bluuebunny/crossref_metadata_2025 huggingface dataset:
Are inequalities in cancer diagnosis through emergency presentation narrowing, widening or remaining unchanged? Longitudinal analysis of English population-based data 2006–2013
Authors: Herbert Annie , Abel Gary A , Winters Sam , McPhail Sean , Elliss-Brookes Lucy , Lyratzopoulos Georgios
Published: November 2018

Background

Diagnosis of cancer through emergency presentation is associated with poorer prognosis. While reductions in emergency presentations have been described, whether known sociodemographic inequalities are changing is uncertain.

Methods

We analysed ‘Routes to Diagnosis’ data on patients aged ≥25 years diagnosed in England during 2006–2013 with any of 33 common or rarer cancers. Using binary logistic regression we determined time-trends in diagnosis through emergency presentation by age, deprivation and cancer site.

Results

Overall adjusted proportions of emergency presentations decreased during the study period (2006: 23%, 2013: 20%). Substantial baseline (2006) inequalities in emergency presentation risk by age and deprivation remained largely unchanged. There was evidence (p<0.05) of reductions in the risk of emergency presentations for most (28/33) cancer sites, without apparent associations between the size of reduction and baseline risk (p=0.26). If there had been modest reductions in age inequalities (ie, patients in each age group acquiring the same percentage of emergency presentations as the adjacent group with lower risk), in the last study year we could have expected around 11 000 fewer diagnoses through emergency presentation (ie, a nationwide percentage of 16% rather than the observed 20%). For similarly modest reductions in deprivation inequalities, we could have expected around 3000 fewer (ie, 19%).

Conclusion

The proportion of cancer diagnoses through emergency presentation is decreasing but age and deprivation inequalities prevail, indicating untapped opportunities for further improvements by reducing these inequalities. The observed reductions in proportions across nearly all cancer sites are likely to reflect both earlier help-seeking and improvements in diagnostic healthcare pathways, across both easier-to-suspect and harder-to-suspect cancers.
Patterns of BMI development between 10 and 42 years of age and their determinants in the 1970 British Cohort Study
Authors: Viner Russell M , Costa Silvia , Johnson William
Published: November 2018

Background

Mixture modelling is a useful approach to identify subgroups in a population who share similar trajectories. We aimed to identify distinct body mass index (BMI) trajectories between 10 and 42 years and investigate how known early-life risk factors are related to trajectories.

Methods

Sample: 9187 participants in the 1970 British Birth Cohort Study, with BMI observations between 10 and 42 years and data on birth weight, parental BMI, socioeconomic status, breast feeding and puberty. Latent growth mixture modelling in Mplus was used to model age-related BMI trajectories and test associations of risk factors with trajectory membership.

Results

A three latent class model was most credible: (1) normative: 92%: started normal weight but gradually increased BMI to become overweight in adulthood; (2) childhood onset persistent obesity (COP): 4%: persistently high BMI from childhood; (3) adolescent and young adulthood onset obesity (AYAO): 4%: normal weight in childhood but had a steep ascending trajectory. Higher maternal and paternal BMI and early puberty increased the probability of being in either the COP or the AYAO classes compared with the normative class.

Conclusion

Most individuals gradually increased BMI and became overweight in mid-adulthood. Only 8% demonstrated more severe BMI trajectories. Further research is needed to understand the underlying body composition changes and health risks in the COP and AYAO classes.
Stress and functional neurological disorders: mechanistic insights
Authors: Keynejad Roxanne C , Frodl Thomas , Kanaan Richard , Pariante Carmine , Reuber Markus , Nicholson Timothy R
Published: November 2018

At the interface between mind and body, psychiatry and neurology, functional neurological disorder (FND) remains poorly understood. Formerly dominant stress-related aetiological models have been increasingly challenged, in part due to cases without any history of past or recent trauma. In this perspective article, we review current evidence for such models, and how research into the role of traumatic stress in other disorders and the neurobiology of the stress response can inform our mechanistic understanding of FND. First, we discuss the association between stress and the onset or exacerbation of a variety of physical and mental health problems. Second, we review the role of hypothalamic-pituitary-adrenal axis dysfunction in the neurobiology of ill-health, alongside evidence for similar mechanisms in FND. Third, we advocate a stress-diathesis model, in which biological susceptibility interacts with early life adversity, where FND can be precipitated by traumatic events later in life and maintained by psychological responses. We hypothesise that greater biological susceptibility to FND is associated with less severe remote and recent stress, and that FND precipitated by more severe stress is associated with lower biological vulnerability. This would explain clinical experience of variable exposure to historical and recent traumatic stress among people with FND and requires empirical investigation. A testable, evidence-based stress-diathesis model can inform nuanced understanding of how biological and psychological factors interact at the individual level, with potential to inform personalised treatment pathways. Much-needed research to establish the aetiology of FND will enhance clinical care and communication, facilitate effective treatment and inform prevention strategies.
Epidemiology of ALS in Korea using nationwide big data
Authors: Jun Kyo Yeon , Park Jinseok , Oh Ki-Wook , Kim Eun Mi , Bae Jong Seok , Kim Inah , Kim Seung Hyun
Published: November 2018

Objective

This study aimed to determine the incidence, prevalence and survival time of Korean patients with amyotrophic lateral sclerosis (ALS) using National Health Insurance Service (NHIS) data.

Methods

Using NHIS data, the Korean nationwide health dataset, we identified patients with motor neuron diseases who were first diagnosed with a KCD-6 code (G12.20–G12.28; modified from ICD-10 codes) between 2011 and 2015. ALS (G12.21 code) epidemiological characteristics, including annual incidence, prevalence, mortality rates and survival time, were analysed and compared with sociodemographic variables.

