bluuebunny/crossref_metadata_2025 huggingface dataset:
Processionary Moths and Associated Urtication Risk: Global Change–Driven Effects
Authors: Battisti Andrea , Larsson Stig , Roques Alain
Published: November 2016

Processionary moths carry urticating setae, which cause health problems in humans and other warm-blooded animals. The pine processionary moth Thaumetopoea pityocampa has responded to global change (climate warming and increased global trade) by extending its distribution range. The subfamily Thaumetopoeinae consists of approximately 100 species. An important question is whether other processionary moth species will similarly respond to these specific dimensions of global change and thus introduce health hazards into new areas. We describe, for the first time, how setae are distributed on different life stages (adult, larva) of major groups within the subfamily. Using the available data, we conclude that there is little evidence that processionary moths as a group will behave like T. pityocampa and expand their distributional range. The health problems caused by setae strongly relate to population density, which may, or may not, be connected to global change.
The Discovery of Suvorexant, the First Orexin Receptor Drug for Insomnia
Authors: Coleman Paul J. , Gotter Anthony L. , Herring W. Joseph , Winrow Christopher J. , Renger John J.
Published: November 2016

Historically, pharmacological therapies have used mechanisms such as γ-aminobutyric acid A (GABAA) receptor potentiation to drive sleep through broad suppression of central nervous system activity. With the discovery of orexin signaling loss as the etiology underlying narcolepsy, a disorder associated with hypersomnolence, orexin antagonism emerged as an alternative approach to attenuate orexin-induced wakefulness more selectively. Dual orexin receptor antagonists (DORAs) block the activity of orexin 1 and 2 receptors to both reduce the threshold to transition into sleep and attenuate orexin-mediated arousal. Among DORAs evaluated clinically, suvorexant has pharmacokinetic properties engineered for a plasma half-life appropriate for rapid sleep onset and maintenance at low to moderate doses. Unlike GABAA receptor modulators, DORAs promote both non-rapid eye movement (NREM) and REM sleep, do not disrupt sleep stage–specific quantitative electroencephalogram spectral profiles, and allow somnolence indistinct from normal sleep. The preservation of cognitive performance and the ability to arouse to salient stimuli after DORA administration suggest further advantages over historical therapies.
Anoctamins/TMEM16 Proteins: Chloride Channels Flirting with Lipids and Extracellular Vesicles
Authors: Whitlock Jarred M. , Hartzell H. Criss
Published: November 2016

Anoctamin (ANO)/TMEM16 proteins exhibit diverse functions in cells throughout the body and are implicated in several human diseases. Although the founding members ANO1 (TMEM16A) and ANO2 (TMEM16B) are Ca2+-activated Cl−channels, most ANO paralogs are Ca2+-dependent phospholipid scramblases that serve as channels facilitating the movement (scrambling) of phospholipids between leaflets of the membrane bilayer. Phospholipid scrambling significantly alters the physical properties of the membrane and its landscape and has vast downstream signaling consequences. In particular, phosphatidylserine exposed on the external leaflet of the plasma membrane functions as a ligand for receptors vital for cell–cell communication. A major consequence of Ca2+-dependent scrambling is the release of extracellular vesicles that function as intercellular messengers by delivering signaling proteins and noncoding RNAs to alter target cell function. We discuss the physiological implications of Ca2+-dependent phospholipid scrambling, the extracellular vesicles associated with this activity, and the roles of ANOs in these processes.
Regulation of Mammalian Oocyte Meiosis by Intercellular Communication Within the Ovarian Follicle
Authors: Jaffe Laurinda A. , Egbert Jeremy R.
Published: November 2016

Meiotic progression in mammalian preovulatory follicles is controlled by the granulosa cells around the oocyte. Cyclic GMP (cGMP) generated in the granulosa cells diffuses through gap junctions into the oocyte, maintaining meiotic prophase arrest. Luteinizing hormone then acts on receptors in outer granulosa cells to rapidly decrease cGMP. This occurs by two complementary pathways: cGMP production is decreased by dephosphorylation and inactivation of the NPR2 guanylyl cyclase, and cGMP hydrolysis is increased by activation of the PDE5 phosphodiesterase. The cGMP decrease in the granulosa cells results in rapid cGMP diffusion out of the oocyte, initiating meiotic resumption. Additional, more slowly developing mechanisms involving paracrine signaling by extracellular peptides (C-type natriuretic peptide and EGF receptor ligands) maintain the low level of cGMP in the oocyte. These coordinated signaling pathways ensure a fail-safe system to prepare the oocyte for fertilization and reproductive success.
The Integrative Physiology of Insect Chill Tolerance
Authors: Overgaard Johannes , MacMillan Heath A.
Published: November 2016

Cold tolerance is important in defining the distribution of insects. Here, we review the principal physiological mechanisms underlying homeostatic failure during cold exposure in this diverse group of ectotherms. When insects are cooled sufficiently, they suffer an initial loss of neuromuscular function (chill coma) that is caused by decreased membrane potential and reduced excitability of the neuromuscular system. For chill-susceptible insects, chronic or severe chilling causes a disruption of ion and water homeostasis across membranes and epithelia that exacerbate the initial effects of chilling on membrane potential and cellular function, and these perturbations are tightly associated with the development of chill injury and mortality. The adaptation and acclimation responses that allow some insects to tolerate low temperatures are multifactorial and involve several physiological systems and biochemical adjustments. In this review, we outline a physiological model that integrates several of these responses and discuss how they collectively help to preserve cellular, organ, and organismal homeostasis at low temperature.
Glycolysis and oxidative phosphorylation are essential for purinergic receptor-mediated angiogenic responses in vasa vasorum endothelial cells
Authors: Lapel Martin , Weston Philip , Strassheim Derek , Karoor Vijaya , Burns Nana , Lyubchenko Taras , Paucek Petr , Stenmark Kurt R. , Gerasimovskaya Evgenia V.
Published: November 2016

