tbuckley/cabot-search huggingface dataset:
The Environmental Sensor AHR Protects from Inflammatory Damage by Maintaining Intestinal Stem Cell Homeostasis and Barrier Integrity
Authors: Amina Metidji, Sara Omenetti, Stefania Crotta, Ying Li, Emma Nye, Ellie Ross, Vivian Li, Muralidhara R. Maradana, Chris Schiering, Brigitta Stockinger
Journal: Immunity (2018)

The epithelium and immune compartment in the intestine are constantly exposed to a fluctuating external environment. Defective communication between these compartments at this barrier surface underlies susceptibility to infections and chronic inflammation. Environmental factors play a significant, but mechanistically poorly understood, role in intestinal homeostasis. We found that regeneration of intestinal epithelial cells (IECs) upon injury through infection or chemical insults was profoundly influenced by the environmental sensor aryl hydrocarbon receptor (AHR). IEC-specific deletion of Ahr resulted in failure to control C. rodentium infection due to unrestricted intestinal stem cell (ISC) proliferation and impaired differentiation, culminating in malignant transformation. AHR activation by dietary ligands restored barrier homeostasis, protected the stem cell niche, and prevented tumorigenesis via transcriptional regulation of of Rnf43 and Znrf3, E3 ubiquitin ligases that inhibit Wnt-β-catenin signaling and restrict ISC proliferation. Thus, activation of the AHR pathway in IECs guards the stem cell niche to maintain intestinal barrier integrity.
Sudden cardiac deaths: one-off screening misses cardiomyopathies in young footballers
Authors: Susan Mayor
Journal: BMJ (2018)

One-off cardiac screening at age 16 failed to detect most cardiomyopathies associated with sudden cardiac deaths in adolescent footballers, a large UK cohort study has found.1 But results from the 20 year study also showed that the rate of sudden cardiac deaths was much higher than expected, prompting the English Football Association (FA) to recommend more frequent cardiac assessments for young footballers.

Sanjay Sharma, study coauthor, said, “The death of a young athlete is highly tragic when one considers that most deaths are due to congenital/inherited diseases of the heart that are detectable during life. Such deaths raise questions about possible preventative strategies.” Sharma is professor of inherited diseases and sports cardiology at St George’s, University of London and chairs the FA’s expert cardiac committee.

The study, funded by the English FA and research charities, screened 11 168 teenage footballers recruited to youth academies at clubs affiliated with the association from 1 January 1996 to 31 December 2016. The mean age of the players at cardiac screening was 16.4 years.

The screening—mandatory for all teenagers joining youth academies who have the potential to become professional footballers—included a health …
Abstract 1093: Epithelial-to-mesenchymal transition conveys resistance to restrictive growth conditions through increased autophagic flux
Authors: Lei Zhao, Jones Nauseef, Marisa Buchakjian, Matthew Barnes, Michael Henry
Journal: Cancer Research (2018)

Abstract Tumor progression requires cancer cells to adapt to varying microenvironments both in the primary tumor and in metastatic end organs. Metastasis is enhanced by epithelial-to-mesenchymal transition (EMT), which facilitates invasiveness and confers resistance to local stresses, such as hypoxia and nutrient limitation, although EMT is not necessarily required for these processes. Among these stressors, growth-factor (GF) deprivation may induce or select for cells that bear the hallmarks of EMT (EMT-like cells). The mechanisms by which EMT-like cells survive GF deprivation (restrictive growth conditions), which may occur when metastatic cancer cells are removed from GFs resident in the primary tumor microenvironment, remain largely uncertain. Herein we show that EMT confers upon cells the ability to maintain proliferative potential, following extended serum deprivation. We found that EMT-like prostate cancer cells (TEM 4-18) demonstrate elevated survival and reduced senescence compared to their more epithelial counterparts (PC-3E) in both short- and long-term exposure to serum withdrawal. In addition, resistance to anchorage-dependent growth-induced apoptosis (Anoikis) due to elevated autophagy is also evident in EMT-like cells. Forced expression of snail1 conferred survival advantages to PC-3 cells. Conversely, CRISPR-mediated knockout of Zeb1 reversed EMT status in TEM4-18 cells and survival advantage in restrictive growth conditions. We found that EMT-like cells exhibit elevated autophagic flux. Genetic interference with autophagy in EMT-like cells reversed their survival advantage and increased senescence in restrictive growth conditions as well as anoikis resistance. Our results suggest that the metastatic capabilities of EMT-like cells depend not only on their established invasive characteristics, but also on increased autophagy tied to the EMT-like state, and its role in surviving restrictive growth conditions. Citation Format: Lei Zhao, Jones Nauseef, Marisa Buchakjian, Matthew Barnes, Michael Henry. Epithelial-to-mesenchymal transition conveys resistance to restrictive growth conditions through increased autophagic flux [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 1093.
Oral steroids for resolution of otitis media with effusion in children (OSTRICH): a double-blinded, placebo-controlled randomised trial
Authors: Nick A Francis, Rebecca Cannings-John, Cherry-Ann Waldron, Emma Thomas-Jones, Tom Winfield, Victoria Shepherd, Debbie Harris, Kerenza Hood, Deborah Fitzsimmons, Amanda Roberts, Colin Powell, Micaela Gal, Christopher C Butler
Journal: The Lancet (2018)

