Simulating the Spitzer mid-IR color-color diagrams

We use a simple parameterization of the mid-IR spectra of a wide range of galaxy types in order to predict their distribution in the Infrared Array Camera (IRAC) 3.6um, 4.5um, 5.8um, and 8.0um and Multiband Photometer for Spitzer (MIPS) 24um color-color diagrams. We distinguish three basic spectral types by the energetically dominant component in the 3--12 micron regime: stellar-dominated; PAH-dominated; and continuum-dominated. We have used a Markov chain Monte Carlo (MCMC) approach to arrive at a more systematic and robust representation of the mid-IR spectra of galaxies than more traditional approaches. We find that IRAC color-color plots are well suited to distinguishing the above spectral types, while the addition of 24 micron data allows us to suggest practical 3-color cuts which preferentially select higher redshift sources of specific type. We compare our simulations with the color-color plot obtained by the Spitzer First Look Survey (FLS) and find reasonable agreement. Lastly, we discuss other applications as well as future directions for this work.Comment: 20p, 12figures, submitted to Ap

Therapeutic drug monitoring of oral targeted antineoplastic drugs

Purpose This review provides an overview of the current challenges in oral targeted antineoplastic drug (OAD) dosing and outlines the unexploited value of therapeutic drug monitoring (TDM). Factors influencing the pharmacokinetic exposure in OAD therapy are depicted together with an overview of different TDM approaches. Finally, current evidence for TDM for all approved OADs is reviewed. Methods A comprehensive literature search (covering literature published until April 2020), including primary and secondary scientific literature on pharmacokinetics and dose individualisation strategies for OADs, together with US FDA Clinical Pharmacology and Biopharmaceutics Reviews and the Committee for Medicinal Products for Human Use European Public Assessment Reports was conducted. Results OADs are highly potent drugs, which have substantially changed treatment options for cancer patients. Nevertheless, high pharmacokinetic variability and low treatment adherence are risk factors for treatment failure. TDM is a powerful tool to individualise drug dosing, ensure drug concentrations within the therapeutic window and increase treatment success rates. After reviewing the literature for 71 approved OADs, we show that exposure-response and/or exposure-toxicity relationships have been established for the majority. Moreover, TDM has been proven to be feasible for individualised dosing of abiraterone, everolimus, imatinib, pazopanib, sunitinib and tamoxifen in prospective studies. There is a lack of experience in how to best implement TDM as part of clinical routine in OAD cancer therapy. Conclusion Sub-therapeutic concentrations and severe adverse events are current challenges in OAD treatment, which can both be addressed by the application of TDM-guided dosing, ensuring concentrations within the therapeutic window

LIBER Open Science Training Methods and Practices Across European Research Libraries - Survey Analysis

LIBER Open Science Training Methods and Practices Across European Research Libraries - Survey Analysis propose une analyse d\u27études de cas sélectionnés, issus de bibliothèques de recherche européennes ayant participé ou mené la mise en place d\u27un programme de formation en sciences ouvertes dans un établissement ou un réseau d\u27enseignement supérieur et de recherche en Europe

The Canadian Women's Heart Health Alliance atlas on the epidemiology, diagnosis, and management of cardiovascular disease in women - Chapter 6 : sex- and gender-specific diagnosis and treatment

