Showing papers by "Fred Hutchinson Cancer Research Center published in 2013"

Software for computing and annotating genomic ranges.

Abstract: We describe Bioconductor infrastructure for representing and computing on annotated genomic ranges and integrating genomic data with the statistical computing features of R and its extensions. At the core of the infrastructure are three packages: IRanges, GenomicRanges, and GenomicFeatures. These packages provide scalable data structures for representing annotated ranges on the genome, with special support for transcript structures, read alignments and coverage vectors. Computational facilities include efficient algorithms for overlap and nearest neighbor detection, coverage calculation and other range operations. This infrastructure directly supports more than 80 other Bioconductor packages, including those for sequence analysis, differential expression analysis and visualization.

Menopausal Hormone Therapy and Health Outcomes During the Intervention and Extended Poststopping Phases of the Women’s Health Initiative Randomized Trials

Abstract: RESULTS During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPA vs 323 for placebo; HR, 1.28 [95% CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR, 0.94; 95% CI, 0.781.14) and 104 vs 135, respectively, for invasive breast cancer (HR, 0.79; 95% CI, 0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomes were similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, younger women (aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10 000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials. CONCLUSIONS AND RELEVANCE Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women.

Absolute quantification by droplet digital PCR versus analog real-time PCR

Abstract: Nanoliter-sized droplet technology paired with digital PCR (ddPCR) holds promise for highly precise, absolute nucleic acid quantification. Our comparison of microRNA quantification by ddPCR and real-time PCR revealed greater precision (coefficients of variation decreased 37-86%) and improved day-to-day reproducibility (by a factor of seven) of ddPCR but with comparable sensitivity. When we applied ddPCR to serum microRNA biomarker analysis, this translated to superior diagnostic performance for identifying individuals with cancer.

50-Year Trends in Smoking-Related Mortality in the United States

Abstract: Background The disease risks from cigarette smoking increased in the United States over most of the 20th century, first among male smokers and later among female smokers. Whether these risks have continued to increase during the past 20 years is unclear. Methods We measured temporal trends in mortality across three time periods (1959-1965, 1982-1988, and 2000-2010), comparing absolute and relative risks according to sex and self-reported smoking status in two historical cohort studies and in five pooled contemporary cohort studies, among participants who became 55 years of age or older during follow-up. Results For women who were current smokers, as compared with women who had never smoked, the relative risks of death from lung cancer were 2.73, 12.65, and 25.66 in the 1960s, 1980s, and contemporary cohorts, respectively; corresponding relative risks for male current smokers, as compared with men who had never smoked, were 12.22, 23.81, and 24.97. In the contemporary cohorts, male and female current smokers also had similar relative risks for death from chronic obstructive pulmonary disease (COPD) (25.61 for men and 22.35 for women), ischemic heart disease (2.50 for men and 2.86 for women), any type of stroke (1.92 for men and 2.10 for women), and all causes combined (2.80 for men and 2.76 for women). Mortality from COPD among male smokers continued to increase in the contemporary cohorts in nearly all the age groups represented in the study and within each stratum of duration and intensity of smoking. Among men 55 to 74 years of age and women 60 to 74 years of age, all-cause mortality was at least three times as high among current smokers as among those who had never smoked. Smoking cessation at any age dramatically reduced death rates. Conclusions The risk of death from cigarette smoking continues to increase among women and the increased risks are now nearly identical for men and women, as compared with persons who have never smoked. Among men, the risks associated with smoking have plateaued at the high levels seen in the 1980s, except for a continuing, unexplained increase in mortality from COPD.

Regulation of nucleosome dynamics by histone modifications

Abstract: The properties of nucleosomes can be altered in various ways, including by covalent modification of histones. In this Review, the known properties of key histone modifications and the biological processes to which they are linked are examined to place the modifications in the context of nucleosome dynamics—that is, processes in which nucleosomes are translocated, unwrapped, evicted or replaced.

