bluuebunny/crossref_metadata_2025 huggingface dataset:
MiR-4674 regulates angiogenesis in tissue injury by targeting p38K signaling in endothelial cells
Authors: Icli Basak , Li Hao , Pérez-Cremades Daniel , Wu Winona , Ozdemir Denizhan , Haemmig Stefan , Guimaraes Raphael Boesch , Manica Andre , Marchini Julio F. , Orgill Dennis P. , Feinberg Mark W.
Published: January 2020

Neoangiogenesis is critical for tissue repair in response to injury such as myocardial ischemia or dermal wound healing. MicroRNAs are small noncoding RNAs and important regulators of angiogenesis under physiological and pathological disease states. Therefore, identification of microRNAs that may restore impaired angiogenesis in response to tissue injury may provide new targets for therapy. Using a microRNA microarray profiling approach, we identified a human-specific microRNA, miR-4674, that was significantly decreased in patients after myocardial tissue injury and had an endothelial cell (EC)-enriched expression pattern. Functionally, overexpression of miR-4674 markedly attenuated EC proliferation, migration, network tube formation, and spheroid sprouting, whereas blockade of miR-4674 had the opposite effects. Transcriptomic profiling, gene set enrichment analyses, bioinformatics, 3′-untranslated region (3’-UTR) reporter and microribonucleoprotein immunoprecipitation (miRNP-IP) assays, and small interfering RNA dependency studies revealed that miR-4674 regulates VEGF stimulated-p38 mitogen-activated protein kinase (MAPK) signaling and targets interleukin 1 receptor-associated kinase 1 (Irak1) and BICD cargo adaptor 2 (Bicd2) in ECs. Furthermore, Irak1 and Bicd2 were necessary for miR-4674-driven EC proliferation and migration. Finally, neutralization of miR-4674 increased angiogenesis, Irak1 and Bicd2 expression, and p38 phosphorylation in human skin organoids as a model of tissue injury. Collectively, targeting miR-4674 may provide a novel therapeutic target for tissue repair in pathological disease states associated with impaired angiogenesis.
Prenatal smoke effect on mouse offspringIgf1promoter methylation from fetal stage to adulthood is organ and sex specific
Authors: Zeng Zhijun , Meyer Karolin F. , Lkhagvadorj Khosbayar , Kooistra Wierd , Reinders-Luinge Marjan , Xu Xijin , Huo Xia , Song Juan , Plösch Torsten , Hylkema Machteld N.
Published: January 2020

Prenatal smoke exposure (PSE) is associated with reduced birth weight, impaired fetal development, and increased risk for diseases later in life. Changes in DNA methylation may be involved, as multiple large-scale epigenome-wide association studies showed that PSE is robustly associated with DNA methylation changes in blood among offspring in early life. Insulin-like growth factor-1 (IGF1) is important in growth, differentiation, and repair processes after injury. However, no studies investigated the organ-specific persistence of PSE-induced methylation change of Igf1 into adulthood. Based on our previous studies on the PSE effect on Igf1 promoter methylation in fetal and neonatal mouse offspring, we now have extended our studies to adulthood. Our data show that basal Igf1 promoter methylation generally increased in the lung but decreased in the liver (except for 2 persistent CpG sites in both organs) across three different developmental stages. PSE changed Igf1 promoter methylation in all three developmental stages, which was organ and sex specific. The PSE effect was less pronounced in adult offspring compared with the fetal and neonatal stages. In addition, the PSE effect in the adult stage was more pronounced in the lung compared with the liver. For most CpG sites, an inverse correlation was found for promoter methylation and mRNA expression when the data of all three stages were combined. This was more prominent in the liver. Our findings provide additional evidence for sex- and organ-dependent prenatal programming, which supports the developmental origins of health and disease (DOHaD) hypothesis.
Muscle sympathetic reactivity to apneic and exercise stress in high-altitude Sherpa
Authors: Busch Stephen A. , Simpson Lydia L. , Sobierajski Frances , Riske Laurel , Ainslie Philip N. , Willie Chris K. , Stembridge Mike , Moore Jonathan P. , Steinback Craig D.
Published: January 2020

Lowland-dwelling populations exhibit persistent sympathetic hyperactivity at altitude that alters vascular function. High-altitude populations, such as Sherpa, have previously exhibited greater peripheral blood flow in response to acute stress than Lowlanders, which may be explained through lower sympathetic activity. Our purpose was to determine whether Sherpa exhibit lower sympathetic reactivity to stress than Lowlanders. Muscle sympathetic nerve activity (MSNA; microneurography) was measured at rest in Lowlanders ( n = 14; age = 27 ± 6 yr) at 344 m and between 1 and 10 days at 5,050 m. Sherpa (age = 32 ± 11 yr) were tested at 5,050 m ( n = 8). Neurovascular reactivity (i.e., change in MSNA patterns) was measured during maximal end-expiratory apnea, isometric hand grip (IHG; 30% maximal voluntary contraction for 2-min), and postexercise circulatory occlusion (PECO; 3 min). Burst frequency (bursts/min) and incidence (bursts/100 heartbeats) and total normalized SNA (arbitrary units/min) were analyzed at rest, immediately before apnea breakpoint, and during the last minute of IHG and PECO. Vascular responses to apnea, IHG, and PECO were also measured. MSNA reactivity to apnea was smaller in Sherpa than Lowlanders at 5,050 m, although blood pressure responses were similar between groups. MSNA increases in Lowlanders during apnea at 5,050 m were significantly lower than at 344 m ( P < 0.05), indicating that a possible sympathetic ceiling was reached in Lowlanders at 5,050 m. MSNA increased similarly during IHG and PECO in Lowlanders at both 334 m and 5,050 m and in Sherpa at 5,050 m, while vascular changes (mean brachial arterial pressure, contralateral brachial flow and resistance) were similar between groups. Sherpa demonstrate overall lower sympathetic reactivity that may be a result of heightened vascular responsiveness to potential apneic stress at altitude.
NO-mediated activation of KATP channels contributes to cutaneous thermal hyperemia in young adults
Authors: Fujii Naoto , McGarr Gregory W. , Kenny Glen P. , Amano Tatsuro , Honda Yasushi , Kondo Narihiko , Nishiyasu Takeshi
Published: January 2020

