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AbstractThis study investigates drug-loaded liposomes designed for controlled release under ionizing radiation to refine cancer treatment precision. Liposomes as carriers enable targeted chemotherapy delivery, reducing healthy tissue damage risk. Liposomes containing poly- or mono-unsaturated fatty acids and various sensitizing agents were assessed for responsiveness to UV light and γ photon irradiation including rose bengal (RB), protoporphyrin IX (PPIX), verteporfin (VP), cercosporin (CERC) and hypericin (HYP). Carboxyfluorescein (CF) was used as a surrogate for drug release measurements. VP and PPIX induced rapid drug release and lipid peroxidation under UV light, while RB prompted quick drug release under UV light and a modest immediate release under γ irradiation, eventually reaching full release a few hours after irradiation, demonstrating dose-dependent effects. Smaller liposomes displayed accelerated release, emphasizing size-dependent kinetics. In vitro analyses evaluated radiosensitizing effects of RB-loaded liposomes. Clonogenic assays indicated that RB-filled liposomes had minimal direct radiobiological effects but increased indirect radiation damage, as shown by the curvature of the cell survival curve. Our study sheds light on factors influencing liposomal drug release under ionizing radiation, spotlighting RB as a promising radiosensitizer requiring further investigation for cancer therapy potential. [ABSTRACT FROM AUTHOR]

New SARS-CoV-2 may pose problems in controlling the COVID-19 pandemic for public health. We aimed to assess and compare the symptoms and severity of cases due to the Alpha and Delta variant dominance periods, taking into account the effect of COVID-19 vaccination. A prospective epidemiological study of SARS-CoV-2 in Lleida was made to determine differences between Alpha and Delta variants periods. We assessed symptoms, specific comorbidities, sociodemographic information and vaccination status. Bivariate and logistic regression analyses were used to estimate the adjusted odds ratio (aOR) and 95% confidence intervals (CI) to investigate the relationship between symptoms and severity and the variants. Alpha variant period compared to the Delta showed an increased risk of ICU admission (aOR 2.0; 95% CI 1.2–2.3) and death (aOR 2.6; 95% CI 1.8–3.9) and cases were associated with people aged > 85 years (aOR 2.1; 95% CI 1.7–2.6) and partially vaccinated (aOR 5.6; 95% CI 3.2–9.9) and unvaccinated people (aOR 27.8; 95% CI 19.7–40.5). Fever, cough and vomiting were significantly associated with the Alpha variant compared to the Delta (aOR 1.6 (95% CI 1.5–1.7), 2.0 (95% CI 1.9–2.2) and 2.5 (95% CI 2.2–2.9, respectively). Our results show that the severity and profile of clinical symptoms varied according to the variant. The risk of ICU admission and death was higher in the Alpha period compared to the Delta as it affected the elderly and cases were less vaccinated. [ABSTRACT FROM AUTHOR]

Characterization of fungal spider pathogens lags far behind their insect counterparts. In addition, little to nothing is known concerning the ecological reservoir and/or fungal entomopathogen community surrounding infection sites. Five infected spider cadavers were identified in the neo-tropical climate of north-central Florida, USA, from three of which viable cultures were obtained. Multi-locus molecular phylogenetic and morphological characterization identified one isolate as a new Gibellula species, here named, Gibellula floridensis, and the other isolates highly similar to Parengyodontium album. The fungal entomopathogen community surrounding infected spiders was sampled at different habitats/trophic levels, including soil, leaf litter, leaf, and twig, and analyzed using ITS amplicon sequencing. These data revealed broad but differential distribution of insect-pathogenic fungi between habitats and variation between sites, with members of genera belonging to Metarhizium and Metacordyceps from Clavicipitaceae, Purpureocillium and Polycephalomyces from Ophiocordyceps, and Akanthomyces and Simplicillium from Cordycipitaceae predominating. However, no sequences corresponding to Gibellula or Parengyodontium, even at the genera levels, could be detected. Potential explanations for these findings are discussed. These data highlight novel discovery of fungal spider pathogens and open the broader question regarding the environmental distribution and ecological niches of such host-specific pathogens. [ABSTRACT FROM AUTHOR]

Background: We previously reported that olaparib led to significantly longer imaging-based progression-free survival than the physician's choice of enzalutamide or abiraterone among men with metastatic castration-resistant prostate cancer who had qualifying alterations in homologous recombination repair genes and whose disease had progressed during previous treatment with a next-generation hormonal agent. The results of the final analysis of overall survival have not yet been reported.Methods: In an open-label, phase 3 trial, we randomly assigned patients in a 2:1 ratio to receive olaparib (256 patients) or the physician's choice of enzalutamide or abiraterone plus prednisone as the control therapy (131 patients). Cohort A included 245 patients with at least one alteration in BRCA1, BRCA2, or ATM, and cohort B included 142 patients with at least one alteration in any of the other 12 prespecified genes. Crossover to olaparib was allowed after imaging-based disease progression for patients who met certain criteria. Overall survival in cohort A, a key secondary end point, was analyzed with the use of an alpha-controlled, stratified log-rank test at a data maturity of approximately 60%. The primary and other key secondary end points were reported previously.Results: The median duration of overall survival in cohort A was 19.1 months with olaparib and 14.7 months with control therapy (hazard ratio for death, 0.69; 95% confidence interval [CI], 0.50 to 0.97; P = 0.02). In cohort B, the median duration of overall survival was 14.1 months with olaparib and 11.5 months with control therapy. In the overall population (cohorts A and B), the corresponding durations were 17.3 months and 14.0 months. Overall, 86 of 131 patients (66%) in the control group crossed over to receive olaparib (56 of 83 patients [67%] in cohort A). A sensitivity analysis that adjusted for crossover to olaparib showed hazard ratios for death of 0.42 (95% CI, 0.19 to 0.91) in cohort A, 0.83 (95% CI, 0.11 to 5.98) in cohort B, and 0.55 (95% CI, 0.29 to 1.06) in the overall population.Conclusions: Among men with metastatic castration-resistant prostate cancer who had tumors with at least one alteration in BRCA1, BRCA2, or ATM and whose disease had progressed during previous treatment with a next-generation hormonal agent, those who were initially assigned to receive olaparib had a significantly longer duration of overall survival than those who were assigned to receive enzalutamide or abiraterone plus prednisone as the control therapy, despite substantial crossover from control therapy to olaparib. (Funded by AstraZeneca and Merck Sharp and Dohme; PROfound ClinicalTrials.gov number, NCT02987543.). [ABSTRACT FROM AUTHOR]

Quambalaria cyanescens was positively identified on the surface of unripened grapes by physiological and molecular techniques; this is the first work describing the isolation of this fungus in European grapes and all of them produced an exocellular β-glucosidase. Once isolates with higher activity were selected, the enzyme has been qualitatively and quantitatively determined and characterized, by spectrophotometric methods, based on its biotechnological properties Exocellular β-glucosidase produced by Q. cyanescens is inhibited by glucose but is an ethanol-tolerant enzyme and its activity is independent of the pH value. Divalent cations, mainly Ca2+, highly increase enzymatic activity. This is the first work describing the isolation, identification and characterization of Q. cyanescens in grapes. Although there is growing interest in the search for new fungal β-glucosidases, the vast majority of studies were performed with imperfect fungi, and there are scant reports that deal with basidiomycetous fungi, not only for biotechnological purposes but also for physiological research. [ABSTRACT FROM AUTHOR]

