bluuebunny/crossref_metadata_2025 huggingface dataset:
Global patterns and trends in colorectal cancer incidence in young adults
Authors: Siegel Rebecca L , Torre Lindsey A , Soerjomataram Isabelle , Hayes Richard B , Bray Freddie , Weber Thomas K , Jemal Ahmedin
Published: September 2019

Objective

Early-onset colorectal cancer (CRC) is increasing in the USA despite rapid declines in older ages. Similar patterns are reported in Australia and Canada, but a comprehensive global analysis of contemporary data is lacking.

Design

We extracted long-term data from Cancer Incidence in Five Continents and supplemental sources to report on worldwide CRC incidence rates and trends by age (20–49 years and ≥50 years) through diagnosis year 2012 or beyond (Australia, Finland, New Zealand, Norway, Sweden, USA).

Results

During 2008–2012, age-standardised CRC incidence rates in adults <50 ranged from 3.5 per 100 000 (95% CI 3.2 to 3.9) in India (Chennai) to 12.9 (95% CI 12.6 to 13.3) in Korea. During the most recent decade of available data, incidence in adults <50 was stable in 14 of 36 countries; declined in Austria, Italy and Lithuania; and increased in 19 countries, nine of which had stable or declining trends in older adults (Australia, Canada, Denmark, Germany, New Zealand, Slovenia, Sweden, UK and USA). In Cyprus, Netherlands and Norway, inclines in incidence in young adults were twice as rapid as those in older adults (eg, Norway average annual per cent change (AAPC), 1.9 (95% CI 1.4 to 2.5) vs 0.5 (95% CI 0.3 to 0.7)). Among most high-income countries with long-term data, the uptick in early-onset disease began in the mid-1990s. The steepest increases in young adults were in Korea (AAPC, 4.2 (95% CI 3.4 to 5.0)) and New Zealand (AAPC, 4.0 (95% CI 2.1 to 6.0)).

Conclusion

CRC incidence increased exclusively in young adults in nine high-income countries spanning three continents, potentially signalling changes in early-life exposures that influence large bowel carcinogenesis.
Assessing the relationship between diet and size-at-age in Pacific halibut (Hippoglossus stenolepis) using δ13C and δ15N analysis
Authors: Wolf Nathan , Webster Sarah R. , Welker Jeffery M. , Harris Bradley P.
Published: September 2019

The ecological mechanisms driving an observed decline in the mean size-at-age of adult Pacific halibut (Hippoglossus stenolepis) in the eastern North Pacific Ocean have yet to be defined. Here, we present the results of a study designed to investigate the relationship between one potential mechanism — diet — and size-at-age using carbon and nitrogen stable isotope analysis. Our results indicate significant differences in the skeletal muscle δ13C and δ15N values between size-at-age categories for each sex, with larger-size-at-age fish consuming diets with higher δ15N values, indicating higher trophic level feeding. Analysis of Bayesian standard ellipse areas showed that for females, intermediate size-at-age categories have the largest dietary range. For males, the largest dietary range was observed in the largest size-at-age category. Our results suggest a size-based stratification in dietary strategy for Pacific halibut with implications for observed declines in size-at-age.
Adverse plasma fatty acid composition in patients with femoral neck fracture1
Authors: Arsic Aleksandra , Pesic Goran , Petrovic Snjezana , Matic Aleksandar , Jeremic Jovana , Jakovljevic Vladimir , Vucic Vesna
Published: September 2019

Our study aimed to examine the status of plasma fatty acids (FAs), inflammatory markers, and lipid peroxidation in patients with femoral neck fractures. The study included 20 patients (64–86 years) with femoral neck fractures indicated for surgery and a control group of 17 elderly subjects without fractures or serious chronic diseases. Plasma was obtained during the first 12 h postfracture and presurgery and 7 days postop. Compared to the control, patients had significantly higher saturated FA (SFA) and monounsaturated FA as well as increased TNF-α and IL-6. Opposite to that, levels of individual and total n-6 polyunsaturated FA (PUFA), individual and total n-3 PUFA, n-6/n-3 ratio, and levels of thiobarbituric acid reactive substances (TBARS) were markedly lower in the patient than in the controls. On the seventh day after the surgery, we showed a further rise in the SFA, oleic acid, and TNF-α and reductions of n-6 PUFA and IL-6. Taken together, our results suggest that altered FA status, especially reduced PUFA, may influence hip fracture repair and even contribute to femoral fracture susceptibility in the elderly. A potential benefit from nutritional intervention with PUFA in prevention and (or) fracture healing should be considered.
Herbage biomass and its relationship to soil carbon under long-term grazing in northern temperate grasslands
Authors: Bork E.W. , Lyseng M.P. , Hewins D.B. , Carlyle C.N. , Chang S.X. , Willms W.D. , Alexander M.J.
Published: September 2019

