bluuebunny/crossref_metadata_2025 huggingface dataset:
Bus Arrival Time Prediction Using Wavelet Neural Network Trained by Improved Particle Swarm Optimization
Authors: Lai Yuanwen , Easa Said , Sun Dazu , Wei Yian
Published: January 2020

Prediction of bus arrival time is an important part of intelligent transportation systems. Accurate prediction can help passengers make travel plans and improve travel efficiency. Given the nonlinearity, randomness, and complexity of bus arrival time, this paper proposes the use of a wavelet neural network (WNN) model with an improved particle swarm optimization algorithm (IPSO) that replaces the gradient descent method. The proposed IPSO-WNN model overcomes the limitations of the gradient-based WNN which can easily produce local optimum solutions and stop the training process and thus improves prediction accuracy. Application of the model is illustrated using operational data of an actual bus line. The results show that the proposed model is capable of accurately predicting bus arrival time, where the root-mean square error and the maximum relative error were reduced by 42% and 49%, respectively.
The Influence of Three Statistical Variables on Self-Similarity in Complex Networks
Authors: Lei Mingli , Liu Lirong , Wei Daijun
Published: January 2020

The reason for the self-similarity property of complex network is still an open issue. In this paper, we focus on the influence of degree, betweenness, and coreness on self-similarity of complex network. Some nodes are removed from the original network based on the definitions of degree, betweenness, and coreness in the ascending and descending order. And then, some new networks are obtained after removing nodes. The self-similarities of original network and new networks are compared. Moreover, two real networks are used for numerical simulation, including aUSAirnetwork and the yeast protein interaction (YPI) network. The effects of the three statistical variables on the two real networks are considered. The results reveal that the nodes with large degree and betweenness have great effects on self-similarity, and the influence of coreness on self-similarity is small.
New Improvement of Labor Accounting in the Sharing Economy
Authors: Zhou Yuanxiang , Yin Weichuan
Published: January 2020

The investigation of labor is a key aspect of population research, and labor accounting, as its foundation, is an important means to judge the degree of economic development and monitor the changes of the labor market, having always been a focus of scholarly research. At present, the sharing economy is on the rise worldwide and influences labor accounting. In this paper, starting from the context of the sharing economy and the current situation of labor accounting, several important aspects of labor accounting will be discussed. In the context of the sharing economy, household subsistence service production is to be included in the production accounting boundary, which is the root of the changes in labor accounting. On this basis, the following findings are drawn. (1) The scope of accounting for employment should be expanded, which puts higher demands on the labor accounting method. (2) Working time should be remeasured, especially indicators based on pay time. (3) Finally, the design of indicators in labor underutilization also requires the formation of new ideas, especially unemployment should be redefined. Finally, in view of the current status of labor accounting in China, policy suggestions for future improvement under the sharing economy are put forward.
Characterization of the Complete Mitochondrial Genome of Fischoederius elongatus Derived from Cows in Shanghai, China
Authors: Han Zhaoqing , Li Kun , Luo Houqiang , Shahzad Muhammad , Mehmood Khalid
Published: January 2020

A study was conducted to reveal the characterization of the complete mitochondrial genome of Fischoederius elongatus derived from cows in Shanghai, China. Results indicated that the complete mt genome of F. elongatus was 14,288 bp and contained 12 protein‐coding genes (cox1-3, nad1-6, nad4L, atp6, and cytb), 22 transfer RNA genes, and two ribosomal RNA genes (l‐rRNA and s‐rRNA). The overall A + T content of the mt genome was 63.83%, and the nucleotide composition was A (19.83%), C (9.75%), G (26.43%), and T (44.00%). A total of 3284 amino acids were encoded by current F. elongatus isolate mt genome, TTT (Phe) (9.84%) and TTG (Leu) (7.73%) codon were the most frequent amino acids, whereas the ACC (Thr) (0.06%), GCC (Ala) (0.09%), CTC (Leu) (0.09%), and AAC (Asn) (0.09%) codon were the least frequent ones. At the third codon position of F. elongatus mt protein genes, T (50.82%) was observed most frequently and C (5.85%) was the least one. The current results can contribute to epidemiology diagnosis, molecular identification, taxonomy, genetic, and drug development researches about this parasite species in cattle.
Reduction of FDTD Stair-Casing Error regarding to Metamaterials by Using High-Order Polynomial Transformation Functions
Authors: Bae Ki-Woong , Seo Dong-Wook , Myung Noh-Hoon
Published: January 2020

The material parameters of a metamaterial (MTM) are determined by the transformation function used in the optical transformation. Some previously reported MTMs, such as the invisibility cloak, the field rotator, and the field concentrator, were designed by a linear transformation. Their impedance was matched to the background so that no reflection was found; however, the material parameters were mismatched to the background due to the linear transformation function. In the present work, the parameters were matched by using high-order polynomial functions as the transformation function. Since similar materials are filled in boundary cells of the finite-difference time-domain (FDTD) algorithm, the stair-casing error was reduced and the tolerance against boundary abrasion was increased. The frequency response of the proposed method was analyzed. The proposed method is applicable to MTM structures that have complex boundary shapes. In this work, circular and elliptic boundary shapes were considered as examples.
20(S)‐Protopanaxdiol Suppresses the Abnormal Granule‐Monocyte Differentiation of Hematopoietic Stem Cells in 4T1 Breast Cancer‐Bearing Mouse
Authors: Guo Wen-Qin , Chen Ying-Ge , Shi Rong-Zhen , He Kai , Wang Jian-Feng , Shao Jin-Hui , Wan Jian-Bo , Gao Jian-Li
Published: January 2020

