bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolution Laws for Frozen Wall Formation under Conditions of Sudden Seepage
Authors: Zhang Song , Yue Zurun , Sun Tiecheng , Han Yufu , Gao Wei , Hu Tianfei , Han Yunxi
Published: December 2020

Sudden seepage is a special working condition affecting artificial ground freezing (AGF) in many projects which results in significant differences within the temperature field. In order to study the characteristics of frozen walls influenced by water flow, a series of model tests were carried out at different seepage velocities. The model test results show that a frozen wall will change from symmetrical to eccentric as the cooling energy absorption of the soil and the brine return temperature increase. In model tests, when the seepage velocity was 0∼30 m/d, the frozen wall was partially destroyed. When the seepage velocity exceeded 30 m/d, the frozen wall was completely destroyed. This study examines the expansion rate of the upstream and downstream freezing fronts, and the distribution law of the freezing temperature field, the average temperature change under different seepage speeds, and the bearing capacity of the freezing wall are analyzed. Research on these factors suggests that a frozen wall has a certain level of resistance to sudden seepage. When the flow velocity is small, the freezing effect will be strengthened. With an increase in the flow velocity, the freezing effect will gradually weaken. Based on these conclusions, the current study points out targeted solutions that should be adopted in cases of sudden seepage in a project.
Research on 3D International River Visualization Simulation Based on Human-Computer Interaction
Authors: Li Shuanhu , Yang Jun , Zhang Ziwen
Published: December 2020

With the development of digitalization in various fields, the water conservancy field is gradually developing digital three-dimensional visualization research to promote the development of digital watershed construction. This paper deeply analyzes and discusses the theory and application of three-dimensional visualization of river water scenes and realizes an interactive visual simulation system based on virtual reality technology, which simulates simulation and operation management, which can greatly accelerate the data. The processing speed makes the huge data be effectively utilized to provide visual interaction means for numerical simulation and data analysis, improve the efficiency of numerical calculation, and realize human-computer interaction communication, so that people can observe the phenomena and laws that are difficult to observe by traditional methods. The rationality of the mathematical model is analyzed for effectiveness.
Dynamic Origin-Destination Matrix Estimation Based on Urban Rail Transit AFC Data: Deep Optimization Framework with Forward Passing and Backpropagation Techniques
Authors: Yang Yuedi , Liu Jun , Shang Pan , Xu Xinyue , Chen Xuchao
Published: December 2020

At present, the existing dynamic OD estimation methods in an urban rail transit network still need to be improved in the factors of the time-dependent characteristics of the system and the estimation accuracy of the results. This study focuses on predicting the dynamic OD demand for a time of period in the future for an urban rail transit system. We propose a nonlinear programming model to predict the dynamic OD matrix based on historic automatic fare collection (AFC) data. This model assigns the passenger flow to the hierarchical flow network, which can be calibrated by backpropagation of the first-order gradients and reassignment of the passenger flow with the updated weights between different layers. The proposed model can predict the time-varying OD matrix, the number of passengers departing at each time, and the travel time spent by passengers, of which the results are shown in the case study. Finally, the results indicate that the proposed model can effectively obtain a relatively accurate estimation result. The proposed model can integrate more traffic characteristics than traditional methods and provides an effective and hierarchical passenger flow estimation framework. This study can provide a rich set of passenger demand for advanced transit planning and management applications, for instance, passenger flow control, adaptive travel demand management, and real-time train scheduling.
Gastroenterologists Reveal More Digestive Symptoms in COVID-19 Patients than Nongastroenterologists in Fever Clinic
Authors: Jiang Yudong , Han Chaoqun , Bai Tao , Zhang Shengyan , Song Jun , Hou Xiaohua
Published: December 2020

The incidence of digestive symptoms may vary depending on doctors’ professional backgrounds when they inquired suspected COVID-19 patients in a fever clinic. We sought to understand the characteristics of inquiries about digestive symptoms by doctors in different specialties; therefore, inquiry records of 2 gastroenterologists and 6 nongastroenterologists were reviewed. We compared the difference in inquiry of digestive symptoms (diarrhea, vomit, distension, anorexia, and abdominal pain) between these two groups among identified COVID-19 patients. And we further compared the difference of digestive symptoms between confirmed patients and suspected cases who excluded from COVID-19. Among 495 confirmed COVID-19 cases (254 cases by gastroenterologists and 241 cases by nongastroenterologists), 22.83% patients experienced various digestive symptoms in the gastroenterologists’ group, while only 4.47% reported digestive symptoms by nongastroenterologists (

p
<
0.0001

). Additionally, among initially suspected 611 patients who presented with similar respiratory symptoms inquired by gastroenterologists, confirmed cases presented far more frequency of digestive symptoms than excluded cases (22.8% vs. 3.64%,

p
<
0.0001

). Furthermore, confirmed patients reported more percentage of watery diarrhea (56% vs. 36%,

p
<
0.0001

) and higher frequent vomit (

2.77
±
0.97

vs.

