bluuebunny/crossref_metadata_2025 huggingface dataset:
Phoenix dactyliferaProtects against Doxorubicin-Induced Cardiotoxicity and Nephrotoxicity
Authors: Wang Yuewen , Chao Xu , Ahmad Fiaz ud Din , Shi Hailong , Mehboob Hania , Hassan Waseem
Published: December 2019

Doxorubicin (DOX) is an important anticancer drug used widely in the treatment of leukemia and lymphoma. The suitability of DOX is enhanced by its high therapeutic index, but its potential to cause cardiotoxicity and nephrotoxicity remains a prime concern in anticancer therapeutics. This study is designed to determine the effect ofPhoenix dactyliferaextract (PDE) on DOX-induced cardiotoxicity and nephrotoxicity. Experimental rats were divided into four groups, receiving normal saline 4 ml/kg, DOX alone, and crude extract of PDE at doses of 1 g/kg and 1.5 g/kg in the presence of DOX, respectively, for 21 days. Cardiac enzymes and serum and urinary sodium and potassium levels were evaluated which were analyzed statistically by using one-way ANOVA. Subsequently, DOX initiated changes in the level of cardiac markers CK-MB, LDH, and troponin I, which were notably reversed by PDE. PDE was also effective against serum and urinary sodium and urinary potassium and protected against DOX-induced nephrotoxicity. Groups treated with different doses of PDE showed marked decrease in levels of cardiac and renal markers. The study concluded that the PDE extract possesses protective effects against DOX-induced cardiotoxicity and nephrotoxicity.
Modeling the Effects of Vaccination and Treatment on Tuberculosis Transmission Dynamics
Authors: Kelemu Mengistu Ashenafi , Witbooi Peter J.
Published: December 2019

In this study, we develop and analyze a deterministic mathematical model for tuberculosis (TB) transmission dynamics. The model includes vaccination for newborns and treatment for both high-risk latent and active TB patients. The stability of disease-free equilibrium point is discussed in detail. In the numerical simulation, the model parameters are estimated using reported TB incidence data in Ethiopia from the years 2003 to 2017, and R0 is calculated as R0≈2.13. Finally, the sensitivity indices of R0 with respect to the model parameters are performed, and their corresponding graphical results are presented. Our results quantify the positive influence of vaccination and the treatment for high-risk latent and active TB patients on the control of tuberculosis.
Prediction of Punching Capacity of Slab‐Column Connections without Transverse Reinforcement Based on a Backpropagation Neural Network
Authors: Bu Jie , Zhang Fanzhen , Zhu Meng , He Zhiyang , Hu Qigao
Published: December 2019

Punching shear failure of slab‐column connections can cause the progressive collapse of a structure. In this study, a punching test database is first established. Then, based on the Levenberg–Marquardt (LM) algorithm and using the nonlinear function of the backpropagation neural network (BPNN), a prediction model of the punching capacity of slab‐column connections without transverse reinforcement is established. Finally, the proposed model is compared with the formulas of the Chinese, American, and European standards using several methods. The statistical eigenvalue method shows that the BPNN model has the highest accuracy and the lowest dispersion. The defect point counting method shows that the BPNN model had the fewest total number of defects and was the safest and most economical. The influencing factor analysis suggests that factors in the BPNN model had the most reasonable influence on the punching bearing capacity of slab‐column connections. Finally, the model is verified using a case study and the Matlab program. The results show that the average error of the formulas in the Chinese, American, and European standards are 21.08%, 30.21%, and 11.47%, respectively, higher than that of the BPNN model.
Uptake and Dissipation of Carbofuran and Its Metabolite in Chinese Kale and Brinjal Cultivated Under Humid Tropic Climate
Authors: Sim Siong Fong , Chung Ling Yan , Jonip Jocephine , Chai Lian Kuet
Published: December 2019

Carbofuran is an insecticide with a broad spectrum of activity and is relatively cheap. It is banned in many countries in the world; however, it remains widely used in Asia, Australia, and South America. Carbofuran is commonly used in vegetable farming in Malaysia and it is a legally registered pesticide. This study reports the uptake and dissipation of carbofuran and 3-ketocarbofuran in Chinese kale and brinjal under humid tropic field conditions. The residue profile in plants demonstrated an increase to a maximum, followed by a consistent reduction to a level below the limit of determination (<0.01 mg/kg) over the experimental period. The maximum residue concentration was attained on Day 3 for kale (1.16 mg/kg fresh weight) and Day 7 for brinjal (0.06 mg/kg fresh weight) after carbofuran application. In order to comply with the maximum residue level (MRL) of 0.01 mg/kg, the preharvest interval for kale and brinjal were suggested at 23 and 28 days, respectively. The preharvest interval indicates that carbofuran is not recommended for Chinese kale but it is acceptable for brinjal. The average half-life of carbofuran in soil is 1.24 days, shorter than the literature values reported based on temperate condition, indicating accelerated dissipation under tropical climate. The estimated half-life of carbofuran in leaves was shorter than that in fruits with kale leaves reported at 2.54 days whilst brinjal leaves and fruits recorded at 3.22 and 10.33 days, respectively.
Research on Pressure Drop in the Accelerate Zone of Horizontal Conveying of Concrete Spraying
Authors: Ma Guanguo , Liu Zhaoxia , Gong Xiaobing , Chen Lianjun , Liu Guoming , Pan Gang , Dong Qizheng
Published: December 2019

