Sialidase Attenuates Epidermal Growth Factor Response and Abolishes Antiproliferative Effects of Erlotinib in A549Alveolar Epithelial Cells.

Erlotinib is a widely used, reversible tyrosine kinase inhibitor (TKI), targeting pro-proliferative signaling of epidermal growth factor receptor (EGFR). The drug is approved for the first-line treatment of patients with metastatic non-small cell lung cancer with EGFR mutations. Extracellular glycans can affect EGFR expression, dimerization, phosphorylation, and EGF binding. In this study we investigated the effects of EGF and erlotinib on the cell cycle of naive and sialidase (alpha-neuraminidase)-pretreated human A549 alveolar epithelial cells. A549 cells were labeled with propidium iodide, and fractions of cells in different phases of cycle were quantified by flow cytometry. We found that neither did desialilation nor EGF, as well as erlotinib treatment, increase the number of damaged cells (subG0/G1 cell fraction), while erlotinib did significantly increase the number of G0/G1 cells and decrease S + G2/M cell fractions. In naive cells, EGF increased proliferating cell numbers by more than 40%, and this effect was blocked by erlotinib. In desialylated cells, however, proliferation was significantly decreased by about 29%, and EGF and erlotinib did not exert significant effects. We conclude that changes in alveolar epithelial cell membrane glycosylation may affect function of growth-promoting receptors and erlotinib effectiveness.

Cigarette Smoke-Induced Oxidative Stress and Autophagy in Human Alveolar Epithelial Cell Line (A549 Cells).

Chronic exposure to cigarette smoke (CS) causes structural and functional changes in the respiratory tract. It is a major risk factor for cardiovascular and systemic pulmonary diseases. The aim of this study was to investigate the effect of acute CS exposure (2 h) on oxidative stress, heat shock protein 70 (HSP70) expression, autophagy (LC3 expression), and oxidative stress (DCF fluorescence) in human alveolar epithelial cell line A549. Cell culture medium was conditioned with CS using commercial cigarettes, and A549 cells were grown in modified media for 2 h. In some experiments, A549 cells were pretreated with 100 µM of L-buthionine-sulfoximine (BSO) for 24 h to induce glutathione (GSH) depletion. In the cells grown in CS-conditioned medium, GSH was depleted by more than 30%, and reactive oxygen species were increased. Moreover, there was a considerable overexpression of HSP70 and a substantial accumulation of LC3. Similar changes were found when the cells were pretreated with BSO. We conclude that the short-term exposure of epithelial cells to CS increases oxidative stress that entails enhanced autophagy activity.

Radiopaque marker colonic transit study in the pediatric population BSPGHAN Motility Working Group consensus statement.

Functional constipation (FC) is a common condition in childhood in the United Kingdom and worldwide. Various radiological approaches have been established for diagnostic purposes. The radiopaque marker study (ROMS) is universally accepted and used to assess colonic transit time (CTT) in children with FC. Despite being widely used, there is a lack of standardization with various technical protocols, reproducibility of different populations, the purpose for using investigation, variance in the number of markers used, the amount of study days and calculations, the need to empty the colon before performing the test, and whether to perform on medication or off, or the use of specific diets. As part of the British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) motility working group (MWG), we decided to explore further into the evidence, in order to provide guidance regarding the use of ROMS in dealing with FC in the pediatric population.

Systematic review of comparative transcriptomic studies of cellular resistance to genotoxic stress.

The development of resistance by tumor cells to various types of therapy is a significant problem that decreases the effectiveness of oncology treatments. For more than two decades, comparative transcriptomic studies of tumor cells with different sensitivities to ionizing radiation and chemotherapeutic agents have been conducted in order to identify the causes and mechanisms underlying this phenomenon. However, the results of such studies have little in common and often contradict each other. We have assumed that a systematic analysis of a large number of such studies will provide new knowledge about the mechanisms of development of therapeutic resistance in tumor cells. Our comparison of 123 differentially expressed gene (DEG) lists published in 98 papers suggests a very low degree of consistency between the study results. Grouping the data by type of genotoxic agent and tumor type did not increase the similarity. The most frequently overexpressed genes were found to be those encoding the transport protein ABCB1 and the antiviral defense protein IFITM1. We put forward a hypothesis that the role played by the overexpression of the latter in the development of resistance may be associated not only with the stimulation of proliferation, but also with the limitation of exosomal communication and, as a result, with a decrease in the bystander effect. Among down regulated DEGs, BNIP3 was observed most frequently. The expression of BNIP3, together with BNIP3L, is often suppressed in cells resistant to non-platinum genotoxic chemotherapeutic agents, whereas it is increased in cells resistant to ionizing radiation. These observations are likely to be mediated by the binary effects of these gene products on survival, and regulation of apoptosis and autophagy. The combined data also show that even such obvious mechanisms as inhibition of apoptosis and increase of proliferation are not universal but show multidirectional changes.