Background: Multiple loss-of-function alterations in genes that are involved in DNA repair, including homologous recombination repair, are associated with response to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition in patients with prostate and other cancers.Methods: We conducted a randomized, open-label, phase 3 trial evaluating the PARP inhibitor olaparib in men with metastatic castration-resistant prostate cancer who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). All the men had a qualifying alteration in prespecified genes with a direct or indirect role in homologous recombination repair. Cohort A (245 patients) had at least one alteration in BRCA1, BRCA2, or ATM; cohort B (142 patients) had alterations in any of 12 other prespecified genes, prospectively and centrally determined from tumor tissue. Patients were randomly assigned (in a 2:1 ratio) to receive olaparib or the physician's choice of enzalutamide or abiraterone (control). The primary end point was imaging-based progression-free survival in cohort A according to blinded independent central review.Results: In cohort A, imaging-based progression-free survival was significantly longer in the olaparib group than in the control group (median, 7.4 months vs. 3.6 months; hazard ratio for progression or death, 0.34; 95% confidence interval, 0.25 to 0.47; P<0.001); a significant benefit was also observed with respect to the confirmed objective response rate and the time to pain progression. The median overall survival in cohort A was 18.5 months in the olaparib group and 15.1 months in the control group; 81% of the patients in the control group who had progression crossed over to receive olaparib. A significant benefit for olaparib was also seen for imaging-based progression-free survival in the overall population (cohorts A and B). Anemia and nausea were the main toxic effects in patients who received olaparib.Conclusions: In men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes with a role in homologous recombination repair, olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone. (Funded by AstraZeneca and Merck Sharp & Dohme; PROfound ClinicalTrials.gov number, NCT02987543.). [ABSTRACT FROM AUTHOR]

Genomic instability is a hallmark of cancer, and often is the result of altered DNA repair capacities in tumour cells. DNA damage repair defects are common in different cancer types; these alterations can also induce tumour-specific vulnerabilities that can be exploited therapeutically. In 2009, a first-in-man clinical trial of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib clinically validated the synthetic lethal interaction between inhibition of PARP1, a key sensor of DNA damage, and BRCA1/BRCA2 deficiency. In this review, we summarize a decade of PARP inhibitor clinical development, a work that has resulted in the registration of several PARP inhibitors in breast (olaparib and talazoparib) and ovarian cancer (olaparib, niraparib and rucaparib, either alone or following platinum chemotherapy as maintenance therapy). Over the past 10 years, our knowledge on the mechanism of action of PARP inhibitor as well as how tumours become resistant has been extended, and we summarise this work here. We also discuss opportunities for expanding the precision medicine approach with PARP inhibitors, identifying a wider population who could benefit from this drug class. This includes developing and validating better predictive biomarkers for patient stratification, mainly based on homologous recombination defects beyond BRCA1/BRCA2 mutations, identifying DNA repair deficient tumours in other cancer types such as prostate or pancreatic cancer, or by designing combination therapies with PARP inhibitors. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • LIBS has been shown to be an efficient method to determine Cl content in mortar. • LIBS is non-destructive technique that allows measurements without material damage. • High resolution metering of mortar affected by Cl ambient can be performed by LIBS. • The development of a portable LIBS device will allow fast Cl measurements on-site. Abstract In a society where the cement and concrete industry is of great importance, the diagnosis of the quality of these materials has become a matter of highest priority. One of the maximum exponents of the deterioration of a reinforced concrete structure is the chloride ion content. In this work it has been shown that its evaluation, traditionally carried out by chemical methods, can also be performed by laser-induced breakdown spectroscopy (LIBS), a much faster and advantageous technique. This work develops an optimal experimental set-up based on the generation of small discharges using a 532 nm Nd:YAG laser of 320 mJ, in a helium atmosphere. The experimental conditions have been optimized and a calibration curve, relating the ratio of intensities of Cl I 837.60 nm and Ca II 849.80 nm obtained from the LIBS and the actual chloride concentration, has been determined from a set of samples with different ion chloride concentrations. These samples have been simultaneously subjected to a traditional chemical analysis, as well as instrumental contrast analysis using energy-dispersive X-ray spectroscopy (EDX). Finally, LIBS technique has been applied to the study of mortar samples that had been submerged in saturated sea salt water for 60 months, and in this way their average ion chloride concentration and their depth profiles have been obtained. [ABSTRACT FROM AUTHOR]

Background In order to facilitate implementation of precision medicine in clinical management of cancer, there is a need to harmonise and standardise the reporting and interpretation of clinically relevant genomics data. Methods The European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group (TR and PM WG) launched a collaborative project to propose a classification system for molecular aberrations based on the evidence available supporting their value as clinical targets. A group of experts from several institutions was assembled to review available evidence, reach a consensus on grading criteria and present a classification system. This was then reviewed, amended and finally approved by the ESMO TR and PM WG and the ESMO leadership. Results This first version of the ESMO Scale of Clinical Actionability for molecular Targets (ESCAT) defines six levels of clinical evidence for molecular targets according to the implications for patient management: tier I, targets ready for implementation in routine clinical decisions; tier II, investigational targets that likely define a patient population that benefits from a targeted drug but additional data are needed; tier III, clinical benefit previously demonstrated in other tumour types or for similar molecular targets; tier IV, preclinical evidence of actionability; tier V, evidence supporting co-targeting approaches; and tier X, lack of evidence for actionability. Conclusions The ESCAT defines clinical evidence-based criteria to prioritise genomic alterations as markers to select patients for targeted therapies. This classification system aims to offer a common language for all the relevant stakeholders in cancer medicine and drug development. [ABSTRACT FROM AUTHOR]

[Display omitted] • Laser-Induced Breakdown Spectroscopy (LIBS) is a powerful tool for the analysis of chloride diffusion in mortar and concrete. • The LIBS measurements shows that chloride ions penetration profiles through the samples fit reasonably well Fick's second law in a modified version. • The apparent diffusion coefficients measured by LIBS for the mortar and concrete samples agree with the results obtained by other techniques. • The LIBS was used to study the aging of mortar samples, an age-factor α = 0.449 ± 0.006 was measured. In this work, the applicability of Laser-Induced Breakdown Spectroscopy (LIBS) for the analysis of chloride diffusion in mortar and concrete has been studied. The high resolution of this technique allows it to obtain a mapping of the chloride ions distribution in these materials upon being exposed to salted environments, thus providing an image of how chlorides diffuse inside them. The technique has been applied to mortar samples submerged in a salt-saturated solution for 3, 9, and 30 months. It has been demonstrated that the penetration profiles fit reasonably well Fick's second law in a modified version. The apparent diffusion coefficients for these samples were obtained (D 3months = (5.94 ± 0.05) × 10−13 m2/s; D 9months = (3.6 ± 0.6) × 10−13 m2/s; D 30months = (2.1 ± 0.8) × 10−13 m2/s). These results are in the range of the values found in other similar studies. The study of the evolution of these parameters over time revealed an age-factor α = 0.449 ± 0.006. Finally, LIBS was also applied to a concrete sample submitted to a long-period (60 months) immersion in the salt-saturated solution, giving similar good results (D 60months = (1.81 ± 0.03) × 10−13 m2/s), which demonstrates its suitability for the study of chloride diffusion in this type of material. [ABSTRACT FROM AUTHOR]

