tbuckley/cabot-search huggingface dataset:
Hypoxia‐inducible factor 2α drives nonalcoholic fatty liver progression by triggering hepatocyte release of histidine‐rich glycoprotein
Authors: Elisabetta Morello, Salvatore Sutti, Beatrice Foglia, Erica Novo, Stefania Cannito, Claudia Bocca, Martina Rajsky, Stefania Bruzzì, Maria Lorena Abate, Chiara Rosso, Cristina Bozzola, Ezio David, Elisabetta Bugianesi, Emanuele Albano, Maurizio Parola
Journal: Hepatology (2017)

Mechanisms underlying progression of nonalcoholic fatty liver disease (NAFLD) are still incompletely characterized. Hypoxia and hypoxia-inducible factors (HIFs) have been implicated in the pathogenesis of chronic liver diseases, but the actual role of HIF-2α in the evolution of NAFLD has never been investigated in detail. In this study, we show that HIF-2α is selectively overexpressed in the cytosol and the nuclei of hepatocytes in a very high percentage (>90%) of liver biopsies from a cohort of NAFLD patients at different stages of the disease evolution. Similar features were also observed in mice with steatohepatitis induced by feeding a methionine/choline-deficient diet. Experiments performed in mice carrying hepatocyte-specific deletion of HIF-2α and related control littermates fed either a choline-deficient L-amino acid-defined or a methionine/choline-deficient diet showed that HIF-2α deletion ameliorated the evolution of NAFLD by decreasing parenchymal injury, fatty liver, lobular inflammation, and the development of liver fibrosis. The improvement in NAFLD progression in HIF-2α-deficient mice was related to a selective down-regulation in the hepatocyte production of histidine-rich glycoprotein (HRGP), recently proposed to sustain macrophage M1 polarization. In vitro experiments confirmed that the up-regulation of hepatocyte HRGP expression was hypoxia-dependent and HIF-2α-dependent. Finally, analyses performed on specimens from NAFLD patients indicated that HRGP was overexpressed in all patients showing hepatocyte nuclear staining for HIF-2α and revealed a significant positive correlation between HIF-2α and HRGP liver transcript levels in these patients.These results indicate that hepatocyte HIF-2α activation is a key feature in both human and experimental NAFLD and significantly contributes to the disease progression through the up-regulation of HRGP production. (Hepatology 2018;67:2196-2214).
Predictors of colorectal cancer screening adherence among African Americans.
Authors: Praveen Ramakrishnan Geethakumari, Ronald Myers, Randa Sifri, Constantine Daskalakis, Melissa DiCarlo, Sally W. Vernon, James Cocroft, Christopher Minnick, Nancy Brisbon
Journal: Journal of Clinical Oncology (2014)

1501 Background: Low colorectal cancer (CRC) screening rates among African Americans (AAs) contribute to higher CRC mortality and lower CRC survival among AAs than whites. We conducted a randomized controlled trial to determine if a preference-based mail and telephone navigation intervention could increase CRC screening adherence among AA patients. Methods: The trial included AA patients who were 50-75 years old, eligible for screening, and received care through primary care practices in Philadelphia. Eligible patients (n=764) were consented, surveyed by telephone, and randomized to a Standard Intervention (SI) Group (n=380) or Tailored Navigation Intervention (TNI) Group (n=384). The SI Group was sent colonoscopy instructions and a stool blood test kit, followed by a reminder. The TNI Group received mailed screening contacts keyed to preference, and also received telephone navigation and a reminder. An endpoint survey was administered and an endpoint review of medical records was performed to determine screening adherence status at 6 months. Multivariable analyses were performed to assess intervention impact on adherence. Results: Background characteristics of study participants were: female (69%), 50-59 years of age (71%), < high school education (59%), and unmarried (69%). At 6 months after randomization, CRC screening adherence was substantially higher in the TNI Group (38%) than the SI Group (24%), a difference that was statistically significant (OR=2.04, 95% CI: 1.47-2.84). Participants who were > 60 years of age also had a significantly higher screening rate than those who were 50 to 59 years of age (OR=1.92, 95% CI: 1.33, 3.77). Screening adherence was marginally higher among participants who were female, married, and had a higher screening decision stage. Conclusions: Exposure to the preference-based mail and telephone navigation intervention increased CRC screening adherence compared to the mailed intervention. Further research is needed to determine how the intervention can be modified to maximize impact and to assess its effect on screening disparity between whites and AAs. To our knowledge, this is the first study to test preference-based tailored navigation for CRC screening in a solely AA patient population. Clinical trial information: NCT00893295.