Targeted therapies for glioblastoma treatment.

Glioblastoma, the most common and aggressive type of brain tumor in adults, poses significant challenges in terms of treatment. Conventional approaches including surgery, chemotherapy, and radiotherapy have yielded limited success, with a median survival of approximately 15 months. However, extensive research into the biology of glioblastoma has identified molecular targets that can be exploited by newly developed drugs, leading to the emergence of precise personalized therapies. Several innovative treatment strategies are currently under development, aiming to enhance effectiveness while minimizing side effects. Clinical trials are underway to evaluate the efficacy of monoclonal antibodies that target glioblastoma cells, either by blocking specific receptors or by modifying molecular interactions that impede cell proliferation. Another promising avenue involves the use of oncolytic viruses designed to selectively infect glioblastoma cells. Additionally, the review explores the utilization of nanocarriers capable of surmounting the formidable obstacle of the blood-brain barrier, enabling efficient drug delivery. Cell therapies represent another promising approach, with dendritic cells, chimeric antigen receptor-T cells, and macrophages emerging as potential treatment modalities. By summarizing recent advances in targeted therapies against glioblastoma, this review aims to provide a comprehensive overview of ongoing efforts to discover effective and safe methods for treating glioblastoma patients. The ultimate goal is to improve patient outcomes and transform the landscape of glioblastoma treatment.

From the original SARS-CoV-2 strain to the Omicron variant: Predictors of COVID-19 in ambulatory symptomatic children.

OBJECTIVES: To determine the predictors of a positive SARS-CoV-2 test in a pediatric ambulatory setting. PATIENTS AND METHODS: We performed a cross-sectional prospective study (November 2020-February 2022) of 93 ambulatory settings in France. We included symptomatic children < 15 years old tested for SARS-CoV-2. For each period corresponding to the spread of the original strain and its variants (period 1: original strain; period 2: Alpha, period 3: Delta; period 4: Omicron), we used a multivariate analysis to estimate adjusted odds ratios (aORs) associated with COVID-19 among age, signs, symptoms or contact, and 95 % confidence intervals (95CIs). RESULTS: Of 5,336 children, 13.9 % (95CI 13.0-14.8) had a positive test. During the first three periods, the positivity rate ranged from 5.6 % (95CI 4.6-6.7) to 12.6 % (95CI 10.8-14.6). The main factors associated with a positive test were contact with an infected adult at home or outside the home (aOR 11.5 [95CI 4.9-26.9] to 38.9 [95CI 19.3-78.7]) or an infected household child (aOR 15.0 [95CI 4.8-47.1] to 28.4 [95CI 8.7-92.6]). By contrast, during period 4, aORs for these predictors were substantially lower (2.3 [95CI 1.1-4.5] to 5.5 [95CI 3.2-7.7]), but the positivity rate was 45.7 % (95CI 42.3-49.2). CONCLUSIONS: In pediatric ambulatory settings, before the Omicron period, the main predictor of a positive test was contact with an infected person. During the Omicron period, the odds of these predictors were substantially lower while the positivity rate was higher. An accurate diagnostic strategy should only rely on testing and not on age, signs, symptoms or contact.

Timeliness of routine immunization in non-preterm children less than 2 years old using electronic data capture in an ambulatory setting in France in the context of vaccine hesitancy.

OBJECTIVES: The vaccine schedule was changed in 2013 in France, which resulted in fewer vaccinations. However, to maintain disease protection, both vaccine timeliness and high coverage should be respected. In the context of growing vaccine hesitancy, we aimed to describe compliance with the immunization program according to the age recommended for each dose for non-preterm children less than 2 years old. METHODS: Between May 2013 and April 2016, we used automated electronic data capture of electronic medical records for non-preterm children less than 2 years old. Children were followed up by 92 randomly selected pediatricians from the French ambulatory pediatricians group. Delayed immunization was defined as more than 15 days after the recommended age for the primary series of diphtheria-tetanus-pertussis-polio-Haemophilus influenzae b-hepatitis B (DTaP-IPV-Hib±HB) and 13-valent pneumococcal vaccine (PCV13), 2 months for boosters, 1 month for measles-mumps-rubella (MMR)/meningococcal C conjugate (Men-C), and 6 months for the second dose of MMR. An association between delayed first dose and other doses delayed were described with odds ratios (ORs) and their 95% confidence intervals (CIs). RESULTS: Data for 22,097 children in France with 124,702 vaccinations were analyzed: 21.8%, 20.4%, and 30.7% of children had one or more delayed doses of DTaP-IPV-Hib±HB, PCV13, and MMR vaccines, respectively. For 47.6% of children, the single-dose Men-C vaccination was delayed. A delayed first dose of DTaP-IPV-Hib±HB, PCV13, and MMR was associated with a delayed second dose of the same vaccine (OR 7.5 [95% CI 6.6-8.6], 39.0 [34.1-44.8], and 23.5 [19.1-29.0], respectively) and with a third dose of DTaP-IPV-Hib±HB and PCV13 (14.7 [13.3-17.7] and 3.7 [3.1-4.5]). CONCLUSION: This large study shows that the proportion of children with delayed vaccination in France was globally high and substantial for Men-C and the first MMR vaccination. Risk of a delayed second and third dose was increased with a delayed first dose, which may reflect vaccine hesitancy.

