Antigen recognition and T-cell mediated cytotoxicity in clear-cell renal cell carcinoma (ccRCC) remains incompletely understood. To address this knowledge gap, we analysed 115 multiregion tumour samples collected from 15 treatment-naive patients pre- and post-nivolumab therapy, and at autopsy in three patients. We performed whole-exome sequencing, RNAseq, TCRseq, multiplex immunofluorescence and flow cytometry analyses and correlated with clinical response. We observed pre-treatment intratumoural TCR clonal expansions suggesting pre-existing immunity. Nivolumab maintained pre-treatment expanded, clustered TCR clones in responders, suggesting ongoing antigen-driven stimulation of T-cells. T-cells in responders were enriched for expanded TCF7+CD8+ T-cells and upregulated GZMK/B upon nivolumab-binding. By contrast, nivolumab promoted accumulation of new TCR clones in non-responders, replacing pre-treatment expanded clonotypes. In this dataset, mutational features did not correlate with response to nivolumab and human endogenous retrovirus expression correlated indirectly. Our data suggests that nivolumab potentiates clinical responses in ccRCC by binding pre-existing expanded CD8+ T-cells to enhance cytotoxicity.

INTRODUCTION:Obstructive Sleep Apnea (OSA)represents the complete or partial obstruction of the airway.Clinically OSA manifests as sleepness during the day,heavy snoring as well as waking up during the night dues the lack of air.Obesity,gender and orthodontic malocclusion are mentioned in the literature as the etiologic factor for Obstructive Sleep Apnea. AIM: The aim of this study was to find the relationship in the analyzed studies between the Obstructive Sleep Apnea and orthodontic malocclusion at non-obese adults. MATERIAL AND METHODS:The electornic search of the database was performed,using PubMed and Googlescholar,with the aim to find the relevante articles which correlate the OSA and orthodontic malocclusion.Keyword included:obstrucitve sleep apnea,orthodontic malocclusion,cephalometric analysis,impact,association,body mass index,obesity,adults,non obesity. Inclusion criteria were:nonobesity,orthodontic malocclusion,adults,articles published from 1999 to 2019,articles in English,full articles avaiable. RESULTS:Two hundred papers included keywords.The number of articles that included the fully set criteria was nine.These nine articles were analyzed in detail. CONCLUSION:Analyzed articles showed that there is relationship between the Obstructive Sleep Apnea and orthodontic malocclusion in non-obese adults.It was also showed that orthodontic malocclusion is etiological factor for OSA in non-obese adults.

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We aimed to evaluate the changes in eating behaviours of the adult population across 16 European countries due to the COVID-19 confinement and to evaluate whether these changes were somehow related to the severity of the containment measures applied in each country. An anonymous online self-reported questionnaire on socio-demographic characteristics, validated 14-items Mediterranean diet (MedDiet) Adherence Screener (MEDAS) as a reference of a healthy diet, eating and lifestyle behaviours prior to and during the COVID-19 confinement was used to collect data. The study included an adult population residing in 16 European countries at the time of the survey. Aggregated Stringency Index (SI) score, based on data from the Oxford COVID-19 Government Response Tracker, was calculated for each country at the time the questionnaire was distributed (range: 0–100). A total of 36,185 participants completed the questionnaire (77.6% female, 75.2% with high educational level and 42.7% aged between 21 and 35 years). In comparison to pre-confinement, a significantly higher adherence to the MedDiet during the confinement was observed across all countries (overall MEDAS score prior to- and during confinement: 5.23 ± 2.06 vs. 6.15 ± 2.06; p < 0.001), with the largest increase seen in Greece and North Macedonia. The highest adherence to MedDiet during confinement was found in Spain and Portugal (7.18 ± 1.84 and 7.34 ± 1.95, respectively). Stricter contingency restrictions seemed to lead to a significantly higher increase in the adherence to the MedDiet. The findings from this cross-sectional study could be used to inform current diet-related public health guidelines to ensure optimal nutrition is followed among the population, which in turn would help to alleviate the current public health crisis.