A phase 1 dose escalation study of RXDX-105, an oral RET and BRAF inhibitor, in patients with advanced solid tumors.
Authors: Manish R. Patel, Marwan Fakih, Anthony J. Olszanski, Albert C. Lockhart, Alexander E. Drilon, Siqing Fu, Lyudmila Bazhenova, Rupal Patel, Jennifer W. Oliver, Pratik S. Multani, Ding Wang
Journal: Journal of Clinical Oncology (2016)

2574 Background: RXDX-105 is a multikinase inhibitor that has demonstrated potent inhibition of RET. RXDX-105 is also active against BRAF. RET alterations are associated with the development of various types of cancer. Acquired BRAF mutations can result in constitutive activation of the MEK/ERK signaling pathway, which fuels cancer growth. Methods: Pts with advanced solid tumors were enrolled in a Phase 1 dose escalation study with a standard 3 + 3 design to determine the recommended Phase 2 dose (RP2D) of RXDX-105, administered once daily on a continuous dosing schedule. Tumor response was assessed every 8 wks (RECIST v1.1). Treatment-emergent adverse events (AEs) were recorded according to NCI CTC v4.03. Pharmacokinetic (PK) analysis was performed. Results: To date, 45 pts (21 m and 24 F) received RXDX-105 across 8 dose levels (20 to 350 mg QD). Median age was 60 years (range 27–81). Median number of cycles was 2 (range 1 to 30). The PK data demonstrate an RXDX-105 half-life of 28 to 42 hrs. At 275 mg fed state, exposure reached the predicted efficacious concentration (Ceff ) based on preclinical data of RET and BRAF inhibition. The most common AEs were: fatigue (19 pts; 42%), vomiting (16 pts; 36%), nausea (16 pts; 36%), rash (15 pts; 33%), and constipation (12 pts; 27%). 4 DLTs occurred: G3 maculopapular rash (n = 1; 200 mg), G3 fatigue (n = 1; 275 mg), G3 diarrhea (n = 1; 275 mg fed state), and G3 hyperbilirubinemia (n = 1; 350 mg fed state). All DLTs resolved with dose hold. 2 SAEs were considered treatment-related: G2 headache, which occurred during hospitalization for disease progression, and G3 hyperbilirubinemia. No treatment-related deaths occurred. 1 durable PR was observed and disease shrinkage was noted in another 3 patients, 1 of whom has BRAF V600E-mutant papillary thyroid cancer and continues on study after over 2 years with SD. Conclusions: In this ongoing study, the predicted efficacious exposure has been achieved and several patients have experienced clinical benefit. The safety profile to date indicates that RXDX-105 is tolerable at doses above the projected Ceff threshold. Dose escalation is ongoing. A Ph 1b basket study in pts with RET or BRAF alterations will commence after RP2D selection. Clinical trial information: NCT01877811.
