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Purpose: The purpose of the article is to present the design and fabrication methodology of metallic scaffolds, with the shape and dimensions defined by the designer, coated with a thin layer of polymer. Design/methodology/approach: The methodology proposed covers Computer Aided Materials Design (CAMD), fabrication of metallic scaffolds using a machine for Selective Laser Melting (SLM), the deposition of a thin layer of polymers onto scaffolds using coldwork and hot-work polymerisers, as well as mechanical finishing. The strength of the newly developed metal-polymer composites to three-point bending was examined and their fractures were viewed with SEM. Findings: A fabrication method of implants in the form of scaffolds coated with a thin layer of polymer with the dimensions and shape closely matching the losses in a patient’s hard and/or soft palate. Practical implications: After clinical tests, a metal-polymer implant may be a very beneficial alternative for patients with palate losses using traditional prostheses until now. Originality/value: The individualised implants of palate pieces in the form of scaffolds coated with a thin layer of polymer, submitted for patent protection, do not have their counterparts, which is representing their originality.

This research investigates the long-term environmental impact and historical temporal pollution patterns caused by a former copper mine in Iwiny (south-western Poland) using a dendrochemical approach. An additional aspect of this research was considering the possibility of using the inductively coupled plasma-optical emission spectrometry (ICP-OES) measurement technique as a cheaper alternative to inductively coupled plasma mass spectrometry (ICP-MS) in dendrochemical analyses conducted in copper mining areas. In the study area, a tailings storage facility (TSF) dam failure (1967) took place and the alkaline flotation waste containing high concentration of Cu and Pb are stored. Tree cores from pedunculate oak (Quercus robur L.) were analysed for the content of 11 trace elements (TEs) (Cd, Mn, Ni, Zn, Cr, Co, Pb, Cu, Fe, Al, Ag) using the ICP-OES technique, while tree rings’ widths (TRWs) were also measured. Samples that were most significant in the context of the research goals were verified with the ICP-MS method. The results revealed the strong long-term impact of the copper industry as reflected in a substantial increase in the mean contents of: (1) Mn, Ni, Zn, Cr, Pb, Cu and Fe in industrial vs. control trees, (2) TRWs for control vs. industrial trees. However, the observed patterns of TEs and TRWs did not correspond to the known timing of pollution inputs (mining activity, tailings spill). Peak levels were observed for Zn and Fe after the mine was closed. The lack of new sources of pollution and the temporal relationship strongly suggests that the tree rings recorded the chemical signal of the TSF reclamation (the use of fertilizers and agrotechnical interventions). Patterns of 7 elements were detected in most of the samples by ICP-OES (Co and Cd were not detected, Al and Ag were partly detected), while ICP-MS detected all of the elements. Significant differences were obtained for Ag, Cd, and Co. Despite challenges with the application of dendrochemistry in research on old mining areas (e.g., lack of old trees), it has proved to be a useful tool for investigating the aggregate environmental impact.

Vitamin K deficiency bleeding (VKDB) is a rare and potentially life-threatening disorder. Infants suffering from cholestasis constitute a risk group of vitamin K deficiency due to intestinal malabsorption defects. The paper presents a case of late-onset VKDB as a result of biliary atresia in an infant.

The article discusses the history of humans in the Vistula Valley east of Kraków from the late Pre-Roman to Roman period (3rd c. BC – 4th c. AD). This area, convenient for settlement, located on a well-preserved section of a loess river terrace, is among the most interesting and richest in Poland at that time. The diversity of habitats on the border of the loess terrace and floodplain ecosystems enabled diverse economic activities, both agricultural and non-agricultural, which was stimulated by easy access to raw materials. This zone is known in archaeological literature mainly from well-developed non-agricultural production (potterymaking, bronzesmithing), dated to the Roman period. It should be emphasized, however, that agriculture was the basis of the economy of the population living here. Distinguished archaeological sites include settlements in Igołomia and Zofipole, both in Kraków district. Trade contacts played an important role in the development of these communities, both in the Pre-Roman and Roman periods.

