tbuckley/cabot-search huggingface dataset:
Impact of sleep alterations on weaning duration of mechanically ventilated patients: how much is bad?
Authors: Antonio M. Esquinas, Joerg S. Steier, Habib M.R. Karim
Journal: European Respiratory Journal (2018)

<b>Sleep disturbance/atypical sleep is common in critically ill patients; however, precise classification of&nbsp;atypical sleep and clinical implication establishment will require direct future research</b>http://ow.ly/pYSF30ketxz
Atopic dermatitis: the skin barrier and beyond
Authors: T. Tsakok, R. Woolf, C.H. Smith, S. Weidinger, C. Flohr
Journal: British Journal of Dermatology (2018)

BackgroundAtopic dermatitis is the most common chronic inflammatory skin disorder, affecting up to 20% of children and 10% of adults in industrialized countries. This highly debilitating condition poses a considerable burden to both the individual and society at large. The pathophysiology of atopic dermatitis is complex, encompassing both genetic and environmental risk factors.
Conflicting vascular and metabolic impact of the IL-33/sST2 axis
Authors: Raffaele Altara, Rana Ghali, Ziad Mallat, Alessandro Cataliotti, George W Booz, Fouad A Zouein
Journal: Cardiovascular Research (2018)

Interleukin 33 (IL-33), which is expressed by several immune cell types, endothelial and epithelial cells, and fibroblasts, is a cytokine of the IL-1 family that acts both intra- and extracellularly to either enhance or resolve the inflammatory response. Intracellular IL-33 acts in the nucleus as a regulator of transcription. Once released from cells by mechanical stress, inflammatory cytokines, or necrosis, extracellular IL-33 is proteolytically processed to act in an autocrine/paracrine manner as an 'alarmin' on neighbouring or various immune cells expressing the ST2 receptor. Thus, IL-33 may serve an important role in tissue preservation and repair in response to injury; however, the actions of IL-33 are dampened by a soluble form of ST2 (sST2) that acts as a decoy receptor and is produced by endothelial and certain immune cells. Accumulating evidence supports the conclusion that sST2 is a biomarker of vascular health with diagnostic and/or prognostic value in various cardiovascular diseases, including coronary artery disease, myocardial infarction, atherosclerosis, giant-cell arteritis, acute aortic dissection, and ischaemic stroke, as well as obesity and diabetes. Although sST2 levels are positively associated with cardiovascular disease severity, the assumption that IL-33 is always beneficial is naïve. It is increasingly appreciated that the pathophysiological importance of IL-33 is highly dependent on cellular and temporal expression. Although IL-33 is atheroprotective and may prevent obesity and type 2 diabetes by regulating lipid metabolism, IL-33 appears to drive endothelial inflammation. Here, we review the current knowledge of the IL-33/ST2/sST2 signalling network and discuss its pathophysiological and translational implications in cardiovascular diseases.
Synaptojanin and Endophilin Mediate Neck Formation during Ultrafast Endocytosis
Authors: Shigeki Watanabe, Lauren Elizabeth Mamer, Sumana Raychaudhuri, Delgermaa Luvsanjav, Julia Eisen, Thorsten Trimbuch, Berit Söhl-Kielczynski, Pascal Fenske, Ira Milosevic, Christian Rosenmund, Erik M. Jorgensen
Journal: Neuron (2018)
Abstract 5184: Expression and role of regulator of G-protein signing 5 in squamous cell carcinoma of the tongue
Authors: Yushi Abe, Hirohisa Yano, Jun Akiba, Reiichirou kondou, Sachiko Ogasawara, Ken Nakamura, Zingo Kusukawa
Journal: Cancer Research (2018)