A pressure transmitter was installed at a specific position in a concrete conveying line to disclose the pressure drop when compressed air was conveyed during concrete spraying. A statistical analysis of the pressure at different positions was undertaken. Experimental results demonstrated that in the accelerate zone of horizontal conveying of concrete in the line, the pressure drop mainly occurred during the acceleration, collision, and friction processes. The momentum equation was introduced during the experiment, which interpreted the pressure drop caused by the accelerated conveying of concrete. The theoretical equation was corrected based on the results of theoretical experiments by introducing the value of α, and the experimental results were then optimized, thus obtaining an approximate model of pressure drop during the conveying of concrete. In addition, experimental results were compared with a model equation that showed the reliability of the proposed model. Research conclusions are of great significance to regulate the pressure drop in the conveying line of concretes, to design working parameters of concrete spraying devices, and to predict the ultimate distance for the conveying of concrete.
Biodegradation Kinetics of Benzene and Naphthalene in the Vadose and Saturated Zones of a (Semi)-arid Saline Coastal Soil Environment
Authors: Ngueleu Stephane K. , Al-Raoush Riyadh I. , Shafieiyoun Saeid , Rezanezhad Fereidoun , Van Cappellen Philippe
Published: December 2019

Biodegradation is a key process for the remediation of sites contaminated by petroleum hydrocarbons (PHCs), but this process is not well known for the (semi)-arid coastal environments where saline conditions and continuous water level fluctuations are common. This study differs from the limited previous studies on the biodegradation of PHCs in Qatari coastal soils mainly by its findings on the biodegradation kinetics of the selected PHCs of benzene and naphthalene by indigenous bacteria. Soil samples were collected above, across, and below the groundwater table at the eastern coast of Qatar within a depth of 0 to -40 cm. Environmental conditions combining low oxygen and high sulfate concentrations were considered in this study which could favor either or both aerobic and anaerobic bacteria including sulfate-reducing bacteria (SRB). The consideration of SRB was motivated by previously reported high sulfate concentrations in Qatari soil and groundwater. Low- and high-salinity conditions were applied in the experiments, and the results showed the sorption of the two PHCs on the soil samples. Sorption was dominant for naphthalene whereas the biodegradation process contributed the most for the removal of benzene from water. Losses of nitrate observed in the biodegradation experiments were attributed to the activity of nitrate-reducing bacteria (NRB). The results suggested that aerobic, NRB, and most likely SRB biodegraded the two PHCs, where the combined contribution of sorption and biodegradation in biotic microcosms led to considerable concentration losses of the two PHCs in the aqueous phase (31 to 58% after 21 to 35 days). Although benzene was degraded faster than naphthalene, the biodegradation of these two PHCs was in general very slow with rate coefficients in the order of 10-3 to 10-2 day-1 and the applied kinetic models fitted the experimental results very well. It is relevant to mention that these rate coefficients are the contribution from all the microbial groups in the soil and not from just one.
Investigation of Dynamic Incentive of Supply Chain under Information Asymmetry for Screening
Authors: Zhou Jianheng , Li Shaokun , Wang Bill
Published: December 2019

More and more high‐end brand companies are exploring new markets by extending low‐end product lines. When selecting agents in new markets, a principal often faces the problem of identifying the promotional ability of agents. This paper aims to study the dynamic incentive of supply chain under information asymmetry for the information screening in long‐term supply chain cooperation. Also, it pioneers the rhythm of information disclosure in the extant literature. By establishing three two‐stage supply chain models, this paper analyzes the impact of agents’ information disclosure speed on the brand. We find that it is better to separate agents earlier out of the brand perspective; the semiseparated contract is beneficial for the brand to control information disclosure speed more flexibly and get more profits from the retailer. But, from the perspective of the supply chain, it is also possible to prefer the mixed contract. Under certain conditions, the pooling contract could also increase the profits of supply chain and improve the allocation efficiency of supply chain.
The Impact of Stroma Admixture on Molecular Subtypes and Prognostic Gene Signatures in Serous Ovarian Cancer
Authors: Schwede Matthew , Waldron Levi , Mok Samuel C. , Wei Wei , Basunia Azfar , Merritt Melissa A. , Mitsiades Constantine S. , Parmigiani Giovanni , Harrington David P. , Quackenbush John , Birrer Michael J. , Culhane Aedín C.
Published: December 2019

Background:

Recent efforts to improve outcomes for high-grade serous ovarian cancer, a leading cause of cancer death in women, have focused on identifying molecular subtypes and prognostic gene signatures, but existing subtypes have poor cross-study robustness. We tested the contribution of cell admixture in published ovarian cancer molecular subtypes and prognostic gene signatures.

Methods:

Gene signatures of tumor and stroma were developed using paired microdissected tissue from two independent studies. Stromal genes were investigated in two molecular subtype classifications and 61 published gene signatures. Prognostic performance of gene signatures of stromal admixture was evaluated in 2,527 ovarian tumors (16 studies). Computational simulations of increasing stromal cell proportion were performed by mixing gene-expression profiles of paired microdissected ovarian tumor and stroma.

Results:

Recently described ovarian cancer molecular subtypes are strongly associated with the cell admixture. Tumors were classified as different molecular subtypes in simulations where the percentage of stromal cells increased. Stromal gene expression in bulk tumors was associated with overall survival (hazard ratio, 1.17; 95% confidence interval, 1.11–1.23), and in one data set, increased stroma was associated with anatomic sampling location. Five published prognostic gene signatures were no longer prognostic in a multivariate model that adjusted for stromal content.

Conclusions:

Cell admixture affects the interpretation and reproduction of ovarian cancer molecular subtypes and gene signatures derived from bulk tissue. Elucidating the role of stroma in the tumor microenvironment and in prognosis is important.

