bluuebunny/crossref_metadata_2025 huggingface dataset:
Trends of Rural/Urban Homicide in Colombia, 1992-2015: Internal Armed Conflict and Hints for Postconflict
Authors: Vallejo Katherine , Tapias Jose , Arroyave Ivan
Published: October 2018

Objective. To analyze the relationship between rural and urban homicide rates in Colombia between 1992 and 2015 and the fluctuations in these rates. Methods. Individual records of homicides and population aggregates in men and women aged 15-64 years were used. The adjusted rates of annual homicides were calculated for urban/rural areas and standardized by age. Rate Ratios (RRs) adjusted by region were calculated. A joinpoint analysis was performed to identify inflection points and the Annual Percentage Change (APC). Results. Four joinpoints were identified in rural and urban rates: after peaking in 1992, homicide rates fell until 1997, and then increased until 2002. From this point on there was a continuous reduction until 2015, although this reduction slowed down from 2005 onward. During almost the whole period, the rates of rural homicides were higher than those of urban homicides, although they equalized at the end of the period. Conclusions. Unlike in other countries, during the study period Colombian homicide rates, which coincided with the dynamics of the armed conflict, were higher in rural than in urban areas. In recent years, a predominance of urban homicides committed by younger men has been identified, which could pose a challenge to postconflict in Colombia.
Structural and Magnetic Properties of Ba3[Cu0.8−xZnxMn0.2]2Fe24O41 Z‐Type Hexaferrites
Authors: Al-Hwaitat Eman S. , Mahmood Sami H. , Al–Hussein Mahmoud , Bsoul Ibrahim
Published: October 2018

We report on the synthesis and characterization of Ba3[Cu0.8−xZnxMn0.2]2Fe24O41 (x = 0.0, 0.2, 0.4, 0.6, and 0.8) barium hexaferrites. The samples were prepared by high‐energy ball‐milling technique and double‐sintering approach. The effects of Zn substitution for Cu on the structural and magnetic properties of the prepared samples were investigated using X‐ray diffraction (XRD), scanning electron microscopy (SEM), and vibrating sample magnetometer (VSM). XRD patterns of the samples revealed the presence of a major Z‐type hexaferrite phase, together with secondary M‐type and Y‐type phases. The magnetic results indicated that the saturation magnetization increased slightly with increasing the Zn content, while the coercivity and magnetocrystalline anisotropy field exhibited a decreasing tendency with the increase of Zn content. The thermomagnetic curves revealed the complex magnetic structure of the prepared samples and confirmed that the Curie temperature of the magnetic phases decreased with increasing x as a result of the reduction of the strength of the superexchange interactions.
A Perspective Analysis of Dams and Water Quality: The Bui Power Project on the Black Volta, Ghana
Authors: Gyasi Samuel Fosu , Boamah Bismark , Awuah Esi , Otabil Kenneth Bentum
Published: October 2018

Large dams play an important role in promoting economic and social development in many countries. However, the construction of such dams can have a detrimental effect on the environment. The aim of this study was to investigate perceptions of drinking water quality among inhabitants of selected communities within the Bui Dam environs. With the help of questionnaires, 100 respondents from communities “near to the dam” were randomly selected and interviewed. Their responses were compared with another 100 respondents selected from “far from the dam” communities. These were augmented with in-depth interviews, focus group discussion, and personal observation. Analysis of the results showed that, there were greater proportions (31%) of the participants who lived in “near communities” within the age category 20–25 compared to 19% of their “far communities” counterparts. There were significantly greater proportions of female respondents in the “near to the dam” (57%) compared to respondents in the “far from the dam” communities (52%). The study further showed that the perception of risk of consuming contaminated drinking water was more common among “far from the dam” communities (odds ratio = 4.57). The perception of the quality of water based on some physical properties was investigated as part of our study. Analysis of the results showed that significantly greater proportion of the “far from the dam” communities (35%) perceived their water had an objectionable smell compared to 7% of inhabitants of their other counterparts (p value = 0.001). The study further showed that significantly greater proportion of the study participants in the far from the communities perceived that their water had colour (65%) and they did not drink water from any other source (63%) apart from their stream. The study demonstrated that generally, inhabitants within the study communities perceived the construction of the Bui Power Project has negatively affected their drinking water quality.
A New Accurate Numerical Method Based on Shifted Chebyshev Series for Nuclear Reactor Dynamical Systems
Authors: Hamada Yasser Mohamed
Published: October 2018

A new method based on shifted Chebyshev series of the first kind is introduced to solve stiff linear/nonlinear systems of the point kinetics equations. The total time interval is divided into equal step sizes to provide approximate solutions. The approximate solutions require determination of the series coefficients at each step. These coefficients can be determined by equating the high derivatives of the Chebyshev series with those obtained by the given system. A new recurrence relation is introduced to determine the series coefficients. A special transformation is applied on the independent variable to map the classical range of the Chebyshev series from [-1,1] to [0,h]. The method deals with the Chebyshev series as a finite difference method not as a spectral method. Stability of the method is discussed and it has proved that the method has an exponential rate of convergence. The method is applied to solve different problems of the point kinetics equations including step, ramp, and sinusoidal reactivities. Also, when the reactivity is dependent on the neutron density and step insertion with Newtonian temperature feedback reactivity and thermal hydraulics feedback are tested. Comparisons with the analytical and numerical methods confirm the validity and accuracy of the method.
On Nearly Prime Submodules of Unitary Modules
Authors: Nghiem Nguyen Dang Hoa , Baupradist Samruam , Chinram Ronnason
Published: October 2018

