bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potentiation of long-acting β2-agonist and glucocorticoid responses in human airway epithelial cells by modulation of intracellular cAMP
Authors: Kim Yechan , Hou Vincent , Huff Ryan D. , Aguiar Jennifer A. , Revill Spencer , Tiessen Nicholas , Cao Quynh , Miller Matthew S. , Inman Mark D. , Ask Kjetil , Doxey Andrew C. , Hirota Jeremy A. 
Published: October 2021

Abstract
Introduction
Over 300 million people in the world live with asthma, resulting in 500,000 annual global deaths with future increases expected. It is estimated that around 50–80% of asthma exacerbations are due to viral infections. Currently, a combination of long-acting beta agonists (LABA) for bronchodilation and glucocorticoids (GCS) to control lung inflammation represent the dominant strategy for the management of asthma, however, it is still sub-optimal in 35–50% of moderate-severe asthmatics resulting in persistent lung inflammation, impairment of lung function, and risk of mortality. Mechanistically, LABA/GCS combination therapy results in synergistic efficacy mediated by intracellular cyclic adenosine monophosphate (cAMP).

Hypothesis
Increasing intracellular cAMP during LABA/GCS combination therapy via inhibiting phosphodiesterase 4 (PDE4) and/or blocking the export of cAMP by ATP Binding Cassette Transporter C4 (ABCC4), will potentiate anti-inflammatory responses of mainstay LABA/GCS therapy.

Methods
Expression and localization experiments were performed using in situ hybridization and immunohistochemistry in human lung tissue from healthy subjects, while confirmatory transcript and protein expression analyses were performed in primary human airway epithelial cells and cell lines. Intervention experiments were performed on the human airway epithelial cell line, HBEC-6KT, by pre-treatment with combinations of LABA/GCS with PDE4 and/or ABCC4 inhibitors followed by Poly I:C or imiquimod challenge as a model for viral stimuli. Cytokine readouts for IL-6, IL-8, CXCL10/IP-10, and CCL5/RANTES were quantified by ELISA.

Results
Using archived human lung and human airway epithelial cells, ABCC4 gene and protein expression were confirmed in vitro and in situ. LABA/GCS attenuation of Poly I:C or imiquimod-induced IL-6 and IL-8 were potentiated with ABCC4 and PDE4 inhibition, which was greater when ABCC4 and PDE4 inhibition was combined. Modulation of cAMP levels had no impact on LABA/GCS modulation of Poly I:C-induced CXCL10/IP-10 or CCL5/RANTES.

Conclusion
Modulation of intracellular cAMP levels by PDE4 or ABCC4 inhibition potentiates LABA/GCS efficacy in human airway epithelial cells challenged with viral stimuli. The data suggest further exploration of the value of adding cAMP modulators to mainstay LABA/GCS therapy in asthma for potentiated anti-inflammatory efficacy.
Dual inhibition of αvβ6 and αvβ1 reduces fibrogenesis in lung tissue explants from patients with IPF
Authors: Decaris Martin L. , Schaub Johanna R. , Chen Chun , Cha Jacob , Lee Gail G. , Rexhepaj Megi , Ho Steve S. , Rao Vikram , Marlow Megan M. , Kotak Prerna , Budi Erine H. , Hooi Lisa , Wu Jianfeng , Fridlib Marina , Martin Shamra P. , Huang Shaoyi , Chen Ming , Muñoz Manuel , Hom Timothy F. , Wolters Paul J. , Desai Tushar J. , Rock Fernando , Leftheris Katerina , Morgans David J. , Lepist Eve-Irene , Andre Patrick , Lefebvre Eric A. , Turner Scott M. 
Published: October 2021

Abstract
Rationale
αv integrins, key regulators of transforming growth factor-β activation and fibrogenesis in in vivo models of pulmonary fibrosis, are expressed on abnormal epithelial cells (αvβ6) and fibroblasts (αvβ1) in fibrotic lungs.

Objectives
We evaluated multiple αv integrin inhibition strategies to assess which most effectively reduced fibrogenesis in explanted lung tissue from patients with idiopathic pulmonary fibrosis.