1.80
±
0.45

per day,

p
=
0.041

) than excluded cases. We concluded that gastroenterologists could detect a greater proportion of gastrointestinal symptoms in COVID-19 patients during fever clinic inquiries. Moreover, confirmed COVID-19 patients are more likely to have higher severity in digestive symptoms than excluded cases. Therefore, physicians in fever clinic should pay more attention to the triage of gastrointestinal symptoms.
Review on Epidemiology and Public Health Significance of Hydatidosis
Authors: Gessese Abebe Tesfaye
Published: December 2020

Hydatidosis is a zoonotic parasitic disease caused by larval stages (hydatid cysts) of cestodes belonging to the genus Echinococcus and the family Taeniidae. Hydatid cyst, which is the larval stage of Echinococcus, is a bladder-like cyst formed in various organs and tissues following the growth of the oncospheres of an Echninoccus tape worm in that specific organ or tissue. The epidemiology and control of hydatidosis is often considered to be a veterinary matter since the disease can be regulated by controlling parasites in animals. However, collaboration between veterinarians and public health workers is essential for the successful control of hydotidosis. Therefore, the objective of this paper was to review The epidemiology, economic and public health importance of hydatidosis. The developmental stage of Echinococcus is that eggs develop to oncospheres, this oncospheres develop to hydatid cyst in the intermediate host and the hydatid cyst if consumed by final host develops to the adult Echinococcus. Human echinococcosis is a zoonotic infection caused by the tape worm of the genus Echinococcus. Echinococcus granucosus granulosis cause cystic echinococcosis (CE), Echinococcus multilocularis cause alveolar echinoloccosis (AE), and Echinococcus vogeli and Echinococcus oligarthus cause polycystic echinococcosis (PE). From these Echinococcus mulitilocularis is rare but is the most virulent, Echinococcus vegeli and Echinococcus oligarthus are the rarest. Hydatidosis is a zoonotic cosmopolitan parasitic disease found in almost all countries of the world. This disease causes a significant economic loss directly by causing organ or carcass condemnation and indirectly by affecting human and animal health which increase the cost for diagnosis, treatment and control of the disease. Public awareness creation about the transmission and control of the disease and its public health significance and collaboration between veterinarians and public health workers in the prevention and control of the disease is mandatory.
Redox Imbalance in CD4+ T Cells of Relapsing-Remitting Multiple Sclerosis Patients
Authors: Tavassolifar Mohammad Javad , Moghadasi Abdorreza Naser , Esmaeili Behnaz , Sadatpour Omid , Vodjgani Mohammad , Izad Maryam
Published: December 2020

As a prevalent autoimmune disease of the central nervous system in young adults, multiple sclerosis (MS) is mediated by T cells, particularly CD4+ subsets. Given the evidence that the perturbation in reactive oxygen species (ROS) production has a pivotal role in the onset and progression of MS, its regulation through the antioxidant molecules is too important. Here, we investigated the level of the redox system components in lymphocytes and CD4+ T cells of MS patients. The study was performed on relapsing-remitting MS (RRMS) patients (

n
=
29

) and age- and sex-matched healthy controls (

n
=
15

). Peripheral blood mononuclear cells (PBMCs) were cultured and stimulated by anti-CD3/CD28. The level of ROS, anion superoxide (O2-), and L-𝛾-glutamyl-Lcysteinylglycine (GSH) was measured by flow cytometry in lymphocytes/CD4+ T cells. The gene expression level of gp91phox, catalase, superoxide dismutase 1/2 (SOD), and nuclear factor-E2-related factor (Nrf2) was also measured by real-time PCR. We found that lymphocytes/CD4+ T cells of RRMS patients at the relapse phase significantly produced higher levels of ROS and O2- compared to patients at the remission phase (

P

value < 0.001) and healthy controls (

P

value < 0.001 and

P

value < 0.05, respectively). Interestingly, the gene expression level of gp91phox, known as the catalytic subunit of the NADPH oxidase, significantly increased in MS patients at the relapse phase (

P

value < 0.05). Furthermore, the catalase expression augmented in patients at the acute phase (

P

value < 0.05), while an increased expression of SOD1 and Nrf2 was found in RRMS patients at relapse and remission phases (

P

value < 0.05). The increased production of ROS in CD4+ T cells of RRMS patients highlights the importance of amplifying antioxidant components as an efficient approach to ameliorate disease activity in MS patients.
The Breakthrough Time Analyses of Lead Ions in CCL considering Different Adsorption Isotherms
Authors: Zeng Xing , Liu Xi , Li Yu-heng
Published: December 2020

As the 2 m thick compacted clay liner with permeability coefficient of 1 × 10−7 cm/s is required in the Chinese technical specifications about landfill, the performance of this compacted clay liner was analyzed considering three different adsorption isotherms (convex, straight, and concave). The effects of source concentration, adsorption mode, and waterhead on the breakthrough curve and breakthrough time of Pb2+ were discussed. The results indicate that reducing the concentration of pollution sources is beneficial to prolonging the breakthrough time. With the waterhead of 10 m, the absolute breakthrough time, respectively, increased from 2.77 to 3.7 years (concave type isotherm), from 17.63 to 26.58 years (straight type isotherm), and from 35.43 to 59.6 years (convex type isotherm), as the source concentration decreased from 1000 mg/L to 10 mg/L. The effect of adsorption isotherm type on the performance of the barrier is very obvious: with the waterhead of 10 m, the absolute breakthrough time corresponding to the convex isotherm is more than twice that of the straight adsorption isotherm, and more than 12.8 times that of the concave isotherm. The absolute breakthrough time corresponding to 0.3 m waterhead is more than 4 times that of 10 m, and reducing the waterhead can effectively increase the breakthrough time.
Preparation of Transparent Film of Layered Double Hydroxide with Anionic Pyrene Derivatives and Its Luminous Toluene Detection Ability
Authors: Fujimura Takuya , Akagashi Yoshiya , Aoyama Yu-hei , Sasai Ryo
Published: December 2020

