bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognosis and causes of death of patients with acute exacerbation of fibrosing interstitial lung diseases
Authors: Salonen Johanna , Purokivi Minna , Bloigu Risto , Kaarteenaho Riitta 
Published: April 2020

BackgroundThe aim of this study was to compare the clinical characteristics, causes of death and factors impacting on the prognosis of patients with idiopathic pulmonary fibrosis (IPF) and other fibrosing interstitial lung disease (FILD) with a history of acute exacerbation (AE) of IPF or FILD.MethodsRetrospective data of hospital treatment periods caused by AE-IPF and AE-FILD were collected from medical records. Clinical features and survival data of IPF and non-IPF cases were evaluated and compared. The underlying and immediate causes of death were gathered from death certificates.ResultsA total of 128 patients fulfilled the criteria for inclusion. IPF (n=79/62%), rheumatoid arthritis-associated interstitial lung disease (RA-ILD; n=17/14%) and asbestosis (n=11/8.6%) were the most common FILD subgroups in the study. The median survival after hospitalisation in AE-IPF was 2.6 months compared with 21 months in other AE-FILDs (p<0.001). The survival difference was not explained by age, gender or pulmonary function test results at the time of hospitalisation. Patients with non-specific interstitial pneumonia and RA-ILD had the most favourable prognosis. ILD was the most common underlying cause of death in both patients with IPF and with other FILD accounting for 87% and 78% of deaths, respectively.ConclusionsWe detected a significantly longer survival in AE of patients with non-IPF compared with that of AE-IPFs. The prognosis of patients was affected by the underlying lung disease since pulmonary fibrosis was the underlying cause of death in the majority of all patients with FILD having experienced an AE.
Predictive value of non-specific bronchial challenge testing for respiratory symptoms and lung function in aluminium smelter workers
Authors: Abramson Michael J , Gwini Stella May , de Klerk Nicholas H , Del Monaco Anthony , Dennekamp Martine , Fritschi Lin , Dimitriadis Christina , Mohebbi Mohammadreza , Musk Arthur William (Bill) , Sim Malcolm Ross 
Published: April 2020

ObjectiveTo assess the predictive value of bronchial hyper-responsiveness (BHR) for the subsequent development of respiratory symptoms, airflow limitation and decline in lung function among aluminium smelter workers.MethodsAn inception cohort study of new employees at two Australian aluminium smelters was conducted. Participants completed a modified British Medical Research Council respiratory questionnaire, spirometry and a methacholine bronchial challenge test at baseline and at annual follow-up reviews. BHR was defined as PD20 ≤4000 µg. Poisson and mixed effects models were fitted to respiratory symptoms and lung function (forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC)).ResultsBaseline interview and lung function testing were completed by 278 workers, who were followed for a median of 4 years. BHR at baseline, present in 82 workers, was not associated with incident wheeze risk ratio (RR)=1.07 (95% CI 0.74 to 1.55) and cough RR=0.78 (95% CI 0.45, 1.35), but there was some increased risk of chest tightness RR=1.40 (95% CI 0.99, 1.98) after adjustment for age, sex, smoking and atopy. BHR at baseline was associated with lower FEV1 and FVC, although the rate of annual decline in FEV1 or FVC was similar between those with or without BHR. The specificity of BHR was 77% for wheeze, 70% for cough and 77% for chest tightness, but the sensitivity was poor, at 33%, 24% and 39%, respectively.ConclusionMethacholine challenge testing at entry to employment was not sufficiently predictive of later adverse respiratory outcomes, and notwithstanding the study limitations is unlikely to be a useful pre-employment or preplacement screening test in the aluminium smelting industry.
Increased extracellular vesicles mediate inflammatory signalling in cystic fibrosis
Authors: Useckaite Zivile , Ward Mark P , Trappe Anne , Reilly Rebecca , Lennon Jenny , Davage Holly , Matallanas David , Cassidy Hilary , Dillon Eugene T , Brennan Kiva , Doyle Sarah L , Carter Suzanne , Donnelly Seamas , Linnane Barry , McKone Edward F , McNally Paul , Coppinger Judith A 
Published: April 2020

