Sample records for aggressive human cancer

  1. Ceramide species are elevated in human breast cancer and are associated with less aggressiveness

    PubMed Central

    Moro, Kazuki; Kawaguchi, Tsutomu; Tsuchida, Junko; Gabriel, Emmanuel; Qi, Qianya; Yan, Li; Wakai, Toshifumi; Takabe, Kazuaki; Nagahashi, Masayuki

    2018-01-01

    Sphingolipids have emerged as key regulatory molecules in cancer cell survival and death. Although important roles of sphingolipids in breast cancer progression have been reported in experimental models, their roles in human patients are yet to be revealed. The aim of this study was to investigate the ceramide levels and its biosynthesis pathways in human breast cancer patients. Breast cancer, peri-tumor and normal breast tissue samples were collected from surgical specimens from a series of 44 patients with breast cancer. The amount of sphingolipid metabolites in the tissue were determined by mass spectrometry. The Cancer Genome Atlas was used to analyze gene expression related to the sphingolipid metabolism. Ceramide levels were higher in breast cancer tissue compared to both normal and peri-tumor breast tissue. Substrates and enzymes that generate ceramide were significantly increased in all three ceramide biosynthesis pathways in cancer. Further, higher levels of ceramide in breast cancer were associated with less aggressive cancer biology presented by Ki-67 index and nuclear grade of the cancer. Interestingly, patients with higher gene expressions of enzymes in the three major ceramide synthesis pathways showed significantly worse prognosis. This is the first study to reveal the clinical relevance of ceramide metabolism in breast cancer patients. We demonstrated that ceramide levels in breast cancer tissue were significantly higher than those in normal tissue, with activation of the three ceramide biosynthesis pathways. We also identified that ceramide levels have a significant association with aggressive phenotype and its enzymes have prognostic impact on breast cancer patients. PMID:29731990

  2. Biomarkers to Distinguish Aggressive Cancers from Non-aggressive or Non-progressing Cancer — EDRN Public Portal

    Cancer.gov

    Distinguishing aggressive cancers from non-aggressive or non-progressing cancers is an issue of both clinical and public health importance particularly for those cancers with an available screening test. With respect to breast cancer, mammographic screening has been shown in randomized trials to reduce breast cancer mortality, but given the limitations of its sensitivity and specificity some breast cancers are missed by screening. These so called interval detected breast cancers diagnosed between regular screenings are known to have a more aggressive clinical profile. In addition, of those cancers detected by mammography some are indolent while others are more likely to recur despite treatment. The pilot study proposed herein is highly responsive to the EDRN supplement titled “Biomarkers to Distinguish Aggressive Cancers from Nonaggressive or Non-progressing Cancers” in that it addresses both of the research objectives related to these issues outlined in the notice for this supplement: Aim 1: To identify biomarkers in tumor tissue related to risk of interval detected vs. mammography screen detected breast cancer focusing on early stage invasive disease. We will compare gene expression profiles using the whole genome-cDNA-mediated Annealing, Selection, extension and Ligation (DASL) assay of 50 screen detected cancers to those of 50 interval detected cancers. Through this approach we will advance our understanding of the molecular characteristics of interval vs. screen detected breast cancers and discover novel biomarkers that distinguish between them. Aim 2: To identify biomarkers in tumor tissue related to risk of cancer recurrence among patients with screen detected early stage invasive breast cancer. Using the DASL assay we will compare gene expression profiles from screen detected early stage breast cancer that either recurred within five years or never recurred within five years. These two groups of patients will be matched on multiple factors including

  3. A basal stem cell signature identifies aggressive prostate cancer phenotypes

    PubMed Central

    Smith, Bryan A.; Sokolov, Artem; Uzunangelov, Vladislav; Baertsch, Robert; Newton, Yulia; Graim, Kiley; Mathis, Colleen; Cheng, Donghui; Stuart, Joshua M.; Witte, Owen N.

    2015-01-01

    Evidence from numerous cancers suggests that increased aggressiveness is accompanied by up-regulation of signaling pathways and acquisition of properties common to stem cells. It is unclear if different subtypes of late-stage cancer vary in stemness properties and whether or not these subtypes are transcriptionally similar to normal tissue stem cells. We report a gene signature specific for human prostate basal cells that is differentially enriched in various phenotypes of late-stage metastatic prostate cancer. We FACS-purified and transcriptionally profiled basal and luminal epithelial populations from the benign and cancerous regions of primary human prostates. High-throughput RNA sequencing showed the basal population to be defined by genes associated with stem cell signaling programs and invasiveness. Application of a 91-gene basal signature to gene expression datasets from patients with organ-confined or hormone-refractory metastatic prostate cancer revealed that metastatic small cell neuroendocrine carcinoma was molecularly more stem-like than either metastatic adenocarcinoma or organ-confined adenocarcinoma. Bioinformatic analysis of the basal cell and two human small cell gene signatures identified a set of E2F target genes common between prostate small cell neuroendocrine carcinoma and primary prostate basal cells. Taken together, our data suggest that aggressive prostate cancer shares a conserved transcriptional program with normal adult prostate basal stem cells. PMID:26460041

  4. Interstitial assessment of aggressive prostate cancer by physio-chemical photoacoustics: an ex vivo study with intact human prostates.

    PubMed

    Huang, Shengsong; Qin, Yu; Chen, Yingna; Pan, Jing; Xu, Chengdang; Wu, Denglong; Chao, Wan-Yu; Wei, John T; Tomlins, Scott A; Wang, Xueding; Brian Fowlkes, J; Carson, Paul L; Cheng, Qian; Xu, Guan

    2018-06-23

    Transrectal ultrasound (TRUS) guided biopsy is the standard procedure for evaluating the presence and aggressiveness of prostate cancer. TRUS biopsy involves tissue removal, and suffers from low core yield as well as high false negative rate. A less invasive and more accurate diagnostic procedure for prostate cancer is therefore highly desired. Combining the optical sensitivity and ultrasonic resolution to resolve the spatial distribution of the major molecular components in tissue, photoacoustic (PA) technology could be an alternative approach for the diagnosis of prostate cancer. The purpose of this study is to examine the feasibility of identifying aggressive prostate cancer using interstitial PA measurements. 17 patients with pre-biopsy magnetic resonance imaging (MRI), TRUS biopsies and planned prostatectomies were enrolled in this study. The interstitial PA measurements were achieved using our recently developed needle PA probe, which was inserted into the ex vivo prostates in the fashion of a biopsy needle. A total of 70 interstitial PA measurements were acquired. The PA measurements were quantified by a previously established PA physio-chemical analysis (PAPCA) method. The histology has confirmed the nonaggressive and aggressive cancerous conditions at the insertion locations. The diagnostic accuracy was also compared to that provided by the pre-biopsy MRI. The quantitative study shows significant differences between the individual parameters of the nonaggressive and the aggressive cancerous regions (p<0.005). Multivariate analysis of the quantitative features achieved a diagnostic accuracy of 78.6% for differentiating nonaggressive and aggressive prostate cancer tissues CONCLUSIONS: The proposed procedure has shown promises in the diagnosis of aggressive prostate cancer. This article is protected by copyright. All rights reserved.

  5. Two types of aggression in human evolution.

    PubMed

    Wrangham, Richard W

    2018-01-09

    Two major types of aggression, proactive and reactive, are associated with contrasting expression, eliciting factors, neural pathways, development, and function. The distinction is useful for understanding the nature and evolution of human aggression. Compared with many primates, humans have a high propensity for proactive aggression, a trait shared with chimpanzees but not bonobos. By contrast, humans have a low propensity for reactive aggression compared with chimpanzees, and in this respect humans are more bonobo-like. The bimodal classification of human aggression helps solve two important puzzles. First, a long-standing debate about the significance of aggression in human nature is misconceived, because both positions are partly correct. The Hobbes-Huxley position rightly recognizes the high potential for proactive violence, while the Rousseau-Kropotkin position correctly notes the low frequency of reactive aggression. Second, the occurrence of two major types of human aggression solves the execution paradox, concerned with the hypothesized effects of capital punishment on self-domestication in the Pleistocene. The puzzle is that the propensity for aggressive behavior was supposedly reduced as a result of being selected against by capital punishment, but capital punishment is itself an aggressive behavior. Since the aggression used by executioners is proactive, the execution paradox is solved to the extent that the aggressive behavior of which victims were accused was frequently reactive, as has been reported. Both types of killing are important in humans, although proactive killing appears to be typically more frequent in war. The biology of proactive aggression is less well known and merits increased attention.

  6. CXCR6, a newly defined biomarker of tissue-specific stem cell asymmetric self-renewal, identifies more aggressive human melanoma cancer stem cells.

    PubMed

    Taghizadeh, Rouzbeh; Noh, Minsoo; Huh, Yang Hoon; Ciusani, Emilio; Sigalotti, Luca; Maio, Michele; Arosio, Beatrice; Nicotra, Maria R; Natali, PierGiorgio; Sherley, James L; La Porta, Caterina A M

    2010-12-22

    A fundamental problem in cancer research is identifying the cell type that is capable of sustaining neoplastic growth and its origin from normal tissue cells. Recent investigations of a variety of tumor types have shown that phenotypically identifiable and isolable subfractions of cells possess the tumor-forming ability. In the present paper, using two lineage-related human melanoma cell lines, primary melanoma line IGR39 and its metastatic derivative line IGR37, two main observations are reported. The first one is the first phenotypic evidence to support the origin of melanoma cancer stem cells (CSCs) from mutated tissue-specific stem cells; and the second one is the identification of a more aggressive subpopulation of CSCs in melanoma that are CXCR6+. We defined CXCR6 as a new biomarker for tissue-specific stem cell asymmetric self-renewal. Thus, the relationship between melanoma formation and ABCG2 and CXCR6 expression was investigated. Consistent with their non-metastatic character, unsorted IGR39 cells formed significantly smaller tumors than unsorted IGR37 cells. In addition, ABCG2+ cells produced tumors that had a 2-fold greater mass than tumors produced by unsorted cells or ABCG2- cells. CXCR6+ cells produced more aggressive tumors. CXCR6 identifies a more discrete subpopulation of cultured human melanoma cells with a more aggressive MCSC phenotype than cells selected on the basis of the ABCG2+ phenotype alone. The association of a more aggressive tumor phenotype with asymmetric self-renewal phenotype reveals a previously unrecognized aspect of tumor cell physiology. Namely, the retention of some tissue-specific stem cell attributes, like the ability to asymmetrically self-renew, impacts the natural history of human tumor development. Knowledge of this new aspect of tumor development and progression may provide new targets for cancer prevention and treatment.

  7. Modifier locus mapping of a transgenic F2 mouse population identifies CCDC115 as a novel aggressive prostate cancer modifier gene in humans.

    PubMed

    Winter, Jean M; Curry, Natasha L; Gildea, Derek M; Williams, Kendra A; Lee, Minnkyong; Hu, Ying; Crawford, Nigel P S

    2018-06-11

    It is well known that development of prostate cancer (PC) can be attributed to somatic mutations of the genome, acquired within proto-oncogenes or tumor-suppressor genes. What is less well understood is how germline variation contributes to disease aggressiveness in PC patients. To map germline modifiers of aggressive neuroendocrine PC, we generated a genetically diverse F2 intercross population using the transgenic TRAMP mouse model and the wild-derived WSB/EiJ (WSB) strain. The relevance of germline modifiers of aggressive PC identified in these mice was extensively correlated in human PC datasets and functionally validated in cell lines. Aggressive PC traits were quantified in a population of 30 week old (TRAMP x WSB) F2 mice (n = 307). Correlation of germline genotype with aggressive disease phenotype revealed seven modifier loci that were significantly associated with aggressive disease. RNA-seq were analyzed using cis-eQTL and trait correlation analyses to identify candidate genes within each of these loci. Analysis of 92 (TRAMP x WSB) F2 prostates revealed 25 candidate genes that harbored both a significant cis-eQTL and mRNA expression correlations with an aggressive PC trait. We further delineated these candidate genes based on their clinical relevance, by interrogating human PC GWAS and PC tumor gene expression datasets. We identified four genes (CCDC115, DNAJC10, RNF149, and STYXL1), which encompassed all of the following characteristics: 1) one or more germline variants associated with aggressive PC traits; 2) differential mRNA levels associated with aggressive PC traits; and 3) differential mRNA expression between normal and tumor tissue. Functional validation studies of these four genes using the human LNCaP prostate adenocarcinoma cell line revealed ectopic overexpression of CCDC115 can significantly impede cell growth in vitro and tumor growth in vivo. Furthermore, CCDC115 human prostate tumor expression was associated with better survival

  8. Metabolomic signatures of aggressive prostate cancer.

    PubMed

    McDunn, Jonathan E; Li, Zhen; Adam, Klaus-Peter; Neri, Bruce P; Wolfert, Robert L; Milburn, Michael V; Lotan, Yair; Wheeler, Thomas M

    2013-10-01

    Current diagnostic techniques have increased the detection of prostate cancer; however, these tools inadequately stratify patients to minimize mortality. Recent studies have identified a biochemical signature of prostate cancer metastasis, including increased sarcosine abundance. This study examined the association of tissue metabolites with other clinically significant findings. A state of the art metabolomics platform analyzed prostatectomy tissues (331 prostate tumor, 178 cancer-free prostate tissues) from two independent sites. Biochemicals were analyzed by gas chromatography-mass spectrometry and ultrahigh performance liquid chromatography-tandem mass spectrometry. Statistical analyses identified metabolites associated with cancer aggressiveness: Gleason score, extracapsular extension, and seminal vesicle and lymph node involvement. Prostate tumors had significantly altered metabolite profiles compared to cancer-free prostate tissues, including biochemicals associated with cell growth, energetics, stress, and loss of prostate-specific biochemistry. Many metabolites were further associated with clinical findings of aggressive disease. Aggressiveness-associated metabolites stratified prostate tumor tissues with high abundances of compounds associated with normal prostate function (e.g., citrate and polyamines) from more clinically advanced prostate tumors. These aggressive prostate tumors were further subdivided by abundance profiles of metabolites including NAD+ and kynurenine. When added to multiparametric nomograms, metabolites improved prediction of organ confinement (AUROC from 0.53 to 0.62) and 5-year recurrence (AUROC from 0.53 to 0.64). These findings support and extend earlier metabolomic studies in prostate cancer and studies where metabolic enzymes have been associated with carcinogenesis and/or outcome. Furthermore, these data suggest that panels of analytes may be valuable to translate metabolomic findings to clinically useful diagnostic tests

  9. Human-directed aggression in the cat.

    PubMed

    Curtis, Terry Marie

    2008-09-01

    Feline aggression-between cats or directed at humans-is, after inappropriate elimination and urine-marking behaviors, the second most common reason cats are seen by behavioral specialists. For diagnosis and treatment it is important to determine the motivation for the aggression. The more common causes for human-directed aggression in cats include play, fear, petting intolerance, and redirected aggression. Other causes include pain and maternal behavior. Sexually motivated and status related aggression are much more rare. Treatment includes a combination of behavioral modification, environmental modification, and, in some cases, medication.

  10. The nature of human aggression.

    PubMed

    Archer, John

    2009-01-01

    Human aggression is viewed from four explanatory perspectives, derived from the ethological tradition. The first consists of its adaptive value, which can be seen throughout the animal kingdom, involving resource competition and protection of the self and offspring, which has been viewed from a cost-benefit perspective. The second concerns the phylogenetic origin of aggression, which in humans involves brain mechanisms that are associated with anger and inhibition, the emotional expression of anger, and how aggressive actions are manifest. The third concerns the origin of aggression in development and its subsequent modification through experience. An evolutionary approach to development yields conclusions that are contrary to the influential social learning perspective, notably that physical aggression occurs early in life, and its subsequent development is characterized by learned inhibition. The fourth explanation concerns the motivational mechanisms controlling aggression: approached from an evolutionary background, these mechanisms range from the inflexible reflex-like responses to those incorporating rational decision-making.

  11. The biological age linked to oxidative stress modifies breast cancer aggressiveness.

    PubMed

    Sáez-Freire, María Del Mar; Blanco-Gómez, Adrián; Castillo-Lluva, Sonia; Gómez-Vecino, Aurora; Galvis-Jiménez, Julie Milena; Martín-Seisdedos, Carmen; Isidoro-García, María; Hontecillas-Prieto, Lourdes; García-Cenador, María Begoña; García-Criado, Francisco Javier; Patino-Alonso, María Carmen; Galindo-Villardón, Purificación; Mao, Jian-Hua; Prieto, Carlos; Castellanos-Martín, Andrés; Kaderali, Lars; Pérez-Losada, Jesús

    2018-05-20

    The incidence of breast cancer increases with age until menopause, and breast cancer is more aggressive in younger women. The existence of epidemiological links between breast cancer and aging indicates that both processes share some common mechanisms of development. Oxidative stress is associated with both cancer susceptibility and aging. Here we observed that ERBB2-positive breast cancer, which developed in genetically heterogeneous ERBB2-positive transgenic mice generated by a backcross, is more aggressive in chronologically younger than in older mice (differentiated by the median survival of the cohort that was 79 weeks), similar to what occurs in humans. In this cohort, we estimated the oxidative biological age using a mathematical model that integrated several subphenotypes directly or indirectly related to oxidative stress. The model selected the serum levels of HDL-cholesterol and magnesium and total AKT1 and glutathione concentrations in the liver. The grade of aging was calculated as the difference between the predicted biological age and the chronological age. This comparison permitted the identification of biologically younger and older mice compared with their chronological age. Interestingly, biologically older mice developed more aggressive breast cancer than the biologically younger mice. Genomic regions on chromosomes 2 and 15 linked to the grade of oxidative aging were identified. The levels of expression of Zbp1 located on chromosome 2, a gene related to necroptosis and inflammation, positively correlated with the grade of aging and tumour aggressiveness. Moreover, the pattern of gene expression of genes linked to the inflammation and the response to infection pathways was enriched in the livers of biologically old mice. This study shows part of the complex interactions between breast cancer and aging. Copyright © 2018 Elsevier Inc. All rights reserved.

  12. C/EBPα-dependent preneoplastic tumor foci are the origin of hepatocellular carcinoma and aggressive pediatric liver cancer.

    PubMed

    Cast, Ashley; Valanejad, Leila; Wright, Mary; Nguyen, Phuong; Gupta, Anita; Zhu, Liqin; Shin, Soona; Timchenko, Nikolai

    2018-05-01

    Recent publications show that classic hepatoblastoma (HBL) is the result of failure of hepatic stem cells to differentiate into hepatocytes, while hepatocellular carcinoma (HCC) is caused by the dedifferentiation of hepatocytes into cancer stem cells. However, the mechanisms of aggressive HBL and the mechanisms that cause dedifferentiation of hepatocytes into cancer stem cells are unknown. We found that, similar to HCC but opposite to classic HBL, aggressive HBL is the result of dedifferentiation of hepatocytes into cancer stem cells. In both cases of liver cancer, the dephosphorylation of tumor suppressor protein CCAAT/enhancer binding protein α (C/EBPα) at Ser193 (Ser190 in human protein) or mutation of Ser193 to Ala results in a modified protein with oncogenic activities. We have investigated liver cancer in a mouse model C/EBPα-S193A, in a large cohort of human HBL samples, and in Pten/p53 double knockout mice and found that these cancers are characterized by elevation of C/EBPα that is dephosphorylated at Ser190/193. We found that dephosphorylated C/EBPα creates preneoplastic foci with cancer stem cells that give rise to HCC and aggressive HBL. C/EBPα-dependent dedifferentiation of hepatocytes into cancer stem cells includes increased proliferation of hepatocytes, followed by generation of multinucleated hepatocytes and subsequent appearance of hepatocytes with delta-like 1 homolog-positive intranuclear inclusions. We further isolated C/EBPα-dependent multinucleated hepatocytes and found that they possess characteristics of tumor-initiating cells, including elevation of stem cell markers. C/EBPα-dependent cancer stem cells are observed in patients with aggressive HBL and in patients with a predisposition for liver cancer. The earliest steps of adult HCC and aggressive pediatric liver cancer have identical features that include conversion of the tumor suppressor C/EBPα into an oncogenic isoform, which further creates preneoplastic foci where

  13. microRNA in Prostate Cancer Racial Disparities and Aggressiveness

    DTIC Science & Technology

    2015-10-01

    1 AWARD NUMBER: W81XWH-13-1-0477 TITLE: microRNA in Prostate Cancer Racial Disparities and Aggressiveness PRINCIPAL INVESTIGATOR: Cathryn...microRNA in Prostate Cancer Racial Disparities and Aggressiveness 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-13-1-0477 5c. PROGRAM ELEMENT NUMBER...final analyses. 15. SUBJECT TERMS prostate cancer, microRNA, racial disparities, African American, genetic polymorphisms, biochemical recurrence

  14. Label free aggressive prostate cancer identification with ultraviolet photoacoustic spectral analysis (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Xu, Guan; Davis, Mandy A.; Siddiqui, Javed; Chao, Wan-yu; Tomlins, Scott A.; Wei, John T.; Wang, Xueding

    2017-03-01

    Prostate cancer (PCa) is the most commonly diagnosed cancer in American men for the past decades. PCa has a relatively low progression rate but the 5 year survival rate decreases dramatically once the cancer has metastasized. Differentiating aggressive from indolent PCa is critical for improving PCa patient outcomes and preventing metastasis and death. Prostate biopsy is the standard procedure for evaluating the presence and aggressiveness of PCa. The microarchitecture of the biopsied tissues visualized by histology process is evaluated by pathologists and assigned a Gleason score as a quantification of the aggressiveness. In our previous study, we have shown that photoacoustic spectral analysis (PASA) is capable of quantifying the Gleason scores of the H&E stained human prostate tissues. In this study, we attempt to assess the Gleason scores without any staining by taking advantage of the strong optical absorption of nucleic acid at ultraviolet wavelengths. PA signals were generated by wide field illumination at 266 nm and received by a hydrophone with a bandwidth of 0-20 MHz. DU145 prostate cancer cells at the concentrations of 0.8, 0.4, 0.05, 0.025 and 0.0125 million per cm3 simulating those in cancerous and normal tissues were first attempted. The measurements were repeated for 10 times at each concentration. A correlation of 0.86 was observed between the PA signal intensities and the cell concentrations. Human PCa tissues with Gleason score 6, 7 and 8 and normal tissues were assessed. With 11 samples, a correlation of 0.89 was found between the Gleason scores and PASA slopes.

  15. Injuries due to human and animal aggression in humans.

    PubMed

    Łabęcka, Marzena; Lorkiewicz-Muszyńska, Dorota E; Przystańska, Agnieszka; Kondrusiewicz, Krzysztof

    2013-01-01

    People breed animals, professionally take care of them, and work with them. To live with animals, however, it is necessary to know their behaviour and habits, as well as fears. Ignorance of this knowledge may lead to tragedy for the victim (a person), as well as for the beast (animal). Then, nobody cares whether the animal behaved itself or not in accordance with its nature. The aim of the presented study is to compare the rate of animal aggression in relation to cases of documented aggression towards humans. The victims were investigated according to the age, gender and types of injuries caused by animal bites. The protocols of autopsies (2,218) and medical-legal examinations (4,569) performed from 2004-2009 in the Department of Forensic Sciences in Poznań were analyzed. The selected data was studied using Microsoft Office Excel 2007 for Windows. Analysis revealed the presence of animal bite injuries in less than 1% of the deceased victims of aggression. The number of individuals who died as a result of animal bites varied from 1-4 a year, and in all cases these were postmortem injuries. Analysis of injuries among surviving victims of aggression showed animal bite injuries were present in 41 out of 4,569 victims, almost equally among males and females. Moreover, in 25 victims the bite injuries recognized as human were found. The majority of animal bites occurred in adults. The medium injuries were the most frequent in the animal bite victims. Animal aggression is a marginal problem considering all cases of aggression towards humans. In contrast to the aggression of humans towards other humans, this is a very rare cause of human death or even major injury.

  16. Prostate Health Index improves multivariable risk prediction of aggressive prostate cancer.

    PubMed

    Loeb, Stacy; Shin, Sanghyuk S; Broyles, Dennis L; Wei, John T; Sanda, Martin; Klee, George; Partin, Alan W; Sokoll, Lori; Chan, Daniel W; Bangma, Chris H; van Schaik, Ron H N; Slawin, Kevin M; Marks, Leonard S; Catalona, William J

    2017-07-01

    To examine the use of the Prostate Health Index (PHI) as a continuous variable in multivariable risk assessment for aggressive prostate cancer in a large multicentre US study. The study population included 728 men, with prostate-specific antigen (PSA) levels of 2-10 ng/mL and a negative digital rectal examination, enrolled in a prospective, multi-site early detection trial. The primary endpoint was aggressive prostate cancer, defined as biopsy Gleason score ≥7. First, we evaluated whether the addition of PHI improves the performance of currently available risk calculators (the Prostate Cancer Prevention Trial [PCPT] and European Randomised Study of Screening for Prostate Cancer [ERSPC] risk calculators). We also designed and internally validated a new PHI-based multivariable predictive model, and created a nomogram. Of 728 men undergoing biopsy, 118 (16.2%) had aggressive prostate cancer. The PHI predicted the risk of aggressive prostate cancer across the spectrum of values. Adding PHI significantly improved the predictive accuracy of the PCPT and ERSPC risk calculators for aggressive disease. A new model was created using age, previous biopsy, prostate volume, PSA and PHI, with an area under the curve of 0.746. The bootstrap-corrected model showed good calibration with observed risk for aggressive prostate cancer and had net benefit on decision-curve analysis. Using PHI as part of multivariable risk assessment leads to a significant improvement in the detection of aggressive prostate cancer, potentially reducing harms from unnecessary prostate biopsy and overdiagnosis. © 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.

  17. Zika Virus Selectively Kills Aggressive Human Embryonal CNS Tumor Cells In Vitro and In Vivo.

    PubMed

    Kaid, Carolini; Goulart, Ernesto; Caires-Júnior, Luiz C; Araujo, Bruno H S; Soares-Schanoski, Alessandra; Bueno, Heloisa M S; Telles-Silva, Kayque A; Astray, Renato M; Assoni, Amanda F; Júnior, Antônio F R; Ventini, Daniella C; Puglia, Ana L P; Gomes, Roselane P; Zatz, Mayana; Okamoto, Oswaldo K

    2018-06-15

    Zika virus (ZIKV) is largely known for causing brain abnormalities due to its ability to infect neural progenitor stem cells during early development. Here, we show that ZIKV is also capable of infecting and destroying stem-like cancer cells from aggressive human embryonal tumors of the central nervous system (CNS). When evaluating the oncolytic properties of Brazilian Zika virus strain (ZIKV BR ) against human breast, prostate, colorectal, and embryonal CNS tumor cell lines, we verified a selective infection of CNS tumor cells followed by massive tumor cell death. ZIKV BR was more efficient in destroying embryonal CNS tumorspheres than normal stem cell neurospheres. A single intracerebroventricular injection of ZIKV BR in BALB/c nude mice bearing orthotopic human embryonal CNS tumor xenografts resulted in a significantly longer survival, decreased tumor burden, fewer metastasis, and complete remission in some animals. Tumor cells closely resembling neural stem cells at the molecular level with activated Wnt signaling were more susceptible to the oncolytic effects of ZIKV BR Furthermore, modulation of Wnt signaling pathway significantly affected ZIKV BR -induced tumor cell death and viral shedding. Altogether, these preclinical findings indicate that ZIKV BR could be an efficient agent to treat aggressive forms of embryonal CNS tumors and could provide mechanistic insights regarding its oncolytic effects. Significance: Brazilian Zika virus strain kills aggressive metastatic forms of human CNS tumors and could be a potential oncolytic agent for cancer therapy. Cancer Res; 78(12); 3363-74. ©2018 AACR . ©2018 American Association for Cancer Research.

  18. Breast Cancers Between Mammograms Have Aggressive Features

    Cancer.gov

    Breast cancers that are discovered in the period between regular screening mammograms—known as interval cancers—are more likely to have features associated with aggressive behavior and a poor prognosis than cancers found via screening mammograms.

  19. Early development of physical aggression and early risk factors for chronic physical aggression in humans.

    PubMed

    Tremblay, Richard E

    2014-01-01

    This chapter describes the state of knowledge on the development of physical aggression from early childhood to adulthood, the long term outcomes of chronic physical aggression during childhood and the risk factors for chronic physical aggression. Unraveling the development of physical aggression is important to understand when and why humans start using physical aggression, to understand why some humans suffer from chronic physical aggression and to understand how to prevent the development of this disorder which causes much distress to the aggressors and their victims. The study of the developmental origins of aggression also sheds light on the reasons why situational prevention of aggression is important at all ages and in all cultures.

  20. Melatonin increases reactive aggression in humans.

    PubMed

    Liu, Jinting; Zhong, Ru; Xiong, Wei; Liu, Haibo; Eisenegger, Christoph; Zhou, Xiaolin

    2017-10-01

    Melatonin, a hormone released preferentially by the pineal gland during the night, affects circadian rhythms and aging processes. As animal studies have shown that melatonin increases resident-intruder aggression, this study aimed to investigate the impact of melatonin treatment on human aggression. In a double-blind, randomized, placebo-controlled between-participant design, 63 healthy male volunteers completed the Taylor Aggression Paradigm (TAP) after oral administration of melatonin or placebo. We found that when given the opportunity to administer high or low punishments to an opponent, participants who ingested melatonin selected the high punishment more often than those who ingested placebo. The increased reactive aggression under melatonin administration remained after controlling for inhibitory ability, trait aggression, trait impulsiveness, circadian preference, perceptual sensibility to noise, and changes in subjective sleepiness and emotional states. This study provides novel and direct evidence for the involvement of melatonin in human social processes.

  1. Human-wildlife conflict: proximate predictors of aggression between humans and rhesus macaques in India.

    PubMed

    Beisner, Brianne A; Heagerty, Allison; Seil, Shannon K; Balasubramaniam, Krishna N; Atwill, Edward R; Gupta, Brij K; Tyagi, Praveen C; Chauhan, Netrapal P S; Bonal, B S; Sinha, P R; McCowan, Brenda

    2015-02-01

    Macaques live in close contact with humans across South and Southeast Asia, and direct interaction is frequent. Aggressive contact is a concern in many locations, particularly among populations of rhesus and longtail macaques that co-inhabit urbanized cities and towns with humans. We investigated the proximate factors influencing the occurrence of macaque aggression toward humans as well as human aggression toward macaques to determine the extent to which human behavior elicits macaque aggression and vice versa. We conducted a 3-month study of four free-ranging populations of rhesus macaques in Dehradun, India from October-December 2012, using event sampling to record all instances of human-macaque interaction (N = 3120). Our results show that while human aggression was predicted by the potential for economic losses or damage, macaque aggression was influenced by aggressive or intimidating behavior by humans as well as recent rates of conspecific aggression. Further, adult female macaques participated in aggression more frequently than expected, whereas adult and subadult males participated as frequently as expected. Our analyses demonstrate that neither human nor macaque aggression is unprovoked. Rather, both humans and macaques are responding to one another's behavior. Mitigation of human-primate conflict, and indeed other types of human-wildlife conflict in such coupled systems, will require a holistic investigation of the ways in which each participant is responding to, and consequently altering, the behavior of the other. © 2015 Wiley Periodicals, Inc.

  2. Leptin increases prostate cancer aggressiveness.

    PubMed

    López Fontana, Constanza M; Maselli, María E; Pérez Elizalde, Rafael F; Di Milta Mónaco, Nicolás A; Uvilla Recupero, Ana L; López Laur, José D

    2011-12-01

    Recent studies indicate that adipose tissue and adipocytokines might affect the development of prostate cancer (PCa). Leptin would have a stimulating effect on prostate cancer cells by inducing promotion and progression, whereas adiponectin would have a protective effect. The aim of this study was to determine the relation between body composition, leptin, and adiponectin levels with the prevalence and aggressiveness of PCa in men of Mendoza, Argentina. Seventy volunteers between 50 and 80 years (35 healthy men as control group and 35 with PCa) were selected. The PCa group was subclassified according to the Gleason Score (GS). Digital rectal examination, transrectal ultrasound, and prostatic biopsy were performed; PSA, testosterone, leptin, and adiponectin levels were determined; and a nutritional interview including anthropometric measurements and a food frequency questionnaire was carried out. Statistical analysis was performed by Student t test, ANOVA I, and Bonferroni (p < 0.05). Body mass index and percentage of body fat mass were not statistically different between PCa and control groups. However, body fat mass was higher in subjects with more aggressive tumors (p = 0.032). No differences were observed regarding leptin levels between the groups. Nevertheless, leptin levels were higher in subjects with high GS (p < 0.001). Adiponectin levels showed no statistical differences regarding the presence and aggressiveness of the tumor (p = 0.131). Finally, consumption and nutrient intake did not differ in the studied groups. In conclusion, body composition and leptin are related to the PCa aggressiveness but not with its prevalence.

  3. Making Aggressive Prostate Cancer Quiescent by Abrogating Cholesterol Esterification

    DTIC Science & Technology

    2015-10-01

    AWARD NUMBER: W81XWH-14-1-0557 TITLE: Making Aggressive Prostate Cancer Quiescent by Abrogating Cholesterol Esterification PRINCIPAL...Aggressive Prostate Cancer Quiescent by Abrogating Cholesterol Esterification 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0557 5c. PROGRAM...application is to establish the viability of a new strategy of treating late stage PCa through therapeutic targeting of cholesterol metabolism in vivo

  4. Assessing the extent of non-aggressive cancer in clinically detected stage I non-small cell lung cancer.

    PubMed

    Kale, Minal S; Sigel, Keith; Mhango, Grace; Wisnivesky, Juan P

    2018-05-01

    Overdiagnosis among clinically detected lung cancers likely consists of cases that are non-aggressive and slowly progressive and will never disseminate, cause symptoms or be a threat to a subject's survival, even if untreated. In this study, we estimate the prevalence of non-aggressive lung cancers from a large, population-based cancer registry. We identified individuals ≥65 years with histologically confirmed, untreated stage I non-small cell lung cancers (NSCLCs) from the Surveillance, Epidemiology, and End Results-Medicare registry. We estimated the rate of non-aggressive lung cancers by determining the point at which the cumulative lung cancer-specific survival curve no longer changed (ie, the slope approaches zero). At this point, there are no additional deaths due to progressive lung cancer observed among untreated patients after adjusting for deaths from competing risks (these long-term survivors can be considered 'non-aggressive cases). The overall rate of non-aggressive cancers among 2197 clinically detected cases of untreated stage I NSCLC was 2.4%, 95% CI: 1.0% to 3.8%. The rate of non-aggressive cancer was 1.9% (95% CI: 0.0% to 4.9%) for women and 2.4% (95% CI: 0.7% to 4.1%) for men (p=0.84). When stratifying by tumour size, non-aggressive cancer rates were 10.2% (95% CI: 0.0% to 29.3%), 2.1% (95% CI: 0.0% to 9.2%), 4.9% (95% CI: 0.0% to 10.3%), 1.8% (95% CI: 0.0% to 5.2%) and 0.0% (95% CI: 0.0% to 1.0%) for tumour sizes <15 mm, 15-24 mm, 25-34 mm, 35-44 mm and ≥45 mm, respectively. In comparison with the smallest tumour sizes (<15 mm), the rates of non-aggressive cancers were not statistically significantly different for tumour sizes 15-24 mm (p=0.36), 25-34 mm (p=0.57), 35-44 mm (p=0.38) and tumour sizes >45 mm (p=0.30). We found relatively low rates of non-aggressive cancers among clinically detected, stage I NSCLC regardless of sex or size. Our findings suggest that most clinically diagnosed early stage cancers should be treated with

  5. Identification and treatment of aggressive thyroid cancers. Part 1: subtypes.

    PubMed

    Sturgeon, Cord; Angelos, Peter

    2006-03-01

    Most thyroid cancers are slow-growing, easily treatable tumors with an excellent prognosis after surgical resection and targeted medical therapy. Unfortunately, 10% to 15% of thyroid cancers exhibit aggressive behavior and do not follow an indolent course. Approximately one-third of patients with differentiated thyroid cancers will have tumor recurrences. Distant metastases are present in about 20% of patients with recurrent cancer. Approximately half of patients with distant metastases die within 5 years. The loss of the ability to concentrate radioiodine and produce thyroglobulin is a sign of dedifferentiation, which occurs in about 30% of patients with persistent or recurrent thyroid cancer. Dedifferentiation is associated with poorer responses to conventional therapy and difficulty monitoring tumor burden. Clinicians must identify tumors with more aggressive biology and treat them accordingly with more aggressive regimens. Part 1 of this two-part article describes in detail the distinct types of thyroid cancer, as well as risk factors, outcomes, and prognostic factors, with a focus on thyroid cancers of follicular cell origin. Part 2, which will appear in next month's issue, covers risk assessment and staging, findings that suggest the presence of aggressive tumors, recurrent/metastatic disease, and the value of treatment with chemotherapy and external-beam radiotherapy. Experimental treatments utilizing molecular targets, redifferentiation agents, and gene therapy are covered briefly as well.

  6. SRC: marker or actor in prostate cancer aggressiveness.

    PubMed

    Vlaeminck-Guillem, Virginie; Gillet, Germain; Rimokh, Ruth

    2014-01-01

    A key question for urologic practitioners is whether an apparently organ-confined prostate cancer (PCa) is actually aggressive or not. The dilemma is to specifically identify among all prostate tumors the very aggressive high-grade cancers that will become life-threatening by developing extra-prostatic invasion and metastatic potential and the indolent cancers that will never modify a patient's life expectancy. A choice must be made between several therapeutic options to achieve the optimal personalized management of the disease that causes as little harm as possible to patients. Reliable clinical, biological, or pathological markers that would enable distinctions to be made between aggressive and indolent PCas in routine practice at the time of initial diagnosis are still lacking. The molecular mechanisms that explain why a PCa is aggressive or not are also poorly understood. Among the potential markers and/or actors in PCa aggressiveness, Src and other members of the Src kinase family, are valuable candidates. Activation of Src-dependent intracellular pathways is frequently observed in PCa. Indeed, Src is at the cross-roads of several pathways [including androgen receptor (AR), TGFbeta, Bcl-2, Akt/PTEN or MAPK, and ERK …], and is now known to influence some of the cellular and tissular events that accompany tumor progression: cell proliferation, cell motility, invasion, epithelial-to-mesenchymal transition, resistance to apoptosis, angiogenesis, neuroendocrine differentiation, and metastatic spread. Recent work even suggests that Src could also play a part in PCa initiation in coordination with the AR. The aim of this review is to gather data that explore the links between the Src kinase family and PCa progression and aggressiveness.

  7. Calix[6]arene bypasses human pancreatic cancer aggressiveness: downregulation of receptor tyrosine kinases and induction of cell death by reticulum stress and autophagy.

    PubMed

    Pelizzaro-Rocha, Karin Juliane; de Jesus, Marcelo Bispo; Ruela-de-Sousa, Roberta Regina; Nakamura, Celso Vataru; Reis, Fabiano Souza; de Fátima, Angelo; Ferreira-Halder, Carmen Veríssima

    2013-12-01

    Pancreatic cancer ranks fourth among cancer-related causes of death in North America. Minimal progress has been made in the diagnosis and treatment of patients with late-stage tumors. Moreover, pancreatic cancer aggressiveness is closely related to high levels of pro-survival mediators, which can ultimately lead to rapid disease progression, resistance and metastasis. The main goal of this study was to define the mechanisms by which calix[6]arene, but not other calixarenes, efficiently decreases the aggressiveness of a drug resistant human pancreas carcinoma cell line (Panc-1). Calix[6]arene was more potent in reducing Panc-1 cell viability than gemcitabine and 5-fluorouracil. In relation to the underlying mechanisms of cytotoxic effects, it led to cell cycle arrest in the G0/G1 phase through downregulation of PIM1, CDK2, CDK4 and retinoblastoma proteins. Importantly, calix[6]arene abolished signal transduction of Mer and AXL tyrosine kinase receptors, both of which are usually overexpressed in pancreatic cancer. Accordingly, inhibition of PI3K and mTOR was also observed, and these proteins are positively modulated by Mer and AXL. Despite decreasing the phosphorylation of AKT at Thr308, calix[6]arene caused an increase in phosphorylation at Ser473. These findings in conjunction with increased BiP and IRE1-α provide a molecular basis explaining the capacity of calix[6]arene to trigger endoplasmic reticulum stress and autophagic cell death. Our findings highlight calix[6]arene as a potential candidate for overcoming pancreatic cancer aggressiveness. Importantly, we provide evidence that calix[6]arene affects a broad array of key targets that are usually dysfunctional in pancreatic cancer, a highly desirable characteristic for chemotherapeutics. © 2013.

  8. Identifying aggressive prostate cancer foci using a DNA methylation classifier.

    PubMed

    Mundbjerg, Kamilla; Chopra, Sameer; Alemozaffar, Mehrdad; Duymich, Christopher; Lakshminarasimhan, Ranjani; Nichols, Peter W; Aron, Manju; Siegmund, Kimberly D; Ukimura, Osamu; Aron, Monish; Stern, Mariana; Gill, Parkash; Carpten, John D; Ørntoft, Torben F; Sørensen, Karina D; Weisenberger, Daniel J; Jones, Peter A; Duddalwar, Vinay; Gill, Inderbir; Liang, Gangning

    2017-01-12

    Slow-growing prostate cancer (PC) can be aggressive in a subset of cases. Therefore, prognostic tools to guide clinical decision-making and avoid overtreatment of indolent PC and undertreatment of aggressive disease are urgently needed. PC has a propensity to be multifocal with several different cancerous foci per gland. Here, we have taken advantage of the multifocal propensity of PC and categorized aggressiveness of individual PC foci based on DNA methylation patterns in primary PC foci and matched lymph node metastases. In a set of 14 patients, we demonstrate that over half of the cases have multiple epigenetically distinct subclones and determine the primary subclone from which the metastatic lesion(s) originated. Furthermore, we develop an aggressiveness classifier consisting of 25 DNA methylation probes to determine aggressive and non-aggressive subclones. Upon validation of the classifier in an independent cohort, the predicted aggressive tumors are significantly associated with the presence of lymph node metastases and invasive tumor stages. Overall, this study provides molecular-based support for determining PC aggressiveness with the potential to impact clinical decision-making, such as targeted biopsy approaches for early diagnosis and active surveillance, in addition to focal therapy.

  9. Understanding human aggression: New insights from neuroscience.

    PubMed

    Siegel, Allan; Victoroff, Jeff

    2009-01-01

    The present paper reviews and summarizes the basic findings concerning the nature of the neurobiological and behavioral characteristics of aggression and rage. For heuristic purposes, the types of aggression will be reduced to two categories - defensive rage (affective defense) and predatory attack. This approach helps explain both the behavioral properties of aggression as well as the underlying neural substrates and mechanisms of aggression both in animals and humans. Defensive rage behavior is activated by a threatening stimulus that is real or perceived and is associated with marked sympathetic output. This yields impulsivity with minimal cortical involvement. Predatory attack behavior in both animals and humans is generally planned, taking minutes, hours, days, weeks, months, or even years (with respect to humans) for it to occur and is directed upon a specific individual target; it reflects few outward sympathetic signs and is believed to require cortical involvement for its expression. Predatory attack requires activation of the lateral hypothalamus, while defensive rage requires activation of the medial hypothalamus and midbrain periaqueductal gray (PAG). Both forms of aggressive behavior are controlled by components of the limbic system, a region of the forebrain that is influenced by sensory inputs from the cerebral cortex and monoaminergic inputs from the brainstem reticular formation. Control of aggressive tendencies is partly modifiable through conditioning and related learning principles generated through the cerebral cortex.

  10. Glucose-regulated protein of 94 kDa contributes to the development of an aggressive phenotype in breast cancer cells.

    PubMed

    Buc Calderon, Pedro; Sennesael, Anne-Laure; Glorieux, Christophe

    2018-05-28

    Grp94 plays an essential role in protein assembly. We previously suggested that Grp94 overexpression is involved in tumor aggressiveness. However, the underlying mechanisms remain unknown. Since many tumors display high Grp94 levels, we investigated the effects of tumor microenvironment on the regulation of this chaperone expression. First, we found out that hypoxia did not change Grp94 expression in the human tumor cell lines MCF-7 (breast cancer) and HepG2 (liver cancer). Second, glucose deprivation significantly increased Grp94 protein levels. Subsequently, we focused in the putative role of Grp94 in the acquisition of an aggressive phenotype by cancer cells. Using a more aggressive cancer cell model (MDA-MB-231 breast tumor cells), we found out that Grp94 knockdown using siRNA decreased the invasive capacity of cancer cells. Moreover, cells with decreased Grp94 levels displayed an enhanced sensitivity of tumor cells to doxorubicin, a standard drug in the treatment of breast cancer. Taken together, our results suggest that the expression of Grp94 is linked to tumor aggressiveness. Therefore, targeting Grp94 could be an effective way to inhibit tumor growth improving chemotherapy outcome. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  11. A mouse model for triple-negative breast cancer tumor-initiating cells (TNBC-TICs) exhibits similar aggressive phenotype to the human disease.

    PubMed

    Kaur, Punit; Nagaraja, Ganachari M; Zheng, Hongying; Gizachew, Dawit; Galukande, Moses; Krishnan, Sunil; Asea, Alexzander

    2012-03-27

    Triple-negative breast cancer (TNBC) exhibit characteristics quite distinct from other kinds of breast cancer, presenting as an aggressive disease--recurring and metastasizing more often than other kinds of breast cancer, without tumor-specific treatment options and accounts for 15% of all types of breast cancer with higher percentages in premenopausal African-American and Hispanic women. The reason for this aggressive phenotype is currently the focus of intensive research. However, progress is hampered by the lack of suitable TNBC cell model systems. To understand the mechanistic basis for the aggressiveness of TNBC, we produced a stable TNBC cell line by sorting for 4T1 cells that do not express the estrogen receptor (ER), progesterone receptor (PgR) or the gene for human epidermal growth factor receptor 2 (HER2). As a control, we produced a stable triple-positive breast cancer (TPBC) cell line by transfecting 4T1 cells with rat HER2, ER and PgR genes and sorted for cells with high expression of ER and PgR by flow cytometry and high expression of the HER2 gene by Western blot analysis. We isolated tumor-initiating cells (TICs) by sorting for CD24+/CD44high/ALDH1+ cells from TNBC (TNBC-TICs) and TPBC (TPBC-TICs) stable cell lines. Limiting dilution transplantation experiments revealed that CD24+/CD44high/ALDH1+ cells derived from TNBC (TNBC-TICs) and TPBC (TPBC-TICs) were significantly more effective at repopulating the mammary glands of naïve female BALB/c mice than CD24-/CD44-/ALDH1- cells. Implantation of the TNBC-TICs resulted in significantly larger tumors, which metastasized to the lungs to a significantly greater extent than TNBC, TPBC-TICs, TPBC or parental 4T1 cells. We further demonstrated that the increased aggressiveness of TNBC-TICs correlates with the presence of high levels of mouse twenty-five kDa heat shock protein (Hsp25/mouse HspB1) and seventy-two kDa heat shock protein (Hsp72/HspA1A). Taken together, we have developed a TNBC-TICs model system

  12. A mouse model for triple-negative breast cancer tumor-initiating cells (TNBC-TICs) exhibits similar aggressive phenotype to the human disease

    PubMed Central

    2012-01-01

    Background Triple-negative breast cancer (TNBC) exhibit characteristics quite distinct from other kinds of breast cancer, presenting as an aggressive disease--recurring and metastasizing more often than other kinds of breast cancer, without tumor-specific treatment options and accounts for 15% of all types of breast cancer with higher percentages in premenopausal African-American and Hispanic women. The reason for this aggressive phenotype is currently the focus of intensive research. However, progress is hampered by the lack of suitable TNBC cell model systems. Methods To understand the mechanistic basis for the aggressiveness of TNBC, we produced a stable TNBC cell line by sorting for 4T1 cells that do not express the estrogen receptor (ER), progesterone receptor (PgR) or the gene for human epidermal growth factor receptor 2 (HER2). As a control, we produced a stable triple-positive breast cancer (TPBC) cell line by transfecting 4T1 cells with rat HER2, ER and PgR genes and sorted for cells with high expression of ER and PgR by flow cytometry and high expression of the HER2 gene by Western blot analysis. Results We isolated tumor-initiating cells (TICs) by sorting for CD24+/CD44high/ALDH1+ cells from TNBC (TNBC-TICs) and TPBC (TPBC-TICs) stable cell lines. Limiting dilution transplantation experiments revealed that CD24+/CD44high/ALDH1+ cells derived from TNBC (TNBC-TICs) and TPBC (TPBC-TICs) were significantly more effective at repopulating the mammary glands of naïve female BALB/c mice than CD24-/CD44-/ALDH1- cells. Implantation of the TNBC-TICs resulted in significantly larger tumors, which metastasized to the lungs to a significantly greater extent than TNBC, TPBC-TICs, TPBC or parental 4T1 cells. We further demonstrated that the increased aggressiveness of TNBC-TICs correlates with the presence of high levels of mouse twenty-five kDa heat shock protein (Hsp25/mouse HspB1) and seventy-two kDa heat shock protein (Hsp72/HspA1A). Conclusions Taken together, we

  13. BRCA1-IRIS Overexpression Promotes Formation of Aggressive Breast Cancers

    PubMed Central

    Shimizu, Yoshiko; Luk, Hugh; Horio, David; Miron, Penelope; Griswold, Michael; Iglehart, Dirk; Hernandez, Brenda; Killeen, Jeffrey; ElShamy, Wael M.

    2012-01-01

    Introduction Women with HER2+ or triple negative/basal-like (TN/BL) breast cancers succumb to their cancer rapidly due, in part to acquired Herceptin resistance and lack of TN/BL-targeted therapies. BRCA1-IRIS is a recently discovered, 1399 residue, BRCA1 locus alternative product, which while sharing 1365 residues with the full-length product of this tumor suppressor gene, BRCA1/p220, it has oncoprotein-like properties. Here, we examine whether BRCA1-IRIS is a valuable treatment target for HER2+ and/or TN/BL tumors. Methodology/Principal Findings Immunohistochemical staining of large cohort of human breast tumor samples using new monoclonal anti-BRCA1-IRIS antibody, followed by correlation of BRCA1-IRIS expression with that of AKT1, AKT2, p-AKT, survivin and BRCA1/p220, tumor status and age at diagnosis. Generation of subcutaneous tumors in SCID mice using human mammary epithelial (HME) cells overexpressing TERT/LT/BRCA1-IRIS, followed by comparing AKT, survivin, and BRCA1/p220 expression, tumor status and aggressiveness in these tumors to that in tumors developed using TERT/LT/RasV12-overexpressing HME cells. Induction of primary and invasive rat mammary tumors using the carcinogen N-methyl-N-nitrosourea (NMU), followed by analysis of rat BRCA1-IRIS and ERα mRNA levels in these tumors. High BRCA1-IRIS expression was detected in the majority of human breast tumors analyzed, which was positively correlated with that of AKT1-, AKT2-, p-AKT-, survivin, but negatively with BRCA1/p220 expression. BRCA1-IRIS-positivity induced high-grade, early onset and metastatic HER2+ or TN/BL tumors. TERT/LT/BRCA1-IRIS overexpressing HME cells formed invasive subcutaneous tumors that express high AKT1, AKT2, p-AKT and vimentin, but no CK19, p63 or BRCA1/p220. NMU-induced primary and invasive rat breast cancers expressed high levels of rat BRCA1-IRIS mRNA but low levels of rat ERα mRNA. Conclusion/Significance BRCA1-IRIS overexpression triggers aggressive breast tumor formation

  14. KIAA0100 Modulates Cancer Cell Aggression Behavior of MDA-MB-231 through Microtubule and Heat Shock Proteins.

    PubMed

    Zhong, Zhenyu; Pannu, Vaishali; Rosenow, Matthew; Stark, Adam; Spetzler, David

    2018-06-04

    The KIAA0100 gene was identified in the human immature myeloid cell line cDNA library. Recent studies have shown that its expression is elevated in breast cancer and associated with more aggressive cancer types as well as poor outcomes. However, its cellular and molecular function is yet to be understood. Here we show that silencing KIAA0100 by siRNA in the breast cancer cell line MDA-MB-231 significantly reduced the cancer cells' aggressive behavior, including cell aggregation, reattachment, cell metastasis and invasion. Most importantly, silencing the expression of KIAA0100 particularly sensitized the quiescent cancer cells in suspension culture to anoikis. Immunoprecipitation, mass spectrometry and immunofluorescence analysis revealed that KIAA0100 may play multiple roles in the cancer cells, including stabilizing microtubule structure as a microtubule binding protein, and contributing to MDA-MB-231 cells Anoikis resistance by the interaction with stress protein HSPA1A. Our study also implies that the interaction between KIAA0100 and HSPA1A may be targeted for new drug development to specifically induce anoikis cell death in the cancer cell.

  15. Msi2 Regulates the Aggressiveness of Non Small Cell Lung Cancer (NSCLC)

    DTIC Science & Technology

    2016-10-01

    AWARD NUMBER: W81XWH-15-1-0192 TITLE: Msi2 Regulates the Aggressiveness of Non -Small Cell Lung Cancer (NSCLC) PRINCIPAL INVESTIGATOR: Yanis...Annual 3. DATES COVERED (From - To) 15 Sep 2015 - 14 Sep 2016 4. TITLE AND SUBTITLE Msi2 Regulates the Aggressiveness of Non -Small Cell Lung Cancer...in vitro and in vivo are ongoing, while immunohistochemistry studies are starting Fall 2016. 15. SUBJECT TERMS Non -small cell lung cancer

  16. Development of a stress response therapy targeting aggressive prostate cancer.

    PubMed

    Nguyen, Hao G; Conn, Crystal S; Kye, Yae; Xue, Lingru; Forester, Craig M; Cowan, Janet E; Hsieh, Andrew C; Cunningham, John T; Truillet, Charles; Tameire, Feven; Evans, Michael J; Evans, Christopher P; Yang, Joy C; Hann, Byron; Koumenis, Constantinos; Walter, Peter; Carroll, Peter R; Ruggero, Davide

    2018-05-02

    Oncogenic lesions up-regulate bioenergetically demanding cellular processes, such as protein synthesis, to drive cancer cell growth and continued proliferation. However, the hijacking of these key processes by oncogenic pathways imposes onerous cell stress that must be mitigated by adaptive responses for cell survival. The mechanism by which these adaptive responses are established, their functional consequences for tumor development, and their implications for therapeutic interventions remain largely unknown. Using murine and humanized models of prostate cancer (PCa), we show that one of the three branches of the unfolded protein response is selectively activated in advanced PCa. This adaptive response activates the phosphorylation of the eukaryotic initiation factor 2-α (P-eIF2α) to reset global protein synthesis to a level that fosters aggressive tumor development and is a marker of poor patient survival upon the acquisition of multiple oncogenic lesions. Using patient-derived xenograft models and an inhibitor of P-eIF2α activity, ISRIB, our data show that targeting this adaptive brake for protein synthesis selectively triggers cytotoxicity against aggressive metastatic PCa, a disease for which presently there is no cure. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  17. Boswellia sacra essential oil induces tumor cell-specific apoptosis and suppresses tumor aggressiveness in cultured human breast cancer cells

    PubMed Central

    2011-01-01

    Background Gum resins obtained from trees of the Burseraceae family (Boswellia sp.) are important ingredients in incense and perfumes. Extracts prepared from Boswellia sp. gum resins have been shown to possess anti-inflammatory and anti-neoplastic effects. Essential oil prepared by distillation of the gum resin traditionally used for aromatic therapy has also been shown to have tumor cell-specific anti-proliferative and pro-apoptotic activities. The objective of this study was to optimize conditions for preparing Boswellea sacra essential oil with the highest biological activity in inducing tumor cell-specific cytotoxicity and suppressing aggressive tumor phenotypes in human breast cancer cells. Methods Boswellia sacra essential oil was prepared from Omani Hougari grade resins through hydrodistillation at 78 or 100 oC for 12 hours. Chemical compositions were identified by gas chromatography-mass spectrometry; and total boswellic acids contents were quantified by high-performance liquid chromatography. Boswellia sacra essential oil-mediated cell viability and death were studied in established human breast cancer cell lines (T47D, MCF7, MDA-MB-231) and an immortalized normal human breast cell line (MCF10-2A). Apoptosis was assayed by genomic DNA fragmentation. Anti-invasive and anti-multicellular tumor properties were evaluated by cellular network and spheroid formation models, respectively. Western blot analysis was performed to study Boswellia sacra essential oil-regulated proteins involved in apoptosis, signaling pathways, and cell cycle regulation. Results More abundant high molecular weight compounds, including boswellic acids, were present in Boswellia sacra essential oil prepared at 100 oC hydrodistillation. All three human breast cancer cell lines were sensitive to essential oil treatment with reduced cell viability and elevated cell death, whereas the immortalized normal human breast cell line was more resistant to essential oil treatment. Boswellia sacra

  18. Identification and treatment of aggressive thyroid cancers. Part 2: risk assessment and treatment.

    PubMed

    Sturgeon, Cord; Angelos, Peter

    2006-04-01

    Most thyroid cancers are slow-growing, easily treatable tumors with an excellent prognosis after surgical resection and targeted medical therapy. Unfortunately, 10% to 15% of thyroid cancers exhibit aggressive behavior and do not follow an indolent course. Approximately one-third of patients with differentiated thyroid cancers will have tumor recurrences. Distant metastases are present in about 20% of patients with recurrent cancer. Approximately half of patients with distant metastases die within 5 years. The loss of the ability to concentrate radio-iodine and produce thyroglobulin is a sign of dedifferentiation, which occurs in about 30% of patients with persistent or recurrent thyroid cancer. Dedifferentiation is associated with poorer responses to conventional therapy and difficulty monitoring tumor burden. Clinicians must identify tumors with more aggressive biology and treat them accordingly with more aggressive regimens. Part 1 of this two-part article, which appeared in March, described in detail the distinct types of thyroid cancer, as well as risk factors, outcomes, treatment, and prognostic factors, with a focus on thyroid cancers of follicular cell origin. Part 2 covers risk assessment and staging, findings that suggest the presence of aggressive tumors, recurrent/metastatic disease, and treatment with chemotherapy and external-beam radiotherapy. Experimental treatments utilizing molecular targets, redifferentiation agents, and gene therapy are covered briefly as well.

  19. Effect of Statins and Anticoagulants on Prostate Cancer Aggressiveness

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Alizadeh, Moein; Sylvestre, Marie-Pierre; Zilli, Thomas

    2012-07-15

    Purpose: Statins and anticoagulants (ACs) have both been associated with a less-aggressive prostate cancer (PCa) and a better outcome after treatment of localized PCa. The results of these studies might have been confounded because patients might often take both medications. We examined their respective influence on PCa aggressiveness at initial diagnosis. Materials and Methods: We analyzed 381 patients treated with either external beam radiotherapy or brachytherapy for low-risk (n = 152), intermediate-risk (n = 142), or high-risk (n = 87) localized PCa. Univariate and multivariate logistic regression analyses were used to investigate an association between these drug classes and prostatemore » cancer aggressiveness. We tested whether the concomitant use of statins and ACs had a different effect than that of either AC or statin use alone. Results: Of the 381 patients, 172 (45.1%) were taking statins and 141 (37.0%) ACs; 105 patients (27.6%) used both. On univariate analysis, the statin and AC users were associated with the prostate-specific antigen (PSA) level (p = .017) and National Comprehensive Cancer Network risk group (p = .0022). On multivariate analysis, statin use was associated with a PSA level <10 ng/mL (odds ratio, 2.9; 95% confidence interval, 1.3-6.8; p = .012) and a PSA level >20 ng/mL (odds ratio, 0.29; 95% confidence interval, 0.08-0.83; p = .03). The use of ACs was associated with a PSA level >20 ng/mL (odds ratio, 0.13; 95% confidence interval, 0.02-0.59, p = .02). Conclusion: Both AC and statins have an effect on PCa aggressiveness, with statins having a more stringent relationship with the PSA level, highlighting the importance of considering statin use in studies of PCa aggressiveness.« less

  20. Analyzing the differentially expressed genes and pathway cross-talk in aggressive breast cancer.

    PubMed

    Chen, Wen-Yan; Wu, Fang; You, Zhen-Yu; Zhang, Zhan-Min; Guo, Yu-Ling; Zhong, Lu-Xing

    2015-01-01

    The aim of this study was to explore the genes and pathways involved in the aggressive breast cancer cells. The gene expression profiles of GSE40057, including four aggressive breast cell lines and six less aggressive cell lines, were downloaded from the Gene Expression Omnibus (GEO) database. The gene differential expression analysis was carried out with limma software with the method of Bayes for multiple tests. The gene ontology (GO) term enrichment and pathway cross-talk analysis were performed with the online tool of DAVID and Cytoscape software. A total of 401 differentially expressed genes (DEG), such as pentraxin 3 (PTX3), snail family zinc finger 2 (SNAI2), interleukin-8/6 (IL-8/6), osteonectin (SPARC), matrix metallopeptidase-1 (MMP-1) and Ras-related protein Rab-25 (Rab 25), were identified between aggressive and less aggressive cell lines. They were mainly enriched in the GO terms of response to wounding, negative regulation of cell proliferation and calcium binding. Pathways in cancer dysfunctionally interacted with glyoxylate and dicarboxylate metabolism (P < 0.0001), basal transcription factors (P < 0.0001), tyrosine metabolism (P < 0.0001), calcium signaling pathway (P = 0.0021), FcγR-mediated phagocytosis (P = 0.0022), metabolism of xenobiotics by cytochrome P450 (P = 0.0097) and phagosome (P = 0.0102). The screened aggressive cancer-associated DEG (PTX3, SNAI2, IL-8/6, SPARC, MMP-1 and Rab25) and significant pathways (calcium signaling pathway, tyrosine metabolism, alanine, aspartate and glutamate metabolism) give us new insights into the mechanism of aggressive breast cancer cells, and these DEG may become promising target genes in the treatment of metastatic breast cancer. © 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.

  1. [Therapeutic Aggressiveness and Liquid Oncology].

    PubMed

    Barón Duarte, F J; Rodríguez Calvo, M S; Amor Pan, J R

    2017-01-01

    Aggressiveness criteria proposed in the scientific literature a decade ago provide a quality judgment and are a reference in the care of patients with advanced cancer, but their use is not generalized in the evaluation of Oncology Services. In this paper we analyze the therapeutic aggressiveness, according to standard criteria, in 1.001 patients with advanced cancer who died in our Institution between 2010 and 2013. The results seem to show that aggressiveness at the end of life is present more frequently than experts recommend. About 25% of patients fulfill at least one criterion of aggressiveness. This result could be explained by a liquid Oncology which does not prioritize the patient as a moral subject in the clinical appointment. Medical care is oriented to necessities and must be articulated in a model focused on dignity and communication. Its implementation through Advanced Care Planning, consideration of patient's values and preferences, and Limitation of therapeutic effort are ways to reduce aggressiveness and improve clinical practice at the end of life. We need to encourage synergic and proactive attitudes, adding the best of cancer research with the best clinical care for the benefit of human being, moral subject and main goal of Medicine.

  2. Trait aggressiveness modulates neurophysiological correlates of laboratory-induced reactive aggression in humans.

    PubMed

    Krämer, Ulrike M; Büttner, Sarah; Roth, Gerhard; Münte, Thomas F

    2008-08-01

    Reactive aggression following provocation is a frequent form of human social behavior. The neural basis of reactive aggression, especially its control, remains poorly understood, however. We conducted an event-related potential (ERP) study using a competitive reaction time task that elicits aggression through provocation. Participants were selected from a larger sample because of extreme scores in trait aggressiveness, yielding high and low trait aggressive groups. As each trial in the task is separated into a decision phase, during which the punishment level for the opponent is set, and an outcome phase, during which the punishment is applied or received, we were able to disentangle provocation-related and evaluation-related modulations of the ERPs during the aggressive interaction. Specifically, we observed an enhanced frontal negativity during the decision phase under high provocation that was positively correlated with the participants' ability to refrain from retaliation. This held true for high trait aggressive participants only, pointing to a higher need for inhibitory and control processes in these people when provoked. During the outcome phase, we detected a mediofrontal negativity in loss compared to win trials, resembling previous ERP findings to negative feedback stimuli, which have been linked to the evaluation of an outcome's valence. This mediofrontal negativity was differentially pronounced in aggressive and nonaggressive participants: Nonaggressive participants showed only a slightly smaller mediofrontal negativity in win than in loss trials, suggesting that for them punishing the opponent had a similar negative valence as being punished.

  3. Toward a nosology of human aggressive behavior.

    PubMed

    Eichelman, B; Hartwig, A

    1993-01-01

    General attempts have been made to catalog or categorize research literature on aggressive behavior. In the animal literature this category has been delineated by clearly observed and described patterns of behavior. These include offensive and defensive expressions in animals and the characterization of attack behaviors by typography into defensive and offensive. The human literature is considerably deficient in the description and categorization of human aggressive behavior. Current nosologies offer no utilitarian schema for characterizing violent behavior in clinical populations regarding the typography of the violence, its prediction, or guidance as to its treatment. The generation of databased nosologies may provide a mechanism for the development of research and clinically relevant nosologies based upon cluster analyses of treatment outcomes and behavioral characteristics. This strategy may provide a more effective approach for further research concerning clinical aggressive or destructive behaviors.

  4. Macrophages induce "budding" in aggressive human colon cancer subtypes by protease-mediated disruption of tight junctions.

    PubMed

    Trumpi, Kari; Frenkel, Nicola; Peters, Timo; Korthagen, Nicoline M; Jongen, Jennifer M J; Raats, Daniëlle; van Grevenstein, Helma; Backes, Yara; Moons, Leon M; Lacle, Miangela M; Koster, Jan; Zwijnenburg, Danny; Borel Rinkes, Inne H M; Kranenburg, Onno

    2018-04-13

    Primary human colorectal tumors with a high stromal content have an increased capacity to metastasize. Cancer-associated fibroblasts (CAFs) promote metastasis, but the contribution of other stromal cell types is unclear. Here we searched for additional stromal cell types that contribute to aggressive tumor cell behavior. By making use of the 'immunome compendium'-a collection of gene signatures reflecting the presence of specific immune cell-types-we show that macrophage signatures are most strongly associated with a high CAF content and with poor prognosis in multiple large cohorts of primary tumors and liver metastases. Co-culturing macrophages with patient-derived colonospheres promoted 'budding' of small clusters of tumor cells from the bulk. Immunohistochemistry showed that budding tumor clusters in stroma-rich areas of T1 colorectal carcinomas were surrounded by macrophages. In vitro budding was accompanied by reduced levels of the tight junction protein occludin, but OCLN mRNA levels did not change, nor did markers of epithelial mesenchymal transition. Budding was accompanied by nuclear accumulation of β-catenin, which was also observed in budding tumor cell clusters in situ . The NFκB inhibitor Sanguinarine resulted in a decrease in MMP7 protein expression and both NFκB inhibitor Sanguinarine and MMP inhibitor Batimastat prevented occludin degradation and budding. We conclude that macrophages contribute to the aggressive nature of stroma-rich colon tumors by promoting an MMP-dependent pathway that operates in parallel to classical EMT and leads to tight junction disruption.

  5. Genetic determinants of aggression and impulsivity in humans.

    PubMed

    Pavlov, Konstantin A; Chistiakov, Dimitry A; Chekhonin, Vladimir P

    2012-02-01

    Human aggression/impulsivity-related traits have a complex background that is greatly influenced by genetic and non-genetic factors. The relationship between aggression and anxiety is regulated by highly conserved brain regions including amygdala, which controls neural circuits triggering defensive, aggressive, or avoidant behavioral models. The dysfunction of neural circuits responsible for emotional control was shown to represent an etiological factor of violent behavior. In addition to the amygdala, these circuits also involve the anterior cingulated cortex and regions of the prefrontal cortex. Excessive reactivity in the amygdala coupled with inadequate prefrontal regulation serves to increase the likelihood of aggressive behavior. Developmental alterations in prefrontal-subcortical circuitry as well as neuromodulatory and hormonal abnormality appear to play a role. Imbalance in testosterone/serotonin and testosterone/cortisol ratios (e.g., increased testosterone levels and reduced cortisol levels) increases the propensity toward aggression because of reduced activation of the neural circuitry of impulse control and self-regulation. Serotonin facilitates prefrontal inhibition, and thus insufficient serotonergic activity can enhance aggression. Genetic predisposition to aggression appears to be deeply affected by the polymorphic genetic variants of the serotoninergic system that influences serotonin levels in the central and peripheral nervous system, biological effects of this hormone, and rate of serotonin production, synaptic release and degradation. Among these variants, functional polymorphisms in the monoamine oxidase A (MAOA) and serotonin transporter (5-HTT) may be of particular importance due to the relationship between these polymorphic variants and anatomical changes in the limbic system of aggressive people. Furthermore, functional variants of MAOA and 5-HTT are capable of mediating the influence of environmental factors on aggression-related traits

  6. Calcium, magnesium, and whole-milk intakes and high-aggressive prostate cancer in the North Carolina-Louisiana Prostate Cancer Project (PCaP).

    PubMed

    Steck, Susan E; Omofuma, Omonefe O; Su, L Joseph; Maise, Amanda A; Woloszynska-Read, Anna; Johnson, Candace S; Zhang, Hongmei; Bensen, Jeannette T; Fontham, Elizabeth T H; Mohler, James L; Arab, Lenore

    2018-05-01

    Calcium and dairy product intakes have been positively associated with prostate cancer risk. An imbalance in concentrations of calcium and magnesium has been associated with multiple chronic diseases, although few studies have examined the relation with prostate cancer aggressiveness. The goal of this study was to examine the association between dietary intakes of calcium and magnesium, the calcium-to-magnesium ratio (Ca:Mg), and dairy products and prostate cancer aggressiveness. Dietary intake was assessed with the use of an interviewer-administered modified National Cancer Institute Diet History Questionnaire in 996 African American and 1064 European American men with a recent histologically confirmed diagnosis of prostate cancer from the North Carolina-Louisiana Prostate Cancer Project (PCaP). High-aggressive disease was defined as Gleason sum ≥8, or prostate-specific antigen (PSA) >20 ng/mL, or Gleason score ≥7 and clinical stage T3-T4. The comparison group was all other prostate cancer cases. Logistic regression was used to determine the adjusted ORs and 95% CIs for high-aggressive prostate cancer by tertile of diet and supplement exposures. There was a positive association across tertiles of dietary Ca:Mg intake, with odds of high-aggressive prostate cancer in the upper tertiles as follows-OR for tertile 2 compared with tertile 1: 1.38 (95% CI: 1.01, 1.88); OR for tertile 3 compared with tertile 1: 1.46 (95% CI: 1.06, 2.02). When stratified by race, the positive association was more pronounced in African American men (OR for tertile 3 compared with tertile 2: 1.62; 95% CI: 1.04, 2.53). Men who reported the highest daily consumption of whole-fat milk had a 74% increased odds of high-aggressive prostate cancer compared with non-whole-fat milk drinkers, which was attenuated after adjustment for potential mediating factors, such as saturated fat and Ca:Mg intake. Among both African American and European American men diagnosed with prostate cancer, a higher Ca

  7. Oncogenic miR-181a/b affect the DNA damage response in aggressive breast cancer.

    PubMed

    Bisso, Andrea; Faleschini, Michela; Zampa, Federico; Capaci, Valeria; De Santa, Jacopo; Santarpia, Libero; Piazza, Silvano; Cappelletti, Vera; Daidone, Mariagrazia; Agami, Reuven; Del Sal, Giannino

    2013-06-01

    Breast cancer is a heterogeneous tumor type characterized by a complex spectrum of molecular aberrations, resulting in a diverse array of malignant features and clinical outcomes. Deciphering the molecular mechanisms that fuel breast cancer development and act as determinants of aggressiveness is a primary need to improve patient management. Among other alterations, aberrant expression of microRNAs has been found in breast cancer and other human tumors, where they act as either oncogenes or tumor suppressors by virtue of their ability to finely modulate gene expression at the post-transcriptional level. In this study, we describe a new role for miR-181a/b as negative regulators of the DNA damage response in breast cancer, impacting on the expression and activity of the stress-sensor kinase ataxia telangiectasia mutated (ATM). We report that miR-181a and miR-181b were overexpressed in more aggressive breast cancers, and their expression correlates inversely with ATM levels. Moreover we demonstrate that deregulated expression of miR-181a/b determines the sensitivity of triple-negative breast cancer cells to the poly-ADP-ribose-polymerase1 (PARP1) inhibition. These evidences suggest that monitoring the expression of miR-181a/b could be helpful in tailoring more effective treatments based on inhibition of PARP1 in breast and other tumor types.

  8. Genetic architecture for human aggression: A study of gene-phenotype relationship in OMIM.

    PubMed

    Zhang-James, Yanli; Faraone, Stephen V

    2016-07-01

    Genetic studies of human aggression have mainly focused on known candidate genes and pathways regulating serotonin and dopamine signaling and hormonal functions. These studies have taught us much about the genetics of human aggression, but no genetic locus has yet achieved genome-significance. We here present a review based on a paradoxical hypothesis that studies of rare, functional genetic variations can lead to a better understanding of the molecular mechanisms underlying complex multifactorial disorders such as aggression. We examined all aggression phenotypes catalogued in Online Mendelian Inheritance in Man (OMIM), an Online Catalog of Human Genes and Genetic Disorders. We identified 95 human disorders that have documented aggressive symptoms in at least one individual with a well-defined genetic variant. Altogether, we retrieved 86 causal genes. Although most of these genes had not been implicated in human aggression by previous studies, the most significantly enriched canonical pathways had been previously implicated in aggression (e.g., serotonin and dopamine signaling). Our findings provide strong evidence to support the causal role of these pathways in the pathogenesis of aggression. In addition, the novel genes and pathways we identified suggest additional mechanisms underlying the origins of human aggression. Genome-wide association studies with very large samples will be needed to determine if common variants in these genes are risk factors for aggression. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  9. Aggression, Social Stress, and the Immune System in Humans and Animal Models

    PubMed Central

    Takahashi, Aki; Flanigan, Meghan E.; McEwen, Bruce S.; Russo, Scott J.

    2018-01-01

    Social stress can lead to the development of psychological problems ranging from exaggerated anxiety and depression to antisocial and violence-related behaviors. Increasing evidence suggests that the immune system is involved in responses to social stress in adulthood. For example, human studies show that individuals with high aggression traits display heightened inflammatory cytokine levels and dysregulated immune responses such as slower wound healing. Similar findings have been observed in patients with depression, and comorbidity of depression and aggression was correlated with stronger immune dysregulation. Therefore, dysregulation of the immune system may be one of the mediators of social stress that produces aggression and/or depression. Similar to humans, aggressive animals also show increased levels of several proinflammatory cytokines, however, unlike humans these animals are more protected from infectious organisms and have faster wound healing than animals with low aggression. On the other hand, subordinate animals that receive repeated social defeat stress have been shown to develop escalated and dysregulated immune responses such as glucocorticoid insensitivity in monocytes. In this review we synthesize the current evidence in humans, non-human primates, and rodents to show a role for the immune system in responses to social stress leading to psychiatric problems such as aggression or depression. We argue that while depression and aggression represent two fundamentally different behavioral and physiological responses to social stress, it is possible that some overlapped, as well as distinct, pattern of immune signaling may underlie both of them. We also argue the necessity of studying animal models of maladaptive aggression induced by social stress (i.e., social isolation) for understanding neuro-immune mechanism of aggression, which may be relevant to human aggression. PMID:29623033

  10. Aggression, Social Stress, and the Immune System in Humans and Animal Models.

    PubMed

    Takahashi, Aki; Flanigan, Meghan E; McEwen, Bruce S; Russo, Scott J

    2018-01-01

    Social stress can lead to the development of psychological problems ranging from exaggerated anxiety and depression to antisocial and violence-related behaviors. Increasing evidence suggests that the immune system is involved in responses to social stress in adulthood. For example, human studies show that individuals with high aggression traits display heightened inflammatory cytokine levels and dysregulated immune responses such as slower wound healing. Similar findings have been observed in patients with depression, and comorbidity of depression and aggression was correlated with stronger immune dysregulation. Therefore, dysregulation of the immune system may be one of the mediators of social stress that produces aggression and/or depression. Similar to humans, aggressive animals also show increased levels of several proinflammatory cytokines, however, unlike humans these animals are more protected from infectious organisms and have faster wound healing than animals with low aggression. On the other hand, subordinate animals that receive repeated social defeat stress have been shown to develop escalated and dysregulated immune responses such as glucocorticoid insensitivity in monocytes. In this review we synthesize the current evidence in humans, non-human primates, and rodents to show a role for the immune system in responses to social stress leading to psychiatric problems such as aggression or depression. We argue that while depression and aggression represent two fundamentally different behavioral and physiological responses to social stress, it is possible that some overlapped, as well as distinct, pattern of immune signaling may underlie both of them. We also argue the necessity of studying animal models of maladaptive aggression induced by social stress (i.e., social isolation) for understanding neuro-immune mechanism of aggression, which may be relevant to human aggression.

  11. Studies into abnormal aggression in humans and rodents: Methodological and translational aspects.

    PubMed

    Haller, Jozsef

    2017-05-01

    Here we review the principles based on which aggression is rendered abnormal in humans and laboratory rodents, and comparatively overview the main methodological approaches based on which this behavior is studied in the two categories of subjects. It appears that the discriminating property of abnormal aggression is rule breaking, which renders aggression dysfunctional from the point of view of the perpetrator. We show that rodent models of abnormal aggression were created by the translation of human conditions into rodent equivalents, and discuss how findings obtained with such models may be "translated back" to human conditions when the mechanisms underlying aggression and its possibilities of treatment are investigated. We suggest that the complementary nature of human and rodent research approaches invite a more intense cross-talk between the two sides of aggression research than the one presently observed. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. A Jagged road to lymphoma aggressiveness

    PubMed Central

    Radojcic, Vedran; Maillard, Ivan

    2014-01-01

    In this issue of Cancer Cell, Cao and colleagues identifyanFGF4/Jagged1-driven crosstalk between tumor cells and their vascular niche that activates Notch signaling, sustaining the aggressiveness of certain mouse and human B cell lymphomas. These findings identify new therapeutic opportunities to target pathogenic angiocrine functions in cancer. PMID:24651005

  13. Merkel Cell Polyomavirus: A New DNA Virus Associated with Human Cancer.

    PubMed

    MacDonald, Margo; You, Jianxin

    2017-01-01

    Merkel cell polyomavirus (MCPyV or MCV) is a novel human polyomavirus that has been discovered in Merkel cell carcinoma (MCC), a highly aggressive skin cancer. MCPyV infection is widespread in the general population. MCPyV-associated MCC is one of the most aggressive skin cancers, killing more patients than other well-known cancers such as cutaneous T-cell lymphoma and chronic myelogenous leukemia (CML). Currently, however, there is no effective drug for curing this cancer. The incidence of MCC has tripled over the past two decades. With the widespread infection of MCPyV and the increase in MCC diagnoses, it is critical to better understand the biology of MCPyV and its oncogenic potential. In this chapter, we summarize recent discoveries regarding MCPyV molecular virology, host cellular tropism, mechanisms of MCPyV oncoprotein-mediated oncogenesis, and current therapeutic strategies for MCPyV-associated MCC. We also present epidemiological evidence for MCPyV infection in HIV patients and links between MCPyV and non-MCC human cancers.

  14. Cancer-associated fibroblast-derived annexin A6+ extracellular vesicles support pancreatic cancer aggressiveness

    PubMed Central

    Leca, Julie; Martinez, Sébastien; Lac, Sophie; Nigri, Jérémy; Secq, Véronique; Rubis, Marion; Bressy, Christian; Lavaut, Marie-Noelle; Dusetti, Nelson; Loncle, Céline; Roques, Julie; Pietrasz, Daniel; Bousquet, Corinne; Garcia, Stéphane; Granjeaud, Samuel; Ouaissi, Mehdi; Bachet, Jean Baptiste; Iovanna, Juan L.; Zimmermann, Pascale; Vasseur, Sophie

    2016-01-01

    The intratumoral microenvironment, or stroma, is of major importance in the pathobiology of pancreatic ductal adenocarcinoma (PDA), and specific conditions in the stroma may promote increased cancer aggressiveness. We hypothesized that this heterogeneous and evolving compartment drastically influences tumor cell abilities, which in turn influences PDA aggressiveness through crosstalk that is mediated by extracellular vesicles (EVs). Here, we have analyzed the PDA proteomic stromal signature and identified a contribution of the annexin A6/LDL receptor-related protein 1/thrombospondin 1 (ANXA6/LRP1/TSP1) complex in tumor cell crosstalk. Formation of the ANXA6/LRP1/TSP1 complex was restricted to cancer-associated fibroblasts (CAFs) and required physiopathologic culture conditions that improved tumor cell survival and migration. Increased PDA aggressiveness was dependent on tumor cell–mediated uptake of CAF-derived ANXA6+ EVs carrying the ANXA6/LRP1/TSP1 complex. Depletion of ANXA6 in CAFs impaired complex formation and subsequently impaired PDA and metastasis occurrence, while injection of CAF-derived ANXA6+ EVs enhanced tumorigenesis. We found that the presence of ANXA6+ EVs in serum was restricted to PDA patients and represents a potential biomarker for PDA grade. These findings suggest that CAF–tumor cell crosstalk supported by ANXA6+ EVs is predictive of PDA aggressiveness, highlighting a therapeutic target and potential biomarker for PDA. PMID:27701147

  15. Anti-cancer activity of myricetin against human papillary thyroid cancer cells involves mitochondrial dysfunction-mediated apoptosis.

    PubMed

    Ha, Tae Kwun; Jung, Inae; Kim, Mi Eun; Bae, Sung Kwon; Lee, Jun Sik

    2017-07-01

    Thyroid cancer is the most common endocrine malignancy and can range in severity from relatively slow-growing occult differentiated thyroid cancer to uniformly aggressive and fatal anaplastic thyroid cancer. A subset of patients with papillary thyroid cancer present with aggressive disease that is refractory to conventional treatment. Myricetin is a flavonol compound found in a variety of berries as well as walnuts and herbs. Previous studies have demonstrated that myricetin exhibits anti-cancer activity against several tumor types. However, an anti-cancer effect of myricetin against human papillary thyroid cancer (HPTC) cells has not been established. The present investigation was undertaken to gain insights into the molecular mechanism of the anti-cancer activity of myricetin against HPTC cells. We examined the cytotoxicity, DNA damaging, and cell cycle arresting activities of myricetin using SNU-790 HPTC cells. We found that myricetin exhibited cytotoxicity and induced DNA condensation in SNU-790 HPTC cells in a dose-dependent manner. Moreover, myricetin up-regulated the activation of caspase cascades and the Bax:Bcl-2 expression ratio. In addition, myricetin induced the release of apoptosis-inducing factor (AIF) and altered the mitochondrial membrane potential. Our results suggest that myricetin induces the death of SNU-790 HPTC cells and thus may prove useful in the development of therapeutic agents for human thyroid cancers. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  16. Sex steroid hormone metabolism in relation to risk of aggressive prostate cancer

    PubMed Central

    Black, Amanda; Pinsky, Paul F.; Grubb, Robert L.; Falk, Roni T.; Hsing, Ann W.; Chu, Lisa; Meyer, Tamra; Veenstra, Timothy D.; Xu, Xia; Yu, Kai; Ziegler, Regina G.; Brinton, Louise A.; Hoover, Robert N.; Cook, Michael B.

    2014-01-01

    Background The combined action of androgens and estrogens—specifically their balance—may play a role in prostate carcinogenesis but existing evidence is sparse and inconsistent. We investigated associations between serum sex steroid hormones, including estrogen metabolites, and risk of aggressive prostate cancer. Methods In a case-control study nested within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial cohort we measured serum estrone, estradiol and 13 estrogen metabolites, in the 2-, 4, or 16-hydroxylation pathways, using a liquid chromatography-tandem mass spectrometry assay. Cases (n=195) were non-Hispanic white men aged 55–70 years when diagnosed with aggressive prostate cancer (stage III or IV and/or Gleason ≥7). Controls (n=195) were non-Hispanic white men without prostate cancer who were frequency-matched to cases by age and year at blood draw, time since baseline screen. Only men with serum testosterone and sex hormone-binding globulin measured previously were eligible. Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (95%CI). Results Risk of aggressive prostate cancer was strongly inversely associated with estradiol:testosterone ratio (OR4th quartile vs. 1st =0.27, 95% CI 0.12–0.59, p trend=0.003) and positively associated with 2:16α-hydroxyestrone ratio (OR4th quartile vs. 1st =2.44, 95% CI 1.34–4.45, p trend=0.001). Estradiol, estrone and estrogen metabolites were unrelated to risk. Conclusions Our findings suggest that sex steroid hormones, specifically the estrogen-androgen balance, may be important in the development of aggressive prostate cancer. Impact Improved understanding of the hormonal etiology of prostate cancer is critical for prevention and therapeutic interventions. PMID:25178985

  17. Risk factors for human-directed canine aggression in a referral level clinical population.

    PubMed

    Lord, M; Casey, R A; Loftus, B A; Blackwell, E J

    2017-07-07

    Risk factors for human-directed aggression were investigated using retrospective analysis of data from a referral-level clinical behaviour population in the UK. A sample of 200 cases involving human-directed canine aggression and 200 control cases involving no instance of human-directed aggression were selected at random from a population of 746 cases. The final model suggested that clinical cases with human-directed aggression were significantly younger than those presenting with other undesired behaviours (P=0.008) and that male dogs were 1.4 times more likely to be aggressive towards human beings than female dogs (P=0.019). Dogs were 1.7 times more likely to be aggressive towards people if they had attended more than five puppy classes than if they had never attended puppy class (P=0.015) and that dogs were 2.8 times more likely to be aggressive towards human beings if there was another dog between 0 months and 24 months of age in the home (P=0.004). These factors only account for 7 per cent to 10 per cent of the variance between the human-directed aggression population and the control population, but factors such as attendance at puppy classes and numbers of dogs in the household suggest the need for longitudinal studies to investigate temporal relationships.

  18. Nine-year prostate cancer survival differences between aggressive versus conservative therapy in men with advanced and metastatic prostate cancer.