The aim of this paper is to introduce the notion of nearly prime submodules as a generalization of prime submodules. We investigate some of their basic properties and point out the similarities between these submodules and the prime submodules. We also indicate some applications of nearly prime submodules. These applications show how nearly prime submodules control the structure of modules and they recover earlier relative theorems.
Lipid and Bile Acid Dysmetabolism in Crohn’s Disease
Authors: Uchiyama Koji , Kishi Hisashi , Komatsu Wataru , Nagao Masanori , Ohhira Shuji , Kobashi Gen
Published: October 2018

Crohn’s disease is one of the systemic autoimmune diseases. It commonly affects the small intestine and colon but may involve any portion of the gastrointestinal tract from the mouth to the anus. The most affected area by Crohn’s disease is the distal part of the small intestine, in which the bile acid molecules are most efficiently reabsorbed. Bile acids form mixed micelles together with fatty acids, which function as a transport vehicle to deliver fatty acids to the apical membrane of enterocytes for absorption. Therefore, if the terminal ileum is impaired, bile acid malabsorption may occur, which may cause congenital diarrhoea in Crohn’s disease. Similarly, the impairment of the terminal ileum also induces fatty acid malabsorption, which may influence the role of fatty acids in Crohn’s disease. In contrast, a recent study reported that multidrug resistance protein 1 (MDR1) regulated effector T-cell function in the ileum from bile acid-driven oxidative stress and MDR1 loss of function in a subset of patients with Crohn’s disease. However, the role of consumption of fatty acids in Crohn’s disease remains to be fully elucidated. This review is aimed at providing an overview of some recent developments in research of Crohn’s disease from comprehensive perspective with a focus on the connection between disease location and behaviour, lipid diets, and bile acid malabsorption.
Investigation into Polyurethane at Varying Dose Rates of Ionizing Radiation for Clinical Application
Authors: Cooke Shelley L. , Whittington Abby R.
Published: October 2018

Polyurethanes (PUs) are commonly used materials for medical devices. These devices are exposed repeatedly to radiation when patients undergo radiotherapy treatments. It has been found that peripherally inserted central catheters (PICCs) and central venous catheters (CVCs) fail at an increased rate (14.7% and 8.8%, respectively) when radiated. Currently, little research is available on increased failure seen in conjunction with radiation, but complex in vivo environments within a human patient make it difficult to isolate effects of individual variables. This research investigated effects of radiation in an aqueous environment to determine whether radiation combined with a mimicked in vivo environment is sufficient to change PU devices. The following dose rates were used in this study: 3.2 Gy·min−1, 4.5 Gy·min−1, 44 Gy·min−1, and 833 Gy·min−1. Samples were characterized in four main ways: cellular response, physical changes, chemical changes, and mechanical changes. Results reveal normal cellular response at all dose rates, indicating dose rate does not alter cellular adhesion or proliferation, and biocompatibility of the material is not being altered. Results from physical, chemical, and mechanical effects confirm that varying dose rates alone do not initiate material changes, which negates the hypothesis that varying dose rates of radiation contribute to the complications in PICC and CVCs.
Vitamin D Deficiency as It Relates to Oral Immunity and Chronic Periodontitis
Authors: Khammissa R. A. G. , Ballyram R. , Jadwat Y. , Fourie J. , Lemmer J. , Feller L.
Published: October 2018

The biologically active form of vitamin D, 1,25 dihydroxyvitamin D (1,25(OH)2D) and its receptor, the vitamin D receptor (VDR), play roles in maintaining oral immunity and the integrity of the periodontium. Results of observational cross-sectional clinical studies investigating the association between vitamin D serum level and the incidence and severity of chronic periodontitis indicate that, perhaps owing to the immunomodulatory, anti-inflammatory, and antibacterial properties of 1,25(OH)2D/VDR signalling, a sufficient serum level of vitamin D is necessary for the maintenance of periodontal health. In cases of established chronic periodontitis, vitamin D supplementation is associated with reduction in the severity of periodontitis. As cross-sectional studies provide only weak evidence for any causal association and therefore are of questionable value, either longitudinal cohort studies, case controlled studies, or randomized control trials are needed to determine whether or not deficiency of vitamin D is a risk factor for chronic periodontitis, and whether or not vitamin D supplementation adjunctive to standard periodontal treatment is in any way beneficial. In this article, we discuss the relationship between vitamin D, oral immunity and periodontal disease and review the rationale for using vitamin D supplementation to help maintain periodontal health and as an adjunct to standard periodontal treatment.
Towards a Novel Trust-Based Multicast Routing for VANETs
Authors: Xia Hui , Zhang San-shun , Li Ben-xia , Li Li , Cheng Xiang-guo
Published: October 2018

The Intelligent Transportation System (ITS) is an important application area of the Cyber-Physical System (CPS). To further promote effective communication between vehicles, vehicular ad hoc networks (VANETs) have been widely used in the ITS. However, the communication efficiency in VANETs is not only affected by the external environment but also more vulnerable to malicious attacks. In order to address the above-mentioned issues, we propose a novel trust-based multicast routing protocol (TMR) to defend against multiple attacks and improve the routing efficiency. In the proposed trust model, direct trust is calculated based on Bayesian theory and indirect trust is computed according to evaluation credibility and activity. The fuzzy logic theory is used to fuzzify the direct and indirect trust values, and then the total trust value of the node is obtained by defuzzification. With the help of the obtained trust values, malicious vehicle nodes are eliminated in the processes of route establishment and route maintenance, and finally, the network establishes trusted and efficient routes for data delivery. Comprehensive simulation experiments show that our new protocol can effectively improve the transmission rate of data packets at the expense of a slight increase in end-to-end delay and control overhead.
Spontaneous Massive Vulvar Edema in Pregnancy: A Case Report
Authors: Mulisya Olivier , Mastaki Mbusa , Gertrude Tambavira , Tasi Kyakimwa , Mathe Jeff K.
Published: October 2018

