Prediction of response to pemetrexed in non-small-cell lung cancer with immunohistochemical phenotyping based on gene expression profiles

Figure S1. Scatter plots of gene expression levels of selected molecular markers and TS gene expression. Dot plots showing correlations between relative mRNA expression of TS and mRNA expression of TOP2A, MCM2, EZH2, CPA3, TPX2. Abbreviations: IHC, immunohistochemical; EZH2, Enhancer of zeste homolog; TOP2A, Topoisomerase II; TPX2, Microtubule Nucleation Factor; CPA3, Carboxypeptidase A3; MCM2, Minichromosome Maintenance Complex Component 2. (EPS 180 kb

Differences of size and shape of active and inactive X-chromosome domains in human amniotic fluid cell nuclei

It is a widely held belief that the inactive X-chromosome (Xi) in female cell nuclei is strongly condensed as compared to the largely decondensed active X-chromosome (Xa). We have reconsidered this problem and painted X-chromosome domains in nuclei of subconfluent, female and male human amniotic fluid cell cultures (46, XX and 46, XY) by chromosomal in situ suppression (CISS) hybridization with biotinylated human X-chromosome specific library DNA. FITC-conjugated avidin was used for probe detection and nuclei were counterstained with propidium iodide (PI). The shape of these nuclei resembling flat ellipsoids or elliptical cylinders makes them suitable for both two-dimensional (2D) and three-dimensional (3D) analyses. 2D analyses of Xi- and Xa-domains were performed in 34 female cell nuclei by outlining of the painted domains using a camera lucida. Identification of the sex chromatin body in DAPI-stained nuclei prior to CISS-hybridization was confirmed by its colocalization with one of the two painted X-domains. In 31 of the 34 nuclei the area AXi for the inactive X-domain was smaller than the area AXa for the active domain (mean ratio AXa/AXi = 1.9 ± 0.8 SD, range 1.0-4.3). The signed rank test showed a highly significant (P r(Xi) demonstrating a generally more elongated structure of Xa. For 3D analysis a confocal scanning laser fluorescence microscope (CSLFM) was used. Ten to 20 light optical sections (PI-image, FITC-image) were registered with equal spacings (approx. 0.4 m). A thresholding procedure was applied to determine the PI-labeled nuclear and FITC-labeled X-domain areas in each section. Estimated slice volumes were used to compute total nuclear and X-domain volumes. In a series of 35 female nuclei most domains extended from the top to the bottom nuclear sections. The larger of the two X-chromosome domains comprised (3.7 ± 1.7 S.D.)% of the nuclear volume. A mean ratio of 1.2 ± 0.2 SD (range 1.1-2.3) was found for the volumes of the larger and the smaller X-domains in these female nuclei. In a series of 27 male amniotic fluid cell nuclei the relative X-chromosome domain volume comprised (4.0 ± 2.6 S.D.)%. These findings indicate that differences in the 3D expansion of active and inactive X-chromosome domains are less pronounced than previously thought. A current model suggests that chromosome domains consist of a compact core surrounded by loosely coiled outer chromatin fiber loops. The latter fraction may be considerably larger in Xa- as compared to Xi-domains. We suggest that the interactive outlining procedure used in the 2D analyses included the loosely structured domain periphery more accurately, while the threshold algorithm applied to light optical sections delineated the more compact core of the domains, leading to smaller and more similar volume estimates of Xa and Xi. Present limitations of nuclear and chromosome domain volume measurements using confocal laser scanning microscopy are discussed

Kinematics of Spiral Arm Streaming in M51

We use CO and H alpha velocity fields to study the gas kinematics in the spiral arms and interarms of M51 (NGC 5194), and fit the 2D velocity field to estimate the radial and tangential velocity components as a function of spiral phase (arm distance). We find large radial and tangential streaming velocities, which are qualitatively consistent with the predictions of density wave theory and support the existence of shocks. The streaming motions are complex, varying significantly across the galaxy as well as along and between arms. Aberrations in the velocity field indicate that the disk is not coplanar, perhaps as far in as 20\arcsec\ (800 pc) from the center. Velocity profile fits from CO and H alpha are typically similar, suggesting that most of the H alpha emission originates from regions of recent star formation. We also explore vortensity and mass conservation conditions. Vortensity conservation, which does not require a steady state, is empirically verified. The velocity and density profiles show large and varying mass fluxes, which are inconsistent with a steady flow for a single dominant global spiral mode. We thus conclude that the spiral arms cannot be in a quasi-steady state in any rotating frame, and/or that out of plane motions may be significant.Comment: 50 pages, including 20 figures; Accepted for publication in ApJ. PDF version with high resolution figures available at http://www.astro.umd.edu/~shetty/Research