Background: Abiraterone and cabazitaxel improve survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We conducted an open-label phase I/II trial of cabazitaxel plus abiraterone to assess the antitumor activity and tolerability in patients with progressive mCRPC after docetaxel (phase I), and after docetaxel and abiraterone (phase II) (NCT01511536). Patients and methods: The primary objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus abiraterone (phase I), and the prostate-specific antigen (PSA) response defined as a≥50% decrease confirmed ≥3 weeks later with this combination (phase II). Results: Ten patients were enrolled in the phase I component; nine were evaluable. No DLTs were identified. The MTD was established as the approved doses for both drugs (cabazitaxel 25 mg/m2 every 3 weeks and abiraterone 1000mg once daily). Daily abiraterone treatment did not impact on cabazitaxel clearance. Twenty-seven patients received cabazitaxel plus abiraterone plus prednisone (5mg twice daily) in phase II. The median number of cycles administered (cabazitaxel) was seven (range: 1-28). Grade 3-4 treatment-emergent adverse events included asthenia (in 5 patients; 14%), neutropenia (in 5 patients; 14%) and diarrhea (in 3 patients; 8%). Nine patients (24%) required dose reductions of cabazitaxel. Of 26 evaluable patients, 12 achieved a PSA response [46%; 95% confidence interval (CI): 26.6-66.6%]. Median PSA-progression-free survival was 6.9 months (95% CI: 4.1-10.3 months). Of 14 patients with measurable disease at baseline, 3 (21%) achieved a partial response per response evaluation criteria in solid tumors. Conclusions: The combination of cabazitaxel and abiraterone has a manageable safety profile and shows antitumor activity in patients previously treated with docetaxel and abiraterone. [ABSTRACT FROM AUTHOR]

Objective Deficient prepulse inhibition ( PPI) of the startle response, indicating sensorimotor gating deficits, has been reported in schizophrenia and other neuropsychiatric disorders. This study aimed to assess sensorimotor gating deficits in patients with euthymic bipolar. Furthermore, we analysed the relationships between PPI and clinical and cognitive measures. Method Prepulse inhibition was measured in 64 patients with euthymic bipolar and in 64 control subjects matched for age, gender, education level and smoking status. Clinical characteristics and level of functioning were assessed in all participants using Hamilton Depression Rating Scale ( HDRS), Young Mania Rating Scale ( YMRS) and Functioning Assessment Short Test ( FAST). Cognition was evaluated using the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery ( MCCB) and the Stroop test as an additional measure of executive function. Results Compared with controls, patients with bipolar disorder exhibited PPI deficits at 60- and 120-millisecond prepulse-pulse intervals. Among patients with bipolar disorder, PPI was correlated with the social cognition domain of the MCCB. PPI was not significantly correlated with other clinical, functional and neurocognitive variables in either group. Conclusions Our data suggest that PPI deficit is a neurobiological marker in euthymic bipolar disorder, which is associated with social cognition but not with other clinical, functional or cognitive measures. [ABSTRACT FROM AUTHOR]

Electroencephalogram (EEG) recordings often experience interference by different kinds of noise, including white, muscle and baseline, severely limiting its utility. Artificial neural networks (ANNs) are effective and powerful tools for removing interference from EEGs. Several methods have been developed, but ANNs appear to be the most effective for reducing muscle and baseline contamination, especially when the contamination is greater in amplitude than the brain signal. An ANN as a filter for EEG recordings is proposed in this paper, developing a novel framework for investigating and comparing the relative performance of an ANN incorporating real EEG recordings. This method is based on a growing ANN that optimized the number of nodes in the hidden layer and the coefficient matrices, which are optimized by the simultaneous perturbation method. The ANN improves the results obtained with the conventional EEG filtering techniques: wavelet, singular value decomposition, principal component analysis, adaptive filtering and independent components analysis. The system has been evaluated within a wide range of EEG signals. The present study introduces a new method of reducing all EEG interference signals in one step with low EEG distortion and high noise reduction. [ABSTRACT FROM AUTHOR]

Background: Inherited mutations in DNA-repair genes such as BRCA2 are associated with increased risks of lethal prostate cancer. Although the prevalence of germline mutations in DNA-repair genes among men with localized prostate cancer who are unselected for family predisposition is insufficient to warrant routine testing, the frequency of such mutations in patients with metastatic prostate cancer has not been established.Methods: We recruited 692 men with documented metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis. We isolated germline DNA and used multiplex sequencing assays to assess mutations in 20 DNA-repair genes associated with autosomal dominant cancer-predisposition syndromes.Results: A total of 84 germline DNA-repair gene mutations that were presumed to be deleterious were identified in 82 men (11.8%); mutations were found in 16 genes, including BRCA2 (37 men [5.3%]), ATM (11 [1.6%]), CHEK2 (10 [1.9% of 534 men with data]), BRCA1 (6 [0.9%]), RAD51D (3 [0.4%]), and PALB2 (3 [0.4%]). Mutation frequencies did not differ according to whether a family history of prostate cancer was present or according to age at diagnosis. Overall, the frequency of germline mutations in DNA-repair genes among men with metastatic prostate cancer significantly exceeded the prevalence of 4.6% among 499 men with localized prostate cancer (P<0.001), including men with high-risk disease, and the prevalence of 2.7% in the Exome Aggregation Consortium, which includes 53,105 persons without a known cancer diagnosis (P<0.001).Conclusions: In our multicenter study, the incidence of germline mutations in genes mediating DNA-repair processes among men with metastatic prostate cancer was 11.8%, which was significantly higher than the incidence among men with localized prostate cancer. The frequencies of germline mutations in DNA-repair genes among men with metastatic disease did not differ significantly according to age at diagnosis or family history of prostate cancer. (Funded by Stand Up To Cancer and others.). [ABSTRACT FROM AUTHOR]

The analysis of the surface Electrocardiogram (ECG) is the most extended non-invasive technique in cardiological diagnosis. The ectopic beats are heart beats remarkably different to the normal beat morphology that provoke serious disturbances in electrocardiographic analysis. These beats are very common in atrial fibrillation (AF), causing important residua when ventricular activity has to be removed for atrial activity (AA) analysis. These beats may occur in both normal subjects and patients with heart disease, and their presence represents an important source of error which must be handled before any other analysis. In this work, a method is proposed to cancel out ectopics by classification between normal and abnormal beats. The systems is based on Radial Basis Function Neural Network (RBFNN). This new approach is compared to state-of-the-art techniques for the ectopic classification and cancellation in the MIT database. The results clearly demonstrated the improved ECG beats classification accuracy compared with other alternatives and a very accurate reduction of ectopic beats together with low distortion of the QRST complex. [ABSTRACT FROM AUTHOR]