    PubMed

    Dall'Era, Marc A; Lo, Mary J; Chen, Jaclyn; Cress, Rosemary; Hamilton, Ann S

    2018-05-01

    To the authors' knowledge, the survival benefit of local therapy in the setting of advanced prostate cancer remains unknown. The authors investigated whether prostate-directed treatment with either surgery or radiotherapy versus conservative treatment in the setting of locally advanced or metastatic disease was associated with improved survival within a cohort of men from the Centers for Disease Control and Prevention's (CDC) Breast and Prostate Cancer Data Quality and Patterns of Care Study (CDC POC-BP). Men diagnosed with locally advanced (cT3-T4 or N+ and M0) or metastatic prostate cancer were identified. The authors compared survival by treatment type, categorized as conservative (androgen deprivation therapy only) versus aggressive (radical prostatectomy or any type of radiotherapy). Nine-year overall survival and prostate cancer-specific survival were estimated using the Kaplan-Meier method. The Cox proportional hazards model was used to determine factors independently associated with 9-year prostate cancer-specific survival. For men with advanced, nonmetastatic prostate cancer, conservative treatment alone was associated with a 4 times higher likelihood of prostate cancer mortality compared with men treated with surgery (hazard ratio, 4.18; 95% confidence interval, 1.44-12.14). In contrast, no difference was found between conservative versus aggressive treatment after adjusting for covariates for men with metastatic disease. The 9-year prostate cancer-specific survival rate was 27% for those receiving aggressive treatment versus 24% for men undergoing conservative treatment. The authors did not observe a survival advantage with local therapy in addition to standard androgen deprivation therapy for men with metastatic prostate cancer. However, the results of the current study did affirm advantages in the setting of locally advanced disease. Aggressive local therapy in the setting of metastatic disease needs to be studied carefully before clinical adoption

  19. Human a-L-fucosidase-1 attenuates the invasive properties of thyroid cancer.

    PubMed

    Vecchio, Giancarlo; Parascandolo, Alessia; Allocca, Chiara; Ugolini, Clara; Basolo, Fulvio; Moracci, Marco; Strazzulli, Andrea; Cobucci-Ponzano, Beatrice; Laukkanen, Mikko O; Castellone, Maria Domenica; Tsuchida, Nobuo

    2017-04-18

    Glycans containing α-L-fucose participate in diverse interactions between cells and extracellular matrix. High glycan expression on cell surface is often associated with neoplastic progression. The lysosomal exoenzyme, α-L-fucosidase-1 (FUCA-1) removes fucose residues from glycans. The FUCA-1 gene is down-regulated in highly aggressive and metastatic human tumors. However, the role of FUCA-1 in tumor progression remains unclear. It is speculated that its inactivation perturbs glycosylation of proteins involved in cell adhesion and promotes cancer. FUCA-1 expression of various thyroid normal and cancer tissues assayed by immunohistochemical (IHC) staining was high in normal thyroids and papillary thyroid carcinomas (PTC), whereas it progressively decreased in poorly differentiated, metastatic and anaplastic thyroid carcinomas (ATC). FUCA-1 mRNA expression from tissue samples and cell lines and protein expression levels and enzyme activity in thyroid cancer cell lines paralleled those of IHC staining. Furthermore, ATC-derived 8505C cells adhesion to human E-selectin and HUVEC cells was inhibited by bovine α-L-fucosidase or Lewis antigens, thus pointing to an essential role of fucose residues in the adhesive phenotype of this cancer cell line. Finally, 8505C cells transfected with a FUCA-1 containing plasmid displayed a less invasive phenotype versus the parental 8505C. These results demonstrate that FUCA-1 is down-regulated in ATC compared to PTC and normal thyroid tissues and cell lines. As shown for other human cancers, the down-regulation of FUCA-1 correlates with increased aggressiveness of the cancer type. This is the first report indicating that the down-regulation of FUCA-1 is related to the increased aggressiveness of thyroid cancer.

  20. Low-grade prostate tumors can harbor signs of aggressive cancer | Center for Cancer Research

    Cancer.gov

    In a new study, Center for Cancer Research investigators found that low-grade and high-grade regions of prostate tumor tissue shared mutations typically linked to aggressive cancer. Testing for mutations to specific genes could help clinicians decide whether a patient with an initial low-grade result should undergo a follow-up biopsy. Learn more...

  1. Differential diagnosis and management of human-directed aggression in cats.

    PubMed

    Frank, Diane; Dehasse, Joel

    2003-03-01

    Human-directed aggression in cats should be evaluated as a multifactorial problem. It results from the combined actions of heredity, environment, learning, human social requirements (or needs), client interactions, lack of understanding of normal feline behavior, unrealistic client expectations, and lack of meeting the cat's basic ethologic needs. Managing human-directed aggression in cats encompasses the use of environmental modification, therapies, and, when and if needed, regulatory drugs so as to increase learning capabilities and adaptation and decrease danger to the human victims.

  2. Identification of proteomic biomarkers predicting prostate cancer aggressiveness and lethality despite biopsy-sampling error.

    PubMed

    Shipitsin, M; Small, C; Choudhury, S; Giladi, E; Friedlander, S; Nardone, J; Hussain, S; Hurley, A D; Ernst, C; Huang, Y E; Chang, H; Nifong, T P; Rimm, D L; Dunyak, J; Loda, M; Berman, D M; Blume-Jensen, P

    2014-09-09

    Key challenges of biopsy-based determination of prostate cancer aggressiveness include tumour heterogeneity, biopsy-sampling error, and variations in biopsy interpretation. The resulting uncertainty in risk assessment leads to significant overtreatment, with associated costs and morbidity. We developed a performance-based strategy to identify protein biomarkers predictive of prostate cancer aggressiveness and lethality regardless of biopsy-sampling variation. Prostatectomy samples from a large patient cohort with long follow-up were blindly assessed by expert pathologists who identified the tissue regions with the highest and lowest Gleason grade from each patient. To simulate biopsy-sampling error, a core from a high- and a low-Gleason area from each patient sample was used to generate a 'high' and a 'low' tumour microarray, respectively. Using a quantitative proteomics approach, we identified from 160 candidates 12 biomarkers that predicted prostate cancer aggressiveness (surgical Gleason and TNM stage) and lethal outcome robustly in both high- and low-Gleason areas. Conversely, a previously reported lethal outcome-predictive marker signature for prostatectomy tissue was unable to perform under circumstances of maximal sampling error. Our results have important implications for cancer biomarker discovery in general and development of a sampling error-resistant clinical biopsy test for prediction of prostate cancer aggressiveness.

  3. Microvascular Channel Device to Study Aggressiveness in Prostate Cancer Metastasis

    DTIC Science & Technology

    2014-08-01

    contributes to PCa’s distant metastasis, which is mediated via an E- selectin ligand, ESL -1. Consequently, the interaction of E-selectin/ ESL -1 transduces...cancer cell, E-selectin, ESL -1. OVERALL PROJECT SUMMARY A. Major goals of the project: 3 Task 1: Correlation of cancers’ aggressiveness with...Determination of the aggressive/metastatic related gene I. 1. ESL -1 expression is high in rolling cells and tissue When PCa cells come in contact with

  4. Effects of cigarette smoking on human aggressive behavior.

    PubMed

    Cherek, D R

    1984-01-01

    Nicotine administered by smoking experimental cigarettes produced decreases in two types of aggressive responses elicited by low and high frequency subtractions of money which were attributed to another "person". The suppressing effects of smoking different doses of nicotine on aggressive responses was dose-dependent, in that smoking the high dose of nicotine produced more suppression than smoking the low dose. The ostensible subtraction of money from another "person", the more aggressive response option available to research subjects, was generally more sensitive to the suppressing effects of nicotine than aggressive noise delivery responses. Although this effect could be attributed to another constituent of tobacco, the dose-dependent effect observed with these cigarettes which contained the same amount of tar suggest the effects are due to nicotine. The relatively selective suppression of aggressive behavior observed in humans in the present study is highly consistent with the effects of nicotine observed in a number of infrahuman species. Nicotine has been found to suppress aggressive behavior in ants (Kostowski 1968), rats (Silverman 1971), and cats (Berntson et. al. 1976). In addition, nicotine has been observed to suppress shock elicited fighting in rats (Driscoll, Baettig 1981; Rodgers 1979; Waldbillig 1980) as well as shock elicited biting in monkeys (Hutchinson, Emley 1973). The importance of determining specificity of drug action on aggressive behavior has been repeatedly emphasized in the field of behavioral pharmacology (Sidman 1959; Cook, Kelleher 1963; Thompson, Boren 1977; Miczek, Krsiak 1979). One method employed to evaluate drug specificity and identify a general non-specific excitatory or depressant drug effect is to determine the drug effect on more than one response option which is available to the subject (Sidman 1959). In this study, the same doses of nicotine which suppressed aggressive responding increased nonaggressive monetary

  5. E-cadherin: A determinant molecule associated with ovarian cancer progression, dissemination and aggressiveness

    PubMed Central

    Devis, Laura; Lapyckyj, Lara; Besso, María José; Llauradó, Marta; Abascal, María Florencia; Matos, María Laura; Lanau, Lucia; Castellví, Josep; Sánchez, José Luis; Pérez Benavente, Asunción; Gil-Moreno, Antonio; Reventós, Jaume; Santamaria Margalef, Anna; Rigau, Marina; Vazquez-Levin, Mónica Hebe

    2017-01-01

    Ovarian cancer (OC) is the fifth cancer death cause in women worldwide. The malignant nature of this disease stems from its unique dissemination pattern. Epithelial-to-mesenchymal transition (EMT) has been reported in OC and downregulation of Epithelial cadherin (E-cadherin) is a hallmark of this process. However, findings on the relationship between E-cadherin levels and OC progression, dissemination and aggressiveness are controversial. In this study, the evaluation of E-cadherin expression in an OC tissue microarray revealed its prognostic value to discriminate between advanced- and early-stage tumors, as well as serous tumors from other histologies. Moreover, E-cadherin, Neural cadherin (N-cadherin), cytokeratins and vimentin expression was assessed in TOV-112, SKOV-3, OAW-42 and OV-90 OC cell lines grown in monolayers and under anchorage-independent conditions to mimic ovarian tumor cell dissemination, and results were associated with cell aggressiveness. According to these EMT-related markers, cell lines were classified as mesenchymal (M; TOV-112), intermediate mesenchymal (IM; SKOV-3), intermediate epithelial (IE; OAW-42) and epithelial (E; OV-90). M- and IM-cells depicted the highest migration capacity when grown in monolayers, and aggregates derived from M- and IM-cell lines showed lower cell death, higher adhesion to extracellular matrices and higher invasion capacity than E- and IE-aggregates. The analysis of E-cadherin, N-cadherin, cytokeratin 19 and vimentin mRNA levels in 20 advanced-stage high-grade serous human OC ascites showed an IM phenotype in all cases, characterized by higher proportions of N- to E-cadherin and vimentin to cytokeratin 19. In particular, higher E-cadherin mRNA levels were associated with cancer antigen 125 levels more than 500 U/mL and platinum-free intervals less than 6 months. Altogether, E-cadherin expression levels were found relevant for the assessment of OC progression and aggressiveness. PMID:28934230

  6. MIF Drives Pancreatic Cancer Aggressiveness by Downregulating NR3C2 | Center for Cancer Research

    Cancer.gov

    Pancreatic cancer, while relatively rare, is an aggressive disease ranked as the fourth leading cause of cancer-related death in the US. Because most patients are diagnosed at an advanced stage and their tumors resist available treatments, novel therapeutic targets are urgently needed. Macrophage Migration Inhibitory Factor (MIF) is a proinflammatory cytokine that is elevated

  7. MIF Drives Pancreatic Cancer Aggressiveness by Downregulating NR3C2 | Center for Cancer Research

    Cancer.gov

    Pancreatic cancer, while relatively rare, is an aggressive disease ranked as the fourth leading cause of cancer-related death in the US. Because most patients are diagnosed at an advanced stage and their tumors resist available treatments, novel therapeutic targets are urgently needed. Macrophage Migration Inhibitory Factor (MIF) is a proinflammatory cytokine that is elevated in pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, and may provide a molecular link between inflammation and cancer, though the mechanism is unknown.

  8. Violence among peoples in the light of human frustration and aggression.

    PubMed

    de Gaay Fortman, Bas

    2005-12-05

    This article sets out to provide a general background to the study of aggression in the social sciences, with a particular focus on its link to collective violence. While the study of what happens in the human brain appears to be already highly complex, analysis of violent behavior appears to be even more intricate. A deductive system in the sense of a general and clear system of propositions logically connected to one another is not feasible, principally because contrary to the natural sciences there are no verities but merely "stylized facts." One of these concerns the setting of human aggression in the light of frustration, as argued in the frustration-aggression hypothesis developed by Dollard et al. in 1939. Apart from conceiving of aggression as a pure human instinct, it may also be seen as externally driven, while a third possibility concerns culturally "learned" aggression. Proof of the latter is that the strongest correlation appears to be that between current violence and previous manifestations thereof. Attention is paid to the way in which Gurr has rooted his relative deprivation theory on causes of collective violence among peoples in mechanisms of frustration and aggression. That theory is taken a bit further in terms of "perceived acquirement failure," which appears to be highly connected to the role of the state. Based on certain observations by Hannah Arendt, the argument then proceeds to violence as a manifestation of powerlessness. Finally, this leads to a discussion of justice as a crucial factor in what Durkheim used to call a "right to conflict." In this way, human aggression is placed in a broad socio-economic context.

  9. Molecular and Clinical Predictors of Aggressive Prostate Cancer

    DTIC Science & Technology

    2007-09-01

    AD_________________ Award Number: W81XWH-05-1-0562 TITLE: Molecular and Clinical Predictors of...DATES COVERED (From - To) 1 SEP 2006 - 31 AUG 2007 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Molecular And Clinical Predictors Of Aggressive...course. We are evaluating molecular and clinical predictors at diagnosis to distinguish lethal and indolent prostate cancer. In a related project, we

  10. Recurrent ESR1-CCDC170 rearrangements in an aggressive subset of estrogen-receptor positive breast cancers

    PubMed Central

    Veeraraghavan, Jamunarani; Tan, Ying; Cao, Xi-Xi; Kim, Jin-Ah; Wang, Xian; Chamness, Gary C.; Maiti, Sourindra N.; Cooper, Laurence J. N.; Edwards, Dean P.; Contreras, Alejandro; Hilsenbeck, Susan G.; Chang, Eric C.; Schiff, Rachel; Wang, Xiao-Song

    2014-01-01

    Characterizing the genetic alterations leading to the more aggressive forms of estrogen receptor positive (ER+) breast cancers are of critical significance in breast cancer management. Here we identify recurrent rearrangements between estrogen receptor gene ESR1 and its neighbor CCDC170, which are enriched in the more aggressive and endocrine-resistant luminal-B tumors, through large-scale analyses of breast cancer transcriptome and copy number alterations. Further screening of 200 ER+ breast cancers identifies eight ESR1-CCDC170 positive tumors. These fusions encode N-terminally truncated CCDC170 proteins (ΔCCDC170). When introduced into ER+ breast cancer cells, ΔCCDC170 leads to markedly increased cell motility and anchorage-independent growth, reduced endocrine sensitivity, and enhanced xenograft tumor formation. Mechanistic studies suggest that ΔCCDC170 engages Gab1 signalosome to potentiate growth factor signaling and enhance cell motility. Together, this study identifies neoplastic ESR1-CCDC170 fusions in a more aggressive subset of ER+ breast cancer, which suggests a new concept of ER pathobiology in breast cancer. PMID:25099679

  11. Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression

    PubMed Central

    Lasorsa, Vito Alessandro; Formicola, Daniela; Pignataro, Piero; Cimmino, Flora; Calabrese, Francesco Maria; Mora, Jaume; Esposito, Maria Rosaria; Pantile, Marcella; Zanon, Carlo; De Mariano, Marilena; Longo, Luca; Hogarty, Michael D.; de Torres, Carmen; Tonini, Gian Paolo; Iolascon, Achille; Capasso, Mario

    2016-01-01

    The spectrum of somatic mutation of the most aggressive forms of neuroblastoma is not completely determined. We sought to identify potential cancer drivers in clinically aggressive neuroblastoma. Whole exome sequencing was conducted on 17 germline and tumor DNA samples from high-risk patients with adverse events within 36 months from diagnosis (HR-Event3) to identify somatic mutations and deep targeted sequencing of 134 genes selected from the initial screening in additional 48 germline and tumor pairs (62.5% HR-Event3 and high-risk patients), 17 HR-Event3 tumors and 17 human-derived neuroblastoma cell lines. We revealed 22 significantly mutated genes, many of which implicated in cancer progression. Fifteen genes (68.2%) were highly expressed in neuroblastoma supporting their involvement in the disease. CHD9, a cancer driver gene, was the most significantly altered (4.0% of cases) after ALK. Other genes (PTK2, NAV3, NAV1, FZD1 and ATRX), expressed in neuroblastoma and involved in cell invasion and migration were mutated at frequency ranged from 4% to 2%. Focal adhesion and regulation of actin cytoskeleton pathways, were frequently disrupted (14.1% of cases) thus suggesting potential novel therapeutic strategies to prevent disease progression. Notably BARD1, CHEK2 and AXIN2 were enriched in rare, potentially pathogenic, germline variants. In summary, whole exome and deep targeted sequencing identified novel cancer genes of clinically aggressive neuroblastoma. Our analyses show pathway-level implications of infrequently mutated genes in leading neuroblastoma progression. PMID:27009842

  12. Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression.

    PubMed

    Lasorsa, Vito Alessandro; Formicola, Daniela; Pignataro, Piero; Cimmino, Flora; Calabrese, Francesco Maria; Mora, Jaume; Esposito, Maria Rosaria; Pantile, Marcella; Zanon, Carlo; De Mariano, Marilena; Longo, Luca; Hogarty, Michael D; de Torres, Carmen; Tonini, Gian Paolo; Iolascon, Achille; Capasso, Mario

    2016-04-19

    The spectrum of somatic mutation of the most aggressive forms of neuroblastoma is not completely determined. We sought to identify potential cancer drivers in clinically aggressive neuroblastoma.Whole exome sequencing was conducted on 17 germline and tumor DNA samples from high-risk patients with adverse events within 36 months from diagnosis (HR-Event3) to identify somatic mutations and deep targeted sequencing of 134 genes selected from the initial screening in additional 48 germline and tumor pairs (62.5% HR-Event3 and high-risk patients), 17 HR-Event3 tumors and 17 human-derived neuroblastoma cell lines.We revealed 22 significantly mutated genes, many of which implicated in cancer progression. Fifteen genes (68.2%) were highly expressed in neuroblastoma supporting their involvement in the disease. CHD9, a cancer driver gene, was the most significantly altered (4.0% of cases) after ALK.Other genes (PTK2, NAV3, NAV1, FZD1 and ATRX), expressed in neuroblastoma and involved in cell invasion and migration were mutated at frequency ranged from 4% to 2%.Focal adhesion and regulation of actin cytoskeleton pathways, were frequently disrupted (14.1% of cases) thus suggesting potential novel therapeutic strategies to prevent disease progression.Notably BARD1, CHEK2 and AXIN2 were enriched in rare, potentially pathogenic, germline variants.In summary, whole exome and deep targeted sequencing identified novel cancer genes of clinically aggressive neuroblastoma. Our analyses show pathway-level implications of infrequently mutated genes in leading neuroblastoma progression.

  13. When Violence Pays: A Cost-Benefit Analysis of Aggressive Behavior in Animals and Humans

    PubMed Central

    Georgiev, Alexander V.; Klimczuk, Amanda C. E.; Traficonte, Daniel M.

    2013-01-01

    An optimization analysis of human behavior from a comparative perspective can improve our understanding of the adaptiveness of human nature. Intra-specific competition for resources provides the main selective pressure for the evolution of violent aggression toward conspecifics, and variation in the fitness benefits and costs of aggression can account for inter-specific and inter-individual differences in aggressiveness. When aggression reflects competition for resources, its benefits vary in relation to the characteristics of the resources (their intrinsic value, abundance, spatial distribution, and controllability) while its costs vary in relation to the characteristics of organisms and how they fight (which, in turn, affects the extent to which aggression entails risk of physical injury or death, energetic depletion, exposure to predation, psychological and physiological stress, or damage to social relationships). Humans are a highly aggressive species in comparison to other animals, probably as a result of an unusually high benefit-to-cost ratio for intra-specific aggression. This conclusion is supported by frequent and widespread occurrence of male-male coalitionary killing and by male-female sexual coercion. Sex differences in violent aggression in humans and other species probably evolved by sexual selection and reflect different optimal competitive strategies for males and females. PMID:23864299

  14. When violence pays: a cost-benefit analysis of aggressive behavior in animals and humans.

    PubMed

    Georgiev, Alexander V; Klimczuk, Amanda C E; Traficonte, Daniel M; Maestripieri, Dario

    2013-07-18

    An optimization analysis of human behavior from a comparative perspective can improve our understanding of the adaptiveness of human nature. Intra-specific competition for resources provides the main selective pressure for the evolution of violent aggression toward conspecifics, and variation in the fitness benefits and costs of aggression can account for inter-specific and inter-individual differences in aggressiveness. When aggression reflects competition for resources, its benefits vary in relation to the characteristics of the resources (their intrinsic value, abundance, spatial distribution, and controllability) while its costs vary in relation to the characteristics of organisms and how they fight (which, in turn, affects the extent to which aggression entails risk of physical injury or death, energetic depletion, exposure to predation, psychological and physiological stress, or damage to social relationships). Humans are a highly aggressive species in comparison to other animals, probably as a result of an unusually high benefit-to-cost ratio for intra-specific aggression. This conclusion is supported by frequent and widespread occurrence of male-male coalitionary killing and by male-female sexual coercion. Sex differences in violent aggression in humans and other species probably evolved by sexual selection and reflect different optimal competitive strategies for males and females.

  15. Imaging Prostatic Lipids to Distinguish Aggressive Prostate Cancer

    DTIC Science & Technology

    2015-10-01

    this application, we propose to build upon our current work to determine the association between fatty acid synthase ( FAS ) overexpression and...cancer (as determined by Gleason scoring) we propose to: 1) Determine the correlation between FAS expression in prostatectomy samples and the amount... FAS expression and FAS activity in prostatectomy samples, intraprostatic lipid as measured by MRSI and prostate tumor aggressiveness. 3) To quantify

  16. Aggression and violence around the world: A model of CLimate, Aggression, and Self-control in Humans (CLASH).

    PubMed

    Van Lange, Paul A M; Rinderu, Maria I; Bushman, Brad J

    2017-01-01

    Worldwide there are substantial differences within and between countries in aggression and violence. Although there are various exceptions, a general rule is that aggression and violence increase as one moves closer to the equator, which suggests the important role of climate differences. While this pattern is robust, theoretical explanations for these large differences in aggression and violence within countries and around the world are lacking. Most extant explanations focus on the influence of average temperature as a factor that triggers aggression (The General Aggression Model), or the notion that warm temperature allows for more social interaction situations (Routine Activity Theory) in which aggression is likely to unfold. We propose a new model, CLimate, Aggression, and Self-control in Humans (CLASH), that helps us to understand differences within and between countries in aggression and violence in terms of differences in climate. Lower temperatures, and especially larger degrees of seasonal variation in climate, call for individuals and groups to adopt a slower life history strategy, a greater focus on the future (vs. present), and a stronger focus on self-control. The CLASH model further outlines that slow life strategy, future orientation, and strong self-control are important determinants of inhibiting aggression and violence. We also discuss how CLASH differs from other recently developed models that emphasize climate differences for understanding conflict. We conclude by discussing the theoretical and societal importance of climate in shaping individual and societal differences in aggression and violence.

  17. Fluorescence-guided surgery of a highly-metastatic variant of human triple-negative breast cancer targeted with a cancer-specific GFP adenovirus prevents recurrence

    PubMed Central

    Yano, Shuya; Takehara, Kiyoto; Miwa, Shinji; Kishimoto, Hiroyuki; Tazawa, Hiroshi; Urata, Yasuo; Kagawa, Shunsuke; Bouvet, Michael; Fujiwara, Toshiyoshi; Hoffman, Robert M.

    2016-01-01

    We have previously developed a genetically-engineered GFP-expressing telomerase-dependent adenovirus, OBP-401, which can selectively illuminate cancer cells. In the present report, we demonstrate that targeting a triple-negative high-invasive human breast cancer, orthotopically-growing in nude mice, with OBP-401 enables curative fluorescence-guided surgery (FGS). OBP-401 enabled complete resection and prevented local recurrence and greatly inhibited lymph-node metastasis due to the ability of the virus to selectively label and subsequently kill cancer cells. In contrast, residual breast cancer cells become more aggressive after bright (white)-light surgery (BLS). OBP-401-based FGS also improved the overall survival compared with conventional BLS. Thus, metastasis from a highly-aggressive triple-negative breast cancer can be prevented by FGS in a clinically-relevant mouse model. PMID:27689331

  18. Behavioural, hormonal and neurobiological mechanisms of aggressive behaviour in human and nonhuman primates.

    PubMed

    de Almeida, Rosa Maria Martins; Cabral, João Carlos Centurion; Narvaes, Rodrigo

    2015-05-01

    Aggression is a key component for social behaviour and can have an adaptive value or deleterious consequences. Here, we review the role of sex-related differences in aggressive behaviour in both human and nonhuman primates. First, we address aggression in primates, which varies deeply between species, both in intensity and in display, ranging from animals that are very aggressive, such as chimpanzees, to the nonaggressive bonobos. Aggression also influences the hierarchical structure of gorillas and chimpanzees, and is used as the main tool for dealing with other groups. With regard to human aggression, it can be considered a relevant adaptation for survival or can have negative impacts on social interaction for both sexes. Gender plays a critical role in aggressive and competitive behaviours, which are determined by a cascade of physiological changes, including GABAergic and serotonergic systems, and sex neurosteroids. The understanding of the neurobiological bases and behavioural determinants of different types of aggression is fundamental for minimising these negative impacts. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Molecular innovations towards theranostics of aggressive prostate cancer

    DTIC Science & Technology

    2016-09-01

    Xiankai Sun, PhD CONTRACTING ORGANIZATION: University of Texas Southwestern Medical Center Dallas, TX 75390-8542 REPORT DATE : September 2016 TYPE OF...number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 1. REPORT DATE (DD-MM-YYYY) September 2016 2. REPORT TYPE Annual 3. DATES COVERED (From...Partner PI’s lab for the treatment of aggressive prostate cancer. To date , we have designed and synthesized the proposed bifunctional chelator

  20. You Smell Dangerous: Communicating Fight Responses Through Human Chemosignals of Aggression.

    PubMed

    Mutic, Smiljana; Parma, Valentina; Brünner, Yvonne F; Freiherr, Jessica

    2016-01-01

    The ability to detect conspecifics that represent a potential harm for an individual represents a high survival benefit. Humans communicate socially relevant information using all sensory modalities, including the chemosensory systems. In study 1, we investigated whether the body odor of a stranger with the intention to harm serves as a chemosignal of aggression. Sixteen healthy male participants donated their body odor while engaging in a boxing session characterized by aggression-induction methods (chemosignal of aggression) and while performing an ergometer session (exercise chemosignal). Self-reports on aggression-related physical activity, motivation to harm and angry emotions selectively increased after aggression induction. In study 2, we examined whether receivers smelling such chemosignals experience emotional contagion (e.g., anger) or emotional reciprocity (e.g., anxiety). The aggression and exercise chemosignals were therefore presented to 22 healthy normosmic participants in a double-blind, randomized exposure during which affective/cognitive processing was examined (i.e., emotion recognition task, emotional stroop task). Behavioral results indicate that chemosignals of aggression induce an affective/cognitive modulation compatible with an anxiety reaction in the recipients. These findings are discussed in light of mechanisms of emotional reciprocity as a way to convey not only affective but also motivational information via chemosensory signals in humans. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  1. PPARGC1A and ADIPOQ polymorphisms are associated with aggressive prostate cancer in Mexican-Mestizo men with overweight or obesity.

    PubMed

    Canto, Patricia; Granados, Jesús Benítez; Feria-Bernal, Guillermo; Coral-Vázquez, Ramón Mauricio; García-García, Eduardo; Tejeda, María Elena; Tapia, André; Rojano-Mejía, David; Méndez, Juan Pablo

    2017-07-04

    Obesity constitutes a risk factor for the development of aggressive forms of prostate cancer. It has been proposed, that prostate cancer has a genetic predisposition and that PPARGC1A and ADIPOQ polymorphisms play a role in the development of this condition. To analyse the association of two PPARGC1A and ADIPOQ polymorphisms as well as their haplotypes, with the development of aggressive prostate cancer in Mexican-Mestizo men with overweight or obesity. Two hundred fifty seven men with prostate cancer of Mexican-Mestizo origin were included. Body mass index (BMI) was determined and the degree of prostate cancer aggressiveness by the D'Amico classification. DNA was obtained. Rs7665116 and rs2970870 of PPARGC1A, and rs266729 and rs1501299 of ADIPOQ were studied by real-time PCR allelic discrimination. Pairwise linkage disequilibrium, between single nucleotide polymorphisms was calculated and haplotype analysis was performed. A higher-risk (D'Amico classification) was observed in 21.8% of patients. An association of cancer aggressiveness with rs2970870 of PPARGC1A, and rs501299 of ADIPOQ, as well as with one haplotype of ADIPOQ was documented. This is the first study regarding the relationship of PPARGC1A and ADIPOQ polymorphisms, and the aggressiveness of prostate cancer in men with overweight or obesity.

  2. Intranasal administration of oxytocin increases human aggressive behavior.

    PubMed

    Ne'eman, R; Perach-Barzilay, N; Fischer-Shofty, M; Atias, A; Shamay-Tsoory, S G

    2016-04-01

    Considering its role in prosocial behaviors, oxytocin (OT) has been suggested to diminish levels of aggression. Nevertheless, recent findings indicate that oxytocin may have a broader influence on increasing the salience of social stimuli and may therefore, under certain circumstances, increase antisocial behaviors such as aggression. This controversy led to the following speculations: If indeed oxytocin promotes primarily prosocial behavior, administration of OT is expected to diminish levels of aggression. However, if oxytocin mainly acts to increase the salience of social stimuli, it is expected to elevate levels of aggression following provocation. In order to test this assumption we used the Social Orientation Paradigm (SOP), a monetary game played against a fictitious partner that allows measuring three types of responses in the context of provocation: an aggressive response - reducing a point from the fictitious partner, an individualistic response - adding a point to oneself, and a collaborative response - adding half a point to the partner and half a point to oneself. In the current double-blind, placebo-controlled, within-subject study design, 45 participants completed the SOP task following the administration of oxytocin or placebo. The results indicated that among subjects naïve to the procedure oxytocin increased aggressive responses in comparison with placebo. These results support the saliency hypothesis of oxytocin and suggest that oxytocin plays a complex role in the modulation of human behavior. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Long Noncoding RNAs AC009014.3 and Newly Discovered XPLAID Differentiate Aggressive and Indolent Prostate Cancers.

    PubMed

    Cesnik, Anthony J; Yang, Bing; Truong, Andrew; Etheridge, Tyler; Spiniello, Michele; Steinbrink, Maisie I; Shortreed, Michael R; Frey, Brian L; Jarrard, David F; Smith, Lloyd M

    2018-06-01

    The molecular mechanisms underlying aggressive versus indolent disease are not fully understood. Recent research has implicated a class of molecules known as long noncoding RNAs (lncRNAs) in tumorigenesis and progression of cancer. Our objective was to discover lncRNAs that differentiate aggressive and indolent prostate cancers. We analyzed paired tumor and normal tissues from six aggressive Gleason score (GS) 8-10 and six indolent GS 6 prostate cancers. Extracted RNA was split for poly(A)+ and ribosomal RNA depletion library preparations, followed byRNA sequencing (RNA-Seq) using an Illumina HiSeq 2000. We developed an RNA-Seq data analysis pipeline to discover and quantify these molecules. Candidate lncRNAs were validated using RT-qPCR on 87 tumor tissue samples: 28 (GS 6), 28 (GS 3+4), 6 (GS 4+3), and 25 (GS 8-10). Statistical correlations between lncRNAs and clinicopathologic variables were tested using ANOVA. The 43 differentially expressed (DE) lncRNAs between aggressive and indolent prostate cancers included 12 annotated and 31 novel lncRNAs. The top six DE lncRNAs were selected based on large, consistent fold-changes in the RNA-Seq results. Three of these candidates passed RT-qPCR validation, including AC009014.3 (P < .001 in tumor tissue) and a newly discovered X-linked lncRNA named XPLAID (P = .049 in tumor tissue and P = .048 in normal tissue). XPLAID and AC009014.3 show promise as prognostic biomarkers. We discovered several dozen lncRNAs that distinguish aggressive and indolent prostate cancers, of which four were validated using RT-qPCR. The investigation into their biology is ongoing. Published by Elsevier Inc.

  4. Human papilloma virus: An etiological and prognostic factor for oral cancer?

    PubMed

    Lafaurie, Gloria I; Perdomo, Sandra J; Buenahora, María R; Amaya, Sandra; Díaz-Báez, David

    2018-05-01

    The increasing prevalence of human papilloma virus (HPV)-positive oral tumors can be considered an epidemic. Although the incidence of HPV cervical cancer is decreasing, the incidence of oral cavity and oropharyngeal cancers associated with HPV is increasing. The presence of certain HPV genotypes could be a predictor of future oral cancer lesions, although lesions associated with HPV could be less aggressive and exhibit a higher survival rate. In the present study, we review the most important biologic, clinic, epidemiologic, and prognostic factors associated with HPV infection and oral cancer. © 2018 John Wiley & Sons Australia, Ltd.

  5. Testosterone treatment and the risk of aggressive prostate cancer in men with low testosterone levels.

    PubMed

    Walsh, Thomas J; Shores, Molly M; Krakauer, Chloe A; Forsberg, Christopher W; Fox, Alexandra E; Moore, Kathryn P; Korpak, Anna; Heckbert, Susan R; Zeliadt, Steven B; Kinsey, Chloe E; Thompson, Mary Lou; Smith, Nicholas L; Matsumoto, Alvin M

    2018-01-01

    Testosterone treatment of men with low testosterone is common and, although relatively short-term, has raised concern regarding an increased risk of prostate cancer (CaP). We investigated the association between modest-duration testosterone treatment and incident aggressive CaP. Retrospective inception cohort study of male Veterans aged 40 to 89 years with a laboratory-defined low testosterone measurement from 2002 to 2011 and recent prostate specific antigen (PSA) testing; excluding those with recent testosterone treatment, prostate or breast cancer, high PSA or prior prostate biopsy. Histologically-confirmed incident aggressive prostate cancer or any prostate cancer were the primary and secondary outcomes, respectively. Of the 147,593 men included, 58,617 were treated with testosterone. 313 aggressive CaPs were diagnosed, 190 among untreated men (incidence rate (IR) 0.57 per 1000 person years, 95% CI 0.49-0.65) and 123 among treated men (IR 0.58 per 1000 person years; 95% CI 0.48-0.69). After adjusting for age, race, hospitalization during year prior to cohort entry, geography, BMI, medical comorbidities, repeated testosterone and PSA testing, testosterone treatment was not associated with incident aggressive CaP (HR 0.89; 95% CI 0.70-1.13) or any CaP (HR 0.90; 95% CI 0.81-1.01). No association between cumulative testosterone dose or formulation and CaP was observed. Among men with low testosterone levels and normal PSA, testosterone treatment was not associated with an increased risk of aggressive or any CaP. The clinical risks and benefits of testosterone treatment can only be fully addressed by large, longer-term randomized controlled trials.

  6. TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup.

    PubMed

    Labbé, David P; Sweeney, Christopher J; Brown, Myles; Galbo, Phillip; Rosario, Spencer; Wadosky, Kristine M; Ku, Sheng-Yu; Sjöström, Martin; Alshalalfa, Mohammed; Erho, Nicholas; Davicioni, Elai; Karnes, R Jeffrey; Schaeffer, Edward M; Jenkins, Robert B; Den, Robert B; Ross, Ashley E; Bowden, Michaela; Huang, Ying; Gray, Kathryn P; Feng, Felix Y; Spratt, Daniel E; Goodrich, David W; Eng, Kevin H; Ellis, Leigh

    2017-11-15

    Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer. Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer-associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of prostate cancer patients; however, they have yet to provide targeted therapy approaches that could inhibit a patient's progression to metastatic disease. Experimental Design: We have interrogated a total of seven primary prostate cancer cohorts ( n = 1,900), two metastatic castration-resistant prostate cancer datasets ( n = 293), and one prospective cohort ( n = 1,385) to assess the impact of TOP2A and EZH2 expression on prostate cancer cellular program and patient outcomes. We also performed IHC staining for TOP2A and EZH2 in a cohort of primary prostate cancer patients ( n = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel prostate cancer-derived murine cell lines. Results: We demonstrate by genome-wide analysis of independent primary and metastatic prostate cancer datasets that concurrent TOP2A and EZH2 mRNA and protein upregulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in prostate cancer cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy. Conclusions: Overall, our data support further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neoadjuvant targeted therapy approaches. Clin Cancer Res; 23(22); 7072-83. ©2017 AACR . ©2017 American Association for Cancer Research.

  7. Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts.

    PubMed

    Seibert, Tyler M; Fan, Chun Chieh; Wang, Yunpeng; Zuber, Verena; Karunamuni, Roshan; Parsons, J Kellogg; Eeles, Rosalind A; Easton, Douglas F; Kote-Jarai, ZSofia; Al Olama, Ali Amin; Garcia, Sara Benlloch; Muir, Kenneth; Grönberg, Henrik; Wiklund, Fredrik; Aly, Markus; Schleutker, Johanna; Sipeky, Csilla; Tammela, Teuvo Lj; Nordestgaard, Børge G; Nielsen, Sune F; Weischer, Maren; Bisbjerg, Rasmus; Røder, M Andreas; Iversen, Peter; Key, Tim J; Travis, Ruth C; Neal, David E; Donovan, Jenny L; Hamdy, Freddie C; Pharoah, Paul; Pashayan, Nora; Khaw, Kay-Tee; Maier, Christiane; Vogel, Walther; Luedeke, Manuel; Herkommer, Kathleen; Kibel, Adam S; Cybulski, Cezary; Wokolorczyk, Dominika; Kluzniak, Wojciech; Cannon-Albright, Lisa; Brenner, Hermann; Cuk, Katarina; Saum, Kai-Uwe; Park, Jong Y; Sellers, Thomas A; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Batra, Jyotsna; Clements, Judith A; Spurdle, Amanda; Teixeira, Manuel R; Paulo, Paula; Maia, Sofia; Pandha, Hardev; Michael, Agnieszka; Kierzek, Andrzej; Karow, David S; Mills, Ian G; Andreassen, Ole A; Dale, Anders M

    2018-01-10

    To develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age. Analysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa. Multiple institutions that were members of international PRACTICAL consortium. All consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men. Prediction with hazard score of age of onset of aggressive cancer in validation set. In the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P<10 -16 ). When men in the validation set with high scores (>98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa

  8. Revisiting the Serotonin-Aggression Relation in Humans: A Meta-analysis

    PubMed Central

    Duke, Aaron A.; Bègue, Laurent; Bell, Rob; Eisenlohr-Moul, Tory

    2013-01-01

    The inverse relation between serotonin and human aggression is often portrayed as “reliable,” “strong,” and “well-established” despite decades of conflicting reports and widely recognized methodological limitations. In this systematic review and meta-analysis we evaluate the evidence for and against the serotonin deficiency hypothesis of human aggression across four methods of assessing serotonin: (a) cerebrospinal fluid levels of 5-hydroxyindoleacetic acid (CSF 5-HIAA), (b) acute tryptophan depletion, (c) pharmacological challenge, and (d) endocrine challenge. Results across 175 independent samples and over 6,500 total participants were heterogeneous, but, in aggregate, revealed a small, inverse correlation between central serotonin functioning and aggression, anger, and hostility, r = −.12. Pharmacological challenge studies had the largest mean weighted effect size, r = −.21, and CSF 5-HIAA studies had the smallest, r = −.06, p = .21. Potential methodological and demographic moderators largely failed to account for variability in study outcomes. Notable exceptions included year of publication (effect sizes tended to diminish with time) and self-versus other-reported aggression (other-reported aggression was positively correlated to serotonin functioning). We discuss four possible explanations for the pattern of findings: unreliable measures, ambient correlational noise, an unidentified higher-order interaction, and a selective serotonergic effect. Finally, we provide four recommendations for bringing much needed clarity to this important area of research: acknowledge contradictory findings and avoid selective reporting practices; focus on improving the reliability and validity of serotonin and aggression measures; test for interactions involving personality and/or environmental moderators; and revise the serotonin deficiency hypothesis to account for serotonin’s functional complexity. PMID:23379963

  9. The 19q12 bladder cancer GWAS signal: association with cyclin E function and aggressive disease

    PubMed Central

    Fu, Yi-Ping; Kohaar, Indu; Moore, Lee E.; Lenz, Petra; Figueroa, Jonine D.; Tang, Wei; Porter-Gill, Patricia; Chatterjee, Nilanjan; Scott-Johnson, Alexandra; Garcia-Closas, Montserrat; Muchmore, Brian; Baris, Dalsu; Paquin, Ashley; Ylaya, Kris; Schwenn, Molly; Apolo, Andrea B.; Karagas, Margaret R.; Tarway, McAnthony; Johnson, Alison; Mumy, Adam; Schned, Alan; Guedez, Liliana; Jones, Michael A.; Kida, Masatoshi; Monawar Hosain, GM; Malats, Nuria; Kogevinas, Manolis; Tardon, Adonina; Serra, Consol; Carrato, Alfredo; Garcia-Closas, Reina; Lloreta, Josep; Wu, Xifeng; Purdue, Mark; Andriole, Gerald L.; Grubb, Robert L.; Black, Amanda; Landi, Maria T.; Caporaso, Neil E.; Vineis, Paolo; Siddiq, Afshan; Bueno-de-Mesquita, H. Bas; Trichopoulos, Dimitrios; Ljungberg, Börje; Severi, Gianluca; Weiderpass, Elisabete; Krogh, Vittorio; Dorronsoro, Miren; Travis, Ruth C.; Tjønneland, Anne; Brennan, Paul; Chang-Claude, Jenny; Riboli, Elio; Prescott, Jennifer; Chen, Constance; De Vivo, Immaculata; Govannucci, Edward; Hunter, David; Kraft, Peter; Lindstrom, Sara; Gapstur, Susan M.; Jacobs, Eric J.; Diver, W. Ryan; Albanes, Demetrius; Weinstein, Stephanie J.; Virtamo, Jarmo; Kooperberg, Charles; Hohensee, Chancellor; Rodabough, Rebecca J.; Cortessis, Victoria K.; Conti, David V.; Gago-Dominguez, Manuela; Stern, Mariana C.; Pike, Malcolm C.; Van Den Berg, David; Yuan, Jian-Min; Haiman, Christopher A.; Cussenot, Olivier; Cancel-Tassin, Geraldine; Roupret, Morgan; Comperat, Eva; Porru, Stefano; Carta, Angela; Pavanello, Sofia; Arici, Cecilia; Mastrangelo, Giuseppe; Grossman, H. Barton; Wang, Zhaoming; Deng, Xiang; Chung, Charles C.; Hutchinson, Amy; Burdette, Laurie; Wheeler, William; Fraumeni, Joseph; Chanock, Stephen J.; Hewitt, Stephen M.; Silverman, Debra T.; Rothman, Nathaniel; Prokunina-Olsson, Ludmila

    2014-01-01

    A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell cycle protein. We performed genetic fine mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r2≥0.7) associated with increased bladder cancer risk. From this group we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWAS, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele odds ratio (OR) =1.18 (95%CI=1.09-1.27, p=4.67×10−5 vs. OR =1.01 (95%CI=0.93-1.10, p=0.79) for non-aggressive disease, with p=0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (p=0.013) and, independently, with each rs7257330-A risk allele (ptrend=0.024). Over-expression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E over-expression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models. PMID:25320178

  10. The Relationship Between Prostate Cancer Aggressiveness and Glycemic Levels in Patients Submitted to Radical Prostatectomy

    PubMed Central

    Goncalves, Suzana Cristina; de Moraes Siqueira, Rafael; Nogueira, Marcus Vinicius F; Pereira-Correia, Joao Antonio; Vaz, Fernando Pires; Peres, Wilza Arantes Ferreira

    2013-01-01

    Background The relationship between hyperglycemia and prostate cancer remains controversial. According to current hypotheses, elevated serum glucose levels may lead to disease development or disease prevention. Our study examined the potential correlation between pre-operative glycemic levels of patients with prostate cancer and the grade of tumor aggressiveness. Method We studied the case files of patients with a diagnosis of prostate cancer who had received putatively curative cancer surgery at the Urology Department of the Servidores do Estado Federal Hospital (RJ/Brazil). We transcribed information related to glycemia - collected up to 3 months before the surgery - and the histopathological grade of tumor aggressiveness (Gleason score) of the surgically removed prostates. Results We analyzed 42 people who met the inclusion criteria. Based on Gleason scores, among the normoglycemic patients, we detected low, moderate, and highly aggressive neoplasias in 13%, 53%, and 36% of the cases, respectively. For the hyperglycemic group, these rates were 30%, 60%, and 10%, respectively. Normoglycemic patients had primary Gleason grade 3 in 40% of the cases and grade 4 in 60% of the cases. For the hyperglycemic patients, these rates were 90% and 10%, respectively (P < 0.05 vs. grade 3 group). Conclusion Both Gleason score and primary Gleason grade were lower in hyperglycemic patients with prostate cancer than in normoglycemic patients, suggesting a “protective action” of hyperglycemic states. PMID:29147337

  11. A20 promotes metastasis of aggressive basal-like breast cancers through multi-monoubiquitylation of Snail1.

    PubMed

    Lee, Ji-Hyung; Jung, Su Myung; Yang, Kyung-Min; Bae, Eunjin; Ahn, Sung Gwe; Park, Jin Seok; Seo, Dongyeob; Kim, Minbeom; Ha, Jihoon; Lee, Jaewon; Kim, Jun-Hyeong; Kim, Jun Hwan; Ooshima, Akira; Park, Jinah; Shin, Donghyuk; Lee, Youn Sook; Lee, Sangho; van Loo, Geert; Jeong, Joon; Kim, Seong-Jin; Park, Seok Hee

    2017-10-01

    Although the ubiquitin-editing enzyme A20 is a key player in inflammation and autoimmunity, its role in cancer metastasis remains unknown. Here we show that A20 monoubiquitylates Snail1 at three lysine residues and thereby promotes metastasis of aggressive basal-like breast cancers. A20 is significantly upregulated in human basal-like breast cancers and its expression level is inversely correlated with metastasis-free patient survival. A20 facilitates TGF-β1-induced epithelial-mesenchymal transition (EMT) of breast cancer cells through multi-monoubiquitylation of Snail1. Monoubiquitylated Snail1 has reduced affinity for glycogen synthase kinase 3β (GSK3β), and is thus stabilized in the nucleus through decreased phosphorylation. Knockdown of A20 or overexpression of Snail1 with mutation of the monoubiquitylated lysine residues into arginine abolishes lung metastasis in mouse xenograft and orthotopic breast cancer models, indicating that A20 and monoubiquitylated Snail1 are required for metastasis. Our findings uncover an essential role of the A20-Snail1 axis in TGF-β1-induced EMT and metastasis of basal-like breast cancers.

  12. The neurobiological basis of human aggression: A review on genetic and epigenetic mechanisms.

    PubMed

    Waltes, Regina; Chiocchetti, Andreas G; Freitag, Christine M

    2016-07-01

    Aggression is an evolutionary conserved behavior present in most species including humans. Inadequate aggression can lead to long-term detrimental personal and societal effects. Here, we differentiate between proactive and reactive forms of aggression and review the genetic determinants of it. Heritability estimates of aggression in general vary between studies due to differing assessment instruments for aggressive behavior (AB) as well as age and gender of study participants. In addition, especially non-shared environmental factors shape AB. Current hypotheses suggest that environmental effects such as early life stress or chronic psychosocial risk factors (e.g., maltreatment) and variation in genes related to neuroendocrine, dopaminergic as well as serotonergic systems increase the risk to develop AB. In this review, we summarize the current knowledge of the genetics of human aggression based on twin studies, genetic association studies, animal models, and epigenetic analyses with the aim to differentiate between mechanisms associated with proactive or reactive aggression. We hypothesize that from a genetic perspective, the aminergic systems are likely to regulate both reactive and proactive aggression, whereas the endocrine pathways seem to be more involved in regulation of reactive aggression through modulation of impulsivity. Epigenetic studies on aggression have associated non-genetic risk factors with modifications of the stress response and the immune system. Finally, we point to the urgent need for further genome-wide analyses and the integration of genetic and epigenetic information to understand individual differences in reactive and proactive AB. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  13. Screening for Novel Germline Rare Mutations Associated with Aggressive Prostate Cancer

    DTIC Science & Technology

    2014-10-01

    Schmidt S., Peshkin L., et al. A method and server for predicting damaging missense mutations. Nat Methods. 7, 248-249 (2010). Akbari MR, Trachtenberg...Inst. 2012 Aug 1;104(16):1260-2. Epub 2012 Jul 9. Castro E. G.C.L., Olmos D., et al. Correlation of germ-line BRCA2 mutations with aggressive...prostate cancer. Clin Cancer Res. 16, 2115-2121 (2010). 20    Hammer GE, Gonzalez F, Champsaur M, Cado D, Shastri N. The aminopeptidase ERAAP shapes the

  14. SERUM THYROTROPIN CONCENTRATIONS ARE NOT PREDICTIVE OF AGGRESSIVE BREAST CANCER BIOLOGY IN EUTHYROID INDIVIDUALS

    PubMed Central

    Villa, Natalie M.; Li, Ning; Yeh, Michael W.; Hurvitz, Sara A.; Dawson, Nicole A.; Leung, Angela M.

    2015-01-01

    Objective The potential influence of hypothyroidism on breast cancer remains incompletely understood. The objective of this study was to investigate the relationship between serum thyrotropin [thyroid-stimulating hormone (TSH)] concentration and markers of aggressive breast cancer biology, as defined by receptor expression profile, tumor grade, and American Joint Committee on Cancer (AJCC) stage characteristics. Methods This was a retrospective cohort study of patients from 2002–2014. All breast cancer patients who had complete receptor (estrogen receptor, ER; progesterone receptor, PR; and Her2/neu) and pre-diagnosis serum TSH data (n=437) were included. All patients had one of six receptor profiles: ER+ PR+ Her2/neu −, ER+ PR− Her2/neu−, ER+ PR+ Her2/neu+, ER+ PRHer2/ neu+, ER− PR− Her2/neu+, ER− PR− Her2/neu−. Log-transformed serum TSH concentrations were analyzed using multinomial and logistic regressions for a potential relationship with markers of breast cancer aggressiveness. Results Increasing serum TSH concentration was associated with a lower probability of having the receptor expression profile ER+ PR+ Her2/neu+ compared to patients with the ER+ PR+ Her2/neu− profile (OR=0.52, p=0.0045). No significant associations between other receptor expression profiles and serum TSH concentration were found. All time-weighted and unweighted median serum TSH concentrations were within normal limits. No significant associations between serum TSH concentration and tumor grade, overall AJCC stage, or tumor size (T), lymph node positivity (N), or presence of metastasis (M) were observed. Conclusions Serum TSH was not associated with markers of breast cancer aggressiveness in our cohort. PMID:26121443

  15. p53 suppresses type II endometrial carcinomas in mice and governs endometrial tumour aggressiveness in humans

    PubMed Central

    Wild, Peter J; Ikenberg, Kristian; Fuchs, Thomas J; Rechsteiner, Markus; Georgiev, Strahil; Fankhauser, Niklaus; Noske, Aurelia; Roessle, Matthias; Caduff, Rosmarie; Dellas, Athanassios; Fink, Daniel; Moch, Holger; Krek, Wilhelm; Frew, Ian J

    2012-01-01

    Type II endometrial carcinomas are a highly aggressive group of tumour subtypes that are frequently associated with inactivation of the TP53 tumour suppressor gene. We show that mice with endometrium-specific deletion of Trp53 initially exhibited histological changes that are identical to known precursor lesions of type II endometrial carcinomas in humans and later developed carcinomas representing all type II subtypes. The mTORC1 signalling pathway was frequently activated in these precursor lesions and tumours, suggesting a genetic cooperation between this pathway and Trp53 deficiency in tumour initiation. Consistent with this idea, analyses of 521 human endometrial carcinomas identified frequent mTORC1 pathway activation in type I as well as type II endometrial carcinoma subtypes. mTORC1 pathway activation and p53 expression or mutation status each independently predicted poor patient survival. We suggest that molecular alterations in p53 and the mTORC1 pathway play different roles in the initiation of the different endometrial cancer subtypes, but that combined p53 inactivation and mTORC1 pathway activation are unifying pathogenic features among histologically diverse subtypes of late stage aggressive endometrial tumours. PMID:22678923

  16. Human Aggression Across the Lifespan: Genetic Propensities and Environmental Moderators

    PubMed Central

    Tuvblad, Catherine; Baker, Laura A.

    2013-01-01

    This chapter reviews the recent evidence of genetic and environmental influences on human aggression. Findings from a large selection of the twin and adoption studies that have investigated the genetic and environmental architecture of aggressive behavior are summarized. These studies together show that about half (50%) of the variance in aggressive behavior is explained by genetic influences in both males and females, with the remaining 50% of the variance being explained by environmental factors not shared by family members. Form of aggression (reactive, proactive, direct/physical, indirect/relational), method of assessment (laboratory observation, self-report, ratings by parents and teachers), and age of the subjects—all seem to be significant moderators of the magnitude of genetic and environmental influences on aggressive behavior. Neither study design (twin vs. sibling adoption design) nor sex (male vs. female) seems to impact the magnitude of the genetic and environmental influences on aggression. There is also some evidence of gene-environment interaction (G × E) from both twin/adoption studies and molecular genetic studies. Various measures of family adversity and social disadvantage have been found to moderate genetic influences on aggressive behavior. Findings from these G × E studies suggest that not all individuals will be affected to the same degree by experiences and exposures, and that genetic predispositions may have different effects depending on the environment. PMID:22078481

  17. Defining Aggressive Prostate Cancer Using a 12-Gene Model1

    PubMed Central

    Riva, Alberto; Kim, Robert; Varambally, Sooryanarayana; He, Le; Kutok, Jeff; Aster, Jonathan C; Tang, Jeffery; Kuefer, Rainer; Hofer, Matthias D; Febbo, Phillip G; Chinnaiyan, Arul M; Rubin, Mark A

    2006-01-01

    Abstract The critical clinical question in prostate cancer research is: How do we develop means of distinguishing aggressive disease from indolent disease? Using a combination of proteomic and expression array data, we identified a set of 36 genes with concordant dysregulation of protein products that could be evaluated in situ by quantitative immunohistochemistry. Another five prostate cancer biomarkers were included using linear discriminant analysis, we determined that the optimal model used to predict prostate cancer progression consisted of 12 proteins. Using a separate patient population, transcriptional levels of the 12 genes encoding for these proteins predicted prostate-specific antigen failure in 79 men following surgery for clinically localized prostate cancer (P = .0015). This study demonstrates that cross-platform models can lead to predictive models with the possible advantage of being more robust through this selection process. PMID:16533427

  18. Fruit and vegetable consumption and risk of aggressive and non-aggressive urothelial cell carcinomas in the European Prospective Investigation into Cancer and Nutrition.

    PubMed

    Ros, Martine M; Bueno-de-Mesquita, H Bas; Kampman, Ellen; Büchner, Frederike L; Aben, Katja K H; Egevad, Lars; Overvad, Kim; Tjønneland, Anne; Roswall, Nina; Clavel-Chapelon, Francoise; Boutron-Ruault, Marie Christine; Morois, Sophie; Kaaks, Rudolf; Teucher, Birgit; Weikert, Steffen; von Ruesten, Anne; Trichopoulou, Antonia; Naska, Androniki; Benetou, Vassiliki; Saieva, Calogero; Pala, Valeria; Ricceri, Fulvio; Tumino, Rosario; Mattiello, Amalia; Peeters, Petra H M; van Gils, Carla H; Gram, Inger T; Engeset, Dagrun; Chirlaque, Maria-Dolores; Ardanazx, Eva; Rodríguez, Laudina; Amanio, Pilar; Gonzalez, Carlos A; Sánchez, María José; Ulmert, David; Ernström, Roy; Ljungberg, Börje; Allen, Naomi E; Key, Timothy J; Khaw, Kee-Tee; Wareham, Nick; Slimani, Nadia; Romieu, Isabelle; Kiemeney, Lambertus A; Riboli, Elio

    2012-11-01

    Many epidemiological studies have examined fruit and vegetable consumption in relation to the risk of urothelial cell carcinoma (UCC) of the bladder, but results are inconsistent. The association between fruit and vegetable consumption and UCC risk may vary by bladder tumour aggressiveness. Therefore, we examined the relation between fruit and vegetable consumption and the risk of aggressive and non-aggressive UCC in the European Prospective Investigation into Cancer and Nutrition (EPIC). After 8.9 years of follow-up, 947UCC were diagnosed among 468,656 EPIC participants. Of these, 421 could be classified as aggressive UCC and 433 as non-aggressive UCC cases. At recruitment, fruit and vegetable consumption was assessed by validated dietary questionnaires. Multivariable hazard ratios were estimated using Cox regression stratified by age, sex and center and adjusted for smoking status, duration and intensity of smoking, and energy intake. Total consumption of fruits and vegetables was not associated with aggressive UCC nor with non-aggressive UCC. A 25 g/day increase in leafy vegetables and grapes consumption was associated with a reduced risk of non-aggressive UCC (hazard ratio (HR) 0.88; 95%confidence interval (CI) 0.78-1.00 and HR 0.87; 95%CI 0.77-0.98, respectively), while the intake of root vegetables was inversely associated with risk of aggressive UCC (HR 0.87; 95%CI 0.77-0.98). Our study did not confirm a protective effect of total fruit and/or vegetable consumption on aggressive or non-aggressive UCC. High consumption of certain types of vegetables and of fruits may reduce the risk of aggressive or non-aggressive UCC; however chance findings cannot be excluded. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. Chronic ethanol exposure enhances the aggressiveness of breast cancer: the role of p38γ

    PubMed Central

    Xu, Mei; Wang, Siying; Ren, Zhenhua; Frank, Jacqueline A.; Yang, Xiuwei H.; Zhang, Zhuo; Ke, Zun-ji; Shi, Xianglin; Luo, Jia

    2016-01-01

    Both epidemiological and experimental studies suggest that ethanol may enhance aggressiveness of breast cancer. We have previously demonstrated that short term exposure to ethanol (12–48 hours) increased migration/invasion in breast cancer cells overexpressing ErbB2, but not in breast cancer cells with low expression of ErbB2, such as MCF7, BT20 and T47D breast cancer cells. In this study, we showed that chronic ethanol exposure transformed breast cancer cells that were not responsive to short term ethanol treatment to a more aggressive phenotype. Chronic ethanol exposure (10 days - 2 months) at 100 (22 mM) or 200 mg/dl (44 mM) caused the scattering of MCF7, BT20 and T47D cell colonies in a 3-dimension culture system. Chronic ethanol exposure also increased colony formation in an anchorage-independent condition and stimulated cell invasion/migration. Chronic ethanol exposure increased cancer stem-like cell (CSC) population by more than 20 folds. Breast cancer cells exposed to ethanol in vitro displayed a much higher growth rate and metastasis in mice. Ethanol selectively activated p38γ MAPK and RhoC but not p38α/β in a concentration-dependent manner. SP-MCF7 cells, a derivative of MCF7 cells which compose mainly CSC expressed high levels of phosphorylated p38γ MAPK. Knocking-down p38γ MAPK blocked ethanol-induced RhoC activation, cell scattering, invasion/migration and ethanol-increased CSC population. Furthermore, knocking-down p38γ MAPK mitigated ethanol-induced tumor growth and metastasis in mice. These results suggest that chronic ethanol exposure can enhance the aggressiveness of breast cancer by activating p38γ MAPK/RhoC pathway. PMID:26655092

  20. Anaplastic lymphoma kinase is expressed in different subtypes of human breast cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Perez-Pinera, Pablo; Chang, Y.; Astudillo, A.

    2007-06-29

    Pleiotrophin (PTN, Ptn) is an 18 kDa cytokine expressed in human breast cancers. Since inappropriate expression of Ptn stimulates progression of breast cancer in transgenic mice and a dominant negative PTN reverses the transformed phenotype of human breast cancer cells that inappropriately express Ptn, it is suggested that constitutive PTN signaling in breast cancer cells that inappropriately express Ptn activates pathways that promote a more aggressive breast cancer phenotype. Pleiotrophin signals by inactivating its receptor, the receptor protein tyrosine phosphatase (RPTP){beta}/{zeta}, and, recently, PTN was found to activate anaplastic lymphoma kinase (ALK) through the PTN/RPTP{beta}/{zeta} signaling pathway in PTN-stimulated cells,more » not through a direct interaction of PTN with ALK and thus not through the PTN-enforced dimerization of ALK. Since full-length ALK is activated in different malignant cancers and activated ALK is a potent oncogenic protein, we examined human breast cancers to test the possibility that ALK may be expressed in breast cancers and potentially activated through the PTN/RPTP{beta}/{zeta} signaling pathway; we now demonstrate that ALK is strongly expressed in different histological subtypes of human breast cancer; furthermore, ALK is expressed in both nuclei and cytoplasm and, in the 'dotted' pattern characteristic of ALK fusion proteins in anaplastic large cell lymphoma. This study thus supports the possibility that activated ALK may be important in human breast cancers and potentially activated either through the PTN/RPTP{beta}/{zeta} signaling pathway, or, alternatively, as an activated fusion protein to stimulate progression of breast cancer in humans.« less

  1. Exosomes secreted by placental stem cells selectively inhibit growth of aggressive prostate cancer cells.

    PubMed

    Peak, Taylor C; Praharaj, Prakash P; Panigrahi, Gati K; Doyle, Michael; Su, Yixin; Schlaepfer, Isabel R; Singh, Ravi; Vander Griend, Donald J; Alickson, Julie; Hemal, Ashok; Atala, Anthony; Deep, Gagan

    2018-05-23

    The current paradigm in the development of new cancer therapies is the ability to target tumor cells while avoiding harm to noncancerous cells. Furthermore, there is a need to develop novel therapeutic options against drug-resistant cancer cells. Herein, we characterized the placental-derived stem cell (PLSC) exosomes (PLSC Exo ) and evaluated their anti-cancer efficacy in prostate cancer (PCa) cell lines. Nanoparticle tracking analyses revealed the size distribution (average size 131.4 ± 0.9 nm) and concentration of exosomes (5.23 × 10 10 ±1.99 × 10 9 per ml) secreted by PLSC. PLSC Exo treatment strongly inhibited the viability of enzalutamide-sensitive and -resistant PCa cell lines (C4-2B, CWR-R1, and LNCaP cells). Interestingly, PLSC Exo treatment had no effect on the viability of a non-neoplastic human prostate cell line (PREC-1). Mass spectrometry (MS) analyses showed that PLSC Exo are loaded with 241 proteins and mainly with saturated fatty acids. Further, Ingenuity Pathway Analysis analyses of proteins loaded in PLSC Exo suggested the role of retinoic acid receptor/liver x receptor pathways in their biological effects. Together, these results suggest the novel selective anti-cancer effects of PLSC Exo against aggressive PCa cells. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. Impact of aggressive management and palliative care on cancer costs in the final month of life.

    PubMed

    Cheung, Matthew C; Earle, Craig C; Rangrej, Jagadish; Ho, Thi H; Liu, Ning; Barbera, Lisa; Saskin, Refik; Porter, Joan; Seung, Soo Jin; Mittmann, Nicole

    2015-09-15

    A significant share of the cost of cancer care is concentrated in the end-of-life period. Although quality measures of aggressive treatment may guide optimal care during this timeframe, little is known about whether these metrics affect costs of care. This study used population data to identify a cohort of patients who died of cancer in Ontario, Canada (2005-2009). Individuals were categorized as having received or having not received aggressive end-of-life care according to quality measures related to acute institutional care or chemotherapy administration in the end-of-life period. Costs (2009 Canadian dollars) were collected over the last month of life through the linkage of health system administrative databases. Multivariate quantile regression was used to identify predictors of increased costs. Among 107,253 patients, the mean per-patient cost over the final month was $18,131 for patients receiving aggressive care and $12,678 for patients receiving nonaggressive care (P < .0001). Patients who received chemotherapy in the last 2 weeks of life also sustained higher costs than those who did not (P < .0001). For individuals receiving end-of-life care in the highest cost quintile, early and repeated palliative care consultation was associated with reduced mean per-patient costs. In a multivariate analysis, chemotherapy in the 2 weeks of life remained predictive of increased costs (median increase, $536; P < .0001), whereas access to palliation remained predictive for lower costs (median decrease, $418; P < .0001). Cancer patients who receive aggressive end-of-life care incur 43% higher costs than those managed nonaggressively. Palliative consultation may partially offset these costs and offer resultant savings. © 2015 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

  3. Tumor necrosis is an important hallmark of aggressive endometrial cancer and associates with hypoxia, angiogenesis and inflammation responses

    PubMed Central

    Stefansson, Ingunn M.; Birkeland, Even; Bø, Trond Hellem; Øyan, Anne M.; Trovik, Jone; Kalland, Karl-Henning; Jonassen, Inge; Salvesen, Helga B.; Wik, Elisabeth; Akslen, Lars A.

    2015-01-01

    Aims Tumor necrosis is associated with aggressive features of endometrial cancer and poor prognosis. Here, we investigated gene expression patterns and potential treatment targets related to presence of tumor necrosis in primary endometrial cancer lesions. Methods and Results By DNA microarray analysis, expression of genes related to tumor necrosis reflected multiple tumor-microenvironment interactions like tissue hypoxia, angiogenesis and inflammation pathways. A tumor necrosis signature of 38 genes and a related patient cluster (Cluster I, 67% of the cases) were associated with features of aggressive tumors such as type II cancers, estrogen receptor negative tumors and vascular invasion. Further, the tumor necrosis signature was increased in tumor cells grown in hypoxic conditions in vitro. Multiple genes with increased expression are known to be activated by HIF1A and NF-kB. Conclusions Our findings indicate that the presence of tumor necrosis within primary tumors is associated with hypoxia, angiogenesis and inflammation responses. HIF1A, NF-kB and PI3K/mTOR might be potential treatment targets in aggressive endometrial cancers with presence of tumor necrosis. PMID:26485755

  4. Tumor necrosis is an important hallmark of aggressive endometrial cancer and associates with hypoxia, angiogenesis and inflammation responses.

    PubMed

    Bredholt, Geir; Mannelqvist, Monica; Stefansson, Ingunn M; Birkeland, Even; Bø, Trond Hellem; Øyan, Anne M; Trovik, Jone; Kalland, Karl-Henning; Jonassen, Inge; Salvesen, Helga B; Wik, Elisabeth; Akslen, Lars A

    2015-11-24

    Tumor necrosis is associated with aggressive features of endometrial cancer and poor prognosis. Here, we investigated gene expression patterns and potential treatment targets related to presence of tumor necrosis in primary endometrial cancer lesions. By DNA microarray analysis, expression of genes related to tumor necrosis reflected multiple tumor-microenvironment interactions like tissue hypoxia, angiogenesis and inflammation pathways. A tumor necrosis signature of 38 genes and a related patient cluster (Cluster I, 67% of the cases) were associated with features of aggressive tumors such as type II cancers, estrogen receptor negative tumors and vascular invasion. Further, the tumor necrosis signature was increased in tumor cells grown in hypoxic conditions in vitro. Multiple genes with increased expression are known to be activated by HIF1A and NF-kB. Our findings indicate that the presence of tumor necrosis within primary tumors is associated with hypoxia, angiogenesis and inflammation responses. HIF1A, NF-kB and PI3K/mTOR might be potential treatment targets in aggressive endometrial cancers with presence of tumor necrosis.

  5. Cdx2 Polymorphism Affects the Activities of Vitamin D Receptor in Human Breast Cancer Cell Lines and Human Breast Carcinomas

    PubMed Central

    Di Benedetto, Anna; Korita, Etleva; Goeman, Frauke; Sacconi, Andrea; Biagioni, Francesca; Blandino, Giovanni; Strano, Sabrina; Muti, Paola; Mottolese, Marcella; Falvo, Elisabetta

    2015-01-01

    Vitamin D plays a role in cancer development and acts through the vitamin D receptor (VDR). It regulates the action of hormone responsive genes and is involved in cell cycle regulation, differentiation and apoptosis. VDR is a critical component of the vitamin D pathway and different common single nucleotide polymorphisms have been identified. Cdx2 VDR polymorphism can play an important role in breast cancer, modulating the activity of VDR. The objective of this study is to assess the relationship between the Cdx2 VDR polymorphism and the activities of VDR in human breast cancer cell lines and carcinomas breast patients. Cdx2 VDR polymorphism and antiproliferative effects of vitamin D treatment were investigated in a panel of estrogen receptor-positive (MCF7 and T-47D) and estrogen receptor-negative (MDA-MB-231, SUM 159PT, SK-BR-3, BT549, MDA-MB-468, HCC1143, BT20 and HCC1954) human breast cancer cell lines. Furthermore, the potential relationship among Cdx2 VDR polymorphism and a number of biomarkers used in clinical management of breast cancer was assessed in an ad hoc set of breast cancer cases. Vitamin D treatment efficacy was found to be strongly dependent on the Cdx2 VDR status in ER-negative breast cancer cell lines tested. In our series of breast cancer cases, the results indicated that patients with variant homozygote AA were associated with bio-pathological characteristics typical of more aggressive tumours, such as ER negative, HER2 positive and G3. Our results may suggest a potential effect of Cdx2 VDR polymorphism on the efficacy of vitamin D treatment in aggressive breast cancer cells (estrogen receptor negative). These results suggest that Cdx2 polymorphism may be a potential biomarker for vitamin D treatment in breast cancer, independently of the VDR receptor expression. PMID:25849303

  6. Denying humanness to others: a newly discovered mechanism by which violent video games increase aggressive behavior.

    PubMed

    Greitemeyer, Tobias; McLatchie, Neil

    2011-05-01

    Past research has provided abundant evidence that playing violent video games increases aggressive behavior. So far, these effects have been explained mainly as the result of priming existing knowledge structures. The research reported here examined the role of denying humanness to other people in accounting for the effect that playing a violent video game has on aggressive behavior. In two experiments, we found that playing violent video games increased dehumanization, which in turn evoked aggressive behavior. Thus, it appears that video-game-induced aggressive behavior is triggered when victimizers perceive the victim to be less human.

  7. The Role of Fluorine-18-Fluorodeoxyglucose Positron Emission Tomography in Aggressive Histological Subtypes of Thyroid Cancer: An Overview

    PubMed Central

    Treglia, Giorgio; Annunziata, Salvatore; Muoio, Barbara; Salvatori, Massimo; Ceriani, Luca; Giovanella, Luca

    2013-01-01

    Aggressive histological subtypes of thyroid cancer are rare and have a poor prognosis. The most important aggressive subtypes of thyroid cancer are Hürthle cell carcinoma (HCTC) and anaplastic and poorly differentiated carcinoma (ATC and PDTC). The American Thyroid Association recently published guidelines for the management of patients with ATC, but no specific guidelines have been done about HCTC. We performed an overview of the literature about the role of Fluorine-18-Fluorodeoxyglucose positron emission tomography or positron emission tomography/computed tomography (FDG-PET or PET/CT) in aggressive histological subtypes of thyroid cancer. Only few original studies about the role of FDG-PET or PET/CT in HCTC, PDTC, and ATC have been published in the literature. FDG-PET or PET/CT seems to be useful in staging or followup of invasive and metastatic HCTC. FDG-PET or PET/CT should be used in patients with ATC in initial staging and in the followup after surgery to evaluate metastatic disease. Some authors suggest the use of FDG-PET/CT in staging of PDTC, but more studies are needed to define the diagnostic use of FDG-PET/CT in this setting. Limited experience suggests the usefulness of FDG-PET or PET/CT in patients with more aggressive histological subtypes of DTC. However, DTC presenting as radioiodine refractory and FDG-PET positive should be considered aggressive tumours with poor prognosis. PMID:23653645

  8. The role of fluorine-18-fluorodeoxyglucose positron emission tomography in aggressive histological subtypes of thyroid cancer: an overview.

    PubMed

    Treglia, Giorgio; Annunziata, Salvatore; Muoio, Barbara; Salvatori, Massimo; Ceriani, Luca; Giovanella, Luca

    2013-01-01

    Aggressive histological subtypes of thyroid cancer are rare and have a poor prognosis. The most important aggressive subtypes of thyroid cancer are Hürthle cell carcinoma (HCTC) and anaplastic and poorly differentiated carcinoma (ATC and PDTC). The American Thyroid Association recently published guidelines for the management of patients with ATC, but no specific guidelines have been done about HCTC. We performed an overview of the literature about the role of Fluorine-18-Fluorodeoxyglucose positron emission tomography or positron emission tomography/computed tomography (FDG-PET or PET/CT) in aggressive histological subtypes of thyroid cancer. Only few original studies about the role of FDG-PET or PET/CT in HCTC, PDTC, and ATC have been published in the literature. FDG-PET or PET/CT seems to be useful in staging or followup of invasive and metastatic HCTC. FDG-PET or PET/CT should be used in patients with ATC in initial staging and in the followup after surgery to evaluate metastatic disease. Some authors suggest the use of FDG-PET/CT in staging of PDTC, but more studies are needed to define the diagnostic use of FDG-PET/CT in this setting. Limited experience suggests the usefulness of FDG-PET or PET/CT in patients with more aggressive histological subtypes of DTC. However, DTC presenting as radioiodine refractory and FDG-PET positive should be considered aggressive tumours with poor prognosis.

  9. Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer

    PubMed Central

    Zhang, Dingxiao; Park, Daechan; Zhong, Yi; Lu, Yue; Rycaj, Kiera; Gong, Shuai; Chen, Xin; Liu, Xin; Chao, Hsueh-Ping; Whitney, Pamela; Calhoun-Davis, Tammy; Takata, Yoko; Shen, Jianjun; Iyer, Vishwanath R.; Tang, Dean G.

    2016-01-01

    The prostate gland mainly contains basal and luminal cells constructed as a pseudostratified epithelium. Annotation of prostate epithelial transcriptomes provides a foundation for discoveries that can impact disease understanding and treatment. Here we describe a genome-wide transcriptome analysis of human benign prostatic basal and luminal epithelial populations using deep RNA sequencing. Through molecular and biological characterizations, we show that the differential gene-expression profiles account for their distinct functional properties. Strikingly, basal cells preferentially express gene categories associated with stem cells, neurogenesis and ribosomal RNA (rRNA) biogenesis. Consistent with this profile, basal cells functionally exhibit intrinsic stem-like and neurogenic properties with enhanced rRNA transcription activity. Of clinical relevance, the basal cell gene-expression profile is enriched in advanced, anaplastic, castration-resistant and metastatic prostate cancers. Therefore, we link the cell-type-specific gene signatures to aggressive subtypes of prostate cancer and identify gene signatures associated with adverse clinical features. PMID:26924072

  10. Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer.

    PubMed

    Zhang, Dingxiao; Park, Daechan; Zhong, Yi; Lu, Yue; Rycaj, Kiera; Gong, Shuai; Chen, Xin; Liu, Xin; Chao, Hsueh-Ping; Whitney, Pamela; Calhoun-Davis, Tammy; Takata, Yoko; Shen, Jianjun; Iyer, Vishwanath R; Tang, Dean G

    2016-02-29

    The prostate gland mainly contains basal and luminal cells constructed as a pseudostratified epithelium. Annotation of prostate epithelial transcriptomes provides a foundation for discoveries that can impact disease understanding and treatment. Here we describe a genome-wide transcriptome analysis of human benign prostatic basal and luminal epithelial populations using deep RNA sequencing. Through molecular and biological characterizations, we show that the differential gene-expression profiles account for their distinct functional properties. Strikingly, basal cells preferentially express gene categories associated with stem cells, neurogenesis and ribosomal RNA (rRNA) biogenesis. Consistent with this profile, basal cells functionally exhibit intrinsic stem-like and neurogenic properties with enhanced rRNA transcription activity. Of clinical relevance, the basal cell gene-expression profile is enriched in advanced, anaplastic, castration-resistant and metastatic prostate cancers. Therefore, we link the cell-type-specific gene signatures to aggressive subtypes of prostate cancer and identify gene signatures associated with adverse clinical features.

  11. Is there a role for voltage-gated Na+ channels in the aggressiveness of breast cancer?

    PubMed

    Rhana, P; Trivelato, R R; Beirão, P S L; Cruz, J S; Rodrigues, A L P

    2017-06-05

    Breast cancer is the most common cancer among women and its metastatic potential is responsible for numerous deaths. Thus, the need to find new targets for improving treatment, and even finding the cure, becomes increasingly greater. Ion channels are known to participate in several physiological functions, such as muscle contraction, cell volume regulation, immune response and cell proliferation. In breast cancer, different types of ion channels have been associated with tumorigenesis. Recently, voltage-gated Na+ channels (VGSC) have been implicated in the processes that lead to increased tumor aggressiveness. To explain this relationship, different theories, associated with pH changes, gene expression and intracellular Ca2+, have been proposed in an attempt to better understand the role of these ion channels in breast cancer. However, these theories are having difficulty being accepted because most of the findings are contrary to the present scientific knowledge. Several studies have shown that VGSC are related to different types of cancer, making them a promising pharmacological target against this debilitating disease. Molecular biology and cell electrophysiology have been used to look for new forms of treatment aiming to reduce aggressiveness and the disease progress.

  12. Is there a role for voltage-gated Na+ channels in the aggressiveness of breast cancer?

    PubMed Central

    Rhana, P.; Trivelato, R.R.; Beirão, P.S.L.; Cruz, J.S.; Rodrigues, A.L.P.

    2017-01-01

    Breast cancer is the most common cancer among women and its metastatic potential is responsible for numerous deaths. Thus, the need to find new targets for improving treatment, and even finding the cure, becomes increasingly greater. Ion channels are known to participate in several physiological functions, such as muscle contraction, cell volume regulation, immune response and cell proliferation. In breast cancer, different types of ion channels have been associated with tumorigenesis. Recently, voltage-gated Na+ channels (VGSC) have been implicated in the processes that lead to increased tumor aggressiveness. To explain this relationship, different theories, associated with pH changes, gene expression and intracellular Ca2+, have been proposed in an attempt to better understand the role of these ion channels in breast cancer. However, these theories are having difficulty being accepted because most of the findings are contrary to the present scientific knowledge. Several studies have shown that VGSC are related to different types of cancer, making them a promising pharmacological target against this debilitating disease. Molecular biology and cell electrophysiology have been used to look for new forms of treatment aiming to reduce aggressiveness and the disease progress. PMID:28591378

  13. GATA3 Inhibits Lysyl Oxidase Mediated Metastases of Human Basal Triple-Negative Breast Cancer Cells

    PubMed Central

    Chu, Isabel M.; Michalowski, Aleksandra M.; Hoenerhoff, Mark; Szauter, Kornelia M.; Luger, Dror; Sato, Misako; Flanders, Kathy; Oshima, Akira; Csiszar, Katalin; Green, Jeffrey E.

    2011-01-01

    Discovery of mechanisms that impede the aggressive and metastatic phenotype of human basal triple-negative type breast cancers (BTNBC) could provide novel targets for therapy for this form of breast cancer that has a relatively poor prognosis. Previous studies have demonstrated that the expression of GATA3, the master transcriptional regulator of mammary luminal differentiation, can reduce the tumorigenicity and metastatic propensity of the human BTNBC MDA-MB-231 cell line (MB231), although the mechanism for reduced metastases was not elucidated. We demonstrate through gene expression profiling that GATA3 expression in 231 cells resulted in the dramatic reduction in the expression of Lysyl oxidase (LOX), a metastasis-promoting matrix remodeling protein, in part, through methylation of the LOX promoter. Suppression of LOX expression by GATA3 was further confirmed in the BTNBC Hs578T cell line. Conversely, reduction of GATA3 expression by siRNA in luminal BT474 cells increased LOX expression. Reconstitution of LOX expression in 231-GATA3 cells restored metastatic propensity. A strong inverse association between high LOX and low GATA3 expression was confirmed in a panel of 51 human breast cancer cell lines. Similarly, human breast cancer microarray data demonstrated that high LOX/low GATA3 expression is associated with the BTNBC subtype of breast cancer and poor patient prognosis. Expression of GATA3 reprograms BTNBC to a less aggressive phenotype and inhibits a major mechanism of metastasis through inhibition of LOX. Induction of GATA3 in BTNBC cells or novel approaches that inhibit LOX expression or activity could be important strategies for treating BTNBC. PMID:21892208

  14. Lunar Influences on Human Aggression.

    ERIC Educational Resources Information Center

    Russell, Gordon W.; Dua, Manjula

    1983-01-01

    Used league records of all Canadian hockey games (N=426) played during a season to test a lunar-aggression hypothesis. Despite the use of multiple measures of lunar phase and interpersonal aggression, support for lunar influence was not forthcoming. Supplemental data revealed that beliefs in lunar influence are fairly common. (JAC)

  15. Vitamin D and Related Genes, Race and Prostate Cancer Aggressiveness

    DTIC Science & Technology

    2015-12-29

    currently a postdoctoral fellow at the Mayo Clinic in Minnesota. 6. Have all raw data sent to USC and to PCaP parent study a. Raw data from Roswell...completion of lab work and raw data deposit at centralized location) were completed. Data were begun to be merged and cleaned, and preliminary data...example, two SNPs in the vitamin D binding protein gene known as GC, were inversely associated with high aggressive prostate cancer (rs222054: OR

  16. Establishment of a novel human medulloblastoma cell line characterized by highly aggressive stem-like cells.

    PubMed

    Silva, Patrícia Benites Gonçalves da; Rodini, Carolina Oliveira; Kaid, Carolini; Nakahata, Adriana Miti; Pereira, Márcia Cristina Leite; Matushita, Hamilton; Costa, Silvia Souza da; Okamoto, Oswaldo Keith

    2016-08-01

    Medulloblastoma is a highly aggressive brain tumor and one of the leading causes of morbidity and mortality related to childhood cancer. These tumors display differential ability to metastasize and respond to treatment, which reflects their high degree of heterogeneity at the genetic and molecular levels. Such heterogeneity of medulloblastoma brings an additional challenge to the understanding of its physiopathology and impacts the development of new therapeutic strategies. This translational effort has been the focus of most pre-clinical studies which invariably employ experimental models using human tumor cell lines. Nonetheless, compared to other cancers, relatively few cell lines of human medulloblastoma are available in central repositories, partly due to the rarity of these tumors and to the intrinsic difficulties in establishing continuous cell lines from pediatric brain tumors. Here, we report the establishment of a new human medulloblastoma cell line which, in comparison with the commonly used and well-established cell line Daoy, is characterized by enhanced proliferation and invasion capabilities, stem cell properties, increased chemoresistance, tumorigenicity in an orthotopic metastatic model, replication of original medulloblastoma behavior in vivo, strong chromosome structural instability and deregulation of genes involved in neural development. These features are advantageous for designing biologically relevant experimental models in clinically oriented studies, making this novel cell line, named USP-13-Med, instrumental for the study of medulloblastoma biology and treatment.

  17. Parametric PET/MR Fusion Imaging to Differentiate Aggressive from Indolent Primary Prostate Cancer with Application for Image-Guided Prostate Cancer Biopsies

    DTIC Science & Technology

    2013-10-01

    AD_________________ Award Number: W81XWH-12-1-0597 TITLE: Parametric PET /MR Fusion Imaging to...Parametric PET /MR Fusion Imaging to Differentiate Aggressive from Indolent Primary Prostate Cancer with Application for Image-Guided Prostate Cancer Biopsies...The study investigates whether fusion PET /MRI imaging with 18F-choline PET /CT and diffusion-weighted MRI can be successfully applied to target prostate

  18. Survival outcomes following aggressive treatment of oligometastatic breast cancer: a systematic review protocol.

    PubMed

    Coombe, Robyn; Lisy, Karolina; Campbell, Jared; Perry, Gajen; Prasannan, Subhita

    2017-08-01

    The objective of this systematic review is to assess the effectiveness of aggressive treatment of oligometastatic breast cancer (OMBC) on survival outcomes by conducting a meta-analysis of current available evidence.More specifically, the objectives are to identify the effectiveness of intensified multidisciplinary treatment with aggressive locoregional therapies on survival time, five-year survival rates and disease free survival. The population is adult women (18 years and over) with OMBC defined as single or few (five or less) metastases limited to a single organ and the comparative group is conventional palliative treatment aimed at disease control. Secondary objectives to be assessed will be adverse outcomes associated with intensified treatment regimes.

  19. Epidermal Growth Factor Increases LRF/Pokemon Expression in Human Prostate Cancer Cells

    PubMed Central

    Aggarwal, Himanshu; Aggarwal, Anshu; Agrawal, Devendra K.

    2011-01-01

    Leukemia/lymphoma related factor/POK erythroid myeloid ontogenic factor (LRF/Pokemon) is a member of the POK family of proteins that promotes oncogenesis in several forms of cancer. Recently, we found higher LRF expression in human breast and prostate carcinomas compared to the corresponding normal tissues. The aim of this study was to examine the regulation of LRF expression in human prostate cells. Epidermal growth factor (EGF) and its receptors mediate several tumorigenic cascades that regulate cell differentiation, proliferation, migration and survival of prostate cancer cells. There was significantly higher level of LRF expression in the nucleus of LNCaP and PC-3 cells than RWPE-1 cells. A significant increase in LRF expression was observed with increasing doses of EGF in more aggressive and androgen-sensitive prostate cancer cells suggesting that EGF signaling pathway is critical in upregulating the expression of LRF/Pokemon to promote oncogenesis. PMID:21640721

  20. Mediterranean Dietary Pattern is Associated with Low Risk of Aggressive Prostate Cancer: MCC-Spain Study.

    PubMed

    Castelló, Adela; Boldo, Elena; Amiano, Pilar; Castaño-Vinyals, Gemma; Aragonés, Nuria; Gómez-Acebo, Inés; Peiró, Rosana; Jimenez-Moleón, Jose Juan; Alguacil, Juan; Tardón, Adonina; Cecchini, Lluís; Lope, Virginia; Dierssen-Sotos, Trinidad; Mengual, Lourdes; Kogevinas, Manolis; Pollán, Marina; Pérez-Gómez, Beatriz

    2018-02-01

    We explored the association of the previously described Western, prudent and Mediterranean dietary patterns with prostate cancer risk by tumor aggressiveness and extension. MCC-Spain (Multicase-Control Study on Common Tumors in Spain) is a population based, multicase-control study that was done in 7 Spanish provinces between September 2008 and December 2013. It collected anthropometric, epidemiological and dietary information on 754 histologically confirmed incident cases of prostate cancer and 1,277 controls 38 to 85 years old. Three previously identified dietary patterns, including Western, prudent and Mediterranean, were reconstructed using MCC-Spain data. The association of each pattern with prostate cancer risk was assessed by logistic regression models with random, province specific intercepts. Risk according to tumor aggressiveness (Gleason score 6 vs greater than 6) and extension (cT1-cT2a vs cT2b-cT4) was evaluated by multinomial regression models. High adherence to a Mediterranean dietary pattern rich not only in fruits and vegetables but also in fish, legumes and olive oil was specifically associated with a lower risk of Gleason score greater than 6 prostate cancer (quartile 3 vs 1 relative RR 0.66, 95% CI 0.46-0.96 and quartile 4 vs 1 relative RR 0.68, 95% CI 0.46-1.01, p-trend = 0.023) or with higher clinical stage (cT2b-T4 quartile 4 vs 1 relative RR 0.49, 95% CI 0.25-0.96, p-trend = 0.024). This association was not observed with the prudent pattern, which combines vegetables and fruits with low fat dairy products, whole grains and juices. The Western pattern did not show any association with prostate cancer risk. Nutritional recommendations for prostate cancer prevention should consider whole dietary patterns instead of individual foods. We found important differences between the Mediterranean dietary pattern, which was associated with a lower risk of aggressive prostate cancer, and Western and prudent dietary patterns, which had no relationship with

  1. Loss of PTEN expression is associated with aggressive behavior and poor prognosis in Middle Eastern triple-negative breast cancer.

    PubMed

    Beg, Shaham; Siraj, Abdul K; Prabhakaran, Sarita; Jehan, Zeenath; Ajarim, Dahish; Al-Dayel, Fouad; Tulbah, Asma; Al-Kuraya, Khawla S

    2015-06-01

    PTEN is a tumor suppressor that negatively regulates the PI3 K-AKT signaling pathway which is involved in the pathogenesis of many different tumor types and serves as a prognostic marker in breast cancer. However, the significance of the role of PTEN in Middle Eastern ethnic breast cancer has not been explored especially with the fact that breast cancer originating from this ethnic population tend to behave more aggressively than breast cancer in the west. In this study, we analyzed PTEN alteration in a tissue microarray format containing more than 1000 primary breast cancers with clinical follow-up data. Tissue Microarray sections were analyzed for protein expression and copy number change using immunohistochemistry and fluorescence in situ hybridization. Loss of PTEN immunostaining was observed in 77 % of the cases. PTEN loss was significantly associated with large tumor size (p = 0.0030), high grade (p = 0.0281), tumor recurrence (p = 0.0333), and triple-negative breast cancers (p = 0.0086). PTEN loss in triple-negative breast cancers was significantly associated with rapid tumor cell proliferation (p = 0.0396) and poor prognosis (p = 0.0408). PTEN deletion was found only in 60 cases (6.4 %). Loss of PTEN protein expression occurs at high frequency in Middle Eastern breast cancer. PTEN inactivation may potentially lead to an aggressive behavior of tumor cells through stimulation of tumor cell proliferation. Furthermore, PTEN signaling pathway might be used as potential therapeutic target in triple-negative breast cancers since loss of its expression is shown to be significantly associated with this aggressive subtype of breast cancer.