Panax notoginseng (PN) has been used as a qi‐ and blood‐activating (Huoxue) drug for thousands of years in China. It has also been widely used as an anticancer drug at present. As a Huoxue drug, the effect of PN on hematopoietic differentiation in tumor‐bearing body has been paid more and more attention. Our research found that panax notoginseng saponins (PNS), especially panaxadiol saponins (PDS) and its aglucon 20(S)-Protopanaxdiol (PPD), could improve the immunosuppressive state by regulating the abnormal hematopoietic differentiation in a tumor‐bearing body by multiple ways. An interesting phenomenon is that PDS reduced the neutrophil‐lymphocyte ratio (NLR) via its inhibition effect on the granule‐monocyte differentiation of spleen cells, which is associated with a decrease in the secretion of tumor MPO, G‐CSF, PU.1, and C/EBPα. Otherwise, PDS increased the proportion of both hematopoietic stem cells and erythroid progenitor cells in the bone marrow, but inhibited spleen erythroid differentiation via inhibiting secretion of tumor EPO, GATA‐1, and GATA‐2. This study suggests that PNS regulated the tumor‐induced abnormal granule‐monocyte differentiation of hematopoietic stem cells, affecting the distribution and function of haemocytes in tumor‐bearing mice.
Damage Detection for Large-Scale Grid Structure Based on Virtual Axial Strain
Authors: Yu Jian-xin , Tan Hui-feng
Published: January 2020

To identify the damaged beams in large-scale spatial structure, a damage indicator based on virtual axial strain calculated from mode shape vectors was proposed. The damage detection process was performed based on the dynamic simulation flowchart. Firstly, random signals were used for excitation and the damage was simulated by decreasing beam elasticity modulus. Then, the NEWMARK-β precision direct integral method was appreciated for calculating time history response. Finally, the frequency-domain decomposition method only using output response signal was selected for modal parameter estimation. A double-layer grid structure was taken as example for verifying the damage detection method. Results indicate that the proposed indicator was insensitive to environmental noise and capable of localizing multiple damaged members in space structure without the baseline data.
Fusobacterium necrophorum subsp. necrophorum Liver Abscess with Pylephlebitis: An Abdominal Variant of Lemierre’s Syndrome
Authors: Radovanovic Natasa , Dumic Igor , Veselinovic Mladjen , Burger Susanne , Milovanovic Tamara , Nordstrom Charles W. , Niendorf Eric , Ramanan Poornima
Published: January 2020

Liver abscess associated with suppurative portal vein thrombosis (pylephlebitis) secondary to Fusobacterium necrophorum has been rarely reported. It is considered to be an abdominal variant of Lemierre’s syndrome associated with significant morbidity and mortality. We report a case of 69-year-old man who developed liver abscess and pylephlebitis due to F. necrophorum with an unclear source of infection. We discuss the pathogenesis, diagnosis, and treatment strategy for this entity, with a review of previously published cases of pyelephlebitis due to F. necrophorum in regard to their clinical presentation and outcome.
Why and How Does a Supplier Choose Factoring Finance?
Authors: Tian Chunying , Chen Dongyan , Chen Zhaobo , Zhang Ding
Published: January 2020

Suppliers offering trade credit to the downstream retailers have to face many problems, such as receivables management, capital occupancy, and buyer’s credit risk. Many of them choose factoring finance to solve those problems simultaneously. This paper develops several supply chain decision models to show the benefits a supplier can obtain from the main functions of factoring and how he should choose between recourse factoring and nonrecourse factoring. In particular, we identify the conditions on which factoring may bring benefits (including financial benefit, guarantee benefit, and receivables management benefit) to the supplier. The supplier’s choice between recourse and nonrecourse factoring relies on his risk attitude. Given that the supplier is risk-neutral and the factoring fees are acceptable, recourse factoring is preferred when the factoring finance ratio is relatively high; otherwise, nonrecourse factoring is preferred. However, if the supplier is risk-averse, his preference for the two factoring schemes under different finance ratios may change when the risk constraints become stricter. If the target profit is lower than a certain level, the supplier’s financial choice will switch from recourse factoring to nonrecourse factoring in the case finance ratio is relatively low; otherwise, his financial choice switches from nonrecourse factoring to recourse factoring in the case finance ratio is relatively high.
Clinicopathological Features, Treatment Strategy, and Prognosis of Primary Non-Hodgkin’s Lymphoma of the Duodenum: A SEER Database Analysis
Authors: Zheng Guoliang , Wang Yue , Zhao Yan , Zheng Zhichao
Published: January 2020

Objective. Primary duodenum lymphoma (PDL) is extremely rare with limited data available in the literature. In this study, we sought to describe clinical features and identify factors affecting survival in patients with PDL using a large population cohort. Methods. The Surveillance, Epidemiology, and End Results (SEER) database was queried from 1998 to 2015. Results. A total of 1060 cases of PDLs were identified. Clinicopathological features as well as survival data of PDLs were analyzed and compared with 10573 primary gastric lymphomas (PGLs) and 3239 primary small intestinal lymphomas (PSILs) from the SEER database. PDL patients were younger in age (60.96 ± 15.205), and the proportion of stage I (53.21%) was higher in Ann Arbor staging. The proportion of PDLs treated by surgery (8.68%) is the lowest among PDLs, PGLs, and PSILs. The DSS of PDLs were significantly better than those of PGLs and PSILs, respectively (10-year survival rate: 21.24% vs. 20.40%, P=0.027; 10-year survival rate: 21.24% vs. 16.79%, P=0.001). Age, gender, Ann Arbor staging, and histological type were regarded as independent prognostic factor for the DSS by multivariate analysis (all P<0.05). Patients with <65 years, female, stage I, and FL were found to be significantly associated with good DSS. The treatment modality (surgery vs. conservative treatment) was not statistically related to DSS. The proportion of PDL patients who received surgical treatment gradually decreased from 15.60% in period 2 to 5.26% in period 4. Conclusions. The clinicopathologic features of duodenal lymphoma were significantly different from those of gastric lymphoma and small intestinal lymphoma. The prognosis of PDLs was significantly better than those of the other two groups, and there was no statistical survival benefit from surgery in PDLs.
Reciprocity and Representation Theorems for Flux- and Field-Normalised Decomposed Wave Fields
Authors: Wapenaar Kees
Published: January 2020