Results

New patients with ALS (n=3049) were enrolled over 5 years. The mean annual incidence was 1.20/100 000, and the sex ratio was 1.60 (male:female). The mean age at the time of diagnosis was 61.4 years. The prevalence rate was 3.43/100 000 in 2015. In this period, riluzole was prescribed to 53.6% of patients with ALS. Furthermore, 20.3% of patients with ALS underwent tracheostomy. When analysed for age and socioeconomic status, ALS prevalence rate was 10.71 in the aged group (≥60) in 2015 and was lowest in the middle-income group compared with that in the high-income and low-income groups. The estimated mean survival time in this population was 50.0 months, and the 3-year and 5-year mortality rates were 52.1% and 63.7%, respectively.

Conclusions

This study is the first nationwide survey for epidemiological characteristics of ALS in Korea using national data. The use of these data substantially advances the understanding of Korean and Asian ALS epidemiology and its relationship with socioeconomic status, age and sex.
Equine piroplasmosis status in the UK: an assessment of laboratory diagnostic submissions and techniques
Authors: Coultous Robert M , Phipps Paul , Dalley Charlie , Lewis Jane , Hammond Toni‐Ann , Shiels Brian R , Weir William , Sutton David G M
Published: November 2018

Equine piroplasmosis (EP) has historically been of minor concern to UK equine practitioners, primarily due to a lack of competent tick vectors. However, increased detection of EP tick vector species in the UK has been reported recently. EP screening is not currently required for equine importation, and when combined with recent relaxations in movement regulations, there is an increased risk regarding disease incursion and establishment into the UK. This study evaluated the prevalence of EP by both serology and PCR among 1242 UK equine samples submitted for EP screening between February and December 2016 to the Animal and Plant Health Agency and the Animal Health Trust. Where information was available, 81.5 per cent of submissions were for the purpose of UK export testing, and less than 0.1 per cent for UK importation. Serological prevalence of EP was 8.0 per cent, and parasite DNA was found in 0.8 per cent of samples. A subsequent analysis of PCR sensitivity in archived clinical samples indicated that the proportion of PCR‐positive animals is likely to be considerably higher. The authors conclude that the current threat imposed by UK carrier horses is not adequately monitored and further measures are required to improve national biosecurity and prevent endemic disease.
Floral organogenesis of Prunus laurocerasus and P. serotina and its significance for the systematics of the genus and androecium diversity in Rosaceae
Authors: Wang Xi , Gong Jing-zhi , Li Qiu-jie , Wang Jun-ru , Ma Yue-ping , Zhang Xiao-hui , Chang Zhao-yang , Wen Jun , Zhao Liang
Published: November 2018

Phylogenetic studies have shown that most clades in Prunus are well-supported by the flower structure, but most taxa in the racemose group have not yet been re-evaluated and could contribute to the understanding of the systematic relationships of the subgenera. We examined the inflorescence and flower development in Prunus laurocerasus L. (subgenus Laurocerasus) and P. serotina Ehrh. (subgenus Padus I) using scanning electron microscopy. Our results indicate that they share several floral development characters but differ in the following aspects: (i) all of their flowers are fully developed and each flower is enclosed by a bract and two bracteoles, which later stop development (vs. the terminal flower degenerates and only a single bract subtends each flower); (ii) the style protrudes from the floral bud (vs. the style is crooked and below the anthers); (iii) the outer integument initiates close to the inner one (vs. in the middle of the ovule); and (iv) an obturator appears after initiation of the two integuments (vs. simultaneously with the inner integument). Although our results are preliminary, differences in floral developmental characters support the different origins of Prunus subgenera Laurocerasus and Padus as based on molecular phylogenetic studies.
Crypto-stego System for Securing Text and Image Data
Authors: Sharma Himani , Mishra D. C. , Sharma R. K. , Kumar Naveen
Published: November 2018

Conventional techniques for security of data, designed by using only one of the security mechanisms, cryptography or steganography, are suitable for limited applications only. In this paper, we propose a crypto-stego system that would be appropriate for secure transmission of different forms of data. In the proposed crypto-stego system, we present a mechanism to provide secure transmission of data by multiple safety measures, firstly by applying encryption using Affine Transform and Discrete Cosine Transform (DCT) and then merging this encrypted data with an image, randomly chosen from a set of available images, and sending the image so obtained to the receiver at the other end through the network. The data to be sent over a communication channel may be a gray-scale or colored image, or a text document (doc, .txt, or .pdf file). As it is encrypted and sent hidden in an image, it avoids any attention to itself by the observers in the network. At the receiver’s side, reverse transformations are applied to obtain the original information. The experimental results, security analysis and statistical analysis for gray-scale images, RGB images, text documents (.doc, .txt, .pdf files), show robustness and appropriateness of the proposed crypto-stego system for secure transmission of the data through unsecured network. The security analysis and key space analysis demonstrate that the proposed technique is immune from cryptanalysis.
Development of Precision Positioning Stage
Authors: Niranjan Prabha , Karinka Shashikantha , Sairam KVSSSS
Published: November 2018

The growing demand for positioning accuracy in machines with high speed plays an important role in achieving high productivity gain. A system that is capable to achieve both coarse (macro) and fine (micro) positioning finds a variety of applications in precision positioning. In the proposed work, a macro positioning stage is developed with a ball screw actuator and a micro positioning stage is developed with an additional gear reduction unit. The coarse and fine positioning with friction compensation is achieved and the steady state error is minimized. The developed system is controlled using a programmable logic controller and operated with human machine interface.
Smoothed Particle Hydrodynamics Simulation of Liquid Drop Impinging Hypoelastic Surfaces
Authors: Dong Xiangwei , Li Zengliang , Mao Zirui , Liu Yanxin
Published: November 2018