A complete room acoustics analysis requires not only measurements of the single-room impulse response, but also a rigorous analysis of the sound field's spatial properties. Angle-dependent information for the direct and reflected waves is needed for a more complete sound field description than can be obtained with single microphone measurements. Analysis techniques based on uniform circular arrays (UCAs) have attracted a lot of attention in recent years. There is also active research on beamforming methods based on circular harmonic plane-wave sound field decomposition. However, to date, there has not been a comprehensive experimental study of the acoustics of real rooms that employs both techniques. In this paper, the UCA topology is used in a comparative study for plane-wave decomposition and enhanced modal beamforming techniques. As a result, room echograms can also be obtained by calculating a set of azimuth-steered impulse responses. Experiments in real and simulated rooms are compared and discussed, with an identification of strengths and weaknesses for both measurement methods. The results show the validity of the modal beamforming approach by comparing its performance with that of the plane-wave decomposition method. [ABSTRACT FROM AUTHOR]

The article focuses on the enforcement of the U.S. Foreign Corrupt Practices Act with regulatory effort with act of legal imperialism and limitations on its extraterritorial reach in light of the interests of foreign jurisdictions, business, and foreign relations. It mentions that courts should analyze prescriptive jurisdiction under the FCPA and the personal jurisdiction in FCPA cases. It also mentions that FCPA regulates bribery and false or inaccurate accounting.

Background: Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.Methods: We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies.Results: Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib.Conclusions: Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.). [ABSTRACT FROM AUTHOR]

Advanced medical diagnosing and research requires precise information which can be obtained from measured electrophysiological data, e.g., electroencephalogram (EEG) and electrocardiograph (ECG). However, they are often contaminated with noise and a variety of bioelectric signals called artefacts, e.g., electromyography (EMG). These noise and artefacts which need to be reduced make it difficult to distinguish normal from abnormal physiological activity. Electromagnetic contamination of recorded signals represents a major source of noise in electrophysiology and impairs the use of recordings for research. In this paper we present an effective method for cancelling 50 Hz (or 60 Hz) interference using a radial basis function (RBF) Wiener hybrid filter. One of the main points of this paper is the hybridization of the RBF filter and a Wiener filter to make full use of both merits. The effectiveness and validity of those filters are verified by applying them to ECG and EEG recordings. The results show that the proposed method is able to reduce powerline interference (PLI) from the noisy ECG and EEG signals more accurately and consistently in comparison to some of the state of-the-art methods and this method can be efficiently used with very low signal-to-noise ratios, while preserving original signal waveform. [ABSTRACT FROM AUTHOR]

Background: The neutrophil-lymphocyte ratio (NLR), proposed as an indicator of cancer-related inflammation, has known prognostic value in prostate cancer. We examine its association with survival (OS) and response in patients treated with second-line chemotherapy. Methods: We analysed patients with metastatic castration-resistant prostate cancer (mCRPC) treated in the TROPIC trial, evaluating cabazitaxel versus mitoxantrone. Cox regression models were used to investigate the association of baseline NLR (BLNLR) with OS and the significance of a change in NLR count with treatment. Logistic regression models were used to determine the association of BLNLR counts with prostate specific antigen (PSA) and RECIST responses. The optimal NLR cut-off was established based on the concordance index of different values. Results: Data from 755, 654 and 405 patients was available for OS, PSA and RECIST response analysis respectively. Median OS was 14.0 months [95% confidence interval (CI) 13.2-14.8]. Median NLR was 2.9 (IQR: 1.9-5.1). BLNLR was associated with survival (HR 1.5, 95%CI 1.1-2.1, P = 0.011) in multivariable analysis (MVA) independently of variables included in the Halabi nomogram, treatment arm and corticosteroid use. The optimal cut-off for a dichotomous NLR was selected at 3.0 based on its higher c-index related to survival. BLNLR ≥3.0 was associated with lower PSA response (40.1% versus 59.9%; P < 0.001) and RECIST response (7.7% versus 15.6%, P = 0.022) in MVA. Conversion from high (≥3) to low (<3) NLR was associated with improved survival (HR 0.66; 95% CI 0.51-0.85; P = 0.001) and higher PSA response rates (66.4% versus 33.6%; P = 0.000). Use of corticosteroids at baseline did not modify the association between NLR and survival. Conclusions: NLR is a valid prognostic biomarker in CRPC and is associated with survival, PSA and RECIST responses in patients treated with second-line chemotherapy. Changes in NLR counts with treatment may indicate benefit. NLR prognostic value is independent of prior use of corticosteroids. [ABSTRACT FROM AUTHOR]

Powerline contamination of recorded signals represents a major source of noise in electrophysiology and impairs the use of recordings for research. Furthermore it degrades the signal quality and overwhelms tiny features that may be critical for clinical monitoring and diagnosis. During last years, notch filters and adaptive cancellers have been suggested to suppress this interference. In this article we present an improved adaptive canceller for the reduction of the fundamental powerline interference component and harmonics in electrocardiogram (ECG) and electrocardiograph (EEG) recordings. In this new ECG and EEG denoising approach is used an affine projection (AP) algorithm based on Gauss-Seidel method. The results show that the proposed method is able to reduce powerline interference from the noisy ECG and EEG signals more accurately and consistently in comparison to some of the state of-the-art methods. Furthermore, AP can be efficiently used with very low signal-to-noise ratios, while preserving original signal waveform. [ABSTRACT FROM AUTHOR]

Purpose: A first-in-human clinical trial of a fully human, Fc-engineered IgG1 monoclonal antibody targeting integrin α5β1 was conducted to evaluate tolerability, maximum tolerated dose, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity.Methods: Escalating doses of PF-04605412 were given IV on day 1, 28 and every 2 weeks thereafter to patients with advanced solid tumors until disease progression or unacceptable toxicity. Sequential dose cohorts were evaluated based on a modified 3 + 3 dose-escalation design. The starting dose was 7.5 mg based on preclinical data.Results: Thirty-three patients were enrolled to six dose levels (7.5, 11.25, 16.9, 34, 68 and 136 mg). Twenty-three patients were evaluable for the primary endpoint (determination of the maximum tolerated dose). Five patients required permanent drug discontinuation due to acute infusion-related reactions, which occurred as grade 3 events in two patients. PK analysis indicated that the targeted drug exposure based on preclinical models was not achieved by the tolerated doses and PK modeling suggesting that doses at least fivefold higher would be necessary. No anti-tumor activity was observed.Conclusion: Based on the safety data, the risks associated with the likelihood of significant cytokine-mediated infusion reactions at higher doses, the projected high dose necessary to affect on the biological target and the lack of anti-tumor activity at the doses explored, the trial was prematurely terminated without determining a formal maximum tolerated dose. Further clinical development of PF-04605412 has been discontinued. [ABSTRACT FROM AUTHOR]