While northern temperate grasslands are important for supporting beef production, it remains unclear how grassland above- and belowground biomass responds to long-term cattle grazing. Here, we use a comprehensive dataset from 73 grasslands distributed across a broad agro-climatic gradient to quantify grassland shoot, litter, and shallow (top 30 cm) root biomass in areas with and without grazing. Additionally, we relate biomass to soil carbon (C) concentrations. Forb biomass was greater (p < 0.05) in grazed areas, particularly those receiving more rainfall. In contrast, grass and total aboveground herbage biomass did not differ with grazing (total: 2320 kg ha−1 for grazed vs. 2210 kg ha−1 for non-grazed; p > 0.05). Forb crude protein concentrations were lower (p < 0.05) in grazed communities compared with those that were non-grazed. Grasslands subjected to grazing had 56% less litter mass. Root biomass down to 30 cm remained similar between areas with (9090 kg ha−1) and without (7130 kg ha−1) grazing (p > 0.05). Surface mineral soil C concentrations were positively related to peak grassland biomass, particularly total (above + belowground) biomass, and with increasing forb biomass in grazed areas. Finally, total aboveground shoot biomass and soil C concentrations in the top 15 cm of soil were both positively related to the proportion of introduced plant diversity in grazed and non-grazed grasslands. Overall, cattle grazing at moderate stocking rates had minimal impact on peak grassland biomass, including above- and belowground, and a positive contribution exists from introduced plant species to maintaining herbage productivity and soil C.
A Benzenoid 4,7-Dimethoxy-5-Methyl-L, 3-Benzodioxole from Antrodia cinnamomea Attenuates Dendritic Cell-Mediated Th2 Allergic Responses
Authors: You Ren-In , Lee Yi-Pang , Su Ting-Yi , Lin Chi-Chien , Chen Chang-Shan , Chu Ching-Liang
Published: September 2019

Dendritic cells (DCs) play a critical role in initiating immune responses; however, DCs also induce Th2-related allergic sensitivities. Thus, DCs become a target for therapeutic design in allergic diseases. In this study, we aim to investigate the anti-allergic effect of pure compounds from a medicinal mushroom Antrodia cinnamomea (Ac) on DC-induced allergic responses. We identified a benzenoid compound 4,7-dimethoxy-5-methyl-l,3-benzodioxole (DMB) which may modulate Th2 polarization in bone marrow-derived DCs (BMDCs) and in a murine food allergy model. DMB effectively reduced the Th2 adjuvant cholera toxin (CT)-induced BMDC maturation and cytokine production. In studying the mechanism, DMB blocked the molecular processes involved in Th2 induction, including cAMP activation, IL-33 production, and IRF4/Tim4 upregulation, in CT-activated BMDCs. Furthermore, DMB treatment attenuated the symptoms, clinical scores, and Th2 responses of CT-induced ovalbumin (OVA)-specific food allergy in mice at sensitization stage. These results indicated that DMB could suppress DC function for Th2 polarization and mitigate allergic responses. Thus, DMB may have potential to be a novel agent for preventing or treating food allergy.
ARITHMETIC ON MORAN SETS
Authors: REN XIAOMIN , TIAN LI , ZHU JIALI , JIANG KAN
Published: September 2019

Let [Formula: see text] be a class of Moran sets. We assume that the convex hull of any [Formula: see text] is [Formula: see text]. Let [Formula: see text] be two nonempty sets in [Formula: see text]. Suppose that [Formula: see text] is a continuous function defined on an open set [Formula: see text]. Denote the continuous image of [Formula: see text] by [Formula: see text] In this paper, we prove the following result. Let [Formula: see text]. Suppose that [Formula: see text] and [Formula: see text] are continuous if there exists some [Formula: see text] such that [Formula: see text] then [Formula: see text] contains an interior.
TRIANGULAR LABYRINTH FRACTALS
Authors: CRISTEA LIGIA L. , SURER PAUL
Published: September 2019

We define and study a class of fractal dendrites called triangular labyrinth fractals. For the construction, we use triangular labyrinth pattern systems, consisting of two triangular patterns: a white and a yellow one. Correspondingly, we have two fractals: a white and a yellow one. The fractals studied here are self-similar, and fit into the framework of graph directed constructions. The main results consist in showing how special families of triangular labyrinth patterns systems, which are defined based on some shape features, can generate exactly three types of dendrites: labyrinth fractals where all nontrivial arcs have infinite length, fractals where all nontrivial arcs have finite length, or fractals where the only arcs of finite lengths are line segments parallel to a certain direction. We also study the existence of tangents to arcs. The paper is inspired by research done on labyrinth fractals in the unit square that have been studied during the last decade. In the triangular case, due to the geometry of triangular shapes, some new techniques and ideas are necessary in order to obtain the results.
THE HOSOYA INDEX OF GRAPHS FORMED BY A FRACTAL GRAPH
Authors: LIU JIA-BAO , ZHAO JING , MIN JIE , CAO JINDE
Published: September 2019

The computational complexity of the Hosoya index of a given graph is NP-Complete. Let [Formula: see text] be the graph constructed from [Formula: see text] by a triangle instead of all vertices of the initial graph [Formula: see text]. In this paper, we characterize the Hosoya index of the graph [Formula: see text]. To our surprise, it shows that the Hosoya index of [Formula: see text] is thoroughly given by the order and degrees of all the vertices of the initial graph [Formula: see text].
Soft Maximal and Irreducible Int-Ideals of a Ring
Authors: Ghosh Jayanta , Mandal Dhananjoy , Samanta Tapas Kumar
Published: September 2019

In this paper, the concepts of soft maximal int-ideal and soft irreducible int-ideal of a ring are introduced and some properties of these notions have been studied. Also we point out some facts of a ring which cannot be extended to the soft setting and it is justified by suitable examples.
Interval-Valued Intuitionistic Fuzzy Linear Programming Problem
Authors: Bharati S. K. , Singh S. R.
Published: September 2019

