bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transient receptor potential vanilloid‐4 channels are involved in diminished myogenic tone in brain parenchymal arterioles in response to chronic hypoperfusion in mice
Authors: Chan Siu‐Lung , Nelson Mark T. , Cipolla Marilyn J. 
Published: August 2018

AbstractAimAdaptive responses of brain parenchymal arterioles (PAs), a target for cerebral small vessel disease, to chronic cerebral hypoperfusion are largely unknown. Previous evidence suggested that transient receptor potential vanilloid 4 channels may be involved in the regulation of cerebrovascular tone. Therefore, we investigated the role of TRPV4 in adaptations of PAs in a mouse model of chronic hypoperfusion.MethodsTRPV4 knockout (−/−) and wild‐type (WT) mice were subjected to unilateral common carotid artery occlusion (UCCAo) for 28 days. Function and structure of PAs ipsilateral to UCCAo were studied isolated and pressurized in an arteriograph.ResultsBasal tone of PAs was similar between WT and TRPV4−/− mice (22 ± 3 vs 23 ± 5%). After UCCAo, active inner diameters of PAs from WT mice were larger than control (41 ± 2 vs 26 ± 5 μm, P < 0.05) that was due to decreased tone (8 ± 2 vs 23 ± 5%, P < 0.05), increased passive inner diameters (46 ± 3 vs 34 ± 2 μm, P < 0.05), and decreased wall‐to‐lumen ratio (0.104 ± 0.01 vs 0.137 ± 0.01, P < 0.05). However, UCCAo did not affect vasodilation to a small‐ and intermediate‐conductance calcium‐activated potassium channel agonist NS309, the nitric oxide (NO) donor sodium nitroprusside, or constriction to a NO synthase inhibitor L‐NNA. Wall thickness and distensibility in PAs from WT mice were unaffected. In TRPV4−/− mice, UCCAo had no effect on active inner diameters or tone and only increased passive inner diameters (53 ± 2 vs 43 ± 3 μm, P < 0.05).ConclusionAdaptive response of PAs to chronic cerebral hypoperfusion includes myogenic tone reduction and outward remodelling. TRPV4 channels were involved in tone reduction but not outward remodelling in response to UCCAo.
Stability of oestrogen and progesterone receptor antigenicity in formalin‐fixed paraffin‐embedded breast cancer tissue over time
Authors: Ehinger Anna , Bendahl Pär‐ola , Rydén Lisa , Fernö Mårten , Alkner Sara 
Published: August 2018

Use of archived formalin‐fixed paraffin‐embedded (FFPE) tissue is a standard method for evaluation of proposed prognostic and predictive tumour markers. However, little is known of the preservation of biomarker expression in old FFPE tumour blocks. We investigate the quality of immunohistochemical (IHC) oestrogen (ER) and progesterone receptor (PR) evaluation in FFPE tissue over time (1978–2000) using a large breast cancer tissue microarray (N = 573) with access to receptor analyses in cytosol (CYT) at diagnosis, coexpression of other biomarkers and follow‐up data. We found a good correlation between ER analysed with CYT at diagnosis and ER analysed with IHC in archived FFPE tissue from the same tumour. ER evaluation did not seem to be affected by tissue storage time. Nor was there any time‐dependent difference in ERIHC correlation with other biomarkers (HER2, Ki67) or survival. Discordant cases were more often classified as ER‐positive with IHC than with CYT. For PR, however, we found an increased correlation between methods in more recent time periods. This may possibly be explained by more reliable PRIHC results in newer samples, although other explanations may also contribute. Our results indicate stable ER expression in FFPE tissue archived for up to 40 years.
Vascular adhesion protein‐1 as indicator of breast cancer tumor aggressiveness and invasiveness
Authors: Lai Yen‐Chang Clark , Chang Shu‐Jyuan , Kostoro Joanna , Kwan Aij‐Lie , Chai Chee‐Yin 
Published: August 2018