This chapter summarizes the sex- and gender-specific diagnosis and treatment of acute/unstable presentations and nacute/stable presentations of cardiovascular disease in women. Guidelines, scientific statements, systematic reviews/meta-analyses, and primary research studies related to diagnosis and treatment of coronary artery disease, cerebrovascular disease (stroke), valvular heart disease, and heart failure in women were reviewed. The evidence is summarized as a narrative, and when available, sex- and gender-specific practice and research recommendations are provided. Acute coronary syndrome presentations and emergency department delays are different in women than they are in men. Coronary angiography remains the gold-standard test for diagnosis of obstructive coronary artery disease. Other diagnostic imaging modalities for ischemic heart disease detection (eg, positron emission tomography, echocardiography, single-photon emission computed tomography, cardiovascular magnetic resonance, coronary computed tomography angiography) have been shown to be useful in women, with their selection dependent upon both the goal of the individualized assessment and the testing resources available. Noncontrast computed tomography and computed tomography angiography are used to diagnose stroke in women. Although sex-specific differences appear to exist in the efficacy of standard treatments for diverse presentations of acute coronary syndrome, many cardiovascular drugs and interventions tested in clinical trials were not powered to detect sex-specific differences, and knowledge gaps remain. Similarly, although knowledge is evolving about sex-specific difference in the management of valvular heart disease, and heart failure with both reduced and preserved ejection fraction, current guidelines are lacking in sex-specific recommendations, and more research is needed.Ce chapitre présente un résumé sur le diagnostic et le traitement des tableaux cliniques aigus/instables et non aigus/stables des maladies cardiovasculaires chez les femmes, et les différences propres à chacun des deux sexes. Les lignes directrices, les énoncés scientifiques, les revues systématiques/méta-analyses et les études de recherche originale sur le diagnostic et le traitement des coronaropathies, des maladies vasculaires cérébrales (AVC), des valvulopathies cardiaques et de l’insuffisance cardiaque chez les femmes ont été examinés. Les données probantes sont résumées sous forme narrative et, lorsqu’elles sont disponibles, des recommandations en matière de pratique et de recherche pour chacun des deux sexes sont présentées. Les tableaux cliniques du syndrome coronarien aigu et les délais d’attente à l’urgence sont différents selon qu’une femme ou un homme en est atteint. L’angiographie coronarienne reste l’examen de référence pour le diagnostic des coronaropathies obstructives. D’autres examens d’imagerie diagnostique (p. ex. la tomographie par émission de positons, l’échocardiographie, la tomographie d'émission à photon unique, la résonance magnétique cardiovasculaire, l’angiographie coronarienne par tomodensitométrie) se sont avérés utiles pour la détection des cardiopathies ischémiques chez les femmes. Le recours à ces modalités dépend de l’objectif de l’évaluation personnalisée et des ressources disponibles. La tomodensitométrie sans agent de contraste et l’angiographie par tomodensitométrie sont utilisées pour le diagnostic des AVC chez les femmes. Malgré les différences entre les sexes quant à l’efficacité des traitements de référence des divers tableaux cliniques du syndrome coronarien aigu, bon nombre des médicaments et des interventions cardiovasculaires qui ont fait l’objet d’essais cliniques n’avaient pas la puissance statistique nécessaire pour détecter des différences selon les sexes, de sorte que les connaissances restent fragmentaires sur ce sujet. De même, malgré l’évolution des connaissances sur les différences sexuelles quant à la prise en charge des valvulopathies cardiaques et de l’insuffisance cardiaque avec fraction d’éjection réduite ou préservée, on ne trouve pas de recommandations pour chaque sexe dans les lignes directrices actuelles, d’où la pertinence d’études supplémentaires portant sur cette question

The Nature of LoBAL QSOs: I. SEDs and mid-infrared spectral properties

We have obtained Spitzer IRS spectra and MIPS 24, 70, and 160 micron photometry for a volume-limited sample of 22 SDSS-selected Low-ionization Broad Absorption Line QSOs (LoBALs) at 0.5 < z < 0.6. By comparing their mid-IR spectral properties and far-IR SEDs with those of a control sample of 35 non-LoBALs matched in M_i, we investigate the differences between the two populations in terms of their infrared emission and star formation activity. Twenty five percent of the LoBALs show PAH features and 45% have weak 9.7 micron silicate dust emission. We model the SEDs and decouple the AGN and starburst contributions to the far-infrared luminosity in LoBALs and in non-LoBALs. Their median total, starburst, and AGN infrared luminosities are comparable. Twenty percent (but no more than 60%) of the LoBALs and 26% of the non-LoBALs are ultra-luminous infrared galaxies (ULIRGs; L_IR>10^12*L_sun). We estimate star formation rates (SFRs) corrected for the AGN contribution to the FIR flux and find that LoBALs have comparable levels of star formation activity to non-LoBALs when considering the entire samples. However, the SFRs of the IR-luminous LoBALs are 80% higher than those of their counterparts in the control sample. The median contribution of star formation to the total far-infrared flux in LoBALs and in non-LoBALs is estimated to be 40-50%, in agreement with previous results for PG QSOs. Overall, our results show that there is no strong evidence from the mid- and far-IR properties that LoBALs are drawn from a different parent population than non-LoBALs.Comment: 28 pages, 8 figures, 7 tables; Accepted for publication in Ap

Developing a Nationwide Infrastructure for Therapeutic Drug Monitoring of Targeted Oral Anticancer Drugs: The ON-TARGET Study Protocol