  2. Comparative evaluation of urinary PCA3 and TMPRSS2: ERG scores and serum PHI in predicting prostate cancer aggressiveness.

    PubMed

    Tallon, Lucile; Luangphakdy, Devillier; Ruffion, Alain; Colombel, Marc; Devonec, Marian; Champetier, Denis; Paparel, Philippe; Decaussin-Petrucci, Myriam; Perrin, Paul; Vlaeminck-Guillem, Virginie

    2014-07-30

    It has been suggested that urinary PCA3 and TMPRSS2:ERG fusion tests and serum PHI correlate to cancer aggressiveness-related pathological criteria at prostatectomy. To evaluate and compare their ability in predicting prostate cancer aggressiveness, PHI and urinary PCA3 and TMPRSS2:ERG (T2) scores were assessed in 154 patients who underwent radical prostatectomy for biopsy-proven prostate cancer. Univariate and multivariate analyses using logistic regression and decision curve analyses were performed. All three markers were predictors of a tumor volume≥0.5 mL. Only PHI predicted Gleason score≥7. T2 score and PHI were both independent predictors of extracapsular extension(≥pT3), while multifocality was only predicted by PCA3 score. Moreover, when compared to a base model (age, digital rectal examination, serum PSA, and Gleason sum at biopsy), the addition of both PCA3 score and PHI to the base model induced a significant increase (+12%) when predicting tumor volume>0.5 mL. PHI and urinary PCA3 and T2 scores can be considered as complementary predictors of cancer aggressiveness at prostatectomy.

  3. MiR-205 and MiR-373 Are Associated with Aggressive Human Mucinous Colorectal Cancer

    PubMed Central

    Eyking, Annette; Reis, Henning; Frank, Magdalena; Gerken, Guido; Schmid, Kurt W.; Cario, Elke

    2016-01-01

    Mucinous adenocarcinoma (MAC) represents a distinct histopathological entity of colorectal cancer (CRC), which is associated with disease progression and poor prognosis. Here, we found that expression levels of miR-205 and miR-373 were specifically upregulated only in patients with mucinous colon cancers, but not in CRC that lack mucinous components. To investigate the effects of miR-205 and miR-373 on intestinal epithelial cell (IEC) biology by gain- and loss-of-function experiments in a proof-of-concept approach, we chose previously established in-vitro human Caco-2-based models of differentiated, non-invasive (expressing TLR4 wild-type; termed Caco-2[WT]) versus undifferentiated, invasive (expressing TLR4 mutant D299G; termed Caco-2[D299G]) IEC. Enterocyte-like Caco-2[WT] showed low levels of miR-205 and miR-373 expression, while both miRNAs were significantly upregulated in colorectal carcinoma-like Caco-2[D299G], thus resembling the miRNA expression pattern of paired normal versus tumor samples from MAC patients. Using stable transfection, we generated miR-205- or miR-373-expressing and miR-205- or miR-373-inhibiting subclones of these IEC lines. We found that introduction of miR-205 into Caco-2[WT] led to expansion of mucus-secreting goblet cell-like cells, which was associated with induction of KLF4, MUC2 and TGFβ1 expression. Activation of miR-205 in Caco-2[WT] induced chemoresistance, while inhibition of miR-205 in Caco-2[D299G] promoted chemosensitivity. Caco-2[WT] overexpressing miR-373 showed mitotic abnormalities and underwent morphologic changes (loss of epithelial polarity, cytoskeletal reorganization, and junctional disruption) associated with epithelial-mesenchymal transition and progression to inflammation-associated colonic carcinoma, which correlated with induction of phosphorylated STAT3 and N-CADHERIN expression. Functionally, introduction of miR-373 into Caco-2[WT] mediated loss of cell-cell adhesion and increased proliferation and invasion

  4. MiR-205 and MiR-373 Are Associated with Aggressive Human Mucinous Colorectal Cancer.

    PubMed

    Eyking, Annette; Reis, Henning; Frank, Magdalena; Gerken, Guido; Schmid, Kurt W; Cario, Elke

    2016-01-01

    Mucinous adenocarcinoma (MAC) represents a distinct histopathological entity of colorectal cancer (CRC), which is associated with disease progression and poor prognosis. Here, we found that expression levels of miR-205 and miR-373 were specifically upregulated only in patients with mucinous colon cancers, but not in CRC that lack mucinous components. To investigate the effects of miR-205 and miR-373 on intestinal epithelial cell (IEC) biology by gain- and loss-of-function experiments in a proof-of-concept approach, we chose previously established in-vitro human Caco-2-based models of differentiated, non-invasive (expressing TLR4 wild-type; termed Caco-2[WT]) versus undifferentiated, invasive (expressing TLR4 mutant D299G; termed Caco-2[D299G]) IEC. Enterocyte-like Caco-2[WT] showed low levels of miR-205 and miR-373 expression, while both miRNAs were significantly upregulated in colorectal carcinoma-like Caco-2[D299G], thus resembling the miRNA expression pattern of paired normal versus tumor samples from MAC patients. Using stable transfection, we generated miR-205- or miR-373-expressing and miR-205- or miR-373-inhibiting subclones of these IEC lines. We found that introduction of miR-205 into Caco-2[WT] led to expansion of mucus-secreting goblet cell-like cells, which was associated with induction of KLF4, MUC2 and TGFβ1 expression. Activation of miR-205 in Caco-2[WT] induced chemoresistance, while inhibition of miR-205 in Caco-2[D299G] promoted chemosensitivity. Caco-2[WT] overexpressing miR-373 showed mitotic abnormalities and underwent morphologic changes (loss of epithelial polarity, cytoskeletal reorganization, and junctional disruption) associated with epithelial-mesenchymal transition and progression to inflammation-associated colonic carcinoma, which correlated with induction of phosphorylated STAT3 and N-CADHERIN expression. Functionally, introduction of miR-373 into Caco-2[WT] mediated loss of cell-cell adhesion and increased proliferation and invasion

  5. Identification of Methylated Genes Associated with Aggressive Bladder Cancer

    PubMed Central

    Marsit, Carmen J.; Houseman, E. Andres; Christensen, Brock C.; Gagne, Luc; Wrensch, Margaret R.; Nelson, Heather H.; Wiemels, Joseph; Zheng, Shichun; Wiencke, John K.; Andrew, Angeline S.; Schned, Alan R.; Karagas, Margaret R.; Kelsey, Karl T.

    2010-01-01

    Approximately 500,000 individuals diagnosed with bladder cancer in the U.S. require routine cystoscopic follow-up to monitor for disease recurrences or progression, resulting in over $2 billion in annual expenditures. Identification of new diagnostic and monitoring strategies are clearly needed, and markers related to DNA methylation alterations hold great promise due to their stability, objective measurement, and known associations with the disease and with its clinical features. To identify novel epigenetic markers of aggressive bladder cancer, we utilized a high-throughput DNA methylation bead-array in two distinct population-based series of incident bladder cancer (n = 73 and n = 264, respectively). We then validated the association between methylation of these candidate loci with tumor grade in a third population (n = 245) through bisulfite pyrosequencing of candidate loci. Array based analyses identified 5 loci for further confirmation with bisulfite pyrosequencing. We identified and confirmed that increased promoter methylation of HOXB2 is significantly and independently associated with invasive bladder cancer and methylation of HOXB2, KRT13 and FRZB together significantly predict high-grade non-invasive disease. Methylation of these genes may be useful as clinical markers of the disease and may point to genes and pathways worthy of additional examination as novel targets for therapeutic treatment. PMID:20808801

  6. Identification of methylated genes associated with aggressive bladder cancer.

    PubMed

    Marsit, Carmen J; Houseman, E Andres; Christensen, Brock C; Gagne, Luc; Wrensch, Margaret R; Nelson, Heather H; Wiemels, Joseph; Zheng, Shichun; Wiencke, John K; Andrew, Angeline S; Schned, Alan R; Karagas, Margaret R; Kelsey, Karl T

    2010-08-23

    Approximately 500,000 individuals diagnosed with bladder cancer in the U.S. require routine cystoscopic follow-up to monitor for disease recurrences or progression, resulting in over $2 billion in annual expenditures. Identification of new diagnostic and monitoring strategies are clearly needed, and markers related to DNA methylation alterations hold great promise due to their stability, objective measurement, and known associations with the disease and with its clinical features. To identify novel epigenetic markers of aggressive bladder cancer, we utilized a high-throughput DNA methylation bead-array in two distinct population-based series of incident bladder cancer (n = 73 and n = 264, respectively). We then validated the association between methylation of these candidate loci with tumor grade in a third population (n = 245) through bisulfite pyrosequencing of candidate loci. Array based analyses identified 5 loci for further confirmation with bisulfite pyrosequencing. We identified and confirmed that increased promoter methylation of HOXB2 is significantly and independently associated with invasive bladder cancer and methylation of HOXB2, KRT13 and FRZB together significantly predict high-grade non-invasive disease. Methylation of these genes may be useful as clinical markers of the disease and may point to genes and pathways worthy of additional examination as novel targets for therapeutic treatment.

  7. Nestin: A biomarker of aggressive uterine cancers.

    PubMed

    Hope, Erica R; Mhawech-Fauceglia, Paulette; Pejovic, Tanja; Zahn, Christopher M; Wang, Guisong; Conrads, Thomas P; Larry Maxwell, G; Hamilton, Chad A; Darcy, Kathleen M; Syed, Viqar

    2016-03-01

    Evidence of potential prognostic and predictive value for nestin was investigated in well-annotated uterine cancers (UCs). Nestin expression and previously-published biomarkers were evaluated by immunohistochemistry (IHC) in UC tissue microarrays. Biomarkers were categorized as low vs. high, and nestin was cut at 10% positive staining. Relationship between nestin and clinicopathologic factors, biomarkers and outcome were evaluated using exact/log-rank testing or logistic/Cox modeling. There were 323 eligible cases, 34% had advanced stage disease, 37% had type II disease, and 5% were carcinosarcomas. High nestin, observed in 19% of cases, was more common in advanced vs. early stage disease, type II cancers or uterine carcinosarcoma vs. type I cancers, grade 3 disease, positive lymphovascular space invasion (LVSI) and tumors >6cm (p<0.05). Nestin was inversely correlated with ER, PR and TFF3, and correlated with p53 and IMP3. Women with high vs. low nestin had worse progression-free survival (PFS) and cancer-specific survival overall, and worse PFS in the subset who received no adjuvant therapy or radiation, or had early stage, type I disease or tumors with both low and high ER, PR, TFF3, PTEN, p53 or IMP3. The relationship between nestin and PFS was independent of stage, LVSI and risk categorization but not type of UC. High nestin was more common in UCs with aggressive features and poor outcome. Nestin may represent a predictive biomarker for treatment selection for patients previously considered to be lower risk and a candidate for no or radiation-based adjuvant therapy, and compliment ER/PR testing. Published by Elsevier Inc.

  8. Study Finds Dual Inhibition Therapy May Lead to Better Outcomes for Aggressive Form of Breast Cancer | Poster

    Cancer.gov

    A collaboration between the National Cancer Institute (NCI); the Frederick National Laboratory (FNL); and the National University of Ireland, Galway, has shown that two key biomarkers are co-expressed in an aggressive subtype of breast cancer and that inhibiting those two molecules can significantly improve patient survival outcomes.

  9. Oxytocin and Aggression.

    PubMed

    de Jong, Trynke R; Neumann, Inga D

    2017-09-02

    The neuropeptide oxytocin (OT) has a solid reputation as a facilitator of social interactions such as parental and pair bonding, trust, and empathy. The many results supporting a pro-social role of OT have generated the hypothesis that impairments in the endogenous OT system may lead to antisocial behavior, most notably social withdrawal or pathological aggression. If this is indeed the case, administration of exogenous OT could be the "serenic" treatment that psychiatrists have for decades been searching for.In the present review, we list and discuss the evidence for an endogenous "hypo-oxytocinergic state" underlying aggressive and antisocial behavior, derived from both animal and human studies. We furthermore examine the reported effects of synthetic OT administration on aggression in rodents and humans.Although the scientific findings listed in this review support, in broad lines, the link between a down-regulated or impaired OT system activity and increased aggression, the anti-aggressive effects of synthetic OT are less straightforward and require further research. The rather complex picture that emerges adds to the ongoing debate questioning the unidirectional pro-social role of OT, as well as the strength of the effects of intranasal OT administration in humans.

  10. Palliative Care is Associated with Reduced Aggressive End-of-Life Care in Patients with Gastrointestinal Cancer.

    PubMed

    Merchant, Shaila J; Brogly, Susan B; Goldie, Craig; Booth, Christopher M; Nanji, Sulaiman; Patel, Sunil V; Lajkosz, Katherine; Baxter, Nancy N

    2018-06-01

    We examined the delivery of physician palliative care (PC) services and its association with aggressive end-of-life care (EOLC) in patients with gastrointestinal (GI) cancer in Ontario, Canada. All patients with primary cause of death from esophageal, gastric, colon, and anorectal cancer from January 2003 to December 2013 were identified. PC services within 2 years of death were classified: (1) any PC; (2) timing of first PC (≤ 7, 8-90, 91-180, and 181-730 days before death); and (3) intensity of PC measured by number of days used (1st-25th, 26th-50th, 51st-75th, and 76th-100th percentiles). Aggressive EOLC was defined as any of the following: chemotherapy, emergency department visits, hospital or intensive care unit (ICU) admissions (all ≤ 30 days of death), and death in hospital and in the ICU; these were combined as a composite outcome (any aggressive EOLC). The cohort included 34,630 patients, of whom 74% had at least one PC service. Timing of the first PC service varied: ≤ 7 (12%), 8-90 (42%), 91-180 (16%), and 181-730 (30%) days before death. Compared with patients not receiving PC, any PC was associated with a reduction in any aggressive EOLC (risk ratio [RR] 0.75, 95% confidence interval [CI] 0.74-0.76); this association was similar regardless of timing of the first PC service. The most dramatic reduction in aggressive EOLC occurred in patients who received the greatest number of days of PC (RR 0.65, 95% CI 0.63-0.67). The majority of patients received PC within 2 years of death. A larger number of days of PC was associated with a greater reduction in aggressive EOLC.

  11. Brain structures and neurotransmitters regulating aggression in cats: implications for human aggression.

    PubMed

    Gregg, T R; Siegel, A

    2001-01-01

    1. Violence and aggression are major public health problems. 2. The authors have used techniques of electrical brain stimulation, anatomical-immunohistochemical techniques, and behavioral pharmacology to investigate the neural systems and circuits underlying aggressive behavior in the cat. 3. The medial hypothalamus and midbrain periaqueductal gray are the most important structures mediating defensive rage behavior, and the perifornical lateral hypothalamus clearly mediates predatory attack behavior. The hippocampus, amygdala, bed nucleus of the stria terminalis, septal area, cingulate gyrus, and prefrontal cortex project to these structures directly or indirectly and thus can modulate the intensity of attack and rage. 4. Evidence suggests that several neurotransmitters facilitate defensive rage within the PAG and medial hypothalamus, including glutamate, Substance P, and cholecystokinin, and that opioid peptides suppress it; these effects usually depend on the subtype of receptor that is activated. 5. A key recent discovery was a GABAergic projection that may underlie the often-observed reciprocally inhibitory relationship between these two forms of aggression. 6. Recently, Substance P has come under scrutiny as a possible key neurotransmitter involved in defensive rage, and the mechanism by which it plays a role in aggression and rage is under investigation. 7. It is hoped that this line of research will provide a better understanding of the neural mechanisms and substrates regulating aggression and rage and thus establish a rational basis for treatment of disorders associated with these forms of aggression.

  12. Epidermal growth factor increases LRF/Pokemon expression in human prostate cancer cells.

    PubMed

    Aggarwal, Himanshu; Aggarwal, Anshu; Agrawal, Devendra K

    2011-10-01

    Leukemia/lymphoma related factor/POK erythroid myeloid ontogenic factor (LRF/Pokemon) is a member of the POK family of proteins that promotes oncogenesis in several forms of cancer. Recently, we found higher LRF expression in human breast and prostate carcinomas compared to the corresponding normal tissues. The aim of this study was to examine the regulation of LRF expression in human prostate cells. Epidermal growth factor (EGF) and its receptors mediate several tumorigenic cascades that regulate cell differentiation, proliferation, migration and survival of prostate cancer cells. There was significantly higher level of LRF expression in the nucleus of LNCaP and PC-3 cells than RWPE-1 cells. A significant increase in LRF expression was observed with increasing doses of EGF in more aggressive and androgen-sensitive prostate cancer cells suggesting that EGF signaling pathway is critical in upregulating the expression of LRF/Pokemon to promote oncogenesis. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. RB loss contributes to aggressive tumor phenotypes in MYC-driven triple negative breast cancer

    PubMed Central

    Knudsen, Erik S; McClendon, A Kathleen; Franco, Jorge; Ertel, Adam; Fortina, Paolo; Witkiewicz, Agnieszka K

    2015-01-01

    Triple negative breast cancer (TNBC) is characterized by multiple genetic events occurring in concert to drive pathogenic features of the disease. Here we interrogated the coordinate impact of p53, RB, and MYC in a genetic model of TNBC, in parallel with the analysis of clinical specimens. Primary mouse mammary epithelial cells (mMEC) with defined genetic features were used to delineate the combined action of RB and/or p53 in the genesis of TNBC. In this context, the deletion of either RB or p53 alone and in combination increased the proliferation of mMEC; however, the cells did not have the capacity to invade in matrigel. Gene expression profiling revealed that loss of each tumor suppressor has effects related to proliferation, but RB loss in particular leads to alterations in gene expression associated with the epithelial-to-mesenchymal transition. The overexpression of MYC in combination with p53 loss or combined RB/p53 loss drove rapid cell growth. While the effects of MYC overexpression had a dominant impact on gene expression, loss of RB further enhanced the deregulation of a gene expression signature associated with invasion. Specific RB loss lead to enhanced invasion in boyden chambers assays and gave rise to tumors with minimal epithelial characteristics relative to RB-proficient models. Therapeutic screening revealed that RB-deficient cells were particularly resistant to agents targeting PI3K and MEK pathway. Consistent with the aggressive behavior of the preclinical models of MYC overexpression and RB loss, human TNBC tumors that express high levels of MYC and are devoid of RB have a particularly poor outcome. Together these results underscore the potency of tumor suppressor pathways in specifying the biology of breast cancer. Further, they demonstrate that MYC overexpression in concert with RB can promote a particularly aggressive form of TNBC. PMID:25602521

  14. Chronic arsenic trioxide exposure leads to enhanced aggressiveness via Met oncogene addiction in cancer cells

    PubMed Central

    Kryeziu, Kushtrim; Pirker, Christine; Englinger, Bernhard; van Schoonhoven, Sushilla; Spitzwieser, Melanie; Mohr, Thomas; Körner, Wilfried; Weinmüllner, Regina; Tav, Koray; Grillari, Johannes; Cichna-Markl, Margit; Berger, Walter; Heffeter, Petra

    2016-01-01

    As an environmental poison, arsenic is responsible for many cancer deaths. Paradoxically, arsenic trioxide (ATO) presents also a powerful therapy used to treat refractory acute promyelocytic leukemia (APL) and is intensively investigated for treatment of other cancer types. Noteworthy, cancer therapy is frequently hampered by drug resistance, which is also often associated with enhancement of tumor aggressiveness. In this study, we analyzed ATO-selected cancer cells (A2780ATO) for the mechanisms underlying their enhanced tumorigenicity and aggressiveness. These cells were characterized by enhanced proliferation and spheroid growth as well as increased tumorigenicity of xenografts in SCID mice. Noteworthy, subsequent studies revealed that overexpression of Met receptor was the underlying oncogenic driver of these effects, as A2780ATO cells were characterized by collateral sensitivity against Met inhibitors. This finding was also confirmed by array comparative genomic hybridization (array CGH) and whole genome gene expression arrays, which revealed that Met overexpression by chronic ATO exposure was based on the transcriptional regulation via activation of AP-1. Finally, it was shown that treatment with the Met inhibitor crizotinib was also effective against A2780ATO cell xenografts in vivo, indicating that targeting of Met presents a promising strategy for the treatment of Met-overexpressing tumors after either arsenic exposure or failure to ATO treatment. PMID:27036042

  15. Differential expression of miR-34b and androgen receptor pathway regulate prostate cancer aggressiveness between African-Americans and Caucasians

    PubMed Central

    Kato, Taku; Yamamura, Soichiro; Tanaka, Yuichiro; Majid, Shahana; Saini, Sharanjot; Varahram, Shahryari; Kulkarni, Priyanka; Dasgupta, Pritha; Mitsui, Yozo; Sumida, Mitsuho; Tabatabai, Laura; Deng, Guoren; Kumar, Deepak; Dahiya, Rajvir

    2017-01-01

    African-Americans are diagnosed with more aggressive prostate cancers and have worse survival than Caucasians, however a comprehensive understanding of this health disparity remains unclear. To clarify the mechanisms leading to this disparity, we analyzed the potential involvement of miR-34b expression in African-Americans and Caucasians. miR-34b functions as a tumor suppressor and has a multi-functional role, through regulation of cell proliferation, cell cycle and apoptosis. We found that miR-34b expression is lower in human prostate cancer tissues from African-Americans compared to Caucasians. DNA hypermethylation of the miR-34b-3p promoter region showed significantly higher methylation in prostate cancer compared to normal samples. We then sequenced the promoter region of miR-34b-3p and found a chromosomal deletion in miR-34b in African-American prostate cancer cell line (MDA-PCA-2b) and not in Caucasian cell line (DU-145). We found that AR and ETV1 genes are differentially expressed in MDA-PCa-2b and DU-145 cells after overexpression of miR-34b. Direct interaction of miR-34b with the 3’ untranslated region of AR and ETV1 was validated by luciferase reporter assay. We found that miR-34b downregulation in African-Americans is inversely correlated with high AR levels that lead to increased cell proliferation. Overexpression of miR-34b in cell lines showed higher inhibition of cell proliferation, apoptosis and G1 arrest in the African-American cells (MDA-PCa-2b) compared to Caucasian cell line (DU-145). Taken together, our results show that differential expression of miR-34b and AR are associated with prostate cancer aggressiveness in African-Americans. PMID:28039468

  16. Interaction of mammographic breast density with menopausal status and postmenopausal hormone use in relation to the risk of aggressive breast cancer subtypes.

    PubMed

    Yaghjyan, Lusine; Tamimi, Rulla M; Bertrand, Kimberly A; Scott, Christopher G; Jensen, Matthew R; Pankratz, V Shane; Brandt, Kathy; Visscher, Daniel; Norman, Aaron; Couch, Fergus; Shepherd, John; Fan, Bo; Chen, Yunn-Yi; Ma, Lin; Beck, Andrew H; Cummings, Steven R; Kerlikowske, Karla; Vachon, Celine M

    2017-09-01

    We examined the associations of mammographic breast density with breast cancer risk by tumor aggressiveness and by menopausal status and current postmenopausal hormone therapy. This study included 2596 invasive breast cancer cases and 4059 controls selected from participants of four nested case-control studies within four established cohorts: the Mayo Mammography Health Study, the Nurses' Health Study, Nurses' Health Study II, and San Francisco Mammography Registry. Percent breast density (PD), absolute dense (DA), and non-dense areas (NDA) were assessed from digitized film-screen mammograms using a computer-assisted threshold technique and standardized across studies. We used polytomous logistic regression to quantify the associations of breast density with breast cancer risk by tumor aggressiveness (defined as presence of at least two of the following tumor characteristics: size ≥2 cm, grade 2/3, ER-negative status, or positive nodes), stratified by menopausal status and current hormone therapy. Overall, the positive association of PD and borderline inverse association of NDA with breast cancer risk was stronger in aggressive vs. non-aggressive tumors (≥51 vs. 11-25% OR 2.50, 95% CI 1.94-3.22 vs. OR 2.03, 95% CI 1.70-2.43, p-heterogeneity = 0.03; NDA 4th vs. 2nd quartile OR 0.54, 95% CI 0.41-0.70 vs. OR 0.71, 95% CI 0.59-0.85, p-heterogeneity = 0.07). However, there were no differences in the association of DA with breast cancer by aggressive status. In the stratified analysis, there was also evidence of a stronger association of PD and NDA with aggressive tumors among postmenopausal women and, in particular, current estrogen+progesterone users (≥51 vs. 11-25% OR 3.24, 95% CI 1.75-6.00 vs. OR 1.93, 95% CI 1.25-2.98, p-heterogeneity = 0.01; NDA 4th vs. 2nd quartile OR 0.43, 95% CI 0.21-0.85 vs. OR 0.56, 95% CI 0.35-0.89, p-heterogeneity = 0.01), even though the interaction was not significant. Our findings suggest that associations of mammographic

  17. Cell Spheroids with Enhanced Aggressiveness to Mimic Human Liver Cancer In Vitro and In Vivo.

    PubMed

    Jung, Hong-Ryul; Kang, Hyun Mi; Ryu, Jea-Woon; Kim, Dae-Soo; Noh, Kyung Hee; Kim, Eun-Su; Lee, Ho-Joon; Chung, Kyung-Sook; Cho, Hyun-Soo; Kim, Nam-Soon; Im, Dong-Soo; Lim, Jung Hwa; Jung, Cho-Rok

    2017-09-05

    We fabricated a spheroid-forming unit (SFU) for efficient and economic production of cell spheroids. We optimized the protocol for generating large and homogenous liver cancer cell spheroids using Huh7 hepatocellular carcinoma (HCC) cells. The large Huh7 spheroids showed apoptotic and proliferative signals in the centre and at the surface, respectively. In particular, hypoxia-induced factor-1 alpha (HIF-1α) and ERK signal activation were detected in the cell spheroids. To diminish core necrosis and increase the oncogenic character, we co-cultured spheroids with 2% human umbilical vein endothelial cells (HUVECs). HUVECs promoted proliferation and gene expression of HCC-related genes and cancer stem cell markers in the Huh7 spheroidsby activating cytokine signalling, mimicking gene expression in liver cancer. HUVECs induced angiogenesis and vessel maturation in Huh7 spheroids in vivo by activating epithelial-mesenchymal transition and angiogenic pathways. The large Huh7 cell spheroids containing HUVECs survived at higher concentrations of anti-cancer drugs (doxorubicin and sorafenib) than did monolayer cells. Our large cell spheroid provides a useful in vitro HCC model to enable intuitive observation for anti-cancer drug testing.

  18. Targeting Metabolic Plasticity in Breast Cancer Cells via Mitochondrial Complex I Modulation

    PubMed Central

    Xu, Qijin; Biener-Ramanujan, Eva; Yang, Wei; Ramanujan, V Krishnan

    2016-01-01

    Purpose Heterogeneity commonly observed in clinical tumors stems both from the genetic diversity as well as from the differential metabolic adaptation of multiple cancer types during their struggle to maintain uncontrolled proliferation and invasion in vivo. This study aims to identify a potential metabolic window of such adaptation in aggressive human breast cancer cell lines. Methods With a multidisciplinary approach using high resolution imaging, cell metabolism assays, proteomic profiling and animal models of human tumor xenografts and via clinically-relevant, pharmacological approach for modulating mitochondrial complex I function in human breast cancer cell lines, we report a novel route to target metabolic plasticity in human breast cancer cells. Results By a systematic modulation of mitochondrial function and by mitigating metabolic switch phenotype in aggressive human breast cancer cells, we demonstrate that the resulting metabolic adaptation signatures can predictably decrease tumorigenic potential in vivo. Proteomic profiling of the metabolic adaptation in these cells further revealed novel protein-pathway interactograms highlighting the importance of antioxidant machinery in the observed metabolic adaptation. Conclusions Improved metabolic adaptation potential in aggressive human breast cancer cells contribute to improving mitochondrial function and reducing metabolic switch phenotype –which may be vital for targeting primary tumor growth in vivo. PMID:25677747

  19. Apparent diffusion coefficient value is a strong predictor of unsuspected aggressiveness of prostate cancer before radical prostatectomy.

    PubMed

    Renard Penna, Raphaele; Cancel-Tassin, Geraldine; Comperat, Eva; Mozer, Pierre; Léon, Priscilla; Varinot, Justine; Roupret, Morgan; Bitker, Marc-Olivier; Lucidarme, Olivier; Cussenot, Olivier

    2016-10-01

    To evaluate the use of multiparametric MRI (mp MRI) parameters in order to predict prostate cancer aggressiveness as defined by pathological Gleason score or molecular markers in a cohort of patients defined with a Gleason score of 6 at biopsy. Sixty-seven men treated by radical prostatectomy (RP) for a low grade (Gleason 6) on biopsy and mp MRI before biopsy were selected. The cycle cell proliferation (CCP) score assessed by the Prolaris test and Ki-67/PTEN expression assessed by immunohistochemistry were quantified on the RP specimens. 49.25 % of the cancers were undergraded on biopsy compared to the RP specimens. Apparent diffusion coefficient (ADC) < 0.80 × 10(-3) mm(2)/s (P value 0.003), Likert score >4 (P value 0.003) and PSA density >0.15 ng/ml/cc (P value 0.035) were significantly associated with a higher RP Gleason score. Regarding molecular markers of aggressiveness, ADC < 0.80 × 10(-3) mm(2)/s and Likert score >4 were also significantly associated with a positive staining for Ki-67 (P value 0.039 and 0.01, respectively). No association was found between any analyzed MRI or clinical parameter and the CCP score. Decreasing ADC value is a stronger indicator of aggressive prostate cancer as defined by molecular markers or postsurgical histology than biopsy characteristics.

  20. Prediction of Aggressive Human Prostate Cancer by Cathepsin B

    DTIC Science & Technology

    2008-03-01

    Cancer Res 2004;10(12 Pt 1):4118-4124. 28. Munoz E, Gomez F, Paz JI, Casado I, Silva JM, Corcuera MT, Alonso MJ. Ki-67 immunolabeling in pre...detected prostate cancer. J Pathol 2002;197(2):148-154. 34. Claudio PP, Zamparelli A, Garcia FU, Claudio L, Ammirati G, Farina A, Bovicelli A, Russo G...JA. Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. Genes Dev 2006;20(5):543-556. 47. Fernandez PL, Farre X, Nadal A

  1. Functional characterisation of osteosarcoma cell lines and identification of mRNAs and miRNAs associated with aggressive cancer phenotypes

    PubMed Central

    Lauvrak, S U; Munthe, E; Kresse, S H; Stratford, E W; Namløs, H M; Meza-Zepeda, L A; Myklebost, O

    2013-01-01

    Background: Osteosarcoma is the most common primary malignant bone tumour, predominantly affecting children and adolescents. Cancer cell line models are required to understand the underlying mechanisms of tumour progression and for preclinical investigations. Methods: To identify cell lines that are well suited for studies of critical cancer-related phenotypes, such as tumour initiation, growth and metastasis, we have evaluated 22 osteosarcoma cell lines for in vivo tumorigenicity, in vitro colony-forming ability, invasive/migratory potential and proliferation capacity. Importantly, we have also identified mRNA and microRNA (miRNA) gene expression patterns associated with these phenotypes by expression profiling. Results: The cell lines exhibited a wide range of cancer-related phenotypes, from rather indolent to very aggressive. Several mRNAs were differentially expressed in highly aggressive osteosarcoma cell lines compared with non-aggressive cell lines, including RUNX2, several S100 genes, collagen genes and genes encoding proteins involved in growth factor binding, cell adhesion and extracellular matrix remodelling. Most notably, four genes—COL1A2, KYNU, ACTG2 and NPPB—were differentially expressed in high and non-aggressive cell lines for all the cancer-related phenotypes investigated, suggesting that they might have important roles in the process of osteosarcoma tumorigenesis. At the miRNA level, miR-199b-5p and mir-100-3p were downregulated in the highly aggressive cell lines, whereas miR-155-5p, miR-135b-5p and miR-146a-5p were upregulated. miR-135b-5p and miR-146a-5p were further predicted to be linked to the metastatic capacity of the disease. Interpretation: The detailed characterisation of cell line phenotypes will support the selection of models to use for specific preclinical investigations. The differentially expressed mRNAs and miRNAs identified in this study may represent good candidates for future therapeutic targets. To our knowledge, this is

  2. Enhancement of the Efficacy of Conventional Anticancer Compounds Through the Repression of SNAI Proteins in Aggressive Breast Cancer Cells

    DTIC Science & Technology

    2014-04-01

    conjugating enzymes . J. Biol. Chem. 270, 30408-30414. [66] Bertone-Johnson, E. R. (2009) Vitamin D and breast cancer . Ann. Epidemiol. 19, 462-467... cancer growth in a murine model of bone metastasis. Cancer Res. 70, 1835- 1844. 22 [68] Ohyama, Y., and Yamasaki, T. (2004) Eight cytochrome ...0697 TITLE: Enhancement of the efficacy of conventional anticancer compounds through the repression of SNAI proteins in aggressive breast cancer

  3. Outpatient Palliative Care and Aggressiveness of End-of-Life Care in Patients with Metastatic Colorectal Cancer.

    PubMed

    Lee, Si Won; Jho, Hyun Jung; Baek, Ji Yeon; Shim, Eun Kyung; Kim, Hyun Mi; Ku, Ji Yeon; Nam, Eun Jung; Chang, Yoon-Jung; Choi, Hye Jin; Kim, Sun Young

    2018-01-01

    Palliative care in outpatient setting has been shown to promote better symptom management and transition to hospice care among patients with advanced cancer. Nevertheless, specialized palliative care is rarely provided at cancer centers in Korea. Herein, we aimed to assess aggressiveness of end-of-life care for patients with metastatic colorectal cancer according to the use of outpatient palliative care (OPC) at a single cancer center in Korea. We performed a retrospective medical record review for 132 patients with metastatic colorectal cancer who died between 2011 and 2014. Fifty patients used OPC (OPC group), while 82 patients did not (non-OPC group). Indicators of aggressiveness of end-of-life care including chemotherapy use, emergency department visits, hospitalization, and utilization of hospice care were analyzed according to the use of OPC. More patients in the OPC group were admitted to hospice than those in the non-OPC group (32% vs 17%, P = .047). The mean of inpatient days within 30 days of death was shorter for the OPC group than the non-OPC group (4.02 days vs 7.77 days, respectively, P = .032). There were no differences in the proportions of patients who received chemotherapy and visited the emergency department within 30 days from death. Among patients with metastatic colorectal cancer, OPC was associated with shorter inpatient days near death and greater hospice utilization. Further prospective studies are needed to evaluate the impact of OPC on end-of-life care in Korea.

  4. The motivation for biological aggression is an inherent and common aspect of the human behavioural repertoire.

    PubMed

    Rózsa, Lajos

    2009-02-01

    According to a widespread opinion shared by the vast majority of historians, instances of aggression using pathogen weapons constitute extremely rare events in human history. Similarly, students of human behaviour tend to believe that their science plays no role in explaining this phenomenon, which is held to be exceptional and abnormal. Contrary to this dominant view, I argue that Hamiltonian spite - like Hamiltonian altruism - is an inherent part of the human behavioural repertoire and it includes the use of pathogens for spiteful purposes. This paradigm is supported by the following observations. The use of pathogens as weapons emerged far before the scientific understanding of the nature of infections and epidemics, though it has been underrepresented in written history ever since. It is also present in our expectations concerning the likely behaviour of an enemy and it is also a frequent component of threats. Several languages appear to bear linguistic references to our motivation for biological aggression in profanity. Finally, given that wartime epidemics kill people at a rate comparable to (or exceeding) that of mechanical weapons, all wars fought in recorded history incorporated an element of aggression through biological means. On the basis of these arguments, I claim that the motivation for biological aggression is an inherent and common aspect of past and present human behaviour.

  5. Human papillomavirus E6 protein enriches the CD55(+) population in cervical cancer cells, promoting radioresistance and cancer aggressiveness.

    PubMed

    Leung, Thomas Ho-Yin; Tang, Hermit Wai-Man; Siu, Michelle Kwan-Yee; Chan, David Wai; Chan, Karen Kar-Loen; Cheung, Annie Nga-Yin; Ngan, Hextan Yuen-Sheung

    2018-02-01

    Accumulating evidence indicates that the human papillomavirus (HPV) E6 protein plays a crucial role in the development of cervical cancer. Subpopulations of cells that reside within tumours are responsible for tumour resistance to cancer therapy and recurrence. However, the identity of such cells residing in cervical cancer and their relationship with the HPV-E6 protein have not been identified. Here, we isolated sphere-forming cells, which showed self-renewal ability, from primary cervical tumours. Gene expression profiling revealed that cluster of differentiation (CD) 55 was upregulated in primary cervical cancer sphere cells. Flow-cytometric analysis detected abundant CD55(+) populations among a panel of HPV-positive cervical cancer cell lines, whereas few CD55(+) cells were found in HPV-negative cervical cancer and normal cervical epithelial cell lines. The CD55(+) subpopulation isolated from the C33A cell line showed significant sphere-forming ability and enhanced tumourigenicity, cell migration, and radioresistance. In contrast, the suppression of CD55 in HPV-positive CaSki cells inhibited tumourigenicity both in vitro and in vivo, and sensitized cells to radiation treatment. In addition, ectopic expression of the HPV-E6 protein in HPV-negative cervical cancer cells dramatically enriched the CD55(+) subpopulation. CRISPR/Cas9 knockout of CD55 in an HPV-E6-overexpressing stable clone abolished the tumourigenic effects of the HPV-E6 protein. Taken together, our data suggest that HPV-E6 protein expression enriches the CD55(+) population, which contributes to tumourigenicity and radioresistance in cervical cancer cells. Targeting CD55 via CRISPR/Cas9 may represent a novel avenue for developing new strategies and effective therapies for the treatment of cervical cancer. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John

  6. Comprehensive Evaluation of the Role of EZH2 in the Growth, Invasion, and Aggression of a Panel of Prostate Cancer Cell Lines

    PubMed Central

    Karanikolas, Breanne D.W.; Figueiredo, Marxa L.; Wu, Lily

    2010-01-01

    Background Although most prostate cancers respond well to initial treatments, a fraction of prostate cancers are more aggressive and will recur and metastasize. At that point, there are few treatment options available. Significant efforts have been made to identify biomarkers that will identify these more aggressive cancers to tailor a more vigorous treatment in order to improve outcome. Polycomb Group protein Enhancer of Zeste 2 (EZH2) was found to be overexpressed in metastatic prostate tumors, and is considered an excellent candidate for such a biomarker. Scattered studies have found that EZH2 overexpression causes neoplastic transformation, invasion, and growth of prostate cells. However, these studies utilized different systems and cell lines, and so are difficult to correlate with one another. Methods In this study, a comprehensive evaluation of the phenotypic effects of EZH2 in a panel of five prostate cancer cell lines was performed. By using multiple cell lines, and examining overexpression and knockdown of EZH2 concurrently, a broad view of EZH2's role in prostate cancer was achieved. Results Overexpression of EZH2 led to more aggressive behaviors in all prostate cell lines tested. In contrast, downregulation of EZH2 reduced invasion and tumorigenicity of androgen-independent cell lines CWR22Rv1, PC3, and DU145, but not of androgen-dependent cell lines LAPC4 and LNCaP. Conclusions Findings from this study suggest androgen-independent prostate tumors are more dependent on EZH2 expression than androgen-dependent tumors. Our observations provide an explanation for the strong correlation between EZH2 overexpression and advanced stage, aggressive prostate cancers. PMID:20087897

  7. Association between aggressive care and bereaved families' evaluation of end-of-life care for veterans with non-small cell lung cancer who died in Veterans Affairs facilities.

    PubMed

    Ersek, Mary; Miller, Susan C; Wagner, Todd H; Thorpe, Joshua M; Smith, Dawn; Levy, Cari R; Gidwani, Risha; Faricy-Anderson, Katherine; Lorenz, Karl A; Kinosian, Bruce; Mor, Vincent

    2017-08-15

    To the authors' knowledge, little is known regarding the relationship between patients' and families' satisfaction with aggressive end-of-life care. Herein, the authors examined the associations between episodes of aggressive care (ie, chemotherapy, mechanical ventilation, acute hospitalizations, and intensive care unit admissions) within the last 30 days of life and families' evaluations of end-of-life care among patients with non-small cell lung cancer (NSCLC). A total of 847 patients with NSCLC (34% of whom were aged <65 years) who died in a nursing home or intensive care, acute care, or hospice/palliative care (HPC) unit at 1 of 128 Veterans Affairs Medical Centers between 2010 and 2012 were examined. Data sources included Veterans Affairs administrative and clinical data, Medicare claims, and the Bereaved Family Survey. The response rate for the Bereaved Family Survey was 62%. Greater than 72% of veterans with advanced lung cancer who died in an inpatient setting had at least 1 episode of aggressive care and 31% received chemotherapy within the last 30 days of life. For all units except for HPC, when patients experienced at least 1 episode of aggressive care, bereaved families rated care lower compared with when patients did not receive any aggressive care. For patients dying in an HPC unit, the associations between overall ratings of care and ≥2 inpatient admissions or any episode of aggressive care were not found to be statistically significant. Rates of aggressive care were not associated with age, and family ratings of care were similar for younger and older patients. Aggressive care within the last month of life is common among patients with NSCLC and is associated with lower family evaluations of end-of-life care. Specialized care provided within an HPC unit may mitigate the negative effects of aggressive care on these outcomes. Cancer 2017;123:3186-94. © 2017 American Cancer Society. © 2017 American Cancer Society.

  8. Chemosensory danger detection in the human brain: Body odor communicating aggression modulates limbic system activation.

    PubMed

    Mutic, Smiljana; Brünner, Yvonne F; Rodriguez-Raecke, Rea; Wiesmann, Martin; Freiherr, Jessica

    2017-05-01

    Although the sense of smell is involved in numerous survival functions, the processing of body odor emitted by dangerous individuals is far from understood. The aim of the study was to explore how human fight chemosignals communicating aggression can alter brain activation related to an attentional bias and danger detection. While the anterior cingulate cortex (ACC) was seen involved in processing threat-related emotional information, danger detection and error evaluation, it still remains unknown whether human chemosignals communicating aggression can potentially modulate this activation. In the fMRI experiment, healthy male and female normosmic odor recipients (n=18) completed a higher-order processing task (emotional Stroop task with the word categories anger, anxiety, happiness and neutral) while exposed to aggression and exercise chemosignals (collected from a different group of healthy male donors; n=16). Our results provide first evidence that aggression chemosignals induce a time-sensitive attentional bias in chemosensory danger detection and modulate limbic system activation. During exposure to aggression chemosignals compared to exercise chemosignals, functional imaging data indicates an enhancement of thalamus, hypothalamus and insula activation (p<.05, FWE-corrected). Together with the thalamus, the ACC was seen activated in response to threat-related words (p<.001). Chemosensory priming and habituation to body odor signals are discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Study in mice shows that an aggressive type of breast cancer is linked to an inflammatory protein

    Cancer.gov

    Aberrant expression of an inflammatory protein, nitric oxide synthase 2 (NOS2), may enhance the progression and metastasis of an aggressive and less common form of breast cancer, known as the estrogen receptor-negative type of disease.

  10. Intratumor heterogeneity and clonal evolution in an aggressive papillary thyroid cancer and matched metastases.

    PubMed

    Le Pennec, Soazig; Konopka, Tomasz; Gacquer, David; Fimereli, Danai; Tarabichi, Maxime; Tomás, Gil; Savagner, Frédérique; Decaussin-Petrucci, Myriam; Trésallet, Christophe; Andry, Guy; Larsimont, Denis; Detours, Vincent; Maenhaut, Carine

    2015-04-01

    The contribution of intratumor heterogeneity to thyroid metastatic cancers is still unknown. The clonal relationships between the primary thyroid tumors and lymph nodes (LN) or distant metastases are also poorly understood. The objective of this study was to determine the phylogenetic relationships between matched primary thyroid tumors and metastases. We searched for non-synonymous single-nucleotide variants (nsSNVs), gene fusions, alternative transcripts, and loss of heterozygosity (LOH) by paired-end massively parallel sequencing of cDNA (RNA-Seq) in a patient diagnosed with an aggressive papillary thyroid cancer (PTC). Seven tumor samples from a stage IVc PTC patient were analyzed by RNA-Seq: two areas from the primary tumor, four areas from two LN metastases, and one area from a pleural metastasis (PLM). A large panel of other thyroid tumors was used for Sanger sequencing screening. We identified seven new nsSNVs. Some of these were early events clonally present in both the primary PTC and the three matched metastases. Other nsSNVs were private to the primary tumor, the LN metastases and/or the PLM. Three new gene fusions were identified. A novel cancer-specific KAZN alternative transcript was detected in this aggressive PTC and in dozens of additional thyroid tumors. The PLM harbored an exclusive whole-chromosome 19 LOH. We have presented the first, to our knowledge, deep sequencing study comparing the mutational spectra in a PTC and both LN and distant metastases. This study has yielded novel findings concerning intra-tumor heterogeneity, clonal evolution and metastases dissemination in thyroid cancer. © 2015 Society for Endocrinology.

  11. [Neurochemistry of impulsiveness and aggression].

    PubMed

    Vetulani, Jerzy

    2013-01-01

    Aggression is the most frequent social reaction among animals and men, and plays an important role in survival of the fittest. The change of social conditions in the course of development of human civilisation rendered some forms of aggression counter-adaptive, but the neurobiological mechanism of expression of aggression have not fundamentally changed in the last stages of human evolution. The two different kinds of aggression: emotional, serving mainly as a threat, and rational, predatory, serving for the attainment of goal in the most effective way, have different anatomical and neurobiological background and reciprocally inhibit each other. Aggression is modulated by several neurotransmitter and hormonal systems, of which the key role is seemingly played by testosterone, a hormone involved in domination behaviour, and serotonin, whose deficit results in increased impulsiveness.

  12. Nonmelanoma Skin Cancer With Aggressive Subclinical Extension in Immunosuppressed Patients.

    PubMed

    Song, Silvia Soohyun; Goldenberg, Alina; Ortiz, Arisa; Eimpunth, Sasima; Oganesyan, Gagik; Jiang, Shang I Brian

    2016-06-01

    Immunosuppression (IS), such as in solid-organ transplant recipients (SOTRs) and patients with human immunodeficiency virus (HIV) or hematologic malignant neoplasms, increases the risk of developing nonmelanoma skin cancers (NMSCs). However, it is unknown whether IS patients are at increased risk of developing NMSCs with aggressive subclinical extensions (NMSC-ASE), which may extend aggressively far beyond conventional surgical margins. To study clinical characteristics of NMSC-ASE among immunocompetent (IC) and various subgroups of IS patients and to suggest a predictive model for NMSC-ASE lesions. A 6-year retrospective review of 2998 NMSC cases between February 26, 2007, and February 17, 2012, at the Dermatologic and Mohs Micrographic Surgery Unit of the University of California, San Diego, Medical Center. Nonmelanoma skin cancers that required at least 3 Mohs micrographic surgery stages with final surgical margins of at least 10 mm were defined as ASE lesions. All cases were categorized into 1 of 2 groups, IS or IC. Immunosuppressed cases were further subcategorized into 3 subgroups: SOTRs and patients with HIV or hematologic malignant neoplasm. The data were analyzed in December 2012. We evaluated the odds ratio of having NMSC-ASE lesions in IS patients (SOTRs, HIV, hematologic malignant neoplasm) compared with IC patients. Other clinical characteristics and preoperative risks were analyzed and compared. Of all 2998 cases, we identified 805 NMSC-ASE cases: 137 IS and 668 IC. Immunosuppressed patients had an odds ratio of 1.94 of having ASE lesions compared with IC patients (95% CI, 1.54-2.44; P < .001). Additionally, the SOTR subgroup was associated with a 2.74 odds of having NSMC-ASE compared with non-SOTRs (95% CI, 2.00-3.76; P < .001), and the presence of hematologic malignant neoplasm was associated with 1.74 times the odds compared with IC patients (95% CI, 1.04-2.90; P = .04). Multivariate analysis found older age (P < .001), lesion

  13. Human PIRH2 Enhances Androgen Receptor Signaling through Inhibition of Histone Deacetylase 1 and Is Overexpressed in Prostate Cancer

    PubMed Central

    Logan, Ian R.; Gaughan, Luke; McCracken, Stuart R. C.; Sapountzi, Vasileia; Leung, Hing Y.; Robson, Craig N.

    2006-01-01

    The androgen receptor (AR) is a hormone-dependent transcription factor critically involved in human prostate carcinogenesis. Optimal transcriptional control of androgen-responsive genes by AR may require complex interaction among multiple coregulatory proteins. We have previously shown that the AR coregulator TIP60 can interact with human PIRH2 (hPIRH2). In this study, we uncover important new functional role(s) for hPIRH2 in AR signaling: (i) hPIRH2 interacts with AR and enhances AR-mediated transcription with a dynamic pattern of recruitment to androgen response elements in the prostate-specific antigen (PSA) gene; (ii) hPIRH2 interacts with the AR corepressor HDAC1, leading to reduced HDAC1 protein levels and inhibition of transcriptional repression; (iii) hPIRH2 is required for optimal PSA expression; and (iv) hPIRH2 is involved in prostate cancer cell proliferation. In addition, overexpression of hPIRH2 protein was detected in 73 of 82 (89%) resected prostate cancers, with a strong correlation between increased hPIRH2 expression and aggressive disease, as signified by high Gleason sum scores and the presence of metastatic disease (P = <0.0001 and 0.0004, respectively). Collectively, our data establish hPIRH2 as a key modulator of AR function, opening a new direction for targeted therapy in aggressive human prostate cancer. PMID:16914734

  14. Human PIRH2 enhances androgen receptor signaling through inhibition of histone deacetylase 1 and is overexpressed in prostate cancer.

    PubMed

    Logan, Ian R; Gaughan, Luke; McCracken, Stuart R C; Sapountzi, Vasileia; Leung, Hing Y; Robson, Craig N

    2006-09-01

    The androgen receptor (AR) is a hormone-dependent transcription factor critically involved in human prostate carcinogenesis. Optimal transcriptional control of androgen-responsive genes by AR may require complex interaction among multiple coregulatory proteins. We have previously shown that the AR coregulator TIP60 can interact with human PIRH2 (hPIRH2). In this study, we uncover important new functional role(s) for hPIRH2 in AR signaling: (i) hPIRH2 interacts with AR and enhances AR-mediated transcription with a dynamic pattern of recruitment to androgen response elements in the prostate-specific antigen (PSA) gene; (ii) hPIRH2 interacts with the AR corepressor HDAC1, leading to reduced HDAC1 protein levels and inhibition of transcriptional repression; (iii) hPIRH2 is required for optimal PSA expression; and (iv) hPIRH2 is involved in prostate cancer cell proliferation. In addition, overexpression of hPIRH2 protein was detected in 73 of 82 (89%) resected prostate cancers, with a strong correlation between increased hPIRH2 expression and aggressive disease, as signified by high Gleason sum scores and the presence of metastatic disease (P = <0.0001 and 0.0004, respectively). Collectively, our data establish hPIRH2 as a key modulator of AR function, opening a new direction for targeted therapy in aggressive human prostate cancer.

  15. Cholesteryl Ester Accumulation Induced by PTEN Loss and PI3K/AKT Activation Underlies Human Prostate Cancer Aggressiveness

    PubMed Central

    Yue, Shuhua; Li, Junjie; Lee, Seung-Young; Lee, Hyeon Jeong; Shao, Tian; Song, Bing; Cheng, Liang; Masterson, Timothy A.; Liu, Xiaoqi; Ratliff, Timothy L.; Cheng, Ji-Xin

    2014-01-01

    Summary Altered lipid metabolism is increasingly recognized as a signature of cancer cells. Enabled by label-free Raman spectromicroscopy, we performed quantitative analysis of lipogenesis at single cell level in human patient cancerous tissues. Our imaging data revealed an unexpected, aberrant accumulation of esterified cholesterol in lipid droplets of high-grade prostate cancer and metastases. Biochemical study showed that such cholesteryl ester accumulation was a consequence of loss of tumor suppressor PTEN and subsequent activation of PI3K/AKT pathway in prostate cancer cells. Furthermore, we found that such accumulation arose from significantly enhanced uptake of exogenous lipoproteins and required cholesterol esterification. Depletion of cholesteryl ester storage significantly reduced cancer proliferation, impaired cancer invasion capability, and suppressed tumor growth in mouse xenograft models with negligible toxicity. These findings open opportunities for diagnosing and treating prostate cancer by targeting the altered cholesterol metabolism. PMID:24606897

  16. Functional activation of PPARγ in human upper aerodigestive cancer cell lines.

    PubMed

    Wright, Simon K; Wuertz, Beverly R; Harris, George; Abu Ghazallah, Raed; Miller, Wendy A; Gaffney, Patrick M; Ondrey, Frank G

    2017-01-01

    Upper aerodigestive cancer is an aggressive malignancy with relatively stagnant long-term survival rates over 20 yr. Recent studies have demonstrated that exploitation of PPARγ pathways may be a novel therapy for cancer and its prevention. We tested whether PPARγ is expressed and inducible in aerodigestive carcinoma cells and whether it is present in human upper aerodigestive tumors. Human oral cancer CA-9-22 and NA cell lines were treated with the PPAR activators eicosatetraynoic acid (ETYA), 15-deoxy-δ- 12,14-prostaglandin J2 (PG-J2), and the thiazolidinedione, ciglitazone, and evaluated for their ability to functionally activate PPARγ luciferase reporter gene constructs. Cellular proliferation and clonogenic potential after PPARγ ligand treatment were also evaluated. Aerodigestive cancer specimens and normal tissues were evaluated for PPARγ expression on gene expression profiling and immunoblotting. Functional activation of PPARγ reporter gene constructs and increases in PPARγ protein were confirmed in the nuclear compartment after PPARγ ligand treatment. Significant decreases in cell proliferation and clonogenic potential resulted from treatment. Lipid accumulation was induced by PPARγ activator treatment. 75% of tumor specimens and 100% of normal control tissues expressed PPARγ RNA, and PPARγ protein was confirmed in 66% of tumor specimens analyzed by immunoblotting. We conclude PPARγ can be functionally activated in upper aerodigestive cancer and that its activation downregulates several features of the neoplastic phenotype. PPARγ expression in human upper aerodigestive tract tumors and normal cells potentially legitimizes it as a novel intervention target in this disease. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  17. An investigation of the mechanism underlying teacher aggression: Testing I3 theory and the General Aggression Model.

    PubMed

    Montuoro, Paul; Mainhard, Tim

    2017-12-01

    Considerable research has investigated the deleterious effects of teachers responding aggressively to students who misbehave, but the mechanism underlying this dysfunctional behaviour remains unknown. This study investigated whether the mechanism underlying teacher aggression follows I 3 theory or General Aggression Model (GAM) metatheory of human aggression. I 3 theory explains exceptional, catastrophic events of human aggression, whereas the GAM explains common human aggression behaviours. A total of 249 Australian teachers participated in this study, including 142 primary school teachers (Mdn [age] = 35-39 years; Mdn [years teaching] = 10-14 years; 84% female) and 107 secondary school teachers (Mdn [age] = 45-49 years; Mdn [years teaching] = 15-19 years; 65% female). Participants completed four online self-report questionnaires, which assessed caregiving responsiveness, trait self-control, misbehaviour provocation, and teacher aggression. Analyses revealed that the GAM most accurately captures the mechanism underlying teacher aggression, with lower caregiving responsiveness appearing to indirectly lead to teacher aggression via higher misbehaviour provocation and lower trait self-control in serial, controlling for gender, age, years teaching, and current role (primary, secondary). This study indicates that teacher aggression proceeds from 'the person in the situation'. Specifically, lower caregiving responsiveness appears to negatively shape a teacher's affective, cognitive, and arousal states, which influence how they perceive and interpret student misbehaviour. These internal states, in turn, appear to negatively influence appraisal and decision processes, leading to immediate appraisal and impulsive actions. These results raise the possibility that teacher aggression is a form of countertransference. © 2017 The British Psychological Society.

  18. Phospho-TCTP as a therapeutic target of dihydroartemisinin for aggressive breast cancer cells

    PubMed Central

    Lucibello, Maria; Adanti, Sara; Antelmi, Ester; Dezi, Dario; Ciafrè, Stefania; Carcangiu, Maria Luisa; Zonfrillo, Manuela; Nicotera, Giuseppe; Sica, Lorenzo; De Braud, Filippo; Pierimarchi, Pasquale

    2015-01-01

    Upregulation of Translationally Controlled Tumor Protein (TCTP) is associated with poorly differentiated aggressive tumors, including breast cancer, but the underlying mechanism(s) are still debated. Here, we show that in breast cancer cell lines TCTP is primarily localized in the nucleus, mostly in the phosphorylated form. The effects of Dihydroartemisinin (DHA), an anti-malaria agent that binds TCTP, were tested on breast cancer cells. DHA decreases cell proliferation and induces apoptotic cell death by targeting the phosphorylated form of TCTP. Remarkably, DHA enhances the anti-tumor effects of Doxorubicin in triple negative breast cancer cells resulting in an increased level of apoptosis. DHA also synergizes with Trastuzumab, used to treat HER2/neu positive breast cancers, to induce apoptosis of tumor cells. Finally, we present new clinical data that nuclear phospho-TCTP overexpression in primary breast cancer tissue is associated with high histological grade, increase expression of Ki-67 and with ER-negative breast cancer subtypes. Notably, phospho-TCTP expression levels increase in trastuzumab-resistant breast tumors, suggesting a possible role of phospho-TCTP as a new prognostic marker. In conclusion, the anti-tumor effect of DHA in vitro with conventional chemotherapeutics suggests a novel therapeutic strategy and identifies phospho-TCTP as a new promising target for advanced breast cancer. PMID:25779659

  19. An integrated analysis of genes and functional pathways for aggression in human and rodent models.

    PubMed

    Zhang-James, Yanli; Fernàndez-Castillo, Noèlia; Hess, Jonathan L; Malki, Karim; Glatt, Stephen J; Cormand, Bru; Faraone, Stephen V

    2018-06-01

    Human genome-wide association studies (GWAS), transcriptome analyses of animal models, and candidate gene studies have advanced our understanding of the genetic architecture of aggressive behaviors. However, each of these methods presents unique limitations. To generate a more confident and comprehensive view of the complex genetics underlying aggression, we undertook an integrated, cross-species approach. We focused on human and rodent models to derive eight gene lists from three main categories of genetic evidence: two sets of genes identified in GWAS studies, four sets implicated by transcriptome-wide studies of rodent models, and two sets of genes with causal evidence from online Mendelian inheritance in man (OMIM) and knockout (KO) mice reports. These gene sets were evaluated for overlap and pathway enrichment to extract their similarities and differences. We identified enriched common pathways such as the G-protein coupled receptor (GPCR) signaling pathway, axon guidance, reelin signaling in neurons, and ERK/MAPK signaling. Also, individual genes were ranked based on their cumulative weights to quantify their importance as risk factors for aggressive behavior, which resulted in 40 top-ranked and highly interconnected genes. The results of our cross-species and integrated approach provide insights into the genetic etiology of aggression.

  20. Neurogenetics of Aggressive Behavior – Studies in Rodents

    PubMed Central

    Takahashi, Aki; Miczek, Klaus A.

    2014-01-01

    Aggressive behavior is observed in many animal species, such as insects, fish, lizards, frogs, and most mammals including humans. This wide range of conservation underscores the importance of aggressive behavior in the animals’ survival and fitness, and the likely heritability of this behavior. Although typical patterns of aggressive behavior differ between species, there are several concordances in the neurobiology of aggression among rodents, primates, and humans. Studies with rodent models may eventually help us to understand the neurogenetic architecture of aggression in humans. However, it is important to recognize the difference between the ecological and ethological significance of aggressive behavior (species-typical aggression) and maladaptive violence (escalated aggression) when applying the findings of aggression research using animal models to human or veterinary medicine. Well-studied rodent models for aggressive behavior in the laboratory setting include the mouse (Mus musculus), rat (Rattus norvegicus), hamster (Mesocricetus auratus), and prairie vole (Microtus ochrogaster). The neural circuits of rodent aggression have been gradually elucidated by several techniques e.g. immunohistochemistry of immediate-early gene (c-Fos) expression, intracranial drug microinjection, in vivo microdialysis, and optogenetics techniques. Also, evidence accumulated from the analysis of gene-knockout mice shows the involvement of several genes in aggression. Here we review the brain circuits that have been implicated in aggression, such as the hypothalamus, prefrontal cortex (PFC), dorsal raphe nucleus (DRN), nucleus accumbens (NAc), and olfactory system. We then discuss the roles of glutamate and γ-aminobutyric acid (GABA), major inhibitory and excitatory amino acids in the brain, as well as their receptors, in controlling aggressive behavior, focusing mainly on recent findings. At the end of this chapter, we discuss how genes can be identified that underlie

  1. Non-invasive estimation of prostate cancer aggressiveness using diffusion-weighted MRI and 3D proton MR spectroscopy at 3.0 T.

    PubMed

    Thörmer, Gregor; Otto, Josephin; Horn, Lars-Christian; Garnov, Nikita; Do, Minh; Franz, Toni; Stolzenburg, Jens-Uwe; Moche, Michael; Kahn, Thomas; Busse, Harald

    2015-01-01

    Clinical management of prostate cancer increasingly aims to distinguish aggressive types that require immediate and radical treatment from indolent tumors that are candidates for watchful waiting. This requires reliable and reproducible parameters to effectively control potential cancer progression. Magnetic resonance imaging (MRI) may provide a non-invasive means for this purpose. To assess the value of diffusion-weighted imaging and proton MR spectroscopy for the prediction of prostate cancer (PCa) aggressiveness. In 39 of 64 consecutive patients who underwent endorectal 3-T MRI prior to radical prostatectomy, prostate specimens were analyzed as whole-mount step sections. Apparent diffusion coefficient (ADC), normalized ADC (nADC: tumor/healthy tissue), choline/citrate (CC), and (choline + creatine)/citrate (CCC) ratios were correlated with Gleason scores (GS) from histopathological results. The power to discriminate low (GS ≤ 6) from higher-risk (GS ≥ 7) tumors was assessed with receiver operating characteristics (area under the curve [AUC]). Resulting threshold values were used by a blinded reader to distinguish between aggressive and indolent tumors. Ninety lesions (1 × GS = 5, 41 × GS = 6, 36 × GS = 7, 12 × GS = 8) were considered. nADC (AUC = 0.90) showed a higher discriminatory power than ADC (AUC = 0.79). AUC for CC and CCC were 0.73 and 0.82, respectively. Using either nADC < 0.46 or CCC > 1.3, as well as both criteria for aggressive PCa, the reader correctly identified aggressive and indolent tumors in 31 (79%), 28 (72%), and 33 of 39 patients (85%), respectively. Predictions of tumor aggressiveness from TRUS-guided biopsies were correct in 27 of 36 patients (75%). The combination of a highly sensitive normalized ADC with a highly specific CCC was found to be well suited to prospectively estimate PCa aggressiveness with a similar diagnostic accuracy as biopsy results. © The Foundation

  2. Contrast-enhanced transrectal ultrasound for prediction of prostate cancer aggressiveness: The role of normal peripheral zone time-intensity curves.

    PubMed

    Huang, Hui; Zhu, Zheng-Qiu; Zhou, Zheng-Guo; Chen, Ling-Shan; Zhao, Ming; Zhang, Yang; Li, Hong-Bo; Yin, Li-Ping

    2016-12-08

    To assess the role of time-intensity curves (TICs) of the normal peripheral zone (PZ) in the identification of biopsy-proven prostate nodules using contrast-enhanced transrectal ultrasound (CETRUS). This study included 132 patients with 134 prostate PZ nodules. Arrival time (AT), peak intensity (PI), mean transit time (MTT), area under the curve (AUC), time from peak to one half (TPH), wash in slope (WIS) and time to peak (TTP) were analyzed using multivariate linear logistic regression and receiver operating characteristic (ROC) curves to assess whether combining nodule TICs with normal PZ TICs improved the prediction of prostate cancer (PCa) aggressiveness. The PI, AUC (p < 0.001 for both), MTT and TPH (p = 0.011 and 0.040 respectively) values of the malignant nodules were significantly higher than those of the benign nodules. Incorporating the PI and AUC values (both, p < 0.001) of the normal PZ TIC, but not the MTT and TPH values (p = 0.076 and 0.159 respectively), significantly improved the AUC for prediction of malignancy (PI: 0.784-0.923; AUC: 0.758-0.891) and assessment of cancer aggressiveness (p < 0.001). Thus, all these findings indicate that incorporating normal PZ TICs with nodule TICs in CETRUS readings can improve the diagnostic accuracy for PCa and cancer aggressiveness assessment.

  3. Feline mammary basal-like adenocarcinomas: a potential model for human triple-negative breast cancer (TNBC) with basal-like subtype.

    PubMed

    Wiese, David A; Thaiwong, Tuddow; Yuzbasiyan-Gurkan, Vilma; Kiupel, Matti

    2013-09-03

    Breast cancer is one of the leading causes of cancer deaths. Triple-negative breast cancer (TNBC), an immunophenotype defined by the absence of immunolabeling for estrogen receptor (ER), progesterone receptor (PR) and HER2 protein, has a highly aggressive behavior. A subpopulation of TNBCs exhibit a basal-like morphology with immunohistochemical positivity for cytokeratins 5/6 (CK5/6) and/or epidermal growth factor receptor (EGFR), and have a high incidence of BRCA (breast cancer susceptibility) mutations. Feline mammary adenocarcinomas (FMAs) are highly malignant and share a similar basal-like subtype. The purpose of this study was to classify FMAs according to the current human classification of breast cancer that includes evaluation of ER, PR and HER2 status and expression of basal CK 5/6 and EGFR. Furthermore, we selected triple negative, basal-like FMAs to screen for BRCA mutations similar to those described in human TNBC. Twenty four FMAs were classified according to the current human histologic breast cancer classification including immunohistochemistry (IHC) for ER, PR HER2, CK5/6 and EGFR. Genetic alteration and loss of heterozygosity of BRCA1 and BRCA2 genes were analyzed in triple negative, basal-like FMAs. IHC for ER, PR and HER2 identified 14 of the 24 (58%) FMAs as a triple negative. Furthermore, 11 of these 14 (79%) triple negative FMAs had a basal-like subtype. However, no genetic abnormalities were detected in BRCA1 and BRCA2 by direct sequencing and loss of heterozygosity analysis. FMAs are highly aggressive neoplasms that are commonly triple negative and exhibit a basal-like morphology. This is similar to human TNBC that are also commonly classified as a basal-like subtype. While sequencing of a select number of triple negative, basal-like FMAs and testing for loss of heterozygosity of BRCA1 and BRCA2 did not identify mutations similar to those described in human TNBC, further in-depth evaluation is required to elucidate a potential role of BRCA

  4. Diagnostic accuracy of prostate health index to identify aggressive prostate cancer. An Institutional validation study.

    PubMed

    Morote, J; Celma, A; Planas, J; Placer, J; Ferrer, R; de Torres, I; Pacciuci, R; Olivan, M

    2016-01-01

    New generations of tumor markers used to detect prostate cancer (PCa) should be able to discriminate men with aggressive PCa of those without PCa or nonaggressive tumors. The objective of this study has been to validate Prostate Health Index (PHI) as a marker of aggressive PCa in one academic institution. PHI was assessed in 357 men scheduled to prostatic biopsy between June of 2013 and July 2014 in one academic institution. Thereafter a subset of 183 men younger than 75 years and total PSA (tPSA) between 3.0 and 10.0 ng/mL, scheduled to it first prostatic biopsy, was retrospectively selected for this study. Twelve cores TRUS guided biopsy, under local anaesthesia, was performed in all cases. Total PSA, free PSA (fPSA), and [-2] proPSA (p2PSA) and prostate volume were determined before the procedure and %fPSA, PSA density (PSAd) and PHI were calculated. Aggressive tumors were considered if any Gleason 4 pattern was found. PHI was compared to %fPSA and PSAd through their ROC curves. Thresholds to detect 90%, 95% of all tumors and 95% and 100% of aggressive tumors were estimated and rates of unnecessary avoided biopsies were calculated and compared. The rate of PCa detection was 37.2% (68) and the rate of aggressive tumors was 24.6% (45). The PHI area under the curve was higher than those of %fPSA and PSAd to detect any PCa (0.749 vs 0.606 and 0.668 respectively) or to detect only aggressive tumors (0.786 vs 0.677 and 0.708 respectively), however, significant differences were not found. The avoided biopsy rates to detect 95% of aggressive tumors were 20.2% for PHI, 14.8% for %fPSA, and 23.5% for PSAd. Even more, to detect all aggressive tumors these rates dropped to 4.9% for PHI, 9.3% for %fPSA, and 7.9% for PSAd. PHI seems a good marker to PCa diagnosis. However, PHI was not superior to %fPSA and PSAd to identify at least 95% of aggressive tumors. Copyright © 2016 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

  5. Organotypic slice cultures of human gastric and esophagogastric junction cancer.

    PubMed

    Koerfer, Justus; Kallendrusch, Sonja; Merz, Felicitas; Wittekind, Christian; Kubick, Christoph; Kassahun, Woubet T; Schumacher, Guido; Moebius, Christian; Gaßler, Nikolaus; Schopow, Nikolas; Geister, Daniela; Wiechmann, Volker; Weimann, Arved; Eckmann, Christian; Aigner, Achim; Bechmann, Ingo; Lordick, Florian

    2016-07-01

    Gastric and esophagogastric junction cancers are heterogeneous and aggressive tumors with an unpredictable response to cytotoxic treatment. New methods allowing for the analysis of drug resistance are needed. Here, we describe a novel technique by which human tumor specimens can be cultured ex vivo, preserving parts of the natural cancer microenvironment. Using a tissue chopper, fresh surgical tissue samples were cut in 400 μm slices and cultivated in 6-well plates for up to 6 days. The slices were processed for routine histopathology and immunohistochemistry. Cytokeratin stains (CK8, AE1/3) were applied for determining tumor cellularity, Ki-67 for proliferation, and cleaved caspase-3 staining for apoptosis. The slices were analyzed under naive conditions and following 2-4 days in vitro exposure to 5-FU and cisplatin. The slice culture technology allowed for a good preservation of tissue morphology and tumor cell integrity during the culture period. After chemotherapy exposure, a loss of tumor cellularity and an increase in apoptosis were observed. Drug sensitivity of the tumors could be assessed. Organotypic slice cultures of gastric and esophagogastric junction cancers were successfully established. Cytotoxic drug effects could be monitored. They may be used to examine mechanisms of drug resistance in human tissue and may provide a unique and powerful ex vivo platform for the prediction of treatment response. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  6. Acute loss of TET function results in aggressive myeloid cancer in mice

    PubMed Central

    An, Jungeun; González-Avalos, Edahí; Chawla, Ashu; Jeong, Mira; López-Moyado, Isaac F.; Li, Wei; Goodell, Margaret A.; Chavez, Lukas; Ko, Myunggon; Rao, Anjana

    2015-01-01

    TET-family dioxygenases oxidize 5-methylcytosine (5mC) in DNA, and exert tumour suppressor activity in many types of cancers. Even in the absence of TET coding region mutations, TET loss-of-function is strongly associated with cancer. Here we show that acute elimination of TET function induces the rapid development of an aggressive, fully-penetrant and cell-autonomous myeloid leukaemia in mice, pointing to a causative role for TET loss-of-function in this myeloid malignancy. Phenotypic and transcriptional profiling shows aberrant differentiation of haematopoietic stem/progenitor cells, impaired erythroid and lymphoid differentiation and strong skewing to the myeloid lineage, with only a mild relation to changes in DNA modification. We also observe progressive accumulation of phospho-H2AX and strong impairment of DNA damage repair pathways, suggesting a key role for TET proteins in maintaining genome integrity. PMID:26607761

  7. Sulforaphane counteracts aggressiveness of pancreatic cancer driven by dysregulated Cx43-mediated gap junctional intercellular communication

    PubMed Central

    Zhang, Yiyao; Isayev, Orkhan; Heilmann, Katharina; Schoensiegel, Frank; Liu, Li; Nessling, Michelle; Richter, Karsten; Labsch, Sabrina; Nwaeburu, Clifford C.; Mattern, Juergen; Gladkich, Jury; Giese, Nathalia; Werner, Jens; Schemmer, Peter; Gross, Wolfgang; Gebhard, Martha M.; Gerhauser, Clarissa; Schaefer, Michael; Herr, Ingrid

    2014-01-01

    The extreme aggressiveness of pancreatic ductal adenocarcinoma (PDA) has been associated with blocked gap junctional intercellular communication (GJIC) and the presence of cancer stem cells (CSCs). We examined whether disturbed GJIC is responsible for a CSC phenotype in established and primary cancer cells and patient tissue of PDA using interdisciplinary methods based in physiology, cell and molecular biology, histology and epigenetics. Flux of fluorescent dyes and gemcitabine through gap junctions (GJs) was intact in less aggressive cells but not in highly malignant cells with morphological dysfunctional GJs. Among several connexins, only Cx43 was expressed on the cell surface of less aggressive and GJIC-competent cells, whereas Cx43 surface expression was absent in highly malignant, E-cadherin-negative and GJIC-incompetent cells. The levels of total Cx43 protein and Cx43 phosphorylated at Ser368 and Ser279/282 were high in normal tissue but low to absent in malignant tissue. si-RNA-mediated inhibition of Cx43 expression in GJIC-competent cells prevented GJIC and induced colony formation and the expression of stem cell-related factors. The bioactive substance sulforaphane enhanced Cx43 and E-cadherin levels, inhibited the CSC markers c-Met and CD133, improved the functional morphology of GJs and enhanced GJIC. Sulforaphane altered the phosphorylation of several kinases and their substrates and inhibition of GSK3, JNK and PKC prevented sulforaphane-induced CX43 expression. The sulforaphane-mediated expression of Cx43 was not correlated with enhanced Cx43 RNA expression, acetylated histone binding and Cx43 promoter de-methylation, suggesting that posttranslational phosphorylation is the dominant regulatory mechanism. Together, the absence of Cx43 prevents GJIC and enhances aggressiveness, whereas sulforaphane counteracts this process, and our findings highlight dietary co-treatment as a viable treatment option for PDA. PMID:24742583

  8. Sulforaphane counteracts aggressiveness of pancreatic cancer driven by dysregulated Cx43-mediated gap junctional intercellular communication.

    PubMed

    Forster, Tobias; Rausch, Vanessa; Zhang, Yiyao; Isayev, Orkhan; Heilmann, Katharina; Schoensiegel, Frank; Liu, Li; Nessling, Michelle; Richter, Karsten; Labsch, Sabrina; Nwaeburu, Clifford C; Mattern, Juergen; Gladkich, Jury; Giese, Nathalia; Werner, Jens; Schemmer, Peter; Gross, Wolfgang; Gebhard, Martha M; Gerhauser, Clarissa; Schaefer, Michael; Herr, Ingrid

    2014-03-30

    The extreme aggressiveness of pancreatic ductal adenocarcinoma (PDA) has been associated with blocked gap junctional intercellular communication (GJIC) and the presence of cancer stem cells (CSCs). We examined whether disturbed GJIC is responsible for a CSC phenotype in established and primary cancer cells and patient tissue of PDA using interdisciplinary methods based in physiology, cell and molecular biology, histology and epigenetics. Flux of fluorescent dyes and gemcitabine through gap junctions (GJs) was intact in less aggressive cells but not in highly malignant cells with morphological dysfunctional GJs. Among several connexins, only Cx43 was expressed on the cell surface of less aggressive and GJIC-competent cells, whereas Cx43 surface expression was absent in highly malignant, E-cadherin-negative and GJIC-incompetent cells. The levels of total Cx43 protein and Cx43 phosphorylated at Ser368 and Ser279/282 were high in normal tissue but low to absent in malignant tissue. si-RNA-mediated inhibition of Cx43 expression in GJIC-competent cells prevented GJIC and induced colony formation and the expression of stem cell-related factors. The bioactive substance sulforaphane enhanced Cx43 and E-cadherin levels, inhibited the CSC markers c-Met and CD133, improved the functional morphology of GJs and enhanced GJIC. Sulforaphane altered the phosphorylation of several kinases and their substrates and inhibition of GSK3, JNK and PKC prevented sulforaphane-induced CX43 expression. The sulforaphane-mediated expression of Cx43 was not correlated with enhanced Cx43 RNA expression, acetylated histone binding and Cx43 promoter de-methylation, suggesting that posttranslational phosphorylation is the dominant regulatory mechanism. Together, the absence of Cx43 prevents GJIC and enhances aggressiveness, whereas sulforaphane counteracts this process, and our findings highlight dietary co-treatment as a viable treatment option for PDA.

  9. The Appetitive Aggression Scale—development of an instrument for the assessment of human's attraction to violence.

    PubMed Central

    Weierstall, Roland; Elbert, Thomas

    2011-01-01

    Background Several instruments, notably Buss and Perry's Aggression Questionnaire, have been developed for the assessment of aggressive behavior. However, in these instruments, the focus has been on reactive rather than instrumental forms of aggression, even though men in particular may find aggressive behavior attractive. A questionnaire or structured interview for the systematic assessment of the attraction to violence is not yet available. Objective We, therefore, developed a freely available short form for the assessment of a person's attraction to violent and planned forms of aggression based on reports of former combatants on the attraction to violence and the characteristics of instrumental aggression described in the literature. Method The Appetitive Aggression Scale (AAS) was administered to nine samples drawn from different populations, with a total of 1,632 former combatants and participants from war-affected regions (1,193 male and 439 female respondents). Results From the initial set of 31 items, a selection of 15 items was extracted to improve the scale's psychometric properties and assess the construct of appetitive aggression validly with respect to content. Cronbach's Alpha coefficient of 0.85 was appropriate. All items loaded significantly on a single factor accounting for 32% of the total variance. Further analysis revealed that the scale measures a specific construct that can be distinguished from other concepts of human aggression. Conclusions With the AAS, we present an easily administrable tool for the assessment of the attraction to violence. PMID:22893817

  10. Expression screening of cancer/testis genes in prostate cancer identifies NR6A1 as a novel marker of disease progression and aggressiveness.

    PubMed

    Mathieu, Romain; Evrard, Bertrand; Fromont, Gaëlle; Rioux-Leclercq, Nathalie; Godet, Julie; Cathelineau, Xavier; Guillé, François; Primig, Michael; Chalmel, Frédéric

    2013-07-01

    Cancer/Testis (CT) genes are expressed in male gonads, repressed in most healthy somatic tissues and de-repressed in various somatic malignancies including prostate cancers (PCa). Because of their specific expression signature and their associations with tumor aggressiveness and poor outcomes, CT genes are considered to be useful biomarkers and they are also targets for the development of new anti-cancer immunotherapies. The aim of this study was to identify novel CT genes associated with hormone-sensitive prostate cancer (HSPC), and castration-resistant prostate cancer (CRPC). To identify novel CT genes we screened genes for which transcripts were detected by RNA profiling specifically in normal testis and in either HSPC or CRPC as compared to normal prostate and 44 other healthy tissues using GeneChips. The expression and clinicopathological significance of a promising candidate--NR6A1--was examined in HSPC, CRPC, and metastatic site samples using tissue microarrays. We report the identification of 98 genes detected in CRPC, HSPC and testicular samples but not in the normal controls. Among them, cellular levels of NR6A1 were found to be higher in HSPC compared to normal prostate and further increased in metastatic lesions and CRPC. Furthermore, increased NR6A1 immunoreactivity was significantly associated with a high Gleason score, advanced pT stage and cancer cell proliferation. Our results show that cellular levels of NR6A1 are correlated with disease progression in PCa. We suggest that this essential orphan nuclear receptor is a potential therapeutic target as well as a biomarker of PCa aggressiveness. Copyright © 2013 Wiley Periodicals, Inc.

  11. A cancer-causing gene is positively correlated with male aggression in Xiphophorus cortezi

    PubMed Central

    Fernandez, André A.

    2010-01-01

    The persistence of seemingly maladaptive genes in organisms challenges evolutionary biological thought. In Xiphophorus fishes, certain melanin patterns form malignant melanomas due to a cancer-causing gene (Xiphophorus melanoma receptor kinase; Xmrk), which arose several millions years ago from unequal meiotic recombination. Xiphophorus melanomas are male biased and induced by androgens however male behavior and Xmrk genotype has not been investigated. This study found that male X. cortezi with the spotted caudal (Sc) pattern, from which melanomas originate, displayed increased aggression in mirror image trials. Furthermore, Xmrk males (regardless of Sc phenotype) bit and performed more agonistic displays than Xmrk deficient males. Male aggressive response decreased when males viewed their Sc image as compared to their non-Sc image. Collectively, these results indicate that Xmrk males experience a competitive advantage over wild-type males and that intrasexual selection could be an important component in the evolutionary maintenance of this oncogene within Xiphophorus. PMID:20021547

  12. Lipid Biomarkers Identified for Liver Cancer | Center for Cancer Research

    Cancer.gov

    Hepatocellular carcinoma (HCC) is an aggressive cancer of the liver with poor prognosis and growing incidence in developed countries. Pathology and genetic profiles of HCC are heterogeneous, suggesting that it can begin growing in different cell types. Although human tumors such as HCC have been profiled in-depth by genomics-based studies, not much is known about their overall metabolite modifications and how these changes can form a network that leads to aggressive disease and poor outcome.

  13. The Immunohistochemical Analysis of SOCS3 Protein Identifies a Subgroup of Prostatic Cancer Biopsies With Aggressive Behavior.

    PubMed

    Pierconti, Francesco; Martini, Maurizio; Cenci, Tonia; Larocca, Luigi M

    Recently, we demonstrated that hypermethylation of SOCS3 determines a significant reduction of its mRNA and protein expression and identifies a subgroup of prostate cancer with aggressive behavior. In this paper, our objective was to investigate whether the immunohistochemical expression of the SOCS3 protein could represent an alternative method to molecular analysis for the individualization of aggressive prostate carcinoma. We analyzed the SOCS3 immunohistochemical expression in 65 patients undergoing biopsies at the Institute of Urology of our hospital between September 2011 and October 2011 (median age, 66.4 y; range, 50 to 73 y), and in 35 cases, a subset of 65 cases originally used for the immunohistochemical study, we studied the methylation status of the SOCS3 promoter. We found that the percentage of cases with SOCS3 negativity (-) or with SOCS3 weak staining in <50% of the neoplastic glands (+/-) correlated to the worst prognosis in terms of the Gleason score (P=0.0001; Fisher's exact test), the pT stage (P=0.012; Fisher's exact test), and progression-free survival (P=0.0334; hazard ratio, 0.34; and 95% confidence interval, from 0.1261 to 0.9188). Moreover, some cases with an SOCS3 unmethylated pattern showed SOCS3-negative immunostaining (-) or SOCS3-negative glands with weak cytoplasmatic staining in <50% of the neoplastic glands (+/-). Our data suggest that in prostatic cancer biopsies, the immunohistochemical analysis of SOCS3 protein expression may provide a method that is less expensive and easier to apply than SOCS3 methylation analysis for the distinction of a subgroup of prostate cancer with a more aggressive behavior.

  14. N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells.

    PubMed

    Lee, John K; Phillips, John W; Smith, Bryan A; Park, Jung Wook; Stoyanova, Tanya; McCaffrey, Erin F; Baertsch, Robert; Sokolov, Artem; Meyerowitz, Justin G; Mathis, Colleen; Cheng, Donghui; Stuart, Joshua M; Shokat, Kevan M; Gustafson, W Clay; Huang, Jiaoti; Witte, Owen N

    2016-04-11

    MYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC with phenotypic and molecular features of aggressive, late-stage human disease. We directly show that prostate adenocarcinoma and NEPC can arise from a common epithelial clone. Further, N-Myc is required for tumor maintenance, and destabilization of N-Myc through Aurora A kinase inhibition reduces tumor burden. Our findings establish N-Myc as a driver of NEPC and a target for therapeutic intervention. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses vasculogenic mimicry and proliferation of highly aggressive pancreatic cancer PaTu8988 cells

    PubMed Central

    2014-01-01

    Background Pancreatic cancer is one of the most aggressive human malignancies with a extremely low 5-year survival rate. Hence, the search for more effective anti-pancreatic cancer agents is urgent. Methods PaTu8988 pancreatic cancer cells were treated with different concentrations of suberoylanilide hydroxamic acid (SAHA), cell survival, proliferation, migration and vasculogenic mimicry (VM) were analyzed. Associated signaling changes were also analyzed by RT-PCR and Western blots. Results Here, we reported that SAHA, a histone deacetylase inhibitor (HDACi), exerted significant inhibitory efficiency against pancreatic cancer cell survival, proliferation, migration and VM. SAHA dose-dependently inhibited PaTu8988 pancreatic cancer cell growth with the IC-50 of 3.4 ± 0. 7 μM. Meanwhile, SAHA suppressed PaTu8988 cell cycle progression through inducing G2/M arrest, which was associated with cyclin-dependent kinase 1 (CDK-1)/cyclin-B1 degradation and p21/p27 upregulation. Further, SAHA induced both apoptotic and non-apoptotic death of PaTu8988 cells. Significantly, SAHA suppressed PaTu8988 cell in vitro migration and cell-dominant tube formation or VM, which was accompanied by semaphorin-4D (Sema-4D) and integrin-β5 down-regulation. Our evidences showed that Akt activation might be important for Sema-4D expression in PaTu8988 cells, and SAHA-induced Sema-4D down-regulation might be associated with Akt inhibition. Conclusions This study is among the first to report the VM formation in cultured human pancreatic cancer cells. And we provided strong evidence to suggest that SAHA executes significant anti-VM efficiency in the progressive pancreatic cancer cells. Thus, SAHA could be further investigated as a promising anti-pancreatic cancer agent. PMID:24886166

  16. The neurobiology of abnormal manifestations of aggression--a review of hypothalamic mechanisms in cats, rodents, and humans.

    PubMed

    Haller, Jozsef

    2013-04-01

    Aggression research was for long dominated by the assumption that aggression-related psychopathologies result from the excessive activation of aggression-promoting brain mechanisms. This assumption was recently challenged by findings with models of aggression that mimic etiological factors of aggression-related psychopathologies. Subjects submitted to such procedures show abnormal attack features (mismatch between provocation and response, disregard of species-specific rules, and insensitivity toward the social signals of opponents). We review here 12 such laboratory models and the available human findings on the neural background of abnormal aggression. We focus on the hypothalamus, a region tightly involved in the execution of attacks. Data show that the hypothalamic mechanisms controlling attacks (general activation levels, local serotonin, vasopressin, substance P, glutamate, GABA, and dopamine neurotransmission) undergo etiological factor-dependent changes. Findings suggest that the emotional component of attacks differentiates two basic types of hypothalamic mechanisms. Aggression associated with increased arousal (emotional/reactive aggression) is paralleled by increased mediobasal hypothalamic activation, increased hypothalamic vasopressinergic, but diminished hypothalamic serotonergic neurotransmission. In aggression models associated with low arousal (unemotional/proactive aggression), the lateral but not the mediobasal hypothalamus is over-activated. In addition, the anti-aggressive effect of serotonergic neurotransmission is lost and paradoxical changes were noticed in vasopressinergic neurotransmission. We conclude that there is no single 'neurobiological road' to abnormal aggression: the neural background shows qualitative, etiological factor-dependent differences. Findings obtained with different models should be viewed as alternative mechanisms rather than conflicting data. The relevance of these findings for understanding and treating of aggression

  17. Predictors of Aggressive Inflammatory Bowel Disease

    PubMed Central

    Yarur, Andres J.; Strobel, Sebastian G.; Deshpande, Amar R.