RationaleMutations in the cystic fibrosis transmembrane regulator (CFTR) gene form the basis of cystic fibrosis (CF). There remains an important knowledge gap in CF as to how diminished CFTR activity leads to the dominant inflammatory response within CF airways.ObjectivesTo investigate if extracellular vesicles (EVs) contribute to inflammatory signalling in CF.MethodsEVs released from CFBE41o-, CuFi-5, 16HBE14o- and NuLi-1 cells were characterised by nanoparticle tracking analysis (NTA). EVs isolated from bronchoalveolar lavage fluid (BALF) from 30 people with CF (PWCF) were analysed by NTA and mass spectrometry and compared with controls. Neutrophils were isolated from the blood of 8 PWCF to examine neutrophil migration in the presence of CFBE41o- EVs.ResultsA significantly higher level of EVs were released from CFBE41o- (p<0.0001) and CuFi-5 (p=0.0209) relative to control cell lines. A significantly higher level of EVs were detected in BALF of PWCF, in three different age groups relative to controls (p=0.01, 0.001, 0.002). A significantly lower level of EVs were released from CFBE41o- (p<0.001) and CuFi-5 (p=0.0002) cell lines treated with CFTR modulators. Significant changes in the protein expression of 126 unique proteins was determined in EVs obtained from the BALF of PWCF of different age groups (p<0.001–0.05). A significant increase in chemotaxis of neutrophils derived from PWCF was observed in the presence of CFBE41o EVs (p=0.0024) compared with controls.ConclusionThis study demonstrates that EVs are produced in CF airway cells, have differential protein expression at different ages and drive neutrophil recruitment in CF.
The behavior of gradual types: a user study
Authors: Tunnell Wilson Preston , Greenman Ben , Pombrio Justin , Krishnamurthi Shriram 
Published: April 2020

There are several different gradual typing semantics, reflecting different trade-offs between performance and type soundness guarantees. Notably absent, however, are any data on which of these semantics developers actually prefer.
We begin to rectify this shortcoming by surveying professional developers, computer science students, and Mechanical Turk workers on their preferences between three gradual typing semantics. These semantics reflect important points in the design space, corresponding to the behaviors of Typed Racket, TypeScript, and Reticulated Python. Our most important finding is that our respondents prefer a runtime semantics that fully enforces statically declared types.
Inferring ownership domains from refinements
Authors: Khalaj Ebrahim , Abi-Antoun Marwan 
Published: April 2020

Ownership type qualifiers clarify aliasing invariants that cannot be directly expressed in mainstream programming languages. Adding qualifiers to code, however, often involves significant overhead and difficult interaction.
We propose an analysis to infer qualifiers in the code based on developer refinements that express strict encapsulation, logical containment and architectural tiers. Refinements include: <pre>makeOwnedBy</pre>, to make an object strictly encapsulated by another; <pre>makePartOf</pre>, to make an object logically contained in another; <pre>makePeer</pre>, to make two objects peers; <pre>makeParam</pre>, to make an object more accessible than the above choices; or <pre>makeShared</pre>, to allow an object to be globally aliased. If the code as-written matches the requested refinements, the analysis generates qualifiers that type-check; otherwise, it reports that the refinements do not match the code, so developers must investigate unexpected aliasing, change their understanding of the code and pick different refinements, or change the code and re-run the analysis.
We implement the analysis and confirm that refinements generate precise qualifiers that express strict encapsulation, logical containment and architectural tiers.
Rash: from reckless interactions to reliable programs
Authors: Hatch William Gallard , Flatt Matthew 
Published: April 2020