Congenital cytomegalovirus (cCMV) infection is the most common intrauterine infection. A non-specific immune response is the first line of host defense mechanism against human cytomegalovirus (HCMV). There is limited data on associations between Single Nucleotide Polymorphisms (SNPs) in genes involving innate immunity and the risk and clinical manifestation of cCMV infection. The aim of the study was to investigate association between selected SNPs in genes encoding cytokines and cytokine receptors, and predisposition to cCMV infection including symptomatic course of disease and symptoms. A panel of eight SNPs: IL1B rs16944, IL12B rs3212227, IL28B rs12979860, CCL2 rs1024611, DC-SIGN rs735240, TLR2 rs5743708, TLR4 rs4986791, TLR9 rs352140 was analyzed in 233 infants (92 cCMV-infected and 141 healthy controls). Associations between genotyped SNPs and predisposition to cCMV infection and symptoms were analyzed. The association analysis was performed using SNPStats software. No statistically significant association was found between any genotyped SNPs and predisposition to cCMV infection and symptomatic course of disease. In relation to particular symptoms, polymorphism of IL12B rs3212227 was linked to decreased risk of prematurity (OR = 0.37;95%CI,0.14-0.98;p = 0.025), while polymorphism of IL1B rs16944 was linked to reduced risk of splenomegaly (OR = 0.36;95%CI,0.14-0.98; p = 0.034) in infants with cCMV infection. An increased risk of thrombocytopenia was associated with IL28B rs12979860 polymorphism (OR = 2.55;95%CI,1.03-6.32;p = 0.042), while hepatitis was associated with SNP of TLR4rs4986791 (OR = 7.80;95%CI,1.49-40,81; p = 0.024). This is the first study to demonstrate four new associations between SNPs in selected genes (IL1B, IL12B, IL28B, TLR4) and particular symptoms in cCMV disease. Further studies on the role of SNPs in the pathogenesis of cCMV infection and incorporation of selected SNPs in the clinical practice might be considered in the future.

Five novel rhodium(II) complexes of general formula [Rh2(μ-OOCCH3)4L2], where L is a triazolopyrimidine derivative, in particular dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp) for (1), 5,7-diethyl-1,2,4-triazolo[1,5-a]pyrimidine (detp) for (2), 7-isobutyl-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine (ibmtp) for (3), 7-hydroxy-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine (HmtpO) for (4) and 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp) for (5) are reported. These first representatives of paddle-wheel dirhodium complexes with triazolopyrimidines have been characterized by IR and NMR spectroscopy as well as by single-crystal X-ray diffraction studies. Three of the new complexes (1), (2) and (5) were thoroughly screened in vitro for their cytotoxicity against human breast cancer cell line MCF-7 and L929 murine fibroblast cells. Favorably, they show significantly less effective inhibition on the cell growth of L929 than cisplatin under identical conditions. Complexes (1) and (5) display moderate cytotoxic activity (IC50 = 16.3–21.5 μM) against MCF-7 cells which is induced via reactive oxygen species-independent pathways. Extensive studies of rhodium complexes (1), (2) and (5) against microorganisms have shown that the tested compounds exhibit antibacterial activity against Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis) while (5) significantly inhibited the growth of Malassezia furfur. The highest antibacterial, and antifungal activity, was observed for (5).

The development of the COVID-19 pandemic and the related lockdown had a major impact on vehicle traffic in cities. Based on available data from the selected city of Rzeszow, Poland, it was decided to assess changes in vehicle traffic and the impact of these changes on roadside environmental pollution. As part of the research, data from the first half of 2020 regarding vehicle traffic on selected streets of the city and on the city’s inlet routes were analyzed. For the selected road sections, changes in hourly traffic volume in 2020, compared with 2019, were also determined. With data on traffic volume, an attempt was made to estimate the impact of changes in traffic volume on air pollution in the city. Research on air pollution from motor vehicles was focused on a selected section of a city road that was equipped with an automatic air pollution measurement station located very close to the road. Additionally, at the road intersection and in the vicinity of the measuring station, a sensor was installed in the roadway to count passing vehicles. A preliminary analysis of air pollution data revealed that factors such as wind speed and direction and outside temperature had a large impact on measurement results. To eliminate the influence of these factors and to obtain data concerning only contamination originating from motor vehicles traveling along the road, an appropriate mathematical model of the traffic flow–roadside environment system was built. This model was designed to determine the air pollution in the vicinity of the road generated by traffic flow. The constructed model was verified, and the conditions for its use were determined in order to study the impact of traffic and roadside environment on the level of air pollution from harmful exhaust substances. It was shown that at certain times of the day, especially at low temperatures, other sources of harmful emissions related to home heating play a major role in air pollution in the city.