Impact:

Single-cell analyses may be required to refine the molecular subtypes of high-grade serous ovarian cancer.
FOXA1 Protein Expression in ER+ and ER− Breast Cancer in Relation to Parity and Breastfeeding in Black and White Women
Authors: Cheng Ting-Yuan David , Yao Song , Omilian Angela R. , Khoury Thaer , Buas Matthew F. , Payne-Ondracek Rochelle , Sribenja Sirinapa , Bshara Wiam , Hong Chi-Chen , Bandera Elisa V. , Davis Warren , Higgins Michael J. , Ambrosone Christine B.
Published: December 2019

Background:

Forkhead box protein A1 (FOXA1) promotes luminal differentiation, and hypermethylation of the gene can be a mechanism of developing estrogen receptor–negative (ER−) breast cancer. We examined FOXA1 in breast tumor and adjacent normal tissue in relation to reproductive factors, particularly higher parity and no breastfeeding, that are associated with ER− tumors.

Methods:

We performed IHC for FOXA1 in breast tumors (n = 1,329) and adjacent normal tissues (n = 298) in the Women's Circle of Health Study (949 Blacks and 380 Whites). Protein expression levels were summarized by histology (H) scores. Generalized linear models were used to assess FOXA1 protein expression in relation to reproductive factors by ER status.

Results:

ER-positive (ER+) versus ER− tumors had higher FOXA1 protein expression (P < 0.001). FOXA1 expression was higher in tumor versus paired adjacent normal tissue in women with ER+ or non-triple–negative cancer (both P < 0.001), but not in those with ER− or triple-negative cancer. Higher number of births (1, 2, and 3+) was associated with lower FOXA1 protein expression in ER+ tumors [differences in H score, or β = −8.5; 95% confidence interval (CI), −15.1 to −2.0], particularly among parous women who never breastfed (β = −10.4; 95% CI, −19.7 to −1.0), but not among those who breastfed (β = −7.5; 95% CI, −16.9 to 1.8). The associations for ER− tumors were similar, although they were not statistically significant.

Conclusions:

In this tumor-based study, higher parity was associated with lower FOXA1 expression in ER+ tumors, and breastfeeding may ameliorate the influence.

Impact:

These findings contribute to our understanding of FOXA1 methylation and breast cancer etiology.
Adherence to Dietary Recommendations among Long-Term Breast Cancer Survivors and Cancer Outcome Associations
Authors: Wang Fei , Cai Hui , Gu Kai , Shi Liang , Yu Danxia , Zhang Minlu , Zheng Wei , Zheng Ying , Bao Pingping , Shu Xiao-Ou
Published: December 2019

Background:

Adherence to dietary recommendations has been shown to be associated with reduced mortality in healthy populations. Little is known about the possible benefits of adherence to dietary recommendations among breast cancer survivors.

Methods:

Dietary information was collected using food frequency questionnaires at the 5-year postdiagnosis survey in 3,450 5-year breast cancer survivors from the Shanghai Breast Cancer Survival Study. Adherence scores to Chinese Food Pagoda (CHFP)-2007, CHFP-2016, modified Dietary Approaches to Stop Hypertension (DASH), and Healthy Eating Index 2015 (HEI-2015) were created. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for total mortality and breast cancer–specific events according to adherence scores.

Results:

Participants in the highest quartiles of CHFP-2007, CHFP-2016, and DASH had 25% to 34% lower risk of total mortality (HR, 0.66; 95% CI, 0.48–0.89 for CHFP-2007; HR, 0.75; 95% CI, 0.55–1.01 for CHFP-2016; HR, 0.66; 95% CI, 0.49–0.91 for DASH), and 36% to 40% lower risk of breast cancer–specific events (HR, 0.64; 95% CI, 0.44–0.93 for CHFP-2007; HR, 0.67; 95% CI, 0.45–0.99 for CHFP-2016; HR, 0.60; 95% CI, 0.40–0.90 for DASH) comparing with the lowest quartiles. Associations did not vary by known prognostic factors. HEI-2015 scores were not significantly associated with breast cancer outcomes.

Conclusions:

Higher adherence to CHFP and DASH dietary guidelines post-cancer diagnosis was associated with reduced risk of both overall death and breast cancer–specific recurrence or death among long-term breast cancer survivors.

Impact:

Our study highlights the importance of overall dietary quality among long-term breast cancer survivors.
Effect of Vitamin D on Relapse-Free Survival in a Subgroup of Patients with p53 Protein–Positive Digestive Tract Cancer: A Post Hoc Analysis of the AMATERASU Trial
Authors: Akutsu Taisuke , Okada Shinya , Hirooka Shinichi , Ikegami Masahiro , Ohdaira Hironori , Suzuki Yutaka , Urashima Mitsuyoshi
Published: December 2019

Background:

The AMATERASU randomized trial of vitamin D3 supplementation (2,000 IU/day; UMIN000001977) showed the potential benefit of vitamin D in a subgroup of patients with digestive tract cancer. By conducting post hoc analyses of this trial, we further explored whether subgroups stratified by expression levels of p53, vitamin D receptor (VDR), and Ki-67 modify the effect of vitamin D supplementation.

Methods:

The primary outcome was relapse-free survival (RFS). On IHC using pathologic specimens, the degree of p53 protein expression parallel with TP53 missense mutations was classified as p53 positive (>10%) and p53 negative (≤10%). In addition, VDR and Ki-67 expression levels were divided into quartiles.

Results:

The p53 status of 372 patients' pathologic specimens was evaluated. In a subgroup of patients with p53-positive cancer (n = 226), 5-year RFS was 79% in the vitamin D group, which was significantly higher than the 57% in the placebo group (HR, 0.52; 95% confidence interval, 0.31–0.88; P = 0.02). In the subgroup of patients with p53-negative cancer, 5-year RFS in the vitamin D group versus placebo group was 72% versus 84% (not significantly different), respectively. Effect modification by p53 positivity was significant (Pinteraction = 0.02). However, no significant effect modification by either VDR or Ki-67 was observed.

