Colorectal cancer in patients of advanced age is associated with increased incidence of BRAF p.V600E mutation and mismatch repair deficiency

IntroductionThe highest incidence of colorectal cancer (CRC) is in patients diagnosed at 80 years or older highlighting a need for understanding the clinical and molecular features of these tumors. Methods. In this retrospective cohort study, 544 CRCs underwent next generation sequencing and mismatch repair (MMR) evaluation. Molecular and clinical features were compared between 251 patients with traditional-onset CRC (50-69 years at diagnosis) and 60 with late-onset CRC (>80 years at diagnosis).ResultsLate-onset CRC showed a significantly higher rate of right-sided tumors (82% vs 35%), MMR deficiency (35% vs. 8%) and BRAF p.V600E mutations (35% vs. 8%) and a significantly lower rate of stage IV disease (15% vs 28%) and APC mutations (52% vs. 78%). Association of these features with advanced age was supported by stratifying patients into 6 age groups (<40, 40-49, 50-59, 60-69, 70-79 and >80 years). However, the age-related rise in MMR deficient (dMMR) CRC was only seen in the female patients with an incidence of 48% (vs. 10% in the male patient) in the >80y group. In addition, BRAF p.V600E was significantly enriched in MMR deficient CRC of advanced age (67% in late-onset CRC). Categorizing CRC by mutational profiling, late-onset CRC revealed a significantly higher rate of dMMR/BRAF+APC- (18% vs. 2.0%), dMMR/BRAF-APC- (8.3% vs. 1.2%) and MMR proficient (pMMR)/BRAF+APC- (12% vs. 4.0%) as compared to traditional-onset CRC.DiscussionIn summary, there was a higher rate of dMMR and BRAF p.V600E in late-onset CRC, independently or in combination. The higher incidence of dMMR in late-onset CRC in females is most likely predominantly driven by BRAF p.V600E induced hypermethylation. Prospective studies with treatment plans designed specifically for these older patients are warranted to improve their outcomes

Critical Dimensions in Architectural Photography: Contributions to Architectural Knowledge

This paper illustrates and explores three critical dimensions of photography in architecture, each of which informs the production of images, texts, and other artifacts which establish what might be called a building’s media footprint. The paper’s broad goal is to question the extent to which these critical dimensions are relevant to architectural decision-making processes. Acknowledging that such dimensions as the ones examined here rarely predict an architect’s specific design decisions in a transparent manner, the paper discusses not only the decisions made by architects during the process of designing buildings, but the decisions made by critics, visitors, and members of the general public as they engage in activities such as visiting buildings, writing about them and, particularly, photographing them. First, the text discusses the potential of buildings to operate as mechanisms for producing images, in the sense originated by Beatriz Colomina. The question is developed through the analysis of the space of photography – mapping of points of view, directions of view, and fields of view of defined photographic collections. Secondly, it considers photography’s complicity in the canonization of buildings, and specifically, the extent to which photography is responsible for distinguishing between major and minor architectural works. Finally, the essay examines the erosion over time of photography’s historical power to frame when confronted with contemporary technologies of virtual reality and photo realistically rendered digital models. Each of these critical dimensions, or concepts, develops a specific aspect of how photographic information about buildings is organized, structured, and disseminated, and is thus only part of the larger project of architectural epistemology, which inquires into this wider field. This will be done through an examination of the Mies van der Rohe-designed Commons Building at ITT in Chicago and the evolution of its relationship with architectural photography and photographic representation – both on its own terms and through the prism of the Rem Koolhaas-designed McCormick Tribune Student Center, which adds to and incorporates the Commons Building. Until the end of the twentieth century, the Commons Building on the campus of the Illinois Institute of Technology was generally considered one of Mies van der Rohe’s lesser works. Reportedly neglected by its own architect during the design process, and frequently marginalized in academic discussions of the campus, when mentioned at all the building was often cited as an unrefined prototype of Crown Hall. This discourse took a new direction when in 1998, Rem Koolhaas/OMA won a design competition for a student center on the IIT campus: uniquely among the competition entries, Koolhaas’s design incorporated the Commons Building within a new context – what ultimately became the McCormick Tribune Campus Center (MTCC). When critics concluded that the incorporation of the Commons Building into the larger whole could compromise its integrity as an exemplar of Mies’s work, the building became the object of renewed interest and controversy. The two projects considered here show a clear evolution in architecture’s relationship with the photographic image. Specifically, the history of the Commons Building can be traced through photographs: during and shortly following its construction, the building was photographed as part of Mies’s own attention to publicity; it was documented as part of historical analyses; and over time it was visited and photographed by casual and amateur photographers. Following the competition results, photographs of the Commons Building were strategically deployed by both proponents and critics of Koolhaas’s design. Contemporary photographs of the building appear in architectural and campus guidebooks and on websites such as Flickr.com. Examining the ways in which photographs of the Commons Building appear in these various contexts allows discussion of the critical dimensions identified above and permits us to trace the evolution of the mutually reinforcing relationship between architecture and photography