O hiperestrogenismo em cães tem várias etiologias, dentre elas, o resultado da excessiva produção de estrógeno por tumores testiculares ou ovarianos. É descrito também que pode ter origem devido a um desequilíbrio entre os hormônios andrógenos e estrógenos. Como resultado do hiperestrogenismo, manifestam-se dermatoses clínicas como, alopecia bilateral simétrica, pelagem rarefeita, facilmente destacáveis, hiperpigmentação variável. O diagnóstico é baseado no histórico, anamnese, sinais clínicos, ultrassonografia testicular, dosagem hormonal de estrógenos séricos e realização de exame histopatológico. O tratamento de eleição é a orquiectomia. O objetivo do presente estudo é relatar a ocorrência de uma dermatose secundária ao hiperestrogenismo em um cão jovem.

The chikungunya virus (CHIKV) is a mosquito‐transmitted alphavirus, which has infected millions of people in Africa, Asia, Americas, and Europe since it remerged in India and Indian Ocean regions in 2005–2006. The purpose of this study was to evaluate the genetic diversity and evolutionary changes in CHIKV from 2016 to 2018 in Pakistan. Blood specimens were collected and processed following the Centers for Disease Control and Prevention Trioplex Protocol. Sequencing and phylogenetic analysis of complete coding sequence of representative isolates from the CHIKV outbreak was carried out during December 2016 to July 2018, a total of 1549 samples were received, out of which 50% (n = 774) were found positive for CHIKV RNA. Mean age of chikungunya positive patients was 31.8 ± 15.7 years and most affected were between 21 and 40 years of age. The Pakistan CHIKV strains clustered with the Indian Ocean sublineage of East/Central/South African with cocirculation of some variants In the structural proteins region, two noteworthy changes (A226V and D284E) were observed in the membrane fusion glycoprotein E1. Key substitutions in the neutralizing epitopes site and a few changes indicative of adaptive to other insect cells were also detected in Pakistani strains. This study provides the emerging trend of CHIKV in the country for early identification of potential variants of high virulence and preventive measures for vector borne disease especially in the endemic areas.

Excessive use of pesticides and fertilizers in agriculture in order to increase yields has proved unnecessary because a large part of them remain unused and have negative effects on the environment and human health. Therefore, it is a great challenge for farmers to replace the application of pesticides and fertilizers with nanopesticides and nanofertilizers, with the aim of reducing the use of mineral fertilizers and increasing yields, as well as supporting agricultural development. This review provides a detailed overview of the classification of pesticides, commonly used nanoparticles in agriculture and their function, as well as impact of nanopesticides and nanofertilizers on the environment. The application of nanopesticides and nanofertilizers and new delivery mechanisms to improve crop productivity are reviewed and described. Particularly, the advantage of the nanoencapsulation process is emphasized for both pesticides and fertilizers. For hydrophobic pesticides, it may be a tool to provide greater stability, dispersion in aqueous media, and allowing a controlled release of the active compound, which increases its effectiveness. In nanofertilizers, micro- or macronutrients can be encapsulated by nanomaterials which allow to release of nutrients into the soil gradually and in a controlled way maintaining soil fertility, thus preventing eutrophication and pollution of water resources. Risks assessment of application of nanopesticides and nanofertilizers in agriculture are required for their correct and safe application.

Background Based on favourable outcomes in clinical trials, immune checkpoint inhibitors (ICIs), most notably programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors, are now widely used across multiple cancer types. However, due to their strict inclusion and exclusion criteria, clinical studies often do not address challenges presented by non-trial populations. Design This review summarises available data on the efficacy and safety of ICIs in trial-ineligible patients, including those with autoimmune disease, chronic viral infections, organ transplants, organ dysfunction, poor performance status, and brain metastases, as well as the elderly, children, and those who are pregnant. In addition, we review data concerning other real-world challenges with ICIs, including timing of therapy switch, relationships to radiotherapy or surgery, re-treatment after an immune-related toxicity, vaccinations in patients on ICIs, and current experience around ICI and coronavirus disease-19. Where possible, we provide recommendations to aid the often-difficult decision-making process in those settings. Conclusions Data suggest that ICIs are often active and have an acceptable safety profile in the populations described above, with the exception of PD-1 inhibitors in solid organ transplant recipients. Decisions about whether to treat with ICIs should be personalised and require multidisciplinary input and careful counselling of patients with respect to potential risks and benefits. Clinical judgements need to be carefully weighed, considering factors such as underlying cancer type, feasibility of alternative treatment options, or activity in trial-eligible patients.