Recent studies suggest that vascular adhesion protein‐1 (VAP‐1), a 180‐KDa homodimeric glycoprotein, may be associated with cancer‐related events including tumor cell migration, motility, invasion, or metastasis. Therefore, this study applies VAP‐1 immunohistochemical staining to demonstrate the invasiveness component of the breast cancer. The VAP‐1 staining results were compared in 148 breast cancer cases to identify possible correlations with clinical status, including age, tumor size, tumor grade, TNM stage, lymphatic invasion, metastasis, recurrence, and survival rate. Immunohistochemical staining results showed VAP‐1 negative or weak staining in normal ducts and ductal carcinoma in situ (DCIS), but these phenotypes were positively associated with a stiffened VAP‐1 that presented at the invasive front of the lesion. Our data demonstrated that VAP‐1 expression was positively associated with lymphatic invasion, distant metastasis, and patient survival in breast carcinoma. Notably, VAP‐1 expression was found to be significantly correlated with the overall survival (p < 0.0001). Multivariate Cox analysis indicated that VAP‐1 expression was a significant independent prognostic indicator of overall survival in breast carcinoma (p < 0.0001). In conclusion, this study suggests that VAP‐1 is linked to progression of tumor invasion and metastasis in breast carcinoma. VAP‐1 is shown to be a biomarker that can be predict invasive potential and clinical outcome in breast cancer.
Soft tissue sarcoma in a short‐beaked echidna (Tachyglossus aculeatus)
Authors: Robey RL , Sangster C , Gabor M , Lindsay SA 
Published: August 2018

Case reportAn adult male short‐beaked echidna in poor body condition was found with a 25 × 12 mm round, ulcerated and bleeding mass on the left side of the face at the base of the beak. The animal responded well to initial supportive care and was referred to a specialist wildlife centre for further assessment and treatment. Clinical pathology showed moderate neutrophilia, mild anaemia, mild elevation in liver enzymes (ALT, AST and ALP) and mild azotaemia. Initial clinical differential diagnoses for the facial mass favoured an inflammatory rather than a neoplastic lesion, based on previous reports. Examination of an incisional biopsy identified a malignant spindle cell proliferation (sarcoma) not amenable to complete surgical excision. The animal was euthanased on humane grounds. Immunohistochemical assessment of the mass showed it to be negative for cytokeratin, desmin, smooth muscle actin, periaxin and MAC387 antibody labelling. Definitive histogenesis was undetermined and a final diagnosis of poorly differentiated sarcoma, unlikely to be of muscle, Schwann cell or histiocytic origin, was made.ConclusionReports of neoplasia in prototherian mammals (monotremes) are rare. To the authors’ knowledge this is the first report of such a tumour in a monotreme species and the first immunohistochemical characterisation of a stromal tumour in these animals. The malignant nature of this tumour contrasts with a previous report of benign neoplasia (fibroma) associated with the beak. Although rare, malignant neoplasia should be included in the differential diagnoses of mass lesions in monotremes, despite inflammatory or traumatic mass lesions being more commonly reported.
Automated identification of intensive animal production locations from aerial photography
Authors: Sheffield KJ , Hunnam JC , Cuzner TN , Morse‐McNabb EM , Sloan SM , Nunan J , Smith J , Harvey W , Lewis H 
Published: August 2018

ObjectiveSuccessful control of an emergency animal disease outbreak requires the timely and accurate identification of properties of interest. The identification of commercial piggeries within study areas in the Goulburn–Murray Irrigation District in Victoria, Australia, is used to demonstrate the innovative application of object‐based image analysis (OBIA) techniques for the identification of intensive animal production land uses, to improve the accuracy of existing datasets.MethodsCharacteristics of infrastructure and landscape features were combined to form a commercial piggery identification algorithm. These criteria were applied to recent aerial photography that had been classified using OBIA techniques. The results were then compared with three datasets containing known commercial piggery locations and visually checked by roadside surveys.ResultsThe OBIA technique identified 21 potential piggery locations across three study areas, 14 of which were identified in existing databases. Of the 7 additional sites, 4 were dairy properties, 1 was a cropping and sheep property and 2 were previously undocumented piggery locations.ConclusionsThe OBIA approach has potential of OBIA for identifying the locations of commercial piggeries. Further development and testing will determine how generic this approach is in terms of industry type and operation size. The method described is cost‐effective, automated and repeatable, and could be used to regularly update existing databases by analysing newly acquired aerial imagery to identify possible land use changes. This would improve the reliability of currently available data and increase the effectiveness of a biosecurity response during an emergency animal disease outbreak.
Anti‐IL‐7 receptor α monoclonal antibody (GSK2618960) in healthy subjects – a randomized, double‐blind, placebo‐controlled study
Authors: Ellis Joanne , van Maurik Andre , Fortunato Lea , Gisbert Sophie , Chen Keguan , Schwartz Ann , McHugh Simon , Want Andrew , Santos Franco Sara , Oliveira Joao‐Joaquim , Price Jeffrey , Coles Alasdair , Brown Kim , Su Donggang , Craigen Jenny L. , Yang Jiansong , Brett Sara , Davis Bill , Cheriyan Joseph , Kousin‐Ezewu Onajite , Gray Frank , Thompson Paul W. , Fernando Disala 
Published: August 2018

