Science.gov

Sample records for cancer reveals loss

  1. Breast Cancer and Bone Loss

    MedlinePlus

    ... Menopause Map Featured Resource Find an Endocrinologist Search Breast Cancer and Bone Loss July 2010 Download PDFs English ... G. Komen Foundation What is the link between breast cancer and bone loss? Certain treatments for breast cancer ...

  2. Target sequencing and CRISPR/Cas editing reveal simultaneous loss of UTX and UTY in urothelial bladder cancer

    PubMed Central

    Ahn, Jinwoo; Kim, Kwang Hyun; Park, Sanghui; Ahn, Young-Ho; Kim, Ha Young; Yoon, Hana; Lee, Ji Hyun; Bang, Duhee; Lee, Dong Hyeon

    2016-01-01

    UTX is a histone demethylase gene located on the X chromosome and is a frequently mutated gene in urothelial bladder cancer (UBC). UTY is a paralog of UTX located on the Y chromosome. We performed target capture sequencing on 128 genes in 40 non-metastatic UBC patients. UTX was the most frequently mutated gene (30%, 12/40). Of the genetic alterations identified, 75% were truncating mutations. UTY copy number loss was detected in 8 male patients (22.8%, 8/35). Of the 9 male patients with UTX mutations, 6 also had copy number loss (66.7%). To evaluate the functional roles of UTX and UTY in tumor progression, we designed UTX and UTY single knockout and UTX-UTY double knockout experiments using a CRISPR/Cas9 lentiviral system, and compared the proliferative capacities of two UBC cell lines in vitro. Single UTX or UTY knockout increased cell proliferation as compared to UTX-UTY wild-type cells. UTX-UTY double knockout cells exhibited greater proliferation than single knockout cells. These findings suggest both UTX and UTY function as dose-dependent suppressors of UBC development. While UTX escapes X chromosome inactivation in females, UTY may function as a male homologue of UTX, which could compensate for dosage imbalances. PMID:27533081

  3. Target sequencing and CRISPR/Cas editing reveal simultaneous loss of UTX and UTY in urothelial bladder cancer.

    PubMed

    Ahn, Jinwoo; Kim, Kwang Hyun; Park, Sanghui; Ahn, Young-Ho; Kim, Ha Young; Yoon, Hana; Lee, Ji Hyun; Bang, Duhee; Lee, Dong Hyeon

    2016-09-27

    UTX is a histone demethylase gene located on the X chromosome and is a frequently mutated gene in urothelial bladder cancer (UBC). UTY is a paralog of UTX located on the Y chromosome. We performed target capture sequencing on 128 genes in 40 non-metastatic UBC patients. UTX was the most frequently mutated gene (30%, 12/40). Of the genetic alterations identified, 75% were truncating mutations. UTY copy number loss was detected in 8 male patients (22.8%, 8/35). Of the 9 male patients with UTX mutations, 6 also had copy number loss (66.7%). To evaluate the functional roles of UTX and UTY in tumor progression, we designed UTX and UTY single knockout and UTX-UTY double knockout experiments using a CRISPR/Cas9 lentiviral system, and compared the proliferative capacities of two UBC cell lines in vitro. Single UTX or UTY knockout increased cell proliferation as compared to UTX-UTY wild-type cells. UTX-UTY double knockout cells exhibited greater proliferation than single knockout cells. These findings suggest both UTX and UTY function as dose-dependent suppressors of UBC development. While UTX escapes X chromosome inactivation in females, UTY may function as a male homologue of UTX, which could compensate for dosage imbalances.

  4. Breast Cancer and Bone Loss

    MedlinePlus

    ... Balance › Breast Cancer and Bone Loss Fact Sheet Breast Cancer and Bone Loss July, 2010 Download PDFs English ... JoAnn Pinkerton, MD What is the link between breast cancer and bone loss? Certain treatments for breast cancer ...

  5. Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability. | Office of Cancer Genomics

    Cancer.gov

    Genomic instability is a hallmark of human cancer, and results in widespread somatic copy number alterations. We used a genome-scale shRNA viability screen in human cancer cell lines to systematically identify genes that are essential in the context of particular copy-number alterations (copy-number associated gene dependencies). The most enriched class of copy-number associated gene dependencies was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes, and spliceosome components were the most prevalent.

  6. Coping with cancer - hair loss

    MedlinePlus

    ... www.cancer.org/treatment/treatments-and-side-effects/physical-side-effects/hair-loss.html . Accessed January 20, 2017. American ... www.cancer.org/treatment/treatments-and-side-effects/physical-side-effects/hair-loss/cold-caps.html . Accessed January 20, ...

  7. Integrative analysis of genome-wide loss of heterozygosity and monoallelic expression at nucleotide resolution reveals disrupted pathways in triple-negative breast cancer.

    PubMed

    Ha, Gavin; Roth, Andrew; Lai, Daniel; Bashashati, Ali; Ding, Jiarui; Goya, Rodrigo; Giuliany, Ryan; Rosner, Jamie; Oloumi, Arusha; Shumansky, Karey; Chin, Suet-Feung; Turashvili, Gulisa; Hirst, Martin; Caldas, Carlos; Marra, Marco A; Aparicio, Samuel; Shah, Sohrab P

    2012-10-01

    Loss of heterozygosity (LOH) and copy number alteration (CNA) feature prominently in the somatic genomic landscape of tumors. As such, karyotypic aberrations in cancer genomes have been studied extensively to discover novel oncogenes and tumor-suppressor genes. Advances in sequencing technology have enabled the cost-effective detection of tumor genome and transcriptome mutation events at single-base-pair resolution; however, computational methods for predicting segmental regions of LOH in this context are not yet fully explored. Consequently, whole transcriptome, nucleotide-level resolution analysis of monoallelic expression patterns associated with LOH has not yet been undertaken in cancer. We developed a novel approach for inference of LOH from paired tumor/normal sequence data and applied it to a cohort of 23 triple-negative breast cancer (TNBC) genomes. Following extensive benchmarking experiments, we describe the nucleotide-resolution landscape of LOH in TNBC and assess the consequent effect of LOH on the transcriptomes of these tumors using RNA-seq-derived measurements of allele-specific expression. We show that the majority of monoallelic expression in the transcriptomes of triple-negative breast cancer can be explained by genomic regions of LOH and establish an upper bound for monoallelic expression that may be explained by other tumor-specific modifications such as epigenetics or mutations. Monoallelically expressed genes associated with LOH reveal that cell cycle, homologous recombination and actin-cytoskeletal functions are putatively disrupted by LOH in TNBC. Finally, we show how inference of LOH can be used to interpret allele frequencies of somatic mutations and postulate on temporal ordering of mutations in the evolutionary history of these tumors.

  8. Integrative analysis of genome-wide loss of heterozygosity and monoallelic expression at nucleotide resolution reveals disrupted pathways in triple-negative breast cancer

    PubMed Central

    Ha, Gavin; Roth, Andrew; Lai, Daniel; Bashashati, Ali; Ding, Jiarui; Goya, Rodrigo; Giuliany, Ryan; Rosner, Jamie; Oloumi, Arusha; Shumansky, Karey; Chin, Suet-Feung; Turashvili, Gulisa; Hirst, Martin; Caldas, Carlos; Marra, Marco A.; Aparicio, Samuel; Shah, Sohrab P.

    2012-01-01

    Loss of heterozygosity (LOH) and copy number alteration (CNA) feature prominently in the somatic genomic landscape of tumors. As such, karyotypic aberrations in cancer genomes have been studied extensively to discover novel oncogenes and tumor-suppressor genes. Advances in sequencing technology have enabled the cost-effective detection of tumor genome and transcriptome mutation events at single-base-pair resolution; however, computational methods for predicting segmental regions of LOH in this context are not yet fully explored. Consequently, whole transcriptome, nucleotide-level resolution analysis of monoallelic expression patterns associated with LOH has not yet been undertaken in cancer. We developed a novel approach for inference of LOH from paired tumor/normal sequence data and applied it to a cohort of 23 triple-negative breast cancer (TNBC) genomes. Following extensive benchmarking experiments, we describe the nucleotide-resolution landscape of LOH in TNBC and assess the consequent effect of LOH on the transcriptomes of these tumors using RNA-seq-derived measurements of allele-specific expression. We show that the majority of monoallelic expression in the transcriptomes of triple-negative breast cancer can be explained by genomic regions of LOH and establish an upper bound for monoallelic expression that may be explained by other tumor-specific modifications such as epigenetics or mutations. Monoallelically expressed genes associated with LOH reveal that cell cycle, homologous recombination and actin-cytoskeletal functions are putatively disrupted by LOH in TNBC. Finally, we show how inference of LOH can be used to interpret allele frequencies of somatic mutations and postulate on temporal ordering of mutations in the evolutionary history of these tumors. PMID:22637570

  9. Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability.

    PubMed

    Paolella, Brenton R; Gibson, William J; Urbanski, Laura M; Alberta, John A; Zack, Travis I; Bandopadhayay, Pratiti; Nichols, Caitlin A; Agarwalla, Pankaj K; Brown, Meredith S; Lamothe, Rebecca; Yu, Yong; Choi, Peter S; Obeng, Esther A; Heckl, Dirk; Wei, Guo; Wang, Belinda; Tsherniak, Aviad; Vazquez, Francisca; Weir, Barbara A; Root, David E; Cowley, Glenn S; Buhrlage, Sara J; Stiles, Charles D; Ebert, Benjamin L; Hahn, William C; Reed, Robin; Beroukhim, Rameen

    2017-02-08

    Genomic instability is a hallmark of human cancer, and results in widespread somatic copy number alterations. We used a genome-scale shRNA viability screen in human cancer cell lines to systematically identify genes that are essential in the context of particular copy-number alterations (copy-number associated gene dependencies). The most enriched class of copy-number associated gene dependencies was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes, and spliceosome components were the most prevalent. One of these, the pre-mRNA splicing factor SF3B1, is also frequently mutated in cancer. We validated SF3B1 as a CYCLOPS gene and found that human cancer cells harboring partial SF3B1 copy-loss lack a reservoir of SF3b complex that protects cells with normal SF3B1 copy number from cell death upon partial SF3B1 suppression. These data provide a catalog of copy-number associated gene dependencies and identify partial copy-loss of wild-type SF3B1 as a novel, non-driver cancer gene dependency.

  10. Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability

    PubMed Central

    Paolella, Brenton R; Gibson, William J; Urbanski, Laura M; Alberta, John A; Zack, Travis I; Bandopadhayay, Pratiti; Nichols, Caitlin A; Agarwalla, Pankaj K; Brown, Meredith S; Lamothe, Rebecca; Yu, Yong; Choi, Peter S; Obeng, Esther A; Heckl, Dirk; Wei, Guo; Wang, Belinda; Tsherniak, Aviad; Vazquez, Francisca; Weir, Barbara A; Root, David E; Cowley, Glenn S; Buhrlage, Sara J; Stiles, Charles D; Ebert, Benjamin L; Hahn, William C; Reed, Robin; Beroukhim, Rameen

    2017-01-01

    Genomic instability is a hallmark of human cancer, and results in widespread somatic copy number alterations. We used a genome-scale shRNA viability screen in human cancer cell lines to systematically identify genes that are essential in the context of particular copy-number alterations (copy-number associated gene dependencies). The most enriched class of copy-number associated gene dependencies was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes, and spliceosome components were the most prevalent. One of these, the pre-mRNA splicing factor SF3B1, is also frequently mutated in cancer. We validated SF3B1 as a CYCLOPS gene and found that human cancer cells harboring partial SF3B1 copy-loss lack a reservoir of SF3b complex that protects cells with normal SF3B1 copy number from cell death upon partial SF3B1 suppression. These data provide a catalog of copy-number associated gene dependencies and identify partial copy-loss of wild-type SF3B1 as a novel, non-driver cancer gene dependency. DOI: http://dx.doi.org/10.7554/eLife.23268.001 PMID:28177281

  11. Exploring Prostate Cancer Genome Reveals Simultaneous Losses of PTEN, FAS and PAPSS2 in Patients with PSA Recurrence after Radical Prostatectomy

    PubMed Central

    Ibeawuchi, Chinyere; Schmidt, Hartmut; Voss, Reinhard; Titze, Ulf; Abbas, Mahmoud; Neumann, Joerg; Eltze, Elke; Hoogland, Agnes Marije; Jenster, Guido; Brandt, Burkhard; Semjonow, Axel

    2015-01-01

    The multifocal nature of prostate cancer (PCa) creates a challenge to patients’ outcome prediction and their clinical management. An approach that scrutinizes every cancer focus is needed in order to generate a comprehensive evaluation of the disease, and by correlating to patients’ clinico-pathological information, specific prognostic biomarker can be identified. Our study utilized the Affymetrix SNP 6.0 Genome-wide assay to investigate forty-three fresh frozen PCa tissue foci from twenty-three patients. With a long clinical follow-up period that ranged from 2.0–9.7 (mean 5.4) years, copy number variation (CNV) data was evaluated for association with patients’ PSA status during follow-up. From our results, the loss of unique genes on 10q23.31 and 10q23.2–10q23.31 were identified to be significantly associated to PSA recurrence (p < 0.05). The implication of PTEN and FAS loss (10q23.31) support previous reports due to their critical roles in prostate carcinogenesis. Furthermore, we hypothesize that the PAPSS2 gene (10q23.2–10q23.31) may be functionally relevant in post-operative PSA recurrence because of its reported role in androgen biosynthesis. It is suggestive that the loss of the susceptible region on chromosome 10q, which implicates PTEN, FAS and PAPSS2 may serve as genetic predictors of PSA recurrence after radical prostatectomy. PMID:25679447

  12. Single-Cell Genetic Analysis Reveals Insights into Clonal Development of Prostate Cancers and Indicates Loss of PTEN as a Marker of Poor Prognosis

    PubMed Central

    Heselmeyer-Haddad, Kerstin M.; Berroa Garcia, Lissa Y.; Bradley, Amanda; Hernandez, Leanora; Hu, Yue; Habermann, Jens K.; Dumke, Christoph; Thorns, Christoph; Perner, Sven; Pestova, Ekaterina; Burke, Catherine; Chowdhury, Salim A.; Schwartz, Russell; Schäffer, Alejandro A.; Paris, Pamela L.; Ried, Thomas

    2015-01-01

    Gauging the risk of developing progressive disease is a major challenge in prostate cancer patient management. We used genetic markers to understand genomic alteration dynamics during disease progression. By using a novel, advanced, multicolor fluorescence in situ hybridization approach, we enumerated copy numbers of six genes previously identified by array comparative genomic hybridization to be involved in aggressive prostate cancer [TBL1XR1, CTTNBP2, MYC (alias c-myc), PTEN, MEN1, and PDGFB] in six nonrecurrent and seven recurrent radical prostatectomy cases. An ERG break-apart probe to detect TMPRSS2-ERG fusions was included. Subsequent hybridization of probe panels and cell relocation resulted in signal counts for all probes in each individual cell analyzed. Differences in the degree of chromosomal and genomic instability (ie, tumor heterogeneity) or the percentage of cells with TMPRSS2-ERG fusion between samples with or without progression were not observed. Tumors from patients that progressed had more chromosomal gains and losses, and showed a higher degree of selection for a predominant clonal pattern. PTEN loss was the most frequent aberration in progressers (57%), followed by TBL1XR1 gain (29%). MYC gain was observed in one progresser, which was the only lesion with an ERG gain, but no TMPRSS2-ERG fusion. According to our results, a probe set consisting of PTEN, MYC, and TBL1XR1 would detect progressers with 86% sensitivity and 100% specificity. This will be evaluated further in larger studies. PMID:25131421

  13. RB Loss Promotes Prostate Cancer Metastasis.

    PubMed

    Thangavel, Chellappagounder; Boopathi, Ettickan; Liu, Yi; Haber, Alex; Ertel, Adam; Bhardwaj, Anshul; Addya, Sankar; Williams, Noelle; Ciment, Stephen J; Cotzia, Paolo; Dean, Jeffry L; Snook, Adam; McNair, Chris; Price, Matt; Hernandez, James R; Zhao, Shuang G; Birbe, Ruth; McCarthy, James B; Turley, Eva A; Pienta, Kenneth J; Feng, Felix Y; Dicker, Adam P; Knudsen, Karen E; Den, Robert B

    2017-02-15

    RB loss occurs commonly in neoplasia but its contributions to advanced cancer have not been assessed directly. Here we show that RB loss in multiple murine models of cancer produces a prometastatic phenotype. Gene expression analyses showed that regulation of the cell motility receptor RHAMM by the RB/E2F pathway was critical for epithelial-mesenchymal transition, motility, and invasion by cancer cells. Genetic modulation or pharmacologic inhibition of RHAMM activity was sufficient and necessary for metastatic phenotypes induced by RB loss in prostate cancer. Mechanistic studies in this setting established that RHAMM stabilized F-actin polymerization by controlling ROCK signaling. Collectively, our findings show how RB loss drives metastatic capacity and highlight RHAMM as a candidate therapeutic target for treating advanced prostate cancer. Cancer Res; 77(4); 982-95. ©2016 AACR.

  14. Weight Loss Intervention for Breast Cancer Survivors: A Systematic Review

    PubMed Central

    Playdon, Mary; Thomas, Gwendolyn; Sanft, Tara; Harrigan, Maura; Ligibel, Jennifer

    2015-01-01

    To determine the effectiveness of weight loss intervention for breast cancer survivors. From October 2012 until March 2013, Pubmed was searched for weight loss intervention trials that reported body weight or weight loss as a primary outcome. Fifteen of these studies are included in this review. Of the 15 studies included, 14 resulted in statistically significant weight loss and 10 obtained clinically meaningful weight loss of ≥5 % from baseline. Evidence was provided of the feasibility of using several methods of weight loss intervention (telephone, in person, individual, group). Successful intervention used a comprehensive approach, with dietary, physical activity, and behavior modification components. Weight loss improved cardiovascular risk factors and markers of glucose homeostasis. However, there is insufficient evidence to identify the components of this intervention that led to successful weight loss, or to determine the weight loss necessary to affect biomarkers linked to breast cancer prognosis. The small number of randomized controlled trials shared several limitations, including small study sample sizes and lack of follow-up beyond 6 months. Intervention with longer follow-up revealed weight regain, showing the importance of considering strategies to promote long-term weight maintenance. Weight loss intervention for breast cancer survivors can lead to statistically significant and clinically meaningful weight loss, but the limited number of interventional studies, small sample sizes, and short duration of follow-up in many studies limit our ability to draw conclusions regarding the most efficacious weight-loss intervention after a breast cancer diagnosis. The findings to date are encouraging, but research on the effect of weight loss on breast cancer recurrence and mortality, and on prevention of weight gain for women newly diagnosed with breast cancer, is needed. PMID:26605003

  15. [Weight loss in cancer patients].

    PubMed

    Lordick, Florian; Hacker, Ulrich

    2016-02-01

    Cancer patients are regularly affected by malnutrition which often leads to a worsened quality of life and activity in daily living, more side effects and complications during anticancer treatment and shorter survival times. The early diagnosis and treatment of malnutrition are therefore relevant components of oncological treatment. The assessment of the nutritional status and determination of the body-mass-index should be done in every patient with cancer. The clinical examination delivers important findings and indications for malnutrition. Bioimpedance analysis can deliver additional objective information. The treatment of malnutrition should start early and follows a step-wise escalation reaching from nutritional counseling to enteral nutritional support to parenteral nutrition.

  16. ING4 Loss in Prostate Cancer Progression

    DTIC Science & Technology

    2016-10-01

    TMA, mouse model , human model . 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON...differentiation, Myc, ING4, chromatin, integrins, Erg, Pten, Miz1, CREB, Notch, p38, prostate cancer oncogenesis, TMA, mouse model , human model 3...of hits in model Months 28-34* Milestone #2: Prepare manuscript for publication Months 35-36 Specific Aim 2: Determine how loss of ING4 impacts

  17. Cancer treatment in determination of hearing loss.

    PubMed

    Oliveira, Priscila Feliciano de; Oliveira, Camila Silva; Andrade, Joice Santos; Santos, Tamara Figueiredo do Carmo; Oliveira-Barreto, Aline Cabral de

    2016-01-01

    Chemotherapy and radiotherapy in oncology have repercussions in hearing health, and can damage structures of the inner ear. These repercussions usually, result in a bilateral and irreversible hearing loss. To identify sensorineural hearing loss cases with complaints of tinnitus and difficulty in speech understanding and investigate their relationship with the types of chemotherapy and radiotherapy the patients received. Cross-sectional, clinical, observational, analytical, historical cohort study of 58 subjects treated in a public hospital in the state of Sergipe, diagnosed with neoplasia. The subjects were submitted to anamnesis, conventional pure tone audiometry, and speech recognition threshold. Of the 116 ears, 25.9% presented sensorioneural hearing loss characterized by changes in high frequencies. There was a positive correlation between hearing loss and the association of chemotherapy and radiotherapy (p=0.035; R=0.196). The auditory complaint analysis shows that most of the subjects had tinnitus and speech understanding difficulty, even with a normal auditory threshold. Cancer treatment causes hearing loss, associated with the administration of chemotherapy and radiotherapy. Cyclophosphamide increased the risk of causing hearing loss. Complaints of tinnitus and speech understanding difficulty were observed. Copyright © 2015 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

  18. Influence of Genetic Variants in TPMT and COMT Associated with Cisplatin Induced Hearing Loss in Patients with Cancer: Two New Cohorts and a Meta-Analysis Reveal Significant Heterogeneity between Cohorts

    PubMed Central

    Hagleitner, Melanie M.; Coenen, Marieke J. H.; Patino-Garcia, Ana; de Bont, Eveline S. J. M.; Gonzalez-Neira, Anna; Vos, Hanneke I.; van Leeuwen, Frank N.; Gelderblom, Hans; Hoogerbrugge, Peter M.; Guchelaar, Henk-Jan; te Loo, Maroeska W. M.

    2014-01-01

    Treatment with cisplatin-containing chemotherapy regimens causes hearing loss in 40–60% of cancer patients. It has been suggested that genetic variants in the genes encoding thiopurine S-methyltransferase (TPMT) and catechol O-methyltransferase (COMT) can predict the development of cisplatin-induced ototoxicity and may explain interindividual variability in sensitivity to cisplatin-induced hearing loss. Two recently published studies however, sought to validate these findings and showed inconsistent results. The aim of this study was to evaluate the role of polymorphisms in the TPMT and COMT genes in cisplatin-induced ototoxicity. Therefore we investigated two independent cohorts of 110 Dutch and 38 Spanish patients with osteosarcoma and performed a meta-analysis including all previously published studies resulting in a total population of 664 patients with cancer. With this largest meta-analysis performed to date, we show that the influence of TPMT and COMT on the development of cisplatin-induced hearing loss may be less important than previously suggested. PMID:25551397

  19. Cancer Prevention Knowledge of People with Profound Hearing Loss

    PubMed Central

    Meador, Helen E.; Reed, Barbara D.; Sen, Ananda; Gorenflo, Daniel W.

    2009-01-01

    BACKGROUND Deaf persons, a documented minority population, have low reading levels and difficulty communicating with physicians. The effect of these on their knowledge of cancer prevention recommendations is unknown. METHODS A cross-sectional study of 222 d/Deaf persons in Michigan, age 18 and older, chose one of four ways (voice, video of a certified American Sign Language interpreter, captions, or printed English) to complete a self-administered computer video questionnaire about demographics, hearing loss, language history, health-care utilization, and health-care information sources, as well as family and social variables. Twelve questions tested their knowledge of cancer prevention recommendations. The outcome measures were the percentage of correct answers to the questions and the association of multiple variables with these responses. RESULTS Participants averaged 22.9% correct answers with no gender difference. Univariate analysis revealed that smoking history, types of medical problems, last physician visit, and women having previous cancer preventive tests did not affect scores. Improved scores occurred with computer use (p = 0.05), higher education (p < 0.01) and income (p = 0.01), hearing spouses (p < 0.01), speaking English in multiple situations (p < 0.001), and in men with previous prostate cancer testing (p = 0.04). Obtaining health information from books (p = 0.05), physicians (p = 0.008), nurses (p = 0.03) or the internet (p = 0.02), and believing that smoking is bad (p < 0.001) also improved scores. Multivariate analysis revealed that English use (p = 0.01) and believing that smoking was bad (p = 0.05) were associated with improved scores. CONCLUSION Persons with profound hearing loss have poor knowledge of recommended cancer prevention interventions. English use in multiple settings was strongly associated with increased knowledge. PMID:19132325

  20. Revealing global regulatory perturbations across human cancers

    PubMed Central

    Goodarzi, Hani; Elemento, Olivier; Tavazoie, Saeed

    2010-01-01

    Summary The discovery of pathways and regulatory networks whose perturbation contributes to neoplastic transformation remains a fundamental challenge for cancer biology. We show that such pathway perturbations, and the cis-regulatory elements through which they operate, can be efficiently extracted from global gene-expression profiles. Our approach utilizes information-theoretic analysis of expression levels, pathways, and genomic sequences. Analysis across a diverse set of human cancers reveals the majority of previously known cancer pathways. Through de novo motif discovery we associate these pathways with transcription-factor binding sites and miRNA targets, including those of E2F, NF-Y, p53, and let-7. Follow-up experiments confirmed that these predictions correspond to functional in vivo regulatory interactions. Strikingly, the majority of the perturbations, associated with putative cis-regulatory elements, fall outside of known cancer pathways. Our study provides a systems-level dissection of regulatory perturbations in cancer—an essential component of a rational strategy for therapeutic intervention and drug-target discovery. PMID:20005852

  1. Projecting productivity losses for cancer-related mortality 2011 - 2030.

    PubMed

    Pearce, Alison; Bradley, Cathy; Hanly, Paul; O'Neill, Ciaran; Thomas, Audrey Alforque; Molcho, Michal; Sharp, Linda

    2016-10-18

    When individuals stop working due to cancer this represents a loss to society - the loss of productivity. The aim of this analysis was to estimate productivity losses associated with premature mortality from all adult cancers and from the 20 highest mortality adult cancers in Ireland in 2011, and project these losses until 2030. An incidence-based method was used to estimate the cost of cancer deaths between 2011 and 2030 using the Human Capital Approach. National data were used for cancer, population and economic inputs. Both paid work and unpaid household activities were included. Sensitivity analyses estimated the impact of assumptions around future cancer mortality rates, retirement ages, value of unpaid work, wage growth and discounting. The 233,000 projected deaths from all invasive cancers in Ireland between 2011 and 2030 will result in lost productivity valued at €73 billion; €13 billion in paid work and €60 billion in household activities. These losses represent approximately 1.4 % of Ireland's GDP annually. The most costly cancers are lung (€14.4 billion), colorectal and breast cancer (€8.3 billion each). However, when viewed as productivity losses per cancer death, testis (€364,000 per death), cervix (€155,000 per death) and brain cancer (€136,000 per death) are most costly because they affect working age individuals. An annual 1 % reduction in mortality reduces productivity losses due to all invasive cancers by €8.5 billion over 20 years. Society incurs substantial losses in productivity as a result of cancer-related mortality, particularly when household production is included. These estimates provide valuable evidence to inform resource allocation decisions in cancer prevention and control.

  2. Obesity and weight loss at presentation of lung cancer are associated with opposite effects on survival.

    PubMed

    Yang, Relin; Cheung, Michael C; Pedroso, Felipe E; Byrne, Margaret M; Koniaris, Leonidas G; Zimmers, Teresa A

    2011-09-01

    Lung cancer is the second most common neoplasm and the leading cause of cancer deaths in the United States. In cancer, weight loss and obesity are associated with reduced survival. However, the effect of obesity or weight loss at presentation on lung cancer survival has not been well studied. Using an extensive cancer dataset, we identified 76,086 patients diagnosed with lung cancer during the period of 1998-2002, of which 14,751 patients presented with obesity and/or weight loss. We examined the relationship between survival and weight loss or obesity at diagnosis using univariate and multivariate analysis. Median survival time (MST) for all lung cancer patients was 8.7 mo. Patients presenting with weight loss (15.8%) had shorter MST versus those who did not (6.4 versus 9.2 mo, P < 0.001) and patients with weight loss had significantly shortened MST for all stages and histologic subtypes. In contrast, obese patients at presentation (5.4%) had longer MST relative to non-obese patients (13.0 versus 8.6 mo, P < 0.001), which was significant across all stages and histologic subtypes. Multivariate analysis revealed that the absence of weight loss was an independent, positive predictor of improved survival (HR = 0.087, P < 0.001), while the absence of obesity was an independent predictor of worsened survival in lung cancer (HR = 1.16, P < 0.001). Our results demonstrate an inverse relationship between survival and weight loss at presentation and a potentially protective effect of obesity in lung cancer survival, which could be due to greater physiologic reserves, thereby prolonging life by slowing the progress of cancer cachexia. Copyright © 2011 Elsevier Inc. All rights reserved.

  3. Obesity and Weight Loss at Presentation of Lung Cancer are Associated with Opposite Effects on Survival

    PubMed Central

    Yang, Relin; Cheung, Michael C.; Pedroso, Felipe E.; Byrne, Margaret M.; Koniaris, Leonidas G.

    2011-01-01

    Background Lung cancer is the second most common neoplasm and the leading cause of cancer deaths in the United States. In cancer, weight loss and obesity are associated with reduced survival. However, the effect of obesity or weight loss at presentation on lung cancer survival has not been well studied. Materials and Methods Using an extensive cancer dataset, we identified 76,086 patients diagnosed with lung cancer during the period of 1998–2002, of which 14,751 patients presented with obesity and/or weight loss. We examined the relationship between survival and weight loss or obesity at diagnosis using univariate and multivariate analysis. Results Median survival time (MST) for all lung cancer patients was 8.7 months. Patients presenting with weight loss (15.8%) had shorter MST versus those who did not (6.4 vs. 9.2 months, p<0.001) and patients with weight loss had significantly shortened MST for all stages and histological subtypes. In contrast, obese patients at presentation (5.4%) had longer MST relative to non-obese patients (13.0 vs. 8.6 months, p<0.001), which was significant across all stages and histological subtypes. Multivariate analysis revealed that the absence of weight loss was an independent, positive predictor of improved survival (HR=0.087, p<0.001), while the absence of obesity was an independent predictor of worsened survival in lung cancer (HR=1.16, p<0.001). Conclusions Our results demonstrate an inverse relationship between survival and weight loss at presentation and a potentially protective effect of obesity in lung cancer survival, which could be due to greater physiologic reserves, thereby prolonging life by slowing the progress of cancer cachexia. PMID:21704331

  4. Estimating the national wage loss from cancer in Canada

    PubMed Central

    Hopkins, R.B.; Goeree, R.; Longo, C.J.

    2010-01-01

    Objectives Using primary and secondary data sources, we set out to estimate the Canadian wage loss from cancer for patients, caregivers, and parents from a patient and a societal perspective. Methods First, a multiple-database literature search was conducted to find Canadian-specific direct surveys of wage loss from cancer. Second, estimates for wage loss were generated from the nationally representative Canadian Community Health Survey (cchs) Cycle 3.1. In addition, both estimates were standardized to derive a friction-period estimate and were extrapolated to produce national annual estimates. Results The literature search identified six direct surveys that included a total of 1632 patients with cancer. The cchs Cycle 3.1 included 2287 patients with cancer. Overall, based on the direct surveys, newly diagnosed cancer patients reduced their labour participation in the friction period by 36% ($4,518), and caregivers lost 23% of their workable hours ($2,887). The cchs estimated that annual household income was 26.5% lower ($4,978) for respondents with cancer as compared with the general population. For the year 2009, results from direct surveys indicated that new cancers in Canada generated a wage loss of $3.18 billion; the cchs Cycle 3.1 estimate was $2.95 billion. Conclusions Wage loss from cancer is a significant economic burden on patients, their families, and society in Canada, with direct surveys and the cchs providing similar estimates. PMID:20404977

  5. Assemblage time series reveal biodiversity change but not systematic loss.

    PubMed

    Dornelas, Maria; Gotelli, Nicholas J; McGill, Brian; Shimadzu, Hideyasu; Moyes, Faye; Sievers, Caya; Magurran, Anne E

    2014-04-18

    The extent to which biodiversity change in local assemblages contributes to global biodiversity loss is poorly understood. We analyzed 100 time series from biomes across Earth to ask how diversity within assemblages is changing through time. We quantified patterns of temporal α diversity, measured as change in local diversity, and temporal β diversity, measured as change in community composition. Contrary to our expectations, we did not detect systematic loss of α diversity. However, community composition changed systematically through time, in excess of predictions from null models. Heterogeneous rates of environmental change, species range shifts associated with climate change, and biotic homogenization may explain the different patterns of temporal α and β diversity. Monitoring and understanding change in species composition should be a conservation priority.

  6. Large-scale analysis of chromosomal aberrations in cancer karyotypes reveals two distinct paths to aneuploidy

    PubMed Central

    2011-01-01

    Background Chromosomal aneuploidy, that is to say the gain or loss of chromosomes, is the most common abnormality in cancer. While certain aberrations, most commonly translocations, are known to be strongly associated with specific cancers and contribute to their formation, most aberrations appear to be non-specific and arbitrary, and do not have a clear effect. The understanding of chromosomal aneuploidy and its role in tumorigenesis is a fundamental open problem in cancer biology. Results We report on a systematic study of the characteristics of chromosomal aberrations in cancers, using over 15,000 karyotypes and 62 cancer classes in the Mitelman Database. Remarkably, we discovered a very high co-occurrence rate of chromosome gains with other chromosome gains, and of losses with losses. Gains and losses rarely show significant co-occurrence. This finding was consistent across cancer classes and was confirmed on an independent comparative genomic hybridization dataset of cancer samples. The results of our analysis are available for further investigation via an accompanying website. Conclusions The broad generality and the intricate characteristics of the dichotomy of aneuploidy, ranging across numerous tumor classes, are revealed here rigorously for the first time using statistical analyses of large-scale datasets. Our finding suggests that aneuploid cancer cells may use extra chromosome gain or loss events to restore a balance in their altered protein ratios, needed for maintaining their cellular fitness. PMID:21714908

  7. Gastrointestinal symptoms and weight loss in cancer patients receiving chemotherapy.

    PubMed

    Sánchez-Lara, Karla; Ugalde-Morales, Emilio; Motola-Kuba, Daniel; Green, Dan

    2013-03-14

    Cancer patients receiving chemotherapy have a high risk of malnutrition secondary to the disease and treatment, and 40-80 % of cancer patients suffer from different degrees of malnutrition, depending on tumour subtype, location, staging and treatment strategy. Malnutrition in cancer patients affects the patient's overall condition, and it increases the number of complications, the adverse effects of chemotherapy and reduces the quality of life. The aim of the present study was to evaluate weight-loss prevalence depending on the tumour site and the gastrointestinal (GI) symptoms of oncology patients receiving chemotherapy. We included 191 cancer patients receiving chemotherapy. Files of all patients were reviewed to identify symptoms that might potentially influence weight loss. The nutritional status of all patients was also determined. The cancer sites in the patients were as follows: breast (31·9 %); non-colorectal GI (18·3 %); colorectal (10·4 %); lung (5·8 %); haematological (13·1 %); others (20·5 %). Of these patients, 58 % experienced some degree of weight loss, and its prevalence was higher among the non-colorectal GI and lung cancer patients. Common symptoms included nausea (59·6 %), anorexia (46 %) and constipation (31·9 %). A higher proportion of patients with ≥ 5 % weight loss experienced anorexia, nausea and vomiting (OR 9·5, 2·15 and 6·1, respectively). In conclusion, these results indicate that GI symptoms can influence weight loss in cancer patients, and they should be included in early nutritional evaluations.

  8. [Prevention and management of appetite loss during cancer chemotherapy].

    PubMed

    Tsujimura, Hideki; Yamada, Mitsugi; Asako, Eri; Kodama, Yukako; Sato, Tsuneo; Nabeya, Yoshihiro

    2014-10-01

    Appetite loss during cancer chemotherapy may lead to malnutrition and a decreased quality of life. To overcome this problem, evidence-based guidelines have been established for chemotherapy-induced emesis and mucositis. However, unsolved issues such as taste alimentation remain. Since the clinical picture of appetite loss is complex, individual management strategies depending on the type of the disease and treatment are required.

  9. Ribosomal DNA copy number loss and sequence variation in cancer

    PubMed Central

    Xu, Baoshan; Li, Hua; Perry, John M.; Singh, Vijay Pratap; Yu, Zulin; Zakari, Musinu; Li, Linheng

    2017-01-01

    Ribosomal DNA is one of the most variable regions in the human genome with respect to copy number. Despite the importance of rDNA for cellular function, we know virtually nothing about what governs its copy number, stability, and sequence in the mammalian genome due to challenges associated with mapping and analysis. We applied computational and droplet digital PCR approaches to measure rDNA copy number in normal and cancer states in human and mouse genomes. We find that copy number and sequence can change in cancer genomes. Counterintuitively, human cancer genomes show a loss of copies, accompanied by global copy number co-variation. The sequence can also be more variable in the cancer genome. Cancer genomes with lower copies have mutational evidence of mTOR hyperactivity. The PTEN phosphatase is a tumor suppressor that is critical for genome stability and a negative regulator of the mTOR kinase pathway. Surprisingly, but consistent with the human cancer genomes, hematopoietic cancer stem cells from a Pten-/- mouse model for leukemia have lower rDNA copy number than normal tissue, despite increased proliferation, rRNA production, and protein synthesis. Loss of copies occurs early and is associated with hypersensitivity to DNA damage. Therefore, copy loss is a recurrent feature in cancers associated with mTOR activation. Ribosomal DNA copy number may be a simple and useful indicator of whether a cancer will be sensitive to DNA damaging treatments. PMID:28640831

  10. Ribosomal DNA copy number loss and sequence variation in cancer.

    PubMed

    Xu, Baoshan; Li, Hua; Perry, John M; Singh, Vijay Pratap; Unruh, Jay; Yu, Zulin; Zakari, Musinu; McDowell, William; Li, Linheng; Gerton, Jennifer L

    2017-06-01

    Ribosomal DNA is one of the most variable regions in the human genome with respect to copy number. Despite the importance of rDNA for cellular function, we know virtually nothing about what governs its copy number, stability, and sequence in the mammalian genome due to challenges associated with mapping and analysis. We applied computational and droplet digital PCR approaches to measure rDNA copy number in normal and cancer states in human and mouse genomes. We find that copy number and sequence can change in cancer genomes. Counterintuitively, human cancer genomes show a loss of copies, accompanied by global copy number co-variation. The sequence can also be more variable in the cancer genome. Cancer genomes with lower copies have mutational evidence of mTOR hyperactivity. The PTEN phosphatase is a tumor suppressor that is critical for genome stability and a negative regulator of the mTOR kinase pathway. Surprisingly, but consistent with the human cancer genomes, hematopoietic cancer stem cells from a Pten-/- mouse model for leukemia have lower rDNA copy number than normal tissue, despite increased proliferation, rRNA production, and protein synthesis. Loss of copies occurs early and is associated with hypersensitivity to DNA damage. Therefore, copy loss is a recurrent feature in cancers associated with mTOR activation. Ribosomal DNA copy number may be a simple and useful indicator of whether a cancer will be sensitive to DNA damaging treatments.

  11. Periodontal Disease, Tooth Loss, and Cancer Risk.

    PubMed

    Michaud, Dominique S; Fu, Zhuxuan; Shi, Jian; Chung, Mei

    2017-01-01

    Periodontal disease, which includes gingivitis and periodontitis, is highly prevalent in adults and disease severity increases with age. The relationship between periodontal disease and oral cancer has been examined for several decades, but there is increasing interest in the link between periodontal disease and overall cancer risk, with systemic inflammation serving as the main focus for biological plausibility. Numerous case-control studies have addressed the role of oral health in head and neck cancer, and several cohort studies have examined associations with other types of cancers over the past decade. For this review, we included studies that were identified from either 11 published reviews on this topic or an updated literature search on PubMed (between 2011 and July 2016). A total of 50 studies from 46 publications were included in this review. Meta-analyses were conducted on cohort and case-control studies separately when at least 4 studies could be included to determine summary estimates of the risk of cancer in relation to 1) periodontal disease or 2) tooth number (a surrogate marker of periodontal disease) with adjustment for smoking. Existing data provide support for a positive association between periodontal disease and risk of oral, lung, and pancreatic cancers; however, additional prospective studies are needed to better inform on the strength of these associations and to determine whether other cancers are associated with periodontal disease. Future studies should include sufficiently large sample sizes, improved measurements for periodontal disease, and thorough adjustment for smoking and other risk factors. © The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  12. The cancer anorexia/weight loss syndrome: therapeutic challenges.

    PubMed

    Giordano, Karin F; Jatoi, Aminah

    2005-07-01

    The cancer anorexia/weight loss syndrome is characterized by loss of weight, loss of appetite, overall decline in quality of life, and shortened survival in patients with advanced incurable cancer. It is highly prevalent. To date, treatment options that have been firmly established with good scientific evidence are limited to progestational agents and corticosteroids, both of which have been demonstrated to improve appetite but have otherwise failed to have a favorable impact on some of the other aspects of this syndrome. As the mechanisms behind this syndrome are further elucidated, more effective therapeutic strategies will likely emerge.

  13. The cavefish genome reveals candidate genes for eye loss

    PubMed Central

    McGaugh, Suzanne E.; Gross, Joshua B.; Aken, Bronwen; Blin, Maryline; Borowsky, Richard; Chalopin, Domitille; Hinaux, Hélène; Jeffery, William R.; Keene, Alex; Ma, Li; Minx, Patrick; Murphy, Daniel; O’Quin, Kelly E.; Rétaux, Sylvie; Rohner, Nicolas; Searle, Steve M. J.; Stahl, Bethany A.; Tabin, Cliff; Volff, Jean-Nicolas; Yoshizawa, Masato; Warren, Wesley C.

    2014-01-01

    Natural populations subjected to strong environmental selection pressures offer a window into the genetic underpinnings of evolutionary change. Cavefish populations, Astyanax mexicanus (Teleostei: Characiphysi), exhibit repeated, independent evolution for a variety of traits including eye degeneration, pigment loss, increased size and number of taste buds and mechanosensory organs, and shifts in many behavioural traits. Surface and cave forms are interfertile making this system amenable to genetic interrogation; however, lack of a reference genome has hampered efforts to identify genes responsible for changes in cave forms of A. mexicanus. Here we present the first de novo genome assembly for Astyanax mexicanus cavefish, contrast repeat elements to other teleost genomes, identify candidate genes underlying quantitative trait loci (QTL), and assay these candidate genes for potential functional and expression differences. We expect the cavefish genome to advance understanding of the evolutionary process, as well as, analogous human disease including retinal dysfunction. PMID:25329095

  14. Loss of LARGE2 disrupts functional glycosylation of α-dystroglycan in prostate cancer.

    PubMed

    Esser, Alison K; Miller, Michael R; Huang, Qin; Meier, Melissa M; Beltran-Valero de Bernabé, Daniel; Stipp, Christopher S; Campbell, Kevin P; Lynch, Charles F; Smith, Brian J; Cohen, Michael B; Henry, Michael D

    2013-01-25

    Dystroglycan (DG) is a cell surface receptor for extracellular matrix proteins and is involved in cell polarity, matrix organization, and mechanical stability of tissues. Previous studies documented loss of DG protein expression and glycosylation in a variety of cancer types, but the underlying mechanisms and the functional consequences with respect to cancer progression remain unclear. Here, we show that the level of expression of the βDG subunit as well as the glycosylation status of the αDG subunit inversely correlate with the Gleason scores of prostate cancers; furthermore, we show that the functional glycosylation of αDG is substantially reduced in prostate cancer metastases. Additionally, we demonstrate that LARGE2 (GYLTL1B), a gene not previously implicated in cancer, regulates functional αDG glycosylation in prostate cancer cell lines; knockdown of LARGE2 resulted in hypoglycosylation of αDG and loss of its ability to bind laminin-111 while overexpression restored ligand binding and diminished growth and migration of an aggressive prostate cancer cell line. Finally, our analysis of LARGE2 expression in human cancer specimens reveals that LARGE2 is significantly down-regulated in the context of prostate cancer, and that its reduction correlates with disease progression. Our results describe a novel molecular mechanism to account for the commonly observed hypoglycosylation of αDG in prostate cancer.

  15. Loss of LARGE2 Disrupts Functional Glycosylation of α-Dystroglycan in Prostate Cancer*

    PubMed Central

    Esser, Alison K.; Miller, Michael R.; Huang, Qin; Meier, Melissa M.; Beltran-Valero de Bernabé, Daniel; Stipp, Christopher S.; Campbell, Kevin P.; Lynch, Charles F.; Smith, Brian J.; Cohen, Michael B.; Henry, Michael D.

    2013-01-01

    Dystroglycan (DG) is a cell surface receptor for extracellular matrix proteins and is involved in cell polarity, matrix organization, and mechanical stability of tissues. Previous studies documented loss of DG protein expression and glycosylation in a variety of cancer types, but the underlying mechanisms and the functional consequences with respect to cancer progression remain unclear. Here, we show that the level of expression of the βDG subunit as well as the glycosylation status of the αDG subunit inversely correlate with the Gleason scores of prostate cancers; furthermore, we show that the functional glycosylation of αDG is substantially reduced in prostate cancer metastases. Additionally, we demonstrate that LARGE2 (GYLTL1B), a gene not previously implicated in cancer, regulates functional αDG glycosylation in prostate cancer cell lines; knockdown of LARGE2 resulted in hypoglycosylation of αDG and loss of its ability to bind laminin-111 while overexpression restored ligand binding and diminished growth and migration of an aggressive prostate cancer cell line. Finally, our analysis of LARGE2 expression in human cancer specimens reveals that LARGE2 is significantly down-regulated in the context of prostate cancer, and that its reduction correlates with disease progression. Our results describe a novel molecular mechanism to account for the commonly observed hypoglycosylation of αDG in prostate cancer. PMID:23223448

  16. Intratumoral heterogeneity analysis reveals hidden associations between protein expression losses and patient survival in clear cell renal cell carcinoma

    PubMed Central

    Devarajan, Karthik; Parsons, Theodore; Wang, Qiong; O'Neill, Raymond; Solomides, Charalambos; Peiper, Stephen C.; Testa, Joseph R.; Uzzo, Robert; Yang, Haifeng

    2017-01-01

    Intratumoral heterogeneity (ITH) is a prominent feature of kidney cancer. It is not known whether it has utility in finding associations between protein expression and clinical parameters. We used ITH that is detected by immunohistochemistry (IHC) to aid the association analysis between the loss of SWI/SNF components and clinical parameters.160 ccRCC tumors (40 per tumor stage) were used to generate tissue microarray (TMA). Four foci from different regions of each tumor were selected. IHC was performed against PBRM1, ARID1A, SETD2, SMARCA4, and SMARCA2. Statistical analyses were performed to correlate biomarker losses with patho-clinical parameters. Categorical variables were compared between groups using Fisher's exact tests. Univariate and multivariable analyses were used to correlate biomarker changes and patient survivals. Multivariable analyses were performed by constructing decision trees using the classification and regression trees (CART) methodology. IHC detected widespread ITH in ccRCC tumors. The statistical analysis of the “Truncal loss” (root loss) found additional correlations between biomarker losses and tumor stages than the traditional “Loss in tumor (total)”. Losses of SMARCA4 or SMARCA2 significantly improved prognosis for overall survival (OS). Losses of PBRM1, ARID1A or SETD2 had the opposite effect. Thus “Truncal Loss” analysis revealed hidden links between protein losses and patient survival in ccRCC. PMID:28445125

  17. ING4 Loss in Prostate Cancer Progression

    DTIC Science & Technology

    2015-10-01

    IHC staining on VARI tester TMA Months 1-6 Subtask 8b: IHC staining of PCBN arrays Months 7-16 Subtask 8c: Statistical analysis of data Months 17...18 Major Task 9: ING4 Loss and Tumor Differentiation Subtask 9a: Optimization of IHC staining on VARI tester TMA Months 19-24 Subtask 9b: IHC... staining of PCBN and VARI arrays Months 25-32 Subtask 9c: Statistical analysis of data Months 32-34 Milestone #5: Prepare manuscript for publication

  18. Differential network entropy reveals cancer system hallmarks

    PubMed Central

    West, James; Bianconi, Ginestra; Severini, Simone; Teschendorff, Andrew E.

    2012-01-01

    The cellular phenotype is described by a complex network of molecular interactions. Elucidating network properties that distinguish disease from the healthy cellular state is therefore of critical importance for gaining systems-level insights into disease mechanisms and ultimately for developing improved therapies. By integrating gene expression data with a protein interaction network we here demonstrate that cancer cells are characterised by an increase in network entropy. In addition, we formally demonstrate that gene expression differences between normal and cancer tissue are anticorrelated with local network entropy changes, thus providing a systemic link between gene expression changes at the nodes and their local correlation patterns. In particular, we find that genes which drive cell-proliferation in cancer cells and which often encode oncogenes are associated with reductions in network entropy. These findings may have potential implications for identifying novel drug targets. PMID:23150773

  19. Differential Bone Loss in Mouse Models of Colon Cancer Cachexia

    PubMed Central

    Bonetto, Andrea; Kays, Joshua K.; Parker, Valorie A.; Matthews, Ryan R.; Barreto, Rafael; Puppa, Melissa J.; Kang, Kyung S.; Carson, James A.; Guise, Theresa A.; Mohammad, Khalid S.; Robling, Alexander G.; Couch, Marion E.; Koniaris, Leonidas G.; Zimmers, Teresa A.

    2017-01-01

    Cachexia is a distinctive feature of colorectal cancer associated with body weight loss and progressive muscle wasting. Several mechanisms responsible for muscle and fat wasting have been identified, however it is not known whether the physiologic and molecular crosstalk between muscle and bone tissue may also contribute to the cachectic phenotype in cancer patients. The purpose of this study was to clarify whether tumor growth associates with bone loss using several experimental models of colorectal cancer cachexia, namely C26, HT-29, and ApcMin/+. The effects of cachexia on bone structure and strength were evaluated with dual energy X-ray absorptiometry (DXA), micro computed tomography (μCT), and three-point bending test. We found that all models showed tumor growth consistent with severe cachexia. While muscle wasting in C26 hosts was accompanied by moderate bone depletion, no loss of bone strength was observed. However, HT-29 tumor bearing mice showed bone abnormalities including significant reductions in whole-body bone mineral density (BMD), bone mineral content (BMC), femoral trabecular bone volume fraction (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th), but no declines in strength. Similarly, cachexia in the ApcMin/+ mice was associated with significant decreases in BMD, BMC, BV/TV, Tb.N, and Tb.Th as well as decreased strength. Our data suggest that colorectal cancer is associated with muscle wasting and may be accompanied by bone loss dependent upon tumor type, burden, stage and duration of the disease. It is clear that preserving muscle mass promotes survival in cancer cachexia. Future studies will determine whether strategies aimed at preventing bone loss can also improve outcomes and survival in colorectal cancer cachexia. PMID:28123369

  20. Differential Bone Loss in Mouse Models of Colon Cancer Cachexia.

    PubMed

    Bonetto, Andrea; Kays, Joshua K; Parker, Valorie A; Matthews, Ryan R; Barreto, Rafael; Puppa, Melissa J; Kang, Kyung S; Carson, James A; Guise, Theresa A; Mohammad, Khalid S; Robling, Alexander G; Couch, Marion E; Koniaris, Leonidas G; Zimmers, Teresa A

    2016-01-01

    Cachexia is a distinctive feature of colorectal cancer associated with body weight loss and progressive muscle wasting. Several mechanisms responsible for muscle and fat wasting have been identified, however it is not known whether the physiologic and molecular crosstalk between muscle and bone tissue may also contribute to the cachectic phenotype in cancer patients. The purpose of this study was to clarify whether tumor growth associates with bone loss using several experimental models of colorectal cancer cachexia, namely C26, HT-29, and Apc(Min/+). The effects of cachexia on bone structure and strength were evaluated with dual energy X-ray absorptiometry (DXA), micro computed tomography (μCT), and three-point bending test. We found that all models showed tumor growth consistent with severe cachexia. While muscle wasting in C26 hosts was accompanied by moderate bone depletion, no loss of bone strength was observed. However, HT-29 tumor bearing mice showed bone abnormalities including significant reductions in whole-body bone mineral density (BMD), bone mineral content (BMC), femoral trabecular bone volume fraction (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th), but no declines in strength. Similarly, cachexia in the Apc(Min/+) mice was associated with significant decreases in BMD, BMC, BV/TV, Tb.N, and Tb.Th as well as decreased strength. Our data suggest that colorectal cancer is associated with muscle wasting and may be accompanied by bone loss dependent upon tumor type, burden, stage and duration of the disease. It is clear that preserving muscle mass promotes survival in cancer cachexia. Future studies will determine whether strategies aimed at preventing bone loss can also improve outcomes and survival in colorectal cancer cachexia.

  1. CHARACTERIZATION OF A LOSS OF HETEROZYGOSITY CANCER HAZARD IDENTIFICATION ASSAY.

    EPA Science Inventory

    Tumor development generally requires the loss of heterozygosity (LOH) at one or more loci. Thus, the ability to determine whether a chemical is capable of causing LOH is an important part of cancer hazard identification. The mouse lymphoma assay detects a broad spectrum of geneti...

  2. CHARACTERIZATION OF A LOSS OF HETEROZYGOSITY CANCER HAZARD IDENTIFICATION ASSAY.

    EPA Science Inventory

    Tumor development generally requires the loss of heterozygosity (LOH) at one or more loci. Thus, the ability to determine whether a chemical is capable of causing LOH is an important part of cancer hazard identification. The mouse lymphoma assay detects a broad spectrum of geneti...

  3. Managing cancer treatment-induced bone loss and osteoporosis in patients with breast or prostate cancer.

    PubMed

    Michaud, Laura Boehnke

    2010-04-01

    To discuss trends in breast and prostate cancer prevalence and survival; risk factors for bone loss, osteoporosis, and fractures and the approach to risk assessment in patients with these malignancies; established and investigational drug therapies for managing cancer treatment-induced bone loss and osteoporosis; and the role of health-system pharmacists in promoting bone health in patients with breast or prostate cancer. Breast cancer and prostate cancer are common, deadly diseases, but many survivors are alive today because of improvements in early detection and treatment over the past 10-15 years. Cancer chemotherapy, corticosteroids, hormone-ablation therapy, and other common risk factors place patients with breast or prostate cancer at high risk for bone loss, osteoporosis, and fractures. Most patients with breast or prostate cancer should undergo assessment of risk for bone loss and osteoporosis that involves a bone-related history and physical examination, dual-energy X-ray absorptiometry scanning, and the FRAX fracture risk assessment tool from the World Health Organization. A recent National Comprehensive Cancer Network task force report on bone health in cancer care provides recommendations for considering the use of pharmacologic therapy on the basis of the results of this assessment. Bisphosphonates are useful for slowing or preventing bone loss associated with hormone-ablation therapy in women with breast cancer and men with prostate cancer, although fracture data are limited in women and not available in men. The usefulness of other therapies (selective estrogen receptor modulators, teriparatide, calcitonin salmon, and estrogens) is limited by adverse effects, a lack of experience with the drugs in these patient populations, or both. Various drug therapies are in development for managing cancer treatment-induced bone loss and osteoporosis. The agent closest to approval by the Food and Drug Administration, denosumab, has been shown to improve bone

  4. Mindfulness: existential, loss, and grief factors in women with breast cancer.

    PubMed

    Tacón, A M

    2011-01-01

    Although a plethora of studies exist as to the efficacy of mindfulness-based interventions with cancer patients, existential, loss, and grief factors are absent. The primary purpose of this exploratory study was to add to the literature by exploring the pre-post effects of an 8-week mindfulness-based intervention on existential well-being, summed self-identified losses, and grief scores as well as assess mental adjustment to cancer; also, 6-month follow-up data as to intervention maintenance were obtained. Sixty-five women, all of whom had been diagnosed with breast cancer within the past 12 months, participated in this study. The data indicated significant improvements for existential well-being, number of self-identified losses, grief scores as well as three mental adjustment styles. Six-month follow-up revealed that of the 58 responding participants, 88% were maintaining mindfulness strategies at varying schedules on a weekly basis with mindfulness-based walking as the preferred strategy. This is the first known mindfulness-based intervention study to investigate existential, loss, and grief factors in those with cancer. Further investigations earnestly are needed in this area to provide full psychosocial care to those confronting cancer.

  5. Tooth loss and liver cancer incidence in a Finnish cohort.

    PubMed

    Yang, Baiyu; Petrick, Jessica L; Abnet, Christian C; Graubard, Barry I; Murphy, Gwen; Weinstein, Stephanie J; Männistö, Satu; Albanes, Demetrius; McGlynn, Katherine A

    2017-08-01

    Periodontal disease, a major cause of tooth loss in adults, may have systemic effects and has been associated with higher risk of several cancer types. However, the associations of periodontal disease or tooth loss with liver cancer have only been examined prospectively in two studies, neither of which had sufficient statistical power. In addition, no studies assessed the potential confounding by viral hepatitis or Helicobacter pylori infection status. In this study, we examined the association between tooth loss and primary liver cancer incidence in a prospective cohort of Finnish male smokers (n = 29,096). We used Cox proportional hazards models to calculate multivariable-adjusted hazard ratios (HRs) and 95% CIs. As a sensitivity analysis, we conducted a nested case-control study within the original cohort to assess confounding by hepatitis B or C virus infection and seropositivity of H. pylori. A total of 213 incident primary liver cancers occurred during a mean follow-up of 17 years. Among these cases, having 11-31 permanent teeth lost (HR 1.42, 95% CI 1.01-1.98) or all 32 teeth lost (HR 1.45, 95% CI 1.00-2.10) was each associated with higher risk of liver cancer, compared to those having 0-10 teeth lost. Adjusting for H. pylori seropositivity yielded a small attenuation of the effect estimate. Greater number of teeth lost was associated with higher risk of primary liver cancer in our study. The role of periodontal infection in the development of liver cancer warrants further investigation.

  6. Microsatellite genotyping reveals a signature in breast cancer exomes.

    PubMed

    McIver, L J; Fonville, N C; Karunasena, E; Garner, H R

    2014-06-01

    Genomic instability at microsatellite loci is a hallmark of many cancers, including breast cancer. However, much of the genomic variation and many of the hereditary components responsible for breast cancer remain undetected. We hypothesized that variation at microsatellites could provide additional genomic markers for breast cancer risk assessment. A total of 1,345 germline and tumor DNA samples from individuals diagnosed with breast cancer, exome sequenced as part of The Cancer Genome Atlas, were analyzed for microsatellite variation. The comparison group for our analysis, representing healthy individuals, consisted of 249 females which were exome sequenced as part of the 1,000 Genomes Project. We applied our microsatellite-based genotyping pipeline to identify 55 microsatellite loci that can distinguish between the germline of individuals diagnosed with breast cancer and healthy individuals with a sensitivity of 88.4 % and a specificity of 77.1 %. Further, we identified additional microsatellite loci that are potentially useful for distinguishing between breast cancer subtypes, revealing a possible fifth subtype. These findings are of clinical interest as possible risk diagnostics and reveal genes that may be of potential therapeutic value, including genes previously not associated with breast cancer.

  7. Allelic loss and linkage studies in prostate cancer

    SciTech Connect

    Johnson, D.R.; Bale, A.E.; Lytton, B.

    1994-09-01

    Prostate cancer is the most common malignancy in U.S. males. Many examples of familial aggregation have been reported, and segregration analysis suggests that an autosomal dominant gene with a penetrance of 88% by age 85 accounts for 9% of all cases. Because many dominant cancer predisposition syndromes are related to germline mutations in tumor suppressor genes, we analyzed a series of sporadic and hereditary tumors for allelic loss. High grade sporadic, paraffin-embedded, primary prostate tumors were obtained from the archival collection in the Department of Pathology at Yale and hereditary tumors from three families were obtained by an advertisement in the New York Times and from referrals by urologists. PCR analysis showed loss in 4/7 informative sporadic prostate tumors with NEFL (8p21), in 8/22 informative tumors with D10S169 (10q26-qter), in 2/8 informative tumors with D10S108 (10q) and in 4/23 informative tumors with D10S89 (10p) in agreement with previous studies. PYGM on chromosome 11 and D9S127 on chromosome 9 showed no loss. Linkage analysis with NEFL in 3 prostate cancer families gave strongly negative results for close linkage (Z=-2.1 at {theta}=0.01) but LOD scores were very dependent on parameters, e.g. gene frequency, phenocopy rate, and penetrance. Linkage analysis with chromosome 10 markers and systematic analysis of the genome for other area of allelic loss are underway.

  8. Infrequent Loss of Luminal Differentiation in Ductal Breast Cancer Metastasis

    PubMed Central

    Calvo, Julia; Sánchez-Cid, Lourdes; Muñoz, Montserrat; Lozano, Juan José; Thomson, Timothy M.; Fernández, Pedro L.

    2013-01-01

    Lymph node involvement is a major prognostic variable in breast cancer. Whether the molecular mechanisms that drive breast cancer cells to colonize lymph nodes are shared with their capacity to form distant metastases is yet to be established. In a transcriptomic survey aimed at identifying molecular factors associated with lymph node involvement of ductal breast cancer, we found that luminal differentiation, assessed by the expression of estrogen receptor (ER) and/or progesterone receptor (PR) and GATA3, was only infrequently lost in node-positive primary tumors and in matched lymph node metastases. The transcription factor GATA3 critically determines luminal lineage specification of mammary epithelium and is widely considered a tumor and metastasis suppressor in breast cancer. Strong expression of GATA3 and ER in a majority of primary node-positive ductal breast cancer was corroborated by quantitative RT-PCR and immunohistochemistry in the initial sample set, and by immunohistochemistry in an additional set from 167 patients diagnosed of node-negative and –positive primary infiltrating ductal breast cancer, including 102 samples from loco-regional lymph node metastases matched to their primary tumors, as well as 37 distant metastases. These observations suggest that loss of luminal differentiation is not a major factor driving the ability of breast cancer cells to colonize regional lymph nodes. PMID:24205108

  9. Fastest Time to Cancer by Loss of Tumor Suppressor Genes

    PubMed Central

    Sanchez-Tapia, Cynthia; Wan, Frederic Y.M.

    2014-01-01

    Genetic instability promotes cancer progression (by increasing the probability of cancerous mutations) as well as hinders it (by imposing a higher cell death rate for cells susceptible to cancerous mutation). With the loss of tumor suppressor gene function known to be responsible for a high percentage of breast and colorectal cancer (and a good fraction of lung and other types as well), it is important to understand how genetic instability can be orchestrated toward carcinogenesis. In this context, this paper gives a complete characterization of the optimal (time-varying) cell mutation rate for the fastest time to a target cancerous cell population through the loss of both copies of a tumor suppressor gene (TSG). Similar to the (1-step) oncogene activation model previously analyzed, the optimal mutation rate of the present 2-step model changes qualitatively with the convexity of the (mutation rate dependent) cell death rate. However, the structure of the Hamiltonian for the new model differs significantly and intrinsically from that of the 1-step model and a completely new approach is needed for the solution of the present 2-step problem. Considerable insight on the biology of optimal switching (between corner controls) is extracted from numerical results for cases with nonconvex death rates. PMID:25338553

  10. A comparison of cancer burden and research spending reveals discrepancies in the distribution of research funding

    PubMed Central

    2012-01-01

    Background Ideally, the distribution of research funding for different types of cancer should be equitable with respect to the societal burden each type of cancer imposes. These burdens can be estimated in a variety of ways; “Years of Life Lost” (YLL) measures the severity of death in regard to the age it occurs, "Disability-Adjusted Life-Years" (DALY) estimates the effects of non-lethal disabilities incurred by disease and economic metrics focus on the losses to tax revenue, productivity or direct medical expenses. We compared research funding from the National Cancer Institute (NCI) to a variety of burden metrics for the most common types of cancer to identify mismatches between spending and societal burden. Methods Research funding levels were obtained from the NCI website and information for societal health and economic burdens were collected from government databases and published reports. We calculated the funding levels per unit burden for a wide range of different cancers and burden metrics and compared these values to identify discrepancies. Results Our analysis reveals a considerable mismatch between funding levels and burden. Some cancers are funded at levels far higher than their relative burden suggests (breast cancer, prostate cancer, and leukemia) while other cancers appear underfunded (bladder, esophageal, liver, oral, pancreatic, stomach, and uterine cancers). Conclusions These discrepancies indicate that an improved method of health care research funding allocation should be investigated to better match funding levels to societal burden. PMID:22800364

  11. FDA Widens Access to 'Cooling Cap' to Stop Hair Loss in Cancer Patients

    MedlinePlus

    ... FDA Widens Access to 'Cooling Cap' to Stop Hair Loss in Cancer Patients Treatment now OK'd ... cancer patients may be able to ward off hair loss during chemotherapy treatment. A cooling cap approved ...

  12. Aromatase inhibitor therapy and hair loss among breast cancer survivors.

    PubMed

    Gallicchio, Lisa; Calhoun, Carla; Helzlsouer, Kathy J

    2013-11-01

    The objective of this study was to examine the associations between aromatase inhibitor therapy and hair loss or hair thinning among female breast cancer survivors. Data were analyzed from 851 female breast cancer survivors who responded to a hospital registry-based survey. Data on hair loss, hair thinning, demographic characteristics, and health habits were based on self-report; data on aromatase inhibitor therapy were collected on the survey and verified using medical record review. Logistic regression was used to estimate the odds ratios (ORs) and 95 % confidence intervals (CIs) for the associations between aromatase inhibitor therapy and the hair outcome variables adjusted for potential confounders, including age and chemotherapy treatment. The results showed that 22.4 % of the breast cancer survivors reported hair loss and 31.8 % reported hair thinning. In the confounder-adjusted analyses, breast cancer survivors who were within 2 years of starting aromatase inhibitor treatment at the time of survey completion were approximately two and a half times more likely to report reporting hair loss (OR 2.55; 95 % CI 1.19-5.45) or hair thinning (OR 2.33; 95 % CI 1.10-4.93) within the past 4 weeks compared to those who were never treated with an aromatase inhibitor. Current aromatase inhibitor use for two or more years at the time of the survey and prior use were significantly associated with hair thinning (current users, ≥2 years: OR 1.86; prior users: OR 1.62), but not hair loss. Findings from this study suggest that aromatase inhibitor use is associated with an increased risk of hair loss and hair thinning independent of chemotherapy and age; these side effects are likely due to the substantial decrease in estrogen concentrations resulting from treatment with this drug. Future research should focus on examining these associations in a prospective manner using more detailed and objective measures of hair loss and thinning.

  13. Loss of Wave1 gene defines a subtype of lethal prostate cancer

    PubMed Central

    Sowalsky, Adam G.; Sager, Rebecca; Schaefer, Rachel J.; Bratslavsky, Gennady; Pandolfi, Pier Paolo; Balk, Steven P.; Kotula, Leszek

    2015-01-01

    Genetic alterations involving TMPRSS2-ERG alterations and deletion of key tumor suppressor genes are associated with development and progression of prostate cancer (PCa). However, less defined are early events that may contribute to the development of high-risk metastatic prostate cancer. Bioinformatic analysis of existing tumor genomic data from PCa patients revealed that WAVE complex gene alterations are associated with a greater likelihood of prostate cancer recurrence. Further analysis of primary vs. castration resistant prostate cancer indicate that disruption of WAVE complex gene expression, and particularly WAVE1 gene (WASF1) loss, is also associated with castration resistance, where WASF1 is frequently co-deleted with PTEN and resists androgen deprivation therapy (ADT). Hence, we propose that WASF1 status defines a subtype of ADT-resistant patients. Better understanding of the effects of WAVE pathway disruption will lead to development of better diagnostic and treatment modalities. PMID:25906751

  14. Platinum-induced hearing loss after treatment for childhood cancer.

    PubMed

    van As, Jorrit W; van den Berg, Henk; van Dalen, Elvira C

    2016-08-03

    Platinum-based therapy, including cisplatin, carboplatin, oxaliplatin or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. There is a wide variation in the reported prevalence of platinum-induced ototoxicity and the associated risk factors. More insight into the prevalence of and risk factors for platinum-induced hearing loss is essential in order to develop less ototoxic treatment protocols for the future treatment of children with cancer and to develop adequate follow-up protocols for childhood cancer survivors treated with platinum-based therapy. To evaluate the existing evidence on the association between childhood cancer treatment including platinum analogues and the occurrence of hearing loss. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 8), MEDLINE (PubMed) (1945 to 23 September 2015) and EMBASE (Ovid) (1980 to 23 September 2015). In addition, we searched reference lists of relevant articles and the conference proceedings of the International Society for Paediatric Oncology (2008 to 2014), the American Society of Pediatric Hematology/Oncology (2008 to 2015) and the International Conference on Long-Term Complications of Treatment of Children and Adolescents for Cancer (2010 to 2015). Experts in the field provided information on additional studies. All study designs, except case reports, case series (i.e. a description of non-consecutive participants) and studies including fewer than 100 participants treated with platinum-based therapy who had an ototoxicity assessment, examining the association between childhood cancer treatment including platinum analogues and the occurrence of hearing loss. Two review authors independently performed the study selection. One review author performed data extraction and risk of bias assessment, which was checked by another review author. We identified

  15. Treatment of unintentional weight loss in patients with cancer.

    PubMed

    Mattox, Todd W

    2005-08-01

    Malnutrition from anorexia and reduced nutrient intake is common in patients with cancer. Abnormalities in gastrointestinal function caused by the tumor or treatment of the tumor may be direct causes for nutrition challenges. However, other patients may present with cancer cachexia, a wasting syndrome characterized by weight loss, anorexia, early satiety, progressive debilitation, and malnutrition that results in a greater risk of organ dysfunction and death. Changes in host metabolism and energy expenditure are thought to contribute to the development of cachexia, although this relationship is not clear. There is evidence that the etiology of these metabolic changes may be mediated by a neurohormonal response stimulated by the tumor. Because a single cause for these metabolic abnormalities has not been identified, several approaches to treatment of cancer cachexia have been reported. After correction of any underlying gastrointestinal abnormalities, single nutrients or other pharmacologic agents have been used in an attempt to favorably affect appetite or counter metabolic abnormalities that cause inefficient nutrient use. A variety of agents have been studied for their positive effects on appetite, including progestational agents, glucocorticoids, cannabinoids, cyproheptadine, olanzapine, and mirtazapine. Other agents have been investigated for their anti-inflammatory properties, including thalidomide, pentoxyphylline, melatonin, and omega-3 fatty acids. Anabolic agents such as testosterone derivatives have been investigated as well. The decision to treat symptoms of cancer cachexia should be based on the patient's desires and current medical condition. Choice of the most appropriate agent to treat unintentional weight loss in patients with cancer should include consideration of effects on appetite, weight, quality of life, and risk of adverse effects according to current evidence-based medicine, and cost and availability of the agent.

  16. Stromal loss of TGFβ drives cancer growth in the epithelium via inflammation | Center for Cancer Research

    Cancer.gov

    Interactions between epithelial and stromal cells play an important role in cancer development and progression. Epithelial cancers develop when changes occur to tumor suppressor genes in stromal fibroblast cells. For example, loss of tumor suppressor, p53, in stromal fibroblasts leads to p53 inactivation in the epithelium in a prostate cancer model, and disruption of the transforming growth factor-b receptor II (TGF-βRII) in stromal fibroblasts results in intraepithelial dysplasia in prostate cancer and invasive squamous cell carcinoma (SCC) in mouse forestomach.

  17. Specific loss of chromosomes 1, 2, 6, 10, 13, 17, and 21 in chromophobe renal cell carcinomas revealed by comparative genomic hybridization.

    PubMed Central

    Speicher, M. R.; Schoell, B.; du Manoir, S.; Schröck, E.; Ried, T.; Cremer, T.; Störkel, S.; Kovacs, A.; Kovacs, G.

    1994-01-01

    We analyzed 19 chromophobe renal cell carcinomas by means of comparative genomic hybridization. Two tumors revealed no numerical abnormalities. In the remaining 17 cases we found loss of entire chromosomes with underrepresentation of chromosome 1 occurring in all 17 cases; loss of chromosomes 2, 10, and 13 in 16 cases; loss of chromosomes 6 and 21 in 15 tumors; and loss of chromosome 17 in 13 cases. The loss of the Y chromosome was observed in 6 of 13 tumors from male patients, whereas 1 X chromosome was lost in 3 of 4 tumors obtained from females. Comparative genomic hybridization results were verified by interphase cytogenetics. We conclude that a specific combination of multiple chromosomal losses characterizes chromophobe renal cell carcinomas and may help to differentiate them unequivocally from other types of kidney cancer. Images Figure 1 Figure 2 PMID:7519827

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

    PubMed

    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.

  19. Body weight loss as an indicator of breast cancer recurrence.

    PubMed

    Marinho, L A; Rettori, O; Vieira-Matos, A N

    2001-01-01

    Body weight loss (BWL), a major prognostic factor in breast cancer, was included as a parameter to be monitored in the recent breast cancer surveillance guidelines of the American Society of Clinical Oncology. The aim of this work was prospectively to evaluate BWL as an indicator of breast cancer recurrence. Body weight was measured every 2 months for 10.4+/-3.7 (SD) months in 109 disease-free breast cancer patients in stage II node-positive and stage III disease. The correlation between unexplained BWL and recurrence was studied. Attempts were made to define the limits in weight variations among disease-free patients beyond which recurrence could be suspected. Unexplained BWL was observed in 16/19 (84%) patients developing recurrence, versus 9/90 (10%) patients remaining disease-free. There was a significant (p < 0.001) correlation between BWL and recurrence. BWL anticipated the diagnosis of recurrence by 6 (range 4-12) months. Based on the average percentage weight variation +/- 2 SD (95% confidence interval) of the disease-free group, the limits for BWL beyond which recurrence could be suspected were a 5.8% decrease in the last 6 months, 3.6% in the last 2 months or 3.0% of the patient's mean weight. However, because of the large variation in the amplitude of individual weight oscillations among disease-free patients (from < 0.5% to > 5.9% of the mean weight), individual limits derived from the patient's own body weight curve seemed more reliable. The results suggest that unexplained BWL is a valuable indicator of incipient breast cancer recurrence. Careful monitoring of body weight in breast cancer patients during follow-up is encouraged.

  20. Frequent loss of sequences from the long arm of chromosome 10 in endometrial cancers

    SciTech Connect

    Peiffer, S.; Tribune, D.; Goodfellow, P.J.

    1994-09-01

    Endometrial cancer is the most common gynecological malignancy in the United States, with an estimated 33,000 new cases diagnosed annually. Cancers develop as the result of the accumulation of mutations in proto-oncogenes and tumor suppressor genes. Mutations in KRAS and TP53 in endometrial cancer have been reported, but for the most part the genetic events underlying endometrial tumorigenesis have not been defined. Previous loss of heterozygosity studies (LOH) in endometrial cancers revealed frequent loss of sequences from 3p, 10q, 17p and 18q, suggesting a role for tumor suppressor genes that lie within these regions of loss. We have undertaken a series of experiments to identify tumor suppressor genes involved in endometrial tumorigenesis, focusing on a region of chromosome 10 that is likely to include a novel tumor suppressor gene. We have allelotyped 40 normal/tumor DNA pairs with 5 microsatellite repeat markers from 10q and one from 10p. LOH for at least one 10q marker was seen in 45% of informative samples. Chromosome 10 LOH was seen most frequently in Grade 1 adenocarcinoma (5/8; 60%). Grade 3 adenocarcinomas were also characterized by LOH of 10q sequences. Grade 2 tumors, on the other hand, did not reveal chromosome 10 LOH but were instead characterized by frequent microsatellite instability (RER). Other tumor types did not show the same patterns of genetic alteration seen in adenocarcinoma. We are currently defining the smallest region(s) of loss on 10q by typing 75 tumor/normal pairs using a set of ordered microsatellite repeat markers from distal 10q. A candidate tumorigenesis gene within what is the common region of deletion is being characterized in detail in a series of tumors.

  1. Microsatellite instability and loss of heterozygosity in gastric cancer

    SciTech Connect

    Schneider, B.G.; Pulitzer, D.R.; Moehlmann, R.D.

    1994-09-01

    In order to detect regions of DNA containing tumor suppressor genes involved in the development of gastric cancer, we evaluated loss of heterozygosity (LOH) in 78 gastric adenocarcinomas. A total of 46 microsatellite markers were employed, which detected at least one site per arm of each autosome in the human genome, including several markers linked to known tumor suppressor genes (TP53, APC, DCC, RB1, and BRCA1). We detected elevated rates of LOH at D3S1478 on chromosome 3p21 (44%, or 22 of 50 cases), at D12S78 at 12q14q24.33 (39%), and 37% at D9S157 on 9p, three sites not previously known to be affected in gastric cancer. Another locus on chromosome 12q, D12S97, showed LOH in 40% of informative cases. LOH was detected on chromosome 17p near TP53 in 66% of informative cases (23 of 35). Microsatellite instability (MI) was observed in 22% of the cancers. Tumors varied greatly in percentage of sites exhibiting MI, from 0% to 77% of sites tested. These findings expand the description of the genetic lesions occurring in gastric cancer.

  2. 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

  3. TP53 loss creates therapeutic vulnerability in colorectal cancer.

    PubMed

    Liu, Yunhua; Zhang, Xinna; Han, Cecil; Wan, Guohui; Huang, Xingxu; Ivan, Cristina; Jiang, Dahai; Rodriguez-Aguayo, Cristian; Lopez-Berestein, Gabriel; Rao, Pulivarthi H; Maru, Dipen M; Pahl, Andreas; He, Xiaoming; Sood, Anil K; Ellis, Lee M; Anderl, Jan; Lu, Xiongbin

    2015-04-30

    TP53, a well-known tumour suppressor gene that encodes p53, is frequently inactivated by mutation or deletion in most human tumours. A tremendous effort has been made to restore p53 activity in cancer therapies. However, no effective p53-based therapy has been successfully translated into clinical cancer treatment owing to the complexity of p53 signalling. Here we demonstrate that genomic deletion of TP53 frequently encompasses essential neighbouring genes, rendering cancer cells with hemizygous TP53 deletion vulnerable to further suppression of such genes. POLR2A is identified as such a gene that is almost always co-deleted with TP53 in human cancers. It encodes the largest and catalytic subunit of the RNA polymerase II complex, which is specifically inhibited by α-amanitin. Our analysis of The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) databases reveals that POLR2A expression levels are tightly correlated with its gene copy numbers in human colorectal cancer. Suppression of POLR2A with α-amanitin or small interfering RNAs selectively inhibits the proliferation, survival and tumorigenic potential of colorectal cancer cells with hemizygous TP53 loss in a p53-independent manner. Previous clinical applications of α-amanitin have been limited owing to its liver toxicity. However, we found that α-amanitin-based antibody-drug conjugates are highly effective therapeutic agents with reduced toxicity. Here we show that low doses of α-amanitin-conjugated anti-epithelial cell adhesion molecule (EpCAM) antibody lead to complete tumour regression in mouse models of human colorectal cancer with hemizygous deletion of POLR2A. We anticipate that inhibiting POLR2A will be a new therapeutic approach for human cancers containing such common genomic alterations.