[Thieno[2,3-d]pyrimidines as antagonists of the glutamate receptors]. / Thieno[2,3-d]pyrimidine als glutamatantagonisten.

Although the function of the kainate receptors in the brain is still not clear, they are increasingly defined as targets in the development of new classes of anti-epileptics. The thienopyrimidines described in this report were tested for their antagonistic effect at the kainate receptor subtypes GluR5 and GluR6. The highest effectiveness was obtained by a 4-ethoxy-thieno[2,3-d]pyrimidin with an IC50 = 68 microM at the GluR6 receptor.

The succession of the plant community on a decontaminated radioactive meadow site.

Long-term observation of the succession in a plant community is considered a fundamental unit used to investigate the expected consequences of soil contamination by radionuclides and to understand restoration of technogeneously disturbed ecosystems. The development of arboreal willow meadow under remediation of a radioactively contaminated site has been studied for half a century. Succession stages in the formation of the de novo community were noted. Changes in the floristic composition, soil structure as well as radionuclide activity concentrations in topsoil were registered on each step. Technical recultivation of the area including covering radioactive wastes with a mixture of sand and gravel led to lower the radiation levels and was suitable for decontamination during first 5-8 years. This allowed the community to develop with maximal effectiveness on the initial steps. Than the covering layer lost its barrier functions but no adverse effects at dose rates up to 150 µGy/h on completion of the community formation were registered. Radioecological conditions and changes in the plant community development were registered simultaneously on the area studied that makes possible to follow main doseforming radionuclides migration and to determine main steps of the succession. The study results is a practical demonstration that edaphic niches, climatic conditions and сoenotic relationships between plants play a more important role in the evolution of the studied community than the contamination type and radiation exposure levels.

The list of species registered in taiga meadow community during succession under enhanced radioactive background.

The data presented in this article are related to the research article entitled "The succession of the plant community on a decontaminated radioactive meadow site" (T. Maystrenko, B. Gruzdev, E. Belykh, A. Rybak, 2018) [1]. Primary data on floristic studies of meadow community development in taiga zone on the site contaminated with naturally occurring radionuclides are shown. The information given allows to follow a process of appearance and exclusion of high plant species from the pioneer step of succession up to stable community formation and to compare the structure and composition of meadow communities formed on territories with the enhanced and natural radioactivity background.

[The Jardé law, a real simplification of research in France?] / La loi Jardé, un nouvel encadrement législatif pour une simplification de la recherche clinique ?

The Jardé law was voted in 2012 and its implementing decrees were published in November 2016. The delay between the vote and the decrees highlights the difficulties encountered. This law concerns all research, interventional and otherwise, involving the human person. Each research study must receive the approval of a randomly assigned ethics committee or Committee for the Protection of Persons. The approach here is based on risk in three types of study: interventional studies, studies with minimal risk and intervention, and non-interventional studies (observational studies). The main changes are: simplified informed consent for pediatric studies and possible enrolment for people not affiliated with a social health care system in non-interventional research. The law provides clarification for changes in the purpose of biological collections. For vigilance, the notions of "new facts" and "urgent security measures" have emerged. Although this law appears to be an advancement, some concerns still need to be clarified. The main problem arises from the foreseeable extension of the delay to implement research. Medical research is a competition where time is valuable. Colleagues working on cosmetics research have already anticipated these difficulties. On February 8, 2017, the decrees of the Jardé law were suspended for cosmetics studies. Will the Jardé law be suspended for all French clinical research?

Sequential incremental doses of bisacodyl increase the diagnostic accuracy of colonic manometry.