AimInterleukin (IL)‐7 signalling modulates T cell activity and is implicated in numerous autoimmune diseases. The present study investigated the safety, pharmacokinetics, target engagement, pharmacodynamics and immunogenicity of GSK2618960, an IL‐7 receptor‐α subunit (CD127) monoclonal antibody.MethodsA double‐blind (sponsor‐unblind) study of a single intravenous infusion of either GSK2618960 (0.6 mg kg–1 or 2.0 mg kg–1) or placebo was carried out in 18 healthy subjects over 24 weeks.ResultsGSK2618960 was well tolerated; there were no serious or significant adverse events. The observed half‐life was 5 (±1) days (2.0 mg kg–1), with nonlinear pharmacokinetics. Full receptor occupancy (>95%) was observed until day 8 (0.6 mg kg–1) and day 22 (2.0 mg kg–1). Maximal inhibition of IL‐7‐mediated signal transducer and activator of transcription 5 (STAT5) phosphorylation was observed in 5/6 subjects until day 22 (2.0 mg kg–1). Mean circulating IL‐7 and soluble receptor (CD127) levels were increased above baseline during days 2 and 15 (0.6 mg kg–1) and days 2 and 22 (2.0 mg kg–1). No meaningful changes were observed in absolute numbers or proportions of immune cell populations or inflammatory cytokine profiles (IL‐6, tumour necrosis factor‐α, interferon‐γ, IL‐2). Persistent antidrug antibodies (ADAs) were detected in 5/6 subjects administered a dose of 0.6 mg kg–1 (neutralizing in 2/6) and in 6/6 subjects administered 2.0 mg kg–1 (neutralizing in 5/6).ConclusionGSK2618960 was well tolerated and blocked IL‐7 receptor signalling upon full target engagement. Although there was no discernible impact on peripheral T cell subsets in healthy subjects, GSK2618960 may effectively modulate the autoinflammatory activity of pathogenic T cells in diseased tissue. A relatively short half‐life is likely the result of target‐mediated rather than ADA‐mediated clearance.
Lysophosphatidic acid acts on LPA1receptor to increase H2O2during flow‐induced dilation in human adipose arterioles
Authors: Chabowski Dawid S , Kadlec Andrew O , Ait‐Aissa Karima , Hockenberry Joseph C , Pearson Paul J , Beyer Andreas M , Gutterman David D 
Published: August 2018

Background and PurposeNO produces arteriolar flow‐induced dilation (FID) in healthy subjects but is replaced by mitochondria‐derived hydrogen peroxide (mtH2O2) in patients with coronary artery disease (CAD). Lysophosphatidic acid (LPA) is elevated in patients with risk factors for CAD, but its functional effect in arterioles is unknown. We tested whether elevated LPA changes the mediator of FID from NO to mtH2O2in human visceral and subcutaneous adipose arterioles.Experimental ApproachArterioles were cannulated on glass micropipettes and pressurized to 60 mmHg. We recorded lumen diameter after graded increases in flow in the presence of either NOS inhibition (L‐NAME) or H2O2scavenging (Peg‐Cat) ± LPA (10 μM, 30 min), ±LPA1/LPA3receptor antagonist (Ki16425) or LPA2receptor antagonist (H2L5186303). We analysed LPA receptor RNA and protein levels in human arterioles and human cultured endothelial cells.Key ResultsFID was inhibited by L‐NAME but not Peg‐Cat in untreated vessels. In vessels treated with LPA, FID was of similar magnitude but inhibited by Peg‐Cat while L‐NAME had no effect. Rotenone attenuated FID in vessels treated with LPA indicating mitochondria as a source of ROS. RNA transcripts from LPA1and LPA2but not LPA3receptors were detected in arterioles. LPA1but not LPA3receptor protein was detected by Western blot. Pretreatment of vessels with an LPA1/LPA3, but not LPA2, receptor antagonist prior to LPA preserved NO‐mediated dilation.Conclusions and ImplicationsThese findings suggest an LPA1receptor‐dependent pathway by which LPA increases arteriolar release of mtH2O2as a mediator of FMD.
Identification and characterization of transforming growth factor beta‐induced in circulating tumor cell subline from pancreatic cancer cell line
Authors: Sato Taku , Muramatsu Tomoki , Tanabe Minoru , Inazawa Johji 
Published: August 2018

