Comprehensive characterization of RNA cargo of extracellular vesicles in breast cancer patients undergoing neoadjuvant chemotherapy

Funding Information: This work was funded by the ERDF project No. 1.1.1.1/18/A/084. Publisher Copyright: Copyright © 2022 Sadovska, Zayakin, Eglītis, Endzeliņš, Radoviča-Spalviņa, Avotiņa, Auders, Keiša, Liepniece-Karele, Leja, Eglītis and Linē.Extracellular vesicles (EVs) are g7aining increased attention as carriers of cancer-derived molecules for liquid biopsies. Here, we studied the dynamics of EV levels in the plasma of breast cancer (BC) patients undergoing neoadjuvant chemotherapy (NAC) and explored the relevance of their RNA cargo for the prediction of patients’ response to the therapy. EVs were isolated from serial blood samples collected at the time of diagnosis, at the end of NAC, and 7 days, 6, and 12 months after the surgery from 32 patients with locally advanced BC, and 30 cancer-free healthy controls (HCs) and quantified by nanoparticle tracking analysis. The pre-treatment levels of EVs in BC patients were higher than in HCs, significantly increased during the NAC and surgery, and decreased to the levels found in HCs 6 months after surgery, thus showing that a substantial fraction of plasma EVs in BC patients are produced due to the disease processes and treatment. RNA sequencing analysis revealed that the changes in the EV levels were associated with the alterations in the proportions of various RNA biotypes in EVs. To search for RNA biomarkers that predict response to the NAC, patients were dichotomized as responders and non-responders based on Miller-Payne grades and differential expression analyses were carried out between responders and non-responders, and HCs. This resulted in the identification of 6 miRNAs, 4 lncRNAs, and 1 snoRNA that had significantly higher levels in EVs from non-responders than responders at the time of diagnosis and throughout the NAC, and significantly lower levels in HCs, thus representing biomarkers for the prediction of response to NAC at the time of diagnosis. In addition, we found 14 RNAs representing piRNA, miRNA, lncRNA, snoRNA, and snRNA biotypes that were induced by NAC in non-responders and 2 snoRNAs and 1 piRNA that were induced by NAC in patients with early disease progression, thus warranting further functional studies on their role in chemoresistance and metastasis.publishersversionPeer reviewe

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

The European Insomnia Guideline : An update on the diagnosis and treatment of insomnia 2023

Publisher Copyright: © 2023 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.Progress in the field of insomnia since 2017 necessitated this update of the European Insomnia Guideline. Recommendations for the diagnostic procedure for insomnia and its comorbidities are: clinical interview (encompassing sleep and medical history); the use of sleep questionnaires and diaries (and physical examination and additional measures where indicated) (A). Actigraphy is not recommended for the routine evaluation of insomnia (C), but may be useful for differential-diagnostic purposes (A). Polysomnography should be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep-related breathing disorders, etc.), treatment-resistant insomnia (A) and for other indications (B). Cognitive-behavioural therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (including patients with comorbidities), either applied in-person or digitally (A). When cognitive-behavioural therapy for insomnia is not sufficiently effective, a pharmacological intervention can be offered (A). Benzodiazepines (A), benzodiazepine receptor agonists (A), daridorexant (A) and low-dose sedating antidepressants (B) can be used for the short-term treatment of insomnia (≤ 4 weeks). Longer-term treatment with these substances may be initiated in some cases, considering advantages and disadvantages (B). Orexin receptor antagonists can be used for periods of up to 3 months or longer in some cases (A). Prolonged-release melatonin can be used for up to 3 months in patients ≥ 55 years (B). Antihistaminergic drugs, antipsychotics, fast-release melatonin, ramelteon and phytotherapeutics are not recommended for insomnia treatment (A). Light therapy and exercise interventions may be useful as adjunct therapies to cognitive-behavioural therapy for insomnia (B).Peer reviewe

Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study

Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases

The Helicobacter pylori Genome Project : insights into H. pylori population structure from analysis of a worldwide collection of complete genomes

Helicobacter pylori, a dominant member of the gastric microbiota, shares co-evolutionary history with humans. This has led to the development of genetically distinct H. pylori subpopulations associated with the geographic origin of the host and with differential gastric disease risk. Here, we provide insights into H. pylori population structure as a part of the Helicobacter pylori Genome Project (HpGP), a multi-disciplinary initiative aimed at elucidating H. pylori pathogenesis and identifying new therapeutic targets. We collected 1011 well-characterized clinical strains from 50 countries and generated high-quality genome sequences. We analysed core genome diversity and population structure of the HpGP dataset and 255 worldwide reference genomes to outline the ancestral contribution to Eurasian, African, and American populations. We found evidence of substantial contribution of population hpNorthAsia and subpopulation hspUral in Northern European H. pylori. The genomes of H. pylori isolated from northern and southern Indigenous Americans differed in that bacteria isolated in northern Indigenous communities were more similar to North Asian H. pylori while the southern had higher relatedness to hpEastAsia. Notably, we also found a highly clonal yet geographically dispersed North American subpopulation, which is negative for the cag pathogenicity island, and present in 7% of sequenced US genomes. We expect the HpGP dataset and the corresponding strains to become a major asset for H. pylori genomics

