bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mapping regional strain in anesthetised healthy subjects during spontaneous ventilation
Authors: Cruces Pablo , Erranz Benjamin , Lillo Felipe , Sarabia-Vallejos Mauricio A , Iturrieta Pablo , Morales Felipe , Blaha Katherine , Medina Tania , Diaz Franco , Hurtado Daniel E 
Published: October 2019

IntroductionBreathing produces a phenomenon of cyclic deformation throughout life. Biomechanically, deformation of the lung is measured as strain. Regional strain recently started to be recognised as a tool in the study of lung pathophysiology, but regional lung strain has not been studied in healthy subjects breathing spontaneously without voluntary or pharmacological control of ventilation. Our aim is to generate three-dimensional (3D) regional strain and heterogeneity maps of healthy rat lungs and describe their changes over time.MethodsMicro-CT and image-based biomechanical analysis by finite element approach were carried out in six anaesthetised rats under spontaneous breathing in two different states, at the beginning of the experiment and after 3 hours of observation. 3D regional strain maps were constructed and divided into 10 isovolumetric region-of-interest (ROI) in three directions (apex to base, dorsal to ventral and costal to mediastinal), allowing to regionally analyse the volumetric strain, the strain progression and the strain heterogeneity. To describe in depth these parameters, and systematise their report, we definedregional strain heterogeneity index[1+strain SD ROI(x)]/[1+strain mean ROI(x)] andregional strain progression index[ROI(x)−mean of final strain/ROI(x)−mean of initial strain].ResultsWe were able to generate 3D regional strain maps of the lung in subjects without respiratory support, showing significant differences among the three analysed axes. We observed a significantly lower regional volumetric strain in the apex sector compared with the base, with no significant anatomical systematic differences in the other directions. This heterogeneity could not be identified with physiological or standard CT methods. There was no progression of the analysed regional volumetric strain when the two time-points were compared.DiscussionIt is possible to map the regional volumetric strain in the lung for healthy subjects during spontaneous breathing. Regional strain heterogeneity and changes over time can be measured using a CT image-based numerical analysis applying a finite element approach. These results support that healthy lung might have significant regional strain and its spatial distribution is highly heterogeneous. This protocol for CT image acquisition and analysis could be a useful tool for helping to understand the mechanobiology of the lung in many diseases.
Disruption of normal patterns of FOXF1 expression in a lethal disorder of lung development
Authors: Steiner Laurie A , Getman Michael , Schiralli Lester Gillian M , Iqbal M Anwar , Katzman Philip , Szafranski Przemyslaw , Stankiewicz Pawel , Bhattacharya Soumyaroop , Mariani Thomas , Pryhuber Gloria , Lin Xin , Young Jennifer L , Dean David A , Scheible Kristin 
Published: October 2019

BackgroundAlveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) is a lethal disorder of lung development. ACDMPV is associated with haploinsufficiency of the transcription factorFOXF1, which plays an important role in the development of the lung and intestine. CNVs upstream of the FOXF1 gene have also been associated with an ACDMPV phenotype, but mechanism(s) by which these deletions disrupt lung development are not well understood. The objective of our study is to gain insights into the mechanisms by which CNVs contribute to an ACDMPV phenotype.MethodsWe analysed primary lung tissue from an infant with classic clinical and histological findings of ACDMPV and harboured a 340 kb deletion on chromosome 16q24.1 located 250 kb upstream ofFOXF1.ResultsIn RNA generated from paraffin-fixed lung sections, our patient had lower expression ofFOXF1than age-matched controls. He also had an abnormal pattern of FOXF1 protein expression, with a dramatic loss ofFOXF1expression in the lung. To gain insights into the mechanisms underlying these changes, we assessed the epigenetic landscape using chromatin immunoprecipitation, which demonstrated loss of histone H3 lysine 27 acetylation (H3K27Ac), an epigenetic mark of active enhancers, in the region of the deletion.ConclusionsTogether, these data suggest that the deletion disrupts an enhancer responsible for directing FOXF1 expression in the developing lung and provide novel insights into the mechanisms underlying a fatal developmental lung disorder.
Coil migration during or after endovascular coiling of cerebral aneurysms
Authors: Abdalkader Mohamad , Piotin Michel , Chen Michael , Ortega-Gutierrez Santiago , Samaniego Edgar , Weill Alain , Norbash Alexander M , Nguyen Thanh N 
Published: October 2019