  4. Denosumab, a RANK ligand inhibitor, for the management of bone loss in cancer patients.

    PubMed

    Yee, Andrew J; Raje, Noopur S

    2012-01-01

    Bone loss is a common side effect of cancer treatments, especially antihormonal treatments used in the treatment of breast and prostate cancer. Denosumab is a monoclonal antibody given subcutaneously that inhibits osteoclast activity by targeting the RANK ligand. It is effective in settings ranging from preventing skeletal-related complications in cancer patients with metastatic disease to increasing bone mineral density in patients with osteoporosis. In cancer patients with early stage disease, denosumab can attenuate bone loss from antihormonal treatments, and in prostate cancer, may reduce disease progression. Here, we will discuss the important role denosumab may play in the management of bone loss in patients with cancer.

  5. Functional photoreceptor loss revealed with adaptive optics: an alternate cause of color blindness.

    PubMed

    Carroll, Joseph; Neitz, Maureen; Hofer, Heidi; Neitz, Jay; Williams, David R

    2004-06-01

    There is enormous variation in the X-linked L/M (long/middle wavelength sensitive) gene array underlying "normal" color vision in humans. This variability has been shown to underlie individual variation in color matching behavior. Recently, red-green color blindness has also been shown to be associated with distinctly different genotypes. This has opened the possibility that there may be important phenotypic differences within classically defined groups of color blind individuals. Here, adaptive optics retinal imaging has revealed a mechanism for producing dichromatic color vision in which the expression of a mutant cone photopigment gene leads to the loss of the entire corresponding class of cone photoreceptor cells. Previously, the theory that common forms of inherited color blindness could be caused by the loss of photoreceptor cells had been discounted. We confirm that remarkably, this loss of one-third of the cones does not impair any aspect of vision other than color.

  6. Aerial photographs reveal late-20th-century dynamic ice loss in northwestern Greenland.

    PubMed

    Kjær, Kurt H; Khan, Shfaqat A; Korsgaard, Niels J; Wahr, John; Bamber, Jonathan L; Hurkmans, Ruud; van den Broeke, Michiel; Timm, Lars H; Kjeldsen, Kristian K; Bjørk, Anders A; Larsen, Nicolaj K; Jørgensen, Lars Tyge; Færch-Jensen, Anders; Willerslev, Eske

    2012-08-03

    Global warming is predicted to have a profound impact on the Greenland Ice Sheet and its contribution to global sea-level rise. Recent mass loss in the northwest of Greenland has been substantial. Using aerial photographs, we produced digital elevation models and extended the time record of recent observed marginal dynamic thinning back to the mid-1980s. We reveal two independent dynamic ice loss events on the northwestern Greenland Ice Sheet margin: from 1985 to 1993 and 2005 to 2010, which were separated by limited mass changes. Our results suggest that the ice mass changes in this sector were primarily caused by short-lived dynamic ice loss events rather than changes in the surface mass balance. This finding challenges predictions about the future response of the Greenland Ice Sheet to increasing global temperatures.

  7. The loss of genetic diversity in Sichuan taimen as revealed by DNA fingerprinting.

    PubMed

    Wu, Xue-Chang

    2006-06-01

    Species endangerment often derives from the "endangerment" of genetic diversity, thus loss of genetic diversity is an important cause of species extinction. Since historical specimens were unavailable, previous studies mainly described the genetic diversity status in the current population rather than the loss of genetic variation over time. In this study, we collected samples during 1998-1999 and obtained historical specimens from 1957 to 1958. Based on the two sets of fish, we determined the changes in genetic diversity of Sichuan taimen using DNA fingerprinting. The differences in genetic parameters between the present samples and historical taimens revealed their loss of genetic variation. As a result, the existing populations have lower viability, and proper management has to be implemented to preserve genetic diversity.

  8. Functional photoreceptor loss revealed with adaptive optics: An alternate cause of color blindness

    PubMed Central

    Carroll, Joseph; Neitz, Maureen; Hofer, Heidi; Neitz, Jay; Williams, David R.

    2004-01-01

    There is enormous variation in the X-linked L/M (long/middle wavelength sensitive) gene array underlying “normal” color vision in humans. This variability has been shown to underlie individual variation in color matching behavior. Recently, red–green color blindness has also been shown to be associated with distinctly different genotypes. This has opened the possibility that there may be important phenotypic differences within classically defined groups of color blind individuals. Here, adaptive optics retinal imaging has revealed a mechanism for producing dichromatic color vision in which the expression of a mutant cone photopigment gene leads to the loss of the entire corresponding class of cone photoreceptor cells. Previously, the theory that common forms of inherited color blindness could be caused by the loss of photoreceptor cells had been discounted. We confirm that remarkably, this loss of one-third of the cones does not impair any aspect of vision other than color. PMID:15148406

  9. Latest Updates on Antiretinal Autoantibodies Associated With Vision Loss and Breast Cancer

    PubMed Central

    Adamus, Grazyna

    2015-01-01

    Cancer-associated retinopathy (CAR) is an uncommon paraneoplastic disorder of the retina that is frequently associated with breast cancer in pre- and postmenopausal women older than 50 years. In this review, we will give an update on the current knowledge regarding the association of antiretinal autoantibodies with the breast-CAR syndrome. Women with breast cancer and visual indications of CAR have a significantly increased incidence of autoantibodies (AAbs) against retinal proteins when compared to healthy women. The onset of visual loss in association with antiretinal AAbs peaks 2 to 3 years after the clinical diagnosis of breast cancer. Differences in severity of symptoms between women with or without antiretinal AAbs are evident, revealing more unfavorable presentation in seropositive women. The incidence of CAR in breast cancer is likely to rise as the survival time of patients with breast cancer increases; consequently, a prediction of breast-CAR based on autoimmunity to individual retinal antigens, or to panels of antigens (signatures), is clinically important. PMID:25754855

  10. Latest updates on antiretinal autoantibodies associated with vision loss and breast cancer.

    PubMed

    Adamus, Grazyna

    2015-03-09

    Cancer-associated retinopathy (CAR) is an uncommon paraneoplastic disorder of the retina that is frequently associated with breast cancer in pre- and postmenopausal women older than 50 years. In this review, we will give an update on the current knowledge regarding the association of antiretinal autoantibodies with the breast-CAR syndrome. Women with breast cancer and visual indications of CAR have a significantly increased incidence of autoantibodies (AAbs) against retinal proteins when compared to healthy women. The onset of visual loss in association with antiretinal AAbs peaks 2 to 3 years after the clinical diagnosis of breast cancer. Differences in severity of symptoms between women with or without antiretinal AAbs are evident, revealing more unfavorable presentation in seropositive women. The incidence of CAR in breast cancer is likely to rise as the survival time of patients with breast cancer increases; consequently, a prediction of breast-CAR based on autoimmunity to individual retinal antigens, or to panels of antigens (signatures), is clinically important. Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.

  11. Loss of Core 1-derived O-Glycans Decreases Breast Cancer Development in Mice*

    PubMed Central

    Song, Kai; Herzog, Brett H.; Fu, Jianxin; Sheng, Minjia; Bergstrom, Kirk; McDaniel, J. Michael; Kondo, Yuji; McGee, Samuel; Cai, Xiaofeng; Li, Ping; Chen, Hong; Xia, Lijun

    2015-01-01

    Mucin-type core 1-derived O-glycans, one of the major types of O-glycans, are highly expressed in mammary gland epithelium. Abnormal O-glycans such as Tn antigen are found in over 90% of breast cancers; however, the in vivo role of these aberrant O-glycans in the etiology of breast cancer is unclear. We generated mice with mammary epithelial specific deletion of core 1-derived O-glycans. By crossing with two spontaneous mouse breast cancer models, we determined that loss of core 1-derived O-glycans delays the onset and progression of breast cancer development. Deficiency of core 1 O-glycosylation impaired the localization of Muc1, a major O-glycoprotein, on the apical surfaces of mammary epithelium. Signaling mediated by Muc1, which is critical for breast cancer development, was also defective in the absence of core 1 O-glycans. This study reveals an unexpected role of core 1-derived O-glycans in breast cancer development in mice. PMID:26124270

  12. Loss of COX5B inhibits proliferation and promotes senescence via mitochondrial dysfunction in breast cancer

    PubMed Central

    Jiang, Hong-Lin; Li, Liang-Dong; Hu, Xin; Xu, Xiao-En; Jin, Wei

    2015-01-01

    COX5B, a peripheral subunit of the cytochrome c oxidase complex, has previously been reported to maintain the stability of this complex. However, its functions and mechanisms involved in breast cancer progression remain unclear. Here, by performing SILAC assays in breast cancer cell models and detecting COX5B expression in tissues, we found that COX5B expression was elevated in breast cancer. Down-regulation of COX5B in breast cancer cell lines can suppress cell proliferation and induced cell senescence which was accompanied by elevating production of IL-8 and other cytokines. Interestingly, conditioned medium from COX5B knockdown cells could promote breast cancer cell migration. Mechanistic studies reveal that COX5B silence induces an increase in production of ROS, depolarization of MMP and a decrease in ATP. What's more, silence of COX5B leads to metabolic disorders, such as increased glucose uptake and decreased lactate secretion. Collectively, our study shows that loss of COX5B induces mitochondrial dysfunction and subsequently leads to cell growth suppression and cell senescence. Cytokines such as IL-8 secreted by senescent cells may in turn alter the microenvironment which could enhance cell migration. These findings may provide a novel paradigm for the treatment which combined anti-cancer drugs with particular cytokine inhibitors such as IL-8 blockers. PMID:26506233

  13. Loss of COX5B inhibits proliferation and promotes senescence via mitochondrial dysfunction in breast cancer.

    PubMed

    Gao, Shui-Ping; Sun, He-Fen; Jiang, Hong-Lin; Li, Liang-Dong; Hu, Xin; Xu, Xiao-En; Jin, Wei

    2015-12-22

    COX5B, a peripheral subunit of the cytochrome c oxidase complex, has previously been reported to maintain the stability of this complex. However, its functions and mechanisms involved in breast cancer progression remain unclear. Here, by performing SILAC assays in breast cancer cell models and detecting COX5B expression in tissues, we found that COX5B expression was elevated in breast cancer. Down-regulation of COX5B in breast cancer cell lines can suppress cell proliferation and induced cell senescence which was accompanied by elevating production of IL-8 and other cytokines. Interestingly, conditioned medium from COX5B knockdown cells could promote breast cancer cell migration. Mechanistic studies reveal that COX5B silence induces an increase in production of ROS, depolarization of MMP and a decrease in ATP. What's more, silence of COX5B leads to metabolic disorders, such as increased glucose uptake and decreased lactate secretion. Collectively, our study shows that loss of COX5B induces mitochondrial dysfunction and subsequently leads to cell growth suppression and cell senescence. Cytokines such as IL-8 secreted by senescent cells may in turn alter the microenvironment which could enhance cell migration. These findings may provide a novel paradigm for the treatment which combined anti-cancer drugs with particular cytokine inhibitors such as IL-8 blockers.

  14. Dermatomyositis revealing breast cancer: report of a case.

    PubMed

    Lamquami, Safae; Errarhay, Sanae; Mamouni, Nisrine; Bouchikhi, Chahrazad; Banani, Abdelaziz

    2015-01-01

    Dermatomyositis (DM) is a rare connective corresponding to an inflammatory disease of skeletal muscles. Paraneoplastic origin must always be sought, primarily gynecological tumor in women, but the investigations are often made difficult by the fact that a primary tumor is often not detectable at the time of the cutaneous manifestations. This approach includes in addition to the monitoring report at regular intervals of 6 to 12 months for two years after diagnosis. We report a case of Dermatomyositis revealing breast cancer.

  15. Sparse expression bases in cancer reveal tumor drivers

    PubMed Central

    Logsdon, Benjamin A.; Gentles, Andrew J.; Miller, Chris P.; Blau, C. Anthony; Becker, Pamela S.; Lee, Su-In

    2015-01-01

    We define a new category of candidate tumor drivers in cancer genome evolution: ‘selected expression regulators’ (SERs)—genes driving dysregulated transcriptional programs in cancer evolution. The SERs are identified from genome-wide tumor expression data with a novel method, namely SPARROW (SPARse selected expRessiOn regulators identified With penalized regression). SPARROW uncovers a previously unknown connection between cancer expression variation and driver events, by using a novel sparse regression technique. Our results indicate that SPARROW is a powerful complementary approach to identify candidate genes containing driver events that are hard to detect from sequence data, due to a large number of passenger mutations and lack of comprehensive sequence information from a sufficiently large number of samples. SERs identified by SPARROW reveal known driver mutations in multiple human cancers, along with known cancer-associated processes and survival-associated genes, better than popular methods for inferring gene expression networks. We demonstrate that when applied to acute myeloid leukemia expression data, SPARROW identifies an apoptotic biomarker (PYCARD) for an investigational drug obatoclax. The PYCARD and obatoclax association is validated in 30 AML patient samples. PMID:25583238

  16. Cancer-associated loss of TARSH gene expression in human primary lung cancer.

    PubMed

    Terauchi, Kunihiko; Shimada, Junichi; Uekawa, Natsuko; Yaoi, Takeshi; Maruyama, Mitsuo; Fushiki, Shinji

    2006-01-01

    We have previously identified mouse Tarsh as one of the cellular senescence-related genes and showed the loss of expression of TARSH mRNA in four human lung cancer cell lines. TARSH is a presumptive signal transduction molecule interacting with NESH, which is implicated to have some roles in lung cancer metastasis. The amplification of complete ORF-encoding TARSH cDNA was done with reverse transcription-PCR. Northern blotting was carried out using TARSH cDNA probes. To clarify the relationship between TARSH and lung cancer, we quantified TARSH mRNA expression in 15 human lung cancer cell lines and 32 primary non-small cell lung cancers. We first determined the complete ORF-encoding cDNA sequence which is expressed in the human lung. On the Northern hybridization analysis, TARSH was strongly expressed in the human lung. The expression of TARSH mRNA is remarkably downregulated in all the lung cancer cell lines examined. Furthermore, TARSH expression was significantly low in all of the tumor specimens when compared to the expression in corresponding non-neoplastic lung tissue specimens. The cancer-associated transcriptional inactivation of TARSH suggests that TARSH could be used as a biomarker for lung cancer development as well as a molecular adjunct for lung carcinogenesis in human.

  17. Cone and Rod Loss in Stargardt Disease Revealed by Adaptive Optics Scanning Light Ophthalmoscopy

    PubMed Central

    Song, Hongxin; Rossi, Ethan A.; Latchney, Lisa; Bessette, Angela; Stone, Edwin; Hunter, Jennifer J.; Williams, David R.; Chung, Mina

    2015-01-01

    Importance Stargardt disease (STGD1) is characterized by macular atrophy and flecks in the retinal pigment epithelium. The causative ABCA4 gene encodes a protein localizing to photoreceptor outer segments. The pathologic steps by which ABCA4 mutations lead to clinically detectable retinal pigment epithelium changes remain unclear. We investigated early STGD1 using adaptive optics scanning light ophthalmoscopy. Observations Adaptive optics scanning light ophthalmoscopy imaging of 2 brothers with early STGD1 and their unaffected parents was compared with conventional imaging. Cone and rod spacing were increased in both patients (P <.001) with a dark cone appearance. No foveal cones were detected in the older brother. In the younger brother, foveal cones were enlarged with low density (peak cone density, 48.3 × 103 cones/mm2). The ratio of cone to rod spacing was increased in both patients, with greater divergence from normal approaching the foveal center, indicating that cone loss predominates centrally and rod loss increases peripherally. Both parents had normal photoreceptor mosaics. Genetic testing revealed 3 disease-causing mutations. Conclusions and Relevance This study provides in vivo images of rods and cones in STGD1. Although the primary clinical features of STGD1 are retinal pigment epithelial lesions, adaptive optics scanning light ophthalmoscopy reveals increased cone and rod spacing in areas that appear normal in conventional images, suggesting that photoreceptor loss precedes clinically detectable retinal pigment epithelial disease in STGD1. PMID:26247787

  18. Comparative analysis reveals loss of the appetite-regulating peptide hormone ghrelin in falcons.

    PubMed

    Seim, Inge; Jeffery, Penny L; Herington, Adrian C; Chopin, Lisa K

    2015-05-15

    Ghrelin and leptin are key peripherally secreted appetite-regulating hormones in vertebrates. Here we consider the ghrelin gene (GHRL) of birds (class Aves), where it has been reported that ghrelin inhibits rather than augments feeding. Thirty-one bird species were compared, revealing that most species harbour a functional copy of GHRL and the coding region for its derived peptides ghrelin and obestatin. We provide evidence for loss of GHRL in saker and peregrine falcons, and this is likely to result from the insertion of an ERVK retrotransposon in intron 0. We hypothesise that the loss of anorexigenic ghrelin is a predatory adaptation that results in increased food-seeking behaviour and feeding in falcons. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  19. A novel meta-analysis approach of cancer transcriptomes reveals prevailing transcriptional networks in cancer cells.

    PubMed

    Niida, Atsushi; Imoto, Seiya; Nagasaki, Masao; Yamaguchi, Rui; Miyano, Satoru

    2010-01-01

    Although microarray technology has revealed transcriptomic diversities underlining various cancer phenotypes, transcriptional programs controlling them have not been well elucidated. To decode transcriptional programs governing cancer transcriptomes, we have recently developed a computational method termed EEM, which searches for expression modules from prescribed gene sets defined by prior biological knowledge like TF binding motifs. In this paper, we extend our EEM approach to predict cancer transcriptional networks. Starting from functional TF binding motifs and expression modules identified by EEM, we predict cancer transcriptional networks containing regulatory TFs, associated GO terms, and interactions between TF binding motifs. To systematically analyze transcriptional programs in broad types of cancer, we applied our EEM-based network prediction method to 122 microarray datasets collected from public databases. The data sets contain about 15000 experiments for tumor samples of various tissue origins including breast, colon, lung etc. This EEM based meta-analysis successfully revealed a prevailing cancer transcriptional network which functions in a large fraction of cancer transcriptomes; they include cell-cycle and immune related sub-networks. This study demonstrates broad applicability of EEM, and opens a way to comprehensive understanding of transcriptional networks in cancer cells.

  20. Evolutionary loss of cone photoreception in balaenid whales reveals circuit stability in the mammalian retina.

    PubMed

    Schweikert, Lorian E; Fasick, Jeffry I; Grace, Michael S

    2016-10-01

    The classical understanding of mammalian vision is that it occurs through "duplex" retinae containing both rod and cone photoreceptors, the signals from which are processed through rod- and/or cone-specific signaling pathways. The recent discovery of rod monochromacy in some cetacean lineages provides a novel opportunity to investigate the effects of an evolutionary loss of cone photoreception on retinal organization. Sequence analysis of right whale (Eubalaena glacialis; family Balaenidae) cDNA derived from long-wavelength sensitive (LWS) cone opsin mRNA identified several mutations in the opsin coding sequence, suggesting the loss of cone cell function, but maintenance of non-photosensitive, cone opsin mRNA-expressing cells in the retina. Subsequently, we investigated the retina of the closely related bowhead whale (Balaena mysticetus; family Balaenidae) to determine how the loss of cone-mediated photoreception affects light signaling pathways in the retina. Anti-opsin immunofluorescence demonstrated the total loss of cone opsin expression in B. mysticetus, whereas light microscopy, transmission electron microscopy, and bipolar cell (protein kinase C-α [PKC-α] and recoverin) immunofluorescence revealed the maintenance of cone soma, putative cone pedicles, and both rod and cone bipolar cell types. These findings represent the first immunological and anatomical evidence of a naturally occurring rod-monochromatic mammalian retina, and suggest that despite the loss of cone-mediated photoreception, the associated cone signaling structures (i.e., cone synapses and cone bipolar cells) may be maintained for multichannel rod-based signaling in balaenid whales. J. Comp. Neurol. 524:2873-2885, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  1. Hearing loss during osteosarcoma chemotherapy: when acute ifosfamide toxicity revealed unnoticed methotrexate encephalopathy.

    PubMed

    Robert, Guillaume; Chappé, Céline; Taque, Sophie; Bruneau, Bertrand; Gandemer, Virginie

    2014-03-01

    Ifosfamide and methotrexate are widely used for the treatment of pediatric osteosarcoma. However, both these chemotherapeutic drugs can cause encephalopathy. A 17-year-old girl presented with profound hearing loss and dizziness during a postoperative course of ifosfamide, 20 days after a course of methotrexate. Cerebral magnetic resonance imaging (MRI) showed bilateral white matter hypersignal in Fluid Attenuated Inversion Recovery sequences. The clinical evolution was rapidly favorable after methylene blue infusion. This is the second reported case of acute deafness, possibly associated with ifosfamide, whereas MRI data revealed unnoticed chronic methotrexate toxicity. Systematic MRI screening and hearing evaluation may be useful in such cases.

  2. Proteomics reveals the effects of sustained weight loss on the human plasma proteome.

    PubMed

    Geyer, Philipp E; Wewer Albrechtsen, Nicolai J; Tyanova, Stefka; Grassl, Niklas; Iepsen, Eva W; Lundgren, Julie; Madsbad, Sten; Holst, Jens J; Torekov, Signe S; Mann, Matthias

    2016-12-22

    Sustained weight loss is a preferred intervention in a wide range of metabolic conditions, but the effects on an individual's health state remain ill-defined. Here, we investigate the plasma proteomes of a cohort of 43 obese individuals that had undergone 8 weeks of 12% body weight loss followed by a year of weight maintenance. Using mass spectrometry-based plasma proteome profiling, we measured 1,294 plasma proteomes. Longitudinal monitoring of the cohort revealed individual-specific protein levels with wide-ranging effects of losing weight on the plasma proteome reflected in 93 significantly affected proteins. The adipocyte-secreted SERPINF1 and apolipoprotein APOF1 were most significantly regulated with fold changes of -16% and +37%, respectively (P < 10(-13)), and the entire apolipoprotein family showed characteristic differential regulation. Clinical laboratory parameters are reflected in the plasma proteome, and eight plasma proteins correlated better with insulin resistance than the known marker adiponectin. Nearly all study participants benefited from weight loss regarding a ten-protein inflammation panel defined from the proteomics data. We conclude that plasma proteome profiling broadly evaluates and monitors intervention in metabolic diseases. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

  3. Most small bowel cancers are revealed by a complication

    PubMed Central

    Negoi, Ionut; Paun, Sorin; Hostiuc, Sorin; Stoica, Bodgan; Tanase, Ioan; Negoi, Ruxandra Irina; Beuran, Mircea

    2015-01-01

    ABSTRACT Objective To characterize the pattern of primary small bowel cancers in a tertiary East-European hospital. Methods A retrospective study of patients with small bowel cancers admitted to a tertiary emergency center, over the past 15 years. Results There were 57 patients with small bowel cancer, representing 0.039% of admissions and 0.059% of laparotomies. There were 37 (64.9%) men, mean age of 58 years; and 72 years for females. Out of 57 patients, 48 (84.2%) were admitted due to an emergency situation: obstruction in 21 (38.9%), perforation in 17 (31.5%), upper gastrointestinal bleeding in 8 (14.8%), and lower gastrointestinal bleeding in 2 (3.7%). There were 10 (17.5%) duodenal tumors, 21 (36.8%) jejunal tumors and 26 (45.6%) ileal tumors. The most frequent neoplasms were gastrointestinal stromal tumor in 24 patients (42.1%), adenocarcinoma in 19 (33.3%), lymphoma in 8 (14%), and carcinoids in 2 (3.5%). The prevalence of duodenal adenocarcinoma was 14.55 times greater than that of the small bowel, and the prevalence of duodenal stromal tumors was 1.818 time greater than that of the small bowel. Obstruction was the complication in adenocarcinoma in 57.9% of cases, and perforation was the major local complication (47.8%) in stromal tumors. Conclusion Primary small bowel cancers are usually diagnosed at advanced stages, and revealed by a local complication of the tumor. Their surgical management in emergency setting is associated to significant morbidity and mortality rates. PMID:26676271

  4. Cooperativity Between Oncogenic PKC Epsilon and Pten Loss in Prostate Cancer Progression

    DTIC Science & Technology

    2016-10-01

    pathway that correlates with motility and metastasis. Based on our preliminary data, PKCε overexpression and Pten loss individually and synergically confer...AWARD NUMBER: W81XWH-14-1-0535 TITLE: Cooperativity Between Oncogenic PKC Epsilon and Pten Loss in Prostate Cancer Progression PRINCIPAL...Sep 2015 - 29 Sep 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Cooperativity Between Oncogenic PKC Epsilon and Pten Loss in Prostate Cancer

  5. The Role of Hair Loss in Cancer Identity: Perceptions of Chemotherapy-Induced Alopecia Among Women Treated for Early-Stage Breast Cancer or Ductal Carcinoma in Situ.

    PubMed

    Trusson, Diane; Pilnick, Alison

    The trauma of chemotherapy-induced alopecia is well documented. However, less is known about how the stereotypical cancer identity affects social interactions. The aim of this study is to explore women's experiences of hair loss resulting from breast cancer treatment, from a sociological perspective. Twenty-four women who had been treated for early-stage breast cancer or ductal carcinoma in situ were interviewed. References to hair (loss) were isolated from their narratives. Findings confirm previous research that hair loss can be traumatic. The stigma attached to both having a cancer patient identity and nonconformity with norms of appearance means that women must decide how much to reveal and to whom. An unexpected finding was that distressing experiences were reported by some women who had not lost their hair. Hair is important to identity; therefore, there are implications for social interactions whether women decide to disguise their hair loss or not. There may also be implications for women who do not lose their hair because they fail to conform to the stereotypical appearance of the bald cancer patient. Future research should consider the role of stereotypes in patient experiences. Nurses should provide sufficient information and support to prepare patients for the impact on self-perception and social interactions when facing hair loss. Also, patients should be forewarned about the possible implications of not conforming to the cancer stereotype. In addition, greater education among the wider population about the possible side effects of cancer treatments may prevent women feeling stigmatized while already undergoing a stressful experience.

  6. Weight loss, appetite loss and food intake in cancer patients with cancer cachexia: three peas in a pod? - analysis from a multicenter cross sectional study.

    PubMed

    Solheim, Tora S; Blum, David; Fayers, Peter M; Hjermstad, Marianne J; Stene, Guro B; Strasser, Florian; Kaasa, Stein

    2014-04-01

    How to assess cachexia is a barrier both in research and in clinical practice. This study examines the need for assessing both reduced food intake and loss of appetite, to see if these variables can be used interchangeably. A secondary aim is to assess the variance explained by food intake, appetite and weight loss by using tumor-related factors, symptoms and biological markers as explanatory variables. One thousand and seventy patients with incurable cancer were registered in an observational, cross sectional multicenter study. A total of 885 patients that had complete data on food intake (PG-SGA), appetite (EORTC QLQ-C30) and weight loss were included in the present analysis. The association between reduced food intake and appetite loss was assessed using Spearman's correlation. To find the explained variance of the three symptoms a multivariate analysis was performed. The mean age was 62 years with a mean survival of 247 days and a mean Karnofsky performance status of 72. Thirteen percent of the patients who reported eating less than normal had good appetite and 25% who had unchanged or increased food intake had reduced appetite. Correlation between appetite loss and food intake was 0.50. Explained variance for the regression models was 44% for appetite loss, 27% for food intake and only 13% for weight loss. Both appetite loss and food intake should be assessed in cachectic patients since conscious control of eating may sometimes overcome appetite loss. The low explained variance for weight loss is probably caused by the need for more knowledge about metabolism and inflammation, and is consistent with the cancer cachexia definition that claims that in cachexia weight loss is not caused by reduced food intake alone. The questions concerning appetite loss from EORTC-QLQ C30 and food intake from PG-SGA seem practical and informative when dealing with advanced cancer patients.

  7. Gain and Loss of Phototrophic Genes Revealed by Comparison of Two Citromicrobium Bacterial Genomes

    PubMed Central

    Zheng, Qiang; Zhang, Rui; Fogg, Paul C. M.; Beatty, J. Thomas; Wang, Yu; Jiao, Nianzhi

    2012-01-01

    Proteobacteria are thought to have diverged from a phototrophic ancestor, according to the scattered distribution of phototrophy throughout the proteobacterial clade, and so the occurrence of numerous closely related phototrophic and chemotrophic microorganisms may be the result of the loss of genes for phototrophy. A widespread form of bacterial phototrophy is based on the photochemical reaction center, encoded by puf and puh operons that typically are in a ‘photosynthesis gene cluster’ (abbreviated as the PGC) with pigment biosynthesis genes. Comparison of two closely related Citromicrobial genomes (98.1% sequence identity of complete 16S rRNA genes), Citromicrobium sp. JL354, which contains two copies of reaction center genes, and Citromicrobium strain JLT1363, which is chemotrophic, revealed evidence for the loss of phototrophic genes. However, evidence of horizontal gene transfer was found in these two bacterial genomes. An incomplete PGC (pufLMC-puhCBA) in strain JL354 was located within an integrating conjugative element, which indicates a potential mechanism for the horizontal transfer of genes for phototrophy. PMID:22558224

  8. PTEN loss is a context-dependent outcome determinant in obese and non-obese endometrioid endometrial cancer patients

    PubMed Central

    Westin, Shannon N.; Ju, Zhenlin; Broaddus, Russell R.; Krakstad, Camilla; Li, Jane; Pal, Navdeep; Lu, Karen H.; Coleman, Robert L.; Hennessy, Bryan T.; Klempner, Samuel J.; Werner, Henrica M. J.; Salvesen, Helga B.; Cantley, Lewis C.; Mills, Gordon B.; Myers, Andrea P.

    2015-01-01

    Endometrial cancer incidence is increasing, due in part to a strong association with obesity. Mutations in the phosphatidylinositol 3-kinase (PI3K) pathway, the central relay pathway of insulin signals, occur in the majority of endometrioid adenocarcinomas, the most common form of endometrial cancer. We sought to determine the impact of PI3K pathway alterations on progression free survival in a cohort of endometrioid endometrial cancers. Prognostic utility of PIK3CA, PIK3R1, and PTEN mutations, as well as PTEN protein loss by immunohistochemistry, was explored in the context of patient body mass index. Reverse-phase protein arrays were utilized to assess protein expression based on PTEN status. Among 187 endometrioid endometrial cancers, there were no statistically significant associations between PFS and PIK3CA, PIK3R1, PTEN mutation or loss. When stratified by body mass index, PTEN loss was associated with improved progression free survival (P<0.006) in obese (body mass index ≥ 30) patients. PTEN loss resulted in distinct protein changes: Canonical PI3K pathway activation was observed only in the non-obese population while decreased expression of β-CATENIN and phosphorylated FOXO3A was observed in obese patients. These data suggest the impact of PTEN loss on tumor biology and clinical outcomes must be interpreted in the context of body mass index, and provide a potential explanation for discrepant reports on the effect of PTEN status and obesity on prognosis in endometrial cancer. This reveals a clinically important interaction between metabolic state and tumor genetics that may unveil the biologic underpinning of obesity-related cancers and impact ongoing clinical trials with PI3K pathway inhibitors. PMID:26045339

  9. PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2.

    PubMed

    German, Natalie J; Yoon, Haejin; Yusuf, Rushdia Z; Murphy, J Patrick; Finley, Lydia W S; Laurent, Gaëlle; Haas, Wilhelm; Satterstrom, F Kyle; Guarnerio, Jlenia; Zaganjor, Elma; Santos, Daniel; Pandolfi, Pier Paolo; Beck, Andrew H; Gygi, Steven P; Scadden, David T; Kaelin, William G; Haigis, Marcia C

    2016-09-15

    While much research has examined the use of glucose and glutamine by tumor cells, many cancers instead prefer to metabolize fats. Despite the pervasiveness of this phenotype, knowledge of pathways that drive fatty acid oxidation (FAO) in cancer is limited. Prolyl hydroxylase domain proteins hydroxylate substrate proline residues and have been linked to fuel switching. Here, we reveal that PHD3 rapidly triggers repression of FAO in response to nutrient abundance via hydroxylation of acetyl-coA carboxylase 2 (ACC2). We find that PHD3 expression is strongly decreased in subsets of cancer including acute myeloid leukemia (AML) and is linked to a reliance on fat catabolism regardless of external nutrient cues. Overexpressing PHD3 limits FAO via regulation of ACC2 and consequently impedes leukemia cell proliferation. Thus, loss of PHD3 enables greater utilization of fatty acids but may also serve as a metabolic and therapeutic liability by indicating cancer cell susceptibility to FAO inhibition.

  10. Annual Economic Burden of Productivity Losses Among Adult Survivors of Childhood Cancers.

    PubMed

    Guy, Gery P; Berkowitz, Zahava; Ekwueme, Donatus U; Rim, Sun Hee; Yabroff, K Robin

    2016-11-01

    Although adult survivors of childhood cancers have poorer health and greater health limitations than other adults, substantial gaps remain in understanding the economic consequences of surviving childhood cancer. Therefore, we estimated the economic burden of productivity losses among adult survivors of childhood cancers. We examined health status, functional limitations, and productivity loss among adult survivors of childhood cancers (n = 239) diagnosed at ≤14 years of age compared with adults without a history of cancer (n = 304 265) by using the 2004-2014 National Health Interview Survey. We estimated economic burden using the productivity loss from health-related unemployment, missed work days, missed household productivity, and multivariable regression models controlling for age, sex, race/ethnicity, education, comorbidities, and survey year. Childhood cancer survivorship is associated with a substantial economic burden. Adult survivors of childhood cancers are more likely to be in poorer health, need assistance with personal care and routine needs, have work limitations, be unable to work because of health, miss more days of work, and have greater household productivity loss compared with adults without a history of cancer (all P < .05). The annual productivity loss for adult survivors of childhood cancer is $8169 per person compared with $3083 per person for individuals without a history of cancer. These findings underscore the importance of efforts to reduce the health and economic burden among adult survivors of childhood cancer. In addition, this study highlights the potential productivity losses that could be avoided during adulthood from the prevention of childhood cancer in the United States. Copyright © 2016 by the American Academy of Pediatrics.

  11. Loss of Raf Kinase Inhibitory Protein Induces Radioresistance in Prostate Cancer

    SciTech Connect

    Woods Ignatoski, Kathleen M.; Grewal, Navdeep K.; Markwart, Sonja M.; Vellaichamy, Adaikkalam; Chinnaiyan, Arul M.; Yeung, Kam; Ray, Michael E.; Keller, Evan T.

    2008-09-01

    Purpose: External beam radiotherapy (RT) is often used in an attempt to cure localized prostate cancer (PCa), but it is only palliative against disseminated disease. Raf kinase inhibitory protein (RKIP) is a metastasis suppressor whose expression is reduced in approximately 50% of localized PCa tissues and is absent in metastases. Chemotherapeutic agents have been shown to induce tumor apoptosis through induction of RKIP expression. Our goal was to test whether RT similarly induces apoptosis through induction of RKIP expression. Methods and Materials: The C4-2B PCa cell line was engineered to overexpress or underexpress RKIP. The engineered cells were tested for apoptosis in cell culture and tumor regression in mice after RT. Results: RT induced both RKIP expression and apoptosis of PCa cells. Overexpression of RKIP sensitized PCa cells to radiation-induced apoptosis. In contrast, short-hairpin targeting of RKIP, so that RT could not induce RKIP expression, protected cells from radiation-induced apoptosis. In a murine model, knockdown of RKIP in PCa cells diminished radiation-induced apoptosis. Molecular concept mapping of genes altered on manipulation of RKIP expression revealed an inverse correlation with the concept of genes altered by RT. Conclusion: The data presented in this report indicate that the loss of RKIP, as seen in primary PCa tumors and metastases, confers protection against radiation-induced apoptosis. Therefore, it is conceivable that the loss of RKIP confers a growth advantage on PCa cells at distant sites, because the loss of RKIP would decrease apoptosis, favoring proliferation.

  12. Loss-of-function screens of druggable targetome against cancer stem–like cells

    PubMed Central

    Song, Mee; Lee, Hani; Nam, Myung-Hee; Jeong, Euna; Kim, Somin; Hong, Yourae; Kim, Nayoung; Yim, Hwa Young; Yoo, Young-Ji; Kim, Jung Seok; Kim, Jin-Seok; Cho, Yong-Yeon; Mills, Gordon B.; Kim, Woo-Young; Yoon, Sukjoon

    2017-01-01

    Cancer stem–like cells (CSLCs) contribute to the initiation and recurrence of tumors and to their resistance to conventional therapies. In this study, small interfering RNA (siRNA)-based screening of ∼4800 druggable genes in 3-dimensional CSLC cultures in comparison to 2-dimensional bulk cultures of U87 glioma cells revealed 3 groups of genes essential for the following: survival of the CSLC population only, bulk-cultured population only, or both populations. While diverse biologic processes were associated with siRNAs reducing the bulk-cultured population, CSLC-eliminating siRNAs were enriched in a few functional categories, such as lipid metabolism, protein metabolism, and gene expression. Interestingly, siRNAs that selectively reduced CSLC only were found to target genes for cholesterol and unsaturated fatty acid synthesis. The lipidomic profile of CSLCs revealed increased levels of monounsaturated lipids. Pharmacologic blockage of these target pathways reduced CSLCs, and this effect was eliminated by addition of downstream metabolite products. The present CSLC-sensitive target categories provide a useful resource that can be exploited for the selective elimination of CSLCs.—Song, M., Lee, H., Nam, M.-H., Jeong, E., Kim, S., Hong, Y., Kim, N., Yim, H. Y., Yoo, Y.-J., Kim, J. S., Kim, J.-S., Cho, Y.-Y., Mills, G. B., Kim, W.-Y., Yoon, S. Loss-of-function screens of druggable targetome against cancer stem–like cells. PMID:27811063

  13. Exome sequencing of a colorectal cancer family reveals shared mutation pattern and predisposition circuitry along tumor pathways

    PubMed Central

    Suleiman, Suleiman H.; Koko, Mahmoud E.; Nasir, Wafaa H.; Elfateh, Ommnyiah; Elgizouli, Ubai K.; Abdallah, Mohammed O. E.; Alfarouk, Khalid O.; Hussain, Ayman; Faisal, Shima; Ibrahim, Fathelrahamn M. A.; Romano, Maurizio; Sultan, Ali; Banks, Lawrence; Newport, Melanie; Baralle, Francesco; Elhassan, Ahmed M.; Mohamed, Hiba S.; Ibrahim, Muntaser E.

    2015-01-01

    The molecular basis of cancer and cancer multiple phenotypes are not yet fully understood. Next Generation Sequencing promises new insight into the role of genetic interactions in shaping the complexity of cancer. Aiming to outline the differences in mutation patterns between familial colorectal cancer cases and controls we analyzed whole exomes of cancer tissues and control samples from an extended colorectal cancer pedigree, providing one of the first data sets of exome sequencing of cancer in an African population against a background of large effective size typically with excess of variants. Tumors showed hMSH2 loss of function SNV consistent with Lynch syndrome. Sets of genes harboring insertions–deletions in tumor tissues revealed, however, significant GO enrichment, a feature that was not seen in control samples, suggesting that ordered insertions–deletions are central to tumorigenesis in this type of cancer. Network analysis identified multiple hub genes of centrality. ELAVL1/HuR showed remarkable centrality, interacting specially with genes harboring non-synonymous SNVs thus reinforcing the proposition of targeted mutagenesis in cancer pathways. A likely explanation to such mutation pattern is DNA/RNA editing, suggested here by nucleotide transition-to-transversion ratio that significantly departed from expected values (p-value 5e-6). NFKB1 also showed significant centrality along with ELAVL1, raising the suspicion of viral etiology given the known interaction between oncogenic viruses and these proteins. PMID:26442106

  14. Exome sequencing of a colorectal cancer family reveals shared mutation pattern and predisposition circuitry along tumor pathways.

    PubMed

    Suleiman, Suleiman H; Koko, Mahmoud E; Nasir, Wafaa H; Elfateh, Ommnyiah; Elgizouli, Ubai K; Abdallah, Mohammed O E; Alfarouk, Khalid O; Hussain, Ayman; Faisal, Shima; Ibrahim, Fathelrahamn M A; Romano, Maurizio; Sultan, Ali; Banks, Lawrence; Newport, Melanie; Baralle, Francesco; Elhassan, Ahmed M; Mohamed, Hiba S; Ibrahim, Muntaser E

    2015-01-01

    The molecular basis of cancer and cancer multiple phenotypes are not yet fully understood. Next Generation Sequencing promises new insight into the role of genetic interactions in shaping the complexity of cancer. Aiming to outline the differences in mutation patterns between familial colorectal cancer cases and controls we analyzed whole exomes of cancer tissues and control samples from an extended colorectal cancer pedigree, providing one of the first data sets of exome sequencing of cancer in an African population against a background of large effective size typically with excess of variants. Tumors showed hMSH2 loss of function SNV consistent with Lynch syndrome. Sets of genes harboring insertions-deletions in tumor tissues revealed, however, significant GO enrichment, a feature that was not seen in control samples, suggesting that ordered insertions-deletions are central to tumorigenesis in this type of cancer. Network analysis identified multiple hub genes of centrality. ELAVL1/HuR showed remarkable centrality, interacting specially with genes harboring non-synonymous SNVs thus reinforcing the proposition of targeted mutagenesis in cancer pathways. A likely explanation to such mutation pattern is DNA/RNA editing, suggested here by nucleotide transition-to-transversion ratio that significantly departed from expected values (p-value 5e-6). NFKB1 also showed significant centrality along with ELAVL1, raising the suspicion of viral etiology given the known interaction between oncogenic viruses and these proteins.

  15. Weight Loss and Mortality in Overweight and Obese Cancer Survivors: A Systematic Review

    PubMed Central

    Heinrich, Malgorzata; Beeken, Rebecca J.

    2017-01-01

    Background Excess adiposity is a risk factor for poorer cancer survival, but there is uncertainty over whether losing weight reduces the risk. We conducted a critical review of the literature examining weight loss and mortality in overweight or obese cancer survivors. Methods We systematically searched PubMed and EMBASE for articles reporting associations between weight loss and mortality (cancer-specific or all-cause) in overweight/obese patients with obesity-related cancers. Where available, data from the same studies on non-overweight patients were compared. Results Five articles describing observational studies in breast cancer survivors were included. Four studies reported a positive association between weight loss and mortality in overweight/obese survivors, and the remaining study observed no significant association. Results were similar for non-overweight survivors. Quality assessment indicated high risk of bias across studies. Conclusions There is currently a lack of observational evidence that weight loss improves survival for overweight and obese cancer survivors. However, the potential for bias in these studies is considerable and the results likely reflect the consequences of disease-related rather than intentional weight loss. There is a need for stronger study designs, incorporating measures of intentionality of weight loss, and extended to other cancers. PMID:28060948

  16. Weight Loss and Mortality in Overweight and Obese Cancer Survivors: A Systematic Review.

    PubMed

    Jackson, Sarah E; Heinrich, Malgorzata; Beeken, Rebecca J; Wardle, Jane

    2017-01-01

    Excess adiposity is a risk factor for poorer cancer survival, but there is uncertainty over whether losing weight reduces the risk. We conducted a critical review of the literature examining weight loss and mortality in overweight or obese cancer survivors. We systematically searched PubMed and EMBASE for articles reporting associations between weight loss and mortality (cancer-specific or all-cause) in overweight/obese patients with obesity-related cancers. Where available, data from the same studies on non-overweight patients were compared. Five articles describing observational studies in breast cancer survivors were included. Four studies reported a positive association between weight loss and mortality in overweight/obese survivors, and the remaining study observed no significant association. Results were similar for non-overweight survivors. Quality assessment indicated high risk of bias across studies. There is currently a lack of observational evidence that weight loss improves survival for overweight and obese cancer survivors. However, the potential for bias in these studies is considerable and the results likely reflect the consequences of disease-related rather than intentional weight loss. There is a need for stronger study designs, incorporating measures of intentionality of weight loss, and extended to other cancers.

  17. Evaluating probability of cancer among older people with unexplained, unintentional weight loss.

    PubMed

    Chen, Shih-Ping; Peng, Li-Ning; Lin, Ming-Hsien; Lai, Hsiu-Yun; Hwang, Shinn-Jang; Chen, Liang-Kung

    2010-02-01

    Unexplained, unintentional weight loss (UUWL) in older people is usually multi-factorial and poses a diagnostic challenge, with cancer being the major concern. The main purpose of this study was to evaluate the effectiveness of a cancer scoring system for predicting cancer in elderly UUWL patients. From 2006 to 2007, 50 patients (mean age, 78.8+/-4.7 years, 82% male) who lost > 5% of usual body weight were enrolled. The subjects' mean body weight loss was 14.1%+/-6.6% (8.7+/-4.6 kg). After evaluation, the common diagnoses were non-malignant organic disorder (22/50, 44%), neuropsychiatric disorder (17/50, 34%), unknown (8/50, 16%), and cancer (3/50, 6%). The most rapid weight loss occurred with cancer (6.5% per month), followed by non-malignant organic disorders (5.6% per month), neuropsychiatric disorders (2.8% per month), and unknown causes (2.4% per month); the difference among the groups was significant (p = 0.023). Using a previously proposed scoring system, 42 patients (84%) had a low probability of cancer; all three cancer patients were in this category. In conclusion, the annual incidence of cancer among elderly UUWL patients was 6%, and the previously developed cancer scoring system did not effectively predict cancer occurrence. Further study is needed to develop an effective instrument to predict cancer in elderly UUWL patients.

  18. SNP Array Analysis Reveals Novel Genomic Abnormalities Including Copy Neutral Loss of Heterozygosity in Anaplastic Oligodendrogliomas

    PubMed Central

    Idbaih, Ahmed; Ducray, François; Dehais, Caroline; Courdy, Célia; Carpentier, Catherine; de Bernard, Simon; Uro-Coste, Emmanuelle; Mokhtari, Karima; Jouvet, Anne; Honnorat, Jérôme; Chinot, Olivier; Ramirez, Carole; Beauchesne, Patrick; Benouaich-Amiel, Alexandra; Godard, Joël; Eimer, Sandrine; Parker, Fabrice; Lechapt-Zalcman, Emmanuelle; Colin, Philippe; Loussouarn, Delphine; Faillot, Thierry; Dam-Hieu, Phong; Elouadhani-Hamdi, Selma; Bauchet, Luc; Langlois, Olivier; Le Guerinel, Caroline; Fontaine, Denys; Vauleon, Elodie; Menei, Philippe; Fotso, Marie Janette Motsuo; Desenclos, Christine; Verelle, Pierre; Ghiringhelli, François; Noel, Georges; Labrousse, François; Carpentier, Antoine; Dhermain, Frédéric; Delattre, Jean-Yves; Figarella-Branger, Dominique

    2012-01-01

    Anaplastic oligodendrogliomas (AOD) are rare glial tumors in adults with relative homogeneous clinical, radiological and histological features at the time of diagnosis but dramatically various clinical courses. Studies have identified several molecular abnormalities with clinical or biological relevance to AOD (e.g. t(1;19)(q10;p10), IDH1, IDH2, CIC and FUBP1 mutations). To better characterize the clinical and biological behavior of this tumor type, the creation of a national multicentric network, named “Prise en charge des OLigodendrogliomes Anaplasiques (POLA),” has been supported by the Institut National du Cancer (InCA). Newly diagnosed and centrally validated AOD patients and their related biological material (tumor and blood samples) were prospectively included in the POLA clinical database and tissue bank, respectively. At the molecular level, we have conducted a high-resolution single nucleotide polymorphism array analysis, which included 83 patients. Despite a careful central pathological review, AOD have been found to exhibit heterogeneous genomic features. A total of 82% of the tumors exhibited a 1p/19q-co-deletion, while 18% harbor a distinct chromosome pattern. Novel focal abnormalities, including homozygously deleted, amplified and disrupted regions, have been identified. Recurring copy neutral losses of heterozygosity (CNLOH) inducing the modulation of gene expression have also been discovered. CNLOH in the CDKN2A locus was associated with protein silencing in 1/3 of the cases. In addition, FUBP1 homozygous deletion was detected in one case suggesting a putative tumor suppressor role of FUBP1 in AOD. Our study showed that the genomic and pathological analyses of AOD are synergistic in detecting relevant clinical and biological subgroups of AOD. PMID:23071531

  19. TMPRSS2-ERG and PTEN loss in prostate cancer.

    PubMed

    Squire, Jeremy A

    2009-05-01

    Two studies show that the common recurrent gene fusion between TMPRSS2 and ERG promotes prostate cancer in both mouse and humans when PTEN is concurrently lost. In human prostate cancer, the presence of both these aberrations may be indicative of poor prognosis, suggesting that preclinical therapeutic research should target both of these pathways.

  20. Weight Loss Tied to Lower Risk of Uterine Cancer

    MedlinePlus

    ... researchers said. More than 75 percent of endometrial cancers occur in women aged 55 and older. The researchers reviewed data from more than 35,000 American women between the ages of 50 and 79. The study ... risk of endometrial cancer, and that benefit was greatest in obese women, ...

  1. Proteomics study reveals that the dysregulation of focal adhesion and ribosome contribute to early pregnancy loss

    PubMed Central

    Xin, Lingli; Xu, Benhong; Ma, Li; Hou, Qingxiang; Ye, Mei; Meng, Shu; Ge, Wei

    2016-01-01

    Purpose Early pregnancy loss (EPL) affects 50–70% pregnant women in first trimester. The precise molecular mechanisms underlying EPL are far from being fully understood. Therefore, we aim to identify the molecular signaling pathways relating to EPL. Experimental design We performed proteomics and bioinformatics analysis of the placental villi in women who have undergone EPL and in normal pregnant women. The proteomics data were validated by Western blot analysis. Results We identified a total of 5952 proteins in placental villi, of which 588 proteins were differentially expressed in the EPL women. Bioinformatics analysis revealed that these differentially expressed proteins participated in a variety of signaling pathways, including the focal adhesion pathway and ribosome pathway. Moreover, results of the Western blot confirmed that Desmin, Lamin A/C, MMP‐9, and histone H4 were upregulated in EPL and the Lamin C/ Lamin A ratio decreased obviously in EPL. These proteins could be associated with the pathophysiology of EPL. The data have been deposited to the ProteomeXchange with identifier PXD002391. Conclusion and clinical relevance Our study demonstrated that the focal adhesion pathway and ribosome pathway are involved in EPL, and these findings might contribute to unveil the pathophysiology of EPL. PMID:26947931

  2. Physical Activity, Body Size, Intentional Weight Loss and Breast Cancer Risk: Fellowship

    DTIC Science & Technology

    1999-10-01

    exercised frequently. More pronounced were results obtained from the model examining the joint effects of early-life physical activity and net lifetime...Number: DAMD17-97-1-7235 TITLE:. Physical Activity , Body Size, Intentional Weight Loss and Breast Cancer Risk: Fellowship PRINCIPAL INVESTIGATOR: Suzanne...SUBTITLE 5. FUNDING NUMBERS Physical Activity , Body Size, Intentional Weight Loss and Breast Cancer: DAMD 17-97-1-7235 Risk: Fellowship 6. AUTHORIS

  3. Analysis of cancer genomes reveals basic features of human aging and its role in cancer development

    PubMed Central

    Podolskiy, Dmitriy I.; Lobanov, Alexei V.; Kryukov, Gregory V.; Gladyshev, Vadim N.

    2016-01-01

    Somatic mutations have long been implicated in aging and disease, but their impact on fitness and function is difficult to assess. Here by analysing human cancer genomes we identify mutational patterns associated with aging. Our analyses suggest that age-associated mutation load and burden double approximately every 8 years, similar to the all-cause mortality doubling time. This analysis further reveals variance in the rate of aging among different human tissues, for example, slightly accelerated aging of the reproductive system. Age-adjusted mutation load and burden correlate with the corresponding cancer incidence and precede it on average by 15 years, pointing to pre-clinical cancer development times. Behaviour of mutation load also exhibits gender differences and late-life reversals, explaining some gender-specific and late-life patterns in cancer incidence rates. Overall, this study characterizes some features of human aging and offers a mechanism for age being a risk factor for the onset of cancer. PMID:27515585

  4. A systems approach reveals distinct metabolic strategies among the NCI-60 cancer cell lines

    PubMed Central

    Aurich, Maike K.; Fleming, Ronan M. T.; Thiele, Ines

    2017-01-01

    The metabolic phenotype of cancer cells is reflected by the metabolites they consume and by the byproducts they release. Here, we use quantitative, extracellular metabolomic data of the NCI-60 panel and a novel computational method to generate 120 condition-specific cancer cell line metabolic models. These condition-specific cancer models used distinct metabolic strategies to generate energy and cofactors. The analysis of the models’ capability to deal with environmental perturbations revealed three oxotypes, differing in the range of allowable oxygen uptake rates. Interestingly, models based on metabolomic profiles of melanoma cells were distinguished from other models through their low oxygen uptake rates, which were associated with a glycolytic phenotype. A subset of the melanoma cell models required reductive carboxylation. The analysis of protein and RNA expression levels from the Human Protein Atlas showed that IDH2, which was an essential gene in the melanoma models, but not IDH1 protein, was detected in normal skin cell types and melanoma. Moreover, the von Hippel-Lindau tumor suppressor (VHL) protein, whose loss is associated with non-hypoxic HIF-stabilization, reductive carboxylation, and promotion of glycolysis, was uniformly absent in melanoma. Thus, the experimental data supported the predicted role of IDH2 and the absence of VHL protein supported the glycolytic and low oxygen phenotype predicted for melanoma. Taken together, our approach of integrating extracellular metabolomic data with metabolic modeling and the combination of different network interrogation methods allowed insights into the metabolism of cells. PMID:28806730

  5. Proteome profiling of breast cancer biopsies reveals a wound healing signature of cancer-associated fibroblasts.

    PubMed

    Groessl, Michael; Slany, Astrid; Bileck, Andrea; Gloessmann, Kerstin; Kreutz, Dominique; Jaeger, Walter; Pfeiler, Georg; Gerner, Christopher

    2014-11-07

    Breast cancer is still the most common type of cancer in women; an important role in carcinogenesis is actually attributed to cancer-associated fibroblasts. In this study, we investigated whether it is possible to assess the functional state of cancer-associated fibroblasts through tumor tissue proteome profiling. Tissue proteomics was performed on tumor-central, tumor-near, and tumor-distant biopsy sections from breast adenocarcinoma patients, which allowed us to identify 2074 proteins. Data were interpreted referring to reference proteome profiles generated from primary human mammary fibroblasts comprising 4095 proteins. These cells were analyzed in quiescent cell state as well as after in vitro treatment with TGFβ or IL-1β, stimulating wound healing or inflammatory processes, respectively. Representative for cancer cells, we investigated the mammary carcinoma cell line ZR-75-1, identifying 5212 proteins. All mass analysis data have been made fully accessible via ProteomeXchange, DOI PXD001311 and PXD001323-8. Comparison of tissue proteomics data with all of those reference profiles revealed predominance of cancer cell-derived proteins within the tumor and fibroblast-derived proteins in the tumor-distant tissue sections. Remarkably, proteins characteristic for acute inflammation were hardly identified in the tissue samples. In contrast, several proteins found by us to be induced by TGFβ in mammary fibroblasts, including fibulin-5, SLC2A1, and MUC18, were positively identified in all tissue samples, with relatively higher abundance in tumor neighboring tissue sections. These findings indicate a predominance of cancer-associated fibroblasts with wound healing activities localized around tumors.

  6. Prognostic value of PTEN loss in men with conservatively managed localised prostate cancer

    PubMed Central

    Cuzick, J; Yang, Z H; Fisher, G; Tikishvili, E; Stone, S; Lanchbury, J S; Camacho, N; Merson, S; Brewer, D; Cooper, C S; Clark, J; Berney, D M; Møller, H; Scardino, P; Sangale, Z

    2013-01-01

    Background: The natural history of prostate cancer is highly variable and difficult to predict. We report on the prognostic value of phosphatase and tensin homologue (PTEN) loss in a cohort of 675 men with conservatively managed prostate cancer diagnosed by transurethral resection of the prostate. Methods: The PTEN status was assayed by immunohistochemistry (PTEN IHC) and fluorescent in situ hybridisation (PTEN FISH). The primary end point was death from prostate cancer. Results: The PTEN IHC loss was observed in 18% cases. This was significantly associated with prostate cancer death in univariate analysis (hazard ratio (HR)=3.51; 95% CI 2.60–4.73; P=3.1 × 10−14). It was highly predictive of prostate cancer death in the 50% of patients with a low risk score based on Gleason score, PSA, Ki-67 and extent of disease (HR=7.4; 95% CI 2.2–24.6; P=0.012) ), but had no prognostic value in the higher risk patients. The PTEN FISH loss was only weakly associated with PTEN IHC loss (κ=0.5). Both PTEN FISH loss and amplification were univariately predictive of death from prostate cancer, but this was not maintained in the multivariate analyses. Conclusion: In low-risk patients, PTEN IHC loss adds prognostic value to Gleason score, PSA, Ki-67 and extent of disease. PMID:23695019

  7. Loss of circadian clock gene expression is associated with tumor progression in breast cancer.

    PubMed

    Cadenas, Cristina; van de Sandt, Leonie; Edlund, Karolina; Lohr, Miriam; Hellwig, Birte; Marchan, Rosemarie; Schmidt, Marcus; Rahnenführer, Jörg; Oster, Henrik; Hengstler, Jan G

    2014-01-01

    Several studies suggest a link between circadian rhythm disturbances and tumorigenesis. However, the association between circadian clock genes and prognosis in breast cancer has not been systematically studied. Therefore, we examined the expression of 17 clock components in tumors from 766 node-negative breast cancer patients that were untreated in both neoadjuvant and adjuvant settings. In addition, their association with metastasis-free survival (MFS) and correlation to clinicopathological parameters were investigated. Aiming to estimate functionality of the clockwork, we studied clock gene expression relationships by correlation analysis. Higher expression of several clock genes (e.g., CLOCK, PER1, PER2, PER3, CRY2, NPAS2 and RORC) was found to be associated with longer MFS in univariate Cox regression analyses (HR<1 and FDR-adjusted P < 0.05). Stratification according to molecular subtype revealed prognostic relevance for PER1, PER3, CRY2 and NFIL3 in the ER+/HER2- subgroup, CLOCK and NPAS2 in the ER-/HER2- subtype, and ARNTL2 in HER2+ breast cancer. In the multivariate Cox model, only PER3 (HR = 0.66; P = 0.016) and RORC (HR = 0.42; P = 0.003) were found to be associated with survival outcome independent of established clinicopathological parameters. Pairwise correlations between functionally-related clock genes (e.g., PER2-PER3 and CRY2-PER3) were stronger in ER+, HER2- and low-grade carcinomas; whereas, weaker correlation coefficients were observed in ER- and HER2+ tumors, high-grade tumors and tumors that progressed to metastatic disease. In conclusion, loss of clock genes is associated with worse prognosis in breast cancer. Coordinated co-expression of clock genes, indicative of a functional circadian clock, is maintained in ER+, HER2-, low grade and non-metastasizing tumors but is compromised in more aggressive carcinomas.

  8. Illustrating the (in)visible: understanding the impact of loss in adults living with secondary lymphedema after cancer.

    PubMed

    Thomas, Roanne; Hamilton, Ryan

    2014-01-01

    Life with a disability is often riddled with paradoxes, one of which is being visibly marked, while personal experiences, losses, and challenges remain hidden. Our article draws attention to this paradox among people who live with secondary lymphedema after cancer (SLC). SLC is a relatively unfamiliar chronic condition within medical and lay discourses of cancer, which proves challenging for the many cancer survivors who are in search of information and understanding. Thirteen men and women with SLC were recruited from two research sites (Fredericton, NB, and Ottawa, ON, Canada) to participate in semi-structured interviews about the physical and psychosocial aspects of SLC. Using a methodology of interpretive description, our analysis of participant interviews reveals the complex ways in which men and women felt both visible and invisible within various contexts. We discuss three majors themes: (in)visibility and appearance related to material losses; (in)visibility and action connected to visible losses in function, as well as invisible struggles to care for oneself; and the loss of present and future well-being, as SLC renders some limitations visible while potentially obscuring a hopeful future indefinitely. Our research indicates that timely diagnosis of SLC would be an immediate first step in recognizing the physical and emotional dimensions of the condition. To accomplish this, increased awareness is needed. To enhance quality of life for those living with SLC, the development of new resources and psychosocial supports is also required.

  9. Clinicopathologic and prognostic relevance of ARID1A protein loss in colorectal cancer.

    PubMed

    Wei, Xiao-Li; Wang, De-Shen; Xi, Shao-Yan; Wu, Wen-Jing; Chen, Dong-Liang; Zeng, Zhao-Lei; Wang, Rui-Yu; Huang, Ya-Xin; Jin, Ying; Wang, Feng; Qiu, Miao-Zhen; Luo, Hui-Yan; Zhang, Dong-Sheng; Xu, Rui-Hua

    2014-12-28

    To explore the association between AT-rich interactive domain 1A (ARID1A) protein loss by immunohistochemistry and both clinicopathologic characteristics and prognosis in patients with colorectal cancer. We retrospectively collected clinicopathologic data and archived paraffin-embedded primary colorectal cancer samples from 209 patients, including 111 patients with colon cancer and 98 patients with rectal cancer. The tumor stage ranged from stage I to stage IV according to the 7(th) edition of the American Joint Committee on Cancer tumor-node-metastasis (TNM) staging system. All patients underwent resection of primary colorectal tumors. The expression of ARID1A protein in primary colorectal cancer tissues was examined by immunohistochemical staining. The clinicopathologic association and survival relevance of ARID1A protein loss in colorectal cancer were analyzed. ARID1A loss by immunohistochemistry was not rare in primary colorectal cancer tumors (25.8%). There were 7.4%, 24.1%, 22.2% and 46.3% of patients with ARID1A loss staged at TNM stage I, II, III and IV, respectively, compared with 20.0%, 22.6%, 27.7% and 29.7% of patients without ARID1A loss staged at TNM stage I, II, III and IV, respectively. In patients with ARID1A loss, the distant metastasis rate was 46.3%. However, only 29.7% of patients without ARID1A loss were found to have distant metastasis. In terms of pathologic differentiation, there were 25.9%, 66.7% and 7.4% with poorly, moderately and well differentiated tumors in patients with ARID1A loss, and 14.2%, 72.3% and 13.5% with poorly, moderately and well differentiated tumors in patients without ARID1A loss, respectively. ARID1A loss was associated with late TNM stage (P = 0.020), distant metastasis (P = 0.026), and poor pathological classification (P = 0.035). However, patients with positive ARID1A had worse overall survival compared to those with negative ARID1A in stage IV colorectal cancer (HR = 2.49, 95%CI: 1.13-5.51). ARID1A protein loss is

  10. Physical Activity, Body Size, Intentional Weight Loss and Breast Cancer Risk: Fellowship

    DTIC Science & Technology

    1998-10-01

    GRANT NUMBER DAMD17-97-1-7235 TITLE: Physical Activity , Body Size, Intentional Weight Loss and Breast Cancer Risk: Fellowship PRINCIPAL INVESTIGATOR...2. REPORT DATE 3. REPORT TYPE AND DATES COVERED October 1998 Annual (1 Oct 97 - 30 Sep 98) 4. TITLE AND SUBTITLE 5. FUNDING NUMBERS Physical Activity ... physical activity and breast cancer risk was evaluated using extant data from a case-control study of breast cancer. Cases (n=6888) were identified

  11. Evolution of cancer suppression as revealed by mammalian comparative genomics.

    PubMed

    Tollis, Marc; Schiffman, Joshua D; Boddy, Amy M

    2017-02-02

    Cancer suppression is an important feature in the evolution of large and long-lived animals. While some tumor suppression pathways are conserved among all multicellular organisms, others mechanisms of cancer resistance are uniquely lineage specific. Comparative genomics has become a powerful tool to discover these unique and shared molecular adaptations in respect to cancer suppression. These findings may one day be translated to human patients through evolutionary medicine. Here, we will review theory and methods of comparative cancer genomics and highlight major findings of cancer suppression across mammals. Our current knowledge of cancer genomics suggests that more efficient DNA repair and higher sensitivity to DNA damage may be the key to tumor suppression in large or long-lived mammals.

  12. The Effects of Revealed Information on Catastrophe Loss Projection Models' Characterization of Risk: Damage Vulnerability Evidence from Florida.

    PubMed

    Karl, J Bradley; Medders, Lorilee A; Maroney, Patrick F

    2016-06-01

    We examine whether the risk characterization estimated by catastrophic loss projection models is sensitive to the revelation of new information regarding risk type. We use commercial loss projection models from two widely employed modeling firms to estimate the expected hurricane losses of Florida Atlantic University's building stock, both including and excluding secondary information regarding hurricane mitigation features that influence damage vulnerability. We then compare the results of the models without and with this revealed information and find that the revelation of additional, secondary information influences modeled losses for the windstorm-exposed university building stock, primarily evidenced by meaningful percent differences in the loss exceedance output indicated after secondary modifiers are incorporated in the analysis. Secondary risk characteristics for the data set studied appear to have substantially greater impact on probable maximum loss estimates than on average annual loss estimates. While it may be intuitively expected for catastrophe models to indicate that secondary risk characteristics hold value for reducing modeled losses, the finding that the primary value of secondary risk characteristics is in reduction of losses in the "tail" (low probability, high severity) events is less intuitive, and therefore especially interesting. Further, we address the benefit-cost tradeoffs that commercial entities must consider when deciding whether to undergo the data collection necessary to include secondary information in modeling. Although we assert the long-term benefit-cost tradeoff is positive for virtually every entity, we acknowledge short-term disincentives to such an effort.

  13. Mapping evaporative water loss in desert passerines reveals an expanding threat of lethal dehydration.

    PubMed

    Albright, Thomas P; Mutiibwa, Denis; Gerson, Alexander R; Smith, Eric Krabbe; Talbot, William A; O'Neill, Jacqueline J; McKechnie, Andrew E; Wolf, Blair O

    2017-02-28

    Extreme high environmental temperatures produce a variety of consequences for wildlife, including mass die-offs. Heat waves are increasing in frequency, intensity, and extent, and are projected to increase further under climate change. However, the spatial and temporal dynamics of die-off risk are poorly understood. Here, we examine the effects of heat waves on evaporative water loss (EWL) and survival in five desert passerine birds across the southwestern United States using a combination of physiological data, mechanistically informed models, and hourly geospatial temperature data. We ask how rates of EWL vary with temperature across species; how frequently, over what areas, and how rapidly lethal dehydration occurs; how EWL and die-off risk vary with body mass; and how die-off risk is affected by climate warming. We find that smaller-bodied passerines are subject to higher rates of mass-specific EWL than larger-bodied counterparts and thus encounter potentially lethal conditions much more frequently, over shorter daily intervals, and over larger geographic areas. Warming by 4 °C greatly expands the extent, frequency, and intensity of dehydration risk, and introduces new threats for larger passerine birds, particularly those with limited geographic ranges. Our models reveal that increasing air temperatures and heat wave occurrence will potentially have important impacts on the water balance, daily activity, and geographic distribution of arid-zone birds. Impacts may be exacerbated by chronic effects and interactions with other environmental changes. This work underscores the importance of acute risks of high temperatures, particularly for small-bodied species, and suggests conservation of thermal refugia and water sources.

  14. Ribosomal DNA copy number amplification and loss in human cancers is linked to tumor genetic context, nucleolus activity, and proliferation

    PubMed Central

    2017-01-01

    Ribosomal RNAs (rRNAs) are transcribed from two multicopy DNA arrays: the 5S ribosomal DNA (rDNA) array residing in a single human autosome and the 45S rDNA array residing in five human autosomes. The arrays are among the most variable segments of the genome, exhibit concerted copy number variation (cCNV), encode essential components of the ribosome, and modulate global gene expression. Here we combined whole genome data from >700 tumors and paired normal tissues to provide a portrait of rDNA variation in human tissues and cancers of diverse mutational signatures, including stomach and lung adenocarcinomas, ovarian cancers, and others of the TCGA panel. We show that cancers undergo coupled 5S rDNA array expansion and 45S rDNA loss that is accompanied by increased estimates of proliferation rate and nucleolar activity. These somatic changes in rDNA CN occur in a background of over 10-fold naturally occurring rDNA CN variation across individuals and cCNV of 5S-45S arrays in some but not all tissues. Analysis of genetic context revealed associations between cancer rDNA CN amplification or loss and the presence of specific somatic alterations, including somatic SNPs and copy number gain/losses in protein coding genes across the cancer genome. For instance, somatic inactivation of the tumor suppressor gene TP53 emerged with a strong association with coupled 5S expansion / 45S loss in several cancers. Our results uncover frequent and contrasting changes in the 5S and 45S rDNA along rapidly proliferating cell lineages with high nucleolar activity. We suggest that 5S rDNA amplification facilitates increased proliferation, nucleolar activity, and ribosomal synthesis in cancer, whereas 45S rDNA loss emerges as a byproduct of transcription-replication conflict in rapidly replicating tumor cells. The observations raise the prospects of using the rDNA arrays as re-emerging targets for the design of novel strategies in cancer therapy. PMID:28880866

  15. Understanding and managing cancer-related weight loss and anorexia: insights from a systematic review of qualitative research

    PubMed Central

    Cooper, Christine; Burden, Sorrel T; Cheng, Huilin; Molassiotis, Alex

    2015-01-01

    The aim of this study was to summarize the existing qualitative literature in order to develop the evidence base for understanding and managing weight loss and anorexia, in order to make recommendations for clinical practice. A systematic search was performed to retrieve English language studies using electronic search and manual checks of selected reference lists. Keywords included qualitative, cancer cachexia, weight loss, anorexia, appetite, malnutrition, food, eating, and drinking. The selection and appraisal of papers were undertaken by two reviewers. Twenty-one qualitative articles were included in the review. There were three major findings emerging from the previous qualitative studies including ‘the multidimensionality of weight loss and anorexia experience’, ‘patients and caregivers' responses to coping with weight loss and anorexia’, and ‘clinical assessment and management of weight loss and anorexia’. The literature review revealed the multidimensional nature of cachexia and weight loss experience by patients and caregivers, which was not recognized and adequately managed by healthcare professionals. Future research in this area would be helpful in enabling a deeper understanding of the complexity of cachexia and weight loss experience in order to move forward to develop an optimal model of supportive care for patients and caregivers. PMID:26136417

  16. Clonal dynamics following p53 loss of heterozygosity in Kras-driven cancers

    PubMed Central

    Muzumdar, Mandar Deepak; Dorans, Kimberly Judith; Chung, Katherine Minjee; Robbins, Rebecca; Tammela, Tuomas; Gocheva, Vasilena; Li, Carman Man-Chung; Jacks, Tyler

    2016-01-01

    Although it has become increasingly clear that cancers display extensive cellular heterogeneity, the spatial growth dynamics of genetically distinct clones within developing solid tumours remain poorly understood. Here we leverage mosaic analysis with double markers (MADM) to trace subclonal populations retaining or lacking p53 within oncogenic Kras-initiated lung and pancreatic tumours. In both models, p53 constrains progression to advanced adenocarcinomas. Comparison of lineage-related p53 knockout and wild-type clones reveals a minor role of p53 in suppressing cell expansion in lung adenomas. In contrast, p53 loss promotes both the initiation and expansion of low-grade pancreatic intraepithelial neoplasia (PanINs), likely through differential expression of the p53 regulator p19ARF. Strikingly, lineage-related cells are often dispersed in lung adenomas and PanINs, contrasting with more contiguous growth of advanced subclones. Together, these results support cancer type-specific suppressive roles of p53 in early tumour progression and offer insights into clonal growth patterns during tumour development. PMID:27585860

  17. Antiresorptive therapy in the management of cancer treatment-induced bone loss.

    PubMed

    Garg, Ashwani; Leitzel, Kim; Ali, Suhail; Lipton, Allan

    2015-04-01

    Cancer treatment-induced bone loss treatment has an important role to prevent bone loss-related events like fracture, significant morbidity, mortality, disfigurement and loss of self-esteem, and health-care expenditure. Numerous factors, including treatment regimens and bone metastasis, increase the risk of osteoporosis or local bone destruction in most breast and prostate cancer patients. Cytotoxic chemotherapies, radiation, and hormonal therapies can lead to premature menopause and decrease bone mineral density. Over 60 % of breast cancer patients within 1 year of beginning postoperative adjuvant chemotherapy experience ovarian failure. Also, ovarian ablation and aromatase inhibitors used to treat breast cancer and orchiectomy and androgen deprivation therapy (ADT; to treat prostate cancer) cause substantial bone loss. In this article, we will focus mainly on antiresorptive therapy in the management of cancer treatment-induced bone loss (CTIBL). An understanding of CTIBL is critical for determining how to assess the risk and identify which patients may benefit from preventive therapy.

  18. Association between Tooth Loss and Gastric Cancer: A Meta-Analysis of Observational Studies

    PubMed Central

    Luo, Hong; Zhao, Ke; Huang, Guang-Lei; Luo, Si-Yang; Peng, Ju-Xiang; Song, Ju-Kun

    2016-01-01

    Observational studies showed that tooth loss is associated with gastric cancer, but the findings are inconsistent. In this study, a meta-analysis was conducted to evaluate the relationship between tooth loss and gastric cancer. Relevant studies were screened in PubMed and Embase databases, and nine observational studies were considered eligible for the analysis. The combined relative risks for the highest versus the lowest categories of tooth loss were 1.86 (95% CI: 1.08–3.21) and 1.31 (95% CI: 1.12–1.53) in case control and cohort studies, respectively. However, unstable results were observed in the stratified and sensitivity analysis. The current evidence, based solely on four case-control studies and five cohort studies, suggested that tooth loss is a potential marker of gastric cancer. However, we can not concluded at this time that tooth loss may be a risk factor for gastric cancer due to significant heterogeneity among studies and mixed results between case-control studies and cohort studies. Additional large-scale and high-quality prospective studies are required to evaluate the association between tooth loss and risk of gastric cancer. PMID:26934048

  19. Loss of hSef promotes metastasis through upregulation of EMT in prostate cancer

    PubMed Central

    Wadhwa, Karan; Pisupati, Venkat; Zecchini, Vincent; Ramos‐Montoya, Antonio; Warren, Anne Y; Neal, David E; Gnanapragasam, Vincent J

    2017-01-01

    We have previously reported that the negative signaling regulator Similar Expression to FGF (hSef) is downregulated in prostate cancer and its loss is associated with clinical metastasis. Here, we explored the mechanistic basis of this finding. We first confirmed our clinical observation by testing hSef manipulation in an in vivo metastasis model. hSef stable expressing cells (PC3M‐hSef) or empty vector controls (PC3M‐EV) were injected subcutaneously into the lateral thoracic walls of NOD‐SCID gamma mice and lungs were harvested at autopsy. In this model, 6/7 PC3M‐EV xenografts had definitive lung micro‐metastasis whilst only 1/6 PC3M‐hSef xenografts exhibited metastasis recapitulating the clinical scenario (p = 0.03). Gene expression studies revealed key perturbations in genes involved in cell motility and epithelial to mesenchymal transition (EMT) along with alterations in cognate signaling pathways. These results were validated in an EMT specific PCR array whereby hSef over‐expression and silencing reciprocally altered E‐Cadherin expression (p = <0.001) amongst other EMT markers. Immunohistochemistry of excised tumors from the xenografts also confirmed the effect of hSef in suppressing E‐Cadherin expression at the protein level. Phosphokinase arrays further demonstrated a role for hSef in attenuating signaling of not only ERK‐MAPK but also the JNK and p38 pathways as well. Taken together, these data suggest evidence that loss of hSef may be a critical event facilitating tumor dissemination of prostate cancer through alteration of EMT. Detection of downregulated hSef, along with other negative regulators, may therefore be a useful biomarker heralding a transition to a metastatic phenotype and warrants further exploration in this context. PMID:28073170

  20. Subclonal diversification of primary breast cancer revealed by multiregion sequencing

    PubMed Central

    Yates, Lucy R; Gerstung, Moritz; Knappskog, Stian; Desmedt, Christine; Gundem, Gunes; Loo, Peter Van; Aas, Turid; Alexandrov, Ludmil B; Larsimont, Denis; Davies, Helen; Li, Yilong; Ju, Young Seok; Ramakrishna, Manasa; Haugland, Hans Kristian; Lilleng, Peer Kaare; Nik-Zainal, Serena; McLaren, Stuart; Butler, Adam; Martin, Sancha; Glodzik, Dominic; Menzies, Andrew; Raine, Keiran; Hinton, Jonathan; Jones, David; Mudie, Laura J; Jiang, Bing; Vincent, Delphine; Greene-Colozzi, April; Adnet, Pierre-Yves; Fatima, Aquila; Maetens, Marion; Ignatiadis, Michail; Stratton, Michael R; Sotiriou, Christos; Richardson, Andrea L; Lønning, Per Eystein; Wedge, David C; Campbell, Peter J

    2015-01-01

    Sequencing cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patient’s tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole genome and targeted sequencing to multiple samples from each of 50 patients’ tumors (total 303). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2 and MYC, occurring early in some tumors and late in others. In 13/50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resisting chemotherapy and acquiring invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer. PMID:26099045

  1. Allelic loss of chromosomes 16q and 10q in human prostate cancer

    SciTech Connect

    Carter, B.S.; Ewing, C.M.; Ward, W.S.; Treiger, B.F.; Isaacs, W.B.; Epstein, J.I. ); Aalders, T.W.; Schalken, J.A. )

    1990-11-01

    Recent advances in understanding the molecular genetics of common adult tumors have indicated that multiple genetic alterations including the activation of oncogenes and the inactivation of tumor suppressor genes are important in the pathogenesis of these tumors. Loss of heterozygosity is a hallmark of tumor suppressor gene inactivation and has been used to identify chromosomal regions that contain these genes. The authors have examines allelic loss in the most common tumor in men, prostate cancer. Twenty-eight prostate cancer specimens have been examined for loss of heterozygosity at 11 different chromosomal arms including 3p, 7q, 9q, 10p, 10q, 11p, 13q, 16p, 17p, and 18q. Fifty-four percent (13/24) of clinically localized tumors and 4 of 4 metastatic tumors showed loss of heterozygosity on at least one chromosome. Chromosomes 16q and 10q exhibited the highest frequency of loss of heterozygosity with 30% of tumors showing loss at these chromosomes. These data demonstrate that allelic loss is a common event in prostate cancer and suggest that chromosomes 16q and 10q may contain the sites of tumor suppressor genes important in the pathogenesis of human prostate cancer.