Distant metastasis to liver, lung, brain, or bone occurs by circulating tumor cells (CTC). We hypothesized that a subset of CTC had features that are more malignant than tumor cells at the primary site. We established a highly malignant cell line, Panc‐1‐CTC, derived from the human pancreatic cancer cell line Panc‐1 using an in vivo selection method. Panc‐1‐CTC cells showed greater migratory and invasive abilities than its parent cell line in vitro. In addition, Panc‐1‐CTC cells had a higher tumor‐forming ability than parent cells in vivo. To examine whether a difference in malignant phenotypes exists between Panc‐1‐CTC cells and parent cells, we carried out comprehensive gene expression array analysis. As a result, Panc‐1‐CTC significantly expressed transforming growth factor beta‐induced (TGFBI), an extracellular matrix protein, more abundantly than did parent cells. TGFBI is considered to regulate cell adhesion, but its functions remain unclear. In the present study, knockdown of TGFBI reduced cell migration and invasion abilities, whereas overexpression of TGFBI increased both abilities. Moreover, elevated expression of TGFBI was associated with poor prognosis in patients with pancreatic cancer.
Immunoregulatory influence of abundant MFG‐E8 expression by esophageal cancer treated with chemotherapy
Authors: Kanemura Takashi , Miyata Hiroshi , Makino Tomoki , Tanaka Koji , Sugimura Keijiro , Hamada‐Uematsu Mika , Mizote Yu , Uchida Hiroaki , Miyazaki Yasuhiro , Takahashi Tsuyoshi , Kurokawa Yukinori , Yamasaki Makoto , Wada Hisashi , Nakajima Kiyokazu , Takiguchi Shuji , Mori Masaki , Doki Yuichiro , Tahara Hideaki 
Published: August 2018

Milk fat globule‐epidermal growth factor factor 8 (MFG‐E8) is secreted from macrophages and is known to induce immunological tolerance mediated by regulatory T cells. However, the roles of the MFG‐E8 that is expressed by cancer cells have not yet been fully examined. Expression of MFG‐E8 was examined using immunohistochemistry in surgical samples from 134 patients with esophageal squamous cell carcinoma. The relationships between MFG‐E8 expression levels and clinicopathological factors, including tumor‐infiltrating lymphocytes, were evaluated. High MFG‐E8 expression was observed in 23.9% of the patients. The patients with tumors highly expressing MFG‐E8 had a significantly higher percentage of neoadjuvant chemotherapy (NAC) history (P < .0001) and shorter relapse‐free survival (P = 0.012) and overall survival (OS; P = .0047). On subgroup analysis, according to NAC history, patients with high MFG‐E8 expression had significantly shorter relapse‐free survival (P = .027) and OS (P = .0039) only when they had been treated with NAC. Furthermore, tumors with high MFG‐E8 expression had a significantly lower ratio of CD8+ T cells/regulatory T cells in tumor‐infiltrating lymphocytes (P = .042) only in the patients treated with NAC, and those with a lower ratio had a shorter OS (P = .026). High MFG‐E8 expression was also found to be an independent prognostic factor in multivariate analysis. The abundant MFG‐E8 expression in esophageal squamous cell carcinoma might have a negative influence on the long‐term survival of patients after chemotherapy by affecting T‐cell regulation in the tumor microenvironment.
Pharmacological andSARanalysis of theLINS01 compounds at the human histamine H1, H2, and H3receptors
Authors: Corrêa Michelle Fidelis , Barbosa Álefe Jhonatas Ramos , Fernandes Gustavo Ariel Borges , Baker Jillian G. , Fernandes João Paulo dos Santos 
Published: August 2018

AbstractHistamine is a transmitter that activates the four receptors H1R to H4R. The H3R is found in the nervous system as an autoreceptor and heteroreceptor, and controls the release of neurotransmitters, making it a potential drug target for neuropsychiatric conditions. We have previously reported that the 1‐(2,3‐dihydro‐1‐benzofuran‐2‐yl)methylpiperazines (LINS01 compounds) have the selectivity for the H3R over the H4R. Here, we describe their pharmacological properties at the human H1R and H2R in parallel with the H3R, thus providing a full analysis of these compounds as histamine receptor ligands through reporter gene assays. Eight of the nineLINS01 compounds inhibited H3R‐induced histamine responses, but no inhibition of H2R‐induced responses was seen. Three compounds were weakly able to inhibit H1R‐induced responses. No agonist responses were seen to any of the compounds at any receptor.SARanalysis shows that theN‐methyl group improves H3R affinity while theN‐phenyl group is detrimental. The methoxy derivative,LINS01009, had the highest affinity.
Sex differences in ADHD trajectories across childhood and adolescence
Authors: Murray Aja Louise , Booth Tom , Eisner Manuel , Auyeung Bonnie , Murray George , Ribeaud Denis 
Published: August 2018