This paper analyzes the impact of multimedia content on success in learning to write and read the letters of the alphabet. For the research purpose and according to the ADDIE model of instructional design, a multimedia application was created for learning to write and read the letters of the alphabet. This paper describes the application interface display, which presents the functions and the parts of the program code. In the focus of the research are the technical possibilities for the use of multimedia application, as well as the impact of its use on the awareness of pupils and teachers on the importance of the introduction of multimedia teaching content. The main research was focused on the effectiveness of learning to write and read the letters of the alphabet and was carried out by comparing the performance of pupils at the end of the school year in two primary schools.Keywords: application; e-learning; education; improving learning. --- U ovom radu ispituje se utjecaj multimedijskoga sadržaja na učenje čitanja i pisanja slova. U svrhu istraživanja izrađena je multimedijska aplikacija za učenje čitanja i pisanja slova, prema ADDIE modelu instrukcijskoga dizajna. U radu je opisana aplikacija prikazom aplikacijskoga sučelja, opisom funkcija i dijelova koda. Istražene su tehničke mogućnosti korištenja multimedijske aplikacije kao i utjecaj njezine uporabe na svijest učenika i nastavnika o važnosti uvođenja multimedijskih nastavnih sadržaja. Glavno se istraživanje odnosi na uspjeh učenja čitanja i pisanja slova, a provedeno je usporedbom postignuća učenika na kraju školske godine u dvije osnovne škole.Ključne riječi: aplikacija; e-učenje; obrazovanje; poboljšavanje nastave.  

This paper describes the influence of deformation by equal-channel angular pressing (ECAP) on the solid particle erosion resistance of the AlSi7Mg0.3 alloy and AlSi7Mg0.3 based composite material reinforced with the addition of 4 % of fly ash (FA) particles. Both, alloy and composite samples were produced using the compo-casting method. The samples have been subjected to ECAP in multiple passes with the rotation of samples around the vertical axis for the angle of 90° after each pass. Particles of silicon carbide (SiC) have been used as erodent while their impact angle was varied (30° and 90°). Observed samples of AlSi7Mg0.3 alloy generally showed higher wear resistance at 90° angle where material fatigue predominates, than at a 30° angle where abrasion-related phenomena predominate. On the other hand, AlSi7Mg0.3 based composite material exhibited erosion wear at 30° angle less than at 90° angle after one ECAP pass. Evaluation of the erosion resistance has been made based on mass and volume loss. After two passes of ECAP, the matrix structure of the AlSi7Mg0.3 based composite material, as well as that of the AlSi7Mg0.3 alloy was improved from the aspect of erosion resistance.

Enabling System-of-Systems (SoS) security is an important activity when engineering SoS solutions like autonomous vehicles, provided that they are also highly safety-critical. An early analysis of such solutions caters for proper security architecture decisions, preventing potential high impact attacks and ensuring people's safety. However, SoS characteristics such as emergent behavior, makes security decision-making at the architectural level a challenging task. To tackle this challenge, it is essential to first address known vulnerabilities related to each CS, that an adversary may exploit to realize his attacks within the unknown SoS environment. In this paper we investigate how to use Game Theory (GT) approaches to guide the architect in choosing an appropriate security solution. We formulate a game with three players and their corresponding strategies and payoffs. The proposal is illustrated on an autonomous quarry example showing its usefulness in supporting a security architect to choose the the most suitable security strategy.