The phenomenon of liquid drops impact on elastic surfaces widely exists in nature and industry. Theoretical description of this phenomenon is relatively difficult, due to its transient and fluid–structure interaction nature. In this study, a numerical model is proposed based on the smoothed particle hydrodynamics (SPH) method to simulate a liquid drop impact on hypoelastic solid surfaces. A key feature of the proposed model is that the surface tension effect is modeled by reconstructing the free surface of the droplet. We simulate water drops impact on super-hydrophobic cantilever beams. Interesting phenomena of droplet bouncing and beam vibration are reproduced by the model. The predicted behavior qualitatively agrees with the experimental observation. These analyses may be beneficial to engineering new materials and new devices in such areas as fabrics, agriculture, petroleum, and micro/nano technology.
The Use of Pistachio Pollen for the Production of Nanostructured Porous Nickel Oxide
Authors: Atalay F. E. , Yigit E. , Biber Z. S. , Kaya H.
Published: November 2018

Natural biotemplates — such as bacteria, fungi and viruses — are used in nanostructured metal oxide production. The pollen can be found abundantly in nature, and their microcapsules can be easily isolated from the pollen by chemical treatments. To date, pollen microcapsules are mostly used as drug carriers and catalytic agent templates. In the present study, nanoporous-structured nickel oxide is produced using Pistachio pollen microcapsules. The raw pollen, chemically treated pollen and metal-coated pollen were characterized using scanning electron microscopy, Brunauer–Emmett–Teller (BET) surface area analysis, thermogravimetric analysis (TGA), differential thermal analysis (DTA) and X-ray diffraction (XRD) techniques. The natural Pistachio pollen which were procured from Gaziantep, Turkey, are spherical, with a diameter of approximately 23[Formula: see text][Formula: see text]m. The maximum surface area obtained for nickel oxide-coated microcapsules is 228.82[Formula: see text]m2/g. This result shows that Pistachio pollen are an excellent candidate for the production of porous nanostructured materials for supercapacitor electrodes.
One-Carbon Metabolism: Linking Nutritional Biochemistry to Epigenetic Programming of Long-Term Development
Authors: Clare Constance E. , Brassington Amey H. , Kwong Wing Yee , Sinclair Kevin D.
Published: November 2018

One-carbon (1C) metabolism comprises a series of interlinking metabolic pathways that include the methionine and folate cycles that are central to cellular function, providing 1C units (methyl groups) for the synthesis of DNA, polyamines, amino acids, creatine, and phospholipids. S-adenosylmethionine is a potent aminopropyl and methyl donor within these cycles and serves as the principal substrate for methylation of DNA, associated proteins, and RNA. We propose that 1C metabolism functions as a key biochemical conduit between parental environment and epigenetic regulation of early development and that interindividual and ethnic variability in epigenetic-gene regulation arises because of genetic variants within 1C genes, associated epigenetic regulators, and differentially methylated target DNA sequences. We present evidence to support these propositions, drawing upon studies undertaken in humans and animals. We conclude that future studies should assess the epigenetic effects of cumulative (multigenerational) dietary imbalances contemporaneously in both parents, as this better represents the human experience.
Sentiment Analysis
Authors: Stine Robert A.
Published: November 2018

Sentiment analysis labels a body of text as expressing either a positive or negative opinion, as in summarizing the content of an online product review. In this sense, sentiment analysis can be considered the challenge of building a classifier from text. Sentiment analysis can be done by counting the words from a dictionary of emotional terms, by fitting traditional classifiers such as logistic regression to word counts, or, most recently, by employing sophisticated neural networks. These methods progressively improve classification at the cost of increased computation and reduced transparency. A common sentiment analysis task, the classification of IMDb (Internet Movie Database) movie reviews, is used to illustrate the methods on a common task that appears frequently in the literature.
Noncoding RNAs: potential regulators in cardioncology
Authors: Chatterjee Shambhabi , Gupta Shashi Kumar , Bär Christian , Thum Thomas
Published: November 2018

Cancer is the leading cause of morbidity and mortality in the United States and globally. Owing to improved early diagnosis and advances in oncological therapeutic options, the number of cancer survivors has steadily increased. Such efficient cancer therapies have also lead to alarming increase in cardiovascular complications in a significant proportion of cancer survivors, due to adverse cardiovascular effects such as cardiotoxicity, cardiac atrophy, and myocarditis. This has emerged as a notable concern in healthcare and given rise to the new field of cardioncology, which aims at understanding the processes that occur in the two distinct disorders and how they interact to influence the progression of each other. A key player in both cancer and heart failure is the genome, which is predominantly transcribed to noncoding RNAs (ncRNAs). Since the emergence of ncRNAs as master regulators of gene expression, several reports have shown the relevance of ncRNAs in cancer and cardiovascular disorders. However, the knowledge is quite limited regarding the relevance of ncRNAs in cardioncology. The objective of this review is to summarize the current knowledge of ncRNAs in the context of cardioncology. Furthermore, the therapeutic strategies as well as the prospective translational applications of these ncRNA molecules to the clinics are also discussed.
Right ventricular dysfunction and remodeling in diabetic cardiomyopathy
Authors: Kang Yin , Wang Sheng , Huang Jiapeng , Cai Lu , Keller Bradley B.
Published: November 2018

