on-site treatment with aggressive cooling measures significantly reduces mortality, improves outcome and avoids hospital transfers. Objective Determine the incidence of EHS in triathlon competition. Design A retrospective analysis of competitor medical records. Setting Data was collected across two UK-based triathlons over six years (11 consecutive triathlons). Patients (or Participants) All casualties diagnosed with EHS by the Triathlon Medical team (TMT). Diagnostic criteria of EHS included a core temperature &gt;40°C and evidence of an altered mental state indicating neurological dysfunction. Interventions (or Assessment of Risk Factors) Age, gender, race distance, co-morbidities and medical management required were recorded. Main Outcome Measurements Incidence of EHS amongst triathlon competitors. Results Of 68557 starting competitors, 429 casualties presented to the TMT. Twelve (2.8%) were diagnosed with EHS, giving an incidence of 1.74/10000 starters. Eight EHS casualties (67%) collapsed during the run phase, with three collapsing after the finish line. One EHS casualty presented during the swim phase in cardiac arrest. This patient was successfully resuscitated with CPR before ice-bath cooling for EHS. Four (36%) EHS casualties were discharged directly from the TMT and the remaining transferred to hospital. Conclusions EHS is a significant risk in mass-participation triathlon events. EHS can be successfully managed on-site with aggressive cooling measures which may reduce hospital transfers. The majority of EHS cases occur during or after the run phase and therefore we recommend event organisers focus both medical resources and prevention strategies at this phase.
Fewer than half of patients take high intensity statins two years after MI
Authors: Jacqui Wise
Journal: BMJ (2017)

A substantial proportion of patients prescribed high intensity statins following a heart attack do not continue to regularly take them after they have been discharged from hospital, a study published in JAMA Cardiology has found.1

Risk of recurrent coronary heart disease events is high after a myocardial infarction. American Heart Association guidelines recommend that patients aged 75 …
WHO condemns suspected use of chemical weapons
Authors: Anne Gulland
Journal: BMJ (2017)

Ammar Abdullah/Reuters

Caves are being used as makeshift hospitals to treat patients injured in a suspected chemical attack last week in Khan Shaykhun, Syria. The World Health Organization condemned the attack, which killed 70 people, including many children, and which led the United States to bomb a Syrian air base.

Peter Salama, executive director of WHO’s health …