Prediction of survival by neutropenia according to delivery schedule of oxaliplatin-5-Fluorouracil-leucovorin for metastatic colorectal cancer in a randomized international trial (EORTC 05963)

Circadian clocks control cellular proliferation and drug metabolism over the 24 h. However, circadian chronomodulated chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (chronoFLO4) offered no survival benefit as compared with the non-time-stipulated FOLFOX2, in an international randomized trial involving patients with previously untreated metastatic colorectal cancer (EORTC 05963). The authors hypothesized that treatment near maximum tolerated dose could disrupt circadian clocks thus impairing the efficacy of chronoFLO4 but not of FOLFOX2. Patients with available data (N = 556) were categorized into three subgroups according to the worst grade (G) of neutropenia experienced during treatment. Distinct multivariate models with time-dependent covariates were constructed for each treatment schedule. Neutropenia incidence (all grades) was 33% on chronoFLO4 and 61% on FOLFOX2 (p < .0001), and G3-4 were 7% and 25%, respectively (p < .0001). Neutropenia was significantly more frequent in women than men on either schedule (FOLFOX2, p = .003; chronoFLO4, p = .04). Median survival was 20.7 mo in patients with G3-4 neutropenia versus 12.5 mo in neutropenia-free patients on FOLFOX2 (p < .0001). Corresponding figures were 13.7 and 19.4 mo, respectively, on chronoFLO4 (p = .36). Multivariate analysis confirmed occurrence of severe neutropenia independently predicted for better overall survival on FOLFOX2 (HR = 0.56; p = .015), and worse survival on chronoFLO4 (HR = 1.77, p = .06), with a significant interaction test (p < .0001). Prediction of better survival in neutropenic patients on FOLFOX2 supports the administration of conventional chemotherapy near maximum tolerated dose. The opposite trend shown here for chronoFLO4 supports the novel concept of jointly optimized hematologic tolerability and efficacy through personalized circadian-timed therapy.info:eu-repo/semantics/publishedVersio

Implementation of the new multichannel X-mode edge density profile reflectometer for the ICRF antenna on ASDEX Upgrade

A new multichannel frequency modulated continuous-wave reflectometry diagnostic has been successfully installed and commissioned on ASDEX Upgrade to measure the plasma edge electron density profile evolution in front of the Ion Cyclotron Range of Frequencies (ICRF) antenna. The design of the new three-strap ICRF antenna integrates ten pairs (sending and receiving) of microwave reflectometry antennas. The multichannel reflectometer can use three of these to measure the edge electron density profiles up to 2 x 10(19) m(-3), at different poloidal locations, allowing the direct study of the local plasma layers in front of the ICRF antenna. ICRF power coupling, operational effects, and poloidal variations of the plasma density profile can be consistently studied for the first time. In this work the diagnostic hardware architecture is described and the obtained density profile measurements were used to track outer radial plasma position and plasma shape

Hyperoside Supplementation in Preservation Media Surpasses Vitamin C Protection Against Oxidative Stress-Induced Damages in Human Spermatozoa

Background/Aims: Oxidative Stress (OS) is reported as one of the main causes of male infertility. Infertile couples often resort to assisted reproductive technology (ART) to achieve parenthood. However, preparation for ART protocols increases the exposer of gametes to OS. Thus, it is crucial to find suitable preservation media that can counteract the OS-induced damages in spermatozoa. In this work, we tested and compared the efficiency of vitamin C (VC) and hyperoside (HYP) as potential antioxidant supplements for sperm preservation media. Methods: We evaluated the cytotoxicity of HYP (0, 5, 50, 100, and 500 µM) in spermatozoa. After incubation of sperm cells with VC (600 µM) and HYP (100 and 500 µM), in the presence and absence of H2O2 (300 µM), the following parameters were assessed: total sperm motility and vitality, OS biomarkers expression, total antioxidant capacity (TAC) of the media, percentage of DNA fragmentation, mitochondrial membrane potential (MMP), and metabolite quantification of the media by proton nuclear magnetic resonance (1H-NMR). Results: The supplementation with VC (600 µM) and HYP (100 and 500 µM) did not induce any deleterious effects to the physiology and metabolism of the spermatozoa, after 1-hour of treatment. In the presence of H2O2 (300 µM), both VC and HYP were able to prevent some of the deleterious effects of H2O2 in sperm, which were represented by an increase in sperm motility, a decrease in DNA fragmentation, and a decreasing trend in lipid peroxidation levels. However, these antioxidants were not able to prevent the decrease of MMP associated with H2O2 treatment, nor were able to prevent the conversion of pyruvate into acetate (a reaction promoted by H2O2). Conclusion: The supplementation of sperm preservation media with VC and HYP could be beneficial for the preservation of sperm physiology. From the antioxidant conditions tested, the supplementation of media with HYP (100 µM) demonstrated the best results regarding sperm preservation, evidencing the higher antioxidant capacity of HYP compared to VC. Nevertheless, none of the antioxidants used was able to prevent the metabolic alterations promoted by H2O2 in spermatozoa.This work was supported by Fundação para a Ciência e a Tecnologia - FCT to Sara C. Pereira (2021.05487.BD); David F. Carrageta (SFRH/BD/136779/2018); Marco G. Alves (IFCT2015 and PTDC/MEC-AND/28691/2017); LAQV-REQUIMTE (UIDB/50006/2020); UMIB (UIDB/00215/2020, and UIDP/00215/2020); ITR - Laboratory for Integrative and Translational Research in Population Health (LA/P/0064/2020). Pedro F. Oliveira was funded by national funds through FCT – Fundação para a Ciência e a Tecnologia, I.P., under the Scientific Employment Stimulus - Institutional Call - reference CEECINST/00026/2018