Command languages like the Bourne Shell provide a terse syntax for exploratory programming and system interaction. Shell users can begin to write programs that automate their tasks by simply copying their interactions verbatim into a script file. However, command languages usually scale poorly beyond small scripts, and they can be difficult to integrate into larger programs. General-purpose languages scale well, but are verbose and unwieldy for common interactive actions such as process composition.
We present Rash, a domain-specific command language embedded in Racket. Rash provides a terse and extensible syntax for interactive system administration and scripting, as well as easy composition of both Racket functions and operating system processes. Rash and normal Racket code can be nested together at the expression level, providing the benefits of a shell language and a general-purpose language together. Thus, Rash provides a gradual scale between shell-style interactions and general-purpose programming.
Tumor-Derived Prostaglandin E2 Promotes p50 NF-κB-Dependent Differentiation of Monocytic MDSCs
Authors: Porta Chiara , Consonni Francesca Maria , Morlacchi Sara , Sangaletti Sabina , Bleve Augusto , Totaro Maria Grazia , Larghi Paola , Rimoldi Monica , Tripodo Claudio , Strauss Laura , Banfi Stefania , Storto Mariangela , Pressiani Tiziana , Rimassa Lorenza , Tartari Silvia , Ippolito Alessandro , Doni Andrea , Soldà Giulia , Duga Stefano , Piccolo Viviana , Ostuni Renato , Natoli Gioacchino , Bronte Vincenzo , Balzac Fiorella , Turco Emilia , Hirsch Emilio , Colombo Mario P. , Sica Antonio 
Published: April 2020

Abstract

Myeloid-derived suppressor cells (MDSC) include immature monocytic (M-MDSC) and granulocytic (PMN-MDSC) cells that share the ability to suppress adaptive immunity and to hinder the effectiveness of anticancer treatments. Of note, in response to IFNγ, M-MDSCs release the tumor-promoting and immunosuppressive molecule nitric oxide (NO), whereas macrophages largely express antitumor properties. Investigating these opposing activities, we found that tumor-derived prostaglandin E2 (PGE2) induces nuclear accumulation of p50 NF-κB in M-MDSCs, diverting their response to IFNγ toward NO-mediated immunosuppression and reducing TNFα expression. At the genome level, p50 NF-κB promoted binding of STAT1 to regulatory regions of selected IFNγ-dependent genes, including inducible nitric oxide synthase (Nos2). In agreement, ablation of p50 as well as pharmacologic inhibition of either the PGE2 receptor EP2 or NO production reprogrammed M-MDSCs toward a NOS2low/TNFαhigh phenotype, restoring the in vivo antitumor activity of IFNγ. Our results indicate that inhibition of the PGE2/p50/NO axis prevents MDSC-suppressive functions and restores the efficacy of anticancer immunotherapy.

Significance:
Tumor-derived PGE2-mediated induction of nuclear p50 NF-κB epigenetically reprograms the response of monocytic cells to IFNγ toward an immunosuppressive phenotype, thus retrieving the anticancer properties of IFNγ.
Peptidylarginine Deiminase IV Regulates Breast Cancer Stem Cells via a Novel Tumor Cell–Autonomous Suppressor Role
Authors: Moshkovich Nellie , Ochoa Humberto J. , Tang Binwu , Yang Howard H. , Yang Yuan , Huang Jing , Lee Maxwell P. , Wakefield Lalage M. 
Published: April 2020

Abstract

Peptidylarginine deiminases (PADI) catalyze posttranslational modification of many target proteins and have been suggested to play a role in carcinogenesis. Citrullination of histones by PADI4 was recently implicated in regulating embryonic stem and hematopoietic progenitor cells. Here, we investigated a possible role for PADI4 in regulating breast cancer stem cells. PADI4 activity limited the number of cancer stem cells (CSC) in multiple breast cancer models in vitro and in vivo. Mechanistically, PADI4 inhibition resulted in a widespread redistribution of histone H3, with increased accumulation around transcriptional start sites. Interestingly, epigenetic effects of PADI4 on the bulk tumor cell population did not explain the CSC phenotype. However, in sorted tumor cell populations, PADI4 downregulated expression of master transcription factors of stemness, NANOG and OCT4, specifically in the cancer stem cell compartment, by reducing the transcriptionally activating H3R17me2a histone mark at those loci; this effect was not seen in the non-stem cells. A gene signature reflecting tumor cell–autonomous PADI4 inhibition was associated with poor outcome in human breast cancer datasets, consistent with a tumor-suppressive role for PADI4 in estrogen receptor–positive tumors. These results contrast with known tumor-promoting effects of PADI4 on the tumor stroma and suggest that the balance between opposing tumor cell–autonomous and stromal effects may determine net outcome. Our findings reveal a novel role for PADI4 as a tumor suppressor in regulating breast cancer stem cells and provide insight into context-specific effects of PADI4 in epigenetic modulation.