Long-Term Functional Outcomes after Treatment for Localized Prostate Cancer

Abstract: Background The purpose of this analysis was to compare long-term urinary, bowel, and sexual function after radical prostatectomy or external-beam radiation therapy. Methods The Prostate Cancer Outcomes Study (PCOS) enrolled 3533 men in whom prostate cancer had been diagnosed in 1994 or 1995. The current cohort comprised 1655 men in whom localized prostate cancer had been diagnosed between the ages of 55 and 74 years and who had undergone either surgery (1164 men) or radiotherapy (491 men). Functional status was assessed at baseline and at 2, 5, and 15 years after diagnosis. We used multivariable propensity scoring to compare functional outcomes according to treatment. Results Patients undergoing prostatectomy were more likely to have urinary incontinence than were those undergoing radiotherapy at 2 years (odds ratio, 6.22; 95% confidence interval [CI], 1.92 to 20.29) and 5 years (odds ratio, 5.10; 95% CI, 2.29 to 11.36). However, no significant between-group difference in the odds of urinary incontinence ...

ISOQOL recommends minimum standards for patient-reported outcome measures used in patient-centered outcomes and comparative effectiveness research

Abstract: Purpose An essential aspect of patient-centered outcomes research (PCOR) and comparative effectiveness research (CER) is the integration of patient perspectives and experiences with clinical data to evaluate interventions. Thus, PCOR and CER require capturing patient-reported outcome (PRO) data appropriately to inform research, healthcare delivery, and policy. This initiative’s goal was to identify minimum standards for the design and selection of a PRO measure for use in PCOR and CER.

Type I and II Endometrial Cancers: Have They Different Risk Factors?

Abstract: Purpose Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors. Patients and Methods Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors. Results Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to...

Washington State cancer patients found to be at greater risk for bankruptcy than people without a cancer diagnosis

Abstract: Much has been written about the relationship between high medical expenses and the likelihood of filing for bankruptcy, but the relationship between receiving a cancer diagnosis and filing for bankruptcy is less well understood. We estimated the incidence and relative risk of bankruptcy for people age twenty-one or older diagnosed with cancer compared to people the same age without cancer by conducting a retrospective cohort analysis that used a variety of medical, personal, legal, and bankruptcy sources covering the Western District of Washington State in US Bankruptcy Court for the period 1995–2009. We found that cancer patients were 2.65 times more likely to go bankrupt than people without cancer. Younger cancer patients had 2–5 times higher rates of bankruptcy than cancer patients age sixty-five or older, which indicates that Medicare and Social Security may mitigate bankruptcy risk for the older group. The findings suggest that employers and governments may have a policy role to play in creating prog...

Critical assessment of automated flow cytometry data analysis techniques

Abstract: Traditional methods for flow cytometry (FCM) data processing rely on subjective manual gating. Recently, several groups have developed computational methods for identifying cell populations in multidimensional FCM data. The Flow Cytometry: Critical Assessment of Population Identification Methods (FlowCAP) challenges were established to compare the performance of these methods on two tasks: (i) mammalian cell population identification, to determine whether automated algorithms can reproduce expert manual gating and (ii) sample classification, to determine whether analysis pipelines can identify characteristics that correlate with external variables (such as clinical outcome). This analysis presents the results of the first FlowCAP challenges. Several methods performed well as compared to manual gating or external variables using statistical performance measures, which suggests that automated methods have reached a sufficient level of maturity and accuracy for reliable use in FCM data analysis.