We consider wave propagation problems in which there is a preferred direction of propagation. To account for propagation in preferred directions, the wave equation is decomposed into a set of coupled equations for waves that propagate in opposite directions along the preferred axis. This decomposition is not unique. We discuss flux-normalised and field-normalised decomposition in a systematic way, analyse the symmetry properties of the decomposition operators, and use these symmetry properties to derive reciprocity theorems for the decomposed wave fields, for both types of normalisation. Based on the field-normalised reciprocity theorems, we derive representation theorems for decomposed wave fields. In particular, we derive double- and single-sided Kirchhoff-Helmholtz integrals for forward and backward propagation of decomposed wave fields. The single-sided Kirchhoff-Helmholtz integrals for backward propagation of field-normalised decomposed wave fields find applications in reflection imaging, accounting for multiple scattering.
Lymphoma Angiogenesis Is Orchestrated by Noncanonical Signaling Pathways
Authors: Gloger Marleen , Menzel Lutz , Grau Michael , Vion Anne-Clemence , Anagnostopoulos Ioannis , Zapukhlyak Myroslav , Gerlach Kerstin , Kammertöns Thomas , Hehlgans Thomas , Zschummel Maria , Lenz Georg , Gerhardt Holger , Höpken Uta E. , Rehm Armin
Published: January 2020

Tumor-induced remodeling of the microenvironment relies on the formation of blood vessels, which go beyond the regulation of metabolism, shaping a maladapted survival niche for tumor cells. In high-grade B-cell lymphoma, angiogenesis correlates with poor prognosis, but attempts to target established proangiogenic pathways within the vascular niche have been inefficient. Here, we analyzed Myc-driven B-cell lymphoma–induced angiogenesis in mice. A few lymphoma cells were sufficient to activate the angiogenic switch in lymph nodes. A unique morphology of dense microvessels emerged without obvious tip cell guidance and reliance on blood endothelial cell (BEC) proliferation. The transcriptional response of BECs was inflammation independent. Conventional HIF1α or Notch signaling routes prevalent in solid tumors were not activated. Instead, a nonconventional hypersprouting morphology was orchestrated by lymphoma-provided VEGFC and lymphotoxin (LT). Interference with VEGF receptor-3 and LTβ receptor signaling pathways abrogated lymphoma angiogenesis, thus revealing targets to block lymphomagenesis.

Significance:

In lymphoma, transcriptomes and morphogenic patterns of the vasculature are distinct from processes in inflammation and solid tumors. Instead, LTβR and VEGFR3 signaling gain leading roles and are targets for lymphomagenesis blockade.
Association of Anti-Mullerian Hormone, Follicle-Stimulating Hormone, and Inhibin B with Risk of Ovarian Cancer in the Janus Serum Bank
Authors: Irvin Sarah R. , Weiderpass Elisabete , Stanczyk Frank Z. , Brinton Louise A. , Trabert Britton , Langseth Hilde , Wentzensen Nicolas
Published: January 2020

Background:

Reproductive factors, including parity, breastfeeding, and contraceptive use, affect lifetime ovulatory cycles and cumulative exposure to gonadotropins and are associated with ovarian cancer. To understand the role of ovulation-regulating hormones in the etiology of ovarian cancer, we prospectively analyzed the association of anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B with ovarian cancer risk.

Methods:

Our study included 370 women from the Janus Serum Bank, including 54 type I and 82 type II invasive epithelial ovarian cancers, 49 borderline tumors, and 185 age-matched controls. We used conditional logistic regression to assess the relationship between hormones and risk of ovarian cancer overall and by subtype (types I and II).

Results:

Inhibin B was associated with increased risk of ovarian cancer overall [OR, 1.97; 95% confidence interval (CI), 1.14–3.39; Ptrend = 0.05] and with type I ovarian (OR, 3.10; 95% CI, 1.04–9.23; Ptrend = 0.06). FSH was not associated with ovarian cancer risk overall, but higher FSH was associated with type II ovarian cancers (OR, 2.78; 95% CI, 1.05–7.38). AMH was not associated with ovarian cancer risk.

Conclusions:

FSH and inhibin B may be associated with increased risk in different ovarian cancer subtypes, suggesting that gonadotropin exposure may influence risk of ovarian cancer differently across subtypes.

Impact:

Associations between prospectively collected AMH, FSH, and inhibin B levels with risk of ovarian cancer provide novel insight on the influence of premenopausal markers of ovarian reserve and gonadotropin signaling. Heterogeneity of inhibin B and FSH effects in different tumor types may be informative of tumor etiology.
Temporal Trends in Population-Level Cure of Cancer: The Australian Context
Authors: Kou Kou , Dasgupta Paramita , Cramb Susanna M. , Yu Xue Qin , Baade Peter D.
Published: January 2020

Background:

With the improvements in cancer diagnosis and treatment, more patients with cancer are surviving for longer periods than before. This study aims to quantify the proportion cured and median survival time for those who are not cured for major cancers in Australia.

Methods:

Australian population-based cohort of 2,164,172 cases, ages 15 to 89 years, whose first cancer diagnosis between 1982 and 2014 was one of 22 leading cancers, were followed up to December 2014. Flexible parametric cure models were used to estimate the proportion cured and median survival time for those uncured by age, sex, and spread of disease, and temporal trends in these measures.