BackgroundCoil migration is a complication of endovascular coiling of cerebral aneurysms that has not been well studied.ObjectiveTo report the frequency, risk factors, management strategies, and outcomes of coil migration.MethodsThis was a retrospective analysis of the clinical and radiological data of patients who underwent cerebral aneurysm coiling complicated by coil migration at five neuroendovascular centers in the United States, Canada, and France between 2008 and 2018.ResultsEighteen cases of coil migration met our study criteria with an occurrence of 0.3% (18/6071 cases) (procedural migration: 55%, delayed migration: 45%). The mean aneurysm maximal diameter, neck, and height to neck ratio in migration cases were 3.4±1.4 mm (range 2–7.6 mm), 2.4±0.9 mm (range 1.2–4.4 mm), and 1.4±0.4 (range 1–2.15), respectively. The 2 mm diameter coil was the most common (39%, range 1–2.5 mm) migrated coil. The length of the migrated coil was ≤4 cm in 95% of cases.Patients managed conservatively (5/18, 28%) did well. Thromboembolic and/or hemorrhagic complications were noted in 6/10 migration patients treated by endovascular modalities and in all migration patients who underwent surgical treatment (4/4). Three deaths occurred (3/18, 17%) related to high Hunt and Hess grade subarachnoid hemorrhage.ConclusionCoil migration is an uncommon but important complication of cerebral aneurysm coiling. Small aneurysms, aspect ratio <1.6, and small coils are significant risk factors. Endovascular treatment, such as using a stent retriever, can be considered for procedural, proximal migration, and/or in cases of vessel occlusion. Delayed or distal migration should be managed conservatively.
Erectile dysfunction and mining-related jobs: an explorative study in Lubumbashi, Democratic Republic of Congo
Authors: Musa Obadia Paul , Kayembe-Kitenge Tony , Banza Lubaba Nkulu Célestin , Enzlin Paul , Nemery Benoit 
Published: October 2019

IntroductionThe African Copperbelt is a site of intense artisanal and industrial mining and refining of copper and cobalt. Anecdotal reports of erectile dysfunction (ED) among mineworkers in the area led us to conduct an explorative study to investigate the possible association between ED and working in mining-related jobs.MethodsWe included 42 consecutive men (18–40 years) buying sildenafil (the active substance of Viagra) from a pharmacy located in a popular neighbourhood in Lubumbashi, and 42 age-matched (±2 years) men buying painkillers. All participants replied to questionnaires administered face-to-face to obtain sociodemographic data, including information on occupation, and a score of erectile function using the International Index of Erectile Function (IIEF6).ResultsThe IIEF6 score (maximum 30) was lower among sildenafil-buyers (median 17, range 8–30) than among painkiller-buyers (median 30, range 17–30). The proportion of mining-related jobs was higher among sildenafil-buyers (19/42, 45%) than among painkiller-buyers (7/42, 17%), yielding an OR of 4.1 (95% CI 1.5 to 11.3; p=0.009). The proportion of mining-related jobs was higher among men with ED (defined as IIEF6 <26) (24/45, 54%) than among men without ED (2/39, 5%) (OR 21.1; 95% CI 4.5 to 98.4; p<0.001). Using a more stringent definition of ED (IIEF6 <22) gave similar results: 55% (20/36) of men with ED had a mining-related job versus 13% (6/48) of men without ED (OR 8.7; 95% CI 2.9 to 25.7; p=0.001).DiscussionThe findings of this preliminary study justify further epidemiological studies of the possible role of occupational exposures in the pathogenesis of male sexual dysfunction among miners and workers in the copper and cobalt industry.
Investigation of the efficacy of a dietetic food in the management of chronic enteropathies in dogs
Authors: Tørnqvist‐Johnsen Camilla , Campbell Susan , Gow Adam , Bommer Nick X , Salavati Silke , Mellanby Richard J 
Published: October 2019