  2. Effect of weight loss on bone health in overweight/obese postmenopausal breast cancer survivors

    PubMed Central

    Toriola, Adetunji T.; Liu, Jingxia; Ganz, Patricia A.; Colditz, Graham A.; Yang, Lin; Izadi, Sonya; Naughton, Michael J.; Schwartz, Anna L.; Wolin, Kathleen Y.

    2015-01-01

    Purpose Current guidelines recommend weight loss in obese cancer survivors. Weight loss, however, has adverse effects on bone health in obese individuals without cancer but this has not been evaluated in breast cancer survivors. We investigated the associations of intentional weight loss with bone mineral density (BMD) and bone turn over markers in overweight/obese postmenopausal breast cancer survivors. Methods Participants were overweight/obese breast cancer survivors (N=81) with stage I, II or IIIA disease enrolled in the St. Louis site of a multi-site Exercise and Nutrition to Enhance Recovery and Good health for You (ENERGY) study; a randomized controlled clinical trial designed to achieve a sustained ≥7% loss in body weight at 2 years. Weight loss was achieved through dietary modification with the addition of physical activity. Generalized estimating equations were used to assess differences in mean values between follow-up and baseline. Results Mean weight decreased by 3% and 2.3% between baseline and 6-month follow-up, and 12-month follow-up, respectively. There were decreases in osteocalcin (10.6%, p-value<0.001), PINP (14.5%, p-value<0.001), NTx (19.2% p-value<0.001), and RANK (48.5%, p-value<0.001), but not BALP and CTX-1 levels between baseline and 12-month follow-up. No significant changes occurred in mean T-scores, pelvis and lumbar spine BMD between baseline and 12-month follow-up. Conclusion A 2.3% weight loss over 12 months among overweight/obese women with early stage breast cancer does not appear to have deleterious effect on bone health, and might even have beneficial effect. These findings warrant confirmation, particularly among breast cancer survivors with a larger magnitude of weight loss. PMID:26175059

  3. Deubiquitinase USP18 Loss Mislocalizes and Destabilizes KRAS in Lung Cancer.

    PubMed

    Mustachio, Lisa Maria; Lu, Yun; Tafe, Laura J; Memoli, Vincent; Rodriguez-Canales, Jaime; Mino, Barbara; Villalobos, Pamela Andrea; Wistuba, Ignacio; Katayama, Hiroyuki; Hanash, Samir M; Roszik, Jason; Kawakami, Masanori; Cho, Kwang-Jin; Hancock, John F; Chinyengetere, Fadzai; Hu, Shanhu; Liu, Xi; Freemantle, Sarah J; Dmitrovsky, Ethan

    2017-02-27

    KRAS is frequently mutated in lung cancers and is associated with aggressive biology and chemotherapy resistance. Therefore, innovative approaches are needed to treat these lung cancers. Prior work implicated the interferon-stimulated gene 15 (ISG15) deubiquitinase (DUB) USP18 as having anti-neoplastic activity by regulating lung cancer growth and oncoprotein stability. This study demonstrates that USP18 affects the stability of the KRAS oncoprotein. Interestingly, loss of USP18 reduced KRAS expression and engineered gain of USP18 expression increased KRAS protein levels in lung cancer cells. Using the protein synthesis inhibitor cycloheximide (CHX), USP18 knockdown significantly reduced the half-life of KRAS, but gain of USP18 expression significantly increased its stability. Intriguingly, loss of USP18 altered KRAS subcellular localization by mislocalizing KRAS from the plasma membrane. To explore the biological consequences, immunohistochemical (IHC) expression profiles of USP18 were compared in lung cancers of KrasLA2/+ versus cyclin E engineered mouse models. USP18 expression was higher in Kras-driven murine lung cancers, indicating a link between KRAS and USP18 expression in vivo. To solidify this association, loss of Usp18 in KrasLA2/+/Usp18-/- mice was found to significantly reduce lung cancers as compared to parental KrasLA2/+ mice. Lastly, translational relevance was confirmed in a human lung cancer panel by showing USP18 IHC expression was significantly higher in KRAS mutant versus wild-type lung adenocarcinomas.

  4. A global synthesis reveals biodiversity loss as a major driver of ecosystem change.

    PubMed

    Hooper, David U; Adair, E Carol; Cardinale, Bradley J; Byrnes, Jarrett E K; Hungate, Bruce A; Matulich, Kristin L; Gonzalez, Andrew; Duffy, J Emmett; Gamfeldt, Lars; O'Connor, Mary I

    2012-05-02

    Evidence is mounting that extinctions are altering key processes important to the productivity and sustainability of Earth's ecosystems. Further species loss will accelerate change in ecosystem processes, but it is unclear how these effects compare to the direct effects of other forms of environmental change that are both driving diversity loss and altering ecosystem function. Here we use a suite of meta-analyses of published data to show that the effects of species loss on productivity and decomposition--two processes important in all ecosystems--are of comparable magnitude to the effects of many other global environmental changes. In experiments, intermediate levels of species loss (21-40%) reduced plant production by 5-10%, comparable to previously documented effects of ultraviolet radiation and climate warming. Higher levels of extinction (41-60%) had effects rivalling those of ozone, acidification, elevated CO(2) and nutrient pollution. At intermediate levels, species loss generally had equal or greater effects on decomposition than did elevated CO(2) and nitrogen addition. The identity of species lost also had a large effect on changes in productivity and decomposition, generating a wide range of plausible outcomes for extinction. Despite the need for more studies on interactive effects of diversity loss and environmental changes, our analyses clearly show that the ecosystem consequences of local species loss are as quantitatively significant as the direct effects of several global change stressors that have mobilized major international concern and remediation efforts.

  5. Loss of heterozygosity of the Mutated in Colorectal Cancer gene is not associated with promoter methylation in non-small cell lung cancer.

    PubMed

    Poursoltan, Pirooz; Currey, Nicola; Pangon, Laurent; van Kralingen, Christa; Selinger, Christina I; Mahar, Annabelle; Cooper, Wendy A; Kennedy, Catherine W; McCaughan, Brian C; Trent, Ronald; Kohonen-Corish, Maija R J

    2012-08-01

    'Mutated in Colorectal Cancer' (MCC) is emerging as a multifunctional protein that affects several cellular processes and pathways. Although the MCC gene is rarely mutated in colorectal cancer, it is frequently silenced through promoter methylation. Previous studies have reported loss of heterozygosity (LOH) of the closely linked MCC and APC loci in both colorectal and lung cancers. APC promoter methylation is a marker of poor survival in non-small cell lung cancer (NSCLC). However, MCC methylation has not been previously studied in lung cancer. Therefore, we wanted to determine if MCC is silenced through promoter methylation in lung cancer and whether this methylation is associated with LOH of the MCC locus or methylation of the APC gene. Three polymorphic markers for the APC/MCC locus were analysed for LOH in 64 NSCLC specimens and matching normal tissues. Promoter methylation of both genes was determined using methylation specific PCR in primary tumours. LOH of the three markers was found in 41-49% of the specimens. LOH within the MCC locus was less common in adenocarcinoma (ADC) (29%) than in squamous cell carcinoma (SCC) (72%; P=0.006) or large cell carcinoma (LCC) (75%; P=0.014). However, this LOH was not accompanied by MCC promoter methylation, which was found in only two cancers (3%). In contrast, 39% of the specimens showed APC methylation, which was more common in ADC (58%) than in SCC (13%). Western blotting revealed that MCC was expressed in a subset of lung tissue specimens but there was marked variation between patients rather than between cancer and matching non-cancer tissue specimens. In conclusion, we have shown that promoter methylation of the APC gene does not extend to the neighbouring MCC gene in lung cancer, but LOH is found at both loci. The variable levels of MCC expression were not associated with promoter methylation and may be regulated through other cellular mechanisms.

  6. Exome sequencing and genome-wide copy number variant mapping reveal novel associations with sensorineural hereditary hearing loss.

    PubMed

    Haraksingh, Rajini R; Jahanbani, Fereshteh; Rodriguez-Paris, Juan; Gelernter, Joel; Nadeau, Kari C; Oghalai, John S; Schrijver, Iris; Snyder, Michael P

    2014-12-20

    The genetic diversity of loci and mutations underlying hereditary hearing loss is an active area of investigation. To identify loci associated with predominantly non-syndromic sensorineural hearing loss, we performed exome sequencing of families and of single probands, as well as copy number variation (CNV) mapping in a case-control cohort. Analysis of three distinct families revealed several candidate loci in two families and a single strong candidate gene, MYH7B, for hearing loss in one family. MYH7B encodes a Type II myosin, consistent with a role for cytoskeletal proteins in hearing. High-resolution genome-wide CNV analysis of 150 cases and 157 controls revealed deletions in genes known to be involved in hearing (e.g. GJB6, OTOA, and STRC, encoding connexin 30, otoancorin, and stereocilin, respectively), supporting CNV contributions to hearing loss phenotypes. Additionally, a novel region on chromosome 16 containing part of the PDXDC1 gene was found to be frequently deleted in hearing loss patients (OR=3.91, 95% CI: 1.62-9.40, p=1.45×10(-7)). We conclude that many known as well as novel loci and distinct types of mutations not typically tested in clinical settings can contribute to the etiology of hearing loss. Our study also demonstrates the challenges of exome sequencing and genome-wide CNV mapping for direct clinical application, and illustrates the need for functional and clinical follow-up as well as curated open-access databases.

  7. TCGA bladder cancer study reveals potential drug targets

    Cancer.gov

    Investigators with TCGA have identified new potential therapeutic targets for a major form of bladder cancer, including important genes and pathways that are disrupted in the disease. They also discovered that, at the molecular level, some subtypes of bla

  8. TCGA Bladder Cancer Study Reveals Potential Drug Targets - TCGA

    Cancer.gov

    Investigators with the TCGA Research Network have identified new potential therapeutic targets for a major form of bladder cancer, including important genes and pathways that are disrupted in the disease.

  9. A Serous Peritoneal Cancer Revealing Itself With Double Breast Cancer Metastases in 2 Different Periods.

    PubMed

    Beksac, Kemal; Irkkan, Cigdem; Argun, Guldeniz; Cetin, Bahadir

    2016-12-09

    A 72-year-old woman presented with a mass on the right axilla. This was thought to be an occult breast cancer case, and the patient was treated with modified radical mastectomy, followed by hormonotherapy. Two years later she presented with incarcerated umbilical hernia. Pathology revealed Sister Mary Joseph's nodule inside the hernia sac. Further evaluation revealed that the primary tumor was papillary serous carcinoma of the peritoneal surface. The patient received adjuvant chemotherapy. Two years later the metastatic tumor was located on the other breast. The disease progressed gradually, and the patient eventually died from disseminated disease. This case is extraordinary in that it first presented with axillary metastasis without abdominal involvement and then later metastasized to the other breast after a long disease-free period.

  10. Revealing the Complexity of Breast Cancer by Next Generation Sequencing

    PubMed Central

    Verigos, John; Magklara, Angeliki

    2015-01-01

    Over the last few years the increasing usage of “-omic” platforms, supported by next-generation sequencing, in the analysis of breast cancer samples has tremendously advanced our understanding of the disease. New driver and passenger mutations, rare chromosomal rearrangements and other genomic aberrations identified by whole genome and exome sequencing are providing missing pieces of the genomic architecture of breast cancer. High resolution maps of breast cancer methylomes and sequencing of the miRNA microworld are beginning to paint the epigenomic landscape of the disease. Transcriptomic profiling is giving us a glimpse into the gene regulatory networks that govern the fate of the breast cancer cell. At the same time, integrative analysis of sequencing data confirms an extensive intertumor and intratumor heterogeneity and plasticity in breast cancer arguing for a new approach to the problem. In this review, we report on the latest findings on the molecular characterization of breast cancer using NGS technologies, and we discuss their potential implications for the improvement of existing therapies. PMID:26561834

  11. Nucleome Analysis Reveals Structure-Function Relationships for Colon Cancer.

    PubMed

    Seaman, Laura; Chen, Haiming; Brown, Markus; Wangsa, Darawalee; Patterson, Geoff; Camps, Jordi; Omenn, Gilbert S; Ried, Thomas; Rajapakse, Indika

    2017-07-01

    Chromosomal translocations and aneuploidy are hallmarks of cancer genomes; however, the impact of these aberrations on the nucleome (i.e., nuclear structure and gene expression) is not yet understood. Here, the nucleome of the colorectal cancer cell line HT-29 was analyzed using chromosome conformation capture (Hi-C) to study genome structure, complemented by RNA sequencing (RNA-seq) to determine the consequent changes in genome function. Importantly, translocations and copy number changes were identified at high resolution from Hi-C data and the structure-function relationships present in normal cells were maintained in cancer. In addition, a new copy number-based normalization method for Hi-C data was developed to analyze the effect of chromosomal aberrations on local chromatin structure. The data demonstrate that at the site of translocations, the correlation between chromatin organization and gene expression increases; thus, chromatin accessibility more directly reflects transcription. In addition, the homogeneously staining region of chromosome band 8q24 of HT-29, which includes the MYC oncogene, interacts with various loci throughout the genome and is composed of open chromatin. The methods, described herein, can be applied to the assessment of the nucleome in other cell types with chromosomal aberrations.Implications: Findings show that chromosome conformation capture identifies chromosomal abnormalities at high resolution in cancer cells and that these abnormalities alter the relationship between structure and function. Mol Cancer Res; 15(7); 821-30. ©2017 AACR. ©2017 American Association for Cancer Research.

  12. TET2 binds the androgen receptor and loss is associated with prostate cancer.

    PubMed

    Nickerson, M L; Das, S; Im, K M; Turan, S; Berndt, S I; Li, H; Lou, H; Brodie, S A; Billaud, J N; Zhang, T; Bouk, A J; Butcher, D; Wang, Z; Sun, L; Misner, K; Tan, W; Esnakula, A; Esposito, D; Huang, W Y; Hoover, R N; Tucker, M A; Keller, J R; Boland, J; Brown, K; Anderson, S K; Moore, L E; Isaacs, W B; Chanock, S J; Yeager, M; Dean, M; Andresson, T

    2016-11-07

    Genetic alterations associated with prostate cancer (PCa) may be identified by sequencing metastatic tumour genomes to identify molecular markers at this lethal stage of disease. Previously, we characterized somatic alterations in metastatic tumours in the methylcytosine dioxygenase ten-eleven translocation 2 (TET2), which is altered in 5-15% of myeloid, kidney, colon and PCas. Genome-wide association studies previously identified non-coding risk variants associated with PCa and melanoma. We perform fine-mapping of PCa risk across TET2 using genotypes from the PEGASUS case-control cohort and identify six new risk variants in introns 1 and 2. Oligonucleotides containing two risk variants are bound by the transcription factor octamer-binding protein 1 (Oct1/POU2F1) and TET2 and Oct1 expression are positively correlated in prostate tumours. TET2 is expressed in normal prostate tissue and reduced in a subset of tumours from the Cancer Genome Atlas (TCGA). Small interfering RNA-mediated TET2 knockdown (KD) increases LNCaP cell proliferation, migration and wound healing, verifying loss drives a cancer phenotype. Endogenous TET2 bound the androgen receptor (AR) and AR-coactivator proteins in LNCaP cell extracts, and TET2 KD increases prostate-specific antigen (KLK3/PSA) expression. Published data reveal TET2 binding sites and hydroxymethylcytosine proximal to KLK3. A gene co-expression network identified using TCGA prostate tumour RNA-sequencing identifies co-regulated cancer genes associated with 2-oxoglutarate (2-OG) and succinate metabolism, including TET2, lysine demethylase (KDM) KDM6A, BRCA1-associated BAP1, and citric acid cycle enzymes IDH1/2, SDHA/B, and FH. The co-expression signature is conserved across 31 TCGA cancers suggesting a putative role for TET2 as an energy sensor (of 2-OG) that modifies aspects of androgen-AR signalling. Decreased TET2 mRNA expression in TCGA PCa tumours is strongly associated with reduced patient survival, indicating reduced

  13. Wage losses in the year after breast cancer: extent and determinants among Canadian women.

    PubMed

    Lauzier, Sophie; Maunsell, Elizabeth; Drolet, Mélanie; Coyle, Douglas; Hébert-Croteau, Nicole; Brisson, Jacques; Mâsse, Benoît; Abdous, Belkacem; Robidoux, André; Robert, Jean

    2008-03-05

    Wage losses after breast cancer may result in considerable financial burden. Their assessment is made more urgent because more women now participate in the workforce and because breast cancer is managed using multiple treatment modalities that could lead to long work absences. We evaluated wage losses, their determinants, and the associations between wage losses and changes for the worse in the family's financial situation among Canadian women over the first 12 months after diagnosis of early breast cancer. We conducted a prospective cohort study among women with breast cancer from eight hospitals throughout the province of Quebec. Information that permitted the calculation of wage losses and information on potential determinants of wage losses were collected by three pretested telephone interviews conducted over the year following the start of treatment. Information on medical characteristics was obtained from medical records. The main outcome was the proportion of annual wages lost because of breast cancer. Multivariable analysis of variance using the general linear model was used to identify personal, medical, and employment characteristics associated with the proportion of wages lost. All statistical tests were two-sided. Among 962 eligible breast cancer patients, 800 completed all three interviews. Of these, 459 had a paying job during the month before diagnosis. On average, these working women lost 27% of their projected usual annual wages (median = 19%) after compensation received had been taken into account. Multivariable analysis showed that a higher percentage of lost wages was statistically significantly associated with a lower level of education (P(trend) = .0018), living 50 km or more from the hospital where surgery was performed (P = .070), lower social support (P = .012), having invasive disease (P = .086), receipt of chemotherapy (P < .001), self-employment (P < .001), shorter tenure in the job (P(trend) < .001), and part-time work (P < .001). Wage

  14. Weight loss and quality of life in patients surviving 2 years after gastric cancer resection.

    PubMed

    Climent, M; Munarriz, M; Blazeby, J M; Dorcaratto, D; Ramón, J M; Carrera, M J; Fontane, L; Grande, L; Pera, M

    2017-07-01

    Malnutrition is common in patients undergoing gastric cancer resection, leading to weight loss, although little is known about how this impacts on health-related quality of life (HRQL). This study aimed to explore the association between HRQL and weight loss in patients 2 years after curative gastric cancer resection. Consecutive patients undergoing curative gastric cancer resection and surviving at least 2 years without disease recurrence were recruited. Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the specific module for gastric cancer (STO22) before and 2 years postoperatively and associations between HRQL scores and patients with and without ≥ 10% body weight loss (BWL) were examined. A total of 76 patients were included, of whom 51 (67%) had BWL ≥10%. At 2 years postoperatively, BWL ≥10% was associated with deterioration of all functional aspects of quality of life, with persistent pain (21.6%), diarrhoea (13.7%) and nausea/vomiting (13.7%). By contrast, none of the patients with BWL <10% experienced severe nausea/vomiting, pain or diarrhoea. Disabling symptoms occurred more frequently in patients with ≥10% BWL than in those with <10% BWL, with a relevant negative impact on HRQL. A cause-effect relationship between weight loss and postoperative outcome remains unsolved. Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

  15. Loss of the coxsackie and adenovirus receptor contributes to gastric cancer progression

    PubMed Central

    Anders, M; Vieth, M; Röcken, C; Ebert, M; Pross, M; Gretschel, S; Schlag, P M; Wiedenmann, B; Kemmner, W; Höcker, M

    2009-01-01

    Loss of the coxsackie and adenovirus receptor (CAR) has previously been observed in gastric cancer. The role of CAR in gastric cancer pathobiology, however, is unclear. We therefore analysed CAR in 196 R0-resected gastric adenocarcinomas and non-cancerous gastric mucosa samples using immunohistochemistry and immunofluorescence. Coxsackie and adenovirus receptor was found at the surface and foveolar epithelium of all non-neoplastic gastric mucosa samples (n=175), whereas only 56% of gastric cancer specimens showed CAR positivity (P<0.0001). Loss of CAR correlated significantly with decreased differentiation, increased infiltrative depths, presence of distant metastases, and was also associated with reduced carcinoma-specific survival. To clarify whether CAR impacts the tumorbiologic properties of gastric cancer, we subsequently determined the role of CAR in proliferation, migration, and invasion of gastric cancer cell lines by application of specific CAR siRNA or ectopic expression of a human full-length CAR cDNA. These experiments showed that RNAi-mediated CAR knock down resulted in increased proliferation, migration, and invasion of gastric cancer cell lines, whereas enforced ectopic CAR expression led to opposite effects. We conclude that the association of reduced presence of CAR in more severe disease states, together with our findings in gastric cancer cell lines, suggests that CAR functionally contributes to gastric cancer pathogenesis, showing features of a tumour suppressor. PMID:19142187

  16. An integrative and comparative study of pan-cancer transcriptomes reveals distinct cancer common and specific signatures

    PubMed Central

    Cao, Zhen; Zhang, Shihua

    2016-01-01

    To investigate the commonalities and specificities across tumor lineages, we perform a systematic pan-cancer transcriptomic study across 6744 specimens. We find six pan-cancer subnetwork signatures which relate to cell cycle, immune response, Sp1 regulation, collagen, muscle system and angiogenesis. Moreover, four pan-cancer subnetwork signatures demonstrate strong prognostic potential. We also characterize 16 cancer type-specific subnetwork signatures which show diverse implications to somatic mutations, somatic copy number aberrations, DNA methylation alterations and clinical outcomes. Furthermore, some of them are strongly correlated with histological or molecular subtypes, indicating their implications with tumor heterogeneity. In summary, we systematically explore the pan-cancer common and cancer type-specific gene subnetwork signatures across multiple cancers, and reveal distinct commonalities and specificities among cancers at transcriptomic level. PMID:27633916

  17. Temporal changes in loss of life expectancy due to cancer in Australia: a flexible parametric approach.

    PubMed

    Baade, Peter D; Youlden, Danny R; Andersson, Therese M; Youl, Philippa H; Walpole, Euan T; Kimlin, Michael G; Aitken, Joanne F; Biggar, Robert J

    2016-08-01

    To evaluate changes in cancer mortality burden over time by assessing temporal trends in life expectation for Australian residents diagnosed with cancer. The study cohort consisted of all people diagnosed with cancer in the period 1990-2000 and aged 15-89 years (n = 1,275,978), with mortality follow-up to 31 December 2010. Flexible parametric survival models incorporating background age-sex-year-specific population mortality rates were applied to generate the observed survival curves for all cancers combined and selected major cancer types. Predicted values of loss of life expectancy (LOLE) in years were generated and then averaged across calendar year and age group (15-49, 50-69 and 70-89 years) or spread of disease (localized, regional, distant, unknown). The greatest LOLE burden was for lung cancer (14.3 years per diagnosis) and lowest for melanoma (2.5 years). There was a significant decrease in LOLE over time (-0.13 LOLE per year) for all cancers combined. Decreases were also observed for female breast cancer (-0.21), prostate cancer (-0.17), colorectal cancer (-0.08), melanoma (-0.07) and stomach cancer (-0.02), with slight increases for lung cancer (+0.04). When restricted to the sub-cohort from New South Wales with spread of disease information, these decreases in LOLE were primarily among cancers categorized as localized or regional spread at diagnosis. In Australia, persons diagnosed with cancer have a steadily improving outlook that exceeds that expected by general improvement in population life expectancy. The overall improvement is observed in persons with localized or regional cancers but not in those with advanced cancers, findings which encourage earlier diagnosis.

  18. Nutritional surveillance and weight loss in head and neck cancer patients.

    PubMed

    Ehrsson, Ylva Tiblom; Langius-Eklöf, Ann; Laurell, Göran

    2012-04-01

    This retrospective single-institution cohort study aims to evaluate if therapeutic approach, tumour site, tumour stage, BMI, gender, age and civil status predict body weight loss and to establish the association between weight loss on postoperative infections and mortality. Consecutive patients with head and neck cancer were seen for nutritional control at a nurse-led outpatient clinic and followed-up for 2 years after radiotherapy. Demographic, disease-specific and nutrition data were collected from case records. The primary outcome measure was maximum body weight loss during the whole study period. The nadir of body weight loss was observed 6 months after radiotherapy. In total, 92 patients of 157 (59%) with no evidence of residual tumour after treatment received enteral nutrition. The mean maximum weight loss for patients receiving enteral nutrition and per oral feeding was 13% and 6%, respectively (p < 0.001). Using multivariate analysis, tumour stage (p < 0.001) was the only independent factor of maximum weight loss. Weight loss was not significantly related to risk for postoperative infection. Weight loss is frequently noted among head and neck cancer patients during and after treatment. Weight loss was not found to be associated with postoperative infections and mortality. Nutritional surveillance is important in all patients, but special attention should be given to those on enteral nutrition and those with more advanced disease.

  19. Identification and functional analysis of a potential key lncRNA involved in fat loss of cancer cachexia.

    PubMed

    Liu, Huiquan; Zhou, Ting; Wang, Bangyan; Li, Lu; Ye, Dawei; Yu, Shiying

    2017-08-07

    Cancer cachexia is a devastating, multifactorial, and irreversible syndrome characterized by skeletal muscle reduction with or without fat loss. Although much attention has been focused on muscle wasting, fat loss may occur earlier and accelerate muscle wasting in cachexia. The cause of 20% of cancer related death makes it urgent to discover molecular mechanisms behind cancer cachexia. Here we applied weighted gene co-expression network analysis (WGCNA) to identify cachexia related gene modules using differentially expressed 3289 genes and 59 long non-coding RNAs based on microarray data of cachectic and non-cachectic subcutaneous adipose tissue. Subsequently, 16 independent modules were acquired and GSAASeqSP Toolset confirmed that black module was significantly associated with fat loss in cancer cachexia. Top 50 hub-genes in black module contained only one lncRNA, VLDLR antisense RNA 1 (VLDLR-AS1). We then explored the function of black module from the view of VLDLR-AS1-connected genes in the network. GO enrichment and KEGG pathways analysis revealed LDLR-AS1-connected genes were involved in Wnt signaling pathway, small GTPase mediated signal transduction, epithelial-mesenchymal transition and so on. Through construction of competing endogenous RNAs (ceRNAs) regulation network, we showed that VLDLR-AS1 may function with hsa-miR-600 to regulate gene GOLGA3, DUSP14, and UCHL1, or interact with hsa-miR-1224-3p to modulate the expression of gene GOLGA3, ZNF219, RNF141, and CALU. After literature validation, we predicted that VLDLR-AS1 most likely interacted with miR-600 to regulate UCH-L1 through Wnt/β-catenin signaling pathway. However, further experiments are still required to validate mechanisms of VLDLR-AS1 in fat reduction of cancer cachexia. © 2017 Wiley Periodicals, Inc.

  20. Subclonal diversification of primary breast cancer revealed by multiregion sequencing

    SciTech Connect

    Yates, Lucy R.; Gerstung, Moritz; Knappskog, Stian; Desmedt, Christine; Gundem, Gunes; Van Loo, Peter; Aas, Turid; Alexandrov, Ludmil B.; Larsimont, Denis; Davies, Helen; Li, Yilong; Ju, Young Seok; Ramakrishna, Manasa; Haugland, Hans Kristian; Lilleng, Peer Kaare; Nik-Zainal, Serena; McLaren, Stuart; Butler, Adam; Martin, Sancha; Glodzik, Dominic; Menzies, Andrew; Raine, Keiran; Hinton, Jonathan; Jones, David; Mudie, Laura J.; Jiang, Bing; Vincent, Delphine; Greene-Colozzi, April; Adnet, Pierre -Yves; Fatima, Aquila; Maetens, Marion; Ignatiadis, Michail; Stratton, Michael R.; Sotiriou, Christos; Richardson, Andrea L.; Lønning, Per Eystein; Wedge, David C.; Campbell, Peter J.

    2015-06-22

    Sequencing cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patient's tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole-genome and targeted sequencing to multiple samples from each of 50 patients' tumors (303 samples in total). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2 and MYC, occurring early in some tumors and late in others. In 13 out of 50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resistance to chemotherapy and the acquisition of invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer.

  1. Subclonal diversification of primary breast cancer revealed by multiregion sequencing.

    PubMed

    Yates, Lucy R; Gerstung, Moritz; Knappskog, Stian; Desmedt, Christine; Gundem, Gunes; Van Loo, Peter; Aas, Turid; Alexandrov, Ludmil B; Larsimont, Denis; Davies, Helen; Li, Yilong; Ju, Young Seok; Ramakrishna, Manasa; Haugland, Hans Kristian; Lilleng, Peer Kaare; Nik-Zainal, Serena; McLaren, Stuart; Butler, Adam; Martin, Sancha; Glodzik, Dominic; Menzies, Andrew; Raine, Keiran; Hinton, Jonathan; Jones, David; Mudie, Laura J; Jiang, Bing; Vincent, Delphine; Greene-Colozzi, April; Adnet, Pierre-Yves; Fatima, Aquila; Maetens, Marion; Ignatiadis, Michail; Stratton, Michael R; Sotiriou, Christos; Richardson, Andrea L; Lønning, Per Eystein; Wedge, David C; Campbell, Peter J

    2015-07-01

    The sequencing of cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patient's tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole-genome and targeted sequencing to multiple samples from each of 50 patients' tumors (303 samples in total). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2 and MYC, occurring early in some tumors and late in others. In 13 out of 50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resistance to chemotherapy and the acquisition of invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer.

  2. Subclonal diversification of primary breast cancer revealed by multiregion sequencing

    DOE PAGES

    Yates, Lucy R.; Gerstung, Moritz; Knappskog, Stian; ...

    2015-06-22

    Sequencing cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patient's tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole-genome and targeted sequencing to multiple samples from each of 50 patients' tumors (303 samples in total). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2 and MYC, occurring early in some tumors and latemore » in others. In 13 out of 50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resistance to chemotherapy and the acquisition of invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer.« less

  3. Evaluation of 1p Losses in Primary Carcinomas, Local Recurrences and Peripheral Metastases from Colorectal Cancer Patients1

    PubMed Central

    Thorstensen, Lin; Qvist, Hanne; Heim, Sverre; Liefers, Gerrit-Jan; Nesland, Jahn M; Giercksky, Karl-Erik; Lothe, Ragnhild A

    2000-01-01

    Abstract Cytogenetic and molecular genetic analyses of colorectal adenomas and carcinomas have shown that loss of the distal part of chromosome arm 1p is common, particularly in tumors of the left colon. Because the importance of 1p loss in colorectal cancer metastases is unknown, we compared the frequency, exact site and extent of 1p deletions in primary carcinomas (n=28), local recurrences (n=19) and metastases (n=33) from 67 colorectal cancer patients using 14 markers in an allelic imbalance study. Loss of 1p was found in 50% of the primary carcinomas, 33% of the local recurrences, and 64% of the metastases, revealing a significant difference between the local recurrences and the metastases (P=.04). The smallest region of 1p deletion overlap (SRO) defined separately for each group of lesions had the region between markers D1S2647 and D1S2644, at 1p35–36, in common. The genes PLA2G2A (1p35.1–36) and TP73 (1p36.3) were shown to lie outside this consistently lost region, suggesting that neither of them are targets for the 1p loss. In the second part of the study, microdissected primary carcinomas and distant metastases from the same colorectal cancer patients (n=18) were analyzed, and the same 1p genotype was found in the majority of patients (12/18, 67%). The finding that primary carcinoma cells with metastatic ability usually contain 1p deletions, and that some cases lacking 1p alterations in the primary tumor acquire such changes during growth of a metastatic lesion, supports the notion that 1p loss may be important both early and late in colorectal carcinogenesis, with the apparent exception of local recurrences. PMID:11228544

  4. Trpc2 pseudogenization dynamics in bats reveal ancestral vomeronasal signaling, then pervasive loss.

    PubMed

    Yohe, Laurel R; Abubakar, Ramatu; Giordano, Christina; Dumont, Elizabeth; Sears, Karen E; Rossiter, Stephen J; Dávalos, Liliana M

    2017-01-27

    Comparative methods are often used to infer loss or gain of complex phenotypes, but few studies take advantage of genes tightly linked with complex traits to test for shifts in the strength of selection. In mammals, vomerolfaction detects chemical cues mediating many social and reproductive behaviors and is highly conserved, but all bats exhibit degraded vomeronasal structures with the exception of two families (Phyllostomidae and Miniopteridae). These families either regained vomerolfaction after ancestral loss, or there were many independent losses after diversification from an ancestor with functional vomerolfaction. In this study, we use the Transient receptor potential cation channel 2 (Trpc2) as a molecular marker for testing the evolutionary mechanisms of loss and gain of the mammalian vomeronasal system. We sequenced Trpc2 exon 2 in over 100 bat species across 17 of 20 chiropteran families. Most families showed independent pseudogenizing mutations in Trpc2, but the reading frame was highly conserved in phyllostomids and miniopterids. Phylogeny-based simulations suggest loss of function occurred after bat families diverged, and purifying selection in two families has persisted since bats shared a common ancestor. As most bats still display pheromone-mediated behavior, they might detect pheromones through the main olfactory system without using the Trpc2 signaling mechanism.

  5. Copy number loss or silencing of apoptosis-effector genes in cancer.

    PubMed

    Mauro, James A; Butler, Shanitra N; Ramsamooj, Michael; Blanck, George

    2015-01-01

    Cancer cells undergo a variety of DNA copy number gains and losses (CNV), raising two important questions related to cancer development: (i) Which genes are affected? (ii) And how do CNVs, that do not represent complete deletions but do represent gene-dosage alterations, impact cancer cell functions? Recent studies have indicated that CNVs in cancer can impact genes for regulatory proteins long known to be associated with cancer development, but less is understood about CNVs affecting effector genes. Also, we have recently indicated the likely importance of transcription factor binding site (TFBS) copies in effector genes, in regulating the transition from a proliferative to an apoptotic state. Here we report data-mining analyses that indicate that copies of apoptosis-effector genes are commonly lost in cancer development, in comparison to proliferation-effector genes, and when not, apoptosis effector genes have silenced chromatin structures. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. Plasma growth differentiation factor 15 is associated with weight loss and mortality in cancer patients

    PubMed Central

    Lerner, Lorena; Hayes, Teresa G; Tao, Nianjun; Krieger, Brian; Feng, Bin; Wu, Zhenhua; Nicoletti, Richard; Chiu, M Isabel; Gyuris, Jeno; Garcia, Jose M

    2015-01-01

    Background Cancer-related weight loss is associated with increased inflammation and decreased survival. The novel inflammatory mediator growth differentiation factor (GDF)15 is associated with poor prognosis in cancer but its role in cancer-related weight loss (C-WL) remains unclear. Our objective was to measure GDF15 in plasma samples of cancer subjects and controls and establish its association with other inflammatory markers and clinical outcomes. Methods We measured body weight, appetite, plasma GDF15, and other inflammatory markers in men with cancer-related weight loss (C-WL, n = 58), weight stable patients with cancer (C-WS, n = 72), and non-cancer controls (Co, n = 59) matched by age and pre-illness body mass index. In a subset of patients we also measured handgrip strength, appendicular lean body mass (aLBM), Eastern Cooperative Oncology Group (ECOG), and Karnofsky performance scores. Results GDF15, interleukin (IL)-6 and IL-8 were increased in C-WL versus other groups. IL-1 receptor antagonist, IL-4, interferon–gamma, tumour necrosis factor alpha, and vascular endothelial growth factor A were increased in C-WL versus C-WS, and Activin A was significantly downregulated in Co versus other groups. C-WL patients had lower handgrip strength, aLBM, and fat mass, and Eastern Cooperative Oncology Group and Karnofsky performance scores were lower in both cancer groups. GDF15, IL-6, and IL-8 significantly correlated with weight loss; GDF15 negatively correlated with aLBM, handgrip strength, and fat mass. IL-8 and Activin A negatively correlated with aLBM and fat mass. GDF15 and IL-8 predicted survival adjusting for stage and weight change (Cox regression P < 0.001 for both). Conclusion GDF15 and other inflammatory markers are associated with weight loss, decreased aLBM and strength, and poor survival in patients with cancer. GDF15 may serve as a prognostic indicator in cancer patients and is being evaluated as a potential therapeutic target for

  7. Dietary and genetic effects on age-related loss of gene silencing reveal epigenetic plasticity of chromatin repression during aging.

    PubMed

    Jiang, Nan; Du, Guyu; Tobias, Ethan; Wood, Jason G; Whitaker, Rachel; Neretti, Nicola; Helfand, Stephen L

    2013-11-01

    During aging, changes in chromatin state that alter gene transcription have been postulated to result in expression of genes that are normally silenced, leading to deleterious age-related effects on cellular physiology. Despite the prevalence of this hypothesis, it is primarily in yeast that loss of gene silencing with age has been well documented. We use a novel position effect variegation (PEV) reporter in Drosophila melanogaster to show that age-related loss of repressive heterochromatin is associated with loss of gene silencing in metazoans and is affected by Sir2, as it is in yeast. The life span-extending intervention, calorie restriction (CR), delays the age-related loss of gene silencing, indicating that loss of gene silencing is a component of normal aging. Diet switch experiments show that such flies undergo a rapid change in their level of gene silencing, demonstrating the epigenetic plasticity of chromatin during aging and highlighting the potential role of diet and metabolism in chromatin maintenance, Thus, diet and related interventions may be of therapeutic importance for age-related diseases, such as cancer.

  8. The gene-reduction effect of chromosomal losses detected in gastric cancers

    PubMed Central

    2010-01-01

    Background The level of loss of heterozygosity (LOH) that reduces a gene dose and exerts a cell-adverse effect is known to be a parameter for the genetic staging of gastric cancers. This study investigated if the cell-adverse effect induced with the gene reduction was a rate-limiting factor for the LOH events in two distinct histologic types of gastric cancers, the diffuse- and intestinal-types. Methods The pathologic specimens obtained from 145 gastric cancer patients were examined for the level of LOH using 40 microsatellite markers on eight cancer-associated chromosomes (3p, 4p, 5q, 8p, 9p, 13q, 17p and 18q). Results Most of the cancer-associated chromosomes were found to belong to the gene-poor chromosomes and to contain a few stomach-specific genes that were highly expressed. A baseline-level LOH involving one or no chromosome was frequent in diffuse-type gastric cancers. The chromosome 17 containing a relatively high density of genes was commonly lost in intestinal-type cancers but not in diffuse-type cancers. A high-level LOH involving four or more chromosomes tended to be frequent in the gastric cancers with intestinal and mixed differentiation. Disease relapse was common for gastric cancers with high-level LOH through both the hematogenous (38%) and non-hematogenous (36%) routes, and for the baseline-level LOH cases through the non-hematogenous route (67%). Conclusions The cell-adverse effect of gene reduction is more tolerated in intestinal-type gastric cancers than in diffuse-type cancers, and the loss of high-dose genes is associated with hematogenous metastasis. PMID:21092121

  9. Potential Biomarkers of Fat Loss as a Feature of Cancer Cachexia.

    PubMed

    Ebadi, Maryam; Mazurak, Vera C

    2015-01-01

    Fat loss is associated with shorter survival and reduced quality of life in cancer patients. Effective intervention for fat loss in cachexia requires identification of the condition using prognostic biomarkers for early detection and prevention of further depletion. No biomarkers of fat mass alterations have been defined for application to the neoplastic state. Several inflammatory cytokines have been implicated in mediating fat loss associated with cachexia; however, plasma levels may not relate to adipose atrophy. Zinc-α2-glycoprotein may be a local catabolic mediator within adipose tissue rather than serving as a plasma biomarker of fat loss. Plasma glycerol and leptin associate with adipose tissue atrophy and mass, respectively; however, no study has evaluated their potential as a prognostic biomarker of cachexia-associated fat loss. This review confirms the need for further studies to identify valid prognostic biomarkers to identify loss of fat based on changes in plasma levels of biomarkers.

  10. Potential Biomarkers of Fat Loss as a Feature of Cancer Cachexia

    PubMed Central

    Ebadi, Maryam; Mazurak, Vera C.

    2015-01-01

    Fat loss is associated with shorter survival and reduced quality of life in cancer patients. Effective intervention for fat loss in cachexia requires identification of the condition using prognostic biomarkers for early detection and prevention of further depletion. No biomarkers of fat mass alterations have been defined for application to the neoplastic state. Several inflammatory cytokines have been implicated in mediating fat loss associated with cachexia; however, plasma levels may not relate to adipose atrophy. Zinc-α2-glycoprotein may be a local catabolic mediator within adipose tissue rather than serving as a plasma biomarker of fat loss. Plasma glycerol and leptin associate with adipose tissue atrophy and mass, respectively; however, no study has evaluated their potential as a prognostic biomarker of cachexia-associated fat loss. This review confirms the need for further studies to identify valid prognostic biomarkers to identify loss of fat based on changes in plasma levels of biomarkers. PMID:26508820

  11. Exercise to Countereact Loss of Bone and Muscle During Androgen Deprivation Therapy in Men with Prostate Cancer

    DTIC Science & Technology

    2007-05-01

    CONTRACT NUMBER Exercise to Counteract Loss of Bone and Muscle during Androgen Deprivation Therapy in Men with Prostate Cancer 5b. GRANT NUMBER...of androgen suppression treatment in men with prostate cancer . Prostate Cancer Prostatic Dis 2007. APPENDICES none ...and Muscle during Androgen Deprivation Therapy in Men with Prostate Cancer PRINCIPAL INVESTIGATOR: Wendy M Kohrt, Ph.D

  12. Loss of tumor suppressor Merlin results in aberrant activation of Wnt/β-catenin signaling in cancer

    PubMed Central

    Meng, Erhong; Menezes, Mitchell E.; Bailey, Sarah K.; Metge, Brandon J.; Buchsbaum, Donald J.; Samant, Rajeev S.; Shevde, Lalita A.

    2016-01-01

    The expression of the tumor suppressor Merlin is compromised in nervous system malignancies due to genomic aberrations. We demonstrated for the first time, that in breast cancer, Merlin protein expression is lost due to proteasome-mediated elimination. Immunohistochemical analysis of tumor tissues from patients with metastatic breast cancer revealed characteristically reduced Merlin expression. Importantly, we identified a functional role for Merlin in impeding breast tumor xenograft growth and reducing invasive characteristics. We sought to determine a possible mechanism by which Merlin accomplishes this reduction in malignant activity. We observed that breast and pancreatic cancer cells with loss of Merlin show an aberrant increase in the activity of β-catenin concomitant with nuclear localization of β-catenin. We discovered that Merlin physically interacts with β-catenin, alters the sub-cellular localization of β-catenin, and significantly reduces the protein levels of β-catenin by targeting it for degradation through the upregulation of Axin1. Consequently, restoration of Merlin inhibited β-catenin-mediated transcriptional activity in breast and pancreatic cancer cells. We also present evidence that loss of Merlin sensitizes tumor cells to inhibition by compounds that target β-catenin-mediated activity. Thus, this study provides compelling evidence that Merlin reduces the malignant activity of pancreatic and breast cancer, in part by suppressing the Wnt/β-catenin pathway. Given the potent role of Wnt/β-catenin signaling in breast and pancreatic cancer and the flurry of activity to test β-catenin inhibitors in the clinic, our findings are opportune and provide evidence for Merlin in restraining aberrant activation of Wnt/β-catenin signaling. PMID:26908451

  13. Sudden hearing loss due to oxaliplatin use in a patient with colon cancer.

    PubMed

    Güvenç, M Güven; Dizdar, Denizhan; Dizdar, Senem Kurt; Okutur, Sadi Kerem; Demir, Gökhan

    2016-08-01

    Oxaliplatin is used to treat advanced colorectal cancer. Platinum-containing chemotherapeutic agents are known to be ototoxic. However, ototoxicity is rare with newer generation platinum-derived agents, such as oxaliplatin. This case report presents a rare case of sudden unilateral sensorineural hearing loss following intravenous (IV) infusion of oxaliplatin in a 64-year-old woman with advanced colon cancer. The hearing loss was severe and did not respond to treatment. To the best of our knowledge, this is the fifth reported case of oxaliplatin ototoxicity. Although oxaliplatin ototoxicity is rare, physicians must be aware of this important adverse effect, and an audiometric evaluation must be performed when necessary. Patients treated with oxaliplatin should be followed closely for early signs and symptoms of hearing loss, and if hearing loss is detected, treatment should be stopped immediately.

  14. In silico Analysis of Combinatorial microRNA Activity Reveals Target Genes and Pathways Associated with Breast Cancer Metastasis

    PubMed Central

    Dombkowski, Alan A.; Sultana, Zakia; Craig, Douglas B.; Jamil, Hasan

    2011-01-01

    This is an open access article. Unrestricted non-commercial use is permitted provided the original work is properly cited. Aberrant microRNA activity has been reported in many diseases, and studies often find numerous microRNAs concurrently dysregulated. Most target genes have binding sites for multiple microRNAs, and mounting evidence indicates that it is important to consider their combinatorial effect on target gene repression. A recent study associated the coincident loss of expression of six microRNAs with metastatic potential in breast cancer. Here, we used a new computational method, miR-AT!, to investigate combinatorial activity among this group of microRNAs. We found that the set of transcripts having multiple target sites for these microRNAs was significantly enriched with genes involved in cellular processes commonly perturbed in metastatic tumors: cell cycle regulation, cytoskeleton organization, and cell adhesion. Network analysis revealed numerous target genes upstream of cyclin D1 and c-Myc, indicating that the collective loss of the six microRNAs may have a focal effect on these two key regulatory nodes. A number of genes previously implicated in cancer metastasis are among the predicted combinatorial targets, including TGFB1, ARPC3, and RANKL. In summary, our analysis reveals extensive combinatorial interactions that have notable implications for their potential role in breast cancer metastasis and in therapeutic development. PMID:21552493

  15. Endonuclease banding reveals that atrazine-induced aneuploidy resembles spontaneous chromosome loss in Crassostrea gigas.

    PubMed

    Bouilly, Karine; Leitão, Alexandra; Chaves, Raquel; Guedes-Pinto, Henrique; Boudry, Pierre; Lapègue, Sylvie

    2005-02-01

    Aneuploidy has previously been observed in the Pacific oyster, Crassostrea gigas, and shown to be negatively correlated with growth. Moreover, a significant impact of atrazine exposure has been described in C. gigas, and persistence of that effect has been observed between generations. Evidence of differential chromosome loss has been demonstrated in aneuploid karyotypes of C. gigas using the G-banding technique. Pairs 1, 5, 9, and 10 are characterized by the loss of 1 chromosome. As restriction enzyme (RE) digestion chromosome banding allows a better identification of chromosome pairs, we used this technique to identify which chromosomes are affected when aneuploidy is increased by exposure to atrazine. The progeny of oysters contaminated by atrazine were analysed using the restriction enzyme HaeIII. The study of 26 RE-banded aneuploid karyotypes showed that the same chromosome pairs (1, 5, 9, and 10) were affected by the loss of 1 chromosome (61%, 15%, 42%, and 42%, respectively). Further investigation is required to enable a better understanding of aneuploidy in oysters, especially with respect to why some chromosomes are more easily lost than others, and why cells tolerate the loss of these chromosomes.

  16. Extensive weight loss reveals distinct gene expression changes in human subcutaneous and visceral adipose tissue

    PubMed Central

    Mardinoglu, Adil; Heiker, John T.; Gärtner, Daniel; Björnson, Elias; Schön, Michael R.; Flehmig, Gesine; Klöting, Nora; Krohn, Knut; Fasshauer, Mathias; Stumvoll, Michael; Nielsen, Jens; Blüher, Matthias

    2015-01-01

    Weight loss has been shown to significantly improve Adipose tissue (AT) function, however changes in AT gene expression profiles particularly in visceral AT (VAT) have not been systematically studied. Here, we tested the hypothesis that extensive weight loss in response to bariatric surgery (BS) causes AT gene expression changes, which may affect energy and lipid metabolism, inflammation and secretory function of AT. We assessed gene expression changes by whole genome expression chips in AT samples obtained from six morbidly obese individuals, who underwent a two step BS strategy with sleeve gastrectomy as initial and a Roux-en-Y gastric bypass as second step surgery after 12 ± 2 months. Global gene expression differences in VAT and subcutaneous (S)AT were analyzed through the use of genome-scale metabolic model (GEM) for adipocytes. Significantly altered gene expressions were PCR-validated in 16 individuals, which also underwent a two-step surgery intervention. We found increased expression of cell death-inducing DFFA-like effector a (CIDEA), involved in formation of lipid droplets in both fat depots in response to significant weight loss. We observed that expression of the genes associated with metabolic reactions involved in NAD+, glutathione and branched chain amino acid metabolism are significantly increased in AT depots after surgery-induced weight loss. PMID:26434764

  17. Loss of the SWI/SNF ATPase subunits BRM and BRG1 drives lung cancer development

    PubMed Central

    Marquez-Vilendrer, Stefanie B.; Rai, Sudhir K.; Gramling, Sarah JB; Lu, Li; Reisman, David N.

    2016-01-01

    Inactivation of Brg1 and Brm accelerated lung tumor development, shortened tumor latency, and caused a loss of differentiation. Tumors with Brg1 and/or Brm loss recapitulated the evolution of human lung cancer as observed by the development of local tumor invasion as well as distal tumor metastasis, thereby making this model useful in lung cancer studies. Brg1 loss contributed to metastasis in part by driving E-cadherin loss and Vimentin up-regulation. By changing more than 6% of the murine genome with the down-regulation of tumor suppressors, DNA repair, differentiation and cell adhesion genes, and the concomitant up-regulation of oncogenes, angiogenesis, metastasis and antiapoptosis genes, caused by the dual loss of Brg1/Brm further accelerated tumor development. Additionally, this Brg1/Brm-driven change in gene expression resulted in a nearly two-fold increase in tumorigenicity in Brg1/Brm knockout mice compared with wild type mice. Most importantly, Brg1/Brm-driven lung cancer development histologically and clinically reflects human lung cancer development thereby making this GEMM model potentially useful. PMID:28105457

  18. Loss of DNA mismatch repair function and cancer predisposition in the mouse: animal models for human hereditary nonpolyposis colorectal cancer.

    PubMed

    Edelmann, Lisa; Edelmann, Winfried

    2004-08-15

    Germline mutations in DNA mismatch repair genes underlie one of the most common hereditary cancer predisposition syndromes known in humans, hereditary nonpolyposis colorectal cancer (HNPCC). Defects of the DNA mismatch repair system are also prevalent in sporadic colorectal cancers. The generation of mice with targeted inactivating mutations in the mismatch repair genes has facilitated the in vivo study of how these genes function and how their individual loss contributes to tumorigenesis. Although there are notable limitations when using murine models to study the molecular basis of human cancer, there is remarkable similarity between the two species with respect to the contribution of individual members of the mismatch repair system to cancer susceptibility, and mouse mutants have greatly enhanced our understanding of the normal role of these genes in mutation avoidance and suppression of tumorigenesis.

  19. Physical activity levels of overweight or obese breast cancer survivors: correlates at entry into a weight loss intervention study.

    PubMed

    Liu, Fred X; Flatt, Shirley W; Pakiz, Bilgé; Sedjo, Rebecca L; Wolin, Kathleen Y; Blair, Cindy K; Demark-Wahnefried, Wendy; Rock, Cheryl L

    2016-01-01

    Physical activity is associated with reduced risk and progression of breast cancer, and exercise can improve physical function, quality of life, and fatigue in cancer survivors. Evidence on factors associated with cancer survivors' adherence to physical activity guidelines from the American Cancer Society and the U.S. Department of Health and Human Services is mixed. This study seeks to help fill this gap in knowledge by examining correlates with physical activity among breast cancer survivors. Overweight or obese breast cancer survivors (N = 692) were examined at enrollment into a weight loss intervention study. Questionnaires and medical record review ascertained data on education, race, ethnicity, menopausal status, physical activity, and medical history. Measures of anthropometrics and fitness level were conducted. Regression analysis examined associations between physical activity and demographic, clinical, and lifestyle factors. Overall, 23% of women met current guidelines. Multivariate analysis revealed that body mass index (p = 0.03), emergency room visits in the past year (p = 0.04), and number of comorbidities (p = 0.02) were associated with less physical activity. Geographic region also was associated with level of physical activity (p = 0.02), with women in Alabama reporting significantly less activity than those in other participating regions. The majority of overweight/obese breast cancer survivors did not meet physical activity recommendations. Physical activity levels were associated with degree of adiposity, geographic location, and number of comorbidities. The majority of overweight breast cancer survivors should be encouraged to increase their level of physical activity. Individualizing exercise prescriptions according to medical comorbidities may improve adherence.

  20. Physical activity levels of overweight or obese breast cancer survivors: Correlates at entry into a weight loss intervention study

    PubMed Central

    Liu, Fred X.; Flatt, Shirley W.; Pakiz, Bilgé; Sedjo, Rebecca L.; Wolin, Kathleen Y.; Blair, Cindy K.; Demark-Wahnefried, Wendy; Rock, Cheryl L.

    2015-01-01

    Purpose Physical activity is associated with reduced risk and progression of breast cancer, and exercise can improve physical function, quality of life and fatigue in cancer survivors. Evidence on factors associated with cancer survivors’ adherence to physical activity guidelines from the American Cancer Society and the U.S. Department of Health and Human Services is mixed. This study seeks to help fill this gap in knowledge by examining correlates with physical activity among breast cancer survivors. Methods Overweight or obese breast cancer survivors (N=692) were examined at enrollment into a weight loss intervention study. Questionnaires and medical record review ascertained data on education, race, ethnicity, menopausal status, physical activity, and medical history. Measures of anthropometrics and fitness level were conducted. Regression analysis examined associations between physical activity and demographic, clinical, and lifestyle factors. Results Overall, 23% of women met current guidelines. Multivariate analysis revealed that body mass index (p=0.03), emergency room visits in the past year (p=0.04), and number of co-morbidities (p=0.02) were associated with less physical activity. Geographic region also was associated with level of physical activity (p=0.02), with women in Alabama reporting significantly less activity than those in other participating regions. Conclusions The majority of overweight/obese breast cancer survivors did not meet physical activity recommendations. Physical activity levels were associated with degree of adiposity, geographic location, and number of co-morbidities. The majority of overweight breast cancer survivors should be encouraged to increase their level of physical activity. Individualizing exercise prescriptions according to medical co-morbidities may improve adherence. PMID:25975675

  1. Barriers and facilitators for return to work in cancer survivors with job loss experience: a focus group study.

    PubMed

    van Egmond, M P; Duijts, S F A; Loyen, A; Vermeulen, S J; van der Beek, A J; Anema, J R

    2015-11-25

    Over 50% of cancer survivors lose their job or quit working. Cancer survivors who experience job loss may face different challenges regarding return to work, compared to cancer survivors with employers. This qualitative study aimed to explore barriers and facilitators for return to work in cancer survivors with job loss and in insurance physicians who assist cancer survivors in their return to work. We conducted five focus groups and one interview (cancer survivors, N = 17; insurance physicians, N = 23). Topics included, among others, experience of job loss and barriers and facilitators for return to work. Data were audio recorded and analysed using thematic analysis. Our main finding was that cancer survivors experienced a double loss: loss of job on top of loss of health. As a result, cancer survivors feared for job applications, lacked opportunities to gradually increase work ability, and faced reluctance from employers in hiring them. Insurance physicians expressed a need for more frequent and longer consultations with cancer survivors with job loss. We conclude that cancer survivors who experience double loss encounter specific barriers in the return to work process. This calls for a tailored approach regarding return to work support.

  2. Novel, gross chromosomal alterations involving PTEN cooperate with allelic loss in prostate cancer.

    PubMed

    Reid, Alison H M; Attard, Gerhardt; Brewer, Daniel; Miranda, Susana; Riisnaes, Ruth; Clark, Jeremy; Hylands, Lucy; Merson, Sue; Vergis, Roy; Jameson, Charles; Høyer, Søren; Sørenson, Karina Dalsgaard; Borre, Michael; Jones, Chris; de Bono, Johann S; Cooper, Colin S

    2012-06-01

    There is increasing evidence that multiple chromosomal rearrangements occur in prostate cancer. PTEN loss is considered to be a key event in prostate carcinogenesis but the mechanisms of loss remain to be fully elucidated. We hypothesised that gross rearrangements may exist that cause disruption of the PTEN gene in the absence of genomic deletion. We therefore designed a novel fluorescence in situ hybridisation (FISH) assay with probes overlying regions 3' and 5' of PTEN and a third probe overlying the gene. We aimed to identify both genomic deletions and gross rearrangements of PTEN that would be overlooked by previously reported single-probe FISH assays. We proceeded to evaluate a tissue microarray with radical prostatectomy and trans-urethral resection of the prostate specimens from 187 patients. We identified PTEN genomic loss in 45/150 (30%) radical prostatectomy patients and 16/37 (43%) trans-urethral resection of the prostate patients. Importantly, our assay detected novel chromosomal alterations in the PTEN gene (characterised by splitting of FISH signals) in 13 tumours (6.9% of all prostate cancers; 21% of PTEN-lost cancers). All PTEN-rearranged tumours had genomic loss at the other allele and had no expression of PTEN by immunohistochemistry. PTEN-rearranged tumours were significantly more likely to have an underlying ERG rearrangement. Our assay differentiated loss of the probe overlying PTEN in isolation or in combination with either one of or both the probes overlying the 3' and 5' regions. This gave an indication of the size of genomic loss and we observed considerable inter-tumoural heterogeneity in the extent of genomic loss in PTEN-lost tumours. In summary, gross rearrangements of the PTEN locus occur in prostate cancer and can be detected by a 'break-apart' FISH assay. This observation could explain the absence of PTEN protein expression in a subgroup of tumours previously classified as having heterozygous genomic loss using single

  3. Productivity Losses Associated with Head and Neck Cancer Using the Human Capital and Friction Cost Approaches.

    PubMed

    Pearce, Alison M; Hanly, Paul; Timmons, Aileen; Walsh, Paul M; O'Neill, Ciaran; O'Sullivan, Eleanor; Gooberman-Hill, Rachael; Thomas, Audrey Alforque; Gallagher, Pamela; Sharp, Linda

    2015-08-01

    Previous studies suggest that productivity losses associated with head and neck cancer (HNC) are higher than in other cancers. These studies have only assessed a single aspect of productivity loss, such as temporary absenteeism or premature mortality, and have only used the Human Capital Approach (HCA). The Friction Cost Approach (FCA) is increasingly recommended, although has not previously been used to assess lost production from HNC. The aim of this study was to estimate the lost productivity associated with HNC due to different types of absenteeism and premature mortality, using both the HCA and FCA. Survey data on employment status were collected from 251 HNC survivors in Ireland and combined with population-level survival estimates and national wage data. The cost of temporary and permanent time off work, reduced working hours and premature mortality using both the HCA and FCA were calculated. Estimated total productivity losses per employed person of working age were EUR253,800 using HCA and EUR6800 using FCA. The main driver of HCA costs was premature mortality (38% of total) while for FCA it was temporary time off (73% of total). The productivity losses associated with head and neck cancer are substantial, and return to work assistance could form an important part of rehabilitation. Use of both the HCA and FCA approaches allowed different drivers of productivity losses to be identified, due to the different assumptions of the two methods. For future estimates of productivity losses, the use of both approaches may be pragmatic.

  4. Hair Loss Induced by Chemotherapy: An Anthropological Study of Women, Cancer and Rehabilitation.

    PubMed

    Hansen, Helle Ploug

    2007-04-01

    Throughout history hair has universally been a powerful symbol of the relationship between individuals and society, denoting religious affiliation, and has acted as a symbol of the social, cultural and political status quo. Hair loss, which is often perceived as a loss of individuality and attractiveness, has been related to the absence of status in these areas. The impact of hair loss on women undergoing chemotherapy treatment for cancer has primarily been explored by health professionals focusing on its psychological effects. This paper looks at women's experiences with hair loss induced by chemotherapy in a Danish context. It draws on an ethnographic fieldwork study comprising participant observation at three residential cancer rehabilitation courses in Denmark, subsequent in-depth interviews with some of the women and examination of written sources. The women equated hair loss with the loss of womanhood, sickness and death, and used wigs and make-up to minimize these effects. The analysis demonstrates how the women's embodied experiences are pervaded by culturally embedded signs, and how cancer rehabilitation is less concerned with total recovery in the sense of 'being cured' than with normalizing and integrating the individual in personal and social contexts.

  5. Prediction of critical weight loss during radiation treatment in head and neck cancer patients is dependent on BMI.

    PubMed

    Lønbro, Simon; Petersen, Gry Bjerg; Andersen, Jens Rikardt; Johansen, Jørgen

    2016-05-01

    The aims of the present study were to explore pre-treatment predictors of weight loss during radiation treatment only in head and neck cancer (HNSCC) patients and investigate the weight loss in patients with or without a feeding tube. Retrospectively, weight change during curative radiotherapy was investigated in 476 consecutive HNSCC patients. Independent predictors were identified using multivariate regression analysis with weight loss below or above 5 % as the primary dependent variable. Baseline BMI, tumor site, and stage predicted weight loss above 5 %. The odds of weight loss above 5 % in patients with BMI >25 were 3.00 ± 0.64 times higher compared with patients with BMI <25 (p < 0.0001). Patients with pharyngeal, oral cavity, or supraglottic tumors had 3.12 ± 0.80 times higher odds of weight loss above 5 % compared with glottic cancer patients (p < 0.0001), and the odds were 1.68 ± 0.40 times higher in stage III-IV patients compared with stage I-II patients (p = 0.03). Seperate analyses revealed that tumor site and stage only predicted weight loss in patients with BMI >25 but not in patients with BMI <25. Patients receiving a feeding tube weighed less than patients without (73.8 vs 78.3 kg) and feeding tube reduced, but did not prevent, weight loss which averaged 6.7 ± 4.7 kg (7.4 ± 4.7 %) compared with 4.7 ± 5.9 kg (5.5 ± 6.0 %) in patients without a feeding tube (P < 0.0001). Pre-treatment BMI, tumor site and stage predicted weight loss above 5 % in HNSCC patients during radiotherapy. BMI should be considered when analyzing weight loss in HNSCC patients receiving curative radiotherapy.

  6. Molecular Subtyping of Serous Ovarian Tumors Reveals Multiple Connections to Intrinsic Breast Cancer Subtypes

    PubMed Central

    Jönsson, Jenny-Maria; Johansson, Ida; Dominguez-Valentin, Mev; Kimbung, Siker; Jönsson, Mats; Bonde, Jesper Hansen; Kannisto, Päivi; Måsbäck, Anna; Malander, Susanne; Nilbert, Mef; Hedenfalk, Ingrid

    2014-01-01

    Objective Transcriptional profiling of epithelial ovarian cancer has revealed molecular subtypes correlating to biological and clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and investigate similarities with the well-established intrinsic molecular subtypes of breast cancer. Methods Global gene expression profiling using Illumina's HT12 Bead Arrays was applied to 59 fresh-frozen serous ovarian malignant, benign and borderline tumors. Nearest centroid classification was performed applying previously published gene profiles for the ovarian and breast cancer subtypes. Correlations to gene expression modules representing key biological breast cancer features were also sought. Validation was performed using an independent, publicly available dataset. Results 5,944 genes were significantly differentially expressed between benign and malignant serous ovarian tumors, with cell cycle processes enriched in the malignant subgroup. Borderline tumors were split between the two clusters. Significant correlations between the malignant serous tumors and the highly aggressive ovarian cancer signatures, and the basal-like breast cancer subtype were found. The benign and borderline serous tumors together were significantly correlated to the normal-like breast cancer subtype and the ovarian cancer signature derived from borderline tumors. The borderline tumors in the study dataset, in addition, also correlated significantly to the luminal A breast cancer subtype. These findings remained when analyzed in an independent dataset, supporting links between the molecular subtypes of ovarian cancer and breast cancer beyond those recently acknowledged. Conclusions These data link the transcriptional profiles of serous ovarian cancer to the intrinsic molecular subtypes of breast cancer, in line with the shared clinical and molecular features between high-grade serous ovarian cancer and basal-like breast

  7. Molecular subtyping of serous ovarian tumors reveals multiple connections to intrinsic breast cancer subtypes.

    PubMed

    Jönsson, Jenny-Maria; Johansson, Ida; Dominguez-Valentin, Mev; Kimbung, Siker; Jönsson, Mats; Bonde, Jesper Hansen; Kannisto, Päivi; Måsbäck, Anna; Malander, Susanne; Nilbert, Mef; Hedenfalk, Ingrid

    2014-01-01

    Transcriptional profiling of epithelial ovarian cancer has revealed molecular subtypes correlating to biological and clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and investigate similarities with the well-established intrinsic molecular subtypes of breast cancer. Global gene expression profiling using Illumina's HT12 Bead Arrays was applied to 59 fresh-frozen serous ovarian malignant, benign and borderline tumors. Nearest centroid classification was performed applying previously published gene profiles for the ovarian and breast cancer subtypes. Correlations to gene expression modules representing key biological breast cancer features were also sought. Validation was performed using an independent, publicly available dataset. 5,944 genes were significantly differentially expressed between benign and malignant serous ovarian tumors, with cell cycle processes enriched in the malignant subgroup. Borderline tumors were split between the two clusters. Significant correlations between the malignant serous tumors and the highly aggressive ovarian cancer signatures, and the basal-like breast cancer subtype were found. The benign and borderline serous tumors together were significantly correlated to the normal-like breast cancer subtype and the ovarian cancer signature derived from borderline tumors. The borderline tumors in the study dataset, in addition, also correlated significantly to the luminal A breast cancer subtype. These findings remained when analyzed in an independent dataset, supporting links between the molecular subtypes of ovarian cancer and breast cancer beyond those recently acknowledged. These data link the transcriptional profiles of serous ovarian cancer to the intrinsic molecular subtypes of breast cancer, in line with the shared clinical and molecular features between high-grade serous ovarian cancer and basal-like breast cancer, and suggest that biomarkers and

  8. Cancer field effects in normal tissues revealed by Raman spectroscopy

    PubMed Central

    Lieber, Chad A.; Nethercott, Hubert E.; Kabeer, Mustafa H.

    2010-01-01

    It has been demonstrated that the presence of cancer results in detectable changes to uninvolved tissues, collectively termed cancer field effects (CFE). In this study, we directly assessed the ability of Raman microspectroscopy to detect CFE via in-vitro study of organotypic tissue rafts approximating human skin. Raman spectra were measured from both epidermis and dermis after transfer of the rafts to dishes containing adherent cultures of either normal human fibroblasts or fibrosarcoma (HT1080) cells. Principal components analyses allowed discrimination between the groups with 86% classification accuracy in the epidermis and 94% in the dermis. These results encourage further study to evaluate the Raman capacity for detecting CFE as a possible tool for noninvasive screening for tumor presence. PMID:21258523

  9. Investigation of seasonal melting of Greenland using GPS records reveals significant ice mass loss in 2010

    NASA Astrophysics Data System (ADS)

    Yang, Q.; Dixon, T.; Wdowinski, S.

    2011-12-01

    Greenland has experienced significant ice mass loss in the past decade. High-precision global positioning system (GPS) data from sites on the rocky margin of Greenland enable measurement of vertical motion of the coastal area, which is an indicator of nearby mass loss. In this study, seasonal melting variation of the Greenland ice sheet (GrIS) is investigated using GPS vertical displacement data. Using a cubic spline fitting model, we retrieve three variables of the seasonal melting pattern for GrIS from 1996 to 2010: date of the beginning and end of melt season, length of melt season, and amount of uplift in the melt season. Data from three long -term sites on the periphery of Greenland show anomalously large uplift in 2010, implying significant melting in 2010. Preliminary results also show an early onset of melting in 2010, about 8 days earlier than the 1996-2009 average. In 2010, Greenland experienced a warmer and drier winter as well as a very warm summer, which presumably contributed to the anomalous ice mass loss of 2010.

  10. Odor-Specific Loss of Smell Sensitivity with Age as Revealed by the Specific Sensitivity Test.

    PubMed

    Seow, Yi-Xin; Ong, Peter K C; Huang, Dejian

    2016-07-01

    The perception of odor mixtures plays an important role in human food intake, behavior, and emotions. Decline of smell acuity with normal aging could impact food perception and preferences at various ages. However, since the landmark Smell Survey by National Geographic, little has been elucidated on differences in the onset and extent of loss in olfactory sensitivity toward single odorants. Here, using the Specific Sensitivity test, we show the onset and extent of loss in both identification and detection thresholds of odorants with age are odorant-specific. Subjects of Chinese descent in Singapore (186 women, 95 men), aged 21-80 years, were assessed for olfactory sensitivity of 10 odorants from various odor groups. Notably, subjects in their 70s required 179 times concentration of rose-like odorant (2-phenylethanol) than subjects in the 20s, while thresholds for onion-like 2-methyloxolane-3-thiol only differed by 3 times between the age groups. In addition, identification rate for 2-phenylethanol was negatively correlated with age throughout adult life whereas mushroom-like oct-1-en-3-ol was equally identified by subjects across all ages. Our results demonstrated the girth of differentiated olfactory loss due to normal ageing, which potentially affect overall perception and preferences of odor mixtures with age. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  11. Characterization of Multiple Light Damage Paradigms Reveals Regional Differences in Photoreceptor Loss

    PubMed Central

    Thomas, Jennifer L.; Nelson, Craig M.; Luo, Xixia; Hyde, David R.; Thummel, Ryan

    2012-01-01

    Zebrafish provide an attractive model to study the retinal response to photoreceptor apoptosis due to its remarkable ability to spontaneously regenerate retinal neurons following damage. There are currently two widely used light-induced retinal degeneration models to damage photoreceptors in the adult zebrafish. One model uses constant bright light, whereas the other uses a short exposure to extremely intense ultraviolet light. Although both models are currently used, it is unclear whether they differ in regard to the extent of photoreceptor damage or the subsequent regeneration response. Here we report a thorough analysis of the photoreceptor damage and subsequent proliferation response elicited by each individual treatment, as well as by the concomitant use of both treatments. We show a differential loss of rod and cone photoreceptors with each treatment. Additionally, we show that the extent of proliferation observed in the retina directly correlates with the severity of photoreceptor loss. We also demonstrate that both the ventral and posterior regions of the retina are partially protected from light damage. Finally, we show that combining a short ultraviolet exposure followed by a constant bright light treatment largely eliminates the neuroprotected regions, resulting in widespread loss of rod and cone photoreceptors and a robust regenerative response throughout the retina. PMID:22425727

  12. Stable metal isotopes reveal copper accumulation and loss dynamics in the freshwater bivalve Corbucula

    USGS Publications Warehouse

    Croteau, M.-N.; Luoma, S.N.; Topping, B.R.; Lopez, C.B.

    2004-01-01

    Characterization of uptake and loss dynamics is critical to understanding risks associated with contaminant exposure in aquatic animals. Dynamics are especially important in addressing questions such as why coexisting species in nature accumulate different levels of a contaminant. Here we manipulated copper (Cu) stable isotopic ratios (as an alternative to radioisotopes) to describe for the first time Cu dynamics in a freshwater invertebrate, the bivalve Corbicula fluminea. In the laboratory, Corbicula uptake and loss rate constants were determined from an environmentally realistic waterborne exposure to 65Cu (5.7 ??g L-1). That is, we spiked deionized water with Cu that was 99.4% 65Cu. Net tracer uptake was detectable after 1 day and strongly evident after 4 days. Thus, short-term exposures necessary to determine uptake dynamics are feasible with stable isotopes of Cu. In Corbicula, 65Cu depuration was biphasic. An unusually low rate constant of loss (0.0038 d-1) characterized the slow component of efflux, explaining why Corbicula strongly accumulates copper in nature. We incorporated our estimates of rate constants for dissolved 65Cu uptake and physiological efflux into a bioaccumulation model and showed that dietary exposure to Cu is likely an important bioaccumulation pathway for Corbicula.

  13. Facial Paralysis and Hearing Loss: A Rare Manifestation of Prostate Cancer Metastases

    PubMed Central

    Saqib, Amina; Mohammad, Farhan; Raza, Muhammad R; Nalluri, Nikhil; Forte, Frank

    2017-01-01

    Dural prostate metastases (DPM) are a rare manifestation of metastatic prostate cancer seen in approximately one to six percent of cases. Presenting symptoms may include signs of elevated intracranial pressure, headache, altered mental status, or cranial nerve palsies. Hearing loss, sensory changes, dysarthria, and dysphagia are rare symptoms in DPM that were present in our patient. We present a case of a 58-year-old male with a known diagnosis of adenocarcinoma of the prostate presenting with symptoms of acute exacerbation of chronic obstructive pulmonary disease (COPD), sub-acute right-sided hearing loss, and right-sided facial paralysis. Over the course of hospitalization, his neurological symptoms worsened and he developed dysarthria, dysphagia, facial numbness, and worsening back pain. He also appeared more withdrawn and lethargic. The symptoms prompted a neurological evaluation and a magnetic resonance imaging (MRI) revealed multiple areas of bone marrow signal abnormality compatible with osseous metastatic disease. There was extensive smooth dural thickening as well as focal nodular thickening, both consistent with dural metastases. The patient was treated with corticosteroids and external beam radiation therapy (EBRT) with improvement in his back pain and facial paralysis. He died two weeks after completing EBRT. Although rare, DPM should be suspected in males over 50 years of age presenting with neurological symptoms. An MRI with gadolinium is most helpful in delineating the presence and extent of dural and calvarial involvement. Corticosteroids and EBRT have been shown to improve neurological function in up to 67% of patients. However, median survival post-radiation remains approximately three months. PMID:28409073

  14. Genome sequencing of Ewing sarcoma patients reveals genetic predisposition | Center for Cancer Research

    Cancer.gov

    The largest and most comprehensive genomic analysis of individuals with Ewing sarcoma performed to date reveals that some patients are genetically predisposed to developing the cancer.  Learn more...

  15. Donation frequency, iron loss, and risk of cancer among blood donors.

    PubMed

    Edgren, Gustaf; Reilly, Marie; Hjalgrim, Henrik; Tran, Trung Nam; Rostgaard, Klaus; Adami, Johanna; Titlestad, Kjell; Shanwell, Agneta; Melbye, Mads; Nyrén, Olof

    2008-04-16

    Long-term deleterious effects of repeated blood donations may be masked by the donors' healthy lifestyle. To investigate possible effects of blood donation and iron loss through blood donation on cancer incidence while minimizing "healthy donor effects," we made dose-response comparisons within a cohort of Swedish and Danish blood donors. We used a nested case-control study design, in which case patients were defined as all donors who were diagnosed with a malignancy between their first recorded blood donation and study termination (n = 10866). Control subjects (n = 107140) were individually matched on sex, age, and county of residence. Using conditional logistic regression, we estimated relative risks of cancer according to number of blood donations made or estimated iron loss 3-12 years before a case patient was diagnosed with cancer. All statistical tests were two-sided. No clear association was observed between number of donations and risk of cancer overall. However, between the lowest (< or = median, < 0.75 g) and highest (> 90th percentile, > 2.7 g) categories of estimated iron loss, there was a trend (P(trend) < .001) of decreasing risk for cancers of the liver, lung, colon, stomach, and esophagus, which are thought to be promoted by iron overload (combined odds ratio [OR] = 0.70, 95% confidence interval [CI] = 0.58 to 0.84), but only among men and only with a latency of 3-7 years. The risk of non-Hodgkin lymphoma was higher among frequent plasma donors (> 25 vs 0 donations, OR = 2.14, 95% CI = 1.22 to 3.74). Repeated blood donation was not associated with increased or decreased risk of cancer overall. The lack of consistency across latency periods casts doubt on an apparent association between reduced cancer risk and iron loss in men. The positive association between frequent plasma donation and risk of non-Hodgkin lymphoma deserves further exploration.

  16. Loss of c-KIT expression in thyroid cancer cells

    PubMed Central

    Panebianco, Federica; Tantillo, Elena; La Ferla, Marco; Menicagli, Michele; Aretini, Paolo; Apollo, Alessandro; Naccarato, Antonio Giuseppe; Marchetti, Ivo; Mazzanti, Chiara Maria

    2017-01-01

    Papillary thyroid carcinoma is the most frequent histologic type of thyroid tumor. Few studies investigated the role of c-KIT expression in thyroid tumors, suggesting a role for this receptor and its ligand in differentiation and growth control of thyroid epithelium and a receptor loss following malignant transformation. We investigated and correlated c-KIT expression levels and two known markers of thyrocytes differentiation, PAX8 and TTF-1, in malignant and benign cytological thyroid samples. Moreover, we performed functional studies on human papillary thyroid carcinoma cell line to associated c-KIT expression to thyrocytes differentiation and tumor proliferation. c-KIT and PAX8 expression resulted higher in benign samples compared to the malignant ones, and the expression levels of these two genes were significantly correlated to each other. We also observed that c-KIT overexpression led to an increase of PAX8 expression level together with a decrease of proliferation. Furthermore, c-KIT overexpressing cells showed a regression of typical morphological features of malignancy. Taken together these results suggest that c-KIT could be involved in the differentiation of thyroid cells and in tumor progression. PMID:28301608

  17. Loss of c-KIT expression in thyroid cancer cells.

    PubMed

    Franceschi, Sara; Lessi, Francesca; Panebianco, Federica; Tantillo, Elena; La Ferla, Marco; Menicagli, Michele; Aretini, Paolo; Apollo, Alessandro; Naccarato, Antonio Giuseppe; Marchetti, Ivo; Mazzanti, Chiara Maria

    2017-01-01

    Papillary thyroid carcinoma is the most frequent histologic type of thyroid tumor. Few studies investigated the role of c-KIT expression in thyroid tumors, suggesting a role for this receptor and its ligand in differentiation and growth control of thyroid epithelium and a receptor loss following malignant transformation. We investigated and correlated c-KIT expression levels and two known markers of thyrocytes differentiation, PAX8 and TTF-1, in malignant and benign cytological thyroid samples. Moreover, we performed functional studies on human papillary thyroid carcinoma cell line to associated c-KIT expression to thyrocytes differentiation and tumor proliferation. c-KIT and PAX8 expression resulted higher in benign samples compared to the malignant ones, and the expression levels of these two genes were significantly correlated to each other. We also observed that c-KIT overexpression led to an increase of PAX8 expression level together with a decrease of proliferation. Furthermore, c-KIT overexpressing cells showed a regression of typical morphological features of malignancy. Taken together these results suggest that c-KIT could be involved in the differentiation of thyroid cells and in tumor progression.