Latent cluster analysis of ALS phenotypes identifies prognostically differing groups

BACKGROUND Amyotrophic lateral sclerosis (ALS) is a degenerative disease predominantly affecting motor neurons and manifesting as several different phenotypes. Whether these phenotypes correspond to different underlying disease processes is unknown. We used latent cluster analysis to identify groupings of clinical variables in an objective and unbiased way to improve phenotyping for clinical and research purposes. METHODS Latent class cluster analysis was applied to a large database consisting of 1467 records of people with ALS, using discrete variables which can be readily determined at the first clinic appointment. The model was tested for clinical relevance by survival analysis of the phenotypic groupings using the Kaplan-Meier method. RESULTS The best model generated five distinct phenotypic classes that strongly predicted survival (p<0.0001). Eight variables were used for the latent class analysis, but a good estimate of the classification could be obtained using just two variables: site of first symptoms (bulbar or limb) and time from symptom onset to diagnosis (p<0.00001). CONCLUSION The five phenotypic classes identified using latent cluster analysis can predict prognosis. They could be used to stratify patients recruited into clinical trials and generating more homogeneous disease groups for genetic, proteomic and risk factor research

Position statement on bioresorbable vascular scaffolds in Portugal

BACKGROUND: Bioresorbable vascular scaffolds (BVS) were recently approved for percutaneous coronary intervention in Europe. The aim of this position statement is to review the information and studies on available BVS, to stimulate discussion on their use and to propose guidelines for this treatment option in Portugal. METHODS AND RESULTS: A working group was set up to reach a consensus based on current evidence, discussion of clinical case models and individual experience. The evidence suggests that currently available BVS can produce physiological and clinical improvements in selected patients. There are encouraging data on their durability and long-term safety. Initial indications were grouped into three categories: (a) consensual and appropriate - young patients, diabetic patients, left anterior descending artery, long lesions, diffuse disease, and hybrid strategy; (b) less consensual but possible - small collateral branches, stabilized acute coronary syndromes; and (c) inappropriate - left main disease, tortuosity, severe calcification. CONCLUSION: BVS are a viable treatment option based on the encouraging evidence of their applicability and physiological and clinical results. They should be used in appropriate indications and will require technical adaptations. Outcome monitoring and evaluation is essential to avoid inappropriate use. It is recommended that medical societies produce clinical guidelines based on high-quality registries as soon as possible

Solução glicosada hipertônica no mesentério e no peritônio de ratos: estudo macroscópico e microscópico