Local skin heating to 42°C causes cutaneous thermal hyperemia largely via nitric oxide (NO) synthase (NOS)-related mechanisms. We assessed the hypothesis that ATP-sensitive K+ (KATP) channels interact with NOS to mediate cutaneous thermal hyperemia. In 13 young adults (6 women, 7 men), cutaneous vascular conductance (CVC) was measured at four intradermal microdialysis sites that were continuously perfused with 1) lactated Ringer solution (control), 2) 5 mM glibenclamide (KATP channel blocker), 3) 20 mM NG-nitro-l-arginine methyl ester (NOS inhibitor), or 4) a combination of KATP channel blocker and NOS inhibitor. Local skin heating to 42°C was administered at all four treatment sites to elicit cutaneous thermal hyperemia. Thirty minutes after the local heating, 1.25 mM pinacidil (KATP channel opener) and subsequently 25 mM sodium nitroprusside (NO donor) were administered to three of the four sites (each 25–30 min). The local heating-induced prolonged elevation in CVC was attenuated by glibenclamide (19%), but the transient initial peak was not. However, glibenclamide had no effect on the prolonged elevation in CVC in the presence of NOS inhibition. Pinacidil caused an elevation in CVC, but this response was abolished at the glibenclamide-treated skin site, demonstrating its effectiveness as a KATP channel blocker. The pinacidil-induced increase in CVC was unaffected by NOS inhibition, whereas the increase in CVC elicited by sodium nitroprusside was partly (15%) inhibited by glibenclamide. In summary, we showed an interactive effect of KATP channels and NOS for the plateau of cutaneous thermal hyperemia. This interplay may reflect a vascular smooth muscle cell KATP channel activation by NO.
Kinetic study of the expression of genes related to hepatic steatosis, glucose and lipid metabolism, and cellular stress during overfeeding in mule ducks
Authors: Pioche Tracy , Skiba Fabien , Bernadet Marie-Dominique , Seiliez Iban , Massimino William , Houssier Marianne , Tavernier Annabelle , Ricaud Karine , Davail Stéphane , Skiba-Cassy Sandrine , Gontier Karine
Published: January 2020

Induced by overfeeding, hepatic steatosis is a process exploited for the “foie gras” production in mule ducks. To better understand the mechanisms underlying its development, the physiological responses of mule ducks overfed with corn for a duration of 11 days were analyzed. A kinetic analysis of glucose and lipid metabolism and cell protection mechanisms was performed on 96 male mule ducks during overfeeding with three sampling times (after the 4th, the 12th, and the 22nd meal). Gene expression and protein analysis realized on the liver, muscle, and abdominal fat showed an activation of a cholesterol biosynthetic pathway during the complete overfeeding period mainly in livers with significant correlations between its weight and its cholesterolemia ( r = 0.88; P < 0.0001) and between the liver weight and the hmgcr and soat1 expression ( r = 0.4, P < 0.0001 and r = 0.67; P < 0.0001, respectively). Results also revealed an activation of insulin and amino acid cells signaling a pathway suggesting that ducks boost insulin sensitivity to raise glucose uptake and use via glycolysis and lipogenesis. Cellular stress analysis revealed an upregulation of key autophagy-related gene expression atg8 and sqstm1( P < 0.0001) during the complete overfeeding period, mainly in the liver, in contrast to an induction of cyp2e1( P < 0.0001), suggesting that autophagy could be suppressed during steatosis development. This study has highlighted different mechanisms enabling mule ducks to efficiently handle the starch overload by keeping its liver in a nonpathological state. Moreover, it has revealed potential biomarker candidates of hepatic steatosis as plasma cholesterol for the liver weight.
Kinetic Freeze-Out Temperature and Transverse Flow Velocity in Au-Au Collisions at RHIC-BES Energies
Authors: Waqas Muhammad , Li Bao-Chun
Published: January 2020

By using the method of data-driven reanalysis, the midrapidity transverse momentum pT spectra of charged hadrons (π+, K+, and p) produced in central and peripheral gold-gold (Au-Au) collisions from the Beam Energy Scan (BES) program at the Relativistic Heavy Ion Collider (RHIC) are fitted by using the blast-wave model with the Boltzmann-Gibbs statistics. The model results are in agreement with the experimental data measured by the STAR Collaboration at the RHIC-BES energies. We observe that the kinetic freeze-out temperature T0, transverse flow velocity βT, mean transverse momentum pT, and initial temperature Ti increase with collision energy as well as with event centrality.
Physiotherapists’ Experiences Using the Ekso Bionic Exoskeleton with Patients in a Neurological Rehabilitation Hospital: A Qualitative Study
Authors: Read Emily , Woolsey Cora , McGibbon Chris A. , O’Connell Colleen
Published: January 2020