  18. [Responsibility for the loss of opportunity in malignant cancer care in the Spanish public healthcare system].

    PubMed

    Sardinero-García, Carlos; Santiago-Sáez, Andrés; Bravo, M Del Carmen; Perea-Pérez, Bernardo; Albarrán-Juan, M Elena; Labajo-González, Elena; Benito-León, Julián

    The loss of chance in healthcare has been forcibly introduced in the adjudications pronounced in recent years. Our objective was to analyse the verdicts of guilt resulting from the loss of chance ordered by the Contentious-Administrative Court (i.e., in the public healthcare system), in which both the origin of the disease to be treated and the sequelae were oncological processes. We analysed 137 cancer-related court judgments from the Contentious-Administrative Court, which referred to the concept of loss of chance, issued in Spain up to May 2014. Of the 137 sentences, 119 (86.9%), were pronounced due to diagnostic error and 14 (10.2%) due to inadequate treatment. Since 2010, 100 sentences have been passed (73.0%), representing an increase of more than 170% with respect to the 37 (27.0%) ordered in the first six years of the study (from 2004 to 2009). Most of the patients (68.6%) died, predominantly from breast cancer and gynaecological cancer (24.1%), and gastrointestinal cancers (21.1%). These malignancies were the ones most often involved in the sentences. The litigant activity due to loss of chance in oncological processes in the public health care has significantly increased in the last years. The judgments were mainly given because of diagnostic error or inadequate treatment. Copyright © 2016 SESPAS. Publicado por Elsevier España, S.L.U. All rights reserved.

  19. Behavioral manifestations of audiometrically-defined "slight" or "hidden" hearing loss revealed by measures of binaural detection.

    PubMed

    Bernstein, Leslie R; Trahiotis, Constantine

    2016-11-01

    This study assessed whether audiometrically-defined "slight" or "hidden" hearing losses might be associated with degradations in binaural processing as measured in binaural detection experiments employing interaurally delayed signals and maskers. Thirty-one listeners participated, all having no greater than slight hearing losses (i.e., no thresholds greater than 25 dB HL). Across the 31 listeners and consistent with the findings of Bernstein and Trahiotis [(2015). J. Acoust. Soc. Am. 138, EL474-EL479] binaural detection thresholds at 500 Hz and 4 kHz increased with increasing magnitude of interaural delay, suggesting a loss of precision of coding with magnitude of interaural delay. Binaural detection thresholds were consistently found to be elevated for listeners whose absolute thresholds at 4 kHz exceeded 7.5 dB HL. No such elevations were observed in conditions having no binaural cues available to aid detection (i.e., "monaural" conditions). Partitioning and analyses of the data revealed that those elevated thresholds (1) were more attributable to hearing level than to age and (2) result from increased levels of internal noise. The data suggest that listeners whose high-frequency monaural hearing status would be classified audiometrically as being normal or "slight loss" may exhibit substantial and perceptually meaningful losses of binaural processing.

  20. Citrus unshiu peel extract alleviates cancer-induced weight loss in mice bearing CT-26 adenocarcinoma

    PubMed Central

    Kim, Aeyung; Im, Minju; Gu, Min Jung; Ma, Jin Yeul

    2016-01-01

    Skeletal muscle atrophy is a critical feature of cancer-induced cachexia, caused by pro-cachectic factors secreted by host cells and tumor cells. Therefore, blockade of these factors has considered a reasonable target for pharmacological and nutritional interventions to prevent skeletal muscle loss under cancer-induced cachexia. Citrus unshiu peel (CUP) has been used for treating the common cold, dyspepsia, and bronchial discomfort and reported to have pharmacological activities against inflammation, allergy, diabetes, and viral infection. In the present study, we observed that daily oral administration of water extract of CUP (WCUP) to male BALB/c mice bearing CT-26 adenocarcinoma remarkably reduced the losses in final body weight, carcass weight, gastrocnemius muscle, epididymal adipose tissue, and hemoglobin (Hb), compared with saline treatment. The levels of serum IL-6 and muscle-specific E3 ligases elevated by tumor burden were also considerably reduced by WCUP administration. In an in vitro experiment, WCUP efficiently suppressed the production of pro-cachectic cytokines in immune cells as well as cancer cells. In addition, WCUP treatment attenuated C2C12 skeletal muscle cell atrophy caused by cancer cells. These findings collectively suggest that WCUP is beneficial as a nutritional supplement for the management of cancer patients with severe weight loss. PMID:27064118

  1. Citrus unshiu peel extract alleviates cancer-induced weight loss in mice bearing CT-26 adenocarcinoma.

    PubMed

    Kim, Aeyung; Im, Minju; Gu, Min Jung; Ma, Jin Yeul

    2016-04-11

    Skeletal muscle atrophy is a critical feature of cancer-induced cachexia, caused by pro-cachectic factors secreted by host cells and tumor cells. Therefore, blockade of these factors has considered a reasonable target for pharmacological and nutritional interventions to prevent skeletal muscle loss under cancer-induced cachexia. Citrus unshiu peel (CUP) has been used for treating the common cold, dyspepsia, and bronchial discomfort and reported to have pharmacological activities against inflammation, allergy, diabetes, and viral infection. In the present study, we observed that daily oral administration of water extract of CUP (WCUP) to male BALB/c mice bearing CT-26 adenocarcinoma remarkably reduced the losses in final body weight, carcass weight, gastrocnemius muscle, epididymal adipose tissue, and hemoglobin (Hb), compared with saline treatment. The levels of serum IL-6 and muscle-specific E3 ligases elevated by tumor burden were also considerably reduced by WCUP administration. In an in vitro experiment, WCUP efficiently suppressed the production of pro-cachectic cytokines in immune cells as well as cancer cells. In addition, WCUP treatment attenuated C2C12 skeletal muscle cell atrophy caused by cancer cells. These findings collectively suggest that WCUP is beneficial as a nutritional supplement for the management of cancer patients with severe weight loss.

  2. Proteogenomic integration reveals therapeutic targets in breast cancer xenografts

    PubMed Central

    Huang, Kuan-lin; Li, Shunqiang; Mertins, Philipp; Cao, Song; Gunawardena, Harsha P.; Ruggles, Kelly V.; Mani, D. R.; Clauser, Karl R.; Tanioka, Maki; Usary, Jerry; Kavuri, Shyam M.; Xie, Ling; Yoon, Christopher; Qiao, Jana W; Wrobel, John; Wyczalkowski, Matthew A.; Erdmann-Gilmore, Petra; Snider, Jacqueline E.; Hoog, Jeremy; Singh, Purba; Niu, Beifung; Guo, Zhanfang; Sun, Sam Qiancheng; Sanati, Souzan; Kawaler, Emily; Wang, Xuya; Scott, Adam; Ye, Kai; McLellan, Michael D.; Wendl, Michael C.; Malovannaya, Anna; Held, Jason M.; Gillette, Michael A.; Fenyö, David; Kinsinger, Christopher R.; Mesri, Mehdi; Rodriguez, Henry; Davies, Sherri R.; Perou, Charles M.; Ma, Cynthia; Reid Townsend, R.; Chen, Xian; Carr, Steven A.; Ellis, Matthew J.; Ding, Li

    2017-01-01

    Recent advances in mass spectrometry (MS) have enabled extensive analysis of cancer proteomes. Here, we employed quantitative proteomics to profile protein expression across 24 breast cancer patient-derived xenograft (PDX) models. Integrated proteogenomic analysis shows positive correlation between expression measurements from transcriptomic and proteomic analyses; further, gene expression-based intrinsic subtypes are largely re-capitulated using non-stromal protein markers. Proteogenomic analysis also validates a number of predicted genomic targets in multiple receptor tyrosine kinases. However, several protein/phosphoprotein events such as overexpression of AKT proteins and ARAF, BRAF, HSP90AB1 phosphosites are not readily explainable by genomic analysis, suggesting that druggable translational and/or post-translational regulatory events may be uniquely diagnosed by MS. Drug treatment experiments targeting HER2 and components of the PI3K pathway supported proteogenomic response predictions in seven xenograft models. Our study demonstrates that MS-based proteomics can identify therapeutic targets and highlights the potential of PDX drug response evaluation to annotate MS-based pathway activities. PMID:28348404

  3. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

    PubMed

    Biankin, Andrew V; Waddell, Nicola; Kassahn, Karin S; Gingras, Marie-Claude; Muthuswamy, Lakshmi B; Johns, Amber L; Miller, David K; Wilson, Peter J; Patch, Ann-Marie; Wu, Jianmin; Chang, David K; Cowley, Mark J; Gardiner, Brooke B; Song, Sarah; Harliwong, Ivon; Idrisoglu, Senel; Nourse, Craig; Nourbakhsh, Ehsan; Manning, Suzanne; Wani, Shivangi; Gongora, Milena; Pajic, Marina; Scarlett, Christopher J; Gill, Anthony J; Pinho, Andreia V; Rooman, Ilse; Anderson, Matthew; Holmes, Oliver; Leonard, Conrad; Taylor, Darrin; Wood, Scott; Xu, Qinying; Nones, Katia; Fink, J Lynn; Christ, Angelika; Bruxner, Tim; Cloonan, Nicole; Kolle, Gabriel; Newell, Felicity; Pinese, Mark; Mead, R Scott; Humphris, Jeremy L; Kaplan, Warren; Jones, Marc D; Colvin, Emily K; Nagrial, Adnan M; Humphrey, Emily S; Chou, Angela; Chin, Venessa T; Chantrill, Lorraine A; Mawson, Amanda; Samra, Jaswinder S; Kench, James G; Lovell, Jessica A; Daly, Roger J; Merrett, Neil D; Toon, Christopher; Epari, Krishna; Nguyen, Nam Q; Barbour, Andrew; Zeps, Nikolajs; Kakkar, Nipun; Zhao, Fengmei; Wu, Yuan Qing; Wang, Min; Muzny, Donna M; Fisher, William E; Brunicardi, F Charles; Hodges, Sally E; Reid, Jeffrey G; Drummond, Jennifer; Chang, Kyle; Han, Yi; Lewis, Lora R; Dinh, Huyen; Buhay, Christian J; Beck, Timothy; Timms, Lee; Sam, Michelle; Begley, Kimberly; Brown, Andrew; Pai, Deepa; Panchal, Ami; Buchner, Nicholas; De Borja, Richard; Denroche, Robert E; Yung, Christina K; Serra, Stefano; Onetto, Nicole; Mukhopadhyay, Debabrata; Tsao, Ming-Sound; Shaw, Patricia A; Petersen, Gloria M; Gallinger, Steven; Hruban, Ralph H; Maitra, Anirban; Iacobuzio-Donahue, Christine A; Schulick, Richard D; Wolfgang, Christopher L; Morgan, Richard A; Lawlor, Rita T; Capelli, Paola; Corbo, Vincenzo; Scardoni, Maria; Tortora, Giampaolo; Tempero, Margaret A; Mann, Karen M; Jenkins, Nancy A; Perez-Mancera, Pedro A; Adams, David J; Largaespada, David A; Wessels, Lodewyk F A; Rust, Alistair G; Stein, Lincoln D; Tuveson, David A; Copeland, Neal G; Musgrove, Elizabeth A; Scarpa, Aldo; Eshleman, James R; Hudson, Thomas J; Sutherland, Robert L; Wheeler, David A; Pearson, John V; McPherson, John D; Gibbs, Richard A; Grimmond, Sean M

    2012-11-15

    Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

  4. Sleeping Beauty screen reveals Pparg activation in metastatic prostate cancer.

    PubMed

    Ahmad, Imran; Mui, Ernest; Galbraith, Laura; Patel, Rachana; Tan, Ee Hong; Salji, Mark; Rust, Alistair G; Repiscak, Peter; Hedley, Ann; Markert, Elke; Loveridge, Carolyn; van der Weyden, Louise; Edwards, Joanne; Sansom, Owen J; Adams, David J; Leung, Hing Y

    2016-07-19

    Prostate cancer (CaP) is the most common adult male cancer in the developed world. The paucity of biomarkers to predict prostate tumor biology makes it important to identify key pathways that confer poor prognosis and guide potential targeted therapy. Using a murine forward mutagenesis screen in a Pten-null background, we identified peroxisome proliferator-activated receptor gamma (Pparg), encoding a ligand-activated transcription factor, as a promoter of metastatic CaP through activation of lipid signaling pathways, including up-regulation of lipid synthesis enzymes [fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), ATP citrate lyase (ACLY)]. Importantly, inhibition of PPARG suppressed tumor growth in vivo, with down-regulation of the lipid synthesis program. We show that elevated levels of PPARG strongly correlate with elevation of FASN in human CaP and that high levels of PPARG/FASN and PI3K/pAKT pathway activation confer a poor prognosis. These data suggest that CaP patients could be stratified in terms of PPARG/FASN and PTEN levels to identify patients with aggressive CaP who may respond favorably to PPARG/FASN inhibition.

  5. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

    PubMed Central

    Biankin, Andrew V.; Waddell, Nicola; Kassahn, Karin S.; Gingras, Marie-Claude; Muthuswamy, Lakshmi B.; Johns, Amber L.; Miller, David K.; Wilson, Peter J.; Patch, Ann-Marie; Wu, Jianmin; Chang, David K.; Cowley, Mark J.; Gardiner, Brooke B.; Song, Sarah; Harliwong, Ivon; Idrisoglu, Senel; Nourse, Craig; Nourbakhsh, Ehsan; Manning, Suzanne; Wani, Shivangi; Gongora, Milena; Pajic, Marina; Scarlett, Christopher J.; Gill, Anthony J.; Pinho, Andreia V.; Rooman, Ilse; Anderson, Matthew; Holmes, Oliver; Leonard, Conrad; Taylor, Darrin; Wood, Scott; Xu, Qinying; Nones, Katia; Fink, J. Lynn; Christ, Angelika; Bruxner, Tim; Cloonan, Nicole; Kolle, Gabriel; Newell, Felicity; Pinese, Mark; Mead, R. Scott; Humphris, Jeremy L.; Kaplan, Warren; Jones, Marc D.; Colvin, Emily K.; Nagrial, Adnan M.; Humphrey, Emily S.; Chou, Angela; Chin, Venessa T.; Chantrill, Lorraine A.; Mawson, Amanda; Samra, Jaswinder S.; Kench, James G.; Lovell, Jessica A.; Daly, Roger J.; Merrett, Neil D.; Toon, Christopher; Epari, Krishna; Nguyen, Nam Q.; Barbour, Andrew; Zeps, Nikolajs; Kakkar, Nipun; Zhao, Fengmei; Wu, Yuan Qing; Wang, Min; Muzny, Donna M.; Fisher, William E.; Brunicardi, F. Charles; Hodges, Sally E.; Reid, Jeffrey G.; Drummond, Jennifer; Chang, Kyle; Han, Yi; Lewis, Lora R.; Dinh, Huyen; Buhay, Christian J.; Beck, Timothy; Timms, Lee; Sam, Michelle; Begley, Kimberly; Brown, Andrew; Pai, Deepa; Panchal, Ami; Buchner, Nicholas; De Borja, Richard; Denroche, Robert E.; Yung, Christina K.; Serra, Stefano; Onetto, Nicole; Mukhopadhyay, Debabrata; Tsao, Ming-Sound; Shaw, Patricia A.; Petersen, Gloria M.; Gallinger, Steven; Hruban, Ralph H.; Maitra, Anirban; Iacobuzio-Donahue, Christine A.; Schulick, Richard D.; Wolfgang, Christopher L.; Morgan, Richard A.; Lawlor, Rita T.; Capelli, Paola; Corbo, Vincenzo; Scardoni, Maria; Tortora, Giampaolo; Tempero, Margaret A.; Mann, Karen M.; Jenkins, Nancy A.; Perez-Mancera, Pedro A.; Adams, David J.; Largaespada, David A.; Wessels, Lodewyk F. A.; Rust, Alistair G.; Stein, Lincoln D.; Tuveson, David A.; Copeland, Neal G.; Musgrove, Elizabeth A.; Scarpa, Aldo; Eshleman, James R.; Hudson, Thomas J.; Sutherland, Robert L.; Wheeler, David A.; Pearson, John V.; McPherson, John D.; Gibbs, Richard A.; Grimmond, Sean M.

    2012-01-01

    Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis. PMID:23103869

  6. Sleeping Beauty screen reveals Pparg activation in metastatic prostate cancer

    PubMed Central

    Ahmad, Imran; Mui, Ernest; Galbraith, Laura; Patel, Rachana; Tan, Ee Hong; Salji, Mark; Rust, Alistair G.; Repiscak, Peter; Hedley, Ann; Markert, Elke; Loveridge, Carolyn; van der Weyden, Louise; Edwards, Joanne; Sansom, Owen J.; Adams, David J.; Leung, Hing Y.

    2016-01-01

    Prostate cancer (CaP) is the most common adult male cancer in the developed world. The paucity of biomarkers to predict prostate tumor biology makes it important to identify key pathways that confer poor prognosis and guide potential targeted therapy. Using a murine forward mutagenesis screen in a Pten-null background, we identified peroxisome proliferator-activated receptor gamma (Pparg), encoding a ligand-activated transcription factor, as a promoter of metastatic CaP through activation of lipid signaling pathways, including up-regulation of lipid synthesis enzymes [fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), ATP citrate lyase (ACLY)]. Importantly, inhibition of PPARG suppressed tumor growth in vivo, with down-regulation of the lipid synthesis program. We show that elevated levels of PPARG strongly correlate with elevation of FASN in human CaP and that high levels of PPARG/FASN and PI3K/pAKT pathway activation confer a poor prognosis. These data suggest that CaP patients could be stratified in terms of PPARG/FASN and PTEN levels to identify patients with aggressive CaP who may respond favorably to PPARG/FASN inhibition. PMID:27357679

  7. Loss of heterozygosity and homozygous deletion of the tpr locus in human gastric cancer.

    PubMed

    Cunningham, J D; Schwartz, G K; Karpeh, M; Blundell, M; Kelson, D P; Jhanwar, S C; Albino, A P

    1997-06-01

    Despite being one of the world's most common neoplasias, there is little information on the molecular events that lead to gastric cancer. Molecular studies have shown that inactivation of tumor suppressor genes by mutation and/or allelic loss is an important genetic alteration in the multistep process of tumorigenesis. In an attempt to identify a putative tumor suppressor gene involved in the carcinogenesis of gastric cancer, we performed Southern blot analysis using the tpr probe for 44 patients with gastric cancer, using tumor tissue and normal tissue from the same specimen. Of the 44 samples, 7 (16%) were informative, heterozygous cases for the tpr probe. Three of the informative cases showed a loss of heterozygosity and 3 cases showed homozygous deletion for the tpr probe (6 of 7; 85%). These findings suggest that tpr gene plays a role in gastric tumorigenesis, and this may be due to a tumor suppressor effect for the tpr gene.

  8. HER2 overcomes PTEN (loss)-induced senescence to cause aggressive prostate cancer

    PubMed Central

    Ahmad, Imran; Patel, Rachana; Singh, Lukram Babloo; Nixon, Colin; Seywright, Morag; Barnetson, Robert J.; Brunton, Valerie G.; Muller, William J.; Edwards, Joanne; Sansom, Owen J.; Leung, Hing Y.

    2011-01-01

    Prostate cancer (CaP) is the most common cancer among adult men in the Western world. Better insight into its tumor-activating pathways may facilitate the development of targeted therapies. In this study, we show that patients who develop prostate tumors with low levels of PTEN and high levels of HER2/3 have a poor prognosis. This is functionally relevant, as targeting Her2 activation to the murine prostate cooperates with Pten loss and drives CaP progression. Mechanistically, this is associated with activation of the MAPK pathway and abrogation of the Pten loss-induced cellular senescence program. Importantly, inhibition of MEK function strongly suppressed proliferation within these tumors by restoring the Pten loss-induced cellular senescence program. Taken together, these data suggest that stratification of CaP patients for HER2/3 and PTEN status could identify patients with aggressive CaP who may respond favorably to MEK inhibition. PMID:21930937

  9. Cancer and Chemotherapy Contribute to Muscle Loss by Activating Common Signaling Pathways

    PubMed Central

    Barreto, Rafael; Mandili, Giorgia; Witzmann, Frank A.; Novelli, Francesco; Zimmers, Teresa A.; Bonetto, Andrea

    2016-01-01

    Cachexia represents one of the primary complications of colorectal cancer due to its effects on depletion of muscle and fat. Evidence suggests that chemotherapeutic regimens, such as Folfiri, contribute to cachexia-related symptoms. The purpose of the present study was to investigate the cachexia signature in different conditions associated with severe muscle wasting, namely Colon-26 (C26) and Folfiri-associated cachexia. Using a quantitative LC-MS/MS approach, we identified significant changes in 386 proteins in the quadriceps muscle of Folfiri-treated mice, and 269 proteins differentially expressed in the C26 hosts (p < 0.05; −1.5 ≥ fold change ≥ +1.5). Comparative analysis isolated 240 proteins that were modulated in common, with a large majority (218) that were down-regulated in both experimental settings. Interestingly, metabolic (47.08%) and structural (21.25%) proteins were the most represented. Pathway analysis revealed mitochondrial dysfunctions in both experimental conditions, also consistent with reduced expression of mediators of mitochondrial fusion (OPA-1, mitofusin-2), fission (DRP-1) and biogenesis (Cytochrome C, PGC-1α). Alterations of oxidative phosphorylation within the TCA cycle, fatty acid metabolism, and Ca2+ signaling were also detected. Overall, the proteomic signature in the presence of both chemotherapy and cancer suggests the activation of mechanisms associated with movement disorders, necrosis, muscle cell death, muscle weakness and muscle damage. Conversely, this is consistent with the inhibition of pathways that regulate nucleotide and fatty acid metabolism, synthesis of ATP, muscle and heart function, as well as ROS scavenging. Interestingly, strong up-regulation of pro-inflammatory acute-phase proteins and a more coordinated modulation of mitochondrial and lipidic metabolisms were observed in the muscle of the C26 hosts that were different from the Folfiri-treated animals. In conclusion, our results suggest that both cancer

  10. Ancient DNA reveals Holocene loss of genetic diversity in a South American rodent.

    PubMed

    Chan, Yvonne L; Lacey, Eileen A; Pearson, Oliver P; Hadly, Elizabeth A

    2005-12-22

    Understanding how animal populations have evolved in response to palaeoenvironmental conditions is essential for predicting the impact of future environmental change on current biodiversity. Analyses of ancient DNA provide a unique opportunity to track population responses to prehistoric environments. We explored the effects of palaeoenvironmental change on the colonial tuco-tuco (Ctenomys sociabilis), a highly endemic species of Patagonian rodent that is currently listed as threatened by the IUCN. By combining surveys of modern genetic variation from throughout this species' current geographic range with analyses of DNA samples from fossil material dating back to 10,000 ybp, we demonstrate a striking decline in genetic diversity that is concordant with environmental events in the study region. Our results highlight the importance of non-anthropogenic factors in loss of diversity, including reductions in smaller mammals such as rodents.

  11. Intravital imaging reveals new ancillary mechanisms co-opted by cancer cells to drive tumor progression

    PubMed Central

    Lucas, Morghan C.; Timpson, Paul

    2016-01-01

    Intravital imaging is providing new insights into the dynamics of tumor progression in native tissues and has started to reveal the layers of complexity found in cancer. Recent advances in intravital imaging have allowed us to look deeper into cancer behavior and to dissect the interactions between tumor cells and the ancillary host niche that promote cancer development. In this review, we provide an insight into the latest advances in cancer biology achieved by intravital imaging, focusing on recently discovered mechanisms by which tumor cells manipulate normal tissue to facilitate disease progression. PMID:27239290

  12. Regional drivers of clutch loss reveal important trade-offs for beach-nesting birds

    PubMed Central

    Schlacher, Thomas A.; Weston, Michael A.; Huijbers, Chantal M.; Anderson, Chris; Gilby, Ben L.; Olds, Andrew D.; Connolly, Rod M.; Schoeman, David S.

    2016-01-01

    Coastal birds are critical ecosystem constituents on sandy shores, yet are threatened by depressed reproductive success resulting from direct and indirect anthropogenic and natural pressures. Few studies examine clutch fate across the wide range of environments experienced by birds; instead, most focus at the small site scale. We examine survival of model shorebird clutches as an index of true clutch survival at a regional scale (∼200 km), encompassing a variety of geomorphologies, predator communities, and human use regimes in southeast Queensland, Australia. Of the 132 model nests deployed and monitored with cameras, 45 (34%) survived the experimental exposure period. Thirty-five (27%) were lost to flooding, 32 (24%) were depredated, nine (7%) buried by sand, seven (5%) destroyed by people, three (2%) failed by unknown causes, and one (1%) was destroyed by a dog. Clutch fate differed substantially among regions, particularly with respect to losses from flooding and predation. ‘Topographic’ exposure was the main driver of mortality of nests placed close to the drift line near the base of dunes, which were lost to waves (particularly during storms) and to a lesser extent depredation. Predators determined the fate of clutches not lost to waves, with the depredation probability largely influenced by region. Depredation probability declined as nests were backed by higher dunes and were placed closer to vegetation. This study emphasizes the scale at which clutch fate and survival varies within a regional context, the prominence of corvids as egg predators, the significant role of flooding as a source of nest loss, and the multiple trade-offs faced by beach-nesting birds and those that manage them. PMID:27672510

  13. Regional drivers of clutch loss reveal important trade-offs for beach-nesting birds.

    PubMed

    Maslo, Brooke; Schlacher, Thomas A; Weston, Michael A; Huijbers, Chantal M; Anderson, Chris; Gilby, Ben L; Olds, Andrew D; Connolly, Rod M; Schoeman, David S

    2016-01-01

    Coastal birds are critical ecosystem constituents on sandy shores, yet are threatened by depressed reproductive success resulting from direct and indirect anthropogenic and natural pressures. Few studies examine clutch fate across the wide range of environments experienced by birds; instead, most focus at the small site scale. We examine survival of model shorebird clutches as an index of true clutch survival at a regional scale (∼200 km), encompassing a variety of geomorphologies, predator communities, and human use regimes in southeast Queensland, Australia. Of the 132 model nests deployed and monitored with cameras, 45 (34%) survived the experimental exposure period. Thirty-five (27%) were lost to flooding, 32 (24%) were depredated, nine (7%) buried by sand, seven (5%) destroyed by people, three (2%) failed by unknown causes, and one (1%) was destroyed by a dog. Clutch fate differed substantially among regions, particularly with respect to losses from flooding and predation. 'Topographic' exposure was the main driver of mortality of nests placed close to the drift line near the base of dunes, which were lost to waves (particularly during storms) and to a lesser extent depredation. Predators determined the fate of clutches not lost to waves, with the depredation probability largely influenced by region. Depredation probability declined as nests were backed by higher dunes and were placed closer to vegetation. This study emphasizes the scale at which clutch fate and survival varies within a regional context, the prominence of corvids as egg predators, the significant role of flooding as a source of nest loss, and the multiple trade-offs faced by beach-nesting birds and those that manage them.

  14. Quantitative Chemical Proteomics Reveals New Potential Drug Targets in Head and Neck Cancer*

    PubMed Central

    Wu, Zhixiang; Doondeea, Jessica B.; Gholami, Amin Moghaddas; Janning, Melanie C.; Lemeer, Simone; Kramer, Karl; Eccles, Suzanne A.; Gollin, Susanne M.; Grenman, Reidar; Walch, Axel; Feller, Stephan M.; Kuster, Bernhard

    2011-01-01

    Tumors of the head and neck represent a molecularly diverse set of human cancers, but relatively few proteins have actually been shown to drive the disease at the molecular level. To identify new targets for individualized diagnosis or therapeutic intervention, we performed a kinase centric chemical proteomics screen and quantified 146 kinases across 34 head and neck squamous cell carcinoma (HNSCC) cell lines using intensity-based label-free mass spectrometry. Statistical analysis of the profiles revealed significant intercell line differences for 42 kinases (p < 0.05), and loss of function experiments using siRNA in high and low expressing cell lines identified kinases including EGFR, NEK9, LYN, JAK1, WEE1, and EPHA2 involved in cell survival and proliferation. EGFR inhibition by the small molecule inhibitors lapatinib, gefitinib, and erlotinib as well as siRNA led to strong reduction of viability in high but not low expressing lines, confirming EGFR as a drug target in 10–20% of HNSCC cell lines. Similarly, high, but not low EPHA2-expressing cells showed strongly reduced viability concomitant with down-regulation of AKT and ERK signaling following EPHA2 siRNA treatment or EPHA1-Fc ligand exposure, suggesting that EPHA2 is a novel drug target in HNSCC. This notion is underscored by immunohistochemical analyses showing that high EPHA2 expression is detected in a subset of HNSCC tissues and is associated with poor prognosis. Given that the approved pan-SRC family kinase inhibitor dasatinib is also a very potent inhibitor of EPHA2, our findings may lead to new therapeutic options for HNSCC patients. Importantly, the strategy employed in this study is generic and therefore also of more general utility for the identification of novel drug targets and molecular pathway markers in tumors. This may ultimately lead to a more rational approach to individualized cancer diagnosis and therapy. PMID:21955398

  15. Mutational profiling of familial male breast cancers reveals similarities with luminal A female breast cancer with rare TP53 mutations.

    PubMed

    Deb, S; Wong, S Q; Li, J; Do, H; Weiss, J; Byrne, D; Chakrabarti, A; Bosma, T; Fellowes, A; Dobrovic, A; Fox, S B

    2014-12-09

    Male breast cancer (MBC) is still poorly understood with a large proportion arising in families with a history of breast cancer. Genomic studies have focused on germline determinants of MBC risk, with minimal knowledge of somatic changes in these cancers. Using a TruSeq amplicon cancer panel, this study evaluated 48 familial MBCs (3 BRCA1 germline mutant, 17 BRCA2 germline mutant and 28 BRCAX) for hotspot somatic mutations and copy number changes in 48 common cancer genes. Twelve missense mutations included nine PIK3CA mutations (seven in BRCAX patients), two TP53 mutations (both in BRCA2 patients) and one PTEN mutation. Common gains were seen in GNAS (34.1%) and losses were seen in GNAQ (36.4%), ABL1 (47.7%) and ATM (34.1%). Gains of HRAS (37.5% vs 3%, P=0.006), STK11 (25.0% vs 0%, P=0.01) and SMARCB1 (18.8% vs 0%, P=0.04) and the loss of RB1 (43.8% vs 13%, P=0.03) were specific to BRCA2 tumours. This study is the first to perform high-throughput somatic sequencing on familial MBCs. Overall, PIK3CA mutations are most commonly seen, with fewer TP53 and PTEN mutations, similar to the profile seen in luminal A female breast cancers. Differences in mutation profiles and patterns of gene gains/losses are seen between BRCA2 (associated with TP53/PTEN mutations, loss of RB1 and gain of HRAS, STK11 and SMARCB1) and BRCAX (associated with PIK3CA mutations) tumours, suggesting that BRCA2 and BRCAX MBCs may be distinct and arise from different tumour pathways. This has implications on potential therapies, depending on the BRCA status of MBC patients.

  16. Contribution of macrophages in the contrast loss in iron oxide-based MRI cancer cell tracking studies

    PubMed Central

    Danhier, Pierre; Deumer, Gladys; Joudiou, Nicolas; Bouzin, Caroline; Levêque, Philippe; Haufroid, Vincent; Jordan, Bénédicte F.; Feron, Olivier; Sonveaux, Pierre; Gallez, Bernard

    2017-01-01

    Magnetic resonance imaging (MRI) cell tracking of cancer cells labeled with superparamagnetic iron oxides (SPIO) allows visualizing metastatic cells in preclinical models. However, previous works showed that the signal void induced by SPIO on T2(*)-weighted images decreased over time. Here, we aim at characterizing the fate of iron oxide nanoparticles used in cell tracking studies and the role of macrophages in SPIO metabolism. In vivo MRI cell tracking of SPIO positive 4T1 breast cancer cells revealed a quick loss of T2* contrast after injection. We next took advantage of electron paramagnetic resonance (EPR) spectroscopy and inductively coupled plasma mass spectroscopy (ICP-MS) for characterizing the evolution of superparamagnetic and non-superparamagnetic iron pools in 4T1 breast cancer cells and J774 macrophages after SPIO labeling. These in vitro experiments and histology studies performed on 4T1 tumors highlighted the quick degradation of iron oxides by macrophages in SPIO-based cell tracking experiments. In conclusion, the release of SPIO by dying cancer cells and the subsequent uptake of iron oxides by tumor macrophages are limiting factors in MRI cell tracking experiments that plead for the use of (MR) reporter-gene based imaging methods for the long-term tracking of metastatic cells. PMID:28467814

  17. TUSC3 Loss Alters the ER Stress Response and Accelerates Prostate Cancer Growth in vivo

    NASA Astrophysics Data System (ADS)

    Horak, Peter; Tomasich, Erwin; Vaňhara, Petr; Kratochvílová, Kateřina; Anees, Mariam; Marhold, Maximilian; Lemberger, Christof E.; Gerschpacher, Marion; Horvat, Reinhard; Sibilia, Maria; Pils, Dietmar; Krainer, Michael

    2014-01-01

    Prostate cancer is the most prevalent cancer in males in developed countries. Tumor suppressor candidate 3 (TUSC3) has been identified as a putative tumor suppressor gene in prostate cancer, though its function has not been characterized. TUSC3 shares homologies with the yeast oligosaccharyltransferase (OST) complex subunit Ost3p, suggesting a role in protein glycosylation. We provide evidence that TUSC3 is part of the OST complex and affects N-linked glycosylation in mammalian cells. Loss of TUSC3 expression in DU145 and PC3 prostate cancer cell lines leads to increased proliferation, migration and invasion as well as accelerated xenograft growth in a PTEN negative background. TUSC3 downregulation also affects endoplasmic reticulum (ER) structure and stress response, which results in increased Akt signaling. Together, our findings provide first mechanistic insight in TUSC3 function in prostate carcinogenesis in general and N-glycosylation in particular.

  18. TUSC3 Loss Alters the ER Stress Response and Accelerates Prostate Cancer Growth in vivo

    PubMed Central

    Horak, Peter; Tomasich, Erwin; Vaňhara, Petr; Kratochvílová, Kateřina; Anees, Mariam; Marhold, Maximilian; Lemberger, Christof E.; Gerschpacher, Marion; Horvat, Reinhard; Sibilia, Maria; Pils, Dietmar; Krainer, Michael

    2014-01-01

    Prostate cancer is the most prevalent cancer in males in developed countries. Tumor suppressor candidate 3 (TUSC3) has been identified as a putative tumor suppressor gene in prostate cancer, though its function has not been characterized. TUSC3 shares homologies with the yeast oligosaccharyltransferase (OST) complex subunit Ost3p, suggesting a role in protein glycosylation. We provide evidence that TUSC3 is part of the OST complex and affects N-linked glycosylation in mammalian cells. Loss of TUSC3 expression in DU145 and PC3 prostate cancer cell lines leads to increased proliferation, migration and invasion as well as accelerated xenograft growth in a PTEN negative background. TUSC3 downregulation also affects endoplasmic reticulum (ER) structure and stress response, which results in increased Akt signaling. Together, our findings provide first mechanistic insight in TUSC3 function in prostate carcinogenesis in general and N-glycosylation in particular. PMID:24435307

  19. Genome sequence of Thermofilum pendens reveals an exceptional loss of biosynthetic pathways without genome reduction

    SciTech Connect

    Kyrpides, Nikos; Anderson, Iain; Rodriguez, Jason; Susanti, Dwi; Porat, Iris; Reich, Claudia; Ulrich, Luke E.; Elkins, James G.; Mavromatis, Kostas; Lykidis, Athanasios; Kim, Edwin; Thompson, Linda S.; Nolan, Matt; Land, Miriam; Copeland, Alex; Lapidus, Alla; Lucas, Susan; Detter, Chris; Zhulin, Igor B.; Olsen, Gary J.; Whitman, William; Mukhopadhyay, Biswarup; Bristow, James; Kyrpides, Nikos

    2008-01-01

    We report the complete genome of Thermofilum pendens, a deep-branching, hyperthermophilic member of the order Thermoproteales within the archaeal kingdom Crenarchaeota. T. pendens is a sulfur-dependent, anaerobic heterotroph isolated from a solfatara in Iceland. It is an extracellular commensal, requiring an extract of Thermoproteus tenax for growth, and the genome sequence reveals that biosynthetic pathways for purines, most amino acids, and most cofactors are absent. In fact T. pendens has fewer biosynthetic enzymes than obligate intracellular parasites, although it does not display other features common among obligate parasites and thus does not appear to be in the process of becoming a parasite. It appears that T. pendens has adapted to life in an environment rich in nutrients. T. pendens was known to utilize peptides as an energy source, but the genome reveals substantial ability to grow on carbohydrates. T. pendens is the first crenarchaeote and only the second archaeon found to have a transporter of the phosphotransferase system. In addition to fermentation, T. pendens may gain energy from sulfur reduction with hydrogen and formate as electron donors. It may also be capable of sulfur-independent growth on formate with formate hydrogenlyase. Additional novel features are the presence of a monomethylamine:corrinoid methyltransferase, the first time this enzyme has been found outside of Methanosarcinales, and a presenilin-related protein. Predicted highly expressed proteins do not include housekeeping genes, and instead include ABC transporters for carbohydrates and peptides, and CRISPR-associated proteins.

  20. Genome Sequence of Thermofilum pendens Reveals an Exceptional Loss of Biosynthetic Pathways without Genome Reduction

    SciTech Connect

    Anderson, Iain; Rodriquez, Jason; Susanti, Dwi; Porat, I.; Reich, Claudia; Ulrich, Luke; Elkins, James G; Mavromatis, K; Lykidis, A; Kim, Edwin; Thompson, Linda S; Nolan, Matt; Land, Miriam L; Copeland, A; Lapidus, Alla L.; Lucas, Susan; Detter, J C; Zhulin, Igor B; Olsen, Gary; Whitman, W. B.; Mukhopadhyay, Biswarup; Bristow, James; Kyrpides, Nikos C

    2008-01-01

    We report the complete genome of Thermofilum pendens, a deep-branching member of class Thermoproteales of Crenarchaeota. T. pendens is a sulfur-dependent, anaerobic heterotroph isolated from a solfatara in Iceland. It was known to utilize peptides as an energy source, but the genome reveals substantial ability to grow on carbohydrates. T. pendens is the first Crenarchaeote and only the second archaeon found to have transporters of the phosphotransferase system. T. pendens is known to require an extract of Thermoproteus tenax for growth, and the genome sequence reveals that biosynthetic pathways for purines, most amino acids, and most cofactors are absent. T. pendens has fewer biosynthetic enzymes than any other free-living organism. In addition to heterotrophy, T. pendens may gain energy from sulfur reduction with hydrogen and formate as electron donors. It may also be capable of sulfur-independent growth on formate with formate hydrogenlyase. Additional novel features are the presence of a monomethylamine:corrinoid methyltransferase, the first time this enzyme has been found outside of Methanosarcinales, and a presenilin-related protein from a new subfamily. Predicted highly expressed proteins include ABC transporters for carbohydrates and peptides, and CRISPR-associated proteins, suggesting that defense against viruses is a high priority.

  1. Loss of modifier of cell adhesion reveals a pathway leading to axonal degeneration.

    PubMed

    Chen, Qi; Peto, Charles A; Shelton, G Diane; Mizisin, Andrew; Sawchenko, Paul E; Schubert, David

    2009-01-07

    Axonal dysfunction is the major phenotypic change in many neurodegenerative diseases, but the processes underlying this impairment are not clear. Modifier of cell adhesion (MOCA) is a presenilin binding protein that functions as a guanine nucleotide exchange factor for Rac1. The loss of MOCA in mice leads to axonal degeneration and causes sensorimotor impairments by decreasing cofilin phosphorylation and altering its upstream signaling partners LIM kinase and p21-activated kinase, an enzyme directly downstream of Rac1. The dystrophic axons found in MOCA-deficient mice are associated with abnormal aggregates of neurofilament protein, the disorganization of the axonal cytoskeleton, and the accumulation of autophagic vacuoles and polyubiquitinated proteins. Furthermore, MOCA deficiency causes an alteration in the actin cytoskeleton and the formation of cofilin-containing rod-like structures. The dystrophic axons show functional abnormalities, including impaired axonal transport. These findings demonstrate that MOCA is required for maintaining the functional integrity of axons and define a model for the steps leading to axonal degeneration.

  2. RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer

    PubMed Central

    Niederst, Matthew J.; Sequist, Lecia V.; Poirier, John T.; Mermel, Craig H.; Lockerman, Elizabeth L.; Garcia, Angel R.; Katayama, Ryohei; Costa, Carlotta; Ross, Kenneth N.; Moran, Teresa; Howe, Emily; Fulton, Linnea E.; Mulvey, Hillary E.; Bernardo, Lindsay A.; Mohamoud, Farhiya; Miyoshi, Norikatsu; VanderLaan, Paul A.; Costa, Daniel B.; Jänne, Pasi A.; Borger, Darrell R.; Ramaswamy, Sridhar; Shioda, Toshi; Iafrate, Anthony J.; Getz, Gad; Rudin, Charles M.; Mino-Kenudson, Mari; Engelman, Jeffrey A.

    2015-01-01

    Tyrosine kinase inhibitors are effective treatments for non-small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, relapse typically occurs after an average of 1 year of continuous treatment. A fundamental histological transformation from NSCLC to small-cell lung cancer (SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of tumour samples and cell lines derived from resistant EGFR mutant patients revealed that Retinoblastoma (RB) is lost in 100% of these SCLC transformed cases, but rarely in those that remain NSCLC. Further, increased neuroendocrine marker and decreased EGFR expression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLC transformed cancers compared with resistant NSCLCs. Together, these findings suggest that this subset of resistant cancers ultimately adopt many of the molecular and phenotypic characteristics of classical SCLC. PMID:25758528

  3. RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer.

    PubMed

    Niederst, Matthew J; Sequist, Lecia V; Poirier, John T; Mermel, Craig H; Lockerman, Elizabeth L; Garcia, Angel R; Katayama, Ryohei; Costa, Carlotta; Ross, Kenneth N; Moran, Teresa; Howe, Emily; Fulton, Linnea E; Mulvey, Hillary E; Bernardo, Lindsay A; Mohamoud, Farhiya; Miyoshi, Norikatsu; VanderLaan, Paul A; Costa, Daniel B; Jänne, Pasi A; Borger, Darrell R; Ramaswamy, Sridhar; Shioda, Toshi; Iafrate, Anthony J; Getz, Gad; Rudin, Charles M; Mino-Kenudson, Mari; Engelman, Jeffrey A

    2015-03-11

    Tyrosine kinase inhibitors are effective treatments for non-small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, relapse typically occurs after an average of 1 year of continuous treatment. A fundamental histological transformation from NSCLC to small-cell lung cancer (SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of tumour samples and cell lines derived from resistant EGFR mutant patients revealed that Retinoblastoma (RB) is lost in 100% of these SCLC transformed cases, but rarely in those that remain NSCLC. Further, increased neuroendocrine marker and decreased EGFR expression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLC transformed cancers compared with resistant NSCLCs. Together, these findings suggest that this subset of resistant cancers ultimately adopt many of the molecular and phenotypic characteristics of classical SCLC.

  4. Both gene amplification and allelic loss occur at 14q13.3 in lung cancer

    PubMed Central

    Harris, Thomas; Pan, Qiulu; Sironi, Juan; Lutz, Dionne; Tian, Jianmin; Sapkar, Jana; Perez-Soler, Roman; Keller, Steven; Locker, Joseph

    2010-01-01

    Purpose Because loss of Nkx2-8 increases lung cancer in the mouse, we studied suppressive mechanisms in human lung cancer. Experimental Design NKX2-8 is located within 14q13.3, adjacent to its close relative TTF1/NKX2-1. We first analyzed loss of heterozygosity (LOH) of 14q13.3 in 45 matched human lung cancer and control specimens. DNA from tumors with LOH was then analyzed with high-density SNP arrays. For correlation with this genetic analysis, we quantified expression of Nkx2-8 and TTF1 mRNA in tumors. Finally, suppressive function of Nkx2-8 was assessed via colony formation assays in 5 lung cancer cell lines. Results 13/45 (29%) tumors had LOH. In 6 tumors, most adenocarcinomas, LOH was caused by gene amplification. The 0.8 Mb common region of amplification included MBIP, SFTA, TTF1, NKX2-8, and PAX9. In 4 squamous or adenosquamous cancers, LOH was caused by deletion. In 3 other tumors, LOH resulted from whole chromosome mechanisms (14−, 14+, or aneuploidy). The 1.2 Mb common region of deletion included MBIP, SFTA, TTF1, NKX2-8, PAX9, SLC25A21, and MIPOL1. Most tumors had low expression of Nkx2-8. Nevertheless, sequencing did not show NKX2-8 mutations that could explain the low expression. TTF1 overexpression, in contrast, was common and usually independent of Nkx2-8 expression. Finally, stable transfection of Nkx2-8 selectively inhibited growth of H522 lung cancer cells. Conclusions 14q13.3, which contains NKX2-8, is subject to both amplification and deletion in lung cancer. Most tumors have low expression of NKX2-8, and its expression can inhibit growth of some lung cancer cells. PMID:21148747

  5. AST-induced bone loss in men with prostate cancer: exercise as a potential countermeasure.

    PubMed

    Bolam, K A; Galvão, D A; Spry, N; Newton, R U; Taaffe, D R

    2012-12-01

    Androgen suppression treatment (AST) for men with prostate cancer is associated with a number of treatment-related side effects including an accelerated rate of bone loss. This loss of bone is greatest within the first year of AST and increases the risk for fracture. Pharmaceutical treatment in the form of bisphosphonates is currently used to counter the effects of hormone suppression on bone but is costly and associated with potential adverse effects. Recently, exercise has been shown to be an important adjuvant therapy to manage a range of treatment-related toxicities and enhance aspects of quality of life for men receiving AST. We propose that physical exercise may also have an important role in not only attenuating the bone loss associated with AST but in improving bone health and reducing fracture risk. In this review, the rationale underlying exercise as a countermeasure to AST-induced bone loss is provided.

  6. Coping Styles of Female Adolescent Cancer Patients with Potential Fertility Loss.

    PubMed

    Quinn, Gwendolyn P; Murphy, Devin; Knapp, Caprice A; Christie, Juliette; Phares, Vicky; Wells, Kristen J

    2013-06-01

    The purpose of this qualitative study was to assess the coping styles of female adolescent cancer patients regarding potential loss of fertility. Expectations and desires for the future, coping styles in typical adolescence, and coping styles when faced with potential loss of fertility due to cancer treatment are discussed. Female adolescents diagnosed with cancer aged 12-18 years at study (N=14) were administered a 10-item values clarification tool to pilot test the readability and relevance of the items on reproductive concerns, followed by a cognitive debriefing interview asking participants how they would respond to each item. These qualitative responses were assessed for coping style type using the constant comparative approach. All adolescent participants reported having a strong desire for biological children in the future. Reactions to questions regarding the loss of fertility fell into two categories of coping styles: emotion-focused coping or problem-focused (engagement) coping. Within emotion-focused coping, there were three distinct styles: externalizing attribution style, internalizing attribution style, and repressive adaptation. Problem-focused coping adolescents displayed optimism. Successful interventions aimed at promoting adaptive coping styles should seek to uncover adolescents' values about future parenthood and reproduction. Development of an age-appropriate assessment to stimulate dialogue regarding fertility and initiate an adolescent's cognitive processing of potential fertility loss is warranted.

  7. Coping Styles of Female Adolescent Cancer Patients with Potential Fertility Loss

    PubMed Central

    Murphy, Devin; Knapp, Caprice A.; Christie, Juliette; Phares, Vicky; Wells, Kristen J.

    2013-01-01

    Purpose The purpose of this qualitative study was to assess the coping styles of female adolescent cancer patients regarding potential loss of fertility. Expectations and desires for the future, coping styles in typical adolescence, and coping styles when faced with potential loss of fertility due to cancer treatment are discussed. Methods Female adolescents diagnosed with cancer aged 12–18 years at study (N=14) were administered a 10-item values clarification tool to pilot test the readability and relevance of the items on reproductive concerns, followed by a cognitive debriefing interview asking participants how they would respond to each item. These qualitative responses were assessed for coping style type using the constant comparative approach. Results All adolescent participants reported having a strong desire for biological children in the future. Reactions to questions regarding the loss of fertility fell into two categories of coping styles: emotion-focused coping or problem-focused (engagement) coping. Within emotion-focused coping, there were three distinct styles: externalizing attribution style, internalizing attribution style, and repressive adaptation. Problem-focused coping adolescents displayed optimism. Conclusion Successful interventions aimed at promoting adaptive coping styles should seek to uncover adolescents' values about future parenthood and reproduction. Development of an age-appropriate assessment to stimulate dialogue regarding fertility and initiate an adolescent's cognitive processing of potential fertility loss is warranted. PMID:23781403

  8. Genome Sequence of Thermofilum pendens Reveals an Exceptional Loss of Biosynthetic Pathways without Genome Reduction▿ †

    PubMed Central

    Anderson, Iain; Rodriguez, Jason; Susanti, Dwi; Porat, Iris; Reich, Claudia; Ulrich, Luke E.; Elkins, James G.; Mavromatis, Kostas; Lykidis, Athanasios; Kim, Edwin; Thompson, Linda S.; Nolan, Matt; Land, Miriam; Copeland, Alex; Lapidus, Alla; Lucas, Susan; Detter, Chris; Zhulin, Igor B.; Olsen, Gary J.; Whitman, William; Mukhopadhyay, Biswarup; Bristow, James; Kyrpides, Nikos

    2008-01-01

    We report the complete genome of Thermofilum pendens, a deeply branching, hyperthermophilic member of the order Thermoproteales in the archaeal kingdom Crenarchaeota. T. pendens is a sulfur-dependent, anaerobic heterotroph isolated from a solfatara in Iceland. It is an extracellular commensal, requiring an extract of Thermoproteus tenax for growth, and the genome sequence reveals that biosynthetic pathways for purines, most amino acids, and most cofactors are absent. In fact, T. pendens has fewer biosynthetic enzymes than obligate intracellular parasites, although it does not display other features that are common among obligate parasites and thus does not appear to be in the process of becoming a parasite. It appears that T. pendens has adapted to life in an environment rich in nutrients. T. pendens was known previously to utilize peptides as an energy source, but the genome revealed a substantial ability to grow on carbohydrates. T. pendens is the first crenarchaeote and only the second archaeon found to have a transporter of the phosphotransferase system. In addition to fermentation, T. pendens may obtain energy from sulfur reduction with hydrogen and formate as electron donors. It may also be capable of sulfur-independent growth on formate with formate hydrogen lyase. Additional novel features are the presence of a monomethylamine:corrinoid methyltransferase, the first time that this enzyme has been found outside the Methanosarcinales, and the presence of a presenilin-related protein. The predicted highly expressed proteins do not include proteins encoded by housekeeping genes and instead include ABC transporters for carbohydrates and peptides and clustered regularly interspaced short palindromic repeat-associated proteins. PMID:18263724

  9. Weight loss interventions for breast cancer survivors: impact of dietary pattern.

    PubMed

    Thompson, Henry J; Sedlacek, Scot M; Playdon, Mary C; Wolfe, Pamela; McGinley, John N; Paul, Devchand; Lakoski, Susan G

    2015-01-01

    Body weight management is not emphasized in clinical practice guidelines for breast cancer survivors, reflecting the lack of evidence that weight loss improves prognosis. Even if this situation changes, the optimal design for weight loss interventions is unclear. We conducted a 6-month non-randomized, controlled weight loss intervention in 249 post-menopausal breast cancer survivors. This paper reports effects on two secondary endpoints, change in body weight and composition. Participants were predominantly non-Hispanic whites (89%) with a mean age of 54.9 ± 9.2 years, a mean BMI of 29.0 ± 2.6 kg/m: (2) and an average of 43 ± 5% body fat. Two dietary interventions, low fat or low carbohydrate, were investigated and consisted of a 42 day cycle of menus and recipes. Weight loss counseling and anthropometric assessment were provided at monthly clinic visits. One hundred ninety-two women completed the trial (77% retention). In comparison to the nonintervention control, both intervention arms achieved significant decreases in body weight (12.5%), body fat (27.5%), waist circumference (9.5%), and hip circumference (7.8%) (all p < 0.001) with minimal effects on lean mass (1.3% decrease). Median time to 5 and 10% weight loss was 2 (95% confidence interval = 1 to 3) and 4 (95% confidence interval = 3 to 5) months, respectively, and 23% of participants experienced ≥ 15% weight loss. Loss of body weight and fat mass was rapid and substantial irrespective of dietary approach when a structured program was provided with monthly anthropometric assessment and weight loss counseling. ClinicalTrials.gov NCT01315483.

  10. The peculiar mass-loss history of SN 2014C as revealed through AMI radio observations

    NASA Astrophysics Data System (ADS)

    Anderson, G. E.; Horesh, A.; Mooley, K. P.; Rushton, A. P.; Fender, R. P.; Staley, T. D.; Argo, M. K.; Beswick, R. J.; Hancock, P. J.; Pérez-Torres, M. A.; Perrott, Y. C.; Plotkin, R. M.; Pretorius, M. L.; Rumsey, C.; Titterington, D. J.

    2017-04-01

    We present a radio light curve of supernova (SN) 2014C taken with the Arcminute Microkelvin Imager (AMI) Large Array at 15.7 GHz. Optical observations presented by Milisavljevic et al. demonstrated that SN 2014C metamorphosed from a stripped-envelope Type Ib SN into a strongly interacting Type IIn SN within 1 yr. The AMI light curve clearly shows two distinct radio peaks, the second being a factor of 4 times more luminous than the first peak. This double bump morphology indicates two distinct phases of mass-loss from the progenitor star with the transition between density regimes occurring at 100-200 d. This reinforces the interpretation that SN 2014C exploded in a low-density region before encountering a dense hydrogen-rich shell of circumstellar material that was likely ejected by the progenitor prior to the explosion. The AMI flux measurements of the first light-curve bump are the only reported observations taken within ˜50 to ˜125 d post-explosion, before the blast-wave encountered the hydrogen shell. Simplistic synchrotron self-absorption and free-free absorption modelling suggest that some physical properties of SN 2014C are consistent with the properties of other Type Ibc and IIn SNe. However, our single frequency data does not allow us to distinguish between these two models, which implies that they are likely too simplistic to describe the complex environment surrounding this event. Lastly, we present the precise radio location of SN 2014C obtained with the electronic Multi-Element Remotely Linked Interferometer Network, which will be useful for future very long baseline interferometry observations of the SN.

  11. The analysis of heterotaxy patients reveals new loss-of-function variants of GRK5

    PubMed Central

    Lessel, Davor; Muhammad, Tariq; Casar Tena, Teresa; Moepps, Barbara; Burkhalter, Martin D.; Hitz, Marc-Phillip; Toka, Okan; Rentzsch, Axel; Schubert, Stephan; Schalinski, Adelheid; Bauer, Ulrike M. M.; Kubisch, Christian; Ware, Stephanie M.; Philipp, Melanie

    2016-01-01

    G protein-coupled receptor kinase 5 (GRK5) is a regulator of cardiac performance and a potential therapeutic target in heart failure in the adult. Additionally, we have previously classified GRK5 as a determinant of left-right asymmetry and proper heart development using zebrafish. We thus aimed to identify GRK5 variants of functional significance by analysing 187 individuals with laterality defects (heterotaxy) that were associated with a congenital heart defect (CHD). Using Sanger sequencing we identified two moderately frequent variants in GRK5 with minor allele frequencies <10%, and seven very rare polymorphisms with minor allele frequencies <1%, two of which are novel variants. Given their evolutionarily conserved position in zebrafish, in-depth functional characterisation of four variants (p.Q41L, p.G298S, p.R304C and p.T425M) was performed. We tested the effects of these variants on normal subcellular localisation and the ability to desensitise receptor signalling as well as their ability to correct the left-right asymmetry defect upon Grk5l knockdown in zebrafish. While p.Q41L, p.R304C and p.T425M responded normally in the first two aspects, neither p.Q41L nor p.R304C were capable of rescuing the lateralisation phenotype. The fourth variant, p.G298S was identified as a complete loss-of-function variant in all assays and provides insight into the functions of GRK5. PMID:27618959

  12. Circulating Carnosine Dipeptidase 1 Associates with Weight Loss and Poor Prognosis in Gastrointestinal Cancer

    PubMed Central

    Arner, Peter; Henjes, Frauke; Schwenk, Jochen M.; Darmanis, Spyros; Dahlman, Ingrid; Iresjö, Britt-Marie; Naredi, Peter; Agustsson, Thorhallur; Lundholm, Kent; Nilsson, Peter; Rydén, Mikael

    2015-01-01

    Background Cancer cachexia (CC) is linked to poor prognosis. Although the mechanisms promoting this condition are not known, several circulating proteins have been proposed to contribute. We analyzed the plasma proteome in cancer subjects in order to identify factors associated with cachexia. Design/Subjects Plasma was obtained from a screening cohort of 59 patients, newly diagnosed with suspected gastrointestinal cancer, with (n = 32) or without (n = 27) cachexia. Samples were subjected to proteomic profiling using 760 antibodies (targeting 698 individual proteins) from the Human Protein Atlas project. The main findings were validated in a cohort of 93 patients with verified and advanced pancreas cancer. Results Only six proteins displayed differential plasma levels in the screening cohort. Among these, Carnosine Dipeptidase 1 (CNDP1) was confirmed by sandwich immunoassay to be lower in CC (p = 0.008). In both cohorts, low CNDP1 levels were associated with markers of poor prognosis including weight loss, malnutrition, lipid breakdown, low circulating albumin/IGF1 levels and poor quality of life. Eleven of the subjects in the discovery cohort were finally diagnosed with non-malignant disease but omitting these subjects from the analyses did not have any major influence on the results. Conclusions In gastrointestinal cancer, reduced plasma levels of CNDP1 associate with signs of catabolism and poor outcome. These results, together with recently published data demonstrating lower circulating CNDP1 in subjects with glioblastoma and metastatic prostate cancer, suggest that CNDP1 may constitute a marker of aggressive cancer and CC. PMID:25898255

  13. Loss of ERα induces amoeboid-like migration of breast cancer cells by downregulating vinculin

    PubMed Central

    Gao, Yuan; Wang, Zhaowei; Hao, Qiang; Li, Weina; Xu, Yujin; Zhang, Juliang; Zhang, Wangqian; Wang, Shuning; Liu, Shuo; Li, Meng; Xue, Xiaochang; Zhang, Wei; Zhang, Cun; Zhang, Yingqi

    2017-01-01

    Oestrogen receptor alpha (ERα) is a well-known target of endocrine therapy for ERα-positive breast cancer. ERα-negative cells, which are enriched during endocrine therapy, are associated with metastatic relapse. Here we determine that loss of ERα in the invasive front and in lymph node metastasis in human breast cancer is significantly correlated with lymphatic metastasis. Using in vivo and in vitro experiments, we demonstrate that ERα inhibits breast cancer metastasis. Furthermore, we find that ERα is a novel regulator of vinculin expression in breast cancer. Notably, ERα suppresses the amoeboid-like movement of breast cancer cells by upregulating vinculin in 3D matrix, which in turn promotes cell–cell and cell–matrix adhesion and inhibits the formation of amoeboid-like protrusions. A positive association between ERα and vinculin expression is found in human breast cancer tissues. The results show that ERα inhibits breast cancer metastasis and suggest that ERα suppresses cell amoeboid-like movement by upregulating vinculin. PMID:28266545

  14. Dysregulation of cholesterol homeostasis in human prostate cancer through loss of ABCA1

    PubMed Central

    Lee, Byron H.; Taylor, Margaret G.; Robinet, Peggy; Smith, Jonathan D.; Schweitzer, Jessica; Sehayek, Ephraim; Falzarano, Sara M.; Magi-Galluzzi, Cristina; Klein, Eric A.; Ting, Angela H.

    2012-01-01

    Recent epidemiologic data show that low serum cholesterol level as well as statin use is associated with a decreased risk of developing aggressive or advanced prostate cancer, suggesting a role for cholesterol in aggressive prostate cancer development. Intracellular cholesterol promotes prostate cancer progression as a substrate for de novo androgen synthesis and through regulation of AKT signaling. By performing next-generation sequencing-based DNA methylome analysis, we have discovered marked hypermethylation at the promoter of the major cellular cholesterol efflux transporter, ABCA1, in LNCaP prostate cancer cells. ABCA1 promoter hypermethylation renders the promoter unresponsive to trans-activation and leads to elevated cholesterol levels in LNCaP. ABCA1 promoter hypermethylation is enriched in intermediate to high grade prostate cancers and not detectable in benign prostate. Remarkably, ABCA1 down-regulation is evident in all prostate cancers examined, and expression levels are inversely correlated with Gleason grade. Our results suggest cancer-specific ABCA1 hypermethylation and loss of protein expression direct high intracellular cholesterol levels and hence contribute to an environment conducive to tumor progression. PMID:23233737

  15. Quantification of lean tissue losses during cancer and HIV infection/AIDS.

    PubMed

    Thibault, Ronan; Cano, Noël; Pichard, Claude

    2011-05-01

    Cancer and HIV infection/AIDS are associated with an increased risk of undernutrition and cachexia. During the past decade, patients became older, frequently overweight or obese and sedentary, conditions which are likely to result in fat-free mass (FFM) loss. This review sustains the hypothesis that FFM measurement should be implemented in routine clinical practice, to optimize the management of cancer and AIDS, as well as disease-related undernutrition. Undernutrition and FFM loss are associated with worse clinical outcome and increased therapy toxicity in cancer and AIDS patients. The emergence of the concept of sarcopenic obesity in cancer patients, a condition associated with decreased survival, demonstrates the necessity to assess their body composition with easily available methods, such as dual energy X-ray absorptiometry, computerized tomography and bioelectrical impedance analysis. FFM measurement could be helpful for guiding the choice of both disease-specific and nutritional therapies and for evaluating their efficacy and putative toxicity. FFM measurement at different steps of disease course could allow improving the guidance and efficacy of both cancer and HIV/AIDS-specific and nutritional therapies. The repeated measurement of FFM could allow reducing undernutrition-related morbidity, mortality and global healthcare costs, and could improve response and tolerance towards therapy, and quality of life.

  16. Effect of MRE11 Loss on PARP-Inhibitor Sensitivity in Endometrial Cancer In Vitro

    PubMed Central

    Noske, Aurelia; von Teichman, Adriana; Dedes, Ioannis; Gwerder, Myriam; Imesch, Patrick; Ikenberg, Kristian; Moch, Holger; Fink, Daniel; Stucki, Manuel; Dedes, Konstantin J.

    2014-01-01

    Aim of the study To evaluate the frequency of MRE11/RAD50/NBS1 (MRN)-complex loss of protein expression in endometrial cancers (EC) and to determine whether loss of MRE11 renders the cancer cells sensitive to Poly(ADP-ribose) polymerase (PARP)-inhibitory treatment. Methods MRN expression was examined in 521 samples of endometrial carcinomas and in 10 cancer cell lines. A putative mutation hotspot in the form of an intronic poly(T) allele in MRE11 was sequenced in selected cases (n = 26). Sensitivity to the PARP-inhibitor, BMN673 was tested in colony formation assays before and after MRE11 silencing using siRNA. Homologous recombination (HR) DNA repair was evaluated by RAD51-foci formation assay upon irradiation and drug treatment. Results Loss of MRE11 protein was found in 30.7% of EC tumours and significantly associated with loss of RAD50, NBS1 and mismatch repair protein expression. One endometrial cell line showed a markedly reduced MRE11 expression due to a homozygous poly(T) mutation of MRE11, thereby exhibiting an increased sensitivity to BMN673. MRE11 depletion sensitizes MRE11 expressing EC cell lines to the treatment with BMN673. The increased sensitivity to PARP-inhibition correlates with reduced RAD51 foci formation upon ionizing radiation in MRE11-depleted cells. Conclusion Loss of the MRE11 protein predicts sensitivity to PARP-inhibitor sensitivity in vitro, defining it as an additional synthetic lethal gene with PARP. The high incidence of MRE11 loss in ECs can be potentially exploited for PARP-inhibitor therapy. Furthermore, MRE11 protein expression using immunohistochemistry could be investigated as a predictive biomarker for PARP-inhibitor treatment. PMID:24927325

  17. A Pilot Trial of Spirituality Counseling for Weight Loss Maintenance in African American Breast Cancer Survivors

    PubMed Central

    Djuric, Zora; Mirasolo, Josephine; Kimbrough, LaVern; Brown, Diane R.; Heilbrun, Lance K.; Canar, Lisa; Venkatranamamoorthy, Raghu; Simon, Michael S.

    2009-01-01

    A continuing challenge in weight loss treatment is attaining maintenance of weight loss. The goal of this study was to develop a counseling method that would assist African American breast cancer survivors with weight loss maintenance. In this pilot study, 31 obese breast cancer survivors were recruited. Individualized, dietitian-led counseling by telephone and free Weight Watchers coupons were provided to all participants for 18 months. At the 6-month time point, women were randomized to receive spirituality counseling or not in addition to the standard program. The spirituality counseling was delivered via telephone using an 8-step framework. Subjects were asked to utilize daily meditation or prayer, daily readings, and the recording of thoughts in a journal. Mean weight loss from baseline to 6 months was a modest 2.0% of baseline weight. From 6 to 18 months, there was no further weight change in the spirituality arm and a gain of 0.7% in the dietitian only arm. Despite little effect on weight loss, it did appear that spirituality counseling positively affected spiritual well-being (FACIT-Sp) scores and dietary quality. The spirituality counseling framework therefore may be further refined and useful for other health promotion studies with African American populations. PMID:19585923

  18. Pharmacologic therapy for the cancer anorexia/weight loss syndrome: A data-driven, practical approach.

    PubMed

    Jatoi, Aminah

    2006-01-01

    The cancer anorexia/weight loss syndrome occurs in over 80% of patients with incurable cancer and is associated with a poor prognosis and negative effects on quality of life. Educating patients and families plays an important role in its management, and caregivers sometimes forget that in select patients who are candidates for it, antineoplastic therapy can occasionally reverse some aspects of this syndrome. Patients may also benefit from appetite stimulants such as corticosteroids and progestational agents,and this review summarizes the benefits of using these agents as well as their contraindications.

  19. Virtual Weight Loss Program in Maintaining Weight in African American Breast Cancer Survivors

    ClinicalTrials.gov

    2017-01-19

    Cancer Survivor; Invasive Breast Carcinoma; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  20. Loss of RUNX3 increases osteopontin expression and promotes cell migration in gastric cancer.

    PubMed

    Cheng, Hui-Chuan; Liu, Yu-Peng; Shan, Yan-Shen; Huang, Chi-Ying; Lin, Forn-Chia; Lin, Li-Ching; Lee, Ling; Tsai, Chen-Hsun; Hsiao, Michael; Lu, Pei-Jung

    2013-11-01

    Loss of RUNX3 expression is frequently observed in gastric cancer and is highly associated with lymph node metastasis and poor prognosis. However, the underlying molecular mechanisms of gastric cancer remain unknown. In this study, we found that the protein levels of RUNX3 and osteopontin (OPN) are inversely correlated in gastric cancer clinical specimens and cell lines. Furthermore, similar inverse trends between RUNX3 and OPN messenger RNA (mRNA) expression were demonstrated in six out of seven normal-tumor-paired gastric cancer clinical specimens. In addition, low RUNX3 and high OPN expression were associated with poor prognosis in gastric cancer patients. Ectopic expression of green fluorescent protein-RUNX3 reduced OPN protein and mRNA expression in the AGS and SCM-1 gastric cancer cell lines. In contrast, knockdown of RUNX3 in GES-1, a normal gastric epithelial cell line, increased OPN expression. Although three RUNX3-binding sequences have been identified in the OPN promoter region, direct binding of RUNX3 to the specific binding site, -142 to -137bp, was demonstrated by chromatin immunoprecipitation assay. The binding of RUNX3 to the OPN promoter significantly decreased OPN promoter activity. The knockdown of OPN or overexpression of RUNX3 inhibited cell migration in AGS and SCM-1 cells; however, the coexpression of RUNX3 and OPN reversed the RUNX3-reduced migration ability in AGS and SCM-1 cells. In contrast, the knockdown of both RUNX3 and OPN inhibited RUNX3-knockdown-induced migration of GES-1 cells. Together, our data demonstrated that RUNX3 is a transcriptional repressor of OPN and that loss of RUNX3 upregulates OPN, which promotes migration in gastric cancer cells.

  1. GRP78 as a regulator of liver steatosis and cancer progression mediated by loss of the tumor suppressor PTEN.

    PubMed

    Chen, W-T; Zhu, G; Pfaffenbach, K; Kanel, G; Stiles, B; Lee, A S

    2014-10-16

    showed no malignancy even at 14 months. These studies reveal that GRP78 is a novel regulator for PTEN-loss-mediated liver injury and cancer progression.

  2. Potential microRNA-mediated oncogenic intercellular communication revealed by pan-cancer analysis

    NASA Astrophysics Data System (ADS)

    Li, Yue; Zhang, Zhaolei

    2014-11-01

    Carcinogenesis consists of oncogenesis and metastasis, and intriguingly microRNAs (miRNAs) are involved in both processes. Although aberrant miRNA activities are prevalent in diverse tumor types, the exact mechanisms for how they regulate cancerous processes are not always clear. To this end, we performed a large-scale pan-cancer analysis via a novel probabilistic approach to infer recurrent miRNA-target interactions implicated in 12 cancer types using data from The Cancer Genome Atlas. We discovered ~20,000 recurrent miRNA regulations, which are enriched for cancer-related miRNAs/genes. Notably, miRNA 200 family (miR-200/141/429) is among the most prominent miRNA regulators, which is known to be involved in metastasis. Importantly, the recurrent miRNA regulatory network is not only enriched for cancer pathways but also for extracellular matrix (ECM) organization and ECM-receptor interactions. The results suggest an intriguing cancer mechanism involving miRNA-mediated cell-to-cell communication, which possibly involves delivery of tumorigenic miRNA messengers to adjacent cells via exosomes. Finally, survival analysis revealed 414 recurrent-prognostic associations, where both gene and miRNA involved in each interaction conferred significant prognostic power in one or more cancer types. Together, our comprehensive pan-cancer analysis provided not only biological insights into metastasis but also brought to bear the clinical relevance of the proposed recurrent miRNA-gene associations.

  3. Potential microRNA-mediated oncogenic intercellular communication revealed by pan-cancer analysis.

    PubMed

    Li, Yue; Zhang, Zhaolei

    2014-11-18

    Carcinogenesis consists of oncogenesis and metastasis, and intriguingly microRNAs (miRNAs) are involved in both processes. Although aberrant miRNA activities are prevalent in diverse tumor types, the exact mechanisms for how they regulate cancerous processes are not always clear. To this end, we performed a large-scale pan-cancer analysis via a novel probabilistic approach to infer recurrent miRNA-target interactions implicated in 12 cancer types using data from The Cancer Genome Atlas. We discovered ~20,000 recurrent miRNA regulations, which are enriched for cancer-related miRNAs/genes. Notably, miRNA 200 family (miR-200/141/429) is among the most prominent miRNA regulators, which is known to be involved in metastasis. Importantly, the recurrent miRNA regulatory network is not only enriched for cancer pathways but also for extracellular matrix (ECM) organization and ECM-receptor interactions. The results suggest an intriguing cancer mechanism involving miRNA-mediated cell-to-cell communication, which possibly involves delivery of tumorigenic miRNA messengers to adjacent cells via exosomes. Finally, survival analysis revealed 414 recurrent-prognostic associations, where both gene and miRNA involved in each interaction conferred significant prognostic power in one or more cancer types. Together, our comprehensive pan-cancer analysis provided not only biological insights into metastasis but also brought to bear the clinical relevance of the proposed recurrent miRNA-gene associations.

  4. Long-term weight loss after colorectal cancer diagnosis is associated with lower survival: The Colon Cancer Family Registry.

    PubMed

    Kocarnik, Jonathan M; Hua, Xinwei; Hardikar, Sheetal; Robinson, Jamaica; Lindor, Noralane M; Win, Aung Ko; Hopper, John L; Figueiredo, Jane C; Potter, John D; Campbell, Peter T; Gallinger, Steven; Cotterchio, Michelle; Adams, Scott V; Cohen, Stacey A; Phipps, Amanda I; Newcomb, Polly A

    2017-08-25

    Body weight is associated with colorectal cancer (CRC) risk and survival, but to the authors' knowledge, the impact of long-term postdiagnostic weight change is unclear. Herein, the authors investigated whether weight change over the 5 years after a diagnosis of CRC is associated with survival. CRC cases diagnosed from 1997 to 2008 were identified through 4 population-based cancer registry sites. Participants enrolled within 2 years of diagnosis and reported their height and weight 2 years prior. Follow-up questionnaires were administered approximately 5 years after diagnosis. Associations between change in weight (in kg) or body mass index (BMI) with overall and CRC-specific survival were estimated using Cox regression analysis adjusted for age, sex, American Joint Committee on Cancer stage of disease, baseline BMI, nonsteroidal anti-inflammatory drug use, smoking, time between diagnosis and enrollment, and study site. At the 5-year postdiagnostic survey, 2049 participants reported higher (53%; median plus 5 kg), unchanged (12%), or lower (35%; median -4 kg) weight. Over a median of 5.1 years of subsequent follow-up (range, 0.3-9.9 years), 344 participants died (91 of CRC). Long-term weight loss (per 5 kg) was found to be associated with poorer overall survival (hazard ratio, 1.13; 95% confidence interval, 1.07-1.21) and CRC-specific survival (hazard ratio, 1.25; 95% confidence interval, 1.13-1.39). Significantly lower survival was similarly observed for relative weight loss (>5% vs ≤5% change), BMI reduction (per 1 unit), or BMI category change (overweight to normal vs remaining overweight). Weight loss 5 years after a diagnosis of CRC was found to be significantly associated with decreased long-term survival, suggesting the importance of avoiding weight loss in survivors of CRC. Future research should attempt to further evaluate this association, accounting for whether this weight change was intentional or represents a marker of declining health. Cancer 2017

  5. Impact of ArcA loss in Shewanella oneidensis revealed by comparative proteomics under aerobic and anaerobic conditions

    SciTech Connect

    Yuan, Jie; Wei, Buyun; Lipton, Mary S.; Gao, Haichun

    2012-06-01

    Shewanella inhabit a wide variety of niches in nature and can utilize a broad spectrum of electron acceptors under anaerobic conditions. How they modulate their gene expression to adapt is poorly understood. ArcA, homologue of a global regulator controlling hundreds of genes involved in aerobic and anaerobic respiration in E. coli, was shown to be important in aerobiosis/anaerobiosis of S. oneidensis as well. Loss of ArcA, in addition to altering transcription of many genes, resulted in impaired growth under aerobic condition, which was not observed in E. coli. To further characterize the impact of ArcA loss on gene expression on the level of proteome under aerobic and anaerobic conditions, liquid-chromatography-mass-spectrometry (LC-MS) based proteomic approach was employed. Results show that ArcA loss led to globally altered gene expression, generally consistent with that observed with transcripts. Comparison of transcriptomic and proteomic data permitted identification of 17 high-confidence ArcA targets. Moreover, our data indicate that ArcA is required for regulation of cytochrome c proteins, and the menaquinone level may play a role in regulating ArcA as in E. coli. Proteomic-data-guided growth assay revealed that the aerobic growth defect of ArcA mutant is presumably due to impaired peptide utilization.

  6. Comparative Genomic Hybridization of Human Malignant Gliomas Reveals Multiple Amplification Sites and Nonrandom Chromosomal Gains and Losses

    PubMed Central

    Schròck, Evelin; Thiel, Gundula; Lozanova, Tanka; du Manoir, Stanislas; Meffert, Marie-Christine; Jauch, Anna; Speicher, Michael R.; Nürnberg, Peter; Vogel, Siegfried; Janisch, Werner; Donis-Keller, Helen; Ried, Thomas; Witkowski, Regine; Cremer, Thomas

    1994-01-01

    Nine human malignant gliomas (2 astrocytomas grade III and 7 glioblastomas) were analyzed using comparative genomic hybridization (CGH). In addition to the amplification of the EGFR gene at 7p12 in 4 of 9 cases, six new amplification sites were mapped to 1q32, 4q12, 7q21.1, 7q21.2-3, 12p, and 22q12. Nonrandom chromosomal gains and losses were identified with overrepresentation of chromosome 7 and underrepresentation of chromosome 10 as the most frequent events (1 of 2 astrocytomas, 7 of 7 glioblastomas). Gain of a part or the whole chromosome 19 and losses of chromosome bands 9pter-23 and 22q13 were detected each in five cases. Loss of chromosome band 17p13 and gain of chromosome 20 were revealed each in three cases. The validity of the CGH data was confirmed using interphase cytogenetics with YAC clones, chromosome painting in tumor metaphase spreads, and DNA fingerprinting. A comparison of CGH data with the results of chromosome banding analyses indicates that metaphase spreads accessible in primary tumor cell cultures may not represent the clones predominant in the tumor tissue ImagesFigure 1Figure 4Figure 6 PMID:8203461

  7. An international survey of physician attitudes and practice in regard to revealing the diagnosis of cancer.

    PubMed

    Holland, J C; Geary, N; Marchini, A; Tross, S

    1987-01-01

    In 1984, questionnaires were sent to members of the International Psycho-Oncology Society concerning the practice in their country with regard to revealing the diagnosis of cancer to patients, their opinion about the effect of their policy, and their impression of local trends and attitudes toward cancer. Data from 90 respondents from 20 countries revealed that use of the word "cancer" was often avoided in discussions with the patient. Words commonly substituted for cancer were those that implied a "swelling" (e.g., tumor, growth, lump), and "inflammation," or a pathophysiologic change (blood disease, precancerous, unclean tissue). Oncologists estimated that a low percentage (less than 40%) of their colleagues revealed the word cancer in Africa, France, Hungary, Italy, Japan, Panama, Portugal, and Spain. Oncologists from Austria, Denmark Finland, The Netherlands, New Zealand, Norway, Sweden, and Switzerland, estimated the percentage to be high (greater than 80%). However, in all countries, the majority of physicians tell the family the diagnosis. The majority (90%) reported a trend toward increased telling of the diagnosis, due to greater patient information and expectations, and increased physician openess in using the word cancer. Most (68%) felt that the overall effect of revealing the diagnosis was positive. While emotional distress was transiently greater when patients were told, there were positive effects concerning coping, compliance, tolerance of treatment, planning for future, communication with physicians and others, and improved prognosis. The transient negative effects were depression, anxiety, and anger. It is important to recognize that efforts to find the "correct" position about revealing or concealing cancer diagnosis must recognize that the language between doctor and patient is constrained by cultural norms. Communication is likely to be far less dependent upon the specific words used then upon the meaning that is conveyed by the doctor.