PURPOSE: The objective of the experimental study is to detect the macroscopic and microscopic alterations of the mesenterium and parietal peritoneum when hypertonic glucose aqueous solution 10%-25% is administrated into the peritoneal cavity of the rat. METHODS: 90 Wistar females young rats adults were used weighin between 180-250 g, numbered 1 to 90, establishing unique group and divided in three groups (A, B, C) of 30 animals chosen aleatory manner. 0,9% saline solution was used called control group, or group A, 10% glucose solution named group B, and in the others 30 was used 25% glucose solution named group C, differing in the observation period, (06h, 24h and 48h), but with the same procedure. A midline abdominal wall laparotomy was made and in the animals of the control group was injected 2 ml of a 0,9% saline solution into the peritoneal cavity. After, we made a suture in mass without to include the peritoneum. For the others groups (B, C) the rats received 10% glucose solution and 25% glucose solution injected into the peritoneal cavity respectively. All groups were kept under observation and the results were submitted to statistical analysis by a longitudinal and transversal comparative study. RESULTS: A new surgery was done in 6h, 24h and 48h, and we observed in macroscopic evaluation, the presence of fluid, serous uniforme and rosy all over the cavity. Vascular congestion was present. We dried out 90 fragments of mesenterium and 90 fragments of parietal peritonium bilateral. In the microscopic study, necrosis was not present. For the mesenterium histological study we observed 16 cases (17,8%) unspecific chronic inflammation, 30 cases (33,4%) hiperplasic linfonod, 10 cases (11,1%) high vascular congestion, 6 cases (6,6%) reaction fibrosis and 28 cases (31,1%) no alteration. For the parietal peritonium histological study we observed 6 cases (3,3%) reaction fibrosis and 174 cases (96,7%) no alteration. Giant cell was not present. In the statistical analisys statistic there is no significance between the groups (p>0,05). CONCLUSION: Hypertonic glucose solution and NaCl 0,9% on the mesenterium and parietal peritonium do not produce tissue necrosis in a rat and the inflammation process has the same intensity.OBJETIVO: Investigar as alterações macroscópicas e microscópicas do mesentério e do peritônio parietal quando se administra a solução aquosa de glicose hipertônica a 10% e a 25% na cavidade peritoneal de rato. MÉTODOS: 90 ratos fêmeas (n=90), adultos, Wistar, jovens, com peso variando de 180 a 250 gramas foram divididos em 3 sub-grupos (A, B e C) contendo cada um 30 animais com procedimentos idênticos, diferindo apenas no período de observação. Os números de 1 a 30 constituem o grupo A ou grupo-controle (NaCl 0,9%), os números de 31 a 60 constituem o grupo B ou grupo-glicose a 10% e os números de 61 a 90 constituem o grupo C ou grupo- glicose a 25%. Realizando-se posteriormente laparotomia com incisão mediana longitudinal de pele a 2 cm abaixo do processo Xiphoideus sterni, estendendo-se por 3 cm caudalmente na linha média ventral. A escolha do procedimento a ser realizado para introdução na cavidade peritoneal de 2 ml de uma solução de cloreto de sódio 0,9% (controle), de glicose hipertônica a 10% e de glicose hipertônica a 25%. Em períodos correspondentes às 6h, 24h e 48h de pós-operatório, os animais de cada grupo foram reoperados, sendo realizada avaliação macroscópica e microscópica além dos registros das alterações histológicas do mesentério e peritônio parietal. RESULTADOS: Na microscopia do mesentério observou-se que 30 animais (33,4%) apresentaram linfonodos hiperplásicos; 6 animais (6,6%) com fibrose reacional; 10 animais (11,1%) com intensa congestão vascular; 16 animais (17,8%) com inflamação crônica inespecífica; 28 casos (31,1%) sem alteração. A microscopia do peritônio revelou 6 casos com fibrose reacional (3,3%) 174 casos (96,7%) sem alteração histológica. CONCLUSÃO: As soluções de glicose a 10% e a 25% não causam necrose tecidual quando introduzidas na cavidade peritoneal. O processo reacional inflamatório é de igual intensidade tecidual comparando-se ao uso da solução de NaCl a 0,9%.UNCISAL DepartmentUFAL Morphology Department and Human AnatomyUNIFESP-EPM Surgery DepartmentUNIFESP, EPM, Surgery DepartmentSciEL

Listeria monocytogenes encodes a functional ESX-1 secretion system whose expression is detrimental to in vivo infection

Bacterial pathogenicity deeply depends on the ability to secrete virulence factors that bind specific targets on host cells and manipulate host responses. The Gram-positive bacterium Listeria monocytogenes is a human foodborne pathogen that remains a seriThis work was supported for the DC lab by national funds through FCT - Fundacao para a Ciencia e a Tecnologia/MEC Ministerio da Educacao e Ciencia and co-funded by FEDER funds within the partnership agreement PT2020 related with the research unit number

Membranes by the Numbers

Many of the most important processes in cells take place on and across membranes. With the rise of an impressive array of powerful quantitative methods for characterizing these membranes, it is an opportune time to reflect on the structure and function of membranes from the point of view of biological numeracy. To that end, in this article, I review the quantitative parameters that characterize the mechanical, electrical and transport properties of membranes and carry out a number of corresponding order of magnitude estimates that help us understand the values of those parameters.Comment: 27 pages, 12 figure