In many existing methods of linear programming problem (LPP), precise values of parameters have been used but parameters of LPP are imprecise and ambiguous due to incomplete information. Several approaches and theories have been developed for dealing LPP based on fuzzy set (FS), intuitionistic fuzzy set (IFS) which are characterized by membership degree, membership and non-membership degrees, respectively. It’s interesting to note that single membership and non-membership degrees do not deal properly the state of uncertainty and hesitation. Further, we face a kind of uncertainty occurs a kind of uncertainty. Interval-valued intuitionistic fuzzy sets (IV-IFS) is a perfect key for handling uncertainty and hesitation than FS and IFS. In this paper, we define an interval-valued intuitionistic fuzzy number (IV-IFN) and its expected interval and expected values. We also introduce the concept of interval-valued intuitionistic fuzzy linear programming problem (IV-IFLPP). Further, we find the solutions of IV-IFLPP and compare the obtained optimal solutions with existing methods [D. Dubey and A. Mehra, Linear programming with Triangular Intuitionistic Fuzzy Numbers, in Proc. of the 7th Conf. and of the European Society for Fuzzy Logic and Technology (EUSFLAT-LFA 2011), R. Parvathi and C. Malathi, Intuitionistic fuzzy linear optimization, Notes on Intuitionistic Fuzzy Sets 18 (2012) 48–56]. Proposed technique may be used successfully in various areas in the formulation of our country’s five year plans, these include transportation, food-grain storage, urban development, national, state and district level plans, etc., The Indian Railways may use IV-IFLPP technique for linking different railway zones in more realistic way. Agricultural research institutes may use proposed technique for crop rotation mix of cash crops, food crops and fertilizer mix. Airlines can apply IV-IFLPP in the selection of routes and allocation of aircrafts to different routes. Private and public sector oil refineries may use IV-IFLPP for blending of oil ingredients to produce finished petroleum products.
Fuzzy Bounded Linear Operator in Fuzzy Normed Linear Spaces and its Fuzzy Compactness
Authors: Sharma Mami , Hazarika Debajit
Published: September 2019

In this paper, we first investigate the relationship between various notions of fuzzy boundedness of linear operators in fuzzy normed linear spaces. We also discuss the fuzzy boundedness of fuzzy compact operators. Furthermore, the spaces of fuzzy compact operators have been studied.
Fuzzification of Zero Forcing Process
Authors: Borzooei R. A. , Hoseini B. Sheikh , Golmohammadian M. , Montazeri Z. , Takallo M. Mohseni
Published: September 2019

In this paper, we investigate the fuzzification of zero forcing process. For this, first we introduce a new embedding of a graph [Formula: see text] by considering a minimal zero forcing set of [Formula: see text] and an arbitrary list of maximal forcing chains of this zero forcing set. Then we get a comparison between zero forcing sets of a graph by using fuzzy concepts. Finally, we give an application for this procedure.
Platelet-rich fibrin in combination with decalcified freeze-dried bone allograft for the management of mandibular degree II furcation defect: A randomised controlled clinical trial
Authors: Agarwal Ashish , Manjunath R. G. Shiva , Sethi Priyamwada , Shankar G. Shiva
Published: September 2019

Background: Treatment of furcation involvement of molars with periodontal disease remains challenging and unpredictable. Platelet-rich fibrin (PRF) has received the attention of researchers due to its pleiotropic properties essential for periodontal wound healing. The osteoinductive property of demineralized freeze-dried bone allograft (DFDBA) has been successfully used in periodontal regeneration.

Aim: The present study aimed to explore the effectiveness of PRF alone and with DFDBA in the treatment of mandibular degree II furcation defects in subjects with chronic periodontitis.

Material and Methods: Patients treated were from the Department of Periodontology and Implantology, Institute of Dental Sciences, Bareilly. A total of 60 mandibular molars were treated with either open flap debridement (OFD) alone, [Formula: see text] combination or [Formula: see text] combination. The soft and hard tissue parameters such as vertical probing depth (VPD), vertical clinical attachment level (VCAL), gingival marginal level (GML), horizontal probing depth (HPD), vertical bone fill (VBF), horizontal bone fill (HBF) and furcation width (FW) were determined at baseline and 9 months postoperatively. A paired [Formula: see text]-test was conducted to assess the statistical significance between time period within each group for clinical and radiographic parameters. ANOVA and post-hoc Tukey’s tests were also conducted for intergroup comparison of soft and hard tissue parameters. Statistical significance was set at [Formula: see text].

Results and Discussion: After 9 months, all treatment groups showed significant ([Formula: see text]) improvement in soft and hard tissue parameters, except GML in all the three groups and HBF and FW in the OFD group as compared to baseline. The mean VBF change was highest in the [Formula: see text] group ([Formula: see text]) mm, followed by that in the [Formula: see text] and OFD groups ([Formula: see text] and [Formula: see text][Formula: see text]mm, respectively).

Conclusions: It was shown that both [Formula: see text] and [Formula: see text] combinations were significantly advantageous for the management of mandibular degree II furcation defects. However, the [Formula: see text] combination has significantly greater benefits than [Formula: see text] combination in terms of VBF.
Leader-Following Adaptive Consensus of Multiple Uncertain Rigid Body Systems over Jointly Connected Networks
Authors: Wang Tianqi , Huang Jie
Published: September 2019

The leader-following consensus problem of a group of uncertain multiple rigid body systems subject to static networks has been solved by a distributed adaptive control law utilizing the distributed observer for the leader system. In this paper, we extend this result to jointly connected switching networks. This extension needs to overcome the discontinuity of some variables caused by the switching network. Additionally, we remove the assumption that every follower knows the system matrix of the leader system by employing an adaptive distributed observer for the leader system.
New developments in field-portable geochemical techniques and on-site technologies and their place in mineral exploration
Authors: Lemière Bruno , Uvarova Yulia A.
Published: September 2019