Purpose: A first-in-human clinical trial of a fully human, Fc-engineered IgG1 monoclonal antibody targeting integrin α5β1 was conducted to evaluate tolerability, maximum tolerated dose, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity. Methods: Escalating doses of PF-04605412 were given IV on day 1, 28 and every 2 weeks thereafter to patients with advanced solid tumors until disease progression or unacceptable toxicity. Sequential dose cohorts were evaluated based on a modified 3 + 3 dose-escalation design. The starting dose was 7.5 mg based on preclinical data. Results: Thirty-three patients were enrolled to six dose levels (7.5, 11.25, 16.9, 34, 68 and 136 mg). Twenty-three patients were evaluable for the primary endpoint (determination of the maximum tolerated dose). Five patients required permanent drug discontinuation due to acute infusion-related reactions, which occurred as grade 3 events in two patients. PK analysis indicated that the targeted drug exposure based on preclinical models was not achieved by the tolerated doses and PK modeling suggesting that doses at least fivefold higher would be necessary. No anti-tumor activity was observed. Conclusion: Based on the safety data, the risks associated with the likelihood of significant cytokine-mediated infusion reactions at higher doses, the projected high dose necessary to affect on the biological target and the lack of anti-tumor activity at the doses explored, the trial was prematurely terminated without determining a formal maximum tolerated dose. Further clinical development of PF-04605412 has been discontinued. [ABSTRACT FROM AUTHOR]

The sensorial characteristics of the wines produced with Muscat grapes are related to the level of terpene alcohols, so an improvement of such a level is expected as a result of hydrolytic processes conducted by Hanseniaspora. The aim of this work was to select and identify new strains for this purpose. In a second step, the strains were assayed to evaluate their oenological abilities. H. uvarum H107 and H. vineae G26 and P38 were proven to be good candidates to be used in commercial vinification processes to enhance wine properties. Wine inoculated with yeasts showed an increase in the level of aromatic compounds. [ABSTRACT FROM AUTHOR]

Abstract: The electroencephalogram (EEG) is the most widely used method for diagnosis of brain diseases, where a good quality of recordings allows the proper interpretation and identification of physiological and pathological phenomena. However, EEG recordings are often contaminated by different kinds of noise. These annoying signals limit severely brain recording utility and, hence, have to be removed. To deal with this problem, in this paper an adaptive filtering framework is proposed for the enhancing of brain signal recordings. This new method is capable of reducing muscle and baseline noise in EEG signals with low EEG distortion and high noise cancellation. The advantages of the proposed method are demonstrated on real and synthetic brain signals with comparisons made to several benchmark methods. Results show that the proposed approach is preferable to the other systems by achieving a better trade-off between deleting noises and preserving inherent brain activities. [Copyright &y& Elsevier]

Abstract: The heterogeneity of local segmental dynamics in a polymer system is analyzed by computer simulation with the Bond Fluctuation Model. A different approach is proposed based on the concept of Dynamically Accessible Volume (DAV) due to the difficulties encountered in the characterization of this heterogeneity by means of the distribution of relaxation times. A DAV value is assigned to each polymer chain as the fraction of cells in its surroundings that could be occupied in one Monte Carlo Step. In this way it is possible to relate the mobility of a chain with the accessible volume around it, due to the relationship between DAV and diffusion coefficient. As temperature decreases in equilibrium the DAV distribution shifts towards lower values, its width decreases and the number of frozen molecules increases. The methodology proposed also provides a way of characterizing the evolution of segmental dynamics distribution in out of equilibrium states below glass transition temperatures. [Copyright &y& Elsevier]

Electroencephalogram (EEG) recordings often experience interference by different kinds of noise, including white, muscle, and baseline, severely limiting its utility. The recent research has demonstrated that discrete-time Volterra models can be successfully applied to reduce the broadband and narrowband noise. Their usefulness is mainly because of their ability to approximate to an arbitrary precision any fading memory system and their property of linearity with respect to parameters, the kernels coefficients. The main drawback of these models is their parametric complexity implying the need to estimate a huge number of parameters. Numerical results show that the developed algorithm achieves performance improvement over the standard filtered algorithm. This paper presents a Volterra filter (VF) algorithm based on a multichannel structure for noise reduction. Several methods have been developed, but the VF appears to be the most effective for reducing muscle and baseline noise, especially when the contamination is greater in amplitude than the brain signal. The present study introduces a new method of reducing noise in EEG signals in one step with low EEG distortion and high noise reduction. Applications with different real and synthetic signals are discussed, showing the validity of the proposed method. [ABSTRACT FROM AUTHOR]

Aims: The purification and biochemical properties of the 1,4-β-xylosidase of an oenological yeast were investigated. Methods and Results: An ethanol-tolerant 1,4-β-xylosidase was purified from cultures of a strain of Pichia membranifaciens grown on xylan at 28°C. The enzyme was purified by sequential chromatography on DEAE cellulose and Sephadex G-100. The relative molecular mass of the enzyme was determined to be 50 kDa by SDS-PAGE. The activity of 1,4-β-xylosidase was optimum at pH 6·0 and at 35°C. The activity had a Km of 0·48 ± 0·06 mmol l-1 and a Vmax of 7·4 ± 0·1 μmol min-1 mg-1 protein for p-nitrophenyl-β-d-xylopyranoside. Conclusions: The enzyme characteristics (pH and thermal stability, low inhibition rate by glucose and ethanol tolerance) make this enzyme a good candidate to be used in enzymatic production of xylose and improvement of hemicellulose saccharification for production of bioethanol. Significance and Impact of the Study: This study may be useful for assessing the ability of the 1,4-β-xylosidase from P. membranifaciens to be used in the bioethanol production process. [ABSTRACT FROM AUTHOR]

The electrocardiogram (ECG) is the most widely used method for diagnosis of heart diseases, where a good quality of recordings allows the proper interpretation and identification of physiological and pathological phenomena. However, ECG recordings often have interference from noises including thermal, muscle, baseline and powerline noises. These signals severely limit ECG recording utility and, hence, have to be removed. To deal with this problem, the present paper proposes an artificial neural network (ANN) as a filter to remove all kinds of noise in just one step. The method is based on a growing ANN which optimizes both the number of nodes in the hidden layer and the coefficient matrices, which are optimized by means of the Widrow-Hoff delta algorithm. The ANN has been trained with a database comprising all kinds of noise, both from synthesized and real ECG recordings, in order to handle any noise signal present in the ECG. The proposed system improves results yielded by conventional techniques of ECG filtering, such as FIR-based systems, adaptive filtering and wavelet filtering. Therefore, the algorithm could serve as an effective framework to substantially reduce noise in ECG recordings. In addition, the resulting ECG signal distortion is notably more reduced in comparison with conventional methodologies. In summary, the current contribution introduces a new method which is able to suppress all ECG interference signals in only one step with low ECG distortion and a high noise reduction. [ABSTRACT FROM AUTHOR]

large number of non- Saccharomyces yeasts were isolated from grapes of Bobal variety and identified according to their physiological and molecular characteristics. The yeasts were tested to determine the presence of β-glucosidase, β-xylosidase, α-arabinosidase, and α-rhamnosidase activities and five isolates were selected. All enzymatic activities were induced by the presence of glycosides as the only carbon source in the medium, which seems to be a characteristic of the yeast isolate, and were characterized according to different parameters of enological interest. [ABSTRACT FROM AUTHOR]