Phreatic eruptions at crater lakes: occurrence statistics and probabilistic hazard forecast

Phreatic eruptions, although posing a serious threat to people in crater proximity, are often underestimated and have been comparatively understudied. The detailed eruption catalogue for Ruapehu Volcano (New Zealand) provides an exceptional opportunity to study the statistics of recurring phreatic explosions at a crater lake volcano. We performed a statistical analysis on this phreatic eruption database, which suggests that phreatic events at Ruapehu do not follow a Poisson process. Instead they tend to cluster, which is possibly linked to an increased heat flow during periods of a more shallow-seated magma column. Larger explosions are more likely to follow shortly after smaller events, as opposed to longer periods of quiescence. The absolute probability for a phreatic explosion to occur at Ruapehu within the next month is about 10%, when averaging over the last 70 years of recording. However, the frequency of phreatic explosions is significantly higher than the background level in years prior to magmatic episodes. Combining clast ejection simulations with a Bayesian event tree tool (PyBetVH) we perform a probabilistic assessment of the hazard due to ballistic ejecta in the summit area of Ruapehu, which is frequently visited by hikers. Resulting hazard maps show that the absolute probability for the summit to be affected by ballistics within the next month is up to 6%. The hazard is especially high on the northern lakeshore, where there is a mountain refuge. Our results contribute to the local hazard assessment as well as the general perception of hazards due to steam-driven explosions

A Study of Time-Dependent CP-Violating Asymmetries and Flavor Oscillations in Neutral B Decays at the Upsilon(4S)

We present a measurement of time-dependent CP-violating asymmetries in neutral B meson decays collected with the BABAR detector at the PEP-II asymmetric-energy B Factory at the Stanford Linear Accelerator Center. The data sample consists of 29.7 ${\rm fb}^{-1}$ recorded at the $\Upsilon(4S)$ resonance and 3.9 ${\rm fb}^{-1}$ off-resonance. One of the neutral B mesons, which are produced in pairs at the $\Upsilon(4S)$, is fully reconstructed in the CP decay modes $J/\psi K^0_S$, $\psi(2S) K^0_S$, $\chi_{c1} K^0_S$, $J/\psi K^{*0}$ ($K^{*0}\to K^0_S\pi^0$) and $J/\psi K^0_L$, or in flavor-eigenstate modes involving $D^{(*)}\pi/\rho/a_1$ and $J/\psi K^{*0}$ ($K^{*0}\to K^+\pi^-$). The flavor of the other neutral B meson is tagged at the time of its decay, mainly with the charge of identified leptons and kaons. The proper time elapsed between the decays is determined by measuring the distance between the decay vertices. A maximum-likelihood fit to this flavor eigenstate sample finds $\Delta m_d = 0.516\pm 0.016 {\rm (stat)} \pm 0.010 {\rm (syst)} {\rm ps}^{-1}$. The value of the asymmetry amplitude $\sin2\beta$ is determined from a simultaneous maximum-likelihood fit to the time-difference distribution of the flavor-eigenstate sample and about 642 tagged $B^0$ decays in the CP-eigenstate modes. We find $\sin2\beta=0.59\pm 0.14 {\rm (stat)} \pm 0.05 {\rm (syst)}$, demonstrating that CP violation exists in the neutral B meson system. (abridged)Comment: 58 pages, 35 figures, submitted to Physical Review