The increasing prevalence of diabetic cardiomyopathy (DCM) is an important threat to health worldwide. While left ventricular (LV) dysfunction in DCM is well recognized, the accurate detection, diagnosis, and treatment of changes in right ventricular (RV) structure and function have not been well characterized. The pathophysiology of RV dysfunction in DCM may share features with LV diastolic and systolic dysfunction, including pathways related to insulin resistance and oxidant injury, although the RV has a unique cellular origin and composition and unique biomechanical properties and is coupled to the lower-impedance pulmonary vascular bed. In this review, we discuss potential mechanisms responsible for RV dysfunction in DCM and review the imaging approaches useful for early detection, protection, and intervention strategies. Additional data are required from animal models and clinical trials to better identify the onset and features of altered RV and pulmonary vascular structure and function during the onset and progression of DCM and to determine the efficacy of early detection and treatment of RV dysfunction on clinical symptoms and outcomes.
Elimination or neutralization of endogenous high-molecular-weight FGF2 mitigates doxorubicin-induced cardiotoxicity
Authors: Koleini Navid , Santiago Jon-Jon , Nickel Barbara E. , Sequiera Glen Lester , Wang Jie , Fandrich Robert R. , Jassal Davinder S. , Dhingra Sanjiv , Kirshenbaum Lorrie A. , Cattini Peter A. , Kardami Elissavet
Published: November 2018

Cardiac fibroblast growth factor 2 (FGF2) exerts multiple paracrine activities related to cardiac response to injury. Endogenous FGF2 is composed of a mixture of 70% high- and 30% low-molecular-weight isoforms (Hi-FGF2 and Lo-FGF2, respectivley); although exogenously added Lo-FGF2 is cardioprotective, the roles of endogenous Hi-FGF2 or Lo-FGF2 have not been well defined. Therefore, we investigated the effect of elimination of Hi-FGF2 expression on susceptibility to acute cardiac damage in vivo caused by an injection of the genotoxic drug doxorubicin (Dox). Mice genetically depleted of endogenous Hi-FGF2 and expressing only Lo-FGF2 [FGF2(Lo) mice] were protected from the Dox-induced decline in ejection fraction displayed by their wild-type FGF2 [FGF2(WT)] mouse counterparts, regardless of sex, as assessed by echocardiography for up to 10 days post-Dox treatment. Because cardiac FGF2 is produced mainly by nonmyocytes, we next addressed potential contribution of fibroblast-produced FGF2 on myocyte vulnerability to Dox. In cocultures of neonatal rat cardiomyocytes (r-cardiomyocytes) with mouse fibroblasts from FGF2(WT) or FGF2(Lo) mice, only the FGF2(Lo)-fibroblast cocultures protected r-cardiomyocytes from Dox-induced mitochondrial and cellular damage. When r-cardiomyocytes were cocultured with or exposed to conditioned medium from human fibroblasts, neutralizing antibodies for human Hi-FGF-2, but not total FGF2, mitigated Dox-induced injury of cardiomyocytes. We conclude that endogenous Hi-FGF2 reduces cardioprotection by endogenous Lo-FGF2. Antibody-based neutralization of endogenous Hi-FGF2 may offer a prophylactic treatment against agents causing acute cardiac damage.

NEW & NOTEWORTHY Cardiomyocytes, in vivo and in vitro, were protected from the deleterious effects of the anticancer drug doxorubicin by the genetic elimination or antibody-based neutralization of endogenous paracrine high-molecular-weight fibroblast growth factor 2 isoforms. These findings have a translational potential for mitigating doxorubicin-induced cardiac damage in patients with cancer by an antibody-based treatment.
Microvascular mechanisms limiting skeletal muscle blood flow with advancing age
Authors: Socha Matthew J. , Segal Steven S.
Published: November 2018

Effective oxygen delivery to active muscle fibers requires that vasodilation initiated in distal arterioles, which control flow distribution and capillary perfusion, ascends the resistance network into proximal arterioles and feed arteries, which govern total blood flow into the muscle. With exercise onset, ascending vasodilation reflects initiation and conduction of hyperpolarization along endothelium from arterioles into feed arteries. Electrical coupling of endothelial cells to smooth muscle cells evokes the rapid component of ascending vasodilation, which is sustained by ensuing release of nitric oxide during elevated luminal shear stress. Concomitant sympathetic neural activation inhibits ascending vasodilation by stimulating α-adrenoreceptors on smooth muscle cells to constrict the resistance vasculature. We hypothesized that compromised muscle blood flow in advanced age reflects impaired ascending vasodilation through actions on both cell layers of the resistance network. In the gluteus maximus muscle of old (24 mo) vs. young (4 mo) male mice (corresponding to mid-60s vs. early 20s in humans) inhibition of α-adrenoreceptors in old mice restored ascending vasodilation, whereas even minimal activation of α-adrenoreceptors in young mice attenuated ascending vasodilation in the manner seen with aging. Conduction of hyperpolarization along the endothelium is impaired in old vs. young mice because of “leaky” membranes resulting from the activation of potassium channels by hydrogen peroxide released from endothelial cells. Exposing the endothelium of young mice to hydrogen peroxide recapitulates this effect of aging. Thus enhanced α-adrenoreceptor activation of smooth muscle in concert with electrically leaky endothelium restricts muscle blood flow by impairing ascending vasodilation in advanced age.
Effect of carbohydrate ingestion on central fatigue during prolonged running exercise in moderate hypoxia
Authors: Paris Hunter L. , Fulton Timothy J. , Chapman Robert F. , Fly Alyce D. , Koceja David M. , Mickleborough Timothy D.
Published: November 2018