This paper focuses on handheld and top-of-hole techniques which have appeared since 2007 or have undergone major improvements, and discusses their benefits, challenges and pitfalls, why we use them and what to expect from them. There is an ongoing need to be innovative with the way we undertake mineral exploration. Recent technological advances that have been applied to successful mineral exploration include on-site or portable instruments, on-site laboratory technologies, various core scanners, and technologies for fluid analysis. Portable or field technologies such as pXRF, pXRD, pNIR-SWIR, µRaman and LIBS aid in obtaining chemical and mineralogical information. Spectral gamma tools, a well-known technology, recently took advantage of improved ground and airborne (drone) instruments, to complement hyperspectral imagery. At mine and exploration sites, top-of-hole sensing technologies, such as Lab-at-Rig® and various core scanners (both spectral- and XRF-based) have become useful tools to analyse metres of core as it is being drilled. Fluid analyses are not as common as analyses of solid materials, but there are advances in such technologies as anodic stripping voltammetry, polarography and ion-exchange electrodes aiming for analysis of commodity or environmentally important elements.

Field-portable geochemical techniques and on-site technologies now offer instant response and flexibility for most exploration tasks. By providing relevant data within minutes, they allow safer field decisions and focus on the most promising finds, while saving valuable resources in sampling grids or drilling. More efficient laboratory analysis programs are supported by sample screening and homogeneity checking on-site. Field analyses are not always as accurate as laboratory ones, but most of the time can be correlated with them, enabling reliable decisions. The level of confidence in field-made decisions needs to be compared between later and less numerous laboratory analyses, and less precise but more abundant and immediate field analyses. It may be demonstrated that, in many cases, the fit–for-purpose nature of the latter allows a better confidence level. Quality compromises associated with field analyses can be reduced by the application of better sample preparation and quality assurance/quality control (QA/QC) procedures. Most of the further development of on-site chemical analysis is expected to be based on its integration with lab methods and on sound QA/QC practice, allowing a precise evaluation of its confidence level and uncertainties. Mineralogical analyses are constrained by our ability to interpret the data in near-real time but offer promising approaches in both surface and drilling exploration campaigns.

Thematic collection:
This article is part of the Exploration 17 collection available at:
https://www.lyellcollection.org/cc/exploration-17
Network Flow-Based Refinement for Multilevel Hypergraph Partitioning
Authors: Heuer Tobias , Sanders Peter , Schlag Sebastian
Published: September 2019

We present a refinement framework for multilevel hypergraph partitioning that uses max-flow computations on pairs of blocks to improve the solution quality of a
k
-way partition. The framework generalizes the flow-based improvement algorithm of the Karlsruhe Fast Flow Partitioner (KaFFPa) from graphs to hypergraphs and is integrated into the hypergraph partitioner Karlsruhe Hypergraph Partitioning (KaHyPar). By reducing the size of hypergraph flow networks, improving the flow model used in KaFFPa, and developing techniques to improve the running time of our algorithm, we obtain a partitioner that computes the best solutions for a wide range of benchmark hypergraphs from different application areas for
both
the connectivity and the cut-net metric while still having a running time comparable to that of hMetis. In the case of graph partitioning, our algorithm compares favorably with KaFFPa, even after enhancing the latter with our improved flow network, and at the same time is more than a factor of two faster. Finally, we show that our algorithm improves the performance of the memetic multilevel hypergraph partitioner KaHyPar-E.
The Microbiome and Aging
Authors: Bana Bianca , Cabreiro Filipe
Published: September 2019

Aging is a natural process of organismal decay that underpins the development of myriad diseases and disorders. Extensive efforts have been made to understand the biology of aging and its regulation, but most studies focus solely on the host organism. Considering the pivotal role of the microbiota in host health and metabolism, we propose viewing the host and its microbiota as a single biological entity whose aging phenotype is influenced by the complex interplay between host and bacterial genetics. In this review we present how the microbiota changes as the host ages, but also how the intricate relationship between host and indigenous bacteria impacts organismal aging and life span. In addition, we highlight other microbiota-dependent mechanisms that potentially regulate aging, and present experimental animal models for addressing these questions. Importantly, we propose microbiome dysbiosis as an additional hallmark and biomarker of aging.
Free Fatty Acid Receptors in Health and Disease
Authors: Kimura Ikuo , Ichimura Atsuhiko , Ohue-Kitano Ryuji , Igarashi Miki
Published: September 2019

Fatty acids are metabolized and synthesized as energy substrates during biological responses. Long- and medium-chain fatty acids derived mainly from dietary triglycerides, and short-chain fatty acids (SCFAs) produced by gut microbial fermentation of the otherwise indigestible dietary fiber, constitute the major sources of free fatty acids (FFAs) in the metabolic network. Recently, increasing evidence indicates that FFAs serve not only as energy sources but also as natural ligands for a group of orphan G protein-coupled receptors (GPCRs) termed free fatty acid receptors (FFARs), essentially intertwining metabolism and immunity in multiple ways, such as via inflammation regulation and secretion of peptide hormones. To date, several FFARs that are activated by the FFAs of various chain lengths have been identified and characterized. In particular, FFAR1 (GPR40) and FFAR4 (GPR120) are activated by long-chain saturated and unsaturated fatty acids, while FFAR3 (GPR41) and FFAR2 (GPR43) are activated by SCFAs, mainly acetate, butyrate, and propionate. In this review, we discuss the recent reports on the key physiological functions of the FFAR-mediated signaling transduction pathways in the regulation of metabolism and immune responses. We also attempt to reveal future research opportunities for developing therapeutics for metabolic and immune disorders.
Analytical Methods Used for the Detection and Quantification of Benzodiazepines
Authors: Qriouet Zidane , Qmichou Zineb , Bouchoutrouch Nadia , Mahi Hassan , Cherrah Yahia , Sefrioui Hassan
Published: September 2019