To prepare the transparent solid film of layered double hydroxide, the filtration-film transfer (FFT) method using LDH nanosheet colloidal suspension was investigated. It was found that the homogeneous LDH solid film with enough transparency in the visible light range could be prepared by the FFT method. Moreover, anionic pyrene (Pyr−) molecules could be incorporated into the transparent LDH solid film by immersing in anionic pyrene solution. From both absorption and emission spectra of the transparent Pyr−/LDH solid film, Pyr− incorporated in the LDH solid film formed aggregates and mainly showed the strong excimer emission. Additionally, the luminous response of the transparent Pyr−/LDH solid film was investigated in ethanol-toluene mixed solution with various toluene contents. As results, the ratio of luminescence intensities from static excimer and monomer of incorporated Pyr− molecules depended on the toluene content, and excimer emission decreased with an increase in the toluene content. This luminous response can be caused by an increase of the monomeric Pyr− species, because Pyr− aggregates are broken by adsorption of toluene molecules into the LDH interlayer space. The obtained transparent hybrid film may be useful as a detectable material of toluene in solvent by luminous change.
Physical, Textural, Rheological, and Sensory Characteristics of Amaranth-Based Wheat Flour Bread
Authors: Nasir Sahreen , Allai Farhana Mehraj , Gani Murtaza , Ganaie Shaiq , Gul Khalid , Jabeen Aabida , Majeed Darakshan
Published: December 2020

In this study, the chemical composition, colour analysis, and antioxidant properties of flour and bread were analysed. We also examined the rheological properties of dough and proximate, colour, textural, and organoleptic properties of amaranth wheat bread. Wheat flour was replaced by amaranth flour (AF) at 0-15% levels (100 : 0, 95 : 5, 90 : 10, and 85 : 15, respectively). AF supplementation increased the moisture (31.06 to 33.24%), ash (0.92 to 1.51%), protein (12.17 to 13.11%), fat (2.16 to 2.77%), and crude fibre content (1.11 to 1.72%) of the bread while the nitrogen-free extract and alkali water retention capacity decreased from 52.58 to 47.65% and 136.00 to 112.02%, respectively. The antioxidant activity evaluated by DPPH, FRAP, and total phenolic content was reduced with increased levels of AF. A significant impact on the physical properties like the weight of bread (increased from 474.00 to 489.30 g), height (went down from 80.00 to 74.33 cm), loaf volume (decreased from 1580.00 to 1518.30 cm3), and specific volume (reduced from 3.32 to 3.10 cm3 g-1) was observed with the replacement of wheat flour. Textural measurement depicted that hardness, chewiness, gumminess, springiness, and cohesiveness increased with the substitution of amaranth flour. Rheological parameters like complex viscosity, loss modulus, and storage modulus were also observed in all dough samples. Bread samples with 5%, 10%, and 15% of AF showed lower yellowness (b∗) and higher lightness (L∗) and redness (a∗) values for crust colour while lowerL∗and highera∗andb∗values for crumb colour. The bread prepared by replacing 5% and 10% of AF is nutritionally as well as sensorially acceptable.
A Systematic Review of the Anti‐Inflammatory and Immunomodulatory Properties of 16 Essential Oils of Herbs
Authors: Zuo Xu , Gu Yinuo , Wang Chao , Zhang Jinrong , Zhang Jing , Wang Guoqiang , Wang Fang
Published: December 2020

Background. Inflammation is a host defense mechanism in the body after it is infected and damaged. If inflammation is not treated in time, then it may cause a variety of diseases, such as cancer and autoimmune diseases. Herbal essential oils are natural extracts that can suppress inflammation effectively and are expected to be used in therapeutic drugs for anti‐inflammatory diseases in the future. Aim of the review. We review the anti‐inflammatory and immunomodulatory effects of essential oils derived from 16 herbs. Materials and methods. We searched the literature of the fields of anti‐inflammatory and immunomodulatory herbal essential oil activity published in English within the past five years via databases (PubMed, EMBASE, Scopus, and The Web of Science). Results. A total of 1932 papers were found by searching, and 132 papers were screened after removing duplicates and reading article titles. Fifteen articles met the requirements to be included in this review. Among those selected, 11 articles reported in vivo research results, and 10 articles showed research results. Conclusion. Essential oils extracted from herbs can reduce inflammation by regulating the release of inflammatory cytokines involved in multiple signalling pathways. Herbal essential oils are expected to be developed as anti‐inflammatory drugs.
An Early Warning Method of Distribution System Fault Risk Based on Data Mining
Authors: Mao Yeying , Huang Zhengyu , Feng Changsen , Chen Hui , Yang Qiming , Ma Junchang
Published: December 2020

