Proteogenomic analysis of human colon cancer reveals new therapeutic opportunities

We performed the first proteogenomic study on a prospectively collected colon cancer cohort. Comparative proteomic and phosphoproteomic analysis of paired tumor and normal adjacent tissues produced a catalog of colon cancer-associated proteins and phosphosites, including known and putative new biomarkers, drug targets, and cancer/testis antigens. Proteogenomic integration not only prioritized genomically inferred targets, such as copy-number drivers and mutation-derived neoantigens, but also yielded novel findings. Phosphoproteomics data associated Rb phosphorylation with increased proliferation and decreased apoptosis in colon cancer, which explains why this classical tumor suppressor is amplified in colon tumors and suggests a rationale for targeting Rb phosphorylation in colon cancer. Proteomics identified an association between decreased CD8 T cell infiltration and increased glycolysis in microsatellite instability-high (MSI-H) tumors, suggesting glycolysis as a potential target to overcome the resistance of MSI-H tumors to immune checkpoint blockade. Proteogenomics presents new avenues for biological discoveries and therapeutic development

Effects of watershed land use on nitrogen concentrations and δ15 Nitrogen in groundwater

Author Posting. © The Authors, 2005. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Biogeochemistry 77 (2006): 199-215, doi:10.1007/s10533-005-1036-2.Eutrophication is a major agent of change affecting freshwater, estuarine, and marine systems. It is largely driven by transportation of nitrogen from natural and anthropogenic sources. Research is needed to quantify this nitrogen delivery and to link the delivery to specific land-derived sources. In this study we measured nitrogen concentrations and δ15N values in seepage water entering three freshwater ponds and six estuaries on Cape Cod, Massachusetts and assessed how they varied with different types of land use. Nitrate concentrations and δ15N values in groundwater reflected land use in developed and pristine watersheds. In particular, watersheds with larger populations delivered larger nitrate loads with higher δ15N values to receiving waters. The enriched δ15N values confirmed nitrogen loading model results identifying wastewater contributions from septic tanks as the major N source. Furthermore, it was apparent that N coastal sources had a relatively larger impact on the N loads and isotopic signatures than did inland N sources further upstream in the watersheds. This finding suggests that management priorities could focus on coastal sources as a first course of action. This would require management constraints on a much smaller population.This work was supported by funds from the Woods Hole Oceanographic Institution Sea Grant Program, from the Cooperative Institute for Coastal and Estuarine Environmental Technology, from Massachusetts Department of Environmental Protection to Applied Science Associates, Narragansett, RI, as well as from Palmer/McLeod and NOAA National Estuarine Research Reserve Fellowships to Kevin Kroeger. This work is the result of research sponsored by NOAA National Sea Grant College Program Office, Department of Commerce, under Grant No. NA86RG0075, Woods Hole Oceanographic Institution Sea Grant Project No. R/M-40

A multi-centred randomised trial of radical surgery versus adjuvant chemoradiotherapy after local excision for early rectal cancer

Background: Rectal cancer surgery is accompanied with high morbidity and poor long term functional outcome. Screening programs have shown a shift towards more early staged cancers. Patients with early rectal cancer can potentially benefit significantly from rectal preserving therapy. For the earliest stage cancers, local excision is sufficient when the risk of lymph node disease and subsequent recurrence is below 5 %. However, the majority of early cancers are associated with an intermediate risk of lymph node involvement (5-20 %) suggesting that local excision alone is not sufficient, while completion radical surgery, which is currently standard of care, could be a substantial overtreatment for this group of patients. Methods/Study design: In this multicentre randomised trial, patients with an intermediate risk T1-2 rectal cancer, that has been locally excised using an endoluminal technique, will be randomized between adjuvant chemo-radiotherapylimited to the mesorectum and standard completion total mesorectal excision (TME). To strictly monitor the risk of locoregional recurrence in the experimental arm and enable early salvage surgery, there will be additional follow up with frequent MRI and endoscopy. The primary outcome of the study is three-year local recurrence rate. Secondary outcomes are morbidity, disease free and overall survival, stoma rate, functional outcomes, health related quality of life and costs. The design is a non inferiority study with a total sample size of 302 patients. Discussion: The results of the TESAR trial will potentially demonstrate that adjuvant chemoradiotherapy is an oncological safe treatment option in patients who are confronted with the difficult clinical dilemma of a radically removed intermediate risk early rectal cancer by polypectomy or transanal surgery that is conventionally treated with subsequent radical surgery. Preserving the rectum using adjuvant radiotherapy is expected to significantly improve morbidity, function and quality of life if compared to completion TME surgery. Trial registration:NCT02371304, registration date: February 2015

Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative

Background: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. Material and methods: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. Results: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. Conclusion: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting

New approaches using mass spectrometry to investigate changes to cytokinin and abscisic acid (ABA) concentrations in soil

Phytohormones such as cytokinins, abscisic acid (ABA) and auxins play a vital role in plant development and regulatory processes. Their role within the plant is a focus for much research, with studies using recent advances in mass spectrometry performance allowing the quantification of low levels of phytohormones extracted from plant tissues. Despite these advances, external factors influencing the production of phytohormones are less well studied. Here, a new approach is presented for the extraction of a range of phytohormones from plant growth media (soil and hydroponic solution), their identification using high mass accuracy mass spectrometry and subsequent quantification using multiple reaction monitoring (MRM). The ability to detect phytohormones in matrices other than plant tissue presents the opportunity to study further the influence of factors such as below ground organisms and soil bacteria on phytohormone production. This novel approach was therefore applied to the plant growth media from a series of experiments comparing plant growth in the presence and absence of earthworms. A small but significant increase in ABA concentration was observed in the presence of earthworms, increasing even further when plants were also present. This finding suggests that earthworms could stimulate plant ABA production. This experiment and its outcomes demonstrate the value of studying phytohormones outside plant tissue, and the potential value of further research in this area

Gendering the careers of young professionals: some early findings from a longitudinal study. in Organizing/theorizing: developments in organization theory and practice

Wonders whether companies actually have employees best interests at heart across physical, mental and spiritual spheres. Posits that most organizations ignore their workforce – not even, in many cases, describing workers as assets! Describes many studies to back up this claim in theis work based on the 2002 Employment Research Unit Annual Conference, in Cardiff, Wales

Mapping child growth failure across low- and middle-income countries

Childhood malnutrition is associated with high morbidity and mortality globally1. Undernourished children are more likely to experience cognitive, physical, and metabolic developmental impairments that can lead to later cardiovascular disease, reduced intellectual ability and school attainment, and reduced economic productivity in adulthood2. Child growth failure (CGF), expressed as stunting, wasting, and underweight in children under five years of age (0�59 months), is a specific subset of undernutrition characterized by insufficient height or weight against age-specific growth reference standards3�5. The prevalence of stunting, wasting, or underweight in children under five is the proportion of children with a height-for-age, weight-for-height, or weight-for-age z-score, respectively, that is more than two standard deviations below the World Health Organization�s median growth reference standards for a healthy population6. Subnational estimates of CGF report substantial heterogeneity within countries, but are available primarily at the first administrative level (for example, states or provinces)7; the uneven geographical distribution of CGF has motivated further calls for assessments that can match the local scale of many public health programmes8. Building from our previous work mapping CGF in Africa9, here we provide the first, to our knowledge, mapped high-spatial-resolution estimates of CGF indicators from 2000 to 2017 across 105 low- and middle-income countries (LMICs), where 99 of affected children live1, aggregated to policy-relevant first and second (for example, districts or counties) administrative-level units and national levels. Despite remarkable declines over the study period, many LMICs remain far from the ambitious World Health Organization Global Nutrition Targets to reduce stunting by 40 and wasting to less than 5 by 2025. Large disparities in prevalence and progress exist across and within countries; our maps identify high-prevalence areas even within nations otherwise succeeding in reducing overall CGF prevalence. By highlighting where the highest-need populations reside, these geospatial estimates can support policy-makers in planning interventions that are adapted locally and in efficiently directing resources towards reducing CGF and its health implications. © 2020, The Author(s)

Erratum: "A Gravitational-wave Measurement of the Hubble Constant Following the Second Observing Run of Advanced LIGO and Virgo" (2021, ApJ, 909, 218)

[no abstract available