Angiogenesis is an energy-demanding process; however, the role of cellular energy pathways and their regulation by extracellular stimuli, especially extracellular nucleotides, remain largely unexplored. Using metabolic inhibitors of glycolysis (2-deoxyglucose) and oxidative phosphorylation (OXPHOS) (oligomycin, rotenone, and FCCP), we demonstrate that glycolysis and OXPHOS are both essential for angiogenic responses of vasa vasorum endothelial cell (VVEC). Treatment with P2R agonists, ATP, and 2-methylthioadenosine diphosphate trisodium salt (MeSADP), but not P1 receptor agonist, adenosine, increased glycolytic activity in VVEC (measured by extracellular acidification rate and lactate production). Stimulation of glycolysis was accompanied by increased levels of phospho-phosphofructokinase B3, hexokinase (HK), and GLUT-1, but not lactate dehydrogenase. Moreover, extracellular ATP and MeSADP, and to a lesser extent adenosine, increased basal and maximal oxygen consumption rates in VVEC. These effects were potentiated when the cells were cultured in 20 mM galactose and 5 mM glucose compared with 25 mM glucose. Treatment with P2R agonists decreased phosphorylation of pyruvate dehydrogenase (PDH)-E1α and increased succinate dehydrogenase (SDH), cytochrome oxidase IV, and β-subunit of F1F0 ATP synthase expression. In addition, P2R stimulation transiently elevated mitochondrial Ca2+ concentration, implying involvement of mitochondria in VVEC angiogenic activation. We also demonstrated a critical role of phosphatidylinositol 3-kinase and Akt pathways in lactate production, PDH-E1α phosphorylation, and the expression of HK, SDH, and GLUT-1 in ATP-stimulated VVEC. Together, our findings suggest that purinergic and metabolic regulation of VVEC energy pathways is essential for VV angiogenesis and may contribute to pathologic vascular remodeling in pulmonary hypertension.
Endoplasmic reticulum proteostasis: a key checkpoint in cancer
Authors: Oakes Scott A.
Published: November 2016

The unfolded protein response (UPR) is an intracellular signaling network largely controlled by three endoplasmic reticulum (ER) transmembrane proteins, inositol-requiring enzyme 1α, PRK-like ER kinase, and activating transcription factor 6, that monitor the protein-folding status of the ER and initiate corrective measures to maintain ER homeostasis. Hypoxia, nutrient deprivation, proteasome dysfunction, sustained demands on the secretory pathway or somatic mutations in its client proteins, conditions often encountered by cancer cells, can lead to the accumulation of misfolded proteins in the ER and cause “ER stress.” Under remediable levels of ER stress, the homeostatic UPR outputs activate transcriptional and translational changes that promote cellular adaptation. However, if the ER stress is irreversible despite these measures, a terminal UPR program supersedes that actively signals cell destruction. In addition to its prosurvival and prodeath outputs, the UPR is now recognized to play a major role in the differentiation and activation of specific immune cells, as well as proinflammatory cytokine production in many cell types. Given the numerous intrinsic and extrinsic factors that threaten the fidelity of the secretory pathway in cancer cells, it is not surprising that ER stress is documented in many solid and hematopoietic malignancies, but whether ongoing UPR signaling is beneficial or detrimental to tumor growth remains hotly debated. Here I review recent evidence that cancer cells are prone to loss of proteostasis within the ER, and hence may be susceptible to targeted interventions that either reduce homeostatic UPR outputs or alternatively trigger the terminal UPR.
Aging is associated with impaired angiogenesis, but normal microvascular network structure, in the rat mesentery
Authors: Sweat Richard S. , Sloas David C. , Stewart Scott A. , Czarny-Ratajczak Malwina , Baddoo Melody , Eastwood James R. , Suarez-Martinez Ariana D. , Azimi Mohammad S. , Burks Hope E. , Chedister Lee O. , Myers Leann , Murfee Walter L.
Published: November 2016

A big problem associated with aging is thought to be impaired microvascular growth or angiogenesis. However, to link the evidence for impaired angiogenesis to microvascular dysfunction in aged tissues, we must compare adult vs. aged microvascular networks in unstimulated scenarios. The objective of this study was to test the hypothesis that aged microvascular networks are characterized by both fewer vessels and the impaired ability to undergo angiogenesis. Mesentery tissues from adult (9-mo) and aged (24-mo) male Fischer 344 rats were harvested and immunolabeled for platelet/endothelial cell adhesion molecule (an endothelial cell marker) according to two scenarios: unstimulated and stimulated. For unstimulated groups, tissues harvested from adult and aged rats were compared. For stimulated groups, tissues were harvested 3 or 10 days after compound 48/80-induced mast cell degranulation stimulation. Unstimulated aged microvascular networks displayed larger mean vascular area per tissue area compared with the unstimulated adult networks. The lack of a decrease in vessel density was supported at the gene expression level with RNA-Seq analysis and with comparison of vessel densities in soleus muscle. Following stimulation, capillary sprouting and vessel density were impaired in aged networks at 3 and 10 days, respectively. Our results suggest that aging associated with impaired angiogenesis mechanisms might not influence normal microvascular function, since unstimulated aged microvascular networks can display a “normal adult-like” vessel density and architecture.