Background: Hematopoietic progenitor kinase 1 (HPK1, MAP4K1) is a member of the serine/threonine MAP4K family predominantly expressed in hematopoietic cell lineages which plays a pivotal role in the negative regulation of the signaling cascade triggered by T cell receptor engagement. Inhibition of its activity promotes secretion of IL-2, T cell maturation, and proliferation. It has been also suggested that inhibition of HPK1 may hyperactivate both B cells and dendritic cells via hampering HPK1- mediated negative feedback mechanisms involved in BCR regulation and enhancement of antigen presenting capability of dendritic cells. Suppression of the TCR inhibitory mechanisms with small molecule HPK1 inhibitors might constitute a novel approach in tumor immunotherapy which enhances neoantigen recognition and boosts immune responses of T and B lymphocytes against cancer cells. Thus, small molecule HPK1 inhibitors may provide additional benefit for patients subjected to existing immunotherapies. Methods: Inhibition of HPK1 was assessed by biochemical assay with recombinant human and mouse protein. Small molecule inhibitors were tested in biochemical assay on selected anti- and off-targets and profiled against a broad kinase panel. Phosphorylation of serine 376 on SLP-76 adaptor protein and specific TCR activation-related markers upon HPK1 inhibition was monitored by either Western Blotting or flow cytometry in human and murine T-cells. IL-2 release was measured in human PBMCs and mouse splenic T cells. PBMC cells were activated and exposed to compounds in the presence of PGE-2, followed by IL-2 release measurement. Mice were challenged with the compounds and pharmacodynamic biomarkers were evaluated through flow cytometry and AlphaLisa. Results: Small molecule Ryvu HPK1 inhibitors block kinase activity of recombinant mouse and human protein with sub-nanomolar IC50 values. Ryvu compounds selectively engage downstream biomarkers in human and murine T cells. While inhibiting phosphorylation of serine 376, Ryvu HPK1 inhibitors do not affect activatory phosphorylation of specific phosphotyrosine residues of SLP-76 in human or mouse CD3+ T cells. Ryvu compounds overcome PGE-2 induced resistance following TCR activation in human PBMCs, and mouse CD3+ T cells, inducing IL-2 release. Ryvu compounds have good physicochemical properties and good overall selectivity. In vivo activity and target engagement have been confirmed in the model with anti-CD3 antibody infusion. Conclusion: Pharmacological inhibition of HPK1 kinase activity has strong potential to become a novel immunomodulatory approach for cancer treatment. Citation Format: Maciej Kujawa, Eliza Zimoląg, Michał Gałęzowski, Paweł Guzik, Agata Dudek, Andrzej Gondela, Marcin Nowogródzki, Marianna Girardi, Kostiantyn Krolenko, Marta Bugaj, Sylwia Sudoł, Agnieszka Gibas, Joanna Szeremeta-Spisak, Aneta Bobowska, Magdalena Zastawna, Przemysław Wyrębek, Nicolas Boutard, Aleksandra Więckowska, Wojciech Jasnosz, Wojciech Schonemann, Karol Zuchowicz, David Synak, Urszula Kulesza, Oleksandr Leventes, Mateusz Świrski, Sujit Sasmal, Karolina Gluza, Patryk Kret, Mateusz Ogórek, Kinga Michalik, Katarzyna Banaszak, Adrian Podkowa, Katarzyna Wnuk-Lipińska, Monika Dobrzańska, Peter Littlewood, Krzysztof Brzózka, Anna Bartosik, Stefan Chmielewski. Development and characterization of small molecule HPK1 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1281.

