Showing papers by "Fred Hutchinson Cancer Research Center published in 2008"
TL;DR: It is shown here that miRNAs are present in human plasma in a remarkably stable form that is protected from endogenous RNase activity and established the measurement of tumor-derived mi RNAs in serum or plasma as an important approach for the blood-based detection of human cancer.
Abstract: Improved approaches for the detection of common epithelial malignancies are urgently needed to reduce the worldwide morbidity and mortality caused by cancer. MicroRNAs (miRNAs) are small (≈22 nt) regulatory RNAs that are frequently dysregulated in cancer and have shown promise as tissue-based markers for cancer classification and prognostication. We show here that miRNAs are present in human plasma in a remarkably stable form that is protected from endogenous RNase activity. miRNAs originating from human prostate cancer xenografts enter the circulation, are readily measured in plasma, and can robustly distinguish xenografted mice from controls. This concept extends to cancer in humans, where serum levels of miR-141 (a miRNA expressed in prostate cancer) can distinguish patients with prostate cancer from healthy controls. Our results establish the measurement of tumor-derived miRNAs in serum or plasma as an important approach for the blood-based detection of human cancer.
7,296 citations
TL;DR: A cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment is suggested.
Abstract: Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays to provide a quantitative assessment of factors secreted by senescent cells. We show that human cells induced to senesce by genotoxic stress secrete myriad factors associated with inflammation and malignancy. This senescence-associated secretory phenotype (SASP) developed slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. Remarkably similar SASPs developed in normal fibroblasts, normal epithelial cells, and epithelial tumor cells after genotoxic stress in culture, and in epithelial tumor cells in vivo after treatment of prostate cancer patients with DNA-damaging chemotherapy. In cultured premalignant epithelial cells, SASPs induced an epithelial-mesenchyme transition and invasiveness, hallmarks of malignancy, by a paracrine mechanism that depended largely on the SASP factors interleukin (IL)-6 and IL-8. Strikingly, two manipulations markedly amplified, and accelerated development of, the SASPs: oncogenic RAS expression, which causes genotoxic stress and senescence in normal cells, and functional loss of the p53 tumor suppressor protein. Both loss of p53 and gain of oncogenic RAS also exacerbated the promalignant paracrine activities of the SASPs. Our findings define a central feature of genotoxic stress-induced senescence. Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment.
2,923 citations
Wellcome Trust Centre for Human Genetics1, University of Oxford2, University of Michigan3, Fred Hutchinson Cancer Research Center4, Duke University5, University of Ottawa6, Foundation for Research & Technology – Hellas7, Tufts University8, Boston Children's Hospital9, Harvard University10, Broad Institute11
TL;DR: This Review highlights the knowledge gained, defines areas of emerging consensus, and describes the challenges that remain as researchers seek to obtain more complete descriptions of the susceptibility architecture of biomedical traits of interest and to translate the information gathered into improvements in clinical management.
Abstract: The past year has witnessed substantial advances in understanding the genetic basis of many common phenotypes of biomedical importance. These advances have been the result of systematic, well-powered, genome-wide surveys exploring the relationships between common sequence variation and disease predisposition. This approach has revealed over 50 disease-susceptibility loci and has provided insights into the allelic architecture of multifactorial traits. At the same time, much has been learned about the successful prosecution of association studies on such a scale. This Review highlights the knowledge gained, defines areas of emerging consensus, and describes the challenges that remain as researchers seek to obtain more complete descriptions of the susceptibility architecture of biomedical traits of interest and to translate the information gathered into improvements in clinical management.
2,908 citations
TL;DR: The generation of induced pluripotent stem cells from patients with a variety of genetic diseases with either Mendelian or complex inheritance are described, offering an unprecedented opportunity to recapitulate both normal and pathologic human tissue formation in vitro, thereby enabling disease investigation and drug development.
2,195 citations
TL;DR: This cell-mediated immunity vaccine did not prevent HIV-1 infection or reduce early viral level and Mechanisms for insufficient efficacy of the vaccine and the increased HIV- 1 infection rates in subgroups of vaccine recipients are being explored.