Immune clearance of highly pathogenic SIV infection

Abstract: Established infections with the human and simian immunodeficiency viruses (HIV and SIV, respectively) are thought to be permanent with even the most effective immune responses and antiretroviral therapies only able to control, but not clear, these infections 1–4 .W hether the residual virus that maintains these infections is vulnerable to clearance is a question of central importance to the future management of millions of HIV-infected individuals. We recently reported that approximately 50% of rhesus macaques (RM; Macaca mulatta) vaccinated with SIV protein-expressing rhesus cytomegalovirus (RhCMV/ SIV) vectors manifest durable, aviraemic control of infection with the highly pathogenic strain SIVmac239 (ref. 5). Here we show that regardless of the route of challenge, RhCMV/SIV vector-elicited immune responses control SIVmac239 after demonstrable lymphatic and haematogenous viral dissemination, and that replicationcompetent SIV persists in several sites for weeks to months. Over time, however, protected RM lost signs of SIV infection, showing a consistent lack of measurable plasma- or tissue-associated virus using ultrasensitive assays, and a loss of T-cell reactivity to SIV determinants not in the vaccine. Extensive ultrasensitive quantitative PCR and quantitative PCR with reverse transcription analyses of tissues from RhCMV/SIV vector-protected RM necropsied 69–172 weeks after challenge did not detect SIV RNA or DNA sequences above background levels, and replication-competent SIV was not detected in these RM by extensive co-culture analysis of tissues or by adoptive transfer of 60 million haematolymphoid cells to naive RM. These data provide compelling evidence for progressive clearance of a pathogenic lentiviral infection, and suggest that some lentiviral reservoirs may be susceptible to the continuous effector memory T-cell-mediated immune surveillance elicited and maintained by cytomegalovirus vectors. Clinical and experimental observations have suggested that HIV and SIV infections might be vulnerable to immune control or pharmacological clearance in the first few hours to days of infection, before both the viral amplification needed for efficient mutational escape and the establishment of the highly resilient viral reservoir that sustains the infection 4,6–8 . Cytomegalovirus (CMV) vectors were designed to exploit this putative window of vulnerability, based on their ability to elicit and indefinitely maintain high frequency, effector-differentiated, and broadly targeted virus-specific T cells in potential sites of early viral replication 5,9,10 . Indeed, the pattern of protection observed in approximately 50% of RhCMV/SIV vector-vaccinated RM after intrarectal SIVmac239 challenge was consistent with early immunological interception of the nascent SIV infection at the portal of viral entry and immune control before irreversible systemic spread 5 . Protected RM manifested a very transient viraemia at the onset of infection, followed by control of plasma SIV levels to below the threshold levels of quantification, except for occasional plasma viral ‘blips’ that waned over time, and after one year, demonstrated only trace levels of tissue-associated SIV RNA and DNA at necropsy using ultrasensitive assays. The occurrence of plasma viral blips and the recurrence of ‘breakthrough’ progressive SIV infection in 1 of the 13 RhCMV/ SIV vector-protected RM at day 77 after infection indicated that SIV was not immediately cleared from these protected RM, but the failure to find more than trace levels of SIV nucleic acid in systemic lymphoid tissues was consistent with the productive infection being largely contained at the portal of entry with the possibility of eventual clearance. Given the crucial importance of understanding the degree to which a highly pathogenic lentivirus can be contained or even cleared by adaptive immunity, we sought to define more precisely the spread and dynamics of SIV infection in RM that controlled the infection as a consequence of RhCMV/ SIV vector vaccination, and in particular, the extent to which residual SIV was eventually cleared from these animals. To establish the extent of SIV spread early after the onset of RhCMV/ SIV vector-mediated control, we studied a group of five RM vaccinated with RhCMV vectors containing SIV Gag, Rev/Tat/Nef, Env and Pol (but not Vif) inserts that were taken to necropsy within 24 days of controlling plasma viraemia after intrarectal inoculation with SIVmac239. All of these RM had measureable SIV RNA in plasma for one or two weekly time points after challenge, followed by at least three consecutive weekly samples with plasma SIV RNA below 30 copy equivalents (equiv.) per

Efficacy Trial of a DNA/rAd5 HIV-1 Preventive Vaccine

Abstract: Background A safe and effective vaccine for the prevention of human immunodeficiency virus type 1 (HIV-1) infection is a global priority. We tested the efficacy of a DNA prime–recombinant adenovirus type 5 boost (DNA/rAd5) vaccine regimen in persons at increased risk for HIV-1 infection in the United States. Methods At 21 sites, we randomly assigned 2504 men or transgender women who have sex with men to receive the DNA/rAd5 vaccine (1253 participants) or placebo (1251 participants). We assessed HIV-1 acquisition from week 28 through month 24 (termed week 28+ infection), viral-load set point (mean plasma HIV-1 RNA level 10 to 20 weeks after diagnosis), and safety. The 6-plasmid DNA vaccine (expressing clade B Gag, Pol, and Nef and Env proteins from clades A, B, and C) was administered at weeks 0, 4, and 8. The rAd5 vector boost (expressing clade B Gag-Pol fusion protein and Env glycoproteins from clades A, B, and C) was administered at week 24. Results In April 2013, the data and safety monitoring board re...