Use of bionic overground exoskeletons to assist with neurological rehabilitation is becoming increasingly prevalent and has important implications for physiotherapists and their patients. Yet, there is a paucity of research about the impact of integrating this technology on physiotherapists’ work. The purpose of this study was to explore how the training and implementation of using the Ekso robotic exoskeleton with patients affects physiotherapists’ work. An exploratory qualitative study of three physiotherapists working at a neurological rehabilitation centre in Eastern Canada was conducted using one-on-one semistructured interviews in July 2017. Audio recordings were transcribed verbatim, and data was coded and analyzed using thematic analysis. Six themes emerged from the data: developing organizational capacity; ethical use of technology; benefits of the equipment; challenges of the equipment; cognitive workload; and the technological environment. The results suggest that the adoption and integration of bionic exoskeletons into rehabilitation practice is not as simple as training physiotherapists and giving them the device. More research is needed to understand the increased cognitive demands of working with patients using technologically advanced exoskeletons within a dynamic, technology-rich healthcare environment, while managing patient expectations and ethical use.
Petrović-Type Inequalities for Harmonic h-convex Functions
Authors: Abbas Baloch Imran , Chu Yu-Ming
Published: January 2020

In the article, we establish several Petrović-type inequalities for the harmonic h-convex (concave) function if h is a submultiplicative (super-multiplicative) function, provide some new majorizaton type inequalities for harmonic convex function, and prove the superadditivity, subadditivity, linearity, and monotonicity properties for the functionals derived from the Petrović type inequalities.
Modified 2D Proca Theory: Revisited under BRST and (Anti-)chiral Superfield Formalisms
Authors: Chauhan B. , Kumar S. , Tripathi A. , Malik R. P.
Published: January 2020

Within the framework of Becchi-Rouet-Stora-Tyutin (BRST) approach, we discuss mainly the fermionic (i.e., off-shell nilpotent) (anti-)BRST, (anti-)co-BRST, and some discrete dual symmetries of the appropriate Lagrangian densities for a two (1+1)-dimensional (2D) modified Proca (i.e., a massive Abelian 1-form) theory without any interaction with matter fields. One of the novel observations of our present investigation is the existence of some kinds of restrictions in the case of our present Stückelberg-modified version of the 2D Proca theory which is not like the standard Curci-Ferrari (CF) condition of a non-Abelian 1-form gauge theory. Some kinds of similarities and a few differences between them have been pointed out in our present investigation. To establish the sanctity of the above off-shell nilpotent (anti-)BRST and (anti-)co-BRST symmetries, we derive them by using our newly proposed (anti-)chiral superfield formalism where a few specific and appropriate sets of invariant quantities play a decisive role. We express the (anti-)BRST and (anti-)co-BRST conserved charges in terms of the superfields that are obtained after the applications of (anti-)BRST and (anti-)co-BRST invariant restrictions and prove their off-shell nilpotency and absolute anticommutativity properties, too. Finally, we make some comments on (i) the novelty of our restrictions/obstructions and (ii) the physics behind the negative kinetic term associated with the pseudoscalar field of our present theory.
Acoustic Emission Characteristics of Normal and Layered Concrete Blocks during Dilating/Static Fracture
Authors: Ma Ji , Du Feng , Zhang Shuai
Published: January 2020

Static fracturing technology is one of the most effective methods for localized breaking of rock and concrete. Layered concrete and rock structures are commonly seen in engineering applications such as breaking of concrete buildings, stone cutting, and excavation of rock in underground spaces. Therefore, it is essential to study the static fracturing characteristics of layered concrete to ensure the safety of engineering construction processes. In this paper, using acoustic emission (AE) technology and surface displacement monitoring, the deformation and fracturing of ordinary‐strength concrete, concrete with a soft interlayer, and layered concrete (with strength decreasing successively by layer) were studied under the effect of a static (or soundless) cracking agent (SCA). The experimental results indicated that (1) AE activity of the two layered concrete test blocks during static fracturing showed a gradually increasing trend, while that of the ordinary‐strength concrete tended to first increase and then decrease; (2) for the concrete test block with a soft interlayer sandwiched by high‐strength layers, the AE events reached a maximum in the transfer of expansion pressure stage, which accounted for 47.11% of the total value in static cracking; the macroscopic damage to layered concrete test blocks comprising multiple interlaid layers with different strengths mainly occurred in the fracturing stage, during which the AE events and AE energy accounted for 76.22% and 66.94%, respectively, of those in the whole static fracturing process; and (3) the duration of static fracturing prolonged with the increase of the overall strength of the concrete test blocks. The results provide a useful experimental reference for the application of static fracturing technology in the breaking of layered concrete and rock.
On Viscosity and Equivalent Notions of Solutions for Anisotropic Geometric Equations
Authors: De Zan Cecilia , Soravia Pierpaolo
Published: January 2020

We prove that viscosity solutions of geometric equations in step two Carnot groups can be equivalently reformulated by restricting the set of test functions at the singular points. These are characteristic points for the level sets of the solutions and are usually difficult to deal with. A similar property is known in the Euclidian space, and in Carnot groups, it is based on appropriate properties of a suitable homogeneous norm. We also use this idea to extend to Carnot groups the definition of generalised flow, and it works similarly to the Euclidian setting. These results simplify the handling of the singularities of the equation, for instance, to study the asymptotic behaviour of singular limits of reaction diffusion equations. We provide examples of using the simplified definition, showing, for instance, that boundaries of strictly convex subsets in the Carnot group structure become extinct in finite time when subject to the horizontal mean curvature flow even if characteristic points are present.
Robust Synthesis Algorithm for Directional Modulation Signal with Array Manifold Vectors Uncertainty
Authors: Hong Tao
Published: January 2020