To determine whether acute exposure to moderate hypoxia alters central and peripheral fatigue and to test whether carbohydrate ingestion impacts fatigue characteristics, 12 trained runners completed three running trials lasting 1 h each at 65% of normoxic maximum oxygen uptake. The first trial was performed in normoxia [inspired O2 fraction ([Formula: see text]) = 0.21], and the last two trials were completed in hypoxia ([Formula: see text] = 0.15). Participants ingested a placebo drink in normoxia (NORM-PLA), a placebo drink in hypoxia (HYP-PLA), or a carbohydrate solution in hypoxia (HYP-CHO). HYP conditions were randomized. Peripheral [change in potentiated quadriceps twitch force (ΔQtw,pot)] and central [change in voluntary activation (ΔVA)] fatigue were assessed via preexercise-to-postexercise changes in magnetically evoked quadriceps twitch. In HYP, blood was drawn to determine the ratio of free-tryptophan (f-TRP) to branched-chain amino acids (BCAA). After exercise, peripheral fatigue was reduced to a similar degree in normoxia and hypoxia (ΔQtw,pot = −4.5 ± 1.3% and −4.0 ± 1.5% in NORM-PLA and HYP-PLA, respectively; P = 0.61). Central fatigue was present after normoxic and hypoxic exercise but to a greater degree in HYP-PLA compared with NORM-PLA (ΔVA: −4.7 ± 0.9% vs. −1.9 ± 0.7%; P < 0.01). Carbohydrate ingestion did not influence central fatigue (ΔVA in HYP-CHO: −5.7 ± 1.2%; P = 0.51 vs. HYP-PLA). After exercise, no differences were observed in the ratio of f-TRP to BCAA between HYP-PLA and HYP-CHO ( P = 0.67). Central fatigue increased during prolonged running exercise in moderate hypoxia although the ratio of f-TRP to BCAA remained unchanged. Ingesting carbohydrates while running in hypoxia did not influence fatigue development.

NEW & NOTEWORTHY Hypoxic exposure influences the origin of exercise-induced fatigue and the rate of fatigue development depending on the severity of hypoxia. Our data suggest that moderate hypoxia increases central, but not peripheral, fatigue in trained runners exercising at 65% of normoxic maximum oxygen uptake. The increase in central fatigue was unaffected by carbohydrate intake and occurred although the ratio of free tryptophan to branched-chain amino acids remained unchanged.
miR-454-3p Is an Exosomal Biomarker and Functions as a Tumor Suppressor in Glioma
Authors: Shao Naiyuan , Xue Lian , Wang Rong , Luo Kaiming , Zhi Feng , Lan Qing
Published: November 2018

Glioma is the most common type of primary malignant brain tumor in adults. Our previous work discovered that plasma miR-454-3p may have some advantages in glioma prognosis, but the clinical significance and the regulatory mechanism of miR-454-3p in glioma have not been systematically investigated, especially regarding the relationship between circulating and tissue miR-454-3p. The expression level of miR-454-3p in glioma serum and tissues was analyzed through quantitative real-time PCR (qRT-PCR). Cell-Counting Kit 8 (CCK-8), wound healing, transwell invasion, apoptosis, and immunofluorescence assays were used to assess the role of miR-454-3p in glioma cancer cells. ATG12 was selected as the target gene of miR-454-3p by bioinformatic analysis. The relationship between ATG12 and miR-454-3p was further validated by luciferase reporter assays and Western blot analysis. miR-454-3p was significantly downregulated in tumor tissues, while it was remarkably upregulated in exosomes from the same patients with glioma. The area under curve (AUC) of exosomal miR-454-3p for glioma diagnosis was 0.8663. The exosomal miR-454-3p was prominently lower in the postoperative serums than that in the preoperative serums. High miR-454-3p expression in exosomes or low miR-454-3p expression in tissue was associated with poor prognosis. Restored expression of miR-454-3p suppressed cell proliferation, migration, invasion, and autophagy in glioma. ATG12 was validated as a direct target of miR-454-3p. The overexpression of ATG12 could partially reverse the effects induced by miR-454-3p suppression. Our data indicate that miR-454-3p may serve as an exosomal biomarker and may be developed into a novel treatment for glioma.
APOMAB Antibody–Drug Conjugates Targeting Dead Tumor Cells are Effective In Vivo
Authors: Staudacher Alexander H. , Li Yanrui , Liapis Vasilios , Hou Jeff Jia Cheng , Chin David , Dolezal Olan , Adams Timothy E. , van Berkel Patrick H. , Brown Michael P.
Published: November 2018

Antibody–drug conjugates (ADC) have revolutionized the field of cancer therapy. ADCs combine the high specificity of tumor-targeting monoclonal antibodies with potent cytotoxic drugs, which cannot be used alone because of their high toxicity. Till date, all ADCs have either targeted cell membrane proteins on tumors or the tumor vasculature and microenvironment. Here, we investigate ADCs of APOMAB (DAB4, or its chimeric derivative, chDAB4), which is a mAb targeting the La/SSB protein, which is only accessible for binding in dying or dead cancer cells. We show that DAB4-labeled dead cells are phagocytosed by macrophages, and that the apoptotic/necrotic areas within lung tumor xenografts are bound by DAB4 and are infiltrated with macrophages. We show that only DAB4–ADCs with a cleavable linker and diffusible drug are effective in two lung cancer models, particularly when given after chemotherapy. These results are consistent with other recent studies showing that direct internalization of ADCs by target cells is not essential for ADC activity because the linker can be cleaved extracellularly or through other mechanisms. Rather than targeting a tumor cell type specific antigen, DAB4–ADCs have the advantage of targeting a common trait in most solid tumors: an excess of post-apoptotic, necrotic cells either adjacent to hypoxic tumor regions or distributed more generally after cytotoxic therapy. Consequently, any antitumor effects are solely the result of bystander killing, either through internalization of the dead, ADC-bound tumor cells by macrophages, or extracellular cleavage of the ADC in the tumor microenvironment.
Prenatal Growth in Fetuses with Isolated Cyanotic and Non-Cyanotic Congenital Heart Defects
Authors: Inversetti Annalisa , Fesslova Vlasta , Deprest Jan , Candiani Massimo , Giorgione Veronica , Cavoretto Paolo
Published: November 2018