Conclusions:

These results generate a hypothesis that vitamin D supplementation may improve RFS in patients with p53-positive digestive tract cancer.

Impact:

The results are still preliminary, but potentially important, because TP53 is the most frequently mutated gene across cancers at all sites.
Germline DNA Sequencing Reveals Novel Mutations Predictive of Overall Survival in a Cohort of Patients with Pancreatic Cancer
Authors: Goldstein Jennifer B. , Zhao Li , Wang Xuemei , Ghelman Yael , Overman Michael J. , Javle Milind M. , Shroff Rachna T. , Varadhachary Gauri R. , Wolff Robert A. , McAllister Florencia , Futreal Andrew , Fogelman David R.
Published: December 2019

Purpose:

Family history of BRCA-related tumors may correlate with response to chemotherapy and overall survival (OS) in pancreatic cancer. The frequency of germline mutations has been reported in patients predominantly under the age of 60 or with strong family history. We examine the incidence of deleterious germline mutations and compare the chemotherapy responses and OS in an unselected group of patients with metastatic pancreatic cancer.

Experimental Design:

Patients with metastatic pancreatic cancer, who were seen at a single cancer center between 2010 and 2016, were included. Germline DNA was sequenced using a 263-gene panel to identify novel mutations (N = 133 MD Anderson cohort, N = 127 TCGA cohort). Chemotherapy response and OS were determined by review of medical records.

Results:

Deleterious germline mutations were identified in 26 of 133 patients (19.5%). Patients with DNA damage repair (DDR) gene mutations (ATM, BRCA1/2, CDKN2A, CHEK2, ERCC4, PALB2, n = 15) had an improved OS as compared with patients without (16.8 vs. 9.1 months, P = 0.03). Conversely, patients with other deleterious mutations had a trend toward worse OS. However, survival in the latter group was longer (P = NS) in those mutants initially treated with gemcitabine/nab-paclitaxel. A family history of multiple breast, ovarian, and pancreatic cancers was associated with DDR gene mutations and better survival.

Conclusions:

We have identified novel germline mutations that are prognostic for survival in patients with pancreatic cancer. We observe improved survival in patients with DDR gene mutations and worsened survival in patients with deleterious mutations in non-DDR genes.
4-1BB Agonism Averts TIL Exhaustion and Licenses PD-1 Blockade in Glioblastoma and Other Intracranial Cancers
Authors: Woroniecka Karolina I. , Rhodin Kristen E. , Dechant Cosette , Cui Xiuyu , Chongsathidkiet Pakawat , Wilkinson Daniel , Waibl-Polania Jessica , Sanchez-Perez Luis , Fecci Peter E.
Published: December 2019

Purpose:

The success of checkpoint blockade against glioblastoma (GBM) has been disappointing. Anti–PD-1 strategies may be hampered by severe T-cell exhaustion. We sought to develop a strategy that might license new efficacy for checkpoint blockade in GBM.

Experimental Design:

We characterized 4-1BB expression in tumor-infiltrating lymphocytes (TIL) from human GBM. We implanted murine tumor models including glioma (CT2A), melanoma (B16), breast (E0771), and lung carcinomas intracranially and subcutaneously, characterized 4-1BB expression, and tested checkpoint blockade strategies in vivo.

Results:

Our data reveal that 4-1BB is frequently present on nonexhausted CD8+ TILs in human and murine GBM. In murine gliomas, 4-1BB agonism and PD-1 blockade demonstrate a synergistic survival benefit in a CD8+ T-cell–dependent manner. The combination decreases TIL exhaustion and improves TIL functionality. This strategy proves most successful against intracranial CT2A gliomas. Efficacy in all instances correlates with the levels of 4-1BB expression on CD8+ TILs, rather than with histology or with intracranial versus subcutaneous tumor location. Proffering 4-1BB expression to T cells licenses combination 4-1BB agonism and PD-1 blockade in models where TIL 4-1BB levels had previously been low and the treatment ineffective.

Conclusions:

Although poor T-cell activation and severe T-cell exhaustion appear to be limiting factors for checkpoint blockade in GBM, 4-1BB agonism obviates these limitations and produces long-term survival when combined with anti–PD-1 therapy. Furthermore, this combination therapy is limited by TIL 4-1BB expression, but not by the intracranial compartment, and therefore may be particularly well-suited to GBM.
Monoclonal Antibody Targeting Sialyl-di-Lewisa–Containing Internalizing and Noninternalizing Glycoproteins with Cancer Immunotherapy Development Potential
Authors: Tivadar Silvana T. , McIntosh Richard S. , Chua Jia Xin , Moss Robert , Parsons Tina , Zaitoun Abed M. , Madhusudan Srinivasan , Durrant Lindy G. , Vankemmelbeke Mireille
Published: December 2019