Results:

Cure estimates could be generated for 19 of the 22 cancer types. The unadjusted proportion cured ranged from 5.0% for pancreatic cancer to 90.0% for melanoma. Median survival time for those uncured ranged from 0.35 years for pancreatic cancer to 6.05 years for prostate cancer. Cancers were divided into four groups according to their proportion cured in the 1980s and the degree of improvement over 28 years. Esophageal, stomach, pancreatic, liver, gallbladder, lung, and brain cancer had lower proportion cured and smaller improvements over time.

Conclusions:

For cancers with poor survival in which little has changed over time either in prolonging life or achieving statistical cure, efforts should be focused on reducing the prevalence of known risk factors and earlier detection, thereby enabling more effective treatment.

Impact:

Cure models provide unique insights into whether survival improvements are due to prolonging life or through curing the disease.
Metabolic Pathway Analysis and Effectiveness of Tamoxifen in Danish Breast Cancer Patients
Authors: Ahern Thomas P. , Collin Lindsay J. , Baurley James W. , Kjærsgaard Anders , Nash Rebecca , Maliniak Maret L. , Damkier Per , Zwick Michael E. , Isett R. Benjamin , Christiansen Peer M. , Ejlertsen Bent , Lauridsen Kristina L. , Christensen Kristina B. , Silliman Rebecca A. , Toft Sørensen Henrik , Tramm Trine , Hamilton-Dutoit Stephen , Lash Timothy L. , Cronin-Fenton Deirdre
Published: January 2020

Background:

Tamoxifen and its metabolites compete with estrogen to occupy the estrogen receptor. The conventional dose of adjuvant tamoxifen overwhelms estrogen in this competition, reducing breast cancer recurrence risk by nearly half. Phase I metabolism generates active tamoxifen metabolites, and phase II metabolism deactivates them. No earlier pharmacogenetic study has comprehensively evaluated the metabolism and transport pathways, and no earlier study has included a large population of premenopausal women.

Methods:

We completed a cohort study of 5,959 Danish nonmetastatic premenopausal breast cancer patients, in whom 938 recurrences occurred, and a case–control study of 541 recurrent cases in a cohort of Danish predominantly postmenopausal breast cancer patients, all followed for 10 years. We collected formalin-fixed paraffin-embedded tumor blocks and genotyped 32 variants in 15 genes involved in tamoxifen metabolism or transport. We estimated conventional associations for each variant and used prior information about the tamoxifen metabolic path to evaluate the importance of metabolic and transporter pathways.

Results:

No individual variant was notably associated with risk of recurrence in either study population. Both studies showed weak evidence of the importance of phase I metabolism in the clinical response to adjuvant tamoxifen therapy.

Conclusions:

Consistent with prior knowledge, our results support the role of phase I metabolic capacity in clinical response to tamoxifen. Nonetheless, no individual variant substantially explained the modest phase I effect on tamoxifen response.

Impact:

These results are consistent with guidelines recommending against genotype-guided prescribing of tamoxifen, and for the first time provide evidence supporting these guidelines in premenopausal women.
A New Comprehensive Colorectal Cancer Risk Prediction Model Incorporating Family History, Personal Characteristics, and Environmental Factors
Authors: Zheng Yingye , Hua Xinwei , Win Aung K. , MacInnis Robert J. , Gallinger Steven , Marchand Loic Le , Lindor Noralane M. , Baron John A. , Hopper John L. , Dowty James G. , Antoniou Antonis C. , Zheng Jiayin , Jenkins Mark A. , Newcomb Polly A.
Published: January 2020

Purpose:

Reducing colorectal cancer incidence and mortality through early detection would improve efficacy if targeted. We developed a colorectal cancer risk prediction model incorporating personal, family, genetic, and environmental risk factors to enhance prevention.

Methods:

A familial risk profile (FRP) was calculated to summarize individuals' risk based on detailed cancer family history (FH), family structure, probabilities of mutation in major colorectal cancer susceptibility genes, and a polygenic component. We developed risk models, including individuals' FRP or binary colorectal cancer FH, and colorectal cancer risk factors collected at enrollment using population-based colorectal cancer cases (N = 4,445) and controls (N = 3,967) recruited by the Colon Cancer Family Registry Cohort (CCFRC). Model validation used CCFRC follow-up data for population-based (N = 12,052) and clinic-based (N = 5,584) relatives with no cancer history at recruitment to assess model calibration [expected/observed rate ratio (E/O)] and discrimination [area under the receiver-operating-characteristic curve (AUC)].

Results:

The E/O [95% confidence interval (CI)] for FRP models for population-based relatives were 1.04 (0.74–1.45) for men and 0.86 (0.64–1.20) for women, and for clinic-based relatives were 1.15 (0.87–1.58) for men and 1.04 (0.76–1.45) for women. The age-adjusted AUCs (95% CI) for FRP models for population-based relatives were 0.69 (0.60–0.78) for men and 0.70 (0.62–0.77) for women, and for clinic-based relatives were 0.77 (0.69–0.84) for men and 0.68 (0.60–0.76) for women. The incremental values of AUC for FRP over FH models for population-based relatives were 0.08 (0.01–0.15) for men and 0.10 (0.04–0.16) for women, and for clinic-based relatives were 0.11 (0.05–0.17) for men and 0.11 (0.06–0.17) for women.

Conclusions:

Both models calibrated well. The FRP-based model provided better risk stratification and risk discrimination than the FH-based model.

Impact:

Our findings suggest detailed FH may be useful for targeted risk-based screening and clinical management.
High Extratumoral Mast Cell Counts Are Associated with a Higher Risk of Adverse Prostate Cancer Outcomes
Authors: Hempel Sullivan Heidi , Heaphy Christopher M. , Kulac Ibrahim , Cuka Nathan , Lu Jiayun , Barber John R. , De Marzo Angelo M. , Lotan Tamara L. , Joshu Corinne E. , Sfanos Karen S.
Published: January 2020

Background:

Given our previous findings that low intratumoral and high extratumoral mast cell numbers are associated with higher risk of biochemical recurrence after radical prostatectomy, we now assessed this relationship with race and the development of metastases.