BackgroundChildren with persistent hearing loss due to otitis media with effusion are commonly managed by surgical intervention. A safe, cheap, and effective medical treatment would enhance treatment options. Underpowered, poor-quality trials have found short-term benefit from oral steroids. We aimed to investigate whether a short course of oral steroids would achieve acceptable hearing in children with persistent otitis media with effusion and hearing loss.MethodsIn this individually randomised, parallel, double-blinded, placebo-controlled trial we recruited children aged 2–8 years with symptoms attributable to otitis media with effusion for at least 3 months and with confirmed bilateral hearing loss. Participants were recruited from 20 ear, nose, and throat (ENT), paediatric audiology, and audiovestibular medicine outpatient departments in England and Wales. Participants were randomly allocated (1:1) to sequentially numbered identical prednisolone (oral steroid) or placebo packs by use of computer-generated random permuted block sizes stratified by site and child's age. The primary outcome was audiometry-confirmed acceptable hearing at 5 weeks. All analyses were by intention to treat. This trial is registered with the ISRCTN Registry, number ISRCTN49798431.FindingsBetween March 20, 2014, and April 5, 2016, 1018 children were screened, of whom 389 were randomised. 200 were assigned to receive oral steroids and 189 to receive placebo. Hearing at 5 weeks was assessed in 183 children in the oral steroid group and in 180 in the placebo group. Acceptable hearing was observed in 73 (40%) children in the oral steroid group and in 59 (33%) in the placebo group (absolute difference 7% [95% CI −3 to 17], number needed to treat 14; adjusted odds ratio 1·36 [95% CI 0·88–2·11]; p=0·16). There was no evidence of any significant differences in adverse events or quality-of-life measures between the groups.InterpretationOtitis media with effusion in children with documented hearing loss and attributable symptoms for at least 3 months has a high rate of spontaneous resolution. A short course of oral prednisolone is not an effective treatment for most children aged 2–8 years with persistent otitis media with effusion, but is well tolerated. One in 14 children might achieve improved hearing but not quality of life. Discussions about watchful waiting and other interventions will be supported by this evidence.FundingNational Institute for Health Research (NIHR) Health Technology Assessment programme.
Negative Inotropic Effect of Adrenomedullin in Isolated Adult Rabbit Cardiac Ventricular Myocytes
Authors: HiroshiIkenouchi, KenjiKangawa, HisayukiMatsuo, YasunobuHirata
Journal: Circulation (1997)

Background Adrenomedullin (AM) is a potent vasodilator peptide. AM-induced vasodilatation is mediated by an increase of NO as well as cAMP. Both AM and binding sites for this peptide have been found in cardiac tissue, indicating the possible existence of an autocrine or paracrine system of AM in the heart. Methods and Results Myocytes were isolated by use of retrograde coronary perfusion with physiological solution containing collagenase and hyaluronidase from adult rabbit ventricles. Contraction of cardiac myocytes was traced with a video motion detector, and [Ca2+]i was measured with indo 1 at 37°C. The ICa was measured with a whole-cell patch clamp at 23°C. AM and calcitonin gene–related peptide (CGRP), another member of the same peptide family, showed a concentration-dependent negative inotropic effect (10−7 mol/L AM: contraction amplitude, 64±7% of control; [Ca2+]i, 52±5% of control; n=10; 10−6 mol/L CGRP: contraction amplitude, 64±25%; [Ca2+]i, 70±3%; n=5; mean±SD). ICa was decreased to 60±39% by su...
Nonpegylated liposomal doxorubicin (nPLD) in neoadjuvant treatment of local advanced breast cancer (LABC) patients (pts).
Authors: Luigi Rossi, Federica Tomao, Anselmo Papa, Federica Zoratto, Fabio Ricci, Gian Paolo Spinelli, Giuseppe Lo Russo, Enrico Basso, Giuliana Caprio, Simona Barberi, Monica Verrico, Erika Giordani, Eleonora Zaccarelli, Giulia Rinaldi, Valeria Stati, Giulia Pasciuti, Martina Strudel, Silverio Tomao
Journal: Journal of Clinical Oncology (2012)