NEW & NOTEWORTHY Using a multidimensional approach, we present evidence supporting that aged microvascular networks display vessel density and patterning similar to adult networks despite also being characterized by a decreased capacity to undergo angiogenesis. Thus, vessel loss is not necessarily a characteristic of aging.
Interruption of perivascular sympathetic nerves of cerebral arteries offers neuroprotection against ischemia
Authors: Lee Reggie H. , Couto e Silva Alexandre , Lerner Francesca M. , Wilkins Carl S. , Valido Stephen E. , Klein Daniel D. , Wu Celeste Y. , Neumann Jake T. , Della-Morte David , Koslow Stephen H. , Minagar Alireza , Lin Hung Wen
Published: November 2016

Sympathetic nervous system activity is increased after cardiopulmonary arrest, resulting in vasoconstrictor release from the perivascular sympathetic nerves of cerebral arteries. However, the pathophysiological function of the perivascular sympathetic nerves in the ischemic brain remains unclear. A rat model of global cerebral ischemia (asphyxial cardiac arrest, ACA) was used to investigate perivascular sympathetic nerves of cerebral arteries via bilateral decentralization (preganglionic lesion) of the superior cervical ganglion (SCG). Decentralization of the SCG 5 days before ACA alleviated hypoperfusion and afforded hippocampal neuroprotection and improved functional outcomes. These studies can provide further insights into the functional mechanism(s) of the sympathetic nervous system during ischemia.

NEW & NOTEWORTHY Interruption of the perivascular sympathetic nerves can alleviate CA-induced hypoperfusion and neuronal cell death in the CA1 region of the hippocampus to enhance functional learning and memory.
IL-23 secreted by bronchial epithelial cells contributes to allergic sensitization in asthma model: role of IL-23 secreted by bronchial epithelial cells
Authors: Lee Hyun Seung , Park Da-Eun , Lee Ji-Won , Chang Yuna , Kim Hye Young , Song Woo-Jung , Kang Hye-Ryun , Park Heung-Woo , Chang Yoon-Seok , Cho Sang-Heon
Published: November 2016

IL-23 has been postulated to be a critical mediator contributing to various inflammatory diseases. Dermatophagoides pteronyssinus (Der p) is one of the most common inhalant allergens. However, the role of IL-23 in Der p-induced mouse asthma model is not well understood, particularly with regard to the development of allergic sensitization in the airways. The objective of this study was to evaluate roles of IL-23 in Der p sensitization and asthma development. BALB/c mice were repeatedly administered Der p intranasally to develop Der p allergic sensitization and asthma. After Der p local administration, changes in IL-23 expression were examined in lung tissues and primary epithelial cells. Anti-IL-23p19 antibody was given during the Der p sensitization period, and its effects were examined. Effects of anti-IL-23p19 antibody at bronchial epithelial levels were also examined in vitro. The expression of IL-23 at bronchial epithelial layers was increased after Der p local administration in mouse. In Der p-induced mouse models, anti-IL-23p19 antibody treatment during allergen sensitization significantly diminished Der p allergic sensitization and several features of allergic asthma including the production of Th2 cytokines and the population of type 2 innate lymphoid cells in lungs. The activation of dendritic cells in lung-draining lymph nodes was also reduced by anti-IL-23 treatment. In murine lung alveolar type II-like epithelial cell line (MLE-12) cells, IL-23 blockade prevented cytokine responses to Der p stimulation, such as IL-1α, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-33, and also bone marrow-derived dendritic cell activation. In conclusion, IL-23 is another important bronchial epithelial cell-driven cytokine which may contribute to the development of house dust mite allergic sensitization and asthma.
Pulmonary vascular collagen content, not cross-linking, contributes to right ventricular pulsatile afterload and overload in early pulmonary hypertension
Authors: Wang Zhijie , Schreier David A. , Abid Hinnah , Hacker Timothy A. , Chesler Naomi C.
Published: November 2016

Hypoxic pulmonary hypertension (HPH) is associated with pulmonary artery (PA) remodeling and right ventricular (RV) overload. We have previously uncovered collagen-mediated mechanisms of proximal PA stiffening in early HPH by manipulating collagen degradation and cross-linking using a transgenic mouse strain and a potent collagen cross-link inhibitor, β-aminopropionitrile (BAPN). However, the roles of collagen in distal PA remodeling, overall RV afterload, and RV hypertrophy in HPH remain unknown. Here, we used the same experimental strategy to investigate the effect of pulmonary vascular collagen content and cross-linking on steady and pulsatile RV afterload and on RV hypertrophy in early HPH. Collagenase-resistant mice (Col1a1R/R) and their littermate controls (Col1a1+/+) were exposed to normobaric hypoxia for 10 days with or without BAPN treatment. In vivo pulmonary vascular impedance, a comprehensive measure of RV afterload, was measured via simultaneous RV catheterization and echocardiography. Morphology and collagen accumulation were examined using histological techniques and ELISA in lungs and RVs. In both mouse strains, BAPN did not limit increases in pulmonary arterial pressure or pulmonary vascular resistance, indicating a negligible effect of either collagen content or cross-linking on steady RV afterload. However, BAPN prevented the increase in pulse pressure and RV hypertrophy in Col1a1+/+ mice and these effects were absent in Col1a1R/R mice, suggesting a role for PA collagen content, not cross-linking, in the pulsatile RV afterload. Moreover, we found a significant correlation between pulse pressure and RV hypertrophy, indicating an important role for pulsatile RV afterload in RV overload in early HPH.