Directional modulation (DM) has become a new research hotspot of physical layer security (PLS) communication at the transmitter side. In this paper, we propose a robust synthesis algorithm for DM signal under the condition of the array manifold vectors perturbation. This algorithm optimizes the constraints of sidelobe level and Euclidean distance of constellation points by considering the worst case performance of array manifold vectors. Furthermore, we also design an active constellation extension (ACE) method to relax the equality constraint of desired modulation symbols into a robust inequality constraint at the desired direction. These constraints can be reformulated in a convex form with l2 and l∞ regularization, which are computationally tractable. Simulation results show better performance of the proposed robust algorithm compared with the benchmark synthesis algorithms in the presence of array manifold vectors uncertainty.
Real‐Time PCR and Quantitative Culture for Mycoplasma pneumoniae Load in Pharyngeal Swabs from Children at Preliminary Diagnosis and Discharge
Authors: Zhao Fei , Guan Xuemei , Li Jing , Liu Liyong , Gong Jie , He Lihua , Meng Fanliang , Zhang Jianzhong
Published: January 2020

Background. Extensive studies have focused on the diagnosis and treatment of Mycoplasma pneumoniae infection; however, rare studies investigated the posttreatment conditions. We analyzed the carrying status of M. pneumoniae in the respiratory tract of children before and after treatment. Methods. Ninety‐two children with M. pneumoniae pneumonia were included in this study. Clinical data were obtained from each patient, and pharyngeal swab sampling was performed at preliminary diagnosis and discharge. Real‐time PCR and dilution quantitative culture were utilized to determine the DNA quantification and number of viable M. pneumoniae from samples collected upon preliminary diagnosis and discharge. Results. All the 92 cases showed DNA positivity upon preliminary diagnosis, serum IgM antibody was detected in 80 patients, and positivity of M. pneumoniae culture was observed in 82 cases. Upon discharge, the M. pneumoniae nucleotide and culture positivity were detected in 87 and 49 cases, respectively. The content of viable M. pneumoniae was 10–104 CCU/mL and 10–102 CCU/mL in the preliminary diagnosis samples and discharge samples, respectively. Conclusions. Real‐time PCR was rapid and effective for the qualitative diagnosis of M. pneumoniae at the early stage, but it cannot be used to evaluate the prognosis of patients with M. pneumoniae infection. Quantitative analysis for M. pneumoniae DNA could not directly reflex the viable strain content.
Computational Staining of Pathology Images to Study the Tumor Microenvironment in Lung Cancer
Authors: Wang Shidan , Rong Ruichen , Yang Donghan M. , Fujimoto Junya , Yan Shirley , Cai Ling , Yang Lin , Luo Danni , Behrens Carmen , Parra Edwin R. , Yao Bo , Xu Lin , Wang Tao , Zhan Xiaowei , Wistuba Ignacio I. , Minna John , Xie Yang , Xiao Guanghua
Published: January 2020

The spatial organization of different types of cells in tumor tissues reveals important information about the tumor microenvironment (TME). To facilitate the study of cellular spatial organization and interactions, we developed Histology-based Digital-Staining, a deep learning-based computation model, to segment the nuclei of tumor, stroma, lymphocyte, macrophage, karyorrhexis, and red blood cells from standard hematoxylin and eosin–stained pathology images in lung adenocarcinoma. Using this tool, we identified and classified cell nuclei and extracted 48 cell spatial organization-related features that characterize the TME. Using these features, we developed a prognostic model from the National Lung Screening Trial dataset, and independently validated the model in The Cancer Genome Atlas lung adenocarcinoma dataset, in which the predicted high-risk group showed significantly worse survival than the low-risk group (P = 0.001), with a HR of 2.23 (1.37–3.65) after adjusting for clinical variables. Furthermore, the image-derived TME features significantly correlated with the gene expression of biological pathways. For example, transcriptional activation of both the T-cell receptor and programmed cell death protein 1 pathways positively correlated with the density of detected lymphocytes in tumor tissues, while expression of the extracellular matrix organization pathway positively correlated with the density of stromal cells. In summary, we demonstrate that the spatial organization of different cell types is predictive of patient survival and associated with the gene expression of biological pathways.

Significance:

These findings present a deep learning-based analysis tool to study the TME in pathology images and demonstrate that the cell spatial organization is predictive of patient survival and is associated with gene expression.

See related commentary by Rodriguez-Antolin, p. 1912
Fusobacterium nucleatum in the Colorectum and Its Association with Cancer Risk and Survival: A Systematic Review and Meta-analysis
Authors: Gethings-Behncke Christian , Coleman Helen G. , Jordao Haydee W.T. , Longley Daniel B. , Crawford Nyree , Murray Liam J. , Kunzmann Andrew T.
Published: January 2020

Background:

The gut microbiome, in particular Fusobacterium nucleatum, has been reported to play a role in colorectal cancer development and in patient prognosis. We aimed to perform a systematic review and meta-analysis of published studies to assess the prevalence of F. nucleatum in colorectal tumors and evaluate the association between F. nucleatum and colorectal cancer development and prognosis.