Methods:

We stained for mast cell tryptase via IHC and fluorescent immunolabeling in 885 men across multiple tissue microarray sets designed to assess biomarkers in association with race and prostate cancer outcomes (median follow-up, 7.0 years).

Results:

Intratumoral and extratumoral mast cell counts were significantly lower in tissues from African-American compared with European-American men, but not within strata of cancer grade. There was no association between mast cell counts and ERG positivity, PTEN loss, or TP53 missense mutation. Higher minimum extratumoral mast cells were associated with an increased risk of biochemical recurrence [comparing highest with lowest tertiles: HR, 1.61; 95% confidence interval (CI), 1.12–2.29; P trend = 0.01]; this pattern was similar among European-American and African-American men and by grade of disease. There was no significant association between minimum intratumoral mast cell count and biochemical recurrence, overall or within strata of race and grade. Finally, high minimum number of extratumoral mast cells was associated with prostate cancer metastases (comparing highest with lowest tertiles: HR, 2.12; 95% CI, 1.24–3.63; P trend = 0.01).

Conclusions:

High extratumoral mast cell numbers are associated with biochemical recurrence and the development of metastases after radical prostatectomy.

Impact:

Higher numbers of benign tissue mast cells are associated with a higher risk of adverse outcomes after radical prostatectomy, including metastatic prostate cancer.
The Association of Modifiable Breast Cancer Risk Factors and Somatic Genomic Alterations in Breast Tumors: The Cancer Genome Atlas Network
Authors: Heng Yujing J. , Hankinson Susan E. , Wang Jun , Alexandrov Ludmil B. , Ambrosone Christine B. , de Andrade Victor P. , Brufsky Adam M. , Couch Fergus J. , King Tari A. , Modugno Francesmary , Vachon Celine M. , Eliassen A. Heather , Tamimi Rulla M. , Kraft Peter
Published: January 2020

Background:

The link between modifiable breast cancer risk factors and tumor genomic alterations remains largely unexplored. We evaluated the association of prediagnostic body mass index (BMI), cigarette smoking, and alcohol consumption with somatic copy number variation (SCNV), total somatic mutation burden (TSMB), seven single base substitution (SBS) signatures (SBS1, SBS2, SBS3, SBS5, SBS13, SBS29, and SBS30), and nine driver mutations (CDH1, GATA3, KMT2C, MAP2K4, MAP3K1, NCOR1, PIK3CA, RUNX1, and TP53) in a subset of The Cancer Genome Atlas (TCGA).

Methods:

Clinical and genomic data were retrieved from the TCGA database. Risk factor information was collected from four TCGA sites (n = 219 women), including BMI (1 year before diagnosis), cigarette smoking (smokers/nonsmokers), and alcohol consumption (current drinkers/nondrinkers). Multivariable regression analyses were conducted in all tumors and stratified according to estrogen receptor (ER) status.

Results:

Increasing BMI was associated with increasing SCNV in all women (P = 0.039) and among women with ER− tumors (P = 0.031). Smokers had higher SCNV and TSMB versus nonsmokers (P < 0.05 all women). Alcohol drinkers had higher SCNV versus nondrinkers (P < 0.05 all women and among women with ER+ tumors). SBS3 (defective homologous recombination-based repair) was exclusively found in alcohol drinkers with ER− disease. GATA3 mutation was more likely to occur in women with higher BMI. No association was significant after multiple testing correction.

Conclusions:

This study provides preliminary evidence that BMI, cigarette smoking, and alcohol consumption can influence breast tumor biology, in particular, DNA alterations.

Impact:

This study demonstrates a link between modifiable breast cancer risk factors and tumor genomic alterations.
Cannabinoids Promote Progression of HPV-Positive Head and Neck Squamous Cell Carcinoma via p38 MAPK Activation
Authors: Liu Chao , Sadat Sayed H. , Ebisumoto Koji , Sakai Akihiro , Panuganti Bharat A. , Ren Shuling , Goto Yusuke , Haft Sunny , Fukusumi Takahito , Ando Mizuo , Saito Yuki , Guo Theresa , Tamayo Pablo , Yeerna Huwate , Kim William , Hubbard Jacqueline , Sharabi Andrew B. , Gutkind J. Silvio , Califano Joseph A.
Published: January 2020

Purpose:

Human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) is associated with daily marijuana use and is also increasing in parallel with increased marijuana use in the United States. Our study is designed to define the interaction between cannabinoids and HPV-positive HNSCC.

Experimental Design:

The expression of cannabinoid receptors CNR1 and CNR2 was analyzed using The Cancer Genome Atlas (TCGA) HNSCC data. We used agonists, antagonists, siRNAs, or shRNA-based models to explore the roles of CNR1 and CNR2 in HPV-positive HNSCC cell lines and animal models. Cannabinoid downstream pathways involved were determined by Western blotting and analyzed in a primary HPV HNSCC cohort with single-sample gene set enrichment analysis (ssGSEA) and the OncoGenome Positioning System (Onco-GPS).

Results:

In TCGA cohort, the expression of CNR1 and CNR2 was elevated in HPV-positive HNSCC compared with HPV-negative HNSCC, and knockdown of CNR1/CNR2 expression inhibited proliferation in HPV-positive HNSCC cell lines. Specific CNR1 and CNR2 activation as well as nonselective cannabinoid receptor activation in cell lines and animal models promoted cell growth, migration, and inhibited apoptosis through p38 MAPK pathway activation. CNR1/CNR2 antagonists suppressed cell proliferation and migration and induced apoptosis. Using whole-genome expression analysis in a primary HPV HNSCC cohort, we identified specific p38 MAPK pathway activation signature in tumors from HPV HNSCC patients with objective measurement of concurrent cannabinoid exposure.