  8. Breast Cancer in Three Dimensions: Revealing Telomere Dysfunction in Breast Cancer

    DTIC Science & Technology

    2006-09-01

    family with multiple cancers. Genetique humaine au Quebec: Qui fait quoi? Réseau de médecine génétique appliqués du FRSQ. Abstract # 46. 12. Evans...Tonin PN, Rosenblatt DS and Foulkes WD: Ascertainment of familial cancers in McGill Hereditary Cancer Clinics. Les Journees Genetiques ’ 98: Réseau de...Founder BRCA1 and BRCA2 mutations in French-Canadian breast and ovarian cancer families. Les Journees Genetiques ’ 98: Réseau de médecine génétique

  9. Selective CD4+ T Cell Loss Promotes Liver Cancer Development | Center for Cancer Research

    Cancer.gov

    Hepatocellular carcinoma (HCC), the second leading cause of cancer deaths worldwide, commonly develops in patients with underlying chronic liver disease, such as hepatitis B or C virus infection or non-alcoholic fatty liver disease (NAFLD).

  10. Genome-wide transcript profiling reveals novel breast cancer-associated intronic sense RNAs.

    PubMed

    Kim, Sang Woo; Fishilevich, Elane; Arango-Argoty, Gustavo; Lin, Yuefeng; Liu, Guodong; Li, Zhihua; Monaghan, A Paula; Nichols, Mark; John, Bino

    2015-01-01

    Non-coding RNAs (ncRNAs) play major roles in development and cancer progression. To identify novel ncRNAs that may identify key pathways in breast cancer development, we performed high-throughput transcript profiling of tumor and normal matched-pair tissue samples. Initial transcriptome profiling using high-density genome-wide tiling arrays revealed changes in over 200 novel candidate genomic regions that map to intronic regions. Sixteen genomic loci were identified that map to the long introns of five key protein-coding genes, CRIM1, EPAS1, ZEB2, RBMS1, and RFX2. Consistent with the known role of the tumor suppressor ZEB2 in the cancer-associated epithelial to mesenchymal transition (EMT), in situ hybridization reveals that the intronic regions deriving from ZEB2 as well as those from RFX2 and EPAS1 are down-regulated in cells of epithelial morphology, suggesting that these regions may be important for maintaining normal epithelial cell morphology. Paired-end deep sequencing analysis reveals a large number of distinct genomic clusters with no coding potential within the introns of these genes. These novel transcripts are only transcribed from the coding strand. A comprehensive search for breast cancer associated genes reveals enrichment for transcribed intronic regions from these loci, pointing to an underappreciated role of introns or mechanisms relating to their biology in EMT and breast cancer.

  11. Genome-Wide Transcript Profiling Reveals Novel Breast Cancer-Associated Intronic Sense RNAs

    PubMed Central

    Lin, Yuefeng; Liu, Guodong; Li, Zhihua; Monaghan, A. Paula; Nichols, Mark; John, Bino

    2015-01-01

    Non-coding RNAs (ncRNAs) play major roles in development and cancer progression. To identify novel ncRNAs that may identify key pathways in breast cancer development, we performed high-throughput transcript profiling of tumor and normal matched-pair tissue samples. Initial transcriptome profiling using high-density genome-wide tiling arrays revealed changes in over 200 novel candidate genomic regions that map to intronic regions. Sixteen genomic loci were identified that map to the long introns of five key protein-coding genes, CRIM1, EPAS1, ZEB2, RBMS1, and RFX2. Consistent with the known role of the tumor suppressor ZEB2 in the cancer-associated epithelial to mesenchymal transition (EMT), in situ hybridization reveals that the intronic regions deriving from ZEB2 as well as those from RFX2 and EPAS1 are down-regulated in cells of epithelial morphology, suggesting that these regions may be important for maintaining normal epithelial cell morphology. Paired-end deep sequencing analysis reveals a large number of distinct genomic clusters with no coding potential within the introns of these genes. These novel transcripts are only transcribed from the coding strand. A comprehensive search for breast cancer associated genes reveals enrichment for transcribed intronic regions from these loci, pointing to an underappreciated role of introns or mechanisms relating to their biology in EMT and breast cancer. PMID:25798919

  12. A Balanced Tissue Composition Reveals New Metabolic and Gene Expression Markers in Prostate Cancer

    PubMed Central

    Tessem, May-Britt; Bertilsson, Helena; Angelsen, Anders; Bathen, Tone F.; Drabløs, Finn; Rye, Morten Beck

    2016-01-01

    Molecular analysis of patient tissue samples is essential to characterize the in vivo variability in human cancers which are not accessible in cell-lines or animal models. This applies particularly to studies of tumor metabolism. The challenge is, however, the complex mixture of various tissue types within each sample, such as benign epithelium, stroma and cancer tissue, which can introduce systematic biases when cancers are compared to normal samples. In this study we apply a simple strategy to remove such biases using sample selections where the average content of stroma tissue is balanced between the sample groups. The strategy is applied to a prostate cancer patient cohort where data from MR spectroscopy and gene expression have been collected from and integrated on the exact same tissue samples. We reveal in vivo changes in cancer-relevant metabolic pathways which are otherwise hidden in the data due to tissue confounding. In particular, lowered levels of putrescine are connected to increased expression of SRM, reduced levels of citrate are attributed to upregulation of genes promoting fatty acid synthesis, and increased succinate levels coincide with reduced expression of SUCLA2 and SDHD. In addition, the strategy also highlights important metabolic differences between the stroma, epithelium and prostate cancer. These results show that important in vivo metabolic features of cancer can be revealed from patient data only if the heterogeneous tissue composition is properly accounted for in the analysis. PMID:27100877

  13. Multiple loss-of-function 5-O-glucosyltransferase alleles revealed in Vitis vinifera, but not in other Vitis species.

    PubMed

    Yang, Yingzhen; Labate, Joanne A; Liang, Zhenchang; Cousins, Peter; Prins, Bernard; Preece, John E; Aradhya, Mallikarjuna; Zhong, Gan-Yuan

    2014-11-01

    Wild and loss-of-function alleles of the 5 - O - glucosyltransferase gene responsible for synthesis of diglucoside anthocyanins in Vitis were characterized. The information aids marker development for tracking this gene in grape breeding. Anthocyanins in red grapes are present in two glycosylation states: monoglucoside (3-O-glucoside) and diglucoside (3, 5-di-O-glucoside). While monoglucoside anthocyanins are present in all pigmented grapes, diglucoside anthocyanins are rarely found in the cultivated grape species Vitis vinifera. Biochemically 3-O-glucoside anthocyanins can be converted into 3,5-di-O-glucoside anthocyanins by a 5-O-glucosyltransferase. In this study, we surveyed allelic variation of the 5-O-glucosyltransferase gene (5GT) in 70 V. vinifera ssp. vinifera cultivars, 52 V. vinifera ssp. sylvestris accessions, 23 Vitis hybrid grapes, and 22 accessions of seven other Vitis species. Eighteen 5GT alleles with apparent loss-of-function mutations, including seven premature stop codon mutations and six frameshift indel mutations, were discovered in V. vinifera, but not in the other Vitis species. A total of 36 5GT alleles without apparent loss-of-function mutations (W-type) were identified. These W-type alleles were predominantly present in wild Vitis species, although a few of them were also found in some V. vinifera accessions. We further evaluated some of these 5GT alleles in producing diglucoside anthocyanins by analyzing the content of diglucoside anthocyanins in a set of representative V. vinifera cultivars. Through haplotype network analysis we revealed that V. vinifera ssp. vinifera and its wild progenitor V. vinifera ssp. sylvestris shared many loss-of-function 5GT alleles and extensive divergence of the 5GT alleles was evident within V. vinifera. This work advances our understanding of the genetic diversity of 5GT and provides a molecular basis for future marker-assisted selection for improving this important wine quality trait.

  14. Unintentional weight loss is the most important indicator of malnutrition among surgical cancer patients.

    PubMed

    Loh, K W; Vriens, M R; Gerritsen, A; Borel Rinkes, I H M; van Hillegersberg, R; Schippers, C; Steenhagen, E; Ong, T A; Moy, F M; Molenaar, I Q

    2012-10-01

    Disease-related malnutrition is highly prevalent in hospital patients and varies from 25-40%. Early nutritional screening of patients at admission helps to improve recognition of malnourished patients to allow early interventions and enhance clinical outcomes. A total of 104 preoperative surgical patients with oesophageal (34), stomach (17) or pancreatic cancer (53) were recruited in our study. The risk of malnutrition was examined using the quick-and-easy Malnutrition Universal Screening Tool (MUST). Anthropometric data and information on percent weight change over the past six months, unintentional weight loss, dietician referrals, and history of nutritional intervention were collected. A total of 75% of our participants were at high malnutrition risk with a mean (±SD) percentage weight loss of 5.18 (±6.23)%, despite a mean BMI of 26.09 (±5.73) kgm-2. Participants with a significantly higher percent weight loss, unintentional weight loss, dietician referral and nutritional intervention had a higher risk of malnutrition (p<0.05). Presence of unintentional weight loss was the only significant predictor (OR 3.22; 95%CI 1.23, 8.40) associated with risk of malnutrition after adjusted for all confounders. In conclusion, our findings highlight the importance of routine screening of malnutrition in oncology patients. Medical personnel must be aware that unintentional weight loss is an important predictor of malnutrition risks even if the patient’s BMI is not suggestive of malnutrition.

  15. Gain- and Loss-of-Function Mutations in the Breast Cancer Gene GATA3 Result in Differential Drug Sensitivity

    PubMed Central

    Kerzendorfer, Claudia; Salic, Sejla; Serra, Violeta; Muellner, Markus K.; Nijman, Sebastian M. B.

    2016-01-01

    Patterns of somatic mutations in cancer genes provide information about their functional role in tumourigenesis, and thus indicate their potential for therapeutic exploitation. Yet, the classical distinction between oncogene and tumour suppressor may not always apply. For instance, TP53 has been simultaneously associated with tumour suppressing and promoting activities. Here, we uncover a similar phenomenon for GATA3, a frequently mutated, yet poorly understood, breast cancer gene. We identify two functional classes of frameshift mutations that are associated with distinct expression profiles in tumours, differential disease-free patient survival and gain- and loss-of-function activities in a cell line model. Furthermore, we find an estrogen receptor-independent synthetic lethal interaction between a GATA3 frameshift mutant with an extended C-terminus and the histone methyltransferases G9A and GLP, indicating perturbed epigenetic regulation. Our findings reveal important insights into mutant GATA3 function and breast cancer, provide the first potential therapeutic strategy and suggest that dual tumour suppressive and oncogenic activities are more widespread than previously appreciated. PMID:27588951

  16. [A questionnaire survey about hair loss after chemotherapy for breast cancer].

    PubMed

    Oshima, Yukiko; Watanabe, Takanori; Nakagawa, Saki; Endo, Ayako; Shiga, Chizuko

    2012-09-01

    Hair loss is one of the most common side effects of chemotherapies such as FEC and taxane, and it greatly affects quality of life. We conducted a questionnaire survey of breast cancer patients who were treated with adjuvant chemotherapy about their hair loss. Eighty-five patients participated. They all had lost their hair and suffered from persistent changes in their hair condition, ranging from thinning to curly. More than 80% of patients had worn wigs until their hair had grown back. Furthermore, a few patients did not remove their wigs for 2 years after treatment. Unfortunately, there is no prevention or medication to combat hair loss due to chemotherapy at present, so cumulative examinations are awaited. We must provide appropriate information and support to the patient.

  17. Characterization of the loss of SUMO pathway function on cancer cells and tumor proliferation.

    PubMed

    He, Xingyue; Riceberg, Jessica; Pulukuri, Sai M; Grossman, Steve; Shinde, Vaishali; Shah, Pooja; Brownell, James E; Dick, Larry; Newcomb, John; Bence, Neil

    2015-01-01

    SUMOylation is a post-translational ubiquitin-like protein modification pathway that regulates important cellular processes including chromosome structure, kinetochore function, chromosome segregation, nuclear and sub-nuclear organization, transcription and DNA damage repair. There is increasing evidence that the SUMO pathway is dysregulated in cancer, raising the possibility that modulation of this pathway may have therapeutic potential. To investigate the importance of the SUMO pathway in the context of cancer cell proliferation and tumor growth, we applied lentivirus-based short hairpin RNAs (shRNA) to knockdown SUMO pathway genes in human cancer cells. shRNAs for SAE2 and UBC9 reduced SUMO conjugation activity and inhibited proliferation of human cancer cells. To expand upon these observations, we generated doxycycline inducible conditional shRNA cell lines for SAE2 to achieve acute and reversible SAE2 knockdown. Conditional SAE2 knockdown in U2OS and HCT116 cells slowed cell growth in vitro, and SAE2 knockdown induced multiple terminal outcomes including apoptosis, endoreduplication and senescence. Multinucleated cells became senescent and stained positive for the senescence marker, SA-β Gal, and displayed elevated levels of p53 and p21. In an attempt to explain these phenotypes, we confirmed that loss of SUMO pathway activity leads to a loss of SUMOylated Topoisomerase IIα and the appearance of chromatin bridges which can impair proper cytokinesis and lead to multinucleation. Furthermore, knockdown of SAE2 induces disruption of PML nuclear bodies which may further promote apoptosis or senescence. In an in vivo HCT116 xenograft tumor model, conditional SAE2 knockdown strongly impaired tumor growth. These data demonstrate that the SUMO pathway is required for cancer cell proliferation in vitro and tumor growth in vivo, implicating the SUMO pathway as a potential cancer therapeutic target.

  18. Association between raf kinase inhibitor protein loss and prognosis in cancers of the digestive system: a meta-analysis.

    PubMed

    Yu, Min; Wang, Qian; Ding, Jiang-Wu; Yang, Zhen; Xie, Chuan; Lu, Nong-Hua

    2014-01-01

    Loss of Raf kinase inhibitor protein (RKIP) may contribute to metastasis in a variety of human cancers. Many studies have evaluated whether loss of RKIP expression is a prognostic factor for survival in cancers of the digestive system, however, its predictive value remains controversial. Thus, we performed a meta-analysis to obtain a more comprehensive estimate of the prognostic value of RKIP expression in digestive system cancers. Studies were identified by searching multiple electronic databases through December 12, 2013, and by reviewing reference lists of obtained articles. Studies reported hazard ratios (HRs) with 95% confidence intervals (CIs) for the association between RKIP and overall survival (OS) and disease-free survival (DFS) in cancers of the digestive system were eligible, including esophageal cancer, gastric cancer, colorectal cancer and pancreatic cancer. Nineteen studies involving approximately 3700 participants were included in the final analysis. The pooled results suggested that loss of RKIP expression was associated with unfavorable OS (HR 0.55, 95% CI 0.46-0.65) and DFS (HR 0.46, 95% CI 0.30-0.62) among patients with digestive system cancers, whereas the difference was not statistically significant in pancreatic cancer specifically (OS, HR 0.76; 95% CI 0.51-1.01; DFS, HR 0.71; 95% CI 0.28-1.13). Loss of RKIP expression might be an independent indicator of poor prognosis in patients with digestive tract cancers, which includes esophageal cancer, gastric cancer and colorectal cancer. More studies are needed to further clarify the prognostic value of RKIP in pancreatic cancer. Future studies, preferably large prospective studies utilizing formal marker assessment processes, are needed to establish the prognostic value of RKIP before these results can be clinically applied.

  19. Metabolomic profiling reveals potential markers and bioprocesses altered in bladder cancer progression.

    PubMed

    Putluri, Nagireddy; Shojaie, Ali; Vasu, Vihas T; Vareed, Shaiju K; Nalluri, Srilatha; Putluri, Vasanta; Thangjam, Gagan Singh; Panzitt, Katrin; Tallman, Christopher T; Butler, Charles; Sana, Theodore R; Fischer, Steven M; Sica, Gabriel; Brat, Daniel J; Shi, Huidong; Palapattu, Ganesh S; Lotan, Yair; Weizer, Alon Z; Terris, Martha K; Shariat, Shahrokh F; Michailidis, George; Sreekumar, Arun

    2011-12-15

    Although alterations in xenobiotic metabolism are considered causal in the development of bladder cancer, the precise mechanisms involved are poorly understood. In this study, we used high-throughput mass spectrometry to measure over 2,000 compounds in 58 clinical specimens, identifying 35 metabolites which exhibited significant changes in bladder cancer. This metabolic signature distinguished both normal and benign bladder from bladder cancer. Exploratory analyses of this metabolomic signature in urine showed promise in distinguishing bladder cancer from controls and also nonmuscle from muscle-invasive bladder cancer. Subsequent enrichment-based bioprocess mapping revealed alterations in phase I/II metabolism and suggested a possible role for DNA methylation in perturbing xenobiotic metabolism in bladder cancer. In particular, we validated tumor-associated hypermethylation in the cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1B1 (CYP1B1) promoters of bladder cancer tissues by bisulfite sequence analysis and methylation-specific PCR and also by in vitro treatment of T-24 bladder cancer cell line with the DNA demethylating agent 5-aza-2'-deoxycytidine. Furthermore, we showed that expression of CYP1A1 and CYP1B1 was reduced significantly in an independent cohort of bladder cancer specimens compared with matched benign adjacent tissues. In summary, our findings identified candidate diagnostic and prognostic markers and highlighted mechanisms associated with the silencing of xenobiotic metabolism. The metabolomic signature we describe offers potential as a urinary biomarker for early detection and staging of bladder cancer, highlighting the utility of evaluating metabolomic profiles of cancer to gain insights into bioprocesses perturbed during tumor development and progression.

  20. Loss of the metastasis suppressor gene KiSS1 is associated with lymph node metastasis and poor prognosis in human colorectal cancer.

    PubMed

    Okugawa, Yoshinaga; Inoue, Yasuhiro; Tanaka, Koji; Toiyama, Yuji; Shimura, Tadanobu; Okigami, Masato; Kawamoto, Aya; Hiro, Junichiro; Saigusa, Susumu; Mohri, Yasuhiko; Uchida, Keiichi; Kusunoki, Masato

    2013-09-01

    Cancer research is currently focused on blocking the metastatic process at its early steps. Some particularly attractive targets are metastasis suppressor genes, which control cancer cell dissemination. The aim of this study was to clarify the relationship between the expression of KiSS1, a metastasis suppressor gene, and disease progression in colorectal cancer patients. One-hundred and seventy-five patients who underwent surgery for colorectal cancer were enrolled in this study. We analyzed KiSS1 mRNA expression by real-time reverse transcription PCR in colorectal cancer tissue and paired adjacent normal mucosa. KiSS1 protein expression in early- and advanced-stage colorectal cancer samples was determined by immunohistochemical analysis. Decreased KiSS1 expression was significantly associated with lymph node metastasis and was an independent prognostic factor. Logistic regression analysis revealed that decreased KiSS1 expression was an independent risk factor for lymph node metastasis. Immunohistochemical analysis indicated that KiSS1 was highly expressed in the cell cytoplasm of early-stage colorectal cancer cells. The loss of KiSS1 appears to correlate with the progression of lymph node metastasis. An assessment of KiSS1 expression may assist in the accurate colorectal cancer diagnosis and may contribute to predict clinical outcomes.

  1. Loss of signal transducer and activator of transcription 1 is associated with prostate cancer recurrence.

    PubMed

    Hatziieremia, Sophia; Mohammed, Zahra; McCall, Pamela; Willder, Jennifer M; Roseweir, Antonia K; Underwood, Mark A; Edwards, Joanne

    2016-11-01

    STAT1 loss has previously been implicated in cell line studies to modify prostate cancer cell growth and survival, however the clinical significance of this has not previously been established. This study investigated if STAT1 loss was associated with patient outcome measures and the phenotypic consequence of STAT1 silencing. STAT1 expression was assessed in two patient cohorts with localised (n = 78) and advanced prostate cancer at initial diagnosis (n = 39) by immunohistochemistry (IHC). Impact of STAT1 silencing on prostate cancer cells lines was assessed using Cell Death detection ELISA, TLDA gene signature apoptosis arrays, WST-1 assay, xCELLigence system, clonogenic assay, and wound healing assay. In the localised patient cohort, low expression of STAT1 was associated with shorter time to disease recurrence (3.8 vs 7.3 years, P = 0.02) and disease specific survival (6.6 vs 9.3 years, P = 0.05). In the advanced patient cohort, low expression was associated with shorter time to disease recurrence (2.0 vs 3.9 years, P = 0.001). When STAT1 was silenced in PC3 cells (AR negative) and LNCaP cells (AR positive) silencing did not influence levels of apoptosis in either cell line and had little effect on cell viability in the LNCaP cells. In contrast, STAT1 silencing in the PC3 cells resulted in a pronounced increase in cell viability (WST-1 assay: mock silenced vs STAT1 silenced, P < 0.001), clonagenicity (clonogenic assay: mock silenced vs STAT1 silenced, P < 0.001), and migration (wound healing: mock silenced vs STAT1 silenced, P < 0.001). In conclusion, loss of STAT1 may promote prostate cancer recurrence in AR negative patients via increasing cell viability. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  2. Loss of 5-hydroxymethylcytosine is linked to gene body hypermethylation in kidney cancer.

    PubMed

    Chen, Ke; Zhang, Jing; Guo, Zhongqiang; Ma, Qin; Xu, Zhengzheng; Zhou, Yuanyuan; Xu, Ziying; Li, Zhongwu; Liu, Yiqiang; Ye, Xiongjun; Li, Xuesong; Yuan, Bifeng; Ke, Yuwen; He, Chuan; Zhou, Liqun; Liu, Jiang; Ci, Weimin

    2016-01-01

    Both 5-methylcytosine (5mC) and its oxidized form 5-hydroxymethylcytosine (5hmC) have been proposed to be involved in tumorigenesis. Because the readout of the broadly used 5mC mapping method, bisulfite sequencing (BS-seq), is the sum of 5mC and 5hmC levels, the 5mC/5hmC patterns and relationship of these two modifications remain poorly understood. By profiling real 5mC (BS-seq corrected by Tet-assisted BS-seq, TAB-seq) and 5hmC (TAB-seq) levels simultaneously at single-nucleotide resolution, we here demonstrate that there is no global loss of 5mC in kidney tumors compared with matched normal tissues. Conversely, 5hmC was globally lost in virtually all kidney tumor tissues. The 5hmC level in tumor tissues is an independent prognostic marker for kidney cancer, with lower levels of 5hmC associated with shorter overall survival. Furthermore, we demonstrated that loss of 5hmC is linked to hypermethylation in tumors compared with matched normal tissues, particularly in gene body regions. Strikingly, gene body hypermethylation was significantly associated with silencing of the tumor-related genes. Downregulation of IDH1 was identified as a mechanism underlying 5hmC loss in kidney cancer. Restoring 5hmC levels attenuated the invasion capacity of tumor cells and suppressed tumor growth in a xenograft model. Collectively, our results demonstrate that loss of 5hmC is both a prognostic marker and an oncogenic event in kidney cancer by remodeling the DNA methylation pattern.

  3. CBP loss cooperates with PTEN haploinsufficiency to drive prostate cancer: implications for epigenetic therapy

    PubMed Central

    Ding, Liya; Chen, Shuai; Liu, Ping; Pan, Yunqian; Zhong, Jian; Regan, Kevin M.; Wang, Liguo; Yu, Chunrong; Rizzardi, Tony; Cheng, Liang; Zhang, Jun; Schmechel, Stephen C.; Cheville, John C.; van Deursen, Jan; Tindall, Donald J.; Huang, Haojie

    2014-01-01

    Despite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbppc−/−;Ptenpc+/− mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbp−/−;Pten+/− and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones, in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27KIP1 and p21CIP1. Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbppc−/−;Ptenpc+/− mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic targeted therapy in prostate cancer patients. PMID:24491799

  4. Mechanical phenotype of cancer cells: cell softening and loss of stiffness sensing.

    PubMed

    Lin, Hsi-Hui; Lin, Hsiu-Kuan; Lin, I-Hsuan; Chiou, Yu-Wei; Chen, Horn-Wei; Liu, Ching-Yi; Harn, Hans I-Chen; Chiu, Wen-Tai; Wang, Yang-Kao; Shen, Meng-Ru; Tang, Ming-Jer

    2015-08-28

    The stiffness sensing ability is required to respond to the stiffness of the matrix. Here we determined whether normal cells and cancer cells display distinct mechanical phenotypes. Cancer cells were softer than their normal counterparts, regardless of the type of cancer (breast, bladder, cervix, pancreas, or Ha-RasV12-transformed cells). When cultured on matrices of varying stiffness, low stiffness decreased proliferation in normal cells, while cancer cells and transformed cells lost this response. Thus, cancer cells undergo a change in their mechanical phenotype that includes cell softening and loss of stiffness sensing. Caveolin-1, which is suppressed in many tumor cells and in oncogene-transformed cells, regulates the mechanical phenotype. Caveolin-1-upregulated RhoA activity and Y397FAK phosphorylation directed actin cap formation, which was positively correlated with cell elasticity and stiffness sensing in fibroblasts. Ha-RasV12-induced transformation and changes in the mechanical phenotypes were reversed by re-expression of caveolin-1 and mimicked by the suppression of caveolin-1 in normal fibroblasts. This is the first study to describe this novel role for caveolin-1, linking mechanical phenotype to cell transformation. Furthermore, mechanical characteristics may serve as biomarkers for cell transformation.

  5. Mechanical phenotype of cancer cells: cell softening and loss of stiffness sensing

    PubMed Central

    Lin, I-Hsuan; Chiou, Yu-Wei; Chen, Horn-Wei; Liu, Ching-Yi; Harn, Hans I-Chen; Chiu, Wen-Tai; Wang, Yang-Kao; Shen, Meng-Ru; Tang, Ming-Jer

    2015-01-01

    The stiffness sensing ability is required to respond to the stiffness of the matrix. Here we determined whether normal cells and cancer cells display distinct mechanical phenotypes. Cancer cells were softer than their normal counterparts, regardless of the type of cancer (breast, bladder, cervix, pancreas, or Ha-RasV12-transformed cells). When cultured on matrices of varying stiffness, low stiffness decreased proliferation in normal cells, while cancer cells and transformed cells lost this response. Thus, cancer cells undergo a change in their mechanical phenotype that includes cell softening and loss of stiffness sensing. Caveolin-1, which is suppressed in many tumor cells and in oncogene-transformed cells, regulates the mechanical phenotype. Caveolin-1-upregulated RhoA activity and Y397FAK phosphorylation directed actin cap formation, which was positively correlated with cell elasticity and stiffness sensing in fibroblasts. Ha-RasV12-induced transformation and changes in the mechanical phenotypes were reversed by re-expression of caveolin-1 and mimicked by the suppression of caveolin-1 in normal fibroblasts. This is the first study to describe this novel role for caveolin-1, linking mechanical phenotype to cell transformation. Furthermore, mechanical characteristics may serve as biomarkers for cell transformation. PMID:26189182

  6. Integration of Metabolomics and Transcriptomics Reveals Major Metabolic Pathways and Potential Biomarker Involved in Prostate Cancer*

    PubMed Central

    Ren, Shancheng; Shao, Yaping; Zhao, Xinjie; Hong, Christopher S.; Wang, Fubo; Lu, Xin; Li, Jia; Ye, Guozhu; Yan, Min; Zhuang, Zhengping; Xu, Chuanliang; Xu, Guowang; Sun, Yinghao

    2016-01-01

    Prostate cancer is a highly prevalent tumor affecting millions of men worldwide, but poor understanding of its pathogenesis has limited effective clinical management of patients. In addition to transcriptional profiling or transcriptomics, metabolomics is being increasingly utilized to discover key molecular changes underlying tumorigenesis. In this study, we integrated transcriptomics and metabolomics to analyze 25 paired human prostate cancer tissues and adjacent noncancerous tissues, followed by further validation of our findings in an additional cohort of 51 prostate cancer patients and 16 benign prostatic hyperplasia patients. We found several altered pathways aberrantly expressed at both metabolic and transcriptional levels, including cysteine and methionine metabolism, nicotinamide adenine dinucleotide metabolism, and hexosamine biosynthesis. Additionally, the metabolite sphingosine demonstrated high specificity and sensitivity for distinguishing prostate cancer from benign prostatic hyperplasia, particularly for patients with low prostate specific antigen level (0–10 ng/ml). We also found impaired sphingosine-1-phosphate receptor 2 signaling, downstream of sphingosine, representing a loss of tumor suppressor gene and a potential key oncogenic pathway for therapeutic targeting. By integrating metabolomics and transcriptomics, we have provided both a broad picture of the molecular perturbations underlying prostate cancer and a preliminary study of a novel metabolic signature, which may help to discriminate prostate cancer from normal tissue and benign prostatic hyperplasia. PMID:26545398

  7. Loss of Smad4 in colorectal cancer induces resistance to 5-fluorouracil through activating Akt pathway

    PubMed Central

    Zhang, B; Zhang, B; Chen, X; Bae, S; Singh, K; Washington, M K; Datta, P K

    2014-01-01

    Background: Higher frequency of Smad4 inactivation or loss of expression is observed in metastasis of colorectal cancer (CRC) leading to unfavourable survival and contributes to chemoresistance. However, the molecular mechanism of how Smad4 regulates chemosensitivity of CRC is unknown. Methods: We evaluated how the loss of Smad4 in CRC enhanced chemoresistance to 5-fluorouracil (5-FU) using two CRC cell lines in vitro and in vivo. Immunoblotting with cell and tumour lysates and immunohistochemical analyses with tissue microarray were performed. Results: Knockdown or loss of Smad4 induced tumorigenicity, migration, invasion, angiogenesis, metastasis, and 5-FU resistance. Smad4 expression in mouse tumours regulated cell-cycle regulatory proteins leading to Rb phosphorylation. Loss of Smad4 activated Akt pathway that resulted in upregulation of anti-apoptotic proteins, Bcl-2 and Bcl-w, and Survivin. Suppression of phosphatidylinositol-3-kinase (PI3K)/Akt pathway by LY294002 restored chemosensitivity of Smad4-deficient cells to 5-FU. Vascular endothelial growth factor-induced angiogenesis in Smad4-deficient cells might also lead to chemoresistance. Low levels of Smad4 expression in CRC tissues correlated with higher levels of Bcl-2 and Bcl-w and with poor overall survival as observed in immunohistochemical staining of tissue microarrays. Conclusion: Loss of Smad4 in CRC patients induces resistance to 5-FU-based therapy through activation of Akt pathway and inhibitors of this pathway may sensitise these patients to 5-FU. PMID:24384683

  8. Multipronged quantitative proteomics reveals serum proteome alterations in breast cancer intrinsic subtypes.

    PubMed

    Gajbhiye, Akshada; Dabhi, Raju; Taunk, Khushman; Jagadeeshaprasad, Mashanipalya G; RoyChoudhury, Sourav; Mane, Anupama; Bayatigeri, Santhakumari; Chaudhury, Koel; Santra, Manas K; Rapole, Srikanth

    2017-06-23

    Being molecularly heterogeneous, breast cancer tends to be a complicated oncological disease with high incidence rates throughout the world. The primary aim of this study was to identify the set of serum proteins with discriminatory capabilities towards the four major subtypes of breast cancer. We employed multipronged quantitative proteomic approaches like 2D-DIGE, iTRAQ and SWATH-MS and identified 307 differentially regulated proteins. Luminal A subtype consisted of 24, Luminal B subtype 38, HER2 Enriched subtype 17 and Triple negative breast cancer subtype 10 differentially regulated subtype specific proteins. These specific proteins were further subjected to bioinformatic tools which revealed the involvement in platelet degranulation, fibrinolysis, lipid metabolism, immune response, complement activation, blood coagulation, glycolysis and cancer signaling pathways in the subtypes of the breast cancer. The significant discrimination efficiency of the models generated through multivariate statistical analysis was decent to distinguish each of the four subtypes from controls. Further, some of the statistically significant differentially regulated proteins were verified and validated by immunoblotting and mass spectrometry based selected reaction monitoring (SRM) approach. Our Multipronged proteomics approaches revealed panel of serum proteins specifically altered for individual subtypes of breast cancer. The mass spectrometry data are available via ProteomeXchange with identifier PXD006441. Worldwide, breast cancer continues to be one of the leading causes of cancer related deaths in women and it encompasses four major molecular subtypes. As breast cancer treatment majorly depends on identification of specific subtype, it is important to diagnosis the disease at subtype level. Our results using multipronged quantitative proteomics identified 307 differentially regulated proteins in which 24 were specific for Luminal A, 38 for Luminal B, 17 for HER2 enriched and 10

  9. Platinum Compound-Related Ototoxicity in Children: Long-Term Follow-Up Reveals Continuous Worsening of Hearing Loss.

    PubMed

    Bertolini, Patrizia; Lassalle, Mathilde; Mercier, Guilaine; Raquin, Marie Anne; Izzi, Giancarlo; Corradini, Nadege; Hartmann, Olivier

    2004-10-01

    The purpose of this study was to evaluate the severity of hearing loss after cisplatin and/or carboplatin treatment in young children and to analyze its evolution and its relation to different therapy schedules. One hundred twenty patients treated in the Pediatrics Department at the Institut Gustave-Roussy from 1987 to 1997 for neuroblastoma, osteosarcoma, hepatoblastoma, or germ cell tumors were analyzed. Median age at diagnosis was 2.6 (range 0-17) years. Median follow-up was 7 (1-13) years. Chemotherapy regimens contained cisplatin and/or carboplatin. Three patients also received high-dose carboplatin. Cisplatin was administered at a dose of 200 mg/m/course in 72% of cases. The median cumulative dose was 400 mg/m for cisplatin and 1,600 mg/m for carboplatin. Hearing loss of grade 2 or above, according to Brock's grading scale, was revealed with pure tone audiometry and behavioral techniques. Carboplatin alone was not ototoxic. Deterioration of hearing of grade 2 or above was observed in 37% of patients treated with cisplatin and 43% of patients treated with cisplatin plus carboplatin (P = NS). Fifteen percent of patients experienced grade 3 or 4 ototoxicity. Ototoxicity was most often observed after a total cisplatin dose of at least 400 mg/m. No improvement was observed with time; on the contrary, worsening or progression of hearing loss at lower frequencies was detected during follow-up. Only 5% of audiograms showed toxicity of at least grade 2 before the end of therapy; in contrast, this level was observed in 11% of early post-therapy evaluations and in 44% after more than 2 years of follow-up. Children treated with cisplatin at cumulative doses approaching 400 mg/m require long-term surveillance to avoid overlooking hearing deficits. Carboplatin, at a standard dose, does not appear to be a significant risk factor for ototoxicity even in patients who have already been treated with cisplatin.

  10. DNA copy number profiling reveals extensive genomic loss in hereditary BRCA1 and BRCA2 ovarian carcinomas

    PubMed Central

    Kamieniak, M M; Muñoz-Repeto, I; Rico, D; Osorio, A; Urioste, M; García-Donas, J; Hernando, S; Robles-Díaz, L; Ramón y Cajal, T; Cazorla, A; Sáez, R; García-Bueno, J M; Domingo, S; Borrego, S; Palacios, J; van de Wiel, M A; Ylstra, B; Benítez, J; García, M J

    2013-01-01

    Background: Few studies have attempted to characterise genomic changes occurring in hereditary epithelial ovarian carcinomas (EOCs) and inconsistent results have been obtained. Given the relevance of DNA copy number alterations in ovarian oncogenesis and growing clinical implications of the BRCA-gene status, we aimed to characterise the genomic profiles of hereditary and sporadic ovarian tumours. Methods: High-resolution array Comparative Genomic Hybridisation profiling of 53 familial (21 BRCA1, 6 BRCA2 and 26 non-BRCA1/2) and 15 sporadic tumours in combination with supervised and unsupervised analysis was used to define common and/or specific copy number features. Results: Unsupervised hierarchical clustering did not stratify tumours according to their familial or sporadic condition or to their BRCA1/2 mutation status. Common recurrent changes, spanning genes potentially fundamental for ovarian carcinogenesis, regardless of BRCA mutations, and several candidate subtype-specific events were defined. Despite similarities, greater contribution of losses was revealed to be a hallmark of BRCA1 and BRCA2 tumours. Conclusion: Somatic alterations occurring in the development of familial EOCs do not differ substantially from the ones occurring in sporadic carcinomas. However, some specific features like extensive genomic loss observed in BRCA1/2 tumours may be of clinical relevance helping to identify BRCA-related patients likely to respond to PARP inhibitors. PMID:23558894

  11. Novel personalized pathway-based metabolomics models reveal key metabolic pathways for breast cancer diagnosis.

    PubMed

    Huang, Sijia; Chong, Nicole; Lewis, Nathan E; Jia, Wei; Xie, Guoxiang; Garmire, Lana X

    2016-03-31

    More accurate diagnostic methods are pressingly needed to diagnose breast cancer, the most common malignant cancer in women worldwide. Blood-based metabolomics is a promising diagnostic method for breast cancer. However, many metabolic biomarkers are difficult to replicate among studies. We propose that higher-order functional representation of metabolomics data, such as pathway-based metabolomic features, can be used as robust biomarkers for breast cancer. Towards this, we have developed a new computational method that uses personalized pathway dysregulation scores for disease diagnosis. We applied this method to predict breast cancer occurrence, in combination with correlation feature selection (CFS) and classification methods. The resulting all-stage and early-stage diagnosis models are highly accurate in two sets of testing blood samples, with average AUCs (Area Under the Curve, a receiver operating characteristic curve) of 0.968 and 0.934, sensitivities of 0.946 and 0.954, and specificities of 0.934 and 0.918. These two metabolomics-based pathway models are further validated by RNA-Seq-based TCGA (The Cancer Genome Atlas) breast cancer data, with AUCs of 0.995 and 0.993. Moreover, important metabolic pathways, such as taurine and hypotaurine metabolism and the alanine, aspartate, and glutamate pathway, are revealed as critical biological pathways for early diagnosis of breast cancer. We have successfully developed a new type of pathway-based model to study metabolomics data for disease diagnosis. Applying this method to blood-based breast cancer metabolomics data, we have discovered crucial metabolic pathway signatures for breast cancer diagnosis, especially early diagnosis. Further, this modeling approach may be generalized to other omics data types for disease diagnosis.

  12. Microarray analysis of colorectal cancer stromal tissue reveals upregulation of two oncogenic miRNA clusters.

    PubMed

    Nishida, Naohiro; Nagahara, Makoto; Sato, Tetsuya; Mimori, Koshi; Sudo, Tomoya; Tanaka, Fumiaki; Shibata, Kohei; Ishii, Hideshi; Sugihara, Kenichi; Doki, Yuichiro; Mori, Masaki

    2012-06-01

    Cancer stroma plays an important role in the progression of cancer. Although alterations in miRNA expression have been explored in various kinds of cancers, the expression of miRNAs in cancer stroma has not been explored in detail. Using a laser microdissection technique, we collected RNA samples specific for epithelium or stroma from 13 colorectal cancer tissues and four normal tissues, and miRNA microarray and gene expression microarray were carried out. The expression status of miRNAs was confirmed by reverse transcriptase PCR. Furthermore, we investigated whether miRNA expression status in stromal tissue could influence the clinicopathologic factors. Oncogenic miRNAs, including two miRNA clusters, miR-17-92a and miR-106b-25 cluster, were upregulated in cancer stromal tissues compared with normal stroma. Gene expression profiles from cDNA microarray analyses of the same stromal tissue samples revealed that putative targets of these miRNA clusters, predicted by Target Scan, such as TGFBR2, SMAD2, and BMP family genes, were significantly downregulated in cancer stromal tissue. Downregulated putative targets were also found to be involved in cytokine interaction and cellular adhesion. Importantly, expression of miR-25 and miR-92a in stromal tissues was associated with a variety of clinicopathologic factors. Oncogenic miRNAs were highly expressed in cancer stroma. Although further validation is required, the finding that stromal miRNA expression levels were associated with clinicopathologic factors suggests the possibility that miRNAs in cancer stroma are crucially involved in cancer progression.

  13. RNASeq analysis reveals biological processes governing the clinical behaviour of endometrioid and serous endometrial cancers.

    PubMed

    Lemetre, Christophe; Vieites, Begoña; Ng, Charlotte K Y; Piscuoglio, Salvatore; Schultheis, Anne M; Marchiò, Caterina; Murali, Rajmohan; Lopez-García, Maria A; Palacios, Jose C; Jungbluth, Achim A; Terracciano, Luigi M; Reis-Filho, Jorge S; Weigelt, Britta

    2016-09-01

    Endometrial carcinoma comprises a group of tumours with distinct histologic and molecular features and clinical behaviour. Here, we sought to define the biological processes that govern the clinical behaviour of endometrial cancers. Sixteen prototype genes representative of different biological processes that would likely play a role in endometrial and other hormone-driven cancers were defined. RNA-sequencing gene expression data from 323 endometrial cancers from The Cancer Genome Atlas (TCGA) were used to determine the transcription module of each prototype gene. The expression of prototype genes and modules and their association with outcome was assessed in univariate and multivariate survival analyses. The association of MSH6 expression with outcome was validated in an independent cohort of 243 primary endometrial cancers using immunohistochemistry. We observed that the clinical behaviour of endometrial cancers as a group was associated with hormone receptor signalling, PI3K pathway signalling and DNA mismatch repair processes. When analysed separately, in endometrioid carcinomas, hormone receptor, PI3K and DNA mismatch repair modules were significantly associated with outcome in univariate analysis, whereas the clinical behaviour of serous cancers was likely governed by apoptosis and Wnt signalling. Multivariate survival analysis revealed that MSH6 gene expression was associated with outcome of endometrial cancer patients independently from traditional prognostic clinicopathologic parameters, which was confirmed in an independent cohort at the protein level. Endometrioid and serous endometrial cancers are underpinned by distinct molecular pathways. MSH6 expression levels may be associated with outcome in endometrial cancers as a group. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. The gain and loss of long noncoding RNA associated-competing endogenous RNAs in prostate cancer

    PubMed Central

    Wang, Shuyuan; Dai, Enyu; Jiang, Leiming; Wang, Jing; Yang, Qian; Yang, Feng; Zhou, Shunheng; Jiang, Wei

    2016-01-01

    Prostate cancer (PC) is one of the most common solid tumors in men. However, the molecular mechanism of PC remains unclear. Numerous studies have demonstrated that long noncoding RNA (lncRNA) can act as microRNA (miRNA) sponge, one type of competing endogenous RNAs (ceRNAs), which offers a novel viewpoint to elucidate the mechanisms of PC. Here, we proposed an integrative systems biology approach to infer the gain and loss of ceRNAs in PC. First, we re-annotated exon microarray data to obtain lncRNA expression profiles of PC. Second, by integrating mRNA and miRNA expression, as well as miRNA targets, we constructed lncRNA-miRNA-mRNA ceRNA networks in cancer and normal samples. The lncRNAs in these two ceRNA networks tended to have a longer transcript length and cover more exons than the lncRNAs not involved in ceRNA networks. Next, we further extracted the gain and loss ceRNA networks in PC. We found that the gain ceRNAs in PC participated in cell cycle, and the loss ceRNAs in PC were associated with metabolism. We also identified potential prognostic ceRNA pairs such as MALAT1-EGR2 and MEG3-AQP3. Finally, we inferred a novel mechanism of known drugs, such as cisplatin, for the treatment of PC through gain and loss ceRNA networks. The potential drugs such as 1,2,6-tri-O-galloyl-beta-D-glucopyranose (TGGP) could modulate lncRNA-mRNA competing relationships, which may uncover new strategy for treating PC. In summary, we systematically investigated the gain and loss of ceRNAs in PC, which may prove useful for identifying potential biomarkers and therapeutics for PC. PMID:27528026

  15. Mutational strand asymmetries in cancer genomes reveal mechanisms of DNA damage and repair

    PubMed Central

    Haradhvala, Nicholas J.; Polak, Paz; Stojanov, Petar; Covington, Kyle R.; Shinbrot, Eve; Hess, Julian; Rheinbay, Esther; Kim, Jaegil; Maruvka, Yosef; Braunstein, Lior Z.; Kamburov, Atanas; Hanawalt, Philip C.; Wheeler, David A.; Koren, Amnon; Lawrence, Michael S.; Getz, Gad

    2016-01-01

    Mutational processes constantly shape the somatic genome, leading to immunity, aging, and other diseases. When cancer is the outcome, we are afforded a glimpse into these processes by the clonal expansion of the malignant cell. Here, we characterize a less explored layer of the mutational landscape of cancer: mutational asymmetries between the two DNA strands. Analyzing whole genome sequences of 590 tumors from 14 different cancer types, we reveal widespread asymmetries across mutagenic processes, with transcriptional (“T-class”) asymmetry dominating UV-, smoking-, and liver-cancer-associated mutations, and replicative (“R-class”) asymmetry dominating POLE-, APOBEC-, and MSI-associated mutations. We report a striking phenomenon of Transcription-Coupled Damage (TCD) on the non-transcribed DNA strand, and provide evidence that APOBEC mutagenesis occurs on the lagging-strand template during DNA replication. As more genomes are sequenced, studying and classifying their asymmetries will illuminate the underlying biological mechanisms of DNA damage and repair. PMID:26806129

  16. Variation in Carbohydrates between Cancer and Normal Cell Membranes Revealed by Super‐Resolution Fluorescence Imaging

    PubMed Central

    Chen, Junling; Liu, Tianzhou; Gao, Jing; Gao, Lan; Zhou, Lulu; Cai, Mingjun; Shi, Yan; Xiong, Wenyong; Jiang, Junguang

    2016-01-01

    Carbohydrate alterations on cell membranes are associated with various cancer processes, including tumorigenesis, malignant transformation, and tumor dissemination. However, variations in the distributions of cancer‐associated carbohydrates are unclear at the molecular level. Herein, direct stochastic optical reconstruction microscopy is used to reveal that seven major types of carbohydrates tended to form obvious clusters on cancer cell membranes compared with normal cell membranes (both cultured and primary cells), and most types of carbohydrates present a similar distributed characteristic on various cancer cells (e.g., HeLa and Os‐Rc‐2 cells). Significantly, sialic acid is found to distribute in larger‐sized clusters with a higher cluster coverage percentage on various cancer cells than normal cells. These findings on the aberrant distributions of cancer‐associated carbohydrates can potentially serve as novel diagnostic and therapeutic targets, as well as making a contribution to clarify how abnormal glycosylations of membrane glycoconjugates participate in tumorigenesis and metastasis. PMID:27981014

  17. A Transposon-based Analysis Reveals RASA1 Is Involved in Triple-Negative Breast Cancer.

    PubMed

    Suárez-Cabrera, Cristian; Quintana, Rita M; Bravo, Ana; Casanova, M Llanos; Page, Angustias; Alameda, Josefa P; Paramio, Jesús M; Maroto, Alicia; Salamanca, Javier; Dupuy, Adam J; Ramírez, Angel; Navarro, Manuel

    2017-03-15

    RAS genes are mutated in 20% of human tumors, but these mutations are very rare in breast cancer. Here, we used a mouse model to generate tumors upon activation of a mutagenic T2Onc2 transposon via expression of a transposase driven by the keratin K5 promoter in a p53(+/-) background. These animals mainly developed mammary tumors, most of which had transposon insertions in one of two RASGAP genes, neurofibromin1 (Nf1) and RAS p21 protein activator (Rasa1). Immunohistochemical analysis of a collection of human breast tumors confirmed that low expression of RASA1 is frequent in basal (triple-negative) and estrogen receptor negative tumors. Bioinformatic analysis of human breast tumors in The Cancer Genome Atlas database showed that although RASA1 mutations are rare, allelic loss is frequent, particularly in basal tumors (80%) and in association with TP53 mutation. Inactivation of RASA1 in MCF10A cells resulted in the appearance of a malignant phenotype in the context of mutated p53. Our results suggest that alterations in the Ras pathway due to the loss of negative regulators of RAS may be a common event in basal breast cancer. Cancer Res; 77(6); 1357-68. ©2017 AACR.

  18. Loss of antigen-presenting molecules (MHC class I and TAP-1) in lung cancer.

    PubMed Central

    Korkolopoulou, P.; Kaklamanis, L.; Pezzella, F.; Harris, A. L.; Gatter, K. C.

    1996-01-01

    Presentation of endogenous antigenic peptides to cytotoxic T lymphocytes is mediated by the major histocompatibility complex (MHC) class I molecules. For the stable assembly of MHC class I complex it is necessary that the antigenic peptide is transported by the MHC-encoded transporters TAP-1 and TAP-2 into a pre-Golgi region. T-cell-mediated host-vs-tumour response might therefore depend on the presence of these molecules on tumour cells. The presence of MHC class I antigens and TAP-1 was studied in a series of 93 resection specimens of non-small-cell lung carcinomas (NSCLCs) by immunohistochemical methods using antibodies against the assembled class I molecule, beta 2-microglobulin (beta 2-m), heavy-chain A locus, A2 allele and TAP-1 protein. Eighty-six patients were included in the survival analysis. Total loss of class I molecule was observed in 38% of the cases and was usually accompanied by loss of beta 2-m and of heavy chain A locus. Selective loss of A locus was seen in 8.3% and of A2 allele in 27% of the cases. TAP-1 loss was always combined with beta 2-m and/or heavy chain A locus loss. No correlation was found between the expressional status of any of the above molecules, including the selective A2 allelic loss and histological type, degree of differentiation, tumoral stage, nodal stage and survival. Our findings suggest that loss of antigen-presenting molecules (including both MHC class I alleles and TAP-1) is a frequent event in lung cancer. However, the immunophenotypic profile of MHC class I and TAP-1 seems to be unrelated in vivo to the phenotype, growth or survival of NSCLC. Images Figure 1 PMID:8546899

  19. Having pancreatic cancer with tumoral loss of ATM and normal TP53 protein expression is associated with a poorer prognosis.

    PubMed

    Kim, Haeryoung; Saka, Burcu; Knight, Spencer; Borges, Michael; Childs, Erica; Klein, Alison; Wolfgang, Christopher; Herman, Joseph; Adsay, Volkan N; Hruban, Ralph H; Goggins, Michael

    2014-04-01

    To determine how often loss of ataxia-telangiectasia-mutated (ATM) protein expression occurs in primary pancreatic ductal adenocarcinomas and to determine its prognostic significance. The expression of ATM and TP53 was determined by immunohistochemistry in 397 surgically resected pancreatic ductal adenocarcinomas (Hopkins; Johns Hopkins Medical Institutions, Baltimore, MD), a second set of 159 cases (Emory; Emory University Hospital, Atlanta, GA), and 21 cancers after neoadjuvant chemoradiotherapy. Expression was correlated with the clinicopathologic parameters, including survival. Tumoral ATM loss was observed in one cancer known to have biallelic inactivation of ATM and 50 of the first 396 (12.8%) cases, significantly more often in patients with a family history of pancreatic cancer (12/49; 24.5%) than in those without (38/347; 11.0%; P = 0.019). In the Hopkins series, ATM loss was associated with a significantly decreased overall survival in patients whose cancers had normal TP53 expression (P = 0.019) and was a significant independent predictor of decreased overall survival (P = 0.014). Seventeen (10.7%) of 159 Emory cases had tumoral ATM loss and tumoral ATM loss/normal TP53 was associated with poorer overall survival (P = 0.1). Multivariate analysis of the combined Hopkins/Emory cases found that tumoral ATM loss/normal TP53 was an independent predictor of decreased overall survival [HR = 2.61; confidence interval (CI), 1.27-5.37; P = 0.009]. Of 21 cancers examined after neoadjuvant chemoradiotherapy, one had tumoral loss of ATM; it had no histologic evidence of tumor response. Tumoral loss of ATM protein was detected more often in patients with a family history of pancreatic cancer than in those without. Patients whose pancreatic cancers had loss of ATM but normal TP53 had worse overall survival after pancreatic resection. ©2014 AACR.

  20. Having pancreatic cancer with tumoral loss of ATM and normal TP53 protein expression is associated with a poorer prognosis

    PubMed Central

    Kim, Haeryoung; Saka, Burcu; Knight, Spencer; Borges, Michael; Childs, Erica; Klein, Alison; Wolfgang, Christopher; Herman, Joseph; Adsay, Volkan N.; Hruban, Ralph H.; Goggins, Michael

    2014-01-01

    Purpose To determine how often loss of ATM protein expression occurs in primary pancreatic ductal adenocarcinomas and to determine its prognostic significance. Experimental Design The expression of ATM and TP53 was determined by immunohistochemistry in 397 surgically-resected pancreatic ductal adenocarcinomas (Hopkins), a second set of 159 cases (Emory) and 21 cancers after neoadjuvant chemoradiotherapy. Expression was correlated with the clinicopathologic parameters, including survival. Results Tumoral ATM loss was observed in one cancer known to have bi-allelic inactivation of ATM and 50 of the first 396 (12.8%) cases, significantly more often in patients with a family history of pancreatic cancer (12/49; 24.5%) than in those without (38/347; 11.0%) (p=0.019). In the Hopkins series, ATM loss was associated with a significantly decreased overall survival in patients whose cancers had normal TP53 expression (p=0.019) and was a significant independent predictor of decreased overall survival (p=0.014). Seventeen (10.7%) of 159 Emory cases had tumoral ATM loss and tumoral ATM loss/normal TP53 was associated with poorer overall survival (p=0.1). Multivariate analysis of the combined Hopkins/Emory cases found tumoral ATM loss/normal TP53 was an independent predictor of decreased overall survival (HR 2.61, CI1.27–5.37, p=0.009). Of 21 cancers examined after neoadjuvant chemoradiotherapy one had tumoral loss of ATM; it had no histological evidence of tumor response. Conclusions Tumoral loss of ATM protein was detected more often in patients with a family history of pancreatic cancer than in those without. Patients whose pancreatic cancers had loss of ATM but normal TP53 had worse overall survival after pancreatic resection. PMID:24486587

  1. Estimating the loss in expectation of life due to cancer using flexible parametric survival models.

    PubMed

    Andersson, Therese M-L; Dickman, Paul W; Eloranta, Sandra; Lambe, Mats; Lambert, Paul C

    2013-12-30

    A useful summary measure for survival data is the expectation of life, which is calculated by obtaining the area under a survival curve. The loss in expectation of life due to a certain type of cancer is the difference between the expectation of life in the general population and the expectation of life among the cancer patients. This measure is used little in practice as its estimation generally requires extrapolation of both the expected and observed survival. A parametric distribution can be used for extrapolation of the observed survival, but it is difficult to find a distribution that captures the underlying shape of the survival function after the end of follow-up. In this paper, we base our extrapolation on relative survival, because it is more stable and reliable. Relative survival is defined as the observed survival divided by the expected survival, and the mortality analogue is excess mortality. Approaches have been suggested for extrapolation of relative survival within life-table data, by assuming that the excess mortality has reached zero (statistical cure) or has stabilized to a constant. We propose the use of flexible parametric survival models for relative survival, which enables estimating the loss in expectation of life on individual level data by making these assumptions or by extrapolating the estimated linear trend at the end of follow-up. We have evaluated the extrapolation from this model using data on four types of cancer, and the results agree well with observed data.

  2. Erythropoietin administration partially prevents adipose tissue loss in experimental cancer cachexia models

    PubMed Central

    Penna, Fabio; Busquets, Silvia; Toledo, Miriam; Pin, Fabrizio; Massa, David; López-Soriano, Francisco J.; Costelli, Paola; Argilés, Josep M.

    2013-01-01

    Cancer-associated cachexia is characterized, among other symptoms, by a dramatic loss of both muscle and fat. In addition, the cachectic syndrome is often associated with anemia. The object of the present investigation was to assess the effects of erythropoietin (EPO) treatment on experimental cancer cachexia models. The results clearly show that, in addition to the improvement of the hematocrit, EPO treatment promoted a partial preservation of adipose tissue while exerting negligible effects on muscle loss. Administration of EPO to tumor-bearing animals resulted in a significant increase of lipoprotein lipase (LPL) activity in adipose tissue, suggesting that the treatment favored triacylglycerol (TAG) accumulation in the adipose tissue. In vitro experiments using both adipose tissue slices and 3T3-L1 adipocytes suggests that EPO is able to increase the lipogenic rate through the activation of its specific receptor (EPOR). This metabolic pathway, in addition to TAG uptake by LPL, may contribute to the beneficial effects of EPO on fat preservation in cancer cachexia. PMID:23966665

  3. Quantitative proteomics reveals middle infrared radiation-interfered networks in breast cancer cells.

    PubMed

    Chang, Hsin-Yi; Li, Ming-Hua; Huang, Tsui-Chin; Hsu, Chia-Lang; Tsai, Shang-Ru; Lee, Si-Chen; Huang, Hsuan-Cheng; Juan, Hsueh-Fen

    2015-02-06

    Breast cancer is one of the leading cancer-related causes of death worldwide. Treatment of triple-negative breast cancer (TNBC) is complex and challenging, especially when metastasis has developed. In this study, we applied infrared radiation as an alternative approach for the treatment of TNBC. We used middle infrared (MIR) with a wavelength range of 3-5 μm to irradiate breast cancer cells. MIR significantly inhibited cell proliferation in several breast cancer cells but did not affect the growth of normal breast epithelial cells. We performed iTRAQ-coupled LC-MS/MS analysis to investigate the MIR-triggered molecular mechanisms in breast cancer cells. A total of 1749 proteins were identified, quantified, and subjected to functional enrichment analysis. From the constructed functionally enriched network, we confirmed that MIR caused G2/M cell cycle arrest, remodeled the microtubule network to an astral pole arrangement, altered the actin filament formation and focal adhesion molecule localization, and reduced cell migration activity and invasion ability. Our results reveal the coordinative effects of MIR-regulated physiological responses in concentrated networks, demonstrating the potential implementation of infrared radiation in breast cancer therapy.

  4. Exome analysis reveals differentially mutated gene signatures of stage, grade and subtype in breast cancers.

    PubMed

    Li, You; Wang, Xiaosheng; Vural, Suleyman; Mishra, Nitish K; Cowan, Kenneth H; Guda, Chittibabu

    2015-01-01

    Breast cancers exhibit highly heterogeneous molecular profiles. Although gene expression profiles have been used to predict the risks and prognostic outcomes of breast cancers, the high variability of gene expression limits its clinical application. In contrast, genetic mutation profiles would be more advantageous than gene expression profiles because genetic mutations can be stably detected and the mutational heterogeneity widely exists in breast cancer genomes. We analyzed 98 breast cancer whole exome samples that were sorted into three subtypes, two grades and two stages. The sum deleterious effect of all mutations in each gene was scored to identify differentially mutated genes (DMGs) for this case-control study. DMGs were corroborated using extensive published knowledge. Functional consequences of deleterious SNVs on protein structure and function were also investigated. Genes such as ERBB2, ESP8, PPP2R4, KIAA0922, SP4, CENPJ, PRCP and SELP that have been experimentally or clinically verified to be tightly associated with breast cancer prognosis are among the DMGs identified in this study. We also identified some genes such as ARL6IP5, RAET1E, and ANO7 that could be crucial for breast cancer development and prognosis. Further, SNVs such as rs1058808, rs2480452, rs61751507, rs79167802, rs11540666, and rs2229437 that potentially influence protein functions are observed at significantly different frequencies in different comparison groups. Protein structure modeling revealed that many non-synonymous SNVs have a deleterious effect on protein stability, structure and function. Mutational profiling at gene- and SNV-level revealed differential patterns within each breast cancer comparison group, and the gene signatures correlate with expected prognostic characteristics of breast cancer classes. Some of the genes and SNVs identified in this study show high promise and are worthy of further investigation by experimental studies.

  5. Exome Analysis Reveals Differentially Mutated Gene Signatures of Stage, Grade and Subtype in Breast Cancers

    PubMed Central

    Li, You; Wang, Xiaosheng; Vural, Suleyman; Mishra, Nitish K.; Cowan, Kenneth H.; Guda, Chittibabu

    2015-01-01

    Breast cancers exhibit highly heterogeneous molecular profiles. Although gene expression profiles have been used to predict the risks and prognostic outcomes of breast cancers, the high variability of gene expression limits its clinical application. In contrast, genetic mutation profiles would be more advantageous than gene expression profiles because genetic mutations can be stably detected and the mutational heterogeneity widely exists in breast cancer genomes. We analyzed 98 breast cancer whole exome samples that were sorted into three subtypes, two grades and two stages. The sum deleterious effect of all mutations in each gene was scored to identify differentially mutated genes (DMGs) for this case-control study. DMGs were corroborated using extensive published knowledge. Functional consequences of deleterious SNVs on protein structure and function were also investigated. Genes such as ERBB2, ESP8, PPP2R4, KIAA0922, SP4, CENPJ, PRCP and SELP that have been experimentally or clinically verified to be tightly associated with breast cancer prognosis are among the DMGs identified in this study. We also identified some genes such as ARL6IP5, RAET1E, and ANO7 that could be crucial for breast cancer development and prognosis. Further, SNVs such as rs1058808, rs2480452, rs61751507, rs79167802, rs11540666, and rs2229437 that potentially influence protein functions are observed at significantly different frequencies in different comparison groups. Protein structure modeling revealed that many non-synonymous SNVs have a deleterious effect on protein stability, structure and function. Mutational profiling at gene- and SNV-level revealed differential patterns within each breast cancer comparison group, and the gene signatures correlate with expected prognostic characteristics of breast cancer classes. Some of the genes and SNVs identified in this study show high promise and are worthy of further investigation by experimental studies. PMID:25803781

  6. Loss of DLG5 promotes breast cancer malignancy by inhibiting the Hippo signaling pathway.

    PubMed

    Liu, Jie; Li, Juan; Li, Pingping; Wang, Yaochun; Liang, Zheyong; Jiang, Yina; Li, Jing; Feng, Chen; Wang, Ruiqi; Chen, He; Zhou, Can; Zhang, Jianmin; Yang, Jin; Liu, Peijun

    2017-02-07

    Discs Large Homolog 5 (DLG5) plays an important role in the maintenance of epithelial cell polarity. Recent research showed that DLG5 is decreased in Yes-associated protein (YAP)-overexpressing cells. However, the exact relationship between DLG5 and YAP is not clear. In this study, we showed that loss of DLG5 promoted breast cancer cell proliferation by inhibiting the Hippo signaling pathway and increasing nuclear YAP expression. Furthermore, depletion of DLG5 induced epithelial-mesenchymal transition (EMT) and disrupted epithelial cell polarity, which was associated with altered expression of Scribble, ZO1, E-cadherin and N-cadherin and their mislocalization. Interestingly, we first reported that loss of DLG5 inhibited the interaction of Mst1 and Lats1 with Scribble, which was crucial for YAP activation and the transcription of TEA domain (TEAD) family members. In summary, loss of DLG5 expression promoted breast cancer malignancy by inactivating the Hippo signaling pathway and increasing nuclear YAP.

  7. Loss of DLG5 promotes breast cancer malignancy by inhibiting the Hippo signaling pathway

    PubMed Central

    Liu, Jie; Li, Juan; Li, Pingping; Wang, Yaochun; Liang, Zheyong; Jiang, Yina; Li, Jing; Feng, Chen; Wang, Ruiqi; Chen, He; Zhou, Can; Zhang, Jianmin; Yang, Jin; Liu, Peijun

    2017-01-01

    Discs Large Homolog 5 (DLG5) plays an important role in the maintenance of epithelial cell polarity. Recent research showed that DLG5 is decreased in Yes-associated protein (YAP)-overexpressing cells. However, the exact relationship between DLG5 and YAP is not clear. In this study, we showed that loss of DLG5 promoted breast cancer cell proliferation by inhibiting the Hippo signaling pathway and increasing nuclear YAP expression. Furthermore, depletion of DLG5 induced epithelial-mesenchymal transition (EMT) and disrupted epithelial cell polarity, which was associated with altered expression of Scribble, ZO1, E-cadherin and N-cadherin and their mislocalization. Interestingly, we first reported that loss of DLG5 inhibited the interaction of Mst1 and Lats1 with Scribble, which was crucial for YAP activation and the transcription of TEA domain (TEAD) family members. In summary, loss of DLG5 expression promoted breast cancer malignancy by inactivating the Hippo signaling pathway and increasing nuclear YAP. PMID:28169360

  8. KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer

    PubMed Central

    Krall, Elsa B; Wang, Belinda; Munoz, Diana M; Ilic, Nina; Raghavan, Srivatsan; Niederst, Matthew J; Yu, Kristine; Ruddy, David A; Aguirre, Andrew J; Kim, Jong Wook; Redig, Amanda J; Gainor, Justin F; Williams, Juliet A; Asara, John M; Doench, John G; Janne, Pasi A; Shaw, Alice T; McDonald III, Robert E; Engelman, Jeffrey A; Stegmeier, Frank; Schlabach, Michael R; Hahn, William C

    2017-01-01

    Inhibitors that target the receptor tyrosine kinase (RTK)/Ras/mitogen-activated protein kinase (MAPK) pathway have led to clinical responses in lung and other cancers, but some patients fail to respond and in those that do resistance inevitably occurs (Balak et al., 2006; Kosaka et al., 2006; Rudin et al., 2013; Wagle et al., 2011). To understand intrinsic and acquired resistance to inhibition of MAPK signaling, we performed CRISPR-Cas9 gene deletion screens in the setting of BRAF, MEK, EGFR, and ALK inhibition. Loss of KEAP1, a negative regulator of NFE2L2/NRF2, modulated the response to BRAF, MEK, EGFR, and ALK inhibition in BRAF-, NRAS-, KRAS-, EGFR-, and ALK-mutant lung cancer cells. Treatment with inhibitors targeting the RTK/MAPK pathway increased reactive oxygen species (ROS) in cells with intact KEAP1, and loss of KEAP1 abrogated this increase. In addition, loss of KEAP1 altered cell metabolism to allow cells to proliferate in the absence of MAPK signaling. These observations suggest that alterations in the KEAP1/NRF2 pathway may promote survival in the presence of multiple inhibitors targeting the RTK/Ras/MAPK pathway. DOI: http://dx.doi.org/10.7554/eLife.18970.001 PMID:28145866

  9. Loss of the desmosomal cadherin desmoglein-2 suppresses colon cancer cell proliferation through EGFR signaling

    PubMed Central

    Kamekura, R; Kolegraff, KN; Nava, P; Hilgarth, RS; Feng, M; Parkos, CA; Nusrat, A

    2014-01-01

    Desmosomal cadherins mediate cell–cell adhesion in epithelial tissues and have been known to be altered in cancer. We have previously shown that one of the two intestinal epithelial desmosomal cadherins, desmocollin-2 (Dsc2) loss promotes colonic epithelial carcinoma cell proliferation and tumor formation. In this study we show that loss of the other intestinal desmosomal cadherin, desmoglein-2 (Dsg2) that pairs with Dsc2, results in decreased epithelial cell proliferation and suppressed xenograft tumor growth in mice. Dsg2-deficient cells demonstrated a compensatory increase in Dsc2 expression, and small interfering RNA-mediated loss of Dsc2 restored proliferation in Dsg2-deficient cells. Dsg2 downregulation inhibited epidermal growth factor receptor (EGFR) signaling and cell proliferation through altered phosphorylation of EGFR and downstream extracellular signal-regulated kinase activation in parallel with inhibited EGFR receptor internalization. Additionally, we demonstrated a central role of Dsc2 in controlling EGFR signaling and cell proliferation in intestinal epithelial cells. Consistent with these findings, analyses of human colon cancers demonstrated increased Dsg2 protein expression. Taken together, these data demonstrate that partner desmosomal cadherins Dsg2 and Dsc2 play opposing roles in controlling colonic carcinoma cell proliferation through differential effects on EGFR signaling. PMID:24166502

  10. Frequent loss of heterozygosity at 7q31.1 in primary prostate cancer is associated with tumor aggressiveness and progression.

    PubMed

    Takahashi, S; Shan, A L; Ritland, S R; Delacey, K A; Bostwick, D G; Lieber, M M; Thibodeau, S N; Jenkins, R B

    1995-09-15

    Cytogenetic analyses have demonstrated that chromosome region 7q22-32 is commonly altered in prostate adenocarcinomas. In addition, in recent fluorescence in situ hybridization studies, we have observed that aneusomy of chromosome 7 is frequent in prostate cancer and is associated with higher tumor grade, advanced pathological stage, and early prostate cancer death. These findings suggest that genetic alterations of chromosome 7 play a significant role in the development of prostate cancer. To better define the chromosome 7 alterations, PCR analysis of 21 microsatellite loci was performed on 54 paired prostate cancer and control DNAs. Overall, chromosome 7 allelic imbalance was identified in 16 of 54 cases (30%). Allelic imbalances of loci mapped to 7q were observed in 15 of the 16 cases. The allelic imbalances were classified as losses in 15 tumors (28%) and as gains in 1 (2%) by comparative multiplex PCR analysis. The most common site of allelic loss included loci D7S523 and D7S486 at 7q31.1. A comparison with clinicopathological features of the tested tumors revealed that the allelic loss of 7q31.1 correlated with higher tumor grade (P = 0.012) and lymph node metastasis (P = 0.017). These results indicate that 7q31 may be the site of a putative suppressor gene(s) important for the pathogenesis of prostate carcinoma, and that the genetic alterations at 7q31.1 may participate in tumor progression and metastasis.

  11. Single cell sequencing reveals heterogeneity within ovarian cancer epithelium and cancer associated stromal cells.

    PubMed

    Winterhoff, Boris J; Maile, Makayla; Mitra, Amit Kumar; Sebe, Attila; Bazzaro, Martina; Geller, Melissa A; Abrahante, Juan E; Klein, Molly; Hellweg, Raffaele; Mullany, Sally A; Beckman, Kenneth; Daniel, Jerry; Starr, Timothy K

    2017-03-01

    The purpose of this study was to determine the level of heterogeneity in high grade serous ovarian cancer (HGSOC) by analyzing RNA expression in single epithelial and cancer associated stromal cells. In addition, we explored the possibility of identifying subgroups based on pathway activation and pre-defined signatures from cancer stem cells and chemo-resistant cells. A fresh, HGSOC tumor specimen derived from ovary was enzymatically digested and depleted of immune infiltrating cells. RNA sequencing was performed on 92 single cells and 66 of these single cell datasets passed quality control checks. Sequences were analyzed using multiple bioinformatics tools, including clustering, principle components analysis, and geneset enrichment analysis to identify subgroups and activated pathways. Immunohistochemistry for ovarian cancer, stem cell and stromal markers was performed on adjacent tumor sections. Analysis of the gene expression patterns identified two major subsets of cells characterized by epithelial and stromal gene expression patterns. The epithelial group was characterized by proliferative genes including genes associated with oxidative phosphorylation and MYC activity, while the stromal group was characterized by increased expression of extracellular matrix (ECM) genes and genes associated with epithelial-to-mesenchymal transition (EMT). Neither group expressed a signature correlating with published chemo-resistant gene signatures, but many cells, predominantly in the stromal subgroup, expressed markers associated with cancer stem cells. Single cell sequencing provides a means of identifying subpopulations of cancer cells within a single patient. Single cell sequence analysis may prove to be critical for understanding the etiology, progression and drug resistance in ovarian cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Productivity losses and public finance burden attributable to breast cancer in Poland, 2010-2014.

    PubMed

    Łyszczarz, Błażej; Nojszewska, Ewelina

    2017-10-10

    Apart from the health and social burden of the disease, breast cancer (BC) has important economic implications for the sick, health system and whole economy. There has been a growing interest in the economic aspects of breast cancer and analyses of the disease costs seem to be the most explored topic. However, the results from these studies are hardly comparable. With this study we aim to contribute to the field by providing estimates of productivity losses and public finance burden attributable to BC in Poland. We used retrospective prevalence-based top-down approach to estimate the productivity losses (indirect costs) of BC in Poland in the period 2010-2014. Human capital method (HCM) and societal perspective were used to estimate the costs of: absenteeism of the sick and caregivers, presenteeism of the sick and caregivers, disability, and premature mortality. We also used figures illustrating public finance burden attributable to the disease. Deterministic sensitivity analysis was performed to assess the stability of the estimates. A variety of data sources were used with the social insurance system and Polish National Cancer Registry being the most important ones. Productivity losses associated with BC in Poland were €583.7 million in 2010 and they increased to €699.7 million in 2014. Throughout the period these costs accounted for 0.162-0.171% of GDP, an equivalent of 62,531-65,816 per capita GDP. Losses attributable to disability and premature mortality proved to be the major cost drivers with 27.6%-30.6% and 22.0%-24.6% of the total costs respectively. The costs due to caregivers' presenteeism were negligible (0.1% of total costs). Public finance expenditure for social insurance benefits to BC sufferers ranged from €50.2 million (2010) to €56.6 million (2014), an equivalent of 0.72-0.79% of expenditures for all diseases. Potential losses in public finance revenues accounted for €173.9 million in 2010 and €211.0 million in 2014. Sensitivity

  13. Weight Loss Intervention in Survivors of ER/PR-negative Breast Cancer.

    PubMed

    Vitolins, Mara Z; Milliron, Brandy-Joe; Hopkins, Judith O; Fulmer, Artie; Lawrence, Julia; Melin, Susan; Case, Douglas

    2014-01-01

    Numerous studies have found that increased body size (weight or body mass index) is a risk factor for breast cancer development, recurrence, and death. The detrimental relationship between body size and breast cancer recurrence may be more pronounced among women with estrogen receptor (ER)/progesterone receptor (PR)-negative breast cancer. Considering the limited availability of treatments, and the association between body size and recurrence, alternative treatments are needed for ER/PR-negative breast cancer survivors, particularly overweight survivors. The objective of this pilot study was to examine the feasibility of a 12-week, multi-component meal-replacement weight loss intervention among overweight or obese ER/PR-negative breast cancer survivors; and to obtain preliminary data on changes in anthropometrics, biomarkers, and health-related quality of life (QOL). The 12-week intervention included a portion-controlled diet (including meal replacements) and a multi-component intervention (including behavioral techniques, diet modification, physical activity, and social support). The goal of the intervention was to help participants lose 5% or more of their initial weight by reducing their caloric intake and increasing their physical activity (to at least 15 minutes each day). Paired t-tests assessed changes in continuous measures. Body weight was measured weekly and mixed-model regression analysis assessed change in weight over time. Nineteen ER/PR-negative breast cancer survivors with a mean age of 59 years participated in the study. All but two of the participants completed the 12-week intervention. Women lost an average of 6.3 ± 4.9 kg (P < 0.001), equivalent to 7.5% of their baseline weight. There were significant reductions in waist circumference (P = 0.001), percent fat mass (P < 0.001), total cholesterol (P = 0.026), and triglycerides (P = 0.002); and improvements in health-related QOL (P = 0.017). Findings suggested that a meal-replacement weight loss

  14. Favorable Changes in Serum Estrogens and Other Biological Factors After Weight Loss in Overweight or Obese Breast Cancer Survivors

    PubMed Central

    Rock, Cheryl L.; Pande, Chetna; Flatt, Shirley W.; Ying, Carl; Pakiz, Bilge; Parker, Barbara A.; Williams, Kathryn; Bardwell, Wayne A.; Heath, Dennis D.; Nichols, Jeanne F.

    2014-01-01

    Background Obesity is associated with increased risk for recurrence and all-cause mortality in breast cancer survivors. Excess adiposity is associated with increased estrogen, insulin, and leptin, and decreased sex hormone binding globulin (SHBG) concentrations, which may promote breast cancer progression and recurrence. This study aimed to assess the effects of weight loss on these factors. Patients and Methods Overweight or obese breast cancer survivors (N = 220) who were enrolled in a weight loss intervention study provided baseline and follow-up blood samples and weight data. Serum estrogens, SHBG, insulin, and leptin were measured at baseline, 6 and 18 months. Results Weight loss of ≥5% of initial weight decreased leptin and insulin compared with those who did not achieve that amount of weight loss (P < .0001). Weight loss also increased SHBG at 6 and 18 months (P < .01). Postmenopausal women who lost ≥5% of body weight at 6 months had lower estrone (P = .02), estradiol (P = .002), and bioavailable estradiol (P = .001) concentrations than women who did not lose at least 5% of body weight, and weight loss at 18 months was significantly related to change in serum bioavailable estradiol concentration (P = 0.02). Conclusion Favorable changes in estrogens, SHBG, insulin, and leptin were observed in association with weight loss in these overweight or obese women who had been diagnosed and treated for breast cancer. Weight loss appears to have favorable effects on hormonal and biological factors associated with increased risk for recurrence and poorer prognosis. PMID:23375717

  15. Base changes in tumour DNA have the power to reveal the causes and evolution of cancer

    SciTech Connect

    Hollstein, M.; Alexandrov, L. B.; Wild, C. P.; Ardin, M.; Zavadil, J.

    2016-06-06

    Next-generation sequencing (NGS) technology has demonstrated that the cancer genomes are peppered with mutations. Although most somatic tumour mutations are unlikely to have any role in the cancer process per se, the spectra of DNA sequence changes in tumour mutation catalogues have the potential to identify the mutagens, and to reveal the mutagenic processes responsible for human cancer. Very recently, a novel approach for data mining of the vast compilations of tumour NGS data succeeded in separating and precisely defining at least 30 distinct patterns of sequence change hidden in mutation databases. At least half of these mutational signatures can be readily assigned to known human carcinogenic exposures or endogenous mechanisms of mutagenesis. A quantum leap in our knowledge of mutagenesis in human cancers has resulted, stimulating a flurry of research activity. We trace here the major findings leading first to the hypothesis that carcinogenic insults leave characteristic imprints on the DNA sequence of tumours, and culminating in empirical evidence from NGS data that well-defined carcinogen mutational signatures are indeed present in tumour genomic DNA from a variety of cancer types. The notion that tumour DNAs can divulge environmental sources of mutation is now a well-accepted fact. This approach to cancer aetiology has also incriminated various endogenous, enzyme-driven processes that increase the somatic mutation load in sporadic cancers. The tasks now confronting the field of molecular epidemiology are to assign mutagenic processes to orphan and newly discovered tumour mutation patterns, and to determine whether avoidable cancer risk factors influence signatures produced by endogenous enzymatic mechanisms. As a result, innovative research with experimental models and exploitation of the geographical heterogeneity in cancer incidence can address these challenges.

  16. Base changes in tumour DNA have the power to reveal the causes and evolution of cancer

    DOE PAGES

    Hollstein, M.; Alexandrov, L. B.; Wild, C. P.; ...