Spontaneous massive vulvar edema in pregnancy is unusual and a cause for concern. This condition should be taken seriously since it might be caused by some conditions such as preeclampsia, diabetes, vulvovaginitis, severe anemia, and neoplasms. We report a case of massive vulvar edema in a 15-year-old primigravida following tocolysis therapy at 33 weeks of gestation. Other causes of vulvar edema were excluded. The vulvar edema appeared spontaneously after tocolysis and rapidly increased in size, associated with severe vulvar pains. The vulvar edema resolved progressively with antibiotics, corticoids, and analgesics. The patient delivered by spontaneous vaginal delivery a term live newborn with an unremarkable postpartum period. The aim of this report is to alert clinicians that conservative attempts could be considered for vulvar edema complicating tocolysis.
Maximin Efficiencies under Treatment-Dependent Costs and Outcome Variances for Parallel, AA/BB, and AB/BA Designs
Authors: Candel Math J. J. M.
Published: October 2018

If there are no carryover effects, AB/BA crossover designs are more efficient than parallel (A/B) and extended parallel (AA/BB) group designs. This study extends these results in that (a) optimal instead of equal treatment allocation is examined, (b) allowance for treatment-dependent outcome variances is made, and (c) next to treatment effects, also treatment by period interaction effects are examined. Starting from a linear mixed model analysis, the optimal allocation requires knowledge on intraclass correlations in A and B, which typically is rather vague. To solve this, maximin versions of the designs are derived, which guarantee a power level across plausible ranges of the intraclass correlations at the lowest research costs. For the treatment effect, an extensive numerical evaluation shows that if the treatment costs of A and B are equal, or if the sum of the costs of one treatment and measurement per person is less than the remaining subject-specific costs (e.g., recruitment costs), the maximin crossover design is most efficient for ranges of intraclass correlations starting at 0.15 or higher. For other cost scenarios, the maximin parallel or extended parallel design can also become most efficient. For the treatment by period interaction, the maximin AA/BB design can be proven to be the most efficient. A simulation study supports these asymptotic results for small samples.
Star Recognition Based on Path Optimization in Star Sensor with Multiple Fields of View
Authors: Jiang Di , Zhang Ke , Debeir Olivier
Published: October 2018

Star sensors make use of astronomical information in stars to determine attitude for spacecrafts by star image recognition. For low-cost star sensors with small field of view, fusion of observed images from multiple fields of view is performed and a novel recognition algorithm based on path optimization by randomly distributed ant colony is proposed. According to pheromone intensity, the ant colony can autonomously figure out a close optimal path without starting or ending point, rather than certifying a starting point first. Feature patterns extracted from the optimal path in guiding template and observed image after fusion are compared to perform star recognition. By the proposed algorithm, starting point for path optimization has no influence on the extracted feature pattern. Thus the star recognition rate is improved due to the higher stability of the extracted pattern. Simulations indicate that the algorithm improves recognition accuracy and robustness against noise for sensors with multiple fields of view.
The Existence Results of Solutions for System of Fractional Differential Equations with Integral Boundary Conditions
Authors: Zan Dongxia , Xu Run
Published: October 2018

In this paper, we investigated the system of fractional differential equations with integral boundary conditions. By using a fixed point theorem in the Banach spaces, we get the existence of solutions for the fractional differential system. By constructing iterative sequences for any given initial point in space, we can approximate this solution. As an application, an example is presented to illustrate our main results.
An Herbal Medicine, Yukgunja‐Tang is more Effective in a Type of Functional Dyspepsia Categorized by Facial Shape Diagnosis: A Placebo‐Controlled, Double‐Blind, Randomized Trial
Authors: Ko Seok-Jae , Park Jae-Woo , Lee Jae-hyung , Lee Jung-eun , Ha Na-yeon , Nam Seong-uk , Lee Jae-hong , Jeon Soo-Hyung , Kim Jong-Won , Kang Changwan , Yeo Inkwon , Kim Jinsung
Published: October 2018

Introduction. Functional dyspepsia (FD) is a functional gastrointestinal disorder characterized by persistent upper dyspeptic symptoms without organic lesions. There is no standard therapy for FD. Yukgunja‐tang (YGJT) is an herbal medicine used for treating upper gastrointestinal symptoms in Asia. Studies on the effect of YGJT on FD have been conducted. However, the results were inconsistent. In Hyungsang medicine, traditional Korean medicine, FD patients are classified into bladder body (BB) or gallbladder body (GB) subtypes by the shape and angle of their faces. Each subtype may have different characteristics, physiology, and pathology of the same disease. YGJT is more effective for patients with BB subtype. The three‐dimensional facial shape diagnostic system (3‐FSDS) was shown to be effective in diagnosing BB or GB subtypes. This study aimed to investigate the effect of YGJT on FD patients classified using the 3‐FSDS. Materials and Methods. The current study was a placebo‐controlled, double‐blinded, randomized, two‐center trial. Eligible patients were diagnosed with either BB or GB FD subtype using the 3‐FSDS. Ninety‐six participants (48 BB and 48 GB subtypes) were randomly allocated to treatment or control groups in a 2:1 ratio. YGJT or placebo was administered for eight weeks. The primary outcome was assessed using the total dyspepsia symptom scale (TDS), while the secondary outcomes were assessed using the single dyspepsia symptom scale (SDS), proportion of responders, visual analog scale, Nepean dyspepsia index, functional dyspepsia‐related quality of life, and spleen qi deficiency questionnaire. Results and Discussion. The result of TDS showed the superior effect of YGJT on BB over GB subtype. The subgroup analysis of TDS and SDS scores showed the superior effect of YGJT over placebo. Other outcome variables did not show any significant differences between groups. Conclusion. YGJT may be considered for FD patients diagnosed with BB subtype using 3‐FSDS.
Effects of Dance on Pain in Patients with Fibromyalgia: A Systematic Review and Meta‐Analysis
Authors: Murillo-García Álvaro , Villafaina Santos , Adsuar José C. , Gusi Narcis , Collado-Mateo Daniel
Published: October 2018