Evidence for transient clumps and gas chemical evolution in the CS core of L673

We present FCRAO maps as well as combined BIMA and FCRAO maps of the high density molecular emission towards the CS core in the L673 region. With the FCRAO telescope, we mapped the emission in the CS(2-1), C34S(2-1), HCO+(1-0), and H13CO+(1-0) lines. The high density molecular emission, which arises from a filamentary structure oriented in the NW-SE direction, shows clear morphological differences for each molecule. We find that HCO+ has an extremely high optical depth, and that the H13CO+ emission is well correlated with submm sources. The BIMA and FCRAO combined maps recover emission from a lot of other structure which was previously undetected or only marginally detected, and show an overall aspect of a filamentary structure connecting several intense clumps. We found a total 15 clumps in our combined data cube, all of them resolved by our angular resolution, with diameters in the 0.03-0.09 pc range. We find a clear segregation between the northern and southern region of the map: the northern section shows the less chemically evolved gas and less massive but more numerous clumps, while the southern region is dominated by the largest and most massive clump, and contains the more evolved gas, as traced by emission of late-time molecules. We find that the derived clump masses are below the virial mass, and that the clumps masses become closer to the virial mass when they get bigger and more massive. This supports the idea that these clumps must be transient, and only the more massive ones have a chance to last long enough to form stars. The clumps we detect are probably in an earlier evolutionary stage than the ``starless cores'' reported recently in the literature. Only the most massive one has properties similar to a ``starless core''.Comment: 12 pages, 8 figures, accepted for publication in Astronomy & Astrophysics; minor revisions after language editin

Dying at home or in an institution: perspectives of Dutch physicians and bereaved relatives

Introduction Previous studies have shown that most people prefer to die at their own home. We investigated whether physicians or bereaved relatives in retrospect differently appreciate the dying of patients in an institution or at home. Materials and methods Of 128 patients with incurable cancer who were followed in the last phase of their lives, 103 passed away during follow-up. After death, physicians filled out a written questionnaire for 102 of these patients, and 63 bereaved relatives were personally interviewed. Results Of 103 patients, 49 died in an institution (mostly a hospital), and 54 died at home (or in two cases in a home-like situation). Patients who had been living with a partner relatively often died at home. Bereaved relatives knew of the patient’s wish to die at home in 25 out of 63 cases; 20 of these patients actually died at home. Thirty-one patients had no known preference concerning their place of dying. Most symptoms and the care provided to address them were equally prevalent in patients dying in an institution and patients dying at home. Bereaved relatives were in general quite satisfied about the provision of medical and nursing care in both settings. Conclusion We conclude that most patients’ preferences concerning the place of dying can be met. In about half of all cases, patients do not seem to have a clear preference concerning their place of dying, which is apparently not a major concern for many people. We found no indication that dying in an institution or at home involves major differences in the process and quality of dying

Satisfaction with social connectedness as a predictor for positive and negative symptoms of psychosis:A PHAMOUS study

PURPOSE: This study examines satisfaction with social connectedness (SSC) as predictor of positive and negative symptoms in people with a psychotic disorder. METHODS: Data from the Pharmacotherapy Monitoring and Outcome Survey (PHAMOUS) was used from patients assessed between 2014 and 2019, diagnosed with a psychotic disorder (N = 2109). Items about social connectedness of the Manchester short assessment of Quality of Life (ManSA) were used to measure SSC. Linear mixed models were used to estimate the association of SSC with the Positive and Negative Syndrome Scale (PANSS) after one and two years against α = 0.01. Analyses were adjusted for symptoms, time since onset, gender and age. Additionally, fluctuation of positive and negative symptom scores over time was estimated. RESULTS: The mean duration of illness of the sample was 18.8 years (SD 10.7) with >65% showing only small variation in positive and negative symptoms over a two to five-year time period. After adjustment for covariates, SSC showed to be negatively associated with positive symptoms after one year (β = -0.47, p < 0.001, 95% CI = -0.70, -025) and two years (β = -0.59, p < 0.001, 95% CI = -0.88, -0.30), and for negative symptoms after one year (β = -0.52, p < 0.001, 95% CI = -0.77, -0.27). The prediction of negative symptoms was not significant at two years. CONCLUSION: This research indicates that interventions on SSC might positively impact mental health for people with psychosis. SSC is a small and robust predictor of future levels of positive symptoms. Negative symptoms could be predicted by SSC at one year