Abstract Objective: Regulator of G-protein signing (RGS) 5 is a member of the RGS family and acts as GTPase-activating proteins for heterotorimeric G protein αsubunits, negatively regulating G-protein signaling. RGS5 was reportedly expressed in the heart, lung, skeletal muscle and small intestine and relates with tumor angiogenesis and gestational hypertension. It was reported that RGS5 was related with the invasion and metastasis of cancers, such as non-small lung cancer and hepatocellular carcinoma. In the present study, we examined RGS5 expression and its relation with invasion in squamous cell carcinoma (SCC) of the tongue. Materials and Methods: For immunohistochemical analysis for RGS5, we used SCC tissues of the tongue obtained from 43 patients who underwent resection at Kurume University Hospital from 2011 to 2015. The staining intensity was graded as 0, negative; 1, weak; 2, moderate; 3, strong. The staining intensity in the normal epithelium was used as an internal control. We examined relationship between RGS5 expression in invasive portions and clinicopathological features (e.g., lymph node metastasis, depth of tumor, and mode of invasion, and so forth). Mode of invasion was classified into 3 levels, i.e., IFNa (expansive), IFNc (invasive), IFNb (between INFa and INFc). Depth of tumor was measured and classified into 2 levels: &amp;lt; 5 mm and ≥ 5mm. Comparison and estimation of cumulative survival rates were performed using the Kaplan-Meier curves and log rank test. Result: Non-cancerous squamous cells expressed RGS5 solely in nucleus. SCC cells in superficial portion of tumor nodules often expressed weak nuclear RGS5 expression. In invasive portions of the tumor nodules, SCC cells expressed significantly lower nuclear and higher cytoplasmic RGS5 expression. A significant correlation was found between the expression score of RGS5 at invasive portions and mode of invasion (P=0.009). When the 43 cases were subdivided into two groups, i.e., expression group (score 1-3) and non-expression group (score 0), significant differences were observed in mode of invasion (P=0.0042), lymph node metastasis (p=0.0314), depth of tumor (p=0.0239) between the two groups. The log-rank test revealed that postoperative early lymph node metastasis was significantly higher in the expression group (p= 0.0415). Conclusion: This study suggests that RGS5 expression is related with tumor invasion in SCC of the tongue and that RGS5 can be a predictor of postoperative early lymph node metastasis. Citation Format: Yushi Abe, Hirohisa Yano, Jun Akiba, Reiichirou kondou, Sachiko Ogasawara, Ken Nakamura, Zingo Kusukawa. Expression and role of regulator of G-protein signing 5 in squamous cell carcinoma of the tongue [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 5184.
Abstract 3269A: 2-Hydroxyflavanone: A novel estrogen receptor alpha downregulator with potent antitumor effect in breast cancer
Authors: Sharad S. Singhal, Shireen Chikara, Lokesh Nagaprashantha, Jyotsana Singhal, David Horne, Sanjay Awasthi
Journal: Cancer Research (2018)

Abstract Breast cancer (BC) remains one of the major causes of cancer deaths in women. 2Hydroxyflavanone (2HF), a constituent of citrus fruits, inhibits growth of human breast cancer cell lines in culture. The present study was undertaken to determine in vivo efficacy of 2HF against MDAMB231 human breast cancer xenografts. The 2HF administration retarded growth of MDAMB231 cells subcutaneously implanted in female nude mice without causing weight loss or any other side effects. The 2HF mediated suppression of MDAMB231 xenograft growth correlated with reduced cell proliferation as revealed by immunohistochemical analysis for Ki67 expression. Analysis of the vasculature in the tumors from 2HF treated mice indicated smaller vessel area compared with control tumors based on immunohistochemistry for angiogenesis marker CD31. The 2HF mediated inhibition of angiogenesis in vivo correlated with downregulation of vascular endothelial growth factor (VEGF) level in the tumor. Consistent with these results, 2HF treatment suppressed cell cycle regulators levels in cultured MDAMB231 cells. Moreover, the 2HF treated MDAMB231 cells exhibited reduced capacity for migration compared with vehicle-treated control cells. In addition, 2HF administration elicits apoptotic response as judged by annexin V and PI staining and TUNEL assay. 2HF treatment reduced the levels of ER alpha in ER positive MCF7 breast cancer cells. In conclusion, the present study demonstrates in vivo anticancer efficacy of 2HF against MDAMB231 xenografts in association with reduced cell proliferation and suppression of neovascularization. Our results indicate that 2HF is a promising anticancer agent for breast cancer due to its ability to collectively inhibit major regulators of breast cancer including RLIP76, ER alpha, and HER2. Interestingly, a spontaneously immortalized non-tumorigenic normal human mammary epithelial cell line (MCF10A) is significantly more resistant to 2HF mediated apoptosis compared with breast cancer cells, demonstrating selectivity of 2HF towards malignant breast cells. These preclinical observations merit clinical investigation to determine efficacy of 2HF against human breast cancers. (This work was supported in part by the Department of Defense grant W81XWH 16 1 0641. Funding from the Beckman Research Institute of City of Hope is also acknowledged). Citation Format: Sharad S. Singhal, Shireen Chikara, Lokesh Nagaprashantha, Jyotsana Singhal, David Horne, Sanjay Awasthi. 2-Hydroxyflavanone: A novel estrogen receptor alpha downregulator with potent antitumor effect in breast cancer [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 3269A.
A non-myeloablative conditioning approach for long-term engraftment of human and mouse hematopoietic stem cells
Authors: Wei Du, Wei Liu, Benjamin Mizukawa, Xun Shang, Jared Sipple, Mark Wunderlich, Hartmut Geiger, Stella Davies, James Mulloy, Qishen Pang, Yi Zheng
Journal: Leukemia (2018)
Linking Endogenous Factor Xa Activity, a Biologically Relevant Pharmacodynamic Marker, to Edoxaban Plasma Concentrations and Clinical Outcomes in the ENGAGE AF-TIMI 48 Trial
Authors: Ophelia Q.P. Yin, Elliott M. Antman, Eugene Braunwald, Michele F. Mercuri, Raymond Miller, David Morrow, Christian T. Ruff, Kenneth Truitt, Jeffrey I. Weitz, Robert P. Giugliano
Journal: Circulation (2018)