BackgroundChronic enteropathies (CEs) are a common cause of morbidity in dogs. CEs are diagnosed in dogs with chronic gastrointestinal clinical signs (>3 weeks), inflammatory changes on intestinal biopsies and where no other underlying cause is determined based on a thorough, standardised diagnostic work‐up. Based on response to therapy, CEs are subclassified into food‐responsive, antibiotic‐responsive or steroid‐responsive enteropathies. A significant proportion of dogs with a CE are food‐responsive; however, there are limited peer‐reviewed publications describing the clinical efficacy of the commercially available diets used to treat CE.MethodsIn this study, the authors evaluated the response of 15 dogs with a CE to a commercially available dietetic food (Hill's Prescription Diet i/d Sensitive Canine Dry). The dogs underwent a standard diagnostic evaluation and did not receive concurrent anthelmintic, antibiotic, glucocorticoid or gastroprotectant therapies. The clinical efficacy of the dietary treatment was assessed by comparing the Canine Inflammatory Bowel Disease Activity Index (CIBDAI) before and a median of 13 days after dietary therapy.ResultsThe authors found that the CIBDAI significantly decreased following the introduction of the dietetic food (median CIBDAI score pretreatment 9, post‐treatment 2; P<0.0005).ConclusionThis study demonstrates that this dietetic food can be used to successfully manage CE in dogs.
Flos Magnoliaeand its Constituent Linoleic Acid Suppress T Lymphocyte ActivationviaStore-Operated Calcium Entry
Authors: Kim Hyun Jong , Woo JooHan , Nam Yu Ran , Nam Joo Hyun , Kim Woo Kyung 
Published: October 2019

Intracellular calcium signaling is crucial for type 2 helper T cell and mast cell activation, which is essential for allergic inflammation. It is initiated by antigen-mediated receptor stimulation that triggers store-operated calcium entry (SOCE) via ORAI1 calcium channel. Flos Magnoliae (FM) is widely used to treat allergic diseases such as allergic rhinitis and asthma. Although many studies have reported that FM regulates intracellular calcium signaling, research on the exact type of calcium channel modulated by FM is scarce. Therefore, we hypothesized that the anti-allergic effects of FM might result from ORAI1 inhibition in T cells. We investigated whether a 70% ethanolic extract of FM (FM[Formula: see text] and its constituents inhibit ORAI1 channel activity and subsequent T cell activation. We performed conventional whole-cell patch clamp studies in hSTIM1 and hORAI1-overexpressing HEK293T cells (HEK[Formula: see text]. Intracellular calcium concentration was determined using Fura-2 dye and cytokine production measurement in Jurkat T lymphocytes. FMEtOH(0.03 mg/mL) and its fractions, especially hexane fraction (FMHex, 0.01 mg/mL), significantly inhibited SOCE and IL-2 cytokine production in Jurkat T lymphocytes. GC/MS analysis showed linoleic acid (LA) as the major component of FMHex. FMHexat 0.01 mg/mL (equivalent to 10 [Formula: see text]M LA) inhibited not only SOCE but also IL-2 production, as well as CD3/CD28 receptor co-stimulation induced calcium signaling in Jurkat T lymphocytes. FMEtOHand LA suppressed CD4[Formula: see text] T lymphocyte activation, at least in part, by inhibiting [Formula: see text]. Thus, [Formula: see text] inhibition may be a potential strategy to inhibit immune responses in inflammation.
How electromagnetic induction and coupled delay affect stochastic resonance in a modified neuronal network subject to phase noise
Authors: Yang Xiao Li , Liu Xiao Qiang 
Published: October 2019

Through introducing the ingredients of electromagnetic induction and coupled time delay into the original Fitzhugh–Nagumo (FHN) neuronal network, the dynamics of stochastic resonance in a model of modified FHN neuronal network in the environment of phase noise is explored by numerical simulations in this study. On one hand, we demonstrate that the phenomenon of stochastic resonance can appear when the intensity of phase noise is appropriately adjusted, which is further verified to be robust to the edge-added probability of small-world network. Moreover, under the influence of electromagnetic induction, the phase noise-induced resonance response is suppressed, meanwhile, a large noise intensity is required to induce stochastic resonance as the feedback gain of induced current increases. On the other hand, when the coupled time delay is incorporated into this model, the results indicate that the properly tuned time delay can induce multiple stochastic resonances in this neuronal network. However, the phenomenon of multiple stochastic resonances is found to be restrained upon increasing feedback gain of induced current. Surprisingly, by changing the period of phase noise, multiple stochastic resonances can still emerge when the coupled time delay is appropriately tuned to be integer multiples of the period of phase noise.
Case Studies of Gastric, Lung, and Oral Cancer Connect Etiologic Agent Prevalence to Cancer Incidence
Authors: Brouwer Andrew F. , Eisenberg Marisa C. , Meza Rafael 
Published: October 2019