    2016-06-06

    Next-generation sequencing (NGS) technology has demonstrated that the cancer genomes are peppered with mutations. Although most somatic tumour mutations are unlikely to have any role in the cancer process per se, the spectra of DNA sequence changes in tumour mutation catalogues have the potential to identify the mutagens, and to reveal the mutagenic processes responsible for human cancer. Very recently, a novel approach for data mining of the vast compilations of tumour NGS data succeeded in separating and precisely defining at least 30 distinct patterns of sequence change hidden in mutation databases. At least half of these mutational signatures canmore » be readily assigned to known human carcinogenic exposures or endogenous mechanisms of mutagenesis. A quantum leap in our knowledge of mutagenesis in human cancers has resulted, stimulating a flurry of research activity. We trace here the major findings leading first to the hypothesis that carcinogenic insults leave characteristic imprints on the DNA sequence of tumours, and culminating in empirical evidence from NGS data that well-defined carcinogen mutational signatures are indeed present in tumour genomic DNA from a variety of cancer types. The notion that tumour DNAs can divulge environmental sources of mutation is now a well-accepted fact. This approach to cancer aetiology has also incriminated various endogenous, enzyme-driven processes that increase the somatic mutation load in sporadic cancers. The tasks now confronting the field of molecular epidemiology are to assign mutagenic processes to orphan and newly discovered tumour mutation patterns, and to determine whether avoidable cancer risk factors influence signatures produced by endogenous enzymatic mechanisms. As a result, innovative research with experimental models and exploitation of the geographical heterogeneity in cancer incidence can address these challenges.« less

  17. Base changes in tumour DNA have the power to reveal the causes and evolution of cancer

    PubMed Central

    Hollstein, M; Alexandrov, L B; Wild, C P; Ardin, M; Zavadil, J

    2017-01-01

    Next-generation sequencing (NGS) technology has demonstrated that the cancer genomes are peppered with mutations. Although most somatic tumour mutations are unlikely to have any role in the cancer process per se, the spectra of DNA sequence changes in tumour mutation catalogues have the potential to identify the mutagens, and to reveal the mutagenic processes responsible for human cancer. Very recently, a novel approach for data mining of the vast compilations of tumour NGS data succeeded in separating and precisely defining at least 30 distinct patterns of sequence change hidden in mutation databases. At least half of these mutational signatures can be readily assigned to known human carcinogenic exposures or endogenous mechanisms of mutagenesis. A quantum leap in our knowledge of mutagenesis in human cancers has resulted, stimulating a flurry of research activity. We trace here the major findings leading first to the hypothesis that carcinogenic insults leave characteristic imprints on the DNA sequence of tumours, and culminating in empirical evidence from NGS data that well-defined carcinogen mutational signatures are indeed present in tumour genomic DNA from a variety of cancer types. The notion that tumour DNAs can divulge environmental sources of mutation is now a well-accepted fact. This approach to cancer aetiology has also incriminated various endogenous, enzyme-driven processes that increase the somatic mutation load in sporadic cancers. The tasks now confronting the field of molecular epidemiology are to assign mutagenic processes to orphan and newly discovered tumour mutation patterns, and to determine whether avoidable cancer risk factors influence signatures produced by endogenous enzymatic mechanisms. Innovative research with experimental models and exploitation of the geographical heterogeneity in cancer incidence can address these challenges. PMID:27270430

  18. Generation and molecular characterization of pancreatic cancer patient-derived xenografts reveals their heterologous nature

    PubMed Central

    Seol, Hyang Sook; Choi, Yeon Sook; Kim, Eunji; Lee, Eun Ji; Rhee, Je-Keun; Singh, Shree Ram; Jun, Eun Sung; Han, Buhm; Hong, Seung Mo; Kim, Song Cheol; Chang, Suhwan

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is the most challenging type of cancer to treat, with a 5-year survival rate of <10%. Furthermore, because of the large portion of the inoperable cases, it is difficult to obtain specimens to study the biology of the tumors. Therefore, a patient-derived xenograft (PDX) model is an attractive option for preserving and expanding these tumors for translational research. Here we report the generation and characterization of 20 PDX models of PDAC. The success rate of the initial graft was 74% and most tumors were re-transplantable. Histological analysis of the PDXs and primary tumors revealed a conserved expression pattern of p53 and SMAD4; an exome single nucleotide polymorphism (SNP) array and Comprehensive Cancer Panel showed that PDXs retained over 94% of cancer-associated variants. In addition, Polyphen2 and the Sorting Intolerant from Tolerant (SIFT) prediction identified 623 variants among the functional SNPs, highlighting the heterologous nature of pancreatic PDXs; an analysis of 409 tumor suppressor genes and oncogenes in Comprehensive Cancer Panel revealed heterologous cancer gene mutation profiles for each PDX-primary tumor pair. Altogether, we expect these PDX models are a promising platform for screening novel therapeutic agents and diagnostic markers for the detection and eradication of PDAC. PMID:27613834

  19. Genomics of Ovarian Cancer Progression Reveals Diverse Metastatic Trajectories Including Intraepithelial Metastasis to the Fallopian Tube.

    PubMed

    Eckert, Mark A; Pan, Shawn; Hernandez, Kyle M; Loth, Rachel M; Andrade, Jorge; Volchenboum, Samuel L; Faber, Pieter; Montag, Anthony; Lastra, Ricardo; Peter, Marcus E; Yamada, S Diane; Lengyel, Ernst

    2016-12-01

    Accumulating evidence has supported the fallopian tube rather than the ovary as the origin for high-grade serous ovarian cancer (HGSOC). To understand the relationship between putative precursor lesions and metastatic tumors, we performed whole-exome sequencing on specimens from eight HGSOC patient progression series consisting of serous tubal intraepithelial carcinomas (STIC), invasive fallopian tube lesions, invasive ovarian lesions, and omental metastases. Integration of copy number and somatic mutations revealed patient-specific patterns with similar mutational signatures and copy-number variation profiles across all anatomic sites, suggesting that genomic instability is an early event in HGSOC. Phylogenetic analyses supported STIC as precursor lesions in half of our patient cohort, but also identified STIC as metastases in 2 patients. Ex vivo assays revealed that HGSOC spheroids can implant in the fallopian tube epithelium and mimic STIC lesions. That STIC may represent metastases calls into question the assumption that STIC are always indicative of primary fallopian tube cancers. We find that the putative precursor lesions for HGSOC, STIC, possess most of the genomic aberrations present in advanced cancers. In addition, a proportion of STIC represent intraepithelial metastases to the fallopian tube rather than the origin of HGSOC. Cancer Discov; 6(12); 1342-51. ©2016 AACR.See related commentary by Swisher et al., p. 1309This article is highlighted in the In This Issue feature, p. 1293. ©2016 American Association for Cancer Research.

  20. Integrated exome and transcriptome sequencing reveals ZAK isoform usage in gastric cancer

    PubMed Central

    Liu, Jinfeng; McCleland, Mark; Stawiski, Eric W.; Gnad, Florian; Mayba, Oleg; Haverty, Peter M.; Durinck, Steffen; Chen, Ying-Jiun; Klijn, Christiaan; Jhunjhunwala, Suchit; Lawrence, Michael; Liu, Hanbin; Wan, Yinan; Chopra, Vivek; Yaylaoglu, Murat B.; Yuan, Wenlin; Ha, Connie; Gilbert, Houston N.; Reeder, Jens; Pau, Gregoire; Stinson, Jeremy; Stern, Howard M.; Manning, Gerard; Wu, Thomas D.; Neve, Richard M.; de Sauvage, Frederic J.; Modrusan, Zora; Seshagiri, Somasekar; Firestein, Ron; Zhang, Zemin

    2014-01-01

    Gastric cancer is the second leading cause of worldwide cancer mortality, yet the underlying genomic alterations remain poorly understood. Here we perform exome and transcriptome sequencing and SNP array assays to characterize 51 primary gastric tumours and 32 cell lines. Meta-analysis of exome data and previously published data sets reveals 24 significantly mutated genes in microsatellite stable (MSS) tumours and 16 in microsatellite instable (MSI) tumours. Over half the patients in our collection could potentially benefit from targeted therapies. We identify 55 splice site mutations accompanied by aberrant splicing products, in addition to mutation-independent differential isoform usage in tumours. ZAK kinase isoform TV1 is preferentially upregulated in gastric tumours and cell lines relative to normal samples. This pattern is also observed in colorectal, bladder and breast cancers. Overexpression of this particular isoform activates multiple cancer-related transcription factor reporters, while depletion of ZAK in gastric cell lines inhibits proliferation. These results reveal the spectrum of genomic and transcriptomic alterations in gastric cancer, and identify isoform-specific oncogenic properties of ZAK. PMID:24807215

  1. Metabolic abnormalities associated with weight loss during chemoirradiation of head-and-neck cancer

    SciTech Connect

    Lin, Alexander; Jabbari, Siavash; Worden, Francis P.; Chepeha, Douglas B.; Teknos, Theodoros N.; Nyquist, Gurston G.; Tsien, Christina; Schipper, Matthew J.; Urba, Susan . E-mail: eisbruch@umich.edu

    2005-12-01

    Purpose: Weight loss caused by acute mucositis and dysphagia is common during concurrent chemoirradiation (chemo-RT) of head-and-neck (HN) cancer. The metabolic consequences of weight loss during chemo-RT were investigated. Patients and Methods: Ninety-six patients with locally advanced HN cancer were treated from 1995 to 2001 on protocols that consisted of 1 to 2 cycles of induction cisplatin/5-fluorouracil followed by irradiation (70 Gy over 7 weeks) concurrent with cisplatin (100 mg/m{sup 2} every 3 weeks). Body weights and metabolic evaluations were obtained before and during induction chemotherapy and chemo-RT. Greatest percent changes in weight and in the laboratory values were calculated for each phase of therapy. Results: During induction chemotherapy, significant changes were found in BUN, BUN:creatinine ratio, HCO{sub 3}, Mg, and albumin, but not in creatinine, Na, K, or weight. During chemo-RT, significant additional changes were observed in all parameters measured, including increases in BUN, creatinine, BUN: creatinine ratio, and HCO{sub 3} and decreases in Mg, albumin, Na, K, and weight. The magnitude of most of these changes was significantly greater during chemo-RT than during induction chemotherapy. During chemo-RT, 35% of the patients had more than 10% body weight loss and 6 patients had an increase in creatinine of more than 100%, including 5 patients with Grade 2 nephrotoxicity, all of whom had weight loss 10% or more. Significant correlations were found between weight loss and creatinine (p < 0.0001) or BUN (p = 0.0002) rises, but not with BUN:creatinine ratio or other metabolic changes. Age, gender, tobacco history, hypertension, and diabetes mellitus were not significant predictors of nephrotoxicity. Conclusions: Weight loss during cisplatin-containing chemo-RT was found to be associated with reduced kidney function. These findings do not establish cause-effect relationships; however, they highlight the importance of intensive supportive

  2. Loss of Cytoplasmic CDK1 Predicts Poor Survival in Human Lung Cancer and Confers Chemotherapeutic Resistance

    PubMed Central

    Zhang, Chunyu; Elkahloun, Abdel G.; Robertson, Matthew; Gills, Joell J.; Tsurutani, Junji; Shih, Joanna H.; Fukuoka, Junya; Hollander, M. Christine; Harris, Curtis C.; Travis, William D.; Jen, Jin; Dennis, Phillip A.

    2011-01-01

    The dismal lethality of lung cancer is due to late stage at diagnosis and inherent therapeutic resistance. The incorporation of targeted therapies has modestly improved clinical outcomes, but the identification of new targets could further improve clinical outcomes by guiding stratification of poor-risk early stage patients and individualizing therapeutic choices. We hypothesized that a sequential, combined microarray approach would be valuable to identify and validate new targets in lung cancer. We profiled gene expression signatures during lung epithelial cell immortalization and transformation, and showed that genes involved in mitosis were progressively enhanced in carcinogenesis. 28 genes were validated by immunoblotting and 4 genes were further evaluated in non-small cell lung cancer tissue microarrays. Although CDK1 was highly expressed in tumor tissues, its loss from the cytoplasm unexpectedly predicted poor survival and conferred resistance to chemotherapy in multiple cell lines, especially microtubule-directed agents. An analysis of expression of CDK1 and CDK1-associated genes in the NCI60 cell line database confirmed the broad association of these genes with chemotherapeutic responsiveness. These results have implications for personalizing lung cancer therapy and highlight the potential of combined approaches for biomarker discovery. PMID:21887332

  3. Pan-cancer analysis reveals technical artifacts in TCGA germline variant calls.

    PubMed

    Buckley, Alexandra R; Standish, Kristopher A; Bhutani, Kunal; Ideker, Trey; Lasken, Roger S; Carter, Hannah; Harismendy, Olivier; Schork, Nicholas J

    2017-06-12

    Cancer research to date has largely focused on somatically acquired genetic aberrations. In contrast, the degree to which germline, or inherited, variation contributes to tumorigenesis remains unclear, possibly due to a lack of accessible germline variant data. Here we called germline variants on 9618 cases from The Cancer Genome Atlas (TCGA) database representing 31 cancer types. We identified batch effects affecting loss of function (LOF) variant calls that can be traced back to differences in the way the sequence data were generated both within and across cancer types. Overall, LOF indel calls were more sensitive to technical artifacts than LOF Single Nucleotide Variant (SNV) calls. In particular, whole genome amplification of DNA prior to sequencing led to an artificially increased burden of LOF indel calls, which confounded association analyses relating germline variants to tumor type despite stringent indel filtering strategies. The samples affected by these technical artifacts include all acute myeloid leukemia and practically all ovarian cancer samples. We demonstrate how technical artifacts induced by whole genome amplification of DNA can lead to false positive germline-tumor type associations and suggest TCGA whole genome amplified samples be used with caution. This study draws attention to the need to be sensitive to problems associated with a lack of uniformity in data generation in TCGA data.

  4. An Initial Investigation into Naturally Occurring Loss- and Gain-Framed Memorable Breast Cancer Messages

    PubMed Central

    LaPlante, Carolyn; Smith, Sandi; Kotowski, Michael; Nazione, Samantha; Stohl, Cynthia; Prestin, Abby; So, Jiyeon; Nabi, Robin

    2012-01-01

    Memorable message research examines interpersonal messages “…remembered for extremely long periods of time and which people perceive as a major influence on the course of their lives” (Knapp, Stohl, & Reardon, 1981, p. 27). They can also guide actions, such as health behaviors. This exploratory research examined self-reported memorable messages about breast cancer to determine if they were framed, emphasizing either the benefits (gain-framed) or the costs (loss-framed) of a behavior. About one-fourth of the messages were framed, with most being gain-framed. The messages tended to emphasize early detection actions. Study limitations and implications for future research are discussed. PMID:22539867

  5. Periodontal disease, tooth loss and colorectal cancer risk: Results from the Nurses' Health Study.

    PubMed

    Momen-Heravi, Fatemeh; Babic, Ana; Tworoger, Shelley S; Zhang, Libin; Wu, Kana; Smith-Warner, Stephanie A; Ogino, Shuji; Chan, Andrew T; Meyerhardt, Jeffrey; Giovannucci, Edward; Fuchs, Charles; Cho, Eunyoung; Michaud, Dominique S; Stampfer, Meir J; Yu, Yau-Hua; Kim, David; Zhang, Xuehong

    2017-02-01

    Periodontal diseases including tooth loss might increase systemic inflammation, lead to immune dysregulation and alter gut microbiota, thereby possibly influencing colorectal carcinogenesis. Few epidemiological studies have examined the association between periodontal diseases and colorectal cancer (CRC) risk. We collected information on the periodontal disease (defined as history of periodontal bone loss) and number of natural teeth in the Nurses' Health Study. A total of 77,443 women were followed since 1992. We used Cox proportional hazard models to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) after adjustment for smoking and other known risk factors for CRC. We documented 1,165 incident CRC through 2010. Compared to women with 25-32 teeth, the multivariable HR (95% CI) for CRC for women with <17 teeth was 1.20 (1.04-1.39). With regard to tumor site, the HRs (95% CIs) for the same comparison were 1.23 (1.01-1.51) for proximal colon cancer, 1.03 (0.76-1.38) for distal colon cancer and 1.48 (1.07-2.05) for rectal cancer. In addition, compared to those without periodontal disease, HRs for CRC were 0.91 (95% CI 0.74-1.12) for periodontal disease, and 1.22 (95% CI 0.91-1.63) when limited to moderate to severe periodontal disease. The results were not modified by smoking status, body mass index or alcohol consumption. Women with fewer teeth, possibly moderate or severe periodontal disease, might be at a modest increased risk of developing CRC, suggesting a potential role of oral health in colorectal carcinogenesis. © 2016 UICC.

  6. Clinical and pathologic features of young endometrial cancer patients with loss of mismatch repair expression.

    PubMed

    Grzankowski, Kassondra S; Shimizu, David M; Kimata, Chieko; Black, Michael; Terada, Keith Y

    2012-09-01

    This study examines premenopausal and early menopause patients in a unique population with endometrial cancer and loss of mismatch repair (MMR) gene expression. The purpose is to compare clinical and pathologic differences in patients with loss of expression (LOE) to those with normal expression (NE). Endometrial cancer patients under age 60 in-between 1998 and 2008 were identified from a single tumor registry. Clinical and pathologic data were abstracted from records. Staining for expression of MSH6, MSH2, MLH1, and PMS2 were performed on archived tissue blocks. Statistical analysis was performed. 158 patients were analyzed; 58% Asian, 34% Pacific Islander, and 8% Caucasian. 31 demonstrated LOE of at least one MMR gene; 127 retained NE. 50% Caucasian, 21.9% Asian, and 12.5% Pacific Island populations had LOE of one or more MMR genes. LOE was found to have a higher incidence of Grade III (p=0.0013) and stage 3-4 tumors (p=0.0079), mean depth of myometrial invasion (p=0.0019), lymphovascular space invasion (p=0.0020), nodal metastases (p=0.0157), and a lower incidence of Grade I (p=0.0020) and stage 1A tumors (p=0.0085). LOE had a significantly lower mean BMI (p=0.0001). 35% of patients in the NE vs zero in the LOE group had a BMI greater than 40. Younger patients with LOE endometrial cancer appear to represent a clinically significant subgroup of patients without features characteristically found in classic type 1 endometrial cancer generally demonstrating lower BMI and tumors associated with poor prognostic characteristics. It is unclear if the distinctive ethnicity found in Hawaii has a significant impact on outcome. Further investigation is necessary to identify appropriate treatment strategies. Copyright © 2012 Elsevier Inc. All rights reserved.

  7. Associations between nutritional status, weight loss, radiotherapy treatment toxicity and treatment outcomes in gastrointestinal cancer patients.

    PubMed

    Hill, Amanda; Kiss, Nicole; Hodgson, Belinda; Crowe, Timothy C; Walsh, Adam D

    2011-02-01

    Patients with gastrointestinal cancers are susceptible to nutritional deterioration which may be compounded by radiotherapy treatment toxicities. This study aimed to determine whether nutritional status at radiotherapy commencement or changes in nutritional status throughout radiotherapy were associated with treatment toxicity and outcomes in gastrointestinal cancer patients. Seventy-three gastrointestinal cancer patients receiving curative radiotherapy underwent medical record audits assessing body weight, radiotherapy toxicity, unplanned treatment breaks or hospital admissions and completion of prescribed treatment/s. Nutritional status was assessed in a subset of patients (n = 11) using the Patient-Generated Subjective Global Assessment tool. Seventy-five percent of patients lost weight throughout radiotherapy. Weight loss was significantly greater in patients experiencing unplanned radiotherapy breaks (-3.1% vs -1.6%, p < 0.05) and in patients not completing prescribed chemotherapy (-3.3% vs -1.6%, p < 0.05). Toxicity severity was strongly correlated with Patient-Generated Subjective Global Assessment score (rho = 0.839, p < 0.001) and was increased in patients experiencing unplanned admissions compared to those without admission (42.1% vs 9.3% with grade 3 toxicity respectively, p < 0.001). Deterioration in nutritional status during radiotherapy (as measured by weight loss) may be associated with poorer short-term treatment outcomes in gastrointestinal cancer patients. Patient numbers were too small to definitively determine the effect of nutritional status at radiotherapy commencement or changes in nutritional status throughout radiotherapy (defined by PG-SGA) on treatment outcomes. Further research is required to investigate this in larger, longer-term studies. Copyright © 2010. Published by Elsevier Ltd.

  8. Loss of HITS (FAM107B) expression in cancers of multiple organs: tissue microarray analysis.

    PubMed

    Nakajima, Hideo; Koizumi, Keita; Tanaka, Takuji; Ishigaki, Yasuhito; Yoshitake, Yoshino; Yonekura, Hideto; Sakuma, Tsutomu; Fukushima, Toshihiro; Umehara, Hisanori; Ueno, Soichiro; Minamoto, Toshinari; Motoo, Yoshiharu

    2012-10-01

    Family with sequence similarity 107 (FAM107) proteins consist of two subtypes, FAM107A and FAM107B in mammals, possessing a conserved N-terminal domain of unknown function. Recently we found that FAM107B, an 18 kDa nuclear protein, is expressed in a broad range of tissues and is downregulated in gastrointestinal cancer. Because FAM107B expression is amplified by heat-shock stimulation, we designated it heat shock-inducible tumor small protein (HITS). Although data related to FAM107A as a candidate tumor suppressor have been accumulated, little biological information is available for HITS. In the present study, we examined HITS expression using immunohistochemistry with tissue microarrays and performed detailed statistical analyses. By screening a high-density multiple organ tumor and normal tissue microarray, HITS expression was decreased in tumor tissues of the breast, thyroid, testis and uterine cervix as well as the stomach and colon. Further analysis of tissue microarrays of individual organs showed that loss of HITS expression in cancer tissues was statistically significant and commonly observed in distinct organs in a histological type-specific manner. The HITS expression intensity was inversely correlated with the primary tumor size in breast and thyroid cancers. In addition, effects of tetracycline-inducible HITS expression on tumor growth were investigated in vivo. Forced expression of HITS inhibited tumor xenograft proliferation, compared with the mock-treated tumor xenograft model. These results show that loss of HITS expression is a common phenomenon observed in cancers of distinct organs and involved in tumor development and proliferation.

  9. Loss of HSulf-1 expression enhances tumorigenicity by inhibiting Bim expression in ovarian cancer.

    PubMed

    He, Xiaoping; Khurana, Ashwani; Roy, Debarshi; Kaufmann, Scott; Shridhar, Viji

    2014-10-15

    The expression of human Sulfatase1 (HSulf-1) is downregulated in the majority of primary ovarian cancer tumors, but the functional consequence of this downregulation remains unclear. Using two different shRNAs (Sh1 and Sh2), HSulf-1 expression was stably downregulated in ovarian cancer OV202 cells. We found that HSulf-1-deficient OV202 Sh1 and Sh2 cells formed colonies in soft agar. In contrast, nontargeting control (NTC) shRNA-transduced OV202 cells did not form any colonies. Moreover, subcutaneous injection of OV202 HSulf-1-deficient cells resulted in tumor formation in nude mice, whereas OV202 NTC cells did not. Also, ectopic expression of HSulf-1 in ovarian cancer SKOV3 cells significantly suppressed tumor growth in nude mice. Here, we show that HSulf-1-deficient OV202 cells have markedly decreased expression of proapoptotic Bim protein, which can be rescued by restoring HSulf-1 expression in OV202 Sh1 cells. Enhanced expression of HSulf-1 in HSulf-1-deficient SKOV3 cells resulted in increased Bim expression. Decreased Bim levels after loss of HSulf-1 were due to increased p-ERK, because inhibition of ERK activity with PD98059 resulted in increased Bim expression. However, treatment with a PI3 kinase/AKT inhibitor, LY294002, failed to show any change in Bim protein level. Importantly, rescuing Bim expression in HSulf-1 knockdown cells significantly retarded tumor growth in nude mice. Collectively, these results suggest that loss of HSulf-1 expression promotes tumorigenicity in ovarian cancer through regulating Bim expression.

  10. KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer. | Office of Cancer Genomics

    Cancer.gov

    Inhibitors that target the receptor tyrosine kinase (RTK)/Ras/mitogen-activated protein kinase (MAPK) pathway have led to clinical responses in lung and other cancers, but some patients fail to respond and in those that do resistance inevitably occurs (Balak et al., 2006; Kosaka et al., 2006; Rudin et al., 2013; Wagle et al., 2011). To understand intrinsic and acquired resistance to inhibition of MAPK signaling, we performed CRISPR-Cas9 gene deletion screens in the setting of BRAF, MEK, EGFR, and ALK inhibition.

  11. Suicide Gene-Engineered Stromal Cells Reveal a Dynamic Regulation of Cancer Metastasis

    NASA Astrophysics Data System (ADS)

    Shen, Keyue; Luk, Samantha; Elman, Jessica; Murray, Ryan; Mukundan, Shilpaa; Parekkadan, Biju

    2016-02-01

    Cancer-associated fibroblasts (CAFs) are a major cancer-promoting component in the tumor microenvironment (TME). The dynamic role of human CAFs in cancer progression has been ill-defined because human CAFs lack a unique marker needed for a cell-specific, promoter-driven knockout model. Here, we developed an engineered human CAF cell line with an inducible suicide gene to enable selective in vivo elimination of human CAFs at different stages of xenograft tumor development, effectively circumventing the challenge of targeting a cell-specific marker. Suicide-engineered CAFs were highly sensitive to apoptosis induction in vitro and in vivo by the addition of a simple small molecule inducer. Selection of timepoints for targeted CAF apoptosis in vivo during the progression of a human breast cancer xenograft model was guided by a bi-phasic host cytokine response that peaked at early timepoints after tumor implantation. Remarkably, we observed that the selective apoptosis of CAFs at these early timepoints did not affect primary tumor growth, but instead increased the presence of tumor-associated macrophages and the metastatic spread of breast cancer cells to the lung and bone. The study revealed a dynamic relationship between CAFs and cancer metastasis that has counter-intuitive ramifications for CAF-targeted therapy.

  12. Suicide Gene-Engineered Stromal Cells Reveal a Dynamic Regulation of Cancer Metastasis.

    PubMed

    Shen, Keyue; Luk, Samantha; Elman, Jessica; Murray, Ryan; Mukundan, Shilpaa; Parekkadan, Biju

    2016-02-19

    Cancer-associated fibroblasts (CAFs) are a major cancer-promoting component in the tumor microenvironment (TME). The dynamic role of human CAFs in cancer progression has been ill-defined because human CAFs lack a unique marker needed for a cell-specific, promoter-driven knockout model. Here, we developed an engineered human CAF cell line with an inducible suicide gene to enable selective in vivo elimination of human CAFs at different stages of xenograft tumor development, effectively circumventing the challenge of targeting a cell-specific marker. Suicide-engineered CAFs were highly sensitive to apoptosis induction in vitro and in vivo by the addition of a simple small molecule inducer. Selection of timepoints for targeted CAF apoptosis in vivo during the progression of a human breast cancer xenograft model was guided by a bi-phasic host cytokine response that peaked at early timepoints after tumor implantation. Remarkably, we observed that the selective apoptosis of CAFs at these early timepoints did not affect primary tumor growth, but instead increased the presence of tumor-associated macrophages and the metastatic spread of breast cancer cells to the lung and bone. The study revealed a dynamic relationship between CAFs and cancer metastasis that has counter-intuitive ramifications for CAF-targeted therapy.

  13. Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins

    PubMed Central

    Guix, Marta; Faber, Anthony C.; Wang, Shizhen Emily; Olivares, Maria Graciela; Song, Youngchul; Qu, Sherman; Rinehart, Cammie; Seidel, Brenda; Yee, Douglas; Arteaga, Carlos L.; Engelman, Jeffrey A.

    2008-01-01

    Although some cancers are initially sensitive to EGFR tyrosine kinase inhibitors (TKIs), resistance invariably develops. We investigated mechanisms of acquired resistance to the EGFR TKI gefitinib by generating gefitinib-resistant (GR) A431 squamous cancer cells. In GR cells, gefitinib reduced phosphorylation of EGFR, ErbB-3, and Erk but not Akt. These cells also showed hyperphosphorylation of the IGFI receptor (IGFIR) and constitutive association of IRS-1 with PI3K. Inhibition of IGFIR signaling disrupted the association of IRS-1 with PI3K and restored the ability of gefitinib to downregulate PI3K/Akt signaling and to inhibit GR cell growth. Gene expression analyses revealed that GR cells exhibited markedly reduced IGF-binding protein 3 (IGFBP-3) and IGFBP-4 RNA. Addition of recombinant IGFBP-3 restored the ability of gefitinib to downregulate PI3K/Akt signaling and to inhibit cell growth. Finally, gefitinib treatment of mice with A431 xenografts in combination with an IGFIR-specific monoclonal antibody prevented tumor recurrence, whereas each drug given alone was unable to do so. These data suggest that loss of expression of IGFBPs in tumor cells treated with EGFR TKIs derepresses IGFIR signaling, which in turn mediates resistance to EGFR antagonists. Moreover, combined therapeutic inhibition of EGFR and IGFIR may abrogate this acquired mechanism of drug resistance and is thus worthy of prospective clinical investigation. PMID:18568074

  14. Comparative Tissue Proteomics of Microdissected Specimens Reveals Novel Candidate Biomarkers of Bladder Cancer*

    PubMed Central

    Chen, Chien-Lun; Chung, Ting; Wu, Chih-Ching; Ng, Kwai-Fong; Yu, Jau-Song; Tsai, Cheng-Han; Chang, Yu-Sun; Liang, Ying; Tsui, Ke-Hung; Chen, Yi-Ting

    2015-01-01

    More than 380,000 new cases of bladder cancer are diagnosed worldwide, accounting for ∼150,200 deaths each year. To discover potential biomarkers of bladder cancer, we employed a strategy combining laser microdissection, isobaric tags for relative and absolute quantitation labeling, and liquid chromatography-tandem MS (LC-MS/MS) analysis to profile proteomic changes in fresh-frozen bladder tumor specimens. Cellular proteins from four pairs of surgically resected primary bladder cancer tumor and adjacent nontumorous tissue were extracted for use in two batches of isobaric tags for relative and absolute quantitation experiments, which identified a total of 3220 proteins. A DAVID (database for annotation, visualization and integrated discovery) analysis of dysregulated proteins revealed that the three top-ranking biological processes were extracellular matrix organization, extracellular structure organization, and oxidation-reduction. Biological processes including response to organic substances, response to metal ions, and response to inorganic substances were highlighted by up-expressed proteins in bladder cancer. Seven differentially expressed proteins were selected as potential bladder cancer biomarkers for further verification. Immunohistochemical analyses showed significantly elevated levels of three proteins—SLC3A2, STMN1, and TAGLN2—in tumor cells compared with noncancerous bladder epithelial cells, and suggested that TAGLN2 could be a useful tumor tissue marker for diagnosis (AUC = 0.999) and evaluating lymph node metastasis in bladder cancer patients. ELISA results revealed significantly increased urinary levels of both STMN1 and TAGLN2 in bladder cancer subgroups compared with control groups. In comparisons with age-matched hernia urine specimens, urinary TAGLN2 in bladder cancer samples showed the largest fold change (7.13-fold), with an area-under-the-curve value of 0.70 (p < 0.001, n = 205). Overall, TAGLN2 showed the most significant

  15. Risk of infection-related cancers after the loss of a child: a follow-up study in Sweden.

    PubMed

    Fang, Fang; Fall, Katja; Sparén, Pär; Adami, Hans-Olov; Valdimarsdóttir, Heiddis B; Lambe, Mats; Valdimarsdóttir, Unnur

    2011-01-01

    It is unknown whether severe emotional stress due to loss of a child influences the risk of cancers susceptible to immune modulation such as infection-related cancers. We conducted a historic cohort study in 1990 to 2004 on the basis of the Swedish Multi-Generation Register including 4,687,073 parents. Death of a child was identified through the Causes of Death Register. Poisson regression was used to derive the relative risks (RR) and 95% confidence intervals (CI) of infection-related cancers, comparing the incidence rates of parents who lost a child with those who never lost a child. A total of 101,306 parents (2%) had lost a child during follow-up, among whom 1,608 subsequently developed infection-related cancers. After adjustment for age, sex, calendar year, educational level, and civil status, the overall RR of 14 cancers studied was 1.07 (95% CI: 1.02-1.12). Parents who lost a child were particularly at a higher risk for cancers potentially associated with human papilloma virus (HPV) infection such as cervical cancer (RR: 1.46; 95% CI: 1.17-1.80). Higher RRs for most cancers were obtained within 5 years after child loss and excess risk for liver and stomach cancers was confined to that period. No association was observed for lymphoma and nonmelanoma skin cancer at any time point after child loss. Although potential confounding by unmeasured factors cannot be ruled out, our findings lend support to the hypothesis that severe life stressors, such as child loss, may raise the risk for several, chiefly HPV-related, cancers. © 2011 AACR.

  16. Loss of ARID1A expression sensitizes cancer cells to PI3K- and AKT-inhibition

    PubMed Central

    Samartzis, Eleftherios P; Gutsche, Katrin; Dedes, Konstantin J; Fink, Daniel; Stucki, Manuel; Imesch, Patrick

    2014-01-01

    ARID1A mutations are observed in various tumors, including ovarian clear cell (OCCC) and endometrioid carcinomas, endometrial, and breast carcinomas. They commonly result in loss of ARID1A-protein expression and frequently co-occur with PI3K/AKT-pathway activating mechanisms. The aim of this study was to test the hypothesis as to whether PI3K/AKT-pathway activation is a critical mechanism in ARID1A-mutated tumors and if consequently ARID1A-deficient tumors show increased sensitivity to treatment with PI3K- and AKT-inhibitors. Upon ARID1A knockdown, MCF7 breast cancer cells and primary MRC5 cells exhibited a significantly increased sensitivity towards the AKT-inhibitors MK-2206 and perifosine, as well as the PI3K-inhibitor buparlisib. Knockdown of ARID1A in MCF7 led to an increase of pAKT-Ser473. AKT-inhibition with MK-2206 led to increased apoptosis and to a decrease of pS6K in ARID1A-depleted MCF7 cells but not in the controls. In five OCCC cell lines ARID1A-deficiency correlated with increased pAKT-Ser473 levels and with sensitivity towards treatment with the AKT-inhibitor MK-2206. In conclusion, ARID1A-deficient cancer cells demonstrate an increased sensitivity to treatment with small molecule inhibitors of the PI3K/AKT-pathway. These findings suggest a specific requirement of the PI3K/AKT pathway in ARID1A-deficient tumors and reveal a synthetic lethal interaction between loss of ARID1A expression and inhibition of the PI3K/AKT pathway. PMID:24979463

  17. Mechanisms and functional consequences of PDEF protein expression loss during prostate cancer progression

    PubMed Central

    Turner, David P; Findlay, Victoria J; Moussa, Omar; Semenchenko, Victor I.; Watson, Patricia M.; LaRue, Amanda C.; Desouki, Mohamed M; Fraig, Mostafa; Watson, Dennis K

    2011-01-01

    BACKGROUND Ets is a large family of transcriptional regulators with functions in most biological processes. While the Ets family gene, PDEF (prostate derived epithelial factor), is expressed in epithelial tissues, PDEF protein expression has been found to be reduced or lost during cancer progression. The goal of this study was to examine the mechanism for and biologic impact of altered PDEF expression in prostate cancer. METHODS PDEF protein expression of prostate specimens was examined by immunohistochemistry. RNA and protein expression in cell lines were measured by q-PCR and western blot, respectively. Cellular growth was determined by quantifying viable and apoptotic cells over time. Cell cycle was measured by flow cytometry. Migration and invasion were determined by transwell assays. PDEF promoter occupancy was determined by chromatin immunoprecipitation (ChIP). RESULTS While normal prostate epithelium expresses PDEF mRNA and protein, tumors show no or decreased PDEF protein expression. Re-expression of PDEF in prostate cancer cells inhibits cell growth. PDEF expression is inversely correlated with survivin, urokinase plasminogen activator (uPA) and slug expression and ChIP studies identify survivin and uPA as direct transcriptional targets of PDEF. This study also shows that PDEF expression is regulated via a functional microRNA-204 (miR-204) binding site within the 3’UTR. Furthermore, we demonstrate the biologic significance of miR-204 expression and that miR-204 is over-expressed in human prostate cancer specimens. CONCLUSIONS Collectively, the reported studies demonstrate that PDEF is a negative regulator of tumor progression and that the miR-204-PDEF regulatory axis contributes to PDEF protein loss and resultant cancer progression. PMID:21446014

  18. Cancer Stem Cell-Based Models of Colorectal Cancer Reveal Molecular Determinants of Therapy Resistance

    PubMed Central

    De Angelis, Maria Laura; Zeuner, Ann; Policicchio, Eleonora; Russo, Giorgio; Bruselles, Alessandro; Signore, Michele; Vitale, Sara; De Luca, Gabriele; Pilozzi, Emanuela; Boe, Alessandra; Stassi, Giorgio; Ricci-Vitiani, Lucia; Amoreo, Carla Azzurra; Pagliuca, Alfredo; Francescangeli, Federica; Tartaglia, Marco

    2016-01-01

    Colorectal cancer (CRC) therapy mainly relies on the use of conventional chemotherapeutic drugs combined, in a subset of patients, with epidermal growth factor receptor [EGFR]-targeting agents. Although CRC is considered a prototype of a cancer stem cell (CSC)-driven tumor, the effects of both conventional and targeted therapies on the CSC compartment are largely unknown. We have optimized a protocol for colorectal CSC isolation that allowed us to obtain CSC-enriched cultures from primary tumor specimens, with high efficiency. CSC isolation was followed by in vitro and in vivo validation, genetic characterization, and drug sensitivity analysis, thus generating panels of CSC lines with defined patterns of genetic mutations and therapy sensitivity. Colorectal CSC lines were polyclonal and maintained intratumor heterogeneity in terms of somatically acquired mutations and differentiation state. Such CSC-enriched cultures were used to investigate the effects of both conventional and targeted therapies on the CSC compartment in vivo and to generate a proteomic picture of signaling pathways implicated in sensitivity/resistance to anti-EGFR agents. We propose CSC lines as a sound preclinical framework to test the effects of therapies in vitro and in vivo and to identify novel determinants of therapy resistance. Significance Colorectal cancer stem cells (CSCs) have been shown to be responsible for tumor propagation, metastatic dissemination, and relapse. However, molecular pathways present in CSCs, as well as mechanisms of therapy resistance, are mostly unknown. Taking advantage of genetically characterized CSC lines derived from colorectal tumors, this study provides an extensive analysis of CSC response to EGFR-targeted therapy in vivo and an overview of factors implicated in therapy response or resistance. Furthermore, the implementation of a biobank of molecularly annotated CSC lines provides an innovative resource for future investigations in colorectal cancer. PMID

  19. Identification of gain- and loss-framed cancer screening messages that appeared in municipal newsletters in Japan.

    PubMed

    Okuhara, Tsuyoshi; Ishikawa, Hirono; Okada, Hiroko; Kiuchi, Takahiro

    2014-12-11

    Research suggests that cancer screening messages are more persuasive when framed in terms of the costs of not obtaining screening (i.e., loss-framed) than when framed in terms of the benefits of obtaining screening (i.e., gain-framed). However, to what extent these findings have been integrated into public health practice is unknown. To analyze message framing of cancer screening information, the present study examined message framing of cancer screening announcement articles that appeared in municipal newsletters published from 23 wards in central Tokyo, Japan. Two independent raters coded the articles. Gain- and loss-framed sentences in each article were identified, and based on what the sentences conveyed, articles were classified into gain-framed, loss-framed, mixed-framed, and non-framed. Inter-rater reliability was acceptable (intraclass correlation coefficient = 0.88). Of the 129 articles evaluated, the total number of gain-framed sentences was 87, while that of loss-framed sentences was six. The total number of gain-framed articles was 32 (24.8%) while that of loss-framed articles was zero (0%). Five (3.9%) articles were mixed-framed. Ninety-two (71.3%) articles were non-framed. Cancer screening announcement articles of municipal newsletters were mostly non-framed or gain-framed in 23 Tokyo wards in Japan. The absence of loss-framed articles and only a small number of loss-framed messages indicate a missed opportunity to persuade readers to obtain cancer screenings. Loss-framed messages and articles need to be increased to enhance the persuasiveness of cancer screening information in municipal newsletters.

  20. Structure–function insights reveal the human ribosome as a cancer target for antibiotics

    PubMed Central

    Myasnikov, Alexander G.; Kundhavai Natchiar, S.; Nebout, Marielle; Hazemann, Isabelle; Imbert, Véronique; Khatter, Heena; Peyron, Jean-François; Klaholz, Bruno P.

    2016-01-01

    Many antibiotics in clinical use target the bacterial ribosome by interfering with the protein synthesis machinery. However, targeting the human ribosome in the case of protein synthesis deregulations such as in highly proliferating cancer cells has not been investigated at the molecular level up to now. Here we report the structure of the human 80S ribosome with a eukaryote-specific antibiotic and show its anti-proliferative effect on several cancer cell lines. The structure provides insights into the detailed interactions in a ligand-binding pocket of the human ribosome that are required for structure-assisted drug design. Furthermore, anti-proliferative dose response in leukaemic cells and interference with synthesis of c-myc and mcl-1 short-lived protein markers reveals specificity of a series of eukaryote-specific antibiotics towards cytosolic rather than mitochondrial ribosomes, uncovering the human ribosome as a promising cancer target. PMID:27665925

  1. Integrative analysis of breast cancer reveals prognostic haematopoietic activity and patient-specific immune response profiles

    PubMed Central

    Varn, Frederick S.; Andrews, Erik H.; Mullins, David W.; Cheng, Chao

    2016-01-01

    Transcriptional programmes active in haematopoietic cells enable a variety of functions including dedifferentiation, innate immunity and adaptive immunity. Understanding how these programmes function in the context of cancer can provide valuable insights into host immune response, cancer severity and potential therapy response. Here we present a method that uses the transcriptomes of over 200 murine haematopoietic cells, to infer the lineage-specific haematopoietic activity present in human breast tumours. Correlating this activity with patient survival and tumour purity reveals that the transcriptional programmes of many cell types influence patient prognosis and are found in environments of high lymphocytic infiltration. Collectively, these results allow for a detailed and personalized assessment of the patient immune response to a tumour. When combined with routinely collected patient biopsy genomic data, this method can enable a richer understanding of the complex interplay between the host immune system and cancer. PMID:26725977

  2. Magnitude of Myocutaneous Flaps and Factors Associated With Loss of Volume in Oral Cancer Reconstructive Surgery.

    PubMed

    Sakamoto, Yuki; Yanamoto, Souichi; Ota, Yoshihide; Furudoi, Shungo; Komori, Takahide; Umeda, Masahiro

    2016-03-01

    Myocutaneous flaps are often used to repair oral and maxillofacial defects after surgery for oral cancer; however, their volume decreases during the postoperative period. To facilitate treatment planning, the authors measured the extent of such postoperative flap volume loss and identified associated factors in patients who underwent oral reconstruction with myocutaneous flaps. The authors designed and performed a retrospective observational study of patients who underwent reconstructive procedures involving rectus abdominal myocutaneous (RAM) or pectoralis major myocutaneous (PMMC) flaps at Tokai University Hospital, Kobe University Hospital, or Nagasaki University Hospital from April 2009 through March 2013. Flap type and other clinical variables were examined as potential predictors of flap loss. The primary outcome was flap loss at 6 months postoperatively. Correlations between each potential predictor and the primary outcome were examined using multiple regression analysis. The subjects were 75 patients whose oral defects were reconstructed with RAM flaps (n = 57) or PMMC flaps (n = 18). RAM flaps exhibited a mean volume shrinkage of 22% at 6 months postoperatively, which was less than the 27.5% displayed by the PMMC flaps, but the difference was not important. Renal failure, previous surgery of the oral region, postoperative radiotherapy, and postoperative serum albumin level were found to be meaningful risk factors for postoperative flap volume loss. The results of this study suggest that larger flaps should be used in patients who possess these risk factors or are scheduled to undergo postoperative radiotherapy. Future studies should examine the utility of postoperative nutritional management for preventing flap volume loss. Copyright © 2016 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

  3. Loss, mutation and deregulation of L3MBTL4 in breast cancers

    PubMed Central

    2010-01-01

    Background Many alterations are involved in mammary oncogenesis, including amplifications of oncogenes and losses of tumor suppressor genes (TSG). Losses may affect almost all chromosome arms and many TSGs remain to be identified. Results We studied 307 primary breast tumors and 47 breast cancer cell lines by high resolution array comparative genomic hybridization (aCGH). We identified a region on 18p11.31 lost in about 20% of the tumors and 40% of the cell lines. The minimal common region of loss (Chr18:6,366,938-6,375,929 bp) targeted the L3MBTL4 gene. This gene was also targeted by breakage in one tumor and in two cell lines. We studied the exon sequence of L3MBTL4 in 180 primary tumor samples and 47 cell lines and found six missense and one nonsense heterozygous mutations. Compared with normal breast tissue, L3MBTL4 mRNA expression was downregulated in 73% of the tumors notably in luminal, ERBB2 and normal-like subtypes. Losses of the 18p11 region were associated with low L3MBTL4 expression level. Integrated analysis combining genome and gene expression profiles of the same tumors pointed to 14 other potential 18p TSG candidates. Downregulated expression of ZFP161, PPP4R1 and YES1 was correlated with luminal B molecular subtype. Low ZFP161 gene expression was associated with adverse clinical outcome. Conclusion We have identified L3MBTL4 as a potential TSG of chromosome arm 18p. The gene is targeted by deletion, breakage and mutations and its mRNA is downregulated in breast tumors. Additional 18p TSG candidates might explain the aggressive phenotype associated with the loss of 18p in breast tumors. PMID:20698951

  4. Identification of lncRNA-associated competing triplets reveals global patterns and prognostic markers for cancer

    PubMed Central

    Wang, Peng; Ning, Shangwei; Zhang, Yunpeng; Li, Ronghong; Ye, Jingrun; Zhao, Zuxianglan; Zhi, Hui; Wang, Tingting; Guo, Zheng; Li, Xia

    2015-01-01

    Recent studies have suggested that long non-coding RNAs (lncRNAs) can interact with microRNAs (miRNAs) and indirectly regulate miRNA targets though competing interactions. However, the molecular mechanisms underlying these interactions are still largely unknown. In this study, these lncRNA–miRNA–gene interactions were defined as lncRNA-associated competing triplets (LncACTs), and an integrated pipeline was developed to identify lncACTs that are active in cancer. Competing lncRNAs had sponge features distinct from non-competing lncRNAs. In the lncACT cross-talk network, disease-associated lncRNAs, miRNAs and coding-genes showed specific topological patterns indicative of their competence and control of communication within the network. The construction of global competing activity profiles revealed that lncACTs had high activity specific to cancers. Analyses of clustered lncACTs revealed that they were enriched in various cancer-related biological processes. Based on the global cross-talk network and cluster analyses, nine cancer-specific sub-networks were constructed. H19- and BRCA1/2-associated lncACTs were able to discriminate between two groups of patients with different clinical outcomes. Disease-associated lncACTs also showed variable competing patterns across normal and cancer patient samples. In summary, this study uncovered and systematically characterized global properties of human lncACTs that may have prognostic value for predicting clinical outcome in cancer patients. PMID:25800746

  5. Proteome–Metabolome Profiling of Ovarian Cancer Ascites Reveals Novel Components Involved in Intercellular Communication*

    PubMed Central

    Shender, Victoria O.; Pavlyukov, Marat S.; Ziganshin, Rustam H.; Arapidi, Georgij P.; Kovalchuk, Sergey I.; Anikanov, Nikolay A.; Altukhov, Ilya A.; Alexeev, Dmitry G.; Butenko, Ivan O.; Shavarda, Alexey L.; Khomyakova, Elena B.; Evtushenko, Evgeniy; Ashrafyan, Lev A.; Antonova, Irina B.; Kuznetcov, Igor N.; Gorbachev, Alexey Yu.; Shakhparonov, Mikhail I.; Govorun, Vadim M.

    2014-01-01

    Ovarian cancer ascites is a native medium for cancer cells that allows investigation of their secretome in a natural environment. This medium is of interest as a promising source of potential biomarkers, and also as a medium for cell–cell communication. The aim of this study was to elucidate specific features of the malignant ascites metabolome and proteome. In order to omit components of the systemic response to ascites formation, we compared malignant ascites with cirrhosis ascites. Metabolome analysis revealed 41 components that differed significantly between malignant and cirrhosis ascites. Most of the identified cancer-specific metabolites are known to be important signaling molecules. Proteomic analysis identified 2096 and 1855 proteins in the ovarian cancer and cirrhosis ascites, respectively; 424 proteins were specific for the malignant ascites. Functional analysis of the proteome demonstrated that the major differences between cirrhosis and malignant ascites were observed for the cluster of spliceosomal proteins. Additionally, we demonstrate that several splicing RNAs were exclusively detected in malignant ascites, where they probably existed within protein complexes. This result was confirmed in vitro using an ovarian cancer cell line. Identification of spliceosomal proteins and RNAs in an extracellular medium is of particular interest; the finding suggests that they might play a role in the communication between cancer cells. In addition, malignant ascites contains a high number of exosomes that are known to play an important role in signal transduction. Thus our study reveals the specific features of malignant ascites that are associated with its function as a medium of intercellular communication. PMID:25271300

  6. Loss of Myoferlin Redirects Breast Cancer Cell Motility towards Collective Migration

    PubMed Central

    Volakis, Leonithas I.; Li, Ruth; Ackerman, William E.; Mihai, Cosmin; Bechel, Meagan; Summerfield, Taryn L.; Ahn, Christopher S.; Powell, Heather M.; Zielinski, Rachel; Rosol, Thomas J.

    2014-01-01

    Cell migration plays a central role in the invasion and metastasis of tumors. As cells leave the primary tumor, they undergo an epithelial to mesenchymal transition (EMT) and migrate as single cells. Epithelial tumor cells may also migrate in a highly directional manner as a collective group in some settings. We previously discovered that myoferlin (MYOF) is overexpressed in breast cancer cells and depletion of MYOF results in a mesenchymal to epithelial transition (MET) and reduced invasion through extracellular matrix (ECM). However, the biomechanical mechanisms governing cell motility during MYOF depletion are poorly understood. We first demonstrated that lentivirus-driven shRNA-induced MYOF loss in MDA-MB-231 breast cancer cells (MDA-231MYOF-KD) leads to an epithelial morphology compared to the mesenchymal morphology observed in control (MDA- 231LTVC) and wild-type cells. Knockdown of MYOF led to significant reductions in cell migration velocity and MDA- 231MYOF-KD cells migrated directionally and collectively, while MDA-231LTVC cells exhibited single cell migration. Decreased migration velocity and collective migration were accompanied by significant changes in cell mechanics. MDA-231MYOF-KD cells exhibited a 2-fold decrease in cell stiffness, a 2-fold increase in cell-substrate adhesion and a 1.5-fold decrease in traction force generation. In vivo studies demonstrated that when immunocompromised mice were implanted with MDA- 231MYOF-KD cells, tumors were smaller and demonstrated lower tumor burden. Moreover, MDA- 231MYOF-KD tumors were highly circularized and did not invade locally into the adventia in contrast to MDA- 231LTVC-injected animals. Thus MYOF loss is associated with a change in tumor formation in xenografts and leads to smaller, less invasive tumors. These data indicate that MYOF, a previously unrecognized protein in cancer, is involved in MDA-MB-231 cell migration and contributes to biomechanical alterations. Our results indicate that changes in

  7. Genome Sequencing and Mapping Reveal Loss of Heterozygosity as a Mechanism for Rapid Adaptation in the Vegetable Pathogen Phytophthora capsici

    SciTech Connect

    Lamour, Kurt H.; Mudge, Joann; Gobena, Daniel; Hurtado-Gonzales, Oscar P.; Schmutz, Jeremy; Kuo, Alan; Miller, Neil A.; Rice, Brandon J.; Raffaele, Sylvain; Cano, Liliana M.; Bharti, Arvind K.; Donahoo, Ryan S.; Finely, Sabra; Huitema, Edgar; Hulvey, Jon; Platt, Darren; Salamov, Asaf; Savidor, Alon; Sharma, Rahul; Stam, Remco; Sotrey, Dylan; Thines, Marco; Win, Joe; Haas, Brian J.; Dinwiddie, Darrell L.; Jenkins, Jerry; Knight, James R.; Affourtit, Jason P.; Han, Cliff S.; Chertkov, Olga; Lindquist, Erika A.; Detter, Chris; Grigoriev, Igor V.; Kamoun, Sophien; Kingsmore, Stephen F.

    2012-02-07

    The oomycete vegetable pathogen Phytophthora capsici has shown remarkable adaptation to fungicides and new hosts. Like other members of this destructive genus, P. capsici has an explosive epidemiology, rapidly producing massive numbers of asexual spores on infected hosts. In addition, P. capsici can remain dormant for years as sexually recombined oospores, making it difficult to produce crops at infested sites, and allowing outcrossing populations to maintain significant genetic variation. Genome sequencing, development of a high-density genetic map, and integrative genomic or genetic characterization of P. capsici field isolates and intercross progeny revealed significant mitotic loss of heterozygosity (LOH) in diverse isolates. LOH was detected in clonally propagated field isolates and sexual progeny, cumulatively affecting >30percent of the genome. LOH altered genotypes for more than 11,000 single-nucleotide variant sites and showed a strong association with changes in mating type and pathogenicity. Overall, it appears that LOH may provide a rapid mechanism for fixing alleles and may be an important component of adaptability for P. capsici.

  8. Genome sequencing and mapping reveal loss of heterozygosity as a mechanism for rapid adaptation in the vegetable pathogen Phytophthora capsici.

    PubMed

    Lamour, Kurt H; Mudge, Joann; Gobena, Daniel; Hurtado-Gonzales, Oscar P; Schmutz, Jeremy; Kuo, Alan; Miller, Neil A; Rice, Brandon J; Raffaele, Sylvain; Cano, Liliana M; Bharti, Arvind K; Donahoo, Ryan S; Finley, Sabra; Huitema, Edgar; Hulvey, Jon; Platt, Darren; Salamov, Asaf; Savidor, Alon; Sharma, Rahul; Stam, Remco; Storey, Dylan; Thines, Marco; Win, Joe; Haas, Brian J; Dinwiddie, Darrell L; Jenkins, Jerry; Knight, James R; Affourtit, Jason P; Han, Cliff S; Chertkov, Olga; Lindquist, Erika A; Detter, Chris; Grigoriev, Igor V; Kamoun, Sophien; Kingsmore, Stephen F

    2012-10-01

    The oomycete vegetable pathogen Phytophthora capsici has shown remarkable adaptation to fungicides and new hosts. Like other members of this destructive genus, P. capsici has an explosive epidemiology, rapidly producing massive numbers of asexual spores on infected hosts. In addition, P. capsici can remain dormant for years as sexually recombined oospores, making it difficult to produce crops at infested sites, and allowing outcrossing populations to maintain significant genetic variation. Genome sequencing, development of a high-density genetic map, and integrative genomic or genetic characterization of P. capsici field isolates and intercross progeny revealed significant mitotic loss of heterozygosity (LOH) in diverse isolates. LOH was detected in clonally propagated field isolates and sexual progeny, cumulatively affecting >30% of the genome. LOH altered genotypes for more than 11,000 single-nucleotide variant sites and showed a strong association with changes in mating type and pathogenicity. Overall, it appears that LOH may provide a rapid mechanism for fixing alleles and may be an important component of adaptability for P. capsici.

  9. The first Chameleon transcriptome: comparative genomic analysis of the OXPHOS system reveals loss of COX8 in Iguanian lizards.

    PubMed

    Bar-Yaacov, Dan; Bouskila, Amos; Mishmar, Dan

    2013-01-01

    Recently, we found dramatic mitochondrial DNA divergence of Israeli Chamaeleo chamaeleon populations into two geographically distinct groups. We aimed to examine whether the same pattern of divergence could be found in nuclear genes. However, no genomic resource is available for any chameleon species. Here we present the first chameleon transcriptome, obtained using deep sequencing (SOLiD). Our analysis identified 164,000 sequence contigs of which 19,000 yielded unique BlastX hits. To test the efficacy of our sequencing effort, we examined whether the chameleon and other available reptilian transcriptomes harbored complete sets of genes comprising known biochemical pathways, focusing on the nDNA-encoded oxidative phosphorylation (OXPHOS) genes as a model. As a reference for the screen, we used the human 86 (including isoforms) known structural nDNA-encoded OXPHOS subunits. Analysis of 34 publicly available vertebrate transcriptomes revealed orthologs for most human OXPHOS genes. However, OXPHOS subunit COX8 (Cytochrome C oxidase subunit 8), including all its known isoforms, was consistently absent in transcriptomes of iguanian lizards, implying loss of this subunit during the radiation of this suborder. The lack of COX8 in the suborder Iguania is intriguing, since it is important for cellular respiration and ATP production. Our sequencing effort added a new resource for comparative genomic studies, and shed new light on the evolutionary dynamics of the OXPHOS system.

  10. The First Chameleon Transcriptome: Comparative Genomic Analysis of the OXPHOS System Reveals Loss of COX8 in Iguanian Lizards

    PubMed Central

    Bar-Yaacov, Dan; Bouskila, Amos; Mishmar, Dan

    2013-01-01

    Recently, we found dramatic mitochondrial DNA divergence of Israeli Chamaeleo chamaeleon populations into two geographically distinct groups. We aimed to examine whether the same pattern of divergence could be found in nuclear genes. However, no genomic resource is available for any chameleon species. Here we present the first chameleon transcriptome, obtained using deep sequencing (SOLiD). Our analysis identified 164,000 sequence contigs of which 19,000 yielded unique BlastX hits. To test the efficacy of our sequencing effort, we examined whether the chameleon and other available reptilian transcriptomes harbored complete sets of genes comprising known biochemical pathways, focusing on the nDNA-encoded oxidative phosphorylation (OXPHOS) genes as a model. As a reference for the screen, we used the human 86 (including isoforms) known structural nDNA-encoded OXPHOS subunits. Analysis of 34 publicly available vertebrate transcriptomes revealed orthologs for most human OXPHOS genes. However, OXPHOS subunit COX8 (Cytochrome C oxidase subunit 8), including all its known isoforms, was consistently absent in transcriptomes of iguanian lizards, implying loss of this subunit during the radiation of this suborder. The lack of COX8 in the suborder Iguania is intriguing, since it is important for cellular respiration and ATP production. Our sequencing effort added a new resource for comparative genomic studies, and shed new light on the evolutionary dynamics of the OXPHOS system. PMID:24009133

  11. Population polymorphism of nuclear mitochondrial DNA insertions reveals widespread diploidy associated with loss of heterozygosity in Debaryomyces hansenii.

    PubMed

    Jacques, Noémie; Sacerdot, Christine; Derkaoui, Meriem; Dujon, Bernard; Ozier-Kalogeropoulos, Odile; Casaregola, Serge

    2010-03-01

    Debaryomyces hansenii, a yeast that participates in the elaboration of foodstuff, displays important genetic diversity. Our recent phylogenetic classification of this species led to the subdivision of the species into three distinct clades. D. hansenii harbors the highest number of nuclear mitochondrial DNA (NUMT) insertions known so far for hemiascomycetous yeasts. Here we assessed the intraspecific variability of the NUMTs in this species by testing their presence/absence first in 28 strains, with 21 loci previously detected in the completely sequenced strain CBS 767(T), and second in a larger panel of 77 strains, with 8 most informative loci. We were able for the first time to structure populations in D. hansenii, although we observed little NUMT insertion variability within the clades. We determined the chronology of the NUMT insertions, which turned out to correlate with the previously defined taxonomy and provided additional evidence that colonization of nuclear genomes by mitochondrial DNA is a dynamic process in yeast. In combination with flow cytometry experiments, the NUMT analysis revealed the existence of both haploid and diploid strains, the latter being heterozygous and resulting from at least four crosses among strains from the various clades. As in the diploid pathogen Candida albicans, to which D. hansenii is phylogenetically related, we observed a differential loss of heterozygosity in the diploid strains, which can explain some of the large genetic diversity found in D. hansenii over the years.

  12. Population Polymorphism of Nuclear Mitochondrial DNA Insertions Reveals Widespread Diploidy Associated with Loss of Heterozygosity in Debaryomyces hansenii ▿ †

    PubMed Central

    Jacques, Noémie; Sacerdot, Christine; Derkaoui, Meriem; Dujon, Bernard; Ozier-Kalogeropoulos, Odile; Casaregola, Serge

    2010-01-01

    Debaryomyces hansenii, a yeast that participates in the elaboration of foodstuff, displays important genetic diversity. Our recent phylogenetic classification of this species led to the subdivision of the species into three distinct clades. D. hansenii harbors the highest number of nuclear mitochondrial DNA (NUMT) insertions known so far for hemiascomycetous yeasts. Here we assessed the intraspecific variability of the NUMTs in this species by testing their presence/absence first in 28 strains, with 21 loci previously detected in the completely sequenced strain CBS 767T, and second in a larger panel of 77 strains, with 8 most informative loci. We were able for the first time to structure populations in D. hansenii, although we observed little NUMT insertion variability within the clades. We determined the chronology of the NUMT insertions, which turned out to correlate with the previously defined taxonomy and provided additional evidence that colonization of nuclear genomes by mitochondrial DNA is a dynamic process in yeast. In combination with flow cytometry experiments, the NUMT analysis revealed the existence of both haploid and diploid strains, the latter being heterozygous and resulting from at least four crosses among strains from the various clades. As in the diploid pathogen Candida albicans, to which D. hansenii is phylogenetically related, we observed a differential loss of heterozygosity in the diploid strains, which can explain some of the large genetic diversity found in D. hansenii over the years. PMID:20048048

  13. Continuously accelerating ice loss over Amundsen Sea catchment, West Antarctica, revealed by integrating altimetry and GRACE data

    NASA Astrophysics Data System (ADS)

    Lee, Hyongki; Shum, C. K.; Howat, Ian M.; Monaghan, Andrew; Ahn, Yushin; Duan, Jianbin; Guo, Jun-Yi; Kuo, Chung-Yen; Wang, Lei

    2012-03-01

    Satellite altimetry and Gravity Recovery and Climate Experiment (GRACE) measurements have provided contemporary, but substantially different Antarctic ice sheet mass balance estimates. Altimetry provides no information about firn density while GRACE data is significantly impacted by poorly constrained glacial isostatic adjustment signals. Here, we combine Envisat radar altimetry and GRACE data over the Amundsen Sea (AS) sector, West Antarctica, to estimate the basin-wide averaged snow and firn column density over a seasonal time scale. Removing the firn variability signal from Envisat-observed ice-sheet elevation changes reveals more rapid dynamic thinning of underlying ice. We report that the net AS sector mass change rates are estimated to be - 47 ± 8 Gt yr- 1 between 2002 and 2006, and - 80 ± 4 Gt yr- 1 between2007 and 2009, equivalent to a sea level rise of 0.13 and 0.22 mm yr- 1, respectively. The acceleration is due to a combination of decreased snowfall accumulation (+ 13 Gt yr- 1 in 2002-2006, and - 6 Gt yr- 1 in 2007-2009) and enhanced ice dynamic thinning (- 60 ± 10 Gt yr- 1 in 2002-2006, and - 74 ± 11 Gt yr- 1 in 2007-2009) after 2007. Because there is no significant snowfall trend over the past 21 yr (1989-2009) and an increase in ice flow speed (2003-2010), the accelerated mass loss is likely to continue.

  14. Genome sequencing and mapping reveal loss of heterozygosity as a mechanism for rapid adaptation in the vegetable pathogen Phytophthora capsici

    PubMed Central

    Lamour, Kurt H.; Mudge, Joann; Gobena, Daniel; Hurtado-Gonzales, Oscar P.; Schmutz, Jeremy; Kuo, Alan; Miller, Neil A.; Rice, Brandon J.; Raffaele, Sylvain; Cano, Liliana M.; Bharti, Arvind K.; Donahoo, Ryan S.; Finley, Sabra; Huitema, Edgar; Hulvey, Jon; Platt, Darren; Salamov, Asaf; Savidor, Alon; Sharma, Rahul; Stam, Remco; Storey, Dylan; Thines, Marco; Win, Joe; Haas, Brian J.; Dinwiddie, Darrell L.; Jenkins, Jerry; Knight, James R.; Affourtit, Jason P.; Han, Cliff S.; Chertkov, Olga; Lindquist, Erika A.; Detter, Chris; Grigoriev, Igor V.; Kamoun, Sophien; Kingsmore, Stephen F.

    2013-01-01

    The oomycete vegetable pathogen Phytophthora capsici has shown remarkable adaptation to fungicides and new hosts. Like other members of this destructive genus, P. capsici has an explosive epidemiology, rapidly producing massive numbers of asexual spores on infected hosts. In addition, P. capsici can remain dormant for years as sexually-recombined oospores, making it difficult to produce crops at infested sites, and allowing outcrossing populations to maintain significant genetic variation. Genome sequencing, development of a high-density genetic map, and integrative genomic/genetic characterization of P. capsici field isolates and intercross progeny revealed significant mitotic loss of heterozygosity (LOH) and higher levels of SNVs than those reported for humans, plants, and P. infestans. LOH was detected in clonally propagated field isolates and sexual progeny, cumulatively affecting >30% of the genome. LOH altered genotypes for more than 11,000 single nucleotide variant (SNV) sites and showed a strong association with changes in mating type and pathogenicity. Overall, it appears that LOH may provide a rapid mechanism for fixing alleles and may be an important component of adaptability for P. capsici. PMID:22712506

  15. Loss of PTEN Is Associated with Aggressive Behavior in ERG-Positive Prostate Cancer

    PubMed Central

    Leinonen, Katri A.; Saramäki, Outi R.; Furusato, Bungo; Kimura, Takahiro; Takahashi, Hiroyuki; Egawa, Shin; Suzuki, Hiroyoshi; Keiger, Kerri; Hahm, Sung Ho; Isaacs, William B.; Tolonen, Teemu T.; Stenman, Ulf-Håkan; Tammela, Teuvo L.J.; Nykter, Matti; Bova, G. Steven; Visakorpi, Tapio

    2014-01-01

    Background The associations of ERG overexpression with clinical behavior and molecular pathways of prostate cancer are incompletely known. We assessed the association of ERG expression with AR, PTEN, SPINK1, Ki-67, and EZH2 expression levels, deletion, and mutations of chromosomal region 3p14 and TP53, and clinicopathologic variables. Methods The material consisted of 326 prostatectomies, 166 needle biopsies from men treated primarily with endocrine therapy, 177 transurethral resections of castration-resistant prostate cancers (CRPC), and 114 CRPC metastases obtained from 32 men. Immunohistochemistry, FISH, and sequencing was used for the measurements. Results ERG expression was found in about 45% of all patient cohorts. In a multivariate analysis, ERG expression showed independent value of favorable prognosis (P = 0.019). ERG positivity was significantly associated with loss of PTEN expression in prostatectomy (P = 0.0348), and locally recurrent CRPCs (P = 0.0042). Loss of PTEN expression was associated (P = 0.0085) with shorter progression-free survival in ERG-positive, but not in negative cases. When metastases in each subject were compared, consistent ERG, PTEN, and AR expression as well as TP53 mutations were found in a majority of subjects. Conclusions A similar frequency of ERG positivity from early to late stage of the disease suggests lack of selection of ERG expression during disease progression. The prognostic significance of PTEN loss solely in ERG-positive cases indicates interaction of these pathways. The finding of consistent genetic alterations in different metastases suggests that the major genetic alterations take place in the primary tumor. Impact Interaction of PTEN and ERG pathways warrants further studies. PMID:24083995

  16. Optimal management of cancer treatment-induced bone loss: considerations for elderly patients.

    PubMed

    Tipples, Karen; Robinson, Anne

    2011-11-01

    Hormone manipulation, commonly used in breast and prostate cancer, can result in significant bone loss. In multiple myeloma (MM), corticosteroids play an important role in therapy but increase the risk of fracture over that expected for any given bone mineral density. These adverse effects on the skeletal system are particularly relevant in the elderly population, in whom osteoporosis can significantly affect not only quality of life but also survival. The associated health and social care costs are becoming increasingly important. Screening with dual energy x-ray absorptiometry (DXA) scans and lifestyle advice on smoking, alcohol and dietary intake are essential parts of the management of patients with cancer treatment-induced bone loss. The value of exercise also cannot be underestimated. A careful drug review should be carried out to eliminate agents that may potentially exacerbate bone toxicity. Therapies to address bone toxicities include bisphosphonates, which have been shown to play an increasingly important role in preventing declines in bone health. The issues of compliance when oral agents are used should not be underestimated. Renal toxicity and osteonecrosis of the jaw are relevant toxicities, especially in the elderly. Cardiac toxicity has not been proven, but there is evidence to suggest that the suppression of bone turnover seen with some, although not all, bisphosphonates is not reversed following cessation of treatment. The implications of this finding need to be borne in mind when treating elderly patients. The possibility of atypical fractures in patients taking bisphosphonates also needs to be given consideration, although this remains a rare complication. Recently, the receptor activator of nuclear factor-κB ligand (RANKL) ligand antibody denosumab has been shown to be of value in fracture prevention, and its subcutaneous route of administration offers a potential advantage. Oncologists should also remember that tamoxifen, which has little

  17. Myeloid-derived suppressor cells function as novel osteoclast progenitors enhancing bone loss in breast cancer

    PubMed Central

    Sawant, Anandi; Deshane, Jessy; Jules, Joel; Lee, Carnella M.; Harris, Brittney A.; Feng, Xu; Ponnazhagan, Selvarangan

    2012-01-01

    Enhanced bone destruction is a hallmark of various carcinomas such as breast cancer, where osteolytic bone metastasis is associated with increased morbidity and mortality. Immune cells contribute to osteolysis in cancer growth but the factors contributing to aggressive bone destruction are not well understood. In this study, we demonstrate the importance of myeloid-derived suppressor cells (MDSC) in this process at bone metastatic sites. Since MDSC originate from the same myeloid lineage as macrophages, which are osteoclast precursors, we hypothesized that MDSC may undergo osteoclast differentiation and contribute to enhanced bone destruction and tumor growth. Using an immunocompetent mouse model of breast cancer bone metastasis, we confirmed that MDSC isolated from the tumor-bone microenvironment differentiated into functional osteoclasts both in vitro and in vivo. Mechanistic investigations revealed that nitric oxide signaling was critical for differentiation of MDSC into osteoclasts. Remarkably, osteoclast differentiation did not occur in MDSC isolated from control or tumor-bearing mice that lacked bone metastasis, signifying the essential cross-talk between tumor cells and myeloid progenitors in the bone microenvironment as a requirement for osteoclast differentiation of MDSC. Overall, our results identify a wholly new facet to the multifunctionality of MDSC in driving tumor progression, in this case as a novel osteoclast progenitor that specifically drives bone metastasis during cancer progression. PMID:23243021

  18. Proteomics Analysis of Ovarian Cancer Cell Lines and Tissues Reveals Drug Resistance-associated Proteins

    PubMed Central

    CRUZ*, ISA N.; COLEY*, HELEN M.; KRAMER, HOLGER B.; MADHURI, THUMULURU KAVITAH; SAFUWAN, NUR A.M.; ANGELINO, ANA RITA; YANG, MIN

    2016-01-01

    Background: Carboplatin and paclitaxel form the cornerstone of chemotherapy for epithelial ovarian cancer, however, drug resistance to these agents continues to present challenges. Despite extensive research, the mechanisms underlying this resistance remain unclear. Materials and Methods: A 2D-gel proteomics method was used to analyze protein expression levels of three human ovarian cancer cell lines and five biopsy samples. Representative proteins identified were validated via western immunoblotting. Ingenuity pathway analysis revealed metabolomic pathway changes. Results: A total of 189 proteins were identified with restricted criteria. Combined treatment targeting the proteasome-ubiquitin pathway resulted in re-sensitisation of drug-resistant cells. In addition, examination of five surgical biopsies of ovarian tissues revealed α-enolase (ENOA), elongation factor Tu, mitochondrial (EFTU), glyceraldehyde-3-phosphate dehydrogenase (G3P), stress-70 protein, mitochondrial (GRP75), apolipoprotein A-1 (APOA1), peroxiredoxin (PRDX2) and annexin A (ANXA) as candidate biomarkers of drug-resistant disease. Conclusion: Proteomics combined with pathway analysis provided information for an effective combined treatment approach overcoming drug resistance. Analysis of cell lines and tissues revealed potential prognostic biomarkers for ovarian cancer. *These Authors contributed equally to this study. PMID:28031236

  19. Loss of the EPH receptor B6 contributes to colorectal cancer metastasis.

    PubMed

    Mateo-Lozano, Silvia; Bazzocco, Sarah; Rodrigues, Paulo; Mazzolini, Rocco; Andretta, Elena; Dopeso, Higinio; Fernández, Yolanda; Del Llano, Edgar; Bilic, Josipa; Suárez-López, Lucía; Macaya, Irati; Cartón-García, Fernando; Nieto, Rocio; Jimenez-Flores, Lizbeth M; de Marcondes, Priscila Guimarães; Nuñez, Yaiza; Afonso, Elsa; Cacci, Karina; Hernández-Losa, Javier; Landolfi, Stefania; Abasolo, Ibane; Ramón Y Cajal, Santiago; Mariadason, John M; Schwartz, Simo; Matsui, Toshimitsu; Arango, Diego

    2017-03-06

    Although deregulation of EPHB signaling has been shown to be an important step in colorectal tumorigenesis, the role of EPHB6 in this process has not been investigated. We found here that manipulation of EPHB6 levels in colon cancer cell lines has no effect on their motility and growth on a solid substrate, soft agar or in a xenograft mouse model. We then used an EphB6 knockout mouse model to show that EphB6 inactivation does not efficiently initiate tumorigenesis in the intestinal tract. In addition, when intestinal tumors are initiated genetically or pharmacologically in EphB6(+/+) and EphB6(-/-) mice, no differences were observed in animal survival, tumor multiplicity, size or histology, and proliferation of intestinal epithelial cells or tumor cells. However, reintroduction of EPHB6 into colon cancer cells significantly reduced the number of lung metastasis after tail-vein injection in immunodeficient mice, while EPHB6 knockdown in EPHB6-expressing cells increased their metastatic spread. Consistently, although EPHB6 protein expression in a series of 130 primary colorectal tumors was not associated with patient survival, EPHB6 expression was significantly lower in lymph node metastases compared to primary tumors. Our results indicate that the loss of EPHB6 contributes to the metastatic process of colorectal cancer.

  20. Recurrent Fusion Genes in Gastric Cancer: CLDN18-ARHGAP26 Induces Loss of Epithelial Integrity.

    PubMed

    Yao, Fei; Kausalya, Jaya P; Sia, Yee Yen; Teo, Audrey S M; Lee, Wah Heng; Ong, Alicia G M; Zhang, Zhenshui; Tan, Joanna H J; Li, Guoliang; Bertrand, Denis; Liu, Xingliang; Poh, Huay Mei; Guan, Peiyong; Zhu, Feng; Pathiraja, Thushangi Nadeera; Ariyaratne, Pramila N; Rao, Jaideepraj; Woo, Xing Yi; Cai, Shaojiang; Mulawadi, Fabianus H; Poh, Wan Ting; Veeravalli, Lavanya; Chan, Chee Seng; Lim, Seong Soo; Leong, See Ting; Neo, Say Chuan; Choi, Poh Sum D; Chew, Elaine G Y; Nagarajan, Niranjan; Jacques, Pierre-Étienne; So, Jimmy B Y; Ruan, Xiaoan; Yeoh, Khay Guan; Tan, Patrick; Sung, Wing-Kin; Hunziker, Walter; Ruan, Yijun; Hillmer, Axel M

    2015-07-14

    Genome rearrangements, a hallmark of cancer, can result in gene fusions with oncogenic properties. Using DNA paired-end-tag (DNA-PET) whole-genome sequencing, we analyzed 15 gastric cancers (GCs) from Southeast Asians. Rearrangements were enriched in open chromatin and shaped by chromatin structure. We identified seven rearrangement hot spots and 136 gene fusions. In three out of 100 GC cases, we found recurrent fusions between CLDN18, a tight junction gene, and ARHGAP26, a gene encoding a RHOA inhibitor. Epithelial cell lines expressing CLDN18-ARHGAP26 displayed a dramatic loss of epithelial phenotype and long protrusions indicative of epithelial-mesenchymal transition (EMT). Fusion-positive cell lines showed impaired barrier properties, reduced cell-cell and cell-extracellular matrix adhesion, retarded wound healing, and inhibition of RHOA. Gain of invasion was seen in cancer cell lines expressing the fusion. Thus, CLDN18-ARHGAP26 mediates epithelial disintegration, possibly leading to stomach H(+) leakage, and the fusion might contribute to invasiveness once a cell is transformed.