Methods:

MEDLINE, EMBASE, and Web of Science databases were systematically searched for studies published until January 2019. Random effects meta-analyses were used to assess the prevalence of F. nucleatum in patients with colorectal cancer or tissues relative to controls and survival in F. nucleatum–positive versus –negative patients.

Results:

Forty-five relevant articles were identified. Meta-analyses indicated higher odds of F. nucleatum being present in colorectal tissue samples from patients with colorectal cancer [n = 6 studies, pooled OR = 10.06; 95% confidence intervals (CI), 4.48–22.58] and individuals with colorectal polyps (n = 5 studies, pooled OR = 1.83; 95% CI, 1.07–3.16) compared with healthy controls. Similar results were apparent in fecal samples, and when comparing tumor with adjacent normal tissue. Meta-analyses indicated poorer survival in patients with colorectal cancer with high versus low F. nucleatum abundance (n = 5 studies, pooled HR = 1.87; 95% CI, 1.12–3.11).

Conclusions:

A consistent increase in the prevalence and/or abundance of F. nucleatum in colorectal cancer tissue and fecal samples compared with controls was apparent. High abundance of F. nucleatum in colorectal tumors was also associated with poorer overall survival.

Impact:

F. nucleatum could be useful as a diagnostic and prognostic marker for colorectal cancer or as a treatment target.
Association of Diet Quality and Physical Activity on Obesity-Related Cancer Risk and Mortality in Black Women: Results from the Women's Health Initiative
Authors: Chebet Joy J. , Thomson Cynthia A. , Kohler Lindsay N. , Ehiri John E. , Luo Juhua , Cheng Ting-Yuan David , Pan Kathy , Chlebowski Rowan T. , Nassir Rami , Sealy-Jefferson Shawnita , Manson JoAnn E. , Saquib Nazmus , Bell Melanie L.
Published: January 2020

Background:

Obesity-related cancers disproportionately affect the Black community. We assessed the relationship between diet quality, physical activity, and their combined effect on obesity-related cancer risk and mortality in Black women enrolled in the Women's Health Initiative (WHI).

Methods:

Data from postmenopausal (50–79 years of age) Black women enrolled in WHI clinical trials or observational studies were analyzed. Exposure variables included baseline physical activity [metabolic equivalent of tasks (MET)-hours/week of moderate-to-vigorous physical activity (MVPA)] and diet quality [Healthy Eating Index (HEI)-2015]. Outcomes included adjudicated obesity-related cancer incidence and mortality. Cox proportional hazard models were used to evaluate the association between MVPA and HEI-2015 and obesity-related cancer risk and mortality.

Results:

The analytical sample included 9,886 Black women, with a baseline mean body mass index (BMI) of 31.1 kg/m2 (SD = 6.8); mean HEI-2015 score of 63.2 (SD = 11.0, possible range 0 to 100); and mean MVPA of 5.0 (SD = 9.4) MET-hours/week. Over an average of 13 years of follow-up, 950 (9.6%) obesity-related cancer cases were observed, with 313 (32.9%) resulting in death. Physical activity [HR, 1.05; 95% confidence interval (CI), 0.86–1.30], diet quality (HR, 0.99; 95% CI, 0.92–1.08), and their combination (HR, 1.05; 95% CI, 0.85–1.29) were not associated with risk for any or site-specific obesity-related cancers. Similarly, these health behaviors had no association with mortality.

Conclusions:

Diet quality, physical activity and their combined effect, as measured, were not associated with obesity-related cancer risk and mortality in Black women enrolled in WHI.

Impact:

Other social, behavioral, and biological factors may contribute to racial disparities observed in obesity-related cancer rates.
Opiate and Tobacco Use and Exposure to Carcinogens and Toxicants in the Golestan Cohort Study
Authors: Etemadi Arash , Poustchi Hossein , Calafat Antonia M. , Blount Benjamin C. , De Jesús Victor R. , Wang Lanqing , Pourshams Akram , Shakeri Ramin , Inoue-Choi Maki , Shiels Meredith S. , Roshandel Gholamreza , Murphy Gwen , Sosnoff Connie S. , Bhandari Deepak , Feng Jun , Xia Baoyun , Wang Yuesong , Meng Lei , Kamangar Farin , Brennan Paul , Boffetta Paolo , Dawsey Sanford M. , Abnet Christian C. , Malekzadeh Reza , Freedman Neal D.
Published: January 2020

Background:

There is little information on human exposure to carcinogens and other toxicants related to opiate use, alone or in combination with tobacco.

Methods:

Among male participants of the Golestan Cohort Study in Northeast Iran, we studied 28 never users of either opiates or tobacco, 33 exclusive cigarette smokers, 23 exclusive users of smoked opiates, and 30 opiate users who also smoked cigarettes (dual users; 21 smoked opiates and 9 ingested them). We quantified urinary concentrations of 39 exposure biomarkers, including tobacco alkaloids, tobacco-specific nitrosamines, polycyclic aromatic hydrocarbons (PAH), and volatile organic compounds (VOC), and used decomposition to parse out the share of the biomarker concentrations explained by opiate use and nicotine dose.

Results:

Dual users had the highest concentrations of all biomarkers, but exclusive cigarette smokers and exclusive opiate users had substantially higher concentrations of PAH and VOC biomarkers than never users of either product. Decomposition analysis showed that opiate use contributed a larger part of the PAH concentrations than nicotine dose, and the sum of 2- and 3-hydroxyphenanthrene (∑2,3-phe) resulted almost completely from opiate use. Concentrations of most VOC biomarkers were explained by both nicotine dose and opiate use. Two acrylamide metabolites, a 1,3-butadiene metabolite and a dimethylformamide metabolite, were more strongly explained by opiate use. Acrylamide metabolites and ∑2,3-phe were significantly higher in opiate smokers than opiate eaters; other biomarkers did not vary by the route of opiate intake.