Conclusions:

Cannabinoids can promote progression of HPV-positive HNSCC through p38 MAPK pathway activation.
Investigating PSMA-Targeted Radioligand Therapy Efficacy as a Function of Cellular PSMA Levels and Intratumoral PSMA Heterogeneity
Authors: Current Kyle , Meyer Catherine , Magyar Clara E. , Mona Christine E. , Almajano Joel , Slavik Roger , Stuparu Andreea D. , Cheng Chloe , Dawson David W. , Radu Caius G. , Czernin Johannes , Lueckerath Katharina
Published: January 2020

Purpose:

Prostate-specific membrane antigen (PSMA) targeting radioligands deliver radiation to PSMA-expressing cells. However, the relationship between PSMA levels and intralesion heterogeneity of PSMA expression, and cytotoxic radiation by radioligand therapy (RLT) is unknown. Here we investigate RLT efficacy as function of PSMA levels/cell, and the fraction of PSMA+ cells in a tumor.

Experimental Design:

RM1 cells expressing different levels of PSMA (PSMA−, PSMA+, PSMA++, PSMA+++; study 1) or a mix of PSMA+ and PSMA− RM1 (study 2, 4) or PC-3/PC-3-PIP (study 3) cells at various ratios were injected into mice. Mice received 177Lu- (studies 1–3) or 225Ac- (study 4) PSMA617. Tumor growth was monitored. Two days post-RLT, tumors were resected in a subset of mice. Radioligand uptake and DNA damage were quantified.

Results:

177Lu-PSMA617 efficacy increased with increasing PSMA levels (study 1) and fractions of PSMA positive cells (studies 2, 3) in both, the RM1 and PC-3-PIP models. In tumors resected 2 days post-RLT, PSMA expression correlated with 177Lu-PSMA617 uptake and the degree of DNA damage. Compared with 177Lu-PSMA617, 225Ac-PSMA617 improved overall antitumor effectiveness and tended to enhance the differences in therapeutic efficacy between experimental groups.

Conclusions:

In the current models, both the degree of PSMA expression and the fraction of PSMA+ cells correlate with 177Lu-/225Ac-PSMA617 tumor uptake and DNA damage, and thus, RLT efficacy. Low or heterogeneous PSMA expression represents a resistance mechanism to RLT.

See related commentary by Ravi Kumar and Hofman, p. 2774
Diverse AR Gene Rearrangements Mediate Resistance to Androgen Receptor Inhibitors in Metastatic Prostate Cancer
Authors: Li Yingming , Yang Rendong , Henzler Christine M. , Ho Yeung , Passow Courtney , Auch Benjamin , Carreira Suzanne , Nava Rodrigues Daniel , Bertan Claudia , Hwang Tae Hyun , Quigley David A. , Dang Ha X. , Morrissey Colm , Fraser Michael , Plymate Stephen R. , Maher Christopher A. , Feng Felix Y. , de Bono Johann S. , Dehm Scott M.
Published: January 2020

Purpose:

Prostate cancer is the second leading cause of male cancer deaths. Castration-resistant prostate cancer (CRPC) is a lethal stage of the disease that emerges when endocrine therapies are no longer effective at suppressing activity of the androgen receptor (AR) transcription factor. The purpose of this study was to identify genomic mechanisms that contribute to the development and progression of CRPC.

Experimental Design:

We used whole-genome and targeted DNA-sequencing approaches to identify mechanisms underlying CRPC in an aggregate cohort of 272 prostate cancer patients. We analyzed structural rearrangements at the genome-wide level and carried out a detailed structural rearrangement analysis of the AR locus. We used genome engineering to perform experimental modeling of AR gene rearrangements and long-read RNA sequencing to analyze effects on expression of AR and truncated AR variants (AR-V).

Results:

AR was among the most frequently rearranged genes in CRPC tumors. AR gene rearrangements promoted expression of diverse AR-V species. AR gene rearrangements occurring in the context of AR amplification correlated with AR overexpression. Cell lines with experimentally derived AR gene rearrangements displayed high expression of tumor-specific AR-Vs and were resistant to endocrine therapies, including the AR antagonist enzalutamide.

Conclusions:

AR gene rearrangements are an important mechanism of resistance to endocrine therapies in CRPC.
Targeting RICTOR Sensitizes SMAD4-Negative Colon Cancer to Irinotecan
Authors: Wong Chen Khuan , Lambert Arthur W. , Ozturk Sait , Papageorgis Panagiotis , Lopez Delia , Shen Ning , Sen Zaina , Abdolmaleky Hamid M. , Győrffy Balázs , Feng Hui , Thiagalingam Sam
Published: January 2020

Deciphering molecular targets to enhance sensitivity to chemotherapy is becoming a priority for effectively treating cancers. Loss of function mutations of SMAD4 in colon cancer are associated with metastatic progression and resistance to 5-fluorouracil (5-FU), the most extensively used drug of almost all chemotherapy combinations used in the treatment of metastatic colon cancer. Here, we report that SMAD4 deficiency also confers resistance to irinotecan, another common chemotherapeutic frequently used alone or in combination with 5-FU against colon cancer. Mechanistically, we find that SMAD4 interacts with and inhibits RICTOR, a component of the mTORC2 complex, resulting in suppression of downstream effector phosphorylation of AKT at Serine 473. In silico meta-analysis of publicly available gene expression datasets derived from tumors indicates that lower levels of SMAD4 or higher levels of RICTOR/AKT, irrespective of the SMAD4 status, correlate with poor survival, suggesting them as strong prognostic biomarkers and targets for therapeutic intervention. Moreover, we find that overexpression of SMAD4 or depletion of RICTOR suppresses AKT signaling and increases sensitivity to irinotecan in SMAD4-deficient colon cancer cells. Consistent with these observations, pharmacologic inhibition of AKT sensitizes SMAD4-negative colon cancer cells to irinotecan in vitro and in vivo. Overall, our study suggests that hyperactivation of the mTORC2 pathway is a therapeutic vulnerability that could be exploited to sensitize SMAD4-negative colon cancer to irinotecan.

