A human ribonuclease induces apoptosis associated with p21WAF1/CIP1 induction and JNK inactivation

<p>Abstract</p> <p>Background</p> <p>Ribonucleases are promising agents for use in anticancer therapy. Among the different ribonucleases described to be cytotoxic, a paradigmatic example is onconase which manifests cytotoxic and cytostatic effects, presents synergism with several kinds of anticancer drugs and is currently in phase II/III of its clinical trial as an anticancer drug against different types of cancer. The mechanism of cytotoxicity of PE5, a variant of human pancreatic ribonuclease carrying a nuclear localization signal, has been investigated and compared to that of onconase.</p> <p>Methods</p> <p>Cytotoxicity was measured by the MTT method and by the tripan blue exclusion assay. Apoptosis was assessed by flow cytometry, caspase enzymatic detection and confocal microscopy. Cell cycle phase analysis was performed by flow cytometry. The expression of different proteins was analyzed by western blot.</p> <p>Results</p> <p>We show that the cytotoxicity of PE5 is produced through apoptosis, that it does not require the proapoptotic activity of p53 and is not prevented by the multiple drug resistance phenotype. We also show that PE5 and onconase induce cell death at the same extent although the latter is also able to arrest the cell growth. We have compared the cytotoxic effects of both ribonucleases in the NCI/ADR-RES cell line by measuring their effects on the cell cycle, on the activation of different caspases and on the expression of different apoptosis- and cell cycle-related proteins. PE5 increases the number of cells in S and G₂/M cell cycle phases, which is accompanied by the increased expression of cyclin E and p21^WAF1/CIP1together with the underphosphorylation of p46 forms of JNK. Citotoxicity of onconase in this cell line does not alter the cell cycle phase distribution and it is accompanied by a decreased expression of XIAP</p> <p>Conclusions</p> <p>We conclude that PE5 kills the cells through apoptosis associated with the p21^WAF1/CIP1induction and the inactivation of JNK. This mechanism is significantly different from that found for onconase.</p

Nursing diagnoses related to skin: operational definitions

OBJECTIVE: to validate the operational definitions of the defining characteristics and risk factors of the three NANDA International (NANDA-I) nursing diagnoses and to revise these diagnoses' definitions. METHOD: content validation of nursing diagnosis. 146 defining characteristics and risk factors were identified in the literature in Brazilian and international databases. This was followed by content validation of the definitions of these diagnoses (presented by NANDA-I) and of the operational definitions (developed by the researchers) of the defining characteristics and risk factors, carried out by six expert nurses, regarding relevance, clarity and comprehensiveness. RESULT: of the 146 defining characteristics and risk factors, 22 were considered redundant and were excluded. The experts proposed changing the definitions of the diagnoses of Impaired Tissue Integrity and Risk for Impaired Skin Integrity. It was possible to identify various defining characteristics and risk factors which are not present in the NANDA-I taxonomy but which are indicated in the literature. CONCLUSION: the process attained its objective of producing valid operational definitions for defining characteristics and risk factors, which will permit the undertaking of validation studies for these diagnoses. The study's contribution to advancing scientific knowledge consists in its presenting clearer operational definitions for these diagnoses and a higher number of defining characteristics and risk factors, which will assist the nurses in the identification and use of the same with greater accuracy in clinical practice.OBJETIVO: validar las definiciones operacionales de las características definidoras y factores de riesgo de los tres diagnósticos de enfermería relacionados a la piel de la NANDA International (NANDA-I) y revisar las definiciones de eses diagnósticos. MÉTODO: validación de contenido de diagnóstico de enfermería. Se identificaron 146 características definidoras y factores de riesgo en la literatura en las bases de datos nacionales e internacionales. Enseguida, se realizó la validación de contenido de las definiciones de estos diagnósticos, presentadas por la NANDA-I y de las definiciones operacionales, elaboradas por las investigadoras, de las características definidoras y factores de riesgo, por seis enfermeras expertas, en cuanto a la pertinencia, clareza y abarcamiento. RESULTADO: de las 146 características definidoras y factores de riesgo, 22 fueron considerados redundantes y excluidos. Los peritos propusieron alterar la definición de los diagnósticos de Integridad Tisular Dañada y Riesgo de Integridad de la Piel Dañada. Fue posible identificar varias características definidoras y factores de riesgo que no están presentes en la taxonomía de la NANDA-I, pero, que fueron apuntados por la literatura. CONCLUSIÓN: el proceso alcanzó el objetivo de producir definiciones operacionales válidas para características definidoras y factores de riesgo, lo que permitirá realizar estudios de validación de estos diagnósticos. La contribución del estudio para el avance del conocimiento científico consiste en presentar definiciones operacionales más claras de estos diagnósticos y un número mayor de características definidoras y factores de riesgo que podrá aportar con los enfermeros en la identificación y utilización de los mismos con mayor precisión en la práctica clínica.OBJETIVO: validar as definições operacionais das características definidoras e fatores de risco dos três diagnósticos de enfermagem, relacionados à pele, da NANDA International (NANDA-I), e revisar as definições desses diagnósticos. MÉTODO: validação de conteúdo de diagnóstico de enfermagem. Identificaram-se 146 características definidoras e fatores de risco na literatura, nas bases de dados nacionais e internacionais. Em seguida, realizou-se a validação de conteúdo das definições desses diagnósticos, apresentadas pela NANDA-I e das definições operacionais, elaboradas pelas pesquisadoras, das características definidoras e fatores de risco, por seis enfermeiras peritas, quanto à pertinência, clareza e abrangência. RESULTADOS: das 146 características definidoras e fatores de risco, 22 foram considerados redundantes e excluídos. Os peritos propuseram mudar a definição dos diagnósticos de Integridade Tissular Prejudicada e Risco de Integridade da Pele Prejudicada. Foi possível identificar várias características definidoras e fatores de risco que não estão presentes na taxonomia da NANDA-I, mas que foram apontados pela literatura. CONCLUSÃO: o processo atingiu o objetivo de produzir definições operacionais válidas para características definidoras e fatores de risco, o que permitirá realizar estudos de validação desses diagnósticos. A contribuição do estudo para o avanço do conhecimento científico consiste em apresentar definições operacionais mais claras desses diagnósticos e número maior de características definidoras e fatores de risco que poderão contribuir para que os enfermeiros identifiquem e se utilizem dos mesmos com maior acurácia na prática clínica