Significance:
These findings demonstrate a novel activity of the citrullinating enzyme PADI4 in suppressing breast cancer stem cells through epigenetic repression of stemness master transcription factors NANOG and OCT4.
IRE1α Disruption in Triple-Negative Breast Cancer Cooperates with Antiangiogenic Therapy by Reversing ER Stress Adaptation and Remodeling the Tumor Microenvironment
Authors: Harnoss Jonathan M. , Le Thomas Adrien , Reichelt Mike , Guttman Ofer , Wu Thomas D. , Marsters Scot A. , Shemorry Anna , Lawrence David A. , Kan David , Segal Ehud , Merchant Mark , Totpal Klara , Crocker Lisa M. , Mesh Kathryn , Dohse Monika , Solon Margaret , Modrusan Zora , Rudolph Joachim , Koeppen Hartmut , Walter Peter , Ashkenazi Avi 
Published: April 2020

Abstract

Cancer cells exploit the unfolded protein response (UPR) to mitigate endoplasmic reticulum (ER) stress caused by cellular oncogene activation and a hostile tumor microenvironment (TME). The key UPR sensor IRE1α resides in the ER and deploys a cytoplasmic kinase–endoribonuclease module to activate the transcription factor XBP1s, which facilitates ER-mediated protein folding. Studies of triple-negative breast cancer (TNBC)—a highly aggressive malignancy with a dismal posttreatment prognosis—implicate XBP1s in promoting tumor vascularization and progression. However, it remains unknown whether IRE1α adapts the ER in TNBC cells and modulates their TME, and whether IRE1α inhibition can enhance antiangiogenic therapy—previously found to be ineffective in patients with TNBC. To gauge IRE1α function, we defined an XBP1s-dependent gene signature, which revealed significant IRE1α pathway activation in multiple solid cancers, including TNBC. IRE1α knockout in TNBC cells markedly reversed substantial ultrastructural expansion of their ER upon growth in vivo. IRE1α disruption also led to significant remodeling of the cellular TME, increasing pericyte numbers while decreasing cancer-associated fibroblasts and myeloid-derived suppressor cells. Pharmacologic IRE1α kinase inhibition strongly attenuated growth of cell line–based and patient-derived TNBC xenografts in mice and synergized with anti-VEGFA treatment to cause tumor stasis or regression. Thus, TNBC cells critically rely on IRE1α to adapt their ER to in vivo stress and to adjust the TME to facilitate malignant growth. TNBC reliance on IRE1α is an important vulnerability that can be uniquely exploited in combination with antiangiogenic therapy as a promising new biologic approach to combat this lethal disease.

Significance:
Pharmacologic IRE1α kinase inhibition reverses ultrastructural distension of the ER, normalizes the tumor vasculature, and remodels the cellular TME, attenuating TNBC growth in mice.
Destablilization of TRAF6 by DRAK1 Suppresses Tumor Growth and Metastasis in Cervical Cancer Cells
Authors: Park Yuna , Pang Kyoungwha , Park Jinah , Hong Eunji , Lee Jihee , Ooshima Akira , Kim Hae-Suk , Cho Jae Hyun , Han Youngjin , Lee Cheol , Song Yong Sang , Park Kyung-Soon , Yang Kyung-Min , Kim Seong-Jin 
Published: April 2020

Abstract

The adaptor protein TNF receptor-associated factor 6 (TRAF6) is a key mediator in inflammation. However, the molecular mechanisms controlling its activity and stability in cancer progression remain unclear. Here we show that death-associated protein kinase-related apoptosis-inducing kinase 1 (DRAK1) inhibits the proinflammatory signaling pathway by targeting TRAF6 for degradation, thereby suppressing inflammatory signaling-mediated tumor growth and metastasis in advanced cervical cancer cells. DRAK1 bound directly to the TRAF domain of TRAF6, preventing its autoubiquitination by interfering with homo-oligomerization, eventually leading to autophagy-mediated degradation of TRAF6. Depletion of DRAK1 in cervical cancer cells resulted in markedly increased levels of TRAF6 protein, promoting activation of the IL1β signaling-associated pathway and proinflammatory cytokine production. DRAK1 was specifically underexpressed in metastatic cervical cancers and inversely correlated with TRAF6 expression in mouse xenograft model tumor tissues and human cervical tumor tissues. Collectively, our findings highlight DRAK1 as a novel antagonist of inflammation targeting TRAF6 for degradation that limits inflammatory signaling-mediated progression of advanced cervical cancer.