Implications:

Hyperactivation of the mTORC2 pathway in SMAD4-negative colon cancer provides a mechanistic rationale for targeted inhibition of mTORC2 or AKT as a distinctive combinatorial therapeutic opportunity with chemotherapy for colon cancer.
Acquired Hemophilia in an Elderly Patient with Carcinoma of the Ampulla of Vater
Authors: Mavroeidis Leonidas , Vassou Amalia , Zarkavelis George , Papadaki Alexandra , Mouzaki Ioanna , Ntellas Panagiotis , Gkoura Stefania , Gazouli Ioanna , Pentheroudakis George
Published: January 2020

Acquired hemophilia is a rare autoimmune bleeding disorder related to the production of autoantibodies that inhibit clotting factor VIII or IX. The underlying cause can be autoimmune disease, malignancy, pregnancy, or medications, but it is most commonly idiopathic. Here we present the case of an 81-year-old patient with locoregionally relapsed periampullary carcinoma who presented with soft tissue hematoma and an abnormally elevated activated partial thromboplastin time (aPTT) in the presence of a normal prothrombin time. A diagnosis of acquired hemophilia was established. The patient was managed with immunosuppressive prednisone and cyclophosphamide plus immunoglobulin G. He also received a cycle of chemotherapy with gemcitabine and oxaliplatin, because the underlying malignancy was the cause of the bleeding disorder. Care was complicated by neutropenia and nosocomial fever, but the patient eventually showed signs of clinical stability, while the aPTT decreased 2-fold. The patient was successfully discharged from the hospital and continued treatment in outpatient care.
Chromosomal Microarray Analysis in Taiwanese Patients with Williams-Beuren Syndrome
Authors: Kuo Haung-Tsung , Chen Chieh-Ho , Lin Chien-Yu , Chang Ya-Sian , Chang Jan-Gowth
Published: January 2020

Williams-Beuren Syndrome (WBS; OMIM #194050) is a rare neurodevelopmental disorder that results from a deletion at 7q11.23 spanning 25-27 genes. We performed chromosomal microarray analysis (CMA) in 9 Taiwanese patients with WBS to confirm the diagnosis. These samples had already been examined by FISH and diagnosed as WBS. Pathogenic copy number variations (CNVs) were identified in all patients, including 24 genes (spanning from FKBP6 to GTF2I) with typical 7q11.23 microdeletion. A deletion in TRIM50 was common in Taiwanese patients with WBS (8/9). Furthermore, 1 patient had 2 additional gene deletions in NCF1 and GTF2IRD2. We also found 4 patients with duplications of 4p16.1, 16p13.11, 10q26.3, and 21q22.3. All 9 WBS patients exhibited distinctive facial dysmorphisms, including a wide mouth, thick prominent lips, short nose with anteverted nares, and periorbital puffiness. However, cardiac defects were not frequent in our patients (3/9). In conclusion, we detected CNVs associated with WBS in a Taiwanese population using CMA. Although CMA is expensive and labor-intensive, it is useful for identifying typical/atypical CNVs, delineating distal break points, and detecting other CNVs.
Inventory prediction and management in Nigeria using market basket analysis associative rule mining: memetic algorithm based approach
Authors: Ojugo Arnold Adimabua , Eboka Andrew Okonji
Published: January 2020

A key challenge in businesses today is determining inventory level for each product (to be) sold to clients. A pre-knowledge will suppress inventory stock-up and help avert unnecessary demurrage. It will also avoid stock out and avert loss of clients to competition. Study aims to unveil customer’s behavior in purchasing goods and thus, predict a next time purchase as well as serve as decision support to determine the required amount of each goods inventory. Study is conducted for Delta Mall (Asaba and Warri branches) department store. We adapt the memetic algorithm on market basket dataset to examine buying behavior of customers, their preference and frequency at which goods are purchased in common (basket). Result shows some items placed in basket allow customers to purchase items of similar value, or best combined with the selected items due to shelf-placement via concept of feature drift. Model yields 21-rules for eight items obtained from data transaction mining dataset acquired from Delta Mall.
Refeudalização revisitada
Authors: Murdock Graham
Published: January 2020

A eleição de Donald Trump como presidente dos Estados Unidos e a bem-sucedida campanha do referendo para saída da União Europeia no Reino Unido provocaram um interesse renovado nos desafios impostos à democracia deliberativa pelo populismo de direita. Este artigo retorna à pesquisa sobre o autoritarismo desenvolvida pela Escola de Frankfurt, na Alemanha e nos Estados Unidos, particularmente à sua ênfase na construção performativa de apelos e à posterior caracterização de Jürgen Habermas da translação dos cidadãos em sujeitos de audiência como uma refeudalização da esfera pública, argumentando que essas análises continuam a fornecer recursos indispensáveis para a compreensão dos desenvolvimentos contemporâneos.
Sympathetic Enhancement of Memory T-Cell Homing and Hypertension Sensitization
Authors: Xiao Liang , do Carmo Luciana Simao , Foss Jason D. , Chen Wei , Harrison David G.
Published: January 2020

Rationale:

Effector memory T lymphocytes (T
EM
cells) exacerbate hypertension in response to repeated hypertensive stimuli. These cells reside in the bone marrow for prolonged periods and can be reactivated on reexposure to the hypertensive stimulus.