Tumor glycans constitute attractive targets for therapeutic antibodies. The sialylated glycocalyx plays a prominent role in cancer progression and immune evasion. Here, we describe the characterization of the mAb, FG129, which targets tumor-associated sialylated glycan, and demonstrate its potential for multimodal cancer therapy. FG129, obtained through BALB/c mouse immunizations with liposomes containing membrane glycan extracts from the colorectal cancer cell line LS180, is an mIgG1κ that targets sialyl-di-Lewisa–containing glycoproteins. FG129, as well as its chimeric human IgG1 variant, CH129, binds with nanomolar functional affinity to a range of colorectal, pancreatic, and gastric cancer cell lines. FG129 targets 74% (135/182) of pancreatic, 50% (46/92) of gastric, 36% (100/281) of colorectal, 27% (89/327) of ovarian, and 21% (42/201) of non–small cell lung cancers, by IHC. In our pancreatic cancer cohort, high FG129 glyco-epitope expression was significantly associated with poor prognosis (P = 0.004). Crucially, the glyco-epitope displays limited normal tissue distribution, with FG129 binding weakly to a small percentage of cells within gallbladder, ileum, liver, esophagus, pancreas, and thyroid tissues. Owing to glyco-epitope internalization, we validated payload delivery by CH129 through monomethyl auristatin E (MMAE) or maytansinoid (DM1 and DM4) conjugation. All three CH129 drug conjugates killed high-binding colorectal and pancreatic cancer cell lines with (sub)nanomolar potency, coinciding with significant in vivo xenograft tumor control by CH129-vcMMAE. CH129, with its restricted normal tissue distribution, avid tumor binding, and efficient payload delivery, is a promising candidate for the treatment of sialyl-di-Lewisa–expressing solid tumors, as an antibody–drug conjugate or as an alternative cancer immunotherapy modality.
Targeting AXL and the DNA Damage Response Pathway as a Novel Therapeutic Strategy in Melanoma
Authors: Flem-Karlsen Karine , McFadden Erin , Omar Nasrin , Haugen Mads H. , Øy Geir Frode , Ryder Truls , Gullestad Hans Petter , Hermann Robert , Mælandsmo Gunhild Mari , Flørenes Vivi Ann
Published: December 2019

Receptor tyrosine kinase AXL is found upregulated in various types of cancer, including melanoma, and correlates with an aggressive cancer phenotype, inducing cell proliferation and epithelial-to-mesenchymal transition. In addition, AXL has recently been linked to chemotherapy resistance, and inhibition of AXL is found to increase DNA damage and reduce expression of DNA repair proteins. In light of this, we aimed to investigate whether targeting AXL together with DNA damage response proteins would be therapeutically beneficial. Using melanoma cell lines, we observed that combined reduction of AXL and CHK1/CHK2 signaling decreased proliferation, deregulated cell-cycle progression, increased apoptosis, and reduced expression of DNA damage response proteins. Enhanced therapeutic effect of combined treatment, as compared with mono-treatment, was further observed in a patient-derived xenograft model and, of particular interest, when applying a three-dimensional ex vivo spheroid drug sensitivity assay on tumor cells harvested directly from 27 patients with melanoma lymph node metastases. Together, these results indicate that targeting AXL together with the DNA damage response pathway could be a promising treatment strategy in melanoma, and that further investigations in patient groups lacking treatment alternatives should be pursued.
Evaluating Lung Cancer Screening Across Diverse Healthcare Systems: A Process Model from the Lung PROSPR Consortium
Authors: Rendle Katharine A. , Burnett-Hartman Andrea N. , Neslund-Dudas Christine , Greenlee Robert T. , Honda Stacey , Elston Lafata Jennifer , Marcus Pamela M. , Cooley Mary E. , Vachani Anil , Meza Rafael , Oshiro Caryn , Simoff Michael J. , Schnall Mitchell D. , Beaber Elisabeth F. , Doria-Rose V. Paul , Doubeni Chyke A. , Ritzwoller Debra P.
Published: December 2019

Numerous organizations, including the United States Preventive Services Task Force, recommend annual lung cancer screening (LCS) with low-dose CT for high risk adults who meet specific criteria. Despite recommendations and national coverage for screening eligible adults through the Centers for Medicare and Medicaid Services, LCS uptake in the United States remains low (<4%). In recognition of the need to improve and understand LCS across the population, as part of the larger Population-based Research to Optimize the Screening PRocess (PROSPR) consortium, the NCI (Bethesda, MD) funded the Lung PROSPR Research Consortium consisting of five diverse healthcare systems in Colorado, Hawaii, Michigan, Pennsylvania, and Wisconsin. Using various methods and data sources, the center aims to examine utilization and outcomes of LCS across diverse populations, and assess how variations in the implementation of LCS programs shape outcomes across the screening process. This commentary presents the PROSPR LCS process model, which outlines the interrelated steps needed to complete the screening process from risk assessment to treatment. In addition to guiding planned projects within the Lung PROSPR Research Consortium, this model provides insights on the complex steps needed to implement, evaluate, and improve LCS outcomes in community practice.
Association Between Central Blood Pressure and Subclinical Cerebrovascular Disease in Older Adults
Authors: Matsumoto Kenji , Jin Zhezhen , Homma Shunichi , Elkind Mitchell S.V. , Rundek Tatjana , Mannina Carlo , Lee Tetz C. , Yoshita Mitsuhiro , DeCarli Charles , Wright Clinton B. , Sacco Ralph L. , Di Tullio Marco R.
Published: December 2019

Elevated blood pressure (BP) level is one of the most consistently identified risk factors for silent brain disease. BP values obtained at the proximal segment of the aorta (central BP) are more directly involved than brachial BP in the pathogenesis of cardiovascular disease. However, the association between central BP and silent cerebrovascular disease has not been clearly established. Participants in the CABL (Cardiovascular Abnormalities and Brain Lesions) study (n=993; mean age, 71.7±9.3 years; 37.9% men) underwent 2-dimensional echocardiography, arterial wave reflection analysis for determination of central BPs, and brain magnetic resonance imaging. Central BPs were calculated from the radial pulse waveform. Subclinical silent cerebrovascular disease was defined as silent brain infarction and white matter hyperintensity volume. Both brachial (
P
=0.014) and central pulse pressure (
P
=0.026) were independently associated with silent brain infarctions after adjustment for clinical variables, but not adjusting for each other. None of the brachial BP values was associated with upper quartile of white matter hyperintensity volume in multivariable analysis. Both central systolic BP (
P
<0.001) and central pulse pressure (
P
<0.001) were significantly associated with upper quartile of white matter hyperintensity volume in multivariable analysis, even after adjustment for brachial BP. In a predominantly older population-based cohort, both brachial and central pulse pressure were independently associated with silent brain infarction. However, higher central systolic BP and central pulse pressure, but not brachial BP, were significantly associated with white matter hyperintensity volume.
Disruption of Pressure-Induced Ca
2+
Spark Vasoregulation of Resistance Arteries, Rather Than Endothelial Dysfunction, Underlies Obesity-Related Hypertension
Authors: Greenstein Adam S. , Kadir Sharifah Zamiah Abdul Syed , Csato Viktoria , Sugden Sarah A. , Baylie Rachael A. , Eisner David A. , Nelson Mark T.
Published: December 2019