Accurate warning information of potential fault risk in the distribution network is essential to the economic operation as well as the rational allocation of maintenance resources. In this paper, we propose a fault risk warning method for a distribution system based on an improved RelieF-Softmax algorithm. Firstly, four categories including 24 fault features of the distribution system are determined through data investigation and preprocessing. Considering the frequency of distribution system faults, and then their consequences, the risk classification method of the distribution system is presented. Secondly, the K-maxmin clustering algorithm is introduced to improve the random sampling process, and then an improved RelieF feature extraction method is proposed to determine the optimal feature subset with the strongest correlation and minimum redundancy. Finally, the loss function of Softmax is improved to cope with the influence of sample imbalance on the prediction accuracy. The optimal feature subset and Softmax classifier are applied to forewarn the fault risk in the distribution system. The 191-feeder power distribution system in south China is employed to demonstrate the effectiveness of the proposed method.
Study of Heat Transfer under the Impact of Thermal Radiation, Ramped Velocity, and Ramped Temperature on the MHD Oldroyd-B Fluid Subject to Noninteger Differentiable Operators
Authors: Saeed Syed Tauseef , Khan Ilyas , Riaz Muhammad Bilal , Husnine Syed Muhammad
Published: December 2020

This theoretical study explores the impact of heat generation/absorption with ramp wall velocity and ramp wall temperature on the magnetohydrodynamic (MHD) time-dependent Oldroyd-B fluid over an unbounded plate embedded in a porous surface. The mathematical analysis of fractional governing partial differential equations has been established using systematic and powerful techniques of Laplace transform with its numerical inversion algorithms. The fractionalized solutions have been traced out separately through all fractional differential operators. Nondimensional parameters along with Laplace transformation are used to find the solution of temperature and velocity profiles. Fractional time derivatives are used to analyze the impact of fractional parameters (memory effect) on the dynamics of the fluid. While making a comparison, it is observed that the fractional-order model is the best to explain the memory effect as compared to classical models. The obtained solutions are plotted graphically for different values of physical parameters. Our results suggest that the velocity profile decreases by increasing the effective Prandtl number. Furthermore, the existence of an effective Prandtl number may reflect the control of the thickness of momentum and enlargement of thermal conductivity.
A Cloud Model‐Based Risk Assessment Methodology for Tunneling‐Induced Damage to Existing Tunnel
Authors: Xu Tian , Song Zhanping , Guo Desai , Song Yuncai
Published: December 2020

This study presents a cloud model‐based approach for risk assessment of existing tunnels in tunneling construction environments where the cloud model provides a basis for uncertainty transformation between its qualitative concepts and quantitative expressions. An evaluation index system is established for risk assessment of existing tunnels based on the tunnel‐induced failure mechanism analysis. The assessment result is obtained through the correlation with the cloud model of each risk level. Risk assessment for existing Guangzhou‐Shenzhen‐Hong Kong Railway Tunnel in the tunneling environment of Shenzhen Metro Line 6 is shown in a case study. Comparisons between Fuzzy Analytic Hierarchy Process (FAHP) methods are further discussed according to results. The proposed evaluation method is verified to be more competitive as the fuzziness and randomness of uncertainties in the risk assessment system can be considered comprehensively. This method can serve as a decision‐making tool for other similar project risk assessment methods to increase the likelihood of a successful project in an uncertain environment.
DMDRMR-Mediated Regulation of m6A-Modified CDK4 by m6A Reader IGF2BP3 Drives ccRCC Progression
Authors: Gu Yinmin , Niu Shaoxi , Wang Yang , Duan Liqiang , Pan Yongbo , Tong Zhou , Zhang Xu , Yang Zhenyu , Peng Bo , Wang Xiaodong , Han Xiaoqi , Li Yuxin , Cheng Tianyou , Liu Yajuan , Shang Lina , Liu Tongfeng , Yang Xiwang , Sun Minxuan , Jiang Siyuan , Zhang Chang , Zhang Ning , Ye Qinong , Gao Shan
Published: December 2020

Aberrant N6-methyladenosine (m6A) modification has emerged as a driver of tumor initiation and progression, yet how long noncoding RNAs (lncRNA) are involved in the regulation of m6A remains unknown. Here we utilize data from 12 cancer types from The Cancer Genome Atlas to comprehensively map lncRNAs that are potentially deregulated by DNA methylation. A novel DNA methylation–deregulated and RNA m6A reader–cooperating lncRNA (DMDRMR) facilitated tumor growth and metastasis in clear cell renal cell carcinoma (ccRCC). Mechanistically, DMDRMR bound insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) to stabilize target genes, including the cell-cycle kinase CDK4 and three extracellular matrix components (COL6A1, LAMA5, and FN1), by specifically enhancing IGF2BP3 activity on them in an m6A-dependent manner. Consequently, DMDRMR and IGF2BP3 enhanced the G1–S transition, thus promoting cell proliferation in ccRCC. In patients with ccRCC, high coexpression of DMDRMR and IGF2BP3 was associated with poor outcomes. Our findings reveal that DMDRMR cooperates with IGF2BP3 to regulate target genes in an m6A-dependent manner and may represent a potential diagnostic, prognostic, and therapeutic target in ccRCC.