AbstractPrevious studies have hinted at sex differences in developmental trajectories in ADHD symptoms; however, little is known about the nature or cause of these differences and their implications for clinical practice. We used growth mixture modelling in a community‐ascertained cohort of n = 1,571 participants to study sex differences in ADHD symptom developmental trajectories across the elementary and secondary school years. Participants were measured at ages 7, 8, 9, 10, 11, 12, 13, and 15. We found that females were more likely to show large symptom increases in early adolescence while males were more likely to show elevated symptoms from childhood. For both males and females, early adolescence represented a period of vulnerability characterized by relatively sudden symptom increases. Females affected by hyperactivity/impulsivity may be more likely to be excluded from diagnosis due to current age of onset criteria. More attention should be paid to early adolescence as a period of risk for hyperactivity/impulsivity symptom onset or worsening.
Rescue therapies for seizure emergencies: New modes of administration
Authors: Maglalang Patricia D. , Rautiola Davin , Siegel Ronald A. , Fine Jared M. , Hanson Leah R. , Coles Lisa D. , Cloyd James C. 
Published: August 2018

SummaryA subgroup of patients with drug‐resistant epilepsy have seizure clusters, which are a part of the continuum of seizure emergencies that includes prolonged episodes and status epilepticus. When the patient or caregiver can identify the beginning of a cluster, the condition is amenable to certain treatments, an approach known as rescue therapy. Intravenous drug administration offers the fastest onset of action, but this route is usually not an option because most seizure clusters occur outside of a medical facility. Alternate routes of administration have been used or are proposed including rectal, buccal, intrapulmonary, subcutaneous, intramuscular, and intranasal. The objective of this narrative review is to describe the (1) anatomical, physiologic, and drug physicochemical properties that need to be considered when developing therapies for seizure emergencies and (2) products currently in development. New therapies must consider parameters of Fick's law such as absorptive surface area, blood flow, membrane thickness, and lipid solubility, because these factors affect both rate and extend of absorption. For example, the lung has a 50 000‐fold greater absorptive surface area than that associated with a subcutaneous injection. Lipid solubility is a physicochemical property that influences the absorption rate of small molecule drugs. Among drugs currently used or under development for rescue therapy, allopregnanolone has the greatest lipid solubility at physiologic pH, followed by propofol, midazolam, diazepam, lorazepam, alprazolam, and brivaracetam. However, greater lipid solubility correlates with lower water solubility, complicating formulation of rescue therapies. One approach to overcoming poor aqueous solubility involves the use of a water‐soluble prodrug coadministered with a converting enzyme, which is being explored for the intranasal delivery of diazepam. With advances in seizure prediction technology and the development of drug delivery systems that provide rapid onset of effect, rescue therapies may prevent the occurrence of seizures, thus greatly improving the management of epilepsy.
Prognostic scores in status epilepticus—a critical appraisal
Authors: Yuan Fang , Gao Qiong , Jiang Wen 
Published: August 2018

SummaryCurrently, there are 4 published scales evaluating status epilepticus (SE) prognosis: the Status Epilepticus Severity Score (STESS), the Epidemiology‐based Mortality score in Status Epilepticus (EMSE), the modified STESS (mSTESS), and the Encephalitis Nonconvulsive Status Epilepticus Diazepam Resistence Imaging Tracheal Intubation (END‐IT) score. The first prognostic score published for SE, the STESS, is a simple and practical scale that evaluates patient prognosis upon admission and is used widely to predict the outcome and stratify patients. Another scale, which was developed based on large epidemiologic studies, the EMSE, is more easily adapted to different regions around the world when assessing individual risk and stratifying patients in interventional studies. The mSTESS was created by adding the modified Rankin Scale (mRS) to the STESS, which decreases the ceiling effect and increases the mortality prediction capabilities of the STESS. The END‐IT is the only prognostic scale assessing functional outcome and is comprehensively simple and satisfyingly accurate. Evaluating the limitations of each of these scales aids in the exploration and advancement of SE prognostic scales, thereby facilitating better clinical interventions and scientific research.