Background. Stimulator of interferon genes, known as STING, is an intracellular sensor of nucleic acids and one of key regulators in activating the innate immune response. Employing synthetic STING agonists has been shown to promote immune-mediated antitumor response in preclinical animal models. Ryvu is developing small-molecule STING agonists suitable for systemic administration. Herein we present unpublished results from characterization of the new generation of our agonist series with significantly improved potency on human immune cells. Methods. Binding to recombinant STING protein was examined using Fluorescence Thermal Shift and Fluorescence Polarisation and was confirmed by X-ray crystallography. Primary screen was performed in THP-1 Dual reporter cells and selectivity was confirmed in THP-1 reporter cells with knocked out STING or expressing varying STING variants. T cell viability and proliferation was assessed by flow cytometry using activated, human T cells exposed to STING agonists. STING pathway activation pattern in cells treated with Ryvu's molecules was confirmed using Western blot analysis. BALB/c mice were injected with compounds and the levels of cytokine release were measured in the plasma. Mice were inoculated with CT26 or EMT6 tumor cells and the compound was administered intravenously followed by the regular monitoring of tumor growth. Results. New generation Ryvu STING agonists are strong binders of human STING protein. Ryvu's compounds show high cellular potency inducing cytokine production in human immune cells at low nM range. Moreover, high activity of developed agonists is maintained irrespective of the natural human STING variant as seen in THP-1 reporter cells as well as in human primary immune cells. High cellular potency of developed compounds also translates into efficacy observed in vivo, where systemic intravenous administration leads to significant tumor growth inhibition and complete tumor regressions in mouse syngeneic models. Conclusion. Ryvu has developed a new generation of potent, direct and selective small-molecule STING agonists. The compounds are characterized by drug-like properties and high in vitro potency on par or outperforming known references. Ryvu agonists are suitable for systemic administration and allow to achieve excellent antitumor efficacy. Taken together, the promising results suggest that the developed series holds high potential for improving immunotherapy in cancer patients. Citation Format: Maciej Krzysztof Rogacki, Stefan Chmielewski, Jolanta Mazurek, Magdalena Zawadzka, Katarzyna Wnuk-Lipińska, Kamil Kuś, Katarzyna Wójcik-Jaszczyńska, Aleksandra Poczkaj, Łukasz Dudek, Wojciech Schonemann, Urszula Głowniak-Kwitek, Marcin Leś, Marek Wronowski, Tushar Mahajan, Urszula Kulesza, Magdalena Zastawna, David Synak, Karol Zuchowicz, Karolina Gluza, Katarzyna Banaszak, Karolina Wiatrowska, Izabela Strojny, Mirosława Gładysz, Justyna Jabłońska, Ewelina Gabor-Worwa, Monika Dobrzańska, Raghuram Tangirala, Peter Littlewood, Krzysztof Brzózka. New generation of STING agonists: Development and characterization of a novel series of systemic immunomodulators with improved potency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1280.

This paper is divided into seven main parts. Its purpose is to review the literature to demonstrate the importance of developing bioengineering and global production of biomaterials to care for the level of healthcare in the world. First, the general description of health as a universal human value and assumptions of a long and healthy life policy is presented. The ethical aspects of the mission of medical doctors and dentists were emphasized. The coronavirus, COVID-19, pandemic has had a significant impact on health issues, determining the world’s health situation. The scope of the diseases is given, and specific methods of their prevention are discussed. The next part focuses on bioengineering issues, mainly medical engineering and dental engineering, and the need for doctors to use technical solutions supporting medicine and dentistry, taking into account the current stage Industry 4.0 of the industrial revolution. The concept of Dentistry 4.0 was generally presented, and a general Bioengineering 4.0 approach was suggested. The basics of production management and the quality loop of the product life cycle were analyzed. The general classification of medical devices and biomedical materials necessary for their production was presented. The paper contains an analysis of the synthesis and characterization of biomedical materials supporting medicine and dentistry, emphasizing additive manufacturing methods. Numerous examples of clinical applications supported considerations regarding biomedical materials. The economic conditions for implementing various biomedical materials groups were supported by forecasts for developing global markets for biomaterials, regenerative medicine, and tissue engineering. In the seventh part, recapitulation and final remarks against the background of historical retrospection, it was emphasized that the technological processes of production and processing of biomedical materials and the systematic increase in their global production are a determinant of the implementation of a long and healthy policy.

Purpose: The aim of this article is to present various carbon-metal nanocomposites considering their constituent elements and fabrication conditions. Design/methodology/approach: The article outlines the results of microscopic examinations performed with a scanning and transmission electron microscope, presenting composites consisting of carbon nanomaterials and selected nanostructured metals. Findings: The investigations performed indicate that high-temperature reduction and chemical reduction are the methods enabling to fabricate carbon-metal nanocomposites with the expected structure and special electrical properties. Practical implications: The newly created composites will be applied as sensors in a gas or liquid environment. It has been evidenced that some of them have also good catalytic (MWCNTs-Re) and electrochemical (MWCNTs-Rh and MWCNTs-Pd) properties. Originality/value: Summary and comparative analysis of composites being a combination of carbon materials and selected nanostructured metals.