Objective. The aim of this study was to perform a systematic review on the effectiveness of dance‐based programs in patients with fibromyalgia, as well as calculate the overall effect size of the improvements, through a meta‐analysis. Methods. The Cochrane Library, Physiotherapy Evidence Database (PEDro), PubMed, TRIP, and Web of Science (WOS) were selected to identify the articles included in this systematic review and meta‐analysis. A total of seven articles fulfilled all inclusion and exclusion criteria. PRISMA guidelines were followed in the data extraction process. The level of evidence was established following guidelines from the Dutch Institute for Healthcare Improvement (CBO). Results. The studies were all randomized controlled trials, but not double‐blind. Duration of dance programs ranged from 12 to 24 weeks. Sessions lasted between 60 and 120 minutes and were performed 1‐2 times per week. The overall effect size for pain was ‐1.64 with a 95% CI from ‐2.69 to ‐0.59 which can be interpreted as large. In addition, significant improvements were observed in quality of life, depression, impact of the disease, anxiety, and physical function. Conclusion. Dance‐based intervention programs can be an effective intervention for people suffering from fibromyalgia, leading to a significant reduction of the level of pain with an effect size that can be considered as large. However, findings and conclusions from this meta‐analysis must be taken with caution due to the small number of articles and the large heterogeneity.
Exponentially Weighted Moving Average Control Charts for the Process Mean Using Exponential Ratio Type Estimator
Authors: Khan Hina , Farooq Saleh , Aslam Muhammad , Khan Masood Amjad
Published: October 2018

This study proposes EWMA-type control charts by considering some auxiliary information. The ratio estimation technique for the mean with ranked set sampling design is used in designing the control structure of the proposed charts. We have developed EWMA control charts using two exponential ratio-type estimators based on ranked set sampling for the process mean to obtain specific ARLs, being suitable when small process shifts are of interest.
Efficacy of Oral Acetaminophen and Intravenous Chlorpheniramine Maleate versus Placebo to Prevent Red Cell Transfusion Reactions in Children and Adolescent with Thalassemia: A Prospective, Randomized, Double-Blind Controlled Trial
Authors: Rujkijyanont Piya , Monsereenusorn Chalinee , Manoonphol Pimpat , Traivaree Chanchai
Published: October 2018

Background. Thalassemia is a common congenital hemolytic disorder. In severe cases, regular blood transfusion is essentially required. The role of premedications to prevent transfusion reactions is varied among institutions with no standard guideline.Objective. To prospectively compare the risk of transfusion reactions in thalassemia patients premedicated with acetaminophen and chlorpheniramine maleate (CPM) versus placebo prior to blood transfusion.Material and Method. A randomized, double-blinded, placebo-controlled transfusion reaction study of 147 eligible patients was analyzed. All administered red blood cell (RBC) products were leukoreduced blood products. Patients were monitored and followed for the development of transfusion reactions for 24 hours after RBC transfusion.Results. A total of 73 patients randomized to receive active drugs consisting of acetaminophen and CPM were compared to 74 patients receiving placebo. The overall incidences of febrile reaction and urticarial rash were 6.9% and 22% in the patients randomized to receive active drugs comparing with 9.5% and 35.2% in the patients receiving placebo with no significant differences between two groups. However, delayed development of urticarial rash at 4-24 hours after RBC transfusion was significantly higher in female and patients receiving placebo.Conclusion. Administration of premedications in thalassemia patients receiving RBC transfusion without a history of transfusion reactions does not decrease the overall risk of transfusion reactions. However, the use of CPM might be beneficial to prevent delayed urticarial rash in those patients especially in females (Thai Clinical Trial Registry (TCTR) study ID:20140526001).
Spectral Functions for the Vector-Valued Fourier Transform
Authors: Mogilevskii Vadim
Published: October 2018

A scalar distribution function σ(s) is called a spectral function for the Fourier transform φ^(s)=∫Reitsφ(t)dt (with respect to an interval I⊂R) if for each function φ∈L2(R) with support in I the Parseval identity ∫Rφ^s2dσ(s)=∫Rφt2dt holds. We show that in the case I=R there exists a unique spectral function σ(s)=(1/2π)s, in which case the above Parseval identity turns into the classical one. On the contrary, in the case of a finite interval I=(0,b), there exist infinitely many spectral functions (with respect to I). We introduce also the concept of the matrix-valued spectral function σ(s) (with respect to a system of intervals {I1,I2,…,In}) for the vector-valued Fourier transform of a vector-function φ(t)={φ1(t),φ2(t),…,φn(t)}∈L2(I,Cn), such that support of φj lies in Ij. The main result is a parametrization of all matrix (in particular scalar) spectral functions σ(s) for various systems of intervals {I1,I2,…,In}.
Sex Differences in Cancer Driver Genes and Biomarkers
Authors: Li Constance H. , Haider Syed , Shiah Yu-Jia , Thai Kevin , Boutros Paul C.
Published: October 2018