The prescription of psychotropic drugs, especially benzodiazepines (BZDs), occupies a preponderant place in the management of mental illnesses. Indeed, the BZDs have been used in different therapeutic areas including insomnia, anxiety, seizure disorders, or general anesthesia. Unfortunately, these drugs are present in the illegal street market, leading to a lot of drug abuse amongst some addicted users, road insecurity, and suicide. Hence, it has become essential to analyze the BZDs drugs in human biological specimens for drug abuse in forensic sciences. The present review provides a summary of sample preparation techniques (solid-phase extraction and Liquid-liquid phase extraction) and the methods for the detection and quantification of BZDs molecules in the commonly used biological specimens over the ten last years which may potentially lead to better and accurate evaluation of the physiological state of a given person. The commonly used methods for the detection and quantification of BZDs include nuclear magnetic resonance (NMR), chromatography (GC-MS, HPLC, and TLC), immunoassay (ELISA, RIA, LFA, CEDEA, FPIA, and KIMS), and electroanalytical methods (voltammetry and potentiometry).
Islet Transplantation Attenuating Testicular Injury in Type 1 Diabetic Rats Is Associated with Suppression of Oxidative Stress and Inflammation via Nrf-2/HO-1 and NF-κB Pathways
Authors: Zhu Xiandong , Guo Feixia , Tang Hengjie , Huang Chongchu , Xie Gangyin , Huang Tingting , Li Yonglin , Liu Chengyang , Wang Hongwei , Chen Bicheng
Published: September 2019

Testicular structural and functional impairment is a serious complication in male diabetes mellitus (DM) patients that leads to impaired fertility in adulthood. In contrast to other endocrine therapies, islet transplantation (IT) can effectively prevent and even reverse diabetic nephropathy and myocardial damage. However, whether IT can alleviate diabetes-induced testicular injury remains unclear. In this study, we sought to investigate the effect of IT on diabetes-induced testicular damage. A diabetic rat model was established by streptozotocin injection. DM, IT, and insulin treatment (INS) groups were compared after 4 weeks of respective treatment. We confirmed that IT could effectively attenuate diabetes-induced testicular damage and recover sperm counts more extensively compared with INS in diabetic rats. In addition, significantly higher levels of superoxide dismutase (SOD) activity and lower contents of malondialdehyde (MDA) were detected in the testes of the IT group versus diabetic rats. Mechanism studies revealed that IT significantly activates the expression of Nrf-2, HO-1, and NQO-1 and inhibits upregulation of the NF-κB expression in response to DM, while INS only exhibit slight impact on the protein expression. Therefore, we speculate that IT may prevent the progression of testicular damage by downregulating oxidative stress and inhibiting inflammation via Nrf-2/HO-1 and NF-κB pathways.
Hyperglycemia-Induced Oxidative Stress Abrogates Remifentanil Preconditioning-Mediated Cardioprotection in Diabetic Rats by Impairing Caveolin-3-Modulated PI3K/Akt and JAK2/STAT3 Signaling
Authors: Lei Shaoqing , Su Wating , Xia Zhong-Yuan , Wang Yafeng , Zhou Lu , Qiao Shigang , Zhao Bo , Xia Zhengyuan , Irwin Michael G.
Published: September 2019

Diabetic hearts are more vulnerable to ischemia/reperfusion (I/R) injury and less responsive to remifentanil preconditioning (RPC), but the underlying mechanisms are incompletely understood. Caveolin-3 (Cav-3), the dominant isoform of cardiomyocyte caveolae, is reduced in diabetic hearts in which oxidative stress is increased. This study determined whether the compromised RPC in diabetes was an independent manifestation of hyperglycemia-induced oxidative stress or linked to impaired Cav-3 expression with associated signaling abnormality. RPC significantly attenuated postischemic infarction, cardiac dysfunction, myocardial apoptosis, and 15-F2t-isoprostane production (a specific marker of oxidative stress), accompanied with increased Cav-3 expression and enhanced Akt and STAT3 activation in control but not in diabetic rats. Pretreatment with the antioxidant N-acetylcysteine (NAC) attenuated hyperglycemia-induced reduction of Cav-3 expression and Akt and STAT3 activation and restored RPC-mediated cardioprotection in diabetes, which was abolished by cardiac-specific knockdown of Cav-3 by AAV9-shRNA-Cav-3, PI3K/Akt inhibitor wortmannin, or JAK2/STAT3 inhibitor AG490, respectively. Similarly, NAC could restore RPC protection from high glucose and hypoxia/reoxygenation-induced injury evidenced by decreased levels of LDH release, 15-F2t-isoprostane, O2-, and JC-1 monomeric cells, which were reversed by caveolae disrupter methyl-β-cyclodextrin, wortmannin, or AG490 in isolated primary cardiomyocytes or siRNAs of Cav-3, Akt, or STAT3 in H9C2 cells. Either methyl-β-cyclodextrin or Cav-3 knockdown reduced Akt and STAT3 activation. Further, the inhibition of Akt activation by a selective inhibitor or siRNA reduced STAT3 activation and vice versa, but they had no effects on Cav-3 expression. Thus, hyperglycemia-induced oxidative stress abrogates RPC cardioprotection by impairing Cav-3-modulated PI3K/Akt and JAK2/STAT3 signaling. Antioxidant treatment with NAC could restore RPC-induced cardioprotection in diabetes by improving Cav-3-dependent Akt and STAT3 activation and by facilitating the cross talk between PI3K/Akt and JAK2/STAT3 signaling pathways.
Mitochondrial NIX Promotes Tumor Survival in the Hypoxic Niche of Glioblastoma
Authors: Jung Jinkyu , Zhang Ying , Celiku Orieta , Zhang Wei , Song Hua , Williams Brian J. , Giles Amber J. , Rich Jeremy N. , Abounader Roger , Gilbert Mark R. , Park Deric M.
Published: September 2019