Abstract
Obtaining detailed individual-level data on both exposure and cancer outcomes is challenging, and it is difficult to understand and characterize how temporal aspects of exposures translate into cancer risk. We show that, in lieu of individual-level information, population-level data on cancer incidence and etiologic agent prevalence can be leveraged to investigate cancer mechanisms and to better characterize and predict cancer trends. We use mechanistic carcinogenesis models [multistage clonal expansion (MSCE) models] and data on smoking, Helicobacter pylori (H. pylori), and HPV infection prevalence to investigate trends of lung, gastric, and HPV-related oropharyngeal cancers. MSCE models are based on the initiation–promotion–malignant conversion paradigm and allow for interpretation of trends in terms of general biological mechanisms. We assumed the rates of initiation depend on the prevalence of the corresponding risk factors. We performed two types of analysis, using the agent prevalence and cancer incidence data to estimate the model parameters and using cancer incidence data to infer the etiologic agent prevalence as well as the model parameters. By including risk factor prevalence, MSCE models with as few as three parameters closely reproduced 40 years of age-specific cancer incidence data. We recovered trends of H. pylori prevalence in the United States and demonstrated that cohort effects can explain the observed bimodal, age-specific pattern of oral HPV prevalence in men. Our results demonstrate the potential for joint analyses of population-level cancer and risk factor data through mechanistic modeling. This approach can be a first step in systematically testing relationships between exposures and cancer risk when individual-level data is lacking.
Significance: Analysis of trends in risk-factor prevalence and cancer incidence can shed light on cancer mechanisms and the way that carcinogen exposure through time shapes the risk of cancer at different ages.
Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/12/3386/F1.large.jpg. Cancer Res; 78(12); 3386–96. ©2018 AACR.
Adhesion of T Cells to Endothelial Cells Facilitates Blinatumomab-Associated Neurologic Adverse Events
Authors: Klinger Matthias , Zugmaier Gerhard , Nägele Virginie , Goebeler Maria-Elisabeth , Brandl Christian , Stelljes Matthias , Lassmann Hans , von Stackelberg Arend , Bargou Ralf C. , Kufer Peter 
Published: October 2019

Abstract

Blinatumomab, a CD19/CD3-bispecific T-cell engager (BiTE) immuno-oncology therapy for the treatment of B-cell malignancies, is associated with neurologic adverse events in a subgroup of patients. Here, we provide evidence for a two-step process for the development of neurologic adverse events in response to blinatumomab: (i) blinatumomab induced B-cell–independent redistribution of peripheral T cells, including T-cell adhesion to blood vessel endothelium, endothelial activation, and T-cell transmigration into the perivascular space, where (ii) blinatumomab induced B-cell–dependent T-cell activation and cytokine release to potentially trigger neurologic adverse events. Evidence for this process includes (i) the coincidence of T-cell redistribution and the early occurrence of most neurologic adverse events, (ii) T-cell transmigration through brain microvascular endothelium, (iii) detection of T cells, B cells, and blinatumomab in cerebrospinal fluid, (iv) blinatumomab-induced T-cell rolling and adhesion to vascular endothelial cells in vitro, and (v) the ability of antiadhesive agents to interfere with blinatumomab-induced interactions between T cells and vascular endothelial cells in vitro and in patients. On the basis of these observations, we propose a model that could be the basis of mitigation strategies for neurologic adverse events associated with blinatumomab treatment and other T-cell therapies.

Significance:
This study proposes T-cell adhesion to endothelial cells as a necessary but insufficient first step for development of blinatumomab-associated neurologic adverse events and suggests interfering with adhesion as a mitigation approach.
Phosphorylation of RAB7 by TBK1/IKKϵ Regulates Innate Immune Signaling in Triple-Negative Breast Cancer
Authors: Ritter Jessica L. , Zhu Zehua , Thai Tran C. , Mahadevan Navin R. , Mertins Philipp , Knelson Erik H. , Piel Brandon P. , Han Saemi , Jaffe Jacob D. , Carr Steven A. , Barbie David A. , Barbie Thanh U. 
Published: October 2019