Cancer differs significantly between men and women; even after adjusting for known epidemiologic risk factors, the sexes differ in incidence, outcome, and response to therapy. These differences occur in many but not all tumor types, and their origins remain largely unknown. Here, we compare somatic mutation profiles between tumors arising in men and in women. We discovered large differences in mutation density and sex biases in the frequency of mutation of specific genes; these differences may be associated with sex biases in DNA mismatch repair genes or microsatellite instability. Sex-biased genes include well-known drivers of cancer such as β-catenin and BAP1. Sex influenced biomarkers of patient outcome, where different genes were associated with tumor aggression in each sex. These data call for increased study and consideration of the molecular role of sex in cancer etiology, progression, treatment, and personalized therapy.

Significance: This study provides a comprehensive catalog of sex differences in somatic alterations, including in cancer driver genes, which influence prognostic biomarkers that predict patient outcome after definitive local therapy. Cancer Res; 78(19); 5527–37. ©2018 AACR.
Gene Regulatory Network Analysis Identifies Sex-Linked Differences in Colon Cancer Drug Metabolism
Authors: Lopes-Ramos Camila M. , Kuijjer Marieke L. , Ogino Shuji , Fuchs Charles S. , DeMeo Dawn L. , Glass Kimberly , Quackenbush John
Published: October 2018

Understanding sex differences in colon cancer is essential to advance disease prevention, diagnosis, and treatment. Males have a higher risk of developing colon cancer and a lower survival rate than women. However, the molecular features that drive these sex differences are poorly understood. In this study, we use both transcript-based and gene regulatory network methods to analyze RNA-seq data from The Cancer Genome Atlas for 445 patients with colon cancer. We compared gene expression between tumors in men and women and observed significant sex differences in sex chromosome genes only. We then inferred patient-specific gene regulatory networks and found significant regulatory differences between males and females, with drug and xenobiotics metabolism via cytochrome P450 pathways more strongly targeted in females. This finding was validated in a dataset of 1,193 patients from five independent studies. While targeting, the drug metabolism pathway did not change overall survival for males treated with adjuvant chemotherapy, females with greater targeting showed an increase in 10-year overall survival probability, 89% [95% confidence interval (CI), 78–100] survival compared with 61% (95% CI, 45–82) for women with lower targeting, respectively (P = 0.034). Our network analysis uncovers patterns of transcriptional regulation that differentiate male and female colon cancer and identifies differences in regulatory processes involving the drug metabolism pathway associated with survival in women who receive adjuvant chemotherapy. This approach can be used to investigate the molecular features that drive sex differences in other cancers and complex diseases.

Significance: A network-based approach reveals that sex-specific patterns of gene targeting by transcriptional regulators are associated with survival outcome in colon cancer. This approach can be used to understand how sex influences progression and response to therapies in other cancers. Cancer Res; 78(19); 5538–47. ©2018 AACR.
Dietary Heterocyclic Amine Intake and Colorectal Adenoma Risk: A Systematic Review and Meta-analysis
Authors: Martínez Góngora Victoria , Matthes Katarina L. , Castaño Patricia Rodríguez , Linseisen Jakob , Rohrmann Sabine
Published: October 2018

Background:

Heterocyclic amines (HCA) are potent carcinogenic substances formed in meat. Because of their mutagenic activity, they may increase the risk of colorectal adenomas, which are the precursors of colorectal cancer, one of the most prevalent cancers worldwide. The aim of this meta-analysis was to synthesize the knowledge about the intake of HCAs and its associations with CRA.

Methods:

We conducted a systematic search in PubMed and EMBASE. We used odds ratios (OR); or relative risks, RR) from every reported intake and compared the highest versus lowest level of dietary HCAs. In addition, we assessed a dose–response relationship.

Results:

Twelve studies on HCA intake and risk of CRA were included in our analysis. We observed a statistically significant association when comparing top versus bottom intake category of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine [PhIP; OR = 1.20; 95% confidence interval (CI) = 1.12–1.29], 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx; OR = 1.20; 95% CI = 1.08–1.34), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx; OR = 1.16; 95% CI = 1.05–1.27), benzo(a)pyrene (BaP; OR = 1.15; 95% CI = 1.04–1.27), and mutagenicity index (OR = 1.22; 95% CI = 1.06–1.41). Furthermore, we observed a significant dose–response effect for PhIP, MeIQx, and mutagenicity index.

Conclusions:

This meta-analysis suggests that there is a positive association of HCAs, BaP, mutagenicity index with risk of CRA. In addition, our dose–response analyses showed an increased risk of CRA for PhIP, MeIQx, and mutagenicity index.

Impact:

This study provides evidence for a positive association between the dietary intake of meat mutagens and CRA risk.
Multilevel Regression for Small-Area Estimation of Mammography Use in the United States, 2014
Authors: Berkowitz Zahava , Zhang Xingyou , Richards Thomas B. , Sabatino Susan A. , Peipins Lucy A. , Holt James , White Mary C.
Published: October 2018

Background:

The U.S. Preventive Services Task Force recommends biennial screening mammography for average-risk women aged 50–74 years. County-level information on population measures of mammography use can inform targeted intervention to reduce geographic disparities in mammography use. County-level estimates for mammography use nationwide are rarely presented.