Cancer cells rely on mitochondrial functions to regulate key survival and death signals. How cancer cells regulate mitochondrial autophagy (mitophagy) in the tumor microenvironment as well as utilize mitophagy as a survival signal is still not well understood. Here, we elucidate a key survival mechanism of mitochondrial NIX-mediated mitophagy within the hypoxic region of glioblastoma, the most malignant brain tumor. NIX was overexpressed in the pseudopalisading cells that envelop the hypoxic–necrotic regions, and mitochondrial NIX expression was robust in patient-derived glioblastoma tumor tissues and glioblastoma stem cells. NIX was required for hypoxia and oxidative stress–induced mitophagy through NFE2L2/NRF2 transactivation. Silencing NIX impaired mitochondrial reactive oxygen species clearance, cancer stem cell maintenance, and HIF/mTOR/RHEB signaling pathways under hypoxia, resulting in suppression of glioblastoma survival in vitro and in vivo. Clinical significance of these findings was validated by the compelling association between NIX expression and poor outcome for patients with glioblastoma. Taken together, our findings indicate that the NIX-mediated mitophagic pathway may represent a key therapeutic target for solid tumors, including glioblastoma.

Significance:

NIX-mediated mitophagy regulates tumor survival in the hypoxic niche of glioblastoma microenvironment, providing a potential therapeutic target for glioblastoma.
First-in-Class Phosphorylated-p68 Inhibitor RX-5902 Inhibits β-Catenin Signaling and Demonstrates Antitumor Activity in Triple-Negative Breast Cancer
Authors: Capasso Anna , Bagby Stacey M. , Dailey Kyrie L. , Currimjee Naomi , Yacob Betelehem W. , Ionkina Anastasia , Frank Julie G. , Kim Deog Joong , George Christina , Lee Young B. , Benaim Ely , Gittleman Brian , Hartman Sarah J. , Tan Aik Choon , Kim Jihye , Pitts Todd M. , Eckhardt S. Gail , Tentler John J. , Diamond Jennifer R.
Published: September 2019

RX-5902 is a first-in-class anticancer agent targeting phosphorylated-p68 and attenuating nuclear shuttling of β-catenin. The purpose of this study was to evaluate the efficacy of RX-5902 in preclinical models of triple-negative breast cancer (TNBC) and to explore effects on β-catenin expression. A panel of 18 TNBC cell lines was exposed to RX-5902, and changes in proliferation, apoptosis, cellular ploidy, and effector protein expression were assessed. Gene expression profiling was used in sensitive and resistant cell lines with pathway analysis to explore pathways associated with sensitivity to RX-5902. The activity of RX-5902 was confirmed in vivo in cell line and patient-derived tumor xenograft (PDX) models. RX-5902 demonstrated potent antiproliferative activity in vitro against TNBC cell lines with an average IC50 of 56 nmol/L in sensitive cell lines. RX-5902 treatment resulted in the induction of apoptosis, G2–M cell-cycle arrest, and aneuploidy in a subset of cell lines. RX-5902 was active in vivo against TNBC PDX models, and treatment resulted in a decrease in nuclear β-catenin. RX-5902 exhibited dose-proportional pharmacokinetics and plasma and tumor tissue in nude mice. Pathway analysis demonstrated an increase in the epithelial-to-mesenchymal transformation (EMT), TGFβ, and Wnt/β-catenin pathways associated with sensitivity to RX-5902. RX-5902 is active against in vitro and in vivo preclinical models of TNBC. Target engagement was confirmed with decreases in nuclear β-catenin and MCL-1 observed, confirming the proposed mechanism of action. This study supports the continued investigation of RX-5902 in TNBC and combinations with immunotherapy.
Clinical Application of Cell-Free DNA Sequencing-Based Noninvasive Prenatal Testing for Trisomies 21, 18, 13 and Sex Chromosome Aneuploidy in a Mixed-Risk Population in Iran
Authors: Garshasbi Masoud , Wang Yicong , Hantoosh Zadeh Sedigheh , Giti Sima , Piri Solmaz , Reza Hekmat Mohammad
Published: September 2019

Purpose: To report the clinical experience and performance of plasma cell-free DNA sequencing-based noninvasive ­prenatal testing (NIPT) as a screening method in detecting trisomy 21, 18, 13 (T21/T18/T13) as well as sex chromosome aneuploidy (SCA) in a mixed-risk population in Iran. Methods: In a 2-year period between January 1, 2015, and December 31, 2016, over 150 medical centers in Iran offered NIPT as clinical screening tests for fetal T21, T18, T13 and SCA. All NIPT positive cases were recommended to undergo invasive prenatal diagnosis. Results: 11,414 maternal blood samples were received for NIPT, for which 11,223 samples obtained NIPT results. Among 11,213 cases with confirmatory results, 94 T21, 39 T18, 8 T13, 15 XO, 6 XXX, 3 XYY, 5 XXY and 11,042 euploid cases were detected. The overall sensitivity of NIPT was 98.90, 100.00, 100.00, 90.91, 100.00, 100.00 and 100.00%, and specificities were 99.96, 99.97, 99.99, 99.96, 99.98, 100.00 and 99.99% for detecting T21, T18, T13, XO, XXX, XYY and XXY, respectively. Conclusion: With a stringent protocol, our prospective large-scale multicentric nationwide study demonstrated that NIPT showed excellent performance as screening test for the detection of fetal T21, T18, T13 and SCA in mixed-risk pregnancies in Iran.
Gamma Knife Radiosurgery for Trigeminal Neuralgia Reduces Neurovascular Compression: A Case Report after 11 Years
Authors: Moosa Shayan , Wang Tony R. , Mastorakos Panagiotis , Sheehan Jason P. , Elias W. Jeffrey
Published: September 2019