Obesity-related hypertension is one of the world’s leading causes of death and yet little is understood as to how it develops. As a result, effective targeted therapies are lacking and pharmacological treatment is unfocused. To investigate underlying microvascular mechanisms, we studied small artery dysfunction in a high fat–fed mouse model of obesity. Pressure-induced constriction and responses to endothelial and vascular smooth muscle agonists were studied using myography; the corresponding intracellular Ca
2+
signaling pathways were examined using confocal microscopy. Principally, we observed that the enhanced basal tone of mesenteric resistance arteries was due to failure of intraluminal pressure-induced Ca
2+
spark activation of the large conductance Ca
2+
activated K
+
potassium channel (BK) within vascular smooth muscle cells. Specifically, the uncoupling site of this mechanotransduction pathway was at the sarcoplasmic reticulum, distal to intraluminal pressure-induced oxidation of Protein Kinase G. In contrast, the vasodilatory function of the endothelium and the underlying endothelial IP-3 and TRPV4 (vanilloid 4 transient receptor potential ion channel) Ca
2+
signaling pathways were not affected by the high-fat diet or the elevated blood pressure. There were no structural alterations of the arterial wall. Our work emphasizes the importance of the intricate cellular pathway by which intraluminal pressure maintains Ca
2+
spark vasoregulation in the origin of obesity-related hypertension and suggests previously unsuspected avenues for pharmacological intervention.
L-(+)-Ergothioneine Significantly Improves the Clinical Characteristics of Preeclampsia in the Reduced Uterine Perfusion Pressure Rat Model
Authors: Williamson Rachel D. , McCarthy Fergus P. , Manna Samprikta , Groarke Emer , Kell Douglas B. , Kenny Louise C. , McCarthy Cathal M.
Published: December 2019

Preeclampsia is a multifactorial hypertensive disorder of pregnancy founded on abnormal placentation, and the resultant placental ischemic microenvironment is thought to play a crucial role in its pathophysiology. Placental ischemia because of fluctuations in the delivery of oxygen results in oxidative stress, and recent evidence suggests that mitochondrial dysfunction may be a prime mediator. However, large clinical trials of therapeutic antioxidants such as vitamins C and E for the treatment of preeclampsia have been disappointing. L-(+)-ergothioneine (ERG)—an unusual amino acid betaine derived from histidine—has important cytoprotective and antioxidant properties under conditions of high oxidative stress. In this study, we investigated the potential therapeutic effects of administration of ERG in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. ERG (25 mg/kg per day) was administered to rats on gestational day 11. On gestational day 14, RUPP surgery was performed, and on gestational day 19, blood pressure (mean arterial pressure) and fetal growth were measured. Production of mitochondria-specific H
2
O
2
was analyzed in vivo in kidney samples. ERG ameliorated the hypertension (129±3 versus 115±4 mm Hg;
P
=0.01; n=8) and significantly increased pup weight in RUPP rats. ERG also significantly decreased circulating levels of antiangiogenic sFlt-1 (soluble fms-like tyrosine kinase-1) in RUPP rats (1367±245 pg/mL;
P
=0.04). Mitochondria-specific H
2
O
2
(0.022±0.003 versus 0.029±0.001; MitoP/B ratio, n=3;
P
=0.05) was also significantly decreased in kidney tissue in RUPP rats treated with ERG. These data support the potential use of ERG for the treatment of preeclampsia.
Endoplasmic Reticulum Chaperone Calmegin Is Upregulated in Aldosterone-Producing Adenoma and Associates With Aldosterone Production
Authors: Itcho Kiyotaka , Oki Kenji , Gomez-Sanchez Celso E. , Gomez-Sanchez Elise P. , Ohno Haruya , Kobuke Kazuhiro , Nagano Gaku , Yoshii Yoko , Baba Ryuta , Hattori Noboru , Yoneda Masayasu
Published: December 2019