1,677 citations
TL;DR: Nonmyeloablative HLA-haploidentical BMT with posttransplantation Cy is associated with acceptable rates of fatal graft failure and severe aGVHD or cGVHD, and there was a trend toward a lower risk of extensive chronic GVHD (cGVHD) among recipients of 2 versus 1 dose of posttrans transplantation Cy.
1,420 citations
TL;DR: Maximal therapeutic efficacy in the treatment of castration-resistant prostate cancer will require novel agents capable of inhibiting intracrine steroidogenic pathways within the prostate tumor microenvironment.
Abstract: Therapy for advanced prostate cancer centers on suppressing systemic androgens and blocking activation of the androgen receptor (AR). Despite anorchid serum androgen levels, nearly all patients develop castration-resistant disease. We hypothesized that ongoing steroidogenesis within prostate tumors and the maintenance of intratumoral androgens may contribute to castration-resistant growth. Using mass spectrometry and quantitative reverse transcription-PCR, we evaluated androgen levels and transcripts encoding steroidogenic enzymes in benign prostate tissue, untreated primary prostate cancer, metastases from patients with castration-resistant prostate cancer, and xenografts derived from castration-resistant metastases. Testosterone levels within metastases from anorchid men [0.74 ng/g; 95% confidence interval (95% CI), 0.59-0.89] were significantly higher than levels within primary prostate cancers from untreated eugonadal men (0.23 ng/g; 95% CI, 0.03-0.44; P < 0.0001). Compared with primary prostate tumors, castration-resistant metastases displayed alterations in genes encoding steroidogenic enzymes, including up-regulated expression of FASN, CYP17A1, HSD3B1, HSD17B3, CYP19A1, and UGT2B17 and down-regulated expression of SRD5A2 (P < 0.001 for all). Prostate cancer xenografts derived from castration-resistant tumors maintained similar intratumoral androgen levels when passaged in castrate compared with eugonadal animals. Metastatic prostate cancers from anorchid men express transcripts encoding androgen-synthesizing enzymes and maintain intratumoral androgens at concentrations capable of activating AR target genes and maintaining tumor cell survival. We conclude that intracrine steroidogenesis may permit tumors to circumvent low levels of circulating androgens. Maximal therapeutic efficacy in the treatment of castration-resistant prostate cancer will require novel agents capable of inhibiting intracrine steroidogenic pathways within the prostate tumor microenvironment.
1,341 citations
International Agency for Research on Cancer1, Russian Academy2, Nofer Institute of Occupational Medicine3, Charles University in Prague4, Fred Hutchinson Cancer Research Center5, University of Liverpool6, Cancer Care Ontario7, Princess Margaret Cancer Centre8, Women's College, Kolkata9, Norwegian University of Science and Technology10, German Cancer Research Center11, University of Cambridge12, Umeå University13, University of Bremen14, French Institute of Health and Medical Research15, University of Turin16, University of Aberdeen17, University of Padua18, Newcastle University19, University of Glasgow20, Trinity College, Dublin21
TL;DR: The results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.
Abstract: Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.
1,226 citations
TL;DR: Using new algorithms that rely on hashing techniques to construct active sites for multistep reactions, retro-aldolases that use four different catalytic motifs to catalyze the breaking of a carbon-carbon bond in a nonnatural substrate are designed.
Abstract: The creation of enzymes capable of catalyzing any desired chemical reaction is a grand challenge for computational protein design. Using new algorithms that rely on hashing techniques to construct active sites for multistep reactions, we designed retro-aldolases that use four different catalytic motifs to catalyze the breaking of a carbon-carbon bond in a nonnatural substrate. Of the 72 designs that were experimentally characterized, 32, spanning a range of protein folds, had detectable retro-aldolase activity. Designs that used an explicit water molecule to mediate proton shuffling were significantly more successful, with rate accelerations of up to four orders of magnitude and multiple turnovers, than those involving charged side-chain networks. The atomic accuracy of the design process was confirmed by the x-ray crystal structure of active designs embedded in two protein scaffolds, both of which were nearly superimposable on the design model.