Background: Trigeminal neuralgia (TN) is a rare and debilitating craniofacial pain syndrome often caused by vascular compression of the trigeminal nerve. Gamma Knife radiosurgery (GKRS) has been shown to offer a less invasive yet effective treatment method for pain reduction in TN. In this case report, we observed radiological evidence of resolved neurovascular compression after 11 years for a patient with recur­rent TN and prior GKRS. Case Report: A 72-year-old ­female presented with TN and radiological evidence of neurovas­cular compression on the affected side. She had complete resolution of her pain for 7 years after treatment with GKRS. The patient experienced recurrence and underwent repeat GKRS, this time resulting in another 3 years of pain relief. After the second recurrence, repeat intracranial imaging demonstrated resolution of neurovascular compression. Discussion: GKRS is an important treatment option for TN, although the mechanisms behind pain relief from this procedure still remain unclear. While prior histological and radiological studies point to ablative mechanisms for pain relief, this case report suggests that GKRS may result in a decompressive effect in TN due to changes in neurovascular architecture. Despite this finding, TN is known to occur and recur in the absence of neurovascular compression; thus, further work is necessary to understand the etiology of TN and its treatments. Conclusion: In this case, we demonstrate that vessel-nerve relationships may change over time in TN patients treated with GKRS, which raises the possibility that GKRS could ease a neurovascular compression.
Trends and Prevalence of Overweight and Obesity among Children Aged 2–7 Years from 2011 to 2017 in Xiamen, China
Authors: Chen Jing , Hu Chaoying , Zeng Guozhang , Xu Chao , Xu Lijun , Shi Junxia , Niu Conway , Zhang Liangwen
Published: September 2019

Background: Childhood overweight and obesity have become some of the most serious public health problems in the 21st century and have a significant impact on affected children as they grow into adulthood. Objective: The purpose of this study was to evaluate the overweight and obesity status and their main influencing factors in preschool children aged 2–7 years in urban areas of China between 2011 and 2017. Methods: A stratified cluster random sampling method was used to conduct a sample survey of children aged 2–7 years in Xiamen, one of China’s five special economic zones. The 56,738 participants (29,444 boys, 27,294 girls) were examined at three time points (15,757 in 2011, 19,098 in 2014, and 21,883 in 2017), and were analyzed for factors influencing obesity. Results: Between 2011 and 2017, the prevalence of overweight and obesity in preschool children between 2 and 7 years old was 10.91 and 5.66%, respectively. The overweight and obesity rates were higher in boys (11.85 and 7.11%) than in girls (9.90 and 4.09%), and the difference was statistically significant (p < 0.01). In the past 7 years, the overweight and obesity rates showed a downward trend in both boys and girls (p < 0.01). The peak ages for overweight were 6 years in boys and 2 years in girls, while the obesity rate peaked at 6 years. In those children with obesity, the proportion of those with moderate to severe obesity decreased from 40.70% in 2011 to 32.80% in 2017. Multiple stepwise regression analysis showed that children who were averse to sports activities preferred greasy foods and had earlier introduction of solid foods as infants, as well as those who were born at a high birth weight, ate fast, and those with parents with obesity were more likely to have obesity themselves (p < 0.05). Conclusions: Although preventative and control measures for childhood obesity have achieved initial results, Chinese preschool children remain to have high levels of overweight and obesity. It is therefore necessary to strengthen monitoring of overweight and obesity in preschool-aged children and implement appropriate interventions when necessary.
Distance Traveled to a Fetal Center and Pregnancy Outcomes in Twin-Twin Transfusion Syndrome
Authors: Bergh Eric P. , Donepudi Roopali , Bell Cynthia S. , Moise Jr. Kenneth J. , Johnson Anthony , Papanna Ramesha
Published: September 2019

Background: Fetoscopic laser photocoagulation (FLP) is the definitive treatment for twin-twin transfusion syndrome (TTTS). Due to variability in geographic proximity to high-volume fetal centers, many patients travel great distances to receive experienced care. We sought to determine whether distance traveled (DT) is associated with gestational age (GA) at delivery and neonatal survival. Methods: A prospective cohort study of patients within the continental United States referred to our center between September 23, 2011 and July 25, 2018 undergoing planned FLP for TTTS (n = 393; GA 20.6 ± 2.5 weeks; stage I: n = 50; stage II: n = 118; stage III: n = 208; stage IV: n = 17) was performed. The great-circle distance to our center was calculated using patients’ home zip codes. DT was stratified into groups containing equal patient numbers and pregnancy outcomes assessed. Results: A total of 393 patients met the inclusion criteria. The threshold distance from our center was <250 miles (n = 181), 250–499 miles (n= 119), and ≥500 miles (n = 93). There was no significant difference between any of the preoperative variables among the three groups, with the exception of race and rural status. Furthermore, there was no significant association between DT and GA at delivery (p = 0.34), time interval from procedure to delivery (p = 0.37), and the number of neonatal survivors (p= 0.21). Preterm premature rupture of membranes (PPROM) at <34 weeks was highest (47.9%, p = 0.04) in the group traveling 250–499 miles. Conclusion: To our knowledge, this is the largest study to show that in TTTS, DT is not associated with GA at delivery, time interval from procedure to delivery, or neonatal survival. Although PPROM at <34 weeks was higher in the group traveling 250–499 miles, there was no significant difference in GA at delivery. While patients with advanced disease may choose to seek treatment based on proximity, traveling long distances does not adversely affect pregnancy outcomes.
Clinical Significance of Increased Cardiac Troponin T in Patients with Chronic Hemodialysis and Cardiovascular Disease: Comparison to B-Type Natriuretic Peptide and A-Type Natriuretic Peptide Increase
Authors: Niizuma Shinichiro , Iwanaga Yoshitaka , Washio Takehiko , Ashida Tadashi , Harasawa Shinsuke , Miyazaki Shunichi , Matsumoto Naoya
Published: September 2019

