A Methodological Framework to Discover Pharmacogenomic Interactions Based on Random Forests

The identification of genomic alterations in tumor tissues, including somatic mutations, deletions, and gene amplifications, produces large amounts of data, which can be correlated with a diversity of therapeutic responses. We aimed to provide a methodological framework to discover pharmacogenomic interactions based on Random Forests. We matched two databases from the Cancer Cell Line Encyclopaedia (CCLE) project, and the Genomics of Drug Sensitivity in Cancer (GDSC) project. For a total of 648 shared cell lines, we considered 48,270 gene alterations from CCLE as input features and the area under the dose-response curve (AUC) for 265 drugs from GDSC as the outcomes. A three-step reduction to 501 alterations was performed, selecting known driver genes and excluding very frequent/infrequent alterations and redundant ones. For each model, we used the concordance correlation coefficient (CCC) for assessing the predictive performance, and permutation importance for assessing the contribution of each alteration. In a reasonable computational time (56 min), we identified 12 compounds whose response was at least fairly sensitive (CCC > 20) to the alteration profiles. Some diversities were found in the sets of influential alterations, providing clues to discover significant drug-gene interactions. The proposed methodological framework can be helpful for mining pharmacogenomic interactions

Radiation Recall Pneumonitis Anticipates Bilateral Immune-Induced Pneumonitis in Non-Small Cell Lung Cancer

Radiation recall pneumonitis (RRP) is a rare inflammatory reaction that occurs in previously irradiated fields, and it may be caused by various triggering agents. Immunotherapy has been reported to potentially be one of these triggers. However, precise mechanisms and specific treatments have not been explored yet due to a lack of data in this setting. Here, we report a case of a patient who received radiation therapy and immune checkpoint inhibitor therapy for non-small cell lung cancer. He developed first radiation recall pneumonitis and subsequently immune-checkpoint inhibitor-induced pneumonitis (IIP). After presenting the case, we discuss the currently available literature on RRP and the challenges of differential diagnosis between RRP, IIP, and other forms of pneumonitis. We believe that this case is of particular clinical value since it highlights the importance of including RRP in a differential diagnosis of lung consolidation during immunotherapy. Furthermore, it suggests that RRP might anticipate more extensive ICI-induced pneumonitis

Pharmacogenomics: A Step forward Precision Medicine in Childhood Asthma

Personalized medicine, an approach to care in which individual characteristics are used for targeting interventions and maximizing health outcomes, is rapidly becoming a reality for many diseases. Childhood asthma is a heterogeneous disease and many children have uncontrolled symptoms. Therefore, an individualized approach is needed for improving asthma outcomes in children. The rapidly evolving fields of genomics and pharmacogenomics may provide a way to achieve asthma control and reduce future risks in children with asthma. In particular, pharmacogenomics can provide tools for identifying novel molecular mechanisms and biomarkers to guide treatment. Emergent high-throughput technologies, along with patient pheno-endotypization, will increase our knowledge of several molecular mechanisms involved in asthma pathophysiology and contribute to selecting and stratifying appropriate treatment for each patient

Dive performance in a small-bodied, semi-aquatic mammal in the wild

Aquatic foraging is a fundamental component of the behavior of a number of small mammals, yet comprehensive observations of diving are often difficult to obtain under natural circumstances. Semiaquatic mammals, having evolved to exploit prey in both aquatic and terrestrial environments, are generally not as well adapted for diving (or for life in the water) as are fully aquatic species. Because dive ability also tends to increase with body size, small, semiaquatic mammals are presumed to have fairly limited dive ability. Nevertheless, diving plays an important role in food acquisition for many such species. We used time–depth recorders (TDRs) to measure and describe the dive performance of 9 female and 5 male free-living American mink (Neovison vison; body mass approximately 1 kg) on lowland rivers in the southern United Kingdom. We recorded dives up to 2.96 m deep (maximum depth X ¯ 5 1.82 m) and up to 57.9 s in duration (maximum duration X ¯ 5 37.2 s). Dive duration was approximately 40% of that predicted by allometry for all air-breathing diving vertebrates (as might be expected for a small, semiaquatic animal) but was twice as long as previously measured for mink in captivity. Mink performed up to 189 dives per day (X ¯ 5 35.7 dives/day), mostly during daylight, and spent a maximum of 38.4 minutes diving per day (X ¯ 5 7.6 min/day). Some individuals maintained particularly high diving rates over the coldest months, suggesting that the benefits of aquatic foraging in winter outweigh the costs of heat loss. We observed a number of very shallow dives (depth approximately 0.3 m) of particularly long duration (up to 30 s). The function of these dives is currently unknown, but possibilities include searching for prey, travelling, or avoidance of threats. There is only 1 other study of which we are aware that presents detailed measurements of dive performance in a small, shallow-diving, semiaquatic mammal.Fil: Harrington, Lauren. University of Oxford; Reino UnidoFil: Hays, Graeme C.. Swansea University; Reino UnidoFil: Fasola, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Harrington, Andrew L.. University of Oxford; Reino UnidoFil: Righton, David. No especifíca;Fil: Macdonald, David W.. University of Oxford; Reino Unid