Background: We previously reported exogenous antifactor Xa (FXa) activity as a pharmacokinetic surrogate marker for edoxaban plasma concentrations. Inhibition of endogenous FXa activity is a more biologically relevant pharmacodynamic measure of edoxaban activity. Here we describe the value of endogenous FXa activity as a pharmacodynamic marker linking edoxaban concentrations and clinical outcomes in the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction Study 48). Methods: In ENGAGE AF-TIMI 48, edoxaban was administered in higher dose (60/30 mg QD) and lower dose (30/15 mg QD) regimens. Both regimens incorporated a 50% dose reduction in patients with characteristics known to increase edoxaban concentration. Pharmacokinetic-pharmacodynamic modeling was performed in a subgroup of 3029 patients who had samples collected for endogenous FXa activity (measured using an assay after endogenous FX was activated with Russell viper venom). Results: Endogenous FXa activity decreased with increasing edoxaban concentrations of ≤440 ng/mL, indicating that inhibition of endogenous FXa activity is saturated above this concentration threshold. Baseline endogenous FXa activity averaged 92.1±20.9% (relative to normal control samples) and was lower with older age, with lower body weight, and in male patients. Model-predicted 24-hour average percentages of inhibition of endogenous FXa activity were 35.8±5.18, 29.1±3.92, 21.9±3.80, and 16.4±2.70 for the higher dose edoxaban regimen 60 mg, dose-reduced higher dose edoxaban regimen 30 mg, lower dose edoxaban regimen 30 mg, and dose-reduced lower dose edoxaban regimen 15 mg groups, respectively. A greater average percentage of inhibition of endogenous FXa activity was associated with a lower incidence of ischemic stroke or systemic embolism and a higher risk of major bleeding ( P &lt;0.001). In a typical subject, the predicted risks for the 10th and 90th percentiles of inhibition of endogenous FXa activity were 1.04% and 0.57% for incidence of ischemic stroke or systemic embolism and 1.35% and 2.33% for major bleeding, respectively. Conclusions: The extent of inhibition of endogenous FXa activity is influenced by edoxaban dosing and clinical characteristics, and it is associated with both antithrombotic benefit and risk of bleeding. This approach of linking endogenous FXa activity to clinical outcomes may be used to guide dose selection in future clinical trials, monitor patients in certain clinical scenarios, or refine the doses of oral FXa inhibitors in patients who require precise anticoagulation therapy. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00781391.
Pathways to Cardiorenal Complications in Type 2 Diabetes Mellitus
Authors: Naveed Sattar, Darren K. McGuire
Journal: Circulation (2018)