Background: An increased cardiac troponin T (cTnT) level identifies a high-risk group in patients with end-stage renal disease; however, the mechanism of cTnT elevation remains unclear in such patients without acute coronary syndrome (ACS). Therefore, we explored the relationship between cTnT levels and the hemodynamic parameters and the prognostic potential of cTnT in stable patients with chronic hemodialysis (HD). Methods: We included consecutive 174 patients with HD who were referred for coronary angiography due to stable coronary artery disease (CAD), peripheral artery disease (PAD), or heart failure (HF). Hemodynamic measurement was performed, and plasma cTnT, B-type natriuretic peptide (BNP), and A-type natriuretic peptide (ANP) were measured at the same time. The potential of 3 biomarkers to predict all-cause mortality, cardiac death or hospitalized HF, and vascular event was assessed. Results: Increased log cTnT levels were correlated with increased log BNP and log ANP levels (r = 0.531, p < 0.001 and r = 0.411, p < 0.001, respectively). Not increased log cTnT, but increased log BNP and log ANP were associated with the presence of CAD and the extent of CAD. In contrast, they were all associated with the New York Heart Association functional classification and the presence of PAD and significantly correlated with left ventricular end-diastolic pressure (LVEDP) in an independent manner. Increased cTnT and BNP levels were associated with the mortality and hospitalized HF. However, increased cTnT was not associated with vascular events, unlike increased BNP. Conclusions: In patients with chronic HD without ACS, increased cTnT reflected increased LVEDP and the presence of HF or PAD independently, and it did not reflect the presence of CAD in contrast to increased BNP. cTnT and BNP were significant prognostic predictors; however, increased cTnT was associated with HF-related events, not with arteriosclerotic events.
Ruptured Hemorrhagic Hepatic Cyst: An Unusual Case Report
Authors: Amaral Maria João , Serôdio Marco , Koch Maria João , Almeida Rui , Campos José Carlos , Tralhão José Guilherme
Published: September 2019

Background: Hemorrhagic rupture of a hepatic cyst is rare. To date, very few cases have been reported in the literature. Case Report: A patient with a history of a suspected liver hydatid cyst presented to the emergency department with abdominal pain and fever. She was admitted with the presumptive diagnosis of acute cholecystitis. During hospitalization, the patient presented with hemodynamic instability and abrupt worsening of the abdominal pain. The abdominal angio-chemotherapy scan showed an abundant free peritoneal effusion and an apparent effacement of the anterior wall of a hepatic cyst of 16 cm. The patient underwent an exploratory laparotomy, deroofing of the cyst, and peritoneal lavage. The anatomopathological results showed a simple hepatic cyst. Discussion: Hemorrhagic rupture of simple hepatic cysts is a life-threatening complication and, although rare, should be included in the differential diagnosis of sudden abdominal pain in patients with a history of simple hepatic cysts.
Mechanisms Underlying Adenomyosis-Related Fibrogenesis
Authors: Kobayashi Hiroshi , Kishi Yohei , Matsubara Sho
Published: September 2019

Adenomyosis is a common gynecologic disorder defined by the presence of endometrial glands and stroma within the uterine myometrium. This review focusses on: (1) current understanding of cellular and molecular mechanisms of adenomyosis-related fibrogenesis, (2) transforming growth factor beta (TGF-β)-dependent or TGF-β-independent mediators of fibrogenesis, and (3) the origin of fibrogenic myofibroblasts. We collected a literature search from PubMed and EMBASE database up to December 2018. First, causative factors of adenomyosis are classified into exogenous traumatic damage (surgical interventions, including curettage, normal delivery, or cesarean section) and endogenous traumatic damage (mechanical strain or myometrial hyperperistalsis). The mechanical forces and injury (microdehiscences) are fundamental regulators of cell behavior and central to our understanding of disease pathogenesis. Adenomyosis is characterized by abnormal response to injury and activation of myofibroblasts in the myometrium through altered barrier function of the endometrial-myometrial junctional zone (EMJZ). Second, we summarize recent advances on the molecular mechanism of fibrosis. Two distinct populations of myofibroblasts, highly myogenic cells, and nonmyogenic cells arise possibly through the TGF-β-dependent and TGF-β-independent processes. TGF-β-independent mechanisms are still intriguing and far from clear. Third, the importance and implications of resident fibroblasts, bone-marrow stem cells-derived fibrocytes, and epithelial-mesenchymal transition-derived myofibroblasts in fibrosis remain uncertain. Finally, originally adenomyosis was believed to be the single entity, but this disorder is composed of multiple heterogeneous subtypes. Key mediators of fibrogenesis may vary widely and largely depend on adenomyosis subtype. In conclusion, both cyclic mechanical strain and EMJZ weakness (microdehiscences) may be a prerequisite for adenomyosis fibrogenesis through the mechanotransduction process. Since there are significant molecular variations among affected individuals, the approach to identify key mediators of fibrosis remains challenging.