Colonoscopy outreach increased CRC screening more than FIT outreach; both were better than usual care
Authors: Robert H. Fletcher
Journal: Annals of Internal Medicine (2017)

Source Citation Singal AG, Gupta S, Skinner CS, et al. Effect of colonoscopy outreach vs fecal immunochemical test outreach on colorectal cancer screening completion: a randomized clinical trial. JAMA. 2017;318:806-15. 28873161
Wnt/β‐catenin signaling controls intrahepatic biliary network formation in zebrafish by regulating notch activity
Authors: Juhoon So, Mehwish Khaliq, Kimberley Evason, Nikolay Ninov, Benjamin L. Martin, Didier Y.R. Stainier, Donghun Shin
Journal: Hepatology (2017)

Malformations of the intrahepatic biliary structure cause cholestasis, a liver pathology that corresponds to poor bile flow, which leads to inflammation, fibrosis, and cirrhosis. Although the specification of biliary epithelial cells (BECs) that line the bile ducts is fairly well understood, the molecular mechanisms underlying intrahepatic biliary morphogenesis remain largely unknown. Wnt/β‐catenin signaling plays multiple roles in liver biology; however, its role in intrahepatic biliary morphogenesis remains unclear. Using pharmacological and genetic tools that allow one to manipulate Wnt/β‐catenin signaling, we show that in zebrafish both suppression and overactivation of Wnt/β‐catenin signaling impaired intrahepatic biliary morphogenesis. Hepatocytes, but not BECs, exhibited Wnt/β‐catenin activity; and the global suppression of Wnt/β‐catenin signaling reduced Notch activity in BECs. Hepatocyte‐specific suppression of Wnt/β‐catenin signaling also reduced Notch activity in BECs, indicating a cell nonautonomous role for Wnt/β‐catenin signaling in regulating hepatic Notch activity. Reducing Notch activity to the same level as that observed in Wnt‐suppressed livers also impaired biliary morphogenesis. Intriguingly, expression of the Notch ligand genes jag1b and jag2b in hepatocytes was reduced in Wnt‐suppressed livers and enhanced in Wnt‐overactivated livers, revealing their regulation by Wnt/β‐catenin signaling. Importantly, restoring Notch activity rescued the biliary defects observed in Wnt‐suppressed livers. Conclusion: Wnt/β‐catenin signaling cell nonautonomously controls Notch activity in BECs by regulating the expression of Notch ligand genes in hepatocytes, thereby regulating biliary morphogenesis. (H epatology 2018;67:2352‐2366).
THU0136 Confidence in the diagnosis of early rheumatoid arthritis: a prospective follow-up of 270 early-arthritis patients
Authors: JM Berthelot, A Saraux, C Le Henaff, G Chalès, JB Thorel, S Hoang, D Baron, P LeGoff, P Youinou
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> The treatment of early rheumatoid arthritis (RA) should not be delayed. However, aggressive therapy is often introduced only when rheumatogists feel confident enough in their diagnosis of RA. <h3>Objectives</h3> We sought the confidence of both office-based-rheumatologists (OBR) and a college of 5 experts in their diagnosis of early-RA. <h3>Methods</h3> 270 patients with early-onset (&lt;1 year) arthritis were prospectively followed-up for 29 ± 11 months. At final examination, OBR and a college of 5 experts rated their confidence in the diagnosis of RA on 0–10 and 1–4 analogue scales respectively. <h3>Results</h3> 35/270 patients (13%) were still unclassified by their OBR. RA was diagnosed in 114 (42%), spondylarthropathy in 56 (21%), and miscellaneous other disorders in 65 (24%). The OBR confidence in their final diagnosis of RA was 7,5 ± 2,3 (68/114 patients with a confidence of 8/10 or more). A collegial diagnosis of certain RA (N = 57) or probable RA (N = 41) was made for 98 patients. The strength of OBR confidence in the diagnosis of RA was strongly correlated to that of the college (r = 0,892). Conversely, the fulfilment of 4 ACR criteria for RA since the first visit was associated with an only slight increase in final OBR confidence (7,9 ± 2,1). <h3>Conclusion</h3> Although only 13/114 (11%) patients finally classified as RA changed from diagnosis during follow-up, the final confidence of OBR in their diagnosis of RA were below 8/10 in 40%, and was only slightly improved by the fulfilment of ACR criteria. This emphasises the need for a close follow-up of these patients during the first years and the use of RA criteria for the classification of early arthritis.