Life in the human stomach: persistence strategies of the bacterial pathogen Helicobacter pylori

Abstract: The bacterial pathogen Helicobacter pylori has co-evolved with humans and colonizes approximately 50% of the human population, but only causes overt gastric disease in a subset of infected hosts. In this Review, we discuss the pathogenesis of H. pylori and the mechanisms it uses to promote persistent colonization of the gastric mucosa, with a focus on recent insights into the role of the virulence factors vacuolating cytotoxin (VacA), cytotoxin-associated gene A (CagA) and CagL. We also describe the immunobiology of H. pylori infection and highlight how this bacterium manipulates the innate and adaptive immune systems of the host to promote its own persistence.

Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array

Abstract: Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10(-8)). More than 70 prostate cancer susceptibility loci, explaining ∼30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.

Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer

Abstract: TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOG, we analyzed similar to 480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 x 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 x 10(-8)) and BRCA1 mutation carrier (P = 1.1 x 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 x 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 x 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 x 10(-12)) and BRCA1 mutation carrier (P = 1.6 x 10-14) breast and invasive ovarian (P = 1.3 x 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.

Modifiable Risk Factors and Major Cardiac Events Among Adult Survivors of Childhood Cancer

Abstract: Purpose To evaluate the relative contribution of modifiable cardiovascular risk factors on the development of major cardiac events in aging adult survivors of childhood cancer. Patients and Methods Among 10,724 5-year survivors (median age, 33.7 years) and 3,159 siblings in the Childhood Cancer Survivor Study, the prevalence of hypertension, diabetes mellitus, dyslipidemia, and obesity was determined, along with the incidence and severity of major cardiac events such as coronary artery disease, heart failure, valvular disease, and arrhythmia. On longitudinal follow-up, rate ratios (RRs) of subsequent cardiac events associated with cardiovascular risk factors and cardiotoxic therapy were assessed in multivariable Poisson regression models. Results Among survivors, the cumulative incidence of coronary artery disease, heart failure, valvular disease, and arrhythmia by 45 years of age was 5.3%, 4.8%, 1.5%, and 1.3%, respectively. Two or more cardiovascular risk factors were reported by 10.3% of survivors and ...

Using synthetic templates to design an unbiased multiplex PCR assay

Abstract: Immunosequencing enables cost-effective sequencing of repertoires of immune cells, but it often suffers from amplification biases when attempting cell quantification. Here, the authors present a powerful multiplex PCR assay that allows for quantitative and unbiased analysis of frequency of different T cell receptors.

Receptor Affinity and Extracellular Domain Modifications Affect Tumor Recognition by ROR1-Specific Chimeric Antigen Receptor T Cells

Abstract: Purpose: The adoptive transfer of T cells modified to express a chimeric antigen receptor (CAR) comprised of an extracellular single-chain antibody (scFV) fragment specific for a tumor cell surface molecule, and linked to an intracellular signaling module, has activity in advanced malignancies. The receptor tyrosine kinase–like orphan receptor 1 (ROR1) is a tumor-associated molecule expressed in prevalent B-lymphoid and epithelial cancers and is absent on normal mature B cells and vital tissues, making it a candidate for CAR T-cell therapy. Experimental Design: We constructed ROR1-CARs from scFVs with different affinities and containing extracellular IgG4-Fc spacer domains of different lengths, and evaluated the ability of T cells expressing each CAR to recognize ROR1 + hematopoietic and epithelial tumors in vitro , and to eliminate human mantle cell lymphoma (MCL) engrafted into immunodeficient mice. Results: ROR1-CARs containing a short “Hinge-only” extracellular spacer conferred superior lysis of ROR1 + tumor cells and induction of T-cell effector functions compared with CARs with long “Hinge-CH2-CH3” spacers. CARs derived from a higher affinity scFV conferred maximum T-cell effector function against primary CLL and ROR1 + epithelial cancer lines in vitro without inducing activation-induced T-cell death. T cells modified with an optimal ROR1-CAR were equivalently effective as CD19-CAR–modified T cells in mediating regression of JeKo-1 MCL in immunodeficient mice. Conclusions: Our results show that customizing spacer design and increasing affinity of ROR1-CARs enhances T-cell effector function and recognition of ROR1 + tumors. T cells modified with an optimized ROR1-CAR have significant antitumor efficacy in a preclinical model in vivo , suggesting they may be useful to treat ROR1 + tumors in clinical applications. Clin Cancer Res; 19(12); 3153–64. ©2013 AACR .