1,083 citations
TL;DR: A complex phosphorylation network modulates Cip/Kip protein functions by altering their subcellular localization, protein-protein interactions, and stability, which are essential for the maintenance of normal cell and tissue homeostasis.
1,009 citations
TL;DR: Structural and functional aspects of FBW7, the substrate recognition component of an evolutionary conserved SCF, and its role in the development of cancer are focused on.
Abstract: FBW7 (F-box and WD repeat domain-containing 7) is the substrate recognition component of an evolutionary conserved SCF (complex of SKP1, CUL1 and F-box protein)-type ubiquitin ligase. SCF(FBW7) degrades several proto-oncogenes that function in cellular growth and division pathways, including MYC, cyclin E, Notch and JUN. FBW7 is also a tumour suppressor, the regulatory network of which is perturbed in many human malignancies. Numerous cancer-associated mutations in FBW7 and its substrates have been identified, and loss of FBW7 function causes chromosomal instability and tumorigenesis. This Review focuses on structural and functional aspects of FBW7 and its role in the development of cancer.
TL;DR: The results suggest that secondary mutations that restore the wild-type BRCA2 reading frame may be a major clinical mediator of acquired resistance to platinum-based chemotherapy.
Abstract: Ovarian carcinomas with mutations in the tumour suppressor BRCA2 are particularly sensitive to platinum compounds. However, such carcinomas ultimately develop cisplatin resistance. The mechanism of that resistance is largely unknown. Here we show that acquired resistance to cisplatin can be mediated by secondary intragenic mutations in BRCA2 that restore the wild-type BRCA2 reading frame. First, in a cisplatin-resistant BRCA2-mutated breast-cancer cell line, HCC1428, a secondary genetic change in BRCA2 rescued BRCA2 function. Second, cisplatin selection of a BRCA2-mutated pancreatic cancer cell line, Capan-1 (refs 3, 4), led to five different secondary mutations that restored the wild-type BRCA2 reading frame. All clones with secondary mutations were resistant both to cisplatin and to a poly(ADP-ribose) polymerase (PARP) inhibitor (AG14361). Finally, we evaluated recurrent cancers from patients whose primary BRCA2-mutated ovarian carcinomas were treated with cisplatin. The recurrent tumour that acquired cisplatin resistance had undergone reversion of its BRCA2 mutation. Our results suggest that secondary mutations that restore the wild-type BRCA2 reading frame may be a major clinical mediator of acquired resistance to platinum-based chemotherapy.
TL;DR: It is shown that the transferred CD4+ T cells mediated a durable clinical remission and led to endogenous responses against melanoma antigens other than NY-ESO-1.
Abstract: We developed an in vitro method for isolating and expanding autologous CD4+ T-cell clones with specificity for the melanoma-associated antigen NY-ESO-1. We infused these cells into a patient with refractory metastatic melanoma who had not undergone any previous conditioning or cytokine treatment. We show that the transferred CD4+ T cells mediated a durable clinical remission and led to endogenous responses against melanoma antigens other than NY-ESO-1.
TL;DR: Systematic searches for plasma proteins that are biological indicators, or biomarkers, for cancer are underway and the expected outcome is the development of panels of biomarkers that will allow early detection of cancer and prediction of the probable response to therapy.
Abstract: Systematic searches for plasma proteins that are biological indicators, or biomarkers, for cancer are underway. The difficulties caused by the complexity of biological-fluid proteomes and tissue proteomes (which contribute proteins to plasma) and by the extensive heterogeneity among diseases, subjects and levels of sample procurement are gradually being overcome. This is being achieved through rigorous experimental design and in-depth quantitative studies. The expected outcome is the development of panels of biomarkers that will allow early detection of cancer and prediction of the probable response to therapy. Achieving these objectives requires high-quality specimens with well-matched controls, reagent resources, and an efficient process to confirm discoveries through independent validation studies.
TL;DR: It is demonstrated that clonally derived CD8+ T cells isolated from central memory T cells are distinct from those derived from effectorMemory T cells and retain an intrinsic capacity that enables them to survive after adoptive transfer and revert to the memory cell pool.