Late Ca <sup>2+</sup> Sparks and Ripples During the Systolic Ca <sup>2+</sup> Transient in Heart Muscle Cells
Authors: Ewan D. Fowler, Cherrie H.T. Kong, Jules C. Hancox, Mark B. Cannell
Journal: Circulation Research (2017)

The development of a refractory period for Ca2+ spark initiation after Ca2+ release in cardiac myocytes should inhibit further Ca2+ release during the action potential plateau. However, Ca2+ release sites that did not initially activate or which have prematurely recovered from refractoriness might release Ca2+ later during the action potential and alter the cell-wide Ca2+ transient.To investigate the possibility of late Ca2+ spark (LCS) activity in intact isolated cardiac myocytes using fast confocal line scanning with improved confocality and signal to noise.We recorded Ca2+ transients from cardiac ventricular myocytes isolated from rabbit hearts. Action potentials were produced by electric stimulation, and rapid solution changes were used to modify the L-type Ca2+ current. After the upstroke of the Ca2+ transient, LCSs were detected which had increased amplitude compared with diastolic Ca2+ sparks. LCS are triggered by both L-type Ca2+ channel activity during the action potential plateau, as well as by the increase of cytosolic Ca2+ associated with the Ca2+ transient itself. Importantly, a mismatch between sarcoplasmic reticulum load and L-type Ca2+ trigger can increase the number of LCS. The likelihood of triggering an LCS also depends on recovery from refractoriness that appears after prior activation. Consequences of LCS include a reduced rate of decline of the Ca2+ transient and, if frequent, formation of microscopic propagating Ca2+ release events (Ca2+ ripples). Ca2+ ripples resemble Ca2+ waves in terms of local propagation velocity but spread for only a short distance because of limited regeneration.These new types of Ca2+ signaling behavior extend our understanding of Ca2+-mediated signaling. LCS may provide an arrhythmogenic substrate by slowing the Ca2+ transient decline, as well as by amplifying maintained Ca2+ current effects on intracellular Ca2+ and consequently Na+/Ca2+ exchange current.
Abstract P085: Use of Mobile Health (mHealth) Technology to Identify Targets for Improving Cardiovascular (CV) Health for Women in a Resource-limited Community: Observations From the Washington, D.C. CV Health and Needs Assessment
Authors: Samantha Thomas, Leah Yingling, Colby Ayers, Gwenyth Wallen, Marlene Peters-Lawrence, Alyssa Todaro-Brooks, Valerie Mitchell, Joel Adu-Brimpong, JaWanna Henry, Johnetta Saygbe, Dana Sampson, Ken Wiley, Jr., Avis Graham, Lennox Graham, Allan Johnson, Tiffany Powell-Wiley
Journal: Circulation (2016)

Introduction: Little is understood about using mHealth technology, particularly wearable devices, to assess CV health factors among women living in resource-limited communities. Hypothesis: mHealth technology could objectively identify targets to improve CV health outcomes for women living in resource-limited settings. Methods: We conducted the Washington, D.C. CV Health and Needs Assessment (NCT01927783), community-based participatory research in predominantly African American (AA), churches in city wards with lowest median household income. Participants underwent a day-long assessment to measure CV health factors [body mass index, fasting blood glucose and cholesterol, blood pressure, fruit/vegetable (F/V) intake, physical activity (PA), smoking]. Each participant was trained on using a mHealth wristband to monitor PA during a 30-day period. PA data was wirelessly uploaded to any PA-data collection hub located at the participating churches. Participants accessed their data on a secure account from a church or home computer, and investigators accessed de-identified data from a password-protected website. CV health factors were compared across weight classes. Results: Among female participants (n=78; 99% AA; mean age= 59 years), 90% had a body mass index (BMI) categorized as overweight or obese, with 30% Class-I obesity, 19% Class-II obesity, and 17% Class-III obesity [Table]. Across weight classes, PA (per mHealth wristband) decreased and self-reported sedentary time (ST) increased (p≤0.05). F/V intake was inadequate across all classes. Diastolic blood pressure (DBP) and glucose increased across weight classes (p≤0.05); however, cholesterol, glucose, and BP were near intermediate CV health goals. Conclusions: Decreased PA, increased ST, and inadequate F/V intake are potential community intervention targets for obese women in resource-limited Washington, D.C. areas. mHealth technology can assist in focusing intervention resources to improve CV health for women in resource-limited settings.