Significance:

This study demonstrates that the lncRNA DMDRMR acts as a cofactor for IGF2BP3 to stabilize target genes in an m6A-dependent manner, thus exerting essential oncogenic roles in ccRCC.
Targeting MARCO and IL37R on Immunosuppressive Macrophages in Lung Cancer Blocks Regulatory T Cells and Supports Cytotoxic Lymphocyte Function
Authors: La Fleur Linnéa , Botling Johan , He Fei , Pelicano Catarina , Zhou Chikai , He Chenfei , Palano Giorgia , Mezheyeuski Artur , Micke Patrick , Ravetch Jeffrey V. , Karlsson Mikael C. I. , Sarhan Dhifaf
Published: December 2020

The progression and metastatic capacity of solid tumors are strongly influenced by immune cells in the tumor microenvironment. In non–small cell lung cancer (NSCLC), accumulation of anti-inflammatory tumor-associated macrophages (TAM) is associated with worse clinical outcome and resistance to therapy. Here we investigated the immune landscape of NSCLC in the presence of protumoral TAMs expressing the macrophage receptor with collagenous structure (MARCO). MARCO-expressing TAM numbers correlated with increased occurrence of regulatory T cells and effector T cells and decreased natural killer (NK) cells in these tumors. Furthermore, transcriptomic data from the tumors uncovered a correlation between MARCO expression and the anti-inflammatory cytokine IL37. In vitro studies subsequently showed that lung cancer cells polarized macrophages to express MARCO and gain an immune-suppressive phenotype through the release of IL37. MARCO-expressing TAMs blocked cytotoxic T-cell and NK-cell activation, inhibiting their proliferation, cytokine production, and tumor killing capacity. Mechanistically, MARCO+ macrophages enhanced regulatory T (Treg) cell proliferation and IL10 production and diminished CD8 T-cell activities. Targeting MARCO or IL37 receptor (IL37R) by antibody or CRISPR knockout of IL37 in lung cancer cell lines repolarized TAMs, resulting in recovered cytolytic activity and antitumoral capacity of NK cells and T cells and downmodulated Treg cell activities. In summary, our data demonstrate a novel immune therapeutic approach targeting human TAMs immune suppression of NK- and T-cell antitumor activities.

Significance:

This study defines tumor-derived IL37 and the macrophage scavenger receptor MARCO as potential therapeutic targets to remodel the immune-suppressive microenvironment in patients with lung cancer.
A Large-Scale Association Study Detects Novel Rare Variants, Risk Genes, Functional Elements, and Polygenic Architecture of Prostate Cancer Susceptibility
Authors: Emami Nima C. , Cavazos Taylor B. , Rashkin Sara R. , Cario Clinton L. , Graff Rebecca E. , Tai Caroline G. , Mefford Joel A. , Kachuri Linda , Wan Eunice , Wong Simon , Aaronson David , Presti Joseph , Habel Laurel A. , Shan Jun , Ranatunga Dilrini K. , Chao Chun R. , Ghai Nirupa R. , Jorgenson Eric , Sakoda Lori C. , Kvale Mark N. , Kwok Pui-Yan , Schaefer Catherine , Risch Neil , Hoffmann Thomas J. , Van Den Eeden Stephen K. , Witte John S.
Published: December 2020

To identify rare variants associated with prostate cancer susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an integrated study of prostate cancer genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 prostate cancer cases and 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 prostate cancer cases and 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency < 0.01, at 3p21.31 and 8p12), were significant genome wide in a meta-analysis. Gene-based rare variant tests implicated a known prostate cancer gene (HOXB13), as well as a novel candidate gene (ILDR1), which encodes a receptor highly expressed in prostate tissue and is related to the B7/CD28 family of T-cell immune checkpoint markers. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants at HOXB13 and other loci, reflecting their evolutionary history. In addition, a polygenic risk score (PRS) of 188 prostate cancer variants was strongly associated with risk (90th vs. 40th–60th percentile OR = 2.62, P = 2.55 × 10−191). Many of the 188 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a 6-fold difference in log-probability of androgen receptor binding at the variant rs2680708 (17q22). Rare variant and PRS associations, with concomitant functional interpretation of risk mechanisms, can help clarify the full genetic architecture of prostate cancer and other complex traits.

Significance:

This study maps the biological relationships between diverse risk factors for prostate cancer, integrating different functional datasets to interpret and model genome-wide data from over 200,000 men with and without prostate cancer.

See related commentary by Lachance, p. 1637
Association Between Serum Iron Biomarkers and Breast Cancer
Authors: Von Holle Ann , O'Brien Katie M. , Sandler Dale P. , Janicek Robert , Weinberg Clarice R.
Published: December 2020

Background:

Iron is both essential to life and potentially toxic at higher levels. Epidemiologic studies of iron and breast cancer are sparse, with substantial heterogeneity found in a recent meta-analysis. Evidence based on a comprehensive set of iron biomarkers and a large sample size could help clarify relationships between iron body stores and breast cancer risk.

Methods:

A case–cohort sample of 6,008 women, including 3,011 incident cases, has been followed for a median of 7.9 years. We estimated breast cancer HRs with Cox models, including age as the primary time scale and including in turn iron, ferritin, percent transferrin saturation, and their first principal component (PC) both as categorical (quartiles) and continuous measures.

Results:

Adjusted HRs for the highest versus lowest quartiles of iron, ferritin, and transferrin saturation (95% confidence interval) were 1.06 (0.90–1.25), 1.03 (0.87–1.23), and 0.94 (0.80–1.12), respectively, and 1.06 (0.90–1.25) for the first principal component (PC). Associations were similar when follow-up time was restricted to ≤4 or >2 years. Post hoc analyses suggested low iron stores were associated with reduced breast cancer risk, in both pre- and postmenopause and the obese.

Conclusions:

A study with one of the largest sample sizes to date and with all three measures of circulating iron, ferritin, and transferrin saturation does not support a strong association between elevated iron stores and breast cancer risk. Further investigation of low iron may be warranted.