  1. Loss of the EPH receptor B6 contributes to colorectal cancer metastasis

    PubMed Central

    Mateo-Lozano, Silvia; Bazzocco, Sarah; Rodrigues, Paulo; Mazzolini, Rocco; Andretta, Elena; Dopeso, Higinio; Fernández, Yolanda; del Llano, Edgar; Bilic, Josipa; Suárez-López, Lucía; Macaya, Irati; Cartón-García, Fernando; Nieto, Rocio; Jimenez-Flores, Lizbeth M.; de Marcondes, Priscila Guimarães; Nuñez, Yaiza; Afonso, Elsa; Cacci, Karina; Hernández-Losa, Javier; Landolfi, Stefania; Abasolo, Ibane; Ramón y Cajal, Santiago; Mariadason, John M.; Schwartz, Simo; Matsui, Toshimitsu; Arango, Diego

    2017-01-01

    Although deregulation of EPHB signaling has been shown to be an important step in colorectal tumorigenesis, the role of EPHB6 in this process has not been investigated. We found here that manipulation of EPHB6 levels in colon cancer cell lines has no effect on their motility and growth on a solid substrate, soft agar or in a xenograft mouse model. We then used an EphB6 knockout mouse model to show that EphB6 inactivation does not efficiently initiate tumorigenesis in the intestinal tract. In addition, when intestinal tumors are initiated genetically or pharmacologically in EphB6+/+ and EphB6−/− mice, no differences were observed in animal survival, tumor multiplicity, size or histology, and proliferation of intestinal epithelial cells or tumor cells. However, reintroduction of EPHB6 into colon cancer cells significantly reduced the number of lung metastasis after tail-vein injection in immunodeficient mice, while EPHB6 knockdown in EPHB6-expressing cells increased their metastatic spread. Consistently, although EPHB6 protein expression in a series of 130 primary colorectal tumors was not associated with patient survival, EPHB6 expression was significantly lower in lymph node metastases compared to primary tumors. Our results indicate that the loss of EPHB6 contributes to the metastatic process of colorectal cancer. PMID:28262839

  2. The cancer anorexia/weight loss syndrome: exploring associations with single nucleotide polymorphisms (SNPs) of inflammatory cytokines in patients with non-small cell lung cancer

    PubMed Central

    Jatoi, Aminah; Qi, Yingwei; Kendall, Glenda; Jiang, Ruoxiang; McNallan, Sheila; Cunningham, Julie; Mandrekar, Sumithra; Yang, Ping

    2010-01-01

    Objective The cancer anorexia/weight loss syndrome commonly occurs in patients with non-small cell lung cancer (NSCLC) and is characterized by loss of weight and appetite as well as diminished survival. The current study explored whether any of 22 single nucleotide polymorphisms (SNPs) of certain previously implicated inflammatory cytokines (interleukin-1 beta, interleukin-1RN, interleukin-6, and tumor necrosis factor) are associated with this syndrome. Patients and Methods All NSCLC patients who had been enrolled in the Mayo Clinic Lung Cancer Cohort, had completed a health-related questionnaire approximately 6 months after enrollment, and had blood drawn were included in this study, thus yielding a sample size of 471 patients. Results Sixty-six (14%) patients manifested weight loss shortly after diagnosis, and 152 (32%) reported appetite loss. Only tumor necrosis factor alpha rs800629 was associated with anorexia (odds ratio: 0.46; 95% confidence interval: 0.29, 0.72; p<0.001); patients who were heterozygous and minor homozygous were less likely to suffer anorexia. Otherwise, there were no statistically significant associations between any of the other 21 SNPs and weight loss and/or anorexia. In univariate analyses, weight loss, anorexia, more advanced cancer stage, and interleukin-1 beta rs1143627 were associated with a worse survival, and interleukin-6 rs2069835 was associated with better survival. However, in multivariate analyses, cancer stage and patient age were the only statistically significant predictors of worse survival. Conclusion No specific SNP was associated with all aspects of the cancer anorexia/weight loss syndrome, but rs800629 may merit further study in cancer-associated anorexia. PMID:20012999

  3. Solutions to Peto's paradox revealed by mathematical modelling and cross-species cancer gene analysis

    SciTech Connect

    Caulin, Aleah F.; Graham, Trevor A.; Wang, Li-San; Maley, Carlo C.

    2015-06-08

    Whales have 1000-fold more cells than humans and mice have 1000-fold fewer; however, cancer risk across species does not increase with the number of somatic cells and the lifespan of the organism. This observation is known as Peto's paradox. How much would evolution have to change the parameters of somatic evolution in order to equalize the cancer risk between species that differ by orders of magnitude in size? Analysis of previously published models of colorectal cancer suggests that a two- to three-fold decrease in the mutation rate or stem cell division rate is enough to reduce a whale's cancer risk to that of a human. Similarly, the addition of one to two required tumour-suppressor gene mutations would also be sufficient. Also, we surveyed mammalian genomes and did not find a positive correlation of tumour-suppressor genes with increasing body mass and longevity. However, we found evidence of the amplification of TP53 in elephants, MAL in horses and FBXO31 in microbats, which might explain Peto's paradox in those species. Lastly, exploring parameters that evolution may have fine-tuned in large, long-lived organisms will help guide future experiments to reveal the underlying biology responsible for Peto's paradox and guide cancer prevention in humans.

  4. Solutions to Peto's paradox revealed by mathematical modelling and cross-species cancer gene analysis

    DOE PAGES

    Caulin, Aleah F.; Graham, Trevor A.; Wang, Li-San; ...

    2015-06-08

    Whales have 1000-fold more cells than humans and mice have 1000-fold fewer; however, cancer risk across species does not increase with the number of somatic cells and the lifespan of the organism. This observation is known as Peto's paradox. How much would evolution have to change the parameters of somatic evolution in order to equalize the cancer risk between species that differ by orders of magnitude in size? Analysis of previously published models of colorectal cancer suggests that a two- to three-fold decrease in the mutation rate or stem cell division rate is enough to reduce a whale's cancer riskmore » to that of a human. Similarly, the addition of one to two required tumour-suppressor gene mutations would also be sufficient. Also, we surveyed mammalian genomes and did not find a positive correlation of tumour-suppressor genes with increasing body mass and longevity. However, we found evidence of the amplification of TP53 in elephants, MAL in horses and FBXO31 in microbats, which might explain Peto's paradox in those species. Lastly, exploring parameters that evolution may have fine-tuned in large, long-lived organisms will help guide future experiments to reveal the underlying biology responsible for Peto's paradox and guide cancer prevention in humans.« less

  5. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin.

    PubMed

    Hoadley, Katherine A; Yau, Christina; Wolf, Denise M; Cherniack, Andrew D; Tamborero, David; Ng, Sam; Leiserson, Max D M; Niu, Beifang; McLellan, Michael D; Uzunangelov, Vladislav; Zhang, Jiashan; Kandoth, Cyriac; Akbani, Rehan; Shen, Hui; Omberg, Larsson; Chu, Andy; Margolin, Adam A; Van't Veer, Laura J; Lopez-Bigas, Nuria; Laird, Peter W; Raphael, Benjamin J; Ding, Li; Robertson, A Gordon; Byers, Lauren A; Mills, Gordon B; Weinstein, John N; Van Waes, Carter; Chen, Zhong; Collisson, Eric A; Benz, Christopher C; Perou, Charles M; Stuart, Joshua M

    2014-08-14

    Recent genomic analyses of pathologically defined tumor types identify "within-a-tissue" disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head and neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multiplatform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All data sets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Solutions to Peto's paradox revealed by mathematical modelling and cross-species cancer gene analysis.

    PubMed

    Caulin, Aleah F; Graham, Trevor A; Wang, Li-San; Maley, Carlo C

    2015-07-19

    Whales have 1000-fold more cells than humans and mice have 1000-fold fewer; however, cancer risk across species does not increase with the number of somatic cells and the lifespan of the organism. This observation is known as Peto's paradox. How much would evolution have to change the parameters of somatic evolution in order to equalize the cancer risk between species that differ by orders of magnitude in size? Analysis of previously published models of colorectal cancer suggests that a two- to three-fold decrease in the mutation rate or stem cell division rate is enough to reduce a whale's cancer risk to that of a human. Similarly, the addition of one to two required tumour-suppressor gene mutations would also be sufficient. We surveyed mammalian genomes and did not find a positive correlation of tumour-suppressor genes with increasing body mass and longevity. However, we found evidence of the amplification of TP53 in elephants, MAL in horses and FBXO31 in microbats, which might explain Peto's paradox in those species. Exploring parameters that evolution may have fine-tuned in large, long-lived organisms will help guide future experiments to reveal the underlying biology responsible for Peto's paradox and guide cancer prevention in humans.

  7. Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value.

    PubMed

    Stirzaker, Clare; Zotenko, Elena; Song, Jenny Z; Qu, Wenjia; Nair, Shalima S; Locke, Warwick J; Stone, Andrew; Armstong, Nicola J; Robinson, Mark D; Dobrovic, Alexander; Avery-Kiejda, Kelly A; Peters, Kate M; French, Juliet D; Stein, Sandra; Korbie, Darren J; Trau, Matt; Forbes, John F; Scott, Rodney J; Brown, Melissa A; Francis, Glenn D; Clark, Susan J

    2015-02-02

    Epigenetic alterations in the cancer methylome are common in breast cancer and provide novel options for tumour stratification. Here, we perform whole-genome methylation capture sequencing on small amounts of DNA isolated from formalin-fixed, paraffin-embedded tissue from triple-negative breast cancer (TNBC) and matched normal samples. We identify differentially methylated regions (DMRs) enriched with promoters associated with transcription factor binding sites and DNA hypersensitive sites. Importantly, we stratify TNBCs into three distinct methylation clusters associated with better or worse prognosis and identify 17 DMRs that show a strong association with overall survival, including DMRs located in the Wilms tumour 1 (WT1) gene, bi-directional-promoter and antisense WT1-AS. Our data reveal that coordinated hypermethylation can occur in oestrogen receptor-negative disease, and that characterizing the epigenetic framework provides a potential signature to stratify TNBCs. Together, our findings demonstrate the feasibility of profiling the cancer methylome with limited archival tissue to identify regulatory regions associated with cancer.

  8. Solutions to Peto's paradox revealed by mathematical modelling and cross-species cancer gene analysis

    PubMed Central

    Caulin, Aleah F.; Graham, Trevor A.; Wang, Li-San; Maley, Carlo C.

    2015-01-01

    Whales have 1000-fold more cells than humans and mice have 1000-fold fewer; however, cancer risk across species does not increase with the number of somatic cells and the lifespan of the organism. This observation is known as Peto's paradox. How much would evolution have to change the parameters of somatic evolution in order to equalize the cancer risk between species that differ by orders of magnitude in size? Analysis of previously published models of colorectal cancer suggests that a two- to three-fold decrease in the mutation rate or stem cell division rate is enough to reduce a whale's cancer risk to that of a human. Similarly, the addition of one to two required tumour-suppressor gene mutations would also be sufficient. We surveyed mammalian genomes and did not find a positive correlation of tumour-suppressor genes with increasing body mass and longevity. However, we found evidence of the amplification of TP53 in elephants, MAL in horses and FBXO31 in microbats, which might explain Peto's paradox in those species. Exploring parameters that evolution may have fine-tuned in large, long-lived organisms will help guide future experiments to reveal the underlying biology responsible for Peto's paradox and guide cancer prevention in humans. PMID:26056366

  9. Analysis of the interplay between methylation and expression reveals its potential role in cancer aetiology.

    PubMed

    Ozer, Bugra; Sezerman, Ugur

    2017-01-01

    With ongoing developments in technology, changes in DNA methylation levels have become prevalent to study cancer biology. Previous studies report that DNA methylation affects gene expression in a direct manner, most probably by blocking gene regulatory regions. In this study, we have studied the interplay between methylation and expression to improve our knowledge of cancer aetiology. For this purpose, we have investigated which genomic regions are of higher importance; hence, first exon, 5'UTR and 200 bp near the transcription start sites are proposed as being more crucial compared to other genomic regions. Furthermore, we have searched for a valid methylation level change threshold, and as a result, 25 % methylation change in previously determined genomic regions showed the highest inverse correlation with expression data. As a final step, we have examined the commonly affected genes and pathways by integrating methylation and expression information. Remarkably, the GPR115 gene and ErbB signalling pathway were found to be significantly altered for all cancer types in our analysis. Overall, combining methylation and expression information and identifying commonly affected genes and pathways in a variety of cancer types revealed new insights of cancer disease mechanisms. Moreover, compared to previous methylation-based studies, we have identified more important genomic regions and have defined a methylation change threshold level in order to obtain more reliable results. In addition to the novel analysis framework that involves the analysis of four different cancer types, our study exposes essential information regarding the contribution of methylation changes and its impact on cancer disease biology, which may facilitate the identification of new drug targets.

  10. Understanding Grief and Loss

    MedlinePlus

    ... Loss > Understanding Grief and Loss Request Permissions Understanding Grief and Loss Approved by the Cancer.Net Editorial ... of grief and mourning after a loss. Common grief reactions Reactions to loss, called grief reactions, vary ...

  11. Characterization of PTEN mutations in brain cancer reveals that pten mono-ubiquitination promotes protein stability and nuclear localization.

    PubMed

    Yang, Jr-M; Schiapparelli, P; Nguyen, H-N; Igarashi, A; Zhang, Q; Abbadi, S; Amzel, L M; Sesaki, H; Quiñones-Hinojosa, A; Iijima, M

    2017-03-06

    PTEN is a PIP3 phosphatase that antagonizes oncogenic PI3-kinase signalling. Due to its critical role in suppressing the potent signalling pathway, it is one of the most mutated tumour suppressors, especially in brain tumours. It is generally thought that PTEN deficiencies predominantly result from either loss of expression or enzymatic activity. By analysing PTEN in malignant glioblastoma primary cells derived from 16 of our patients, we report mutations that block localization of PTEN at the plasma membrane and nucleus without affecting lipid phosphatase activity. Cellular and biochemical analyses as well as structural modelling revealed that two mutations disrupt intramolecular interaction of PTEN and open its conformation, enhancing polyubiquitination of PTEN and decreasing protein stability. Moreover, promoting mono-ubiquitination increases protein stability and nuclear localization of mutant PTEN. Thus, our findings provide a molecular mechanism for cancer-associated PTEN defects and may lead to a brain cancer treatment that targets PTEN mono-ubiquitination.Oncogene advance online publication, 6 March 2017; doi:10.1038/onc.2016.493.

  12. Functional proteomic analysis reveals the involvement of KIAA1199 in breast cancer growth, motility and invasiveness

    PubMed Central

    2014-01-01

    Background KIAA1199 is a recently identified novel gene that is up-regulated in human cancer with poor survival. Our proteomic study on signaling polarity in chemotactic cells revealed KIAA1199 as a novel protein target that may be involved in cellular chemotaxis and motility. In the present study, we examined the functional significance of KIAA1199 expression in breast cancer growth, motility and invasiveness. Methods We validated the previous microarray observation by tissue microarray immunohistochemistry using a TMA slide containing 12 breast tumor tissue cores and 12 corresponding normal tissues. We performed the shRNA-mediated knockdown of KIAA1199 in MDA-MB-231 and HS578T cells to study the role of this protein in cell proliferation, migration and apoptosis in vitro. We studied the effects of KIAA1199 knockdown in vivo in two groups of mice (n = 5). We carried out the SILAC LC-MS/MS based proteomic studies on the involvement of KIAA1199 in breast cancer. Results KIAA1199 mRNA and protein was significantly overexpressed in breast tumor specimens and cell lines as compared with non-neoplastic breast tissues from large-scale microarray and studies of breast cancer cell lines and tumors. To gain deeper insights into the novel role of KIAA1199 in breast cancer, we modulated KIAA1199 expression using shRNA-mediated knockdown in two breast cancer cell lines (MDA-MB-231 and HS578T), expressing higher levels of KIAA1199. The KIAA1199 knockdown cells showed reduced motility and cell proliferation in vitro. Moreover, when the knockdown cells were injected into the mammary fat pads of female athymic nude mice, there was a significant decrease in tumor incidence and growth. In addition, quantitative proteomic analysis revealed that knockdown of KIAA1199 in breast cancer (MDA-MB-231) cells affected a broad range of cellular functions including apoptosis, metabolism and cell motility. Conclusions Our findings indicate that KIAA1199 may play an important role in breast

  13. A Pilot Randomized Controlled Trial of a Commercial Diet and Exercise Weight Loss Program in Minority Breast Cancer Survivors

    PubMed Central

    Greenlee, Heather A.; Crew, Katherine D.; Mata, Jennie M.; McKinley, Paula S.; Rundle, Andrew G.; Zhang, Wenfei; Liao, Yuyan; Tsai, Wei Y.; Hershman, Dawn L.

    2015-01-01

    Objective Obesity is associated with poorer breast cancer outcomes and losing weight postdiagnosis may improve survival. As Hispanic and black women have poorer breast cancer prognosis than non-Hispanic whites diagnosed at similar age and stage, and have higher rates of obesity, effective weight loss strategies are needed. We piloted a randomized, waitlist-controlled, crossover study to examine the effects and feasibility of the commercial Curves weight loss program among Hispanic, African American and Afro-Caribbean breast cancer survivors. Design and Methods Women with stage 0– IIIa breast cancer ≥6 months posttreatment, sedentary, and BMI ≥25 kg/m2 were randomized to the immediate arm (IA): 6 months of the Curves program followed by 6 months of observation; or the waitlist control arm (WCA): 6 months of observation followed by 6 months of the Curves program. The Curves program uses a 30-min exercise circuit and a high-vegetable/low-fat/calorie-restricted diet. Results A total of 42 women enrolled (79% Hispanic, 21% black), mean age 51 (range 32–69) and mean BMI 33.2(±5.9) kg/m2; 91% were retained at month 12. At month 6, women in the IA lost an average 3.3% (±3.5%) of body weight (range: 1.7% gain to 10.6% loss), as compared with 1.8% (±2.9%) weight loss in the WCA (P = 0.04). At month 12, on average women in the IA regained some but not all of the weight lost during the first 6 months (P = 0.02). Conclusions Minority breast cancer survivors were recruited and retained in a weight loss study. Six months of the Curves program resulted in moderate weight loss, but weight loss was not maintained postintervention. Future interventions should identify methods to increase uptake and maintenance of weight loss behaviors. PMID:23505170

  14. Outcomes of a weight loss intervention among rural breast cancer survivors.

    PubMed

    Befort, Christie A; Klemp, Jennifer R; Austin, Heather L; Perri, Michael G; Schmitz, Kathryn H; Sullivan, Debra K; Fabian, Carol J

    2012-04-01

    Obese breast cancer survivors have increased risk of recurrence and death compared to their normal weight counterparts. Rural women have significantly higher obesity rates, thus weight control intervention may be a key strategy for prevention of breast cancer recurrence in this population. This one-arm treatment study examined the impact of a group-based weight control intervention delivered through conference call technology to obese breast cancer survivors living in remote rural locations. The intervention included a reduced calorie diet incorporating prepackaged entrees and shakes, physical activity gradually increased to 225 min/week of moderate intensity exercise, and weekly group phone sessions. Outcomes included anthropomorphic, diet, physical activity, serum biomarker, and quality of life changes. Ninety-one percent of participants (31 of 34) attended >75% of intervention sessions and completed post-treatment data collection visits. At 6 months, significant changes were observed for weight (-12.5 ± 5.8 kg, 13.9% of baseline weight), waist circumference (-9.4 ± 6.3 cm), daily energy intake (-349 ± 550 kcal/day), fruits, and vegetables (+3.7 ± 4.3 servings/day), percent kcal from fat (-12.6 ± 8.6%), physical activity (+1235 ± 832 kcal/week; all P values <0.001), as well as significant reductions in fasting insulin (16.7% reduction, P = 0.006), and leptin (37.1% reduction, P < 0.001). Significant improvements were also seen for quality of life domains including mood, body image, and sexuality. In conclusion, the intervention produced >10% weight loss as well as significant improvements across multiple endpoints. The group phone-based treatment delivery approach may help disseminate effective weight control intervention to hard-to-reach breast cancer survivors.

  15. Dies1/VISTA expression loss is a recurrent event in gastric cancer due to epigenetic regulation

    PubMed Central

    Oliveira, Patrícia; Carvalho, Joana; Rocha, Sara; Azevedo, Mafalda; Reis, Inês; Camilo, Vânia; Sousa, Bárbara; Valente, Sofia; Paredes, Joana; Almeida, Raquel; Huntsman, David; Oliveira, Carla

    2016-01-01

    Dies1/VISTA induces embryonic stem-cell differentiation, via BMP-pathway, but also acts as inflammation regulator and immune-response modulator. Dies1 inhibition in a melanoma-mouse model led to increased tumour-infiltrating T-cells and decreased tumour growth, emphasizing Dies1 relevance in tumour-microenvironment. Dies1 is involved in cell de/differentiation, inflammation and cancer processes, which mimic those associated with Epithelial-to-Mesenchymal-Transition (EMT). Despite this axis linking Dies1 with EMT and cancer, its expression, modulation and relevance in these contexts is unknown. To address this, we analysed Dies1 expression, its regulation by promoter-methylation and miR-125a-5p overexpression, and its association with BMP-pathway downstream-effectors, in a TGFβ1-induced EMT-model, cancer cell-lines and primary samples. We detected promoter-methylation as a mechanism controlling Dies1 expression in our EMT-model and in several cancer cell-lines. We showed that the relationship between Dies1 expression and BMP-pathway effectors observed in the EMT-model, was not present in all cell-lines, suggesting that Dies1 has other cell-specific effectors, beyond the BMP-pathway. We further demonstrated that: Dies1 expression loss is a recurrent event in GC, caused by promoter methylation and/or miR-125a-5p overexpression and; GC-microenvironment myofibroblasts overexpress Dies1. Our findings highlight Dies1 as a novel player in GC, with distinct roles within tumour cells and in the tumour-microenvironment. PMID:27721458

  16. Dies1/VISTA expression loss is a recurrent event in gastric cancer due to epigenetic regulation.

    PubMed

    Oliveira, Patrícia; Carvalho, Joana; Rocha, Sara; Azevedo, Mafalda; Reis, Inês; Camilo, Vânia; Sousa, Bárbara; Valente, Sofia; Paredes, Joana; Almeida, Raquel; Huntsman, David; Oliveira, Carla

    2016-10-10

    Dies1/VISTA induces embryonic stem-cell differentiation, via BMP-pathway, but also acts as inflammation regulator and immune-response modulator. Dies1 inhibition in a melanoma-mouse model led to increased tumour-infiltrating T-cells and decreased tumour growth, emphasizing Dies1 relevance in tumour-microenvironment. Dies1 is involved in cell de/differentiation, inflammation and cancer processes, which mimic those associated with Epithelial-to-Mesenchymal-Transition (EMT). Despite this axis linking Dies1 with EMT and cancer, its expression, modulation and relevance in these contexts is unknown. To address this, we analysed Dies1 expression, its regulation by promoter-methylation and miR-125a-5p overexpression, and its association with BMP-pathway downstream-effectors, in a TGFβ1-induced EMT-model, cancer cell-lines and primary samples. We detected promoter-methylation as a mechanism controlling Dies1 expression in our EMT-model and in several cancer cell-lines. We showed that the relationship between Dies1 expression and BMP-pathway effectors observed in the EMT-model, was not present in all cell-lines, suggesting that Dies1 has other cell-specific effectors, beyond the BMP-pathway. We further demonstrated that: Dies1 expression loss is a recurrent event in GC, caused by promoter methylation and/or miR-125a-5p overexpression and; GC-microenvironment myofibroblasts overexpress Dies1. Our findings highlight Dies1 as a novel player in GC, with distinct roles within tumour cells and in the tumour-microenvironment.

  17. DAPK loss in colon cancer tumor buds: implications for migration capacity of disseminating tumor cells

    PubMed Central

    Karamitopoulou, Eva; Dawson, Heather; Koelzer, Viktor Hendrik; Agaimy, Abbas; Garreis, Fabian; Söder, Stephan; Laqua, William; Lugli, Alessandro; Hartmann, Arndt; Rau, Tilman T.; Schneider-Stock, Regine

    2015-01-01

    Defining new therapeutic strategies to overcome therapy resistance due to tumor heterogeneity in colon cancer is challenging. One option is to explore the molecular profile of aggressive disseminating tumor cells. The cytoskeleton-associated Death-associated protein kinase (DAPK) is involved in the cross talk between tumor and immune cells at the invasion front of colorectal cancer. Here dedifferentiated tumor cells histologically defined as tumor budding are associated with a high risk of metastasis and poor prognosis. Analyzing samples from 144 colorectal cancer patients we investigated immunhistochemical DAPK expression in different tumor regions such as center, invasion front, and buds. Functional consequences for tumor aggressiveness were studied in a panel of colon tumor cell lines using different migration, wound healing, and invasion assays. DAPK levels were experimentally modified by siRNA transfection and overexpression as well as inhibitor treatments. We found that DAPK expression was reduced towards the invasion front and was nearly absent in tumor buds. Applying the ECIS system with HCT116 and HCT116 stable lentiviral DAPK knock down cells (HCTshDAPK) we identified an important role for DAPK in decreasing the migratory capacity whereas proliferation was not affected. Furthermore, the migration pattern differed with HCTshDAPK cells showing a cluster-like migration of tumor cell groups. DAPK inhibitor treatment revealed that the migration rate was independent of DAPK's catalytic activity. Modulation of DAPK expression level in SW480 and DLD1 colorectal cancer cells significantly influenced wound closure rate. DAPK seems to be a major player that influences the migratory capability of disseminating tumor cells and possibly affects the dynamic interface between pro- and anti-survival factors at the invasion front of colorectal cancer. This interesting and new finding requires further evaluation. PMID:26405175

  18. Offering a tailored return to work program to cancer survivors with job loss: a process evaluation.

    PubMed

    van Egmond, M P; Duijts, S F A; Scholten, A P J; van der Beek, A J; Anema, J R

    2016-09-06

    In Europe, 1.7 million persons of working age are diagnosed with cancer each year. During or after treatment, cancer survivors (CSs) are vulnerable for job loss, and many CSs struggle with return to work (RTW). When offering RTW interventions to CSs, it is important to conduct a process evaluation to assess such factors as the population reached and implementation problems. Recently, we developed an innovative RTW program, tailored specifically to the needs of CSs with job loss in the Netherlands. The aim of this study was to evaluate the likelihood of theory and implementation failure, as well as to evaluate procedures for recruitment, execution and implementation of the tailored RTW program for CSs with job loss. Six components were evaluated in the RTW program: Recruitment, Reach, Dosage, Implementation, Satisfaction, and Experienced Barriers. Data were provided by logbooks and questionnaires from participating CSs, occupational health care (OHC) professionals, and re-integration coaches and job hunting officers who delivered the RTW program. SPSS and Excel were used to conduct the analyses. 85 CSs received the tailored RTW program. Their mean age was 47.9 years (SD 8.5). The majority were female (72 %), married (52 %), and of Dutch nationality (91 %). The program reached 88.2 % of the target population and 52 % of participants who started the program received the adequate dosage. The program implementation score was 45.9 %. Participants' mean overall program duration remained within the protocol boundaries. Re-integration coaches were more satisfied with the program than job hunting officers or OHC professionals. Likewise, participants were more satisfied with the program delivery by the re-integration coaches than with the delivery by the job hunting officers. Reported barriers within the RTW program were a lack of communication, high program intensity and short program duration, and, with regard to the job hunting officers, a lack of experience with

  19. Analysis of Epithelial and Mesenchymal Markers in Ovarian Cancer Reveals Phenotypic Heterogeneity and Plasticity

    PubMed Central

    Strauss, Robert; Li, Zong-Yi; Liu, Ying; Beyer, Ines; Persson, Jonas; Sova, Pavel; Möller, Thomas; Pesonen, Sari; Hemminki, Akseli; Hamerlik, Petra; Drescher, Charles; Urban, Nicole; Bartek, Jiri; Lieber, André

    2011-01-01

    In our studies of ovarian cancer cells we have identified subpopulations of cells that are in a transitory E/M hybrid stage, i.e. cells that simultaneously express epithelial and mesenchymal markers. E/M cells are not homogenous but, in vitro and in vivo, contain subsets that can be distinguished based on a number of phenotypic features, including the subcellular localization of E-cadherin, and the expression levels of Tie2, CD133, and CD44. A cellular subset (E/M-MP) (membrane E-cadherinlow/cytoplasmic E-cadherinhigh/CD133high, CD44high, Tie2low) is highly enriched for tumor-forming cells and displays features which are generally associated with cancer stem cells. Our data suggest that E/M-MP cells are able to differentiate into different lineages under certain conditions, and have the capacity for self-renewal, i.e. to maintain a subset of undifferentiated E/M-MP cells during differentiation. Trans-differentiation of E/M-MP cells into mesenchymal or epithelial cells is associated with a loss of stem cell markers and tumorigenicity. In vivo xenograft tumor growth is driven by E/M-MP cells, which give rise to epithelial ovarian cancer cells. In contrast, in vitro, we found that E/M-MP cells differentiate into mesenchymal cells, in a process that involves pathways associated with an epithelial-to-mesenchymal transition. We also detected phenotypic plasticity that was dependent on external factors such as stress created by starvation or contact with either epithelial or mesenchymal cells in co-cultures. Our study provides a better understanding of the phenotypic complexity of ovarian cancer and has implications for ovarian cancer therapy. PMID:21264259

  20. Productivity loss due to premature mortality caused by blood cancer: a study based on patients undergoing stem cell transplantation.

    PubMed

    Ortega-Ortega, Marta; Oliva-Moreno, Juan; Jiménez-Aguilera, Juan de Dios; Romero-Aguilar, Antonio; Espigado-Tocino, Ildefonso

    2015-01-01

    Stem cell transplantation has been used for many years to treat haematological malignancies that could not be cured by other treatments. Despite this medical breakthrough, mortality rates remain high. Our purpose was to evaluate labour productivity losses associated with premature mortality due to blood cancer in recipients of stem cell transplantations. We collected primary data from the clinical histories of blood cancer patients who had undergone stem cell transplantation between 2006 and 2011 in two Spanish hospitals. We carried out a descriptive analysis and calculated the years of potential life lost and years of potential productive life lost. Labour productivity losses due to premature mortality were estimated using the Human Capital method. An alternative approach, the Friction Cost method, was used as part of the sensitivity analysis. Our findings suggest that, in a population of 179 transplanted and deceased patients, males and people who die between the ages of 30 and 49 years generate higher labour productivity losses. The estimated loss amounts to over €31.4 million using the Human Capital method (€480,152 using the Friction Cost method), which means an average of €185,855 per death. The highest labour productivity losses are produced by leukaemia. However, lymphoma generates the highest loss per death. Further efforts are needed to reduce premature mortality in blood cancer patients undergoing transplantations and reduce economic losses. Copyright © 2014 SESPAS. Published by Elsevier Espana. All rights reserved.

  1. COE Loss-of-Function Analysis Reveals a Genetic Program Underlying Maintenance and Regeneration of the Nervous System in Planarians

    PubMed Central

    Cowles, Martis W.; Omuro, Kerilyn C.; Stanley, Brianna N.; Quintanilla, Carlo G.; Zayas, Ricardo M.

    2014-01-01

    Members of the COE family of transcription factors are required for central nervous system (CNS) development. However, the function of COE in the post-embryonic CNS remains largely unknown. An excellent model for investigating gene function in the adult CNS is the freshwater planarian. This animal is capable of regenerating neurons from an adult pluripotent stem cell population and regaining normal function. We previously showed that planarian coe is expressed in differentiating and mature neurons and that its function is required for proper CNS regeneration. Here, we show that coe is essential to maintain nervous system architecture and patterning in intact (uninjured) planarians. We took advantage of the robust phenotype in intact animals to investigate the genetic programs coe regulates in the CNS. We compared the transcriptional profiles of control and coe RNAi planarians using RNA sequencing and identified approximately 900 differentially expressed genes in coe knockdown animals, including 397 downregulated genes that were enriched for nervous system functional annotations. Next, we validated a subset of the downregulated transcripts by analyzing their expression in coe-deficient planarians and testing if the mRNAs could be detected in coe+ cells. These experiments revealed novel candidate targets of coe in the CNS such as ion channel, neuropeptide, and neurotransmitter genes. Finally, to determine if loss of any of the validated transcripts underscores the coe knockdown phenotype, we knocked down their expression by RNAi and uncovered a set of coe-regulated genes implicated in CNS regeneration and patterning, including orthologs of sodium channel alpha-subunit and pou4. Our study broadens the knowledge of gene expression programs regulated by COE that are required for maintenance of neural subtypes and nervous system architecture in adult animals. PMID:25356635

  2. COE loss-of-function analysis reveals a genetic program underlying maintenance and regeneration of the nervous system in planarians.

    PubMed

    Cowles, Martis W; Omuro, Kerilyn C; Stanley, Brianna N; Quintanilla, Carlo G; Zayas, Ricardo M

    2014-10-01

    Members of the COE family of transcription factors are required for central nervous system (CNS) development. However, the function of COE in the post-embryonic CNS remains largely unknown. An excellent model for investigating gene function in the adult CNS is the freshwater planarian. This animal is capable of regenerating neurons from an adult pluripotent stem cell population and regaining normal function. We previously showed that planarian coe is expressed in differentiating and mature neurons and that its function is required for proper CNS regeneration. Here, we show that coe is essential to maintain nervous system architecture and patterning in intact (uninjured) planarians. We took advantage of the robust phenotype in intact animals to investigate the genetic programs coe regulates in the CNS. We compared the transcriptional profiles of control and coe RNAi planarians using RNA sequencing and identified approximately 900 differentially expressed genes in coe knockdown animals, including 397 downregulated genes that were enriched for nervous system functional annotations. Next, we validated a subset of the downregulated transcripts by analyzing their expression in coe-deficient planarians and testing if the mRNAs could be detected in coe+ cells. These experiments revealed novel candidate targets of coe in the CNS such as ion channel, neuropeptide, and neurotransmitter genes. Finally, to determine if loss of any of the validated transcripts underscores the coe knockdown phenotype, we knocked down their expression by RNAi and uncovered a set of coe-regulated genes implicated in CNS regeneration and patterning, including orthologs of sodium channel alpha-subunit and pou4. Our study broadens the knowledge of gene expression programs regulated by COE that are required for maintenance of neural subtypes and nervous system architecture in adult animals.

  3. Priming in a permissive type I-C CRISPR-Cas system reveals distinct dynamics of spacer acquisition and loss.

    PubMed

    Rao, Chitong; Chin, Denny; Ensminger, Alexander W

    2017-10-01

    CRISPR-Cas is a bacterial and archaeal adaptive immune system that uses short, invader-derived sequences termed spacers to target invasive nucleic acids. Upon recognition of previously encountered invaders, the system can stimulate secondary spacer acquisitions, a process known as primed adaptation. Previous studies of primed adaptation have been complicated by intrinsically high interference efficiency of most systems against bona fide targets. As such, most primed adaptation to date has been studied within the context of imperfect sequence complementarity between spacers and targets. Here, we take advantage of a native type I-C CRISPR-Cas system in Legionella pneumophila that displays robust primed adaptation even within the context of a perfectly matched target. Using next-generation sequencing to survey acquired spacers, we observe strand bias and positional preference that are consistent with a 3'-5' translocation of the adaptation machinery. We show that spacer acquisition happens in a wide range of frequencies across the plasmid, including a remarkable hotspot that predominates irrespective of the priming strand. We systematically characterize protospacer sequence constraints in both adaptation and interference and reveal extensive flexibilities regarding the protospacer adjacent motif in both processes. Lastly, in a strain with a genetically truncated CRISPR array, we observe increased interference efficiency, which, when coupled with forced maintenance of a targeted plasmid, provides a useful experimental system to study spacer loss. Based on these observations, we propose that the Legionella pneumophila type I-C system represents a powerful model to study primed adaptation and the interplay between CRISPR interference and adaptation. © 2017 Rao et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

  4. A synthetic lethal screen reveals enhanced sensitivity to ATR inhibitor treatment in mantle cell lymphoma with ATM loss-of-function.

    PubMed

    Menezes, Daniel L; Holt, Jenny; Tang, Yan; Feng, Jiajia; Barsanti, Paul; Pan, Yue; Ghoddusi, Majid; Zhang, Wei; Thomas, George; Holash, Jocelyn; Lees, Emma; Taricani, Lorena

    2015-01-01

    Mechanisms to maintain genomic integrity are essential for cells to remain viable. Not surprisingly, disruption of key DNA damage response pathway factors, such as ataxia telangiectasia-mutated (ATM)/ataxia telangiectasia and RAD3-related (ATR) results in loss of genomic integrity. Here, a synthetic lethal siRNA-screening approach not only confirmed ATM but identified additional replication checkpoint proteins, when ablated, enhanced ATR inhibitor (ATRi) response in a high-content γ-H2AX assay. Cancers with inactivating ATM mutations exhibit impaired DNA double-stranded break (DSB) repair and rely on compensatory repair pathways for survival. Therefore, impairing ATR activity may selectively sensitize cancer cells to killing. ATR inhibition in an ATM-deficient context results in phosphorylation of DNA-dependent protein kinase catalytic subunits (DNA-PKcs) and leads to induction of γ-H2AX. Using both in vitro and in vivo models, ATR inhibition enhanced efficacy in ATM loss-of-function mantle cell lymphoma (MCL) compared with ATM wild-type cancer cells. In summary, single-agent ATR inhibitors have therapeutic utility in the treatment of cancers, like MCL, in which ATM function has been lost. These data suggest that single-agent ATR inhibitors have therapeutic utility and that ATR uses a complex and coordinated set of proteins to maintain genomic stability that could be further exploited. ©2014 American Association for Cancer Research.

  5. Effect of aspirin continuation on blood loss and postoperative morbidity in patients undergoing laparoscopic cholecystectomy or colorectal cancer resection.

    PubMed

    Ono, Kazumi; Idani, Hitoshi; Hidaka, Hidekuni; Kusudo, Kazuhito; Koyama, Yusuke; Taguchi, Shinya

    2013-02-01

    No consensus exists whether to continue or withdraw aspirin therapy perioperatively in patients undergoing major laparoscopic abdominal surgery. To investigate whether preoperative continuation of aspirin therapy increases blood loss and associated morbidity during laparoscopic cholecystectomy and colorectal cancer resection, we compared duration of surgical procedures, amount of intraoperative blood loss, rate of blood transfusion, length of postoperative stay, rate of conversion to open surgery, and reoperation within 48 hours between patients with and without aspirin therapy preoperatively. Twenty-nine of 270 patients who underwent laparoscopic cholecystectomy and 23 of 218 patients who underwent laparoscopic colorectal cancer resection, respectively, were on aspirin therapy. We found no significant difference in the investigated outcome between groups with the exception of longer surgical duration of laparoscopic cholecystectomy in aspirin-treated patients. Although underpowered, above findings may suggest that aspirin continuation is unlikely to increase blood loss or postoperative morbidity in patients undergoing laparoscopic cholecystectomy or colorectal cancer resection.

  6. Physiological responses of a rodent to heliox reveal constancy of evaporative water loss under perturbing environmental conditions.

    PubMed

    Cooper, Christine Elizabeth; Withers, Philip Carew

    2014-10-15

    Total evaporative water loss of endotherms is assumed to be determined essentially by biophysics, at least at temperatures below thermoneutrality, with evaporative water loss determined by the water vapor deficit between the animal and the ambient air. We present here evidence, based on the first measurements of evaporative water loss for a small mammal in heliox, that mammals may have a previously unappreciated ability to maintain acute constancy of total evaporative water loss under perturbing environmental conditions. Thermoregulatory responses of ash-grey mice (Pseudomys albocinereus) to heliox were as expected, with changes in metabolic rate, conductance, and respiratory ventilation consistent with maintaining constancy of body temperature under conditions of enhanced heat loss. However, evaporative water loss did not increase in heliox. This is despite our confirmation of the physical effect that heliox augments evaporation from nonliving surfaces, which should increase cutaneous water loss, and increases minute volume of live ash-grey mice in heliox to accommodate their elevated metabolic rate, which should increase respiratory water loss. Therefore, mice had not only a thermoregulatory but also a hygroregulatory response to heliox. We interpret these results as evidence that ash-grey mice can acutely control their evaporative water loss under perturbing environmental conditions and suggest that hygroregulation at and below thermoneutrality is an important aspect of the physiology of at least some small mammals.

  7. Kinome sequencing reveals RET G691S polymorphism in human neuroendocrine lung cancer cell lines

    PubMed Central

    Sosonkina, Nadiya; Hong, Seung-Keun; Starenki, Dmytro; Park, Jong-In

    2014-01-01

    Neuroendocrine (NE) lung tumors comprise 20–25% of all invasive lung malignancies. Currently, no effective treatments are available to cure these tumors, and it is necessary to identify a molecular alteration(s) that characterizes NE lung tumor cells. We aimed to identify a kinase mutation(s) associated with NE lung tumor by screening 517 kinase-encoding genes in human lung cancer cell lines. Our next-generation sequencing analysis of six NE lung tumor cell lines (four small cell lung cancer lines and two non-small cell lung cancer lines) and three non-NE lung tumor lines revealed various kinase mutations, including a nonsynonymous mutation in the proto-oncogene RET (c.2071G>A; p.G691S). Further evaluation of the RET polymorphism in total 15 lung cancer cell lines by capillary sequencing suggested that the frequency of the minor allele (A-allele) in NE lung tumor lines was significantly higher than its frequency in a reference population (p = 0.0001). However, no significant difference between non-NE lung tumor lines and a reference group was detected (p = 1.0). Nevertheless, neither RET expression levels were correlated with the levels of neuron-specific enolase (NSE), a key NE marker, nor vandetanib and cabozantinib, small molecule compounds that inhibit RET, affected NSE levels in lung cancer cells. Our data suggest a potential association of G691S RET polymorphism with NE lung tumor, proposing the necessity of more thorough evaluation of this possibility. The dataset of kinase mutation profiles in this report may help choosing cell line models for study of lung cancer. PMID:25530832

  8. Genome-wide copy number analysis reveals candidate gene loci that confer susceptibility to high-grade prostate cancer.

    PubMed

    Poniah, Prevathe; Mohd Zain, Shamsul; Abdul Razack, Azad Hassan; Kuppusamy, Shanggar; Karuppayah, Shankar; Sian Eng, Hooi; Mohamed, Zahurin

    2017-09-01

    Two key issues in prostate cancer (PCa) that demand attention currently are the need for a more precise and minimally invasive screening test owing to the inaccuracy of prostate-specific antigen and differential diagnosis to distinguish advanced vs. indolent cancers. This continues to pose a tremendous challenge in diagnosis and prognosis of PCa and could potentially lead to overdiagnosis and overtreatment complications. Copy number variations (CNVs) in the human genome have been linked to various carcinomas including PCa. Detection of these variants may improve clinical treatment as well as an understanding of the pathobiology underlying this complex disease. To this end, we undertook a pilot genome-wide CNV analysis approach in 36 subjects (18 patients with high-grade PCa and 18 controls that were matched by age and ethnicity) in search of more accurate biomarkers that could potentially explain susceptibility toward high-grade PCa. We conducted this study using the array comparative genomic hybridization technique. Array results were validated in 92 independent samples (46 high-grade PCa, 23 benign prostatic hyperplasia, and 23 healthy controls) using polymerase chain reaction-based copy number counting method. A total of 314 CNV regions were found to be unique to PCa subjects in this cohort (P<0.05). A log2 ratio-based copy number analysis revealed 5 putative rare or novel CNV loci or both associated with susceptibility to PCa. The CNV gain regions were 1q21.3, 15q15, 7p12.1, and a novel CNV in PCa 12q23.1, harboring ARNT, THBS1, SLC5A8, and DDC genes that are crucial in the p53 and cancer pathways. A CNV loss and deletion event was observed at 8p11.21, which contains the SFRP1 gene from the Wnt signaling pathway. Cross-comparison analysis with genes associated to PCa revealed significant CNVs involved in biological processes that elicit cancer pathogenesis via cytokine production and endothelial cell proliferation. In conclusion, we postulated that the CNVs

  9. Quantitative measures to reveal coordinated cytoskeleton-nucleus reorganization during in vitro invasion of cancer cells

    NASA Astrophysics Data System (ADS)

    Dvir, Liron; Nissim, Ronen; Alvarez-Elizondo, Martha B.; Weihs, Daphne

    2015-04-01

    Metastasis formation is a major cause of mortality in cancer patients and includes tumor cell relocation to distant organs. A metastatic cell invades through other cells and extracellular matrix by biochemical attachment and mechanical force application. Force is used to move on or through a 2- or 3-dimensional (3D) environment, respectively, or to penetrate a 2D substrate. We have previously shown that even when a gel substrate is impenetrable, metastatic breast cancer cells can still indent it by applying force. Cells typically apply force through the acto-myosin network, which is mechanically connected to the nucleus. We develop a 3D image-analysis to reveal relative locations of the cell elements, and show that as cells apply force to the gel, a coordinated process occurs that involves cytoskeletal remodeling and repositioning of the nucleus. Our approach shows that the actin and microtubules reorganize in the cell, bringing the actin to the leading edge of the cell. In parallel, the nucleus is transported behind the actin, likely by the cytoskeleton, into the indentation dimple formed in the gel. The nucleus volume below the gel surface correlates with indentation depth, when metastatic breast cancer cells indent gels deeply. However, the nucleus always remains above the gel in benign cells, even when small indentations are observed. Determining mechanical processes during metastatic cell invasion can reveal how cells disseminate in the body and can uncover targets for diagnosis and treatment.

  10. Recruitment strategies, design, and participant characteristics in a trial of weight-loss and metformin in breast cancer survivors.

    PubMed

    Patterson, Ruth E; Marinac, Catherine R; Natarajan, Loki; Hartman, Sheri J; Cadmus-Bertram, Lisa; Flatt, Shirley W; Li, Hongying; Parker, Barbara; Oratowski-Coleman, Jesica; Villaseñor, Adriana; Godbole, Suneeta; Kerr, Jacqueline

    2016-03-01

    Weight loss and metformin are hypothesized to improve breast cancer outcomes; however the joint impacts of these treatments have not been investigated. Reach for Health is a randomized trial using a 2 × 2 factorial design to investigate the effects of weight loss and metformin on biomarkers associated with breast cancer prognosis among overweight/obese postmenopausal breast cancer survivors. This paper describes the trial recruitment strategies, design, and baseline sample characteristics. Participants were randomized in equal numbers to (1) placebo, (2) metformin, (3) weight loss intervention and placebo, or (4) weight-loss intervention and metformin. The lifestyle intervention was a personalized, telephone-based program targeting a 7% weight-loss in the intervention arm. The metformin dose was 1500 mg/day. The duration of the intervention was 6 months. Main outcomes were biomarkers representing 3 metabolic systems putatively related to breast cancer mortality: glucoregulation, inflammation, and sex hormones. Between August 2011 and May 2015, we randomized 333 breast cancer survivors. Mass mailings from the California Cancer Registry were the most successful recruitment strategy with over 25,000 letters sent at a cost of $191 per randomized participant. At baseline, higher levels of obesity were significantly associated with worse sleep disturbance and impairment scores, lower levels of physical activity and higher levels of sedentary behavior, hypertension, hypercholesterolemia, and lower quality of life (p<0.05 for all). These results illustrate the health burden of obesity. Results of this trial will provide mechanistic data on biological pathways and circulating biomarkers associated with lifestyle and pharmacologic interventions to improve breast cancer prognosis.

  11. Recruitment Strategies, Design, and Participant Characteristics in a Trial of Weight-Loss and Metformin in Breast Cancer Survivors

    PubMed Central

    Patterson, Ruth E.; Marinac, Catherine R.; Natarajan, Loki; Hartman, Sheri J.; Cadmus-Bertram, Lisa; Flatt, Shirley W.; Li, Hongying; Parker, Barbara; Oratowski-Coleman, Jesica; Villaseñor, Adriana; Godbole, Suneeta; Kerr, Jacqueline

    2016-01-01

    Weight loss and metformin are hypothesized to improve breast cancer outcomes; however the joint impacts of these treatments have not been investigated. Reach for Health is a randomized trial using a 2×2 factorial design to investigate the effects of weight loss and metformin on biomarkers associated with breast cancer prognosis among overweight/obese postmenopausal breast cancer survivors. This paper describes the trial recruitment strategies, design, and baseline sample characteristics. Participants were randomized in equal numbers to (1) placebo, (2) metformin, (3) weight loss intervention and placebo, or (4) weight-loss intervention and metformin. The lifestyle intervention was a personalized, telephone-based program targeting a 7% weight-loss in the intervention arm. The metformin dose was 1500 mg/day. The duration of the intervention was 6 months. Main outcomes were biomarkers representing 3 metabolic systems putatively related to breast cancer mortality: glucoregulation, inflammation, and sex hormones. Between August 2011 and May 2015, we randomized 333 breast cancer survivors. Mass mailings from the California Cancer Registry were the most successful recruitment strategy with over 25,000 letters sent at a cost of $191 per randomized participant. At baseline, higher levels of obesity were significantly associated with worse sleep disturbance and impairment scores, lower levels of physical activity and higher levels of sedentary behavior, hypertension, hypercholesterolemia, and lower quality of life (p<0.05 for all). These results illustrate the health burden of obesity. Results of this trial will provide mechanistic data on biological pathways and circulating biomarkers associated with lifestyle and pharmacologic interventions to improve breast cancer prognosis. PMID:26706665

  12. Detection of recurrent alternative splicing switches in tumor samples reveals novel signatures of cancer

    PubMed Central

    Sebestyén, Endre; Zawisza, Michał; Eyras, Eduardo

    2015-01-01

    The determination of the alternative splicing isoforms expressed in cancer is fundamental for the development of tumor-specific molecular targets for prognosis and therapy, but it is hindered by the heterogeneity of tumors and the variability across patients. We developed a new computational method, robust to biological and technical variability, which identifies significant transcript isoform changes across multiple samples. We applied this method to more than 4000 samples from the The Cancer Genome Atlas project to obtain novel splicing signatures that are predictive for nine different cancer types, and find a specific signature for basal-like breast tumors involving the tumor-driver CTNND1. Additionally, our method identifies 244 isoform switches, for which the change occurs in the most abundant transcript. Some of these switches occur in known tumor drivers, including PPARG, CCND3, RALGDS, MITF, PRDM1, ABI1 and MYH11, for which the switch implies a change in the protein product. Moreover, some of the switches cannot be described with simple splicing events. Surprisingly, isoform switches are independent of somatic mutations, except for the tumor-suppressor FBLN2 and the oncogene MYH11. Our method reveals novel signatures of cancer in terms of transcript isoforms specifically expressed in tumors, providing novel potential molecular targets for prognosis and therapy. Data and software are available at: http://dx.doi.org/10.6084/m9.figshare.1061917 and https://bitbucket.org/regulatorygenomicsupf/iso-ktsp. PMID:25578962

  13. Detection of recurrent alternative splicing switches in tumor samples reveals novel signatures of cancer.

    PubMed

    Sebestyén, Endre; Zawisza, Michał; Eyras, Eduardo

    2015-02-18

    The determination of the alternative splicing isoforms expressed in cancer is fundamental for the development of tumor-specific molecular targets for prognosis and therapy, but it is hindered by the heterogeneity of tumors and the variability across patients. We developed a new computational method, robust to biological and technical variability, which identifies significant transcript isoform changes across multiple samples. We applied this method to more than 4000 samples from the The Cancer Genome Atlas project to obtain novel splicing signatures that are predictive for nine different cancer types, and find a specific signature for basal-like breast tumors involving the tumor-driver CTNND1. Additionally, our method identifies 244 isoform switches, for which the change occurs in the most abundant transcript. Some of these switches occur in known tumor drivers, including PPARG, CCND3, RALGDS, MITF, PRDM1, ABI1 and MYH11, for which the switch implies a change in the protein product. Moreover, some of the switches cannot be described with simple splicing events. Surprisingly, isoform switches are independent of somatic mutations, except for the tumor-suppressor FBLN2 and the oncogene MYH11. Our method reveals novel signatures of cancer in terms of transcript isoforms specifically expressed in tumors, providing novel potential molecular targets for prognosis and therapy. Data and software are available at: http://dx.doi.org/10.6084/m9.figshare.1061917 and https://bitbucket.org/regulatorygenomicsupf/iso-ktsp.

  14. Differential Patterns of Allelic Loss in Estrogen Receptor-Positive Infiltrating Lobular and Ductal Breast Cancer

    PubMed Central

    Loo, L.W.M.; Ton, C.; Wang, Y.-W.; Grove, D.I.; Bouzek, H.; Vartanian, N.; Lin, M.-G.; Yuan, X.; Lawton, T.L.; Daling, J.R.; Malone, K.E.; Li, C.I.; Hsu, L.; Porter, P.L.

    2009-01-01

    The two main histological types of infiltrating breast cancer, lobular (ILC) and the more common ductal (IDC) carcinoma are morphologically and clinically distinct. To assess the molecular alterations associated with these breast cancer subtypes, we conducted a whole-genome study of 166 archival estrogen receptor (ER)-positive tumors (89 IDC and 77 ILC) using the Affymetrix GeneChip® Mapping 10K Array to identify sites of loss of heterozygosity (LOH) that either distinguished, or were shared by, the two phenotypes. We found single nucleotide polymorphisms (SNPs) of high-frequency LOH (>50%) common to both ILC and IDC tumors predominately in 11q, 16q, and 17p. Overall, IDC had a slightly higher frequency of LOH events across the genome than ILC (fractional allelic loss = 0.186 and 0.156). By comparing the average frequency of LOH by chromosomal arm, we found IDC tumors with significantly (P < 0.05) higher frequency of LOH on 3p, 5q, 8p, 9p, 20p, and 20q than ILC tumors. We identified additional chromosomal arms differentiating the subtypes when tumors were stratified by tumor size, mitotic rate, or DNA content. Of 5,754 informative SNPs (>25% informativity), we identified 78 and 466 individual SNPs with a higher frequency of LOH (P < 0.05) in ILC and IDC tumors, respectively. Hierarchical clustering of these 544 SNPs grouped tumors into four major groups based on their patterns of LOH and retention of heterozygosity. LOH in chromosomal arms 8p and 5q was common in higher grade IDC tumors, whereas ILC and low-grade IDC grouped together by virtue of LOH in 16q. PMID:18720524

  15. Prevention and treatment of bone loss in patients with nonmetastatic breast or prostate cancer who receive hormonal ablation therapy.

    PubMed

    Limburg, Connie; Maxwell, Cathy; Mautner, Beatrice

    2014-04-01

    Hormone ablation therapy is a mainstay in the treatment of breast and prostate cancers. However, aromatase inhibitors (AIs) used in postmenopausal women with breast cancer and androgen-deprivation therapy (ADT) used in men with prostate cancer contribute to substantial bone loss, thereby increasing the risk of osteoporotic fractures. Evidence-based guidelines, therefore, urge oncology practices to screen these patients for bone loss and, if needed, provide treatment to maintain bone health. In addition to lifestyle modification and calcium or vitamin D supplementation, bone protection strategies include treatment with bisphosphonates and denosumab, a monoclonal antibody against RANK ligand. Identification of patients at greater risk for bone loss and fracture and proper interventions can reduce fracture rates. Oncology nurses can play an important role in screening these patients. The purpose of this article is to inform oncology nurses about the effects of cancer treatment on bone health, review current prevention and treatment options for cancer treatment-induced bone loss, and discuss recommendations for identifying high-risk individuals.

  16. Pancreatic cancer risk after loss of a child: a register-based study in Sweden during 1991-2009.

    PubMed

    Huang, Jiaqi; Valdimarsdóttir, Unnur; Fall, Katja; Ye, Weimin; Fang, Fang

    2013-08-15

    The potential role of psychological stress in pancreatic cancer has rarely been investigated in epidemiologic studies. During 1991-2009, we conducted a nested case-control study based on Swedish national population and health registers to investigate whether severe psychological stress induced by the death of a child was associated with subsequent risk of pancreatic cancer. The study included 16,522 cases and 82,107 controls who were matched to the cases on sex and year of birth. Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals. Overall, loss of a child was associated with an odds ratio of 1.09 for pancreatic cancer (95% confidence interval (CI): 1.02, 1.17). The risk elevation was mainly seen during the first 5 years after the loss (odds ratio (OR) = 1.27, 95% CI: 1.12, 1.45) and for loss of a child due to suicide (OR = 1.23, 95% CI: 1.03, 1.46). The association was statistically significant among women but not among men, and it appeared stronger for early-onset pancreatic cancer. Persons with a history of psychiatric illness had the greatest risk increase after child loss (OR = 1.43, 95% CI: 1.17, 1.76). Although other explanations are possible, our findings provide some evidence that psychological stress may be associated with pancreatic cancer.

  17. Loss of constitutive ABCB1 expression in breast cancer associated with worse prognosis.

    PubMed

    Delou, João Marcos de Azevedo; Vignal, Giselle Maria; Índio-do-Brasil, Vanessa; Accioly, Maria Theresa de Souza; da Silva, Taiana Sousa Lopes; Piranda, Diogo Nascimento; Sobral-Leite, Marcelo; de Carvalho, Marcelo Alex; Capella, Márcia Alves Marques; Vianna-Jorge, Rosane

    2017-01-01

    ABCB1 gene encodes an adenosine 5'-triphosphate-binding cassette transporter, which not only confers multidrug resistance phenotype in malignant cells, but is also present in several nonmalignant tissues. For the last thirty years, ABCB1 expression in breast cancer has been described by many authors, but the extent of expression differs among the studies, and there is no consensus regarding its potential role in carcinogenesis or in the tumor response to antineoplastic drugs. This study aimed to characterize the expression of ABCB1 in breast tumors as a function of genetic, clinical, and histopathological variables. The ABCB1 expression was also evaluated in nonmalignant mammary tissues adjacent to tumors and in benign lesions. The detection of ABCB1 protein was performed by immunohistochemistry in tissue specimens of excised breasts obtained from a prospective cohort of Brazilian women with breast cancer. The association of ABCB1 protein levels with ABCB1 mRNA, gene polymorphisms, and clinical and histopathological variables was also evaluated. The Kaplan-Meier curves and multivariate Cox regression analyses were conducted to identify independent predictors of disease-free survival of patients with breast cancer. ABCB1 was detected in 86.3% (656) of breast tumors, 98.8% (606) of nonmalignant mammary tissue adjacent to tumors, and 100% (28) of benign lesions. Reduced ABCB1 protein levels in breast tumors was associated with triple-negative subtype (adjusted odds ratio [ORadj] =0.24; 95% confidence interval [CI] =0.13-0.45), lymph node status < pN2 (ORadj =0.27; 95% CI =0.10-0.71), tumor size >2 cm (ORadj =0.55; 95% CI =0.32-0.93), and hypertensive status (ORadj =0.42; 95% CI =0.24-0.73), and it was significantly associated with shorter disease-free survival, either for all breast cancer patients (p log-rank =0.012; hazard ratio [HR] =3.46; 95% CI =1.21-9.91) or for those with triple-negative tumors (p log-rank =0.007; HR =11.41; 95% CI =1.29-100.67). The loss of

  18. Structure-Based Analysis Reveals Cancer Missense Mutations Target Protein Interaction Interfaces

    PubMed Central

    Engin, H. Billur; Kreisberg, Jason F.; Carter, Hannah

    2016-01-01

    Recently it has been shown that cancer mutations selectively target protein-protein interactions. We hypothesized that mutations affecting distinct protein interactions involving established cancer genes could contribute to tumor heterogeneity, and that novel mechanistic insights might be gained into tumorigenesis by investigating protein interactions under positive selection in cancer. To identify protein interactions under positive selection in cancer, we mapped over 1.2 million nonsynonymous somatic cancer mutations onto 4,896 experimentally determined protein structures and analyzed their spatial distribution. In total, 20% of mutations on the surface of known cancer genes perturbed protein-protein interactions (PPIs), and this enrichment for PPI interfaces was observed for both tumor suppressors (Odds Ratio 1.28, P-value < 10−4) and oncogenes (Odds Ratio 1.17, P-value < 10−3). To study this further, we constructed a bipartite network representing structurally resolved PPIs from all available human complexes in the Protein Data Bank (2,864 proteins, 3,072 PPIs). Analysis of frequently mutated cancer genes within this network revealed that tumor-suppressors, but not oncogenes, are significantly enriched with functional mutations in homo-oligomerization regions (Odds Ratio 3.68, P-Value < 10−8). We present two important examples, TP53 and beta-2-microglobulin, for which the patterns of somatic mutations at interfaces provide insights into specifically perturbed biological circuits. In patients with TP53 mutations, patient survival correlated with the specific interactions that were perturbed. Moreover, we investigated mutations at the interface of protein-nucleotide interactions and observed an unexpected number of missense mutations but not silent mutations occurring within DNA and RNA binding sites. Finally, we provide a resource of 3,072 PPI interfaces ranked according to their mutation rates. Analysis of this list highlights 282 novel candidate cancer

  19. Structure-Based Analysis Reveals Cancer Missense Mutations Target Protein Interaction Interfaces.

    PubMed

    Engin, H Billur; Kreisberg, Jason F; Carter, Hannah

    2016-01-01

    Recently it has been shown that cancer mutations selectively target protein-protein interactions. We hypothesized that mutations affecting distinct protein interactions involving established cancer genes could contribute to tumor heterogeneity, and that novel mechanistic insights might be gained into tumorigenesis by investigating protein interactions under positive selection in cancer. To identify protein interactions under positive selection in cancer, we mapped over 1.2 million nonsynonymous somatic cancer mutations onto 4,896 experimentally determined protein structures and analyzed their spatial distribution. In total, 20% of mutations on the surface of known cancer genes perturbed protein-protein interactions (PPIs), and this enrichment for PPI interfaces was observed for both tumor suppressors (Odds Ratio 1.28, P-value < 10(-4)) and oncogenes (Odds Ratio 1.17, P-value < 10(-3)). To study this further, we constructed a bipartite network representing structurally resolved PPIs from all available human complexes in the Protein Data Bank (2,864 proteins, 3,072 PPIs). Analysis of frequently mutated cancer genes within this network revealed that tumor-suppressors, but not oncogenes, are significantly enriched with functional mutations in homo-oligomerization regions (Odds Ratio 3.68, P-Value < 10(-8)). We present two important examples, TP53 and beta-2-microglobulin, for which the patterns of somatic mutations at interfaces provide insights into specifically perturbed biological circuits. In patients with TP53 mutations, patient survival correlated with the specific interactions that were perturbed. Moreover, we investigated mutations at the interface of protein-nucleotide interactions and observed an unexpected number of missense mutations but not silent mutations occurring within DNA and RNA binding sites. Finally, we provide a resource of 3,072 PPI interfaces ranked according to their mutation rates. Analysis of this list highlights 282 novel candidate cancer

  20. Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability

    PubMed Central

    Akagi, Keiko; Li, Jingfeng; Broutian, Tatevik R.; Padilla-Nash, Hesed; Xiao, Weihong; Jiang, Bo; Rocco, James W.; Teknos, Theodoros N.; Kumar, Bhavna; Wangsa, Danny; He, Dandan; Ried, Thomas; Symer, David E.; Gillison, Maura L.

    2014-01-01

    Genomic instability is a hallmark of human cancers, including the 5% caused by human papillomavirus (HPV). Here we report a striking association between HPV integration and adjacent host genomic structural variation in human cancer cell lines and primary tumors. Whole-genome sequencing revealed HPV integrants flanking and bridging extensive host genomic amplifications and rearrangements, including deletions, inversions, and chromosomal translocations. We present a model of “looping” by which HPV integrant-mediated DNA replication and recombination may result in viral–host DNA concatemers, frequently disrupting genes involved in oncogenesis and amplifying HPV oncogenes E6 and E7. Our high-resolution results shed new light on a catastrophic process, distinct from chromothripsis and other mutational processes, by which HPV directly promotes genomic instability. PMID:24201445

  1. α-Amino Acid Rich Photophytonic Nanoparticles of Algal Origin Serendipitously Reveal Antimigratory Property against Cancer.

    PubMed

    Misra, Santosh K; Schwartz-Duval, Aaron S; Ostadhossein, Fatemeh; Daza, Enrique A; Saldivar, Zachary M; Sharma, Brajendra K; Pan, Dipanjan

    2017-06-28

    Spheroidal nanoparticles of algal ("phytonic") origin were synthesized and composed of carbonaceous architectures and surface-rich oxygenated functional groups. Nanoparticles were negatively charged and efficiently luminescent after ultraviolet-range excitation and called as "photophytonic" nanoparticles. A multitude of analytical techniques confirmed the rich profusion of hydroxyl, carboxylate, and amines at the nanoscale, while spectroscopic investigation indicated the presence of α-amines, a signature functionality present in amino acids. Confirmed via a series of biological assays, i.e., growth regression, antimigration, and protein-regression studies, photophytonic nanoparticles serendipitously revealed remarkable anticancer activity against various stages of breast cancer cells, barring the need for an encapsulated drug. We report that nanoparticles derived from algal biomass exhibit intrinsic antimigratory properties against cancer, likely due to the rich abundance of α-amino acids.

  2. Genome evolution predicts genetic interactions in protein complexes and reveals cancer drug targets

    PubMed Central

    Lu, Xiaowen; Kensche, Philip R.; Huynen, Martijn A.; Notebaart, Richard A.

    2013-01-01

    Genetic interactions reveal insights into cellular function and can be used to identify drug targets. Here we construct a new model to predict negative genetic interactions in protein complexes by exploiting the evolutionary history of genes in parallel converging pathways in metabolism. We evaluate our model with protein complexes of Saccharomyces cerevisiae and show that the predicted protein pairs more frequently have a negative genetic interaction than random proteins from the same complex. Furthermore, we apply our model to human protein complexes to predict novel cancer drug targets, and identify 20 candidate targets with empirical support and 10 novel targets amenable to further experimental validation. Our study illustrates that negative genetic interactions can be predicted by systematically exploring genome evolution, and that this is useful to identify novel anti-cancer drug targets. PMID:23851603

  3. Loss of ARID1A expression leads to sensitivity to ROS-inducing agent elesclomol in gynecologic cancer cells

    PubMed Central

    Kwan, Suet-Yan; Cheng, Xuanjin; Tsang, Yvonne T.M.; Choi, Jong-Sun; Kwan, Suet-Ying; Izaguirre, Daisy I.; Kwan, Hoi-Shan; Gershenson, David M.; Wong, Kwong-Kwok

    2016-01-01

    Inactivating mutations in ARID1A are found in a broad spectrum of cancer types, with the highest frequency in gynecologic cancers. However, therapeutic strategies targeting ARID1A-mutant cancer cells remain limited. In this study, we aimed to identify drugs sensitivities in ARID1A-mutant cancer cell lines. By analyzing the Genomics of Drug Sensitivity in Cancer database, we found that ARID1A-mutant cancer cell lines were more sensitive to treatment with the reactive oxygen species (ROS)-inducing agent elesclomol. In a panel of 14 gynecologic cancer cell lines, treatment with elesclomol inhibited growth and induced apoptosis more potently in ARID1A-mutant cells. Knockdown of ARID1A in RMG1 and OVCA432 ovarian cancer cells resulted in increased sensitivity to elesclomol, whereas restoration of ARID1A expression in TOV21G ovarian cancer cells resulted in increased resistance to elesclomol. Furthermore, we found that knockdown of ARID1A expression resulted in increased intracellular ROS levels. In ovarian clear cell carcinoma patient samples, low expression of ARID1A correlated with high expression of 8-hydroxyguanosine, a marker for oxidative stress. In summary, we demonstrate for the first time that loss of ARID1A leads to accumulation of ROS and suggest that elesclomol may be used to target ARID1A-mutant gynecologic cancer cells. PMID:27486766

  4. MS-20, a chemotherapeutical adjuvant, reduces chemo-associated fatigue and appetite loss in cancer patients.

    PubMed

    Chi, Kwan-Hwa; Chiou, Tzeon-Jye; Li, Chung-Pin; Chen, Sheng-Yu; Chao, Yee

    2014-01-01

    A small pilot study of the fermented soybean extract MicrSoy-20(MS-20) demonstrated its ability to restore chemotherapy-induced immunosuppression and improve quality of life (QoL). This randomized, cross-over, comparative trial was conducted to confirm the effects of MS-20 on QoL and to understand its underlying mechanism when used in conjunction with chemotherapy. One hundred forty-three patients undergoing cancer chemotherapy were randomly assigned to 2 groups. Group 1 was administered MS-20 for 1 wk followed by 3 wk of concomitant MS-20 plus chemotherapy. Group 2 was administered chemotherapy for 3 wk. QoL was assessed by the EORTC/QLQ-C30 questionnaire and visual analogue scales (VAS). Changes in immunological parameters and antioxidant profiles were also examined. Significant increases were observed in EORTC/QLQ-C30 scores for physical (4.45, P = 0.023) and social (3.99, P = 0.023) functioning in Group 1 patients compared to Group 2 patients. VAS scores for fatigue and appetite loss significantly improved with MS-20 treatment (P < 0.001). Group 1 patients exhibited smaller decreases in peripheral blood mononuclear cells compared to Group 2 patients (P = 0.026). Other immunological parameters, antioxidant, and safety profiles were not significantly different between treatment groups. Addition of MS-20 as an adjuvant to chemotherapy can be effective in improving QoL for cancer patients.

  5. [Frequent allelic losses in tumor-associated stromal cells and tumor epitelium of prostate cancer].

    PubMed

    Kekeeva, T V; Popova, O P; Shegaĭ, P V; Zavalishina, L E; Andreeva, Iu Iu; Zaletaev, D V; Nemtsova, M V

    2008-01-01

    It has become increasingly clear that tumor microenvironment plays a critical role in carcinogenesis. Accumulation of genetic alterations is typical not only for cancer epithelial cells but tumor-associated fibroblasts as well. Tumor epithelia, tumor-associated stroma from prostatectomy specimens of patients with prostate cancer and cells from prostatic intraepithelial neoplasia (PIN) and adjacent stroma from males with PIN were isolated by using laser capture microdissection. Microsatellite allelotyping was evaluated using 4 highly polymorphic markers for chromosomal regions 8p22, 16q23-24 and 13q14. Incidences of alterations (loss of heterozygosity or allelic imbalance) were 48% for region 8p22, 72% for 16q23 and 37% for 13q14. The LOH frequencies in tumor-associated stroma cells were very similar. Alterations at chromosome 13q were significantly associated with advanced tumor stage, whereas AI at 16q was also associated with high Gleason score and lymph node metastasis. We find some incidences of allelic imbalance in premalignant lesions in epithelial (16-27%) and stromal (7-22%) components. Our results show that the frequencies of genetic aberrations are as high in stromal cells as in tumor cells.

  6. Revealing selection in cancer using the predicted functional impact of cancer mutations. Application to nomination of cancer drivers

    PubMed Central

    2013-01-01

    Every malignant tumor has a unique spectrum of genomic alterations including numerous protein mutations. There are also hundreds of personal germline variants to be taken into account. The combinatorial diversity of potential cancer-driving events limits the applicability of statistical methods to determine tumor-specific "driver" alterations among an overwhelming majority of "passengers". An alternative approach to determining driver mutations is to assess the functional impact of mutations in a given tumor and predict drivers based on a numerical value of the mutation impact in a particular context of genomic alterations. Recently, we introduced a functional impact score, which assesses the mutation impact by the value of entropic disordering of the evolutionary conservation patterns in proteins. The functional impact score separates disease-associated variants from benign polymorphisms with an accuracy of ~80%. Can the score be used to identify functionally important non-recurrent cancer-driver mutations? Assuming that cancer-drivers are positively selected in tumor evolution, we investigated how the functional impact score correlates with key features of natural selection in cancer, such as the non-uniformity of distribution of mutations, the frequency of affected tumor suppressors and oncogenes, the frequency of concurrent alterations in regions of heterozygous deletions and copy gain; as a control, we used presumably non-selected silent mutations. Using mutations of six cancers studied in TCGA projects, we found that predicted high-scoring functional mutations as well as truncating mutations tend to be evolutionarily selected as compared to low-scoring and silent mutations. This result justifies prediction of mutations-drivers using a shorter list of predicted high-scoring functional mutations, rather than the "long tail" of all mutations. PMID:23819556

  7. Evaluation of the expression of stem cell markers in human breast cancer reveals a correlation with clinical progression and metastatic disease in ductal carcinoma.

    PubMed

    Martin, Tracey Amanda; Jiang, Wen Guo

    2014-01-01

    The tumor stem cell theory could explain how patients with metastatic disease show clinical relapse several months after starting treatment due to the survival of a small group of cells with unique characteristics. We examined the distribution and expression of a panel of stem cell markers in human breast cancer primary tumors. Human breast tissues were processed for immunohistochemistry, and RNA was extracted for analysis by quantitative-PCR. Immunohistochemical assay revealed that CD44 was strongly expressed in background endothelia and epithelia. CD133 expression was lost in tumor-associated endothelial cells. Conversely, CD49b was strongly stained in the tumors, associated vessels and ducts but was weakly stained in the background epithelia. q-PCR analysis revealed that CD44 and PSCA were reduced in patients with poor outcome (metastatic disease and death from breast cancer), with a marked reduction in ductal carcinoma, particularly with metastasis to bone although these did not reach significant difference. CD133 was significantly reduced in patients with metastatic disease and was also significantly reduced in patients with ductal carcinoma/bone metastasis. Conversely, CD49F was increased in patients with a poor outcome and those with ductal cancer and bone metastases. This is the first study to determine the distribution and expression pattern of these stem cell markers in human breast cancer. There was a significant association between loss of expression and metastatic disease in patients with breast cancer. Such differential expression may play a part in breast cancer disease progression, and suggests that the current stem cell theory may not hold true for all cancer types.

  8. Network modelling reveals the mechanism underlying colitis-associated colon cancer and identifies novel combinatorial anti-cancer targets.

    PubMed

    Lu, Junyan; Zeng, Hanlin; Liang, Zhongjie; Chen, Limin; Zhang, Liyi; Zhang, Hao; Liu, Hong; Jiang, Hualiang; Shen, Bairong; Huang, Ming; Geng, Meiyu; Spiegel, Sarah; Luo, Cheng

    2015-10-08

    The connection between inflammation and tumourigenesis has been well established. However, the detailed molecular mechanism underlying inflammation-associated tumourigenesis remains unknown because this process involves a complex interplay between immune microenvironments and epithelial cells. To obtain a more systematic understanding of inflammation-associated tumourigenesis as well as to identify novel therapeutic approaches, we constructed a knowledge-based network describing the development of colitis-associated colon cancer (CAC) by integrating the extracellular microenvironment and intracellular signalling pathways. Dynamic simulations of the CAC network revealed a core network module, including P53, MDM2, and AKT, that may govern the malignant transformation of colon epithelial cells in a pro-tumor inflammatory microenvironment. Furthermore, in silico mutation studies and experimental validations led to a novel finding that concurrently targeting ceramide and PI3K/AKT pathway by chemical probes or marketed drugs achieves synergistic anti-cancer effects. Overall, our network model can guide further mechanistic studies on CAC and provide new insights into the design of combinatorial cancer therapies in a rational manner.

  9. Network modelling reveals the mechanism underlying colitis-associated colon cancer and identifies novel combinatorial anti-cancer targets

    PubMed Central

    Lu, Junyan; Zeng, Hanlin; Liang, Zhongjie; Chen, Limin; Zhang, Liyi; Zhang, Hao; Liu, Hong; Jiang, Hualiang; Shen, Bairong; Huang, Ming; Geng, Meiyu; Spiegel, Sarah; Luo, Cheng

    2015-01-01

    The connection between inflammation and tumourigenesis has been well established. However, the detailed molecular mechanism underlying inflammation-associated tumourigenesis remains unknown because this process involves a complex interplay between immune microenvironments and epithelial cells. To obtain a more systematic understanding of inflammation-associated tumourigenesis as well as to identify novel therapeutic approaches, we constructed a knowledge-based network describing the development of colitis-associated colon cancer (CAC) by integrating the extracellular microenvironment and intracellular signalling pathways. Dynamic simulations of the CAC network revealed a core network module, including P53, MDM2, and AKT, that may govern the malignant transformation of colon epithelial cells in a pro-tumor inflammatory microenvironment. Furthermore, in silico mutation studies and experimental validations led to a novel finding that concurrently targeting ceramide and PI3K/AKT pathway by chemical probes or marketed drugs achieves synergistic anti-cancer effects. Overall, our network model can guide further mechanistic studies on CAC and provide new insights into the design of combinatorial cancer therapies in a rational manner. PMID:26446703

  10. Differentially expressed genes and interacting pathways in bladder cancer revealed by bioinformatic analysis.

    PubMed

    Shen, Yinzhou; Wang, Xuelei; Jin, Yongchao; Lu, Jiasun; Qiu, Guangming; Wen, Xiaofei

    2014-10-01

    The goal of this study was to identify cancer-associated differentially expressed genes (DEGs), analyze their biological functions and investigate the mechanism(s) of cancer occurrence and development, which may provide a theoretical foundation for bladder cancer (BCa) therapy. We downloaded the mRNA expression profiling dataset GSE13507 from the Gene Expression Omnibus database; the dataset includes 165 BCa and 68 control samples. T‑tests were used to identify DEGs. To further study the biological functions of the identified DEGs, we performed a Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Next, we built a network of potentially interacting pathways to study the synergistic relationships among DEGs. A total of 12,105 genes were identified as DEGs, of which 5,239 were upregulated and 6,866 were downregulated in BCa. The DEGs encoding activator protein 1 (AP-1), nuclear factor of activated T-cells (NFAT) proteins, nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and interleukin (IL)-10 were revealed to participate in the significantly enriched immune pathways that were downregulated in BCa. KEGG enrichment analysis revealed 7 significantly upregulated and 47 significantly downregulated pathways enriched among the DEGs. We found a crosstalk interaction among a total of 44 pathways in the network of BCa-affected pathways. In conclusion, our results show that BCa involves dysfunctions in multiple systems. Our study is expected to pave ways for immune and inflammatory research and provide molecular insights for cancer therapy.

  11. Loss of Bad expression confers poor prognosis in non-small cell lung cancer.

    PubMed

    Huang, Yi; Liu, Dan; Chen, Bojiang; Zeng, Jing; Wang, Lei; Zhang, Shangfu; Mo, Xianming; Li, Weimin

    2012-09-01

    Proapoptotic BH-3-only protein Bad (Bcl-Xl/Bcl-2-associated death promoter homolog, Bad) initiates apoptosis in human cells, and contributes to tumorigenesis and chemotherapy resistant in malignancies. This study explored association between the Bad expression level and prognosis in patients with non-small cell lung cancer (NSCLC). In our study, a cohort of 88 resected primary NSCLC cases were collected and analyzed. Bad expression level was determined via immunohistochemical staining assay. The prognostic significances of Bad expression were evaluated with univariate and multivariate survival analysis. The results showed that compared with normal lung tissues, Bad expression level significantly decreased in NSCLC (P < 0.05). Bad expression was associated with adjuvant therapy status. Loss of Bad independently predicted poor prognosis in whole NSCLC cohort and early stage subjects (T1 + T2 and N0 + N1) (all P < 0.05). Overall survival time was also drastically shortened for Bad negative phenotype in NSCLC patients with smoking history, especially lung squamous cell carcinoma (all P < 0.05). In conclusion, this study provided clinical evidence that loss of Bad is an independent and powerful predictor of adverse prognosis in NSCLC. Bad protein could be a new biomarker for selecting individual therapy strategies and predicting therapeutic response in subjects with NSCLC.