Abstract: Arresting of segmental mobility in polymer systems on cooling from the melt was simulated by means of the Bond Fluctuation Model. In order to represent the behaviour of the system, three potentials were included: a Lennard–Jones potential, a bond length potential and a bond angle potential. The effect of the bond angle and bond length potential combination is to stretch the chains, while the Lennard–Jones potential leads to a lack of free volume which appears when temperature decreases. So, when a cooling ramp is applied, depending on the balance of these potentials, the system shows a transition in which molecules densely pack or, on the contrary, remains amorphous. Therefore, the choice in the weighting of these three potentials is a key point to simulate a physical system by using the Bond Fluctuation Model. [ABSTRACT FROM AUTHOR]

Abstract: A quite simple Markov chain model is presented in an attempt to understand several characteristic properties of the structural relaxation in glass-former materials. A second order Markov model is proposed for a small region of the material. Only a few parameters are necessary for the definition of the material in the model equations namely the energy levels accessible to that small region and the transition probabilities between them. The later are considered dependent on the energy levels and the potential barrier heights between them, on temperature, on a reference transition rate parameter and on a cooperativity or memory parameter related to the interaction with the neighbour regions. Isothermal relaxations at different temperatures were simulated with selected values of the model parameters. As a result, non-exponentiality of energy relaxations and its temperature dependence appears directly related to the cooperativity parameter. Markov chain model shows also non-linearity and memory effects, and a transition between two different regimes in the dependence of the relaxation times with temperature. [ABSTRACT FROM AUTHOR]

Background: Tissue hypercarbia is related to hypoperfusion and microcirculatory disturbances in patients with septic shock. Transcutaneous Pco₂ devices using a heated sensor to arterialize the tissue have been used as an alternative method for estimation of Paco₂. This study investigates whether a cutaneous sensor attached to an ear lobe and regulated to 37°C could be used to measure cutaneous Pco₂ (Pcco₂) and evaluate microperfusion in patients with septic shock.Methods: Fifteen stable patients in an ICU were studied as a control group. Forty-six patients with septic shock who were ventilated were enrolled as the study group. The difference of the gradients between Pcco₂ and Paco₂ (Pc-aco₂) and between Pcco₂ and end-tidal Pco₂(Pc-etco₂) were evaluated for 36 h. Variations of the Pc-aco₂ and Pc-etco₂ during fluid challenge were compared with microcirculatory skin blood flow (mBFskin) assessed by laser Doppler flowmetry.Results: The baseline levels for Pc-aco₂ and Pc-etco₂ were significantly higher in the patients with septic shock than in the control group (14.8 [12.6] vs 6 [2.7] mm Hg and 25 [16.3] vs 9 [3.8] mm Hg, P < .0001, respectively). During the following 36 h, the Pc-aco₂ and Pc-etco₂ for the surviving patients with septic shock decreased significantly compared with the nonsurvivors (P < .01). The evolution of macrohemodynamic parameters showed no differences between survivors and nonsurvivors. At hour 24, a Pc-aco₂ > 16 mm Hg and a Pc-etco₂ > 26 mm Hg were related to poor outcome. Pc-aco₂ and Pc-etco₂ variations during fluid challenge were inversely correlated with changes in mBFskin (r² = 0.7).Conclusions: Ear lobe cutaneous Pco₂ at 37°C represents a noninvasive technique to assess tissue Pco₂ measurement. Pc-aco₂ and Pc-etco₂ were related to outcome and provide continuous information on microperfusion in patients with septic shock. [ABSTRACT FROM AUTHOR]

Abstract: The structural relaxation process of an amorphous polymer has been simulated using the Bond Fluctuation Model with a quite simple description of the polymer system. The glass transition, that is apparent when a cooling ramp is simulated, comes as a consequence of chain connectivity and a bond length potential. Annealing of the system at temperatures below the glass transition, in the glassy state, produces a continuous decrease of the total energy of the system at a rate that depends on temperature. The energy evolution is shown to be clearly nonexponential in a certain temperature interval. In this temperature interval, molecular mobility was characterized using different definitions of the relaxation times and calculating a distribution of relaxation times in the system by studying the motions of small regions of the lattice. As annealing temperature decreases the distribution of relaxation times shifts to longer times and slightly broadens. The maxima of the distributions of relaxation times obey the Vogel, Fulcher and Tammann equation. [Copyright &y& Elsevier]

Seaweeds form the second largest global aquaculture product in volume, and despite rapid growth of the sector over the last 25 years, production and quality in top producing regions is becoming increasingly limited due to disease and pest outbreaks, the spread of non-native cultivars and the degradation of genetic health due to inbreeding. Most notably, the lack of biosecurity measures leading to disease and pest outbreaks are reported to cause the most significant production losses in the seaweed industry. This study uses the Knowledge, Attitude and Practice (KAP) survey tool to quantify and compare biosecurity cross-culturally, in two major red seaweed producing countries, the Philippines and Tanzania. Both countries have significantly different political contexts and the seaweed sector sits within two very different value chains. Seaweed-based commodities from these countries, however, enters the same international market for carrageenan, a thickening agent used for a variety of products globally. This study uses the KAP survey tool to assess currently-adopted biosecurity control measures and understand how potential policy strategies could be developed on an international scale. Farmers from both producing countries have good biosecurity knowledge. In Tanzania 64% farmers scored Fair or Good, and in the Philippines this was 95%. Corresponding scores in practices were lower, 85% Poor for Tanzania, and 88% Fair for the Philippines, indicating there is a lack of resources for farmers to implement additional practices. The information gathered using the KAP tool in the context of the global seaweed industry can be used to facilitate compromise between science, policy and practice whilst taking into consideration smaller-scale regional challenges. Given the results from the seaweed industry were similar to that of smallholder agricultural sectors, it is suggested that governmental programs to incentivise biosecurity in smallholder rural agriculture could be adapted for the seaweed industry. This study also demonstrates the potential use of the KAP survey, as a tool to accurately compare biosecurity challenges faced by farmers in different aquaculture sectors globally, and to encourage alignment in international approaches to aquaculture biosecurity policies. • Farmers have good biosecurity knowledge, but lack resources to implement practices. • Biosecurity policies should include smallholder and large commercial farms. • The KAP tool can facilitate compromise between science, policy and practice. • Programs to incentivise biosecurity in smallholder agriculture could be adapted. [ABSTRACT FROM AUTHOR]

• Emergence of the glass transition is related to dynamical disorder, not static. • Non-Markovian model provides relaxation times distribution of supercooled liquid and ideal glass. • Fragility is related to the interaction of a small region with its environment. • Out of equilibrium relaxation times provide interpretation of the expansion gap paradox. [Display omitted] Glass transition processes have often been explained in terms of wide distributions of relaxation times. By means of a simple stochastic model we here show how dynamic heterogeneity is the key to the emergence of the glass transition. A non-Markovian model representing a small open region of the amorphous material was previously shown to reproduce the time and thermal characteristic behavior of supercooled liquids and glasses. Due to the interaction of the open regions with their environment, the temperature dependence of the equilibrium relaxation times differs from the featureless behavior of the relaxation times of closed regions, whose static disorder does not lead to a glass transition, even with wider distributions of equilibrium relaxation times. The dynamic heterogeneity of the open region produces a glass transition between two different regimes: a faster-than-Arrhenius and non-diverging growth of the supercooled liquid relaxation times and an average Arrhenius behavior of the ideal glass. The Kovacs' expansion gap was studied by evaluating the nonequilibrium distribution of relaxation times after the temperature quenches. [ABSTRACT FROM AUTHOR]