Impact:

These results do not support a strong association between iron overload and breast cancer incidence.
Molecular Imaging of Prostate Cancer Targeting CD46 Using ImmunoPET
Authors: Wang Sinan , Li Jun , Hua Jun , Su Yang , Beckford-Vera Denis R. , Zhao Walter , Jayaraman Mayuri , Huynh Tony L. , Zhao Ning , Wang Yung-hua , Huang Yangjie , Qin Fujun , Shen Sui , Gioeli Daniel , Dreicer Robert , Sriram Renuka , Egusa Emily A. , Chou Jonathan , Feng Felix Y. , Aggarwal Rahul , Evans Michael J. , Seo Youngho , Liu Bin , Flavell Robert R. , He Jiang
Published: December 2020

Purpose:

We recently identified CD46 as a novel therapeutic target in prostate cancer. In this study, we developed a CD46-targeted PET radiopharmaceutical, [89Zr]DFO-YS5, and evaluated its performance for immunoPET imaging in murine prostate cancer models.

Experimental Design:

[89Zr]DFO-YS5 was prepared and its in vitro binding affinity for CD46 was measured. ImmunoPET imaging was conducted in male athymic nu/nu mice bearing DU145 [AR−, CD46+, prostate-specific membrane antigen–negative (PSMA−)] or 22Rv1 (AR+, CD46+, PSMA+) tumors, and in NOD/SCID gamma mice bearing patient-derived adenocarcinoma xenograft, LTL-331, and neuroendocrine prostate cancers, LTL-331R and LTL-545.

Results:

[89Zr]DFO-YS5 binds specifically to the CD46-positive human prostate cancer DU145 and 22Rv1 xenografts. In biodistribution studies, the tumor uptake of [89Zr]DFO-YS5 was 13.3 ± 3.9 and 11.2 ± 2.5 %ID/g, respectively, in DU145 and 22Rv1 xenografts, 4 days postinjection. Notably, [89Zr]DFO-YS5 demonstrated specific uptake in the PSMA- and AR-negative DU145 model. [89Zr]DFO-YS5 also showed uptake in the patient-derived LTL-331 and -331R models, with particularly high uptake in the LTL-545 neuroendocrine prostate cancer tumors (18.8 ± 5.3, 12.5 ± 1.8, and 32 ± 5.3 %ID/g in LTL-331, LTL-331R, and LTL-545, respectively, at 4 days postinjection).

Conclusions:

[89Zr]DFO-YS5 is an excellent PET imaging agent across a panel of prostate cancer models, including in both adenocarcinoma and neuroendocrine prostate cancer, both cell line- and patient-derived xenografts, and both PSMA-positive and -negative tumors. It demonstrates potential for clinical translation as an imaging agent, theranostic platform, and companion biomarker in prostate cancer.
Tissue Hypoxia and Alterations in Microvascular Architecture Predict Glioblastoma Recurrence in Humans
Authors: Stadlbauer Andreas , Kinfe Thomas M. , Eyüpoglu Ilker , Zimmermann Max , Kitzwögerer Melitta , Podar Klaus , Buchfelder Michael , Heinz Gertraud , Oberndorfer Stefan , Marhold Franz
Published: December 2020

Purpose:

Insufficient control of infiltrative glioblastoma (GBM) cells is a major cause of treatment failure and tumor recurrence. Hence, detailed insights into pathophysiologic changes that precede GBM recurrence are needed to develop more precise neuroimaging modalities for tailored diagnostic monitoring and therapeutic approaches.

Experimental Design:

Overall, 168 physiologic MRI follow-up examinations of 56 patients with GBM who developed recurrence after standard therapy were retrospectively evaluated, that is, two post–standard-therapeutic follow-ups before and one at radiological recurrence. MRI biomarkers for microvascular architecture and perfusion, neovascularization activity, oxygen metabolism, and hypoxia were determined for brain areas that developed in the further course into recurrence and for the recurrent GBM itself. The temporal pattern of biomarker changes was fitted with locally estimated scatterplot smoothing functions and analyzed for pathophysiologic changes preceding radiological GBM recurrence.

Results:

Our MRI approach demonstrated early pathophysiologic changes prior to radiological GBM recurrence in all patients. Analysis of the time courses revealed a model for the pathophysiology of GBM recurrence: 190 days prior to radiological recurrence, vascular cooption by GBM cells induced vessel regression, detected as decreasing vessel density/perfusion and increasing hypoxia. Seventy days later, neovascularization activity was upregulated, which reincreased vessel density and perfusion. Hypoxia, however, continued to intensify for 30 days and peaked 90 days before radiological recurrence.