Significance:
Serine/threonine kinase DRAK1 serves a unique role as a novel negative regulator of the inflammatory signaling mediator TRAF6 in cervical cancer progression.
Technology in Nonprofit Organizations and Voluntary Action
Authors: McNutt John , Guo Chao , Goldkind Lauri , An Seongho 
Published: April 2020

Abstract
Information and communication technologies (ICT) are major forces shaping our current age. ICT affects many areas of human existence and influences the both human wellbeing and human evil. The nonprofit sector is already heavily involved in technology both as a way to pursue its mission and as an influential factor in the evolution of the sector. This article examines how technology affects the sector and how the sector uses technology in its work.
The article begins with a discussion of how the emerging information society will change the nonprofit sector. The sector that we know is grounded on our experience in the agrarian and industrial periods in the United States and Europe. We then explore how technology evolved in the sector. This is followed by an examination of technology and nonprofit organizational behavior. Technology changes the organizations that make use of its capacities. Next is a discussion of the types of technology that nonprofit organizations use. The final three sections deal with technology and social change, technology in nonprofit settings, and issues and trends. This article provides the reader with a current appreciation of the scholarly and professional literature on ICT in the nonprofit sector.
Potential Vorticity Mixing and Rapid Intensification in the Numerically Simulated Supertyphoon Haiyan (2013)
Authors: Tsujino Satoki , Kuo Hung-Chi 
Published: April 2020

AbstractThe inner-core dynamics of Supertyphoon Haiyan (2013) undergoing rapid intensification (RI) are studied with a 2-km-resolution cloud-resolving model simulation. The potential vorticity (PV) field in the simulated storm reveals an elliptical and polygonal-shaped eyewall at the low and middle levels during RI onset. The PV budget analysis confirms the importance of PV mixing at this stage, that is, the asymmetric transport of diabatically generated PV to the storm center from the eyewall and the ejection of PV filaments outside the eyewall. We employ a piecewise PV inversion (PPVI) and an omega equation to interpret the model results in balanced dynamics. The omega equation diagnosis suggests eye dynamical warming is associated with the PV mixing. The PPVI indicates that PV mixing accounts for about 50% of the central pressure fall during RI onset. The decrease of central pressure enhances the boundary layer (BL) inflow. The BL inflow leads to contraction of the radius of the maximum tangential wind (RMW) and the formation of a symmetric convective PV tower inside the RMW. The eye in the later stage of the RI is warmed by the subsidence associated with the convective PV towers. The results suggest that the pressure change associated with PV mixing, the increase of the symmetric BL radial inflow, and the development of a symmetric convective PV tower are the essential collaborating dynamics for RI. An experiment with 500-m resolution shows that the convergence of BL inflow can lead to an updraft magnitude of 20 m s−1and to a convective PV tower with a peak value of 200 PVU (1 PVU = 10−6K kg−1m2s−1).
The Dynamics of Mixed Layer Deepening during Open-Ocean Convection
Authors: Sohail Taimoor , Gayen Bishakhdatta , McC. Hogg Andrew 
Published: April 2020

AbstractOpen-ocean convection is a common phenomenon that regulates mixed layer depth and ocean ventilation in the high-latitude oceans. However, many climate model simulations overestimate mixed layer depth during open-ocean convection, resulting in excessive formation of dense water in some regions. The physical processes controlling transient mixed layer depth during open-ocean convection are examined using two different numerical models: a high-resolution, turbulence-resolving nonhydrostatic model and a large-scale hydrostatic ocean model. An isolated destabilizing buoyancy flux is imposed at the surface of both models and a quasi-equilibrium flow is allowed to develop. Mixed layer depth in the turbulence-resolving and large-scale models closely aligns with existing scaling theories. However, the large-scale model has an anomalously deep mixed layer prior to quasi-equilibrium. This transient mixed layer depth bias is a consequence of the lack of resolved turbulent convection in the model, which delays the onset of baroclinic instability. These findings suggest that in order to reduce mixed layer biases in ocean simulations, parameterizations of the connection between baroclinic instability and convection need to be addressed.