Methods
Selective αvβ6 and αvβ1, dual αvβ6/αvβ1, and multi-αv integrin inhibitors were characterized for potency, selectivity, and functional activity by ligand binding, cell adhesion, and transforming growth factor-β cell activation assays. Precision-cut lung slices generated from lung explants from patients with idiopathic pulmonary fibrosis or bleomycin-challenged mouse lungs were treated with integrin inhibitors or standard-of-care drugs (nintedanib or pirfenidone) and analyzed for changes in fibrotic gene expression or TGF-β signaling. Bleomycin-challenged mice treated with dual αvβ6/αvβ1 integrin inhibitor, PLN-74809, were assessed for changes in pulmonary collagen deposition and Smad3 phosphorylation.

Measurements and main results
Inhibition of integrins αvβ6 and αvβ1 was additive in reducing type I collagen gene expression in explanted lung tissue slices from patients with idiopathic pulmonary fibrosis. These data were replicated in fibrotic mouse lung tissue, with no added benefit observed from inhibition of additional αv integrins. Antifibrotic efficacy of dual αvβ6/αvβ1 integrin inhibitor PLN-74809 was confirmed in vivo, where dose-dependent inhibition of pulmonary Smad3 phosphorylation and collagen deposition was observed. PLN-74809 also, more potently, reduced collagen gene expression in fibrotic human and mouse lung slices than clinically relevant concentrations of nintedanib or pirfenidone.

Conclusions
In the fibrotic lung, dual inhibition of integrins αvβ6 and αvβ1 offers the optimal approach for blocking fibrogenesis resulting from integrin-mediated activation of transforming growth factor-β.
Small-molecule Akt-activation in airway cells induces NO production and reduces IL-8 transcription through Nrf-2
Authors: Gopallawa Indiwari , Kuek Li Eon , Adappa Nithin D. , Palmer James N. , Lee Robert J. 
Published: October 2021

Abstract
Background
The non-cancerous functions of Akt in the airway are understudied. In some tissues, Akt phosphorylates and activates endothelial nitric oxide synthase (eNOS) to produce nitric oxide (NO) that has anti-inflammatory effects. NO production has antibacterial and antiviral effects in the airway, and increasing NO may be a useful anti-pathogen strategy. Akt also stimulates the nuclear factor erythroid 2–related factor 2 (Nrf-2) transcription factor, which transcribes antioxidant genes. Therefore, we hypothesized that activation of the Akt/eNOS pathway, which also activates Nrf-2, may have protective effects in human airway cells against injury.

Methods
To directly test the effects of Akt signaling in the airway, we treated A549 and 16HBE cells as well as primary bronchial, nasal, and type II alveolar epithelial cells with small molecule Akt activator SC79. We examined the effects of SC79 on eNOS activation, NO production, Nrf-2 target levels, and interleukin-8 (IL-8) transcription during exposure to TNF-α or Pseudomonas flagellin (TLR5 agonist). Additionally, air–liquid interface bronchial cultures were treated with cadmium, an oxidative stressor that causes airway barrier breakdown.

Results
SC79 induced a ~ twofold induction of p-eNOS and Nrf-2 protein levels blocked by PI3K inhibitor LY294002. Live cell imaging revealed SC79 increased acute NO production. Quantitative RT-PCR showed a ~ twofold increase in Nrf-2 target gene transcription. TNF-α or flagellin-induced IL-8 levels were also significantly reduced with SC79 treatment. Moreover, the transepithelial electrical resistance decrease observed with cadmium was ameliorated by SC79, likely by an acute increase in tight junction protein ZO-1 levels.

Conclusions
Together, the data presented here demonstrate SC79 activation of Akt induces potentially anti-pathogenic NO production, antioxidant gene transcription, reduces IL-8 transcription, and may protect against oxidative barrier dysfunction in a wide range of airway epithelial cells.
An equity and efficiency integrated grid-to-level 2SFCA approach: spatial accessibility of multilevel healthcare
Authors: Zhang Shaoyao , Song Xueqian , Zhou Jie 
Published: October 2021

Abstract
Background
Equity of healthcare spatial access is essential for the health outcomes of medical investments and the welfare of populations, and efficiency of medical resource allocation is important for obtaining a supply-demand equilibrium with lower cost and higher outputs with limited inputs. However, the literature that involves both equity and efficiency in its analysis of healthcare spatial allocation is rare, and the spatial accessibility of multilevel healthcare is difficult to measure by traditional methods in a large region with diversified population distribution.

Methods
To assist in solving these issues, this paper aims to build an equity and efficiency integrated analytical framework by proposing a new “GTL-2SFCA” approach to analyze the spatial accessibility of multilevel healthcare; maximum and minimum floating catchments of different levels of healthcare were assigned to ensure a combination of universal search coverage and efficient hospitalization behavior simulation.