Conclusions:

Hypoxia may represent an early sign for GBM recurrence. This might become useful in the development of new combined diagnostic–therapeutic approaches for tailored clinical management of recurrent GBM. Further preclinical and in-human studies are required for validation and evaluation.
Single-Dose Anti–PD-L1/IL-15 Fusion Protein KD033 Generates Synergistic Antitumor Immunity with Robust Tumor-Immune Gene Signatures and Memory Responses
Authors: Martomo Stella A. , Lu Dan , Polonskaya Zhanna , Luna Xenia , Zhang Zhikai , Feldstein Sam , Lumban-Tobing Radovan , Almstead Danielle K. , Miyara Faical , Patel Jeegar
Published: December 2020

Immunocytokines hold great potential as anticancer agents, as they use a specific antitumor antibody to deliver an immune-activating cytokine directly to the immunosuppressive tumor microenvironment (TME). We have developed a novel immunocytokine (KD033) composed of a fully human, high-affinity antiprogrammed death-ligand 1 (PD-L1) linked to the sushi-domain of the human IL-15/IL-15 receptor alpha (IL-15/IL-15Rα) complex. A murine PD-L1 cross-reactive KD033 surrogate (srKD033) and a nontargeting antibody (ntKD033) were also developed to investigate mechanism of action in murine tumor models. Efficacy analyses showed a robust antitumor effect of single-dose srKD033 in several diverse syngeneic murine tumor models. In a CT26 murine colon tumor model, single-dose srKD033 produced durable antitumor immunity as evidenced by resistance to subsequent tumor rechallenges. Mice responding to srKD033 treatment showed increased retention of PD-L1/IL-15 in the TME which likely facilitated prolonged IL-15–induced expansion of cytotoxic cells. Importantly, target-based PD-L1/IL-15 delivery via srKD033 was well-tolerated and induced significant antitumor activity in murine carcinoma models that are non- or minimally responsive to IL-15 or anti–PD-L1/PD-1 monotherapy.
Leflunomide Suppresses the Growth of LKB1-Inactivated Tumors in the Immune-Competent Host and Attenuates Distant Cancer Metastasis
Authors: Jin Rui , Liu Boxuan , Liu Xiuju , Fan Yijian , Peng Wei , Huang Chunzi , Marcus Adam , Sica Gabriel , Gilbert-Ross Melissa , Liu Yuan , Zhou Wei
Published: December 2020

Liver kinase B1 (LKB1)–inactivated tumors are vulnerable to the disruption of pyrimidine metabolism, and leflunomide emerges as a therapeutic candidate because its active metabolite, A77–1726, inhibits dihydroorotate dehydrogenase, which is essential for de novo pyrimidine biosynthesis. However, it is unclear whether leflunomide inhibits LKB1-inactivated tumors in vivo, and whether its inhibitory effect on the immune system will promote tumor growth. Here, we carried out a comprehensive analysis of leflunomide treatment in various LKB1-inactivated murine xenografts, patient-derived xenografts, and genetically engineered mouse models. We also generated a mouse tumor–derived cancer cell line, WRJ388, that could metastasize to the lung within a month after subcutaneous implantation in all animals. This model was used to assess the ability of leflunomide to control distant metastasis. Leflunomide treatment shrank a HeLa xenograft and attenuated the growth of an H460 xenograft, a patient-derived xenograft, and lung adenocarcinoma in the immune-competent genetically engineered mouse models. Interestingly, leflunomide suppressed tumor growth through at least three different mechanisms. It caused apoptosis in HeLa cells, induced G1 cell-cycle arrest in H460 cells, and promoted S-phase cell-cycle arrest in WRJ388 cells. Finally, leflunomide treatment prevented lung metastasis in 78% of the animals in our novel lung cancer metastasis model. In combination, these results demonstrated that leflunomide utilizes different pathways to suppress the growth of LKB1-inactivated tumors, and it also prevents cancer metastasis at distant sites. Therefore, leflunomide should be evaluated as a therapeutic agent for tumors with LKB1 inactivation.
Asthma with Irreversible Airway Obstruction in Smokers and Nonsmokers: Links between Airway Inflammation and Structural Changes
Authors: Boulet Louis-Philippe , Boulay Marie-Eve , Coxson Harvey O. , Hague Cameron J. , Milot Joanne , Lepage Johane , Maltais François
Published: December 2020

Background: The development of irreversible airway obstruction (IRAO) in asthma is related to lung/airway inflammatory and structural changes whose characteristics are likely influenced by exposure to tobacco smoke. Objective: To investigate the interplay between airway and lung structural changes, airway inflammation, and smoking exposure in asthmatics with IRAO. Methods: We studied asthmatics with IRAO who were further classified according to their smoking history, those with ≥20 pack-years of tobacco exposure (asthmatics with smoking-related IRAO [AwS-IRAO]) and those with <5 pack-years of tobacco exposure (asthmatics with nonsmoking-related IRAO [AwNS-IRAO]). In addition to recording baseline clinical and lung function features, all patients had a chest computed tomography (CT) from which airway wall thickness was measured and quantitative and qualitative assessment of emphysema was performed. The airway inflammatory profile was documented from differential inflammatory cell counts on induced sputum. Results: Ninety patients were recruited (57 AwS-IRAO and 33 AwNS-IRAO). There were no statistically significant differences in the extent of emphysema and gas trapping between groups on quantitative chest CT analysis, although Pi10, a marker of airway wall thickness, was significantly higher in AwS-IRAO (p = 0.0242). Visual analysis showed a higher prevalence of emphysema (p = 0.0001) and higher emphysema score (p < 0.0001) in AwS-IRAO compared to AwNS-IRAO and distribution of emphysema was different between groups. Correlations between radiological features and lung function were stronger in AwS-IRAO. In a subgroup analysis, we found a correlation between airway neutrophilia and emphysematous features in AwS-IRAO and between eosinophilia and both airway wall thickness and emphysematous changes in AwNS-IRAO. Conclusions: Although bronchial structural changes were relatively similar in smoking and nonsmoking patients with asthma and IRAO, emphysematous changes were more predominant in smokers. However, neutrophils in AwS-IRAO and eosinophils in AwNS-IRAO were associated with lung and airway structural changes.
How to Intervene in the Caries Process in Older Adults: A Joint ORCA and EFCD Expert Delphi Consensus Statement
Authors: Paris Sebastian , Banerjee Avijit , Bottenberg Peter , Breschi Lorenzo , Campus Guglielmo , Doméjean Sophie , Ekstrand Kim , Giacaman Rodrigo A. , Haak Rainer , Hannig Matthias , Hickel Reinhard , Juric Hrvoje , Lussi Adrian , Machiulskiene Vita , Manton David , Jablonski-Momeni Anahita , Santamaria Ruth , Schwendicke Falk , Splieth Christian H. , Tassery Hervé , Zandona Andrea , Zero Domenick , Zimmer Stefan , Opdam Niek
Published: December 2020