Methods:

We used data from the 2014 Behavioral Risk Factor Surveillance System (BRFSS; n = 130,289 women), linked it to the American Community Survey poverty data, and fitted multilevel logistic regression models with two outcomes: mammography within the past 2 years (up-to-date), and most recent mammography 5 or more years ago or never (rarely/never). We poststratified the data with U.S. Census population counts to run Monte Carlo simulations. We generated county-level estimates nationally and by urban–rural county classifications. County-level prevalence estimates were aggregated into state and national estimates. We validated internal consistency between our model-based state-specific estimates and urban–rural estimates with BRFSS direct estimates using Spearman correlation coefficients and mean absolute differences.

Results:

Correlation coefficients were 0.94 or larger. Mean absolute differences for the two outcomes ranged from 0.79 to 1.03. Although 78.45% (95% confidence interval, 77.95%–78.92%) of women nationally were up-to-date with mammography, more than half of the states had counties with >15% of women rarely/never using a mammogram, many in rural areas.

Conclusions:

We provided estimates for all U.S. counties and identified marked variations in mammography use. Many states and counties were far from the 2020 target (81.1%).

Impact:

Our results suggest a need for planning and resource allocation on a local level to increase mammography uptake.
Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER+/HER2+ Breast Cancers: Implications to the ExteNET Trial
Authors: Sudhan Dhivya R. , Schwarz Luis J. , Guerrero-Zotano Angel , Formisano Luigi , Nixon Mellissa J. , Croessmann Sarah , González Ericsson Paula I. , Sanders Melinda , Balko Justin M. , Avogadri-Connors Francesca , Cutler Richard E. , Lalani Alshad S. , Bryce Richard , Auerbach Alan , Arteaga Carlos L.
Published: October 2018

Purpose:

The phase III ExteNET trial showed improved invasive disease-free survival in patients with HER2+ breast cancer treated with neratinib versus placebo after trastuzumab-based adjuvant therapy. The benefit from neratinib appeared to be greater in patients with ER+/HER2+ tumors. We thus sought to discover mechanisms that may explain the benefit from extended adjuvant therapy with neratinib.

Experimental Design: Mice with established ER+/HER2+ MDA-MB-361 tumors were treated with paclitaxel plus trastuzumab ± pertuzumab for 4 weeks, and then randomized to fulvestrant ± neratinib treatment. The benefit from neratinib was evaluated by performing gene expression analysis for 196 ER targets, ER transcriptional reporter assays, and cell-cycle analyses.

Results:

Mice receiving “extended adjuvant” therapy with fulvestrant/neratinib maintained a complete response, whereas those treated with fulvestrant relapsed rapidly. In three ER+/HER2+ cell lines (MDA-MB-361, BT-474, UACC-893) but not in ER+/HER2− MCF7 cells, treatment with neratinib induced ER reporter transcriptional activity, whereas treatment with fulvestrant resulted in increased HER2 and EGFR phosphorylation, suggesting compensatory reciprocal crosstalk between the ER and ERBB RTK pathways. ER transcriptional reporter assays, gene expression, and immunoblot analyses showed that treatment with neratinib/fulvestrant, but not fulvestrant, potently inhibited growth and downregulated ER reporter activity, P-AKT, P-ERK, and cyclin D1 levels. Finally, similar to neratinib, genetic and pharmacologic inactivation of cyclin D1 enhanced fulvestrant action against ER+/HER2+ breast cancer cells.

Conclusions:

These data suggest that ER blockade leads to reactivation of ERBB RTKs and thus extended ERBB blockade is necessary to achieve durable clinical outcomes in patients with ER+/HER2+ breast cancer.
The Role of Angiogenesis in Hepatocellular Carcinoma
Authors: Morse Michael A. , Sun Weijing , Kim Richard , He Aiwu Ruth , Abada Paolo B. , Mynderse Michelle , Finn Richard S.
Published: October 2018

Hepatocellular carcinoma (HCC) accounts for about 90% of all primary liver cancers and is the second leading cause of cancer-related deaths worldwide. The hypervascular nature of most HCC tumors underlines the importance of angiogenesis in the pathobiology of these tumors. Several angiogenic pathways have been identified as being dysregulated in HCC, suggesting they may be involved in the development and pathogenesis of HCC. These data provide practical targets for systemic treatments such as those targeting the vascular endothelial growth factor receptor and its ligand. However, the clinical relevance of other more recently identified angiogenic pathways in HCC pathogenesis or treatment remains unclear. Research into molecular profiles and validation of prognostic or predictive biomarkers will be required to identify the patient subsets most likely to experience meaningful benefit from this important class of agents.
Targeting Resistance against the MDM2 Inhibitor RG7388 in Glioblastoma Cells by the MEK Inhibitor Trametinib
Authors: Berberich Anne , Kessler Tobias , Thomé Carina M. , Pusch Stefan , Hielscher Thomas , Sahm Felix , Oezen Iris , Schmitt Lara-Marie , Ciprut Sara , Hucke Nanina , Ruebmann Petra , Fischer Manuel , Lemke Dieter , Breckwoldt Michael O. , von Deimling Andreas , Bendszus Martin , Platten Michael , Wick Wolfgang
Published: October 2018

Purpose:

Resistance is an obstacle of glioma therapy. Despite targeted interventions, tumors harbor primary resistance or become resistant over short course of treatment. This study examined the mouse double minute 2 (MDM2) inhibitor RG7388 together with radiotherapy and analyzed strategies to overcome acquired MDM2 inhibitor resistance in glioblastoma.