    2011-01-01

    Inflammatory bowel disease comprises a group of conditions characterized by idiopathic inflammation of the gastrointestinal tract. The natural course of disease can range from an indolent course with prolonged periods of remission to aggressive, incapacitating disease. Predicting which patients are more susceptible to developing severe disease is important, especially when choosing therapeutic agents and treatment strategies. This paper reviews current evidence on the main demographic, clinical, endoscopic, histologic, serologic, and genetic markers that predict aggressive inflammatory bowel disease. In ulcerative colitis, we considered disease to be aggressive when patients had a high relapse rate, need for admission and/or surgery, development of colon cancer, or extraintestinal manifestations. We defined aggressive Crohn's disease as having a high relapse rate, development of penetrating disease, need for repeat surgery, or multiple admissions for flares. In Crohn's disease, involvement of the upper gastrointestinal tract and ileum, penetrating disease, early age at diagnosis, smoking, extensive ulceration of the mucosa, high titers of serum antibodies, and mutations of the NOD2 gene are markers of aggressive disease. In ulcerative colitis, patients with more extensive involvement of the colon (pancolitis) have more symptomatology and are at higher risk for needing a colectomy and developing colon cancer. Also, plasmocytic infiltration of the colonic mucosa and crypt atrophy predict treatment failure. As with diagnosis, no single method can predict disease aggressiveness. Multiple serologic and genetic tests are being developed to refine the accuracy of prediction. Endoscopic findings can also predict the future course of disease. At present, clinical manifestations are the most useful way to make therapeutic decisions. PMID:22298958

  18. RANK-c attenuates aggressive properties of ER-negative breast cancer by inhibiting NF-κB activation and EGFR signaling.

    PubMed

    Sirinian, Chaido; Papanastasiou, Anastasios D; Schizas, Michail; Spella, Magda; Stathopoulos, Georgios T; Repanti, Maria; Zarkadis, Ioannis K; King, Tari A; Kalofonos, Haralabos P

    2018-05-29

    The RANK/RANKL axis emerges as a key regulator of breast cancer initiation, progression, and metastasis. RANK-c is a RANK receptor isoform produced through alternative splicing of the TNFRSF11A (RANK) gene and a dominant-negative regulator of RANK-induced nuclear factor-κB (NF-κB) activation. Here we report that RANK-c transcript is expressed in 3.2% of cases in The Cancer Genome Atlas breast cancer cohort evenly between ER-positive and ER-negative cases. Nevertheless, the ratio of RANK to RANK-c (RANK/RANK-c) is increased in ER-negative breast cancer cell lines compared to ER-positive breast cancer cell lines. In addition, forced expression of RANK-c in ER-negative breast cancer cell lines inhibited stimuli-induced NF-κB activation and attenuated migration, invasion, colony formation, and adhesion of cancer cells. Further, RANK-c expression in MDA-MB-231 cells inhibited lung metastasis and colonization in vivo. The RANK-c-mediated inhibition of cancer cell aggressiveness and nuclear factor-κB (NF-κB) activation in breast cancer cells seems to rely on a RANK-c/TNF receptor-associated factor-2 (TRAF2) protein interaction. This was further confirmed by a mutated RANK-c that is unable to interact with TRAF2 and abolishes the ability to attenuate NF-κB activation, migration, and invasion. Additional protein interaction characterization revealed epidermal growth factor receptor (EGFR) as a novel interacting partner for RANK-c in breast cancer cells with a negative effect on EGFR phosphorylation and EGF-dependent downstream signaling pathway activation. Our findings further elucidate the complex molecular biology of the RANKL/RANK system in breast cancer and provide preliminary data for RANK-c as a possible marker for disease progression and aggressiveness.

  19. The dopaminergic system and aggression in laying hens

    USDA-ARS?s Scientific Manuscript database

    The dopaminergic system regulates aggression in humans and other mammals. To investigate if birds with genetic propensity for high and low aggressiveness may exhibit distinctly different aggressive mediation via dopamine (DA) D1 and D2 receptor pathways, two high aggressive (DXL and LGPS) and one lo...

  20. Canine aggression toward people: a guide for practitioners.

    PubMed

    Sueda, Karen Lynn C; Malamed, Rachel

    2014-05-01

    This article reviews the various causes of human-directed aggression in dogs and provides a step-by-step plan guiding the general practitioner through history taking, behavior observations, diagnosis, consultation, treatment, and follow-up care. Charts summarizing how to obtain behavioral information, the client's management options, treatment recommendations, diagnosis and treatment of human-directed aggression, and the clinician's role in preventing human-directed aggression are included. A graphic illustration of canine body language is also provided. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Does sexual selection explain human sex differences in aggression?

    PubMed

    Archer, John

    2009-08-01

    I argue that the magnitude and nature of sex differences in aggression, their development, causation, and variability, can be better explained by sexual selection than by the alternative biosocial version of social role theory. Thus, sex differences in physical aggression increase with the degree of risk, occur early in life, peak in young adulthood, and are likely to be mediated by greater male impulsiveness, and greater female fear of physical danger. Male variability in physical aggression is consistent with an alternative life history perspective, and context-dependent variability with responses to reproductive competition, although some variability follows the internal and external influences of social roles. Other sex differences, in variance in reproductive output, threat displays, size and strength, maturation rates, and mortality and conception rates, all indicate that male aggression is part of a sexually selected adaptive complex. Physical aggression between partners can be explained using different evolutionary principles, arising from the conflicts of interest between males and females entering a reproductive alliance, combined with variability following differences in societal gender roles. In this case, social roles are particularly important since they enable both the relatively equality in physical aggression between partners from Western nations, and the considerable cross-national variability, to be explained.

  2. Aggressive resection of frequent peritoneal recurrences in colorectal cancer contributes to long-term survival.

    PubMed

    Komori, Koji; Kinoshita, Takashi; Taihei, Oshiro; Ito, Seiji; Abe, Tetsuya; Senda, Yoshiki; Misawa, Kazunari; Ito, Yuich; Uemura, Norihisa; Natsume, Seiji; Kawakami, Jiro; Ouchi, Akira; Tsutsuyama, Masayuki; Hosoi, Takahiro; Shigeyoshi, Itaru; Akazawa, Tomoyuki; Hayashi, Daisuke; Tanaka, Hideharu; Shimizu, Yasuhiro

    2016-12-01

    We report a long-term survivor of colorectal cancer who underwent aggressive, frequent resection for peritoneal recurrences. A 58-year-old woman was diagnosed with descending colon cancer. Resection of the descending colon along with lymph node dissection was performed in September 2006. The pathological findings revealed Stage IIA colorectal cancer. The following peritoneal recurrences were removed: two in July 2007, two in the omental fat and two in the pouch of Douglas in June 2008 resected by low anterior resection of the rectum, one in the uterus and right ovarian recurrence resected via bilateral adnexectomy and Hartmann's procedure in May 2011, and one in the ascending colon by partial resection of the colon wall in December 2011. Postoperative adjuvant chemotherapy (uracil and tegafur/leucovorin, fluorouracil/levofolinate/oxaliplatin/bevacizumab, 5-fluorouracil/leucovorin/bevacizumab, irinotecan/bevacizumab, and irinotecan/panitumumab) was administered. The patient did not desire postoperative adjuvant chemotherapy after the fourth operation. The long-term survival was 6 years and 7 months.

  3. Hyperspectral-stimulated Raman scattering imaging of cholesteryl ester accumulation: new avenue to diagnosis of human prostate cancer

    NASA Astrophysics Data System (ADS)

    Du, Jun; Wang, Ping; Yue, Shuhua

    2016-10-01

    Most prostate cancers (PCa) are slowly growing, and only the aggressive ones require early diagnosis and effective treatment. The current standard for PCa diagnosis remains histopathology. Nonetheless, for the differentiation between Gleason score 6 (low-risk PCa), which can be left without treatment, and Gleason score 7 (high-risk PCa), which requires active treatment, the inter-observer discordance can be up to 40%. Our previous study reveals that cholesteryl ester (CE) accumulation induced by PI3K/AKT activation underlies human PCa aggressiveness. However, Raman spectromicroscopy used in this study could only provide compositional information of certain lipid droplets (LDs) selected by the observer, which overlooked cell-to-cell variation and hindered translation to accurate automated diagnosis. Here, we demonstrated quantitative mapping of CE level in human prostate tissues using hyperspectral stimulated Raman scattering (SRS) microscopy that renders compositional information for every pixel in the image. Specifically, hundreds of SRS images at Raman shift between 1620-1800 cm-1 were taken, and multivariate curve resolution algorism was used to retrieve concentration images of acyl C=C bond, sterol C=C bond, and ester C=O bond. Given that the ratio between images of sterol C=C and ester C=O (sterol C=C/C=O) is nonlinearly proportional to CE percentage out of total lipid, we were able to quantitatively map CE level. Our data showed that CE level was significantly greater in high Gleason grade compared to low Gleason grade, and could be a factor that significantly contributed to cancer recurrence. Our study provides an opportunity towards more accurate PCa diagnosis and prediction of aggressiveness.

  4. Glycoprotein Biomarkers for the Early Detection of Aggressive Prostate Cancer — EDRN Public Portal

    Cancer.gov

    The Early Detection Research Network of the NCI is charged with the discovery, development and validation of biomarkers for early detection and prognosis related to neoplastic disease. Our laboratory is an NCI EDRN (U01CA152813) working on "Glycoprotein biomarkers for the early detection of aggressive prostate cancer". This EDRN administratiVE! supplement is a collaboration with Robert Veltri on his project to identify men with very low risk (indolent) prostate cancer (CaP) at the diagnostic biopsy at selection for active surveillance (AS). We will assess biopsy tissue using quantitative nuclear histomorphometric measurements and molecular biomarkers to predict an unexpected catastrophic CaP in such men with indolent CaP. At Johns Hopkins Hospital w1e use the Epstein criteria that includes; PSA density (PSAD) <0.15 ng/mVcm3, Gleason score SS, S2 cons involved with cancer, and ::;;SO% of any core involved with cancer to select AS. Our approach will study 140 AS men (70 with a expected outcome and 70 with a disastrous outcome) using nuclear histomorphometry and pre-qualified biomarkers quantified by digital microscopy. Previously, our laboratory combined measurements of DNA content and (-2)pPSA in the serum and (-5,-?)pPSA in biopsy tissue to identify 7/10 men that would fail surveillance based on the primary diagnostic biopsy. We now will devHiop a clinical, morphological and biomarker 'signature' for identifying severe aggressive disease from a AS diagnostic biopsy. Our approach will combine nuclear morphometry measured by digital microscopy with a unique biopsy tissue biomarker profile (DNA content, Ki67, Her2neu, CACND1 and periostin). Fc•r the molecular targets we will us•e a multiplex tissue blot (MTB) immunohistochemistry method. The Aims o'f our work include 1) to utilize retrospective archival biopsy material from 70 AS cases where the outcome was unexpected and disastrous and collect an equal number of AS cases (n=140) and perform assays for morphology

  5. Human cancers converge at the HIF-2alpha oncogenic axis.

    PubMed

    Franovic, Aleksandra; Holterman, Chet E; Payette, Josianne; Lee, Stephen

    2009-12-15

    Cancer development is a multistep process, driven by a series of genetic and environmental alterations, that endows cells with a set of hallmark traits required for tumorigenesis. It is broadly accepted that growth signal autonomy, the first hallmark of malignancies, can be acquired through multiple genetic mutations that activate an array of complex, cancer-specific growth circuits [Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57-70; Vogelstein B, Kinzler KW (2004) Cancer genes and the pathways they control. Nat Med 10:789-799]. The superfluous nature of these pathways is thought to severely limit therapeutic approaches targeting tumor proliferation, and it has been suggested that this strategy be abandoned in favor of inhibiting more systemic hallmarks, including angiogenesis (Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: Mechanisms of anti-tumor activity. Nat Rev Cancer 8:579-591; Stommel JM, et al. (2007) Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318:287-290; Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727-739; Kaiser J (2008) Cancer genetics: A detailed genetic portrait of the deadliest human cancers. Science 321:1280-1281]. Here, we report the unexpected observation that genetically diverse cancers converge at a common and obligatory growth axis instigated by HIF-2alpha, an element of the oxygen-sensing machinery. Inhibition of HIF-2alpha prevents the in vivo growth and tumorigenesis of highly aggressive glioblastoma, colorectal, and non-small-cell lung carcinomas and the in vitro autonomous proliferation of several others, regardless of their mutational status and tissue of origin. The concomitant deactivation of select receptor tyrosine kinases, including the EGFR and IGF1R, as well as downstream ERK/Akt signaling, suggests that HIF-2alpha exerts its proliferative effects by endorsing these major pathways. Consistently

  6. Human directed aggression in Brazilian domestic cats: owner reported prevalence, contexts and risk factors.

    PubMed

    Ramos, Daniela; Mills, Daniel Simon

    2009-10-01

    Aggression by cats towards humans is a serious behavioural, welfare and public health problem, although owners may believe it is an inevitable part of cat ownership. There has been little scientific investigation of the risk factors associated with this problem. One hundred and seven owners in the Sao Paulo region of Brazil, took part in a survey aimed at investigating the perceived prevalence of the problem, defining the most common contexts of human directed aggression and identifying associated potential risk factors. Human directed aggression occurred in 49.5% of cats and was most commonly associated with situations involving petting and play, followed by protection of a resource, when startled, when observing an unfamiliar animal and least commonly when unfamiliar people were present. Pedigree status, neuter status, a history of early trauma, sensitivity to being stroked, the absence of other cats in the home, relationship with other animals, level of background activity at home, access to the outside and tendency to be alone (meaning tendency to staying far from the family members) were all associated with an increased risk in one or more context. However, sex, age, age when acquired, source of pet, attachment to a specific household member, type of domestic accommodation, relationship with another cat if present and contact with other animals did not appear to increase the risk. The results suggest sensitivity to being stroked and background levels of stress in the home are the most pervasive risk factors, and future research should aim to investigate these factors further. These data are of relevance when advising owners about the risk and development of this problem.

  7. The genetics of aggression: Where are we now?

    PubMed

    Asherson, Philip; Cormand, Bru

    2016-07-01

    Aggression, an overt behaviour with the intention to inflict damage, is a physiological trait with important roles throughout evolution, both in defence and predation. However, when expressed in humans in the wrong context, aggression leads to social maladjustment and crime. This special issue is about the genetic and neurobiological basis for aggression. Most of the 12 works presented here have been prepared by members of five international consortia established under the auspice of the FP7 and H2020 programs of the European Union to investigate different aspects of aggression and related behavioural phenotypes, including delineation of subtypes, aetiological mechanisms, neurobiology, neuroimaging, biomarkers, animal models and development and assessment of new treatments. Research on human aggression has largely focused on the societal causes of violent behaviour with relatively little focus on the underlying neuroscientific basis. However, interesting findings are emerging which suggest that by identifying distinct pathways to aggression, better targeting of social, psychological and medical treatments, can lead to improved outcomes for individuals and society. This issue represents a state of the art review of current neurobiological understanding of human aggression and a starting point for concerted efforts to move the field towards the development of new strategies for prevention and treatment. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  8. Association between Plasma 25-Hydroxyvitamin D, Ancestry and Aggressive Prostate Cancer among African Americans and European Americans in PCaP

    PubMed Central

    Steck, Susan E.; Arab, Lenore; Zhang, Hongmei; Bensen, Jeannette T.; Fontham, Elizabeth T. H.; Johnson, Candace S.; Mohler, James L.; Smith, Gary J.; Su, Joseph L.; Trump, Donald L.; Woloszynska-Read, Anna

    2015-01-01

    Background African Americans (AAs) have lower circulating 25-hydroxyvitamin D3 [25(OH)D3] concentrations and higher prostate cancer (CaP) aggressiveness than other racial/ethnic groups. The purpose of the current study was to examine the relationship between plasma 25(OH)D3, African ancestry and CaP aggressiveness among AAs and European Americans (EAs). Methods Plasma 25(OH)D3 was measured using LC-MS/MS (Liquid Chromatography Tandem Mass Spectrometry) in 537 AA and 663 EA newly-diagnosed CaP patients from the North Carolina-Louisiana Prostate Cancer Project (PCaP) classified as having either ‘high’ or ‘low’ aggressive disease based on clinical stage, Gleason grade and prostate specific antigen at diagnosis. Mean plasma 25(OH)D3 concentrations were compared by proportion of African ancestry. Logistic regression was used to calculate multivariable adjusted odds ratios (OR) and 95% confidence intervals (95%CI) for high aggressive CaP by tertile of plasma 25(OH)D3. Results AAs with highest percent African ancestry (>95%) had the lowest mean plasma 25(OH)D3 concentrations. Overall, plasma 25(OH)D3 was associated positively with aggressiveness among AA men, an association that was modified by calcium intake (ORT3vs.T1: 2.23, 95%CI: 1.26–3.95 among men with low calcium intake, and ORT3vs.T1: 0.19, 95%CI: 0.05–0.70 among men with high calcium intake). Among EAs, the point estimates of the ORs were <1.0 for the upper tertiles with CIs that included the null. Conclusions Among AAs, plasma 25(OH)D3 was associated positively with CaP aggressiveness among men with low calcium intake and inversely among men with high calcium intake. The clinical significance of circulating concentrations of 25(OH)D3 and interactions with calcium intake in the AA population warrants further study. PMID:25919866

  9. Endometrial cancer

    MedlinePlus

    ... aggressive, and grade 3 is the most aggressive. Aggressive means that the cancer grows and spreads quickly. Treatment Treatment options include surgery, radiation therapy , and chemotherapy . Surgery to remove the uterus ( hysterectomy ) may be done in women with early stage 1 cancer. The doctor may ...

  10. Maternal defense: breast feeding increases aggression by reducing stress.

    PubMed

    Hahn-Holbrook, Jennifer; Holt-Lunstad, Julianne; Holbrook, Colin; Coyne, Sarah M; Lawson, E Thomas

    2011-10-01

    Mothers in numerous species exhibit heightened aggression in defense of their young. This shift typically coincides with the duration of lactation in nonhuman mammals, which suggests that human mothers may display similarly accentuated aggressiveness while breast feeding. Here we report the first behavioral evidence for heightened aggression in lactating humans. Breast-feeding mothers inflicted louder and longer punitive sound bursts on unduly aggressive confederates than did formula-feeding mothers or women who had never been pregnant. Maternal aggression in other mammals is thought to be facilitated by the buffering effect of lactation on stress responses. Consistent with the animal literature, our results showed that while lactating women were aggressing, they exhibited lower systolic blood pressure than did formula-feeding or never-pregnant women while they were aggressing. Mediation analyses indicated that reduced arousal during lactation may disinhibit female aggression. Together, our results highlight the contributions of breast feeding to both protecting infants and buffering maternal stress.

  11. Maternal Defense: Breast Feeding Increases Aggression by Reducing Stress

    PubMed Central

    Hahn-Holbrook, Jennifer; Holt-Lunstad, Julianne; Holbrook, Colin; Coyne, Sarah M.; Lawson, E. Thomas

    2012-01-01

    Mothers in numerous species exhibit heightened aggression in defense of their young. This shift typically coincides with the duration of lactation in nonhuman mammals, which suggests that human mothers may display similarly accentuated aggressiveness while breast feeding. Here we report the first behavioral evidence for heightened aggression in lactating humans. Breast-feeding mothers inflicted louder and longer punitive sound bursts on unduly aggressive confederates than did formula-feeding mothers or women who had never been pregnant. Maternal aggression in other mammals is thought to be facilitated by the buffering effect of lactation on stress responses. Consistent with the animal literature, our results showed that while lactating women were aggressing, they exhibited lower systolic blood pressure than did formula-feeding or never-pregnant women while they were aggressing. Mediation analyses indicated that reduced arousal during lactation may disinhibit female aggression. Together, our results highlight the contributions of breast feeding to both protecting infants and buffering maternal stress. PMID:21873570

  12. Estrogen contributes to the onset, persistence, and malignant progression of cervical cancer in a human papillomavirus-transgenic mouse model

    PubMed Central

    Brake, Tiffany; Lambert, Paul F.

    2005-01-01

    Cervical cancer is a leading cause of death by cancer among women worldwide. High-risk human papillomaviruses (HPVs) are the major etiological agents for cervical cancer, but other factors likely contribute to cervical cancer, because these cancers commonly arise decades after initial exposure to HPV. Estrogen is thought to be one such cofactor; however, its temporal requirements in human cervical cancer are not known. Here we evaluate the temporal requirements of estrogen in cervical carcinogenesis in a mouse model for HPV-associated cervical cancer. Tumors arising in HPV16 transgenic mice treated with estrogen for 9 months were greatly increased in their size compared with tumors developing after 6 months of estrogen treatment. HPV16 transgenic mice treated 6 months with estrogen followed by 3 months without exogenous estrogen had significantly fewer tumors and the tumors were smaller and less aggressive than those arising in mice treated the full 9 months. Importantly, cervical cancers that arose in the mice treated the first 6 of 9 months with estrogen must have regressed, based upon the reduced incidence of cancers in these mice compared with those treated for 6 months with estrogen, then immediately analyzed. We conclude that estrogen plays a critical role not only in the genesis of cervical cancer but also in its persistence and continued development in this mouse model. These findings raise the clinically relevant possibility that, if human cervical cancer has a similar dependence on estrogen for continued tumor growth, then antiestrogen therapy may be effective in the treatment of cervical cancer. PMID:15699322

  13. Expression of matrix metalloproteinase-9 and bombesin/gastrin-releasing peptide in human prostate cancers and their lymph node metastases.

    PubMed

    Ishimaru, Hisashi; Kageyama, Yukio; Hayashi, Tetsuo; Nemoto, Tetsuo; Eishi, Yoshinobu; Kihara, Kazunori

    2002-01-01

    Neuroendocrine differentiation and subsequent excretion of neuropeptides have been demonstrated to be associated with progression of human prostate cancer. Among neuropeptides found to exist in the prostate, bombesin/gastrin-releasing peptide has been shown to upregulate matrix metalloproteinase-9 (MMP-9) in human prostate cancer cell lines. Expression levels of bombesin, MMP-9, and neuron-specific enolase were examined by immunohistochemistry in 41 cases of clinically organ-confined prostate cancers including 9 with microscopic lymph node metastases. Twenty-seven (64%) of the 41 radical prostatectomy specimens were positive for both MMP-9 and bombesin. Expression of these molecules was observed in almost the same population of the cancer cells. The remaining 14 cases were negative for both MMP-9 and bombesin. High-grade tumors (Gleason sum > or = 7) were more likely to express MMP-9 and bombesin (21/24:88%) than low-grade tumors (Gleason sum > or = 6) (7/17:41%). In eight of the nine cases with pathological lymph node metastases, expression of MMP-9 and bombesin was also noted in metastatic sites. Neuron-specific enolase was positive in 16 cases (39%) and not always associated with the expression of bombesin. Expression of bombesin and expression of MMP-9 are common in human prostate cancers and may be related to an aggressive phenotype.

  14. miR-124 radiosensitizes human esophageal cancer cell TE-1 by targeting CDK4.

    PubMed

    Zhang, Y H; Wang, Q Q; Li, H; Ye, T; Gao, F; Liu, Y C

    2016-06-03

    Radiotherapy is one of the most important treatments for esophageal cancer, but radioresistance remains a major challenge. Previous studies have shown that microRNAs (miRNAs or miRs) are involved in human cancers. miR-124 has been widely reported in various cancers and it is intimately involved in proliferation, cell cycle regulation, apoptosis, migration, and invasion of cancer cells. The aim of this study was to explore the relationship between the miR-124/cyclin-dependent kinase 4 (CDK4) axis and the radiosensitivity of esophageal cancer cells. In this study, we identified the reduced expression of miR-124 in 18 paired esophageal cancer tissues compared to their matched normal tissues. In order to investigate the physiological role of miR-124 in esophageal cancer, the cell counting kit-8 (CCK-8) assay and wound healing assay were performed, and the results suggest that miR-124 overexpression decreases tumor growth and aggression. Next, we detected the effects of ectopic miR-124 expression on the apoptosis of an esophageal cancer cell line (TE-1) following radiotherapy. Using the CCK-8 assay and Hoechst 332528 stain, we found that ectopic expression of miR-124 led to a higher percentage of apoptotic cells. Finally, we identified that CDK4 is a direct target of miR-124 in TE-1 cells using target prediction algorithms and a luciferase reporter assay. Moreover, western blot assay confirmed that CDK4 was downregulated during miR-124 transfection. Taken together, we illustrate that the miR-124/CDK4 axis plays an important role in radiation sensitivity of human esophageal cancer cells by targeting CDK4.

  15. Trichomonas vaginalis infection and risk of prostate cancer: associations by disease aggressiveness and race/ethnicity in the PLCO Trial.

    PubMed

    Marous, Miguelle; Huang, Wen-Yi; Rabkin, Charles S; Hayes, Richard B; Alderete, John F; Rosner, Bernard; Grubb, Robert L; Winter, Anke C; Sutcliffe, Siobhan

    2017-08-01

    Results from previous sero-epidemiologic studies of Trichomonas vaginalis infection and prostate cancer (PCa) support a positive association between this sexually transmitted infection and aggressive PCa. However, findings from previous studies are not entirely consistent, and only one has investigated the possible relation between T. vaginalis seropositivity and PCa in African-American men who are at highest risk of both infection and PCa. Therefore, we examined this possible relation in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, including separate analyses for aggressive PCa and African-American men. We included a sample of participants from a previous nested case-control study of PCa, as well as all additional Caucasian, aggressive, and African-American cases diagnosed since the previous study (total n = 438 Gleason 7 Caucasian cases, 487 more advanced Caucasian cases (≥Gleason 8 or stage III/IV), 201 African-American cases, and 1216 controls). We tested baseline sera for T. vaginalis antibodies. No associations were observed for risk of Gleason 7 (odds ratio (OR) = 0.87, 95% confidence interval (CI) 0.55-1.37) or more advanced (OR = 0.90, 95% CI 0.58-1.38) PCa in Caucasian men, or for risk of any PCa (OR = 1.06, 95% CI 0.67-1.68) in African-American men. Our findings do not support an association between T. vaginalis infection and PCa.

  16. Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model

    PubMed Central

    Zhou, Kejin; Nguyen, Liem H.; Miller, Jason B.; Yan, Yunfeng; Kos, Petra; Xiong, Hu; Li, Lin; Hao, Jing; Minnig, Jonathan T.; Siegwart, Daniel J.

    2016-01-01

    RNA-based cancer therapies are hindered by the lack of delivery vehicles that avoid cancer-induced organ dysfunction, which exacerbates carrier toxicity. We address this issue by reporting modular degradable dendrimers that achieve the required combination of high potency to tumors and low hepatotoxicity to provide a pronounced survival benefit in an aggressive genetic cancer model. More than 1,500 dendrimers were synthesized using sequential, orthogonal reactions where ester degradability was systematically integrated with chemically diversified cores, peripheries, and generations. A lead dendrimer, 5A2-SC8, provided a broad therapeutic window: identified as potent [EC50 < 0.02 mg/kg siRNA against FVII (siFVII)] in dose–response experiments, and well tolerated in separate toxicity studies in chronically ill mice bearing MYC-driven tumors (>75 mg/kg dendrimer repeated dosing). Delivery of let-7g microRNA (miRNA) mimic inhibited tumor growth and dramatically extended survival. Efficacy stemmed from a combination of a small RNA with the dendrimer’s own negligible toxicity, therefore illuminating an underappreciated complication in treating cancer with RNA-based drugs. PMID:26729861

  17. Contribution of an alveolar cell of origin to the aggressive phenotype of pregnancy-associated breast cancer

    PubMed Central

    Haricharan, Svasti; Hein, Sarah; Dong, Jie; Toneff, Michael; Aina, Olulana; Rao, Pulivarthi H.; Cardiff, Robert; Li, Yi

    2014-01-01

    Pregnancy-associated breast cancers (PABCs) are malignancies diagnosed during pregnancy or up to five years following parturition, and are usually aggressive, stroma-rich, and estrogen receptor/progesterone receptor-negative; but little is known about the cellular origin of PABCs or the mechanisms by which PABCs initiate. Using the RCAS retrovirus to deliver the ErbB2 oncogene into the mammary epithelium of our previous reported MMTV-tva transgenic mice, we detected human PABC-like tumors during pregnancy and lactation but not in involuted mice or in age-matched virgin mice. More importantly, by generating a WAP-tva transgenic line for expression of ErbB2 selectively in WAP+ mammary alveolar cells, we found that the resulting tumors exhibited the hallmarks of PABCs irrespective of the time since pregnancy and even in the absence of pregnancy. These data suggest that PABCs arise preferentially from an alveolar cell population that expands during pregnancy and lactation. This somatic mouse model may also be useful for preclinical testing of new prophylactic and therapeutic strategies against PABC. PMID:24317513

  18. Timing of palliative care needs reporting and aggressiveness of care near the end of life in metastatic lung cancer: A national registry-based study.

    PubMed

    Goldwasser, François; Vinant, Pascale; Aubry, Régis; Rochigneux, Philippe; Beaussant, Yvan; Huillard, Olivier; Morin, Lucas

    2018-05-09

    Early integration of palliative care for patients with metastatic lung cancer improves their quality of life and survival and reduces the aggressiveness of care near the end of life. This study examined the association between the timing of palliative care needs reporting and the aggressiveness of end-of-life care. This retrospective cohort study used the French National Hospital Registry to identify all hospitalized adults (≥20 years old) who died of metastatic lung cancer in France between 2010 and 2013. It compared the use of care and treatments near the end of life as a function of the timing of the first reporting of palliative care needs. The use of chemotherapy and the use of invasive ventilation were defined as primary outcomes. Propensity score weighting was used to control for potential confounders. Among a total of 64,950 deceased patients with metastatic lung cancer, the reporting of palliative care needs was characterized as timely (from 91 to 31 days before death) for 26.3%, late (from 30 to 8 days before death) for 31.5%, and very late (from 7 to 0 days before death) for 12.8%. Palliative care needs were not reported for 19,106 patients (29.4%). Patients with timely reporting of palliative care needs had the earliest and most progressive decrease in the use of anticancer therapy. The use of invasive ventilation also increased with a delay in palliative care needs reporting. There is a clear association between the timing of palliative care needs reporting and the aggressiveness of care near the end of life. Cancer 2018. © 2018 American Cancer Society. © 2018 American Cancer Society.

  19. Aggression, science, and law: The origins framework. Introduction.

    PubMed

    Victoroff, Jeff

    2009-01-01

    Human societies have formalized instincts for compliance with reciprocal altruism in laws that sanction some aggression and not other aggression. Neuroscience makes steady advances toward measurements of various aspects of brain function pertinent to the aggressive behaviors that laws are designed to regulate. Consciousness, free will, rationality, intent, reality testing, empathy, moral reasoning, and capacity for self-control are somewhat subject to empirical assessment. The question becomes: how should law accommodate the wealth of information regarding these elements of mind that the science of aggression increasingly makes available? This essay discusses the evolutionary purpose of aggression, the evolutionary purpose of law, the problematic assumptions of the mens rea doctrine, and the prospects for applying the neuroscience of aggression toward the goal of equal justice for unequal minds. Nine other essays are introduced, demonstrating how each of them fits into the framework of the permanent debate about neuroscience and justice. It is concluded that advances in the science of human aggression will have vital, but biologically limited, impact on the provision of justice.

  20. Human mammary microenvironment better regulates the biology of human breast cancer in humanized mouse model.

    PubMed

    Zheng, Ming-Jie; Wang, Jue; Xu, Lu; Zha, Xiao-Ming; Zhao, Yi; Ling, Li-Jun; Wang, Shui

    2015-02-01

    During the past decades, many efforts have been made in mimicking the clinical progress of human cancer in mouse models. Previously, we developed a human breast tissue-derived (HB) mouse model. Theoretically, it may mimic the interactions between "species-specific" mammary microenvironment of human origin and human breast cancer cells. However, detailed evidences are absent. The present study (in vivo, cellular, and molecular experiments) was designed to explore the regulatory role of human mammary microenvironment in the progress of human breast cancer cells. Subcutaneous (SUB), mammary fat pad (MFP), and HB mouse models were developed for in vivo comparisons. Then, the orthotopic tumor masses from three different mouse models were collected for primary culture. Finally, the biology of primary cultured human breast cancer cells was compared by cellular and molecular experiments. Results of in vivo mouse models indicated that human breast cancer cells grew better in human mammary microenvironment. Cellular and molecular experiments confirmed that primary cultured human breast cancer cells from HB mouse model showed a better proliferative and anti-apoptotic biology than those from SUB to MFP mouse models. Meanwhile, primary cultured human breast cancer cells from HB mouse model also obtained the migratory and invasive biology for "species-specific" tissue metastasis to human tissues. Comprehensive analyses suggest that "species-specific" mammary microenvironment of human origin better regulates the biology of human breast cancer cells in our humanized mouse model of breast cancer, which is more consistent with the clinical progress of human breast cancer.

  1. Some Issues Concerning Aggression and Violence in Human Beings.

    ERIC Educational Resources Information Center

    Ponton, Elizabeth

    1986-01-01

    Examines aggression and violence from an interdisciplinary perspective. Humanistic psychologist Rollo May sees violence as the end product of power deprivation. Anthropologists Konrad Lorenz and Robert Ardrey regard aggression as an innate biological drive. Anthropologist Richard Leakey views it as a learned, culturally determined response.…

  2. Neurobiology of aggressive behavior.

    PubMed

    Delgado, J M

    1976-10-30

    Causality, neurological mechanisms, and behavioral manifestations may be heterogeneous in different forms of aggressive behavior, but some elements are shared by all forms of violence, including the necessity of sensory inputs, the coding and decoding of information according to acquired frames of reference, and the activation of pre-established patterns of response. Understanding and prevention of violence requires a simultaneous study of its social, cultural, and economic aspects, at parity with an investigation of its neurological mechanisms. Part of the latter information may be obtained through animal experimentation, preferably in non-human primates. Feline predatory behavior has no equivalent in man, and therefore its hypothalamic representation probably does not exist in the human brain. Codes of information, frames of reference for sensory perception, axis to evaluate threats, and formulas for aggressive performance are not established genetically but must be learned individually. We are born with the capacity to learn aggressive behavior, but not with established patterns of violence. Mechanisms for fighting which are acquired by individual experience may be triggered in a similar way by sensory cues, volition, and by electrical stimulation of specific cerebral areas. In monkeys, aggressive responses may be modified by changing the hierarchical position of the stimulated animal, indicating the physiological quality of the neurological mechanisms electrically activated.

  3. P3 and provoked aggressive behavior.

    PubMed

    Fanning, Jennifer R; Berman, Mitchell E; Long, James M

    2014-01-01

    Cognitive and biological processes play a role in human aggression. However, relatively little is known about the neural correlates of cognitive processes in aggressive individuals, particularly as they unfold during an aggressive encounter. We investigated whether the P3 event-related potential (ERP) discriminates aggressive versus nonaggressive individuals during a provocative, aggressive encounter. Forty-eight participants (23 men and 25 women) were classified as aggressive or nonaggressive based on self-reported life history of aggression. Aggressive behavior was assessed using a modification of a well-validated laboratory task during which the participant and a fictitious opponent ostensibly delivered and received noise blasts of low, medium, and high intensity. Provocation was manipulated by altering the level of noise set by the opponent. Aggression was defined as the number of high-intensity noise blasts the participant set for the opponent. As predicted, P3 amplitude in response to provocation differed as a function of aggressive history. Nonaggressive individuals showed enhanced P3 when provoked by the opponent relative to low provocation, but this effect was absent in aggressive individuals. The results suggest that aggressive individuals engage fewer neural processing resources in response to provoking social cues, which may reflect aberrant cognitive and emotional processes.

  4. On complexity and homogeneity measures in predicting biological aggressiveness of prostate cancer; Implication of the cellular automata model of tumor growth.

    PubMed

    Tanase, Mihai; Waliszewski, Przemyslaw

    2015-12-01

    We propose a novel approach for the quantitative evaluation of aggressiveness in prostate carcinomas. The spatial distribution of cancer cell nuclei was characterized by the global spatial fractal dimensions D0, D1, and D2. Two hundred eighteen prostate carcinomas were stratified into the classes of equivalence using results of ROC analysis. A simulation of the cellular automata mix defined a theoretical frame for a specific geometric representation of the cell nuclei distribution called a local structure correlation diagram (LSCD). The LSCD and dispersion Hd were computed for each carcinoma. Data mining generated some quantitative criteria describing tumor aggressiveness. Alterations in tumor architecture along progression were associated with some changes in both shape and the quantitative characteristics of the LSCD consistent with those in the automata mix model. Low-grade prostate carcinomas with low complexity and very low biological aggressiveness are defined by the condition D0 < 1.545 and Hd < 38. High-grade carcinomas with high complexity and very high biological aggressiveness are defined by the condition D0 > 1.764 and Hd < 38. The novel homogeneity measure Hd identifies carcinomas with very low aggressiveness within the class of complexity C1 or carcinomas with very high aggressiveness in the class C7. © 2015 Wiley Periodicals, Inc.

  5. Integration of high-risk human papillomavirus into cellular cancer-related genes in head and neck cancer cell lines.

    PubMed

    Walline, Heather M; Goudsmit, Christine M; McHugh, Jonathan B; Tang, Alice L; Owen, John H; Teh, Bin T; McKean, Erin; Glover, Thomas W; Graham, Martin P; Prince, Mark E; Chepeha, Douglas B; Chinn, Steven B; Ferris, Robert L; Gollin, Susanne M; Hoffmann, Thomas K; Bier, Henning; Brakenhoff, Ruud; Bradford, Carol R; Carey, Thomas E

    2017-05-01

    Human papillomavirus (HPV)-positive oropharyngeal cancer is generally associated with excellent response to therapy, but some HPV-positive tumors progress despite aggressive therapy. The purpose of this study was to evaluate viral oncogene expression and viral integration sites in HPV16- and HPV18-positive squamous cell carcinoma lines. E6/E7 alternate transcripts were assessed by reverse transcriptase-polymerase chain reaction (RT-PCR). Detection of integrated papillomavirus sequences (DIPS-PCR) and sequencing identified viral insertion sites and affected host genes. Cellular gene expression was assessed across viral integration sites. All HPV-positive cell lines expressed alternate HPVE6/E7 splicing indicative of active viral oncogenesis. HPV integration occurred within cancer-related genes TP63, DCC, JAK1, TERT, ATR, ETV6, PGR, PTPRN2, and TMEM237 in 8 head and neck squamous cell carcinoma (HNSCC) lines but UM-SCC-105 and UM-GCC-1 had only intergenic integration. HPV integration into cancer-related genes occurred in 7 of 9 HPV-positive cell lines and of these 6 were from tumors that progressed. HPV integration into cancer-related genes may be a secondary carcinogenic driver in HPV-driven tumors. © 2017 Wiley Periodicals, Inc. Head Neck 39: 840-852, 2017. © 2017 Wiley Periodicals, Inc.

  6. MUC1-C ONCOPROTEIN CONFERS ANDROGEN-INDEPENDENT GROWTH OF HUMAN PROSTATE CANCER CELLS

    PubMed Central

    Rajabi, Hasan; Ahmad, Rehan; Jin, Caining; Joshi, Maya Datt; Guha, Minakshi; Alam, Maroof; Kharbanda, Surender; Kufe, Donald

    2012-01-01

    Background The mucin 1 (MUC1) heterodimeric oncoprotein is overexpressed in human prostate cancers with aggressive pathologic and clinical features. However, few insights are available regarding the functional role of MUC1 in prostate cancer. Methods Effects of MUC1-C on AR expression were determined by RT-PCR, immunoblotting and AR promoter activation. Coimmunoprecipitations, direct binding assays and chromatin immunoprecipitation (ChIP) studies were performed to assess the interaction between MUC1-C and AR. Cells were analyzed for invasion, growth in androgen-depleted medium and sensitivity to MUC1-C inhibitors. Results The present studies in androgen-dependent LNCaP and LAPC4 prostate cancer cells demonstrate that the oncogenic MUC1-C subunit suppresses AR expression. The results show that MUC1-C activates a posttranscriptional mechanism involving miR-135b-mediated downregulation of AR mRNA levels. The results further demonstrate that MUC1-C forms a complex with AR through a direct interaction between the MUC1-C cytoplasmic domain and the AR DNA-binding domain. In addition, MUC1-C associates with AR in a complex that occupies the PSA promoter. The interaction between MUC1-C and AR is associated with induction of the epithelial-mesenchymal transition (EMT) and increased invasion. MUC1-C also conferred growth in androgen-depleted medium and resistance to bicalutamide treatment. Moreover, expression of MUC1-C resulted in sensitivity to the MUC1-C inhibitor GO-203 with inhibition of growth in vitro. GO-203 treatment also inhibited growth of established tumor xenografts in nude mice. Conclusions These findings indicate that MUC1-C suppresses AR expression in prostate cancer cells and confers a more aggressive androgen-independent phenotype that is sensitive to MUC1-C inhibition. PMID:22473899

  7. Adolescent cancer survivors’ smoking intentions are associated with aggression, attention, and smoking history

    PubMed Central

    Tyc, Vida L.; Wilson, Stephanie J.; Nelms, Jenna; Hudson, Melissa M.; Wu, Shengjie; Xiong, Xiaoping; Hinds, Pamela S.

    2011-01-01

    Introduction The present study examines behavioral and psychosocial factors associated with smoking intentions and experimentation among adolescent survivors of pediatric cancer. Methods Adolescent survivors of brain tumor and acute lymphoblastic leukemia (n=99) provided information about their smoking histories and their intentions to smoke in the future. Behavior rating scales were completed by survivors, parents, and teachers. Results Past experimentation with smoking and higher levels of self-reported aggression were associated with intentions to smoke in the future (OR=4.18, 95%CI 1.02–17.04, and OR=1.08, 95% CI 1.01–1.15, respectively), while teacher-ratings of inattention in the classroom were negatively associated with intentions to smoke (OR=0.94, 95% CI.88–.99), all p<.05. Experimentation with smoking was more likely among older survivors (OR=1.76, 95% CI 1.16–2.66, p<.01) and those whose parents had divorced (OR=4.40, 95% CI 1.21–16.06, p<.05). Discussion A concerning minority of adolescent survivors have clear intentions to smoke, a behavior that adds to their overall health risk. Smoking intentions and experimentation are important precursors to regular smoking. Prevention efforts are needed to interrupt the progression from intentions and experimentation to established smoking and nicotine dependence in this medically vulnerable population. Implications for cancer survivors Assessment of an adolescent’s history of parental divorce, past experimentation with smoking, and aggressive behavior will identify those survivors who are likely to consider smoking in the future. Screening for these characteristics will allow clinicians to be more vigilant in health promotion. PMID:20922493

  8. Neurogenomic Mechanisms of Aggression in Songbirds

    PubMed Central

    Maney, Donna L.; Goodson, James L.

    2017-01-01

    Our understanding of the biological basis of aggression in all vertebrates, including humans, has been built largely upon discoveries first made in birds. A voluminous literature now indicates that hormonal mechanisms are shared between humans and a number of avian species. Research on genetics mechanisms in birds has lagged behind the more typical laboratory species because the necessary tools have been lacking until recently. Over the past 30 years, three major technical advances have propelled forward our understanding of the hormonal, neural, and genetic bases of aggression in birds: (1) the development of assays to measure plasma levels of hormones in free-living individuals, or “field endocrinology”; (2) the immunohistochemical labeling of immediate early gene products to map neural responses to social stimuli; and (3) the sequencing of the zebra finch genome, which makes available a tremendous set of genomic tools for studying gene sequences, expression, and chromosomal structure in species for which we already have large datasets on aggressive behavior. This combination of hormonal, neuroendocrine, and genetic tools has established songbirds as powerful models for understanding the neural basis and evolution of aggression in vertebrates. In this chapter, we discuss the contributions of field endocrinology toward a theoretical framework linking aggression with sex steroids, explore evidence that the neural substrates of aggression are conserved across vertebrate species, and describe a promising new songbird model for studying the molecular genetic mechanisms underlying aggression. PMID:22078478

  9. The Control of Human Aggression: An Incompatible Response Strategy.

    ERIC Educational Resources Information Center

    Baron, Robert A.

    This is a brief report discussing ways of dealing with aggression in individuals. The author feels that previous approaches, such as catharsis or punishment, have proved inadequate, and that a more successful approach to reducing aggression involves the induction of incompatible reactions among aggressors. In the author's opinion, when angry…

  10. Quetiapine modulates functional connectivity in brain aggression networks.

    PubMed

    Klasen, Martin; Zvyagintsev, Mikhail; Schwenzer, Michael; Mathiak, Krystyna A; Sarkheil, Pegah; Weber, René; Mathiak, Klaus

    2013-07-15

    Aggressive behavior is associated with dysfunctions in an affective regulation network encompassing amygdala and prefrontal areas such as orbitofrontal (OFC), anterior cingulate (ACC), and dorsolateral prefrontal cortex (DLPFC). In particular, prefrontal regions have been postulated to control amygdala activity by inhibitory projections, and this process may be disrupted in aggressive individuals. The atypical antipsychotic quetiapine successfully attenuates aggressive behavior in various disorders; the underlying neural processes, however, are unknown. A strengthened functional coupling in the prefrontal-amygdala system may account for these anti-aggressive effects. An inhibition of this network has been reported for virtual aggression in violent video games as well. However, there have been so far no in-vivo observations of pharmacological influences on corticolimbic projections during human aggressive behavior. In a double-blind, placebo-controlled study, quetiapine and placebo were administered for three successive days prior to an fMRI experiment. In this experiment, functional brain connectivity was assessed during virtual aggressive behavior in a violent video game and an aggression-free control task in a non-violent modification. Quetiapine increased the functional connectivity of ACC and DLPFC with the amygdala during virtual aggression, whereas OFC-amygdala coupling was attenuated. These effects were observed neither for placebo nor for the non-violent control. These results demonstrate for the first time a pharmacological modification of aggression-related human brain networks in a naturalistic setting. The violence-specific modulation of prefrontal-amygdala networks appears to control aggressive behavior and provides a neurobiological model for the anti-aggressive effects of quetiapine. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Expression between African American and Caucasian Prostate Cancer Tissue Reveals that Stroma is the Site of Aggressive Changes

    PubMed Central

    Kinseth, Matthew A.; Jia, Zhenyu; Rahmatpanah, Farahnaz; Sawyers, Anne; Sutton, Manuel; Wang-Rodriguez, Jessica; Mercola, Dan; McGuire, Kathleen L.

    2013-01-01

    In prostate cancer, race/ethnicity is the highest risk factor after adjusting for age. African Americans have more aggressive tumors at every clinical stage of the disease, resulting in poorer prognosis and increased mortality. A major barrier to identifying crucial gene activity differences is heterogeneity, including tissue composition variation intrinsic to the histology of prostate cancer. We hypothesized differences in gene expression in specific tissue types would reveal mechanisms involved in the racial disparities of prostate cancer. We examined seventeen pairs of arrays for African Americans and Caucasians that were formed by closely matching the samples based on the known tissue type composition of the tumors. Using pair wise T-test we found significantly altered gene expression between African Americans and Caucasians. Independently, we performed multiple linear regression analyses to associate gene expression with race considering variation in percent tumor and stroma tissue. The majority of differentially expressed genes were associated with tumor-adjacent stroma rather than tumor tissue. Extracellular matrix, Integrin family and signaling mediators of the epithelial-to-mesenchymal transition pathways were all down regulated in stroma of African Americans. Using MetaCore (GeneGo Inc.) analysis, we observed that 35% of significant (p < 10-3) pathways identified EMT and 25% identified immune response pathways especially for Interleukins -2, -4, -5, -6, -7, -10, -13, -15 and -22 as the major changes. Our studies reveal that altered immune and EMT processes in tumor-adjacent stroma may be responsible for the aggressive nature of prostate cancer in African Americans. PMID:23754304

  12. Study shows aspirin reduces the risk and recurrence of prostate cancer in African-American men | Center for Cancer Research

    Cancer.gov

    African-American men who take a daily dose of aspirin experience a significantly lower risk of developing advanced prostate cancer – the aggressive and deadly form of the disease – than African-American men who do not regularly use aspirin, according to a study from the Center for Cancer Research (CCR) Laboratory of Human Carcinogenesis. Learn more...

  13. Human Cancer Models Initiative | Office of Cancer Genomics

    Cancer.gov

    The Human Cancer Models Initiative (HCMI) is an international consortium that is generating novel human tumor-derived culture models, which are annotated with genomic and clinical data. In an effort to advance cancer research and more fully understand how in vitro findings are related to clinical biology, HCMI-developed models and related data will be available as a community resource for cancer and other research.

  14. Human Cancer Models Initiative | Office of Cancer Genomics

    Cancer.gov

    The Human Cancer Models Initiative (HCMI) is an international consortium that is generating novel human tumor-derived culture models, which are annotated with genomic and clinical data. In an effort to advance cancer research and more fully understand how in vitro findings are related to clinical biology, HCMI-developed models and related data will be available as a community resource for cancer research.

  15. Genetics Home Reference: prostate cancer

    MedlinePlus

    ... prostate cancer Genetic Testing Registry: Prostate cancer aggressiveness quantitative trait locus on chromosome 19 Genetic Testing Registry: ... OMIM (25 links) PROSTATE CANCER PROSTATE CANCER AGGRESSIVENESS QUANTITATIVE TRAIT LOCUS ON CHROMOSOME 19 PROSTATE CANCER ANTIGEN ...

  16. Cognition, emotion, and the alcohol--aggression relationship: comment on Giancola (2000).

    PubMed

    Lyvers, M

    2000-11-01

    P. R. Giancola's (2000) thesis that the alcohol-aggression relationship can be explained by alcohol-induced disruption of executive cognitive functions mediated by the prefrontal cortex is critically examined. At moderate doses, alcohol has been reported to increase aggression in animals as diverse as fish, rats, cats, monkeys, and humans. Although alcohol depresses prefrontal cortex activity and disrupts executive cognitive performance in humans, alcohol's anxiolytic actions, and its disinhibiting effects on subcortical structures implicated in anger and aggression, may be at least as important as the higher cognitive functions cited by Giancola in accounting for the alcohol-aggression relationship. Other drugs that alter prefrontal cortex activity have also been reported to influence aggressive responding in humans and other animals, and implications of this are briefly discussed.

  17. Viral Carcinogenesis Beyond Malignant Transformation: EBV in the Progression of Human Cancers

    PubMed Central

    Müller-Coan, Bárbara G.; Pagano, Joseph S.

    2017-01-01

    Cancer progression begins when malignant cells colonize adjacent sites, and it is characterized by increasing tumor heterogeneity, invasion and dissemination of cancer cells. Clinically, progression is the most relevant stage in the natural history of cancers. A given virus is usually regarded as oncogenic because of its ability to induce malignant transformation of cells. Nonetheless, oncogenic viruses may also be important for the progression of infection-associated cancers. Recently this hypothesis has been addressed because of studies on the contribution of the Epstein–Barr virus (EBV) to the aggressiveness of nasopharyngeal carcinoma (NPC). Several EBV products modulate cancer progression phenomena, such as the epithelial–mesenchymal transition, cell motility, invasiveness, angiogenesis, and metastasis. In this regard, there are compelling data about the effects of EBV latent membrane proteins (LMPs) and EBV nuclear antigens (EBNAs), as well as nontranslated viral RNAs, such as the EBV-encoded small nonpolyadenylated RNAs (EBERs) and viral microRNAs, notably EBV miR-BARTs. The available data on the mechanisms and players involved in the contribution of EBV infection to the aggressiveness of NPC are discussed in this review. Overall, this conceptual framework may be valuable for the understanding of the contribution of some infectious agents in the progression of cancers. PMID:27068530

  18. Genetics of Aggression in Voles

    PubMed Central

    Gobrogge, Kyle L.; Wang, Zuoxin

    2016-01-01

    Prairie voles (Microtus ochrogaster) are socially monogamous rodents that form pair bonds—a behavior composed of several social interactions including attachment with a familiar mate and aggression toward conspecific strangers. Therefore, this species has provided an excellent opportunity for the study of pair bonding behavior and its underlying neural mechanisms. In this chapter, we discuss the utility of this unique animal model in the study of aggression and review recent findings illustrating the neurochemical mechanisms underlying pair bonding-induced aggression. Implications of this research for our understanding of the neurobiology of human violence are also discussed. PMID:22078479

  19. Lipid Biomarkers Identified for Liver Cancer | Center for Cancer Research

    Cancer.gov

    Hepatocellular carcinoma (HCC) is an aggressive cancer of the liver with poor prognosis and growing incidence in developed countries. Pathology and genetic profiles of HCC are heterogeneous, suggesting that it can begin growing in different cell types. Although human tumors such as HCC have been profiled in-depth by genomics-based studies, not much is known about their overall

  20. Pathophysiological basis of human papillomavirus in penile cancer: Key to prevention and delivery of more effective therapies.

    PubMed

    Spiess, Philippe E; Dhillon, Jasreman; Baumgarten, Adam S; Johnstone, Peter A; Giuliano, Anna R

    2016-06-17

    Answer questions and earn CME/CNE Squamous cell carcinoma (SCC) of the penis is a rare malignancy in the United States, with a significantly higher incidence-up to 20 to 30 times greater-in areas of Africa and South America. This can be explained in part by the significantly greater prevalence of sexually transmitted diseases among high-risk males often having unprotected sex with multiple sexual partners. Human papillomavirus (HPV) has been implicated as the infectious pathway by which several these penile neoplasms originate from precursor lesions. In this regard, a fundamental understanding of HPV in penile carcinogenesis can have meaningful implications in understanding 1) the diagnosis of HPV-related precursor penile lesions, 2) targeting HPV-specific molecular pathways, and 3) cancer prevention. Using vaccination programs not only may improve patient outcomes but also may minimize the need for highly aggressive and often debilitating surgical resection. CA Cancer J Clin 2016. © 2016 American Cancer Society. © 2016 American Cancer Society, Inc.

  1. Dietary, supplement, and adipose tissue tocopherol levels in relation to prostate cancer aggressiveness among African and European Americans: The North Carolina-Louisiana Prostate Cancer Project (PCaP).

    PubMed

    Antwi, Samuel O; Steck, Susan E; Su, L Joseph; Hébert, James R; Zhang, Hongmei; Fontham, Elizabeth T H; Smith, Gary J; Bensen, Jeannette T; Mohler, James L; Arab, Lenore

    2015-09-01

    Controversies remain over the safety and efficacy of vitamin E (i.e., α-tocopherol) supplementation use for the prevention of prostate cancer (CaP); however, associations of different tocopherol forms and CaP aggressiveness have yet to be examined. This study examined whether food intake of tocopherols, vitamin E supplement use, and adipose tissue biomarkers of tocopherol were associated with CaP aggressiveness among African-American (AA, n = 1,023) and European-American (EA, n = 1,079) men diagnosed with incident CaP. Dietary tocopherols were estimated from a food frequency questionnaire, supplement use from questionnaire/inventory, and biomarkers from abdominal adipose samples measured using high-performance liquid chromatography. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were estimated from logistic regression comparing high-aggressive CaP to low/intermediate aggressive CaP, adjusting for covariates. Dietary intakes of α-and δ-tocopherol were related inversely to CaP aggressiveness among EAs [OR (95%CI), highest versus lowest quartile: α-tocopherol, 0.34 (0.17-0.69), P(trend)  = 0.006; δ-tocopherol, 0.45 (0.21-0.95) P(trend)  = 0.007]. Inverse associations between dietary and supplemental α-tocopherol and CaP aggressiveness were observed among AAs, though these did not reach statistical significance [OR (95%CI), highest versus lowest quartile: dietary α-tocopherol, 0.58 (0.28-1.19), P(trend)  = 0.20; supplemental α-tocopherol, 0.64 (0.31-1.21) P(trend)  = 0.15]. No significant association was observed between adipose tocopherol levels and CaP aggressiveness [OR (95%CI), highest versus lowest quartiles of α-tocopherol for EAs 1.43 (0.66-3.11) and AAs 0.66 (0.27-1.62)]. The inverse associations observed between dietary sources of tocopherols and CaP aggressiveness suggests a beneficial role of food sources of these tocopherols in CaP aggressiveness. © 2015 Wiley Periodicals, Inc.

  2. Dietary, Supplement, and Adipose Tissue Tocopherols Levels in Relation to Prostate Cancer Aggressiveness Among African and European Americans: The North Carolina-Louisiana Prostate Cancer Project (PCaP)

    PubMed Central

    Antwi, Samuel; Steck, Susan E.; Su, L. Joseph; Hebert, James R.; Zhang, Hongmei; Fontham, Elizabeth T. H.; Smith, Gary; Bensen, Jeannette T.; Mohler, James L.; Arab, Lenore

    2016-01-01

    Background Controversies remain over the safety and efficacy of vitamin E (i.e., α–tocopherol) supplementation use for the prevention of prostate cancer (CaP); however, associations of different tocopherol forms and CaP aggressiveness have yet to be examined. Methods This study examined whether food intake of tocopherols, vitamin E supplement use, and adipose tissue biomarkers of tocopherol were associated with CaP aggressiveness among African-American (AA, n=1,023) and European-American (EA, n=1,079) men diagnosed with incident CaP. Dietary tocopherols were estimated from a food frequency questionnaire, supplement use from questionnaire/inventory, and biomarkers from abdominal adipose samples measured using high-performance liquid chromatography. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated from logistic regression comparing high aggressive CaP to low/intermediate aggressive CaP, adjusting for covariates. Results Dietary intakes of α-and δ-tocopherol were related inversely to CaP aggressiveness among EAs [OR (95% CI), highest versus lowest quartile: α-tocopherol, 0.34 (0.17–0.69), Ptrend = 0.006; δ-tocopherol, 0.45 (0.21–0.95) Ptrend = 0.007]. Inverse associations between dietary and supplemental α-tocopherol and CaP aggressiveness were observed among AAs, though these did not reach statistical significance [OR (95% CI), highest versus lowest quartile: dietary α-tocopherol, 0.58 (0.28–1.19), Ptrend = 0.20; supplemental α-tocopherol, 0.64 (0.31–1.21) Ptrend = 0.15]. No significant association was observed between adipose tocopherol levels and CaP aggressiveness [OR (95% CI), highest versus lowest quartiles of α-tocopherol for EAs 1.43 (0.66–3.11) and AAs 0.66 (0.27–1.62)]. Conclusions The inverse associations observed between dietary sources of tocopherols and CaP aggressiveness suggests a beneficial role of food sources of these tocopherols in CaP aggressiveness. PMID:26053590

  3. Cytokeratin 19 (KRT19) has a Role in the Reprogramming of Cancer Stem Cell-Like Cells to Less Aggressive and More Drug-Sensitive Cells.

    PubMed

    Saha, Subbroto Kumar; Kim, Kyeongseok; Yang, Gwang-Mo; Choi, Hye Yeon; Cho, Ssang-Goo

    2018-05-09

    Cytokeratin 19 ( KRT19 ) is a cytoplasmic intermediate filament protein, which is responsible for structural rigidity and multipurpose scaffolds. In several cancers, KRT19 is overexpressed and may play a crucial role in tumorigenic transformation. In our previous study, we revealed the role of KRT19 as signaling component which mediated Wnt/NOTCH crosstalk through NUMB transcription in breast cancer. Here, we investigated the function of KRT19 in cancer reprogramming and drug resistance in breast cancer cells. We found that expression of KRT19 was attenuated in several patients-derived breast cancer tissues and patients with a low expression of KRT19 were significantly correlated with poor prognosis in breast cancer patients. Consistently, highly aggressive and drug-resistant breast cancer patient-derived cancer stem cell-like cells (konkuk university-cancer stem cell-like cell (KU-CSLCs)) displayed higher expression of cancer stem cell (CSC) markers, including ALDH1 , CXCR4 , and CD133 , but a much lower expression of KRT19 than that is seen in highly aggressive triple negative breast cancer MDA-MB231 cells. Moreover, we revealed that the knockdown of KRT19 in MDA-MB231 cells led to an enhancement of cancer properties, such as cell proliferation, sphere formation, migration, and drug resistance, while the overexpression of KRT19 in KU-CSLCs resulted in the significant attenuation of cancer properties. KRT19 regulated cancer stem cell reprogramming by modulating the expression of cancer stem cell markers ( ALDH1 , CXCR4 , and CD133 ), as well as the phosphorylation of Src and GSK3β (Tyr216). Therefore, our data may imply that the modulation of KRT19 expression could be involved in cancer stem cell reprogramming and drug sensitivity, which might have clinical implications for cancer or cancer stem cell treatment.

  4. Cytokeratin 19 (KRT19) has a Role in the Reprogramming of Cancer Stem Cell-Like Cells to Less Aggressive and More Drug-Sensitive Cells

    PubMed Central

    Kim, Kyeongseok; Yang, Gwang-Mo; Choi, Hye Yeon

    2018-01-01

    Cytokeratin 19 (KRT19) is a cytoplasmic intermediate filament protein, which is responsible for structural rigidity and multipurpose scaffolds. In several cancers, KRT19 is overexpressed and may play a crucial role in tumorigenic transformation. In our previous study, we revealed the role of KRT19 as signaling component which mediated Wnt/NOTCH crosstalk through NUMB transcription in breast cancer. Here, we investigated the function of KRT19 in cancer reprogramming and drug resistance in breast cancer cells. We found that expression of KRT19 was attenuated in several patients-derived breast cancer tissues and patients with a low expression of KRT19 were significantly correlated with poor prognosis in breast cancer patients. Consistently, highly aggressive and drug-resistant breast cancer patient-derived cancer stem cell-like cells (konkuk university-cancer stem cell-like cell (KU-CSLCs)) displayed higher expression of cancer stem cell (CSC) markers, including ALDH1, CXCR4, and CD133, but a much lower expression of KRT19 than that is seen in highly aggressive triple negative breast cancer MDA-MB231 cells. Moreover, we revealed that the knockdown of KRT19 in MDA-MB231 cells led to an enhancement of cancer properties, such as cell proliferation, sphere formation, migration, and drug resistance, while the overexpression of KRT19 in KU-CSLCs resulted in the significant attenuation of cancer properties. KRT19 regulated cancer stem cell reprogramming by modulating the expression of cancer stem cell markers (ALDH1, CXCR4, and CD133), as well as the phosphorylation of Src and GSK3β (Tyr216). Therefore, our data may imply that the modulation of KRT19 expression could be involved in cancer stem cell reprogramming and drug sensitivity, which might have clinical implications for cancer or cancer stem cell treatment. PMID:29747452

  5. Evaluating a 4-marker signature of aggressive prostate cancer using time-dependent AUC.

    PubMed

    Gerke, Travis A; Martin, Neil E; Ding, Zhihu; Nuttall, Elizabeth J; Stack, Edward C; Giovannucci, Edward; Lis, Rosina T; Stampfer, Meir J; Kantoff, Phillip W; Parmigiani, Giovanni; Loda, Massimo; Mucci, Lorelei A

    2015-12-01

    We previously identified a protein tumor signature of PTEN, SMAD4, SPP1, and CCND1 that, together with clinical features, was associated with lethal outcomes among prostate cancer patients. In the current study, we sought to validate the molecular model using time-dependent measures of AUC and predictive values for discriminating lethal from non-lethal prostate cancer. Using data from the initial study, we fit survival models for men with prostate cancer who were participants in the Physicians' Health Study (PHS; n = 276). Based on these models, we generated prognostic risk scores in an independent population, the Health Professionals Follow-up Study (HPFS; n = 347) to evaluate external validity. In each cohort, men were followed prospectively from cancer diagnosis through 2011 for development of distant metastasis or cancer mortality. We measured protein tumor expression of PTEN, SMAD4, SPP1, and CCND1 on tissue microarrays. During a median of 11.9 and 14.3 years follow-up in the PHS and HPFS cohorts, 24 and 32 men (9%) developed lethal disease. When used as a prognostic factor in a new population, addition of the four markers to clinical variables did not improve discriminatory accuracy through 15 years of follow-up. Although the four markers have been identified as key biological mediators in metastatic progression, they do not provide independent, long-term prognostic information beyond clinical factors when measured at diagnosis. This finding may underscore the broad heterogeneity in aggressive prostate tumors and highlight the challenges that may result from overfitting in discovery-based research. © 2015 Wiley Periodicals, Inc.

  6. Genetic polymorphism and prostate cancer aggressiveness: A case-only study of 1536 GWAS and candidate SNPs in African Americans and European Americans

    PubMed Central

    Bensen, Jeannette T.; Xu, Zongli; Smith, Gary J.; Mohler, James L.; Fontham, Elizabeth T.H.; Taylor, Jack A.

    2012-01-01

    BACKGROUND Genome-wide association studies have established a number of replicated single nucleotide polymorphisms (SNPs) for susceptibility to prostate cancer (CaP), but it is unclear whether these susceptibility SNPs are also associated with disease aggressiveness. This study evaluates whether such replication SNPs or other candidate SNPs are associated with CaP aggressiveness in African-American (AA) and European-American (EA) men. METHODS A 1,536 SNP panel which included 34 genome-wide association study (GWAS) replication SNPs, 38 flanking SNPs, a set of ancestry informative markers, and SNPs in candidate genes and other areas was genotyped in 1,060 AA and 1,087 EA men with incident CaP from the North Carolina-Louisiana Prostate Cancer Project (PCaP). Tests for association were conducted using ordinal logistic regression with a log-additive genotype model and a 3-category CaP aggressiveness variable. RESULTS 4 GWAS replication SNPs (rs2660753, rs13254738, rs10090154, rs2735839) and 7 flanking SNPs were associated with CaP aggressiveness (P<0.05) in 3 genomic regions: one at 3p12 (EA), 7 at 8q24 (5 AA, 2 EA), and 3 at 19q13 at the kallilkrein-related peptidase 3 (KLK3) locus (2 AA, 1 AA and EA). The KLK3 SNPs also were associated with serum prostate-specific antigen (PSA) levels in AA (p < 0.001) but not in EA. A number of the other SNPs showed some evidence of association but none met study-wide significance levels after adjusting for multiple comparisons. CONCLUSIONS Some replicated GWAS susceptibility SNPs may play a role in CaP aggressiveness. However, like susceptibility, these associations are not consistent between racial groups. PMID:22549899

  7. The YAP1/SIX2 axis is required for DDX3-mediated tumor aggressiveness and cetuximab resistance in KRAS-wild-type colorectal cancer

    PubMed Central

    Wu, De-Wei; Lin, Po-Lin; Wang, Lee; Huang, Chi-Chou; Lee, Huei

    2017-01-01

    The mechanism underlying tumor aggressiveness and cetuximab (CTX) resistance in KRAS-wild-type (KRAS -WT) colorectal cancer remains obscure. We here provide evidence that DDX3 promoted soft agar growth and invasiveness of KRAS-WT cells, as already confirmed in KRAS-mutated cells. Mechanistically, increased KRAS expression induced ROS production, which elevated HIF-1α and YAP1 expression. Increased HIF-1α persistently promoted DDX3 expression via a KRAS/ROS/HIF-1α feedback loop. DDX3-mediated aggressiveness and CTX resistance were regulated by the YAP1/SIX2 axis in KRAS-WT cells and further confirmed in animal models. Kaplan-Meier and Cox regression analysis indicated that DDX3, KRAS, and YAP1 expression had prognostic value for OS and RFS in KRAS-WT and KRAS-mutated tumors, but SIX2 and YAP1/SIX2 were prognostic value only in KRAS-WT patients. The observation from patients seemed to support the mechanistic action of cell and animal models. We therefore suggest that combining YAP1 inhibitors with CTX may therefore suppress DDX3-mediated tumor aggressiveness and enhance CTX sensitivity in KRAS-WT colorectal cancer. PMID:28435452

  8. The HDL receptor SR-BI is associated with human prostate cancer progression and plays a possible role in establishing androgen independence.

    PubMed

    Schörghofer, David; Kinslechner, Katharina; Preitschopf, Andrea; Schütz, Birgit; Röhrl, Clemens; Hengstschläger, Markus; Stangl, Herbert; Mikula, Mario

    2015-08-07

    Human prostate cancer represents one of the most frequently diagnosed cancers in men worldwide. Currently, diagnostic methods are insufficient to identify patients at risk for aggressive prostate cancer, which is essential for early treatment. Recent data indicate that elevated cholesterol levels in the plasma are a prerequisite for the progression of prostate cancer. Here, we analyzed clinical prostate cancer samples for the expression of receptors involved in cellular cholesterol uptake. We screened mRNA microarray files of prostate cancer samples for alterations in the expression levels of cholesterol transporters. Furthermore, we performed immunohistochemistry analysis on human primary prostate cancer tissue sections derived from patients to investigate the correlation of SR-BI with clinicopathological parameters and the mTOR target pS6. In contrast to LDLR, we identified SR-BI mRNA and protein expression to be induced in high Gleason grade primary prostate cancers. Histologic analysis of prostate biopsies revealed that 53.6 % of all cancer samples and none of the non-cancer samples showed high SR-BI staining intensity. The disease-free survival time was reduced (P = 0.02) in patients expressing high intra-tumor levels of SR-BI. SR-BI mRNA correlated with HSD17B1 and HSD3B1 and SR-BI protein staining showed correlation with active ribosomal protein S6 (RS = 0.828, P < 0.00001). We identified SR-BI to indicate human prostate cancer formation, suggesting that increased levels of SR-BI may be involved in the generation of a castration-resistant phenotype.

  9. Swooping in the Suburbs; Parental Defence of an Abundant Aggressive Urban Bird against Humans

    PubMed Central

    Lees, Daniel; Sherman, Craig D. H.; Maguire, Grainne S.; Dann, Peter; Cardilini, Adam P. A.; Weston, Michael A.

    2013-01-01

    Simple Summary We studied the defensive behaviour of 94 pairs of nesting Masked Lapwings, Vanellus miles, in response to two types of human stimuli: a pedestrian and a person pushing a lawn mower. We also examined the effectiveness of a commonly promoted deterrent to swooping (the presence of mock eyes placed on the back of a person’s head) for each stimulus type. Masked Lapwings responded more aggressively to a person pushing a lawn mower compared with pedestrians. Birds also remained closer to the nest in the presence of a lawn mower. The presence of eye stickers on the back of a pedestrian’s head decreased swooping behaviour; however, the presence of eye stickers worn by a person pushing a lawn mower increased swooping behaviour. Abstract Masked Lapwings, Vanellus miles, often come into ‘conflict’ with humans, because they often breed in close proximity to humans and actively defend their ground nests through aggressive behaviour, which typically involves swooping. This study examined whether defensive responses differed when nesting birds were confronted with different human stimuli (‘pedestrian alone’ vs. ‘person pushing a lawn mower’ approaches to nests) and tested the effectiveness of a commonly used deterrent (mock eyes positioned on the top or back of a person’s head) on the defensive response. Masked Lapwings did not swoop closer to a person with a lawn mower compared with a pedestrian, but flushed closer and remained closer to the nest in the presence of a lawn mower. The presence of eye stickers decreased (pedestrians) and increased (lawn mowers) swooping behaviour. Masked Lapwings can discriminate between different human activities and adjust their defensive behaviour accordingly. We also conclude that the use of eye stickers is an effective method to mitigate the human-lapwing ‘conflict’ in some, but not all, circumstances. PMID:26479532

  10. Primary cultures of human colon cancer as a model to study cancer stem cells.

    PubMed

    Koshkin, Sergey; Danilova, Anna; Raskin, Grigory; Petrov, Nikolai; Bajenova, Olga; O'Brien, Stephen J; Tomilin, Alexey; Tolkunova, Elena

    2016-09-01

    The principal cause of death in cancer involves tumor progression and metastasis. Since only a small proportion of the primary tumor cells, cancer stem cells (CSCs), which are the most aggressive, have the capacity to metastasize and display properties of stem cells, it is imperative to characterize the gene expression of diagnostic markers and to evaluate the drug sensitivity in the CSCs themselves. Here, we have examined the key genes that are involved in the progression of colorectal cancer and are expressed in cancer stem cells. Primary cultures of colorectal cancer cells from a patient's tumors were studied using the flow cytometry and cytological methods. We have evaluated the clinical and stem cell marker expression in these cells, their resistance to 5-fluorouracil and irinotecan, and the ability of cells to form tumors in mice. The data shows the role of stem cell marker Oct4 in the resistance of primary colorectal cancer tumor cells to 5-fluorouracil.

  11. DBGC: A Database of Human Gastric Cancer

    PubMed Central

    Wang, Chao; Zhang, Jun; Cai, Mingdeng; Zhu, Zhenggang; Gu, Wenjie; Yu, Yingyan; Zhang, Xiaoyan

    2015-01-01

    The Database of Human Gastric Cancer (DBGC) is a comprehensive database that integrates various human gastric cancer-related data resources. Human gastric cancer-related transcriptomics projects, proteomics projects, mutations, biomarkers and drug-sensitive genes from different sources were collected and unified in this database. Moreover, epidemiological statistics of gastric cancer patients in China and clinicopathological information annotated with gastric cancer cases were also integrated into the DBGC. We believe that this database will greatly facilitate research regarding human gastric cancer in many fields. DBGC is freely available at http://bminfor.tongji.edu.cn/dbgc/index.do PMID:26566288

  12. Association between body condition score and cancer prognosis in dogs with lymphoma and osteosarcoma

    USDA-ARS?s Scientific Manuscript database

    Background: In humans and rodents obesity appears to promote some cancers by increasing incidence, tumor aggressiveness, recurrence, and mortality. However, the relationship between obesity and cancer in dogs has not been thoroughly evaluated. Hypothesis/Objectives: We examined whether body conditio...

  13. Benzodiazepine use and aggressive behaviour: a systematic review.

    PubMed

    Albrecht, Bonnie; Staiger, Petra K; Hall, Kate; Miller, Peter; Best, David; Lubman, Dan I

    2014-12-01

    The relationship between benzodiazepine consumption and subsequent increases in aggressive behaviour in humans is not well understood. The current study aimed to identify, via a systematic review, whether there is an association between benzodiazepine consumption and aggressive responding in adults. A systematic review was conducted and reported in line with the PRISMA statement. English articles within MEDLINE, PsycARTICLES, PsycINFO, Academic Search Complete, and Psychology and Behavioural Sciences Collection databases were searched. Additional studies were identified by searching reference lists of reviewed articles. Only articles that explicitly investigated the relationship between benzodiazepine consumption and subsequent aggressive behaviour, or a lack thereof, in human adults were included. Forty-six studies met the inclusion criteria. It was not possible to conduct a meta-analysis due to the heterogeneity of study design and benzodiazepine type and dose. An association between benzodiazepine use and subsequent aggressive behaviour was found in the majority of the more rigorous studies, although there is a paucity of high-quality research with clinical or forensic populations. Diazepam and alprazolam have received the most attention. Dose-related findings are inconsistent: therapeutic doses may be more likely to be associated with aggressive responding when administered as a once-off, whereas higher doses may be more risky following repeated administration. Trait levels of anxiety and hostility may indicate a vulnerability to the experience of benzodiazepine-related aggression. There appears to be a moderate association between some benzodiazepines and subsequent aggressive behaviour in humans. The circumstances under which aggressive responding may be more likely to follow benzodiazepine use remain unclear, although some evidence suggests dose and/or personality factors may influence this effect. © The Royal Australian and New Zealand College of

  14. Targeted Vaccination against Human α-Lactalbumin for Immunotherapy and Primary Immunoprevention of Triple Negative Breast Cancer

    PubMed Central

    Tuohy, Vincent K.; Jaini, Ritika; Johnson, Justin M.; Loya, Matthew G.; Wilk, Dennis; Downs-Kelly, Erinn; Mazumder, Suparna

    2016-01-01

    We have proposed that safe and effective protection against the development of adult onset cancers may be achieved by vaccination against tissue-specific self-proteins that are “retired” from expression at immunogenic levels in normal tissues as we age, but are overexpressed in emerging tumors. α-Lactalbumin is an example of a “retired” self-protein because its expression in normal tissues is confined exclusively to the breast during late pregnancy and lactation, but is also expressed in the vast majority of human triple negative breast cancers (TNBC)—the most aggressive and lethal form of breast cancer and the predominant form that occurs in women at high genetic risk including those with mutated BRCA1 genes. In anticipation of upcoming clinical trials, here we provide preclinical data indicating that α-lactalbumin has the potential as a vaccine target for inducing safe and effective primary immunoprevention as well as immunotherapy against TNBC. PMID:27322324

  15. Human Viruses and Cancer

    PubMed Central

    Morales-Sánchez, Abigail; Fuentes-Pananá, Ezequiel M.

    2014-01-01

    The first human tumor virus was discovered in the middle of the last century by Anthony Epstein, Bert Achong and Yvonne Barr in African pediatric patients with Burkitt’s lymphoma. To date, seven viruses -EBV, KSHV, high-risk HPV, MCPV, HBV, HCV and HTLV1- have been consistently linked to different types of human cancer, and infections are estimated to account for up to 20% of all cancer cases worldwide. Viral oncogenic mechanisms generally include: generation of genomic instability, increase in the rate of cell proliferation, resistance to apoptosis, alterations in DNA repair mechanisms and cell polarity changes, which often coexist with evasion mechanisms of the antiviral immune response. Viral agents also indirectly contribute to the development of cancer mainly through immunosuppression or chronic inflammation, but also through chronic antigenic stimulation. There is also evidence that viruses can modulate the malignant properties of an established tumor. In the present work, causation criteria for viruses and cancer will be described, as well as the viral agents that comply with these criteria in human tumors, their epidemiological and biological characteristics, the molecular mechanisms by which they induce cellular transformation and their associated cancers. PMID:25341666

  16. Asthma status is associated with decreased risk of aggressive urothelial bladder cancer.

    PubMed

    Rava, Marta; Czachorowski, Maciej J; Silverman, Debra; Márquez, Mirari; Kishore, Sirish; Tardón, Adonina; Serra, Consol; García-Closas, Montse; Garcia-Closas, Reina; Carrato, Alfredo; Rothman, Nathaniel; Real, Francisco X; Kogevinas, Manolis; Malats, Núria

    2018-02-01

    Previous studies suggested an association between atopic conditions and specific cancers. The results on the association with urothelial bladder cancer (UBC) are scarce and inconsistent. To evaluate the association between asthma and risk of UBC, we considered 936 cases and 1,022 controls from the Spanish Bladder Cancer/EPICURO Study (86% males, mean age 65.4 years), a multicenter and hospital-based case-control study conducted during 1998-2001. Participants were asked whether they had asthma and detailed information about occupational exposures, smoking habits, dietary factors, medical conditions and history of medication was collected through face-to-face questionnaires performed by trained interviewers. Since asthma and UBC might share risk factors, association between patients' characteristics and asthma was studied in UBC controls. Association between UBC and asthma was assessed using logistic regression unadjusted and adjusted for potential confounders. The complex interrelationships, direct and mediating effect of asthma on UBC, were appraised using counterfactual mediation models. Asthma was associated with a reduced risk of UBC (odds ratio (OR) = 0.54, 95% confidence interval (CI) 0.37, 0.79) after adjusting for a wide range of confounders. No mediating effect was identified. The reduced risk associated with asthma was restricted to patients with high-risk non-muscle invasive (OR = 0.25, 95%CI 0.10, 0.62) and muscle invasive UBC (OR = 0.32, 95%CI 0.15, 0.69). Our results support that asthma is associated with a decreased risk of UBC, especially among aggressive tumors. Further work on the relationship between asthma and other atopic conditions and cancer risk should shed light on the relationship between immune response mechanisms and bladder carcinogenesis. © 2017 UICC.

  17. A theoretical framework for antigay aggression: Review of established and hypothesized effects within the context of the general aggression model⋆

    PubMed Central

    Parrott, Dominic J.

    2008-01-01

    Theory and research on antigay aggression has identified different motives that facilitate aggression based on sexual orientation. However, the individual and situational determinants of antigay aggression associated with these motivations have yet to be organized within a single theoretical framework. This limits researchers’ ability to organize existing knowledge, link that knowledge with related aggression theory, and guide the application of new findings. To address these limitations, this article argues for the use of an existing conceptual framework to guide thinking and generate new research in this area of study. Contemporary theories of antigay aggression, and empirical support for these theories, are reviewed and interpreted within the unifying framework of the general aggression model [Anderson, C.A. & Bushman, B.J. (2002). Human aggression. Annual Review of Psychology, 53, 27–51.]. It is concluded that this conceptual framework will facilitate investigation of individual and situational risk factors that may contribute to antigay aggression and guide development of individual-level intervention. PMID:18355952

  18. Prostate cancer staging

    MedlinePlus

    ... test. A faster increase could show a more aggressive tumor. A prostate biopsy is done in your ... suggest the cancer is slow growing and not aggressive. Higher numbers indicate a faster growing cancer that ...

  19. SSeCKS/AKAP12 induces repulsion between human prostate cancer and microvessel endothelial cells through the activation of Semaphorin 3F.

    PubMed

    Xie, Wen; Su, Wei; Zhang, Lijuan; Shang, Qingkun; Su, Bing

    2017-09-02

    Metastasis remains the primary cause of prostate cancer related death. Cancer cells need to contact endothelial cells and disrupt endothelial junctions to cross the endothelium for invasion and metastasis. The suppression of heterotypic repulsion between cancer and endothelial cells allows cancer cells to invade into the surrounding tissue. Here, we demonstrate that SSeCKS/AKAP12 induced repulsion between human prostate cancer and microvessel endothelial cells, which was mediated by an angiogenesis inhibitor Semaphorin 3F. Moreover, we examined AKAP12 and Semaphorin 3F mRNA expression in 42 prostate cancer and 30 benign prostatic hyperplasia tissue samples, and found that the expression of AKAP12 and Semaphorin 3F mRNA was inversely associated with the degree of aggressiveness of prostate cancer cells and tissues. An ordinal logistic regression analysis indicates that there is a positive association between the expression of AKAP12 and Semaphorin 3F in prostate cancer, suggesting that the activation of Semaphorin 3F by SSeCKS/AKAP12 may be involved in prostate cancer progression and metastasis. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Early-life experience affects honey bee aggression and resilience to immune challenge

    PubMed Central

    Rittschof, Clare C.; Coombs, Chelsey B.; Frazier, Maryann; Grozinger, Christina M.; Robinson, Gene E.

    2015-01-01

    Early-life social experiences cause lasting changes in behavior and health for a variety of animals including humans, but it is not well understood how social information ‘‘gets under the skin’’ resulting in these effects. Adult honey bees (Apis mellifera) exhibit socially coordinated collective nest defense, providing a model for social modulation of aggressive behavior. Here we report for the first time that a honey bee’s early-life social environment has lasting effects on individual aggression: bees that experienced high-aggression environments during pre-adult stages showed increased aggression when they reached adulthood relative to siblings that experienced low-aggression environments, even though all bees were kept in a common environment during adulthood. Unlike other animals including humans however, high-aggression honey bees were more, rather than less, resilient to immune challenge, assessed as neonicotinoid pesticide susceptibility. Moreover, aggression was negatively correlated with ectoparasitic mite presence. In honey bees, early-life social experience has broad effects, but increased aggression is decoupled from negative health outcomes. Because honey bees and humans share aspects of their physiological response to aggressive social encounters, our findings represent a step towards identifying ways to improve individual resiliency. Pre-adult social experience may be crucial to the health of the ecologically threatened honey bee. PMID:26493190

  1. Genetic polymorphism and prostate cancer aggressiveness: a case-only study of 1,536 GWAS and candidate SNPs in African-Americans and European-Americans.

    PubMed

    Bensen, Jeannette T; Xu, Zongli; Smith, Gary J; Mohler, James L; Fontham, Elizabeth T H; Taylor, Jack A

    2013-01-01

    Genome-wide association studies have established a number of replicated single nucleotide polymorphisms (SNPs) for susceptibility to prostate cancer (CaP), but it is unclear whether these susceptibility SNPs are also associated with disease aggressiveness. This study evaluates whether such replication SNPs or other candidate SNPs are associated with CaP aggressiveness in African-American (AA) and European-American (EA) men. A 1,536 SNP panel which included 34 genome-wide association study (GWAS) replication SNPs, 38 flanking SNPs, a set of ancestry informative markers, and SNPs in candidate genes and other areas was genotyped in 1,060 AA and 1,087 EA men with incident CaP from the North Carolina-Louisiana Prostate Cancer Project (PCaP). Tests for association were conducted using ordinal logistic regression with a log-additive genotype model and a 3-category CaP aggressiveness variable. Four GWAS replication SNPs (rs2660753, rs13254738, rs10090154, rs2735839) and seven flanking SNPs were associated with CaP aggressiveness (P < 0.05) in three genomic regions: One at 3p12 (EA), seven at 8q24 (5 AA, 2 EA), and three at 19q13 at the kallilkrein-related peptidase 3 (KLK3) locus (two AA, one AA and EA). The KLK3 SNPs also were associated with serum prostate-specific antigen (PSA) levels in AA (P < 0.001) but not in EA. A number of the other SNPs showed some evidence of association but none met study-wide significance levels after adjusting for multiple comparisons. Some replicated GWAS susceptibility SNPs may play a role in CaP aggressiveness. However, like susceptibility, these associations are not consistent between racial groups. Copyright © 2012 Wiley Periodicals, Inc.

  2. Phospholipase PLA2G7, associated with aggressive prostate cancer, promotes prostate cancer cell migration and invasion and is inhibited by statins

    PubMed Central

    Vainio, Paula; Lehtinen, Laura; Mirtti, Tuomas; Hilvo, Mika; Seppänen-Laakso, Tuulikki; Virtanen, Johannes; Sankila, Anna; Nordling, Stig; Lundin, Johan; Rannikko, Antti; Orešič, Matej; Kallioniemi, Olli; Iljin, Kristiina

    2011-01-01

    Prostate cancer is the second leading cause of cancer mortality in men in developed countries. Due to the heterogeneous nature of the disease, design of novel personalized treatments is required to achieve efficient therapeutic responses. We have recently identified phospholipase 2 group VII (PLA2G7) as a potential drug target especially in ERG oncogene positive prostate cancers. Here, the expression profile of PLA2G7 was studied in 1137 prostate cancer and 409 adjacent non-malignant prostate tissues using immunohistochemistry to validate its biomarker potential and putative association with disease progression. In order to reveal the molecular alterations induced by PLA2G7 impairment, lipidomic and gene expression profiling was performed in response to PLA2G7 silencing in cultured prostate cancer cells. Moreover, the antineoplastic effect of statins combined with PLA2G7 impairment was studied in prostate cancer cells to evaluate the potential of repositioning of in vivo compatible drugs developed for other indications towards anti-cancer purposes. The results indicated that PLA2G7 is a cancer-selective biomarker in 50% of prostate cancers and associates with aggressive disease. The alterations induced by PLA2G7 silencing highlighted the potential of PLA2G7 inhibition as an anti-proliferative, pro-apoptotic and anti-migratorial therapeutic approach in prostate cancer. Moreover, the anti-proliferative effect of PLA2G7 silencing was potentiated by lipid-lowering statins in prostate cancer cells. Taken together, our results support the potential of PLA2G7 as a biomarker and a drug target in prostate cancer and present a rationale for combining PLA2G7 inhibition with the use of statins in prostate cancer management. PMID:22202492

  3. Calcium Sensor, NCS-1, Promotes Tumor Aggressiveness and Predicts Patient Survival.

    PubMed

    Moore, Lauren M; England, Allison; Ehrlich, Barbara E; Rimm, David L

    2017-07-01

    Neuronal Calcium Sensor 1 (NCS-1) is a multi-functional Ca 2+ -binding protein that affects a range of cellular processes beyond those related to neurons. Functional characterization of NCS-1 in neuronal model systems suggests that NCS-1 may influence oncogenic processes. To this end, the biological role of NCS-1 was investigated by altering its endogenous expression in MCF-7 and MB-231 breast cancer cells. Overexpression of NCS-1 resulted in a more aggressive tumor phenotype demonstrated by a marked increase in invasion and motility, and a decrease in cell-matrix adhesion to collagen IV. Overexpression of NCS-1 was also shown to increase the efficacy of paclitaxel-induced cell death in a manner that was independent of cellular proliferation. To determine the association between NCS-1 and clinical outcome, NCS-1 expression was measured in two independent breast cancer cohorts by the Automated Quantitative Analysis method of quantitative immunofluorescence. Elevated levels of NCS-1 were significantly correlated with shorter survival rates. Furthermore, multivariate analysis demonstrated that NCS-1 status was prognostic, independent of estrogen receptor, progesterone receptor, HER2, and lymph node status. These findings indicate that NCS-1 plays a role in the aggressive behavior of a subset of breast cancers and has therapeutic or biomarker potential. Implications: NCS-1, a calcium-binding protein, is associated with clinicopathologic features of aggressiveness in breast cancer cells and worse outcome in two breast cancer patient cohorts. Mol Cancer Res; 15(7); 942-52. ©2017 AACR . ©2017 American Association for Cancer Research.