e11514 Background: Anthracycline is very effective in treatment of breast cancer, however it can cause cardiac toxicity events. nPLD has greater safety profile and comparable efficacy than conventional anthracyclines. We evaluated safety and efficacy, in neoadjuvant setting, of nPLD in pts with LABC. Methods: 11 pts (median age 57 years). Their clinical stage was: stages IIA and IIB 1 pt respectively, IIIB 7 pts, IIIC 2 pts. 8 pts presented at diagnosis with cT4 disease. All pts were treated with nPLD (50 mg/mq, d1q21) plus Docetaxel (75 mg/mq, d1q21) and Cyclophosphamide (500 mg/mq, d1q21); only 1 pt received Cyclophosphamide, nPLD and Trastuzumab. At beginning of therapy, overall population had left ventricular ejection fraction (LVEF) ≥55%. Results: After a median of 4 chemotherapy cycles, we observed following clinical response: stable disease 2 pts (18%); partial response 7 pts (64%); complete response 2 pts (18%). 9 pts were evaluable for radiological response: objective response rate and clinical benefit were 78 % and 100% respectively. 8 pts underwent surgery, in 3 pts was performed breast-conserving surgery. At the definitive histological examination pathologic stage was: IA 4 pts (50%), IIIA 1 pts (12,5%), IIIB 2 pts (25%) and IIIC 1 pts (12,5%). 2 pts experienced cardiac toxicity: 1 pt had an atrial fibrillation G2 while 1 pt had an symptomatic decline of LVEF G3 after first cycle, causing interruption of treatment. Other pts not showed clinically significant reduction of LVEF (&gt;5%). Conclusions: Despite small number of pts, our experience suggests a safety profile and efficacy of nPLD in neoadjuvant settings for LABC; breast conservation was possible in 3 pts, in other pts (73%) this was not possible mainly for the advanced stage (T4).
Peer support reduces hospital readmissions for mental health crises, shows study
Authors: Susan Mayor
Journal: BMJ (2018)

Self management training provided by peer workers with personal experience of mental illness significantly reduced readmission to mental health crisis units in patients discharged from acute mental healthcare, a randomised controlled trial has found.1

The lead author, Sonia Johnson, professor of social and community psychiatry at University College London, UK, said, “People discharged from community crisis services are often readmitted to acute care. Not only does this impede recovery but it also consumes resources that might otherwise be dedicated to longer term improvements in functioning and quality of life.”

Over half of people currently admitted to acute mental healthcare in the UK are readmitted …
Early Signals in Cardiac Development
Authors: StéphaneZaffran, ManfredFrasch
Journal: Circulation Research (2002)

The heart is the first organ to form during embryogenesis and its circulatory function is critical from early on for the viability of the mammalian embryo. Developmental abnormalities of the heart have also been widely recognized as the underlying cause of many congenital heart malformations. Hence, the developmental mechanisms that orchestrate the formation and morphogenesis of this organ have received much attention among classical and molecular embryologists. Due to the evolutionary conservation of many of these processes, major insights have been gained from the studies of a number of vertebrate and invertebrate models, including mouse, chick, amphibians, zebrafish, and Drosophila. In all of these systems, the heart precursors are generated within bilateral fields in the lateral mesoderm and then converge toward the midline to form a beating linear heart tube. The specification of heart precursors is a result of multiple tissue and cell-cell interactions that involve temporally and spatially integrate...
Atrial Contractile Dysfunction After Short-term Atrial Fibrillation Is Reduced by Verapamil but Increased by BAY K8644
Authors: ElisabethLeistad, GunnarAksnes, EstherVerburg, GeirChristensen
Journal: Circulation (1996)

Background Reduced atrial contractility occurs after cessation of atrial fibrillation. Its mechanism is unknown, and no pharmacological treatment exists. It has been hypothesized that this atrial contractile dysfunction results from intracellular calcium overload due to rapid depolarizations during fibrillation. Accordingly, we examined the effects of drugs that reduce or increase transsarcolemmal calcium influx on postfibrillation atrial dysfunction. Furthermore, we examined whether the dysfunction could be attributed to atrial ischemia. Methods and Results Atrial contractility after atrial fibrillation was examined in open-chest pigs paced with a constant ventricular rate after complete AV block. Atrial contractility was computed as systolic shortening of left atrial diameter divided by atrial preload. Three groups of six pigs each were subjected to two 5-minute periods of atrial fibrillation separated by 1 hour of AV pacing. Verapamil or the calcium channel agonist BAY K8644 was administered intravenou...
Evaluating Shared Decision Making for Lung Cancer Screening
Authors: Alison T. Brenner, Teri L. Malo, Marjorie Margolis, Jennifer Elston Lafata, Shynah James, Maihan B. Vu, Daniel S. Reuland
Journal: JAMA Internal Medicine (2018)