Intermittent versus continuous androgen deprivation in prostate cancer.

Abstract: Background Castration resistance occurs in most patients with metastatic hormone-sensitive prostate cancer who are receiving androgen-deprivation therapy. Replacing androgens before progression of the disease is hypothesized to prolong androgen dependence. Methods Men with newly diagnosed, metastatic, hormone-sensitive prostate cancer, a performance status of 0 to 2, and a prostate-specific antigen (PSA) level of 5 ng per milliliter or higher received a luteinizing hormone–releasing hormone analogue and an antiandrogen agent for 7 months. We then randomly assigned patients in whom the PSA level fell to 4 ng per milliliter or lower to continuous or intermittent androgen deprivation, with patients stratified according to prior or no prior hormonal therapy, performance status, and extent of disease (minimal or extensive). The coprimary objectives were to assess whether intermittent therapy was noninferior to continuous therapy with respect to survival, with a one-sided test with an upper boundary of the haza...

Overdiagnosis and Overtreatment in Cancer: An Opportunity for Improvement

Abstract: Over the past 30 years, awareness and screening have led to an emphasis on early diagnosis of cancer. Although the goals of these efforts were to reduce the rate of late-stage disease and decrease cancer mortality, secular trends and clinical trials suggest that these goals have not been met; national data demonstrate significant increases in early-stage disease, without a proportional decline in later-stage disease. What has emerged has been an appreciation of the complexity of the pathologic condition called cancer. The word “cancer” often invokes the specter of an inexorably lethal process; however, cancers are heterogeneous and can follow multiple paths, not all of which progress to metastases and death, and include indolent disease that causes no harm during the patient’s lifetime. Better biology alone can explain better outcomes. Although this complexity complicates the goal of early diagnosis, its recognition provides an opportunity to adapt cancer screening with a focus on identifying and treating those conditions most likely associated with morbidity and mortality. Changes in cancer incidence and mortality 1 reveal

Cytomegalovirus Vectors Violate CD8+ T Cell Epitope Recognition Paradigms

Abstract: CD8(+) T cell responses focus on a small fraction of pathogen- or vaccine-encoded peptides, and for some pathogens, these restricted recognition hierarchies limit the effectiveness of antipathogen immunity. We found that simian immunodeficiency virus (SIV) protein-expressing rhesus cytomegalovirus (RhCMV) vectors elicit SIV-specific CD8(+) T cells that recognize unusual, diverse, and highly promiscuous epitopes, including dominant responses to epitopes restricted by class II major histocompatibility complex (MHC) molecules. Induction of canonical SIV epitope-specific CD8(+) T cell responses is suppressed by the RhCMV-encoded Rh189 gene (corresponding to human CMV US11), and the promiscuous MHC class I- and class II-restricted CD8(+) T cell responses occur only in the absence of the Rh157.5, Rh157.4, and Rh157.6 (human CMV UL128, UL130, and UL131) genes. Thus, CMV vectors can be genetically programmed to achieve distinct patterns of CD8(+) T cell epitope recognition.

Computational design of ligand-binding proteins with high affinity and selectivity.

Abstract: The ability to design proteins with high affinity and selectivity for any given small molecule is a rigorous test of our understanding of the physiochemical principles that govern molecular recognition. Attempts to rationally design ligand-binding proteins have met with little success, however, and the computational design of protein-small-molecule interfaces remains an unsolved problem. Current approaches for designing ligand-binding proteins for medical and biotechnological uses rely on raising antibodies against a target antigen in immunized animals and/or performing laboratory-directed evolution of proteins with an existing low affinity for the desired ligand, neither of which allows complete control over the interactions involved in binding. Here we describe a general computational method for designing pre-organized and shape complementary small-molecule-binding sites, and use it to generate protein binders to the steroid digoxigenin (DIG). Of seventeen experimentally characterized designs, two bind DIG; the model of the higher affinity binder has the most energetically favourable and pre-organized interface in the design set. A comprehensive binding-fitness landscape of this design, generated by library selections and deep sequencing, was used to optimize its binding affinity to a picomolar level, and X-ray co-crystal structures of two variants show atomic-level agreement with the corresponding computational models. The optimized binder is selective for DIG over the related steroids digitoxigenin, progesterone and β-oestradiol, and this steroid binding preference can be reprogrammed by manipulation of explicitly designed hydrogen-bonding interactions. The computational design method presented here should enable the development of a new generation of biosensors, therapeutics and diagnostics.