  4. Economic Analysis of Neoadjuvant Chemotherapy Versus Primary Debulking Surgery for Advanced Epithelial Ovarian Cancer Using an Aggressive Surgical Paradigm.

    PubMed

    Cole, Ashley L; Barber, Emma L; Gogate, Anagha; Tran, Arthur-Quan; Wheeler, Stephanie B

    2018-04-21

    Neoadjuvant chemotherapy (NACT) versus primary debulking surgery (PDS) for advanced epithelial ovarian cancer (AEOC) remains controversial in the United States. Generalizability of existing trial results has been criticized because of less aggressive debulking procedures than commonly used in the United States. As a result, economic evaluations using input data from these trials may not accurately reflect costs and outcomes associated with more aggressive primary surgery. Using data from an ongoing trial performing aggressive debulking, we investigated the cost-effectiveness and cost-utility of NACT versus PDS for AEOC. A decision tree model was constructed to estimate differences in short-term outcomes and costs for a hypothetical cohort of 15,000 AEOC patients (US annual incidence of AEOC) treated with NACT versus PDS over a 1-year time horizon from a Medicare payer perspective. Outcomes included costs per cancer-related death averted, life-years and quality-adjusted life-years (QALYs) gained. Base-case probabilities, costs, and utilities were based on the Surgical Complications Related to Primary or Interval Debulking in Ovarian Neoplasms trial. Base-case analyses assumed equivalent survival; threshold analysis estimated the maximum survival difference that would result in NACT being cost-effective at $50,000/QALY and $100,000/QALY willingness-to-pay thresholds. Probabilistic sensitivity analysis was used to characterize model uncertainty. Compared with PDS, NACT was associated with $142 million in cost savings, 1098 fewer cancer-related deaths, and 1355 life-years and 1715 QALYs gained, making it the dominant treatment strategy for all outcomes. In sensitivity analysis, NACT remained dominant in 99.3% of simulations. Neoadjuvant chemotherapy remained cost-effective at $50,000/QALY and $100,000/QALY willingness-to-pay thresholds if survival differences were less than 2.7 and 1.4 months, respectively. In the short term, NACT is cost-saving with improved outcomes

  5. Reprogramming of human cancer cells to pluripotency for models of cancer progression

    PubMed Central

    Kim, Jungsun; Zaret, Kenneth S

    2015-01-01

    The ability to study live cells as they progress through the stages of cancer provides the opportunity to discover dynamic networks underlying pathology, markers of early stages, and ways to assess therapeutics. Genetically engineered animal models of cancer, where it is possible to study the consequences of temporal-specific induction of oncogenes or deletion of tumor suppressors, have yielded major insights into cancer progression. Yet differences exist between animal and human cancers, such as in markers of progression and response to therapeutics. Thus, there is a need for human cell models of cancer progression. Most human cell models of cancer are based on tumor cell lines and xenografts of primary tumor cells that resemble the advanced tumor state, from which the cells were derived, and thus do not recapitulate disease progression. Yet a subset of cancer types have been reprogrammed to pluripotency or near-pluripotency by blastocyst injection, by somatic cell nuclear transfer and by induced pluripotent stem cell (iPS) technology. The reprogrammed cancer cells show that pluripotency can transiently dominate over the cancer phenotype. Diverse studies show that reprogrammed cancer cells can, in some cases, exhibit early-stage phenotypes reflective of only partial expression of the cancer genome. In one case, reprogrammed human pancreatic cancer cells have been shown to recapitulate stages of cancer progression, from early to late stages, thus providing a model for studying pancreatic cancer development in human cells where previously such could only be discerned from mouse models. We discuss these findings, the challenges in developing such models and their current limitations, and ways that iPS reprogramming may be enhanced to develop human cell models of cancer progression. PMID:25712212

  6. Perceived aggressiveness predicts fighting performance in mixed-martial-arts fighters.

    PubMed

    Trebicky, Vít; Havlícek, Jan; Roberts, S Craig; Little, Anthony C; Kleisner, Karel

    2013-09-01

    Accurate assessment of competitive ability is a critical component of contest behavior in animals, and it could be just as important in human competition, particularly in human ancestral populations. Here, we tested the role that facial perception plays in this assessment by investigating the association between both perceived aggressiveness and perceived fighting ability in fighters' faces and their actual fighting success. Perceived aggressiveness was positively associated with the proportion of fights won, after we controlled for the effect of weight, which also independently predicted perceived aggression. In contrast, perception of fighting ability was confounded by weight, and an association between perceived fighting ability and actual fighting success was restricted to heavyweight fighters. Shape regressions revealed that aggressive-looking faces are generally wider and have a broader chin, more prominent eyebrows, and a larger nose than less aggressive-looking faces. Our results indicate that perception of aggressiveness and fighting ability might cue different aspects of success in male-male physical confrontation.

  7. Impact of cachexia on outcomes in aggressive lymphomas.

    PubMed

    Karmali, Reem; Alrifai, Taha; Fughhi, Ibtihaj A M; Ng, Ronald; Chukkapalli, Vineela; Shah, Palmi; Basu, Sanjib; Nathan, Sunita; Szymanski-Grant, Kelly; Gordon, Leo I; Venugopal, Parameswaran; Penedo, Frank J; Borgia, Jeffrey A

    2017-06-01

    Cancer cachexia is defined as a state of involuntary weight loss, attributed to altered body composition with muscle mass loss and/or loss of adiposity. Identifying the association between cancer cachexia and outcomes may pave the way for novel agents that target the cancer cachexia process. Clinical parameters for measurement of cancer cachexia are needed. We conducted a single-institution retrospective analysis that included 86 NHL patients with the aim of identifying an association between cancer cachexia and outcomes in aggressive lymphomas using the cachexia index (CXI) suggested by Jafri et al. (Clin Med Insights Oncol 9:87-93, 15). Impact of cachexia factors on progression-free survival (PFS) and overall survival (OS) were assessed using log-rank test and Cox proportional hazards regression. Patients were dichotomized around the median CXI into "non-cachectic" (CXI ≥49.8, n = 41) and "cachectic" (CXI <49.8, n = 40) groups. Cachectic patients had significantly worse PFS (HR 2.18, p = 0.044) and OS (HR = 4.05, p = 0.004) than non-cachectic patients. Cachexia as defined by the CXI is prognostic in aggressive lymphomas and implies that novel therapeutic strategies directed at reversing cachexia may improve survival in this population.

  8. Cyclical thrombocytosis, acquired von Willebrand syndrome and aggressive non-melanoma skin cancers are common in patients with Philadelphia-negative myeloproliferative neoplasms treated with hydroxyurea.

    PubMed

    Verner, Emma; Forsyth, Cecily; Grigg, Andrew

    2014-05-01

    Abstract Cyclical thrombocytosis, acquired von Willebrand syndrome, aggressive non-melanoma skin cancers and other hydroxyurea complications have been reported in Philadelphia-negative myeloproliferative neoplasms (MPNs), but their incidence and clinical consequences have not been defined in a large cohort of patients. We conducted a retrospective analysis of 188 consecutive patients with MPNs specifically addressing the incidence of these complications. Cyclical thrombocytosis was documented in 29 patients (15%), the majority of whom were receiving hydroxyurea. Acquired von Willebrand syndrome was identified in 17 of the 84 screened patients (20%), but was not associated with any major bleeding complications. Non-melanoma skin cancers were reported in 51 patients (27%). Hydroxyurea-related fever occurred in nine of 149 patients (6%) who received hydroxyurea. Seventy-three patients (39%) experienced a total of 98 major thrombotic events, with the majority of these occurring prior to or within 3 months of the diagnosis. Cyclical thrombocytosis, acquired von Willebrand syndrome, aggressive non-melanoma skin cancers and other hydroxyurea-related complications are not infrequent in MPNs and have important clinical consequences for management.

  9. Neural and Behavioral Correlates of Alcohol-Induced Aggression Under Provocation

    PubMed Central

    Gan, Gabriela; Sterzer, Philipp; Marxen, Michael; Zimmermann, Ulrich S; Smolka, Michael N

    2015-01-01

    Although alcohol consumption is linked to increased aggression, its neural correlates have not directly been studied in humans so far. Based on a comprehensive neurobiological model of alcohol-induced aggression, we hypothesized that alcohol-induced aggression would go along with increased amygdala and ventral striatum reactivity and impaired functioning of the prefrontal cortex (PFC) under alcohol. We measured neural and behavioral correlates of alcohol-induced aggression in a provoking vs non-provoking condition with a variant of the Taylor aggression paradigm (TAP) allowing to differentiate between reactive (provoked) and proactive (unprovoked) aggression. In a placebo-controlled cross-over design with moderate alcohol intoxication (~0.6 g/kg), 35 young healthy adults performed the TAP during functional magnetic resonance imaging (fMRI). Analyses revealed that provoking vs non-provoking conditions and alcohol vs placebo increased aggression and decreased brain responses in the anterior cingulate cortex/dorso-medial PFC (provokingaggression (alcohol × provocation interaction). However, investigation of inter-individual differences revealed (1) that pronounced alcohol-induced proactive aggression was linked to higher levels of aggression under placebo, and (2) that pronounced alcohol-induced reactive aggression was related to increased amygdala and ventral striatum reactivity under alcohol, providing evidence for their role in human alcohol-induced reactive aggression. Our findings suggest that in healthy young adults a liability for alcohol-induced aggression in a non-provoking context might depend on overall high levels of aggression, but on alcohol-induced increased striatal and amygdala reactivity when triggered by provocation. PMID:25971590

  10. Hypoxia-induced carbonic anhydrase IX facilitates lactate flux in human breast cancer cells by non-catalytic function.

    PubMed

    Jamali, Somayeh; Klier, Michael; Ames, Samantha; Barros, L Felipe; McKenna, Robert; Deitmer, Joachim W; Becker, Holger M

    2015-09-04

    The most aggressive tumour cells, which often reside in hypoxic environments, rely on glycolysis for energy production. Thereby they release vast amounts of lactate and protons via monocarboxylate transporters (MCTs), which exacerbates extracellular acidification and supports the formation of a hostile environment. We have studied the mechanisms of regulated lactate transport in MCF-7 human breast cancer cells. Under hypoxia, expression of MCT1 and MCT4 remained unchanged, while expression of carbonic anhydrase IX (CAIX) was greatly enhanced. Our results show that CAIX augments MCT1 transport activity by a non-catalytic interaction. Mutation studies in Xenopus oocytes indicate that CAIX, via its intramolecular H(+)-shuttle His200, functions as a "proton-collecting/distributing antenna" to facilitate rapid lactate flux via MCT1. Knockdown of CAIX significantly reduced proliferation of cancer cells, suggesting that rapid efflux of lactate and H(+), as enhanced by CAIX, contributes to cancer cell survival under hypoxic conditions.

  11. Hypoxia-induced carbonic anhydrase IX facilitates lactate flux in human breast cancer cells by non-catalytic function

    PubMed Central

    Jamali, Somayeh; Klier, Michael; Ames, Samantha; Felipe Barros, L.; McKenna, Robert; Deitmer, Joachim W.; Becker, Holger M.

    2015-01-01

    The most aggressive tumour cells, which often reside in hypoxic environments, rely on glycolysis for energy production. Thereby they release vast amounts of lactate and protons via monocarboxylate transporters (MCTs), which exacerbates extracellular acidification and supports the formation of a hostile environment. We have studied the mechanisms of regulated lactate transport in MCF-7 human breast cancer cells. Under hypoxia, expression of MCT1 and MCT4 remained unchanged, while expression of carbonic anhydrase IX (CAIX) was greatly enhanced. Our results show that CAIX augments MCT1 transport activity by a non-catalytic interaction. Mutation studies in Xenopus oocytes indicate that CAIX, via its intramolecular H+-shuttle His200, functions as a “proton-collecting/distributing antenna” to facilitate rapid lactate flux via MCT1. Knockdown of CAIX significantly reduced proliferation of cancer cells, suggesting that rapid efflux of lactate and H+, as enhanced by CAIX, contributes to cancer cell survival under hypoxic conditions. PMID:26337752

  12. Aloe-emodin inhibits HER-2 expression through the downregulation of Y-box binding protein-1 in HER-2-overexpressing human breast cancer cells.

    PubMed

    Ma, Jui-Wen; Hung, Chao-Ming; Lin, Ying-Chao; Ho, Chi-Tang; Kao, Jung-Yie; Way, Tzong-Der

    2016-09-13

    Human epidermal growth factor receptor-2 (HER-2)-positive breast cancer tends to be aggressive, highly metastatic, and drug resistant and spreads rapidly. Studies have indicated that emodin inhibits HER-2 expression. This study compared the HER-2-inhibitory effects of two compounds extracted from rhubarb roots: aloe-emodin (AE) and rhein. Our results indicated that AE exerted the most potent inhibitory effect on HER-2 expression. Treatment of HER-2-overexpressing breast cancer cells with AE reduced tumor initiation, cell migration, and cell invasion. AE was able to suppress YB-1 expression, further suppressing downstream HER-2 expression. AE suppressed YB-1 expression through the inhibition of Twist in HER-2-overexpressing breast cancer cells. Our data also found that AE inhibited cancer metastasis and cancer stem cells through the inhibition of EMT. Interestingly, AE suppressed YB-1 expression through the downregulation of the intracellular integrin-linked kinase (ILK)/protein kinase B (Akt)/mTOR signaling pathway in HER-2-overexpressing breast cancer cells. In vivo study showed the positive result of antitumor activity of AE in nude mice injected with human HER-2-overexpressing breast cancer cells. These findings suggest the possible application of AE in the treatment of HER-2-positive breast cancer.

  13. Downregulation of the Sonic Hedgehog/Gli pathway transcriptional target Neogenin-1 is associated with basal cell carcinoma aggressiveness.

    PubMed

    Casas, Bárbara S; Adolphe, Christelle; Lois, Pablo; Navarrete, Nelson; Solís, Natalia; Bustamante, Eva; Gac, Patricio; Cabané, Patricio; Gallegos, Ivan; Wainwright, Brandon J; Palma, Verónica

    2017-10-13

    Basal Cell Carcinoma (BCC) is one of the most diagnosed cancers worldwide. It develops due to an unrestrained Sonic Hedgehog (SHH) signaling activity in basal cells of the skin. Certain subtypes of BCC are more aggressive than others, although the molecular basis of this phenomenon remains unknown. We have previously reported that Neogenin-1 (NEO1) is a downstream target gene of the SHH/GLI pathway in neural tissue. Given that SHH participates in epidermal homeostasis, here we analyzed the epidermal expression of NEO1 in order to identify whether it plays a role in adult epidermis or BCC. We describe the mRNA and protein expression profile of NEO1 and its ligands (Netrin-1 and RGMA) in human and mouse control epidermis and in a broad range of human BCCs. We identify in human BCC a significant positive correlation in the levels of NEO1 receptor, NTN-1 and RGMA ligands with respect to GLI1 , the main target gene of the canonical SHH pathway. Moreover, we show via cyclopamine inhibition of the SHH/GLI pathway of ex vivo cultures that NEO1 likely functions as a downstream target of SHH/GLI signaling in the skin. We also show how Neo1 expression decreases throughout BCC progression in the K14-Cre:Ptch1 lox/lox mouse model and that aggressive subtypes of human BCC exhibit lower levels of NEO1 than non-aggressive BCC samples. Taken together, these data suggest that NEO1 is a SHH/GLI target in epidermis. We propose that NEO1 may be important in tumor onset and is then down-regulated in advanced BCC or aggressive subtypes.

  14. Downregulation of the Sonic Hedgehog/Gli pathway transcriptional target Neogenin-1 is associated with basal cell carcinoma aggressiveness

    PubMed Central

    Casas, Bárbara S.; Adolphe, Christelle; Lois, Pablo; Navarrete, Nelson; Solís, Natalia; Bustamante, Eva; Gac, Patricio; Cabané, Patricio; Gallegos, Ivan; Wainwright, Brandon J.; Palma, Verónica

    2017-01-01

    Basal Cell Carcinoma (BCC) is one of the most diagnosed cancers worldwide. It develops due to an unrestrained Sonic Hedgehog (SHH) signaling activity in basal cells of the skin. Certain subtypes of BCC are more aggressive than others, although the molecular basis of this phenomenon remains unknown. We have previously reported that Neogenin-1 (NEO1) is a downstream target gene of the SHH/GLI pathway in neural tissue. Given that SHH participates in epidermal homeostasis, here we analyzed the epidermal expression of NEO1 in order to identify whether it plays a role in adult epidermis or BCC. We describe the mRNA and protein expression profile of NEO1 and its ligands (Netrin-1 and RGMA) in human and mouse control epidermis and in a broad range of human BCCs. We identify in human BCC a significant positive correlation in the levels of NEO1 receptor, NTN-1 and RGMA ligands with respect to GLI1, the main target gene of the canonical SHH pathway. Moreover, we show via cyclopamine inhibition of the SHH/GLI pathway of ex vivo cultures that NEO1 likely functions as a downstream target of SHH/GLI signaling in the skin. We also show how Neo1 expression decreases throughout BCC progression in the K14-Cre:Ptch1lox/lox mouse model and that aggressive subtypes of human BCC exhibit lower levels of NEO1 than non-aggressive BCC samples. Taken together, these data suggest that NEO1 is a SHH/GLI target in epidermis. We propose that NEO1 may be important in tumor onset and is then down-regulated in advanced BCC or aggressive subtypes. PMID:29137400

  15. Aggress to impress: hostility as an evolved context-dependent strategy.

    PubMed

    Griskevicius, Vladas; Tybur, Joshua M; Gangestad, Steven W; Perea, Elaine F; Shapiro, Jenessa R; Kenrick, Douglas T

    2009-05-01

    Given the high costs of aggression, why have people evolved to act aggressively? Comparative biologists have frequently observed links between aggression, status, and mating in nonhuman animals. In this series of experiments, the authors examined the effects of status, competition, and mating motives on men's and women's aggression. For men, status motives increased direct aggression (face-to-face confrontation). Men's aggression was also boosted by mating motives, but only when observers were other men. For women, both status and mating motives increased indirect aggression (e.g., socially excluding the perpetrator). Although neither status nor mating motives increased women's direct aggression, women did become more directly aggressive when motivated to compete for scarce resources. These context- and sex-specific effects on human aggression contribute to a broader understanding of the functional nature of aggressive behavior. Copyright (c) 2009 APA, all rights reserved.

  16. Human gastric cancer modelling using organoids.

    PubMed

    Seidlitz, Therese; Merker, Sebastian R; Rothe, Alexander; Zakrzewski, Falk; von Neubeck, Cläre; Grützmann, Konrad; Sommer, Ulrich; Schweitzer, Christine; Schölch, Sebastian; Uhlemann, Heike; Gaebler, Anne-Marlene; Werner, Kristin; Krause, Mechthild; Baretton, Gustavo B; Welsch, Thilo; Koo, Bon-Kyoung; Aust, Daniela E; Klink, Barbara; Weitz, Jürgen; Stange, Daniel E

    2018-04-27

    Gastric cancer is the second leading cause of cancer-related deaths and the fifth most common malignancy worldwide. In this study, human and mouse gastric cancer organoids were generated to model the disease and perform drug testing to delineate treatment strategies. Human gastric cancer organoid cultures were established, samples classified according to their molecular profile and their response to conventional chemotherapeutics tested. Targeted treatment was performed according to specific druggable mutations. Mouse gastric cancer organoid cultures were generated carrying molecular subtype-specific alterations. Twenty human gastric cancer organoid cultures were established and four selected for a comprehensive in-depth analysis. Organoids demonstrated divergent growth characteristics and morphologies. Immunohistochemistry showed similar characteristics to the corresponding primary tissue. A divergent response to 5-fluoruracil, oxaliplatin, irinotecan, epirubicin and docetaxel treatment was observed. Whole genome sequencing revealed a mutational spectrum that corresponded to the previously identified microsatellite instable, genomic stable and chromosomal instable subtypes of gastric cancer. The mutational landscape allowed targeted therapy with trastuzumab for ERBB2 alterations and palbociclib for CDKN2A loss. Mouse cancer organoids carrying Kras and Tp53 or Apc and Cdh1 mutations were characterised and serve as model system to study the signalling of induced pathways. We generated human and mouse gastric cancer organoids modelling typical characteristics and altered pathways of human gastric cancer. Successful interference with activated pathways demonstrates their potential usefulness as living biomarkers for therapy response testing. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  17. Activation of autophagy by stress-activated signals as a cellular self-defense mechanism against the cytotoxic effects of MBIC in human breast cancer cells in vitro.

    PubMed

    Hasanpourghadi, Mohadeseh; Majid, Nazia Abdul; Mustafa, Mohd Rais

    2018-06-01

    We recently reported that methyl 2-(-5-fluoro-2-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylate (MBIC) is a microtubule targeting agent (MTA) with multiple mechanisms of action including apoptosis in two human breast cancer cell-lines MCF-7 and MDA-MB-231. In the present study, investigation of early molecular events following MBIC treatment demonstrated the induction of autophagy. This early (<24 h) response to MBIC was characterized by accumulation of autophagy markers; LC3-II, Beclin1, autophagic proteins (ATGs) and collection of autophagosomes but with different variations in the two cell-lines. MBIC-induced autophagy was associated with generation of reactive oxygen species (ROS). In parallel, an increased activation of SAPK/JNK pathway was detected, as an intersection of ROS production and induction of autophagy. The cytotoxic effect of MBIC was enhanced by inhibition of autophagy through blockage of SAPK/JNK signaling, suggesting that MBIC-induced autophagy, is a possible cellular self-defense mechanism against toxicity of this agent in both breast cancer cell-lines. The present findings suggest that inhibition of autophagy eliminates the cytoprotective activity of MDA-MB-231 and MCF-7 cells, and sensitizes both the aggressive and non-aggressive human breast cancer cell-lines to the cytotoxic effects of MBIC. Copyright © 2018 Elsevier Inc. All rights reserved.

  18. Carotenoid Intake and Adipose Tissue Carotenoid Levels in Relation to Prostate Cancer Aggressiveness among African-American and European-American Men in the North Carolina-Louisiana Prostate Cancer Project (PCaP)

    PubMed Central

    Antwi, Samuel O.; Steck, Susan E.; Su, L. Joseph; Hebert, James R.; Zhang, Hongmei; Craft, Neal E.; Fontham, Elizabeth T. H.; Smith, Gary J.; Bensen, Jeannette T.; Mohler, James L.; Arab, Lenore

    2016-01-01

    Background Associations between carotenoid intake and prostate cancer (CaP) incidence have varied across studies. This may be due to combining indolent with aggressive disease in most studies. This study examined whether carotenoid intake and adipose tissue carotenoid levels were inversely associated with CaP aggressiveness. Methods Data on African-American (AA, n=1,023) and European-American (EA, n=1,079) men with incident CaP from North Carolina and Louisiana were analyzed. Dietary carotenoid intake was assessed using a detailed food frequency questionnaire, and abdominal adipose tissue samples were analyzed for carotenoid concentrations using high-performance liquid chromatography. Multivariable logistic regression was used in race-stratified analysis to calculate odds ratios (ORs) and 95% confidence intervals (95%CI) comparing high aggressive CaP with low/intermediate aggressive CaP. Results Carotenoid intake differed significantly between AAs and EAs, which included higher intake of lycopene among EAs and higher β–cryptoxanthin intake among AAs. Comparing the highest and lowest tertiles, dietary lycopene was associated inversely with high aggressive CaP among EAs (OR=0.55, 95%CI: 0.34–0.89, Ptrend=0.02), while an inverse association was observed between dietary β–cryptoxanthin intake and high aggressive CaP among AAs (OR=0.56, 95%CI: 0.36–0.87, Ptrend=0.01). Adipose tissue α–carotene and lycopene (cis + trans) concentrations were higher among EAs than AAs, and marginally significant inverse linear trends were observed for adipose α–carotene (Ptrend=0.07) and lycopene (Ptrend=0.11), and CaP aggressiveness among EAs only. Conclusions These results suggest that diets high in lycopene and β–cryptoxanthin may protect against aggressive CaP among EAs and AAs, respectively. Differences in dietary behaviors may explain the racial differences in associations. PMID:27271547

  19. Expression Profiling of Primary and Metastatic Ovarian Tumors Reveals Differences Indicative of Aggressive Disease

    PubMed Central

    Brodsky, Alexander S.; Fischer, Andrew; Miller, Daniel H.; Vang, Souriya; MacLaughlan, Shannon; Wu, Hsin-Ta; Yu, Jovian; Steinhoff, Margaret; Collins, Colin; Smith, Peter J. S.; Raphael, Benjamin J.; Brard, Laurent

    2014-01-01

    The behavior and genetics of serous epithelial ovarian cancer (EOC) metastasis, the form of the disease lethal to patients, is poorly understood. The unique properties of metastases are critical to understand to improve treatments of the disease that remains in patients after debulking surgery. We sought to identify the genetic and phenotypic landscape of metastatic progression of EOC to understand how metastases compare to primary tumors. DNA copy number and mRNA expression differences between matched primary human tumors and omental metastases, collected at the same time during debulking surgery before chemotherapy, were measured using microarrays. qPCR and immunohistochemistry validated findings. Pathway analysis of mRNA expression revealed metastatic cancer cells are more proliferative and less apoptotic than primary tumors, perhaps explaining the aggressive nature of these lesions. Most cases had copy number aberrations (CNAs) that differed between primary and metastatic tumors, but we did not detect CNAs that are recurrent across cases. A six gene expression signature distinguishes primary from metastatic tumors and predicts overall survival in independent datasets. The genetic differences between primary and metastatic tumors, yet common expression changes, suggest that the major clone in metastases is not the same as in primary tumors, but the cancer cells adapt to the omentum similarly. Together, these data highlight how ovarian tumors develop into a distinct, more aggressive metastatic state that should be considered for therapy development. PMID:24732363

  20. Review of the gut microbiome and esophageal cancer: Pathogenesis and potential clinical implications.

    PubMed

    Baba, Yoshifumi; Iwatsuki, Masaaki; Yoshida, Naoya; Watanabe, Masayuki; Baba, Hideo

    2017-06-01

    Esophageal cancer ranks among the most aggressive malignant diseases. The limited improvements in treatment outcomes provided by conventional therapies have prompted us to seek innovative strategies for treating this cancer. More than 100 trillion microorganisms inhabit the human intestinal tract and play a crucial role in health and disease conditions, including cancer. The human intestinal microbiome is thought to influence tumor development and progression in the gastrointestinal tract by various mechanisms. For example, Fusobacterium nucleatum , which primarily inhabits the oral cavity and causes periodontal disease, might contribute to aggressive tumor behavior through activation of chemokines such as CCL20 in esophageal cancer tissue. Composition of the intestinal microbiota is influenced by diet, lifestyle, antibiotics, and pro- and prebiotics. Therefore, by better understanding how the bacterial microbiota contributes to esophageal carcinogenesis, we might develop novel cancer prevention and treatment strategies through targeting the gastrointestinal microflora. This review discusses the current knowledge, available data and information on the relationship of microbiota with esophagitis, Barrett's esophagus, esophageal adenocarcinoma and squamous cell carcinoma.

  1. Dietary Pterostilbene is a novel MTA1-targeted chemopreventive and therapeutic agent in prostate cancer

    USDA-ARS?s Scientific Manuscript database

    Dietary nutrients with ability to reverse adverse epigenetic events have great potential for cancer chemoprevention. Overexpression of the epigenetic modifier metastasis-associated protein 1 (MTA1) is associated with aggressive human prostate cancer. The purpose of this study was to determine MTA1-d...

  2. Effects of Symbolic Modeling on Children's Interpersonal Aggression.

    ERIC Educational Resources Information Center

    Liebert, Robert M.; Baron, Robert A.

    Does exposure to symbolically modeled aggression (aggression in cartoons, movies, stories and simulated television programs) increase children's willingness to engage in behavior which might actually harm another human being? This paper presents a summary of three recent experiments offering affirmative answers to the question. A fourth experiment…

  3. Overexpression of Plasminogen Activator Inhibitor-1 in Advanced Gastric Cancer with Aggressive Lymph Node Metastasis

    PubMed Central

    Suh, Yun-Suhk; Yu, Jieun; Kim, Byung Chul; Choi, Boram; Han, Tae-Su; Ahn, Hye Seong; Kong, Seong-Ho; Lee, Hyuk-Joon; Kim, Woo Ho; Yang, Han-Kwang

    2015-01-01

    Purpose The purpose of this study is to investigate differentially expressed genes using DNA microarray between advanced gastric cancer (AGC) with aggressive lymph node (LN) metastasis and that with a more advanced tumor stage but without LN metastasis. Materials and Methods Five sample pairs of gastric cancer tissue and normal gastric mucosa were taken from three patients with T3N3 stage (highN) and two with T4N0 stage (lowN). Data from triplicate DNA microarray experiments were analyzed, and candidate genes were identified using a volcano plot that showed ≥ 2-fold differential expression and were significant by Welch's t test (p < 0.05) between highN and lowN. Those selected genes were validated independently by reverse-transcriptase–polymerase chain reaction (RT-PCR) using five AGC patients, and tissue-microarray (TMA) comprising 47 AGC patients. Results CFTR, LAMC2, SERPINE2, F2R, MMP7, FN1, TIMP1, plasminogen activator inhibitor-1 (PAI-1), ITGB8, SDS, and TMPRSS4 were commonly up-regulated over 2-fold in highN. REG3A, CD24, ITLN1, and WBP5 were commonly down-regulated over 2-fold in lowN. Among these genes, overexpression of PAI-1 was validated by RT-PCR, and TMA showed 16.7% (7/42) PAI-1 expression in T3N3, but none (0/5) in T4N0 (p=0.393). Conclusion DNA microarray analysis and validation by RT-PCR and TMA showed that overexpression of PAI-1 is related to aggressive LN metastasis in AGC. PMID:25687870

  4. Friendliness to humans and defensive aggression in cats: the influence of handling and paternity.

    PubMed

    Reisner, I R; Houpt, K A; Erb, H N; Quimby, F W

    1994-06-01

    This study was undertaken to examine and reduce the stress and aggressiveness associated with fear of handling in laboratory cats (Felis sylvestris catus). Thirteen litters of kittens from a specific pathogen-free breeding colony were divided into three treatment groups: two were early weaned, removed from the colony and caged individually with or without handling up to 8 weeks of age, and the third served as a control group, removed from the colony just before testing. Behavior tests measuring degree of friendliness to humans and response to physical restraint were performed at ages 8, 12, 16, and 20 weeks. Serum cortisol concentrations were measured after each test. Results indicate that litter and sire influenced tractability but that handling or individual caging of kittens did not. Posttest serum cortisol concentrations were below normal adult levels in most kittens, including those reacting fearfully during testing and aggressively during restraint, and, therefore, are not a reliable indicator of stress in juvenile cats.

  5. End-of-life chemotherapy is associated with poor survival and aggressive care in patients with small cell lung cancer.

    PubMed

    Zhu, Yingming; Tang, Ke; Zhao, Fen; Zang, Yuanwei; Wang, Xiaodong; Li, Zhenxiang; Sun, Xindong; Yu, Jinming

    2018-05-29

    Concerns regarding end-of-life (EOL) chemotherapy are being increasingly raised. Tumor chemosensitivity may influence the decision for aggressive chemotherapy near the EOL. Data on EOL chemotherapy in highly chemosensitive tumors, such as small cell lung cancer (SCLC), are scarce. A total of 143 SCLC decedents were consecutively included. Data about clinical factors and treatment modalities were obtained from the electronic medical records. The relationships among EOL chemotherapy, clinical features, overall survival (OS), and aggressive care were investigated. About 64% of patients had chemosensitive disease. In total, 30.8 and 16.1% of patients received EOL chemotherapy within the last 1 and 2 months of life, respectively. Younger age was associated with a higher rate of EOL chemotherapy. We determined that EOL chemotherapy was related to inferior OS not only in the entire group, but also in the chemosensitive subgroup. Furthermore, more intensive care was observed among patients who underwent EOL chemotherapy compared with those who did not. EOL chemotherapy was correlated with shorter survival and more aggressive care in patients with SCLC. More research is needed to develop indications for terminating palliative chemotherapy, to help physicians and patients with their difficult choices.

  6. Neural Correlates of Aggressive Behavior in Real Time: a Review of fMRI Studies of Laboratory Reactive Aggression

    PubMed Central

    Keedy, Sarah; Berman, Mitchell E.; Lee, Royce; Coccaro, Emil F.

    2017-01-01

    Purpose of review Aggressive behavior has adaptive value in many natural environments; however, it places substantial burden and costs on human society. For this reason, there has long been interest in understanding the neurobiological basis of aggression. This interest, and the flourishing of neuroimaging research in general, has spurred the development of a large and growing scientific literature on the topic. As a result, a neural circuit model of aggressive behavior has emerged that implicates interconnected brain regions that are involved in emotional reactivity, emotion regulation, and cognitive control. Recent findings Recently, behavioral paradigms that simulate provocative interactions have been adapted to neuroimaging protocols, providing an opportunity to directly probe the involvement of neural circuits in an aggressive interaction. Here we review neuroimaging studies of simulated aggressive interactions in research volunteers. We focus on studies that use a well-validated laboratory paradigm for reactive physical aggression and examine the neural correlates of provocation, retaliation, and evaluating punishment of an opponent. Summary Overall, the studies reviewed support the involvement of neural circuits that support emotional reactivity, emotion regulation, and cognitive control in aggressive behavior. Based on a synthesis of this literature, future research directions are discussed. PMID:29607288

  7. Red clothing increases perceived dominance, aggression and anger

    PubMed Central

    Wiedemann, Diana; Burt, D. Michael; Hill, Russell A.; Barton, Robert A.

    2015-01-01

    The presence and intensity of red coloration correlate with male dominance and testosterone in a variety of animal species, and even artificial red stimuli can influence dominance interactions. In humans, red stimuli are perceived as more threatening and dominant than other colours, and wearing red increases the probability of winning sporting contests. We investigated whether red clothing biases the perception of aggression and dominance outside of competitive settings, and whether red influences decoding of emotional expressions. Participants rated digitally manipulated images of men for aggression and dominance and categorized the emotional state of these stimuli. Men were rated as more aggressive and more dominant when presented in red than when presented in either blue or grey. The effect on perceived aggression was found for male and female raters, but only male raters were sensitive to red as a signal of dominance. In a categorization test, images were significantly more often categorized as ‘angry’ when presented in the red condition, demonstrating that colour stimuli affect perceptions of emotions. This suggests that the colour red may be a cue used to predict propensity for dominance and aggression in human males. PMID:25972401

  8. Reducing proactive aggression through non-invasive brain stimulation

    PubMed Central

    Schuhmann, Teresa; Lobbestael, Jill; Arntz, Arnoud; Brugman, Suzanne; Sack, Alexander T.

    2015-01-01

    Aggressive behavior poses a threat to human collaboration and social safety. It is of utmost importance to identify the functional mechanisms underlying aggression and to develop potential interventions capable of reducing dysfunctional aggressive behavior already at a brain level. We here experimentally shifted fronto-cortical asymmetry to manipulate the underlying motivational emotional states in both male and female participants while assessing the behavioral effects on proactive and reactive aggression. Thirty-two healthy volunteers received either anodal transcranial direct current stimulation to increase neural activity within right dorsolateral prefrontal cortex, or sham stimulation. Aggressive behavior was measured with the Taylor Aggression Paradigm. We revealed a general gender effect, showing that men displayed more behavioral aggression than women. After the induction of right fronto-hemispheric dominance, proactive aggression was reduced in men. This study demonstrates that non-invasive brain stimulation can reduce aggression in men. This is a relevant and promising step to better understand how cortical brain states connect to impulsive actions and to examine the causal role of the prefrontal cortex in aggression. Ultimately, such findings could help to examine whether the brain can be a direct target for potential supportive interventions in clinical settings dealing with overly aggressive patients and/or violent offenders. PMID:25680991

  9. Growth characteristics and metastatic properties of human breast cancer xenografts in immunodeficient mice.

    PubMed Central

    Visonneau, S.; Cesano, A.; Torosian, M. H.; Miller, E. J.; Santoli, D.

    1998-01-01

    We evaluated the growth and metastatic potential of two human breast cancer cell lines and 16 patient-derived biopsy specimens, representing the most common histological types of breast carcinomas, upon subcutaneous implantation into severe combined immunodeficient (SCID) mice. The method of engraftment we used, based on implantation of intact tissue specimens and complete immunosuppression of the host, provided an easier system to grow human breast carcinoma specimens in mouse models and resulted in a 50% success rate of tumor take. No correlation was found between growth in SCID mice and pathological diagnosis, grading, or estrogen/progesterone receptor expression by the tumor biopsy specimen. Serial passage of the tumor fragments in SCID mice resulted in increased metastasis rates and more rapid emergence of a palpable tumor mass. A tumor from a patient with infiltrating ductal carcinoma, which grew aggressively and metastasized in 100% of the female SCID mice, was also successfully engrafted in 100% of nonobese diabetic (NOD)/SCID female mice, but systemic spread was minimal. Fragments of the same tumor grew in only 33% of male SCID mice with very limited metastases. A strong correlation (r = 0.997) was observed between tumor burden and the presence of soluble (serum) interleukin-2 receptor, a marker associated with a subset of human breast tumors. All together, these data indicate the usefulness of SCID/human breast tumor xenografts for measuring tumor progression and evaluating novel therapeutic approaches to breast cancer. Images Figure 1 Figure 2 Figure 3 Figure 5 PMID:9588898

  10. Female competition and aggression: interdisciplinary perspectives

    PubMed Central

    Stockley, Paula; Campbell, Anne

    2013-01-01

    This paper introduces a Theme Issue combining interdisciplinary perspectives in the study of female competition and aggression. Despite a history of being largely overlooked, evidence is now accumulating for the widespread evolutionary significance of female competition. Here, we provide a synthesis of contributions to this Theme Issue on humans and other vertebrates, and highlight directions for future research. Females compete for resources needed to survive and reproduce, and for preferred mates. Although female aggression takes diverse forms, under most circumstances relatively low-risk competitive strategies are favoured, most probably due to constraints of offspring production and care. In social species, dominance relationships and threats of punishment can resolve social conflict without resort to direct aggression, and coalitions or alliances may reduce risk of retaliation. Consistent with these trends, indirect aggression is a low cost but effective form of competition among young women. Costs are also minimized by flexibility in expression of competitive traits, with aggressive behaviour and competitive signalling tailored to social and ecological conditions. Future research on female competition and the proximate mediators of female aggression will be greatly enhanced by opportunities for interdisciplinary exchange, as evidenced by contributions to this Theme Issue. PMID:24167303

  11. Sex differences in structural brain asymmetry predict overt aggression in early adolescents.

    PubMed

    Visser, Troy A W; Ohan, Jeneva L; Whittle, Sarah; Yücel, Murat; Simmons, Julian G; Allen, Nicholas B

    2014-04-01

    The devastating social, emotional and economic consequences of human aggression are laid bare nightly on newscasts around the world. Aggression is principally mediated by neural circuitry comprising multiple areas of the prefrontal cortex and limbic system, including the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), amygdala and hippocampus. A striking characteristic of these regions is their structural asymmetry about the midline (i.e. left vs right hemisphere). Variations in these asymmetries have been linked to clinical disorders characterized by aggression and the rate of aggressive behavior in psychiatric patients. Here, we show for the first time that structural asymmetries in prefrontal cortical areas are also linked to aggression in a normal population of early adolescents. Our findings indicate a relationship between parent reports of aggressive behavior in adolescents and structural asymmetries in the limbic and paralimbic ACC and OFC, and moreover, that this relationship varies by sex. Furthermore, while there was no relationship between aggression and structural asymmetries in the amygdala or hippocampus, hippocampal volumes did predict aggression in females. Taken together, the results suggest that structural asymmetries in the prefrontal cortex may influence human aggression, and that the anatomical basis of aggression varies substantially by sex.

  12. Analysis of renal cancer cell lines from two major resources enables genomics-guided cell line selection

    NASA Astrophysics Data System (ADS)

    Sinha, Rileen; Winer, Andrew G.; Chevinsky, Michael; Jakubowski, Christopher; Chen, Ying-Bei; Dong, Yiyu; Tickoo, Satish K.; Reuter, Victor E.; Russo, Paul; Coleman, Jonathan A.; Sander, Chris; Hsieh, James J.; Hakimi, A. Ari

    2017-05-01

    The utility of cancer cell lines is affected by the similarity to endogenous tumour cells. Here we compare genomic data from 65 kidney-derived cell lines from the Cancer Cell Line Encyclopedia and the COSMIC Cell Lines Project to three renal cancer subtypes from The Cancer Genome Atlas: clear cell renal cell carcinoma (ccRCC, also known as kidney renal clear cell carcinoma), papillary (pRCC, also known as kidney papillary) and chromophobe (chRCC, also known as kidney chromophobe) renal cell carcinoma. Clustering copy number alterations shows that most cell lines resemble ccRCC, a few (including some often used as models of ccRCC) resemble pRCC, and none resemble chRCC. Human ccRCC tumours clustering with cell lines display clinical and genomic features of more aggressive disease, suggesting that cell lines best represent aggressive tumours. We stratify mutations and copy number alterations for important kidney cancer genes by the consistency between databases, and classify cell lines into established gene expression-based indolent and aggressive subtypes. Our results could aid investigators in analysing appropriate renal cancer cell lines.

  13. Polyunsaturated fatty acid content is increased in the milk of women with pregnancy associated breast cancer

    USDA-ARS?s Scientific Manuscript database

    Background: Pregnancy associated breast cancer (PABC) is aggressive and difficult to diagnose. High intake of most types of dietary fat is thought to increase breast cancer risk, however results in humans supporting this premise remain equivocal. Fatty acid (FA) concentrations in the body comprise b...

  14. PRKC-ζ Expression Promotes the Aggressive Phenotype of Human Prostate Cancer Cells and Is a Novel Target for Therapeutic Intervention

    PubMed Central

    Yao, Sheng; Bee, Alix; Brewer, Daniel; Dodson, Andrew; Beesley, Carol; Ke, Youqiang; Ambroisine, Laurence; Fisher, Gabrielle; Møller, Heinrich; Dickinson, Tim; Gerard, Patricia; Lian, Lu-Yu; Risk, Janet; Lane, Brian; Smith, Paul; Reuter, Victor; Berney, Daniel; Gosden, Christine; Scardino, Peter; Cuzick, Jack; Djamgoz, Mustafa B.A.; Cooper, Colin; Foster, Christopher S.

    2010-01-01

    We show protein kinase C–zeta (PKC-ζ) to be a novel predictive biomarker for survival from prostate cancer (P < 0.001). We also confirm that transcription of the PRKC-ζ gene is crucial to the malignant phenotype of human prostate cancer. Following siRNA silencing of PRKC-ζ in PC3-M prostate cancer cells, stable transfectant cell line si-PRKC-ζ-PC3-MT1-6 is phenotypically nonmalignant in vitro and in vivo. Genome-wide expression analysis identified 373 genes to be differentially expressed in the knockdown cells and 4 key gene networks to be significantly perturbed during phenotype modulation. Functional interconnection between some of the modulated genes is revealed, although these may be within different regulatory pathways, emphasizing the complexity of their mutual interdependence. Genes with altered expression following PRKC-ζ knockdown include HSPB1, RAD51, and ID1 that we have previously described to be critical in prostatic malignancy. Because expression of PRKC-ζ is functionally involved in promoting the malignant phenotype, we propose PKC-ζ as a novel and biologically relevant target for therapeutic intervention in prostate cancer. PMID:21779455

  15. Role of microRNA in Aggressive Prostate Cancer

    DTIC Science & Technology

    2015-09-01

    j.issn.2223-4683.2013.08.01 Scan to your mobile device or view this article at: http://www.amepc.org/tau/article/view/2550/3635 229Translational Andrology...of Ezh2, accompanied with diminished clonogenic ability and sphere formation in PCa cells (45). Another let-7 target gene is High- mobility group AT...2013;32:4139-47. 89. Motoyama K, Inoue H, Nakamura Y, et al. Clinical significance of high mobility group A2 in human gastric cancer and its

  16. Lithium in the treatment of aggression.

    PubMed

    Sheard, M H

    1975-02-01

    Lithium has become a widely accepted treatment for manic-depressive psychosis. It is dramatically effective for many cases of mania and is useful in the prevention of manic and depressive episodes. Hyperaggressiveness and hypersexuality are frequent components of manic-depressive illness and abate under the influence of lithium. A brief review is presented of the behavioral and biochemical pharmacology of lithium. This documents the inhibitory role which lithium can play in several examples of animal aggressive behavior including pain-elicited aggression, mouse killing in rats, isolation-induced aggression in mice, p-chlorophenylalanine-induced aggression in rats, and hypothalamically induced aggression in cats. The use of lithium to control human aggressive behavior has resulted in controversial findings. In epileptic conditions, improvement has been reported in interseizure aggressivity, but other reports indicate the possibility of increased seizures. Improvement in aggressive behavior in childhood has occasionally been reported as well as in emotionally unstable character disorders in young female patients. Te was a single blind study and the other a large but uncontrolled study. Both studies reported an improvement in aggressiveness as indicated by fewer recorded reports (tickets) for fighting. The final study reported is a study of 12 male delinquents age 16 to 23. They received lithium or placebo for 4 months inside an institution and then a trial of lithium for 1 to 12 months on an outpatient basis. Analysis of results in terms of the number of aggressive antisocial acts showed fewer serious aggressive episodes when the lithium level was between 0.6 and 1 meq/liter than when it was between 0.0 and 0.6 meq/liter. These results must be viewed with caution and are only suggestive since the study was not double blind.

  17. [Aggressive and prosocial behavior in childhood psychopathology].

    PubMed

    Vida, Péter; Halász, József; Gádoros, Júlia

    2013-01-01

    Aggressive/attacking and helpful/emphatic/prosocial behaviors are extremely important in human relationships. Both high levels of aggression and deficits of prosociality play important role in the development and conservation of mental disorders. We review the measurement options and clinical importance of aggressive and prosocial behavior. The typical developmental pathways and the genetic and environmental background of these behaviors are presented. The clinical tools used in the measurement of aggression and prosociality are summarized in the present paper, with specific attention on questionnaires applied in Hungarian practice. The connections between diagnostic categories (conduct disorder, oppositional-defiant disorder, attention deficit and hyperactive disorder, autism spectrum disorders) and the two behaviors are evaluated. In the end, we present those additional research projects that explore the cognitive-emotional background of aggressive or prosocial behavior with clinical relevance either in the diagnosis or in the treatment of child psychiatric diseases.

  18. Ventromedial Hypothalamus and the Generation of Aggression

    PubMed Central

    Hashikawa, Yoshiko; Hashikawa, Koichi; Falkner, Annegret L.; Lin, Dayu

    2017-01-01

    Aggression is a costly behavior, sometimes with severe consequences including death. Yet aggression is prevalent across animal species ranging from insects to humans, demonstrating its essential role in the survival of individuals and groups. The question of how the brain decides when to generate this costly behavior has intrigued neuroscientists for over a century and has led to the identification of relevant neural substrates. Various lesion and electric stimulation experiments have revealed that the hypothalamus, an ancient structure situated deep in the brain, is essential for expressing aggressive behaviors. More recently, studies using precise circuit manipulation tools have identified a small subnucleus in the medial hypothalamus, the ventrolateral part of the ventromedial hypothalamus (VMHvl), as a key structure for driving both aggression and aggression-seeking behaviors. Here, we provide an updated summary of the evidence that supports a role of the VMHvl in aggressive behaviors. We will consider our recent findings detailing the physiological response properties of populations of VMHvl cells during aggressive behaviors and provide new understanding regarding the role of the VMHvl embedded within the larger whole-brain circuit for social sensation and action. PMID:29375329

  19. Orthotopic mouse models for the preclinical and translational study of targeted therapies against metastatic human thyroid carcinoma with BRAFV600E or wild-type BRAF

    PubMed Central

    Antonello, ZA; Nucera, C

    2015-01-01

    Molecular signature of advanced and metastatic thyroid carcinoma involves deregulation of multiple fundamental pathways activated in the tumor microenvironment. They include BRAFV600E and AKT that affect tumor initiation, progression and metastasis. Human thyroid cancer orthotopic mouse models are based on human cell lines that generally harbor genetic alterations found in human thyroid cancers. They can reproduce in vivo and in situ (into the thyroid) many features of aggressive and refractory human advanced thyroid carcinomas, including local invasion and metastasis. Humanized orthotopic mouse models seem to be ideal and commonly used for preclinical and translational studies of compounds and therapies not only because they may mimic key aspects of human diseases (e.g. metastasis), but also for their reproducibility. In addition, they might provide the possibility to evaluate systemic effects of treatments. So far, human thyroid cancer in vivo models were mainly used to test single compounds, non selective and selective. Despite the greater antitumor activity and lower toxicity obtained with different selective drugs in respect to non-selective ones, most of them are only able to delay disease progression, which ultimately could restart with similar aggressive behavior. Aggressive thyroid tumors (for example, anaplastic or poorly differentiated thyroid carcinoma) carry several complex genetic alterations that are likely cooperating to promote disease progression and might confer resistance to single-compound approaches. Orthotopic models of human thyroid cancer also hold the potential to be good models for testing novel combinatorial therapies. In this article, we will summarize results on preclinical testing of selective and nonselective single compounds in orthotopic mouse models based on validated human thyroid cancer cell lines harboring the BRAFV600E mutation or with wild-type BRAF. Furthermore, we will discuss the potential use of this model also for

  20. Aggressive behavior in transgenic animal models: A systematic review.

    PubMed

    Jager, Amanda; Maas, Dorien A; Fricke, Kim; de Vries, Rob B; Poelmans, Geert; Glennon, Jeffrey C

    2018-08-01

    Aggressive behavior is often core or comorbid to psychiatric and neurodegenerative disorders. Transgenic animal models are commonly used to study the neurobiological mechanisms underlying aggressive phenotypes and have led to new insights into aggression. This systematic review critically evaluates the available literature on transgenic animal models tested for aggression with the resident-intruder test. By combining the available literature on this topic, we sought to highlight effective methods for laboratory aggression testing and provide recommendations for study design as well as aggression induction and measurement in rodents that are translational to humans, taking into consideration possible confounding factors. In addition, we built a molecular landscape of interactions between the proteins encoded by the aggression-linked genes from our systematic search. Some molecular pathways within this landscape overlap with psychiatric and neurodegenerative disorders and the landscapes point towards a number of putative (drug) targets for aggression that need to be validated in future studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Dominant-Negative TGF-β Receptor Enhances PSMA-Targeted Human CAR T Cell Proliferation And Augments Prostate Cancer Eradication.

    PubMed

    Kloss, Christopher C; Lee, Jihyun; Zhang, Aaron; Chen, Fang; Melenhorst, Jan Joseph; Lacey, Simon F; Maus, Marcela V; Fraietta, Joseph A; Zhao, Yangbing; June, Carl H

    2018-05-08

    Cancer has an impressive ability to evolve multiple processes to evade therapies. While immunotherapies and vaccines have shown great promise, particularly in certain solid tumors such as prostate cancer, they have been met with resistance from tumors that use a multitude of mechanisms of immunosuppression to limit effectiveness. Prostate cancer, in particular, secretes transforming growth factor β (TGF-β) as a means to inhibit immunity while allowing for cancer progression. Blocking TGF-β signaling in T cells increases their ability to infiltrate, proliferate, and mediate antitumor responses in prostate cancer models. We tested whether the potency of chimeric antigen receptor (CAR) T cells directed to prostate-specific membrane antigen (PSMA) could be enhanced by the co-expression of a dominant-negative TGF-βRII (dnTGF-βRII). Upon expression of the dominant-negative TGF-βRII in CAR T cells, we observed increased proliferation of these lymphocytes, enhanced cytokine secretion, resistance to exhaustion, long-term in vivo persistence, and the induction of tumor eradication in aggressive human prostate cancer mouse models. Based on our observations, we initiated a phase I clinical trial to assess these CAR T cells as a novel approach for patients with relapsed and refractory metastatic prostate cancer (ClinicalTrials.gov: NCT03089203). Copyright © 2018. Published by Elsevier Inc.

  2. (−)-Xanthatin Selectively Induces GADD45γ and Stimulates Caspase-Independent Cell Death in Human Breast Cancer MDA-MB-231 Cells

    PubMed Central

    Takeda, Shuso; Matsuo, Kazumasa; Yaji, Kentaro; Okajima-Miyazaki, Shunsuke; Harada, Mari; Miyoshi, Hiroko; Okamoto, Yoshiko; Amamoto, Toshiaki; Shindo, Mitsuru; Omiecinski, Curtis J.; Aramaki, Hironori

    2014-01-01

    exo-Methylene lactone group-containing compounds, such as (−)-xanthatin, are present in a large variety of biologically active natural products, including extracts of Xanthium strumarium (Cocklebur). These substances are reported to possess diverse functional activities, exhibiting anti-inflammatory, antimalarial, and anticancer potential. In this study, we synthesized six structurally related xanthanolides containing exo-methylene lactone moieties, including (−)-xanthatin and (+)-8-epi-xanthatin, and examined the effects of these chemically defined substances on the highly aggressive and farnesyltransferase inhibitor (FTI)-resistant MDA-MB-231 cancer cell line. The results obtained demonstrate that (−)-xanthatin was a highly effective inhibitor of MDA-MB-231 cell growth, inducing caspase-independent cell death, and that these effects were independent of FTase inhibition. Further, our results show that among the GADD45 isoforms, GADD45γ was selectively induced by (−)-xanthatin and that GADD45γ-primed JNK and p38 signaling pathways are, at least in part, involved in mediating the growth inhibition and potential anticancer activities of this agent. Given that GADD45γ is becoming increasingly recognized for its tumor suppressor function, the results presented here suggest the novel possibility that (−)-xanthatin may have therapeutic value as a selective inducer of GADD45γ in human cancer cells, in particular in FTI-resistant aggressive breast cancers. PMID:21568272

  3. Reducing proactive aggression through non-invasive brain stimulation.

    PubMed

    Dambacher, Franziska; Schuhmann, Teresa; Lobbestael, Jill; Arntz, Arnoud; Brugman, Suzanne; Sack, Alexander T

    2015-10-01

    Aggressive behavior poses a threat to human collaboration and social safety. It is of utmost importance to identify the functional mechanisms underlying aggression and to develop potential interventions capable of reducing dysfunctional aggressive behavior already at a brain level. We here experimentally shifted fronto-cortical asymmetry to manipulate the underlying motivational emotional states in both male and female participants while assessing the behavioral effects on proactive and reactive aggression. Thirty-two healthy volunteers received either anodal transcranial direct current stimulation to increase neural activity within right dorsolateral prefrontal cortex, or sham stimulation. Aggressive behavior was measured with the Taylor Aggression Paradigm. We revealed a general gender effect, showing that men displayed more behavioral aggression than women. After the induction of right fronto-hemispheric dominance, proactive aggression was reduced in men. This study demonstrates that non-invasive brain stimulation can reduce aggression in men. This is a relevant and promising step to better understand how cortical brain states connect to impulsive actions and to examine the causal role of the prefrontal cortex in aggression. Ultimately, such findings could help to examine whether the brain can be a direct target for potential supportive interventions in clinical settings dealing with overly aggressive patients and/or violent offenders. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  4. Association between Prostinogen (KLK15) Genetic Variants and Prostate Cancer Risk and Aggressiveness in Australia and a Meta-Analysis of GWAS Data

    PubMed Central

    Batra, Jyotsna; Lose, Felicity; O'Mara, Tracy; Marquart, Louise; Stephens, Carson; Alexander, Kimberly; Srinivasan, Srilakshmi; Eeles, Rosalind A.; Easton, Douglas F.; Olama, Ali Amin Al; Kote-Jarai, Zsofia; Guy, Michelle; Muir, Kenneth; Lophatananon, Artitaya; Rahman, Aneela A.; Neal, David E.; Hamdy, Freddie C.; Donovan, Jenny L.; Chambers, Suzanne; Gardiner, Robert A.; Aitken, Joanne; Yaxley, John; Kedda, Mary-Anne

    2011-01-01

    Background Kallikrein 15 (KLK15)/Prostinogen is a plausible candidate for prostate cancer susceptibility. Elevated KLK15 expression has been reported in prostate cancer and it has been described as an unfavorable prognostic marker for the disease. Objectives We performed a comprehensive analysis of association of variants in the KLK15 gene with prostate cancer risk and aggressiveness by genotyping tagSNPs, as well as putative functional SNPs identified by extensive bioinformatics analysis. Methods and Data Sources Twelve out of 22 SNPs, selected on the basis of linkage disequilibrium pattern, were analyzed in an Australian sample of 1,011 histologically verified prostate cancer cases and 1,405 ethnically matched controls. Replication was sought from two existing genome wide association studies (GWAS): the Cancer Genetic Markers of Susceptibility (CGEMS) project and a UK GWAS study. Results Two KLK15 SNPs, rs2659053 and rs3745522, showed evidence of association (p<0.05) but were not present on the GWAS platforms. KLK15 SNP rs2659056 was found to be associated with prostate cancer aggressiveness and showed evidence of association in a replication cohort of 5,051 patients from the UK, Australia, and the CGEMS dataset of US samples. A highly significant association with Gleason score was observed when the data was combined from these three studies with an Odds Ratio (OR) of 0.85 (95% CI = 0.77–0.93; p = 2.7×10−4). The rs2659056 SNP is predicted to alter binding of the RORalpha transcription factor, which has a role in the control of cell growth and differentiation and has been suggested to control the metastatic behavior of prostate cancer cells. Conclusions Our findings suggest a role for KLK15 genetic variation in the etiology of prostate cancer among men of European ancestry, although further studies in very large sample sets are necessary to confirm effect sizes. PMID:22132073

  5. A tissue-engineered humanized xenograft model of human breast cancer metastasis to bone

    PubMed Central

    Thibaudeau, Laure; Taubenberger, Anna V.; Holzapfel, Boris M.; Quent, Verena M.; Fuehrmann, Tobias; Hesami, Parisa; Brown, Toby D.; Dalton, Paul D.; Power, Carl A.; Hollier, Brett G.; Hutmacher, Dietmar W.

    2014-01-01

    ABSTRACT The skeleton is a preferred homing site for breast cancer metastasis. To date, treatment options for patients with bone metastases are mostly palliative and the disease is still incurable. Indeed, key mechanisms involved in breast cancer osteotropism are still only partially understood due to the lack of suitable animal models to mimic metastasis of human tumor cells to a human bone microenvironment. In the presented study, we investigate the use of a human tissue-engineered bone construct to develop a humanized xenograft model of breast cancer-induced bone metastasis in a murine host. Primary human osteoblastic cell-seeded melt electrospun scaffolds in combination with recombinant human bone morphogenetic protein 7 were implanted subcutaneously in non-obese diabetic/severe combined immunodeficient mice. The tissue-engineered constructs led to the formation of a morphologically intact ‘organ’ bone incorporating a high amount of mineralized tissue, live osteocytes and bone marrow spaces. The newly formed bone was largely humanized, as indicated by the incorporation of human bone cells and human-derived matrix proteins. After intracardiac injection, the dissemination of luciferase-expressing human breast cancer cell lines to the humanized bone ossicles was detected by bioluminescent imaging. Histological analysis revealed the presence of metastases with clear osteolysis in the newly formed bone. Thus, human tissue-engineered bone constructs can be applied efficiently as a target tissue for human breast cancer cells injected into the blood circulation and replicate the osteolytic phenotype associated with breast cancer-induced bone lesions. In conclusion, we have developed an appropriate model for investigation of species-specific mechanisms of human breast cancer-related bone metastasis in vivo. PMID:24713276

  6. [Comparisons of aggressive behavior for Tibetan Macaques (Macaca thibetana) to tourists from Mt. Huangshan, China].

    PubMed

    Ji, Huan; Li, Jin-Hua; Sun, Bing-Hua; Zhu, Yong

    2010-08-01

    To investigate the relationship between monkey-human aggressive behaviors and age/sex classes of monkey (initiator) and human (recipient), by using all-occurrence sampling and continuous recording, we evaluated the monkey-human aggressive behaviors between macaques (Macaca thibetana) and tourists at Mt. Huangshan in two periods (Nov.-Dec.2008 and Apr.-May 2009). After we divide the aggression into three types according to the dangerous level to tourists, some significant patterns were observed.Our observations indicate that Tibetan macaques respond differently to human according to the age/sex classes involved. On one hand, We found that the adult male monkeys tend to be more aggressive than expected (P<0.01), while the adult female monkeys and immature monkeys participated in AGIII behaviors (threat) less than expected (P<0.01); On the other hand, The adult male human received more aggressive behaviors than expected (P<0.01), while the adult female human and child received less aggressive in AGIII behaviors (threat) (P<0.01). Our results provide not only a scientific basis for the management advice that adult male monkeys and adult male human should be given special attention, but also a good management model of Huangshan for other primate tourist exploring places.

  7. Parents’ Aggressive Influences and Children's Aggressive Problem Solutions with Peers

    PubMed Central

    Duman, Sarah; Margolin, Gayla

    2009-01-01

    This study examined children's aggressive and assertive solutions to hypothetical peer scenarios in relation to parents’ responses to similar hypothetical social scenarios and parents’ actual marital aggression. The study included 118 9−10 year old children, and their mothers and fathers. Children's aggressive solutions correlated with same-sex parents’ actual marital aggression. For children with mothers who exhibit low actual marital aggression, mothers’ aggressive solutions to hypothetical situations corresponded with children's tendencies to propose aggressive but not assertive solutions. In a 3-way interaction, fathers’ aggressive solutions to peer scenarios and marital aggression, combined, exacerbated girls’ aggressive problem solving, but had the opposite effect for boys. Discussion addresses the complexity, particularly with respect to parent and child gender combinations, in understanding parents’ aggressive influences on children's peer relationships. PMID:17206880

  8. Carotenoid intake and adipose tissue carotenoid levels in relation to prostate cancer aggressiveness among African-American and European-American men in the North Carolina-Louisiana prostate cancer project (PCaP).

    PubMed

    Antwi, Samuel O; Steck, Susan E; Su, L Joseph; Hebert, James R; Zhang, Hongmei; Craft, Neal E; Fontham, Elizabeth T H; Smith, Gary J; Bensen, Jeannette T; Mohler, James L; Arab, Lenore

    2016-09-01

    Associations between carotenoid intake and prostate cancer (CaP) incidence have varied across studies. This may result from combining indolent with aggressive disease in most studies. This study examined whether carotenoid intake and adipose tissue carotenoid levels were inversely associated with CaP aggressiveness. Data on African-American (AA, n = 1,023) and European-American (EA, n = 1,079) men with incident CaP from North Carolina and Louisiana were analyzed. Dietary carotenoid intake was assessed using a detailed-food frequency questionnaire (FFQ), and abdominal adipose tissue samples were analyzed for carotenoid concentrations using high-performance liquid chromatography. Multivariable logistic regression was used in race-stratified analyses to calculate odds ratios (ORs) and 95% confidence intervals (95%CI) comparing high aggressive CaP with low/intermediate aggressive CaP. Carotenoid intake differed significantly between AAs and EAs, which included higher intake of lycopene among EAs and higher β-cryptoxanthin intake among AAs. Comparing the highest and lowest tertiles, dietary lycopene was associated inversely with high aggressive CaP among EAs (OR = 0.55, 95%CI: 0.34-0.89, Ptrend  = 0.02), while an inverse association was observed between dietary β-cryptoxanthin intake and high aggressive CaP among AAs (OR = 0.56, 95%CI: 0.36-0.87, Ptrend  = 0.01). Adipose tissue α-carotene and lycopene (cis + trans) concentrations were higher among EAs than AAs, and marginally significant inverse linear trends were observed for adipose α-carotene (Ptrend  = 0.07) and lycopene (Ptrend  = 0.11), and CaP aggressiveness among EAs only. These results suggest that diets high in lycopene and β-cryptoxanthin may protect against aggressive CaP among EAs and AAs, respectively. Differences in dietary behaviors may explain the observed racial differences in associations. Prostate 76:1053-1066, 2016. © 2016 Wiley Periodicals, Inc. © 2016

  9. Cerebrospinal fluid GABA concentration: relationship with impulsivity and history of suicidal behavior, but not aggression, in human subjects.

    PubMed

    Lee, Royce; Petty, Frederick; Coccaro, Emil F

    2009-01-01

    The objective of this study was to assess the relationship between cerebrospinal fluid concentrations of the neurotransmitter gamma-aminobutyric acid (GABA) and measures of impulsivity and related behaviors (aggression and suicidality) in healthy volunteer and personality disordered subjects. CSF GABA levels, and measures of impulsivity, aggression, and history of suicidal behavior were obtained by morning lumbar puncture in 57 healthy volunteer subjects and in subjects with personality disorder. CSF GABA levels were not found to correlate with measures of aggression but were found to correlate directly with measures of impulsivity; e.g., a composite measure of impulsivity in all subjects (r=0.35, df=46, P=0.015) and in personality disordered subjects examined separately (r=0.39, df=30, P=0.029). In the personality disorder group, CSF GABA levels were higher among subjects with a history of suicidal behavior compared with those without this history. These data suggest that central GABAergic function correlates directly with impulsiveness and history of suicidal behavior, but not aggressiveness, in personality disordered subjects. This may be consistent with observations that high doses of benzodiazepines can lead to "behavioral disinhibition" in human subjects. Further work assessing this and other aspects of the central GABA system in personality disordered subjects are warranted.

  10. Estrogenic encounters: How interactions between aromatase and the environment modulate aggression

    PubMed Central

    Trainor, Brian C.; Kyomen, Helen H.; Marler, Catherine A.

    2007-01-01

    Initial investigations into the mechanistic basis of aggression focused on the role of testosterone (T) and a variety of studies on non-human animals found that elevated T levels promote aggression. However, many correlational studies have not detected a significant association between aggression and peripheral T levels. One reason for this inconsistency may be due to differential metabolism of T within the brain, in particular, the conversion of T to estrogen by aromatase. Thus, differences in aromatase enzyme activity, estrogen receptor expression, and related cofactors may have important effects on how steroids affect aggressive behavior. Hormone manipulation studies conducted in a wide variety of species indicate that estrogens modulate aggression. There is also growing evidence that social experience has important effects on the production of estrogen within the brain, and some cases can not be explained by androgenic regulation of aromatase. Such changes in central aromatase activity may play an important role in determining how social experiences affect the probability of whether an individual engages in aggressive behavior. Although studies have been conducted in many taxa, there has been relatively little integration between literatures examining aggression in different species. In this review, we compare and contrast studies examining aggression in birds, mammals, and humans. By taking an integrative approach to our review, we consider mechanisms that could explain species differences in how estrogen modulates aggression. PMID:16376420

  11. Transcriptional landscape of human cancers.

    PubMed

    Li, Mengyuan; Sun, Qingrong; Wang, Xiaosheng

    2017-05-23

    The homogeneity and heterogeneity in somatic mutations, copy number alterations and methylation across different cancer types have been extensively explored. However, the related exploration based on transcriptome data is lacking. In this study we explored gene expression profiles across 33 human cancer types using The Cancer Genome Atlas (TCGA) data. We identified consistently upregulated genes (such as E2F1, EZH2, FOXM1, MYBL2, PLK1, TTK, AURKA/B and BUB1) and consistently downregulated genes (such as SCARA5, MYOM1, NKAPL, PEG3, USP2, SLC5A7 and HMGCLL1) across various cancers. The dysregulation of these genes is likely to be associated with poor clinical outcomes in cancer. The dysregulated pathways commonly in cancers include cell cycle, DNA replication, repair, and recombination, Notch signaling, p53 signaling, Wnt signaling, TGFβ signaling, immune response etc. We also identified genes consistently upregulated or downregulated in highly-advanced cancers compared to lowly-advanced cancers. The highly (low) expressed genes in highly-advanced cancers are likely to have higher (lower) expression levels in cancers than in normal tissue, indicating that common gene expression perturbations drive cancer initiation and cancer progression. In addition, we identified a substantial number of genes exclusively dysregulated in a single cancer type or inconsistently dysregulated in different cancer types, demonstrating the intertumor heterogeneity. More importantly, we found a number of genes commonly dysregulated in various cancers such as PLP1, MYOM1, NKAPL and USP2 which were investigated in few cancer related studies, and thus represent our novel findings. Our study provides comprehensive portraits of transcriptional landscape of human cancers.

  12. Transcriptional landscape of human cancers

    PubMed Central

    Li, Mengyuan; Sun, Qingrong; Wang, Xiaosheng

    2017-01-01

    The homogeneity and heterogeneity in somatic mutations, copy number alterations and methylation across different cancer types have been extensively explored. However, the related exploration based on transcriptome data is lacking. In this study we explored gene expression profiles across 33 human cancer types using The Cancer Genome Atlas (TCGA) data. We identified consistently upregulated genes (such as E2F1, EZH2, FOXM1, MYBL2, PLK1, TTK, AURKA/B and BUB1) and consistently downregulated genes (such as SCARA5, MYOM1, NKAPL, PEG3, USP2, SLC5A7 and HMGCLL1) across various cancers. The dysregulation of these genes is likely to be associated with poor clinical outcomes in cancer. The dysregulated pathways commonly in cancers include cell cycle, DNA replication, repair, and recombination, Notch signaling, p53 signaling, Wnt signaling, TGFβ signaling, immune response etc. We also identified genes consistently upregulated or downregulated in highly-advanced cancers compared to lowly-advanced cancers. The highly (low) expressed genes in highly-advanced cancers are likely to have higher (lower) expression levels in cancers than in normal tissue, indicating that common gene expression perturbations drive cancer initiation and cancer progression. In addition, we identified a substantial number of genes exclusively dysregulated in a single cancer type or inconsistently dysregulated in different cancer types, demonstrating the intertumor heterogeneity. More importantly, we found a number of genes commonly dysregulated in various cancers such as PLP1, MYOM1, NKAPL and USP2 which were investigated in few cancer related studies, and thus represent our novel findings. Our study provides comprehensive portraits of transcriptional landscape of human cancers. PMID:28427185

  13. Swooping in the Suburbs; Parental Defence of an Abundant Aggressive Urban Bird against Humans.

    PubMed

    Lees, Daniel; Sherman, Craig D H; Maguire, Grainne S; Dann, Peter; Cardilini, Adam P A; Weston, Michael A

    2013-08-13

    Masked Lapwings, Vanellus miles, often come into 'conflict' with humans, because they often breed in close proximity to humans and actively defend their ground nests through aggressive behaviour, which typically involves swooping. This study examined whether defensive responses differed when nesting birds were confronted with different human stimuli ('pedestrian alone' vs. 'person pushing a lawn mower' approaches to nests) and tested the effectiveness of a commonly used deterrent (mock eyes positioned on the top or back of a person's head) on the defensive response. Masked Lapwings did not swoop closer to a person with a lawn mower compared with a pedestrian, but flushed closer and remained closer to the nest in the presence of a lawn mower. The presence of eye stickers decreased (pedestrians) and increased (lawn mowers) swooping behaviour. Masked Lapwings can discriminate between different human activities and adjust their defensive behaviour accordingly. We also conclude that the use of eye stickers is an effective method to mitigate the human-lapwing 'conflict' in some, but not all, circumstances.

  14. Gene Therapy of Human Breast Cancer.

    DTIC Science & Technology

    1998-10-01

    gene product of human papilloma virus . They transduced this modified cell line with B7 and showed that immunization with the B7- transduced cell...adeno-LacZ virus , aliquots of 106 human breast cancer cells, purified using methods described above, will be incubated in suspension with adeno-LacZ...v.- Final Report:«DAMD17-94-J-4385 "Gene Therapy of Human Cancer" Page 1 AD GRANT NUMBER DAMD17-94-J-4385 TITLE: Gene Therapy of Human

  15. Cognitive and neurobiological mechanisms of alcohol-related aggression.

    PubMed

    Heinz, Adrienne J; Beck, Anne; Meyer-Lindenberg, Andreas; Sterzer, Philipp; Heinz, Andreas

    2011-06-02

    Alcohol-related violence is a serious and common social problem. Moreover, violent behaviour is much more common in alcohol-dependent individuals. Animal experiments and human studies have provided insights into the acute effect of alcohol on aggressive behaviour and into common factors underlying acute and chronic alcohol intake and aggression. These studies have shown that environmental factors, such as early-life stress, interact with genetic variations in serotonin-related genes that affect serotonergic and GABAergic neurotransmission. This leads to increased amygdala activity and impaired prefrontal function that, together, predispose to both increased alcohol intake and impulsive aggression. In addition, acute and chronic alcohol intake can further impair executive control and thereby facilitate aggressive behaviour.

  16. IQGAP1 Is Involved in Enhanced Aggressive Behavior of Epithelial Ovarian Cancer Stem Cell-Like Cells During Differentiation.

    PubMed

    Huang, Lu; Xu, Shanshan; Hu, Dongxiao; Lu, Weiguo; Xie, Xing; Cheng, Xiaodong

    2015-05-01

    Wide metastasis is one of characteristics of ovarian cancer. Cancer stem cells, as a source in cancer invasion and metastasis, possess powerful potential of differentiation. Scaffolding IQ domain GTPase-activating protein 1 (IQGAP1) plays a key role in the invasion and metastasis of cancer cells, but IQGAP1's role in cancer stem cells including ovarian cancer was unclear. Spheroid culture with serum-free medium was used for enriching ovarian cancer stem cell-like cells (CSC-LCs) from 3AO cell line, and a medium with 10% fetal bovine serum was used to induce the differentiation of CSC-LCs. Immunofluorescence was for detecting the stem markers OCT4 and SOX2. The quantitative real-time-polymerase chain reaction and Western blotting were performed to determine the messenger RNA and protein expression of IQGAP1, respectively. The capacity of cell invasion was evaluated by transwell chamber assay. Ovarian CSC-LCs obtained through spheroid culture showed irregularly elongated appearance, CD24 negative, and OCT4 and SOX2 positive. IQGAP1 expression was decreased in ovarian CSC-LCs compared with parental 3AO cells, but increased de novo during the differentiation of CSC-LCs. Knockdown of IQGAP1 by specific small interfering RNA remarkably weakened invasion capacity of 2-day differentiated ovarian CSC-LCs. Increased IQGAP1 expression during the differentiation of CSC-LCs is involved in an aggressive cell behavior, which may contribute to metastasis of ovarian cancer.

  17. Viruses and human cancer: from detection to causality.

    PubMed

    Sarid, Ronit; Gao, Shou-Jiang

    2011-06-28

    The study of cancer is incomplete without taking into consideration of tumorigenic viruses. Initially, searches for human cancer viruses were fruitless despite an expansion of our knowledge in the same period concerning acute-transforming retroviruses in animals. However, over the last 40 years, we have witnessed rapid progress in the tumor virology field. Currently, acknowledged human cancer viruses include Epstein-Barr virus, hepatitis B virus, hepatitis C virus, high-risk human papilloma viruses, human T-cell lymphotropic virus type 1 and Kaposi's sarcoma-associated herpesvirus. Extensive epidemiological and mechanistic studies have led to the development of novel preventive and therapeutic approaches for managing some of these infections and associated cancers. In addition, recent advances in molecular technologies have enabled the discovery of a new potential human tumor virus, Merkel cell polyomavirus, but its association with cancer remains to be validated. It is anticipated that in the next few decades many additional human cancer viruses will be discovered and the mechanisms underlying viral oncogenesis delineated. Thus, it can be expected that better tools for preventing and treating virus-associated cancer will be available in the near future. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  18. Viruses and Human Cancer: From Detection to Causality

    PubMed Central

    Sarid, Ronit; Gao, Shou-Jiang

    2010-01-01

    The study of cancer is incomplete without taking into consideration of tumorigenic viruses. Initially, searches for human cancer viruses were fruitless despite an expansion of our knowledge in the same period concerning acute-transforming retroviruses in animals. However, over the last 40 years, we have witnessed rapid progress in the tumor virology field. Currently, acknowledged human cancer viruses include Epstein-Barr virus, Hepatitis B virus, Hepatitis C virus, High-risk human papilloma viruses, Human T-cell lymphotropic virus type 1 and Kaposi’s sarcoma-associated herpesvirus. Extensive epidemiological and mechanistic studies have led to the development of novel preventive and therapeutic approaches for managing some of these infections and associated cancers. In addition, recent advances in molecular technologies have enabled the discovery of a new potential human tumor virus, Merkel cell polyomavirus, but its association with cancer remains to be validated. It is anticipated that in the next few decades many additional human cancer viruses will be discovered and the mechanisms underlying viral oncogenesis delineated. Thus, it can be expected that better tools for preventing and treating virus-associated cancer will be available in the near future. PMID:20971551

  19. Cholesterol and Prostate Cancer

    PubMed Central

    Pelton, Kristine; Freeman, Michael R.; Solomon, Keith R.

    2012-01-01

    Summary Prostate cancer risk can be modified by environmental factors, however the molecular mechanisms affecting susceptibility to this disease are not well understood. As a result of a series of recently published studies, the steroidal lipid, cholesterol, has emerged as a clinically relevant therapeutic target in prostate cancer. This review summarizes the findings from human studies as well as animal and cell biology models which suggest that high circulating cholesterol increases risk of aggressive prostate cancer, while cholesterol lowering strategies may confer protective benefit. Relevant molecular processes that have been experimentally tested and might explain these associations are described. We suggest that these promising results now could be applied prospectively to attempt to lower risk of prostate cancer in select populations. PMID:22824430

  20. Big bad wolf or man's best friend? Unmasking a false wolf aggression on humans.

    PubMed

    Caniglia, R; Galaverni, M; Delogu, M; Fabbri, E; Musto, C; Randi, E

    2016-09-01

    The return of the wolf in its historical range is raising social conflicts with local communities for the perceived potential threat to people safety. In this study we applied molecular methods to solve an unusual case of wolf attack towards a man in the Northern Italian Apennines. We analysed seven biological samples, collected from the clothes of the injured man, using mtDNA sequences, the Amelogenin gene, 39 unlinked autosomal and four Y-linked microsatellites. Results indicated that the aggression was conducted by a male dog and not by a wolf nor a wolf x dog hybrid. Our findings were later confirmed by the victim, who confessed he had been attacked by the guard dog of a neighbour. The genetic profile of the owned dog perfectly matched with that identified from the samples previously collected. Our results prove once again that the wolf does not currently represent a risk for human safety in developed countries, whereas most animal aggressions are carried out by its domestic relative, the dog. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  1. Cancer stage at diagnosis in patients infected with the human immunodeficiency virus and transplant recipients.

    PubMed

    Shiels, Meredith S; Copeland, Glenn; Goodman, Marc T; Harrell, Janna; Lynch, Charles F; Pawlish, Karen; Pfeiffer, Ruth M; Engels, Eric A

    2015-06-15

    It is unknown whether immunosuppression results in more aggressive, advanced stage cancers. Because cancer stage is influenced both by tumor biology and medical surveillance, the authors assessed cancer stage in individuals infected with the human immunodeficiency virus (HIV) and solid organ transplant recipients, 2 immunosuppressed groups with differences in their health care use. The authors used data on all cases of 15 cancer types diagnosed during 1996 through 2010 in 2 studies that linked US cancer registries with HIV and transplant registries. Odds ratios (ORs) for advanced (vs local) disease were estimated comparing HIV and transplant populations with immunocompetent individuals in polytomous logistic regression models adjusted for age, sex, race, registry, and year. A total of 8411 of 4.5 million cancer cases occurred in HIV-infected individuals and 7322 of 6.4 million cancer cases occurred in transplant recipients. Compared with immunocompetent patients with cancer, those infected with HIV were more likely to be diagnosed with distant stage lung (OR, 1.13), female breast (OR, 1.99), and prostate (OR, 1.57) cancers, whereas transplant recipients had fewer distant stage lung (OR, 0.54), female breast (OR, 0.75), and prostate (OR, 0.72) cancers. Both immunosuppressed populations had a shift toward advanced stage melanoma (ORs of 1.97 for HIV-infected individuals and 1.82 for transplant recipients) and bladder cancer (ORs of 1.42 for HIV-infected individuals and 1.54 for transplant recipients). Bladder cancer and melanoma were more likely to be diagnosed at a nonlocal stage in both HIV-infected individuals and transplant recipients, suggesting a role for immunosuppression in their progression. In addition, we observed a shift for some common cancers toward later stages in HIV-infected individuals and toward earlier stages in transplant recipients, which is consistent with differential access to medical care or surveillance. © 2015 American Cancer Society.

  2. Pathobiological implications of the d16HER2 splice variant for stemness and aggressiveness of HER2-positive breast cancer

    PubMed Central

    Castagnoli, L; Ghedini, G C; Koschorke, A; Triulzi, T; Dugo, M; Gasparini, P; Casalini, P; Palladini, A; Iezzi, M; Lamolinara, A; Lollini, P L; Nanni, P; Chiodoni, C; Tagliabue, E; Pupa, S M

    2017-01-01

    We have previously shown that the d16HER2 splice variant is linked to HER2-positive breast cancer (BC) tumorigenesis, progression and response to Trastuzumab. However, the mechanisms by which d16HER2 contributes to HER2-driven aggressiveness and targeted therapy susceptibility remain uncertain. Here, we report that the d16HER2-positive mammary tumor cell lines MI6 and MI7, derived from spontaneous lesions of d16HER2 transgenic (tg) mice and resembling the aggressive features of primary lesions, are enriched in the expression of Wnt, Notch and epithelial–mesenchymal transition pathways related genes compared with full-length wild-type (WT) HER2-positive cells (WTHER2_1 and WTHER2_2) derived from spontaneous tumors arising in WTHER2 tg mice. MI6 cells exhibited increased resistance to anoikis and significantly higher mammosphere-forming efficiency (MFE) and self-renewal capability than the WTHER2-positive counterpart. Furthermore, d16HER2-positive tumor cells expressed a higher fraction of CD29High/CD24+/SCA1Low cells and displayed greater in vivo tumor engraftment in serial dilution conditions than WTHER2_1 cells. Accordingly, NOTCH inhibitors impaired mammosphere formation only in MI6 cells. A comparative analysis of stemness-related features driven by d16HER2 and WTHER2 in ad hoc engineered human BC cells (MCF7 and T47D) revealed a higher MFE and aldehyde dehydrogenase-positive staining in d16HER2- vs WTHER2-infected cells, sustaining consistent BC-initiating cell enrichment in the human setting. Moreover, marked CD44 expression was found in MCF7_d16 and T47D_d16 cells vs their WTHER2 and Mock counterparts. Clinically, BC cases from two distinct HER2-positive cohorts characterized by high levels of expression of the activated-d16HER2 metagene were significantly enriched in the Notch family and signal transducer genes vs those with low levels of the metagene. PMID:27641338

  3. Preventable Exposures Associated With Human Cancers

    PubMed Central

    Baan, Robert; Straif, Kurt; Grosse, Yann; Lauby-Secretan, Béatrice; El Ghissassi, Fatiha; Bouvard, Véronique; Benbrahim-Tallaa, Lamia; Guha, Neela; Freeman, Crystal; Galichet, Laurent; Wild, Christopher P.

    2011-01-01

    Information on the causes of cancer at specific sites is important to cancer control planners, cancer researchers, cancer patients, and the general public. The International Agency for Research on Cancer (IARC) Monograph series, which has classified human carcinogens for more than 40 years, recently completed a review to provide up-to-date information on the cancer sites associated with more than 100 carcinogenic agents. Based on IARC’s review, we listed the cancer sites associated with each agent and then rearranged this information to list the known and suspected causes of cancer at each site. We also summarized the rationale for classifications that were based on mechanistic data. This information, based on the forthcoming IARC Monographs Volume 100, offers insights into the current state-of-the-science of carcinogen identification. Use of mechanistic data to identify carcinogens is increasing, and epidemiological research is identifying additional carcinogens and cancer sites or confirming carcinogenic potential under conditions of lower exposure. Nevertheless, some common human cancers still have few (or no) identified causal agents. PMID:22158127

  4. Plasma cell leukaemia and other aggressive plasma cell malignancies

    PubMed Central

    Sher, Taimur; Miller, Kena C.; Deeb, George; Lee, Kelvin; Chanan-Khan, Asher

    2014-01-01

    Summary Extramedullary plasma cell cancers, such as plasma cell leukemia (PCL) and multiple extramedullary plasmacytomas (MEP) are very aggressive malignancies. These can be primary (de-novo) or secondary due to progressive prior multiple myeloma (MM). Recent reports suggest an increase in incidence of these disorders. Compared to MM, organ invasion is common in PCL, while soft tissue tumors involving the head, neck or paraspinal area are common sites for MEP. Markers of poor prognosis are frequently observed in these extramedullary forms of plasma cell cancers, and survival is significantly inferior compared to patients with MM. Conventional chemotherapeutic and radiotherapy approaches have been employed with variable results. Even high dose chemotherapy with autologous stem cell rescue has not been able to demonstrate consistent improvement in survival outcome. Although not specifically evaluated, novel anti-plasma cell agents, such as the proteasome inhibitor bortezomib, and immunomodulatory drugs, such as lenalidomide, appear to be active against these aggressive cancers. Clinical and translational research directed at improved understanding of disease biology and development of novel therapeutics is urgently needed. PMID:20701603

  5. A genome-wide pleiotropy scan for prostate cancer risk.

    PubMed

    Panagiotou, Orestis A; Travis, Ruth C; Campa, Daniele; Berndt, Sonja I; Lindstrom, Sara; Kraft, Peter; Schumacher, Fredrick R; Siddiq, Afshan; Papatheodorou, Stefania I; Stanford, Janet L; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie J; Diver, W Ryan; Gapstur, Susan M; Stevens, Victoria L; Boeing, Heiner; Bueno-de-Mesquita, H Bas; Barricarte Gurrea, Aurelio; Kaaks, Rudolf; Khaw, Kay-Tee; Krogh, Vittorio; Overvad, Kim; Riboli, Elio; Trichopoulos, Dimitrios; Giovannucci, Edward; Stampfer, Meir; Haiman, Christopher; Henderson, Brian; Le Marchand, Loic; Gaziano, J Michael; Hunter, David J; Koutros, Stella; Yeager, Meredith; Hoover, Robert N; Chanock, Stephen J; Wacholder, Sholom; Key, Timothy J; Tsilidis, Konstantinos K

    2015-04-01

    No single-nucleotide polymorphisms (SNPs) specific for aggressive prostate cancer have been identified in genome-wide association studies (GWAS). To test if SNPs associated with other traits may also affect the risk of aggressive prostate cancer. SNPs implicated in any phenotype other than prostate cancer (p≤10(-7)) were identified through the catalog of published GWAS and tested in 2891 aggressive prostate cancer cases and 4592 controls from the Breast and Prostate Cancer Cohort Consortium (BPC3). The 40 most significant SNPs were followed up in 4872 aggressive prostate cancer cases and 24,534 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. Odds ratios (ORs) and 95% confidence intervals (CIs) for aggressive prostate cancer were estimated. A total of 4666 SNPs were evaluated by the BPC3. Two signals were seen in regions already reported for prostate cancer risk. rs7014346 at 8q24.21 was marginally associated with aggressive prostate cancer in the BPC3 trial (p=1.6×10(-6)), whereas after meta-analysis by PRACTICAL the summary OR was 1.21 (95% CI 1.16-1.27; p=3.22×10(-18)). rs9900242 at 17q24.3 was also marginally associated with aggressive disease in the meta-analysis (OR 0.90, 95% CI 0.86-0.94; p=2.5×10(-6)). Neither of these SNPs remained statistically significant when conditioning on correlated known prostate cancer SNPs. The meta-analysis by BPC3 and PRACTICAL identified a third promising signal, marked by rs16844874 at 2q34, independent of known prostate cancer loci (OR 1.12, 95% CI 1.06-1.19; p=4.67×10(-5)); it has been shown that SNPs correlated with this signal affect glycine concentrations. The main limitation is the heterogeneity in the definition of aggressive prostate cancer between BPC3 and PRACTICAL. We did not identify new SNPs for aggressive prostate cancer. However, rs16844874 may provide preliminary genetic evidence on the role of the glycine pathway in

  6. Adolescents’ Aggression to Parents: Longitudinal Links with Parents’ Physical Aggression

    PubMed Central

    Margolin, Gayla; Baucom, Brian R.