Aim: To provide recommendations for dental clinicians for the management of dental caries in older adults with special emphasis on root caries lesions. Methods: A consensus workshop followed by a Delphi consensus process were conducted with an expert panel nominated by ORCA, EFCD, and DGZ boards. Based on a systematic review of the literature, as well as non-systematic literature search, recommendations for clinicians were developed and consented in a two-stage Delphi process. Results: Demographic and epidemiologic changes will significantly increase the need of management of older adults and root caries in the future. Ageing is associated with a decline of intrinsic capacities and an increased risk of general diseases. As oral and systemic health are linked, bidirectional consequences of diseases and interventions need to be considered. Caries prevention and treatment in older adults must respond to the patient’s individual abilities for self-care and cooperation and often involves the support of caregivers. Systemic interventions may involve dietary counselling, oral hygiene instruction, the use of fluoridated toothpastes, and the stimulation of salivary flow. Local interventions to manage root lesions may comprise local biofilm control, application of highly fluoridated toothpastes or varnishes as well as antimicrobial agents. Restorative treatment is often compromised by the accessibility of such root caries lesions as well as the ability of the senior patient to cooperate. If optimum restorative treatment is impossible or inappropriate, long-term stabilization, e.g., by using glass-ionomer cements, and palliative treatments that aim to maintain oral function as long and as well as possible may be the treatment of choice for the individual.
Endoscopic Treatment of Post-Cholecystectomy Biliary Leaks
Authors: Rio-Tinto Ricardo , Canena Jorge
Published: December 2020

Postcholecystectomy leaks may occur in 0.3–2.7% of patients. Bile leaks associated with laparoscopy are often more complex and difficult to treat than those occurring after open cholecystectomy. Furthermore, their incidence has remained unchanged despite improvements in laparoscopic training and technological developments. The management of biliary leaks has evolved from surgery into a minimally invasive endoscopic procedural approach, namely, endoscopic retrograde cholangiopancreatography (ERCP), which decreases or eliminates the pressure gradient between the bile duct and the duodenum, thus creating a preferential transpapillary bile flow and allowing the leak to seal. For simple leaks, the success rate of endotherapy is remarkably high. However, there are more severe and complex leaks that require multiple endoscopic interventions, and clear strategies for endoscopic treatment have not emerged. Therefore, there is still some debate regarding the optimal time point at which to intervene, which technique to use (sphincterotomy alone or in association with the placement of stents, whether metallic or plastic stents should be used, and, if plastic stents are used, whether they should be single or multiple), how long the stents should remain in place, and when to consider treatment failure. Here, we review the types and classification of postoperative biliary injuries, particularly leaks, as well as the evidence for endoscopic treatment of the latter.
Distance Assessment for Detecting Cognitive Impairment in Older Adults: A Systematic Review of Psychometric Evidence
Authors: Binng Davina , Splonskowski Moriah , Jacova Claudia
Published: December 2020

Introduction: Distance or remote cognitive assessments, administered via phone or computer platforms, have emerged as possible alternatives to traditional assessments performed during office visits. Distance refers to any nontraditional assessment feature, not only or necessarily location. We conducted a systematic review to examine the psychometric soundness of these approaches. Method: We searched PubMed, PsycINFO, AgeLine, and Academic Search Premier for articles published between January 2008 and June 2020. Studies were included if participants were over the age of 50, a structured assessment of cognitive function in older adults was evaluated, the assessment method was deemed distant, and validity and/or reliability data were reported. Assessment distance was defined as having any of the following features: use of an electronic test interface, nonroutine test location (e.g., home), test self-administered, and test unsupervised. Distance was categorized as low, intermediate, or high. Results/Discussion: Twenty-six studies met inclusion criteria. Sample sizes ranged from n = 8 to 8,627, and the mean age ranged from 57 to 83. Assessments included screens, brief or full batteries, and were performed via videoconferencing, phone, smartphone, or tablet/computer. Ten studies reported on low distance, 11 on intermediate distance, and 5 studies for high distance assessments. Invalid performance data were observed with older age and cognitive impairment. Convergent validity data were reported consistently and suggested a decline with increasing distance: r = 0.52–0.80 for low, 0.49–0.75 for intermediate, and 0.41–0.53 for high distance. Diagnostic validity estimates presented a similar pattern. Reliability data were reported too inconsistently to allow evaluation. Conclusion: The validity of cognitive assessments with older adults appears supported at lower but not higher distance. Less is known about the reliability of such assessments. Future research should delineate the person and procedure boundaries for valid and reliable test results.