<h3>Importance</h3> The US Preventive Services Task Force recommends that shared decision making (SDM) involving a thorough discussion of benefits and harms should occur between clinicians and patients before initiating lung cancer screening (LCS) with low-dose computed tomography. The Centers for Medicare &amp; Medicaid Services require an SDM visit using a decision aid as a prerequisite for LCS coverage. However, little is known about how SDM about LCS occurs in practice. <h3>Objective</h3> To assess the quality of SDM about the initiation of LCS in clinical practice. <h3>Design, Setting, and Participants</h3> A qualitative content analysis was performed of transcribed conversations between primary care or pulmonary care physicians and 14 patients presumed to be eligible for LCS, recorded between April 1, 2014, and March 1, 2018, that were identified within a large database. <h3>Main Outcomes and Measures</h3> Independent observer ratings of communication behaviors of physicians using the OPTION (Observing Patient Involvement in Decision Making) scale, a validated 12-item measure of SDM (total score, 0-100 points, where 0 indicates no evidence of SDM and 100 indicates evidence of SDM at the highest skill level); time spent discussing LCS during visits; and evidence of decision aid use. <h3>Results</h3> A total of 14 conversations about initiating LCS were identified; 9 patients were women, and 5 patients were men; the mean (SD) patient age was 63.9 (5.1) years; 7 patients had Medicare, and 8 patients were current smokers. Half the conversations were conducted by primary care physicians. The mean total OPTION score for the 14 LCS conversations was 6 on a scale of 0 to 100 (range, 0-17). None of the conversations met the minimum skill criteria for 8 of the 12 SDM behaviors. Physicians universally recommended LCS. Discussion of harms (such as false positives and their sequelae or overdiagnosis) was virtually absent. The mean total visit length of a discussion was 13:07 minutes (range, 3:48-27:09 minutes). The mean time spent discussing LCS was 0:59 minute (range, 0:16-2:19 minutes), or 8% of the total visit time (range, 1%-18%). There was no evidence that decision aids or other patient education materials for LCS were used. <h3>Conclusions and Relevance</h3> In this small sample of recorded encounters about initiating LCS, the observed quality of SDM was poor and explanation of potential harms of screening was virtually nonexistent. Time spent discussing LCS was minimal, and there was no evidence that decision aids were used. Although these findings are preliminary, they raise concerns that SDM for LCS in practice may be far from what is intended by guidelines.
Abstract 13522: Annexin-A1 Bioactive Peptide Ameliorates Cardiac Surgery-Associated Acute Kidney Injury (CSA-AKI) in Rats by Upregulating the Sirtuin6/FoxO3 Pathway
Authors: Zhiquan Zhang, Qing Ma, Mihai V Podgoreanu
Journal: Circulation (2015)

Introduction: Acute kidney injury (AKI) is a prevalent and prognostically important complication of cardiac surgery. The complex multifactorial pathogenesis and lack of appropriate animal models to recapitulate the clinical insults leading to CSA-AKI have been implicated in the failure of multiple pharmacologic renoprotective strategies. We have reported anti-inflammatory and renoprotective effects of a novel Annexin-A1 (ANXA1) tripeptide (Ac-QAW) in a rodent model of experimental cardiac surgery. Here, we tested the hypothesis that Ac-QAW attenuates CSA-AKI by upregulating Sirtuin6 and Forkhead box protein O3 (SIRT6/FoxO3), key players in stress resistance, cell survival, and life span. Methods: Male Sprague-Dawley rats underwent 75 min of cardiopulmonary bypass (CPB) with 45 min of cardioplegic arrest (CA). Animals were treated (iv) with 1 mg/kg Ac-QAW (n = 6), the commercially available ANXA1 peptide Ac2-26 (as a positive control; n = 5), or vehicle (n = 6) at 1 h before CPB, during CA, and 1 h after CPB. At 24 h post-reperfusion, renal levels of activated caspase-3, ANXA1, SIRT6, and FoxO3 were determined by Western blot; renal and plasma levels of myeloperoxidase (MPO) were determined by ELISA. Results: At 24 hours post-reperfusion following CPB/CA, rats treated with Ac-QAW showed a) reduced renal caspase-3 activity (P &lt; 0.05); b) decreased MPO in both blood and kidney; and c) increased renal levels of ANXA1 (P &lt; 0.05), SIRT6, and FoxO3 (P &lt; 0.01) (Figure). Conclusions: Using a clinically relevant animal model, we provide preliminary translatable evidence that administration of Ac-QAW attenuates CSA-AKI. This may result from action by Ac-QAW to 1) reduce inflammation by increasing inflammation-resolving molecule ANXA1; 2) inhibit neutrophil transmigration; and 3) promote pro-survival mechanisms by increasing SIRT6/FoxO3 expression. More Ac-QAW studies are needed to define its exact mechanism of action and its impact on long-term functional outcomes.
Structure of the Type B Human Natriuretic Peptide Receptor Gene and Association of a Novel Microsatellite Polymorphism With Essential Hypertension
Authors: DuolikunRehemudula, TomohiroNakayama, MasayoshiSoma, YukieTakahashi, JiroUwabo, MikanoSato, YoichiIzumi, KatsuoKanmatsuse, YukioOzawa
Journal: Circulation Research (1999)