The hypoxia-inducible factor 1 (HIF-1) plays a critical role for tumour adaptation to microenvironmental hypoxia, and represents an appealing chemotherapeutic target. Silibinin is a nontoxic flavonoid reported to exhibit anticancer properties. However, the mechanisms by which silibinin inhibits tumour growth are not fully understood. In this study, silibinin was found to inhibit hypoxia-induced HIF-1α accumulation and HIF-1 transcriptional activity in human cervical (HeLa) and hepatoma (Hep3B) cells. Neither HIF-1α protein degradation rate nor HIF-1α steady-state mRNA level was affected by silibinin. Rather, we found that suppression of HIF-1α accumulation by silibinin correlated with strong dephosphorylation of mammalian target of rapamycin (mTOR) and its effectors ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), a pathway known to regulate HIF-1α expression at the translational level. Silibinin also activated Akt, a mechanistic feature exhibited by established mTOR inhibitors in many tumour cells. Moreover, silibinin reduced hypoxia-induced vascular endothelial growth factor (VEGF) release by HeLa and Hep3B cells, and this effect was potentiated by the PI3K/Akt inhibitor LY294002. Finally, silibinin was found to be a potent inhibitor of cell proliferation. These results show that silibinin is an effective inhibitor of HIF-1 and provide new perspectives into the mechanism of its anticancer activity.Oncogene (2009) 28, 313–324; doi:10.1038/onc.2008.398; published online 3 November 2008 [ABSTRACT FROM AUTHOR]

Aims:  To analyse phenotypical characteristics of Shiga toxin-producing Escherichia coli (STEC) strains from ovine origin. Methods and Results:  A total of 13 STEC strains (eight O157 and five non-O157) isolated from sheep dairy products were used in this study. Biochemical traits, motility, haemolytic activity, resistance to tellurite–cefixime, maximum growth temperature and antibiotic resistance were determined. The STEC strains were grouped into nine biochemical and physiological biotypes (five for the O157 and four for the non-O157 strains). All STEC strains showed resistance to bacitracin, cloxacilin, penicillin and tylosin. Conclusions:  Different biotypes and antibiotic resistance patterns of STEC isolated from sheep dairy products were observed. Significance and Impact of the Study:  This work will be a contribution to the better characterization of STEC isolated from sheep dairy products, which have, to date, been scarcely studied, and to the better understanding of the risks associated with its consumption. [ABSTRACT FROM AUTHOR]

Abstract: The geometry of the Dynamically Accessible Volume, DAV, in polymeric materials has been observed by means of the Bond Fluctuation Model. Simulations were conducted in conditions that yield varying amounts of accessible volume in the lattice, acting on the density of the system, and introducing geometrical restrictions to motion. A parameter has been defined to characterise the connectivity of holes characterising the number and size of hole clusters. The mobility of the accessible cells during athermal simulations has also been characterised concluding that all the holes in the lattice are in motion, contributing to the diffusion of the molecules even for the lowest values of DAV. The number of clusters increases with decreasing DAV reaching a maximum. For values of DAV below that of the maximum number of hole clusters, the diffusion coefficient becomes smaller than that predicted by the quadratic ratio The differences in the dynamics of individual molecules and polymer chain systems are studied. [Copyright &y& Elsevier]

Poster Highlights: Poster highlights 20 PH: Autocontouring using deep learning PH-0608: Identifying systematic edits in the clinical use of Deep Learning Contours J. Mateo, P. Aljabar, C. Brouwer, S. Both, M. Gooding, H. Langendijk. [Extracted from the article]

Abstract: The dependence of the diffusion coefficient, D, of polymer systems on the Dynamically Accessible Volume (DAV) was calculated in the framework of the Bond Fluctuation Model. The quadratic relationship between dynamically accessible volume and diffusion coefficient, which has been observed for some other models, has been confirmed for high values of DAV, whereas smaller diffusion coefficients than those predicted by the model were shown for DAV values lower than 0.1 independently of the chain length. This critical value is related to the loss of connectivity of the holes of the system and the consequent diminution of the diffusion of the system. The influence of the chain length on this behaviour has been established, showing that there is a linear relationship between the γ parameter (the proportionality constant between D and the squared DAV) and the reciprocal of the chain length. [Copyright &y& Elsevier]

Abstract: The glass transition of linear chain polymers was simulated by means of the bond fluctuation model, employing a Lennard–Jones inter-molecular potential and a bond-length intra-molecular potential. The influence of the balance between inter- and intra-molecular potentials on the model prediction was studied and an appropriate range was determined in order to simulate physical ageing. The relationship between molecular mobility and the dynamically accessible volume was shown in comparison with other definitions of specific volume or free volume. The temperature dependence of the dynamically accessible volume shows the vitrification of the material analogously to the temperature dependence of the lattice energy. Dynamically accessible volume has been proposed as a universal parameter to explain glass transition, but in the bond fluctuation model it does not give the same value for all simulated glass transitions. This fact could be corrected by including the Metropolis criterion in the dynamically accessible volume in order to extend the concept to thermal systems. [Copyright &y& Elsevier]

Several indexes have been reported to improve the accuracy of exercise test electrocardiogram (ECG) analysis in the diagnosis of coronary artery disease (CAD), compared with the classical ST depression criterion. Some of them combine repolarisation measurements with heart rate (HR) information (such as the so-called ST/HR hysteresis); others are obtained from the depolarisation period (such as the Athens QRS score); finally, there are heart rate variability (HRV) indexes that account for the nervous system activity. The aim of this study was to identify the best exercise ECG indexes for CAD diagnosis. First, a method to automatically estimate repolarisation and depolarisation indexes in the presence of noise during a stress test was developed. The method is divided into three stages: first, a preprocessing step, where QRS detection, filtering and baseline beat rejection are applied to the raw ECG, prior to a weighted averaging; secondly, a post-processing step in which potentially noisy averaged beats are identified and discarded based on their noise variance; finally, the measurement step, in which ECG indexes are computed from the averaged beats. Then, a multivariate discriminant analysis was applied to classify patients referred for the exercise test into two groups: ischaemic (positive coronary angiography) and low-risk (Framingham risk index < 5%). HR-corrected repolarisation indexes improved the sensitivity (SE) and specificity (SP) of the classical exercise test (SE = 90%, SP = 79% against SE = 65%, SP = 66%). Depolarisation indexes also achieved an improvement over ST depression measurements (SE = 78%, SP = 81%). HRV indexes obtained the best classification results in our study population (SE = 94%, SP = 92%) by means of the very high-frequency power (VHF) (0.4-1Hz) at stress peak. [ABSTRACT FROM AUTHOR]