The shaping and functional consequences of the microRNA landscape in breast cancer

Abstract: MicroRNAs (miRNAs) show differential expression across breast cancer subtypes, and have both oncogenic and tumour-suppressive roles. Here we report the miRNA expression profiles of 1,302 breast tumours with matching detailed clinical annotation, long-term follow-up and genomic and messenger RNA expression data. This provides a comprehensive overview of the quantity, distribution and variation of the miRNA population and provides information on the extent to which genomic, transcriptional and post-transcriptional events contribute to miRNA expression architecture, suggesting an important role for post-transcriptional regulation. The key clinical parameters and cellular pathways related to the miRNA landscape are characterized, revealing context-dependent interactions, for example with regards to cell adhesion and Wnt signalling. Notably, only prognostic miRNA signatures derived from breast tumours devoid of somatic copy-number aberrations (CNA-devoid) are consistently prognostic across several other subtypes and can be validated in external cohorts. We then use a data-driven approach to seek the effects of miRNAs associated with differential co-expression of mRNAs, and find that miRNAs act as modulators of mRNA-mRNA interactions rather than as on-off molecular switches. We demonstrate such an important modulatory role for miRNAs in the biology of CNA-devoid breast cancers, a common subtype in which the immune response is prominent. These findings represent a new framework for studying the biology of miRNAs in human breast cancer.

The global hidden hunger indices and maps: an advocacy tool for action.

Abstract: The unified global efforts to mitigate the high burden of vitamin and mineral deficiency, known as hidden hunger, in populations around the world are crucial to the achievement of most of the Millennium Development Goals (MDGs). We developed indices and maps of global hidden hunger to help prioritize program assistance, and to serve as an evidence-based global advocacy tool. Two types of hidden hunger indices and maps were created based on i) national prevalence data on stunting, anemia due to iron deficiency, and low serum retinol levels among preschool-aged children in 149 countries; and ii) estimates of Disability Adjusted Life Years (DALYs) attributed to micronutrient deficiencies in 136 countries. A number of countries in sub-Saharan Africa, as well as India and Afghanistan, had an alarmingly high level of hidden hunger, with stunting, iron deficiency anemia, and vitamin A deficiency all being highly prevalent. The total DALY rates per 100,000 population, attributed to micronutrient deficiencies, were generally the highest in sub-Saharan African countries. In 36 countries, home to 90% of the world’s stunted children, deficiencies of micronutrients were responsible for 1.5-12% of the total DALYs. The pattern and magnitude of iodine deficiency did not conform to that of other micronutrients. The greatest proportions of children with iodine deficiency were in the Eastern Mediterranean (46.6%), European (44.2%), and African (40.4%) regions. The current indices and maps provide crucial data to optimize the prioritization of program assistance addressing global multiple micronutrient deficiencies. Moreover, the indices and maps serve as a useful advocacy tool in the call for increased commitments to scale up effective nutrition interventions.

Antimicrobial Prophylaxis and Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology Clinical Practice Guideline

Abstract: Purpose To provide guidelines on antimicrobial prophylaxis for adult neutropenic oncology outpatients and on selection and treatment as outpatients of those with fever and neutropenia. Methods A literature search identified relevant studies published in English. Primary outcomes included: development of fever and/or infections in afebrile neutropenic outpatients and recovery without complications and overall mortality in febrile neutropenic outpatients. Secondary outcomes included: in afebrile neutropenic outpatients, infection-related mortality; in outpatients with fever and neutropenia, defervescence without regimen change, time to defervescence, infectious complications, and recurrent fever; and in both groups, hospital admissions, duration, and adverse effects of antimicrobials. An Expert Panel developed guidelines based on extracted data and informal consensus. Results Forty-seven articles from 43 studies met selection criteria.