The Intrinsic Resolution Limit in the Atomic Force Microscope: Implications for Heights of Nano-Scale Features

Background; Accurate mechanical characterization by the atomic force microscope at the highest spatial resolution requires that topography is deconvoluted from indentation. The measured height of nanoscale features in the atomic force microscope (AFM) is almost always smaller than the true value, which is often explained away as sample deformation, the formation of salt deposits and/or dehydration. We show that the real height of nano-objects cannot be obtained directly: a result arising as a consequence of the local probe-sample geometry. Methods and Findings; We have modeled the tip-surface-sample interaction as the sum of the interaction between the tip and the surface and the tip and the sample. We find that the dynamics of the AFM cannot differentiate between differences in force resulting from 1) the chemical and/or mechanical characteristics of the surface or 2) a step in topography due to the size of the sample; once the size of a feature becomes smaller than the effective area of interaction between the AFM tip and sample, the measured height is compromised. This general result is a major contributor to loss of height and can amount to up to ∼90% for nanoscale features. In particular, these very large values in height loss may occur even when there is no sample deformation, and, more generally, height loss does not correlate with sample deformation. DNA and IgG antibodies have been used as model samples where experimental height measurements are shown to closely match the predicted phenomena. Conclusions; Being able to measure the true height of single nanoscale features is paramount in many nanotechnology applications since phenomena and properties in the nanoscale critically depend on dimensions. Our approach allows accurate predictions for the true height of nanoscale objects and will lead to reliable mechanical characterization at the highest spatial resolution

Anamnestic risk factor questionnaire as reliable diagnostic instrument for osteoporosis (reduced bone morphogenic density)

<p>Abstract</p> <p>Background</p> <p>Osteoporosis is a major health problem worldwide, and is included in the WHO list of the top 10 major diseases. However, it is often undiagnosed until the first fracture occurs, due to inadequate patient education and lack of insurance coverage for screening tests. Anamnestic risk factors like positive family anamnesis or early menopause are assumed to correlate with reduced BMD.</p> <p>Methods</p> <p>In our study of 78 patients with metaphyseal long bone fractures, we searched for a correlation between anamnestic risk factors, bone specific laboratory values, and the bone morphogenic density (BMD). Each indicator was examined as a possible diagnostic instrument for osteoporosis. The secondary aim of this study was to demonstrate the high prevalence of osteoporosis in patients with metaphyseal fractures.</p> <p>Results</p> <p>76.9% of our fracture patients had decreased bone density and 43.6% showed manifest osteoporosis in DXA (densitometry) measurements. Our questionnaire, identifying anamnestic risk factors, correlated highly significantly (p = 0.01) with reduced BMD, whereas seven bone-specific laboratory values (p = 0.046) correlated significantly.</p> <p>Conclusions</p> <p>Anamnestic risk factors correlate with pathological BMD. The medical questionnaire used in this study would therefore function as a cost-effective primary diagnostic instrument for identification of osteoporosis patients.</p

Large scale genome-wide association and LDLA mapping study identifies QTLs for boar taint and related sex steroids