Abstract: The adoptive transfer of antigen-specific T cells that have been expanded ex vivo is being actively pursued to treat infections and malignancy in humans. The T cell populations that are available for adoptive immunotherapy include both effector memory and central memory cells, and these differ in phenotype, function, and homing. The efficacy of adoptive immunotherapy requires that transferred T cells persist in vivo, but identifying T cells that can reproducibly survive in vivo after they have been numerically expanded by in vitro culture has proven difficult. Here we show that in macaques, antigen-specific CD8+ T cell clones derived from central memory T cells, but not effector memory T cells, persisted long-term in vivo, reacquired phenotypic and functional properties of memory T cells, and occupied memory T cell niches. These results demonstrate that clonally derived CD8+ T cells isolated from central memory T cells are distinct from those derived from effector memory T cells and retain an intrinsic capacity that enables them to survive after adoptive transfer and revert to the memory cell pool. These results could have significant implications for the selection of T cells to expand or to engineer for adoptive immunotherapy of human infections or malignancy.
TL;DR: The most significant features can be summarized in an acronym: AEIOU (asymptomatic/lack of tenderness, expanding rapidly, immune suppression, older than 50 years, and ultraviolet-exposed site on a person with fair skin) and 89% of primary MCCs had 3 or more of these findings.
Abstract: Background Merkel cell carcinoma (MCC) is an aggressive skin cancer with a mortality of 33%. Advanced disease at diagnosis is a poor prognostic factor, suggesting that earlier detection may improve outcome. No systematic analysis has been published to define the clinical features that are characteristic of MCC. Objective We sought to define the clinical characteristics present at diagnosis to identify features that may aid clinicians in recognizing MCC. Methods We conducted a cohort study of 195 patients given the diagnosis of MCC between 1980 and 2007. Data were collected prospectively in the majority of cases, and medical records were reviewed. Results An important finding was that 88% of MCCs were asymptomatic (nontender) despite rapid growth in the prior 3 months (63% of lesions) and being red or pink (56%). A majority of MCC lesions (56%) were presumed at biopsy to be benign, with a cyst/acneiform lesion being the single most common diagnosis (32%) given. The median delay from lesion appearance to biopsy was 3 months (range 1-54 months), and median tumor diameter was 1.8 cm. Similar to earlier studies, 81% of primary MCCs occurred on ultraviolet-exposed sites, and our cohort was elderly (90% >50 years), predominantly white (98%), and often profoundly immune suppressed (7.8%). An additional novel finding was that chronic lymphocytic leukemia was more than 30-fold overrepresented among patients with MCC. Limitations The study was limited to patients seen at a tertiary care center. Complete clinical data could not be obtained on all patients. This study could not assess the specificity of the clinical characteristics of MCC. Conclusions To our knowledge, this study is the first to define clinical features that may serve as clues in the diagnosis of MCC. The most significant features can be summarized in an acronym: AEIOU ( a symptomatic/lack of tenderness, e xpanding rapidly, i mmune suppression, o lder than 50 years, and u ltraviolet-exposed site on a person with fair skin). In our series, 89% of primary MCCs had 3 or more of these findings. Although MCC is uncommon, when present in combination, these features may indicate a concerning process that would warrant biopsy. In particular, a lesion that is red and expanding rapidly yet asymptomatic should be of concern.
TL;DR: In this paper, the authors identify microsatellite instability and chromosome instability in colorectal cancer cells and determine the effects of the different forms of genomic instability on the biological and clinical behavior of colon tumors.
TL;DR: Consistent with previous trials, the MRKAd5 HIV-1 gag/pol/nef vaccine was highly immunogenic for inducing HIV-specific CD8+ T cells and suggest that future candidate vaccines have to elicit responses that either exceed in magnitude or differ in breadth or function from those recorded in this trial.
TL;DR: The results of a proof-of-concept clinical trial in which patients with relapsed or refractory indolent B-cell lymphoma or mantle cell lymphoma were treated with autologous T cells genetically modified by electroporation with a vector plasmid encoding a CD20-specific chimeric T- cell receptor and neomycin resistance gene show the safety, feasibility, and potential antitumor activity of adoptive T-cell therapy using this approach.