    2014-01-01

    Purpose To investigate whether parents’ previous physical aggression (PPA) exhibited during early adolescence is associated with adolescents’ subsequent parent-directed aggression even beyond parents’ concurrent physical aggression (CPA); to investigate whether adolescents’ emotion dysregulation and attitudes condoning child-to-parent aggression moderate associations. Methods Adolescents (N = 93) and their parents participated in a prospective, longitudinal study. Adolescents and parents reported at waves 1–3 on four types of parents’ PPA (mother-to-adolescent, father-to-adolescent, mother-to-father, father-to-mother). Wave 3 assessments also included adolescents’ emotion dysregulation, attitudes condoning aggression, and externalizing behaviors. At waves 4 and 5, adolescents and parents reported on adolescents’ parent-directed physical aggression, property damage, and verbal aggression, and on parents’ CPA Results Parents’ PPA emerged as a significant indicator of adolescents’ parent-directed physical aggression (odds ratio [OR]: 1.25, 95% confidence interval [CI]: 1.0–1.55; p = .047), property damage (OR: 1.29, 95% CI: 1.1–1.5, p = .002), and verbal aggression (OR: 1.35, 95% CI: 1.15–1.6, p < .001) even controlling for adolescents’ sex, externalizing behaviors, and family income. When controlling for parents’ CPA, previous mother-to-adolescent aggression still predicted adolescents’ parent-directed physical aggression (OR: 5.56, 95% CI: 1.82–17.0, p = .003), and father-to-mother aggression predicted adolescents’ parent-directed verbal aggression (OR: 1.86, 95% CI: 1.0–3.3, p = .036). Emotion dysregulation and attitudes condoning aggression did not produce direct or moderated effects. Conclusions Adolescents’ parent-directed aggression deserves greater attention in discourse about lasting, adverse effects of even minor forms of parents’ physical aggression. Future research should investigate parent-directed aggression as

  7. An Aggressive Surgical Approach Leads to Improved Survival in Patients With Gallbladder Cancer

    PubMed Central

    Dixon, Elijah; Vollmer, Charles M.; Sahajpal, Ajay; Cattral, Mark; Grant, David; Doig, Christopher; Hemming, Al; Taylor, Bryce; Langer, Bernard; Greig, Paul; Gallinger, Steven

    2005-01-01

    Objective: To determine if an aggressive surgical approach, with an increase in R0 resections, has resulted in improved survival for patients with gallbladder cancer. Summary Background Data: Many physicians express a relatively nihilistic approach to the treatment of gallbladder cancer; consensus among surgeons regarding the indications for a radical surgical approach has not been reached. Methods: A retrospective review of all patients with gallbladder cancer admitted during the past 12 years was conducted. Ninety-nine patients were identified. Cases treated during the 12-year period 1990 to 2002 were divided into 2 time-period (TP) cohorts, those treated in the first 6 years (TP1, N = 35) and those treated in the last 6 years (TP2, N = 64). Results: Disease stratification by stage and other demographic features were similar in the 2 time periods. An operation with curative intent was performed on 38 patients. Nine (26%) R0 resections were performed in TP1 and 24 (38%) in TP2. The number of liver resections, as well as the frequency of extrahepatic biliary resections, was greater in TP2 (P < 0.04). In both time periods, an R0 resection was associated with improved survival (P < 0.02 TP1, P < 0.0001 TP2). Overall survival of all patients in TP2 was significantly greater than in TP1 (P < 0.03), with a median survival of 9 months in TP1 and 17 months in TP2. The median 5-year survival in TP1 was 7%, and 35% in TP2. The surgical mortality rate for the entire cohort was 2%, with a 49% morbidity rate. Conclusions: A margin-negative, R0 resection leads to improved survival in patients with gallbladder cancer. PMID:15729060

  8. Discovery of biochemical biomarkers for aggression: A role for metabolomics in psychiatry.

    PubMed

    Hagenbeek, Fiona A; Kluft, Cornelis; Hankemeier, Thomas; Bartels, Meike; Draisma, Harmen H M; Middeldorp, Christel M; Berger, Ruud; Noto, Antonio; Lussu, Milena; Pool, René; Fanos, Vassilios; Boomsma, Dorret I

    2016-07-01

    Human aggression encompasses a wide range of behaviors and is related to many psychiatric disorders. We introduce the different classification systems of aggression and related disorders as a basis for discussing biochemical biomarkers and then present an overview of studies in humans (published between 1990 and 2015) that reported statistically significant associations of biochemical biomarkers with aggression, DSM-IV disorders involving aggression, and their subtypes. The markers are of different types, including inflammation markers, neurotransmitters, lipoproteins, and hormones from various classes. Most studies focused on only a limited portfolio of biomarkers, frequently a specific class only. When integrating the data, it is clear that compounds from several biological pathways have been found to be associated with aggressive behavior, indicating complexity and the need for a broad approach. In the second part of the paper, using examples from the aggression literature and psychiatric metabolomics studies, we argue that a better understanding of aggression would benefit from a more holistic approach such as provided by metabolomics. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  9. Cancer Stem Cells: Cellular Plasticity, Niche, and its Clinical Relevance.

    PubMed

    Lee, Gina; Hall, Robert R; Ahmed, Atique U

    2016-10-01

    Cancer handles an estimated 7.6 million deaths worldwide per annum. A recent theory focuses on the role Cancer Stem Cells (CSCs) in driving tumorigenesis and disease progression. This theory hypothesizes that a population of the tumor cell with similar functional and phenotypic characteristics as normal tissue stem cells are responsible for formation and advancement of many human cancers. The CSCs subpopulation can differentiate into non-CSC tumor cells and promote phenotypic and functional heterogeneity within the tumor. The presence of CSCs has been reported in a number of human cancers including blood, breast, brain, colon, lung, pancreas prostate and liver. Although the origin of CSCs remains a mystery, recent reports suggest that the phenotypic characteristics of CSCs may be plastic and are influenced by the microenvironment specific for the individual tumor. Such factors unique to each tumor preserve the dynamic balance between CSCs to non-CSCs cell fate, as well as maintain the proper equilibrium. Alternating such equilibrium via dedifferentiation can result in aggressiveness, as CSCs are considered to be more resistant to the conventional cancer treatments of chemotherapy and radiation. Understanding how the tumoral microenvironment affects the plasticity driven CSC niche will be critical for developing a more effective treatment for cancer by eliminating its aggressive and recurring nature that now is believed to be perpetuated by CSCs.

  10. Human Prostate Cancer Hallmarks Map

    PubMed Central

    Datta, Dipamoy; Aftabuddin, Md.; Gupta, Dinesh Kumar; Raha, Sanghamitra; Sen, Prosenjit

    2016-01-01

    Human prostate cancer is a complex heterogeneous disease that mainly affects elder male population of the western world with a high rate of mortality. Acquisitions of diverse sets of hallmark capabilities along with an aberrant functioning of androgen receptor signaling are the central driving forces behind prostatic tumorigenesis and its transition into metastatic castration resistant disease. These hallmark capabilities arise due to an intense orchestration of several crucial factors, including deregulation of vital cell physiological processes, inactivation of tumor suppressive activity and disruption of prostate gland specific cellular homeostasis. The molecular complexity and redundancy of oncoproteins signaling in prostate cancer demands for concurrent inhibition of multiple hallmark associated pathways. By an extensive manual curation of the published biomedical literature, we have developed Human Prostate Cancer Hallmarks Map (HPCHM), an onco-functional atlas of human prostate cancer associated signaling and events. It explores molecular architecture of prostate cancer signaling at various levels, namely key protein components, molecular connectivity map, oncogenic signaling pathway map, pathway based functional connectivity map etc. Here, we briefly represent the systems level understanding of the molecular mechanisms associated with prostate tumorigenesis by considering each and individual molecular and cell biological events of this disease process. PMID:27476486

  11. Sphingosine 1-phosphate and human ether-a'-go-go-related gene potassium channels modulate migration in human anaplastic thyroid cancer cells.

    PubMed

    Asghar, Muhammad Yasir; Viitanen, Tero; Kemppainen, Kati; Törnquist, Kid

    2012-10-01

    Anaplastic thyroid cancer (ATC) is the most aggressive form of human thyroid cancer, lacking any effective treatment. Sphingosine 1-phosphate (S1P) receptors and human ether-a'-go-go-related gene (HERG (KCNH2)) potassium channels are important modulators of cell migration. In this study, we have shown that the S1P(1-3) receptors are expressed in C643 and THJ-16T human ATC cell lines, both at mRNA and protein level. S1P inhibited migration of these cells and of follicular FTC-133 thyroid cancer cells. Using the S1P(1,3) inhibitor VPC-23019, the S1P(2) inhibitor JTE-013, and the S1P(2) receptor siRNA, we showed that the effect was mediated through S1P(2). Treatment of the cells with the Rho inhibitor C3 transferase abolished the effect of S1P on migration. S1P attenuated Rac activity, and inhibiting Rac decreased migration. Sphingosine kinase inhibitor enhanced basal migration of cells, and addition of exogenous S1P inhibited migration. C643 cells expressed a nonconducting HERG protein, and S1P decreased HERG protein expression. The HERG blocker E-4031 decreased migration. Interestingly, downregulating HERG protein with siRNA decreased the basal migration. In experiments using HEK cells overexpressing HERG, we showed that S1P decreased channel protein expression and current and that S1P attenuated migration of the cells. We conclude that S1P attenuates migration of C643 ATC cells by activating S1P(2) and the Rho pathway. The attenuated migration is also, in part, dependent on a S1P-induced decrease of HERG protein.

  12. The human polyomavirus BK: Potential role in cancer.

    PubMed

    Fioriti, D; Videtta, M; Mischitelli, M; Degener, A M; Russo, G; Giordano, A; Pietropaolo, V

    2005-08-01

    In human cancer, a role has been suggested for the human polyomavirus BK, primarily associated with tubulointerstitial nephritis and ureteric stenosis in renal transplant recipients, and with hemorrhagic cystitis in bone marrow transplant (BMT) recipients. After the initial infection, primarily unapparent and without clinical signs, the virus disseminates and establishes a persistent infection in the urinary tract and lymphocytes. There is correlative evidence regarding potential role of polyomavirus BK in cancer. In fact, the BK virus (BKV) DNA (complete genome and/or subgenomic fragments containing the early region) is able to transform embryonic fibroblasts and cells cultured from kidney and brain of hamster, mouse, rat, rabbit, and monkey. Nevertheless, transformation of human cells by BKV is inefficient and often abortive. Evidence supporting a possible role for BKV in human cancer has accumulated slowly in recent years, after the advent of polymerase chain reaction (PCR). BKV is known to commonly establish persistent infections in people and to be excreted in the urine by individuals who are asymptomatic, complicating the evaluation of its potential role in development of human cancer. Therefore, there is no certain proof that human polyomavirus BK directly causes the cancer in humans or acts as a cofactor in the pathogenesis of some types of human cancer. (c) 2005 Wiley-Liss, Inc.

  13. Reduced expression of α-L-Fucosidase-1 (FUCA-1) predicts recurrence and shorter cancer specific survival in luminal B LN+ breast cancer patients.

    PubMed

    Bonin, Serena; Parascandolo, Alessia; Aversa, Cinzia; Barbazza, Renzo; Tsuchida, Nobuo; Castellone, Maria Domenica; Stanta, Giorgio; Vecchio, Giancarlo

    2018-03-16

    The lysosomal enzyme α-L-Fucosidase-1 (FUCA-1) catalyzes the hydrolytic cleavage of terminal fucose residues. FUCA-1 gene is down-regulated in highly aggressive and metastatic human tumors as its inactivation perturbs the fucosylation of proteins involved in cell adhesion, migration and metastases. Negativity to FUCA-1 was significantly related to the development of later recurrences in breast cancer patients with lymph node involvement at diagnosis. Cancer specific survival of luminal B LN+ patients was influenced by FUCA-1 expression as luminal B LN+ patients with positive expression had a longer cancer specific survival. FUCA-1 mRNA expression was inversely related to cancer stage and lymph node involvement. WB and qPCR analysis of FUCA-1 expression in breast cancer-derived cell lines confirmed an inverse relationship with tumor aggressiveness. This study shows that, within LN+ breast cancer patients, FUCA-1 is able to identify a sub-set of non recurrent patients characterized by the positive expression of FUCA-1 and that, within luminal B LN+ patients, the expression of FUCA-1 predicts longer cancer specific survival. We have analyzed FUCA-1 in 305 breast cancer patients by Immunohistochemistry (IHC), and by qPCR in breast cancer patients and in breast cancer cell lines.

  14. CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells. | Office of Cancer Genomics

    Cancer.gov

    Metabolic reprogramming by oncogenic signals promotes cancer initiation and progression. The oncogene KRAS and tumor suppressor STK11, which encodes the kinase LKB1, regulate metabolism and are frequently mutated in non-small-cell lung cancer(NSCLC). Concurrent occurrence of oncogenic KRAS and loss of LKB1 (KL) in cells specifies aggressive oncological behavior. Here we show that human KL cells and tumors share metabolic signatures of perturbed nitrogen handling.

  15. Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer.

    PubMed

    Sunamura, Makoto; Duda, Dan G; Ghattas, Maivel H; Lozonschi, Lucian; Motoi, Fuyuhiko; Yamauchi, Jun-Ichiro; Matsuno, Seiki; Shibahara, Shigeki; Abraham, Nader G

    2003-01-01

    Angiogenesis is necessary for the continued growth of solid tumors, invasion and metastasis. Several studies clearly showed that heme oxygenase-1 (HO-1) plays an important role in angiogenesis. In this study, we used the vital microscope system, transparent skinfold model, lung colonization model and transduced pancreatic cancer cell line (Panc-1)/human heme oxygenase-1 (hHO-1) cells, to precisely analyze, for the first time, the effect of hHO-1 gene on tumor growth, angiogenesis and metastasis. Our results revealed that HO-1 stimulates angiogenesis of pancreatic carcinoma in severe combined immune deficient mice. Overexpression of human hHO-1 after its retroviral transfer into Panc-1 cells did not interfere with tumor growth in vitro. While in vivo the development of tumors was accelerated upon transfection with hHO-1. On the other hand, inhibition of heme oxygenase (HO) activity by stannous mesoporphyrin was able transiently to delay tumor growth in a dose dependent manner. Tumor angiogenesis was markedly increased in Panc-1/hHO-1 compared to mock transfected and wild type. Lectin staining and Ki-67 proliferation index confirmed these results. In addition hHO-1 stimulated in vitro tumor angiogenesis and increased endothelial cell survival. In a lung colonization model, overexpression of hHO-1 increased the occurrence of metastasis, while inhibition of HO activity by stannous mesoporphyrin completely inhibited the occurrence of metastasis. In conclusion, overexpression of HO-1 genes potentiates pancreatic cancer aggressiveness, by increasing tumor growth, angiogenesis and metastasis and that the inhibition of the HO system may be of useful benefit for the future treatment of the disease.

  16. Aggression Can be Contagious: Longitudinal Associations between Proactive Aggression and Reactive Aggression Among Young Twins

    PubMed Central

    Dickson, Daniel J.; Richmond, Ashley; Brendgen, Mara; Vitaro, Frank; Laursen, Brett; Dionne, Ginette; Boivin, Michel

    2015-01-01

    The present study examined sibling influence over reactive and proactive aggression in a sample of 452 same-sex twins (113 male dyads, 113 female dyads). Between and within siblings influence processes were examined as a function of relative levels of parental coercion and hostility to test the hypothesis that aggression contagion between twins occurs only among dyads who experience parental coerciveness. Teacher reports of reactive and proactive aggression were collected for each twin in kindergarten (M = 6.04 years; SD = 0.27) and in first grade (M = 7.08 years; SD = 0.27). Families were divided into relatively low, average, and relatively high parental coercion-hostility groups on the basis of maternal reports collected when the children were 5 years old. In families with relatively high levels of parental coercion-hostility, there was evidence of between-sibling influence, such that one twin’s reactive aggression at age 6 predicted increases in the other twin’s reactive aggression from ages 6 to 7, and one twin’s proactive aggression at age 6 predicted increases in the other twin’s proactive aggression from ages 6 to 7. There was also evidence of within-sibling influence such that a child’s level of reactive aggression at age 6 predicted increases in the same child’s proactive aggression at age 7, regardless of parental coercion-hostility. The findings provide new information about the etiology of reactive and proactive aggression and individual differences in their developmental interplay. PMID:25683448

  17. Aggression can be contagious: Longitudinal associations between proactive aggression and reactive aggression among young twins.

    PubMed

    Dickson, Daniel J; Richmond, Ashley D; Brendgen, Mara; Vitaro, Frank; Laursen, Brett; Dionne, Ginette; Boivin, Michel

    2015-01-01

    The present study examined sibling influence over reactive and proactive aggression in a sample of 452 same-sex twins (113 male dyads, 113 female dyads). Between and within siblings influence processes were examined as a function of relative levels of parental coercion and hostility to test the hypothesis that aggression contagion between twins occurs only among dyads who experience parental coerciveness. Teacher reports of reactive and proactive aggression were collected for each twin in kindergarten (M = 6.04 years; SD = 0.27) and in first grade (M = 7.08 years; SD = 0.27). Families were divided into relatively low, average, and relatively high parental coercion-hostility groups on the basis of maternal reports collected when the children were 5 years old. In families with relatively high levels of parental coercion-hostility, there was evidence of between-sibling influence, such that one twin's reactive aggression at age 6 predicted increases in the other twin's reactive aggression from ages 6 to 7, and one twin's proactive aggression at age 6 predicted increases in the other twin's proactive aggression from ages 6 to 7. There was also evidence of within-sibling influence such that a child's level of reactive aggression at age 6 predicted increases in the same child's proactive aggression at age 7, regardless of parental coercion-hostility. The findings provide new information about the etiology of reactive and proactive aggression and individual differences in their developmental interplay. © 2015 Wiley Periodicals, Inc.

  18. Endothelin-1 Expression in Prostate Needle Biopsy Specimens Correlated With Aggressiveness of Prostatic Cancer

    PubMed Central

    Asgari, Mojgan; Eftekhar, Elham; Abolhasani, Maryam; Shahrokh, Hossein

    2017-01-01

    Background & Objective: As the prostate adenocarcinoma is one of the most common malignant tumors in males, looking for a marker to effectively predict aggressiveness and metastatic potential in an apparently localized cancer in initial needle biopsy specimens can help the clinicians to make more appropriate decision for treatment, planning, and choosing appropriate targeted therapy. The present study assessed the value of Endothelin-1 expression to predict prognosis of prostatic cancer Methods: In a cross sectional study, 83 patients who underwent radical prostatectomy in Hasheminejad Kidney Center in 2008 through 2012 were assigned to two groups including 43 with and 40 without extra-prostatic extension (EPE). Endothelin-1 staining was performed on Paraffin Embedded blocks of preoperative needle biopsies. Results: The expression of Endothelin-1 increased in 72% of patients in the group with EPE (P<0.001). The group with Endothelin-1 positivity showed higher serum level of prostate specific antigen (PSA) (p = 0.039). Endothelin-1 expression was positive in 67% of patients with perineurial invasion (P<0.001). Adjusting the baseline variables of PSA and PN in a multivariable logistic regression model, the Endothelin-1 positivity could effectively predict EPE in patients with prostatic cancer (OR: 5.46, p = 0.010). Conclusion: Correlation of Endothelin-1 expression in needle biopsy specimens in expected with extra-prostatic extension of tumor in radical prostatectomy specimens, perineurial invasion and serum PSA level at the time of diagnosis. PMID:29515640

  19. Mild expression differences of MECP2 influencing aggressive social behavior.

    PubMed

    Tantra, Martesa; Hammer, Christian; Kästner, Anne; Dahm, Liane; Begemann, Martin; Bodda, Chiranjeevi; Hammerschmidt, Kurt; Giegling, Ina; Stepniak, Beata; Castillo Venzor, Aracely; Konte, Bettina; Erbaba, Begun; Hartmann, Annette; Tarami, Asieh; Schulz-Schaeffer, Walter; Rujescu, Dan; Mannan, Ashraf U; Ehrenreich, Hannelore

    2014-05-01

    The X-chromosomal MECP2/Mecp2 gene encodes methyl-CpG-binding protein 2, a transcriptional activator and repressor regulating many other genes. We discovered in male FVB/N mice that mild (~50%) transgenic overexpression of Mecp2 enhances aggression. Surprisingly, when the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This suggests that Mecp2 modulates aggressive social behavior. To test this hypothesis in humans, we performed a phenotype-based genetic association study (PGAS) in >1000 schizophrenic individuals. We found MECP2 SNPs rs2239464 (G/A) and rs2734647 (C/T; 3'UTR) associated with aggression, with the G and C carriers, respectively, being more aggressive. This finding was replicated in an independent schizophrenia cohort. Allele-specific MECP2 mRNA expression differs in peripheral blood mononuclear cells by ~50% (rs2734647: C > T). Notably, the brain-expressed, species-conserved miR-511 binds to MECP2 3'UTR only in T carriers, thereby suppressing gene expression. To conclude, subtle MECP2/Mecp2 expression alterations impact aggression. While the mouse data provides evidence of an interaction between genetic background and mild Mecp2 overexpression, the human data convey means by which genetic variation affects MECP2 expression and behavior.

  20. A definition for aggressive disease in patients with HER-2 negative metastatic breast cancer: an expert consensus of the Spanish Society of Medical Oncology (SEOM).

    PubMed

    González, A; Lluch, A; Aba, E; Albanell, J; Antón, A; Álvarez, I; Ayala, F; Barnadas, A; Calvo, L; Ciruelos, E; Cortés, J; de la Haba, J; López-Vega, J M; Martínez, E; Muñoz, M; Peláez, I; Redondo, A; Rodríguez, Á; Rodríguez, C A; Ruíz, A; Llombart, A

    2017-05-01

    To converge on an expert opinion to define aggressive disease in patients with HER2-negative mBC using a modified Delphi methodology. A panel of 21 breast cancer experts from the Spanish Society of Medical Oncology agreed upon a survey which comprised 47 questions that were grouped into three sections: relevance for defining aggressive disease, aggressive disease criteria and therapeutic goals. Answers were rated using a 9-point Likert scale of relevance or agreement. Among the 88 oncologists that were invited to participate, 81 answered the first round (92%), 70 answered the second round (80%), and 67 answered the third round (76%) of the survey. There was strong agreement regarding the fact that identifying patients with aggressive disease needs to be adequately addressed to help practitioners to decide the best treatment options for patients with HER2-negative mBC. The factors that were considered to be strongly relevant to classifying patients with aggressive HER2-negative mBC were a high tumor burden, a disease-free interval of less than 12-24 months after surgery, the presence of progressive disease during adjuvant or neoadjuvant chemotherapy and having a triple-negative phenotype. The main therapeutic goals were controlling symptoms, improving quality of life and increasing the time to progression and overall survival. High tumor burden, time to recurrence after prior therapy and having a triple-negative phenotype were the prognostic factors for which the greatest consensus was found for identifying patients with aggressive HER2-negative mBC. Identifying patients with aggressive disease leads to different therapeutic approaches.

  1. Endoplasmic reticulum factor ERLIN2 regulates cytosolic lipid content in cancer cells

    PubMed Central

    Wang, Guohui; Zhang, Xuebao; Lee, Jin-Sook; Wang, Xiaogang; Yang, Zeng-Quan; Zhang, Kezhong

    2013-01-01

    Increased de novo lipogenesis is a hallmark of aggressive cancers. Lipid droplets, the major form of cytosolic lipid storage, have been implicated in cancer cell proliferation and tumorigenesis. Recently, we identified the ERLIN2 [ER (endoplasmic reticulum) lipid raft-associated 2) gene that is amplified and overexpressed in aggressive human breast cancer. Previous studies demonstrated that ERLIN2 plays a supporting oncogenic role by facilitating the transformation of human breast cancer cells. In the present study, we found that ERLIN2 supports cancer cell growth by regulating cytosolic lipid droplet production. ERLIN2 is preferably expressed in human breast cancer cells or hepatoma cells and is inducible by insulin signalling or when cells are cultured in lipoprotein-deficient medium. Increased expression of ERLIN2 promotes the accumulation of cytosolic lipid droplets in breast cancer cells or hepatoma cells in response to insulin or overload of unsaturated fatty acids. ERLIN2 regulates activation of SREBP (sterol regulatory element-binding protein) 1c, the key regulator of de novo lipogenesis, in cancer cells. ERLIN2 was found to bind to INSIG1 (insulin-induced gene 1), a key ER membrane protein that blocks SREBP activation. Consistent with the role of ERLIN2 in regulating cytosolic lipid content, down-regulation of ERLIN2 in breast cancer or hepatoma cells led to lower cell proliferation rates. The present study revealed a novel role for ERLIN2 in supporting cancer cell growth by promoting the activation of the key lipogenic regulator SREBP1c and the production of cytosolic lipid droplets. The identification of ERLIN2 as a regulator of cytosolic lipid content in cancer cells has important implications for understanding the molecular basis of tumorigenesis and the treatment of cancer. PMID:22690709

  2. From hitting to tattling to gossip: an evolutionary rationale for the development of indirect aggression.

    PubMed

    Ingram, Gordon P D

    2014-04-29

    Adult humans are characterized by low rates of intra-group physical aggression. Since children tend to be more physically aggressive, an evolutionary developmental account shows promise for explaining how physical aggression is suppressed in adults. I argue that this is achieved partly through extended dominance hierarchies, based on indirect reciprocity and linguistic transmission of reputational information, mediated by indirectly aggressive competition. Reviewing the literature on indirect and related forms of aggression provides three pieces of evidence for the claim that evolutionarily old impulses towards physical aggression are socialized into indirect aggression in humans: (i) physical aggression falls in early childhood over the same age range at which indirect aggression increases; (ii) the same individuals engage in both direct and indirect aggression; and (iii) socially dominant individuals practice indirect aggression more frequently. Consideration of the developmental course of indirect aggression is complemented by analysis of similar developments in verbal behaviors that are not always thought of as aggressive, namely tattling and gossip. An important puzzle concerns why indirect aggression becomes more covert, and tattling more derogated, in preadolescence and adolescence. This may be due to the development of new strategies aimed at renegotiating social identity and friendship alliances in the peer group.

  3. School Aggression and Dispositional Aggression among Middle School Boys

    ERIC Educational Resources Information Center

    Ballard, Mary E.; Rattley, Kelvin T.; Fleming, Willie C.; Kidder-Ashley, Pamela

    2004-01-01

    We examined the relationship between dispositional (trait) aggression and administrative reports of school aggression among 100 adolescent male participants from an urban middle school. Aggression was fairly common among the sample; 58 boys had a record of school aggression, and many of those were repeat offenders. Our hypothesis that those higher…

  4. Tocotrienols promote apoptosis in human breast cancer cells by inducing poly(ADP-ribose) polymerase cleavage and inhibiting nuclear factor kappa-B activity.

    PubMed

    Loganathan, R; Selvaduray, K R; Nesaretnam, K; Radhakrishnan, A K

    2013-04-01

    Tocotrienols and tocopherols are members of the vitamin E family, with similar structures; however, only tocotrienols have been reported to achieve potent anti-cancer effects. The study described here has evaluated anti-cancer activity of vitamin E to elucidate mechanisms of cell death, using human breast cancer cells. Anti-cancer activity of a tocotrienol-rich fraction (TRF) and a tocotrienol-enriched fraction (TEF) isolated from palm oil, as well as pure vitamin E analogues (α-tocopherol, α-, δ- and γ-tocotrienols) were studied using highly aggressive triple negative MDA-MB-231 cells and oestrogen-dependent MCF-7 cells, both of human breast cancer cell lines. Cell population growth was evaluated using a Coulter particle counter. Cell death mechanism, poly(ADP-ribose) polymerase cleavage and levels of NF-κB were determined using commercial ELISA kits. Tocotrienols exerted potent anti-proliferative effects on both types of cell by inducing apoptosis, the underlying mechanism of cell death being ascertained using respective IC50 concentrations of all test compounds. There was marked induction of apoptosis in both cell lines by tocotrienols compared to treatment with Paclitaxel, which was used as positive control. This activity was found to be associated with cleavage of poly(ADP-ribose) polymerase (a DNA repair protein), demonstrating involvement of the apoptotic cell death signalling pathway. Tocotrienols also inhibited expression of nuclear factor kappa-B (NF-κB), which in turn can increase sensitivity of cancer cells to apoptosis. Tocotrienols induced anti-proliferative and apoptotic effects in association with DNA fragmentation, poly(ADP-ribose) polymerase cleavage and NF-κB inhibition in the two human breast cancer cell lines. © 2013 Blackwell Publishing Ltd.

  5. Higher serum concentrations of vimentin and DAKP1 are associated with aggressive breast tumour phenotypes in Ghanaian women.

    PubMed

    Arko-Boham, Benjamin; Lomotey, Justice Tanihu; Tetteh, Emmanuel Nomo; Tagoe, Emmanuel Ayitey; Aryee, Nii Ayite; Owusu, Ewurama Ampadu; Okai, Isaac; Blay, Richard Michael; Clegg-Lamptey, Joe-Nat

    2017-01-01

    Breast cancer, the most commonly diagnosed cancer among women and leading cause of cancer-related deaths worldwide, exhibits aggressive behavior in indigenous African women evidenced by high histologic grade tumours with low hormone receptor positivity. Aggressive breast cancers grow quickly, easily metastasize and recur and often have unfavourable outcomes. The current study investigated candidate genes that may regulate tumour aggression in Ghanaian women. We hypothesize that increased expression and function of certain genes other than the widely-held view attributing breast cancer aggression in African populations to their younger population age may be responsible for the aggressive nature of tumours. Employing ELISA, we assayed for vimentin and death-associated protein kinase 1 (DAPK1) from thawed archived (stored at -80 °C) serum samples obtained from 40 clinically confirmed Ghanaian breast cancer patients and 40 apparently healthy controls. Patients' clinical records and tumour parameters matching the samples were retrieved from the database of the hospital. ANOVA was used to compare means of serum protein concentration among groups while Chi-square analysis was used for the categorical data sets with p -value ≤0.05 considered significant. Multiple logistic regression analysis was conducted to determine the association between protein concentration and tumour parameters. Of the 80 samples, 27 (33.8%) and 53 (66.2%) were from young (<35 years) and old (≥35 years), respectively. Vimentin and DAPK1 concentration were higher in patients than controls with higher levels in "young" age group than "old" age group. Vimentin concentration was highest in grade 3 tumours followed by grade 2 and 1 but that for DAPK1 was not significant. For vimentin, tumour area strongly correlated with tumour grade ( r  = 0.696, p  < 0.05) but weakly correlated with tumour stage ( r  = 0.420, p  < 0.05). Patient's age correlated with DAPK1 concentration ( r  = 0

  6. The global cancer burden and human development: A review.

    PubMed

    Fidler, Miranda M; Bray, Freddie; Soerjomataram, Isabelle

    2018-02-01

    This review examines the links between human development and cancer overall and for specific types of cancer, as well as cancer-related risk-factors and outcomes, such as disability and life expectancy. To assess human development, the Human Development Index was utilized continuously and according to four levels (low, medium, high, very high), where the low and very high categories include the least and most developed countries, respectively. All studies that assessed aspects of the global cancer burden using this measure were reviewed. Although the present cancer incidence burden is greater in higher Human Development Index countries, a greater proportion of the global mortality burden is observed in less developed countries, with a higher mean fatality rate in the latter countries. Further, the future cancer burden is expected to disproportionally affect less developed regions; in particular, it has been estimated that low and medium Human Development Index countries will experience a 100% and 81% increase in cancer incidence from 2008 to 2030, respectively. Disparities were also observed in risk factors and average health outcomes, such as a greater number of years of life lost prematurely and fewer cancer-related gains in life expectancy observed in lower versus higher Human Development Index settings. From a global perspective, there remain clear disparities in the cancer burden according to national Human Development Index scores. International efforts are needed to aid countries in social and economic transition in order to efficiently plan, implement and evaluate cancer control initiatives as a means to reduce the widening gap in cancer occurrence and survival worldwide.

  7. CONCEPT ANALYSIS: AGGRESSION

    PubMed Central

    Liu, Jianghong

    2006-01-01

    The concept of aggression is important to nursing because further knowledge of aggression can help generate a better theoretical model to drive more effective intervention and prevention approaches. This paper outlines a conceptual analysis of aggression. First, the different forms of aggression are reviewed, including the clinical classification and the stimulus-based classification. Then the manifestations and measurement of aggression are described. Finally, the causes and consequences of aggression are outlined. It is argued that a better understanding of aggression and the causal factors underlying it are essential for learning how to prevent negative aggression in the future. PMID:15371137

  8. Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis

    PubMed Central

    Murase, Ryuichi; Christian, Rigel T.; Lau, Darryl; Zielinski, Anne J.; Allison, Juanita; Almanza, Carolina; Pakdel, Arash; Lee, Jasmine; Limbad, Chandani; Liu, Yong; Debs, Robert J.; Moore, Dan H.; Desprez, Pierre-Yves

    2012-01-01

    Invasion and metastasis of aggressive breast cancer cells are the final and fatal steps during cancer progression. Clinically, there are still limited therapeutic interventions for aggressive and metastatic breast cancers available. Therefore, effective, targeted, and non-toxic therapies are urgently required. Id-1, an inhibitor of basic helix-loop-helix transcription factors, has recently been shown to be a key regulator of the metastatic potential of breast and additional cancers. We previously reported that cannabidiol (CBD), a cannabinoid with a low toxicity pro-file, down-regulated Id-1 gene expression in aggressive human breast cancer cells in culture. Using cell proliferation and invasion assays, cell flow cytometry to examine cell cycle and the formation of reactive oxygen species, and Western analysis, we determined pathways leading to the down-regulation of Id-1 expression by CBD and consequently to the inhibition of the proliferative and invasive phenotype of human breast cancer cells. Then, using the mouse 4T1 mammary tumor cell line and the ranksum test, two different syngeneic models of tumor metastasis to the lungs were chosen to determine whether treatment with CBD would reduce metastasis in vivo. We show that CBD inhibits human breast cancer cell proliferation and invasion through differential modulation of the extracellular signal-regulated kinase (ERK) and reactive oxygen species (ROS) pathways, and that both pathways lead to down-regulation of Id-1 expression. Moreover, we demonstrate that CBD up-regulates the pro-differentiation factor, Id-2. Using immune competent mice, we then show that treatment with CBD significantly reduces primary tumor mass as well as the size and number of lung metastatic foci in two models of metastasis. Our data demonstrate the efficacy of CBD in pre-clinical models of breast cancer. The results have the potential to lead to the development of novel non-toxic compounds for the treatment of breast cancer metastasis

  9. Sense of control and adolescents' aggression: The role of aggressive cues.

    PubMed

    Guo, Xucheng; Egan, Vincent; Zhang, Jianxin

    2016-12-01

    The misperception of aggressive cues is considered a risk factor for inducing adolescent aggression. Poor coping with life stress is also considered a major influence on aggression. The current study examined the relationship between subjective sense of control and adolescent aggression, considering influences upon the perception of these aggressive cues. In Study 1, 60 participants took part in a 2 (sense of control: high sense of control vs. low sense of control) × 2 (aggressive cue: aggressive vs. neutral) between-subjects contextual experiment. The result found that a lower sense of control led to an increase in adolescents' aggression; only in the low-sense-of-control condition did exposure to aggressive cues boost aggression. In Study 2, the catalytic effect of aggressive cues was further explored by an experiment in which 40 adolescents were randomly assigned to a low- or high-sense-of-control condition to test the importance of aggressive cues. The results suggest that adolescents in the low-sense-of-control condition show a higher salience for aggressive cues. © 2016 The Institute of Psychology, Chinese Academy of Sciences and John Wiley & Sons Australia, Ltd.

  10. Subjective aggression during alcohol and cannabis intoxication before and after aggression exposure.

    PubMed

    De Sousa Fernandes Perna, E B; Theunissen, E L; Kuypers, K P C; Toennes, S W; Ramaekers, J G

    2016-09-01

    Alcohol and cannabis use have been implicated in aggression. Alcohol consumption is known to facilitate aggression, whereas a causal link between cannabis and aggression has not been clearly demonstrated. This study investigated the acute effects of alcohol and cannabis on subjective aggression in alcohol and cannabis users, respectively, following aggression exposure. Drug-free controls served as a reference. It was hypothesized that aggression exposure would increase subjective aggression in alcohol users during alcohol intoxication, whereas it was expected to decrease subjective aggression in cannabis users during cannabis intoxication. Heavy alcohol (n = 20) and regular cannabis users (n = 21), and controls (n = 20) were included in a mixed factorial study. Alcohol and cannabis users received single doses of alcohol and placebo or cannabis and placebo, respectively. Subjective aggression was assessed before and after aggression exposure consisting of administrations of the point-subtraction aggression paradigm (PSAP) and the single category implicit association test (SC-IAT). Testosterone and cortisol levels in response to alcohol/cannabis treatment and aggression exposure were recorded as secondary outcome measures. Subjective aggression significantly increased following aggression exposure in all groups while being sober. Alcohol intoxication increased subjective aggression whereas cannabis decreased the subjective aggression following aggression exposure. Aggressive responses during the PSAP increased following alcohol and decreased following cannabis relative to placebo. Changes in aggressive feeling or response were not correlated to the neuroendocrine response to treatments. It is concluded that alcohol facilitates feelings of aggression whereas cannabis diminishes aggressive feelings in heavy alcohol and regular cannabis users, respectively.

  11. Human pancreatic cancer xenografts recapitulate key aspects of cancer cachexia.

    PubMed

    Delitto, Daniel; Judge, Sarah M; Delitto, Andrea E; Nosacka, Rachel L; Rocha, Fernanda G; DiVita, Bayli B; Gerber, Michael H; George, Thomas J; Behrns, Kevin E; Hughes, Steven J; Wallet, Shannon M; Judge, Andrew R; Trevino, Jose G

    2017-01-03

    Cancer cachexia represents a debilitating syndrome that diminishes quality of life and augments the toxicities of conventional treatments. Cancer cachexia is particularly debilitating in patients with pancreatic cancer (PC). Mechanisms responsible for cancer cachexia are under investigation and are largely derived from observations in syngeneic murine models of cancer which are limited in PC. We evaluate the effect of human PC cells on both muscle wasting and the systemic inflammatory milieu potentially contributing to PC-associated cachexia. Specifically, human PC xenografts were generated by implantation of pancreatic cancer cells, L3.6pl and PANC-1, either in the flank or orthotopically within the pancreas. Mice bearing orthotopic xenografts demonstrated significant muscle wasting and atrophy-associated gene expression changes compared to controls. Further, despite the absence of adaptive immunity, splenic tissue from orthotopically engrafted mice demonstrated elevations in several pro-inflammatory cytokines associated with cancer cachexia, including TNFα, IL1β, IL6 and KC (murine IL8 homologue), when compared to controls. Therefore, data presented here support further investigation into the complexity of cancer cachexia in PC to identify potential targets for this debilitating syndrome.

  12. Tryptophan, kynurenine, and kynurenine metabolites: Relationship to lifetime aggression and inflammatory markers in human subjects

    PubMed Central

    Coccaro, Emil F.; Lee, Royce; Fanning, Jennifer R.; Fuchs, Dietmar; Goiny, Michel; Erhardt, Sophie; Christensen, Kyle; Brundin, Lena; Coussons-Read, Mary

    2017-01-01

    Inflammatory proteins are thought to be causally involved in the generation of aggression, possibly due to direct effects of cytokines in the central nervous system and/or by generation of inflammatory metabolites along the tryptophan-kynurenine (TRP/KYN) pathway, including KYN and its active metabolites kynurenic acid (KA), quinolinic acid (QA), and picolinic acid (PA). We examined plasma levels of TRP, KYN, KA, QA, and PA in 172 medication-free, medically healthy, human subjects to determine if plasma levels of these substances are altered as a function of trait aggression, and if they correlate with current plasma levels of inflammatory markers. Plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6), and soluble interleukin-1 receptor-II (sIL-1RII) protein were also available in these subjects. We found normal levels of TRP but reduced plasma levels of KYN (by 48%), QA (by 6%), and a QA/KA (by 5%) ratio in subjects with Intermittent Explosive Disorder (IED) compared to healthy controls and psychiatric controls. Moreover, the metabolites were not associated with any of the inflammatory markers studied. These data do not support the hypothesis that elevated levels of KYN metabolites would be present in plasma of subjects with IED, and associated with plasma inflammation. However, our data do point to a dysregulation of the KYN pathway metabolites in these subjects. Further work will be necessary to replicate these findings and to understand their role in inflammation and aggression in these subjects. PMID:27318828

  13. The Relationship Between Coat Color and Aggressive Behaviors in the Domestic Cat.

    PubMed

    Stelow, Elizabeth A; Bain, Melissa J; Kass, Philip H

    2016-01-01

    The authors explored a possible relationship between coat color and aggressive behaviors in the domestic cat. This study used an Internet-based survey to collect information on coat color, affiliative behaviors toward cats/humans, agonistic behaviors toward cats/humans, other "problem" behaviors, and cat and guardian demographic data. A total of 1,432 cat guardians completed the online survey; after exclusions based on study protocol, data analysis included 1,274 completed surveys. Guardians reported sex-linked orange female (tortoiseshells, calicos, and "torbies"), black-and-white, and gray-and-white cats to be more frequently aggressive toward humans in 3 settings: during everyday interactions, during handling, and during veterinary visits. Kruskal-Wallis 1-way analysis of variance was used to compare possible differences between the 2 sexes and among different coat colors. Analyses of aggression due to handling, as well as aggression displayed during veterinarian visits, showed little difference among coat colors in these settings.

  14. Region 2 of 8q24 is associated with the risk of aggressive prostate cancer in Caribbean men of African descent from Guadeloupe (French West Indies)

    PubMed Central

    Cancel-Tassin, Geraldine; Romana, Marc; Gaffory, Cecile; Blanchet, Pascal; Cussenot, Olivier; Multigner, Luc

    2015-01-01

    Multiple regions of the genome have been associated with the risk of prostate cancer in Caucasians, particularly including several polymorphisms located at 8q24. Region 2 of 8q24 has been repeatedly found to be associated with the risk of prostate cancer among men of African descent, although one study performed in the Caribbean island of Jamaica did not report this finding. In this study, the single nucleotide polymorphism rs16901979, located in region 2 of 8q24, was genotyped in 498 cases of histologically confirmed prostate cancer and 541 controls from the French Caribbean islands of Guadeloupe, where the population is largely of African descent. The AA genotype and the A allele at rs16901979 were associated with elevated risks of prostate cancer (odds ratios [ORs] = 1.84, 95% confidence interval [95% CI] = 1.26–2.69, P = 0.002 and OR = 1.36, 95% CI = 1.13–1.64, P = 0.001, respectively). Following stratification of the patients by disease aggressiveness, as defined by the Gleason score, the pooled genotypes AC + AA were associated with a higher risk of a Gleason score ≥7 at diagnosis (OR = 1.79, 95% CI = 1.17–2.73, P = 0.007). In summary, the A allele at rs16901979 was associated with the risk of prostate cancer in the Caribbean population of Guadeloupe, confirming its involvement in populations of African descent. Moreover, our study provides the first evidence of an association between this variant and the risk of aggressive prostate cancer. PMID:25130587

  15. Integrin activation controls metastasis in human breast cancer

    NASA Astrophysics Data System (ADS)

    Felding-Habermann, Brunhilde; O'Toole, Timothy E.; Smith, Jeffrey W.; Fransvea, Emilia; Ruggeri, Zaverio M.; Ginsberg, Mark H.; Hughes, Paul E.; Pampori, Nisar; Shattil, Sanford J.; Saven, Alan; Mueller, Barbara M.

    2001-02-01

    Metastasis is the primary cause of death in human breast cancer. Metastasis to bone, lungs, liver, and brain involves dissemination of breast cancer cells via the bloodstream and requires adhesion within the vasculature. Blood cell adhesion within the vasculature depends on integrins, a family of transmembrane adhesion receptors, and is regulated by integrin activation. Here we show that integrin v3 supports breast cancer cell attachment under blood flow conditions in an activation-dependent manner. Integrin v3 was found in two distinct functional states in human breast cancer cells. The activated, but not the nonactivated, state supported tumor cell arrest during blood flow through interaction with platelets. Importantly, activated αvβ3 was expressed by freshly isolated metastatic human breast cancer cells and variants of the MDA-MB 435 human breast cancer cell line, derived from mammary fat pad tumors or distant metastases in severe combined immunodeficient mice. Expression of constitutively activated mutant αvβ3D723R, but not αvβ3WT, in MDA-MB 435 cells strongly promoted metastasis in the mouse model. Thus breast cancer cells can exhibit a platelet-interactive and metastatic phenotype that is controlled by the activation of integrin αvβ3. Consequently, alterations within tumors that lead to the aberrant control of integrin activation are expected to adversely affect the course of human breast cancer.

  16. HUMAN PROSTATE CANCER RISK FACTORS

    EPA Science Inventory

    Prostate cancer has the highest prevalence of any non-skin cancer in the human body, with similar likelihood of neoplastic foci found within the prostates of men around the world regardless of diet, occupation, lifestyle, or other factors. Essentially all men with circulating an...

  17. A mouse model for human anal cancer.

    PubMed

    Stelzer, Marie K; Pitot, Henry C; Liem, Amy; Schweizer, Johannes; Mahoney, Charles; Lambert, Paul F

    2010-12-01

    Human anal cancers are associated with high-risk human papillomaviruses (HPV) that cause other anogenital cancers and head and neck cancers. As with other cancers, HPV16 is the most common high-risk HPV in anal cancers. We describe the generation and characterization of a mouse model for human anal cancer. This model makes use of K14E6 and K14E7 transgenic mice in which the HPV16 E6 and E7 genes are directed in their expression to stratified squamous epithelia. HPV16 E6 and E7 possess oncogenic properties including, but not limited to, their capacity to inactivate the cellular tumor suppressors p53 and pRb, respectively. Both E6 and E7 were found to be functionally expressed in the anal epithelia of K14E6/K14E7 transgenic mice. To assess the susceptibility of these mice to anal cancer, mice were treated topically with dimethylbenz[a]anthracene (DMBA), a chemical carcinogen that is known to induce squamous cell carcinomas in other sites. Nearly 50% of DMBA-treated HPV16 E6/E7 transgenic mice showed overt signs of tumors, whereas none of the like-treated nontransgenic mice showed tumors. Histopathologic analyses confirmed that the HPV16 transgenic mice were increased in their susceptibility to anal cancers and precancerous lesions. Biomarker analyses demonstrated that these mouse anal cancers exhibit properties that are similar to those observed in HPV-positive precursors to human anal cancer. This is the first mouse model for investigating the contributions of viral and cellular factors in anal carcinogenesis, and should provide a platform for assessing new therapeutic modalities for treating and/or preventing this type of cancer. ©2010 AACR.

  18. A Mouse Model for Human Anal Cancer

    PubMed Central

    Stelzer, Marie K.; Pitot, Henry C.; Liem, Amy; Schweizer, Johannes; Mahoney, Charles; Lambert, Paul F.

    2010-01-01

    Human anal cancers are associated with high-risk human papillomaviruses (HPVs) that cause other anogenital cancers and head and neck cancers. As with other cancers, HPV16 is the most common high-risk HPV in anal cancers. We describe the generation and characterization of a mouse model for human anal cancer. This model makes use of K14E6 and K14E7 transgenic mice in which the HPV16 E6 and E7 genes are directed in their expression to stratified squamous epithelia. HPV16 E6 and E7 possess oncogenic properties including but not limited to their capacity to inactivate the cellular tumor suppressors p53 and pRb, respectively. Both E6 and E7 were found to be functionally expressed in the anal epithelia of K14E6/K14E7 transgenic mice. To assess the susceptibility of these mice to anal cancer, mice were treated topically with dimethylbenz[a]anthracene (DMBA), a chemical carcinogen that is known to induce squamous cell carcinomas in other sites. Nearly 50% of DMBA-treated HPV16 E6/E7 transgenic mice showed overt signs of tumors; whereas, none of the like treated non-transgenic mice showed tumors. Histopathological analyses confirmed that the HPV16 transgenic mice were increased in their susceptibility to anal cancers and precancerous lesions. Biomarker analyses demonstrated that these mouse anal cancers exhibit properties that are similar to those observed in HPV-positive precursors to human anal cancer. This is the first mouse model for investigating the contributions of viral and cellular factors in anal carcinogenesis, and should provide a platform for assessing new therapeutic modalities for treating and/or preventing this type of cancer. PMID:20947489

  19. Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes.

    PubMed

    Dobroff, Andrey S; D'Angelo, Sara; Eckhardt, Bedrich L; Ferrara, Fortunato; Staquicini, Daniela I; Cardó-Vila, Marina; Staquicini, Fernanda I; Nunes, Diana N; Kim, Kisu; Driessen, Wouter H P; Hajitou, Amin; Lomo, Lesley C; Barry, Marc; Krishnamurthy, Savitri; Sahin, Aysegul; Woodward, Wendy A; Prossnitz, Eric R; Anderson, Robin L; Dias-Neto, Emmanuel; Brown-Glaberman, Ursa A; Royce, Melanie E; Ueno, Naoto T; Cristofanilli, Massimo; Hortobagyi, Gabriel N; Marchiò, Serena; Gelovani, Juri G; Sidman, Richard L; Arap, Wadih; Pasqualini, Renata

    2016-10-24

    Inflammatory breast carcinoma (IBC) is one of the most lethal forms of human breast cancer, and effective treatment for IBC is an unmet clinical need in contemporary oncology. Tumor-targeted theranostic approaches are emerging in precision medicine, but only a few specific biomarkers are available. Here we report up-regulation of the 78-kDa glucose-regulated protein (GRP78) in two independent discovery and validation sets of specimens derived from IBC patients, suggesting translational promise for clinical applications. We show that a GRP78-binding motif displayed on either bacteriophage or adeno-associated virus/phage (AAVP) particles or loop-grafted onto a human antibody fragment specifically targets orthotopic IBC and other aggressive breast cancer models in vivo. To evaluate the theranostic value, we used GRP78-targeting AAVP particles to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) transgene, obtaining simultaneous in vivo diagnosis through PET imaging and tumor treatment by selective activation of the prodrug ganciclovir at tumor sites. Translation of this AAVP system is expected simultaneously to image, monitor, and treat the IBC phenotype and possibly other aggressive (e.g., invasive and/or metastatic) subtypes of breast cancer, based on the inducible cell-surface expression of the stress-response chaperone GRP78, and possibily other cell-surface receptors in human tumors.

  20. War: Anthropologists and Sociologists Ask Whether Warfare and Aggression are Inherited or Learned

    ERIC Educational Resources Information Center

    Trotter, Robert J.

    1973-01-01

    Presents opposing philosophies relating to the nature of aggression in man. One position advocates that human aggression is the product of evolution and is inherited, while the other proposes a cultural pattern model of aggression and uses two empirical tests in an attempt to disprove the genetic model. (JR)

  1. Glycolysis is the primary bioenergetic pathway for cell motility and cytoskeletal remodeling in human prostate and breast cancer cells.

    PubMed

    Shiraishi, Takumi; Verdone, James E; Huang, Jessie; Kahlert, Ulf D; Hernandez, James R; Torga, Gonzalo; Zarif, Jelani C; Epstein, Tamir; Gatenby, Robert; McCartney, Annemarie; Elisseeff, Jennifer H; Mooney, Steven M; An, Steven S; Pienta, Kenneth J

    2015-01-01

    The ability of a cancer cell to detach from the primary tumor and move to distant sites is fundamental to a lethal cancer phenotype. Metabolic transformations are associated with highly motile aggressive cellular phenotypes in tumor progression. Here, we report that cancer cell motility requires increased utilization of the glycolytic pathway. Mesenchymal cancer cells exhibited higher aerobic glycolysis compared to epithelial cancer cells while no significant change was observed in mitochondrial ATP production rate. Higher glycolysis was associated with increased rates of cytoskeletal remodeling, greater cell traction forces and faster cell migration, all of which were blocked by inhibition of glycolysis, but not by inhibition of mitochondrial ATP synthesis. Thus, our results demonstrate that cancer cell motility and cytoskeleton rearrangement is energetically dependent on aerobic glycolysis and not oxidative phosphorylation. Mitochondrial derived ATP is insufficient to compensate for inhibition of the glycolytic pathway with regard to cellular motility and CSK rearrangement, implying that localization of ATP derived from glycolytic enzymes near sites of active CSK rearrangement is more important for cell motility than total cellular ATP production rate. These results extend our understanding of cancer cell metabolism, potentially providing a target metabolic pathway associated with aggressive disease.

  2. Glycolysis is the primary bioenergetic pathway for cell motility and cytoskeletal remodeling in human prostate and breast cancer cells

    PubMed Central

    Shiraishi, Takumi; Verdone, James E.; Huang, Jessie; Kahlert, Ulf D.; Hernandez, James R.; Torga, Gonzalo; Zarif, Jelani C.; Epstein, Tamir; Gatenby, Robert; McCartney, Annemarie; Elisseeff, Jennifer H.; Mooney, Steven M.; An, Steven S.; Pienta, Kenneth J.

    2015-01-01

    The ability of a cancer cell to detach from the primary tumor and move to distant sites is fundamental to a lethal cancer phenotype. Metabolic transformations are associated with highly motile aggressive cellular phenotypes in tumor progression. Here, we report that cancer cell motility requires increased utilization of the glycolytic pathway. Mesenchymal cancer cells exhibited higher aerobic glycolysis compared to epithelial cancer cells while no significant change was observed in mitochondrial ATP production rate. Higher glycolysis was associated with increased rates of cytoskeletal remodeling, greater cell traction forces and faster cell migration, all of which were blocked by inhibition of glycolysis, but not by inhibition of mitochondrial ATP synthesis. Thus, our results demonstrate that cancer cell motility and cytoskeleton rearrangement is energetically dependent on aerobic glycolysis and not oxidative phosphorylation. Mitochondrial derived ATP is insufficient to compensate for inhibition of the glycolytic pathway with regard to cellular motility and CSK rearrangement, implying that localization of ATP derived from glycolytic enzymes near sites of active CSK rearrangement is more important for cell motility than total cellular ATP production rate. These results extend our understanding of cancer cell metabolism, potentially providing a target metabolic pathway associated with aggressive disease. PMID:25426557

  3. Influence of the neural microenvironment on prostate cancer

    PubMed Central

    Coarfa, Christian; Florentin, Diego; Putluri, NagiReddy; Ding, Yi; Au, Jason; He, Dandan; Ragheb, Ahmed; Frolov, Anna; Michailidis, George; Lee, MinJae; Kadmon, Dov; Miles, Brian; Smith, Christopher; Ittmann, Michael; Rowley, David; Sreekumar, Arun; Creighton, Chad J.

    2017-01-01

    Background Nerves are key factors in prostate cancer (PCa), but the functional role of innervation in prostate cancer is poorly understood. PCa induced neurogenesis and perineural invasion (PNI), are associated with aggressive disease. Method We denervated rodent prostates chemically and physically, before orthotopically implanting cancer cells. We also performed a human neoadjuvant clinical trial using botulinum toxin type A (Botox) and saline in the same patient, before prostatectomy. Result Bilateral denervation resulted in reduced tumor incidence and size in mice. Botox treatment in humans resulted in increased apoptosis of cancer cells in the Botox treated side. A similar denervation gene array profile was identified in tumors arising in denervated rodent prostates, in spinal cord injury patients and in the Botox treated side of patients. Denervation induced exhibited a signature gene profile, indicating translation and bioenergetic shutdown. Nerves also regulate basic cellular functions of non‐neoplastic epithelial cells. Conclusion Nerves play a role in the homeostasis of normal epithelial tissues and are involved in prostate cancer tumor survival. This study confirms that interactions between human cancer and nerves are essential to disease progression. This work may make a major impact in general cancer treatment strategies, as nerve/cancer interactions are likely important in other cancers as well. Targeting the neural microenvironment may represent a therapeutic approach for the treatment of human prostate cancer. PMID:29131367

  4. Influence of the neural microenvironment on prostate cancer.

    PubMed

    Coarfa, Christian; Florentin, Diego; Putluri, NagiReddy; Ding, Yi; Au, Jason; He, Dandan; Ragheb, Ahmed; Frolov, Anna; Michailidis, George; Lee, MinJae; Kadmon, Dov; Miles, Brian; Smith, Christopher; Ittmann, Michael; Rowley, David; Sreekumar, Arun; Creighton, Chad J; Ayala, Gustavo

    2018-02-01

    Nerves are key factors in prostate cancer (PCa), but the functional role of innervation in prostate cancer is poorly understood. PCa induced neurogenesis and perineural invasion (PNI), are associated with aggressive disease. We denervated rodent prostates chemically and physically, before orthotopically implanting cancer cells. We also performed a human neoadjuvant clinical trial using botulinum toxin type A (Botox) and saline in the same patient, before prostatectomy. Bilateral denervation resulted in reduced tumor incidence and size in mice. Botox treatment in humans resulted in increased apoptosis of cancer cells in the Botox treated side. A similar denervation gene array profile was identified in tumors arising in denervated rodent prostates, in spinal cord injury patients and in the Botox treated side of patients. Denervation induced exhibited a signature gene profile, indicating translation and bioenergetic shutdown. Nerves also regulate basic cellular functions of non-neoplastic epithelial cells. Nerves play a role in the homeostasis of normal epithelial tissues and are involved in prostate cancer tumor survival. This study confirms that interactions between human cancer and nerves are essential to disease progression. This work may make a major impact in general cancer treatment strategies, as nerve/cancer interactions are likely important in other cancers as well. Targeting the neural microenvironment may represent a therapeutic approach for the treatment of human prostate cancer. © 2017 The Authors. The Prostate Published by Wiley Periodicals, Inc.

  5. Cerebrospinal fluid and plasma C-reactive protein and aggression in personality-disordered subjects: a pilot study.

    PubMed

    Coccaro, Emil F; Lee, Royce; Coussons-Read, Mary

    2015-02-01

    C-reactive protein (CRP), in the plasma, serves as a marker of systemic inflammation and has been shown to correlate with history of actual aggressive behavior, and as a personality trait of aggressive tendency, in human subjects. This pilot study was conducted to determine if plasma CRP levels are correlated with cerebrospinal fluid levels (CSF CRP) and if CSF CRP also correlates with aggression. If so, this would suggest a role for central inflammatory processes in human aggression. Both plasma and basal lumbar CSF samples were obtained from 17 subjects with DSM-5 personality disorder and assayed for CRP. Plasma and CSF CRP levels were correlated (r = 0.65, p = 0.005) and each correlated with aggression (Plasma: r = 0.53, p = 0.029; CSF: r = 0.84, p < 0.001). When considered simultaneously, CSF CRP, but not plasma CRP, uniquely correlated with aggression. No relationship was seen with other measures of psychopathology. These data suggest a positive relationship between central nervous system CRP and aggression in humans.

  6. Effects of Intranasal Oxytocin on Aggressive Responding in Antisocial Personality Disorder.

    PubMed

    Alcorn, Joseph L; Rathnayaka, Nuvan; Swann, Alan C; Moeller, F Gerard; Lane, Scott D

    2015-12-01

    The oxytocin receptor is important in several domains of social behavior, and administration of oxytocin modulates social responding in several mammalian species, including humans. Oxytocin has both therapeutic and scientific potential for elucidating the neural and behavioral mechanisms governing social behavior. In the present study, operationally-defined aggressive behavior of six males with Antisocial Personality Disorder (ASPD) was measured following acute intranasal oxytocin dosing (12, 24, and 48 international units) and placebo, using a well-validated laboratory task of human aggression (Point-Subtraction Aggression Paradigm, or PSAP). The PSAP provides participants with concurrently available monetary-earning and operationally-defined aggressive response options, maintained by fixed ratio schedules of consequences. Shifts in response rates and inter-response time (IRT) distributions were observed on the aggressive response option following oxytocin doses, relative to placebo. Few changes were observed in monetary-reinforced responding. However, across participants the direction and magnitude of changes in aggressive responding were not systematically related to dose. No trends were observed between psychometric or physiological data and oxytocin dosing or aggressive behavior. While this report is to our knowledge the first to examine the acute effects of oxytocin in this population at high risk for violence and other forms of antisocial behavior, several limitations in the experimental design and the results cast the study as a preliminary report. Strategies for more extensive future projects are discussed.

  7. Genetic Mutation and Exosome Signature of Human Papilloma Virus Associated Oropharyngeal Cancer

    PubMed Central

    Kannan, Anbarasu; Hertweck, Kate L.; Philley, Julie V.; Wells, Robert B.; Dasgupta, Santanu

    2017-01-01

    Human papilloma virus-16 (HPV-16) associated oropharyngeal cancer (HPVOPC) is increasing alarmingly in the United States. We performed whole genome sequencing of a 44 year old, male HPVOPC subject diagnosed with moderately differentiated tonsillar carcinoma. We identified new somatic mutation in MUC16 (A.k.a. CA-125), MUC12, MUC4, MUC6, MUC2, SIRPA, HLA-DRB1, HLA-A and HLA-B molecules. Increased protein expression of MUC16, SIRPA and decreased expression of HLA-DRB1 was further demonstrated in this HPVOPC subject and an additional set of 15 HPVOPC cases. Copy number gain (3 copies) was also observed for MUC2, MUC4, MUC6 and SIRPA. Enhanced expression of MUC16, SIRPA and HPV-16-E7 protein was detectable in the circulating exosomes of numerous HPVOPC subjects. Treatment of non-tumorigenic mammary epithelial cells with exosomes derived from aggressive HPVOPC cells harboring MUC16, SIRPA and HPV-16-E7 proteins augmented invasion and induced epithelial to mesenchymal transition (EMT) accompanied by an increased expression ratio of the EMT markers Vimentin/E-cadherin. Exosome based screening of key HPVOPC associated molecules could be beneficial for early cancer diagnosis, monitoring and surveillance. PMID:28383029

  8. Mild expression differences of MECP2 influencing aggressive social behavior

    PubMed Central

    Tantra, Martesa; Hammer, Christian; Kästner, Anne; Dahm, Liane; Begemann, Martin; Bodda, Chiranjeevi; Hammerschmidt, Kurt; Giegling, Ina; Stepniak, Beata; Castillo Venzor, Aracely; Konte, Bettina; Erbaba, Begun; Hartmann, Annette; Tarami, Asieh; Schulz-Schaeffer, Walter; Rujescu, Dan; Mannan, Ashraf U; Ehrenreich, Hannelore

    2014-01-01

    The X-chromosomal MECP2/Mecp2 gene encodes methyl-CpG-binding protein 2, a transcriptional activator and repressor regulating many other genes. We discovered in male FVB/N mice that mild (∼50%) transgenic overexpression of Mecp2 enhances aggression. Surprisingly, when the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This suggests that Mecp2 modulates aggressive social behavior. To test this hypothesis in humans, we performed a phenotype-based genetic association study (PGAS) in >1000 schizophrenic individuals. We found MECP2 SNPs rs2239464 (G/A) and rs2734647 (C/T; 3′UTR) associated with aggression, with the G and C carriers, respectively, being more aggressive. This finding was replicated in an independent schizophrenia cohort. Allele-specific MECP2mRNA expression differs in peripheral blood mononuclear cells by ∼50% (rs2734647: C > T). Notably, the brain-expressed, species-conserved miR-511 binds to MECP2 3′UTR only in T carriers, thereby suppressing gene expression. To conclude, subtle MECP2/Mecp2 expression alterations impact aggression. While the mouse data provides evidence of an interaction between genetic background and mild Mecp2 overexpression, the human data convey means by which genetic variation affects MECP2 expression and behavior. PMID:24648499

  9. Signaling aggression.

    PubMed

    van Staaden, Moira J; Searcy, William A; Hanlon, Roger T

    2011-01-01

    From psychological and sociological standpoints, aggression is regarded as intentional behavior aimed at inflicting pain and manifested by hostility and attacking behaviors. In contrast, biologists define aggression as behavior associated with attack or escalation toward attack, omitting any stipulation about intentions and goals. Certain animal signals are strongly associated with escalation toward attack and have the same function as physical attack in intimidating opponents and winning contests, and ethologists therefore consider them an integral part of aggressive behavior. Aggressive signals have been molded by evolution to make them ever more effective in mediating interactions between the contestants. Early theoretical analyses of aggressive signaling suggested that signals could never be honest about fighting ability or aggressive intentions because weak individuals would exaggerate such signals whenever they were effective in influencing the behavior of opponents. More recent game theory models, however, demonstrate that given the right costs and constraints, aggressive signals are both reliable about strength and intentions and effective in influencing contest outcomes. Here, we review the role of signaling in lieu of physical violence, considering threat displays from an ethological perspective as an adaptive outcome of evolutionary selection pressures. Fighting prowess is conveyed by performance signals whose production is constrained by physical ability and thus limited to just some individuals, whereas aggressive intent is encoded in strategic signals that all signalers are able to produce. We illustrate recent advances in the study of aggressive signaling with case studies of charismatic taxa that employ a range of sensory modalities, viz. visual and chemical signaling in cephalopod behavior, and indicators of aggressive intent in the territorial calls of songbirds. Copyright © 2011 Elsevier Inc. All rights reserved.

  10. Linking Y-chromosomal short tandem repeat loci to human male impulsive aggression.

    PubMed

    Yang, Chun; Ba, Huajie; Cao, Yin; Dong, Guoying; Zhang, Shuyou; Gao, Zhiqin; Zhao, Hanqing; Zhou, Xianju

    2017-11-01

    Men are more susceptible to impulsive behavior than women. Epidemiological studies revealed that the impulsive aggressive behavior is affected by genetic factors, and the male-specific Y chromosome plays an important role in this behavior. In this study, we investigated the association between the impulsive aggressive behavior and Y-chromosomal short tandem repeats (Y-STRs) loci. The collected biologic samples from 271 offenders with impulsive aggressive behavior and 492 healthy individuals without impulsive aggressive behavior were amplified by PowerPlex R Y23 PCR System and the resultant products were separated by electrophoresis and further genotyped. Then, comparisons in allele and haplotype frequencies of the selected 22 Y-STRs were made in the two groups. Our results showed that there were significant differences in allele frequencies at DYS448 and DYS456 between offenders and controls ( p  < .05). Univariate analysis further revealed significant frequency differences for alleles 18 and 22 at DYS448 (0.18 vs 0.27, compared to the controls, p  = .003, OR=0.57,95% CI=0.39-0.82; 0.03 vs 0.01, compared to the controls, p  = .003, OR=7.45, 95% CI=1.57-35.35, respectively) and for allele 17 at DYS456 (0.07 vs 0.14, compared to the controls, p  = .006, OR=0.48, 95% CI =0.28-0.82) between two groups. Interestingly, the frequency of haploid haplotype 22-15 on the DYS448-DYS456 (DYS448-DYS456-22-15) was significantly higher in offenders than in controls (0.033 vs 0.004, compared to the control, p  = .001, OR = 8.42, 95%CI =1.81-39.24). Moreover, there were no significant differences in allele frequencies of other Y-STRs loci between two groups. Furthermore, the unconditional logistic regression analysis confirmed that alleles 18 and 22 at DYS448 and allele 17 at DYS456 are associated with male impulsive aggression. However, the DYS448-DYS456-22-15 is less related to impulsive aggression. Our results suggest a link between Y-chromosomal allele types and male

  11. NOTCH2 signaling confers immature morphology and aggressiveness in human hepatocellular carcinoma cells

    PubMed Central

    HAYASHI, YOSHIHIRO; OSANAI, MAKOTO; LEE, GANG-HONG

    2015-01-01

    The NOTCH family of membranous receptors plays key roles during development and carcinogenesis. Since NOTCH2, yet not NOTCH1 has been shown essential for murine hepatogenesis, NOTCH2 rather than NOTCH1 may be more relevant to human hepatocarcinogenesis; however, no previous studies have supported this hypothesis. We therefore assessed the role of NOTCH2 in human hepatocellular carcinoma (HCC) by immunohistochemistry and cell culture. Immunohistochemically, 19% of primary HCCs showed nuclear staining for NOTCH2, indicating activated NOTCH2 signaling. NOTCH2-positive HCCs were on average in more advanced clinical stages, and exhibited more immature cellular morphology, i.e. higher nuclear-cytoplasmic ratios and nuclear densities. Such features were not evident in NOTCH1-positive HCCs. In human HCC cell lines, abundant NOTCH2 expression was associated with anaplasia, represented by loss of E-cadherin. When NOTCH2 signaling was stably downregulated in HLF cells, an anaplastic HCC cell line, the cells were attenuated in potential for in vitro invasiveness and migration, as well as in vivo tumorigenicity accompanied by histological maturation. Generally, inverse results were obtained for a differentiated HCC cell line, Huh7, manipulated to overexpress activated NOTCH2. These findings suggested that the NOTCH2 signaling may confer aggressive behavior and immature morphology in human HCC cells. PMID:26252838

  12. NOTCH2 signaling confers immature morphology and aggressiveness in human hepatocellular carcinoma cells.

    PubMed

    Hayashi, Yoshihiro; Osanai, Makoto; Lee, Gang-Hong

    2015-10-01

    The NOTCH family of membranous receptors plays key roles during development and carcinogenesis. Since NOTCH2, yet not NOTCH1 has been shown essential for murine hepatogenesis, NOTCH2 rather than NOTCH1 may be more relevant to human hepatocarcinogenesis; however, no previous studies have supported this hypothesis. We therefore assessed the role of NOTCH2 in human hepatocellular carcinoma (HCC) by immunohistochemistry and cell culture. Immunohistochemically, 19% of primary HCCs showed nuclear staining for NOTCH2, indicating activated NOTCH2 signaling. NOTCH2-positive HCCs were on average in more advanced clinical stages, and exhibited more immature cellular morphology, i.e. higher nuclear-cytoplasmic ratios and nuclear densities. Such features were not evident in NOTCH1‑positive HCCs. In human HCC cell lines, abundant NOTCH2 expression was associated with anaplasia, represented by loss of E-cadherin. When NOTCH2 signaling was stably downregulated in HLF cells, an anaplastic HCC cell line, the cells were attenuated in potential for in vitro invasiveness and migration, as well as in vivo tumorigenicity accompanied by histological maturation. Generally, inverse results were obtained for a differentiated HCC cell line, Huh7, manipulated to overexpress activated NOTCH2. These findings suggested that the NOTCH2 signaling may confer aggressive behavior and immature morphology in human HCC cells.

  13. PO-12 - The key role of talin-1 in cancer cell extravasation dissected through human vascularized 3D microfluidic model.

    PubMed

    Gilardi, M; Bersini, S; Calleja, A Boussomier; Kamm, R D; Vanoni, M; Moretti, M

    2016-04-01

    Metastases are responsible for more than 90% of cancer related mortality. The hematogenous metastatic invasion is a complex process in which the endothelium plays a key role. Extravasation is a dynamic process involving remodeling and change in cell shape and in cytoskeleton whereby a series of strongly dependent interactions between CTCs and endothelium occurs [1]. Talins are proteins regulating focal adhesions and cytoskeleton remodeling. Talin-1 seems to be involved in the aggressiveness, motility, survival and invadopodia formation of cancer cells throughout the entire metastatic cascade [2], being up-regulated in breast cancer cells and mutated in sarcomas. Understand the implication of talin-1 in extravasation could facilitate the design of new therapies and finally fight cancer. We hypothesized that Talin-1 could be specifically involved in extravasation driving each of its steps. We developed a human 3D microfluidic model that enables the study of human cancer cell extravasation within a perfusable human microvascularized organ specific environment[3]. For the study of extravasation we applied microfluidic approach through the development of a microfluidic device in which endothelial cells and fibroblasts generated a 3D human functional vascular networks. Microvessel characterization was performed with immunofluorescence and permeability assays. We knocked-down talin-1 in triple negative breast cancer cell line MDA-MB231 and metastatic fibro-sarcoma cell line HT1080 with SiRNA and verified by Western-blot. Cancer cells were then perfused in the vessels and extravasation monitored through confocal imaging. We developed a human vascularized 3D microfluidic device with human perfusable capillary-like structures embedded in fibrin matrix, characterized by mature endothelium markers and physiological permeability (1.5±0.76)×10(-6) cm/s. We focused on the role of Talin-1 in adhesion to endothelium, trans-endothelial migration (TEM) and early invasion. Adhesion

  14. Epidemiologic studies of the human microbiome and cancer.

    PubMed

    Vogtmann, Emily; Goedert, James J

    2016-02-02

    The human microbiome, which includes the collective genome of all bacteria, archaea, fungi, protists, and viruses found in and on the human body, is altered in many diseases and may substantially affect cancer risk. Previously detected associations of individual bacteria (e.g., Helicobacter pylori), periodontal disease, and inflammation with specific cancers have motivated studies considering the association between the human microbiome and cancer risk. This short review summarises microbiome research, focusing on published epidemiological associations with gastric, oesophageal, hepatobiliary, pancreatic, lung, colorectal, and other cancers. Large, prospective studies of the microbiome that employ multidisciplinary laboratory and analysis methods, as well as rigorous validation of case status, are likely to yield translational opportunities to reduce cancer morbidity and mortality by improving prevention, screening, and treatment.

  15. Epidemiologic studies of the human microbiome and cancer

    PubMed Central

    Vogtmann, Emily; Goedert, James J

    2016-01-01

    The human microbiome, which includes the collective genome of all bacteria, archaea, fungi, protists, and viruses found in and on the human body, is altered in many diseases and may substantially affect cancer risk. Previously detected associations of individual bacteria (e.g., Helicobacter pylori), periodontal disease, and inflammation with specific cancers have motivated studies considering the association between the human microbiome and cancer risk. This short review summarises microbiome research, focusing on published epidemiological associations with gastric, oesophageal, hepatobiliary, pancreatic, lung, colorectal, and other cancers. Large, prospective studies of the microbiome that employ multidisciplinary laboratory and analysis methods, as well as rigorous validation of case status, are likely to yield translational opportunities to reduce cancer morbidity and mortality by improving prevention, screening, and treatment. PMID:26730578

  16. Epidemiology of virus infection and human cancer.

    PubMed

    Chen, Chien-Jen; Hsu, Wan-Lun; Yang, Hwai-I; Lee, Mei-Hsuan; Chen, Hui-Chi; Chien, Yin-Chu; You, San-Lin

    2014-01-01

    The International Agency for Research on Cancer (IARC) has comprehensively assessed the human carcinogenicity of biological agents. Seven viruses including Epstein-Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), Kaposi's sarcoma herpes virus (KSHV), human immunodeficiency virus, type-1 (HIV-1), human T cell lymphotrophic virus, type-1 (HTLV-1), and human papillomavirus (HPV) have been classified as Group 1 human carcinogens by IARC. The conclusions are based on the findings of epidemiological and mechanistic studies. EBV, HPV, HTLV-1, and KSHV are direct carcinogens; HBV and HCV are indirect carcinogens through chronic inflammation; HIV-1 is an indirect carcinogen through immune suppression. Some viruses may cause more than one cancer, while some cancers may be caused by more than one virus. However, only a proportion of persons infected by these oncogenic viruses will develop specific cancers. A series of studies have been carried out to assess the viral, host, and environmental cofactors of EBV-associated nasopharyngeal carcinoma, HBV/HCV-associated hepatocellular carcinoma, and HPV-associated cervical carcinoma. Persistent infection and high viral load are important risk predictors of these virus-caused cancers. Risk calculators incorporating host and viral factors have also been developed for the prediction of long-term risk of hepatocellular carcinoma. These risk calculators are useful for the triage and clinical management of infected patients. Both clinical trials and national programs of immunization or antiviral therapy have demonstrated a significant reduction in the incidence of cancers caused by HBV, HCV, and HPV. Future researches on gene-gene and gene-environment interaction of oncogenic viruses and human host are in urgent need.

  17. Aurora-A Oncogene in Human Ovarian Cancer

    DTIC Science & Technology

    2006-11-01

    AD_________________ Award Number: W81XWH-05-1-0021 TITLE: Aurora-A Oncogene in Human Ovarian... in Human Ovarian Cancer 5b. GRANT NUMBER W81XWH-05-1-0021 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER Jin Q. Cheng, M.D...is frequently altered in human ovarian cancer (1). Overexpressing Aurora-A induces centrosome amplification and G2/M cell cycle progression

  18. Aggression By Whom–Aggression Toward Whom: Behavioral Predictors of Same- and Other-Gender Aggression in Early Childhood

    PubMed Central

    Hanish, Laura D.; Sallquist, Julie; DiDonato, Matthew; Fabes, Richard A.; Martin, Carol Lynn

    2012-01-01

    This study assessed girls’ and boys’ dominance-related behaviors (aggressive, commanding, submissive, and neutral behaviors) as they naturally occurred during interactions with male and female peers and evaluated the possibility that such behaviors elicit aggression from peers. Using a focal observational procedure, young girls’ and boys’ (N = 170; 54% boys) naturally occurring dominance-related behaviors and male and female peers’ aggressive responses to those behaviors were recorded multiple times each week across the academic year. Findings suggested that same-gender aggression occurred at similar rates as other-gender aggression once tendencies toward gender segregated play were controlled. Additionally, there were both gender-based similarities and differences in children’s use of dominance-related behaviors in peer interactions and as antecedents for peers’ aggression. The findings have implications for the literatures on aggression and gendered peer interactions. PMID:22369337

  19. Overview of Genetically Engineered Mouse Models of Papillary and Anaplastic Thyroid Cancers: Enabling Translational Biology for Patient Care Improvement.

    PubMed

    Charles, Roch-Philippe

    2015-06-01

    The prognosis from thyroid cancer subtypes in humans covers a spectrum from "cured at almost 90%" to "100% lethal." Invasive and poorly differentiated forms of thyroid cancer are among the most aggressive human cancers, and there are few effective therapeutic options. Genetically engineered mice, based on mutations observed in patients, can accurately recapitulate the human disease and its progression, providing invaluable tools for the preclinical evaluation of novel therapeutic approaches. This overview details models developed to date as well as their uses for identifying novel anticancer agents. Copyright © 2013 John Wiley & Sons, Inc. All rights reserved.

  20. Religiousness and aggression in adolescents: The mediating roles of self-control and compassion.

    PubMed

    Shepperd, James A; Miller, Wendi A; Smith, Colin Tucker

    2015-01-01

    Although people have used religion to justify aggression, evidence suggests that greater religiousness corresponds with less aggression. We explored two explanations for the religion-aggression link. First, most major religions teach self-control (e.g., delaying gratification, resisting temptation), which diminishes aggression. Second, most major religions emphasize compassionate beliefs and behavior (i.e., perspective taking, forgiveness, a broader love of humanity) that are incompatible with aggression. We tested whether self-control and compassion mediated the relationship between religion and aggression (direct and indirect) in a longitudinal study of 1,040 adolescents in the United States. Structural equation analyses revealed that self-control and compassion together completely mediated the religion-aggression relationship for both types of aggression. © 2015 Wiley Periodicals, Inc.

  1. Expression profiles of SnoN in normal and cancerous human tissues support its tumor suppressor role in human cancer.

    PubMed

    Jahchan, Nadine S; Ouyang, Gaoliang; Luo, Kunxin

    2013-01-01

    SnoN is a negative regulator of TGF-β signaling and also an activator of the tumor suppressor p53 in response to cellular stress. Its role in human cancer is complex and controversial with both pro-oncogenic and anti-oncogenic activities reported. To clarify its role in human cancer and provide clinical relevance to its signaling activities, we examined SnoN expression in normal and cancerous human esophageal, ovarian, pancreatic and breast tissues. In normal tissues, SnoN is expressed in both the epithelium and the surrounding stroma at a moderate level and is predominantly cytoplasmic. SnoN levels in all tumor epithelia examined are lower than or similar to that in the matched normal samples, consistent with its anti-tumorigenic activity in epithelial cells. In contrast, SnoN expression in the stroma is highly upregulated in the infiltrating inflammatory cells in high-grade esophageal and ovarian tumor samples, suggesting that SnoN may potentially promote malignant progression through modulating the tumor microenvironment in these tumor types. The overall levels of SnoN expression in these cancer tissues do not correlate with the p53 status. However, in human cancer cell lines with amplification of the snoN gene, a strong correlation between increased SnoN copy number and inactivation of p53 was detected, suggesting that the tumor suppressor SnoN-p53 pathway must be inactivated, either through downregulation of SnoN or inactivation of p53, in order to allow cancer cell to proliferate and survive. These data strongly suggest that SnoN can function as a tumor suppressor at early stages of tumorigenesis in human cancer tissues.

  2. Agreeableness and alcohol-related aggression: the mediating effect of trait aggressivity.

    PubMed

    Miller, Cameron A; Parrott, Dominic J; Giancola, Peter R

    2009-12-01

    This study investigated the mediating effect of trait aggressivity on the relation between agreeableness and alcohol-related aggression in a laboratory setting. Participants were 116 healthy male social drinkers between 21 and 30 years of age. Agreeableness and trait aggressivity were measured using the Big Five Inventory and the Buss-Perry Aggression Questionnaire, respectively. Following the consumption of an alcohol or no-alcohol control beverage, participants completed a modified version of the Taylor Aggression Paradigm, in which electric shocks were received from and administered to a fictitious opponent during a competitive task. Aggression was operationalized as the proportion of the most extreme shocks delivered to the fictitious opponent under conditions of low and high provocation. Results indicated that lower levels of agreeableness were associated with higher levels of trait aggressivity. In turn, higher levels of trait aggressivity predicted extreme aggression in intoxicated, but not sober, participants under low, but not high, provocation. Findings highlight the importance of examining determinants of intoxicated aggression within a broader theoretical framework of personality.

  3. Normative beliefs about aggression and cyber aggression among young adults: a longitudinal investigation.

    PubMed

    Wright, Michelle F; Li, Yan

    2013-01-01

    This longitudinal study examined normative beliefs about aggression (e.g., face-to-face, cyber) in relation to the engagement in cyber aggression 6 months later among 126 (69 women) young adults. Participants completed electronically administered measures assessing their normative beliefs, face-to-face and cyber aggression at Time 1, and cyber aggression 6 months later (Time 2). We found that men reported more cyber relational and verbal aggression when compared to women. After controlling for each other, Time 1 face-to-face relational aggression was positively related to Time 2 cyber relational aggression, whereas Time 1 face-to-face verbal aggression was positively related to Time 2 cyber verbal aggression. Normative beliefs regarding cyber aggression was positively related to both forms of cyber aggression 6 months later, after controlling for normative beliefs about face-to-face aggression. Furthermore, a significant two-way interaction between Time 1 cyber relational aggression and normative beliefs about cyber relational aggression was found. Follow-up analysis showed that Time 1 cyber relational aggression was more strongly related to Time 2 cyber relational aggression when young adults held higher normative beliefs about cyber relational aggression. A similar two-way interaction was found for cyber verbal aggression such that the association between Time 1 and Time 2 cyber verbal aggression was stronger at higher levels of normative beliefs about cyber verbal aggression. Results are discussed in terms of the social cognitive and behavioral mechanisms associated with the engagement of cyber aggression. © 2013 Wiley Periodicals, Inc.

  4. Muscarine- and carbachol-induced aggressions: fear and irritable kinds of aggressions.

    PubMed

    Beleslin, D B; Samardzić, R

    1977-12-28

    In unaneasthetized and unrestrained cats, muscarine and carbachol were injected into the cerebral ventricles. The kind of aggressive behaviour depended on the cholinomimetic drug and was classified as fear and an irritable kind of aggression. Muscarine induced the fear kind of aggression. The aggressive behaviour was usually preceded by attempts to escape and the attack was relevant to the situation. For the attack the presence of some threatening agent was needed. The aggression was accompanied by intense motor but less autonomic activation. On the other hand, carbachol induced an irritable kind of aggression and had the following characteristics: for the attack the presence of some threatening agent was not needed; the attack was not relevant to the situation; the aggression was not preceded by attempts to escape; and the aggressive behaviour was accompanied by intense motor and autonomic activation. It is concluded that cholinoceptive mechanisms are involved in the control of aggressive behaviour.

  5. The Art of Interpreting Epigenetic Activity | Center for Cancer Research

    Cancer.gov

    Even though all the cells of the human body share a common genomic blueprint, epigenetic activity such as DNA methylation, introduces molecular diversity that results in functionally and biologically different cellular constituents. In cancers, this ability of epigenetic activity to introduce molecular diversity is emerging as a powerful classifier of biological aggressiveness.

  6. In Vitro and In Vivo Activity of IMGN853, an Antibody-Drug Conjugate Targeting Folate Receptor Alpha Linked to DM4, in Biologically Aggressive Endometrial Cancers.

    PubMed

    Altwerger, Gary; Bonazzoli, Elena; Bellone, Stefania; Egawa-Takata, Tomomi; Menderes, Gulden; Pettinella, Francesca; Bianchi, Anna; Riccio, Francesco; Feinberg, Jacqueline; Zammataro, Luca; Han, Chanhee; Yadav, Ghanshyam; Dugan, Katherine; Morneault, Ashley; Ponte, Jose F; Buza, Natalia; Hui, Pei; Wong, Serena; Litkouhi, Babak; Ratner, Elena; Silasi, Dan-Arin; Huang, Gloria S; Azodi, Masoud; Schwartz, Peter E; Santin, Alessandro D

    2018-05-01

    Grade 3 endometrioid and uterine serous carcinomas (USC) account for the vast majority of endometrial cancer deaths. The purpose of this study was to determine folic acid receptor alpha (FRα) expression in these biologically aggressive (type II) endometrial cancers and evaluate FRα as a targetable receptor for IMGN853 (mirvetuximab soravtansine). The expression of FRα was evaluated by immunohistochemistry (IHC) and flow cytometry in 90 endometrioid and USC samples. The in vitro cytotoxic activity and bystander effect were studied in primary uterine cancer cell lines expressing differential levels of FRα. In vivo antitumor efficacy of IMGN853 was evaluated in xenograft/patient-derived xenograft (PDX) models. Semiquantitative IHC analysis indicated that 41% of the USC patients overexpress FRα. Further, overexpression of FRα (i.e., 2+) was detected via flow cytometry in 22% (2/9) of primary endometrioid and in 27% (3/11) of primary USC cell lines. Increased cytotoxicity was seen with IMGN853 treatment compared with control in 2+ expressing uterine tumor cell lines. In contrast, tumor cell lines with low FRα showed no difference when exposed to IMGN853 versus control. IMGN853 induced bystander killing of FRα = 0 tumor cells. In an endometrioid xenograft model (END(K)265), harboring 2+ FRα, IMGN853 treatment showed complete resolution of tumors ( P < 0.001). Treatment with IMGN853 in the USC PDX model (BIO(K)1), expressing 2+ FRα, induced twofold increase in median survival ( P < 0.001). IMGN853 shows impressive antitumor activity in biologically aggressive FRα 2+ uterine cancers. These preclinical data suggest that patients with chemotherapy resistant/recurrent endometrial cancer overexpressing FRα may benefit from this treatment. Mol Cancer Ther; 17(5); 1003-11. ©2018 AACR . ©2018 American Association for Cancer Research.