Purpose: The article characterises rhenium in terms of its physiochemical properties,most popular methods of manufacturing and key applications. The examples of rhenium ata nanometric scales are also presented, taking into account the latest literature reports inthis field. The objective of the article is also to present advanced nanocomposite materialsconsisting of nanostructured rhenium permanently attached to selected carbon nanomaterials- Single Walled Carbon NanoTubes (SWCNTs), Double Walled Carbon NanoTubes (DWCNTs),Multi Walled Carbon NanoTubes (MWCNTs) and Single Walled Carbon Nanohorns (SWCNHs).Design/methodology/approach: The article delineates various manufacturing methodsat a mass and nanometric scale. It also describes a custom fabrication method of carbonrheniumnanocomposites and the results of investigations performed in a transmissionelectron microscope (TEM) for nanocomposites of the following type: MWCNTs-Re,SWCNTs/DWCNTs-Re, SWCNTs-Re and SWCNHs-Re.Findings: Rhenium has been gaining growing importance in industry for years, and itsapplications are very diverse, including: heat resistant alloys, anti-corrosive alloys, rheniumand rhenium alloy coatings, elements of electrical equipment, radiotherapy, chemistry andanalytical technology and catalysis. Carbon-metallic nanocomposites are currently enjoyingstrong attention of research institutions.Research limitations/implications: The development and optimisation of fabricationprocesses of materials containing carbon nanotubes or carbon nanotubes coated with metalnanoparticles, especially rhenium, is a weighty aspect of advanced materials engineering.Practical implications: Newly created nanocomposite materials, developed as a responseto the market demand, are interesting, state-of-the-art materials dedicated to variousapplications, especially as gas or fluid sensors, and as materials possessing catalytic properties.Originality/value: The article describes nanocomposites of the following types: MWCNTs-Re, SWCNTs/DWCNTs-Re, SWCNTs-Re, SWCNHs-Re, created as a result of hightemperaturereduction of a precursor of rhenium (HReO4 or NH4ReO4) to metallic rhenium.This metal is deposited on carbon nanomaterials as nanoparticles, or inside of them asnanoparticles or nanowires whose size and dispersion are dependent upon the conditionsof a technological process.

In the framework of the made researches nanocomposite of CNT-NPs type (Carbon Nanotube-Nanoparticles) consisting of multiwalled carbon nanotubes coated by rhodium nanoparticles and/or palladium using the two-step indirect method: chemical reduction have been produced. In the researches high-quality multi-walled carbon nanotubes MWCNTs with a length of 100 to 500 nm and a diameter of 8 to 20 nm previously obtained in the catalytic-chemical vapour deposition CCVD have been used. Nanotubes produced within the framework of own researches contain minor amounts of metallic impurities and amorphous carbon deposits. In order to deposit the noble metal nanoparticles on the surface of carbon nanotubes functionalization of multi-walled carbon nanotubes in a mixture of H2SO4 and HNO3 acids have been used. The prepared material has been subjected chemical reduction using noble metal precursors (RhCI3, PdCl2). The characterization of the produced material including the examination of the structure, morphology, chemical composition and evaluation of the size and distribution of rhodium and/or palladium nanoparticles on the surface of carbon nanotubes has been performed using: scanning electron microscopy (SEM), scanning transmission electron microscopy (STEM), transmission electron microscopy (TEM), energy dispersive spectroscopy (EDS). The produced nanomaterials may be used as the active layer of sensors of chemical/biological agents.

The goal of the carried out research is to fabricate, by selective laser melting (SLM), a metallic and/or ceramic scaffold based on a virtual model corresponding to the actual loss of a patient's craniofacial bone. Scaffolds are produced with biocompatible materials that can be employed for a long time in an organism or may be subject to gradual degradation and resorption. The real manufacturing process of a scaffold is preceded with creating a model of an element in the stl format that allows to present the element surface by means of a net of triangles. Once the shape is defined of a unit cell and its net parameters, i.e. height, depth and width, they are duplicated with appropriate mathematical algorithms as a result of which a strictly defined, densed and complicated structure of pores defined by a designer is created. The data concerning a virtual 3D porous implant model was transferred into a SLM device and a scaffold was produced from metallic and/or ceramic powders with this machine. The s...