<p>Abstract</p> <p>Background</p> <p>Boar taint is observed in a high proportion of uncastrated male pigs and is characterized by an unpleasant odor/flavor in cooked meat, primarily caused by elevated levels of androstenone and skatole. Androstenone is a steroid produced in the testis in parallel with biosynthesis of other sex steroids like testosterone and estrogens. This represents a challenge when performing selection against androstenone in breeding programs, without simultaneously decreasing levels of other steroids. The aim of this study was to use high-density genome wide association (GWA) in combination with linkage disequilibrium-linkage analysis (LDLA) to identify quantitative trait loci (QTL) associated with boar taint compounds and related sex steroids in commercial Landrace (n = 1,251) and Duroc (n = 918) breeds.</p> <p>Results</p> <p>Altogether, 14 genome wide significant (GWS) QTL regions for androstenone in subcutaneous fat were obtained from the LDLA study in Landrace and 14 GWS QTL regions in Duroc. LDLA analysis revealed that 7 of these QTL regions, located on SSC 1, 2, 3, 7 and 15, were obtained in both breeds. All 14 GWS androstenone QTLs in Landrace are also affecting the estrogens at chromosome wise significance (CWS) or GWS levels, while in Duroc, 3 of the 14 QTLs affect androstenone without affecting any of the estrogens. For skatole, 10 and 4 QTLs were GWS in the LDLA analysis for Landrace and Duroc respectively, with 4 of these detected in both breeds. The GWS QTLs for skatole obtained by LDLA are located at SSC 1, 5, 6, 7, 10, 11, 13 and 14.</p> <p>Conclusion</p> <p>This is the first report applying the Porcine 60 K SNP array for simultaneous analysis of boar taint compounds and related sex hormones, using both GWA and LDLA approaches. Several QTLs are involved in regulation of androstenone and skatole, and most of the QTLs for androstenone are also affecting the levels of estrogens. Seven QTLs for androstenone were detected in one breed and confirmed in the other, i.e. in an independent sample, although the majority of QTLs are breed specific. Most QTLs for skatole do not negatively affect other sex hormones and should be easier to implement into the breeding scheme.</p

Transcriptome Analysis of the Desert Locust Central Nervous System: Production and Annotation of a Schistocerca gregaria EST Database

) displays a fascinating type of phenotypic plasticity, designated as ‘phase polyphenism’. Depending on environmental conditions, one genome can be translated into two highly divergent phenotypes, termed the solitarious and gregarious (swarming) phase. Although many of the underlying molecular events remain elusive, the central nervous system (CNS) is expected to play a crucial role in the phase transition process. Locusts have also proven to be interesting model organisms in a physiological and neurobiological research context. However, molecular studies in locusts are hampered by the fact that genome/transcriptome sequence information available for this branch of insects is still limited. EST information is highly complementary to the existing orthopteran transcriptomic data. Since many novel transcripts encode neuronal signaling and signal transduction components, this paper includes an overview of these sequences. Furthermore, several transcripts being differentially represented in solitarious and gregarious locusts were retrieved from this EST database. The findings highlight the involvement of the CNS in the phase transition process and indicate that this novel annotated database may also add to the emerging knowledge of concomitant neuronal signaling and neuroplasticity events. EST data constitute an important new source of information that will be instrumental in further unraveling the molecular principles of phase polyphenism, in further establishing locusts as valuable research model organisms and in molecular evolutionary and comparative entomology

Green Synthesis as a Simple and Rapid Route to Protein Modified Magnetic Nanoparticles for Use in the Development of a Fluorometric Molecularly Imprinted Polymer-Based Assay for Detection of Myoglobin.

We have developed a low-cost molecularly imprinted polymer (MIP)-based fluorometric assay to directly quantify myoglobin in a biological sample. The assay uses a previously unreported method for the development of microwave-assisted rapid synthesis of aldehyde functionalized magnetic nanoparticles, in just 20 minutes. The aldehyde functionalized nanoparticles have an average size of 7.5 nm ± 1.8 and saturation magnetizations of 31.8 emu g-1 with near-closed magnetization loops, confirming their superparamagnetic properties. We have subsequently shown that protein tethering was possible to the aldehyde particles, with 0.25 ± 0.013 mg of myoglobin adsorbed to 20 mg of the nanomaterial. Myoglobin-specific fluorescently tagged MIP (F-MIP) particles were synthesized and used within the assay to capture myoglobin from a test sample. Excess F-MIP was removed from the sample using protein functionalized magnetic nanoparticles (Mb-SPION), with the remaining sample analysed using fluorescence spectroscopy. The obtained calibration plot of myoglobin showed a linear correlation ranging from 60 pg mL-1 to 6 mg mL-1 with the limit of detection of 60 pg mL-1. This method was successfully used to detect myoglobin in spiked fetal calf serum, with a recovery rate of more than 93%