Conclusions:

Both cigarette smokers and opiate users (by smoking or ingestion) were exposed to many toxicants and carcinogens.

Impact:

This high exposure, particularly among dual opiate and cigarette users, can have a substantial global public health impact.
Racial Difference in Prostate Cancer Cell Telomere Lengths in Men with Higher Grade Prostate Cancer: A Clue to the Racial Disparity in Prostate Cancer Outcomes
Authors: Heaphy Christopher M. , Joshu Corinne E. , Barber John R. , Davis Christine , Zarinshenas Reza , De Marzo Angelo M. , Lotan Tamara L. , Sfanos Karen S. , Meeker Alan K. , Platz Elizabeth A.
Published: January 2020

Background:

Black men have worse prostate cancer outcomes following treatment than White men even when accounting for prognostic factors. However, biological explanations for this racial disparity have not been fully identified. We previously showed that more variable telomere lengths among cancer cells and shorter telomere lengths in cancer-associated stromal (CAS) cells individually and together (“telomere biomarker”) are associated with prostate cancer–related death in surgically treated men independent of currently used prognostic indicators. Here, we hypothesize that Black–White differences in the telomere biomarker and/or in its components may help explain the racial disparity in prostate cancer outcomes.

Methods:

Black [higher grade (Gleason ≥4+3) = 34 and lower grade = 93] and White (higher grade = 34 and lower grade = 89) surgically treated men were frequency matched on age, pathologic stage, and grade. We measured telomere lengths in cancer and CAS cells using a robust telomere-specific FISH assay. Tissue microarray and grade-specific distributional cutoff points without regard to race were evaluated.

Results:

Among men with higher grade disease, the proportion of Black men (47.1%) with more variable cancer cell telomere lengths was 2.3-times higher (P = 0.02) than that in White men (20.6%). In contrast, among men with lower grade disease, cancer cell telomere length variability did not differ by race. The proportion of men with shorter CAS cell telomeres did not differ by race for either higher or lower grade disease.

Conclusions:

A greater proportion of Black men with higher grade disease have an adverse prostate cancer cell telomere phenotype than White men with higher grade disease.

Impact:

Our findings suggest a possible explanation for the racial disparity in prostate cancer outcomes.
Combination Lenalidomide/Bortezomib Treatment Synergistically Induces Calpain-Dependent Ikaros Cleavage and Apoptosis in Myeloma Cells
Authors: Ganesan Saravanan , Palani Hamenth Kumar , Balasundaram Nithya , David Sachin , Devasia Anup J. , George Biju , Mathews Vikram
Published: January 2020

Multiple myeloma had been successfully treated by combining lenalidomide and bortezomib with reports suggesting benefits of such a combination even in relapsed/refractory cases. Recently, it was demonstrated that Ikaros degradation by lenalidomide happens via proteasome-dependent pathway and this process is critical for the eradication of myeloma cells. On the basis of this, an antagonistic effect should be observed if a combination of both these agents were used, which however is not the observation seen in the clinical setting. Our study demonstrates that when these agents are combined they exhibit a synergistic activity against myeloma cells and degradation of Ikaros happens by a proteasome-independent calcium-induced calpain pathway. Our study identifies the crucial role of calcium-induced calpain pathway in inducing apoptosis of myeloma cells when this combination or lenalidomide and bortezomib is used. We also report that this combination enhanced the expression of CD38 compared with lenalidomide alone. Thus, data from our study would establish the rationale for the addition of daratumumab along with this combination to further enhance therapeutic activity against multiple myeloma.

Implications:

Lenalidomide and bortezomib combination degrades IKZF1 in multiple myeloma through a calcium-dependent calpain and caspase pathway.

Visual Overview:

http://mcr.aacrjournals.org/content/molcanres/18/4/529/F1.large.jpg.
The Role of MicroRNAs in Influencing Body Growth and Development
Authors: Cirillo Francesca , Catellani Cecilia , Lazzeroni Pietro , Sartori Chiara , Street Maria Elisabeth
Published: January 2020

Body growth and development are regulated among others by genetic and epigenetic factors. MicroRNAs (miRNAs) are epigenetic regulators of gene expression that act at the post-transcriptional level, thereby exerting a strong influence on regulatory gene networks. Increasing studies suggest the importance of miRNAs in the regulation of the growth plate and growth hormone (GH)-insulin-like growth factor (IGF) axis during the life course in a broad spectrum of animal species, contributing to longitudinal growth. This review summarizes the role of miRNAs in regulating growth in different in vitro and in vivo models acting on GH, GH receptor (GHR), IGFs, and IGF1R genes besides current knowledge in humans, and highlights that this regulatory system is of importance for growth.
Effects of Receptor for Advanced Glycation End-Products (RAGE) Signaling on Intestinal Ischemic Damage in Mice
Authors: Makino Yurika , Munakata Shinya , Ueyama Takae , Honjo Kumpei , Kawano Shingo , Takahashi Makoto , Kojima Yutaka , Tomiki Yuichi , Sakamoto Kazuhiro
Published: January 2020