Results
The analytical framework was applied and tested in Hubei, China. Almost half of the residents (47.95%) and townships (44.98%) have access to both public general hospitals (PGHs) and primary healthcare centers (PHCs) services, 36.89% of the residents enjoy only one sufficient service, either PGHs or PHCs, and the remaining residents (15.16%) are faced with the risk of lacking access to both services. The results reveal that there are core-periphery effects of multilevel healthcare throughout Hubei and isolate clusters that have adequate access in the western region. The polarization effect of higher-level healthcare and the polycentric pattern of lower-level healthcare coexist. The multilevel healthcare shortage was identified in some areas in boundary and peripheral regions.

Conclusions
This study integrates equity and efficiency into the GTL-2SFCA framework, enriches the FCA series methodologies and provides a more operational solution for evaluating the access of residents in more sophisticated spatial units to each level of healthcare. By more significantly differing and quantifying the catchment area and distance decay effect, this methodology avoids overestimating or underestimating accessibility and discovers some imperceptible spatial inequities. This study has application value for researchers and decision-makers in other scenarios and regions with significant heterogeneity in medical resources and where the population has greater mobility.
A novel dual-prodrug carried by cyclodextrin inclusion complex for the targeting treatment of colon cancer
Authors: Chen Lin , Lin Yan , Zhang Zijun , Yang Ruisheng , Bai Xiaosheng , Liu Zhongbing , Luo Zhongling , Zhou Meiling , Zhong Zhirong 
Published: October 2021

Abstract
Background
There is an obvious correlation between ulcerative colitis and colorectal cancer, and the risk of colorectal cancer in patients with ulcerative colitis is increasing. Therefore, the combination therapy of anti-inflammatory and anti-tumor drugs may show promising to inhibit colon cancer. 5-aminosalicylic acid (5-ASA) with anti-inflammatory function is effective for maintaining remission in patients with ulcerative colitis and may also reduce colorectal cancer risk. Histone deacetylase (HDAC) plays an essential role in the progression of colon cancer. Butyric acid (BA) is a kind of HDAC inhibitor and thus shows tumor suppression to colon cancer. However, the volatile and corrosive nature of BA presents challenges in practical application. In addition, its clinical application is limited due to its non-targeting ability and low bioavailability. We aimed to synthesize a novel dual-prodrug of 5-ASA and BA, referred as BBA, to synergistically inhibit colon cancer. Further, based on the fact that folate receptor (FR) is over-expressed in most solid tumors and it has been identified to be a cancer stem cell surface marker in colon cancer, we took folate as the targeting ligand and used carboxymethyl-β-cyclodextrin (CM-β-CD) to carry BBA and thus prepared a novel inclusion complex of BBA/FA-PEG-CM-β-CD.

Results
It was found that BBA/FA-PEG-CM-β-CD showed significant inhibition in cell proliferation against colon cancer cells SW620. It showed a pro-longed in vivo circulation and mainly accumulated in tumor tissue. More importantly, BBA/FA-PEG-CM-β-CD gave great tumor suppression effect against nude mice bearing SW620 xenografts.

Conclusions
Therefore, BBA/FA-PEG-CM-β-CD may have clinical potential in colon cancer therapy.

Graphical Abstract
A case-control study on factor V Leiden: an independent, gender-dependent risk factor for venous thromboembolism
Authors: Takhviji Vahideh , Zibara Kazem , Maleki Asma , Azizi Ebrahim , Hommayoun Sanaz , Tabatabaei Mohammadreza , Ahmadi Seyed Esmaeil , Soleymani Maral , Ghalesardi Omid Kiani , Farokhian Mina , Davari Afshin , Paridar Pouria , Kalantari Anahita , Khosravi Abbas 
Published: October 2021

Abstract
Background
Activated protein C resistance (APCR) due to factor V Leiden (FVL) mutation (R506Q) is a major risk factor in patients with venous thromboembolism (VTE). The present study investigated the clinical manifestations and the risk of venous thromboembolism regarding multiple clinical, laboratory, and demographic properties in FVL patients.

Material and methods
A retrospective cross-sectional analysis was conducted on a total of 288 FVL patients with VTE according to APCR. In addition, 288 VET control samples, without FVL mutation, were also randomly selected. Demographic information, clinical manifestations, family and treatment history were recorded, and specific tests including t-test, chi-square and uni- and multi-variable regression tests applied.