SST-GATE: A dual mirror telescope for the Cherenkov Telescope Array

The Cherenkov Telescope Array (CTA) will be the world's first open observatory for very high energy gamma-rays. Around a hundred telescopes of different sizes will be used to detect the Cherenkov light that results from gamma-ray induced air showers in the atmosphere. Amongst them, a large number of Small Size Telescopes (SST), with a diameter of about 4 m, will assure an unprecedented coverage of the high energy end of the electromagnetic spectrum (above ~1TeV to beyond 100 TeV) and will open up a new window on the non-thermal sky. Several concepts for the SST design are currently being investigated with the aim of combining a large field of view (~9 degrees) with a good resolution of the shower images, as well as minimizing costs. These include a Davies-Cotton configuration with a Geiger-mode avalanche photodiode (GAPD) based camera, as pioneered by FACT, and a novel and as yet untested design based on the Schwarzschild-Couder configuration, which uses a secondary mirror to reduce the plate-scale and to allow for a wide field of view with a light-weight camera, e.g. using GAPDs or multi-anode photomultipliers. One objective of the GATE (Gamma-ray Telescope Elements) programme is to build one of the first Schwarzschild-Couder prototypes and to evaluate its performance. The construction of the SST-GATE prototype on the campus of the Paris Observatory in Meudon is under way. We report on the current status of the project and provide details of the opto-mechanical design of the prototype, the development of its control software, and simulations of its expected performance.Comment: In Proceedings of the 33rd International Cosmic Ray Conference (ICRC2013), Rio de Janeiro (Brazil). All CTA contributions at arXiv:1307.223

Association between Asthma Control and Exposure to Greenness and Other Outdoor and Indoor Environmental Factors: A Longitudinal Study on a Cohort of Asthmatic Children

Achieving and maintaining asthma control (AC) is the main goal of asthma management. Indoor and outdoor environmental factors may play an important role on AC. The aim of this longitudinal study was to evaluate the association between AC and exposure to greenness and other outdoor or indoor environmental factors in a cohort of asthmatic children. This study involved 179 asthmatic children (5–16 years). Parents were interviewed through a modified version of the SIDRIA questionnaire. AC was assessed at each visit. Exposure to greenness was measured using the normalized difference vegetation index (NDVI). A logistic regression model was applied for assessing risk factors for uncontrolled asthma (UA). Low NDVI exposure was a risk factor for UA (OR: 2.662, 95% CI (1.043–6.799)); children exposed to passive smoke during pregnancy had a higher risk of UA than those non-exposed to passive smoke during pregnancy (OR: 3.816, 95% CI (1.114–13.064)); and a unit increase in the crowding index was associated with an increased risk of UA (OR: 3.376, 95% CI (1.294–8.808)). In conclusion, the current study provided a comprehensive assessment of urban-related environmental exposures on asthma control in children, using multiple indicators of greenness and other outdoor or indoor environmental factors

Sperm traits negatively covary with size and asymmetry of a secondary sexual trait in a freshwater crayfish

In species where females mate promiscuously, the reproductive success of males depends both on their ability to acquire mates (pre-copulatory sexual selection) and ability of their ejaculates to outcompete those of other males (post-copulatory sexual selection). Sperm competition theory predicts a negative relationship between investment in body traits favouring mate acquisition (secondary sexual characters, SSCs) and investment in ejaculate size or quality, due to the inherent costs of sperm production. In contrast, the phenotype-linked fertility hypothesis posits that male fertilizing efficiency is reliably reflected by the phenotypic expression of male SSCs, allowing females to obtain direct benefits by selecting more ornamented males as copulation partners. In this study, we investigated the relationships between male SSCs and size and quality (viability and longevity) of ejaculates allocated to females in mating trials of the freshwater crayfish Austropotamobius italicus. We showed that the relative size of male weapons, the chelae, was negatively related to ejaculate size, and that chelae asymmetry, resulting from regeneration of lost chelipeds, negatively covaried with sperm longevity. Moreover, males allocated more viable sperm to mates from their own rather than different stream of origin. Our findings thus suggest that, according to sperm competition theory, pre-copulatory sexual selection for large weapons used in male fighting may counteract post-copulatory sperm competition in this crayfish species, and that investment in cheliped regeneration may impair ejaculate quality

Assessing repeatability and reproducibility of Anterior Active Rhinomanometry (AAR) in children

BACKGROUND: Repeatability and reproducibility are essential for clinicians for several purposes. Although discouraged, use of the Coefficient of Variation (CV) for assessing repeatability and reproducibility, rather than the Intraclass Correlation Coefficient (ICC), is still widespread. The aim of the present study was to highlight how using inappropriate indices may lead to misleading results, and this is done by simulation study and using real data on Anterior Active Rhinomanometry (AAR) in both healthy children and ones with rhinitis. METHODS: A simulation study was carried out to highlight how using inappropriate indices could be misleading. Then a comparison was made between CV and ICC to assess repeatability and reproducibility of AAR, for which previous studies have given underestimated results. AAR is recommended as the gold standard tool for measuring nasal resistance in clinical practice. RESULTS: A simulation study showed that the ICCs estimated from data generated assuming a true CV yielded results in agreement with estimated CVs; by contrast, if data were generated assuming a true ICC, CVs yielded conflicting results. For AAR, ICCs showed good repeatability, whereas CVs showed unacceptable repeatability. AUC and 95% CI for AAR showed good performance in predicting current symptoms of rhinitis in the overall study population. CONCLUSIONS: The present study focused on the importance of the choice of appropriate indices of repeatability and reproducibility, demonstrating the repeatability of AAR in both healthy children and ones with rhinitis