ccasionally, an unexpected clinical trial result makes us reevaluate what we think we know about pathogenic pathways linking 1 condition to another.The EMPA-REG OUTCOME trial ([Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) results demonstrating cardiovascular and kidney benefits with the type 2 diabetes mellitus (T2DM) drug empagliflozin, 1 a sodium-glucose cotransporter 2 inhibitor (SGLT2i), did just this.It forced us to reconsider and expand our notions of the risk pathways leading to specific T2DM complications, particularly cardiovascular death, heart failure (HF), and kidney disease.For decades, the cardiac risks of T2DM had been selectively focused on incremental atherosclerotic vascular disease (ASCVD) risk.We were comfortable in the knowledge that ASCVD risk associated with T2DM stems from associated hypertension, dyslipidemia, hyperglycemia, prothrombotic tendencies, insulin resistance, endothelial dysfunction, and inflammatory stress.Thus, whenever the potential for T2DM drugs to mitigate cardiovascular risk was considered, it was most often within this narrow ASCVD and related risk framework.Likewise, cardiovascular outcomes trials in the T2DM field have focused primarily on ASCVD outcomes.Certainly lessening ASCVD risk matters, with substantial successes realized in patients with T2DM over recent decades-mostly reductions of nonfatal myocardial infarction and stroke risks-via better blood pressure and low-density lipoprotein cholesterol management, with less certainty with regard to the influence of glucose lowering on ASCVD risk.However, then came the EMPA-REG OUTCOME results, demonstrating risk reduction for cardiovascular death and hospitalization for HF with empagliflozin. 1 These results were most surprising for the speed and magnitude of reduction in cardiovascular risks, as well as favorable effects on kidney outcomes-findings broadly confirmed with the SGLT2i canagliflozin in the CANVAS trial program (Canagliflozin Cardiovascular Assessment Study). 2 As a result, researchers and providers alike began asking how the SGLT2is could lead to such benefits.HF is a common complication of T2DM, now occurring more frequently than incident myocardial infarction, thus hinting at non-ASCVD pathways to HF.Although several hypotheses have emerged with regard to the mechanism of HF and cardiovascular death benefit of the SGLT2is, indirect evidence suggests a potential role of modest and sustained plasma volume reduction via effects that likely include reduction of cardiac pre-and afterload, thereby favorably affecting cardiac workload and myocardial energetics.Because of hyperglycemia-associated glomerular hyperfiltration and increased reclamation of filtered glucose, and with it sodium by SGTL2 in patients with T2DM, these patients tend to have persistent mild intravascular volume expansion. 3The HF benefits observed with SGLT2is added to the existing knowledge regarding HF risk in T2DM have helped reshape our understanding of the patho-
Abstract LB-039: PDX and PDX-derived cell line development from peritoneal metastasis of micropapillary serous carcinoma of the ovary
Authors: Elien De Thaye, An Vermeulen, Wim Ceelen, Jan Van Bocxlaer, Olivier De Wever
Journal: Cancer Research (2018)

Abstract Peritoneal spread is an indicator of poor prognosis in patients with micropapillary serous carcinoma of the ovary. In general, these patients are treated by surgical cytoreduction followed by intraperitoneal chemotherapy. Although this strategy has encouraging efficacy, personalized treatment regimens may potentially further improve efficacy of cancer management. To investigate such a personalized approach, patient-derived xenografts (PDX) and PDX-derived cell lines from peritoneal implants from micropapillary serous carcinoma of the ovary are developed and characterized. Freshly resected peritoneal implants from consenting donors were obtained. A cell suspension was made and immediately subperitoneally implanted in female immunocompromised mice and expanded as peritoneal metastasis (PM)-PDX. A transplantable PM-PDX was established from 1/1 donor. Histology confirmed the micropapillary and cribriform growth pattern, which was further characterized by intraluminal tumor budding. PM-PDX dissociated cells were maintained as a plastic-adherent cell culture up to 20 passages. The PM-PDX derived cell line is characterized by an epithelial morphotype with doubling time of 42 hours and shows a colony formation efficiency of 25-40% independent of estrogen signaling. The cell line is sensitive to the microtubule stabilizing agent paclitaxel (IC50 = 1.485 nM) and the allosteric MEK inhibitor trametinib (IC50 = 1.299 nM). Future work will provide insights on the mutational status of RAS and RAF, important indicators of potential MEK-targeted personalized medicine. Citation Format: Elien De Thaye, An Vermeulen, Wim Ceelen, Jan Van Bocxlaer, Olivier De Wever. PDX and PDX-derived cell line development from peritoneal metastasis of micropapillary serous carcinoma of the ovary [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 LB-039.
EZH2-Mediated Primary Cilium Deconstruction Drives Metastatic Melanoma Formation
Authors: Daniel Zingg, Julien Debbache, Rodrigo Peña-Hernández, Ana T. Antunes, Simon M. Schaefer, Phil F. Cheng, Dario Zimmerli, Jessica Haeusel, Raquel R. Calçada, Eylul Tuncer, Yudong Zhang, Raphaël Bossart, Kwok-Kin Wong, Konrad Basler, Reinhard Dummer, Raffaella Santoro, Mitchell P. Levesque, Lukas Sommer
Journal: Cancer Cell (2018)
Cardiomyocyte-specific deficiency of HSPB1 worsens cardiac dysfunction by activating NFκB-mediated leucocyte recruitment after myocardial infarction
Authors: Yana Wang, Jiali Liu, Qiuyue Kong, Hao Cheng, Fei Tu, Peng Yu, Ying Liu, Xiaojin Zhang, Chuanfu Li, Yuehua Li, Xinxu Min, Shuya Du, Zhengnian Ding, Li Liu
Journal: Cardiovascular Research (2018)