TL;DR: Evidence is provided that NKG2D was not necessary for NK cell development but was critical for immunosurveillance of epithelial and lymphoid malignancies in two transgenic models of de novo tumorigenesis, providing important genetic evidence for surveillance of primary tumors by an NK receptor.
TL;DR: The simulations suggest that at the expected transmissibility of a pandemic strain, timely implementation of a combination of targeted household antiviral prophylaxis, and social distancing measures could substantially lower the illness attack rate before a highly efficacious vaccine could become available.
Abstract: Planning a response to an outbreak of a pandemic strain of influenza is a high public health priority. Three research groups using different individual-based, stochastic simulation models have examined the consequences of intervention strategies chosen in consultation with U.S. public health workers. The first goal is to simulate the effectiveness of a set of potentially feasible intervention strategies. Combinations called targeted layered containment (TLC) of influenza antiviral treatment and prophylaxis and nonpharmaceutical interventions of quarantine, isolation, school closure, community social distancing, and workplace social distancing are considered. The second goal is to examine the robustness of the results to model assumptions. The comparisons focus on a pandemic outbreak in a population similar to that of Chicago, with ≈8.6 million people. The simulations suggest that at the expected transmissibility of a pandemic strain, timely implementation of a combination of targeted household antiviral prophylaxis, and social distancing measures could substantially lower the illness attack rate before a highly efficacious vaccine could become available. Timely initiation of measures and school closure play important roles. Because of the current lack of data on which to base such models, further field research is recommended to learn more about the sources of transmission and the effectiveness of social distancing measures in reducing influenza transmission.
Duke University1, Fred Hutchinson Cancer Research Center2, Los Alamos National Laboratory3, University of North Carolina at Chapel Hill4, University of California, Irvine5, University of Alabama at Birmingham6, Centre for the AIDS Programme of Research in South Africa7, University of Maryland, Baltimore8
TL;DR: It is demonstrated that the first IgM and IgG antibodies induced by transmitted HIV-1 are capable of binding virions but have little impact on acute-phase viremia at the timing and magnitude that they occur in natural infection.
Abstract: A window of opportunity for immune responses to extinguish human immunodeficiency virus type 1 (HIV-1) exists from the moment of transmission through establishment of the latent pool of HIV-1-infected cells. A critical time to study the initial immune responses to the transmitted/founder virus is the eclipse phase of HIV-1 infection (time from transmission to the first appearance of plasma virus), but, to date, this period has been logistically difficult to analyze. To probe B-cell responses immediately following HIV-1 transmission, we have determined envelope-specific antibody responses to autologous and consensus Envs in plasma donors from the United States for whom frequent plasma samples were available at time points immediately before, during, and after HIV-1 plasma viral load (VL) ramp-up in acute infection, and we have modeled the antibody effect on the kinetics of plasma viremia. The first detectable B-cell response was in the form of immune complexes 8 days after plasma virus detection, whereas the first free plasma anti-HIV-1 antibody was to gp41 and appeared 13 days after the appearance of plasma virus. In contrast, envelope gp120-specific antibodies were delayed an additional 14 days. Mathematical modeling of the earliest viral dynamics was performed to determine the impact of antibody on HIV replication in vivo as assessed by plasma VL. Including the initial anti-gp41 immunoglobulin G (IgG), IgM, or both responses in the model did not significantly impact the early dynamics of plasma VL. These results demonstrate that the first IgM and IgG antibodies induced by transmitted HIV-1 are capable of binding virions but have little impact on acute-phase viremia at the timing and magnitude that they occur in natural infection.
TL;DR: A nested case–control study design that involves prospective collection of specimens before outcome ascertainment from a study cohort that is relevant to the clinical application and common biases that pervade the biomarker research literature would be eliminated if rigorous standards were followed.