Experimental Design:

Effects of RG7388 and radiotherapy were analyzed in p53 wild-type glioblastoma cell lines and glioma-initiating cells. RG7388 resistant cells were generated by increasing RG7388 doses over 3 months. Regulated pathways were investigated by microarray, qRT-PCR, and immunoblot analysis and specifically inhibited to evaluate rational salvage therapies at RG7388 resistance. Effects of RG7388 and trametinib treatment were challenged in an orthotopical mouse model with RG7388 resistant U87MG glioblastoma cells.

Results:

MDM2 inhibition required functional p53 and showed synergistic activity with radiotherapy in first-line treatment. Long-term exposure to RG7388 induced resistance by activation of the extracellular signal-regulated kinases 1/2 (ERK1/2)–insulin growth factor binding protein 1 (IGFBP1) signaling cascade, which was specifically overcome by ERK1/2 pathway inhibition with trametinib and knockdown of IGFBP1. Combining trametinib with continued RG7388 treatment enhanced antitumor effects at RG7388 resistance in vitro and in vivo.

Conclusions:

These data provide a rationale for combining RG7388 and radiotherapy as first-line therapy with a specific relevance for tumors insensitive to alkylating standard chemotherapy and for the addition of trametinib to continued RG7388 treatment as salvage therapy after acquired resistance against RG7388 for clinical practice.
RON Receptor Tyrosine Kinase as a Therapeutic Target for Eradication of Triple-Negative Breast Cancer: Efficacy of Anti-RON ADC Zt/g4-MMAE
Authors: Suthe Sreedhar Reddy , Yao Hang-Ping , Weng Tian-Hao , Hu Chen-Yu , Feng Liang , Wu Zhi-Gang , Wang Ming-Hai
Published: October 2018

Triple-negative breast cancer (TNBC) is a highly diverse group of malignant neoplasia with poor outcome. Currently, the lack of effective therapy has fostered a major effort to discover new targets to treat this malignant cancer. Here we identified the RON receptor tyrosine kinase as a therapeutic target for potential TNBC treatment. We analyzed RON expression in 168 primary TNBC samples via tissue microarray using anti-RON IHC staining and demonstrated that RON was widely expressed in 76.8% TNBC samples with overexpression in 76 cases (45.2%). These results provide the molecular basis to target RON for TNBC therapy. To this end, anti-RON monoclonal antibody Zt/g4-drug monomethyl auristatin E conjugate (Zt/g4-MMAE) was developed with a drug to antibody ratio of 3.29 and tested in a panel of TNBC cell lines with different phenotypes. In vitro, Zt/g4-MMAE rapidly induced RON internalization, resulted in cell-cycle arrest followed by massive cell death. The calculated IC50 values ranged from 0.06 to 3.46 μg/mL dependent on individual TNBC cell lines tested. Zt/g4-MMAE also effectively killed TNBC stem-like cells with RON+/CD44+/CD24− phenotypes and RON-negative TNBC cells through the bystander effect. In vivo, Zt/g4-MMAE at 10 mg/kg in a Q12 × 2 regimen completely eradicated TNBC xenografts without the regrowth of xenograft tumors. In conclusion, increased RON expression is a pathogenic feature in primary TNBC samples. Zt/g4-MMAE is highly effective in eradicating TNBC xenografts in preclinical models. These findings lay the foundation for using anti-RON Zt/g4-MMAE in clinical trials as a novel strategy for TNBC treatment.
Efficacy of a Covalent ERK1/2 Inhibitor, CC-90003, in KRAS-Mutant Cancer Models Reveals Novel Mechanisms of Response and Resistance
Authors: Aronchik Ida , Dai Yumin , Labenski Matt , Barnes Carmen , Jones Terri , Qiao Lixin , Beebe Lisa , Malek Mehnaz , Elis Winfried , Shi Tao , Mavrommatis Konstantinos , Bray Gordon L. , Filvaroff Ellen H.
Published: October 2018

As a critical signaling node, ERK1/2 are attractive drug targets, particularly in tumors driven by activation of the MAPK pathway. Utility of targeting the MAPK pathway has been demonstrated by clinical responses to inhibitors of MEK1/2 or RAF kinases in some mutant BRAF-activated malignancies. Unlike tumors with mutations in BRAF, those with mutations in KRAS (>30% of all cancers and >90% of certain cancer types) are generally not responsive to inhibitors of MEK1/2 or RAF. Here, a covalent ERK1/2 inhibitor, CC-90003, was characterized and shown to be active in preclinical models of KRAS-mutant tumors. A unique occupancy assay was used to understand the mechanism of resistance in a KRAS-mutant patient-derived xenograft (PDX) model of colorectal cancer. Finally, combination of CC-90003 with docetaxel achieved full tumor regression and prevented tumor regrowth after cessation of treatment in a PDX model of lung cancer. This effect corresponded to changes in a stemness gene network, revealing a potential effect on tumor stem cell reprograming.

Implications:

Here, a covalent ERK1/2 inhibitor (CC-90003) is demonstrated to have preclinical efficacy in models of KRAS-mutant tumors, which present a therapeutic challenge for currently available therapies.
High Prevalence of Hereditary Cancer Syndromes and Outcomes in Adults with Early-Onset Pancreatic Cancer
Authors: Bannon Sarah A. , Montiel Maria F. , Goldstein Jennifer B. , Dong Wenli , Mork Maureen E. , Borras Ester , Hasanov Merve , Varadhachary Gauri R. , Maitra Anirban , Katz Matthew H. , Feng Lei , Futreal Andrew , Fogelman David R. , Vilar Eduardo , McAllister Florencia
Published: October 2018

Introduction: We aimed to determine the prevalence and landscape of germline mutations among patients with young-onset pancreatic ductal adenocarcinoma (PDAC) as well as their influence in prognosis.

