Cryo-electron tomography of biological specimens

Cryo-electron tomography (CET) is an imaging technique capable of visualizing the three-dimensional (3-D) structure of complex viruses, cells, and tissues in hydrated state. With the current resolution of 4-5 nm, CET can resolve supramolecular complexes that are responsible for many cellular functions. This paper discusses the important considerations in CET of biological specimens and identify areas where digital signal processing can make a decisive contribution. Topics discussed include the principles of electron tomography and CET, image background and feature contrasts in CET, acquisition and alignment of projection images, reconstruction of the image volume, denoising and segmentation of tomograms, and feature recognition in cellular tomograms

Evolution of a Holocene delta driven by episodic sediment delivery and coseismic deformation, Puget Sound, Washington, USA

This paper is not subject to U.S. copyright. The definitive version was published in Sedimentology 53 (2006): 1211-1228, doi:10.1111/j.1365-3091.2006.00809.x.Episodic, large-volume pulses of volcaniclastic sediment and coseismic subsidence of the coast have influenced the development of a late Holocene delta at southern Puget Sound. Multibeam bathymetry, ground-penetrating radar (GPR) and vibracores were used to investigate the morphologic and stratigraphic evolution of the Nisqually River delta. Two fluvial–deltaic facies are recognized on the basis of GPR data and sedimentary characteristics in cores, which suggest partial emplacement from sediment-rich floods that originated on Mount Rainier. Facies S consists of stacked, sheet-like deposits of andesitic sand up to 4 m thick that are continuous across the entire width of the delta. Flat-lying, highly reflective surfaces separate the sand sheets and comprise important facies boundaries. Beds of massive, pumice- and charcoal-rich sand overlie one of the buried surfaces. Organic-rich material from that surface, beneath the massive sand, yielded a radiocarbon age that is time-correlative with a series of known eruptive events that generated lahars in the upper Nisqually River valley. Facies CF consists of linear sandbodies or palaeochannels incised into facies S on the lower delta plain. Radiocarbon ages of wood fragments in the sandy channel-fill deposits also correlate in time to lahar deposits in upstream areas. Intrusive, sand-filled dikes and sills indicate liquefaction caused by post-depositional ground shaking related to earthquakes. Continued progradation of the delta into Puget Sound is currently balanced by tidal-current reworking, which redistributes sediment into large fields of ebb- and flood-oriented bedforms.This study was supported by the Coastal and Marine Geology Program, and the Earthquake Hazards Program of the U.S. Geological Survey

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Preoperative radiotherapy in patients with primary retroperitoneal sarcoma: EORTC-62092 trial (STRASS) versus off-trial (STREXIT) results

Objective: The aim of the present study was to compare the effect of radiotherapy (RT) on abdominal recurrence-free survival (ARFS) in patients with primary retroperitoneal sarcoma treated in the EORTC-STBSG-62092 (STRASS) phase 3 randomized controlled trial (STRASS cohort) and off-trial (STREXIT cohort) and to pool STRASS and STREXIT data to test the hypothesis that RT improves ARFS in patients with liposarcoma.Background: The STRASS trial did not show any difference in ARFS between patients treated with preoperative radiotherapy+surgery (RT+S) versus surgery alone (S).Methods: All consecutive adult patients not enrolled in STRASS and underwent curative-intent surgery for a primary retroperitoneal sarcoma with or without preoperative RT between 2012 and 2017 (STRASS recruiting period) among ten STRASS-recruiting centres formed the STREXIT cohort. The effect of RT in STREXIT was explored with a propensity score (PS)-matching analysis. Primary endpoint was ARFS defined as macroscopically incomplete resection or abdominal recurrence or death of any cause, whichever occurred first.Results: STRASS included 266 patients, STREXIT included 831 patients (727 after excluding patients who received preoperative chemotherapy, 202 after 1:1 PS-matching). The effect of RT on ARFS in STRASS and 1:1 PS-matched STREXIT cohorts, overall and in patients with liposarcoma, was similar. In the pooled cohort analysis, RT administration was associated with better ARFS in patients with liposarcoma [N=321, hazard ratio (HR), 0.61; 95% confidence interval (CI), 0.42–0.89]. In particular, patients with well-differentiated liposarcoma and G1-2 dedifferentiated liposarcoma (G1-2 DDLPS, n=266) treated with RT+S had better ARFS (HR, 0.63; 95% CI, 0.40–0.97) while patients with G3 DDLPS and leiomyosarcoma had not. At the current follow-up, there was no association between RT and overall survival or distant metastases-free survival.Conclusions: In this study, preoperative RT was associated with better ARFS in patients with primary well-differentiated liposarcoma and G1-2 DDLPS.Experimentele farmacotherapi