Abstract: With the emergence of new molecular biotechnologies, the intensity of biomarker research has increased greatly, yet the scientific rigor of biomarker research lags far behind that of therapeutic research ( 1 – 3 ). In therapeutic research, the randomized placebocontrolled, blinded clinical trial takes the central role in pivotal evaluation of a new therapy. Standards for the conduct of such studies have been agreed upon internationally ( 4 ) ( www.ich.org ), and books and journals have been devoted to nuances of their design and analysis. Analogously, in this commentary, we consider key aspects of design for pivotal evaluation of a biomarker ’ s capacity to correctly classify a subject’s outcome (ie, classification accuracy), in which a subject’s outcome may be his or her current disease status or a future event for him or her. We propose a prospective-specimencollection, retrospective-blinded-evaluation (PRoBE) design in which biologic specimens are collected prospectively from a cohort that represents the target population that is envisioned for clinical application of the biomarker. Specimens and clinical data are collected in the absence of knowledge about patient outcome. After outcome status is ascertained, case patients with the outcome and control subjects without it are selected randomly from the cohort and their specimens are assayed for the biomarker in a fashion that is blinded to case – control status. Although every biomarker study has its own special considerations, as does every randomized clinical trial, we propose that elucidation of the key design issues in this commentary will help move the field toward standards of practice. Biomarkers are developed for many different purposes, including for classifi cation and prediction, as surrogate outcomes in clinical trials, as measures of toxic or preventive exposures, or as a guide to individual treatment choice ( 5 ). In this commentary, we consider only the fi rst category, which includes diagnostic, screening, and prognostic markers. A diagnostic marker is used in people with signs or symptoms to aid in assessing whether they have a condition. A screening marker is used in asymptomatic people to detect a disease or condition at an early stage. A prognostic marker is used in subjects diagnosed with a condition to predict subsequent outcomes, such as disease recurrence or progression. The PRoBE design is intended for all of these applications. Development of a biomarker is a process that begins with biomarker discovery, is followed by rigorous evaluation of classifi cation accuracy, and then terminates with the evaluation of the impact of the biomarker on clinical outcomes ( 6 , 7 ). Multiple studies may be involved in each stage. For example, in the discovery stage, a sequence of studies may be performed to identify biomarkers from among a large pool of candidates, to validate these individual markers in independent samples, and to optimally combine markers from a panel. We focus on the intermediate stage, after all discovery work is completed. We assume that a well-defi ned biomarker, or marker combination, is to be defi nitively evaluated for its classifi cation accuracy in a specifi c clinical application. If it can be shown that the marker has acceptable classifi cation accuracy, the marker should move to the fi nal stage of evaluation, in which the net benefi t to patients is assessed by incorporating effects of clinical interventions recommended for patients on the basis of their biomarker results. Clearly, before biomarker results are used in making medical decisions for individuals, it is crucial to know how accurately the marker classifi es or predicts their outcomes.
TL;DR: At 20 years of follow-up (25 years after first cancer diagnosis), the death rate due to a subsequent malignancy exceeded that due to all other causes and indicates that excess mortality persists long after diagnosis.
Abstract: Background
The proportion of pediatric and adolescent cancer patients surviving 5 years has increased during the past four decades. This growing population of survivors remains at risk for disease- and treatment-associated late mortality.
TL;DR: Randomized clinical trials have shown that physical activity interventions can change biomarkers of cancer risk, and Observational studies can also provide useful information on mechanisms that might link physical activity to cancer.
Abstract: About 25% of cancer cases globally are due to excess weight and a sedentary lifestyle. Physical activity may decrease risk for various cancers by several mechanisms, including decreasing sex hormones, metabolic hormones and inflammation, and improving immune function. The level of physical activity might also be associated with prognosis among individuals with cancer. Randomized clinical trials have shown that physical activity interventions can change biomarkers of cancer risk. Observational studies can also provide useful information on mechanisms that might link physical activity to cancer.
TL;DR: Recent advances in understanding the interactions of the HIV-1 Nef, Vif, Vpu, and Vpr proteins with factors and pathways expressed in cells of the immune system are discussed.
TL;DR: This work shows that in the plant Arabidopsis thaliana regions of DNA methylation are quantitatively deficient in H2A.Z, and indicates that DNA methylisation can influence chromatin structure and effect gene silencing by excluding H2 A.Z.