NEW & NOTEWORTHY The present study found an important role for collagen content, but not collagen cross-linking, in the pulsatile right ventricular (RV) afterload, which is correlated with RV hypertrophy. These results uncover a new collagen-mediated mechanical mechanism of RV dysfunction in early pulmonary hypertension progression. Furthermore, our results suggest that measures and metrics of pulsatile hemodynamics such as pulse pressure and pulse wave velocity are potentially important to cardiovascular mortality in patients with pulmonary hypertension.
Rates of performance loss and neuromuscular activity in men and women during cycling: evidence for a common metabolic basis of muscle fatigue
Authors: Sundberg Christopher W. , Hunter Sandra K. , Bundle Matthew W.
Published: November 2016

The durations that muscular force and power outputs can be sustained until failure fall predictably on an exponential decline between an individual’s 3-s burst maximum to the maximum performance they can sustain aerobically. The exponential time constants describing these rates of performance loss are similar across individuals, suggesting that a common metabolically based mechanism governs muscle fatigue; however, these conclusions come from studies mainly on men. To test whether the same physiological understanding can be applied to women, we compared the performance-duration relationships and neuromuscular activity between seven men [23.3 ± 1.9 (SD) yr] and seven women (21.7 ± 1.8 yr) from multiple exhaustive bouts of cycle ergometry. Each subject performed trials to obtain the peak 3-s power output (Pmax), the mechanical power at the aerobic maximum (Paer), and 11–14 constant-load bouts eliciting failure between 3 and 300 s. Collectively, men and women performed 180 exhaustive bouts spanning an ~6-fold range of power outputs (118–1116 W) and an ~35-fold range of trial durations (8–283 s). Men generated 66% greater Pmax(956 ± 109 W vs. 632 ± 74 W) and 68% greater Paer(310 ± 47 W vs. 212 ± 15 W) than women. However, the metabolically based time constants describing the time course of performance loss were similar between men (0.020 ± 0.003/s) and women (0.021 ± 0.003/s). Additionally, the fatigue-induced increases in neuromuscular activity did not differ between the sexes when compared relative to the pedal forces at Paer. These data suggest that muscle fatigue during short-duration dynamic exercise has a common metabolically based mechanism determined by the extent that ATP is resynthesized by anaerobic metabolism.

NEW & NOTEWORTHY Although men and women differed considerably in their absolute cycling performances, there was no sex difference in the metabolically based exponential time constant that described the performance-duration relationship. Similarly, the fatigue-induced increases in neuromuscular activity were not different between the sexes when compared from a metabolic perspective. These data suggest that men and women have similar rate-limiting mechanisms for short-duration dynamic exercise that are determined by the extent the exercise is supported by anaerobic metabolism.
TTI-621 (SIRPαFc): A CD47-Blocking Innate Immune Checkpoint Inhibitor with Broad Antitumor Activity and Minimal Erythrocyte Binding
Authors: Petrova Penka S. , Viller Natasja Nielsen , Wong Mark , Pang Xinli , Lin Gloria H.Y. , Dodge Karen , Chai Vien , Chen Hui , Lee Vivian , House Violetta , Vigo Noel T. , Jin Debbie , Mutukura Tapfuma , Charbonneau Marilyse , Truong Tran , Viau Stephane , Johnson Lisa D. , Linderoth Emma , Sievers Eric L. , Maleki Vareki Saman , Figueredo Rene , Pampillo Macarena , Koropatnick James , Trudel Suzanne , Mbong Nathan , Jin Liqing , Wang Jean C.Y. , Uger Robert A.
Published: November 2016

Purpose: The ubiquitously expressed transmembrane glycoprotein CD47 delivers an anti-phagocytic (do not eat) signal by binding signal-regulatory protein α (SIRPα) on macrophages. CD47 is overexpressed in cancer cells and its expression is associated with poor clinical outcomes. TTI-621 (SIRPαFc) is a fully human recombinant fusion protein that blocks the CD47–SIRPα axis by binding to human CD47 and enhancing phagocytosis of malignant cells. Blockade of this inhibitory axis using TTI-621 has emerged as a promising therapeutic strategy to promote tumor cell eradication.

Experimental Design: The ability of TTI-621 to promote macrophage-mediated phagocytosis of human tumor cells was assessed using both confocal microscopy and flow cytometry. In vivo antitumor efficacy was evaluated in xenograft and syngeneic models and the role of the Fc region in antitumor activity was evaluated using SIRPαFc constructs with different Fc tails.

Results: TTI-621 enhanced macrophage-mediated phagocytosis of both hematologic and solid tumor cells, while sparing normal cells. In vivo, TTI-621 effectively controlled the growth of aggressive AML and B lymphoma xenografts and was efficacious in a syngeneic B lymphoma model. The IgG1 Fc tail of TTI-621 plays a critical role in its antitumor activity, presumably by engaging activating Fcγ receptors on macrophages. Finally, TTI-621 exhibits minimal binding to human erythrocytes, thereby differentiating it from CD47 blocking antibodies.