AbstractTriple-negative breast cancer (TNBC) is a heterogeneous disease enriched for mutations in PTEN and dysregulation of innate immune signaling. Here, we demonstrate that Rab7, a recently identified substrate of PTEN phosphatase activity, is also a substrate of the innate immune signaling kinases TANK-binding kinase 1 (TBK1)/IκB kinase ϵ (IKKϵ) on the same serine-72 (S72) site. An unbiased search for novel TBK1/IKKϵ substrates using stable isotope labeling with amino acids in cell culture phosphoproteomic analysis identified Rab7-S72 as a top hit. PTEN-null TNBC cells expressing a phosphomimetic version of Rab7-S72 exhibited diffuse cytosolic Rab7 localization and enhanced innate immune signaling, in contrast to a kinase-resistant version, which localized to active puncta that promote lysosomal-mediated stimulator of interferon genes (STING) degradation. Thus, convergence of PTEN loss and TBK1/IKKϵ activation on Rab7-S72 phosphorylation limited STING turnover and increased downstream production of IRF3 targets including CXCL10, CCL5, and IFNβ. Consistent with this data, PTEN-null TNBC tumors expressed higher levels of STING, and PTEN-null TNBC cell lines were hyperresponsive to STING agonists. Together, these findings begin to uncover how innate immune signaling is dysregulated downstream of TBK1/IKKϵ in a subset of TNBCs and reveals previously unrecognized cross-talk with STING recycling that may have implications for STING agonism in the clinic.Significance:These findings identify Rab7 as a substrate for TBK1 for regulation of innate immune signaling, thereby providing important insight for strategies aimed at manipulating the immune response to enhance therapeutic efficacy in TNBC.
SRSF2 Regulation of MDM2 Reveals Splicing as a Therapeutic Vulnerability of the p53 Pathway
Authors: Comiskey Daniel F. , Montes Matías , Khurshid Safiya , Singh Ravi K. , Chandler Dawn S. 
Published: October 2019

Abstract

MDM2 is an oncogene and critical negative regulator of tumor suppressor p53. Genotoxic stress causes alternative splicing of MDM2 transcripts, which leads to alterations in p53 activity and contributes to tumorigenesis. MDM2-ALT1 is one of the alternatively spliced transcripts predominantly produced in response to genotoxic stress, and is comprised of terminal coding exons 3 and 12. Previously, we found that SRSF1 induces MDM2-ALT1 by promoting MDM2 exon 11 skipping. Here we report that splicing regulator SRSF2 antagonizes the regulation of SRSF1 by facilitating the inclusion of exon 11 through binding at two conserved exonic splicing enhancers. Overexpression of SRSF2 reduced the generation of MDM2-ALT1 under genotoxic stress, whereas SRSF2 knockdown induced the expression of MDM2-ALT1 in the absence of genotoxic stress. Blocking the exon 11 SRSF2-binding sites using oligonucleotides promoted MDM2-ALT1 splicing and induced p53 protein expression, and apoptosis in p53 wild-type cells. The regulation of MDM2 splicing by SRSF2 is also conserved in mice, as mutation of one SRSF2-binding site in Mdm2 exon 11, using CRISPR-Cas9, increased the expression of the MDM2-ALT1 homolog Mdm2-MS2.

Implications:
Taken together, the data indicate that modulating MDM2 splicing may be a useful tool for fine-tuning p53 activity in response to genotoxic stress.
miR-29a Is Repressed by MYC in Pancreatic Cancer and Its Restoration Drives Tumor-Suppressive Effects via Downregulation of LOXL2
Authors: Dey Shatovisha , Kwon Jason J. , Liu Sheng , Hodge Gabriel A. , Taleb Solaema , Zimmers Teresa A. , Wan Jun , Kota Janaiah 
Published: October 2019

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an intractable cancer with a dismal prognosis. miR-29a is commonly downregulated in PDAC; however, mechanisms for its loss and role still remain unclear. Here, we show that in PDAC, repression of miR-29a is directly mediated by MYC via promoter activity. RNA sequencing analysis, integrated with miRNA target prediction, identified global miR-29a downstream targets in PDAC. Target enrichment coupled with gene ontology and survival correlation analyses identified the top five miR-29a–downregulated target genes (LOXL2, MYBL2, CLDN1, HGK, and NRAS) that are known to promote tumorigenic mechanisms. Functional validation confirmed that upregulation of miR-29a is sufficient to ablate translational expression of these five genes in PDAC. We show that the most promising target among the identified genes, LOXL2, is repressed by miR-29a via 3′-untranslated region binding. Pancreatic tissues from a PDAC murine model and patient biopsies showed overall high LOXL2 expression with inverse correlations with miR-29a levels. Collectively, our data delineate an antitumorigenic, regulatory role of miR-29a and a novel MYC–miR-29a–LOXL2 regulatory axis in PDAC pathogenesis, indicating the potential of the molecule in therapeutic opportunities.

Implications:
This study unravels a novel functional role of miR-29a in PDAC pathogenesis and identifies an MYC–miR-29a–LOXL2 axis in regulation of the disease progression, implicating miR-29a as a potential therapeutic target for PDAC.

Visual Overview:
http://mcr.aacrjournals.org/content/molcanres/18/2/311/F1.large.jpg.