Abstract: Although DNA methylation has been actively studied for several decades, the mechanism by which it causes gene silencing remains largely unknown. In contrast to DNA methylation, the histone variant H2A.Z promotes transcriptional competence in plants, animals and fungi. This paper reports the finding that regions of DNA methylation in the Arabidopsis thaliana genome are deficient in H2A.Z. DNA methylation appears to repress transcription by exclusion of H2A.Z. This suggets a novel relationship between a covalent modification of DNA and a core nucleosome component with an important role in organizing eukaryotic chromatin. Eukaryotic chromatin is separated into functional domains differentiated by post-translational histone modifications, histone variants and DNA methylation1,2,3,4,5,6. Methylation is associated with repression of transcriptional initiation in plants and animals, and is frequently found in transposable elements. Proper methylation patterns are crucial for eukaryotic development4,5, and aberrant methylation-induced silencing of tumour suppressor genes is a common feature of human cancer7. In contrast to methylation, the histone variant H2A.Z is preferentially deposited by the Swr1 ATPase complex near 5′ ends of genes where it promotes transcriptional competence8,9,10,11,12,13,14,15,16,17,18,19,20. How DNA methylation and H2A.Z influence transcription remains largely unknown. Here we show that in the plant Arabidopsis thaliana regions of DNA methylation are quantitatively deficient in H2A.Z. Exclusion of H2A.Z is seen at sites of DNA methylation in the bodies of actively transcribed genes and in methylated transposons. Mutation of the MET1 DNA methyltransferase, which causes both losses and gains of DNA methylation4,5, engenders opposite changes (gains and losses) in H2A.Z deposition, whereas mutation of the PIE1 subunit of the Swr1 complex that deposits H2A.Z17 leads to genome-wide hypermethylation. Our findings indicate that DNA methylation can influence chromatin structure and effect gene silencing by excluding H2A.Z, and that H2A.Z protects genes from DNA methylation.
International Agency for Research on Cancer1, University of Toronto2, National Institutes of Health3, Charles University in Prague4, Palacký University, Olomouc5, Cancer Care Ontario6, Ontario Institute for Cancer Research7, McGill University8, Women's College, Kolkata9, Norwegian University of Science and Technology10, University of Tromsø11, Uppsala University12, Fred Hutchinson Cancer Research Center13, Pomeranian Medical University14, University of Liverpool15, French Alternative Energies and Atomic Energy Commission16, Council on Education for Public Health17
TL;DR: The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology, and two uncorrelated disease markers at 5p15.33 are detected.
Abstract: We carried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899 cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33, rs402710 and rs2736100 were detected by the genome-wide data (P - 2 x 10(-7) and P = 4 x 10(-6)) and replicated by the independent study series (P = 7 x 10(-5) and P = 0.016). The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology.
TL;DR: Major depression is a frequent but underrecognized and undertreated condition among breast cancer patients, which causes amplification of physical symptoms, increased functional impairment and poor treatment adherence.
TL;DR: The physical and psychological long‐term and late effects among adult survivors of pediatric and adult cancers are described and the emergence of public health initiatives and large‐scale research activities that address the issues of long-term cancer survivorship are discussed.
Abstract: The number of long-term cancer survivors (> or =5 years after diagnosis) in the U.S. continues to rise, with more than 10 million Americans now living with a history of cancer. Along with such growth has come increasing attention to the continued health problems and needs of this population. Many cancer survivors return to normal functioning after the completion of treatment and are able to live relatively symptom-free lives. However, cancer and its treatment can also result in a wide range of physical and psychological problems that do not recede with time. Some of these problems emerge during or after cancer treatment and persist in a chronic, long-term manner. Other problems may not appear until months or even years later. Regardless of when they present, long-term and late effects of cancer can have a negative effect on cancer survivors' quality of life. This article describes the physical and psychological long-term and late effects among adult survivors of pediatric and adult cancers. The focus is on the prevalence and correlates of long-term and late effects as well as the associated deficits in physical and emotional functioning. In addition, the emergence of public health initiatives and large-scale research activities that address the issues of long-term cancer survivorship are discussed. Although additional research is needed to fully understand and document the long-term and late effects of cancer, important lessons can be learned from existing knowledge. Increased awareness of these issues is a key component in the development of follow-up care plans that may allow for adequate surveillance, prevention, and the management of long-term and late effects of cancer.