Results
APCR was found to be 2.3 times significantly more likely in men (OR: 2.1, p < 0.05) than women. The risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in APCR patients was 4.5 and 3.2 times more than the control group, respectively (p < 0.05). However, APCR could not be an independent risk factor for arterial thrombosis (AT) and pregnancy complications. Moreover, patients were evaluated for thrombophilia panel tests and showed significantly lower protein C and S than the control group and patients without DVT (p < 0.0001).

Conclusion
FVL mutation and APCR abnormality are noticeable risk factors for VTE. Screening strategies for FVL mutation in patients undergoing surgery, oral contraceptive medication, and pregnancy cannot be recommended, but a phenotypic test for activated protein C resistance should be endorsed in patients with VTE.
Inhibition of lysophosphatidic acid receptor 1–3 deteriorates experimental autoimmune encephalomyelitis by inducing oxidative stress
Authors: Choi Jong Hee , Oh Jinhee , Lee Min Jung , Bae Hyunsu , Ko Seong-Gyu , Nah Seung-Yeol , Cho Ik-Hyun 
Published: October 2021

Abstract
Background
Lysophosphatidic acid receptors (LPARs) are G-protein-coupled receptors involved in many physiological functions in the central nervous system. However, the role of the LPARs in multiple sclerosis (MS) has not been clearly defined yet.

Methods
Here, we investigated the roles of LPARs in myelin oligodendrocyte glycoprotein peptides-induced experimental autoimmune encephalomyelitis (EAE), an animal model of MS.

Results
Pre-inhibition with LPAR1–3 antagonist Ki16425 deteriorated motor disability of EAElow. Specifically, LPAR1–3 antagonist (intraperitoneal) deteriorated symptoms of EAElow associated with increased demyelination, chemokine expression, cellular infiltration, and immune cell activation (microglia and macrophage) in spinal cords of mice compared to the sham group. This LPAR1–3 antagonist also increased the infiltration of CD4+/IFN-γ+ (Th1) and CD4+/IL-17+ (Th17) cells into spinal cords of EAElow mice along with upregulated mRNA expression of IFN-γ and IL-17 and impaired blood–brain barrier (BBB) in the spinal cord. The underlying mechanism for negative effects of LPAR1–3 antagonist was associated with the overproduction of reactive oxygen species (ROS)-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) 2 and NOX3. Interestingly, LPAR1/2 agonist 1-oleoyl-LPA (LPA 18:1) (intraperitoneal) ameliorated symptoms of EAEhigh and improved representative pathological features of spinal cords of EAEhigh mice.

Conclusions
Our findings strongly suggest that some agents that can
stimulate LPARs might have potential therapeutic implications for autoimmune demyelinating diseases such as MS.
Long-term remission of AIDS-related primary central nervous system lymphoma in a patient under antiretroviral therapy: a case report and review of the literature
Authors: Gijs Pieter-Jan , Clerc Olivier 
Published: October 2021

Abstract
Background
AIDS-related primary central nervous system lymphoma (AR-PCNSL) is an AIDS-defining disease that usually occurs when the CD4 count is less than 50 cells/μl. The frequency of the disease has substantially decreased in the era of highly active antiretroviral therapy (HAART). Prognosis is poor with rapid progression leading to death within 2–3 months if left untreated.

Case description
A 65 years old male presented to medical attention with gait disturbance, weight loss and slight left-sided hemiparesis. Human immunodeficiency virus infection was diagnosed with an initial CD4 count of 116 cells/µl and a viral load of 260,000 copies/ml. Magnetic resonance imaging of the brain revealed three brain lesions involving the right frontal lobe and the left parietal lobe, which on biopsy led to a diagnosis of AR-PCNSL. HAART was initiated with whole-brain radiotherapy (WBRT), and the patient declined systemic chemotherapy. Due to poor performance status, he was transferred to palliative care. Under HAART, he slowly recovered with normalization of CD4 count and undetectable viral load. Medical imaging showed complete remission (CR) of the brain lesions. At 3-year follow-up, the patient remains in CR, but presented mild neurocognitive dysfunction possibly secondary to WBRT.