Conclusions: These data indicate that TTI-621 is active across a broad range of human tumors. These results further establish CD47 as a critical regulator of innate immune surveillance and form the basis for clinical development of TTI-621 in multiple oncology indications. Clin Cancer Res; 23(4); 1068–79. ©2016 AACR.
The Efflux Transporter ABCG2 Maintains Prostate Stem Cells
Authors: Sabnis Neha G. , Miller Austin , Titus Mark A. , Huss Wendy J.
Published: November 2016

Prostate stem cells (PSC) are characterized by their intrinsic resistance to androgen deprivation therapy (ADT), possibly due to the lack of androgen receptor (AR) expression. PSCs resistance to ADT and PSC expansion in castration resistant prostate cancer (CRPC) has sparked great interest in using differentiation therapy as an adjuvant to ADT. Understanding the mechanisms, by which PSCs maintain their undifferentiated phenotype, thus has important implications in differentiation therapy. In the prostate, the ATP binding cassette sub-family G member 2 (ABCG2) transporters, which enrich for AR-positive, ADT-resistant PSCs, play an important role in regulating the intracellular androgen levels by effluxing androgens. We hypothesized that the ABCG2-mediated androgen efflux is responsible for maintaining PSCs in an undifferentiated state. Using the HPr-1-AR (nontumorigenic) and CWR-R1 (tumorigenic) prostate cell lines, it was demonstrated that inhibiting the ABCG2-mediated androgen efflux, with Ko143 (ABCG2 inhibitor), increased the nuclear AR expression due to elevated intracellular androgen levels. Increased nuclear translocation of AR is followed by increased expression of AR regulated genes, a delayed cell growth response, and increased luminal differentiation. Furthermore, Ko143 reduced tumor growth rates in mice implanted with ABCG2-expressing CWR-R1 cells. In addition, Ko143-treated mice had more differentiated tumors as evidenced by an increased percentage of CK8+/AR+ luminal cells and decreased percentage of ABCG2-expressing cells. Thus, inhibiting ABCG2-mediated androgen efflux forces the PSCs to undergo an AR-modulated differentiation to an ADT-sensitive luminal phenotype.

Implications: This study identifies the mechanism by which the prostate stem cell marker, ABCG2, plays a role in prostate stem cell maintenance and provides a rationale for targeting ABCG2 for differentiation therapy in prostate cancer. Mol Cancer Res; 15(2); 128–40. ©2016 AACR.
Genome-Wide STAT3 Binding Analysis after Histone Deacetylase Inhibition Reveals Novel Target Genes in Dendritic Cells
Authors: Sun Yaping , Iyer Matthew , McEachin Richard , Zhao Meng , Wu Yi-Mi , Cao Xuhong , Oravecz-Wilson Katherine , Zajac Cynthia , Mathewson Nathan , Wu Shin-Rong Julia , Rossi Corinne , Toubai Tomomi , Qin Zhaohui S. , Chinnaiyan Arul M. , Reddy Pavan
Published: November 2016

STAT3 is a master transcriptional regulator that plays an important role in the induction of both immune activation and immune tolerance in dendritic cells (DCs). The transcriptional targets of STAT3 in promoting DC activation are becoming increasingly understood; however, the mechanisms underpinning its role in causing DC suppression remain largely unknown. To determine the functional gene targets of STAT3, we compared the genome-wide binding of STAT3 using ChIP sequencing coupled with gene expression microarrays to determine STAT3-dependent gene regulation in DCs after histone deacetylase (HDAC) inhibition. HDAC inhibition boosted the ability of STAT3 to bind to distinct DNA targets and regulate gene expression. Among the top 500 STAT3 binding sites, the frequency of canonical motifs was significantly higher than that of noncanonical motifs. Functional analysis revealed that after treatment with an HDAC inhibitor, the upregulated STAT3 target genes were those that were primarily the negative regulators of proinflammatory cytokines and those in the IL-10 signaling pathway. The downregulated STAT3-dependent targets were those involved in immune effector processes and antigen processing/presentation. The expression and functional relevance of these genes were validated. Specifically, functional studies confirmed that the upregulation of IL-10Ra by STAT3 contributed to the suppressive function of DCs following HDAC inhibition.
The Experience of Relations in Persons with Dementia: A Systematic Meta-Synthesis
Authors: Eriksen Siren , Helvik Anne-Sofie , Juvet Lene Kristin , Skovdahl Kirsti , Førsund Linn Hege , Grov Ellen Karine
Published: November 2016

Background: Dementia influences a person's experience of social relationships, as described in several studies. In this systematic meta-synthesis of qualitative studies, we aim to interpret and synthesize the experiences of persons with dementias and their relations with others. Summary: Living with dementia changes life, leading to new social roles and different social statuses. Persons with dementia experience being disconnected and dependent on others, feeling like being a burden, and being a person who is treated in paternalistic ways. Family, friends and others with dementia might play significant roles in their ability to maintain a meaningful life. Key Messages: Three categories emerged from the data, change in life, change in relations, and maintenance of meaningful aspects in life; these categories are intertwined and essential in sustaining a lifeline for persons with dementia. The comprehensive meaning of the material is understood as the expression: Living a meaningful life in relational changes.
Local Ecological Knowledge about Endangered Primates in a Rural Community in Paraíba, Brazil
Authors: Junior Emanuel Ubaldino Torres , Valença-Montenegro Mônica Mafra , de Castro Carla Soraia Soares
Published: November 2016