  12. Long-term hearing loss after chemoradiation in patients with head and neck cancer.

    PubMed

    Theunissen, Eleonoor A R; Zuur, Charlotte L; Bosma, Sophie C J; Lopez-Yurda, Marta; Hauptmann, Michael; van der Baan, Sieberen; de Boer, Jan Paul; van der Molen, Lisette; Rasch, Coen R N; Dreschler, Wouter A; Balm, Alfons J M

    2014-12-01

    The purpose of this study was to determine whether concomitant chemoradiation (CCRT)-induced hearing loss is progressive over time or not. Long-term (LT) follow-up study. Between 1999 and 2004, 158 patients with head and neck cancer were treated with intravenous (IV) CCRT (n = 80) or intraarterial CCRT (n = 78). Audiometry was performed before, short-term (ST), and LT posttreatment. Differences in hearing were assessed with a multivariable linear regression analysis, incorporating the effect of aging. Long-term audiometry (median 4.5 years) was available in 67 patients (42%). At ST follow-up, a deterioration of 21.6 decibel was seen compared to baseline at pure-tone averages (PTA) 8-10-12.5 kHz. At LT follow-up, this deterioration further increased with 5 decibel (P = 0.005). Only in CCRT-IV patients was a significant progressive treatment-induced hearing loss seen, at PTA 8-10-12.5 kHz (P = 0.005), PTA 1-2-4 kHz air conduction (P = 0.014), and PTA 0.5-1-2 kHz bone conduction (P = 0.045). CCRT-induced hearing impairment was progressive over time, especially in higher frequencies and only in CCRT-IV patients, with a modest deterioration of 5 decibel 4.5 years post-treatment. 4. © 2014 The American Laryngological, Rhinological and Otological Society, Inc.

  13. Simultaneous loss of the DLC1 and PTEN tumor suppressors enhances breast cancer cell migration

    SciTech Connect

    Heering, Johanna; Erlmann, Patrik; Olayioye, Monilola A.

    2009-09-10

    The phosphatase and tensin homolog (PTEN) gene is a tumor suppressor frequently deleted or mutated in sporadic tumors of the breast, prostate, endometrium and brain. The protein acts as a dual specificity phosphatase for lipids and proteins. PTEN loss confers a growth advantage to cells, protects from apoptosis and favors cell migration. The deleted in liver cancer 1 (DLC1) gene has emerged as a novel tumor suppressor downregulated in a variety of tumor types including those of the breast. DLC1 contains a Rho GTPase activating domain that is involved in the inhibition of cell proliferation, migration and invasion. To investigate how simultaneous loss of PTEN and DLC1 contributes to cell transformation, we downregulated both proteins by RNA interference in the non-invasive MCF7 breast carcinoma cell line. Joint depletion of PTEN and DLC1 resulted in enhanced cell migration in wounding and chemotactic transwell assays. Interestingly, both proteins were found to colocalize at the plasma membrane and interacted physically in biochemical pulldowns and coimmunoprecipitations. We therefore postulate that the concerted local inactivation of signaling pathways downstream of PTEN and DLC1, respectively, is required for the tight control of cell migration.

  14. From elasticity to inelasticity in cancer cell mechanics: A loss of scale-invariance

    NASA Astrophysics Data System (ADS)

    Laperrousaz, B.; Drillon, G.; Berguiga, L.; Nicolini, F.; Audit, B.; Satta, V. Maguer; Arneodo, A.; Argoul, F.

    2016-08-01

    Soft materials such as polymer gels, synthetic biomaterials and living biological tissues are generally classified as viscoelastic or viscoplastic materials, because they behave neither as pure elastic solids, nor as pure viscous fluids. When stressed beyond their linear viscoelastic regime, cross-linked biopolymer gels can behave nonlinearly (inelastically) up to failure. In living cells, this type of behavior is more frequent because their cytoskeleton is basically made of cross-linked biopolymer chains with very different structural and flexibility properties. These networks have high sensitivity to stress and great propensity to local failure. But in contrast to synthetic passive gels, they can "afford" these failures because they have ATP driven reparation mechanisms which often allow the recovery of the original texture. A cell pressed in between two plates for a long period of time may recover its original shape if the culture medium brings all the nutrients for keeping it alive. When the failure events are too frequent or too strong, the reparation mechanisms may abort, leading to an irreversible loss of mechanical homeostasis and paving the way for chronic diseases such as cancer. To illustrate this discussion, we consider a model of immature cell transformation during cancer progression, the chronic myelogenous leukemia (CML), where the formation of the BCR-ABL oncogene results from a single chromosomal translocation t(9; 22). Within the assumption that the cell response to stress is scale invariant, we show that the power-law exponent that characterizes their mechanosensitivity can be retrieved from AFM force indentation curves. Comparing control and BCR-ABL transduced cells, we observe that in the later case, one month after transduction, a small percentage the cancer cells no longer follows the control cell power law, as an indication of disruption of the initial cytoskeleton network structure.

  15. Loss of PTEN causes SHP2 activation, making lung cancer cells unresponsive to IFN-γ

    SciTech Connect

    Chen, Chia-Ling; Chiang, Tzu-Hui; Tseng, Po-Chun; Wang, Yu-Chih; Lin, Chiou-Feng

    2015-10-23

    Src homology-2 domain-containing phosphatase (SHP) 2, an oncogenic phosphatase, inhibits type II immune interferon (IFN)-γ signaling by subverting signal transducers and activators of transcription 1 tyrosine phosphorylation and activation. For cancer immunoediting, this study aimed to investigate the decrease of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor protein, leading to cellular impairment of IFN-γ signaling. In comparison with human lung adenocarcinoma A549 cells, the natural PTEN loss in another human lung adenocarcinoma line, PC14PE6/AS2 cells, presents reduced responsiveness in IFN-γ-induced IFN regulatory factor 1 activation and CD54 expression. Artificially silencing PTEN expression in A549 cells also caused cells to be unresponsive to IFN-γ without affecting IFN-γ receptor expression. IFN-γ-induced inhibition of cell proliferation and cytotoxicity were demonstrated in A549 cells but were defective in PC14PE6/AS2 cells and in PTEN-deficient A549 cells. Aberrant activation of SHP2 by ROS was specifically shown in PC14PE6/AS2 cells and PTEN-deficient A549 cells. Inhibiting ROS and SHP2 rescued cellular responses to IFN-γ-induced cytotoxicity and inhibition of cell proliferation in PC14PE6/AS2 cells. These results demonstrate that a decrease in PTEN facilitates ROS/SHP2 signaling, causing lung cancer cells to become unresponsive to IFN-γ. - Highlights: • This study demonstrates that PTEN decrease causes cellular unresponsive to IFN-γ. • Lung cancer cells with PTEN deficiency show unresponsive to IFN-γ signaling. • PTEN decrease inhibits IFN-γ-induced CD54, cell proliferation inhibition, and cytotoxicity. • ROS-mediated SHP2 activation makes PTEN-deficient cells unresponsive to IFN-γ.

  16. Erbin loss promotes cancer cell proliferation through feedback activation of Akt-Skp2-p27 signaling

    SciTech Connect

    Huang, Hao; Song, Yuhua; Wu, Yan; Guo, Ning; Ma, Yuanfang; Qian, Lu

    2015-07-31

    Erbin localizes at the basolateral membrane to regulate cell junctions and polarity in epithelial cells. Dysregulation of Erbin has been implicated in tumorigenesis, and yet it is still unclear if and how disrupted Erbin regulates the biological behavior of cancer cells. We report here that depletion of Erbin leads to cancer cell excessive proliferation in vitro and in vivo. Erbin deficiency accelerates S-phase entry by down-regulating CDK inhibitors p21 and p27 via two independent mechanisms. Mechanistically, Erbin loss promotes p27 degradation by enhancing E3 ligase Skp2 activity though augmenting Akt signaling. Interestingly, we also show that Erbin is an unstable protein when the Akt-Skp2 signaling is aberrantly activated, which can be specifically destructed by SCF-Skp2 ligase. Erbin loss facilitates cell proliferation and migration in Skp2-dependent manner. Thus, our finding illustrates a novel negative feedback loop between Erbin and Akt-Skp2 signaling. It suggests disrupted Erbin links polarity loss, hyperproliferation and tumorigenesis. - Highlights: • Erbin loss leads to cancer cell excessive proliferation in vitro and in vivo. • Erbin loss accelerates cell cycle though down-regulating p21 and p27 expression. • Erbin is a novel negative modulator of Akt1-Skp2-p27 signaling pathway. • Our study suggests that Erbin loss contributes to Skp2 oncogenic function.

  17. OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory neuropathy allele

    PubMed Central

    Varga, R; Avenarius, M R; Kelley, P M; Keats, B J; Berlin, C I; Hood, L J; Morlet, T G; Brashears, S M; Starr, A; Cohn, E S; Smith, R J H; Kimberling, W J

    2006-01-01

    Introduction The majority of hearing loss in children can be accounted for by genetic causes. Non‐syndromic hearing loss accounts for 80% of genetic hearing loss in children, with mutations in DFNB1/GJB2 being by far the most common cause. Among the second tier genetic causes of hearing loss in children are mutations in the DFNB9/OTOF gene. Methods In total, 65 recessive non‐syndromic hearing loss families were screened by genotyping for association with the DFNB9/OTOF gene. Families with genotypes consistent with linkage or uninformative for linkage to this gene region were further screened for mutations in the 48 known coding exons of otoferlin. Results Eight OTOF pathological variants were discovered in six families. Of these, Q829X was found in two families. We also noted 23 other coding variant, believed to have no pathology. A previously published missense allele I515T was found in the heterozygous state in an individual who was observed to be temperature sensitive for the auditory neuropathy phenotype. Conclusions Mutations in OTOF cause both profound hearing loss and a type of hearing loss where otoacoustic emissions are spared called auditory neuropathy. PMID:16371502

  18. Association of osteoprotegerin and bone loss after adjuvant chemotherapy in early-stage breast cancer

    PubMed Central

    Oostra, Drew R.; Lustberg, Maryam B.; Reinbolt, Raquel E.; Pan, Xueliang; Wesolowski, Robert; Shapiro, Charles L.

    2015-01-01

    Purpose Chemotherapy induced ovarian failure (CIOF) results in rapid bone loss. Receptor Activator of Nuclear Factor Kappa-B (RANK)-RANK ligand (RANK-L) signaling balances bone resorption and formation. Osteoprotegerin (OPG) acts as a decoy receptor for RANK, interrupting osteoclast activation and bone resorption. This study examined the relationship between OPG and bone loss in women with CIOF. Methods Premenopausal women with stage I/II breast cancers receiving adjuvant chemotherapy were evaluated at chemotherapy initiation, 6 and 12 months. Bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), follicle stimulating hormone (FSH), ionized calcium, osteocalcin, and OPG were serially measured. CIOF was defined as a negative pregnancy test, FSH levels >30 MIU/mL, and ≥3 months of amenorrhea. Results Forty women were enrolled; 31 (77.5%) met CIOF criteria. BMD significantly decreased (p < 0.001) in the CIOF group at both time points: LS BMD decreased from a median of 0.993 g/cm2 to 0.976 g/cm2 and 0.937 g/cm2 at 6 and 12 months, respectively. OPG was significantly elevated at 6 months (median increase 0.30 pmol/L, p = 0.015) and then decreased at 12 months to levels still above baseline (median difference 0.2 pmol/L, p = 0.70). Conclusions In what was likely a compensatory response to rapid bone loss, CIOF patients’ OPG levels increased at 6 months and then decreased at 12 months to values greater than baseline assessments. This phenomenon is described in other diseases, but never before in CIOF. PMID:25575458

  19. HPV DNA testing with cytology triage in cervical cancer screening: Influence of revealing HPV infection status.

    PubMed

    Richardson, Lyndsay Ann; El-Zein, Mariam; Ramanakumar, Agnihotram V; Ratnam, Samuel; Sangwa-Lugoma, Ghislain; Longatto-Filho, Adhemar; Cardoso, Marly Augusto; Coutlée, Francois; Franco, Eduardo L

    2015-12-01

    Knowledge of cervical human papillomavirus (HPV) status might influence a cytotechnician's assessment of cellular abnormalities. The authors compared original cytotechnicians' Papanicolaou (Pap) readings for which HPV status was concealed with Pap rereads for which HPV status was revealed separately for 3 screening populations. Previously collected cervical Pap smears and clinical data were obtained from the Canadian Cervical Cancer Screening Trial (study A), the Democratic Republic of Congo Community-Based Screening Study (study B), and the Brazilian Investigation into Nutrition and Cervical Cancer Prevention (study C). Smears were reread with knowledge of HPV status for all HPV-positive women as well as a sample of HPV-negative women. Diagnostic performance of Pap cytology was compared between original readings and rereads. A total of 1767 Pap tests were reread. Among 915 rereads for HPV-positive women, the contrast between "revealed" and "concealed" Pap readings demonstrated revisions from negative to positive results for 109 women (cutoff was atypical squamous cells of undetermined significance or worse) and 124 women (cutoff was low-grade squamous intraepithelial lesions [LSIL] or worse). For a disease threshold of cervical intraepithelial neoplasia of grade 2 or worse, specificity significantly declined at the atypical squamous cells of undetermined significance cutoff for studies A (86.6% to 75.3%) and C (42.5% to 15.5%), and at the LSIL cutoff for study C (61.9% to 37.6%). Sensitivity remained nearly unchanged between readings, except in study C, in which reread performance was superior (91.3% vs 71.9% for the LSIL cutoff). A reduction in the diagnostic accuracy of Pap cytology was observed when revealing patients' cervical HPV status, possibly due to a heightened awareness of potential abnormalities, which led to more false-positive results. © 2015 American Cancer Society.

  20. Mitochondrial haplogroups and polymorphisms reveal no association with sporadic prostate cancer in a southern European population.

    PubMed

    Álvarez-Cubero, María Jesús; Saiz Guinaldo, María; Martínez-González, Luís Javier; Álvarez Merino, Juan Carlos; Cózar Olmo, José Manuel; Acosta, José Antonio Lorente

    2012-01-01

    It is known that mitochondria play an important role in certain cancers (prostate, renal, breast, or colorectal) and coronary disease. These organelles play an essential role in apoptosis and the production of reactive oxygen species; in addition, mtDNA also reveals the history of populations and ancient human migration. All these events and variations in the mitochondrial genome are thought to cause some cancers, including prostate cancer, and also help us to group individuals into common origin groups. The aim of the present study is to analyze the different haplogroups and variations in the sequence in the mitochondrial genome of a southern European population consisting of subjects affected (n = 239) and non-affected (n = 150) by sporadic prostate cancer. Using primer extension analysis and DNA sequencing, we identified the nine major European haplogroups and CR polymorphisms. The frequencies of the haplogroups did not differ between patients and control cohorts, whereas the CR polymorphism T16356C was significantly higher in patients with PC compared to the controls (p = 0.029). PSA, staging, and Gleason score were associated with none of the nine major European haplogroups. The CR polymorphisms G16129A (p = 0.007) and T16224C (p = 0.022) were significantly associated with Gleason score, whereas T16311C (p = 0.046) was linked with T-stage. Our results do not suggest that mtDNA haplogroups could be involved in sporadic prostate cancer etiology and pathogenesis as previous studies performed in middle Europe population. Although some significant associations have been obtained in studying CR polymorphisms, further studies should be performed to validate these results.

  1. Mitochondrial Haplogroups and Polymorphisms Reveal No Association with Sporadic Prostate Cancer in a Southern European Population

    PubMed Central

    Álvarez-Cubero, María Jesús; Saiz Guinaldo, María; Martínez-González, Luís Javier; Álvarez Merino, Juan Carlos; Cózar Olmo, José Manuel; Acosta, José Antonio Lorente

    2012-01-01

    Background It is known that mitochondria play an important role in certain cancers (prostate, renal, breast, or colorectal) and coronary disease. These organelles play an essential role in apoptosis and the production of reactive oxygen species; in addition, mtDNA also reveals the history of populations and ancient human migration. All these events and variations in the mitochondrial genome are thought to cause some cancers, including prostate cancer, and also help us to group individuals into common origin groups. The aim of the present study is to analyze the different haplogroups and variations in the sequence in the mitochondrial genome of a southern European population consisting of subjects affected (n = 239) and non-affected (n = 150) by sporadic prostate cancer. Methodology and Principal Findings Using primer extension analysis and DNA sequencing, we identified the nine major European haplogroups and CR polymorphisms. The frequencies of the haplogroups did not differ between patients and control cohorts, whereas the CR polymorphism T16356C was significantly higher in patients with PC compared to the controls (p = 0.029). PSA, staging, and Gleason score were associated with none of the nine major European haplogroups. The CR polymorphisms G16129A (p = 0.007) and T16224C (p = 0.022) were significantly associated with Gleason score, whereas T16311C (p = 0.046) was linked with T-stage. Conclusions and Significance Our results do not suggest that mtDNA haplogroups could be involved in sporadic prostate cancer etiology and pathogenesis as previous studies performed in middle Europe population. Although some significant associations have been obtained in studying CR polymorphisms, further studies should be performed to validate these results. PMID:22815971

  2. Heterogeneity of pancreatic cancer metastases in a single patient revealed by quantitative proteomics.

    PubMed

    Kim, Min-Sik; Zhong, Yi; Yachida, Shinichi; Rajeshkumar, N V; Abel, Melissa L; Marimuthu, Arivusudar; Mudgal, Keshav; Hruban, Ralph H; Poling, Justin S; Tyner, Jeffrey W; Maitra, Anirban; Iacobuzio-Donahue, Christine A; Pandey, Akhilesh

    2014-11-01

    Many patients with pancreatic cancer have metastases to distant organs at the time of initial presentation. Recent studies examining the evolution of pancreatic cancer at the genetic level have shown that clonal complexity of metastatic pancreatic cancer is already initiated within primary tumors, and organ-specific metastases are derived from different subclones. However, we do not yet understand to what extent the evolution of pancreatic cancer contributes to proteomic and signaling alterations. We hypothesized that genetic heterogeneity of metastatic pancreatic cancer results in heterogeneity at the proteome level. To address this, we employed a model system in which cells isolated from three sites of metastasis (liver, lung, and peritoneum) from a single patient were compared. We used a SILAC-based accurate quantitative proteomic strategy combined with high-resolution mass spectrometry to analyze the total proteome and tyrosine phosphoproteome of each of the distal metastases. Our data revealed distinct patterns of both overall proteome expression and tyrosine kinase activities across the three different metastatic lesions. This heterogeneity was significant because it led to differential sensitivity of the neoplastic cells to small molecule inhibitors targeting various kinases and other pathways. For example, R428, a tyrosine kinase inhibitor that targets Axl receptor tyrosine kinase, was able to inhibit cells derived from lung and liver metastases much more effectively than cells from the peritoneal metastasis. Finally, we confirmed that administration of R428 in mice bearing xenografts of cells derived from the three different metastatic sites significantly diminished tumors formed from liver- and lung-metastasis-derived cell lines as compared with tumors derived from the peritoneal metastasis cell line. Overall, our data provide proof-of-principle support that personalized therapy of multiple organ metastases in a single patient should involve the

  3. Annual Medical Expenditure and Productivity Loss Among Colorectal, Female Breast, and Prostate Cancer Survivors in the United States.

    PubMed

    Zheng, Zhiyuan; Yabroff, K Robin; Guy, Gery P; Han, Xuesong; Li, Chunyu; Banegas, Matthew P; Ekwueme, Donatus U; Jemal, Ahmedin

    2016-05-01

    There are limited nationally representative estimates of the annual economic burden among survivors of the three most prevalent cancers (colorectal, female breast, and prostate) in both nonelderly and elderly populations in the United States. The 2008 to 2012 Medical Expenditure Panel Survey data were used to identify colorectal (n = 540), female breast (n = 1568), and prostate (n = 1170) cancer survivors and individuals without a cancer history (n = 109 423). Excess economic burden attributable to cancer included per-person excess annual medical expenditures and productivity losses (employment disability, missed work days, and days stayed in bed). All analyses were stratified by cancer site and age (nonelderly: 18-64 years vs elderly: ≥ 65 years). Multivariable analyses controlled for age, sex, race/ethnicity, marital status, education, number of comorbidities, and geographic region. All statistical tests were two-sided. Compared with individuals without a cancer history, cancer survivors experienced annual excess medical expenditures (for the nonelderly population, colorectal: $8647, 95% confidence interval [CI] = $4932 to $13 974, P < .001; breast: $5119, 95% CI = $3439 to $7158, P < .001; prostate: $3586, 95% CI = $1792 to $6076, P < .001; for the elderly population, colorectal: $4913, 95% CI = $2768 to $7470, P < .001; breast: $2288, 95% CI = $814 to $3995, P = .002; prostate: $3524, 95% CI = $1539 to $5909, P < .001). Nonelderly colorectal and breast cancer survivors experienced statistically significant annual excess employment disability (13.6%, P < .001, and 4.8%, P = .001) and productivity loss at work (7.2 days, P < .001, and 3.3 days, P = .002) and at home (4.5 days, P < .001, and 3.3 days, P = .003). In contrast, elderly survivors of all three cancer sites had comparable productivity losses as those without a cancer history. Colorectal, breast, and prostate cancer survivors experienced statistically significantly higher economic burden compared with

  4. Annual Medical Expenditure and Productivity Loss Among Colorectal, Female Breast, and Prostate Cancer Survivors in the United States

    PubMed Central

    Yabroff, K. Robin; Guy, Gery P.; Han, Xuesong; Li, Chunyu; Banegas, Matthew P.; Ekwueme, Donatus U.; Jemal, Ahmedin

    2016-01-01

    Background: There are limited nationally representative estimates of the annual economic burden among survivors of the three most prevalent cancers (colorectal, female breast, and prostate) in both nonelderly and elderly populations in the United States. Methods: The 2008 to 2012 Medical Expenditure Panel Survey data were used to identify colorectal (n = 540), female breast (n = 1568), and prostate (n = 1170) cancer survivors and individuals without a cancer history (n = 109 423). Excess economic burden attributable to cancer included per-person excess annual medical expenditures and productivity losses (employment disability, missed work days, and days stayed in bed). All analyses were stratified by cancer site and age (nonelderly: 18–64 years vs elderly: ≥65 years). Multivariable analyses controlled for age, sex, race/ethnicity, marital status, education, number of comorbidities, and geographic region. All statistical tests were two-sided. Results: Compared with individuals without a cancer history, cancer survivors experienced annual excess medical expenditures (for the nonelderly population, colorectal: $8647, 95% confidence interval [CI] = $4932 to $13 974, P < .001; breast: $5119, 95% CI = $3439 to $7158, P < .001; prostate: $3586, 95% CI = $1792 to $6076, P < .001; for the elderly population, colorectal: $4913, 95% CI = $2768 to $7470, P < .001; breast: $2288, 95% CI = $814 to $3995, P = .002; prostate: $3524, 95% CI = $1539 to $5909, P < .001). Nonelderly colorectal and breast cancer survivors experienced statistically significant annual excess employment disability (13.6%, P < .001, and 4.8%, P = .001) and productivity loss at work (7.2 days, P < .001, and 3.3 days, P = .002) and at home (4.5 days, P < .001, and 3.3 days, P = .003). In contrast, elderly survivors of all three cancer sites had comparable productivity losses as those without a cancer history. Conclusions: Colorectal, breast, and prostate cancer survivors experienced statistically

  5. Loss of heterozygosis on chromosome 18q21-23 and muscle-invasive bladder cancer natural history

    PubMed Central

    CAI, TOMMASO; MONDAINI, NICOLA; TISCIONE, DANIELE; DAL CANTO, MAURIZIO; SANTI, RAFFAELLA; BARTOLETTI, RICCARDO; NESI, GABRIELLA

    2015-01-01

    Loss of heterozygosis (LOH) on chromosome (Chr) 18q21-23 was reported to be one of the most common genetic alterations identified in bladder cancer. The current study aimed to determine the prognostic role of LOH on Chr 18q21-23 in patients diagnosed with muscle-invasive urothelial bladder carcinoma (MIBC). A total of 34 consecutive patients were enrolled in the present prospective study. LOH on Chr 18 was assessed by performing multiplex polymerase chain reaction on paired blood and tumour tissue samples from each patient. The following primers were used in the present study: D18S51, MBP LW and MBP H. These data were then compared with follow-up information. The main outcome measure was patient status at the end of the follow-up. Cox regression was used to evaluate the impact of each parameter on cancer-specific survival and the Kaplan Meier test for disease-free survival was plotted in order to estimate survival. Out of 34 patients, 18 (52.9%) exhibited ≥1 alteration in one of the loci analysed on chromosome 18, while 16 (47.1%) revealed no alterations. No correlation was identified with stage (P=0.18) or grade (P=0.06); however, LOH on Chr 18q21-23 was significantly associated with a lower recurrence-free probability (P<0.0001). Kaplan-Meier curves demonstrated a significant association between patient status at follow-up and LOH on Chr 18 (P<0.001). In addition, multivariate analysis identified LOH on Chr 18 (P<0.001) and stage (P=0.01) as independent survival predictors. Furthermore, artificial neural network analysis was consistent with the results of the multivariate analysis. In conclusion, the present study highlighted the role of LOH on Chr 18q21-23 in predicting the clinical outcome of patients with MIBC. PMID:26622891

  6. Genome-wide allelotyping indicates increased loss of heterozygosity on 9p and 14q in early age of onset colorectal cancer.

    PubMed

    Weber, T K; Conroy, J; Keitz, B; Rodriguez-Bigas, M; Petrelli, N J; Stoler, D L; Anderson, G R; Shows, T B; Nowak, N J

    1999-01-01

    Colorectal cancer remains a significant public health challenge, despite our increased understanding of the genetic mechanisms involved in the initiation and progression of this disorder. It has become clear that multiple mechanisms lead to the tumorigenic phenotype, with familial predisposition syndromes accounting for less than 15% of all colorectal cancers. A genome-wide scan for loss of heterozygosity (LOH) was carried out with 150 highly polymorphic markers in an effort to identify additional loci involved in colorectal tumorigenesis in DNA samples from 42 colorectal cancer patients. The results confirm earlier observations that tumor DNAs from patients with hereditary nonpolyposis colon cancer (HNPCC) either maintain heterozygosity or exhibit altered or additional alleles. DNAs from patients with early onset colorectal carcinomas (diagnosed prior to age 50) revealed a higher overall degree of LOH than DNAs from patients with sporadic colorectal cancers diagnosed later in life (after age 50). While regions on 1p, 10q and 14q are suggestive, statistical analysis of LOH at these regions failed to reach significance. However, LOH at 9p did reveal a statistically significant increase in the early onset patient group, compared to the greater than age 50 group. LOH on 9p may involve inactivation of p16/CDKN2 through aberrant DNA methylation on the remaining chromosome, resulting in a situation analogous to a homozygous deletion of p16 and providing a selective growth advantage to these cells. This marker may prove to be a useful prognostic indicator for patient stratification in the design of therapy for early onset colorectal cancer patients.

  7. Diffuse Muscular Pain, Skin Tightening, and Nodular Regenerative Hyperplasia Revealing Paraneoplastic Amyopathic Dermatomyositis due to Testicular Cancer.

    PubMed

    Norrenberg, Sarah; Gangji, Valérie; Del Marmol, Véronique; Soyfoo, Muhammad S

    2012-01-01

    Paraneoplastic dermatomyositis (DM) associated with testicular cancer is extremely rare. We report the case of a patient with skin tightening, polymyalgia, hypereosinophilia, and nodular regenerative hyperplasia revealing seminoma and associated paraneoplastic DM.

  8. The Adaptive Response in p53 Cancer Prone Mice: Loss of heterozygosity and Genomic Instability

    SciTech Connect

    Josee, Lavoie; Dolling, Jo-Anna; Mitchel, Ron E.J.; Boreham, Douglas R.

    2004-09-28

    The Trp53 gene is clearly associated with increased cancer risk. This, coupled with the broad understanding of its mode of action at the molecular level, makes this gene a good candidate for investigating the relationship between genetic risk factors and spontaneous cancer occurring in a mouse model exposed to low dose radiation. We have shown that adaptive response to chronic low dose radiation could increase cancer latency, as well as overall lifespan. To better understand the molecular processes that influence cellular risk, modern tools in molecular biology were used to evaluate the loss of heterozigozity (LOH) at the Trp53 locus, and chromosomal instability in the cells from mice exposed to chronic low dose radiation. Female mice carrying a single defective copy of the Trp53 gene were irradiated with doses of gamma-radiation delivered at a low dose rate of about 0.7 mGy/hr. Groups of mice (5 irradiated and 5 unexposed) were exposed to 0.33 mGy per day for 15, 30, 45, 60, 67 and 75 weeks equaling total body doses of 2.4, 4.7, 7.2, 9.7, 10.9 and 12.1 cGy, respectively. The presence of a single defective copy of the Trp53 gene increases cancer risk in these mice. However, in vivo exposure to low dose radiation increased cancer latency. We hypothesized that: (1) These mice might have spontaneous chromosome instability, and (2) that this low dose adaptive exposure would reduce the chromosomal instability. This instability was investigated using spectral karyotyping (SKY). Bone marrow cells from 5 irradiated mice (doses of 10.9 and 12.1 cGy) and 5 control mice were collected for metaphase harvest. Briefly, the cells were incubated at 37 C for 4 hours in RPMI containing 25% heat-inactivated FBS and 0.1 mg/ml colcemid, and then given a hypotonic treatment of 0.075M KCl for 20 minutes at 37 C. An average of 100 metaphases per mouse were karyotyped. The Trp53 heterozygous mice do not show apparent structural chromosome instability. From both unexposed and irradiated

  9. Clinical impact of detection of loss of heterozygosity of BRCA1 and BRCA2 markers in sporadic breast cancer.

    PubMed Central

    Beckmann, M. W.; Picard, F.; An, H. X.; van Roeyen, C. R.; Dominik, S. I.; Mosny, D. S.; Schnürch, H. G.; Bender, H. G.; Niederacher, D.

    1996-01-01

    The development of familial and sporadic breast cancer is based on genetic alterations of tumour-suppressor genes, for which loss of heterozygosity (LOH) is one mechanism of gene inactivation. To investigate LOH of BRCA1 (17q21) and BRCA2 (13-q12-13) in sporadic breast cancer, polymerase chain reaction (PCR)-based fluorescent DNA technology for detection of microsatellite polymorphisms was applied. A total of 137 breast cancer and 15 benign breast specimens with matched normal tissue were examined. Fluorescent-labelled PCR products were analysed in an automated DNA sequencer (ALFTM Pharmacia). Losses at both loci were correlated with different histological types, age, tumour size, lymph node status, grading and steroid hormone receptor expression, [SHR: oestrogen receptor (ER), progesterone receptor (PgR)]. For BRCA1 (D17S855, THRA1, D17S579) losses could be detected in invasive ductal carcinoma (IDC; n = 108) in 32-38%, invasive lobular carcinoma (ILC; n = 19) in 21-42% depending on the marker applied, but not in benign breast tumours (n = 15). Losses of BRCA1 markers correlated with larger tumour size, higher grade, and PgR expression. For BRCA2 (D13S260, D13S267, D13S171) losses could be detected in 108 IDCs in 30-38%, in 19 ILCs in 17-39% depending on the marker applied, but not in benign breast tumours. Losses of BRCA2 markers correlated only with higher grade. Microsatellite analyses combined with detection of fluorescent-labelled PCR products by an automated laser DNA sequencer can be used for routine determination of LOH. In sporadic breast cancer, LOH of BRCA1 of BRCA2 does not add decisive prognostic value as stated for familial breast cancer. Images Figure 1 PMID:8630282

  10. Quantitative Proteomics Reveals That Enzymes of the Ketogenic Pathway Are Associated with Prostate Cancer Progression*

    PubMed Central

    Saraon, Punit; Cretu, Daniela; Musrap, Natasha; Karagiannis, George S.; Batruch, Ihor; Drabovich, Andrei P.; van der Kwast, Theodorus; Mizokami, Atsushi; Morrissey, Colm; Jarvi, Keith; Diamandis, Eleftherios P.

    2013-01-01

    Prostate cancer is the most common malignancy and the second leading cause of cancer-related deaths in men. One common treatment is androgen-deprivation therapy, which reduces symptoms in most patients. However, over time, patients develop tumors that are androgen-independent and ultimately fatal. The mechanisms that cause this transition remain largely unknown, and as a result, there are no effective treatments against androgen-independent prostate cancer. As a model platform, we used the LNCaP cell line and its androgen-independent derivative, LNCaP-SF. Utilizing stable isotope labeling with amino acids in cell culture coupled to mass spectrometry, we assessed the differential global protein expression of the two cell lines. Our proteomic analysis resulted in the quantification of 3355 proteins. Bioinformatic prioritization resulted in 42 up-regulated and 46 down-regulated proteins in LNCaP-SF cells relative to LNCaP cells. Our top candidate, HMGCS2, an enzyme involved in ketogenesis, was found to be 9-fold elevated in LNCaP-SF cells, based on peptide ratios. After analyzing the remaining enzymes of this pathway (ACAT1, BDH1, HMGCL, and OXCT1), we observed increased expression of these proteins in the LNCaP-SF cells, which was further verified using Western blotting. To determine whether these enzymes were up-regulated in clinical samples, we performed quantitative PCR and immunohistochemistry on human prostate cancer tissues, from which we observed significantly increased transcript and protein levels in high-grade cancer (Gleason grade ≥ 8). In addition, we observed significant elevation of these enzymes in the LuCaP 96AI castration-resistant xenograft. Further assessment of ACAT1 on human castration-resistant metastatic prostate cancer tissues revealed substantially elevated expression of ACAT1 in these specimens. Taken together, our results indicate that enzymes of the ketogenic pathway are up-regulated in high-grade prostate cancer and could serve as

  11. Return to work in sick-listed cancer survivors with job loss: design of a randomised controlled trial.

    PubMed

    van Egmond, Martine P; Duijts, Saskia F A; Vermeulen, Sylvia J; van der Beek, Allard J; Anema, Johannes R

    2015-02-18

    Despite long-term or permanent health problems, cancer survivors are often motivated to return to work. For cancer survivors who have lost their job, return to work can be more challenging compared to employed survivors, as they generally find themselves in a more vulnerable social and financial position. Cancer survivors with job loss may therefore be in need of tailored return to work support. However, there is a lack of return to work intervention programs specifically targeting these cancer survivors. The number of cancer survivors with job loss in developed countries is rising due to, amongst others, increases in the incidence and survivor rate of cancer, the retirement age and the proportion of flexible employment contracts. Hence, we consider it important to develop a tailored return to work intervention program for cancer survivors with job loss, and to evaluate its effectiveness compared to usual care. This study employs a two-armed randomised controlled trial with a follow-up period of 12 months. The study population (n = 164) will be recruited from a national sample of cancer survivors (18-60 years), who have been sick-listed for 12-36 months. Participants will be randomised by using computerized blocked randomisation (blocks of four). All participants will receive usual care as provided by the Dutch Social Security Agency. Additionally, participants in the intervention group will receive a tailored return to work intervention program, which includes vocational rehabilitation and supportive psychosocial components, as well as (therapeutic) placement at work. The primary outcome measure is duration until sustainable return to work; the secondary outcome measure is rate of return to work. Other parameters include, amongst others, fatigue, coping strategy and quality of life. We will perform Cox regression analyses to estimate hazard ratios for time to sustainable return to work. The hypothesis of this study is that a tailored approach for cancer

  12. Site-to-site interdomain communication may mediate different loss-of-function mechanisms in a cancer-associated NQO1 polymorphism.

    PubMed

    Medina-Carmona, Encarnación; Neira, Jose L; Salido, Eduardo; Fuchs, Julian E; Palomino-Morales, Rogelio; Timson, David J; Pey, Angel L

    2017-03-14

    Disease associated genetic variations often cause intracellular enzyme inactivation, dysregulation and instability. However, allosteric communication of mutational effects to distant functional sites leading to loss-of-function remains poorly understood. We characterize here interdomain site-to-site communication by which a common cancer-associated single nucleotide polymorphism (c.C609T/p.P187S) reduces the activity and stability in vivo of NAD(P)H:quinone oxidoreductase 1 (NQO1). NQO1 is a FAD-dependent, two-domain multifunctional stress protein acting as a Phase II enzyme, activating cancer pro-drugs and stabilizing p53 and p73α oncosuppressors. We show that p.P187S causes structural and dynamic changes communicated to functional sites far from the mutated site, affecting the FAD binding site located at the N-terminal domain (NTD) and accelerating proteasomal degradation through dynamic effects on the C-terminal domain (CTD). Structural protein:protein interaction studies reveal that the cancer-associated polymorphism does not abolish the interaction with p73α, indicating that oncosuppressor destabilization largely mirrors the low intracellular stability of p.P187S. In conclusion, we show how a single disease associated amino acid change may allosterically perturb several functional sites in an oligomeric and multidomain protein. These results have important implications for the understanding of loss-of-function genetic diseases and the identification of novel structural hot spots as targets for pharmacological intervention.

  13. Site-to-site interdomain communication may mediate different loss-of-function mechanisms in a cancer-associated NQO1 polymorphism

    NASA Astrophysics Data System (ADS)

    Medina-Carmona, Encarnación; Neira, Jose L.; Salido, Eduardo; Fuchs, Julian E.; Palomino-Morales, Rogelio; Timson, David J.; Pey, Angel L.

    2017-03-01

    Disease associated genetic variations often cause intracellular enzyme inactivation, dysregulation and instability. However, allosteric communication of mutational effects to distant functional sites leading to loss-of-function remains poorly understood. We characterize here interdomain site-to-site communication by which a common cancer-associated single nucleotide polymorphism (c.C609T/p.P187S) reduces the activity and stability in vivo of NAD(P)H:quinone oxidoreductase 1 (NQO1). NQO1 is a FAD-dependent, two-domain multifunctional stress protein acting as a Phase II enzyme, activating cancer pro-drugs and stabilizing p53 and p73α oncosuppressors. We show that p.P187S causes structural and dynamic changes communicated to functional sites far from the mutated site, affecting the FAD binding site located at the N-terminal domain (NTD) and accelerating proteasomal degradation through dynamic effects on the C-terminal domain (CTD). Structural protein:protein interaction studies reveal that the cancer-associated polymorphism does not abolish the interaction with p73α, indicating that oncosuppressor destabilization largely mirrors the low intracellular stability of p.P187S. In conclusion, we show how a single disease associated amino acid change may allosterically perturb several functional sites in an oligomeric and multidomain protein. These results have important implications for the understanding of loss-of-function genetic diseases and the identification of novel structural hot spots as targets for pharmacological intervention.

  14. Site-to-site interdomain communication may mediate different loss-of-function mechanisms in a cancer-associated NQO1 polymorphism

    PubMed Central

    Medina-Carmona, Encarnación; Neira, Jose L.; Salido, Eduardo; Fuchs, Julian E.; Palomino-Morales, Rogelio; Timson, David J.; Pey, Angel L.

    2017-01-01

    Disease associated genetic variations often cause intracellular enzyme inactivation, dysregulation and instability. However, allosteric communication of mutational effects to distant functional sites leading to loss-of-function remains poorly understood. We characterize here interdomain site-to-site communication by which a common cancer-associated single nucleotide polymorphism (c.C609T/p.P187S) reduces the activity and stability in vivo of NAD(P)H:quinone oxidoreductase 1 (NQO1). NQO1 is a FAD-dependent, two-domain multifunctional stress protein acting as a Phase II enzyme, activating cancer pro-drugs and stabilizing p53 and p73α oncosuppressors. We show that p.P187S causes structural and dynamic changes communicated to functional sites far from the mutated site, affecting the FAD binding site located at the N-terminal domain (NTD) and accelerating proteasomal degradation through dynamic effects on the C-terminal domain (CTD). Structural protein:protein interaction studies reveal that the cancer-associated polymorphism does not abolish the interaction with p73α, indicating that oncosuppressor destabilization largely mirrors the low intracellular stability of p.P187S. In conclusion, we show how a single disease associated amino acid change may allosterically perturb several functional sites in an oligomeric and multidomain protein. These results have important implications for the understanding of loss-of-function genetic diseases and the identification of novel structural hot spots as targets for pharmacological intervention. PMID:28291250

  15. A change in the study evaluation paradigm reveals that larynx preservation compromises survival in T4 laryngeal cancer patients.

    PubMed

    Dyckhoff, Gerhard; Plinkert, Peter K; Ramroth, Heribert

    2017-09-01

    Larynx preservation (LP) is recommended for up to low-volume T4 laryngeal cancer as an evidence-based treatment option that does not compromise survival. However, a reevaluation of the current literature raises questions regarding whether there is indeed reliable evidence to support larynx preservation for T4 tumor patients. In an observational cohort study of 810 laryngeal cancer patients, we evaluated the outcomes of all T4 tumor patients treated with primary chemo-radiotherapy (CRT) or primary radiotherapy alone (RT) compared with upfront total laryngectomy followed by adjuvant (chemo)radiotherapy (TL + a[C]RT). Additionally, we reevaluated the studies that form the evidence base for the recommendation of LP for patients with up to T4 tumors (Pfister et al., J Clin Oncol 24:3693-704, 2006). The evaluation of all 288 stage III and IV patients together did not show a significant difference in overall survival (OS) between CRT-LP and TL + a(C)RT (hazard ratio (HR) 1.23; 95% confidence interval (CI): 0.82-1.86; p = 0.31) using a multivariate proportional hazard model. However, a subgroup analysis of T4 tumor patients alone (N = 107; 13.9%) revealed significantly worse OS after CRT compared with TL + a(C)RT (HR 2.0; 95% CI: 1.04-3.7; p = 0.0369). A reevaluation of the subgroup of T4 patients in the 5 LP studies that led to the ASCO clinical practice guidelines revealed that only 21-45 T4 patients had differential data on survival outcome. These data, however, showed a markedly worse outcome for T4 patients after LP. T4 laryngeal cancer patients who reject TL as a treatment option should be informed that their chance of organ preservation with primary conservative treatment is likely to result in a significantly worse outcome in terms of OS. Significant loss of survival in T4 patients after LP is also confirmed in recent literature.

  16. Daughters and Mothers Against Breast Cancer (DAMES): Main outcomes of a randomized controlled trial of weight loss in overweight mothers with breast cancer and their overweight daughters

    PubMed Central

    Demark-Wahnefried, Wendy; Jones, Lee W; Snyder, Denise C; Sloane, Richard J; Kimmick, Gretchen G; Hughes, Daniel C; Badr, Hoda J; Miller, Paige E; Burke, Lora E; Lipkus, Isaac M

    2014-01-01

    BACKGROUND Few studies to date have used the cancer diagnosis as a teachable moment to promote healthy behavior changes in survivors of cancer and their family members. Given the role of obesity in the primary and tertiary prevention of breast cancer, the authors explored the feasibility of a mother-daughter weight loss intervention. METHODS A randomized controlled trial of a mailed weight loss intervention was undertaken among 68 mother-daughter dyads (n = 136), each comprised of a survivor of breast cancer (AJCC stage 0-III) and her adult biological daughter. All women had body mass indices ≥ 25 kg/m2 and underwent in-person assessments at baseline, 6 months, and 12 months, with accelerometry and exercise capacity performed on a subset of individuals. All women received a personalized workbook and 6 newsletters over a 1-year period that promoted weight loss; exercise; and a nutrient-rich, low-energy density diet. A total of 25 dyads received individually tailored instruction (INDIVIDUAL), 25 dyads received team-tailored instruction (TEAM), and 18 dyads received standardized brochures (CONTROL). RESULTS The trial met its accrual target, experienced 90% retention, and caused no serious adverse events. Significant differences in baseline to 12-month changes were observed between INDIVIDUAL versus CONTROL mothers for body mass index, weight, and waist circumference (WC); significant differences also were observed in the WC of corresponding daughters (P < .05). Significant differences were found between INDIVIDUAL versus CONTROL and TEAM versus CONTROL dyads for WC (P = .0002 and .018, respectively), minutes per week of physical activity (P = .031 and .036, respectively), and exercise capacity (P = .047 for both). CONCLUSIONS Significant improvements in lifestyle behaviors and health outcomes are possible with tailored print interventions directed toward survivors of cancer and their family members. For greater impact, more research is needed

  17. Distinct outcomes of CRL–Nedd8 pathway inhibition reveal cancer cell plasticity

    PubMed Central

    Rulina, Anastasia V; Mittler, Frédérique; Obeid, Patricia; Gerbaud, Sophie; Guyon, Laurent; Sulpice, Eric; Kermarrec, Frédérique; Assard, Nicole; Dolega, Monika E; Gidrol, Xavier; Balakirev, Maxim Y

    2016-01-01

    Inhibition of protein degradation by blocking Cullin-RING E3 ligases (CRLs) is a new approach in cancer therapy though of unknown risk because CRL inhibition may stabilize both oncoproteins and tumor suppressors. Probing CRLs in prostate cancer cells revealed a remarkable plasticity of cells with TMPRSS2-ERG translocation. CRL suppression by chemical inhibition or knockdown of RING component RBX1 led to reversible G0/G1 cell cycle arrest that prevented cell apoptosis. Conversely, complete blocking of CRLs at a higher inhibitor dose-induced cytotoxicity that was amplified by knockdown of CRL regulator Cand1. We analyzed cell signaling to understand how varying degrees of CRL inhibition translated to distinct cell fates. Both tumor suppressor and oncogenic cell signaling pathways and transcriptional activities were affected, with pro-metastatic Wnt/β-catenin as the most upregulated. Suppression of the NF-κB pathway contributed to anti-apoptotic effect, and androgen receptor (AR) and ERG played decisive, though opposite, roles: AR was involved in protective quiescence, whereas ERG promoted apoptosis. These data define AR–ERG interaction as a key plasticity and survival determinant in prostate cancer and suggest supplementary treatments that may overcome drug resistance mechanisms regulated by AR–ERG interaction. PMID:27906189

  18. Deep Sequencing Reveals New Aspects of Progesterone Receptor Signaling in Breast Cancer Cells

    PubMed Central

    Kougioumtzi, Anastasia; Tsaparas, Panayiotis; Magklara, Angeliki

    2014-01-01

    Despite the pleiotropic effects of the progesterone receptor in breast cancer, the molecular mechanisms in play remain largely unknown. To gain a global view of the PR-orchestrated networks, we used next-generation sequencing to determine the progestin-regulated transcriptome in T47D breast cancer cells. We identify a large number of PR target genes involved in critical cellular programs, such as regulation of transcription, apoptosis, cell motion and angiogenesis. Integration of the transcriptomic data with the PR-binding profiling of hormonally treated cells identifies numerous components of the small-GTPases signaling pathways as direct PR targets. Progestin-induced deregulation of the small GTPases may contribute to the PR's role in mammary tumorigenesis. Transcript expression analysis reveals significant expression changes of specific transcript variants in response to the extracellular hormonal stimulus. Using the NET1 gene as an example, we show that the PR can dictate alternative promoter usage leading to the upregulation of an isoform that may play a role in metastatic breast cancer. Future studies should aim to characterize these selectively regulated variants and evaluate their clinical utility in prognosis and targeted therapy of hormonally responsive breast tumors. PMID:24897521

  19. Endogenous molecular network reveals two mechanisms of heterogeneity within gastric cancer

    PubMed Central

    Li, Site; Zhu, Xiaomei; Liu, Bingya; Wang, Gaowei; Ao, Ping

    2015-01-01

    Intratumor heterogeneity is a common phenomenon and impedes cancer therapy and research. Gastric cancer (GC) cells have generally been classified into two heterogeneous cellular phenotypes, the gastric and intestinal types, yet the mechanisms of maintaining two phenotypes and controlling phenotypic transition are largely unknown. A qualitative systematic framework, the endogenous molecular network hypothesis, has recently been proposed to understand cancer genesis and progression. Here, a minimal network corresponding to such framework was found for GC and was quantified via a stochastic nonlinear dynamical system. We then further extended the framework to address the important question of intratumor heterogeneity quantitatively. The working network characterized main known features of normal gastric epithelial and GC cell phenotypes. Our results demonstrated that four positive feedback loops in the network are critical for GC cell phenotypes. Moreover, two mechanisms that contribute to GC cell heterogeneity were identified: particular positive feedback loops are responsible for the maintenance of intestinal and gastric phenotypes; GC cell progression routes that were revealed by the dynamical behaviors of individual key components are heterogeneous. In this work, we constructed an endogenous molecular network of GC that can be expanded in the future and would broaden the known mechanisms of intratumor heterogeneity. PMID:25962957

  20. Singularity analysis of the AKT signaling pathway reveals connections between cancer and metabolic diseases

    NASA Astrophysics Data System (ADS)

    Wang, Guanyu

    2010-12-01

    Connections between cancer and metabolic diseases may consist in the complex network of interactions among a common set of biomolecules. By applying singularity and bifurcation analysis, the phenotypes constrained by the AKT signaling pathway are identified and mapped onto the parameter space, which include cancer and certain metabolic diseases. By considering physiologic properties (sensitivity, robustness and adaptivity) the AKT pathway must possess in order to efficiently sense growth factors and nutrients, the region of normal responses is located. To optimize these properties, the intracellular concentration of the AKT protein must be sufficiently high to saturate its enzymes; the strength of the positive feedback must be stronger than that of the negative feedback. The analysis illuminates the parameter space and reveals system-level mechanisms in regulating biological functions (cell growth, survival, proliferation and metabolism) and how their deregulation may lead to the development of diseases. The analytical expressions summarize the synergistic interactions among many molecules, which provides valuable insights into therapeutic interventions. In particular, a strategy for overcoming the limitations of mTOR inhibition is proposed for cancer therapy.

  1. Integrated analysis reveals tubal and ovarian originated serous ovarian cancer and predicts differential therapeutic responses.

    PubMed

    Hao, Dapeng; Li, Jingjing; Jia, Shanshan; Meng, Yuan; Wang, Li; Zhang, Chao; Di, Li-Jun

    2017-09-22

    The relative importance of fallopian tube (FT) compared to ovarian surface epithelium (OSE) in the genesis of serous type of ovarian cancer (SOC) is still unsettled. Here, we followed an integrated approach to study the tissue origin of SOC, as well as its association with clinical outcome and response to therapeutic drugs. A collection of transcriptome data of 80 FTs, 89 OSEs and 2,668 SOCs was systematically analyzed to determine the characteristic of FT-like and OSE-like tumors. A molecular signature was developed for identifying tissue origin of SOC and then was used to re-evaluate the prognostic genes and therapeutic biomarkers of SOC of different tissue origins. IHC staining of tissue array and functional experiments on a panel of ovarian cancer cell lines were used to further validate the key findings. The expression patterns of tissue specific genes, prognostic genes and molecular markers all support a dualistic tissue origin of SOC, from either FT or OSE. A molecular signature was established to identify the tissue identity of SOCs. Surprisingly, the signature showed a strong association with overall survival [OSE-like versus FT-like, HR = 4.16, 95%CI, 2.67-6.48, p<10-9]. The phamacogenomic approach revealed AXL to be a therapeutic target of the aggressive OSE-derived SOC. SOC has two subtypes originated from either FT or OSE, which show different clinical and pathological features. Copyright ©2017, American Association for Cancer Research.

  2. Microbial genomic analysis reveals the essential role of inflammation in bacteria-induced colorectal cancer

    PubMed Central

    Arthur, Janelle C.; Gharaibeh, Raad Z.; Mühlbauer, Marcus; Perez-Chanona, Ernesto; Uronis, Joshua M.; McCafferty, Jonathan; Fodor, Anthony A.; Jobin, Christian

    2014-01-01

    Enterobacteria, especially Escherichia coli, are abundant in patients with inflammatory bowel disease or colorectal cancer (CRC). However, it is unclear whether cancer is promoted by inflammation-induced expansion of E. coli and/or changes in expression of specific microbial genes. Here we use longitudinal (2, 12 and 20 weeks) 16S rRNA sequencing of luminal microbiota from ex-germ free mice to show that inflamed Il10−/− mice maintain a higher abundance of Enterobacteriaceae than healthy wild-type mice. Experiments with mono-colonized Il10−/− mice reveal that host inflammation is necessary for E. coli cancer-promoting activity. RNA-sequence analysis indicates significant changes in E. coli gene catalogue in Il10−/− mice, with changes mostly driven by adaptation to the intestinal environment. Expression of specific genes present in the tumor-promoting E. coli pks island are modulated by inflammation/CRC development. Thus, progression of inflammation in Il10−/− mice supports Enterobacteriaceae and alters a small subset of microbial genes important for tumor development. PMID:25182170

  3. Systems Perturbation Analysis of a Large-Scale Signal Transduction Model Reveals Potentially Influential Candidates for Cancer Therapeutics.

    PubMed

    Puniya, Bhanwar Lal; Allen, Laura; Hochfelder, Colleen; Majumder, Mahbubul; Helikar, Tomáš

    2016-01-01

    Dysregulation in signal transduction pathways can lead to a variety of complex disorders, including cancer. Computational approaches such as network analysis are important tools to understand system dynamics as well as to identify critical components that could be further explored as therapeutic targets. Here, we performed perturbation analysis of a large-scale signal transduction model in extracellular environments that stimulate cell death, growth, motility, and quiescence. Each of the model's components was perturbed under both loss-of-function and gain-of-function mutations. Using 1,300 simulations under both types of perturbations across various extracellular conditions, we identified the most and least influential components based on the magnitude of their influence on the rest of the system. Based on the premise that the most influential components might serve as better drug targets, we characterized them for biological functions, housekeeping genes, essential genes, and druggable proteins. The most influential components under all environmental conditions were enriched with several biological processes. The inositol pathway was found as most influential under inactivating perturbations, whereas the kinase and small lung cancer pathways were identified as the most influential under activating perturbations. The most influential components were enriched with essential genes and druggable proteins. Moreover, known cancer drug targets were also classified in influential components based on the affected components in the network. Additionally, the systemic perturbation analysis of the model revealed a network motif of most influential components which affect each other. Furthermore, our analysis predicted novel combinations of cancer drug targets with various effects on other most influential components. We found that the combinatorial perturbation consisting of PI3K inactivation and overactivation of IP3R1 can lead to increased activity levels of apoptosis

  4. Mutation at intronic repeats of the ataxia-telangiectasia mutated (ATM) gene and ATM protein loss in primary gastric cancer with microsatellite instability.

    PubMed

    Kim, Hee Sung; Choi, Seung Im; Min, Hae Lim; Kim, Min A; Kim, Woo Ho

    2013-01-01

    Ataxia-telangiectasia mutated (ATM) is a Ser/Thr protein kinase that plays a critical role in DNA damage-induced signaling and initiation of cell cycle checkpoint signaling in response to DNA-damaging agents such as ionizing radiation. We have previously reported the ATM protein loss by immunohistochemistry (IHC) in 16% of human gastric cancer (GC) tissue. We hypothesized that ATM gene intron mutations targeted by microsatellite instability (MSI) cause ATM protein loss in a subset of GC. We studied mononucleotide mutations at the intron of ATM gene, ATM IHC and MSI in GC. Ten human gastric cancer cell lines were studied for the ATM gene mutation at introns, RT-PCR, direct sequencing, and immunohistochemistry. GC tissues of 839 patients were analyzed for MSI and ATM IHC. Among them, 604 cases were analyzed for the ATM mutations at introns preceding exon 6, exon 10 and exon 20. Two human GC cell lines (SNU-1 and -638) showed ATM intron mutations, deletion in RT-PCR and direct sequencing, and ATM protein loss by IHC. The frequencies of ATM mutation, MSI, and ATM protein loss were 12.9% (78/604), 9.2% (81/882) and 15.2% (134/839), respectively. Analysis of associations among MSI, ATM gene mutation, and ATM protein loss revealed highly co-existing ATM gene alterations and MSI. ATM intron mutation and ATM protein loss were detected in 69.3% (52/75) and 53.3% (40/75) of MSI positive GC. MSI positivity and ATM protein loss were present in 68.4% (52/76) and 48.7% (37/76) of GC with ATM intron mutation. ATM mutation and ATM protein loss had characteristics of old age, distal location of tumor, large tumor size, and histologic intestinal type. Our study might be interpreted as that ATM gene mutation at intron might be targeted by MSI and lead to ATM protein loss in a selected group of GC.

  5. Mutation at Intronic Repeats of the Ataxia-Telangiectasia Mutated (ATM) Gene and ATM Protein Loss in Primary Gastric Cancer with Microsatellite Instability

    PubMed Central

    Kim, Hee Sung; Choi, Seung Im; Min, Hae Lim; Kim, Min A.; Kim, Woo Ho

    2013-01-01

    Ataxia-telangiectasia mutated (ATM) is a Ser/Thr protein kinase that plays a critical role in DNA damage-induced signaling and initiation of cell cycle checkpoint signaling in response to DNA-damaging agents such as ionizing radiation. We have previously reported the ATM protein loss by immunohistochemistry (IHC) in 16% of human gastric cancer (GC) tissue. We hypothesized that ATM gene intron mutations targeted by microsatellite instability (MSI) cause ATM protein loss in a subset of GC. We studied mononucleotide mutations at the intron of ATM gene, ATM IHC and MSI in GC. Ten human gastric cancer cell lines were studied for the ATM gene mutation at introns, RT-PCR, direct sequencing, and immunohistochemistry. GC tissues of 839 patients were analyzed for MSI and ATM IHC. Among them, 604 cases were analyzed for the ATM mutations at introns preceding exon 6, exon 10 and exon 20. Two human GC cell lines (SNU-1 and -638) showed ATM intron mutations, deletion in RT-PCR and direct sequencing, and ATM protein loss by IHC. The frequencies of ATM mutation, MSI, and ATM protein loss were 12.9% (78/604), 9.2% (81/882) and 15.2% (134/839), respectively. Analysis of associations among MSI, ATM gene mutation, and ATM protein loss revealed highly co-existing ATM gene alterations and MSI. ATM intron mutation and ATM protein loss were detected in 69.3% (52/75) and 53.3% (40/75) of MSI positive GC. MSI positivity and ATM protein loss were present in 68.4% (52/76) and 48.7% (37/76) of GC with ATM intron mutation. ATM mutation and ATM protein loss had characteristics of old age, distal location of tumor, large tumor size, and histologic intestinal type. Our study might be interpreted as that ATM gene mutation at intron might be targeted by MSI and lead to ATM protein loss in a selected group of GC. PMID:24324828

  6. Extracellular Matrix-dependent Pathways in Colorectal Cancer Cell Lines Reveal Potential Targets for Anticancer Therapies.

    PubMed

    Stankevicius, Vaidotas; Vasauskas, Gintautas; Noreikiene, Rimante; Kuodyte, Karolina; Valius, Mindaugas; Suziedelis, Kestutis

    2016-09-01

    Cancer cells grown in a 3D culture are more resistant to anticancer therapy treatment compared to those in a monolayer 2D culture. Emerging evidence has suggested that the key reasons for increased cell survival could be gene expression changes in cell-extracellular matrix (ECM) interaction-dependent manner. Global gene-expression changes were obtained in human colorectal carcinoma HT29 and DLD1 cell lines between 2D and laminin-rich (lr) ECM 3D growth conditions by gene-expression microarray analysis. The most significantly altered functional categories were revealed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The microarray data revealed that 841 and 1190 genes were differentially expressed in colorectal carcinoma DLD1 and HT29 cells. KEGG analysis indicated that the most significantly altered categories were cell adhesion, mitogen-activated protein kinase and immune response. Our results indicate altered pathways related to cancer development and progression and suggest potential ECM-regulated targets for the development of anticancer therapies. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  7. [Malnutrition and weight loss - nurse assessment of nutritional status and counselling: experiences of patients with newly diagnosed or relapsed cancer].

    PubMed

    Kröner, A; Stoll, H; Spichiger, E

    2012-04-01

    Due to the anorexia-cachexia syndrome, cancer patients are already suffering from nutritional problems and weight loss by the time they receive their diagnosis and start chemotherapy. In the oncology outpatient clinic of a Swiss university hospital, patients currently undergo a nutritional assessment and receive individual counselling at the beginning of cancer treatment. This qualitative study explored cancer patients' experiences with weight loss and nutritional problems as well as how they experienced the assessment and the consecutive counselling by nurses. Interviews were conducted with 12 patients and qualitative content analysis was used for data analysis. Results showed that patients barely registered the weight loss and did not interpret it as an early warning signal. Nevertheless, they attempted to improve their nutritional habits soon after diagnosis, prior to receiving any counselling. The patients did not experience the assessment as troublesome. They appreciated the nurses' advice and implemented the suggestions they found appropriate. This study highlights the importance of patient education regarding weight loss and nutritional problems early in the course of an illness. Patients may not be aware of nutritional problems at this early stage and may lack the necessary specialised knowledge. Assessment and counselling provided by nurses offer targeted measures for prevention of malnutrition and weight loss.

  8. The impacts of vicarious illness experience on response to gain- versus loss-framed breast cancer screening (BCS) messages.

    PubMed

    Kim, Hyo Jung

    2014-01-01

    Although vicarious experience with certain illnesses has been found to be influential on people's illness perceptions and related behaviors, the concept of vicarious experience has been understudied in health communication research. This study aims to ground possible effects of vicarious illness experience (VIE) into theory, specifically concerning the developments in gain versus loss framing literature. An experiment using 154 African American participants (mean age = 46 years) found that participants who had close women affected by breast cancer and those who had no close women affected by breast cancer responded to gain- versus loss-framed breast cancer screening (BCS) messages differently. Compared to the loss frame, the gain frame was more effective for participants with VIE in increasing their favorable attitudes toward BCS, BCS recommendation intentions, and memory of the BCS message. In contrast, when compared to the gain frame, the loss frame was more effective for those without VIE in increasing their cognitive elaboration of the BCS message. The findings suggest the strategic potential of VIE in developing health interventions, and they also provide practical implications for health communication practitioners into how to strategically use gain versus loss framing in accordance with their target publics.

  9. Integrative Analysis of Metabolomic, Proteomic and Genomic Data to Reveal Functional Pathways and Candidate Genes for Drip Loss in Pigs

    PubMed Central

    Welzenbach, Julia; Neuhoff, Christiane; Heidt, Hanna; Cinar, Mehmet Ulas; Looft, Christian; Schellander, Karl; Tholen, Ernst; Große-Brinkhaus, Christine

    2016-01-01

    The aim of this study was to integrate multi omics data to characterize underlying functional pathways and candidate genes for drip loss in pigs. The consideration of different omics levels allows elucidating the black box of phenotype expression. Metabolite and protein profiling was applied in Musculus longissimus dorsi samples of 97 Duroc × Pietrain pigs. In total, 126 and 35 annotated metabolites and proteins were quantified, respectively. In addition, all animals were genotyped with the porcine 60 k Illumina beadchip. An enrichment analysis resulted in 10 pathways, amongst others, sphingolipid metabolism and glycolysis/gluconeogenesis, with significant influence on drip loss. Drip loss and 22 metabolic components were analyzed as intermediate phenotypes within a genome-wide association study (GWAS). We detected significantly associated genetic markers and candidate genes for drip loss and for most of the metabolic components. On chromosome 18, a region with promising candidate genes was identified based on SNPs associated with drip loss, the protein “phosphoglycerate mutase 2” and the metabolite glycine. We hypothesize that association studies based on intermediate phenotypes are able to provide comprehensive insights in the genetic variation of genes directly involved in the metabolism of performance traits. In this way, the analyses contribute to identify reliable candidate genes. PMID:27589727

  10. Dramatic loss of glacier accumulation area on the Tibetan Plateau revealed by ice core tritium and mercury records

    NASA Astrophysics Data System (ADS)

    Kang, S.; Wang, F.; Morgenstern, U.; Zhang, Y.; Grigholm, B.; Kaspari, S.; Schwikowski, M.; Ren, J.; Yao, T.; Qin, D.; Mayewski, P. A.

    2015-06-01

    Two ice cores were retrieved from high elevations (~5800 m a.s.l.) at Mt. Nyainqêntanglha and Mt. Geladaindong in the southern and central Tibetan Plateau region. The combined tracer analysis of tritium (3H), 210Pb and mercury, along with other chemical records, provided multiple lines of evidence supporting that the two coring sites had not received net ice accumulation since at least the 1950s and 1980s, respectively. These results implied an annual ice loss rate of more than several hundred millimeter water equivalent over the past 30-60 years. Both mass balance modeling at the sites and in situ data from the nearby glaciers confirmed a continuously negative mass balance (or mass loss) in the region due to dramatic warming in recent decades. Along with a recent report on Naimona'nyi Glacier in the Himalayas, the findings suggest that the loss of accumulation area of glacier is a possibility from the southern to central Tibetan Plateau at high elevations, probably up to about 5800 m a.s.l. This mass loss raises concerns over the rapid rate of glacier ice loss and associated changes in surface glacier runoff, water availability, and sea levels.

  11. BRCA1 loss pre-existing in small subpopulations of prostate cancer is associated with advanced disease and metastatic spread to lymph nodes and peripheral blood

    PubMed Central

    Bednarz, Natalia; Eltze, Elke; Semjonow, Axel; Rink, Michael; Andreas, Antje; Mulder, Lennart; Hannemann, Juliane; Fisch, Margit; Pantel, Klaus; Weier, Heinz-Ulrich G.; Bielawski, Krzysztof P.; Brandt, Burkhard

    2011-01-01

    Purpose A preliminary study performed on a small cohort of multifocal prostate cancer (PCa) detected BRCA1 allelic imbalances (AI) among circulating tumor cells (CTCs). The present analysis was aimed to elucidate the biological and clinical role of BRCA1 losses on metastatic spread and tumor progression in prostate cancer patients. Experimental Design To map molecular progression in PCa outgrowth we used FISH analysis of tissue microarrays (TMA), lymph node sections and CTC from peripheral blood. Results We found that 14% of 133 tested patients carried monoallelic BRCA1 loss in at least one tumor focus. Extended molecular analysis of chr17q revealed that this aberration was often a part of larger cytogenetic rearrangement involving chr17q21 accompanied by AI of the tumor suppressor gene PTEN and lack of the BRCA1 promoter methylation. The BRCA1 losses correlated with advanced T stage (p < 0.05), invasion to pelvic lymph nodes (LN, p < 0.05) as well as BR (p < 0.01). Their prevalence was twice as high within 62 LN metastases (LNMs) as in primary tumors (27%, p < 0.01). The analysis of 11 matched primary PCa – LNM pairs confirmed the suspected transmission of genetic abnormalities between those two sites. In 4 of 7 patients with metastatic disease, BRCA1 losses appeared in a minute fraction of cytokeratin- and vimentin-positive CTCs. Conclusions Small subpopulations of PCa cells bearing BRCA1 losses might be one confounding factor initiating tumor dissemination and might provide an early indicator of shortened disease-free survival. PMID:20592016

  12. Breast cancer revealed by a paraneoplastic cerebellar syndrome: about one case and literature review.

    PubMed

    Adama, Dembélé; Moussa, Bambara; Emmanuel, Macoumi; Dennis, Ullmann

    2015-01-01

    To describe a case of breast cancer manifested by cerebellar syndrome and to establish a relationship between breast cancer and Paraneoplastic syndromes through the presence of anti- yo antibodies in serum and cerebrospinal fluid of a patient. Our patient was 52 years old, Multipara with 5 children alive. She had been 3 years post-menopausal under Hormonal Replacement Therapy. Weight: 46.7 Kg; Height: 1.60 m; Body Surface Area: 1.59 m(2). Nil history of alcohol or tobacco smoking. Nil history suggestive of malignancies or autoimmune diseases. Her Blood group was oRh positive, nil presence of irregular agglutinins. She was admitted to the neurology service for vertigo and it was determined an isolated cerebellar syndrome. All tests were negative including tumor markers and radiological imaging. The clinical gynecological examination was perfectly normal. The diagnosis hypothesis was "meningo-encephalocerebellitis of viral origin" but with persistence and aggravation of the cerebellar syndrome, despite treatment. We decided to search, antibodies, anti-Hu, anti-Yo, anti-Ri, and anti Ta. Anti Yo was positive + + + in the cerebrospinal fluid and serum of the patient. The search for a gynecological cancer included a mammography which revealed micro calcifications in the left breast + + +. A lumpectomy of the left breast accompanied with x-ray identification of the micro calcifications was done and the histology showed a High Grade Intraductal carcinoma of the left breast with two homes of 3mm and 1 mm, corresponding to an infiltrating carcinoma of the left breast, grade II tumor of Scarff and Bloom (SBRII, 21 N + / 26, RH +, low Ki 67) and Estrogen and progesterone receptor positive +: multifocal cancer. Following the lumpectomy, mastectomy with ganglion clearing was done with adjuvant chemotherapy (FEC 6 Cycles): histology still showed Infiltrating Intraductal Carcinoma of the left breast, grade II tumor of Scarff and Bloom. Radiotherapy was followed and he patient was

  13. Hysterectomy-corrected cervical cancer mortality rates reveal a larger racial disparity in the United States.

    PubMed

    Beavis, Anna L; Gravitt, Patti E; Rositch, Anne F

    2017-05-15

    The objectives of this study were to determine the age-standardized and age-specific annual US cervical cancer mortality rates after correction for the prevalence of hysterectomy and to evaluate disparities by age and race. Estimates for deaths due to cervical cancer stratified by age, state, year, and race were derived from the National Center for Health Statistics county mortality data (2000-2012). Equivalently stratified data on the prevalence of hysterectomy for women 20 years old or older from the Behavioral Risk Factor Surveillance System survey were used to remove women who were not at risk from the denominator. Age-specific and age-standardized mortality rates were computed, and trends in mortality rates were analyzed with Joinpoint regression. Age-standardized rates were higher for both races after correction. For black women, the corrected mortality rate was 10.1 per 100,000 (95% confidence interval [CI], 9.6-10.6), whereas the uncorrected rate was 5.7 per 100,000 (95% CI, 5.5-6.0). The corrected rate for white women was 4.7 per 100,000 (95% CI, 4.6-4.8), whereas the uncorrected rate was 3.2 per 100,000 (95% CI, 3.1-3.2). Without the correction, the disparity in mortality between races was underestimated by 44%. Black women who were 85 years old or older had the highest corrected rate: 37.2 deaths per 100,000. A trend analysis of corrected rates demonstrated that white women's rates decreased at 0.8% per year, whereas the annual decrease for black women was 3.6% (P < .05). A correction for hysterectomy has revealed that cervical cancer mortality rates are underestimated, particularly in black women. The highest rates are seen in the oldest black women, and public health efforts should focus on appropriate screening and adequate treatment in this population. Cancer 2017;123:1044-50. © 2016 American Cancer Society. © 2017 American Cancer Society.

  14. Identification of colonic fibroblast secretomes reveals secretory factors regulating colon cancer cell proliferation.

    PubMed

    Chen, Sun-Xia; Xu, Xiao-En; Wang, Xiao-Qing; Cui, Shu-Jian; Xu, Lei-Lei; Jiang, Ying-Hua; Zhang, Yang; Yan, Hai-Bo; Zhang, Qian; Qiao, Jie; Yang, Peng-Yuan; Liu, Feng

    2014-10-14

    Stromal microenvironment influences tumor cell proliferation and migration. Fibroblasts represent the most abundant stromal constituents. Here, we established two pairs of normal fibroblast (NF) and cancer-associated fibroblast (CAF) cultures from colorectal adenocarcinoma tissues and the normal counterparts. The NFs and CAFs were stained positive for typical fibroblast markers and inhibited colon cancer (CC) cell proliferation in in vitro cocultures and in xenograft mouse models. The fibroblast conditioned media were analyzed using LC-MS and 227 proteins were identified at a false discovery rate of 1.3%, including 131 putative secretory and 20 plasma membrane proteins. These proteins were enriched for functional categories of extracellular matrix, adhesion, cell motion, inflammatory response, redox homeostasis and peptidase inhibitor. Secreted protein acidic and rich in cysteine, transgelin, follistatin-related protein 1 (FSTL1) and decorin was abundant in the fibroblast secretome as confirmed by Western blot. Silencing of FSTL1 and transgelin in colonic fibroblast cell line CCD-18Co induced an accelerated proliferation of CC cells in cocultures. Exogenous FSTL1 attenuates CC cell proliferation in a negative fashion. FSTL1 was upregulated in CC patient plasma and cancerous tissues but had no implication in prognosis. Our results provided novel insights into the molecular signatures and modulatory role of CC associated fibroblasts. In this study, a label-free LC-MS was performed to analyze the secretomes of two paired primary fibroblasts, which were isolated from fresh surgical specimen of colorectal adenocarcinoma and adjacent normal colonic tissues and exhibited negative modulatory activity for colon cancer cell growth in in vitro cocultures and in vivo xenograph mouse models. Follistatin-related protein 1 was further revealed to be one of the stroma-derived factors of potential suppression role for colon cancer cell proliferation. Our results provide novel

  15. Loss of RasGAP Tumor Suppressors Underlies the Aggressive Nature of Luminal B Breast Cancers.

    PubMed

    Olsen, Sarah Naomi; Wronski, Ania; Castaño, Zafira; Dake, Benjamin; Malone, Clare; De Raedt, Thomas; Enos, Miriam; DeRose, Yoko S; Zhou, Wenhui; Guerra, Stephanie; Loda, Massimo; Welm, Alana; Partridge, Ann H; McAllister, Sandra S; Kuperwasser, Charlotte; Cichowski, Karen

    2017-02-01

    Luminal breast cancers are typically estrogen receptor-positive and generally have the best prognosis. However, a subset of luminal tumors, namely luminal B cancers, frequently metastasize and recur. Unfortunately, the causal events that drive their progression are unknown, and therefore it is difficult to identify individuals who are likely to relapse and should receive escalated treatment. Here, we identify a bifunctional RasGAP tumor suppressor whose expression is lost in almost 50% of luminal B tumors. Moreover, we show that two RasGAP genes are concomitantly suppressed in the most aggressive luminal malignancies. Importantly, these genes cooperatively regulate two major oncogenic pathways, RAS and NF-κB, through distinct domains, and when inactivated drive the metastasis of luminal tumors in vivo Finally, although the cooperative effects on RAS drive invasion, NF-κB activation triggers epithelial-to-mesenchymal transition and is required for metastasis. Collectively, these studies reveal important mechanistic insight into the pathogenesis of luminal B tumors and provide functionally relevant prognostic biomarkers that may guide treatment decisions.

  16. Interplay between promoter methylation and chromosomal loss in gene silencing at 3p11-p14 in cervical cancer.

    PubMed

    Lando, Malin; Fjeldbo, Christina S; Wilting, Saskia M; C Snoek, Barbara; Aarnes, Eva-Katrine; Forsberg, Malin F; Kristensen, Gunnar B; Steenbergen, Renske Dm; Lyng, Heidi

    2015-01-01

    Loss of 3p11-p14 is a frequent event in epithelial cancer and a candidate prognostic biomarker in cervical cancer. In addition to loss, promoter methylation can participate in gene silencing and promote tumor aggressiveness. We have performed a complete mapping of promoter methylation at 3p11-p14 in two independent cohorts of cervical cancer patients (n = 149, n = 121), using Illumina 450K methylation arrays. The aim was to investigate whether hyperm-ethylation was frequent and could contribute to gene silencing and disease aggressiveness either alone or combined with loss. By comparing the methylation level of individual CpG sites with corresponding data of normal cervical tissue, 26 out of 41 genes were found to be hypermethylated in both cohorts. The frequency of patients with hypermethylation of these genes was found to be higher at tumor stages of 3 and 4 than in stage 1 tumors. Seventeen of the 26 genes were transcriptionally downregulated in cancer compared to normal tissue, whereof 6 genes showed a significant correlation between methylation and expression. Integrated analysis of methylation, gene dosage, and expression of the 26 hypermethylated genes identified 3 regulation patterns encompassing 8 hypermethylated genes; a methylation driven pattern (C3orf14, GPR27, ZNF717), a gene dosage driven pattern (THOC7, PSMD6), and a combined methylation and gene dosage driven pattern (FHIT, ADAMTS9, LRIG1). In survival analysis, patients with both hypermethylation and loss of LRIG1 had a worse outcome compared to those harboring only hypermethylation or none of the events. C3orf14 emerged as a novel methylation regulated suppressor gene, for which knockdown was found to promote invasive growth in human papilloma virus (HPV)-transformed keratinocytes. In conclusion, hypermethylation at 3p11-p14 is common in cervical cancer and may exert a selection pressure during carcinogenesis alone or combined with loss. Information on both events could lead to improved

  17. Scenarios for future biodiversity loss due to multiple drivers reveal conflict between mitigating climate change and preserving biodiversity

    NASA Astrophysics Data System (ADS)

    Powell, Thomas W. R.; Lenton, Timothy M.

    2013-06-01

    We assess the potential for future biodiversity loss due to three interacting factors: energy withdrawal from ecosystems due to biomass harvest, habitat loss due to land-use change, and climate change. We develop four scenarios to 2050 with different combinations of high or low agricultural efficiency and high or low meat diets, and use species-energy and species-area relationships to estimate their effects on biodiversity. In our scenarios, natural ecosystems are protected except when additional land is necessary to fulfil the increasing dietary demands of the global population. Biomass energy with carbon capture and storage (BECCS) is used as a means of carbon dioxide removal (CDR) from the atmosphere (and offsetting fossil fuel emissions). BECCS is based on waste biomass, with the addition of bio-energy crops only when already managed land is no longer needed for food production. Forecast biodiversity loss from natural biomes increases by more than a factor of five in going from high to low agricultural efficiency scenarios, due to destruction of productive habitats by the expansion of pasture. Biodiversity loss from energy withdrawal on managed land varies by a factor of two across the scenarios. Biodiversity loss due to climate change varies only modestly across the scenarios. Climate change is lowest in the ‘low meat high efficiency’ scenario, in which by 2050 around 660 million hectares of pasture are converted to biomass plantation that is used for BECCS. However, the resulting withdrawal of energy from managed ecosystems has a large negative impact on biodiversity. Although the effects of energy withdrawal and climate change on biodiversity cannot be directly compared, this suggests that using bio-energy to tackle climate change in order to limit biodiversity loss could instead have the opposite effect.

  18. Different infusion durations for preventing platinum-induced hearing loss in children with cancer.

    PubMed

    van As, Jorrit W; van den Berg, Henk; van Dalen, Elvira C

    2014-06-26

    Platinum-based therapy, including cisplatin, carboplatin or oxaliplatin, or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this ototoxicity, different platinum infusion durations have been studied. To assess the effects of different durations of platinum infusion to prevent hearing loss or tinnitus, or both, in children with cancer. Secondary objectives were to assess possible effects of these infusion durations on: a) anti-tumour efficacy of platinum-based therapy, b) adverse effects other than hearing loss or tinnitus, and c) quality of life. We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 12), MEDLINE (PubMed) (1945 to 4 December 2013) and EMBASE (Ovid) (1980 to 4 December 2013). In addition, we handsearched reference lists of relevant articles and the conference proceedings of the International Society for Paediatric Oncology (2009 to 2013). We scanned ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (http://www.who.int/ictrp/en/) for ongoing trials (both searched on 13 December 2013). Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing different platinum infusion durations in children with cancer. Only the platinum infusion duration could differ between the treatment groups. Two review authors independently performed the study selection, risk of bias assessment and GRADE assessment of included studies, and data extraction including adverse effects. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We identified one RCT and no CCTs. The RCT (total number of children = 91) evaluated the use of a continuous cisplatin infusion (N = 43) versus a one hour bolus