Abstract Aims Inadequate healing after myocardial infarction (MI) leads to heart failure and fatal ventricular rupture, while optimal healing requires timely induction and resolution of inflammation. This study tested the hypothesis that heat shock protein B1 (HSPB1), which limits myocardial inflammation during endotoxemia, modulates wound healing after MI. Methods and results To test this hypothesis, cardiomyocyte-specific HSPB1 knockout (Hspb1−/−) mice were generated using the Cre-LoxP recombination system. MI was induced by ligation of the left anterior descending coronary artery in Hspb1−/− and wild-type (WT) littermates. HSPB1 was up-regulated in cardiomyocytes of WT animals in response to MI, and deficiency of cardiomyocyte HSPB1 increased MI-induced cardiac rupture and mortality within 21 days after MI. Serial echocardiography showed more aggravated remodelling and cardiac dysfunction in Hspb1−/− mice than in WT mice at 1, 3, and 7 days after MI. Decreased collagen deposition and angiogenesis, as well as increased MMP2 and MMP9 activity, were also observed in Hspb1−/− mice compared with WT controls after MI, using immunofluorescence, polarized light microscopy, and zymographic analyses. Notably, Hspb1−/− hearts exhibited enhanced and prolonged leucocyte infiltration, enhanced expression of inflammatory cytokines, and enhanced TLR4/MyD88/NFκB activation compared with WT controls after MI. In-depth molecular analyses in both mice and primary cardiomyocytes demonstrated that cardiomyocyte-specific knockout of HSPB1 increased nuclear factor-κB (NFκB) activation, which promoted the expression of proinflammatory mediators. This led to increased leucocyte recruitment, thereby to excessive inflammation, ultimately resulting in adverse remodelling, cardiac dysfunction, and cardiac rupture following MI. Conclusion These data suggest that HSPB1 acts as a negative regulator of NFκB-mediated leucocyte recruitment and the subsequent inflammation in cardiomyocytes. Cardiomyocyte HSPB1 is required for wound healing after MI and could be a target for myocardial repair in MI patients.
Abstract 1773: HPN424, a half-life extended, PSMA/CD3-specific TriTAC for the treatment of metastatic prostate cancer
Authors: Bryan Lemon, Wade Aaron, Richard Austin, Patrick Baeuerle, Manasi Barath, Adrie Jones, Susan D. Jones, Kathryn Kwant, Che-Leung Law, Anna Muchnik, Kenneth Sexton, Laurie Tatalick, Holger Wesche, Timothy Yu
Journal: Cancer Research (2018)

Abstract Metastatic, castrate-resistant prostate cancer (mCRPC) is diagnosed in up to 50,000 patients each year in the US alone, and roughly 27,000 patients will succumb to it every year. Once metastasized beyond regional lymph nodes, the 5-year survival rate is 30%. While novel therapeutics like abiraterone and enzalutamide have improved the treatment options for mCRPC, no curative treatment is available, and new therapies are urgently needed. HPN424 is a ~50-kDa antibody derivative called TriTAC (Tri-specific T cell Activating Construct) under development for the treatment of mCRPC. It is designed to simultaneously bind to CD3ε on T cells and to prostate specific membrane antigen (PSMA, FOLH1) on prostate cancer cells. A third domain of HPN424 binds non-covalently to serum albumin for extension of serum half-life. PSMA is expressed in &amp;gt;90% of malignant lesions of patients, and outside the central nervous system, its expression on normal tissue is largely restricted to the prostate. HPN424 binds human PSMA with sub-nanomolar affinity. When incubated in co-cultures with resting, human T cells and prostate cancer cells, it activates T cells and induces cytokine production, proliferation and redirected target cell killing with EC50 values in the single digit picomolar range. When administered to mice bearing human prostate cancer xenografts and human T cells, HPN424 eradicates subcutaneous tumors. The affinities of HPN424 for human and cynomolgus monkey CD3 and albumin are comparable, while HPN424 binds only marginally to cynomolgus PSMA. HPN424 is very well tolerated in non-human primates, even at high doses, indicating that CD3-binding has little if any pharmacological effect in the absence of target binding. Pharmacokinetic analysis supports weekly administration in humans. Our preclinical data suggest that HPN424 will be highly efficacious, safe and convenient for the treatment of patients with mCRPC. Citation Format: Bryan Lemon, Wade Aaron, Richard Austin, Patrick Baeuerle, Manasi Barath, Adrie Jones, Susan D. Jones, Kathryn Kwant, Che-Leung Law, Anna Muchnik, Kenneth Sexton, Laurie Tatalick, Holger Wesche, Timothy Yu. HPN424, a half-life extended, PSMA/CD3-specific TriTAC for the treatment of metastatic prostate cancer [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 1773.