Exposure-efficacy and/or exposure-toxicity relationships have been identified for up to 80% of oral anticancer drugs (OADs). Usually, OADs are administered at fixed doses despite their high interindividual pharmacokinetic variability resulting in large differences in drug exposure. Consequently, a substantial proportion of patients receive a suboptimal dose. Therapeutic Drug Monitoring (TDM), i.e., dosing based on measured drug concentrations, may be used to improve treatment outcomes. The prospective, multicenter, non-interventional ON-TARGET study (DRKS00025325) aims to investigate the potential of routine TDM to reduce adverse drug reactions in renal cell carcinoma patients receiving axitinib or cabozantinib. Furthermore, the feasibility of using volumetric absorptive microsampling (VAMS), a minimally invasive and easy to handle blood sampling technique, for sample collection is examined. During routine visits, blood samples are collected and sent to bioanalytical laboratories. Venous and VAMS blood samples are collected in the first study phase to facilitate home-based capillary blood sampling in the second study phase. Within one week, the drug plasma concentrations are measured, interpreted, and reported back to the physician. Patients report their drug intake and toxicity using PRO-CTCAE-based questionnaires in dedicated diaries. Ultimately, the ON-TARGET study aims to develop a nationwide infrastructure for TDM for oral anticancer drugs

Therapeutic drug monitoring of oral targeted antineoplastic drugs

Purpose: This review provides an overview of the current challenges in oral targeted antineoplastic drug (OAD) dosing and outlines the unexploited value of therapeutic drug monitoring (TDM). Factors influencing the pharmacokinetic exposure in OAD therapy are depicted together with an overview of different TDM approaches. Finally, current evidence for TDM for all approved OADs is reviewed. Methods: A comprehensive literature search (covering literature published until April 2020), including primary and secondary scientific literature on pharmacokinetics and dose individualisation strategies for OADs, together with US FDA Clinical Pharmacology and Biopharmaceutics Reviews and the Committee for Medicinal Products for Human Use European Public Assessment Reports was conducted. Results: OADs are highly potent drugs, which have substantially changed treatment options for cancer patients. Nevertheless, high pharmacokinetic variability and low treatment adherence are risk factors for treatment failure. TDM is a powerful tool to individualise drug dosing, ensure drug concentrations within the therapeutic window and increase treatment success rates. After reviewing the literature for 71 approved OADs, we show that exposure-response and/or exposure-toxicity relationships have been established for the majority. Moreover, TDM has been proven to be feasible for individualised dosing of abiraterone, everolimus, imatinib, pazopanib, sunitinib and tamoxifen in prospective studies. There is a lack of experience in how to best implement TDM as part of clinical routine in OAD cancer therapy. Conclusion: Sub-therapeutic concentrations and severe adverse events are current challenges in OAD treatment, which can both be addressed by the application of TDM-guided dosing, ensuring concentrations within the therapeutic window

Metabolic Activation of Intrahepatic CD8+ T Cells and NKT Cells Causes Nonalcoholic Steatohepatitis and Liver Cancer via Cross-Talk with Hepatocytes

SummaryHepatocellular carcinoma (HCC), the fastest rising cancer in the United States and increasing in Europe, often occurs with nonalcoholic steatohepatitis (NASH). Mechanisms underlying NASH and NASH-induced HCC are largely unknown. We developed a mouse model recapitulating key features of human metabolic syndrome, NASH, and HCC by long-term feeding of a choline-deficient high-fat diet. This induced activated intrahepatic CD8+ T cells, NKT cells, and inflammatory cytokines, similar to NASH patients. CD8+ T cells and NKT cells but not myeloid cells promote NASH and HCC through interactions with hepatocytes. NKT cells primarily cause steatosis via secreted LIGHT, while CD8+ and NKT cells cooperatively induce liver damage. Hepatocellular LTβR and canonical NF-κB signaling facilitate NASH-to-HCC transition, demonstrating that distinct molecular mechanisms determine NASH and HCC development

Potent Nonnucleoside Reverse Transcriptase Inhibitors Target HIV-1 Gag-Pol

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) target HIV-1 reverse transcriptase (RT) by binding to a pocket in RT that is close to, but distinct, from the DNA polymerase active site and prevent the synthesis of viral cDNA. NNRTIs, in particular, those that are potent inhibitors of RT polymerase activity, can also act as chemical enhancers of the enzyme's inter-subunit interactions. However, the consequences of this chemical enhancement effect on HIV-1 replication are not understood. Here, we show that the potent NNRTIs efavirenz, TMC120, and TMC125, but not nevirapine or delavirdine, inhibit the late stages of HIV-1 replication. These potent NNRTIs enhanced the intracellular processing of Gag and Gag-Pol polyproteins, and this was associated with a decrease in viral particle production from HIV-1-transfected cells. The increased polyprotein processing is consistent with premature activation of the HIV-1 protease by NNRTI-enhanced Gag-Pol multimerization through the embedded RT sequence. These findings support the view that Gag-Pol multimerization is an important step in viral assembly and demonstrate that regulation of Gag-Pol/Gag-Pol interactions is a novel target for small molecule inhibitors of HIV-1 production. Furthermore, these drugs can serve as useful probes to further understand processes involved in HIV-1 particle assembly and maturation