  7. Immunological responses against human papilloma virus and human papilloma virus induced laryngeal cancer.

    PubMed

    Chitose, Shun-ichi; Sakazaki, T; Ono, T; Kurita, T; Mihashi, H; Nakashima, T

    2010-06-01

    This study aimed to clarify the local immune status in the larynx in the presence of infection or carcinogenesis associated with human papilloma virus. Cytological samples (for human papilloma virus detection) and laryngeal secretions (for immunoglobulin assessment) were obtained from 31 patients with laryngeal disease, during microscopic laryngeal surgery. On histological examination, 12 patients had squamous cell carcinoma, four had laryngeal papilloma and 15 had other benign laryngeal disease. Cytological samples were tested for human papilloma virus DNA using the Hybrid Capture 2 assay. High risk human papilloma virus DNA was detected in 25 per cent of patients (three of 12) with laryngeal cancer. Low risk human papilloma virus DNA was detected only in three laryngeal papilloma patients. The mean laryngeal secretion concentrations of immunoglobulins M, G and A and secretory immunoglobulin A in human papilloma virus DNA positive patients were more than twice those in human papilloma virus DNA negative patients. A statistically significant difference was observed between the secretory immunoglobulin A concentrations in the two groups. Patients with laryngeal cancer had higher laryngeal secretion concentrations of each immunoglobulin type, compared with patients with benign laryngeal disease. The study assessed the mean laryngeal secretion concentrations of each immunoglobulin type in the 12 laryngeal cancer patients, comparing human papilloma virus DNA positive patients (n = 3) and human papilloma virus DNA negative patients (n = 9); the mean concentrations of immunoglobulins M, G and A and secretory immunoglobulin A tended to be greater in human papilloma virus DNA positive cancer patients, compared with human papilloma virus DNA negative cancer patients. These results suggest that the local laryngeal immune response is activated by infection or carcinogenesis due to human papilloma virus. The findings strongly suggest that secretory IgA has inhibitory activity

  8. Implicit cognitive aggression among young male prisoners: Association with dispositional and current aggression.

    PubMed

    Ireland, Jane L; Adams, Christine

    2015-01-01

    The current study explores associations between implicit and explicit aggression in young adult male prisoners, seeking to apply the Reflection-Impulsive Model and indicate parity with elements of the General Aggression Model and social cognition. Implicit cognitive aggressive processing is not an area that has been examined among prisoners. Two hundred and sixty two prisoners completed an implicit cognitive aggression measure (Puzzle Test) and explicit aggression measures, covering current behaviour (DIPC-R) and aggression disposition (AQ). It was predicted that dispositional aggression would be predicted by implicit cognitive aggression, and that implicit cognitive aggression would predict current engagement in aggressive behaviour. It was also predicted that more impulsive implicit cognitive processing would associate with aggressive behaviour whereas cognitively effortful implicit cognitive processing would not. Implicit aggressive cognitive processing was associated with increased dispositional aggression but not current reports of aggressive behaviour. Impulsive implicit cognitive processing of an aggressive nature predicted increased dispositional aggression whereas more cognitively effortful implicit cognitive aggression did not. The article concludes by outlining the importance of accounting for implicit cognitive processing among prisoners and the need to separate such processing into facets (i.e. impulsive vs. cognitively effortful). Implications for future research and practice in this novel area of study are indicated. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Understanding the origins of human cancer

    DOE PAGES

    Alexandrov, L. B.

    2015-12-04

    All cancers originate from a single cell that starts to behave abnormally, to divide uncontrollably, and, eventually, to invade adjacent tissues (1). The aberrant behavior of this single cell is due to somatic mutations—changes in the genomic DNA produced by the activity of different mutational processes (1). These various mutational processes include exposure to exogenous or endogenous mutagens, abnormal DNA editing, the incomplete fidelity of DNA polymerases, and failure of DNA repair mechanisms (2). Early studies that sequenced TP53, the most commonly mutated gene in human cancer, provided evidence that mutational processes leave distinct imprints of somatic mutations on themore » genome of a cancer cell (3). For example, C:G>A:T transversions predominate in smoking-associated lung cancer, whereas C:G>T:A transitions occurring mainly at dipyrimidines and CC:GG>TT:AA double-nucleotide substitutions are common in ultraviolet light–associated skin cancers. Moreover, these patterns of mutations matched the ones induced experimentally by tobacco mutagens and ultraviolet light, respectively, the major, known, exogenous carcinogenic influences in these cancer types, and demonstrated that examining patterns of mutations in cancer genomes can yield information about the mutational processes that cause human cancer (4).« less

  10. Antecedents and Correlates of the Popular-Aggressive Phenomenon in Elementary School

    ERIC Educational Resources Information Center

    Rodkin, Philip C.; Roisman, Glenn I.

    2010-01-01

    This study identified correlates and developmental antecedents that distinguish popular-aggressive elementary school children from other youth. Drawing on the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development (N = 1022), popular-aggressive children were identified through teacher ratings over…

  11. Neuroendocrine aspects of pediatric aggression: Can hormone measures be clinically useful?

    PubMed Central

    Barzman, Drew H; Patel, Avni; Sonnier, Loretta; Strawn, Jeffrey R

    2010-01-01

    Pediatric aggression is common in human societies, mainly presenting as impulsive aggression or predatory aggression. Numerous psychiatric disorders can contain aggression as a symptom, leading to difficulties in diagnosis and treatment. This review focuses on the biological systems that affect pediatric aggression. We review the hypothalamic–pituitary–adrenal (HPA) axis, the hypothalamic–pituitary–gonadal (HPG) axis, and the mechanisms by which these axes influence the body and mind of aggressive children and adolescents. Although this review focuses on the HPA and HPG axes, it is important to note that other biological systems have relationships with these two axes. Based on the results of the studies reviewed, elevated cortisol concentrations were associated with impulsive aggression, whereas, low levels of cortisol were associated with callous-unemotional traits similar to predatory aggression. Higher levels of dehydroepiandrosterone were correlated with higher levels of aggression as were higher levels of testosterone. However, there have been discrepancies in the results between various studies, indicating the need for more research on hormonal levels and pediatric aggression. In the future, hormonal levels may be useful in determining what treatments will work best for certain pediatric patients. PMID:21127686

  12. Current understanding of mdig/MINA in human cancers.

    PubMed

    Thakur, Chitra; Chen, Fei

    2015-07-01

    Mineral dust-induced gene, mdig has recently been identified and is known to be overexpressed in a majority of human cancers and holds predictive power in the poor prognosis of the disease. Mdig is an environmentally expressed gene that is involved in cell proliferation, neoplastic transformation and immune regulation. With the advancement in deciphering the prognostic role of mdig in human cancers, our understanding on how mdig renders a normal cell to undergo malignant transformation is still very limited. This article reviews the current knowledge of the mdig gene in context to human neoplasias and its relation to the clinico-pathologic factors predicting the outcome of the disease in patients. It also emphasizes on the promising role of mdig that can serve as a potential candidate for biomarker discovery and as a therapeutic target in inflammation and cancers. Considering the recent advances in understanding the underlying mechanisms of tumor formation, more preclinical and clinical research is required to validate the potential of using mdig as a novel biological target of therapeutic and diagnostic value. Expression level of mdig influences the prognosis of several human cancers especially cancers of the breast and lung. Evaluation of mdig in cancers can offer novel biomarker with potential therapeutic interventions for the early assessment of cancer development in patients.

  13. Pathology and behaviour in feline medicine: investigating the link between vomeronasalitis and aggression.

    PubMed

    Asproni, Pietro; Cozzi, Alessandro; Verin, Ranieri; Lafont-Lecuelle, Céline; Bienboire-Frosini, Cécile; Poli, Alessandro; Pageat, Patrick

    2016-12-01

    The aim of the study was to investigate if the feline vomeronasal organ (VNO) can be affected by inflammatory lesions and if these changes are associated with behavioural alterations. VNOs from 20 cats were sampled during necropsy, submitted for routine tissue processing and stained with haematoxylin and eosin for histopathological evaluation. For the 20 cats, data on the presence of aggressive behaviours towards cats or humans were collected by questionnaire survey at the point of death. Inflammatory lesions were classified depending on the duration of the process as acute or chronic, both in vomeronasal sensory epithelium (VNSE) and in non-sensory epithelium (NSE). Fisher's exact test was used to compare VNO inflammation with behavioural data. The VNSE was inflamed in 11/20 VNOs (55%) while the NSE was inflamed in 13/20 (65%). Overall, the VNO was affected by inflammation in 14/20 (70%) cats, and all the lesions were classified as chronic. Five out of 20 cats (25%) had documented intraspecific aggressive behaviours and 8/20 (40%) had shown aggression towards humans. Fisher's exact test showed a statistically significant correlation between inflammation of the VNSE and intraspecific aggression (P = 0.038). No statistically correlations were observed between VNSE inflammation and aggression towards humans and between NSE inflammation and aggression towards cats or humans. Our results show, for the first time, the existence of vomeronasalitis in animals and its possible association with intraspecific aggressive behaviours. The inflammatory microenvironment could impair VNSE functionality, causing intraspecific communication alterations, probably through a reduction in chemical communication action and perception. Owing to the pivotal role of the VNO in the social life of cats and other species, this report provides a rationale to further investigate this disease in relation to a variety of behavioural disorders. © The Author(s) 2015.

  14. NOTCH pathway inactivation promotes bladder cancer progression

    PubMed Central

    Maraver, Antonio; Fernandez-Marcos, Pablo J.; Cash, Timothy P.; Mendez-Pertuz, Marinela; Dueñas, Marta; Maietta, Paolo; Martinelli, Paola; Muñoz-Martin, Maribel; Martínez-Fernández, Mónica; Cañamero, Marta; Roncador, Giovanna; Martinez-Torrecuadrada, Jorge L.; Grivas, Dimitrios; de la Pompa, Jose Luis; Valencia, Alfonso; Paramio, Jesús M.; Real, Francisco X.; Serrano, Manuel

    2015-01-01

    NOTCH signaling suppresses tumor growth and proliferation in several types of stratified epithelia. Here, we show that missense mutations in NOTCH1 and NOTCH2 found in human bladder cancers result in loss of function. In murine models, genetic ablation of the NOTCH pathway accelerated bladder tumorigenesis and promoted the formation of squamous cell carcinomas, with areas of mesenchymal features. Using bladder cancer cells, we determined that the NOTCH pathway stabilizes the epithelial phenotype through its effector HES1 and, consequently, loss of NOTCH activity favors the process of epithelial-mesenchymal transition. Evaluation of human bladder cancer samples revealed that tumors with low levels of HES1 present mesenchymal features and are more aggressive. Together, our results indicate that NOTCH serves as a tumor suppressor in the bladder and that loss of this pathway promotes mesenchymal and invasive features. PMID:25574842

  15. CDKL2 promotes epithelial-mesenchymal transition and breast cancer progression

    PubMed Central

    Li, Linna; Liu, Chunping; Amato, Robert J.; Chang, Jeffrey T.; Du, Guangwei; Li, Wenliang

    2014-01-01

    The epithelial–mesenchymal transition (EMT) confers mesenchymal properties on epithelial cells and has been closely associated with the acquisition of aggressive traits by epithelial cancer cells. To identify novel regulators of EMT, we carried out cDNA screens that covered 500 human kinases. Subsequent characterization of candidate kinases led us to uncover cyclin-dependent kinase-like 2 (CDKL2) as a novel potent promoter for EMT and breast cancer progression. CDKL2-expressing human mammary gland epithelial cells displayed enhanced mesenchymal traits and stem cell-like phenotypes, which was acquired through activating a ZEB1/E-cadherin/β-catenin positive feedback loop and regulating CD44 mRNA alternative splicing to promote conversion of CD24high cells to CD44high cells. Furthermore, CDKL2 enhanced primary tumor formation and metastasis in a breast cancer xenograft model. Notably, CDKL2 is expressed significantly higher in mesenchymal human breast cancer cell lines than in epithelial lines, and its over-expression/amplification in human breast cancers is associated with shorter disease-free survival. Taken together, our study uncovered a major role for CDKL2 in promoting EMT and breast cancer progression. PMID:25333262

  16. Macrophage migration inhibitory factor induces epithelial to mesenchymal transition, enhances tumor aggressiveness and predicts clinical outcome in resected pancreatic ductal adenocarcinoma.

    PubMed

    Funamizu, Naotake; Hu, Chaoxin; Lacy, Curtis; Schetter, Aaron; Zhang, Geng; He, Peijun; Gaedcke, Jochen; Ghadimi, Michael B; Ried, Thomas; Yfantis, Harris G; Lee, Dong H; Subleski, Jeffrey; Chan, Tim; Weiss, Jonathan M; Back, Timothy C; Yanaga, Katsuhiko; Hanna, Nader; Alexander, H Richard; Maitra, Anirban; Hussain, S Perwez

    2013-02-15

    MIF is a proinflammatory cytokine and is implicated in cancer. A higher MIF level is found in many human cancer and cancer-prone inflammatory diseases, including chronic pancreatitis and pancreatic cancer. We tested the hypothesis that MIF contributes to pancreatic cancer aggressiveness and predicts disease outcome in resected cases. Consistent with our hypothesis we found that an elevated MIF mRNA expression in tumors was significantly associated with poor outcome in resected cases. Multivariate Cox-regression analysis further showed that MIF is independently associated with patients' survival (HR = 2.26, 95% CI = 1.17-4.37, p = 0.015). Mechanistic analyses revealed that MIF overexpression decreased E-cadherin and increased vimentin mRNA and protein levels in pancreatic cancer cell lines, consistent with the features of epithelial-to-mesenchymal transition (EMT). Furthermore, MIF-overexpression significantly increased ZEB1/2 and decreased miR-200b expression, while shRNA-mediated inhibition of MIF increased E-cadherin and miR-200b expression, and reduced the expression of ZEB1/2 in Panc1 cells. Re-expression of miR-200b in MIF overexpressing cells restored the epithelial characteristics, as indicated by an increase in E-cadherin and decrease in ZEB1/2 and vimentin expression. A reduced sensitivity to the chemotherapeutic drug, gemcitabine, occurred in MIF-overexpressing cells. Indicative of an increased malignant potential, MIF over-expressing cells showed significant increase in their invasion ability in vitro, and tumor growth and metastasis in an orthotopic xenograft mouse model. These results support a role of MIF in disease aggressiveness, indicating its potential usefulness as a candidate target for designing improved treatment in pancreatic cancer. Copyright © 2012 UICC.

  17. Mouse Models of Gastric Cancer

    PubMed Central

    Hayakawa, Yoku; Fox, James G.; Gonda, Tamas; Worthley, Daniel L.; Muthupalani, Sureshkumar; Wang, Timothy C.

    2013-01-01

    Animal models have greatly enriched our understanding of the molecular mechanisms of numerous types of cancers. Gastric cancer is one of the most common cancers worldwide, with a poor prognosis and high incidence of drug-resistance. However, most inbred strains of mice have proven resistant to gastric carcinogenesis. To establish useful models which mimic human gastric cancer phenotypes, investigators have utilized animals infected with Helicobacter species and treated with carcinogens. In addition, by exploiting genetic engineering, a variety of transgenic and knockout mouse models of gastric cancer have emerged, such as INS-GAS mice and TFF1 knockout mice. Investigators have used the combination of carcinogens and gene alteration to accelerate gastric cancer development, but rarely do mouse models show an aggressive and metastatic gastric cancer phenotype that could be relevant to preclinical studies, which may require more specific targeting of gastric progenitor cells. Here, we review current gastric carcinogenesis mouse models and provide our future perspectives on this field. PMID:24216700

  18. L1CAM in human cancer.

    PubMed

    Altevogt, Peter; Doberstein, Kai; Fogel, Mina

    2016-04-01

    L1 cell adhesion molecule (L1CAM) is one of the first neural adhesion molecules described with important functions in the development of the nervous system. Subsequent work discovered that L1CAM is expressed in many human cancers and is often associated with bad prognosis. This is most likely due to the motility and invasion promoting function of L1CAM. Here, we describe the path L1CAM has taken from a neural adhesion molecule to a recognized tumor antigen. We summarize the literature on L1CAM expression in cancers and pre-cancerous lesions. We focus on the genetic elements required for its re-expression and highlight preclinical studies for targeted therapy. The data suggest that L1CAM is a valuable diagnostic/prognostic marker and an attractive target for the therapy of several human cancers. © 2015 UICC.

  19. RETREG1 (FAM134B): A new player in human diseases: 15 years after the discovery in cancer.

    PubMed

    Islam, Farhadul; Gopalan, Vinod; Lam, Alfred King-Yin

    2018-06-01

    FAM134B (family with sequence similarity 134, member B)/RETREG1 and its functional roles are relatively new in human diseases. This review aimed to summarize various functions of FAM134B since our first discovery of the gene in 2001. The protein encoded by FAM134B is a reticulophagy receptor that regulates turnover of the endoplasmic reticulum (ER) by selective phagocytosis. Absence or non-functional expression of FAM134B protein impairs ER-turnover and thereby is involved in the pathogenesis of some human diseases. FAM134B inhibition contributes to impair proteostasis in the ER due to the accumulation of misfolded or aggregated proteins, which in turn leads to compromised neuronal survival and progressive neuronal degenerative diseases. Mutations in FAM134B associated with hereditary sensory and autonomic neuropathy type IIB (HSAN IIB). Selective cleavage of FAM134B by Dengue, Zika, and West Nile virus encoded protease NS2B3 leads to the increased production of infection units, whereas upregulation of FAM134B inhibits viral replication. In cancer, FAM134B acts as a tumor suppressor and inhibit cancer growth both in-vitro and in-vivo. Pharmacological upregulation of FAM134B resulted in reduced cancer cell growth and proliferation. In addition, FAM134B mutations are common in patients with colorectal adenocarcinoma, and oesophageal squamous cell carcinoma. These mutations and expression changes of FAM134B were associated with the biological aggressiveness of these cancers. FAM134B also plays a role in allergic rhinitis, vascular dementia, and identification of stem cells. Taken together, information available in the literature suggests that FAM134B plays critical roles in human diseases, by interacting with different biological and chemical mediators, which are primarily regulated by ER turnover. © 2017 Wiley Periodicals, Inc.

  20. Survival and human papillomavirus in oropharynx cancer in TAX 324: a subset analysis from an international phase III trial.

    PubMed

    Posner, M R; Lorch, J H; Goloubeva, O; Tan, M; Schumaker, L M; Sarlis, N J; Haddad, R I; Cullen, K J

    2011-05-01

    The association between human papillomavirus (HPV) and overall survival (OS) in oropharynx cancer (OPC) was retrospectively examined in TAX 324, a phase III trial of sequential therapy for locally advanced head and neck cancer. Accrual for TAX 324 was completed in 2003 and data updated through 2008. Pretherapy tumor biopsies were studied by PCR for human papillomavirus type 16 and linked to OS, progression-free survival (PFS) and demographics. Of 264 patients with OPC, 111 (42%) had evaluable biopsies; 56 (50%) were HPV+ and 55 (50%) were HPV-. HPV+ patients were significantly younger (54 versus 58 years, P = 0.02), had T1/T2 primary cancers (49% versus 20%, P = 0.001), and had a performance status of zero (77% versus 49%, P = 0.003). OS and PFS were better for HPV+ patients (OS, hazard ratio = 0.20, P < 0.0001). Local-regional failure was less in HPV+ patients (13% versus 42%, P = 0.0006); at 5 years, 82% of HPV+ patients were alive compared with 35% of HPV- patients (P < 0.0001). HPV+ OPC has a different biology compared with HPV- OPC; 5-year OS, PFS, and local-regional control are unprecedented. These results support the possibility of selectively reducing therapy and long-term morbidity in HPV+ OPC while preserving survival and approaching HPV- disease with more aggressive treatment.

  1. Suppression of the Aggressive Impulse: Conceptual Difficulties in Anti-Violence Programs

    ERIC Educational Resources Information Center

    Goodman, Joan F.; Kitzmiller, Erika

    2010-01-01

    School anti-violence programs are united in their radical condemnation of aggression, generally equated with violence. The programs advocate its elimination by priming children's emotional and cognitive controls. What goes unrecognized is the embeddedness of aggression in human beings, as well as its positive psychological and moral functions. In…

  2. Defining the cellular precursors to human breast cancer

    PubMed Central

    Keller, Patricia J.; Arendt, Lisa M.; Skibinski, Adam; Logvinenko, Tanya; Klebba, Ina; Dong, Shumin; Smith, Avi E.; Prat, Aleix; Perou, Charles M.; Gilmore, Hannah; Schnitt, Stuart; Naber, Stephen P.; Garlick, Jonathan A.; Kuperwasser, Charlotte

    2012-01-01

    Human breast cancers are broadly classified based on their gene-expression profiles into luminal- and basal-type tumors. These two major tumor subtypes express markers corresponding to the major differentiation states of epithelial cells in the breast: luminal (EpCAM+) and basal/myoepithelial (CD10+). However, there are also rare types of breast cancers, such as metaplastic carcinomas, where tumor cells exhibit features of alternate cell types that no longer resemble breast epithelium. Until now, it has been difficult to identify the cell type(s) in the human breast that gives rise to these various forms of breast cancer. Here we report that transformation of EpCAM+ epithelial cells results in the formation of common forms of human breast cancer, including estrogen receptor-positive and estrogen receptor-negative tumors with luminal and basal-like characteristics, respectively, whereas transformation of CD10+ cells results in the development of rare metaplastic tumors reminiscent of the claudin-low subtype. We also demonstrate the existence of CD10+ breast cells with metaplastic traits that can give rise to skin and epidermal tissues. Furthermore, we show that the development of metaplastic breast cancer is attributable, in part, to the transformation of these metaplastic breast epithelial cells. These findings identify normal cellular precursors to human breast cancers and reveal the existence of a population of cells with epidermal progenitor activity within adult human breast tissues. PMID:21940501

  3. Human cancer stem cells are a target for cancer prevention using (-)-epigallocatechin gallate.

    PubMed

    Fujiki, Hirota; Sueoka, Eisaburo; Rawangkan, Anchalee; Suganuma, Masami

    2017-12-01

    Our previous experiments show that the main constituent of green-tea catechins, (-)-epigallocatechin gallate (EGCG), completely prevents tumor promotion on mouse skin initiated with 7,12-dimethylbenz(a)anthracene followed by okadaic acid and that EGCG and green tea extract prevent cancer development in a wide range of target organs in rodents. Therefore, we focused our attention on human cancer stem cells (CSCs) as targets of cancer prevention and treatment with EGCG. The numerous reports concerning anticancer activity of EGCG against human CSCs enriched from cancer cell lines were gathered from a search of PubMed, and we hope our review of the literatures will provide a broad selection for the effects of EGCG on various human CSCs. Based on our theoretical study, we discuss the findings as follows: (1) Compared with the parental cells, human CSCs express increased levels of the stemness markers Nanog, Oct4, Sox2, CD44, CD133, as well as the EMT markers, Twist, Snail, vimentin, and also aldehyde dehydrogenase. They showed decreased levels of E-cadherin and cyclin D1. (2) EGCG inhibits the transcription and translation of genes encoding stemness markers, indicating that EGCG generally inhibits the self-renewal of CSCs. (3) EGCG inhibits the expression of the epithelial-mesenchymal transition phenotypes of human CSCs. (4) The inhibition of EGCG of the stemness of CSCs was weaker compared with parental cells. (5) The weak inhibitory activity of EGCG increased synergistically in combination with anticancer drugs. Green tea prevents human cancer, and the combination of EGCG and anticancer drugs confers cancer treatment with tissue-agnostic efficacy.

  4. Gene expression signature in urine for diagnosing and assessing aggressiveness of bladder urothelial carcinoma.

    PubMed

    Mengual, Lourdes; Burset, Moisès; Ribal, María José; Ars, Elisabet; Marín-Aguilera, Mercedes; Fernández, Manuel; Ingelmo-Torres, Mercedes; Villavicencio, Humberto; Alcaraz, Antonio

    2010-05-01

    To develop an accurate and noninvasive method for bladder cancer diagnosis and prediction of disease aggressiveness based on the gene expression patterns of urine samples. Gene expression patterns of 341 urine samples from bladder urothelial cell carcinoma (UCC) patients and 235 controls were analyzed via TaqMan Arrays. In a first phase of the study, three consecutive gene selection steps were done to identify a gene set expression signature to detect and stratify UCC in urine. Subsequently, those genes more informative for UCC diagnosis and prediction of tumor aggressiveness were combined to obtain a classification system of bladder cancer samples. In a second phase, the obtained gene set signature was evaluated in a routine clinical scenario analyzing only voided urine samples. We have identified a 12+2 gene expression signature for UCC diagnosis and prediction of tumor aggressiveness on urine samples. Overall, this gene set panel had 98% sensitivity (SN) and 99% specificity (SP) in discriminating between UCC and control samples and 79% SN and 92% SP in predicting tumor aggressiveness. The translation of the model to the clinically applicable format corroborates that the 12+2 gene set panel described maintains a high accuracy for UCC diagnosis (SN = 89% and SP = 95%) and tumor aggressiveness prediction (SN = 79% and SP = 91%) in voided urine samples. The 12+2 gene expression signature described in urine is able to identify patients suffering from UCC and predict tumor aggressiveness. We show that a panel of molecular markers may improve the schedule for diagnosis and follow-up in UCC patients. Copyright 2010 AACR.

  5. Androgen Receptor Gene Polymorphism, Aggression, and Reproduction in Tanzanian Foragers and Pastoralists

    PubMed Central

    Butovskaya, Marina L.; Lazebny, Oleg E.; Vasilyev, Vasiliy A.; Dronova, Daria A.; Karelin, Dmitri V.; Mabulla, Audax Z. P.; Shibalev, Dmitri V.; Shackelford, Todd K.; Fink, Bernhard; Ryskov, Alexey P.

    2015-01-01

    The androgen receptor (AR) gene polymorphism in humans is linked to aggression and may also be linked to reproduction. Here we report associations between AR gene polymorphism and aggression and reproduction in two small-scale societies in northern Tanzania (Africa)—the Hadza (monogamous foragers) and the Datoga (polygynous pastoralists). We secured self-reports of aggression and assessed genetic polymorphism of the number of CAG repeats for the AR gene for 210 Hadza men and 229 Datoga men (aged 17–70 years). We conducted structural equation modeling to identify links between AR gene polymorphism, aggression, and number of children born, and included age and ethnicity as covariates. Fewer AR CAG repeats predicted greater aggression, and Datoga men reported more aggression than did Hadza men. In addition, aggression mediated the identified negative relationship between CAG repeats and number of children born. PMID:26291982

  6. Genomic Analysis of Genotype-by-Social Environment Interaction for Drosophila melanogaster Aggressive Behavior.

    PubMed

    Rohde, Palle Duun; Gaertner, Bryn; Ward, Kirsty; Sørensen, Peter; Mackay, Trudy F C

    2017-08-01

    Human psychiatric disorders such as schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder often include adverse behaviors including increased aggressiveness. Individuals with psychiatric disorders often exhibit social withdrawal, which can further increase the probability of conducting a violent act. Here, we used the inbred, sequenced lines of the Drosophila Genetic Reference Panel (DGRP) to investigate the genetic basis of variation in male aggressive behavior for flies reared in a socialized and socially isolated environment. We identified genetic variation for aggressive behavior, as well as significant genotype-by-social environmental interaction (GSEI); i.e. , variation among DGRP genotypes in the degree to which social isolation affected aggression. We performed genome-wide association (GWA) analyses to identify genetic variants associated with aggression within each environment. We used genomic prediction to partition genetic variants into gene ontology (GO) terms and constituent genes, and identified GO terms and genes with high prediction accuracies in both social environments and for GSEI. The top predictive GO terms significantly increased the proportion of variance explained, compared to prediction models based on all segregating variants. We performed genomic prediction across environments, and identified genes in common between the social environments that turned out to be enriched for genome-wide associated variants. A large proportion of the associated genes have previously been associated with aggressive behavior in Drosophila and mice. Further, many of these genes have human orthologs that have been associated with neurological disorders, indicating partially shared genetic mechanisms underlying aggression in animal models and human psychiatric disorders. Copyright © 2017 by the Genetics Society of America.

  7. Autophagy sustains the survival of human pancreatic cancer PANC-1 cells under extreme nutrient deprivation conditions.

    PubMed

    Kim, Sang Eun; Park, Hye-Jin; Jeong, Hye Kyoung; Kim, Mi-Jung; Kim, Minyeong; Bae, Ok-Nam; Baek, Seung-Hoon

    2015-07-31

    Pancreatic ductal adenocarcinomas are an extremely aggressive and devastating type of cancer with high mortality. Given the dense stroma and poor vascularization, accessibility to nutrients is limited in the tumor microenvironment. Here, we aimed to elucidate the role of autophagy in promoting the survival of human pancreatic cancer PANC-1 cells exposed to nutrient-deprived media (NDM) lacking glucose, amino acids, and serum. NDM inhibited Akt activity and phosphorylation of p70 S6K, and induced AMPK activation and mitochondrial depolarization. NDM also time-dependently increased LC3-II accumulation, number of GFP-LC3 puncta, and colocalization between GFP-LC3 and lysosomes. These results suggested that autophagy was progressively activated through Akt- and AMPK-mTOR pathway in nutrient-deficient PANC-1 cells. Autophagy inhibitors (chloroquine and wortmannin) or silencing of Atg5 augmented PANC-1 cell death in NDM. In cells exposed to NDM, chloroquine and wortmannin induced apoptosis and Z-VAD-fmk inhibited cytotoxicity of these inhibitors. These data demonstrate that autophagy is anti-apoptotic and sustains the survival of PANC-1 cells following extreme nutrient deprivation. Autophagy modulation may be a viable therapeutic option for cancer cells located in the core of solid tumors with a nutrient-deficient microenvironment. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Molecular Biology In Young Women With Breast Cancer: From Tumor Gene Expression To DNA Mutations.

    PubMed

    Gómez-Flores-Ramos, Liliana; Castro-Sánchez, Andrea; Peña-Curiel, Omar; Mohar-Betancourt, Alejandro

    2017-01-01

    Young women with breast cancer (YWBC) represent roughly 15% of breast cancer (BC) cases in Latin America and other developing regions. Breast tumors occurring at an early age are more aggressive and have an overall worse prognosis compared to breast tumors in postmenopausal women. The expression of relevant proliferation biomarkers such as endocrine receptors and human epidermal growth factor receptor 2 appears to be unique in YWBC. Moreover, histopathological, molecular, genetic, and genomic studies have shown that YWBC exhibit a higher frequency of aggressive subtypes, differential tumor gene expression, increased genetic susceptibility, and specific genomic signatures, compared to older women with BC. This article reviews the current knowledge on tumor biology and genomic signatures in YWBC.

  9. Proactive and Reactive Aggressive Behavior in Bullying: The Role of Values

    ERIC Educational Resources Information Center

    Jara, Natalia; Casas, Jose A.; Ortega-Ruiz, Rosario

    2017-01-01

    The study of violence and bullying in schools is a line of scientific research that has contributed significantly to knowledge on human aggressiveness, especially in children and adolescents. This article shows that there are two patterns of aggressive behavior: proactive and reactive. Both are present in bullying, as are other psychological…

  10. Probing HER2-PUMA and EGFR-PUMA Crosstalks in Aggressive Breast Cancer

    DTIC Science & Technology

    2012-09-01

    phosphorylation on PUMA properties. REPORTABLE OUTCOMES Peer-reviewed publications: Carpenter, RL. and Lo, H.-W. Hedgehog Pathway and GLI1 Isoforms in...Carpenter R, Lo HW. Hedgehog Pathway and GLI1 Isoforms in Human Cancer. Discovery Medicine 13. 2012. 7. Han W, Lo H-W. Landscape of EGFR signaling

  11. End-of-life care in lung cancer patients in Ontario: aggressiveness of care in the population and a description of hospital admissions.

    PubMed

    Barbera, Lisa; Paszat, Lawrence; Qiu, Feng

    2008-03-01

    The purpose of this study was to describe (1) the aggressiveness of care in a population of patients who die of lung cancer and (2) differences in care between a sample of lung cancer patients who died in an acute care hospital (DH) and a sample of lung cancer patients who were admitted to hospital during the last six months of life but were discharged and died elsewhere (DO). All lung cancer deaths in 2002 were identified in the provincial registry. Cases were linked to administrative sources of health care data to describe the population as a whole and the aggressiveness of the care that they received. Primary data were collected from a province-wide sample of patients' hospital charts focusing on reasons for admission, care in hospital, advanced planning, pain, and disposition. In total, 5,855 patients who died of lung cancer in 2002 were eligible for inclusion in the cohort. Rates of in-hospital death, emergency room visits, intensive care unit admissions, and chemotherapy use near the end of life were 59.5%, 32.2%, 5.5%, and 4.6%, respectively. The records of 491 patients were abstracted for this study. The DH and DO groups were similar with respect to age, gender, neighborhood income level, and extent of metastatic disease. The most common chief complaints were shortness of breath, pain, inability to cope at home, and altered level of consciousness. Compared to patients in the DO group, those in the DH group presented with pain more often (19% vs. 10%, P<0.005) and were more likely to be admitted with progressive chest malignancy (30% vs. 21%, P<0.05). Regardless of reason for admission, pain was commonly documented as a problem during admission: 73.5% in the DH group and 62.4% in the DO group (P<0.05). Lung cancer patients are heavy users of acute care beds and the emergency room at the end of life. Those who do or do not die in hospital are similar in many respects but our results suggest those dying in hospital have more problems with pain and burden from

  12. Current understanding of mdig/MINA in human cancers

    PubMed Central

    Thakur, Chitra; Chen, Fei

    2015-01-01

    Mineral dust-induced gene, mdig has recently been identified and is known to be overexpressed in a majority of human cancers and holds predictive power in the poor prognosis of the disease. Mdig is an environmentally expressed gene that is involved in cell proliferation, neoplastic transformation and immune regulation. With the advancement in deciphering the prognostic role of mdig in human cancers, our understanding on how mdig renders a normal cell to undergo malignant transformation is still very limited. This article reviews the current knowledge of the mdig gene in context to human neoplasias and its relation to the clinico-pathologic factors predicting the outcome of the disease in patients. It also emphasizes on the promising role of mdig that can serve as a potential candidate for biomarker discovery and as a therapeutic target in inflammation and cancers. Considering the recent advances in understanding the underlying mechanisms of tumor formation, more preclinical and clinical research is required to validate the potential of using mdig as a novel biological target of therapeutic and diagnostic value. Summary Expression level of mdig influences the prognosis of several human cancers especially cancers of the breast and lung. Evaluation of mdig in cancers can offer novel biomarker with potential therapeutic interventions for the early assessment of cancer development in patients. PMID:26413213

  13. Human Breast Cancer Histoid

    PubMed Central

    Kaur, Pavinder; Ward, Brenda; Saha, Baisakhi; Young, Lillian; Groshen, Susan; Techy, Geza; Lu, Yani; Atkinson, Roscoe; Taylor, Clive R.; Ingram, Marylou

    2011-01-01

    Progress in our understanding of heterotypic cellular interaction in the tumor microenvironment, which is recognized to play major roles in cancer progression, has been hampered due to unavailability of an appropriate in vitro co-culture model. The aim of this study was to generate an in vitro 3-dimensional human breast cancer model, which consists of cancer cells and fibroblasts. Breast cancer cells (UACC-893) and fibroblasts at various densities were co-cultured in a rotating suspension culture system to establish co-culture parameters. Subsequently, UACC-893, BT.20, or MDA.MB.453 were co-cultured with fibroblasts for 9 days. Co-cultures resulted in the generation of breast cancer histoid (BCH) with cancer cells showing the invasion of fibroblast spheroids, which were visualized by immunohistochemical (IHC) staining of sections (4 µm thick) of BCH. A reproducible quantitative expression of C-erbB.2 was detected in UACC-893 cancer cells in BCH sections by IHC staining and the Automated Cellular Imaging System. BCH sections also consistently exhibited qualitative expression of pancytokeratins, p53, Ki-67, or E-cadherin in cancer cells and that of vimentin or GSTPi in fibroblasts, fibronectin in the basement membrane and collagen IV in the extracellular matrix. The expression of the protein analytes and cellular architecture of BCH were markedly similar to those of breast cancer tissue. PMID:22034518

  14. Anti-aggressive effect elicited by coca-paste in isolation-induced aggression of male rats: influence of accumbal dopamine and cortical serotonin.

    PubMed

    Meikle, María Noel; Prieto, José Pedro; Urbanavicius, Jessika; López, Ximena; Abin-Carriquiry, Juan Andrés; Prunell, Giselle; Scorza, María Cecilia

    2013-09-01

    Coca-paste (CP), an illicit drug of abuse, has been frequently associated with aggressive and impulsive behaviors in humans. However, preclinical studies have not been carried out in order to characterize CP effects on aggression. The acute effect of CP, cocaine and caffeine (the main adulterant present in seized samples) on aggression was assessed using the isolation-induced aggression paradigm in male rats. The dopaminergic (DA) neurotransmission in the nucleus accumbens (NAcc) and serotonergic (5-HT) activity in the frontal cortex were explored. CP and cocaine induced a similar anti-aggressive effect on isolated rats although CP-treated animals showed a shorter latency to the first attack. Aggressive behavior was not increased per se by caffeine. Social investigation time was slightly reduced only by cocaine while exploratory activity and time spent walking were increased by the three drugs. Accumbal DA levels were significantly augmented by CP, cocaine and caffeine, although differences in DOPAC and HVA levels were evidenced. A decrease in DA turnover was only observed after CP and cocaine administration. Increased cortical 5-HT levels with a concomitant decrease in 5-HT turnover were observed after CP and cocaine whereas caffeine did not alter it. As cocaine but not caffeine reduced aggression, it seems like cocaine content was mainly responsible for CP anti-aggressive action; however, the presence of caffeine in CP may have a role in the shorter latency to attack compared to cocaine. Despite the increase in NAcc DA, the enhancement of cortical 5-HT levels can likely underlie the anti-aggression observed in CP-treated animals. © 2013 Elsevier Inc. All rights reserved.

  15. Cell membrane softening in human breast and cervical cancer cells

    NASA Astrophysics Data System (ADS)

    Händel, Chris; Schmidt, B. U. Sebastian; Schiller, Jürgen; Dietrich, Undine; Möhn, Till; Kießling, Tobias R.; Pawlizak, Steve; Fritsch, Anatol W.; Horn, Lars-Christian; Briest, Susanne; Höckel, Michael; Zink, Mareike; Käs, Josef A.

    2015-08-01

    Biomechanical properties are key to many cellular functions such as cell division and cell motility and thus are crucial in the development and understanding of several diseases, for instance cancer. The mechanics of the cellular cytoskeleton have been extensively characterized in cells and artificial systems. The rigidity of the plasma membrane, with the exception of red blood cells, is unknown and membrane rigidity measurements only exist for vesicles composed of a few synthetic lipids. In this study, thermal fluctuations of giant plasma membrane vesicles (GPMVs) directly derived from the plasma membranes of primary breast and cervical cells, as well as breast cell lines, are analyzed. Cell blebs or GPMVs were studied via thermal membrane fluctuations and mass spectrometry. It will be shown that cancer cell membranes are significantly softer than their non-malignant counterparts. This can be attributed to a loss of fluid raft forming lipids in malignant cells. These results indicate that the reduction of membrane rigidity promotes aggressive blebbing motion in invasive cancer cells.

  16. Extraosseous Extension of Aggressive Vertebral Hemangioma as a Potential Pitfall on 68Ga-PSMA PET/CT.

    PubMed

    Probst, Stephan; Bladou, Franck; Abikhzer, Gad

    2017-08-01

    A 74-year-old man with newly diagnosed prostate cancer underwent Ga-PSMA PET/CT, which demonstrated intense uptake in and adjacent the L2 vertebral body. Subsequent MRI of the lumbar spine showed an aggressive L2 hemangioma with adjacent soft tissue extension. There was congruence of the intraosseous and extraosseous components of the hemangioma and the PSMA PET uptake. This is a rare but important potential pitfall in Ga-PSMA PET/CT-a soft tissue lesion with intense tracer uptake related not to a nodal metastasis of prostate cancer but to extraosseous extension of an aggressive vertebral body hemangioma.

  17. Effect of obese and lean Zucker rat sera on human and rat prostate cancer cells: implications in obesity-related prostate tumor biology.

    PubMed

    Lamarre, Neil S; Ruggieri, Michael R; Braverman, Alan S; Gerstein, Matthew I; Mydlo, Jack H

    2007-01-01

    Several reports have demonstrated the effects of obesity on prostate cancer. Also several reports have linked expression of vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor (FGF-2) to prostate cancer aggressiveness. The objective of this study was to determine whether a difference exists between lean and obese Zucker rat sera on proliferation prostate cancer cell lines, as well as to examine the differences in FGF-2 and VEGF concentrations. Ten-week-old female obese and lean Zucker rat sera were subjected to charcoal stripping and tested for the proliferation of human LNCaP and rat AT3B-1 prostate cancer cells. An acetonitrile extract of the charcoal used to strip the sera was also tested for mitogenicity. VEGF and FGF-2 concentrations were determined by enzyme-linked immunosorbent assay. Both unstripped and charcoal-stripped obese rat sera had a greater mitogenic effect than did the lean sera on the LNCaP cell line. Charcoal stripping of both obese and lean sera reduced the mitogenic effect on the AT3B-1 cell line. The acetonitrile extract of the charcoal used to strip the sera was unable to recover this proliferative effect. The concentration of VEGF was greater in the obese serum than in the lean serum, and charcoal stripping reduced the concentrations of both FGF-2 and VEGF. The finding of greater VEGF in obese rat sera, as well as greater mitogenic responses on human prostate cancer cells in vitro, suggests this as one of the many possible mechanisms involved in obesity-related prostate cancer biology.

  18. Exclusive destruction of mitotic spindles in human cancer cells.

    PubMed

    Visochek, Leonid; Castiel, Asher; Mittelman, Leonid; Elkin, Michael; Atias, Dikla; Golan, Talia; Izraeli, Shai; Peretz, Tamar; Cohen-Armon, Malka

    2017-03-28

    We identified target proteins modified by phenanthrenes that cause exclusive eradication of human cancer cells. The cytotoxic activity of the phenanthrenes in a variety of human cancer cells is attributed by these findings to post translational modifications of NuMA and kinesins HSET/kifC1 and kif18A. Their activity prevented the binding of NuMA to α-tubulin and kinesins in human cancer cells, and caused aberrant spindles. The most efficient cytotoxic activity of the phenanthridine PJ34, caused significantly smaller aberrant spindles with disrupted spindle poles and scattered extra-centrosomes and chromosomes. Concomitantly, PJ34 induced tumor growth arrest of human malignant tumors developed in athymic nude mice, indicating the relevance of its activity for cancer therapy.

  19. LIPG signaling promotes tumor initiation and metastasis of human basal-like triple-negative breast cancer

    PubMed Central

    Lo, Pang-Kuo; Yao, Yuan; Lee, Ji Shin; Zhang, Yongshu; Huang, Weiliang; Kane, Maureen A

    2018-01-01

    Current understanding of aggressive human basal-like triple-negative breast cancer (TNBC) remains incomplete. In this study, we show endothelial lipase (LIPG) is aberrantly overexpressed in basal-like TNBCs. We demonstrate that LIPG is required for in vivo tumorigenicity and metastasis of TNBC cells. LIPG possesses a lipase-dependent function that supports cancer cell proliferation and a lipase-independent function that promotes invasiveness, stemness and basal/epithelial-mesenchymal transition features of TNBC. Mechanistically, LIPG executes its oncogenic function through its involvement in interferon-related DTX3L-ISG15 signaling, which regulates protein function and stability by ISGylation. We show that DTX3L, an E3-ubiquitin ligase, is required for maintaining LIPG protein levels in TNBC cells by inhibiting proteasome-mediated LIPG degradation. Inactivation of LIPG impairs DTX3L-ISG15 signaling, indicating the existence of DTX3L-LIPG-ISG15 signaling. We further reveal LIPG-ISG15 signaling is lipase-independent. We demonstrate that DTX3L-LIPG-ISG15 signaling is essential for malignancies of TNBC cells. Targeting this pathway provides a novel strategy for basal-like TNBC therapy. PMID:29350614

  20. Testing the direct, indirect, and moderated effects of childhood animal cruelty on future aggressive and non-aggressive offending.

    PubMed

    Walters, Glenn D

    2014-01-01

    The relationship between childhood cruelty toward animals and subsequent aggressive offending was explored in 1,336 (1,154 male, 182 female) participants from the 11-wave Pathways to Desistance study (Mulvey, 2013). Aggressive and income offending at Waves 1 through 10 were regressed onto a dichotomous measure of prior involvement in animal cruelty and four control variables (age, race, sex, early onset behavior problems) assessed at Wave 0 (baseline). Results indicated that childhood animal cruelty was equally predictive of aggressive and non-aggressive (income) offending, a finding inconsistent with the hypothesis that cruelty toward animals desensitizes a person to future interpersonal aggression or in some way prepares the individual for interpersonal violence toward humans. Whereas a significant sex by animal cruelty interaction was predicted, there was no evidence that sex or any of the other demographic variables included in this study (age, race) consistently moderated the animal cruelty-subsequent offending relationship. On the other hand, two cognitive-personality measures (interpersonal hostility, callousness/unemotionality) were found to successfully mediate the animal cruelty-subsequent offending relationship. Outcomes from this study imply that a causal nexus-partially or fully mediated by hostility, callousness/unemotionality, and other cognitive-personality variables-may exist between childhood animal cruelty and subsequent offending, although the effect is not specific to violence. © 2013 Wiley Periodicals, Inc.

  1. A clitoral verrucous carcinoma in an area of lichen planus has aggressive features.

    PubMed

    Tjalma, Wiebren A A; Siozopoulou, Vasiliki; Huizing, Manon T

    2017-01-06

    Verrucous carcinoma of the vulva is extremely rare. It is a slow growing, low malignant variant of a squamous cell carcinoma with a cauliflower appearance. Women with lichen planus have an increased risk of developing vulval cancer. A 79-year-old woman consulted for vulval itching. On clinical examination, a 3-cm large verrucous clitoral cancer in an area of lichen planus was seen. Based on her last clinical examination, the growth was estimated to be 1 cm 2 per month with an invasion depth after 6 months of 5 mm. A tumor developing in an area of lichen planus appears to have more aggressive features. This is the first time that the growth of a verrucous carcinoma has been documented in an area of lichen planus. Clinicians and patients should be aware of the aggressive behavior of cancers developing in areas of lichen planus and adjust their surgical management together with the follow-up strategy.

  2. Disentangling functions of online aggression: The Cyber-Aggression Typology Questionnaire (CATQ).

    PubMed

    Runions, Kevin C; Bak, Michal; Shaw, Thérèse

    2017-01-01

    Aggression in online contexts has received much attention over the last decade, yet there is a need for measures identifying the proximal psychological drivers of cyber-aggressive behavior. The purpose of this study was to present data on the newly developed Cyber-Aggression Typology Questionnaire (CATQ) designed to distinguish between four distinct types of cyber-aggression on dimensions of motivational valence and self-control. A sample 314 undergraduate students participated in the study. The results confirmed the predicted four-factor structure providing evidence for distinct and independent impulsive-aversive, controlled-aversive, impulsive-appetitive, and controlled-appetitive cyber-aggression types. Further analyses with the Berlin Cyberbullying Questionnaire, Reactive Proactive Aggression Questionnaire, and the Behavior Inhibition and Activation Systems Scale provide support for convergent and divergent validity. Understanding the motivations facilitating cyber-aggressive behavior could aid researchers in the development of new prevention and intervention strategies that focus on individual differences in maladaptive proximal drivers of aggression. Aggr. Behav. 43:74-84, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  3. Fellowship To Study the Involvement of Heat Shock Proteins in Drug Resistance in Human Breast Cancer.

    DTIC Science & Technology

    1996-10-01

    in cells in response to environmental stresses. It has been shown that breast cancer cells sometimes express high levels of hsp27 , which may augment...the aggressiveness of these tumors and make them more resistant to treatment. The research funded by this fellowship is directed at regulating hsp27 ...specific aim 1, the examination of the regulatory mechanisms controlling the expression of hsp27 in breast cancer cells. We worked on two regions of

  4. Prenatal androgen exposure and children's aggressive behavior and activity level.

    PubMed

    Spencer, Debra; Pasterski, Vickie; Neufeld, Sharon; Glover, Vivette; O'Connor, Thomas G; Hindmarsh, Peter C; Hughes, Ieuan A; Acerini, Carlo L; Hines, Melissa

    2017-11-01

    Some human behaviors, including aggression and activity level, differ on average for males and females. Here we report findings from two studies investigating possible relations between prenatal androgen and children's aggression and activity level. For study 1, aggression and activity level scores for 43 girls and 38 boys, aged 4 to 11years, with congenital adrenal hyperplasia (CAH, a genetic condition causing increased adrenal androgen production beginning prenatally) were compared to those of similarly-aged, unaffected relatives (41 girls, 31 boys). Girls with CAH scored higher on aggression than unaffected girls, d=0.69, and unaffected boys scored higher on activity level than unaffected girls, d=0.50. No other group differences were significant. For study 2, the relationship of amniotic fluid testosterone to aggression and activity level was investigated in typically-developing children (48 girls, 44 boys), aged 3 to 5years. Boys scored higher than girls on aggression, d=0.41, and activity level, d=0.50. However, amniotic fluid testosterone was not a significant predictor of aggression or activity level for either sex. The results of the two studies provide some support for an influence of prenatal androgen exposure on children's aggressive behavior, but not activity level. The within-sex variation in amniotic fluid testosterone may not be sufficient to allow reliable assessment of relations to aggression or activity level. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Impact of Radiation Therapy on Aggressive Care and Quality of Life near Death

    PubMed Central

    Li, David; Prigerson, Holly G.; Kang, Josephine; Maciejewski, Paul K.

    2016-01-01

    Context Radiation therapy (RT) is used with palliative intent in patients with advanced stage cancer. Prior studies, primarily in patients with poor performance status (PS), suggest that RT is associated with aggressive medical care, which may impact patients’ quality of life near death (QoD) adversely. Objective This study examines associations between RT use and patients’ receipt of aggressive care and QoD based on patients’ PS. Methods Multi-institutional, prospective cohort study of patients with end-stage cancers (N=312) and identified as terminally ill at study enrollment. RT use (n=24; 7.7%) and Eastern Cooperative Oncology Group (ECOG) PS were assessed at study entry (median = 3.8 months before death). Aggressive care near death was operationalized as use of mechanical ventilation and/or resuscitation in the last week of life. QoD was determined using validated caregiver ratings of patients’ physical and mental distress in their final week. Results RT use was associated with higher QoD (8/8, 100.0%, versus 58/114, 50.9%; p=0.006) among patients with good PS (ECOG=1), more aggressive care near death (3/9, 33.3%, versus 6/107, 5.6%; p=0.020) among patients with moderate PS (ECOG=2), and lower QoD (1/7, 14.3%, versus 28/51, 54.9%; p=0.046) among patients with poor PS (ECOG=3). Conclusions Targeted use of RT in end-of-life cancer care may benefit patients with good PS, but its use may adversely affect patients with poorer PS. Decisions about RT use in this setting should consider likely end-of-life outcomes based on patients’ current PS. PMID:27720786

  6. The Quantitative Criteria Based on the Fractal Dimensions, Entropy, and Lacunarity for the Spatial Distribution of Cancer Cell Nuclei Enable Identification of Low or High Aggressive Prostate Carcinomas

    PubMed Central

    Waliszewski, Przemyslaw

    2016-01-01

    Background: Tumor grading, PSA concentration, and stage determine a risk of prostate cancer patients with accuracy of about 70%. An approach based on the fractal geometrical model was proposed to eliminate subjectivity from the evaluation of tumor aggressiveness and to improve the prediction. This study was undertaken to validate classes of equivalence for the spatial distribution of cancer cell nuclei in a larger, independent set of prostate carcinomas. Methods: The global fractal capacity D0, information D1 and correlation D2 dimension, the local fractal dimension (LFD) and the local connected fractal dimension (LCFD), Shannon entropy H and lacunarity λ were measured using computer algorithms in digitalized images of both the reference set (n = 60) and the test set (n = 208) of prostate carcinomas. Results: Prostate carcinomas were re-stratified into seven classes of equivalence. The cut-off D0-values 1.5450, 1.5820, 1.6270, 1.6490, 1.6980, 1.7640 defined the classes from C1 to C7, respectively. The other measures but the D1 failed to define the same classes of equivalence. The pairs (D0, LFD), (D0, H), (D0, λ), (D1, LFD), (D1, H), (D1, λ) characterized the spatial distribution of cancer cell nuclei in each class. The co-application of those measures enabled the subordination of prostate carcinomas to one out of three clusters associated with different tumor aggressiveness. For D0 < 1.5820, LFD < 1.3, LCFD > 1.5, H < 0.7, and λ > 0.8, the class C1 or C2 contains low complexity low aggressive carcinomas exclusively. For D0 > 1.6980, LFD > 1.7644, LCFD > 1.7051, H > 0.9, and λ < 0.7, the class C6 or C7 contains high complexity high aggressive carcinomas. Conclusions: The cut-off D0-values defining the classes of equivalence were validated in this study. The cluster analysis suggested that the number of the subjective Gleason grades and the number of the objective classes of equivalence could be decreased from seven to three without a loss of clinically

  7. Cancer Diagnosis? Advice for Dealing with What Comes Next

    MedlinePlus

    ... viewed as a slow-growing cancer or an aggressive one. Ask about the available treatment options, the ... enhance your quality of life. Other cancers are aggressive and will likely cause major problems. Treatment in ...

  8. Investigating the Role of NOS2 in Breast Cancer | Center for Cancer Research

    Cancer.gov

    Inducible nitric oxide synthase (NOS2) is often elevated in breast tumors that lack expression of the estrogen receptor (ER) and predicts a poor prognosis for patients with these tumors. However, it is unclear whether NOS2 directly contributes to ER-negative breast cancer aggressiveness or how NOS2 expression is controlled within the tumor microenvironment. To tease apart the regulatory pathways upstream and downstream of NOS2, David Wink, Jr., Ph.D., Senior Investigator in CCR’s Radiation Biology Branch, along with colleagues from CCR’s Pediatric Oncology Branch, Laboratory of Human Carcinogenesis, and Laboratory of Experimental Immunology and from the Prostate Cancer Institute in Ireland, carried out studies in cell culture and mouse models.

  9. NF-kappaB Is Involved in the Regulation of EMT Genes in Breast Cancer Cells

    PubMed Central

    Mencalha, Andre L.; Ferreira, Gerson M.; de Souza, Waldemir F.; Morgado-Díaz, José A.; Maia, Amanda M.; Corrêa, Stephany; Abdelhay, Eliana S. F. W.

    2017-01-01

    The metastatic process in breast cancer is related to the expression of the epithelial-to-mesenchymal transition transcription factors (EMT-TFs) SNAIL, SLUG, SIP1 and TWIST1. EMT-TFs and nuclear factor-κB (NF-κB) activation have been associated with aggressiveness and metastatic potential in carcinomas. Here, we sought to examine the role of NF-κB in the aggressive properties and regulation of EMT-TFs in human breast cancer cells. Blocking NF-κB/p65 activity by reducing its transcript and protein levels (through siRNA-strategy and dehydroxymethylepoxyquinomicin [DHMEQ] treatment) in the aggressive MDA-MB-231 and HCC-1954 cell lines resulted in decreased invasiveness and migration, a downregulation of SLUG, SIP1, TWIST1, MMP11 and N-cadherin transcripts and an upregulation of E-cadherin transcripts. No significant changes were observed in the less aggressive cell line MCF-7. Bioinformatics tools identified several NF-κB binding sites along the promoters of SNAIL, SLUG, SIP1 and TWIST1 genes. Through chromatin immunoprecipitation and luciferase reporter assays, the NF-κB/p65 binding on TWIST1, SLUG and SIP1 promoter regions was confirmed. Thus, we suggest that NF-κB directly regulates the transcription of EMT-TF genes in breast cancer. Our findings may contribute to a greater understanding of the metastatic process of this neoplasia and highlight NF-κB as a potential target for breast cancer treatment. PMID:28107418

  10. NF-kappaB Is Involved in the Regulation of EMT Genes in Breast Cancer Cells.

    PubMed

    Pires, Bruno R B; Mencalha, Andre L; Ferreira, Gerson M; de Souza, Waldemir F; Morgado-Díaz, José A; Maia, Amanda M; Corrêa, Stephany; Abdelhay, Eliana S F W

    2017-01-01

    The metastatic process in breast cancer is related to the expression of the epithelial-to-mesenchymal transition transcription factors (EMT-TFs) SNAIL, SLUG, SIP1 and TWIST1. EMT-TFs and nuclear factor-κB (NF-κB) activation have been associated with aggressiveness and metastatic potential in carcinomas. Here, we sought to examine the role of NF-κB in the aggressive properties and regulation of EMT-TFs in human breast cancer cells. Blocking NF-κB/p65 activity by reducing its transcript and protein levels (through siRNA-strategy and dehydroxymethylepoxyquinomicin [DHMEQ] treatment) in the aggressive MDA-MB-231 and HCC-1954 cell lines resulted in decreased invasiveness and migration, a downregulation of SLUG, SIP1, TWIST1, MMP11 and N-cadherin transcripts and an upregulation of E-cadherin transcripts. No significant changes were observed in the less aggressive cell line MCF-7. Bioinformatics tools identified several NF-κB binding sites along the promoters of SNAIL, SLUG, SIP1 and TWIST1 genes. Through chromatin immunoprecipitation and luciferase reporter assays, the NF-κB/p65 binding on TWIST1, SLUG and SIP1 promoter regions was confirmed. Thus, we suggest that NF-κB directly regulates the transcription of EMT-TF genes in breast cancer. Our findings may contribute to a greater understanding of the metastatic process of this neoplasia and highlight NF-κB as a potential target for breast cancer treatment.

  11. Interplay between aggression, brain monoamines and fur color mutation in the American mink.

    PubMed

    Kulikov, A V; Bazhenova, E Y; Kulikova, E A; Fursenko, D V; Trapezova, L I; Terenina, E E; Mormede, P; Popova, N K; Trapezov, O V

    2016-11-01

    Domestication of wild animals alters the aggression towards humans, brain monoamines and coat pigmentation. Our aim is the interplay between aggression, brain monoamines and depigmentation. The Hedlund white mutation in the American mink is an extreme case of depigmentation observed in domesticated animals. The aggressive (-2.06 ± 0.03) and tame (+3.5 ± 0.1) populations of wild-type dark brown color (standard) minks were bred during 17 successive generations for aggressive or tame reaction towards humans, respectively. The Hedlund mutation was transferred to the aggressive and tame backgrounds to generate aggressive (-1.2 ± 0.1) and tame (+3.0 ± 0.2) Hedlund minks. Four groups of 10 males with equal expression of aggressive (-2) or tame (+5) behavior, standard or with the Hedlund mutation, were selected to study biogenic amines in the brain. Decreased levels of noradrenaline in the hypothalamus, but increased concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid and dopamine metabolite, homovanillic acid, in the striatum were measured in the tame compared with the aggressive standard minks. The Hedlund mutation increased noradrenaline level in the hypothalamus and substantia nigra, serotonin level in the substantia nigra and striatum and decreased dopamine concentration in the hypothalamus and striatum. Significant interaction effects were found between the Hedlund mutation and aggressive behavior on serotonin metabolism in the substantia nigra (P < 0.001), dopamine level in the midbrain (P < 0.01) and its metabolism in the striatum (P < 0.05). These results provide the first experimental evidence of the interplay between aggression, brain monoamines and the Hedlund mutation in the American minks. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  12. Association of prostate cancer risk variants with clinicopathologic characteristics of the disease

    PubMed Central

    Xu, Jianfeng; Isaacs, Sarah D.; Sun, Jielin; Li, Ge; Wiley, Kathleen E.; Zhu, Yi; Hsu, Fang-Chi; Wiklund, Fredrik; Turner, Aubrey R.; Adams, Tamara S.; Liu, Wennuan; Trock, Bruce J.; Partin, Alan W.; Chang, Baoli; Walsh, Patrick C.; Grönberg, Henrik; Isaacs, William; Zheng, Siqun

    2009-01-01

    Purpose Fifteen independent genetic variants have been implicated in prostate cancer risk by recent genome-wide association studies. However, their association with clinicopathologic features of prostate cancer is uncertain. Experimental Design We systematically evaluated these 15 variants in 1,563 prostate cancer patients undergoing radical prostatectomy, taking advantage of the uniform tumor stage and grade information available for each of these cases. Associations of these variants with aggressiveness, pathologic Gleason scores, pathologic stage, age at diagnosis, or serum PSA levels were tested. Results After adjusting for multiple testing, none of the SNPs was individually or cumulatively associated with aggressiveness or individual clinicopathologic variables of prostate cancer such as Gleason scores, pathologic stage, or age at diagnosis of prostate cancer. The reported risk allele (G) for SNP rs2735839 in the KLK3 gene at 19q13 was more frequent in less aggressive prostate cancer patients (0.89) than in more aggressive prostate cancer patients (0.86), nominal P = 0.03, or in controls (0.86), nominal P = 0.04. Considering that this allele was also significantly associated with higher serum PSA levels among controls (nominal P = 0.003), the observed trend of higher frequency of this risk allele between less and more aggressive prostate cancer, or between less aggressive and controls may be due to detection bias of PSA screening. Conclusions Prostate cancer risk variants recently discovered from genome-wide case-control association studies are not associated with clinicopathologic variables in this population. Case-case studies are urgently needed in order to discover genetic variants that predict tumor aggressiveness. PMID:18794092

  13. Bidirectional Regulation of Aggression in Mice by Hippocampal Alpha-7 Nicotinic Acetylcholine Receptors.

    PubMed

    Lewis, Alan S; Pittenger, Steven T; Mineur, Yann S; Stout, Dawson; Smith, Philip H; Picciotto, Marina R

    2018-05-01

    Humans with 15q13.3 microdeletion syndrome (15q13.3DS) are typically hemizygous for CHRNA7, the gene coding for the α7 nicotinic acetylcholine receptor (nAChR), and manifest a variable neuropsychiatric phenotype that frequently includes persistent aggression. In mice, nAChR activation by nicotine is anti-aggressive, or 'serenic,' an effect which requires α7 nAChRs and is recapitulated by GTS-21, an α7 nAChR partial agonist. Pharmacotherapies potentiating α7 nAChR signaling have also been shown to reduce aggression in human 15q13.3DS. These findings identify the α7 nAChR as an important regulator of aggressive behavior, but the underlying neurobiological substrates remain to be determined. We therefore investigated the brain regions and potential neural circuits in which α7 nAChRs regulate aggressive behavior in male mice. As in 15q13.3DS, mice heterozygous for Chrna7 were significantly more aggressive compared to wild-type controls in the resident-intruder test. We subsequently examined the hippocampus, where α7 nAChRs are highly expressed, particularly in GABAergic interneurons. Resident-intruder interactions strongly activated granule cells in the dentate gyrus (DG). In contrast, GTS-21, which reduces aggression in mice, reduced DG granule cell activity during resident-intruder interactions. Short hairpin RNA knockdown of Chrna7 in the DG enhanced baseline aggression and eliminated the serenic effects of both nicotine and GTS-21 on attack latency. These data further implicate α7 nAChRs in regulation of aggression, and demonstrate that hippocampal α7 nAChR signaling is necessary and sufficient to limit aggression. These findings suggest that nAChR-mediated regulation of hippocampal excitatory-inhibitory balance could be a promising therapeutic intervention for aggression arising in certain forms of neuropsychiatric disease.

  14. Antiangiogenic therapy for patients with aggressive or refractory advanced non-small cell lung cancer in the second-line setting.

    PubMed

    Reck, Martin; Garassino, Marina Chiara; Imbimbo, Martina; Shepherd, Frances A; Socinski, Mark A; Shih, Jin-Yuan; Tsao, Anne; Lee, Pablo; Winfree, Katherine B; Sashegyi, Andreas; Cheng, Rebecca; Varea, Rocio; Levy, Benjamin; Garon, Edward

    2018-06-01

    A majority of patients with advanced or metastatic non-small cell lung cancer (NSCLC) will experience disease progression after first-line therapy. Patients who have advanced NSCLC that is especially aggressive, which is defined as disease that rapidly progresses on first-line treatment or disease that is refractory to first-line treatment, have a critical unmet medical need. These patients have a poor prognosis in the second-line setting. Several studies have recently shown that treatment with an antiangiogenic therapy may benefit these patients. This review summarizes the approved antiangiogenic therapies for the treatment of patients with advanced NSCLC in the second-line setting, specifically focusing on the outcomes from subgroups of patients with rapidly progressing or refractory disease. Several antiangiogenic agents, as monotherapy or in combination with other treatments, have been or are currently being studied in patients with advanced NSCLC. Antiangiogenics that are approved for use in patients with advanced NSCLC are limited to bevacizumab in combination with chemotherapy (nonsquamous NSCLC), ramucirumab in combination with docetaxel (all histologies), and nintedanib in combination with docetaxel (adenocarcinoma histology). This review focuses on the efficacy, safety, and quality of life outcomes in the subpopulation of patients with rapidly progressing or refractory NSCLC treated with approved antiangiogenic therapies in the second-line setting. We also discuss the impact of newly approved immunotherapy agents on the outcomes of patients with aggressive or refractory disease. Studies in progress and planned future research will determine if combination treatment with antiangiogenics and immunotherapies will benefit patients with aggressive, advanced NSCLC. Copyright © 2018. Published by Elsevier B.V.

  15. Aggressive behavior and performance in the Tegu lizard Tupinambis merianae.

    PubMed

    Herrel, Anthony; Andrade, Denis V; de Carvalho, José Eduardo; Brito, Ananda; Abe, Augusto; Navas, Carlos

    2009-01-01

    Aggression is an important component of behavior in many animals and may be crucial to providing individuals with a competitive advantage when resources are limited. Although much is known about the effects of catecholamines and hormones on aggression, relatively few studies have examined the effects of physical performance on aggression. Here we use a large, sexually dimorphic teiid lizard to test whether individuals that show high levels of physical performance (bite force) are also more aggressive toward a potential threat (i.e., a human approaching the lizard). Our results show that independent of their sex, larger individuals with higher bite forces were indeed more aggressive. Moreover, our data show that individuals with higher bite forces tend to show decreased escape responses and are slower, providing evidence for a trade-off between fight and flight abilities. As bite force increased dramatically with body size, we suggest that large body size and bite force may reduce the threshold for an individual to engage in an aggressive encounter, allowing it to potentially gain or maintain resources and fight off predators while minimizing the risk of injury.

  16. Aberrant p63 and WT-1 expression in myoepithelial cells of pregnancy-associated breast cancer: implications for tumor aggressiveness and invasiveness

    PubMed Central

    Xu, Zheli; Wang, Wan; Deng, Chu-Xia; Man, Yan-gao

    2009-01-01

    Our recent studies revealed that focal alterations in breast myoepithelial cell layers significantly impact the biological presentation of associated epithelial cells. As pregnancy-associated breast cancer (PABC) has a significantly more aggressive clinical course and mortality rate than other forms of breast malignancies, our current study compared tumor suppressor expression in myoepithelial cells of PABC and non-PABC, to determine whether myoepithelial cells of PABC may have aberrant expression of tumor suppressors. Tissue sections from 20 cases of PABC and 20 cases of stage, grade, and age matched non-PABC were subjected to immunohistochemistry, and the expression of tumor suppressor maspin, p63, and Wilms' tumor 1 (WT-1) in calponin positive myoepithelial cells were statistically compared. The expression profiles of maspin, p63, and WT-1 in myoepithelial cells of all ducts encountered were similar between PABC and non-PABC. PABC, however, displayed several unique alterations in terminal duct and lobular units (TDLU), acini, and associated tumor tissues that were not seen in those of non-PABC, which included the absence of p63 and WT-1 expression in a vast majority of the myoepithelial cells, cytoplasmic localization of p63 in the entire epithelial cell population of some lobules, and substantially increasing WT-1 expression in vascular structures of the invasive cancer component. All or nearly all epithelial cells with aberrant p63 and WT-1 expression lacked the expression of estrogen receptor and progesterone receptor, whereas they had a substantially higher proliferation index than their counterparts with p63 and WT-1 expression. Hyperplastic cells with cytoplasmic p63 expression often adjacent to, and share a similar immunohistochemical and cytological profile with, invasive cancer cells. To our best knowledge, our main finings have not been previously reported. Our findings suggest that the functional status of myoepithelial cells may be significantly

  17. Children's aggressive responses to neutral peer behavior: a form of unprovoked reactive aggression.

    PubMed

    Kempes, Maaike; Matthys, Walter; de Vries, Han; van Engeland, Herman

    2010-04-30

    Previous studies that operationalized reactive aggression using behavioral observations in general populations have not taken into account the type of stimulus that elicits reactive aggression. In the present study we define a specific form of reactive aggression, i.e., reactive aggression in response to neutral behavior of a peer, which we will call unprovoked reactive aggression. We were specifically interested in children with severe aggressive behavior problems, since they may respond with reactive aggression even though the opponent did not clearly provoke them, but instead showed neutral behavior. Children with a disruptive behavior disorder (DBD) and normal control (NC) children participated in separate play sessions in which they played with a normal peer (NP). Children with DBD showed more unprovoked reactive aggression than NC children, during a cooperative game. Moreover, for children with DBD, unprovoked reactive aggressive behavior in this game correlated with parent-rated reactive aggression. Results of this study suggest that an unprovoked reactive form of aggression can be identified in children with DBD. Copyright (c) 2008. Published by Elsevier Ireland Ltd.

  18. Plasma butyrylcholinesterase regulates ghrelin to control aggression

    PubMed Central

    Chen, Vicky Ping; Gao, Yang; Geng, Liyi; Parks, Robin J.; Pang, Yuan-Ping; Brimijoin, Stephen

    2015-01-01

    Ongoing mouse studies of a proposed therapy for cocaine abuse based on viral gene transfer of butyrylcholinesterase (BChE) mutated for accelerated cocaine hydrolysis have yielded surprising effects on aggression. Further investigation has linked these effects to a reduction in circulating ghrelin, driven by BChE at levels ∼100-fold above normal. Tests with human BChE showed ready ghrelin hydrolysis at physiologic concentrations, and multiple low-mass molecular dynamics simulations revealed that ghrelin’s first five residues fit sterically and electrostatically into BChE’s active site. Consistent with in vitro results, male BALB/c mice with high plasma BChE after gene transfer exhibited sharply reduced plasma ghrelin. Unexpectedly, such animals fought less, both spontaneously and in a resident/intruder provocation model. One mutant BChE was found to be deficient in ghrelin hydrolysis. BALB/c mice transduced with this variant retained normal plasma ghrelin levels and did not differ from untreated controls in the aggression model. In contrast, C57BL/6 mice with BChE gene deletion exhibited increased ghrelin and fought more readily than wild-type animals. Collectively, these findings indicate that BChE-catalyzed ghrelin hydrolysis influences mouse aggression and social stress, with potential implications for humans. PMID:25646463

  19. Long-Term Remission of an Aggressive Sebaceous Carcinoma following Chemotherapy

    PubMed Central

    Orcurto, Angela; Gay, Béatrice E.; Sozzi, Wendy Jeanneret; Gilliet, Michel; Leyvraz, Serge

    2014-01-01

    Sebaceous carcinoma (SC) is an uncommon neoplasm manifesting itself either in the eyelid or extraocularly in the head and neck area. Surgery is the standard of care. Irradiation is rarely proposed as monotherapy but is frequently administered as an adjuvant regimen following surgical resection. There is no known strategy concerning chemotherapeutic treatment in highly aggressive recurrent – or metastatic – forms of the disease. Our patient presented with an aggressive SC of the scalp recurring after multiple excisions and local radiotherapy. Chemotherapy with 5-fluorouracil, cisplatin and docetaxel was then initiated; 4 cycles were administered, followed by capecitabine maintenance. Shortly after starting chemotherapy, dermal lesions had completely disappeared and radiological response could be seen. The patient experienced an extended period (>20 months) of complete remission. In this report, we show an excellent response of a highly aggressive SC after a combination of chemotherapy as for head and neck cancers. PMID:24748864

  20. Alpha-particle-induced cancer in humans

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Mays, C.W.

    Updated information is given on alpha-particle-induced cancer in persons internally exposed to 222Rn progeny, Thorotrast, long-lived 226Ra and 228Ra, and short-lived 224Ra. The lung cancer risk to persons breathing 222Rn progeny in the indoor air of offices, schools, and homes is of increasing concern. About half of the recent deaths among the German Thorotrast patients have been from liver cancer. Animal studies indicate that the liver cancer risk from Thorotrast is mainly from its radioactivity and that the risk coefficient for the Thorotrast patients can be used provisionally for other alpha emitters in the human liver. Six skeletal cancers havemore » occurred in persons with average skeletal doses between 0.85 and 11.8 Gy from 226Ra and 228Ra. In the low-dose German 224Ra patients, two skeletal sarcomas have occurred at about 0.7 Gy compared to about six cases predicted by results from 224Ra patients at higher doses. The minimal appearance time for radiation-induced bone sarcomas in humans is about 4 y. Following brief irradiation, the vast majority of induced bone sarcomas are expressed by about 30 y. Recent evidence against the practical threshold hypothesis is given. With the downward revision of neutron doses to the atomic-bomb survivors, the follow-up of persons exposed to alpha particles may be the best opportunity to evaluate directly the effects of high LET radiation on humans. 90 references.« less

  1. Human retroviruses: their role in cancer.

    PubMed

    Blattner, W A

    1999-01-01

    Viruses are etiologically linked to approximately 20% of all malignancies worldwide. Retroviruses account for approximately 8%-10% of the total. For human T-cell leukemia virus 1 (HTLV-I), the viral regulatory tax gene product is responsible for enhanced transcription of viral and cellular genes that promote cell growth by stimulating various growth factors and through dysregulation of cellular regulatory suppressor genes, such as p53. After a long latent period, adult T-cell leukemia/lymphoma (ATL) occurs in 1 per 1000 carriers per year, resulting in 2500-3000 cases per year worldwide and over half of the adult lymphoid malignancies in endemic areas. Human immunodeficiency virus 1 (HIV-1) accounts for a significant cancer burden, and its transactivating regulatory protein Tat enhances direct and indirect cytokine and immunological dysregulation to cause diverse cancers. Kaposi's sarcoma (KS) is a very rare tumor except after HIV-1 infection, when its incidence is greatly amplified reaching seventy thousand-fold in HIV-infected homosexual men. Human herpesvirus 8 (HHV-8), which is also known as Kaposi's sarcoma-associated virus (KSHV), is a necessary but not sufficient etiological factor in KS. The dramatic decline of KS since the introduction of highly active antiretroviral therapy (HAART) could be due to suppression of HIV-1 tat. B-cell non-Hodgkin's lymphoma occurs as their first acquired immunodeficiency syndrome-defining diagnosis in 3%-4% of HIV-infected patients. Hodgkin's lymphoma is also associated with HIV infection but at a lower risk. Human papillomaviruses are linked to invasive cervical cancer and anogenital cancers among HIV-infected patients. Human retroviruses cause malignancy via direct effects as well as through interactions with other oncogenic herpesviruses and other viruses.

  2. Relational Aggression and Physical Aggression among Adolescent Cook Islands Students

    ERIC Educational Resources Information Center

    Page, Angela; Smith, Lisa F.

    2016-01-01

    Both physical and relational aggression are characterised by the intent to harm another. Physical aggression includes direct behaviours such as hitting or kicking; relational aggression involves behaviours designed to damage relationships, such as excluding others, spreading rumours, and delivering threats and verbal abuse. This study extended…

  3. Symposium on Understanding Human Behavior and Experience -- Traits, States, and Situations -- Perspectives from Research on Aggression and Violent Behavior.

    ERIC Educational Resources Information Center

    Eron, L. D.

    This paper analyzes precursors of aggressive behavior and discusses the trait characteristics of aggression. The accumulating evidence for the heritability of aggression, the consistent physiological differences found between aggressive and non-aggressive subjects, the fact that males exhibit more aggression than females, and the belief that…

  4. Prenatal, perinatal, and adolescent exposure to marijuana: Relationships with aggressive behavior.

    PubMed

    Barthelemy, Olivier J; Richardson, Mark A; Cabral, Howard J; Frank, Deborah A

    This manuscript reviews research exploring the relationship between prenatal, perinatal, and adolescent exposure to marijuana and aggressive behavior, including physical aggression. Areas of inquiry include animal research, as well as human research, on prenatal exposure and on marijuana use during adolescence. Potential psychosocial and psychopharmacological mechanisms are identified, as well as relevant confounds. The prenatal marijuana exposure literature provides minimal support for a direct relationship with aggressive behavior in childhood. The adolescent use literature suggests a marginal (at best) association between acute intoxication and aggressive behavior, and an association between chronic use and aggressive behavior heavily influenced by demographic variables, rather than direct, psychopharmacological mechanisms. Cannabis withdrawal symptoms also may include aggression and anger, but there is little evidence to suggest that these effects are large or specific to withdrawal from marijuana compared to other substances. This review will offer recommendations for clinical care and public policy, as well as important questions for future research. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Longitudinal Relations between Beliefs Supporting Aggression,Anger Regulation, and Dating Aggression among Early Adolescents.

    PubMed

    Sullivan, Terri N; Garthe, Rachel C; Goncy, Elizabeth A; Carlson, Megan M; Behrhorst, Kathryn L

    2017-05-01

    Dating aggression occurs frequently in early to mid-adolescence and has negative repercussions for psychosocial adjustment and physical health. The patterns of behavior learned during this developmental timeframe may persist in future dating relationships, underscoring the need to identify risk factors for this outcome. The current study examined longitudinal relations between beliefs supporting aggression, anger regulation, and dating aggression. Participants were 176 middle school students in sixth, seventh, and eighth grade (50 % female; 82 % African American). No direct effects were found between beliefs supporting reactive or proactive aggression and dating aggression. Beliefs supporting reactive aggression predicted increased rates of anger dysregulation, and beliefs supporting proactive aggression led to subsequent increases in anger inhibition. Anger dysregulation and inhibition were associated with higher frequencies of dating aggression. An indirect effect was found for the relation between beliefs supporting reactive aggression and dating aggression via anger dysregulation. Another indirect effect emerged for the relation between beliefs supporting proactive aggression and dating aggression through anger inhibition. The study's findings suggested that beliefs supporting proactive and reactive aggression were differentially related to emotion regulation processes, and identified anger dysregulation and inhibition as risk factors for dating aggression among adolescents.

  6. Antiproliferative effects of ruthenium-based nucleolipidic nanoaggregates in human models of breast cancer in vitro: insights into their mode of action

    PubMed Central

    Irace, Carlo; Misso, Gabriella; Capuozzo, Antonella; Piccolo, Marialuisa; Riccardi, Claudia; Luchini, Alessandra; Caraglia, Michele; Paduano, Luigi; Montesarchio, Daniela; Santamaria, Rita

    2017-01-01

    Looking for new metal-based anticancer treatments, in recent years many ruthenium complexes have been proposed as effective and safe potential drugs. In this context we have recently developed a novel approach for the in vivo delivery of Ru(III) complexes, preparing stable ruthenium-based nucleolipidic nanoaggregates endowed with significant antiproliferative activity. Herein we describe the cellular response to our ruthenium-containing formulations in selected models of human breast cancer. By in vitro bioscreens in the context of preclinical studies, we have focused on their ability to inhibit breast cancer cell proliferation by the activation of the intrinsic apoptotic pathway, possibly via mitochondrial perturbations involving Bcl-2 family members and predisposing to programmed cell death. In addition, the most efficient ruthenium-containing cationic nanoaggregates we have hitherto developed are able to elicit both extrinsic and intrinsic apoptosis, as well as autophagy. To limit chemoresistance and counteract uncontrolled proliferation, multiple cell death pathways activation by metal-based chemotherapeutics is a challenging, yet very promising strategy for targeted therapy development in aggressive cancer diseases, such as triple-negative breast cancer with limited treatment options. These outcomes provide valuable, original knowledge on ruthenium-based candidate drugs and new insights for future optimized cancer treatment protocols. PMID:28349991

  7. Parents' Aggressive Influences and Children's Aggressive Problem Solutions with Peers

    ERIC Educational Resources Information Center

    Duman, Sarah; Margolin, Gayla

    2007-01-01

    This study examined children's aggressive and assertive solutions to hypothetical peer scenarios in relation to parents' responses to similar hypothetical social scenarios and parents' actual marital aggression. The study included 118 children ages 9 to 10 years old and their mothers and fathers. Children's aggressive solutions correlated with…

  8. Aggressive temperament predicts ethanol self-administration in late adolescent male and female rhesus macaques

    PubMed Central

    McClintick, Megan N.; Grant, Kathleen A.

    2017-01-01

    Rationale Anxiety and aggression are associated with ethanol self-administration, but these behaviors can serve as either risk factors for or consequences of heavy drinking in rodents and humans. Baseline levels of aggressive-like and anxious-like behavior in non-human primates have not yet been characterized in relation to future or prior ethanol intake. Objective To test the association between temperament at baseline with future ethanol self-administration in late adolescent male (n=21) and female (n=11) rhesus monkeys. Methods Shortly after entering the laboratory and before exposure to ethanol, the Human Intruder Test (HIT) and the Novel Object Test (NOT) were used to determine baseline anxious-like and aggressive-like behavior in age-matched male and female rhesus monkeys (Macaca mulatta). The monkeys were induced to drink ethanol 4% (w/v) using a schedule-induced polydipsia procedure, followed by “open-access” ethanol self-administration in which the monkeys were allowed a choice of water or 4% ethanol (w/v) for 22 hours/day (h/d) for 52 weeks. Results Aggressive monkeys self-administered more ethanol and attained higher Blood Ethanol Concentrations (BECs). No significant differences in ethanol intakes or BECs were found between anxious and non-anxious monkeys or between behaviorally inhibited and non-inhibited monkeys. Baseline aggressive behavior positively correlated with ethanol intake and intoxication. Conclusions Baseline reactive aggression was associated with higher future ethanol intake and intoxication. While significant sex differences in HIT reactivity were observed, the relationship between aggression and ethanol drinking was observed across sex and is not sex-specific. PMID:27627910

  9. Elevated expression of Thoc1 is associated with aggressive phenotype and poor prognosis in colorectal cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Liu, Chenchen; Yue, Ben; Yuan, Chenwei

    The THO complex 1 (Thoc1) is a nuclear matrix protein playing vital roles in transcription elongation and mRNA export. Recently, aberrant expression of Thoc1 has been reported in an increasing array of tumor types. However, the clinical significance of Thoc1 expression in colorectal cancer (CRC) is still unknown. The present study aimed to characterize the expression of Thoc1 in human CRC and evaluate its clinical significance. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting analyses showed that the mRNA and protein expression of Thoc1 in CRC specimens was significantly higher than that in adjacent normal colon mucosae. Immunohistochemistry (IHC)more » was conducted to characterize the expression pattern of Thoc1 in 185 archived paraffin-embedded CRC specimens. Statistical analyses revealed that high levels of Thoc1 expression were associated with the clinical stages and tumor differentiation. CRC patients with high levels of Thoc1 expression had poorer overall-survival and disease-free survival, whereas those with lower levels of Thoc1 expression survived longer. Furthermore, multivariate Cox regression analyses demonstrated that Thoc1 expression remained an independent prognostic factor for increased disease recurrence and decreased survival. Our results suggest for the first time that Thoc1 is involved in the development and progression of CRC, and elevated expression of Thoc1 is associated with aggressive phenotype and poor prognosis in CRC. These findings may prove to be clinically useful for developing a new therapeutic target of CRC treatment.« less

  10. Combined effect of Hashimoto's thyroiditis and BRAF(V600E) mutation status on aggressiveness in papillary thyroid cancer.

    PubMed

    Kim, Su-jin; Myong, Jun Pyo; Jee, Hyeon-Gun; Chai, Young Jun; Choi, June Young; Min, Hye Sook; Lee, Kyu Eun; Youn, Yeo-Kyu

    2016-01-01

    The purpose of this study was to evaluate the association between Hashimoto's thyroiditis and BRAF(V600E) mutation status in patients with papillary thyroid cancer (PTC) and to determine their combined association with tumor aggressiveness in PTC. A total of 1780 patients with PTC who underwent surgery were enrolled in this study. Simple and multiple analyses were performed to determine the association between Hashimoto's thyroiditis and the BRAF(V600E) mutation in PTC. Hashimoto's thyroiditis was present in 11.5% of patients (204/1780) with PTC. Multiple logistic regressions showed that BRAF(V600E) (odds ratio [OR] = 0.493; 95% confidence interval [CI] = 0.360-0.678) and the female sex (OR = 7.146; 95% CI = 3.408-18.347) were independent factors associated with Hashimoto's thyroiditis in PTC. BRAF(V600E) mutation and the Hashimoto's thyroiditis-negative PTC group were associated with aggressive disease (OR = 3.069; 95% CI = 1.654-5.916). Hashimoto's thyroiditis was associated less frequently with BRAF(V600E) , and frequently with the female sex in patients with PTC. Hashimoto's thyroiditis and BRAF(V600E) status may help to predict clinical outcome of PTC. © 2015 Wiley Periodicals, Inc.

  11. Psychophysiological correlates of interpersonal cooperation and aggression.

    PubMed

    Wang, Yiwen; Roberts, Kathryn; Yuan, Bo; Zhang, Wenxin; Shen, Deli; Simons, Robert

    2013-07-01

    Mimicking real world situations, the Chicken Game allows scientists to examine human decision-making when the outcome is not entirely within one person's control. In this social dilemma task, two players independently choose either to safely cooperate with, or riskily aggress against, the other player, and the unique combination of their choices specifies the outcome for each. Coupling the Chicken Game with psychophysiological measures, we confirmed our two hypotheses: that an individual perceives an outcome as most negative when she chooses to cooperate and the other player violates that trust and aggresses, and that motivational salience of an outcome is greater when an individual chooses to aggress and when she gains money. Collectively, the data demonstrate the utility of pairing true social dilemma tasks like the Chicken Game with psychophysiological measures to better understand decision-making. Copyright © 2013 Elsevier B.V. All rights reserved.

  12. Orca Behavior and Subsequent Aggression Associated with Oceanarium Confinement

    PubMed Central

    Anderson, Robert; Waayers, Robyn; Knight, Andrew

    2016-01-01

    Simple Summary Orca behaviors interacting with humans within apparent friendship bonds are reviewed, and some impediments to the human evaluation of delphinid intelligence are discussed. The subsequent involvement of these orcas and their offspring in aggressive incidents with humans is also documented and examined. This is particularly relevant given that the highest recorded rates of aggressive incidents have occurred among orcas who had previously established unstructured human friendship bonds prior to their inclusion within oceanaria performances. It is concluded that the confinement of orcas within aquaria, and their use in entertainment programs, is morally indefensible, given their high intelligence, complex behaviors, and the apparent adverse effects on orcas of such confinement and use. Abstract Based on neuroanatomical indices such as brain size and encephalization quotient, orcas are among the most intelligent animals on Earth. They display a range of complex behaviors indicative of social intelligence, but these are difficult to study in the open ocean where protective laws may apply, or in captivity, where access is constrained for commercial and safety reasons. From 1979 to 1980, however, we were able to interact with juvenile orcas in an unstructured way at San Diego’s SeaWorld facility. We observed in the animals what appeared to be pranks, tests of trust, limited use of tactical deception, emotional self-control, and empathetic behaviors. Our observations were consistent with those of a former Seaworld trainer, and provide important insights into orca cognition, communication, and social intelligence. However, after being trained as performers within Seaworld’s commercial entertainment program, a number of orcas began to exhibit aggressive behaviors. The orcas who previously established apparent friendships with humans were most affected, although significant aggression also occurred in some of their descendants, and among the orcas they lived

  13. Examining human behavior in video games: The development of a computational model to measure aggression.

    PubMed

    Lamb, Richard; Annetta, Leonard; Hoston, Douglas; Shapiro, Marina; Matthews, Benjamin

    2018-06-01

    Video games with violent content have raised considerable concern in popular media and within academia. Recently, there has been considerable attention regarding the claim of the relationship between aggression and video game play. The authors of this study propose the use of a new class of tools developed via computational models to allow examination of the question of whether there is a relationship between violent video games and aggression. The purpose of this study is to computationally model and compare the General Aggression Model with the Diathesis Mode of Aggression related to the play of violent content in video games. A secondary purpose is to provide a method of measuring and examining individual aggression arising from video game play. Total participants examined for this study are N = 1065. This study occurs in three phases. Phase 1 is the development and quantification of the profile combination of traits via latent class profile analysis. Phase 2 is the training of the artificial neural network. Phase 3 is the comparison of each model as a computational model with and without the presence of video game violence. Results suggest that a combination of environmental factors and genetic predispositions trigger aggression related to video games.