Several indexes have been reported to improve the accuracy of exercise test electrocardiogram (ECG) analysis in the diagnosis of coronary artery disease (CAD), compared with the classical ST depression criterion. Some of them combine repolarisation measurements with heart rate (HR) information (such as the so-called ST/HR hysteresis); others are obtained from the depolarisation period (such as the Athens QRS score); finally, there are heart rate variability (HRV) indexes that account for the nervous system activity. The aim of this study was to identify the best exercise ECG indexes for CAD diagnosis. First, a method to automatically estimate repolarisation and depolarisation indexes in the presence of noise during a stress test was developed. The method is divided into three stages: first, a preprocessing step, where QRS detection, filtering and baseline beat rejection are applied to the raw ECG, prior to a weighted averaging; secondly, a post-processing step in which potentially noisy averaged beats are identified and discarded based on their noise variance; finally, the measurement step, in which ECG indexes are computed from the averaged beats. Then, a multivariate discriminant analysis was applied to classify patients referred for the exercise test into two groups: ischaemic (positive coronary angiography) and low-risk (Framingham risk index < 5%). HR-corrected repolarisation indexes improved the sensitivity (SE) and specificity (SP) of the classical exercise test (SE = 90%, SP = 79% against SE = 65%, SP = 66%). Depolarisation indexes also achieved an improvement over ST depression measurements (SE = 78%, SP = 81%). HRV indexes obtained the best classification results in our study population (SE = 94%, SP = 92%) by means of the very high-frequency power (VHF) (0.4-1 Hz) at stress peak. [ABSTRACT FROM AUTHOR]

The simultaneous determination of two dissolution profiles with the aid of a Flow Injection Analysis assembly has been applied to: (a) sulfadiazine-trimethoprim in tablets and (b) amitriptyline-perphenazine in sugar coated pills. The selected combinations are drugs which have overlapping UV-vis spectra. The officially proposed procedure from the pharmacopoeias has been adapted for the FIA methodology and derivative spectrophotometry and zero crossing. Preliminary experiments on the suitability of the simultaneous determination of both drugs were performed. The empirical profiles were adjusted by regression analysis using different approaches. The 3-parameter plot method was finally selected as the most suitable for the sulfadiazine-trimethoprim and the 4-parameter equation plot for amitriptyline-perphenazine. [Copyright &y& Elsevier]

Advances in precision oncology led to approval of tumour-agnostic molecularly guided treatment options (MGTOs). The minimum requirements for claiming tumour-agnostic potential remain elusive. The European Society for Medical Oncology (ESMO) Precision Medicine Working Group (PMWG) coordinated a project to optimise tumour-agnostic drug development. International experts examined and summarised the publicly available data used for regulatory assessment of the tumour-agnostic indications approved by the US Food and Drug Administration and/or the European Medicines Agency as of December 2023. Different scenarios of minimum objective response rate (ORR), number of tumour types investigated, and number of evaluable patients per tumour type were assessed for developing a screening tool for tumour-agnostic potential. This tool was tested using the tumour-agnostic indications approved during the first half of 2024. A taxonomy for MGTOs and a framework for tumour-agnostic drug development were conceptualised. Each tumour-agnostic indication had data establishing objective response in at least one out of five patients (ORR ≥ 20%) in two-thirds (≥4) of the investigated tumour types, with at least five evaluable patients in each tumour type. These minimum requirements were met by tested indications and may serve as a screening tool for tumour-agnostic potential, requiring further validation. We propose a conceptual taxonomy classifying MGTOs based on the therapeutic effect obtained by targeting a driver molecular aberration across tumours and its modulation by tumour-specific biology: tumour-agnostic, tumour-modulated, or tumour-restricted. The presence of biology-informed mechanistic rationale, early regulatory advice, and adequate trial design demonstrating signs of biology-driven tumour-agnostic activity, followed by confirmatory evidence, should be the principles for tumour-agnostic drug development. The ESMO Tumour-Agnostic Classifier (ETAC) focuses on the interplay of targeted driver molecular aberration and tumour-specific biology modulating the therapeutic effect of MGTOs. We propose minimum requirements to screen for tumour-agnostic potential (ETAC-S) as part of tumour-agnostic drug development. Definition of ETAC cut-offs is warranted. • Advances in precision oncology led to the approval of tumour-agnostic therapies, challenging conventional drug development. • There is a need to establish a minimum set of requirements for a therapy to be eligible for tumour-agnostic potential. • Approved tumour-agnostic therapies had ORR ≥ 20% in 2/3 of tumour types (≥4) with ≥5 evaluable patients per tumour type. • Tumour-agnostic effect results from targeted driver molecular aberration interplay with tumour-specific modulating biology. • The ESMO PMWG proposes a framework to foster and accelerate tumour-agnostic drug development for patients with cancer. [ABSTRACT FROM AUTHOR]

Low salinity water injection (LSWI) has been studied by several researchers as an enhanced oil recovery (EOR) method in laboratory experiments, numerical simulations, and field applications. However, its effects on oil recovery remain uncertain due to the complexity of the interactions among crude oil, brine, and the rock surface, for both sandstone and carbonate reservoirs, particularly when they contain a diversity of clay minerals. This paper investigates LSWI performance and mechanisms in sandstone rock, brine, and light crude oil with low polar compounds from a reservoir in Brazil. Core flooding experiments and reservoir simulations were carried out to understand the influence of key parameters on oil recovery. Zeta potential measurements were performed to investigate the influence of the formation water and NaCl and CaCl 2 brine solutions on rock and oil surface charges. Increased oil recovery, Ca++ desorption from the rock surface, and a substantial pH increase in the effluent were noticed during LSWI. Based on the zeta potential measurement, a thicker water film was also formed on the rock and oil surface with brine dilution. A recovery factor of 64% was reached by testing LSWI from the beginning of the waterflooding (secondary mode) and this was the highest recovery of all the scenarios evaluated. Ten parameters were successfully history matched to core flood data, and optimization and sensitivity analysis showed that the concentration of Na+ and Ca++, and the water injection rate were the most important parameters in the LSWI process. Overall, this study sheds light on the LSWI mechanisms for the Brazilian oil field investigated and provides useful operational parameters for designing and achieving better LSWI performance. [Display omitted] • Core flooding performed with samples from an oil field in northeastern Brazil. • Higher oil recovery the earlier the diluted SFW cycling is applied. • Development of core flooding model with laboratory data for similar reservoirs. • Optimization and uncertainty assessment of critical operational parameters. [ABSTRACT FROM AUTHOR]

Presents a study which used fluorogenic analogs of Ap...A, the di(1,N6-ethenoadenosine) 5,5'''-P1,P...-polyphosphates[...-(Ap...A)] to investigate the extracellular degradation of diadenosine polyphosphates (Ap...A) by cultured adrenomedullary endothelial cells. How the kinetic parameters of ...-(Ap...A) cleavage and effects of pH, ions and inhibitors were determined; Information on the experiments conducted.

Investigates the extracellular degradation of diadenosine polyphosphates (ApnA) by cultured adrenomedullary vascular endothelial cells. Endothelial cell cultures on microcarriers and their ability to cleave ApnA analogues di(1, N6-ethanoadenosine) 5',5'''-P1, Pn-polyphosphates compounds; Effect of pH and ions on ApnA analogues hydrolysis.