The COSPAR planetary protection policy for missions to Icy Worlds: A review of history, current scientific knowledge, and future directions

Recent discoveries related to the habitability and astrobiological relevance of the outer Solar System have expanded our understanding of where and how life may have originated. As a result, the Icy Worlds of the outer Solar System have become among the highest priority targets for future spacecraft missions dedicated to astrobiology-focused and/or direct life detection objectives. This, in turn, has led to a renewed interest in planetary protection concerns and policies for the exploration of these worlds and has been a topic of discussion within the COSPAR (Committee on Space Research) Panel on Planetary Protection. This paper summarizes the results of those discussions, reviewing the current knowledge and the history of planetary protection considerations for Icy Worlds as well as suggesting ways forward. Based on those discussions, we therefore suggest to (1) Establish a new definition for Icy Worlds for Planetary Protection that captures the outer Solar System moons and dwarf planets like Pluto, but excludes more primitive bodies such as comets, centaurs, and asteroids: Icy Worlds in our Solar System are defined as all bodies with an outermost layer that is believed to be greater than 50% water ice by volume and have enough mass to assume a nearly round shape. (2) Establish indices for the lower limits of Earth life with regards to water activity (LLAw) and temperature (LLT) and apply them into all areas of the COSPAR Planetary Protection Policy. These values are currently set at 0.5 and -28°C and were originally established for defining Mars Special Regions; (3) Establish LLT as a parameter to assign categorization for Icy Worlds missions. The suggested categorization will have a 1000-year period of biological exploration, to be applied to all Icy Worlds and not just Europa and Enceladus as is currently the case. (4) Have all missions consider the possibility of impact. Transient thermal anomalies caused by impact would be acceptable so long as there is less than 10−4, probability of a single microbe reaching deeper environments where temperature is >LLT in the period of biological exploration. (5) Restructure or remove Category II* from the policy as it becomes largely redundant with this new approach, (6) Establish that any sample return from an Icy World should be Category V restricted Earth return

Personalized peptide-based vaccination for treatment of colorectal cancer: rational and progress

Colorectal cancer (CRC) is one of the most common cancers globally and is associated with a high rate of morbidity and mortality. A large proportion of patients with early stage CRC who undergo conventional treatments develop local recurrence or distant metastasis and in this group of advanced disease, the survival rate is low. Furthermore there is often a poor response and/or toxicity associated with chemotherapy and chemo-resistance may limit continuing conventional treatment alone. Choosing novel and targeted therapeutic approaches based on clinicopathological and molecular features of tumors in combination with conventional therapeutic approach could be used to eradicate residual micrometastasis and therefore improve patient prognosis and also be used preventively. Peptide-based vaccination therapy is one class of cancer treatment that could be used to induce tumor-specific immune responses, through the recognition of specific antigen-derived peptides in tumor cells, and this has emerged as a promising anti-cancer therapeutic strategy. The aim of this review was to summarize the main findings of recent studies in exciting field of peptide-based vaccination therapy in CRC patients as a novel therapeutic approach in treatment of CRC

Nongenetic Determinants of Risk for Early-Onset Colorectal Cancer

Background: Incidence of early-onset (younger than 50 years of age) colorectal cancer (CRC) is increasing in many countries. Thus, elucidating the role of traditional CRC risk factors in early-onset CRC is a high priority. We sought to determine whether risk factors associated with late-onset CRC were also linked to early-onset CRC and whether association patterns differed by anatomic subsite. Methods: Using data pooled from 13 population-based studies, we studied 3767 CRC cases and 4049 controls aged younger than 50 years and 23 437 CRC cases and 35 311 controls aged 50 years and older. Using multivariable and multinomial logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to assess the association between risk factors and early-onset CRC and by anatomic subsite. Results: Early-onset CRC was associated with not regularly using nonsteroidal anti-inflammatory drugs (OR = 1.43, 95% CI = 1.21 to 1.68), greater red meat intake (OR = 1.10, 95% CI = 1.04 to 1.16), lower educational attainment (OR = 1.10, 95% CI = 1.04 to 1.16), alcohol abstinence (OR = 1.23, 95% CI = 1.08 to 1.39), and heavier alcohol use (OR = 1.25, 95% CI = 1.04 to 1.50). No factors exhibited a greater excess in early-onset compared with late-onset CRC. Evaluating risks by anatomic subsite, we found that lower total fiber intake was linked more strongly to rectal (OR = 1.30, 95% CI = 1.14 to 1.48) than colon cancer (OR = 1.14, 95% CI = 1.02 to 1.27; P =. 04). Conclusion: In this large study, we identified several nongenetic risk factors associated with early-onset CRC, providing a basis for targeted identification of those most at risk, which is imperative in mitigating the rising burden of this disease