Objective:

Because hypertension is associated with increased sympathetic outflow to the bone marrow, we hypothesized that sympathetic nerves regulate accumulation and reactivation of bone marrow–residing hypertension-specific T
EM
cells.

Methods and Results:

Using unilateral superior cervical ganglionectomy in wild-type C57BL/6 mice, we showed that sympathetic nerves create a bone marrow environment that supports residence of hypertension-specific CD8
+
T cells. These cells, defined by their proliferative response on coculture with dendritic cells from Ang (angiotensin) II–infused mice, were reduced in denervated compared with innervated bone of Ang II–infused mice. Adoptively transferred CD8
+
T cells from Ang II–infused mice preferentially homed to innervated compared with denervated bone. In contrast, ovalbumin responsive T cells from OT-I mice did not exhibit this preferential homing. Increasing superior cervical ganglion activity by activating Gq-coupled designer receptor exclusively activated by designer drug augmented CD8
+
T
EM
bone marrow accumulation. Adoptive transfer studies using mice lacking β2AR (β2 adrenergic receptors) indicate that β2AR in the bone marrow niche, rather than T-cell β2AR is critical for T
EM
cell homing. Inhibition of global sympathetic outflow using Gi-coupled DREADD (designer receptor exclusively activated by designer drug) injected into the rostral ventrolateral medulla or treatment with a β2AR antagonist reduced hypertension-specific CD8
+
T
EM
cells in the bone marrow and reduced the hypertensive response to a subsequent response to low dose Ang II.

Conclusions:

Sympathetic nerves contribute to the homing and survival of hypertension-specific T
EM
cells in the bone marrow after they are formed in hypertension. Inhibition of sympathetic nerve activity and β2AR blockade reduces these cells and prevents the blood pressure elevation and renal inflammation on reexposure to hypertension stimuli.
Oleic Acid Attenuates Ang II (Angiotensin II)-Induced Cardiac Remodeling by Inhibiting FGF23 (Fibroblast Growth Factor 23) Expression in Mice
Authors: Liu Tianlong , Wen Hongyan , Li Hao , Xu Haochen , Xiao Ning , Liu Rui , Chen Luonan , Sun Yingying , Song Li , Bai Congxia , Ge Jing , Zhang Yinhui , Chen Jingzhou
Published: January 2020

Plasma metabolic profiles were compared between patients with hypertension with and without left ventricular hypertrophy and significantly decreased oleic acid (OA) levels were observed in the peripheral blood of patients with hypertension with left ventricular hypertrophy. We sought to determine the effect and underlying mechanisms of OA on cardiac remodeling. In vitro studies with isolated neonatal mouse cardiomyocytes and cardiac fibroblasts revealed that OA significantly attenuated Ang II (angiotensin II)-induced cardiomyocyte growth and cardiac fibroblast collagen expression. In vivo, cardiac function, hypertrophic growth of cardiomyocytes, and fibrosis were analyzed after an Ang II (1000 ng/kg/minute) pump was implanted for 14 days. We found that OA could significantly prevent Ang II-induced cardiac remodeling in mice. RNA sequencing served as a gene expression roadmap highlighting gene expression changes in the hearts of Ang II-induced mice and OA-treated mice. The results revealed that FGF23 (fibroblast growth factor 23) expression was significantly upregulated in mouse hearts in response to Ang II infusion, which was significantly suppressed in the hearts of OA-treated mice. Furthermore, overexpression of FGF23 in the heart by injection of an AAV-9 vector aggravated Ang II-induced cardiac remodeling and impaired the protective effect of OA on cardiac remodeling. Further study found that OA could suppress Ang II-induced FGF23 expression by inhibiting the translocation of Nurr1 (nuclear receptor–related 1 protein) from the cytoplasm to the nucleus. Our findings suggest a novel role of OA in preventing Ang II-induced cardiac remodeling via suppression of FGF23 expression.
Left Ventricular Mass and Incident Chronic Kidney Disease
Authors: Agarwal Rajiv , Song Rebecca J. , Vasan Ramachandran S. , Xanthakis Vanessa
Published: January 2020

Chronic kidney disease (CKD) is associated with incident cardiovascular morbidity and mortality. Whether subclinical cardiovascular disease and target organ damage is associated with incident CKD is unknown. We investigated the relations of echocardiographic left ventricular mass (LVM) with incident CKD. We evaluated 2258 Framingham Offspring cohort participants (mean age, 57 years; 56% women) who underwent echocardiography at a routine examination and had an estimated glomerular filtration rate ≥60 mL/min per 1.73 m
2
. We used Cox proportional hazards regression with discrete time intervals to relate sex-standardized LVM (independent variable) to the incidence of CKD, defined as estimated glomerular filtration rate <60 L/min per 1.73 m
2
, on follow-up. During a median follow-up of 14.6 years, 373 (16.5%) participants developed incident CKD. Higher LVM was associated with higher risk of CKD after adjusting for prevalent cardiovascular disease, body mass index, systolic blood pressure, total and HDL (high-density lipoprotein) cholesterol, antihypertensive medication, smoking, and diabetes mellitus (hazard ratio, 1.15 [95% CI, 1.03–1.29];
P
=0.017) per 1-SD increase in LVM g/m
2
. Further adjustment for baseline estimated glomerular filtration rate (adjusted hazard ratio, 1.16 [95% CI, 1.04–1.31];
P
=0.010) and baseline urine albumin/creatinine ratio (adjusted hazard ratio, 1.18 [95% CI, 1.04–1.33];
P
=0.009) slightly attenuated the association. In our community-based sample, LVM was associated with incident CKD prospectively, which suggests that the relations between CKD and subclinical cardiovascular disease may be bidirectional. Further studies are needed to confirm our findings.