Background: Fetal growth may vary significantly in different congenital heart defects (CHDs). Objectives: To investigate prenatal growth of CHD fetuses and its correlation with classifications based upon expected oxygen delivery to the fetal brain or structural findings. Methods: Seventy-nine euploid fetuses with isolated CHD were recruited prospectively and categorized by the expected oxygen supply to the brain (low, intermediate, and high) or by the expected arterial mixing considering two categories (cyanotic or non-cyanotic). Biometry and Doppler were recorded, and Z-scores (Zs) calculated. Growth changes at different time points were analyzed and compared with 150 controls. Results: A total of 664 exams were performed on 229 fetuses. Median head circumference (HC) Zs were lower in all CHD fetuses from the second trimester onwards and in cyanotic CHD fetuses from the first onwards, with associated smaller abdominal circumference (AC) in the third trimester (first-trimester biparietal diameter Zs cyanotic: –1.3 [–2.36; –0.98], non-cyanotic –0.72 [–1.25; –0.6], p = 0.044, second-trimester HC Zs cyanotic: –1.47 [–2.3; –0.84]; non-cyanotic –0.45 [–0.83; –0.02], p < 0.0001; AC Zs cyanotic 0.0 [–0.44; 0.86]; non-cyanotic 0.65 [0.31; 1], p = 0.0006). Birth-weight centiles were smaller in CHDs (particularly in cyanotic) with no differences between categories of brain oxygen delivery. Conclusions: Fetuses with cyanotic CHD have fetal growth restriction, impaired head growth, yet normal posterior fossa dimensions and fetal-placental Doppler.
Evolution of Endolymph Secretion and Endolymphatic Potential Generation in the Vertebrate Inner Ear
Authors: Köppl Christine , Wilms Viviane , Russell Ian John , Nothwang Hans Gerd
Published: November 2018

The ear of extant vertebrates reflects multiple independent evolutionary trajectories. Examples include the middle ear or the unique specializations of the mammalian cochlea. Another striking difference between vertebrate inner ears concerns the differences in the magnitude of the endolymphatic potential. This differs both between the vestibular and auditory part of the inner ear as well as between the auditory periphery in different vertebrates. Here we provide a comparison of the cellular and molecular mechanisms in different endorgans across vertebrates. We begin with the lateral line and vestibular systems, as they likely represent plesiomorphic conditions, then review the situation in different vertebrate auditory endorgans. All three systems harbor hair cells bathed in a high (K+) environment. Superficial lateral line neuromasts are bathed in an electrogenically maintained high (K+) microenvironment provided by the complex gelatinous cupula. This is associated with a positive endocupular potential. Whether this is a special or a universal feature of lateral line and possibly vestibular cupulae remains to be discovered. The vestibular system represents a closed system with an endolymph that is characterized by an enhanced (K+) relative to the perilymph. Yet only in land vertebrates does (K+) exceed (Na+). The endolymphatic potential ranges from +1 to +11 mV, albeit we note intriguing reports of substantially higher potentials of up to +70 mV in the cupula of ampullae of the semicircular canals. Similarly, in the auditory system, a high (K+) is observed. However, in contrast to the vestibular system, the positive endolymphatic potential varies more substantially between vertebrates, ranging from near zero mV to approximately +100 mV. The tissues generating endolymph in the inner ear show considerable differences in cell types and location. So-called dark cells and the possibly homologous ionocytes in fish appear to be the common elements, but there is always at least one additional cell type present. To inspire research in this field, we propose a classification for these cell types and discuss potential evolutionary relationships. Their molecular repertoire is largely unknown and provides further fertile ground for future investigation. Finally, we propose that the ultimate selective pressure for an increased endolymphatic potential, as observed in mammals and to a lesser extent in birds, is specifically to maintain the AC component of the hair-cell receptor potential at high frequencies. In summary, we identify intriguing questions for future directions of research into the molecular and cellular basis of the endolymph in the different compartments of the inner ear. The answers will provide important insights into evolutionary and developmental processes in a sensory organ essential to many species, including humans.
Mini-Percutaneous Nephrolithotomy with Ureter Catheter: A Safe and Effective form of mPCNL Offers Better Quality of Life
Authors: Zhang Yucong , Wei Chao , Pokhrel Gaurab , Liu Xiaming , Ouyang Wei , Gan Jiahua , Ding Beichen , Liu Zhuo , Peng Ejun , Chen Zhiqiang
Published: November 2018