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Mathematical Model and Synthetic Data Generation for Infra-Red Sensors

A key challenge in further improving infrared (IR) sensor capabilities is the development of efficient data pre-processing algorithms. This paper addresses this challenge by providing a mathematical model and synthetic data generation framework for an uncooled IR sensor. The developed model is capable of generating synthetic data for the design of data pre-processing algorithms of uncooled IR sensors. The mathematical model accounts for the physical characteristics of the focal plane array, bolometer readout, optics and the environment. The framework permits the sensor simulation with a range of sensor configurations, pixel defectiveness, non-uniformity and noise parameters

Modeling heat generation and transfer processes on graphs

Šajā maģistra darbā ir apskatīts siltuma pārneses un starojuma pārneses process siltumvadīšanas vienādojumam, ar kuriem tālāk izveidoti matemātiskie modeļi. Vispirms analizē diskrēto Laplasa operatoru siltumvadīšanas vienādojumiem tas attēlots ar grafu palīdzību. Tika izveidoti matemātiskie modeļi diskrētiem gadījumiem ar avota locekļiem un bez tiem un veikti to skaitliskie eksperimenti. Ar Furjē likumu siltuma plūsmai tika veidota diskretizācija no vienas grafa virsotnes uz otru. Pēc tam tiek aplūkots ēnošanas efekts un radiatīvā pārnese un modeļiem veiktas simulācijas ar taišņu metodi programmu paketē MATLAB. Darbā ir aprakstīts kāda ir saistība siltumvadīšanas vienādojumiem uz grafiem un metriskiem grafiem. Visbeidzot izstrādāta siltumenerģijas plūsmas matemātiskā analīze maksimuma principam.In this master's thesis, the process of heat transfer and radiation transfer for the heat conduction equation is considered, with which mathematical models are further developed. First, the discrete Laplace operators for the thermal conduction equations are represented by graphs. Mathematical models for discrete cases with and without source members were developed and their numerical experiments were performed. With Fourier's law, the flow of heat was discretization from one vertex of the graph to another. Then the shading effect and radiative transfer are considered and simulations of the models are performed with the method of lines in the MATLAB software package. Describes the relationship between heat conduction equations on graphs and metric graphs. Finally, the principle of maximum for temperature is obtained

On a model of biomass gasification

Darbā ir izveidots un analizēts matemātiskais modelis biomasas gazifikācijai ar nelineāru diferenciālvienādojumu sistēmu. Pirmkārt, tiek iegūta parasto diferenciālvienādojumu sistēma. Simulācijas tiek veiktas, izmantojot Runges-Kutas ar 4. kārtas punktu šablonu un iebūvēto funkciju programpaketē MATLAB. Tika izveidots reālistisks modelis ar daļēju parciālo diferenciālvienādojumu. Telpiskā diskretizācija tiek veikta, izmantojot galīgo tilpuma metodi. Izmantojot programmu MATLAB tika veiktas simulācijas vairākiem gazifikācijas procesu scenārijiem. Optimālākam rezultātu novērtējumam papildus apskata un ilustrē piemēru sērkociņu degšanai un to atkarībai no izvēlētajiem parametriem.In this thesis a mathematical model for biomass gasification with a nonlinear differential equation system is developed and analyzed. First a system of ordinary differential equations is obtained. Simulations are performed using the 4th order Runge-Kutta method and the built in functions in program package MATLAB. A more realistic model with partial differential equations is then developed. The spatial discretization is performed using a finite volume method. Several scenarios of the gasification process have been simulated using MATLAB. To illustrate the power of this model, simulations of the burning match are included

Universal Nuclear Equation of State Introducing the Hypothetical X17 Boson

Within the scope of the Symmetry journal special issue on: “The Nuclear Physics of Neutron Stars”, we complemented the nuclear equation of state (EoS) with a hypothetical 17 MeV boson and observed that only instances with an admixture of 30%–40% satisfy all of the constraints. The successful EoS resulted in a radius of around 13 km for a neutron star with mass MNS≈1.4M⊙ and in a maximum mass of around MNS≈2.5M⊙. The value of the radius is in agreement with the recent measurement by NICER. The maximum mass is also in agreement with the mass of the remnant of the gravitational wave event GW190814. Thus, it appears that these EoSs satisfy all of the existing experimental constraints and can be considered as universal nuclear equations of state