Abstract—The natriuretic peptide (NP) system may play a crucial role in development of essential hypertension (EH). C-type NP dilates arteries and lowers blood pressure and inhibits proliferation of vascular smooth muscle cells via the type B NP receptor (NPR-B). However, the association of the human NPR-B gene with EH has not been studied, because little is known about the genomic organization of this gene. We designed oligonucleotide primers based on the cDNA sequence of the human NPR-B gene, and long-range polymerase chain reaction (PCR) was performed. The amplified fragments were sequenced directly, and the exon/intron organization of the human NPR-B gene was determined. The gene, which spans ≈16.5 kbp, is composed of 22 exons, and the intron-exon junctions follow the GT-AG rule. Seven hundred fifty base pairs of the 5′-flanking region were sequenced using a thermal asymmetric interlaced–PCR (TAIL-PCR) method. This region contains 10 potential Sp1 binding sites and lacks a TATA box. Rapid amplificatio...
A possible mechanism for the growth inhibitory action of curcumin on HER-2 over expressing SK-BR-3 breast cancer cells involves the polyamine pathway
Authors: T. J. Thomas, Latha M. Santhakumaran, Miral S. Parikh, Thresia Thomas
Journal: Cancer Research (2004)

728  Celecoxib has shown great promise in cancer chemoprevention and treatment. Its tumor suppression activity has been related to the induction of apoptosis in many cancer cell lines and animal models. While celecoxib is potent inhibitor of cyclooxygenase-2 (COX-2), recent data using non-COX inhibiting first and second generation derivatives of celecoxib indicates that apoptosis is mediated through COX-independent pathways. We used a premalignant and malignant human oral cell culture model to determine mechanisms and signaling pathways leading to derivative induced apoptosis. Treatment of the oral cell lines with celecoxib and the second generation derivatives induced cell cycle arrest in the G2/M phase and apoptosis. The derivatives with apolar substituents at the terminal phenyl moiety of celecoxib greatly enhanced both cell cycle arrest and apoptosis activity compared to celecoxib. While all of the derivatives inhibited Akt and Erk1/2 phosphorylation, these pathways did not appear to be directly linked to apoptosis. Infecting cells with dominant negative FADD (Ad-FADD-DN) and incubating cells with a caspase 8 inhibitor did not protect cells from derivative induced apoptosis. LEHD, a caspase 9 inhibitor, and cyclosporin A, a mitochondrial membrane potential stabilizer blocked derivative induced activation of caspase 3 and caspase 8 and PARP cleavage. DEVD, a caspase 3 inhibitor, abrogated derivative induced activation of caspase 8, suggesting a loop-back activation of caspase 8 by caspase 3. DEVD also blocked derivative induced PARP cleavage and morphological changes associated with apoptosis. These data indicate that the second generation celecoxib derivatives induce apoptosis in premalignant and malignant human oral cell lines by the disruption of mitochondrial membrane potential initiating the caspase 9/3 apoptotic cascade. Supported in part by P01-DE-12704.
Abstract 12833: Hospital Variation in Bleeding Complications Following Percutaneous Coronary Intervention (PCI): Results from the National Cardiovascular Data Registry (NCDR)
Authors: Eric D Peterson, Lisa A Kaltenbach, Mandeep Singh, John A Spertus, Ronald Krone, W. D Weaver, Sunil V Rao
Journal: Circulation (2011)

Background: There is increasing interest in benchmarking hospital PCI outcomes. We sought to determine: a) site-level variation in post-PCI bleeding rates; and b) the degree to which hospital bleed...