Objective: To compare outcomes and postoperative quality of life (QoL) among patients with kidney stone who received mini-percutaneous nephrolithotomy (mPCNL), partial tubeless mPCNL or mPCNL with ureter catheter in a prospective randomized clinical trial. Methods: From May 2017 to December 2017, 60 patients with kidney stone who underwent mPCNL were randomized into 3 groups: Group I (mPCNL), Group II (partial tubeless mPCNL), Group III (mPCNL with ureter catheter). We evaluated perioperative characteristics, stone clearance, analgesic requirements and QoL by using the Wisconsin Stone QOL questionnaire. Results: The age, gender, stone diameter, body mass index, length of operation, drop in hemoglobin and stone-free rates for the 3 groups were similar among these groups. However, the postoperative visual analog scale and the analgesic requirement in Group II were significantly the lowest (p < 0.05). According to Wisconsin Stone QOL questionnaire, compared to Group I, statistical significant difference in the QoL was seen in Group II and III, indicating a meaningful and immediate improvement in the postoperative QoL following mPCNL. Conclusion: Compared with standard and partial tubeless mPCNL, mPCNL with ureter catheter is a safe and useful form of mPCNL, which can offer better QoL and is more cost effective.
Low Skeletal Muscle Mass Predicts Incident Dipstick Albuminuria in Korean Adults without Chronic Kidney Disease: A Prospective Cohort Study
Authors: Lim Sung Yoon , Lee Kyu-Beck , Kim Hyang , Hyun Young Youl
Published: November 2018

Background: Previous cross-sectional studies have shown that low muscle mass is associated with albuminuria in the general population. However, the longitudinal association of low muscle mass with the development of albuminuria is not well known at this time. Methods: We evaluated 48,101 individuals without chronic kidney disease (CKD) who underwent 2 health check-ups in 2012 and 2016. Participants’ skeletal muscle masses were measured using a bioelectrical impedance analyzer and compared via a skeletal muscle mass index (SMI; SMI [%] = total skeletal muscle mass [kg]/body weight [kg] × 100). Urine albumin was determined by dipstick semi-quantitative analysis and incident albuminuria was defined as ≥1+ dipstick albumin at the time of the second check-up. We used logistic regression analysis to determine the relationship between skeletal muscle mass and incident albuminuria. Results: The study participants were divided into quartiles according to baseline SMI. After 4 years, 305 cases of incident albuminuria were observed. The cumulative incidences of albuminuria were 0.78, 0.66, 0.62, and 0.47% for the first through fourth quartiles of SMI respectively. Multivariable logistic analysis revealed that the ORs (95% CIs) for incident albuminuria were 1.63 (1.05–2.55) in the first quartile compared with those in the fourth quartile and 1.40 (1.05–1.88) in the participants with sarcopenia versus those without sarcopenia. Conclusions: Low skeletal muscle mass was independently associated with the development of dipstick albuminuria after 4 years in Korean adults without CKD. Further research is needed to verify the role of low muscle mass in the development of albuminuria and renal injury.
PFKFB4 Promotes Breast Cancer Metastasis via Induction of Hyaluronan Production in a p38-Dependent Manner
Authors: Gao Ruifang , Liu Yanhua , Li Dan , Xun Jing , Zhou Wei , Wang Peng , Liu Chen , Li Xiru , Shen Wenzhi , Su Weijun , Qiao Huan , Stupack Dwayne G. , Luo Na
Published: November 2018

Background/Aims: The bi-functional enzyme 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase-4 (PFKFB4) is highly expressed in many types of cancer and its requirement for tumor survival has been demonstrated in glioma, lung, and prostate cancers. However, whether PFKFB4 plays a role in the tumor metastasis remains uncertain. This study explores the role of PFKFB4 in tumor metastasis and its underlying mechanisms in breast cancer cells. Methods: The expression of PFKFB4 was first analyzed using the Cancer Genome Atlas (TCGA) dataset, and confirmed by immunohistochemical staining of tissue microarray and breast cancer tissues from patient samples. Gain- and loss-of- function approaches were used to investigate the effects of PFKFB4 on breast cancer cell migration in vitro. Orthotopic xenograft model and experimental metastasis model were used to assess the effects of PFKFB4 on breast cancer cell metastasis in vivo. ELISA and immunofluorescence staining were used to examine HA production. Quantitative RT-PCR and western blotting were used to explore the mRNA and protein levels of HAS2, respectively. Results: We found that PFKFB4 enhances the migration/invasiveness of breast cancer cells in vitro as well as in vivo. Notably, the effects of PFKFB4 on migration are mediated by induction of HAS2 expression and HA production. Moreover, PFKFB4-induced HAS2 up-regulation depends upon the activation of p38 signaling. Conclusion: PFKFB4 promotes the metastasis of breast cancer cells via induction of HAS2 expression and HA production in a p38-dependent manner. Therefore, the PFKFB4/p38/HAS2 signaling pathway may serve as a potential therapeutic target for metastatic breast cancer.
Identification of Novel LncRNA Biomarkers and Construction of LncRNA-Related Networks in Han Chinese Patients with Ischemic Stroke
Authors: Guo Xiaojing , Yang Jialei , Liang Baoyun , Shen Tingting , Yan Yan , Huang Siyun , Zhou Jinying , Huang Jiao , Gu Lian , Su Li
Published: November 2018