Methods: Patients from two cohorts were studied, the high-risk cohort (HRC), which included 584 PDAC patients who received genetic counseling at The University of Texas MD Anderson Cancer Center, and a general cohort (GC) with 233 metastatic PDAC patients. We defined germline DNA sequencing on 13 known pancreatic cancer susceptibility genes. The prevalence and landscape of mutations were determined, and clinical characteristics including survival were analyzed.

Results: A total of 409 patients underwent genetic testing (277 from HRC and 132 from GC). As expected, the HRC had higher prevalence of germline mutations compared with the GC: 17.3% versus 6.81%. The most common mutations in both cohorts were in BRCA1/2 and mismatch-repair (MMR) genes. Patients younger than 60 years old had significantly higher prevalence of germline mutations in both the HRC [odds ratios (OR), 1.93 ± 1.03–3.70, P = 0.039] and GC (4.78 ± 1.10–32.95, P = 0.036). Furthermore, PDAC patients with germline mutations in the GC had better overall survival than patients without mutations (HR, 0.44; 95% CI of HR, 0.25–0.76, P = 0.030).

Discussion: Germline mutations are highly prevalent in patients with PDAC of early onset and can be predictive of better outcomes. Considering emerging screening strategies for relatives carrying susceptibility genes as well as impact on therapy choices, genetic counseling and testing should be encouraged in PDAC patients, particularly those of young onset. Cancer Prev Res; 11(11); 679–86. ©2018 AACR.
Clinical Significance of Pancreatic Atrophy Induced by Immune-Checkpoint Inhibitors: A Case–Control Study
Authors: Eshet Yael , Baruch Erez Nissim , Shapira-Frommer Ronnie , Steinberg-Silman Yael , Kuznetsov Teodor , Ben-Betzalel Guy , Daher Sameh , Gluck Iris , Asher Nethanel , Apter Sara , Schachter Jacob , Bar Jair , Boursi Ben , Markel Gal
Published: October 2018

Immune-checkpoint inhibitor (ICI)–related diarrhea is attributed to inflammatory colitis, with no other drug-related differential diagnosis. Here, we investigated the occurrence of pancreatic atrophy (PA) in ICI-treated cancer patients and its correlation to exocrine pancreatic insufficiency (EPI). Metastatic melanoma, non–small cell lung carcinoma, and head and neck squamous cell carcinoma patients (n = 403) treated with anti–PD-1 (n = 356) or anti–CTLA-4 (n = 47) were divided into a case group (radiologic evidence of PA); control group matched by age, gender, and previous lines of treatment; and colitis group (ICI-induced colitis). Quantitative pancreatic volumetry was used for calculation of the decrease in pancreatic volume over time (atrophy rate). Thirty-one patients (7.7%) developed PA compared with 41 matched controls (P = 0.006). Four patients developed EPI, all from the anti–PD-1–treated group, which resolved with oral enzyme supplementation. The atrophy rate did not correlate with EPI (P = 0.87). EPI-related diarrhea presented at a median of 9 months, whereas the diarrhea of anti–PD-1–induced colitis patients (n = 22) was presented at a median of 2 months (P = 0.029). ICI-induced PA is irreversible and can result in EPI. EPI should be suspected in cases of late-onset steroid-resistant diarrhea with features of steatorrhea and treated with oral enzyme supplements.
KU70 Inhibition Impairs Both Non-Homologous End Joining and Homologous Recombination DNA Damage Repair Through SHP-1 Induced Dephosphorylation of SIRT1 in Adult T-Cell Leukemia-Lymphoma Cells
Authors: Yu Wenlei , Li Liang , Wang Guangming , Zhang Wenjun , Xu Jun , Liang Aibin
Published: October 2018

Background/Aims: Adult T-cell leukemia-lymphoma (ATL) is an aggressive disease which is highly resistant to chemotherapy. Studies show that enhanced ability of DNA damage repair (DDR) in cancer cells plays a key role in chemotherapy resistance. Here, we suggest that defect in DDR related genes might be a promising target to destroy the genome stability of tumor cells. Methods: Since KU70 is highly expressed in Jurkat cells, one of the most representative cell lines of ATL, we knocked down KU70 by shRNA and analyzed the impact of KU70 deficiency in Jurkat cells as well as in NOD-SCID animal models by western blot, immunofluorescence, flow cytometry and measuring DNA repair efficiency. Results: It is observed that silencing of KU70 resulted in accumulated DNA damage and impaired DDR in Jurkat cells, resulting in more apoptosis, decreased cell proliferation and cell cycle arrest. DNA damage leads to DNA double-strand breaks (DSBs), which are processed by either non-homologous end joining(NHEJ) or homologous recombination(HR). In our study, both NHEJ and HR are impaired because of KU70 defect, accompanied with increased protein level of SHP-1, a dephosphorylation enzyme. In turn, SHP-1 led to dephosphorylation of SIRT1, which further impaired HR repair efficiency. Moreover, KU70 deficiency prolonged survival of Jurkat-xenografted mice. Conclusion: These findings suggest that targeting KU70 is a promising target for ATL and might overcome the existing difficulties in chemotherapy.