The endoplasmic reticulum (ER) plays a pivotal role in syntheses of proteins and steroid hormones and regulation of intracellular Ca
2+
level. We aimed to investigate ER-associated genes in aldosterone-producing adenomas (APAs) and clarify their effect on aldosterone production. Microarray analysis targeting 288 ER-associated genes was conducted using nonfunctioning adrenocortical adenomas (n=5) and APAs (n=19). Immunohistochemistry and quantitative polymerase chain reaction analyses were performed with 13 nonfunctioning adrenocortical adenoma and 48 APA samples. Functional studies were performed with human adrenocortical carcinoma (HAC15) cells, some of which were genetically modified using lentiviruses. The ER chaperone calmegin (
CLGN
) was the most highly expressed ER-associated gene in APAs relative to nonfunctioning adrenocortical adenomas. Analysis with quantitative polymerase chain reaction revealed
CLGN
to be 9.5-fold upregulated in APAs relative to nonfunctioning adrenocortical adenomas. There were no differences among different APA genotypes affecting aldosterone production. Immunohistochemistry analysis revealed that CLGN was strongly expressed in APAs and aldosterone-producing cell clusters. Angiotensin II stimulation or KCNJ5 T158A overexpression in HAC15 cells did not affect
CLGN
mRNA levels.
CLGN
overexpression in HAC15 cells increased aldosterone levels but did not stimulate
CYP11B2
mRNA levels. Pathway and gene ontology analyses using RNA sequencing results showed that tRNA aminoacyl metabolism was the most enriched pathway in
CLGN
-overexpressing cells. CYP11B2 (aldosterone synthase) and HSD3B2 (3 beta-hydroxysteroid dehydrogenase/delta 5->4-isomerase type 2) protein expression were more abundant in
CLGN
-overexpressing cells.
CLGN
knockdown using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9) method in HAC15 cells that carry the
KCNJ5
mutation did not affect aldosterone production. To summarize,
CLGN
was upregulated and associated with aldosterone production via translational regulation of CYP11B2 in APAs.
Association of Extreme Nocturnal Dipping With Cardiovascular Events Strongly Depends on Age
Authors: Palatini Paolo , Verdecchia Paolo , Beilin Lawrence J. , Eguchi Kazuo , Imai Yutaka , Kario Kazuomi , Ohkubo Takayoshi , Pierdomenico Sante D. , Saladini Francesca , Schwartz Joseph E. , Wing Lindon , Signorotti Sara , Reboldi Gianpaolo
Published: December 2019

Whether extreme dipping is associated with cardiovascular events (CVE) is unclear. The present study was conducted to test the hypothesis that the prognostic role of extreme dipping varies as a function of age. The analysis was performed in 10 868 participants (53% men) aged 53±15 (mean±SD) years enrolled in 8 prospective studies. Using the ambulatory systolic blood pressure nocturnal decline, we identified 4 groups: dippers (>10%–20%), nondippers (>0%–10%), reverse dippers (≤0%), and extreme dippers (>20%). The association between dipping category and CVE was estimated as a function of age using Cox models adjusted for sex, average 24-hour systolic blood pressure, and traditional risk factors. During a median follow-up of 5.7 years, there were a total of 829 CVE (168 fatal). For extreme dippers, no increase in risk of CVE was observed among the participants <70 years (hazard ratio, 0.99 [95% CI, 0.73–1.34];
P
=0.93) compared with dippers. In contrast, among the participants ≥70 years, there was a significant increase in risk (hazard ratio, 1.88 [95% CI, 1.14–3.11];
P
=0.013). Among the octogenarians, the hazard ratio (95% CI) for CVE were 2.34 (1.12–4.93) for nondippers (
P
=0.024), 3.91 (1.75–8.73) for reverse dippers (
P
=0.001), and 4.12 (1.64–10.37) for extreme dippers (
P
=0.003) compared with dippers. These data show that extreme dipping is not associated with poorer outcome in people younger than 70 years. A U-shaped relationship between nocturnal blood pressure dipping and adverse outcome is present in subjects older than 70 years. In the octogenarian extreme dippers, the risk of CVEs was 4× higher than in the dippers and similar to that in the reverse dippers.
Estimated Stroke-Free Survival of Folic Acid Therapy for Hypertensive Adults
Authors: Zhang Tiantian , Lin Tengfei , Wang Yang , Wang Binyan , Qin Xianhui , Xie Feng , Cui Yimin , Huo Yong , Wang Xiaobin , Zhang Zugui , Jiang Jie
Published: December 2019

The CSPPT (China Stroke Primary Prevention Trial) demonstrated a significant risk reduction of first stroke in hypertensive patients treated with enalapril plus folic acid compared with those with enalapril alone, but the lifetime stroke-free survival associated with the treatment is unknown. By establishing adjusted models for competing risks and an age-based time scale using data from 19 053 participants of the CSPPT, we estimated lifetime incremental stroke-free survival for enalapril-folic acid versus enalapril alone. Compared with enalapril alone, the enalapril plus folic acid treatment projected a mean lifetime stroke-free survival gain of 1.75 months, with an interquartile range from 0.73 to 2.39 months and the maximum gain up to 12.95 months. Subgroup analyses showed greater gain in stroke-free survival in younger, male patients, those with lower baseline folate levels, higher baseline systolic blood pressure, higher baseline total cholesterol and blood glucose, and with MTHFR (methylenetetrahydrofolate reductase) C677T CT or TT genotype. Overall, besides significant benefit in certain subgroups, enalapril plus folic acid treatment for hypertensive patients is associated with a modest gain in lifetime stroke-free survival, compared with enalapril alone.
A preliminary checklist of the Coccinellidae of Bhutan (Insecta: Coleoptera)
Authors: DORJI CHETEN , LODAY PHUNTSHO , VORST OSCAR
Published: December 2019

An annotated distributional checklist of the Coccinellidae of Bhutan is presented, enumerating 91 species, 17 of which are here recorded for the first time: Shirozuella tibetina Wang, Ge & Ren, 2012, Jauravia limbata (Motschulsky, 1858), Scymnus bourdilloni (Kapur, 1958), Illeis confusa Timberlake, 1943, Calvia albida Bielawski, 1972, Harmonia expalliata Sicard, 1913, H. octomaculata (Fabricius, 1781), H. sedecimnotata (Fabricius, 1801), Micraspis allardi (Mulsant, 1866), M. discolor (Fabricius, 1798), M. univittata (Hope, 1831), Oenopia adelgivora Poorani, 2002, O. billieti (Mulsant, 1853), O. smetanai Canepari, 1997, Afissula mysticoides (Sicard, 1913), Henosepilachna processa Li & Cook, 1961 and H. septima (Dieke, 1947). One species, Propylea japonica (Thunberg, 1781), has to be removed from the list.                Nine species and two subspecies are hitherto only reported from the territory of Bhutan. The Bhutanese coccinellid fauna is still insufficiently known.
Facebook posts as performatives in Bulgarian political life: A sociolinguistic investigation
Authors: Tincheva Nelly
Published: December 2019