  14. The Influence of Classroom Aggression and Classroom Climate on Aggressive-Disruptive Behavior

    PubMed Central

    Thomas, Duane E.; Bierman, Karen L.; Powers, CJ

    2011-01-01

    Research suggests that early classroom experiences influence the socialization of aggression. Tracking changes in the aggressive behavior of 4179 children from kindergarten to second-grade (ages 5–8) this study examined the impact of two important features of the classroom context–aggregate peer aggression and climates characterized by supportive teacher-student interactions. The aggregate aggression scores of children assigned to first-grade classrooms predicted the level of classroom aggression (assessed by teacher ratings) and quality of classroom climate (assessed by observers) that emerged by the end of grade 1. HLM analyses revealed that first-grade classroom aggression and quality of classroom climate made independent contributions to changes in student aggression, as students moved from kindergarten to second grade. Implications for policy and practice are discussed. PMID:21434887

  15. Molecular Mechanisms of Metastasis Suppression in Human Breast Cancer

    DTIC Science & Technology

    2000-07-01

    September 29 Identifying and characterizing human metastasis-suppressor genes. Novartis Pharma , May WELCH, Danny R, Ph.D...Growth and Differentiation Chemica -Biological Interactions CRC Press - Reviews European Journal of Cancer and Clinical Oncology Journal of...September 29 Identifying and characterizing human metastasis-suppressor genes. Novartis Pharma , May 27 Regulation of Metastasis in Human Cancers

  16. Highly differentiated keratinizing squamous cell cancer of the cervix: a rare, locally aggressive tumor not associated with human papillomavirus or squamous intraepithelial lesions.

    PubMed

    Morrison, C; Catania, F; Wakely, P; Nuovo, G J

    2001-10-01

    The purpose of this study is to report an unusual variant of cervical squamous cell carcinoma, not associated with either human papillomavirus infection or antecedent squamous intraepithelial lesions. Five women had a diagnosis of invasive cervical cancer discovered at hysterectomy performed for prolapse (two cases), leiomyoma (one case), or a vaginal fistula (two cases). The women ranged in age from 47 to 78 years (mean 59 years). Four of the five had a history of normal Papanicolaou (Pap) smears; the other had a Pap smear diagnosis of atypical squamous cells of undetermined significance (ASCUS). All had large cervical tumors (two with parametrial involvement and one with vaginal involvement) that showed extensive keratin formation, an inverted pattern of growth, and, except for one case, minimal cytologic atypia. There was extensive hyperkeratosis and parakeratosis adjacent to each tumor; none had evidence of squamous intraepithelial lesion. Human papillomavirus testing by polymerase chain reaction in situ hybridization and reverse-transcribed polymerase chain reaction in situ was negative in each case, compared with a detection rate of 107 of 108 (99%) for squamous intraepithelial lesion-associated cervical squamous cell and adenocarcinomas. Two of the women died of extensive local recurrence; two other women were recently diagnosed. We conclude that highly differentiated keratinizing squamous cell carcinoma of the cervix is a rare entity not associated with human papillomavirus infection or squamous intraepithelial lesion and thus difficult to detect on routine cervical cancer screening.

  17. Clinical correlates of verbal aggression, physical aggression and inappropriate sexual behaviour after brain injury.

    PubMed

    James, Andrew I W; Young, Andrew W

    2013-01-01

    To explore the relationships between verbal aggression, physical aggression and inappropriate sexual behaviour following acquired brain injury. Multivariate statistical modelling of observed verbal aggression, physical aggression and inappropriate sexual behaviour utilizing demographic, pre-morbid, injury-related and neurocognitive predictors. Clinical records of 152 participants with acquired brain injury were reviewed, providing an important data set as disordered behaviours had been recorded at the time of occurrence with the Brain Injury Rehabilitation Trust (BIRT) Aggression Rating Scale and complementary measures of inappropriate sexual behaviour. Three behavioural components (verbal aggression, physical aggression and inappropriate sexual behaviour) were identified and subjected to separate logistical regression modelling in a sub-set of 77 participants. Successful modelling was achieved for both verbal and physical aggression (correctly classifying 74% and 65% of participants, respectively), with use of psychotropic medication and poorer verbal function increasing the odds of aggression occurring. Pre-morbid history of aggression predicted verbal but not physical aggression. No variables predicted inappropriate sexual behaviour. Verbal aggression, physical aggression and inappropriate sexual behaviour following acquired brain injury appear to reflect separate clinical phenomena rather than general behavioural dysregulation. Clinical markers that indicate an increased risk of post-injury aggression were not related to inappropriate sexual behaviour.

  18. Early-life adversity-induced long-term epigenetic programming associated with early onset of chronic physical aggression: Studies in humans and animals.

    PubMed

    Chistiakov, Dimitry A; Chekhonin, Vladimir P

    2017-06-05

    To examine whether chronic physical aggression (CPA) in adulthood can be epigenetically programmed early in life due to exposure to early-life adversity. Literature search of public databases such as PubMed/MEDLINE and Scopus. Children/adolescents susceptible for CPA and exposed to early-life abuse fail to efficiently cope with stress that in turn results in the development of CPA later in life. This phenomenon was observed in humans and animal models of aggression. The susceptibility to aggression is a complex trait that is regulated by the interaction between environmental and genetic factors. Epigenetic mechanisms mediate this interaction. Subjects exposed to stress early in life exhibited long-term epigenetic programming that can influence their behaviour in adulthood. This programming affects expression of many genes not only in the brain but also in other systems such as neuroendocrine and immune. The propensity to adult CPA behaviour in subjects experienced to early-life adversity is mediated by epigenetic programming that involves long-term systemic epigenetic alterations in a whole genome.

  19. The effect of digital rectal exam on the 4Kscore for aggressive prostate cancer.

    PubMed

    Maccini, Michael A; Westfall, Nicholas J; Van Bokhoven, Adrie; Lucia, Marshall Scott; Poage, Wendy; Maroni, Paul D; Wilson, Shandra S; Glodé, Leonard Michael; Arangua, Paul; Newmark, Jay; Steiner, Mitchell; Werahera, Priya N; Crawford, Elward David

    2018-05-01

    The 4Kscore is a new commercially available blood-based diagnostic test which predicts risk for aggressive, clinically significant prostate cancer on prostate biopsy. The 4Kscore is currently restricted to patients who have not had a digital rectal exam (DRE) in the previous 96 h, owing to prior mixed data suggesting that prostate specific antigen (PSA) isoforms may increase by a statistically significant-if not necessarily clinically significant-amount shortly after DRE. Our primary objective was to determine if 4Kscore test results are affected by a preceding DRE. Participants at a Prostate Cancer Awareness Week screening event sponsored by the Prostate Conditions Education Council filled out clinical history questionnaires and had blood samples for 4Kscore testing drawn prior to DRE, then 15-45 min following DRE. Patients with prior cancer diagnosis, 5-alpha reductase inhibitor medication use, or lower urinary tract procedures in the prior 6 months were excluded, resulting in a population of 162 participants for analysis. Values were then compared to determine if there was a significant difference in 4Kscore following DRE. A statistically significant increase was seen in levels of 3 kallikreins measured (total PSA, free PSA, and intact PSA; median <0.03 ng/mL for all). This resulted in a small but statistically significant decrease in post-DRE 4Kscore (median absolute score decrease 0.43%). Using a 4Kscore cutoff of 7.5% resulted in reclassification of 10 patients (6.2%), nine of whom were "downgraded" from above the cutoff to below. If the blood draw for the 4 K score is performed after a screening DRE, there is a statistically significant difference in the 4 K score results, but in the vast majority of cases it would not affect clinical decision making. © 2018 Wiley Periodicals, Inc.

  20. Kindergarten Children's Genetic Vulnerabilities Interact with Friends' Aggression to Promote Children's Own Aggression

    ERIC Educational Resources Information Center

    van Lier, Pol; Boivin, Michel; Dionne, Ginette; Vitaro, Frank; Brendgen, Mara; Koot, Hans; Tremblay, Richard E.; Perusse, Daniel

    2007-01-01

    Objective: To examine whether kindergarten children's genetic liability to physically aggress moderates the contribution of friends' aggression to their aggressive behaviors. Method: Teacher and peer reports of aggression were available for 359 6-year-old twin pairs (145 MZ, 212 DZ) as well as teacher and peer reports of aggression of the two best…

  1. Poor sleep as a potential causal factor in aggression and violence.

    PubMed

    Kamphuis, Jeanine; Meerlo, Peter; Koolhaas, Jaap M; Lancel, Marike

    2012-04-01

    Clinical observations suggest that sleep problems may be a causal factor in the development of reactive aggression and violence. In this review we give an overview of existing literature on the relation between poor sleep and aggression, irritability, and hostility. Correlational studies are supporting such a relationship. Although limited in number, some studies suggest that treatment of sleep disturbances reduces aggressiveness and problematic behavior. In line with this is the finding that sleep deprivation actually increases aggressive behavior in animals and angriness, short-temperedness, and the outward expression of aggressive impulses in humans. In most people poor sleep will not evoke actual physical aggression, but certain individuals, such as forensic psychiatric patients, may be particularly vulnerable to the emotional dysregulating effects of sleep disturbances. The relation between sleep problems and aggression may be mediated by the negative effect of sleep loss on prefrontal cortical functioning. This most likely contributes to loss of control over emotions, including loss of the regulation of aggressive impulses to context-appropriate behavior. Other potential contributing mechanisms connecting sleep problems to aggression and violence are most likely found within the central serotonergic and the hypothalamic-pituitary-adrenal-axis. Individual variation within these neurobiological systems may be responsible for amplified aggressive responses induced by sleep loss in certain individuals. It is of great importance to identify the individuals at risk, since recognition and adequate treatment of their sleep problems may reduce aggressive and violent incidents. Copyright © 2012 Elsevier B.V. All rights reserved.

  2. Hollingsworth - Aggressive vs Indolent 2012 — EDRN Public Portal

    Cancer.gov

    Study Overview. We will examine DNA extracted from FFPE sections from approximately 200 different surgically resected primary pancreatic tumors from the UNMC Department of Pathology and Microbiology. DNA will be purified from those sections and subjected to deep sequencing for the entire TP53 locus. Expected Outcomes We expect to find a difference in the p53 mutation status between tumor samples from patients that ultimately experienced tumor recurrence (more aggressive) compared to those that did not. Parallel studies to develop ICP will enable us to rapidly develop a low cost platform to extend these studies to larger patient populations for future validation studies. Future Studies The experiments proposed in this application represent a state-of-the-art approach to identify molecular markers that will help clinicians to ascertain the tumor recurrence risk for their pancreatic cancer patients who have undergone a Whipple procedure. If our initial studies support the hypothesis that p53 mutations are associated with early metastasis of pancreatic cancer, these studies would be extended to other cohorts of patient samples that are available at other major centers that see pancreatic cancer patients. Development of ICE COLD-PCR platforms to screen for these mutations will facilitate a reliable, rapid and low cost method for predicting tumor aggressiveness in these patients, which will be deployed in future studies should the hypothesis be supported.

  3. Circulating mutational portrait of cancer: manifestation of aggressive clonal events in both early and late stages.

    PubMed

    Yang, Meng; Topaloglu, Umit; Petty, W Jeffrey; Pagni, Matthew; Foley, Kristie L; Grant, Stefan C; Robinson, Mac; Bitting, Rhonda L; Thomas, Alexandra; Alistar, Angela T; Desnoyers, Rodwige J; Goodman, Michael; Albright, Carol; Porosnicu, Mercedes; Vatca, Mihaela; Qasem, Shadi A; DeYoung, Barry; Kytola, Ville; Nykter, Matti; Chen, Kexin; Levine, Edward A; Staren, Edgar D; D'Agostino, Ralph B; Petro, Robin M; Blackstock, William; Powell, Bayard L; Abraham, Edward; Pasche, Boris; Zhang, Wei

    2017-05-04

    to EGFR drug treatment. This study demonstrates that ctDNA mutation rates in the key tumor-associated genes are clinical parameters relevant to smoking status and mortality. Mutations in ctDNA may serve as an early detection tool for cancer. This study quantitatively confirms the hypothesis that ctDNAs in circulation is the result of dissemination of aggressive tumor clones and survival of resistant clones. This study supports the use of ctDNA profiling as a less-invasive approach to monitor cancer progression and selection of appropriate drugs during cancer evolution.

  4. Characterizing Aggressive Behavior with the Impulsive/Premeditated Aggression Scale among Adolescents with Conduct Disorder

    PubMed Central

    Mathias, Charles W.; Stanford, Matthew S.; Marsh, Dawn M.; Frick, Paul J.; Moeller, F. Gerard; Swann, Alan C.; Dougherty, Donald M.

    2007-01-01

    This study extends the use of the Impulsive/Premeditated Aggression Scale for subtyping aggressive behavior among adolescents with Conduct Disorder. Of the Conduct Disorder symptoms, aggression has the strongest prognostic and treatment implications. While aggression is a complex construct, convergent evidence supports a dichotomy of impulsive and premeditated aggressive subtypes that are qualitatively different from one another in terms of phenomenology and neurobiology. Previous attempts at measuring subtypes of aggression in children and adults are not clearly generalizable to adolescents. Sixty-six adolescents completed a questionnaire for characterizing aggression (Impulsive/Premeditated Aggression Scale), along with standard measures of personality and general functioning. Principal components analysis demonstrated two stable factors of aggression with good internal consistency and construct validity. Compared to the premeditated aggression factor, the impulsive aggression factor was associated with a broader range of personality, thought, emotional, and social problems. As in the adult and child literature, characterization of aggressive behavior into two subtypes appears to be relevant to understanding individual differences among adolescents with Conduct Disorder. PMID:17383014

  5. Involvement of a Non-Human Sialic Acid in Human Cancer

    PubMed Central

    Samraj, Annie N.; Läubli, Heinz; Varki, Nissi; Varki, Ajit

    2014-01-01

    Sialic acids are common monosaccharides that are widely expressed as outer terminal units on all vertebrate cell surfaces, and play fundamental roles in cell–cell and cell–microenvironment interactions. The predominant sialic acids on most mammalian cells are N-glycolylneuraminic acid (Neu5Gc) and N-acetylneuraminic acid (Neu5Ac). Neu5Gc is notable for its deficiency in humans due to a species-specific and species-universal inactivating deletion in the CMAH gene encoding the hydroxylase that converts CMP-Neu5Ac to CMP-Neu5Gc. However, Neu5Gc is metabolically incorporated into human tissues from dietary sources (particularly red meat), and detected at even higher levels in some human cancers. Early life exposure to Neu5Gc-containing foods in the presence of certain commensal bacteria that incorporate dietary Neu5Gc into lipooligosaccharides can lead to generation of antibodies that are also cross-reactive against Neu5Gc-containing glycans in human tissues (“xeno-autoantigens”). Such anti-Neu5Gc “xeno-autoantibodies” are found in all humans, although ranging widely in levels among individuals, and displaying diverse and variable specificities for the underlying glycan. Experimental evidence in a human-like Neu5Gc-deficient Cmah−/−mouse model shows that inflammation due to “xenosialitis” caused by this antigen–antibody interaction can promote tumor progression, suggesting a likely mechanism for the well-known epidemiological link between red meat consumption and carcinoma risk. In this review, we discuss the history of this field, mechanisms of Neu5Gc incorporation into tissues, the origin and specificities of human anti-Neu5Gc antibodies, their use as possible cancer biomarkers, implications of xenosialitis in cancer initiation and progression, and current and future approaches toward immunotherapy that could take advantage of this unusual human-specific phenomenon. PMID:24600589

  6. Alcohol Expectancies and Evaluations of Aggression in Alcohol-Related Intimate-Partner Verbal and Physical Aggression

    PubMed Central

    Kachadourian, Lorig K; Quigley, Brian M; Leonard, Kenneth E

    2014-01-01

    Objective: Alcohol aggression expectancies have been found to be associated with increases in aggressive behavior. However, research has not consistently examined evaluations of such behavior. This is unfortunate as both expectancies and evaluations may play a role in whether such behavior will occur. Given this, the current study cross-sectionally examined the associations between alcohol aggression expectancies, evaluations of alcohol-related aggression, indicators of excessive drinking, and alcohol-related verbal and physical aggression. Method: The sample consisted of 280 married and cohabiting couples. These couples reported on excessive drinking indicators, alcohol expectancies and evaluations, and alcohol-related verbal and physical aggression during the past year. Results: Findings showed that verbal aggression was positively associated with indicators of excessive drinking among females and with alcohol aggression expectancies for females who evaluated such aggression positively. For males, aggression expectancies and indicators of excessive drinking were positively associated with verbal aggression. For physical aggression, results showed that indicators of excessive drinking and aggression expectancies were associated with physical aggression for females. For males, aggression expectancies were positively associated and evaluations were negatively associated with physical aggression. Conclusions: These findings add to previous research on alcohol aggression expectancies in close relationships and emphasize the importance of considering evaluations of alcohol-related behavior and how they may play a role in intimate-partner violence and aggression. PMID:25208191

  7. Genetics of Aggression in Alzheimer’s Disease (AD)

    PubMed Central

    Lukiw, Walter J.; Rogaev, Evgeny I.

    2017-01-01

    Alzheimer’s disease (AD) is a terminal, age-related neurological syndrome exhibiting progressive cognitive and memory decline, however AD patients in addition exhibit ancillary neuropsychiatric symptoms (NPSs) and these include aggression. In this communication we provide recent evidence for the mis-regulation of a small family of genes expressed in the human hippocampus that appear to be significantly involved in expression patterns common to both AD and aggression. DNA array- and mRNA transcriptome-based gene expression analysis and candidate gene association and/or genome-wide association studies (CGAS, GWAS) of aggressive attributes in humans have revealed a surprisingly small subset of six brain genes that are also strongly associated with altered gene expression patterns in AD. These genes encoded on five different chromosomes (chr) include the androgen receptor (AR; chrXq12), brain-derived neurotrophic factor (BDNF; chr11p14.1), catechol-O-methyl transferase (COMT; chr22q11.21), neuronal specific nitric oxide synthase (NOS1; chr12q24.22), dopamine beta-hydroxylase (DBH chr9q34.2) and tryptophan hydroxylase (TPH1, chr11p15.1 and TPH2, chr12q21.1). Interestingly, (i) the expression of three of these six genes (COMT, DBH, NOS1) are highly variable; (ii) three of these six genes (COMT, DBH, TPH1) are involved in DA or serotonin metabolism, biosynthesis and/or neurotransmission; and (iii) five of these six genes (AR, BDNF, COMT, DBH, NOS1) have been implicated in the development, onset and/or propagation of schizophrenia. The magnitude of the expression of genes implicated in aggressive behavior appears to be more pronounced in the later stages of AD when compared to MCI. These recent genetic data further indicate that the extent of cognitive impairment may have some bearing on the degree of aggression which accompanies the AD phenotype. PMID:28443016

  8. Survival and human papillomavirus in oropharynx cancer in TAX 324: a subset analysis from an international phase III trial

    PubMed Central

    Posner, M. R.; Lorch, J. H.; Goloubeva, O.; Tan, M.; Schumaker, L. M.; Sarlis, N. J.; Haddad, R. I.; Cullen, K. J.

    2011-01-01

    Background: The association between human papillomavirus (HPV) and overall survival (OS) in oropharynx cancer (OPC) was retrospectively examined in TAX 324, a phase III trial of sequential therapy for locally advanced head and neck cancer. Methods: Accrual for TAX 324 was completed in 2003 and data updated through 2008. Pretherapy tumor biopsies were studied by PCR for human papillomavirus type 16 and linked to OS, progression-free survival (PFS) and demographics. Results: Of 264 patients with OPC, 111 (42%) had evaluable biopsies; 56 (50%) were HPV+ and 55 (50%) were HPV−. HPV+ patients were significantly younger (54 versus 58 years, P = 0.02), had T1/T2 primary cancers (49% versus 20%, P = 0.001), and had a performance status of zero (77% versus 49%, P = 0.003). OS and PFS were better for HPV+ patients (OS, hazard ratio = 0.20, P < 0.0001). Local–regional failure was less in HPV+ patients (13% versus 42%, P = 0.0006); at 5 years, 82% of HPV+ patients were alive compared with 35% of HPV− patients (P < 0.0001). Conclusions: HPV+ OPC has a different biology compared with HPV− OPC; 5-year OS, PFS, and local–regional control are unprecedented. These results support the possibility of selectively reducing therapy and long-term morbidity in HPV+ OPC while preserving survival and approaching HPV− disease with more aggressive treatment. PMID:21317223

  9. The influence of classroom aggression and classroom climate on aggressive-disruptive behavior.

    PubMed

    Thomas, Duane E; Bierman, Karen L; Powers, C J

    2011-01-01

    Research suggests that early classroom experiences influence the socialization of aggression. Tracking changes in the aggressive behavior of 4,179 children from kindergarten to second-grade (ages 5-8), this study examined the impact of 2 important features of the classroom context--aggregate peer aggression and climates characterized by supportive teacher-student interactions. The aggregate aggression scores of children assigned to first-grade classrooms predicted the level of classroom aggression (assessed by teacher ratings) and quality of classroom climate (assessed by observers) that emerged by the end of Grade 1. Hierarchical linear model analyses revealed that first-grade classroom aggression and quality of classroom climate made independent contributions to changes in student aggression, as students moved from kindergarten to second grade. Implications for policy and practice are discussed. © 2011 The Authors. Child Development © 2011 Society for Research in Child Development, Inc.

  10. Malonyl-coenzyme-A is a potential mediator of cytotoxicity induced by fatty-acid synthase inhibition in human breast cancer cells and xenografts.

    PubMed

    Pizer, E S; Thupari, J; Han, W F; Pinn, M L; Chrest, F J; Frehywot, G L; Townsend, C A; Kuhajda, F P

    2000-01-15

    A biologically aggressive subset of human breast cancers and other malignancies is characterized by elevated fatty-acid synthase (FAS) enzyme expression, elevated fatty acid (FA) synthesis, and selective sensitivity to pharmacological inhibition of FAS activity by cerulenin or the novel compound C75. In this study, inhibition of FA synthesis at the physiologically regulated step of carboxylation of acetyl-CoA to malonyl-CoA by 5-(tetradecyloxy)-2-furoic acid (TOFA) was not cytotoxic to breast cancer cells in clonogenic assays. FAS inhibitors induced a rapid increase in intracellular malonyl-CoA to several fold above control levels, whereas TOFA reduced intracellular malonyl-CoA by 60%. Simultaneous exposure of breast cancer cells to TOFA and an FAS inhibitor resulted in significantly reduced cytotoxicity and apoptosis. Subcutaneous xenografts of MCF7 breast cancer cells in nude mice treated with C75 showed FA synthesis inhibition, apoptosis, and inhibition of tumor growth to less than 1/8 of control volumes, without comparable toxicity in normal tissues. The data suggest that differences in intermediary metabolism render tumor cells susceptible to toxic fluxes in malonyl-CoA, both in vitro and in vivo.

  11. Association analysis of 9,560 prostate cancer cases from the International Consortium of Prostate Cancer Genetics confirms the role of reported prostate-cancer associated SNPs for familial disease

    PubMed Central

    Teerlink, Craig C.; Thibodeau, Stephen N.; McDonnell, Shannon K.; Schaid, Daniel J.; Rinckleb, Antje; Maier, Christiane; Vogel, Walther; Cancel-Tassin, Geraldine; Egrot, Christophe; Cussenot, Olivier; Foulkes, William D.; Giles, Graham G.; Hopper, John L.; Severi, Gianluca; Eeles, Ros; Easton, Douglas; Kote-Jarai, Zsofia; Guy, Michelle; Cooney, Kathleen A.; Ray, Anna M.; Zuhlke, Kimberly A.; Lange, Ethan M.; FitzGerald, Liesel M.; Stanford, Janet L.; Ostrander, Elaine A.; Wiley, Kathleen E.; Isaacs, Sarah D.; Walsh, Patrick C.; Isaacs, William B.; Wahlfors, Tiina; Tammela, Teuvo; Schleutker, Johanna; Wiklund, Fredrik; Grönberg, Henrik; Emanuelsson, Monica; Carpten, John; Bailey-Wilson, Joan; Whittemore, Alice S.; Oakley-Girvan, Ingrid; Hsieh, Chih-Lin; Catalona, William J.; Zheng, S. Lilly; Jin, Guangfu; Lu, Lingyi; Xu, Jianfeng; Camp, Nicola J.; Cannon-Albright, Lisa A.

    2013-01-01

    Previous GWAS studies have reported significant associations between various common SNPs and prostate cancer risk using cases unselected for family history. How these variants influence risk in familial prostate cancer is not well studied. Here, we analyzed 25 previously reported SNPs across 14 loci from prior prostate cancer GWAS. The International Consortium for Prostate Cancer Genetics (ICPCG) previously validated some of these using a family-based association method (FBAT). However, this approach suffered reduced power due to the conditional statistics implemented in FBAT. Here, we use a case-control design with an empirical analysis strategy to analyze the ICPCG resource for association between these 25 SNPs and familial prostate cancer risk. Fourteen sites contributed 12,506 samples (9,560 prostate cancer cases, 3,368 with aggressive disease, and 2,946 controls from 2,283 pedigrees). We performed association analysis with Genie software which accounts for relationships. We analyzed all familial prostate cancer cases and the subset of aggressive cases. For the familial prostate cancer phenotype, 20 of the 25 SNPs were at least nominally associated with prostate cancer and 16 remained significant after multiple testing correction (p≤1E−3) occurring on chromosomal bands 6q25, 7p15, 8q24, 10q11, 11q13, 17q12, 17q24, and Xp11. For aggressive disease, 16 of the SNPs had at least nominal evidence and 8 were statistically significant including 2p15. The results indicate that the majority of common, low-risk alleles identified in GWAS studies for all prostate cancer also contribute risk for familial prostate cancer, and that some may be contribute risk to aggressive disease. PMID:24162621

  12. Candidate SNP markers of aggressiveness-related complications and comorbidities of genetic diseases are predicted by a significant change in the affinity of TATA-binding protein for human gene promoters.

    PubMed

    Chadaeva, Irina V; Ponomarenko, Mikhail P; Rasskazov, Dmitry A; Sharypova, Ekaterina B; Kashina, Elena V; Matveeva, Marina Yu; Arshinova, Tatjana V; Ponomarenko, Petr M; Arkova, Olga V; Bondar, Natalia P; Savinkova, Ludmila K; Kolchanov, Nikolay A

    2016-12-28

    Aggressiveness in humans is a hereditary behavioral trait that mobilizes all systems of the body-first of all, the nervous and endocrine systems, and then the respiratory, vascular, muscular, and others-e.g., for the defense of oneself, children, family, shelter, territory, and other possessions as well as personal interests. The level of aggressiveness of a person determines many other characteristics of quality of life and lifespan, acting as a stress factor. Aggressive behavior depends on many parameters such as age, gender, diseases and treatment, diet, and environmental conditions. Among them, genetic factors are believed to be the main parameters that are well-studied at the factual level, but in actuality, genome-wide studies of aggressive behavior appeared relatively recently. One of the biggest projects of the modern science-1000 Genomes-involves identification of single nucleotide polymorphisms (SNPs), i.e., differences of individual genomes from the reference genome. SNPs can be associated with hereditary diseases, their complications, comorbidities, and responses to stress or a drug. Clinical comparisons between cohorts of patients and healthy volunteers (as a control) allow for identifying SNPs whose allele frequencies significantly separate them from one another as markers of the above conditions. Computer-based preliminary analysis of millions of SNPs detected by the 1000 Genomes project can accelerate clinical search for SNP markers due to preliminary whole-genome search for the most meaningful candidate SNP markers and discarding of neutral and poorly substantiated SNPs. Here, we combine two computer-based search methods for SNPs (that alter gene expression) {i} Web service SNP_TATA_Comparator (DNA sequence analysis) and {ii} PubMed-based manual search for articles on aggressiveness using heuristic keywords. Near the known binding sites for TATA-binding protein (TBP) in human gene promoters, we found aggressiveness-related candidate SNP markers

  13. Intra- Versus Intersex Aggression: Testing Theories of Sex Differences Using Aggression Networks.

    PubMed

    Wölfer, Ralf; Hewstone, Miles

    2015-08-01

    Two theories offer competing explanations of sex differences in aggressive behavior: sexual-selection theory and social-role theory. While each theory has specific strengths and limitations depending on the victim's sex, research hardly differentiates between intrasex and intersex aggression. In the present study, 11,307 students (mean age = 14.96 years; 50% girls, 50% boys) from 597 school classes provided social-network data (aggression and friendship networks) as well as physical (body mass index) and psychosocial (gender and masculinity norms) information. Aggression networks were used to disentangle intra- and intersex aggression, whereas their class-aggregated sex differences were analyzed using contextual predictors derived from sexual-selection and social-role theories. As expected, results revealed that sexual-selection theory predicted male-biased sex differences in intrasex aggression, whereas social-role theory predicted male-biased sex differences in intersex aggression. Findings suggest the value of explaining sex differences separately for intra- and intersex aggression with a dual-theory framework covering both evolutionary and normative components. © The Author(s) 2015.

  14. Relationship between boys' normative beliefs about aggression and their physical, verbal, and indirect aggressive behaviors.

    PubMed

    Lim, Si Huan; Ang, Rebecca P

    2009-01-01

    This study examined the contribution of general normative beliefs about aggression and specific normative beliefs about retaliatory aggression in predicting physical, verbal, and indirect aggressive behaviors. Two hundred and forty-nine Grade 4 and Grade 5 boys completed the Normative Beliefs about Aggression Scale (NOBAGS) and provided self-reports on the frequency of their physical, verbal, and indirect aggressive behaviors. A series of hierarchical multiple regression analyses revealed that general normative beliefs about aggression contributed significantly in predicting all three types of aggressive behaviors. When general normative beliefs about aggression were controlled for, specific normative beliefs about retaliatory aggression against males but not specific normative beliefs about retaliatory aggression against females, contributed significantly to predict physical, verbal, and indirect aggressive behaviors. Implications for intervention programs are discussed.

  15. Thyroid Hormone Differentially Modulates Warburg Phenotype in Breast Cancer Cells

    PubMed Central

    Suhane, Sonal; Ramanujan, V Krishnan

    2011-01-01

    Sustenance of cancer cells in vivo critically depends on a variety of genetic and metabolic adaptations. Aerobic glycolysis or Warburg effect has been a defining biochemical hallmark of transformed cells for more than five decades although a clear molecular basis of this observation is emerging only in recent years. In this study, we present our findings that thyroid hormone exerts its non-genomic and genomic actions in two model human breast cancer cell lines differentially. By laying a clear foundation for experimentally monitoring the Warburg phenotype in living cancer cells, we demonstrate that thyroid hormone-induced modulation of bioenergetic profiles in these two model cell lines depends on the degree of Warburg phenotype that they display. Further we also show that thyroid hormone can sensitize mitochondria in aggressive, triple-negative breast cancer cells favorably to increase the chemotherapeutic efficacy in these cells. Even though the role of thyroid hormone in modulating mitochondrial metabolism has been known, the current study accentuates the critical role it plays in modulating Warburg phenotype in breast cancer cells. The clinical significance of this finding is the possibility to devise strategies for metabolically modulating aggressive triple-negative tumors so as to enhance their chemosensitivity in vivo. PMID:21945435

  16. Whole-genome sequencing of an aggressive BRAF wild-type papillary thyroid cancer identified EML4-ALK translocation as a therapeutic target.

    PubMed

    Demeure, Michael J; Aziz, Meraj; Rosenberg, Richard; Gurley, Steven D; Bussey, Kimberly J; Carpten, John D

    2014-06-01

    Recent advances in the treatment of cancer have focused on targeting genomic aberrations with selective therapeutic agents. In radioiodine resistant aggressive papillary thyroid cancers, there remain few effective therapeutic options. A 62-year-old man who underwent multiple operations for papillary thyroid cancer and whose metastases progressed despite standard treatments provided tumor tissue. We analyzed tumor and whole blood DNA by whole genome sequencing, achieving 80× or greater coverage over 94 % of the exome and 90 % of the genome. We determined somatic mutations and structural alterations. We found a total of 57 somatic mutations in 55 genes of the cancer genome. There was notably a lack of mutations in NRAS and BRAF, and no RET/PTC rearrangement. There was a mutation in the TRAPP oncogene and a loss of heterozygosity of the p16, p18, and RB1 tumor suppressor genes. The oncogenic driver for this tumor is a translocation involving the genes for anaplastic lymphoma receptor tyrosine kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4). The EML4-ALK translocation has been reported in approximately 5 % of lung cancers, as well as in pediatric neuroblastoma, and is a therapeutic target for crizotinib. This is the first report of the whole genomic sequencing of a papillary thyroid cancer in which we identified an EML4-ALK translocation of a TRAPP oncogene mutation. These findings suggest that this tumor has a more distinct oncogenesis than BRAF mutant papillary thyroid cancer. Whole genome sequencing can elucidate an oncogenic context and expose potential therapeutic vulnerabilities in rare cancers.

  17. HPV epigenetic mechanisms related to Oropharyngeal and Cervix cancers.

    PubMed

    Di Domenico, Marina; Giovane, Giancarlo; Kouidhi, Soumaya; Iorio, Rosamaria; Romano, Maurizio; De Francesco, Francesco; Feola, Antonia; Siciliano, Camilla; Califano, Luigi; Giordano, Antonio

    2017-03-31

    Human Papilloma Virus infection is very frequent in humans and is mainly transmitted sexually. The majority of infections are transient and asymptomatic, however, if the infection persists, it can occur with a variety of injuries to skin and mucous membranes, depending on the type of HPV involved. Some types of HPV are classified as high oncogenic risk as associated with the onset of cancer. The tumors most commonly associated with HPV are cervical and oropharyngeal cancer, epigenetic mechanisms related to HPV infection include methylation changes to host and viral DNA and chromatin modification in host species. This review is focused about epigenethic mechanism, such as MiRNAs expression, related to cervix and oral cancer. Specifically it discuss about molecular markers associated to a more aggressive phenotype. In this way we will analyze genes involved in meiotic sinaptonemal complex, transcriptional factors, of orthokeratins, sinaptogirin, they are all expressed in cancer in a way not more dependent on cell differentiation but HPV-dependent.

  18. The displaced aggression questionnaire.

    PubMed

    Denson, Thomas F; Pedersen, William C; Miller, Norman

    2006-06-01

    Previous measures of aggressive personality have focused on direct aggression (i.e., retaliation toward the provoking agent). An original self-report measure of trait displaced aggression is presented. Exploratory and confirmatory factor analyses provided support for a 3-factor conceptualization of the construct. These analyses identified an affective dimension (angry rumination), a cognitive dimension (revenge planning), and a behavioral dimension (general tendency to engage in displaced aggression). The trait measure demonstrated good internal consistency and test-retest reliability as well as convergent and discriminant construct validity. Unlike other related personality measures, trait displaced aggression significantly predicted indirect indicators of real-world displaced aggression (i.e., self-reported domestic abuse and road rage) as well as laboratory displaced aggression in 2 experiments. Copyright 2006 APA, all rights reserved.

  19. Hearing regulates Drosophila aggression.

    PubMed

    Versteven, Marijke; Vanden Broeck, Lies; Geurten, Bart; Zwarts, Liesbeth; Decraecker, Lisse; Beelen, Melissa; Göpfert, Martin C; Heinrich, Ralf; Callaerts, Patrick

    2017-02-21

    Aggression is a universal social behavior important for the acquisition of food, mates, territory, and social status. Aggression in Drosophila is context-dependent and can thus be expected to involve inputs from multiple sensory modalities. Here, we use mechanical disruption and genetic approaches in Drosophila melanogaster to identify hearing as an important sensory modality in the context of intermale aggressive behavior. We demonstrate that neuronal silencing and targeted knockdown of hearing genes in the fly's auditory organ elicit abnormal aggression. Further, we show that exposure to courtship or aggression song has opposite effects on aggression. Our data define the importance of hearing in the control of Drosophila intermale aggression and open perspectives to decipher how hearing and other sensory modalities are integrated at the neural circuit level.

  20. Integration of High-Risk Human Papillomavirus into Cellular Cancer-Related Genes in Head and Neck Cancer Cell Lines

    PubMed Central

    Walline, Heather M; Komarck, Christine M; McHugh, Jonathan B; Tang, Alice L; Owen, John H; Teh, Bin T; McKean, Erin; Glover, Thomas; Graham, Martin P; Prince, Mark E; Chepeha, Douglas B; Chinn, Steven B; Ferris, Robert L; Gollin, Susanne M; Hoffmann, Thomas K; Bier, Henning; Brakenhoff, Ruud; Bradford, Carol R; Carey, Thomas E

    2017-01-01

    Background HPV-positive oropharyngeal cancer is generally associated with excellent response to therapy, but some HPV-positive tumors progress despite aggressive therapy. This study evaluates viral oncogene expression and viral integration sites in HPV16 and HPV18-positive squamous carcinoma cell lines. Methods E6-E7 alternate transcripts were assessed by RT-PCR. Detection of integrated papillomavirus sequences (DIPS-PCR) and sequencing identified viral insertion sites and affected host genes. Cellular gene expression was assessed across viral integration sites. Results All HPV-positive cell lines expressed alternate HPVE6/E7 splicing indicative of active viral oncogenesis. HPV integration occurred within cancer-related genes TP63, DCC, JAK1, TERT, ATR, ETV6, PGR, PTPRN2, and TMEM237 in 8 HNSCC lines but UM-SCC-105 and UM-GCC-1 had only intergenic integration. Conclusions HPV integration into cancer-related genes occurred in 7/9 HPV-positive cell lines and of these six were from tumors that progressed. HPV integration into cancer-related genes may be a secondary carcinogenic driver in HPV-driven tumors. PMID:28236344

  1. Human Papillomaviruses As Therapeutic Targets in Human Cancer

    PubMed Central

    Hellner, Karin; Münger, Karl

    2011-01-01

    Cervical carcinomas are almost universally associated with high-risk human papillomavirus (HPV) infections, and are a leading cause of cancer death in women worldwide. HPV oncoproteins contribute to cancer initiation and progression and their expression is necessary for the maintenance of the transformed state. The fact that the initiating oncogenic insult, infection with a high-risk HPV and viral oncoprotein expression, is common to almost all cervical cancers offers unique opportunities for prevention, early detection, and therapy. The potential for prevention has been realized by introduction of prophylactic vaccines that are to prevent transmission of specific high-risk HPVs. Given, however, that these vaccines have no therapeutic efficacy and HPV-associated cervical cancers arise years if not decades after the initial infection, it has been estimated that there will be no measurable decline of HPV-associated tumors before 2040. Cervical cancer alone will be diagnosed in more than 375,000 US women between now and 2040. Other HPV-associated anogenital and head and neck cancers are predicted to afflict another 700,000 men and women over this time period. Hence, therapeutic efforts to combat high-risk HPV-associated disease remain of critical importance. PMID:21220591

  2. Predictive and therapeutic markers in ovarian cancer

    DOEpatents

    Gray, Joe W.; Guan, Yinghui; Kuo, Wen-Lin; Fridlyand, Jane; Mills, Gordon B.

    2013-03-26

    Cancer markers may be developed to detect diseases characterized by increased expression of apoptosis-suppressing genes, such as aggressive cancers. Genes in the human chromosomal regions, 8q24, 11q13, 20q11-q13, were found to be amplified indicating in vivo drug resistance in diseases such as ovarian cancer. Diagnosis and assessment of amplification levels certain genes shown to be amplified, including PVT1, can be useful in prediction of poor outcome of patient's response and drug resistance in ovarian cancer patients with low survival rates. Certain genes were found to be high priority therapeutic targets by the identification of recurrent aberrations involving genome sequence, copy number and/or gene expression are associated with reduced survival duration in certain diseases and cancers, specifically ovarian cancer. Therapeutics to inhibit amplification and inhibitors of one of these genes, PVT1, target drug resistance in ovarian cancer patients with low survival rates is described.

  3. Aggressive defensive behavior by free-ranging white-tailed deer

    USGS Publications Warehouse

    Grovenburg, T.W.; Jenks, J.A.; Jacques, C.N.; Klaver, R.W.; Swanson, C.C.

    2009-01-01

    Maternal investment plays a critical role in neonate survival, and adults can improve survival of offspring by defending them against predators. However, limited information exists documenting ungulate aggression toward humans in defense of neonates. During captures of neonates in spring 2007 and 2008 in north-central South Dakota, we documented 24 aggressive encounters by adult female and yearling male and female white-tailed deer (Odocoileus virginianus) defending neonates. Eleven (45.8%) aggressive encounters included yearlings accompanying adult females. Mean ages and weights of neonates that were aggressively defended were greater (P < 0.0001) than ages and weights of those that were not; adults began protecting neonates at approximately 4 days of age. Male fawns were more likely (P = 0.013) to be defended than female fawns. Examination of our data suggests that sex- and age-biased maternal defensive behavior exists in white-tailed deer, and that deer biased maternal investment toward older, male neonates.

  4. Forming groups of aggressive sows based on a predictive test of aggression does not affect overall sow aggression or welfare.

    PubMed

    Verdon, Megan; Morrison, R S; Hemsworth, P H

    2018-05-01

    This experiment examined the effects of group composition on sow aggressive behaviour and welfare. Over 6 time replicates, 360 sows (parity 1-6) were mixed into groups (10 sows per pen, 1.8 m 2 /sow) composed of animals that were predicted to be aggressive (n = 18 pens) or groups composed of animals that were randomly selected (n = 18 pens). Predicted aggressive sows were selected based on a model-pig test that has been shown to be related to the aggressive behaviour of parity 2 sows when subsequently mixed in groups. Measurements were taken on aggression delivered post-mixing, and aggression delivered around feeding, fresh skin injuries and plasma cortisol concentrations at days 2 and 24 post-mixing. Live weight gain, litter size (born alive, total born, stillborn piglets), and farrowing rate were also recorded. Manipulating the group composition based on predicted sow aggressiveness had no effect (P > 0.05) on sow aggression delivered at mixing or around feeding, fresh injuries, cortisol, weight gain from day 2 to day 24, farrowing rate, or litter size. The lack of treatment effects in the present experiment could be attributed to (1) a failure of the model-pig test to predict aggression in older sows in groups, or (2) the dependence of the expression of the aggressive phenotype on factors such as social experience and characteristics (e.g., physical size and aggressive phenotype) of pen mates. This research draws attention to the intrinsic difficulties associated with predicting behaviour across contexts, particularly when the behaviour is highly dependent on interactions with conspecifics, and highlights the social complexities involved in the presentation of a behavioural phenotype. Copyright © 2018 Elsevier B.V. All rights reserved.

  5. Recklessness as a hallmark of aggressive cancer.

    PubMed

    Noda, Makoto; Takahashi, Chiaki

    2007-11-01

    Cancer recurrence after surgical treatment is a major concern for patients and doctors. Understanding what makes tumors prone to recurrence would be an important step toward its prevention. Accumulating evidence indicates that the level of membrane-associated protease regulator reversion-inducing cysteine-rich protein with Kazal motifs (RECK) expressed in tumor tissue is a good prognostic indicator in several common cancers. Certain members of the matrix metalloproteinase family are often upregulated in advanced cancers and are known to play important roles in tumor angiogenesis, invasion and metastasis. RECK negatively regulates several matrix metalloproteinases. Therefore, RECK itself may well be considered a promising tool or target molecule to be activated in cancer therapy. Here we review the recent advances in RECK research and discuss some of the important issues to be addressed in future studies.

  6. Squamous cell cancer (image)

    MedlinePlus

    Squamous cell cancer involves cancerous changes to the cells of the middle portion of the epidermal skin layer. It is ... malignant tumor, and is more aggressive than basal cell cancer, but still may be relatively slow-growing. It ...

  7. Hearing regulates Drosophila aggression

    PubMed Central

    Versteven, Marijke; Vanden Broeck, Lies; Geurten, Bart; Zwarts, Liesbeth; Decraecker, Lisse; Beelen, Melissa; Göpfert, Martin C.; Heinrich, Ralf; Callaerts, Patrick

    2017-01-01

    Aggression is a universal social behavior important for the acquisition of food, mates, territory, and social status. Aggression in Drosophila is context-dependent and can thus be expected to involve inputs from multiple sensory modalities. Here, we use mechanical disruption and genetic approaches in Drosophila melanogaster to identify hearing as an important sensory modality in the context of intermale aggressive behavior. We demonstrate that neuronal silencing and targeted knockdown of hearing genes in the fly’s auditory organ elicit abnormal aggression. Further, we show that exposure to courtship or aggression song has opposite effects on aggression. Our data define the importance of hearing in the control of Drosophila intermale aggression and open perspectives to decipher how hearing and other sensory modalities are integrated at the neural circuit level. PMID:28115690

  8. Prospective Evaluation of Self-Reported Aggression in Transgender Persons.

    PubMed

    Defreyne, Justine; T'Sjoen, Guy; Bouman, Walter Pierre; Brewin, Nicola; Arcelus, Jon

    2018-05-01

    Although research on the relation between testosterone and aggression in humans is inconclusive, guidelines (including the World Professional Association for Transgender Health Standards of Care, edition 7) have warned for an increase in aggression in transgender men taking testosterone treatment. To investigate the association between levels of testosterone and aggression in treatment-seeking transgender people and explore the role of mental health psychopathology (anxiety and depressive symptoms) and social support in aggression in this population. Every transgender person invited for assessment at a national transgender health clinic in the United Kingdom during a 3-year period (2012-2015) completed self-report measures for interpersonal problems, including levels of aggression (Inventory of Interpersonal Problems [IIP-32]), symptoms of anxiety and depression (Hospital Anxiety and Depression Scale [HADS]), social support (Multidimensional Scale of Perceived Social Support), and experiences of transphobia before and 1 year after the initiation of gender-affirming hormonal therapy. Correlations between prospective scores for the IIP-32 factor "too aggressive" and prospective levels of sex steroids, prospective psychological (HADS), and baseline psychosocial measurements were tested. Prospective scores for the factor "too aggressive" were not correlated to prospective serum testosterone levels. Results of 140 people (56 transgender men, 84 transgender women) were analyzed. A prospective increase in scores for the factor "too aggressive" of the IIP-32 in transgender men 1 year after being treated with testosterone treatment or a decrease of the IIP-32 aggression scores in transgender women 1 year after gender-affirming hormonal therapy was not found. However, a positive correlation was found between increasing HADS anxiety scores and increasing scores for the IIP-32 "too aggressive" score in the entire study population and a positive correlation with lower support

  9. Men in Groups: Anthropology and Aggression, 1965-84.

    PubMed

    Milam, Erika Lorraine

    2015-01-01

    By the late 1950s, Harry Frank Guggenheim was concerned with understanding why some charismatic leaders fought for freedom, while others sought power and domination. He believed that best-selling books on ethological approaches to animal and human behavior, especially those by playwright and screenwriter Robert Ardrey, promised a key to this dilemma, and he created a foundation that would fund research addressing problems of violence, aggression, and dominance. Under the directorship of Rutgers University professors Robin Fox and Lionel Tiger, the Harry Frank Guggenheim Foundation fostered scientific investigations into the biological basis of human nature. This essay analyzes their discussions of aggression as fundamental to the behavior of men in groups in order to elucidate the private and professional dimensions of masculine networks of US philanthropic and academic authority in the late 1960s and 1970s.

  10. Maternal Depression and Childhood Aggression: Literature Review

    PubMed Central

    Hendricks, Katherine; Liu, Jianghong

    2012-01-01

    Introduction Childbearing depression (CBD) and childhood aggression are serious and international problems that encumber public health. Although maternal depression has received much attention in the literature in the last three decades, clinically it remains under-diagnosed and under-treated, especially during pregnancy. As a result, many mothers and families are left to suffer its long-lasting physical and psychosocial effects. This article's aim is to review the current literature on whether CBD increases the likelihood of childhood aggression in children ages six years and younger. Methods Using keywords, an electronic search was performed using Cumulative Index of Nursing and Allied Health, PsycINFO, and PubMed databases. Search limits included the following: 2000-2010, English, peer-review, human, All Child: 0-18. From more than 2,000 search results, 13 articles were reviewed based on relevance to paper's inquiry and sample size greater than 50. Results In all, the articles agreed that depression in women increases the likelihood of early childhood aggression by causing negative parenting behaviors. However, this finding is tempered by a number of weaknesses in the quality of articles reviewed and by the complexity of the topic. Conclusion More research is needed to determine the etiology and interplay of mediating factors between CBD and childhood aggression. This could inform the study and implementation of effective and early prevention, screening, and treatment measures and programs for maternal depression and childhood aggression. PMID:22739482

  11. Aggressive Variants of Papillary Thyroid Carcinoma: Hobnail, Tall Cell, Columnar, and Solid.

    PubMed

    Nath, Meryl C; Erickson, Lori A

    2018-05-01

    Papillary thyroid carcinomas are the most common endocrine cancer and are usually associated with good survival. However, some variants of papillary thyroid carcinomas may behave more aggressively than classic papillary thyroid carcinomas. The tall cell variant of papillary thyroid carcinoma is the most common aggressive variant of papillary thyroid carcinoma. The aggressive behavior has been ascribed to the histologic subtype and/or to the clinicopathologic features, an issue that remains controversial. The columnar variant of papillary thyroid carcinoma can be aggressive, particularly in older patients, with larger tumors showing a diffusely infiltrative growth pattern and extrathyroidal extension. A papillary thyroid carcinoma is designated as solid/trabecular variant when all or nearly all of a tumor not belonging to any of the other variants has a solid, trabecular, or nested (insular) appearance. This tumor must be distinguished from poorly differentiated thyroid carcinoma which has the same growth pattern but lacks nuclear features of papillary thyroid carcinoma and may show tumor necrosis and high mitotic activity. New to the fourth edition of the WHO Classification of Tumours of Endocrine Organs, the hobnail variant of papillary thyroid carcinoma is a moderately differentiated papillary thyroid carcinoma variant with aggressive clinical behavior and significant mortality. All of these variants are histologically unique and important to recognize due to their aggressive behavior.

  12. miR-888: A Novel Cancer-Testis Antigen that Targets the Progesterone Receptor in Endometrial Cancer12

    PubMed Central

    Hovey, Adriann M.; Devor, Eric J.; Breheny, Patrick J.; Mott, Sarah L.; Dai, Donghai; Thiel, Kristina W.; Leslie, Kimberly K.

    2015-01-01

    Cancer-testis (CT) antigens are a large family of genes that are selectively expressed in human testis germ cells, overexpressed in a variety of tumors and predominantly located on the X chromosome. To date, all known CT antigens are protein-coding genes. Here, we identify miR-888 as the first miRNA with features characteristic of a CT antigen. In a panel of 21 normal human tissues, miR-888 expression was high in testes and minimal or absent in all other examined tissues. In situ hybridization localized miR-888 expression specifically to the early stages of sperm development within the testes. Using The Cancer Genome Atlas database, we discovered that miR-888 was predominately expressed in endometrial tumors, with a significant association to high-grade tumors and increased percent invasion. In a separate panel of endometrial tumor specimens, we validated overexpression of miR-888 by real-time polymerase chain reaction. In addition, miR-888 expression was highest in endometrial carcinosarcoma, a rare and aggressive type of endometrial tumor. Moreover, we identified the progesterone receptor (PR), a potent endometrial tumor suppressor, as a direct target of miR-888. These data define miR-888 as the first miRNA CT antigen and a potential mediator of an aggressive endometrial tumor phenotype through down-regulation of PR. PMID:25926074

  13. Friend leukemia virus integration 1 activates the Rho GTPase pathway and is associated with metastasis in breast cancer.

    PubMed

    Song, Wei; Li, Wei; Li, Lingyu; Zhang, Shilin; Yan, Xu; Wen, Xue; Zhang, Xiaoying; Tian, Huimin; Li, Ailing; Hu, Ji-Fan; Cui, Jiuwei

    2015-09-15

    Breast cancer is the most prevalent malignant disease in women worldwide. In patients with breast cancer, metastasis to distant sites directly determines the survival outcome. However, the molecular mechanism underlying metastasis in breast cancer remains to be defined. In this report, we found that Friend leukemia virus integration 1 (FLI1) proto-oncogene was differentially expressed between the aggressive MDA-MB231 and the non-aggressive MCF-7 breast cancer cells. Congruently, immunohistochemical staining of clinical samples revealed that FLI1 was overexpressed in breast cancers as compared with the adjacent tissues. The abundance of FLI1 protein was strongly correlated with the advanced stage, poor differentiation, and lymph node metastasis in breast cancer patients. Knockdown of FLI1 with small interfering RNAs significantly attenuated the potential of migration and invasion in highly metastatic human breast cancer cells. FLI1 oncoprotein activated the Rho GTPase pathway that is known to play a role in tumor metastasis. This study for the first time identifies FLI1 as a clinically and functionally important target gene of metastasis, providing a rationale for developing FLI1 inhibitors in the treatment of breast cancer.

  14. Testing the myth: tolerant dogs and aggressive wolves.

    PubMed

    Range, Friederike; Ritter, Caroline; Virányi, Zsófia

    2015-05-22

    Cooperation is thought to be highly dependent on tolerance. For example, it has been suggested that dog-human cooperation has been enabled by selecting dogs for increased tolerance and reduced aggression during the course of domestication ('emotional reactivity hypothesis'). However, based on observations of social interactions among members of captive packs, a few dog-wolf comparisons found contradictory results. In this study, we compared intraspecies aggression and tolerance of dogs and wolves raised and kept under identical conditions by investigating their agonistic behaviours and cofeeding during pair-wise food competition tests, a situation that has been directly linked to cooperation. We found that in wolves, dominant and subordinate members of the dyads monopolized the food and showed agonistic behaviours to a similar extent, whereas in dogs these behaviours were privileges of the high-ranking individuals. The fact that subordinate dogs rarely challenged their higher-ranking partners suggests a steeper dominance hierarchy in dogs than in wolves. Finally, wolves as well as dogs showed only rare and weak aggression towards each other. Therefore, we suggest that wolves are sufficiently tolerant to enable wolf-wolf cooperation, which in turn might have been the basis for the evolution of dog-human cooperation (canine cooperation hypothesis).

  15. Testing the myth: tolerant dogs and aggressive wolves

    PubMed Central

    Range, Friederike; Ritter, Caroline; Virányi, Zsófia

    2015-01-01

    Cooperation is thought to be highly dependent on tolerance. For example, it has been suggested that dog–human cooperation has been enabled by selecting dogs for increased tolerance and reduced aggression during the course of domestication (‘emotional reactivity hypothesis’). However, based on observations of social interactions among members of captive packs, a few dog–wolf comparisons found contradictory results. In this study, we compared intraspecies aggression and tolerance of dogs and wolves raised and kept under identical conditions by investigating their agonistic behaviours and cofeeding during pair-wise food competition tests, a situation that has been directly linked to cooperation. We found that in wolves, dominant and subordinate members of the dyads monopolized the food and showed agonistic behaviours to a similar extent, whereas in dogs these behaviours were privileges of the high-ranking individuals. The fact that subordinate dogs rarely challenged their higher-ranking partners suggests a steeper dominance hierarchy in dogs than in wolves. Finally, wolves as well as dogs showed only rare and weak aggression towards each other. Therefore, we suggest that wolves are sufficiently tolerant to enable wolf–wolf cooperation, which in turn might have been the basis for the evolution of dog–human cooperation (canine cooperation hypothesis). PMID:25904666

  16. Tailless and Atrophin control Drosophila aggression by regulating neuropeptide signalling in the pars intercerebralis

    NASA Astrophysics Data System (ADS)

    Davis, Shaun M.; Thomas, Amanda L.; Nomie, Krystle J.; Huang, Longwen; Dierick, Herman A.

    2014-02-01

    Aggressive behaviour is widespread throughout the animal kingdom. However, its mechanisms are poorly understood, and the degree of molecular conservation between distantly related species is unknown. Here we show that knockdown of tailless (tll) increases aggression in Drosophila, similar to the effect of its mouse orthologue Nr2e1. Tll localizes to the adult pars intercerebralis (PI), which shows similarity to the mammalian hypothalamus. Knockdown of tll in the PI is sufficient to increase aggression and is rescued by co-expressing human NR2E1. Knockdown of Atrophin, a Tll co-repressor, also increases aggression, and both proteins physically interact in the PI. tll knockdown-induced aggression is fully suppressed by blocking neuropeptide processing or release from the PI. In addition, genetically activating PI neurons increases aggression, mimicking the aggression-inducing effect of hypothalamic stimulation. Together, our results suggest that a transcriptional control module regulates neuropeptide signalling from the neurosecretory cells of the brain to control aggressive behaviour.

  17. Flavonoid and lignan intake in relation to bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

    PubMed

    Zamora-Ros, R; Sacerdote, C; Ricceri, F; Weiderpass, E; Roswall, N; Buckland, G; St-Jules, D E; Overvad, K; Kyrø, C; Fagherazzi, G; Kvaskoff, M; Severi, G; Chang-Claude, J; Kaaks, R; Nöthlings, U; Trichopoulou, A; Naska, A; Trichopoulos, D; Palli, D; Grioni, S; Mattiello, A; Tumino, R; Gram, I T; Engeset, D; Huerta, J M; Molina-Montes, E; Argüelles, M; Amiano, P; Ardanaz, E; Ericson, U; Lindkvist, B; Nilsson, L M; Kiemeney, L A; Ros, M; Bueno-de-Mesquita, H B; Peeters, P H M; Khaw, K-T; Wareham, N J; Knaze, V; Romieu, I; Scalbert, A; Brennan, P; Wark, P; Vineis, P; Riboli, E; González, C A

    2014-10-28

    There is growing evidence of the protective role of dietary intake of flavonoids and lignans on cancer, but the association with bladder cancer has not been thoroughly investigated in epidemiological studies. We evaluated the association between dietary intakes of total and subclasses of flavonoids and lignans and risk of bladder cancer and its main morphological type, urothelial cell carcinoma (UCC), within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. A cohort of 477 312 men and women mostly aged 35-70 years, were recruited in 10 European countries. At baseline, dietary flavonoid and lignan intakes were estimated using centre-specific validated questionnaires and a food composition database based on the Phenol-Explorer, the UK Food Standards Agency and the US Department of Agriculture databases. During an average of 11 years of follow-up, 1575 new cases of primary bladder cancer were identified, of which 1425 were UCC (classified into aggressive (n=430) and non-aggressive (n=413) UCC). No association was found between total flavonoid intake and bladder cancer risk. Among flavonoid subclasses, significant inverse associations with bladder cancer risk were found for intakes of flavonol (hazard ratio comparing fifth with first quintile (HRQ5-Q1) 0.74, 95% confidence interval (CI): 0.61-0.91; P-trend=0.009) and lignans (HRQ5-Q1 0.78, 95% CI: 0.62-0.96; P-trend=0.046). Similar results were observed for overall UCC and aggressive UCC, but not for non-aggressive UCC. Our study suggests an inverse association between the dietary intakes of flavonols and lignans and risk of bladder cancer, particularly aggressive UCC.

  18. Preliminary evidence that testosterone's association with aggression depends on self-construal.

    PubMed

    Welker, Keith M; Norman, Rachel E; Goetz, Stefan; Moreau, Benjamin J P; Kitayama, Shinobu; Carré, Justin M

    2017-06-01

    A contribution to a special issue on Hormones and Human Competition. Previous research and theory suggest testosterone is an important hormone for modulating aggression and self-regulation. We propose that self-construal, a culturally-relevant difference in how individuals define the self in relation to others, may be an important moderator of the relationship between testosterone and behaviors linked to aggression. Within two studies (Study 1 N=80; Study 2 N=237) and an integrated data analysis, we find evidence suggesting that acute testosterone changes in men are positively associated with aggressive behavior for those with more independent self-construals, whereas basal testosterone is negatively associated with aggression when individuals have more interdependent self-construals. Although preliminary, these findings suggest that self-construal moderates the association between testosterone and aggression, thereby paving the way toward future work examining the potential cultural moderation of the behavioral effects of testosterone. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Hurthle Cell Cancer

    MedlinePlus

    ... can be more aggressive than other types of thyroid cancer. Surgery to remove the thyroid gland is the ... factors Factors that increase the risk of developing thyroid cancer include: Being female Being older Having a history ...

  20. Fundamental differences in promoter CpG island DNA hypermethylation between human cancer and genetically engineered mouse models of cancer.

    PubMed

    Diede, Scott J; Yao, Zizhen; Keyes, C Chip; Tyler, Ashlee E; Dey, Joyoti; Hackett, Christopher S; Elsaesser, Katrina; Kemp, Christopher J; Neiman, Paul E; Weiss, William A; Olson, James M; Tapscott, Stephen J

    2013-12-01

    Genetic and epigenetic alterations are essential for the initiation and progression of human cancer. We previously reported that primary human medulloblastomas showed extensive cancer-specific CpG island DNA hypermethylation in critical developmental pathways. To determine whether genetically engineered mouse models (GEMMs) of medulloblastoma have comparable epigenetic changes, we assessed genome-wide DNA methylation in three mouse models of medulloblastoma. In contrast to human samples, very few loci with cancer-specific DNA hypermethylation were detected, and in almost all cases the degree of methylation was relatively modest compared with the dense hypermethylation in the human cancers. To determine if this finding was common to other GEMMs, we examined a Burkitt lymphoma and breast cancer model and did not detect promoter CpG island DNA hypermethylation, suggesting that human cancers and at least some GEMMs are fundamentally different with respect to this epigenetic modification. These findings provide an opportunity to both better understand the mechanism of aberrant DNA methylation in human cancer and construct better GEMMs to serve as preclinical platforms for therapy development.

  1. Cancer driver-passenger distinction via sporadic human and dog cancer comparison: a proof of principle study with colorectal cancer

    PubMed Central

    Tang, Jie; Li, Yaping; Lyon, Kenneth; Camps, Jordi; Dalton, Stephen; Ried, Thomas; Zhao, Shaying

    2014-01-01

    Herein we report a proof of principle study illustrating a novel dog-human comparison strategy that addresses a central aim of cancer research, namely cancer driver–passenger distinction. We previously demonstrated that sporadic canine colorectal cancers (CRCs) share similar molecular pathogenesis mechanisms as their human counterparts. In this study, we compared the genome-wide copy number abnormalities between 29 human- and 10 canine sporadic CRCs. This led to the identification of 73 driver candidate genes (DCGs), altered in both species and with 27 from the whole genome and 46 from dog-human genomic rearrangement breakpoint (GRB) regions, as well as 38 passenger candidate genes (PCGs), altered in humans only and located in GRB regions. We noted that DCGs significantly differ from PCGs in every analysis conducted to assess their cancer relevance and biological functions. Importantly, while PCGs are not enriched in any specific functions, DCGs possess significantly enhanced functionality closely associated with cell proliferation and death regulation, as well as with epithelial cell apicobasal polarity establishment/maintenance. These observations support the notion that, in sporadic CRCs of both species, cell polarity genes not only contribute in preventing cancer cell invasion and spreading, but also likely serve as tumor suppressors by modulating cell growth. This pilot study validates our novel strategy and has uncovered four new potential cell polarity and colorectal tumor suppressor genes (RASA3, NUPL1, DENND5A, and AVL9). Expansion of this study would make more driver-passenger distinctions for cancers with large genomic amplifications or deletions, and address key questions regarding the relationship between cancer pathogenesis and epithelial cell polarity control in mammals. PMID:23416983

  2. Cancer driver-passenger distinction via sporadic human and dog cancer comparison: a proof-of-principle study with colorectal cancer.

    PubMed

    Tang, J; Li, Y; Lyon, K; Camps, J; Dalton, S; Ried, T; Zhao, S

    2014-02-13

    Herein we report a proof-of-principle study illustrating a novel dog-human comparison strategy that addresses a central aim of cancer research, namely cancer driver-passenger distinction. We previously demonstrated that sporadic canine colorectal cancers (CRCs) share similar molecular pathogenesis mechanisms as their human counterparts. In this study, we compared the genome-wide copy number abnormalities between 29 human and 10 canine sporadic CRCs. This led to the identification of 73 driver candidate genes (DCGs), altered in both species, and with 27 from the whole genome and 46 from dog-human genomic rearrangement breakpoint (GRB) regions, as well as 38 passenger candidate genes (PCGs), altered in humans only and located in GRB regions. We noted that DCGs significantly differ from PCGs in every analysis conducted to assess their cancer relevance and biological functions. Importantly, although PCGs are not enriched in any specific functions, DCGs possess significantly enhanced functionality closely associated with cell proliferation and death regulation, as well as with epithelial cell apicobasal polarity establishment/maintenance. These observations support the notion that, in sporadic CRCs of both species, cell polarity genes not only contribute in preventing cancer cell invasion and spreading, but also likely serve as tumor suppressors by modulating cell growth. This pilot study validates our novel strategy and has uncovered four new potential cell polarity and colorectal tumor suppressor genes (RASA3, NUPL1, DENND5A and AVL9). Expansion of this study would make more driver-passenger distinctions for cancers with large genomic amplifications or deletions, and address key questions regarding the relationship between cancer pathogenesis and epithelial cell polarity control in mammals.

  3. The object of my aggression: Sexual objectification increases physical aggression toward women.

    PubMed

    Vasquez, Eduardo A; Ball, Louisa; Loughnan, Steve; Pina, Afroditi

    2018-01-01

    Objectification involves reducing someone to a sexual object, rather than seeing them as a full person. Despite numerous theoretical claims that people are more aggressive toward the objectified, and empirical evidence that objectification is linked to high willingness to aggress, rape proclivity, and aggressive attitudes, no research has examined a causal link between objectification and physical aggression, particularly in the context of provocation. In two experiments, we examined this predicted link. In Experiment 1, using a 2 (objectification: no/yes) × 2 (provocation: no/yes) factorial between-subjects design, we investigated the effects of objectification, induced via body focus during a face-to-face interaction, and provocation on physical aggression toward a female confederate. Our results revealed a significant main effect of provocation, a marginal main effect of objectification, and a significant interaction between these variables. In the absence of a provocation, focusing on a woman's body increased aggression toward her. Experiment 2 replicated Experiment 1 using a video of a target woman instead of a face-to-face interaction. Again, our results showed a significant two-way interaction between objectification and provocation, wherein objectification increased aggression in the absence of provocation. Overall, this research indicates that objectification can lead to heightened physical aggression toward objectified women. © 2017 Wiley Periodicals, Inc.

  4. Human CD3+ T-Cells with the Anti-ERBB2 Chimeric Antigen Receptor Exhibit Efficient Targeting and Induce Apoptosis in ERBB2 Overexpressing Breast Cancer Cells

    PubMed Central

    Munisvaradass, Rusheni; Kumar, Suresh; Govindasamy, Chandramohan; Alnumair, Khalid S.; Mok, Pooi Ling

    2017-01-01

    Breast cancer is a common malignancy among women. The innate and adaptive immune responses failed to be activated owing to immune modulation in the tumour microenvironment. Decades of scientific study links the overexpression of human epidermal growth factor receptor 2 (ERBB2) antigen with aggressive tumours. The Chimeric Antigen Receptor (CAR) coding for specific tumour-associated antigens could initiate intrinsic T-cell signalling, inducing T-cell activation, and cytotoxic activity without the need for major histocompatibility complex recognition. This renders CAR as a potentially universal immunotherapeutic option. Herein, we aimed to establish CAR in CD3+ T-cells, isolated from human peripheral blood mononucleated cells that could subsequently target and induce apoptosis in the ERBB2 overexpressing human breast cancer cell line, SKBR3. Constructed CAR was inserted into a lentiviral plasmid containing a green fluorescent protein tag and produced as lentiviral particles that were used to transduce activated T-cells. Transduced CAR-T cells were then primed with SKBR3 cells to evaluate their functionality. Results showed increased apoptosis in SKBR3 cells co-cultured with CAR-T cells compared to the control (non–transduced T-cells). This study demonstrates that CAR introduction helps overcome the innate limitations of native T-cells leading to cancer cell apoptosis. We recommend future studies should focus on in vivo cytotoxicity of CAR-T cells against ERBB2 expressing tumours. PMID:28885562

  5. Human CD3+ T-Cells with the Anti-ERBB2 Chimeric Antigen Receptor Exhibit Efficient Targeting and Induce Apoptosis in ERBB2 Overexpressing Breast Cancer Cells.

    PubMed

    Munisvaradass, Rusheni; Kumar, Suresh; Govindasamy, Chandramohan; Alnumair, Khalid S; Mok, Pooi Ling

    2017-09-08

    Breast cancer is a common malignancy among women. The innate and adaptive immune responses failed to be activated owing to immune modulation in the tumour microenvironment. Decades of scientific study links the overexpression of human epidermal growth factor receptor 2 (ERBB2) antigen with aggressive tumours. The Chimeric Antigen Receptor (CAR) coding for specific tumour-associated antigens could initiate intrinsic T-cell signalling, inducing T-cell activation, and cytotoxic activity without the need for major histocompatibility complex recognition. This renders CAR as a potentially universal immunotherapeutic option. Herein, we aimed to establish CAR in CD3+ T-cells, isolated from human peripheral blood mononucleated cells that could subsequently target and induce apoptosis in the ERBB2 overexpressing human breast cancer cell line, SKBR3. Constructed CAR was inserted into a lentiviral plasmid containing a green fluorescent protein tag and produced as lentiviral particles that were used to transduce activated T-cells. Transduced CAR-T cells were then primed with SKBR3 cells to evaluate their functionality. Results showed increased apoptosis in SKBR3 cells co-cultured with CAR-T cells compared to the control (non-transduced T-cells). This study demonstrates that CAR introduction helps overcome the innate limitations of native T-cells leading to cancer cell apoptosis. We recommend future studies should focus on in vivo cytotoxicity of CAR-T cells against ERBB2 expressing tumours.

  6. Husbands' and Wives' Marital Adjustment, Verbal Aggression, and Physical Aggression as Longitudinal Predictors of Physical Aggression in Early Marriage

    ERIC Educational Resources Information Center

    Schumacher, Julie A.; Leonard, Kenneth E.

    2005-01-01

    Marital adjustment, verbal aggression, and physical aggression have long been associated in the marital literature, but the nature of their associations remains unclear. In this study, the authors examined these 3 constructs as risk factors for physical aggression during the first 2 years of marriage in 634 couples recruited as they applied for…

  7. Lnc2Cancer: a manually curated database of experimentally supported lncRNAs associated with various human cancers

    PubMed Central

    Ning, Shangwei; Zhang, Jizhou; Wang, Peng; Zhi, Hui; Wang, Jianjian; Liu, Yue; Gao, Yue; Guo, Maoni; Yue, Ming; Wang, Lihua; Li, Xia

    2016-01-01

    Lnc2Cancer (http://www.bio-bigdata.net/lnc2cancer) is a manually curated database of cancer-associated long non-coding RNAs (lncRNAs) with experimental support that aims to provide a high-quality and integrated resource for exploring lncRNA deregulation in various human cancers. LncRNAs represent a large category of functional RNA molecules that play a significant role in human cancers. A curated collection and summary of deregulated lncRNAs in cancer is essential to thoroughly understand the mechanisms and functions of lncRNAs. Here, we developed the Lnc2Cancer database, which contains 1057 manually curated associations between 531 lncRNAs and 86 human cancers. Each association includes lncRNA and cancer name, the lncRNA expression pattern, experimental techniques, a brief functional description, the original reference and additional annotation information. Lnc2Cancer provides a user-friendly interface to conveniently browse, retrieve and download data. Lnc2Cancer also offers a submission page for researchers to submit newly validated lncRNA-cancer associations. With the rapidly increasing interest in lncRNAs, Lnc2Cancer will significantly improve our understanding of lncRNA deregulation in cancer and has the potential to be a timely and valuable resource. PMID:26481356

  8. Modeling Aggressive Medulloblastoma Using Human Induced Pluripotent Stem Cells

    DTIC Science & Technology

    2017-09-01

    and Myc in turn induces expression of AT1R creating a positive feedback loop and development of aggression tumor phenotype. The therapeutic...strengths are the relevant expertise of the applicant and his collaborating team, the novel paracrine positive feedback loop in EC-tumor cell...to as MYC-driven MB. The molecular mechanisms that drive MYC hyper -activation in MB remain incompletely understood. MB cells in actual tumors interact

  9. Social Aggression on Television and Its Relationship to Children's Aggression in the Classroom

    ERIC Educational Resources Information Center

    Martins, Nicole; Wilson, Barbara J.

    2012-01-01

    A survey was conducted with over 500 children in grades K-5 to examine whether exposure to socially aggressive content was related to children's use of social aggression. The results of the survey revealed a significant relationship between exposure to televised social aggression and increased social aggression at school, but only for girls and…

  10. Aggression in pigtailed macaque (Macaca nemestrina) breeding groups affects pregnancy outcome

    PubMed Central

    Ha, James; Alloway, Hayley; Sussman, Adrienne

    2011-01-01

    Past research has shown that aggressive behaviors can affect female reproductive outcome in non-human primate captive breeding programs. In this study, aggressive behaviors were recorded in a colony of pigtailed macaque monkeys (Macaca nemestrina) and related to pregnancy outcome. For twenty-two weeks, behavioral data were collected from nine breeding groups, consisting of zero to one male (some males were removed after a cycle of conceptions for husbandry reasons) and four to eight females. Observations included all occurrences of eleven aggressive behaviors during 15-minute observation sessions, one to three times a week. Mean weekly aggression levels during the study period were determined for each group, as well as for each pregnancy. Aggression data were summarized with Principal Components Analyses (PCA). Results indicate that pigtailed macaque aggression falls into five distinctive categories: warn, engage, threaten, pursue, and attack. Breeding groups differed in their levels of aggression, even after controlling for group size, presence of a sire, and group stability. Levels of the five aggression categories were found to affect the probability that a pregnancy ended in either a natural birth of a live infant, a clinical intervention producing a live infant, or a nonviable outcome. The predictive value of aggression was significant when clinical interventions were included as possible reproductive outcomes, Behavioral observation of captive groups could identify “risk” conditions affecting pregnancy outcome and the requirement for clinical intervention. PMID:21898511

  11. The Role of Executive Functions in the Control of Aggressive Behavior

    PubMed Central

    Krämer, Ulrike M.; Kopyciok, Robert P. J.; Richter, Sylvia; Rodriguez-Fornells, Antoni; Münte, Thomas F.

    2011-01-01

    An extensive literature suggests a link between executive functions and aggressive behavior in humans, pointing mostly to an inverse relationship, i.e., increased tendencies toward aggression in individuals scoring low on executive function tests. This literature is limited, though, in terms of the groups studied and the measures of executive functions. In this paper, we present data from two studies addressing these issues. In a first behavioral study, we asked whether high trait aggressiveness is related to reduced executive functions. A sample of over 600 students performed in an extensive behavioral test battery including paradigms addressing executive functions such as the Eriksen Flanker task, Stroop task, n-back task, and Tower of London (TOL). High trait aggressive participants were found to have a significantly reduced latency score in the TOL, indicating more impulsive behavior compared to low trait aggressive participants. No other differences were detected. In an EEG-study, we assessed neural and behavioral correlates of error monitoring and response inhibition in participants who were characterized based on their laboratory-induced aggressive behavior in a competitive reaction time task. Participants who retaliated more in the aggression paradigm and had reduced frontal activity when being provoked did not, however, show any reduction in behavioral or neural correlates of executive control compared to the less aggressive participants. Our results question a strong relationship between aggression and executive functions at least for healthy, high-functioning people. PMID:21747775

  12. Molecular and Clinical Predictors of Aggressive Prostate Cancer

    DTIC Science & Technology

    2008-09-01

    Trichomonas vaginalis and subsequent risk of prostate cancer. Cancer Epidemiology Biomarkers and Prevention 2006;15: 939-45. 12. Urisman A, Molinaro...combined with the findings of serologic evidence of T vaginalis and prostate cancer mortality provide supportive evidence for the study hypothesis

  13. Cruel intentions on television and in real life: can viewing indirect aggression increase viewers' subsequent indirect aggression?

    PubMed

    Coyne, Sarah M; Archer, John; Eslea, Mike

    2004-07-01

    Numerous studies have shown that viewing violence in the media can influence an individual's subsequent aggression, but none have examined the effect of viewing indirect aggression. This study examines the immediate effect of viewing indirect and direct aggression on subsequent indirect aggression among 199 children ages 11 to 14 years. They were shown an indirect, direct, or no-aggression video and their subsequent indirect aggression was measured by negative evaluation of a confederate and responses to a vignette. Participants viewing indirect or direct aggression gave a more negative evaluation of and less money to a confederate than participants viewing no-aggression. Participants viewing indirect aggression gave less money to the confederate than those viewing direct aggression. Participants viewing indirect aggression gave more indirectly aggressive responses to an ambiguous situation and participants viewing direct aggression gave more directly aggressive responses. This study provides the first evidence that viewing indirect aggression in the media can have an immediate impact on subsequent aggression.

  14. Theranostic Profiling for Actionable Aberrations in Advanced High Risk Osteosarcoma with Aggressive Biology Reveals High Molecular Diversity: The Human Fingerprint Hypothesis.

    PubMed

    Egas-Bejar, Daniela; Anderson, Pete M; Agarwal, Rishi; Corrales-Medina, Fernando; Devarajan, Eswaran; Huh, Winston W; Brown, Robert E; Subbiah, Vivek

    2014-03-12

    The survival of patients with advanced osteosarcoma is poor with limited therapeutic options. There is an urgent need for new targeted therapies based on biomarkers. Recently, theranostic molecular profiling services for cancer patients by CLIA-certified commercial companies as well as in-house profiling in academic medical centers have expanded exponentially. We evaluated molecular profiles of patients with advanced osteosarcoma whose tumor tissue had been analyzed by one of the following methods: 1. 182-gene next-generation exome sequencing (Foundation Medicine, Boston, MA), 2. Immunohistochemistry (IHC)/PCR-based panel (CARIS Target Now, Irving, Tx), 3.Comparative genome hybridization (Oncopath, San Antonio, TX). 4. Single-gene PCR assays, PTEN IHC (MDACC CLIA), 5. UT Houston morphoproteomics (Houston, TX). The most common actionable aberrations occur in the PI3K/PTEN/mTOR pathway. No patterns in genomic alterations beyond the above are readily identifiable, and suggest both high molecular diversity in osteosarcoma and the need for more analyses to define distinct subgroups of osteosarcoma defined by genomic alterations. Based on our preliminary observations we hypothesize that the biology of aggressive and the metastatic phenotype osteosarcoma at the molecular level is similar to human fingerprints, in that no two tumors are identical. Further large scale analyses of osteosarcoma samples are warranted to test this hypothesis.

  15. Genetically defined fear-induced aggression: Focus on BDNF and its receptors.

    PubMed

    Ilchibaeva, Tatiana V; Tsybko, Anton S; Kozhemyakina, Rimma V; Kondaurova, Elena M; Popova, Nina K; Naumenko, Vladimir S

    2018-05-02

    Brain-derived neurotrophic factor (BDNF), its precursor proBDNF, BDNF pro-peptide, BDNF mRNA levels, as well as TrkB and p75 NTR receptors mRNA and protein levels, were studied in the brain of rats, selectively bred for more than 85 generations for either the high level or the lack of fear-induced aggressive behavior. Furthermore, we have found that rats of aggressive strain demonstrated both high level of aggression toward humans and increased amplitude of acoustic startle response compared to rats selectively bred for the lack of fear-induced aggression. Significant increase in the BDNF mRNA, mature BDNF and proBDNF protein levels in the raphe nuclei (RN), hippocampus (Hc), nucleus accumbens (NAcc), amygdala, striatum and hypothalamus (Ht) of aggressive rats was revealed. The BDNF/proBDNF ratio was significantly reduced in the Hc and NAcc of highly aggressive rats suggesting prevalence of the proBDNF in these structures. In the Hc and frontal cortex (FC) of aggressive rats, the level of the full-length TrkB (TrkB-FL) receptor form was decreased, whereas the truncated TrkB (TrkB-T) protein level was increased in the RN, FC, substantia nigra and Ht. The TrkB-FL/TrkB-T ratio was significantly decreased in highly aggressive rats suggesting TrkB-T is predominant in highly aggressive rats. The p75 NTR expression was slightly changed in majority of studied brain structures of aggressive rats. The data indicate the BDNF system in the brain of aggressive and nonaggressive animals is extremely different at all levels, from transcription to reception, suggesting significant role of BDNF system in the development of highly aggressive phenotype. Copyright © 2018 Elsevier B.V. All rights reserved.

  16. Thalamic modulation of aggression.

    PubMed

    Andy, O J; Giurintano, L; Giurintano, S; McDonald, T

    1975-01-01

    This experiment extends Pavlov's method of contrasts for 8 components of aggression were quantitatively evaluated in 11 freely moving adult cats. Aggression was elicited from the perifornix septohypothalamic areas by a series of progressively increasing and decreasing stimulation parameters. Three levels of thalamic stimulation (low, medium, and high) were combined with the perifornix stimulations. High level thalamic stimulation tended to facilitate the aggressive response elicited by low level perifornix stimulation. Thalamic lesions attenuated the aggression response, especially those elicited during high level perifornix stimulation. It was suggested that within the hypothalamic induced aggression circuitry the center median nucleus modulates the excitatory state of the system. The discussion concerns anatomic and physiologic pathways through which the center median nucleus may modulate the sensory, motor, and affective-autonomic subsystems into a well integrated aggressive state. These experimental findings are supported by the clinically established treatment of aggression by stereotaxic lesions placed in the center median nucleus.

  17. MYCN repression of Lifeguard/FAIM2 enhances neuroblastoma aggressiveness.

    PubMed

    Planells-Ferrer, L; Urresti, J; Soriano, A; Reix, S; Murphy, D M; Ferreres, J C; Borràs, F; Gallego, S; Stallings, R L; Moubarak, R S; Segura, M F; Comella, J X

    2014-09-04

    Neuroblastoma (NBL) is the most common solid tumor in infants and accounts for 15% of all pediatric cancer deaths. Several risk factors predict NBL outcome: age at the time of diagnosis, stage, chromosome alterations and MYCN (V-Myc Avian Myelocytomatosis Viral Oncogene Neuroblastoma-Derived Homolog) amplification, which characterizes the subset of the most aggressive NBLs with an overall survival below 30%. MYCN-amplified tumors develop exceptional chemoresistance and metastatic capacity. These properties have been linked to defects in the apoptotic machinery, either by silencing components of the extrinsic apoptotic pathway (e.g. caspase-8) or by overexpression of antiapoptotic regulators (e.g. Bcl-2, Mcl-1 or FLIP). Very little is known on the implication of death receptors and their antagonists in NBL. In this work, the expression levels of several death receptor antagonists were analyzed in multiple human NBL data sets. We report that Lifeguard (LFG/FAIM2 (Fas apoptosis inhibitory molecule 2)/NMP35) is downregulated in the most aggressive and undifferentiated tumors. Intringuingly, although LFG has been initially characterized as an antiapoptotic protein, we have found a new association with NBL differentiation. Moreover, LFG repression resulted in reduced cell adhesion, increased sphere growth and enhanced migration, thus conferring a higher metastatic capacity to NBL cells. Furthermore, LFG expression was found to be directly repressed by MYCN at the transcriptional level. Our data, which support a new functional role for a hitherto undiscovered MYCN target, provide a new link between MYCN overexpression and increased NBL metastatic properties.

  18. MYCN repression of Lifeguard/FAIM2 enhances neuroblastoma aggressiveness

    PubMed Central

    Planells-Ferrer, L; Urresti, J; Soriano, A; Reix, S; Murphy, D M; Ferreres, J C; Borràs, F; Gallego, S; Stallings, R L; Moubarak, R S; Segura, M F; Comella, J X

    2014-01-01

    Neuroblastoma (NBL) is the most common solid tumor in infants and accounts for 15% of all pediatric cancer deaths. Several risk factors predict NBL outcome: age at the time of diagnosis, stage, chromosome alterations and MYCN (V-Myc Avian Myelocytomatosis Viral Oncogene Neuroblastoma-Derived Homolog) amplification, which characterizes the subset of the most aggressive NBLs with an overall survival below 30%. MYCN-amplified tumors develop exceptional chemoresistance and metastatic capacity. These properties have been linked to defects in the apoptotic machinery, either by silencing components of the extrinsic apoptotic pathway (e.g. caspase-8) or by overexpression of antiapoptotic regulators (e.g. Bcl-2, Mcl-1 or FLIP). Very little is known on the implication of death receptors and their antagonists in NBL. In this work, the expression levels of several death receptor antagonists were analyzed in multiple human NBL data sets. We report that Lifeguard (LFG/FAIM2 (Fas apoptosis inhibitory molecule 2)/NMP35) is downregulated in the most aggressive and undifferentiated tumors. Intringuingly, although LFG has been initially characterized as an antiapoptotic protein, we have found a new association with NBL differentiation. Moreover, LFG repression resulted in reduced cell adhesion, increased sphere growth and enhanced migration, thus conferring a higher metastatic capacity to NBL cells. Furthermore, LFG expression was found to be directly repressed by MYCN at the transcriptional level. Our data, which support a new functional role for a hitherto undiscovered MYCN target, provide a new link between MYCN overexpression and increased NBL metastatic properties. PMID:25188511

  19. Human papilloma virus in oral cancer

    PubMed Central

    2016-01-01

    Cervical cancer is the second most prevalent cancer among women, and it arises from cells that originate in the cervix uteri. Among several causes of cervical malignancies, infection with some types of human papilloma virus (HPV) is well known to be the greatest cervical cancer risk factor. Over 150 subtypes of HPV have been identified; more than 40 types of HPVs are typically transmitted through sexual contact and infect the anogenital region and oral cavity. The recently introduced vaccine for HPV infection is effective against certain subtypes of HPV that are associated with cervical cancer, genital warts, and some less common cancers, including oropharyngeal cancer. Two HPV vaccines, quadrivalent and bivalent types that use virus-like particles (VLPs), are currently used in the medical commercial market. While the value of HPV vaccination for oral cancer prevention is still controversial, some evidence supports the possibility that HPV vaccination may be effective in reducing the incidence of oral cancer. This paper reviews HPV-related pathogenesis in cancer, covering HPV structure and classification, trends in worldwide applications of HPV vaccines, effectiveness and complications of HPV vaccination, and the relationship of HPV with oral cancer prevalence. PMID:28053902

  20. Human papilloma virus in oral cancer.

    PubMed

    Kim, Soung Min

    2016-12-01

    Cervical cancer is the second most prevalent cancer among women, and it arises from cells that originate in the cervix uteri. Among several causes of cervical malignancies, infection with some types of human papilloma virus (HPV) is well known to be the greatest cervical cancer risk factor. Over 150 subtypes of HPV have been identified; more than 40 types of HPVs are typically transmitted through sexual contact and infect the anogenital region and oral cavity. The recently introduced vaccine for HPV infection is effective against certain subtypes of HPV that are associated with cervical cancer, genital warts, and some less common cancers, including oropharyngeal cancer. Two HPV vaccines, quadrivalent and bivalent types that use virus-like particles (VLPs), are currently used in the medical commercial market. While the value of HPV vaccination for oral cancer prevention is still controversial, some evidence supports the possibility that HPV vaccination may be effective in reducing the incidence of oral cancer. This paper reviews HPV-related pathogenesis in cancer, covering HPV structure and classification, trends in worldwide applications of HPV vaccines, effectiveness and complications of HPV vaccination, and the relationship of HPV with oral cancer prevalence.