BACKGROUND: Colonic manometry is the standard diagnostic modality for evaluating colonic motility in children. Intraluminal bisacodyl is routinely used to trigger high-amplitude propagating contractions (HAPCs), a feature of normal colonic motility. Usually, only a single dose (0.2 mg/kg) is suggested. We retrospectively explored whether the use of an additional higher (0.4 mg/kg) dose of bisacodyl increases the yield of colonic manometry. METHODS: In 103 children (median age: 8.8 years, range 3.2-15.7 years) with a diagnosis of slow transit constipation, colonic motility was recorded for 1 h before and 1 h after each of two incremental doses of bisacodyl (low, L, dose: 0.2 mg/kg, max 10 mg; high, H, dose: 0.4 mg/kg, max 20 mg) and the characteristics of HAPCs analyzed. KEY RESULTS: High-amplitude propagating contractions were seen in 85 children. H dose significantly increased the proportion of patients with fully propagated HAPCs (H dose: 57/103 [55%], L dose: 27/103 [26%], p < 0.001), paralleling the significant decrease in the proportion with partially propagated HAPCs (H dose: 29/103 [28%], L dose: 47/103 [46%], p < 0.01). Mean HAPC number significantly increased throughout the colon at H compared to L dose (7.2 ± 5.05 vs 5.6 ± 5.1, p < 0.05). Finally, the proportion of patients with normal pressure wave morphology of HAPCs significantly increased with higher dose (H dose: 55/85 [65%], L dose: 27/85 [32%], p < 0.001). CONCLUSIONS & INTERFERENCES: An additional higher dose of bisacodyl during colonic manometry improves colonic neuromuscular function suggesting its use might improve interpretation and decision making in children with slow transit constipation.

[Protected mercaptoalkylpyrimidinones: synthesis and test for immunostimulating activity]. / Maskierte Mercaptoalkylpyrimidinone: Synthese und Prüfung auf immunstimulierende Wirkung.

Protected mercaptoalkylpyrimidinones: synthesis and test for immunostimulating activity 3-Hydroxyalkyl-pyrimidine 1 reacts with phosphoroxychloride and thioglycolic acid or thiourea to yield pyrimidin-3-ylalkylthioacetic acids 3 or pyrimidin-3-ylalkylthiouroniumsalts 5 respectively. Some of the pyrimidines 3 and 5 showed immunomodulatory activity.

[Procalcitonin in diagnosis of purulent and aseptic meningitis in children]. / Prokalcytonina w diagnostyce róznicowej ropnego i surowiczego zapalenia opon mózgowo-rdzeniowych u dzieci.

UNLABELLED: Procalcitonin (PCT) is a new indicator of the systemic response to severe infections. To evaluate clinical usefulness of serum procalcitonin measurements in the differential diagnosis of purulent versus aseptic meningitis in children was the aim of the study. Fifteen children (aged 1 month-14 years) with purulent meningitis and 12 children (aged 6 months-12 years) with aseptic meningitis were included into the study. Serum PCT concentration was measured on admission by immunoluminometric assay. Thirty healthy controls (aged 3 months-14 years) were also enrolled into the study. Serum PCT concentration was above 0.5 ng/ml in 14 out of 15 children with purulent meningitis (range 0.0-95.2 ng/ml; arrhythmetic mean--28.2 ng/ml). In all children with aseptic meningitis (range 0.0-0.3 ng/ml; mean--0.1 ng/ml) as well as in healthy controls (range 0.0-0.3 ng/ml; mean--0.1 ng/ml) serum PCT was below 0.5 ng/ml. CONCLUSION: Elevated serum PCT concentration in child with meningitis suggests bacterial aetiology.

[Level of magnesium in blood serum in children from the province of Rzesz'ow]. / Poziom magnezu w surowicy krwi u dzieci województwa rzeszowskiego.

In 142 girls and 107 boys aged 5-15 years serum magnesium level was determined by the colorimetric method. Decreased values were found in 24 children including 7 boys and 17 girls. In 21 of them neurotic reactions or concentration disturbances were observed.

Substituted 2-aminothiopen-derivatives: a potential new class of GluR6-antagonists.

In the course of search for new therapeutic agents against epilepsy new inhibitors for the kainate receptor subtypes GluR5 and GluR6 were synthesized. We were able to synthesize new substituted thieno[2,3-d]pyrimidines 3a,b, 4a,b, 5a,b as well as thiophene-3-carboxamides 2a-d and a multitude of substituted 4-methyl-5-phenylthiophene-3-carboxylic acids. All compounds described herein were tested for their antagonistic effect towards the kainate receptor subtypes GluR5 and GluR6. The highest activity was observed for ethyl 2-amino-4-methyl-5-phenylthiophene-3-carboxylate 1c with an IC50=0.75 microM at the GluR6 receptor.