Programs for the persistence, vigilance and control of human CD8(+) lung-resident memory T cells (vol 17, pg 1467, 2016)
Authors: Pleun Hombrink, Christina Helbig, Ronald A. Backer, Berber Piet, Anna E. Oja, Regina Stark, Giso Brasser, Aldo Jongejan, René E. Jonkers, Benjamin Nota, Onur Basak, Hans C. Clevers, Perry D. Moerland, Derk Amsen, René A. W. van Lier
Journal: Nature Immunology (2017)
An informative intragenic microsatellite marker suggests the IL-1 receptor as a genetic modifier in cystic fibrosis
Authors: Frauke Stanke, Andreas Hector, Silke Hedtfeld, Dominik Hartl, Matthias Griese, Burkhard Tümmler, Marcus A. Mall
Journal: European Respiratory Journal (2017)

Recent studies in mice with cystic fibrosis (CF)-like lung disease identified interleukin (IL)-1 receptor (IL-1R) signalling as an important pathway triggering neutrophilic airway inflammation that constitutes a key risk factor in the onset and progression of lung disease in patients with CF [1–4]. These studies demonstrated that CF-like airway mucus obstruction causes epithelial hypoxia and necrosis, which in turn leads to the release of IL-1α from dying cells and activation of IL-1R signalling triggering neutrophilic inflammation and structural lung damage in vivo [1, 5]. Further, necrotic epithelial cells were detected in mucus-obstructed airways in lung sections from patients with CF [1]. Hypoxic cell death is a well-established trigger of sterile neutrophilic inflammation in many other organs and previous studies have identified IL-1R signalling as a key pathway required for triggering this inflammatory response to dying cells [6]. In addition, the gene encoding the IL-1R ligand IL-1β that is induced by bacterial infection has been identified as a genetic modifier of CF by independent North American and European CF modifier studies [7, 8]. Collectively, these studies suggest that IL-1R signalling may play an important role in the pathogenesis of neutrophilic inflammation that is invariably detected in the airways of patients with CF, in the absence and presence of bacterial infection [2, 3]. However, the role of IL-1R and its association with disease severity in patients with CF remains unknown. IL1R modifies disease severity in CF patients, emphasizing the significance of IL-1 signalling for CF pathogenesis <http://ow.ly/pIN730gL10G> We thank the organisers of the PopGen Biobank (<https://www.epidemiologie.uni-kiel.de/biobanking/biobank-popgen>) for providing DNA samples from a control population. Author contributions: conception and design of the study: F. Stanke, B. Tümmler, M.A. Mall; acquisition, analysis and interpretation of data: F. Stanke, A. Hector, S. Hedtfeld, D. Hartl, M. Griese, B. Tümmler, M.A. Mall; drafting the article or revising it critically for important intellectual content: F. Stanke, M.A. Mall.