Objective: Superior mesenteric artery ischemia and nonocclusive mesenteric ischemia are representative diseases of the vascular emergency known as irreversible transmural intestinal necrosis (ITIN). The receptor for advanced glycation end-products (RAGE) belongs to the immunoglobulin superfamily of extracellular ligands, which also includes high-mobility group box 1 (HMGB-1) and proteins of the S100 family. The HMGB-1 ligands have been implicated in the pathogenesis of various inflammatory disorders. This study was designed to investigate the relation between RAGE and ITIN in a murine acute intestinal ischemic model. Materials and Methods: ITIN was induced by clipping the cranial mesenteric artery and the peripheral blood vessels. Mucosal and blood samples were collected and analyzed by reverse-transcription PCR and immunohistochemistry for mucosal inflammation and levels of RAGE-related proteins. The influence of RAGE signaling on intestinal cell reproduction was investigated using the cell scratch test, an in vitro wound-healing assay. Finally, RAGE-related proteins and their respective inhibitors were administered intraperitoneally to ITIN model mice to determine their effects. Results: RAGE-expressing cells were located at the base of the intestinal crypts at day 0. As ITIN progressed, most of the damaged intestinal cells expressed RAGE, and ligands of RAGE such as HMGB-1, S100 A8/A9, and S100β were present in the crypt cells from the bottom to the top. The quantities of S100 A8/A9 and S100β were particularly high, above the levels found in other diseases. When S100 A8/A9 and S100β were applied to small intestinal epithelial cells in vitro, regeneration was significantly impeded. Inflammatory Gr1+ neutrophils and F4/80+ macrophages are involved in tissue ischemia. S100 A8/A9 enhances inflammatory myeloid cell influx. Conclusions: RAGE-related proteins are elevated in ITIN model mice and impede intestinal regeneration in vitro. RAGE-related proteins may be a new therapeutic target or a new marker for ITIN.
OUTSMART HF
Authors: Paterson D. Ian , Wells George , Erthal Fernanda , Mielniczuk Lisa , O’Meara Eileen , White James , Connelly Kim A. , Knuuti Juhani , Radja Miroslaw , Laine Mika , Chow Benjamin J.W. , Kandolin Riina , Chen Li , Dick Alexander , Dennie Carole , Garrard Linda , Ezekowitz Justin , Beanlands Rob , Chan Kwan-Leung , Brown Peter , Kartikainen Juha , Hedman Marja , Larose Eric , Pibarot Philippe , Tardif Jean-Claude , Leipsic Jonathan , Kiess Marla , Howarth Andrew , Hanninen Helena , Duchesne Lloyd , Freeman Michael , Leong-Poi Howard , Wright Graham , Ukkonen Heikki
Published: January 2020

Background:

Cardiac magnetic resonance (CMR) is a recommended imaging test for patients with heart failure (HF); however, there is a lack of evidence showing incremental benefit over transthoracic echocardiography. Our primary hypothesis was that routine use of CMR will yield more specific diagnoses in nonischemic HF. Our secondary hypothesis was that routine use of CMR will improve patient outcomes.

Methods:

Patients with nonischemic HF were randomized to routine versus selective CMR. Patients in the routine strategy underwent echocardiography and CMR, whereas those assigned to selective use underwent echocardiography with or without CMR according to the clinical presentation. HF causes was classified from the imaging data as well as by the treating physician at 3 months (primary outcome). Clinical events were collected for 12 months.

Results:

A total of 500 patients (344 male) with mean age 59±13 years were randomized. The routine and selective CMR strategies had similar rates of specific HF causes at 3 months clinical follow-up (44% versus 50%, respectively;
P
=0.22). At image interpretation, rates of specific HF causes were also not different between routine and selective CMR (34% versus 30%, respectively;
P
=0.34). However, 24% of patients in the selective group underwent a nonprotocol CMR. Patients with specific HF causes had more clinical events than those with nonspecific caused on the basis of imaging classification (19% versus 12%, respectively;
P
=0.02), but not on clinical assessment (15% versus 14%, respectively;
P
=0.49).

Conclusions:

In patients with nonischemic HF, routine CMR does not yield more specific HF causes on clinical assessment. Patients with specific HF causes from imaging had worse outcomes, whereas HF causes defined clinically did not.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01281384.
Philippine Civil Society and WTO Negotiations: Opportunities and Challenges
Authors: Encarnacion Tadem Teresa S.
Published: January 2020

The essay discusses how civil society has found an opening in intervening in the decision-making process on the country’s negotiating position in the World Trade Organization (WTO). It particularly looks at political opportunity structures which made this possible including the following external and domestic factors: 1) the anti-globalization movement which has pressured states to be more transparent and accountable to the manner in which WTO policymaking is being undertaken, 2) the failure of the Uruguay Round to provide the economic benefits to the Philippines inducing the government to be more open to civil society intervention, 3) the effort of the Department of Agriculture (DA), the lead agency for the negotiations of the WTO’s Agreement on Agriculture (AoA), to bring in civil society players, which was exemplified by the DA’s establishment of the Task Force on the WTO (Re)Negotiations on the Agreement on Agriculture (TFWAR), and 4) the emergence of coalition-building in the WTO, particularly among developing countries. However, there are also challenges which civil society groups face such as the need for the active involvement of the legislators in the WTO negotiations; the institutionalization of civil society participation at the local and global levels; and the prioritization of civil society strategies on dealing with the WTO and their respective governments.
Social Representations of a Controversial Peace Agreement: Subjective Public Meanings of the GRP-MILF MOA
Authors: Montiel Cristina Jayme , de Guzman Judith M.
Published: January 2020