The study of local ecological knowledge (LEK) fosters a better understanding of the relationship between humans and the environment. We assessed respondents' ecological knowledge of primates in a rural community located near the Atlantic Forest remnants in the state of Paraíba, Brazil. Populations of Alouatta belzebul (red-handed howler monkeys), Sapajus flavius (blonde capuchins), and Callithrix jacchus (the common marmoset) inhabit the region. We conducted 200 semi-structured interviews and applied thematic content analysis, with weighting, to the responses to quantify the LEK. Respondents showed a low LEK, despite the community's proximity to forest remnants. However, the LEK was significantly higher among men, as well as among those who had a greater degree of contact with the primates. Age did not influence LEK. The studied community apparently does not intensively exploit the forest resources nor does it economically depend on primates, which may explain these individuals' low levels of knowledge about these animals. Such data may support future studies, as well as environmental education and action plans, especially for A. belzebul and S. flavius, both of which are endangered species and targets of the National Action Plan for the Conservation of the Primates of the Northeast.
Dietary Genistein Rescues Reduced Basal Chloride Secretion in Diabetic Jejunum via Sex-Dependent Mechanisms
Authors: Catmull Shawn , Masood Faisal , Schacht Sydney , Dolan Robert , Stegman Daniel , Leung Lana , Al-Nakkash Layla
Published: November 2016

Background/Aims: The goal of this study was to determine the effect of dietary genistein (naturally occurring phytoestrogen) on jejunal secretory function in a clinically relevant model of diabetes and obesity, the leptin-defIcient ob/ob mouse. Methods: We measured transepithelial short circuit current (Isc), across freshly isolated segments of jejunum from 12-week old male and female ob/ob and lean C57Bl/6J mice fed a genistein diet (600 mg genistein/kg diet) for 4-weeks. Separate segments of jejunum were frozen for western blot determination of key proteins involved in secretory transport. Results: Basal Isc was signifIcantly decreased (by 33%, P<0.05) in ob/ob females versus leans, and genistein-diet reversed this. Similarly, in males, basal Isc was decreased (by 47%, P<0.05) in ob/ob mice versus leans, and genistein-diet reversed this. Inhibition with either clotrimazole (100 µM, bilateral) or ouabain (100 µM, basolateral) was signifIcantly reduced in ob/ob mice compared to leans (P<0.05), and genistein-diet reversed clotrimazole-sensitive inhibition in ob/ob females, and reversed the ouabain-sensitive inhibition in males (indicating sex-dependent mechanisms). Our data suggested that PDE3 levels were dysregulated in ob/ob females and genistein reversed this. Expression of total CFTR (normalized to actin) was signifIcantly decreased ∼80% (P<0.05) in all ob/ob mice compared to leans, and genistein-diet was without effect. Expression of total NKCC1 (normalized to actin) was signifIcantly decreased ∼80% (P<0.05) in ob/ob male mice versus leans, and genistein-diet reversed this. Conclusions: Our data suggests that the reduced basal jejunal Isc in ob/ob female mice is a consequence of reduced CFTR expression, decreased activities of the basolateral KCa channel and Na+/K+-ATPase, and in male mice reduced basal jejunal Isc is a consequence of reduced CFTR and NKCC1 expression, along with decreased activities of the basolateral KCa channel and Na+/K+-ATPase. Genistein-diet has beneficial effects on basal Isc mediated by sex-dependent mechanisms in diabetic mice: in females via increased KCa-sensitive Isc and in males via increased Na+/K+-ATPase activity and increased NKCC1 expression. Improved understanding of intestinal dysfunctions in the ob/ob jejunum, may allow for the development of novel drug targets to treat obesity and diabetes, and may also be of benefit in CF-related diabetes.
Efficacy of Bevacizumab in the First-Line Treatment of Patients with RAS Mutations Metastatic Colorectal Cancer: a Systematic Review and Network Meta-Analysis
Authors: Zhou Mingyi , Yu Ping , Qu Jinglei , Chen Ying , Zhou Yang , Fu Lingyu , Zhang Jingdong
Published: November 2016

Background/Aims: Whether patients with RAS mutation metastatic colorectal cancer (mCRC) obtain benefits from bevacizumab added to first-line chemotherapy remains unclear. Methods: PubMed, Cochrane Systematic Reviews, the Cochrane Collaboration Central Register of Controlled Clinical Trials, ClinicalTrials.gov, and the American Society of Clinical Oncology and European Society for Medical Oncology databases were searched to identify abstracts for randomized controlled trials (RCTs) evaluating the efficacy of bevacizumab for the first-line treatment of patients with RAS mutations mCRC from inception to the end of April 2016. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were estimated. Results: Ten eligible papers reporting six RCTs were included. In the network meta-analysis of patients with RAS mutations, bevacizumab + chemotherapy prolonged PFS compared with chemotherapy alone (HR 0.75, 95% CI 0.51-1.10), but the difference was not statistically significant. Bevacizumab + chemotherapy did not prolong OS compared with chemotherapy alone (HR 1.10, 95% CI 0.73-1.66). Conclusion: There was insufficient evidence to definitively state that patients with RAS mutations mCRC could benefit from bevacizumab combined with chemotherapy as first-line treatment.
Rs56288038 (C/G) in 3'UTR of IRF-1 Regulated by MiR-502-5p Promotes Gastric Cancer Development
Authors: Wang Bo , Yang Huan , Shen Liqin , Wang Ji , Pu Wangyang , Chen Zhigang , Shen Xudong , Fu Jinxiang , Zhuang Zhixiang
Published: November 2016