Prediction of response to pemetrexed in non-small-cell lung cancer with immunohistochemical phenotyping based on gene expression profiles

Background: Palliative pemetrexed-based chemotherapy remains a standard of care treatment for the majority of patients with advanced non-squamous non-small-cell lung cancer (NSCLC). Currently, no predictive markers for pemetrexed treatment are available. Methods: Resected tumour samples from pemetrexed-naïve NSCLC patients were collected. Gene expression profiling with respect to predicted sensitivity to pemetrexed classified predicted responders (60%) and nonresponders (40%) based on differentially expressed genes encoding for pemetrexed target enzymes. Genes showing a strong correlation with these target genes were selected for measurement of corresponding protein expressions by immunohistochemical (IHC) staining. A semi-quantitative IHC scoring method was applied to construct a prediction model for response to pemetrexed. A retrospective cohort of patients with advanced NSCLC treated with first-line pemetrexed-based chemotherapy was used for external validation. Results: From ninety-one patients resected tumour samples were collected. The majority of patients had early or locally advanced NSCLC (96.3%). Gene expression profiling revealed five markers, which mRNA levels strongly correlated to pemetrexed target genes mRNA levels: TPX2, CPA3, EZH2, MCM2 and TOP2A. Of 63 (69%) patients IHC staining scores of these markers were obtained, which significantly differed between predicted non-responders and responders (P < 0.05). The optimized prediction model included EZH2 (OR = 0.56, 95% CI 0.35–0.90) and TPX2 (OR = 0.55, 95% CI 0.30–1.01). The model had a sensitivity of 86.8%, specificity of 63.6% and showed a good ability to distinct between responders and non-responders (C-index 0.86). In the external study population (N = 23) the majority of patients had metastatic NSCLC (95.7%). Partial response (PR) was established in 26.1%. The sensitivity decreased drastically to 33.3%, with a specificity of 82.4% and a C-index of 0.73. Conclusions: Using external validation this prediction model with IHC staining of target enzyme correlated markers showed a good discrimination, but lacked sensitivity. The role of IHC markers as response predictors for pemetrexed in clinical practice remains questionable

Blink and shrink: The effect of the attentional blink on spatial processing.

The detection or discrimination of the second of 2 targets in a rapid serial visual presentation (RSVP) task is often temporarily impaired - a phenomenon termed the attentional blink. This study demonstrated that the attentional blink also affects localization performance. Spatial cues pointed out the possible target positions in a subsequent visual search display. When cues were presented inside an attentional blink (as induced by an RSVP task), the observers' capacity to use them was reduced. This effect was not due to attention being highly focused, to general task switching costs, or to complete unawareness of the cues. Instead, the blink induced a systematic localization bias toward the fovea, reflecting what appears to be spatial compression

Reprint: Learning With a Strategic Management Simulation Q2 Game: A Case Study

The use of simulation games as a pedagogic method is well established though its effective use is context-driven. This study adds to the increasing growing body of empirical evidence of the effectiveness of simulation games but more importantly emphasises why by explaining the instructional design implemented reflecting best practices. This multimethod study finds evidence that student learning was enhanced through the use of simulation games, reflected in the two key themes; simulation games as a catalyst for learning and simulation games as a vehicle for learning. In so doing the research provides one of the few empirically based studies that support simulation games in enhancing learning and, more importantly, contextualizes the enhancement in terms of the instructional design of the curriculum. This research should prove valuable for those with an academic interest in the use of simulation games and management educators who use, or are considering its use. Further, the findings contribute to the academic debate concerning the effective implementation of simulation game-based training in business and management education