Using social representations theory, we studied the social meanings of a controversial Memorandum of Agreement (MOA) between the Government of the Republic of the Philippines and the Moro Islamic Liberation Front. In Study One, we describe the discursive content of the social debate by content analyzing articles from newspapers and selected websites. Study Two uses a survey to examine the fit between social representations of the political elite, as found in media, and the nonelite in Mindanao territories where the MOA was hotly contested. Study Three presents the social representations of the MOA at the local level through analysis of key informant interviews and archival data. Discriminant analysis on survey data shows that in general, the debate of political elites in media mirrors the contentions on-the-ground. However, the issue of constitutionality was only taken up by the political elite. Our findings suggest that the political stumble of the GRP-MILF peace process lay in a lack of procedural fairness and an on-the-ground participatory process acceptable to all antagonistic parties. However, the socially represented fair procedure is not about conventional democratic ways like using or not using a constitutional frame, but rather about pragmatic positioning and public consultations.
Principles and Pragmatism in State Succession: Bargaining in the Economic Affairs Commission of the Tartu Peace Conference
Authors: Kalmo Hent
Published: January 2020

The conventions of legal argumentation have the tendency to reinforce the notion that the development of international law is a principled affair. This article will examine the elaboration of one particular treaty – the Tartu Peace Treaty signed between Estonia and Soviet Russia in 1920 – in order to see to what extent it lends support to the idea that treaties grow out of principles. The Tartu Peace Treaty perfectly illustrates the point that the contents of a treaty can be entirely indeterminate with regard to their underlying principles. My conclusion is not that, in this case, pragmatism triumphed over principles: that the negotiating parties refrained from debates over abstract principles and took the more pragmatic route of finding an array of concrete solutions. Whilst it is true that the end result – the Treaty as it finally stood – was detached from any single foundational idea, it was not obtained by putting principles aside. The Tartu Peace Conference rather offers us a particularly good example of how principles can be used as rhetorical ploys.
Queen Saint Margaret, Jesuit Devotion, and Seventeenth-Century Scottish Catholicism
Authors: Horan Mary Elizabeth
Published: January 2020

From one small devotional book about Queen Saint Margaret and its three translations we can learn much about the nature of post-Reformation, seventeenth-century Scottish Catholicism. First, the style of the book’s meditation informs us of the influential role that the Jesuits played in forming the next generation of Scottish men and priests, as well as shaping the intellectual and devotional culture of post-Reformation Scottish Catholicism. Second, this book was part of a larger movement of writings and devotional practices designed to emphasize the “Scottishness” of Catholics’ faith while in exile among other Western European traditions. Third, the paratextual elements provide evidence that the Scots colleges were closely aligned with the royalist cause. And finally, this book and others like it were used to solicit aid and support for the Scots colleges.
“So What?”: A Conversation with John W. O’Malley
Authors: Colombo Emanuele
Published: January 2020

John W. O’Malley, a member of the Society of Jesus, is currently a university professor in the Theology Department of Georgetown University, Washington, DC. He holds a PhD in history from Harvard University. His specialty is the religious culture of early modern Europe. O’Malley has written and edited a number of books, eight of which have won best-book awards. The First Jesuits (Cambridge, MA: Harvard University Press, 1993), perhaps his best-known work, received both the Jacques Barzun Prize for Cultural History from the American Philosophical Society and the Philip Schaff Prize from the American Society for Church History. It has been translated into twelve languages and its publication opened a new era in the study of the Society. Since then, the Jesuits have attracted greater attention from scholars of all disciplines on an international basis. O’Malley has continued to write about early Jesuits and the subsequent history of the Jesuits: his main essays on Jesuit history are now collected in the first volume of Brill’s Jesuit Studies series, Saints or Devils Incarnate?: Studies in Jesuit History (Leiden, 2013).

In the last few years, O’Malley published with Harvard University Press a trilogy on the three last councils in the history of the Catholic Church: What Happened at Vatican ii
(2008), Trent: What Happened at the Council (2012), and Vatican I: The Council and the Making of the Ultramontane Church (2018). A comparative view of the three councils is offered now in his most recent book, When Bishops Meet: An Essay Comparing Trent, Vatican I, and Vatican ii
(2019). O’Malley has lectured widely around the world to both professional and general audiences. He is past president of the Renaissance Society of America and the American Catholic Historical Association. He holds the Johannes Quasten Medal from The Catholic University of America for distinguished service in religious studies. In 1995, he was elected to the American Academy of Arts and Sciences; in 1997, to the American Philosophical Society; and in 2001, to the Accademia Ambrosiana, Milan. He holds lifetime achievement awards from the Society for Italian Historical Studies, the Renaissance Society of America, and the American Catholic Historical Association.

At the origin of the following interview there are three conversations Emanuele Colombo had with O’Malley in Chicago, in 2017 and 2018, as a follow-up of a lecture he gave on his life, “My Life of Learning,” now published in The Catholic Historical Review.
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Two new species of Neoperla montivaga group (Plecoptera: Perlidae) from Guangxi Zhuang Autonomous Region of southern China
Authors: LI WEIHAI , MO RAORAO , WANG GUOQUAN
Published: January 2020

Two new stonefly species of the Neoperla montivaga species group, N. delphina sp. nov. and N. quadrispina sp. nov. are described from the Guangxi Zhuang Autonomous Region of southern China and compared with other taxa of the diehli subgroup.