Background/Aims: Long non-coding RNAs (lncRNAs) are potential biomarkers of tumors, cardiac disease, and cerebral disease because of their interaction with coding RNAs. This work focused on ischemic stroke (IS) and aimed to identify novel lncRNA biomarkers and construct lncRNA-related networks in IS. Methods: Differentially expressed lncRNAs were identified using Arraystar Human LncRNA Microarray v4.0, and validated with qRT-PCR. A lncRNA–mRNA co-expression network and a lncRNA–miRNA–mRNA regulatory network were constructed. Functional and pathway analyses were then performed. Results: In total, 560 up-regulated and 690 down-regulated differentially expressed lncRNAs were found (P < 0.05, false discovery rate < 0.05, absolute fold change ≥ 2). qRT-PCR results confirmed that lncRNA-ENST00000568297, lncRNA-ENST00000568243, and lncRNA-NR_046084 exhibited significant differential expression between IS and controls (all P < 0.05). Areas under the curves (AUCs) for these lncRNAs were 0.733, 0.743, and 0.690, respectively, and the combined AUC was 0.843. A coding–noncoding co-expression (CNC) network was constructed based on Pearson’s correlation coefficient. A specific lncRNA–miRNA–mRNA regulatory network of ENST00000568297, ENST00000568243, and NR_046084 was also constructed. Functional annotation of the up- and down-regulated mRNAs was performed. Pathway analysis enriched IS-related pathways with mRNAs in the lncRNA–miRNA–mRNA regulatory network. Conclusion: LncRNA and mRNA expression profiles in human peripheral blood were altered after IS. ENST00000568297, ENST00000568243, and NR_046084 were identified as novel potential diagnostic biomarkers of IS. Analysis of the CNC network and lncRNA–miRNA–mRNA regulatory network suggested that lncRNAs may participate in IS pathophysiology by regulating pivotal miRNAs, mRNAs, or IS-related pathways.
MicroRNA-323a-3p Promotes Pressure Overload-Induced Cardiac Fibrosis by Targeting TIMP3
Authors: Zhang JingChao  , Lang Yan , Guo LongHui , Pei Yu , Hao Shuang , Liang ZhenXing , Su Gang , Shu LiLiang , Liu Hai , Huang Chen , Xu Jing
Published: November 2018

Background/Aims: Cardiac fibrosis is a major cause of diverse cardiovascular diseases. MicroRNAs have recently been proven a novel class of regulators of cardiac fibrosis. In this study, we sought to investigate the role of miR-323a-3p and its mechanisms in regulating cardiac fibrosis. Methods: The transverse aortic constriction (TAC) mice model was induced and neonatal cardiac fibroblasts (CFs) were cultured. MTT (3- [4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide) assay was used to detect the cell viability. Echocardiography was used to evaluate cardiac function. Masson’s Trichrome stain was used to evaluate the development of fibrosis. Luciferase activity assay was performed to confirm the miRNA’s binding site. Real-time PCR and Western blot were used to evaluate the level of mRNA and protein. Results: MiR-323a-3p was found up-regulated in myocardial tissues subjected to TAC and in CFs cultured with Angiotensin Ⅱ (Ang Ⅱ). Overexpression of miR-323a-3p significantly increased the mRNA levels of collagen Ⅰ, collagen Ⅲ, MMP2 and MMP9, while inhibition of miR-323a-3p prevented the proliferation, collagen production and the protein level of transforming growth factor (TGF-β) in rat neonatal CFs. Strikingly, injection of antagomiR-323a-3p elevated cardiac function and inhibited the expression of TGF-β in the TAC mice. TIMP3 was a direct target of miR-323a-3p, as the overexpression of miR-323a-3p decreased the protein and mRNA levels of TIMP3. In the CFs with pre-treatment of Ang Ⅱ, siRNA-TIMP abolished the effects of AMO-323a-3p on the inhibition of the proliferation of CFs, the down-regulation of collagen Ⅰ and collagen Ⅲ, and the expression of TGF-β. Conclusion: Our findings provide evidence that miR-323a-3p promotes cardiac fibrosis via miR-323a-3p-TIMP3-TGF-β pathway. miR-323a-3p may be a new marker for cardiac fibrosis progression and that inhibition of miR-323a-3p may be a promising therapeutic target for the treatment of cardiac fibrosis.
Pro-Angiogenic Role of LncRNA HULC in Microvascular Endothelial Cells via Sequestrating miR-124
Authors: Yin Dexin , Li Yezhou , Fu Changgeng , Feng Ye
Published: November 2018

Background/Aims: HULC is a multifunctional lncRNA that has pro-angiogenic function in various cancers. The present study was designed to see the role of lncRNA HULC in normal endothelial cells angiogenesis. Methods: Cell viability, apoptosis, migration, tube formation and expression levels of angiogenesis-related proteins were respectively assessed in human microvascular endothelial HMEC-1 cells after lncRNA HULC was silenced by shRNA transfection. Cross-regulation between lncRNA HULC and miR-124, and between miR-124 and MCL-1 were detected by qRT-PCR, sequence analysis, and luciferase reporter assay. Results: Silence of lncRNA HULC significantly reduced viability, migration, tube formation and protein levels of VEGF, VEGFR2, CD144 and eNOS in HMEC-1 cells. Meanwhile, silence of lncRNA HULC induced apoptosis in HMEC-1 cells, as Bcl-2 was down-regulated, Bax was up-regulated, and caspase-3 and -9 were cleaved. miR-124 expression was negatively regulated by lncRNA HULC, and HULC worked as a molecular sponge for miR-124, in having miR-124 exhausted. Besides, MCL-1 was a target gene of miR-124. Rescue assay results showed that the effects of lncRNA HULC silence on HMEC-1 cells growth, migration and angiogenesis were abolished by miR-124 suppression. Similarly, the effects of miR-124 on HMEC-1 cells were abolished by MCL-1 overexpression. Furthermore, MCL-1 activated PI3K/AKT and JAK/STAT signaling pathways. Conclusion: These findings suggest a pro-angiogenic role of lncRNA HULC in endothelial cells. The pro-angiogenic actions of lncRNA HULC may be through sponging miR-124, preventing MCL-1 from degradation by miR-124.