First- and second-line treatment strategies for hormone-receptor (HR)-positive HER2-negative metastatic breast cancer: A real-world study

Background: Endocrine therapy (ET) plus cyclin-dependent-kinases 4/6 inhibitors (CDK4/6i) represents the standard treatment for luminal-metastatic breast cancer (MBC). However, prospective head-to-head comparisons are still lacking for 1st line (L) options, and it is still crucial to define the best strategy between 1st and 2nd L. Materials and methods: 717 consecutive luminal-MBC pts treated between 2008 and 2020 were analyzed at the Oncology Department of Aviano and Udine, Italy. Differences about survival outcomes (OS, PFS and PPS) were tested by log-rank test. The attrition rate (AR) between 1st and 2ndL was calculated. Results: At 1stL, pts were treated with ET (49%), chemotherapy (CT) (31%) and ET-CDKi (20%) while, at 2ndL, 33% received ET, 33% CT and 8% ET-CDKi. Overall AR was 10%, 7% for CT, 8% for ET and 17% for ET-CDKi. By multivariate analysis, 1stL ET-CDK4/6i showed a better mPFS1 and OS. Moreover, 2ndL ET-CDK4/6i demonstrated better mPFS2 compared to ET and CT. Notably, 1stL ET-CDKi resulted in higher mPFS than 2ndL ET-CDKi. Intriguingly, 1stL ET-CDK4/6i was associated with worse mPPS compared to CT and ET. Secondarily, 1stL ET-CDK4/6i followed by CT had worse OS compared to 1stL ET-CDK4/6i followed by ET. Notably, none of baseline characteristics at 2ndL influenced 2ndL treatment choice (ET vs. CT) after ET-CDKi. Conclusion: Our real-world data demonstrated that ET-CDKi represents the best option for 1stL luminal-MBC compared to ET and CT. Also, the present study pointed out that 2ndL ET, potentially combined with other molecules, could be a feasible option after CDK4/6i failure, postponing CT on later lines

Aflibercept Plus FOLFIRI in the Real-life Setting: Safety and Quality of Life Data From the Italian Patient Cohort of the Aflibercept Safety and Quality-of-Life Program Study

The Italian subset of the real-life Aflibercept Safety and Quality-of-Life Program study evaluated the safety and health-related quality of life (HRQL) of aflibercept plus FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) in 200 patients with pretreated metastatic colorectal cancer (mCRC). No significant worsening of HRQL occurred, and the safety profile was consistent with the reported data. The combination was well tolerated as second-line treatment for patients with mCRC in a real-life setting. Background: Aflibercept combined with FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) as second-line treatment of metastatic colorectal cancer (mCRC) significantly improved survival compared with FOLFIRI alone in the pivotal VELOUR (aflibercept vs. placebo in combination with irinotecan and 5-fluorouracil in the treatment of patients with metastatic colorectal cancer after failure of an oxaliplatin-based regimen) trial. No quality-of-life assessment was performed in VELOUR; therefore, the ASQoP (Aflibercept Safety and Quality-of-Life Program) trial was designed to capture the safety and health-related quality of life (HRQL). Patients and Methods: ASQoP was an international, open-label, single-arm trial evaluating the safety and HRQL of aflibercept combined with FOLFIRI administered in a real-life setting to 781 patients with mCRC, pretreated with an oxaliplatin-based regimen with or without bevacizumab. The Italian subset of ASQoP enrolled 200 patients from 28 institutions. The primary endpoint was safety; HRQL was a secondary endpoint, assessed by validated questionnaires (European quality of life 5-dimension instrument 3-level; European Organization for Research and Treatment for Cancer Quality of Life Questionnaire Core 30, version 3; and EORTC-CR29) at baseline, during treatment, and at the end of treatment. Results: The median age of the Italian ASQoP population was 63 years; the median number of aflibercept and FOLFIRI cycles was 7. Treatment-emergent adverse events were reported in 97.5% of patients. Hypertension (28.5%), neutropenia (27.5%; from laboratory data), asthenic conditions (20.0%), diarrhea (17.0%), and stomatitis (13.0%) were the most frequent (incidence, ≥ 5%) grade 3/4 toxicities. One toxic death occurred during the study period due to sepsis, without neutropenic complications. No significant worsening of HRQL was shown during treatment. Conclusion: Aflibercept combined with FOLFIRI was well tolerated when administered as second-line treatment for patients with mCRC in a real-life setting. It did not affect HRQL and showed similar rates of treatment-emergent adverse events as those observed in the VELOUR trial. No new safety signals were identified