Conclusion
Nowadays, treatment paradigm parallels that of primary central nervous system lymphoma in the immunocompetent population based on systemic chemotherapy (primarily high-dose intravenous methotrexate and steroids) in association with HAART. The role of WBRT is questionable because of late neurotoxic effects.
Adjunctive cytoprotective therapies in acute ischemic stroke: a systematic review
Authors: Mulder I. A. , van Bavel E. T. , de Vries H. E. , Coutinho J. M. 
Published: October 2021

AbstractWith the introduction of endovascular thrombectomy (EVT), a new era for treatment of acute ischemic stroke (AIS) has arrived. However, despite the much larger recanalization rate as compared to thrombolysis alone, final outcome remains far from ideal. This raises the question if some of the previously tested neuroprotective drugs warrant re-evaluation, since these compounds were all tested in studies where large-vessel recanalization was rarely achieved in the acute phase. This review provides an overview of compounds tested in clinical AIS trials and gives insight into which of these drugs warrant a re-evaluation as an add-on therapy for AIS in the era of EVT. A literature search was performed using the search terms “ischemic stroke brain” in title/abstract, and additional filters. After exclusion of papers using pre-defined selection criteria, a total of 89 trials were eligible for review which reported on 56 unique compounds. Trial compounds were divided into 6 categories based on their perceived mode of action: systemic haemodynamics, excitotoxicity, neuro-inflammation, blood–brain barrier and vasogenic edema, oxidative and nitrosative stress, neurogenesis/-regeneration and -recovery. Main trial outcomes and safety issues are summarized and promising compounds for re-evaluation are highlighted. Looking at group effect, drugs intervening with oxidative and nitrosative stress and neurogenesis/-regeneration and -recovery appear to have a favourable safety profile and show the most promising results regarding efficacy. Finally, possible theories behind individual and group effects are discussed and recommendation for promising treatment strategies are described.
Effects of foreign direct investment and trade on the prevalence of tobacco consumption in Africa: a panel study
Authors: Immurana Mustapha , Boachie Micheal Kofi , Kisseih Kwame Godsway 
Published: October 2021

AbstractBackgroundAs African governments take measures to enhance international trade and Foreign Direct Investment (FDI) inflows, a major concern is that, these measures can make Africa more vulnerable to the strategies of the tobacco industry. This concern is based on the fact that, each year, tobacco use is estimated to be responsible for the deaths of over eight million people in the world. However, there is very little empirical evidence to refute or confirm the above concern, especially in the African context. This study therefore investigates the effects of FDI and trade on the prevalence of tobacco consumption in Africa.MethodsData on a sample of 31 African countries for the period, 2010–2018 are used. The system Generalised Method of Moments (GMM) regression model is employed as the empirical estimation technique.ResultsThe findings show that, FDI and trade have negative and positive significant association with the prevalence of tobacco consumption respectively. These findings are robust even after using different specifications and indicators of FDI and trade.ConclusionRising trade (and not FDI) should be of concern to African governments in the quest to reduce the prevalence of tobacco consumption on the continent.
Wheat physiology predictor: predicting physiological traits in wheat from hyperspectral reflectance measurements using deep learning
Authors: Furbank Robert T. , Silva-Perez Viridiana , Evans John R. , Condon Anthony G. , Estavillo Gonzalo M. , He Wennan , Newman Saul , Poiré Richard , Hall Ashley , He Zhen 
Published: October 2021

Abstract
Background
The need for rapid in-field measurement of key traits contributing to yield over many thousands of genotypes is a major roadblock in crop breeding. Recently, leaf hyperspectral reflectance data has been used to train machine learning models using partial least squares regression (PLSR) to rapidly predict genetic variation in photosynthetic and leaf traits across wheat populations, among other species. However, the application of published PLSR spectral models is limited by a fixed spectral wavelength range as input and the requirement of separate custom-built models for each trait and wavelength range. In addition, the use of reflectance spectra from the short-wave infrared region requires expensive multiple detector spectrometers. The ability to train a model that can accommodate input from different spectral ranges would potentially make such models extensible to more affordable sensors. Here we compare the accuracy of prediction of PLSR with various deep learning approaches and an ensemble model, each trained and tested using previously published data sets.

Results
We demonstrate that the accuracy of PLSR to predict photosynthetic and related leaf traits in wheat can be improved with deep learning-based and ensemble models without overfitting. Additionally, these models can be flexibly applied across spectral ranges without significantly compromising accuracy.

Conclusion
The method reported provides an improved prediction of wheat leaf and photosynthetic traits from leaf hyperspectral reflectance and do not require a full range, high cost leaf spectrometer. We provide a web service for deploying these algorithms to predict physiological traits in wheat from a variety of spectral data sets, with important implications for wheat yield prediction and crop breeding.