Background/Aims: Interferon regulatory factor 1 (IRF-1) has been shown to function as a transcriptional activator or repressor of a variety of target genes. However, its upstream, non-coding RNA-related regulatory capacity remains unknown. In this study, we focus on the miRNA-associated single nucleotide polymorphisms (SNPs) in the 3′untranslated region (UTR) of IRF-1 to further investigate the functional relationship and potential diagnostic value of the SNPs and miRNAs among Chinese gastric cancer (GC) patients. Methods: We performed a case-control study with 819 GC patients and 756 cancer-free controls. Genotyping by realtime PCR assay, cell transfection, and the dual luciferase reporter assay were used in our study, and the 5-year overall survival rate and relapse-free survival rate in different groups were investigated. Results: We found that patients suffering from Helicobacter pylori (Hp) infection were the susceptible population compared to controls. SNP rs56288038 (C/G) in IRF-1 3′UTR was involved in the occurrence of GC by acting as a tumor promoter factor. SNP rs56288038 (C/G) could be up-regulated by miR-502-5p, which caused a down-regulation of IRF-1 in cell lines and decreased apoptosis induced by IFN-γ. Carrying the G genotype was related to significantly low expression of IRF-1 and Hp infection, poor differentiation, big tumor size, invasion depth, as well as the high probability of metastasis, and moreover, the C/G SNP was associated with shorter survival of GC patients with five years of follow-up study. Conclusions: our findings have shown that the SNP rs56288038 (C/G) in IRF-1 3′UTR acted as a promotion factor in GC development through enhancing the regulatory role of miR-502-5p in IRF-1 expression.
Wilms Tumor 1 (WT1) mRNA Expression Level at Diagnosis Is a Significant Prognostic Marker in Elderly Patients with Myelodysplastic Syndrome
Authors: Nagasaki Joji , Aoyama Yasutaka , Hino Masayuki , Ido Kentaro , Ichihara Hiroyoshi , Manabe Masahiro , Ohta Tadanobu , Mugitani Atsuko
Published: November 2016

Background/Aims: A high expression of Wilms tumor 1 (WT1) mRNA occurs in most cases of acute leukemia and myelodysplastic syndrome (MDS). Although there are many reports suggesting that acute myeloid leukemia patients with high expression levels of WT1 mRNA have a relatively poor long-term survival, there are few reports addressing the relationship between WT1 levels and prognosis in MDS. Methods: We retrospectively analyzed 42 elderly patients with MDS whose WT1 levels at diagnosis were available, and we assessed the relationships between WT1 levels in peripheral blood and preexisting prognostic factors such as World Health Organization prognostic scores and Revised International Prognostic Scoring System risk categories, bone marrow blast percentages, and chromosomal abnormalities linked to a poor prognosis. We also evaluated the relationship between WT1 levels and prognosis. Results:WT1 levels were significantly different between high- and low-risk MDS patients (p < 0.05). There was a trend towards a significant difference between those with and those without poor prognostic chromosomal rearrangements (p = 0.051). Moreover, the overall survival and progression-free survival were significantly worse in elderly patients with higher levels of WT1 (p = 0.00039 and p = 0.00077, respectively). Conclusions: The WT1 mRNA expression level at diagnosis may be a significant independent prognostic marker for elderly patients with MDS.
Frontal Assessment Battery as a Useful Tool to Differentiate Mild Cognitive Impairment due to Subcortical Ischemic Vascular Disease from Alzheimer Disease
Authors: Hsu Yen-Hsuan , Huang Ching-Feng , Lo Chung-Ping , Wang Tzu-Lan , Yang Chi-Cheng , Tu Min-Chien
Published: November 2016

Background: Prominent executive dysfunction can differentiate vascular dementia from Alzheimer disease (AD). However, it is unclear whether the Frontal Assessment Battery (FAB) screening tool can differentiate subcortical ischemic vascular disease (SIVD) from AD at the pre-dementia stage. In addition, the neural correlates of FAB performance have yet to be clarified. Methods: Patients with mild cognitive impairment (MCI) due to SIVD (MCI-V), MCI due to AD (MCI-A), and demographically matched controls completed the Mini-Mental State Examination, Taiwanese FAB (TFAB), Category Fluency, and Chinese Version of the Verbal Learning Test, and underwent magnetic resonance imaging. White matter hyperintensities were rated according to the Scheltens scale. Results: TFAB total scale and its Orthographical Fluency subtest were the only measures that could differentiate MCI-V from MCI-A. Discriminative analysis showed that Orthographical Fluency scores successfully identified 73.2% of the cases with MCI-V, with 85.0% sensitivity. Orthographical Fluency scores were specifically associated with lesion load within frontal periventricular, frontal deep white matter, and basal ganglia regions. Conclusion: The TFAB, and especially its 1-min Orthographical Fluency subtest, is a useful screening procedure to differentiate MCI due to SIVD from MCI due to AD. The discriminative ability is probably due to frontosubcortical white matter pathologies disproportionately involved in the two disease entities.
ENTRE ARIEL E CALIBÃ: RICHARD MORSE E A DEFINIÇÃO DO “OBJETO AMÉRICA LATINA”
Authors: Zagni Rodrigo Medina
Published: November 2016

Richard Morse, um dos mais importantes estudiosos norte-americanos da História do Brasil, teve na obra O Espelho de Próspero sua mais importante e polêmica argumentação já publicada e cujos interlocutores foram, essencialmente, historiadores brasileiros. Nosso objetivo, é o de mapear, por meio de revisão bibliográfica, a discussão historiográfica que se deu a partir do impacto da publicação da obra no Brasil, revelando distintas e significativas visões sobre as relações entre a América Latina e os Estados Unidos, e entre ambos e a Europa; contribuindo assim com este denso e complexo campo de estudos.
Inflammatory Obesity Phenotypes, Gender Effects, and Subclinical Atherosclerosis in African Americans
Authors: Lin Albert , Lacy Mary E. , Eaton Charles , Correa Adolfo , Wu Wen-Chih
Published: November 2016

Objective—

Reasons for variations in atherosclerotic burden among individuals with similar levels of obesity are poorly understood, especially in African Americans. This study examines whether high-sensitivity C-reactive protein (hsCRP) is useful for discriminating between benign and high-risk obesity phenotypes for subclinical atherosclerosis in African Americans.