Facebook posts as performatives in Bulgarian political life: A sociolinguistic investigationThe paper provides a snapshot of how the Bulgarian political public interprets the notion of ‘political action’. The paper argues there are two basic notions (‘performing’ and ‘performativity’) which are fundamental to present-day interpretations of ‘political action’, and that these two notions need to be approached through quantitative analysis of actual respondents’ interpretations. The paper addresses this analytical niche and in doing so draws on a previous sociolinguistic study which strongly suggests that the modern genre of the Facebook post has special social and political significance in pro-active Bulgarian political life. The paper systematizes and discusses the results from a questionnaire-based study on Bulgarian recipients’ expectations about the communicative and political effect of the Facebook post. The results of the study reveal that Bulgarian political audiences perceive the Facebook post not simply as a genre in Bulgarian political discourse but, crucially, as a vehicle for actual political performance in present-day Bulgarian political life. Posty na Facebooku jako performatywy w bułgarskim życiu politycznym. Ujęcie socjolingwistyczneArtykuł dotyczy tego, jak bułgarska społeczność pojmuje ideę „aktu politycznego”. Autorka broni tezy, że istnieją dwie kluczowe idee – „publiczne przedstawienie” i „performatywność” (tj. wypowiedzi performatywne) – które determinują współczesne bułgarskie interpretacje „aktu politycznego” oraz że obie te idee należy badać jakościowo, poprzez analizę danych wziętych od realnych respondentów, będących zarówno nosicielami języka, jak i aktywnymi politycznie obywatelami. Podejmując próbę zapełnienia analitycznej niszy, autorka wskazuje, że współczesny gatunek, jakim jest post na Facebooku, ma szczególne znaczenie w życiu codziennym aktywnych politycznie i społecznie Bułgarów. W artykule zostały usystematyzowane i omówione rezultaty badania, które dotyczyło nastawienia i oczekiwań bułgarskich recypientów w odniesieniu do efektu komunikacyjnego i politycznego postów na Facebooku. Okazuje się, że bułgarska społeczność polityczna pojmuje ten nowy gatunek nie tylko jako narzędzie do uczestnictwa w dyskursie politycznym, ale także jako sposób na realne działanie polityczne.
Was the United Kingdom's policy of pushing for the return of Rohingya refugees to Myanmar following ethnic cleansing in 2017 realistic?
Authors: Holmes Arthur Joseph
Published: December 2019

Was the United Kingdom's policy of pushing for the return of Rohingya refugees to Myanmar following ethnic cleansing in 2017 realistic?This article explores the United Kingdom’s response to the Rohingya Crisis which began in August 2017, resulting in the ethnic cleansing of 600,000 Rohingya Muslims in the first nine weeks of violence, with a minimum of 6,700 people being killed in the process. The United Kingdom reacted with condemnation, and began immediately calling for the safe return of refugees who had fled the violence, to their homes in Rakhine state, Myanmar. Using the testimony from Mark Field MP, Minister for Asia, in a Foreign Affairs Committee meeting, this essay assesses this policy of pushing for the return of the Rohingya to their homes. Using primary sources available to Britain at the time its policy was formed, this essay argues that Britain’s approach was not only unrealistic with regards to providing an environment in which Rohingya refugees would be provided safety, but also in relation to Burmese authorities’ desires to take back Rohingya refugees. Myanmar’s campaign of ethnic cleansing intentionally created the environment in which either the Rohingya would never return, or they would return to state-controlled concentration camps. Secondary material expires the history of violent state policies against the Rohingya in Myanmar, and Britain’s policy is shown to not only be unworkable due to such policies, but would actively endanger those refugees who chose to return. Czy polityka Wielkiej Brytanii w kwestii powrotu uchodźców Rohyngia do Birmy po czystkach etnicznych w 2007 roku była realistyczna?Artykuł omawia kryzys, który rozpoczął się w sierpniu 2017 roku i spowodował czystki etniczne obejmujące około 600 000 muzułmanów z ludu Rohyngya, przy czym w pierwszych 9 tygodniach gwałtownych zamieszek śmierć poniosło co najmniej 6700 osób. Zjednoczone Królestwo potępiło czystki i natychmiast wezwało do umożliwienia uchodźcom bezpiecznego powrotu do ich domów w Birmie. Na podstawie wyjaśnień ministra ds. Azji Marka Fielda, członka parlamentu, Komitet ds. Spraw Zagranicznych na swym posiedzeniu dokonał oceny tej polityki, polegającej na nakłanianiu ich do powrotu do Birmy. Opierając się na źródłach dostępnych w Wielkiej Brytanii w chwili, gdy tworzyły się zręby tej polityki, autor eseju dowodzi, że ten kierunek polityczny był nie tylko nierealistyczny w odniesieniu do możliwości zapewnienia uchodźcom bezpieczeństwa, ale także sprzeczny z zamiarami władz Birmy w kwestii przyjęcia uchodźców. Birmańska kampania czystek etnicznych świadomie stworzyła sytuację, w której Rohingya nigdy nie powrócą bądź wracaliby do kontrolowanych przez państwo obozów koncentracyjnych. Dostępne opracowania analizują historię przemocy wobec ludności Rohyngya w Birmie i ukazują politykę Wielkiej Brytanii nie tylko jako nieskuteczną z powodu takich posunięć politycznych, ale także wskazują, że zagrażałaby ona życiu decydujących się na powrót uchodźców.