Abstract 45: The Dark Side of Parkin: The Toxic Effects of Enhanced Parkin Levels
Authors: Sarah E Shires, Mark A Lampert, Dieter A Kubli, Eileen R Gonzalez, Nicole H Purcell, Åsa B Gustafsson
Journal: Circulation Research (2016)

Parkin is an E3 ubiquitin ligase that facilitates clearance of damaged mitochondria. We have previously shown that Parkin is important for cardiac adaptation to myocardial infarction and that loss of Parkin leads to accumulation of dysfunctional mitochondria. As Parkin is upregulated in response to cardiac stress, we sought to determine the effect of overexpression of Parkin in response to hemodynamic stress. Wild type (WT) and cardiac-specific Parkin transgenic (Parkin-TG) mice were subjected to trans-aortic constriction. Surprisingly, Parkin-TG mice rapidly developed hypertrophy, pulmonary edema, and ventricular dysfunction compared to WT mice. We observed no differences in either mitochondrial content or LC3 levels in Parkin-TG hearts, suggesting that the early progression to heart failure was not due to excessive mitophagy. Cardiac contractility is regulated by intracellular calcium and abnormalities in calcium homeostasis are associated with cardiac dysfunction. To investigate whether Parkin affects calcium homeostasis in the heart, we performed a subcellular fractionation on Parkin -/- , WT, and Parkin-TG hearts. We found that Parkin localizes to the sarcoplasmic reticulum where it ubiquitinates proteins under baseline conditions. Furthermore, Parkin-TG mice had increased levels Phospholamban (PLB), but did not alter SERCA, suggesting that Parkin may alter calcium homeostasis via PLB. In addition, loss of-function mutations in Parkin are found in patients with familial Parkinson’s disease (PD). Because Parkin is upregulated in response to stress, we overexpressed either WT Parkin or PD-associated Parkin mutants in HeLa cells to evaluate how elevated Parkin affects cell function. Interestingly, Parkin mutants, but not WT Parkin, caused rapid cell death when overexpressed in HeLa cells. Overexpressing Parkin mutants also triggered elevated autophagic activity, and cells with impaired autophagy were more susceptible to toxicity induced by overexpression of the Parkin mutants. This suggests that cells upregulate autophagy to protect against toxic Parkin mutants. Therefore, in addition to defects in mitophagy, upregulation of mutant Parkin in patients may also detrimentally contribute to cell death and development of disease.
Abstract 13842: Fat Free Mass Index is an Important Predictor for Future Cardiac Events in Patients After Cardiac Surgery
Authors: Daisuke Kinoshita, Tetsu Watanabe, Takayuki Sugai, Taku Toshima, Tetsuya Takahashi, Miyuki Yokoyama, Taro Narumi, Tetsuro Shishido, Isao Kubota
Journal: Circulation (2015)

Introduction: Sarcopenia is defined as skeletal muscle loss and dysfunction in aging and chronic disease, and associated with increased occurrence of complication after cardiac surgery. Fat-free mass index (FFMI) is used for the clinical diagnosis of sarcopenia. We previously reported sarcopenia evaluated by FFMI were associated with an unfavorable prognosis in patients with chronic heart failure (CHF). However, the impact of sarcopenia on long term prognosis after cardiac surgery remains to be determined Method and Resultss: We included 135 patients who underwent cardiac surgery including coronary artery bypass graft and valve replacement in our hospital between 2007 and 2009. We calculated fat free mass (FFM) by using following formula before cardiac surgery: FFM=7.38+0.02908хurinary creatinine (mg/day), and FFM was normalized by square of their height in meter (FFMI). Primary endpoint was major adverse cardiac events (MACE). Secondary endpoint was extended hospital length of stay. There were 3 perioperative deaths and 34 MACEs during the follow-up periods (median 3.8 years). Patients with MACE had significantly lower FFMI than those who without (12.7 vs 14.7 kg/m 2 , p&lt;0.01). Logistic analysis showed that FFMI was independently associated with extended length of hospital stay [Odds ratio: 0.82, 95% confidence interval (CI) 0.65-0.98, p&lt;0.05]. Multivariate Cox proportional hazard analysis revealed FFMI was independently associated with poor outcomes after adjustment of confounding factors (Hazard ratio: 0.86, 95% CI 0.75-0.98, p&lt;0.05). Kaplan-Meier analysis showed that a higher cardiac event rate was observed in patients with low FFMI compared with those who with high FFMI. Conclusions: Decreased FFMI was associated with poor outcomes after cardiac surgery.