Probing Galaxy Evolution in Massive Clusters Using ACT and DES: Splashback as a Cosmic Clock

We measure the projected number density profiles of galaxies and the splashback feature in clusters selected by the Sunyaev–Zel'dovich effect from the Advanced Atacama Cosmology Telescope (AdvACT) survey using galaxies observed by the Dark Energy Survey (DES). The splashback radius is consistent with CDM-only simulations and is located at ${2.4}_{-0.4}^{+0.3}\,\mathrm{Mpc}\,{h}^{-1}$. We split the galaxies on color and find significant differences in their profile shapes. Red and green-valley galaxies show a splashback-like minimum in their slope profile consistent with theory, while the bluest galaxies show a weak feature at a smaller radius. We develop a mapping of galaxies to subhalos in simulations and assign colors based on infall time onto their hosts. We find that the shift in location of the steepest slope and different profile shapes can be mapped to the average time of infall of galaxies of different colors. The steepest slope traces a discontinuity in the phase space of dark matter halos. By relating spatial profiles to infall time, we can use splashback as a clock to understand galaxy quenching. We find that red galaxies have on average been in clusters over 3.2 Gyr, green galaxies about 2.2 Gyr, while blue galaxies have been accreted most recently and have not reached apocenter. Using the full radial profiles, we fit a simple quenching model and find that the onset of galaxy quenching occurs after a delay of about a gigayear and that galaxies quench rapidly thereafter with an exponential timescale of 0.6 Gyr

The mass and galaxy distribution around SZ-selected clusters

We present measurements of the radial profiles of the mass and galaxy number density around Sunyaev–Zel’dovich (SZ)-selected clusters using both weak lensing and galaxy counts. The clusters are selected from the Atacama Cosmology Telescope Data Release 5 and the galaxies from the Dark Energy Survey Year 3 data set. With signal-to-noise ratio of 62 (45) for galaxy (weak lensing) profiles over scales of about 0.2–20 h−1 Mpc, these are the highest precision measurements for SZ-selected clusters to date. Because SZ selection closely approximates mass selection, these measurements enable several tests of theoretical models of the mass and light distribution around clusters. Our main findings are: (1) The splashback feature is detected at a consistent location in both the mass and galaxy profiles and its location is consistent with predictions of cold dark matter N-body simulations. (2) The full mass profile is also consistent with the simulations. (3) The shapes of the galaxy and lensing profiles are remarkably similar for our sample over the entire range of scales, from well inside the cluster halo to the quasilinear regime. We measure the dependence of the profile shapes on the galaxy sample, redshift, and cluster mass. We extend the Diemer & Kravtsov model for the cluster profiles to the linear regime using perturbation theory and show that it provides a good match to the measured profiles. We also compare the measured profiles to predictions of the standard halo model and simulations that include hydrodynamics. Applications of these results to cluster mass estimation, cosmology, and astrophysics are discussed

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

The XMM cluster survey: exploring scaling relations and completeness of the dark energy survey year 3 redMaPPer cluster catalogue

We cross-match and compare characteristics of galaxy clusters identified in observations from two sky surveys using two completely different techniques. One sample is optically selected from the analysis of 3 years of Dark Energy Survey observations using the redMaPPer cluster detection algorithm. The second is X-ray selected from XMM observations analysed by the XMM Cluster Survey. The samples comprise a total area of 57.4 deg2, bounded by the area of four contiguous XMM survey regions that overlap the DES footprint. We find that the X-ray-selected sample is fully matched with entries in the redMaPPer catalogue, above λ > 20 and within 0.1 <z <0.9. Conversely, only 38 per cent of the redMaPPer catalogue is matched to an X-ray extended source. Next, using 120 optically clusters and 184 X-ray-selected clusters, we investigate the form of the X-ray luminosity-temperature (LX -TX ), luminosity-richness (LX -λ), and temperature-richness (TX -λ) scaling relations. We find that the fitted forms of the LX -TX relations are consistent between the two selection methods and also with other studies in the literature. However, we find tentative evidence for a steepening of the slope of the relation for low richness systems in the X-ray-selected sample. When considering the scaling of richness with X-ray properties, we again find consistency in the relations (i.e. LX -λ and TX -λ) between the optical and X-ray-selected samples. This is contrary to previous similar works that find a significant increase in the scatter of the luminosity scaling relation for X-ray-selected samples compared to optically selected samples