Approach and Results—

Participants from the Jackson Heart Study (n=4682) were stratified into 4 phenotypes based on the presence of National Heart and Lung and Blood Institute definition of obesity or obesity-equivalent (body mass index ≥30 or body mass index 25–30 with waist circumference >102 cm in men and >88 cm in women) and inflammation by hsCRP ≥2 mg/L. Using multivariate regression models, we conducted cross-sectional analyses of the association between inflammatory obesity phenotypes and subclinical atherosclerosis determined by carotid intima–media thickness or coronary artery calcium scores. Sex-specific analyses were conducted given significant interaction for gender (
P
=0.03). The prevalence of obesity or equivalent was 65%, of which 30% did not have inflammation. Conversely, 37% of nonobese individuals had inflammation. Among nonobese men, hsCRP ≥2 mg/L identified a subset of individuals with higher carotid intima–media thickness (adjusted mean difference =0.05, 95% confidence interval 0.02, 0.08 mm) compared with their noninflammatory counterparts. Among obese men, hsCRP <2 mg/L identified a subset of individuals with lower coronary artery calcium compared with their inflammatory counterparts. Among women, associations between hsCRP and carotid intima–media thickness or coronary artery calcium were not found.

Conclusions—

In the largest African American population-based cohort to date, hsCRP was useful in identifying a subset of nonobese men with higher carotid intima–media thickness, but not in women. hsCRP did not identify a subset of obese individuals with less subclinical atherosclerosis.
Challenges and Opportunities in Linking Long Noncoding RNAs to Cardiovascular, Lung, and Blood Diseases
Authors: Freedman Jane E. , Miano Joseph M.
Published: November 2016

The new millennium heralds an unanticipated surge of genomic information, most notably an expansive class of long noncoding RNAs (lncRNAs). These transcripts, which now outnumber all protein-coding genes, often exhibit the same characteristics as mRNAs (RNA polymerase II–dependent, 5′ methyl-capped, multiexonic, polyadenylated); yet, they do not encode for stable, well-conserved proteins. Elucidating the function of all relevant lncRNAs in heart, vasculature, lung, and blood is essential for generating a complete interactome in these tissues. This is particularly evident because an increasing number of investigators perform RNA-sequencing experiments where, typically, annotated lncRNAs exhibit impressive changes in gene expression. How does one go about evaluating an lncRNA when the sequence of the transcript lends no insight into how it may function within a cell type? Here, we provide a brief overview for the rational study of lncRNAs.
Map3k8 Modulates Monocyte State and Atherogenesis in ApoE
−/−
Mice
Authors: Sanz-Garcia Carlos , Sánchez Ángela , Contreras-Jurado Constanza , Cales Carmela , Barranquero Cristina , Muñoz Marta , Merino Ramón , Escudero Paula , Sanz Maria-Jesús , Osada Jesús , Aranda Ana , Alemany Susana
Published: November 2016

Objective—

Map3k8 (Cot/Tpl2) activates the MKK1/2-ERK1/2, MAPK pathway downstream from interleukin-1R, tumor necrosis factor-αR, NOD-2R (nucleotide-binding oligomerization domain-like 2R), adiponectinR, and Toll-like receptors. Map3k8 plays a key role in innate and adaptive immunity and influences inflammatory processes by modulating the functions of different cell types. However, its role in atherogenesis remains unknown. In this study, we analyzed the role of this kinase in this pathology.

Approach and Results—

We show here that Map3k8 deficiency results in smaller numbers of Ly6C
high
CD11c
low
and Ly6C
low
CD11c
high
monocytes in ApoE
−
/−
mice fed a high-fat diet (HFD). Map3k8
−/−
ApoE
−/−
monocytes displayed high rates of apoptosis and reduced amounts of Nr4a1, a transcription factor known to modulate apoptosis in Ly6C
low
CD11c
high
monocytes. Map3k8
−/−
ApoE
−/−
splenocytes and macrophages showed irregular patterns of cytokine and chemokine expression. Map3k8 deficiency altered cell adhesion and migration in vivo and decreased CCR2 expression, a determinant chemokine receptor for monocyte mobilization, on circulating Ly6C
high
CD11c
low
monocytes. Map3k8
−/−
ApoE
−/−
mice fed an HFD showed decreased cellular infiltration in the atherosclerotic plaque, with low lipid content. Lesions had similar size after Map3k8
+/+
ApoE
−/−
bone marrow transplant into Map3k8
−/−
ApoE
−/−
and Map3k8
+/+
ApoE
−/−
mice fed an HFD, whereas smaller plaques were observed after the transplantation of bone marrow lacking both ApoE and Map3k8.

Conclusions—

Map3k8 decreases apoptosis of monocytes and enhances CCR2 expression on Ly6C
high
CD11c
low
monocytes of ApoE
−/−
mice fed an HFD. These findings explain the smaller aortic lesions in ApoE
−/−
mice with Map3k8
−/−
ApoE
−/−
bone marrow cells fed an HFD, supporting further studies of Map3k8 as an antiatherosclerotic target.