Beckwith-Wiedemann syndrome is an overgrowth syndrome complicated both phenotypically and genetically. The aim of the study is to present a few cases of newborn babies with B-W syndrome in order to let especially neonatologists and pediatricians follow the diagnostic process. It may make it easier for them to suggest the diagnosis of this syndrome. According to an increased risk for embryonal tumor development, the prophylaxis needs to be taken as well. Children with B-W syndrome need a multi-specialty care.

Background: Stimulator of Interferon Genes (STING) is a major player in the activation of robust innate immune response leading to initiation and enhancement of tumor-specific adaptive immunity. Several clinical and pre-clinical programs are developing cyclic dinucleotides - analogues of endogenous STING ligands. However their chemical nature and stability limit their use as systemic immuno-therapeutics. Herein, we present potent and selective non-nucleotide, non-macrocyclic, small molecule direct STING agonists, structurally unrelated to known chemotypes and suitable for systemic administration. Methods: Binding to recombinant STING protein was examined using FTS, MST, FP and crystallography studies. Phenotypic screen was performed in THP-1 Dual reporter cells. Human macrophages (HMDM) and dendritic cells (HMDC) were differentiated from monocytes (obtained from PBMC) in the presence of M-CSF and GM-CSF/IL-4 for HMDM and HMDC, respectively. Mouse bone marrow-derived dendritic cells (BMDC) were obtained from C57BL/6 or STING KO mice and differentiated with mIL-4 and mGM-CSF. STING agonists were administered into BALB/c mice and cytokine release was measured in plasma. Additionally, mice were inoculated with CT26 murine colon carcinoma cells and the compound was administered, followed by the regular tumor growth monitoring. Finally, the compound was administered to C57BL/6 WT and STING KO mice in several escalating doses. Results: Ryvu's agonists demonstrate a strong binding affinity to recombinant STING proteins across tested species. They trigger pro-inflammatory cytokine release from human PBMC and HMDC and induce dendritic cell maturation regardless of the STING haplotype. Systemic in vivo administration leads to dose-dependent upregulation of STING-dependent pro-inflammatory cytokines, suggesting immune activation which translates into efficacy in vivo in CT26 mouse colorectal cancer model and complete tumor remissions. Furthermore, cured animals develop lasting immunological response demonstrated by diminished tumor growth or lack of palpable tumors in re-challenged mice. Conclusion: Ryvu's STING agonists selectively activate STING-dependent signaling in both mouse and human immune cells promoting anti-tumor immunity. Treatment with Ryvu's STING agonists leads to engagement of the immune system which results in complete tumor remission and development of immunological memory against cancer cells. The compounds show good selectivity and ADME properties enabling development for systemic administration as a single agent or in combinations with immunotherapies or targeted agents. Citation Format: Stefan Chmielewski, Magdalena Zawadzka, Jolanta Mazurek, Maciej K. Rogacki, Karolina Gluza, Katarzyna Wójcik-Jaszczyńska, Aleksandra Poczkaj, Grzegorz Ćwiertnia, Grzegorz Topolnicki, Maciej Kujawa, Eliza Zimoląg, Urszula Głowniak-Kwitek, Magdalena Mroczkowska, Agnieszka Gibas, Marcin Leś, Sylwia Sudoł, Marek Wronowski, Kinga Michalik, Katarzyna Banaszak, Katarzyna Wiklik, Federico Malusa, Michał Combik, Karolina Wiatrowska, Łukasz Dudek, Jose Alvarez, Anna Rajda, Faustyna Gajdosz, Aniela Gołas, Katarzyna Wnuk-Lipińska, Kamil Kuś, Ewelina Gabor-Worwa, Charles Fabritius, Luigi Stasi, Peter Littlewood, Krzysztof Brzózka, Monika Dobrzańska. Development of selective small molecule STING agonists suitable for systemic administration [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4532A.

Background: Hematopoietic progenitor kinase 1 (HPK1, MAP4K1) is predominantly expressed in hematopoietic cell linages and serves as a negative regulator of T cells and dendritic cells (DC). Alteration of ERK/MAPK pathway by HPK1 in T-cells and dendritic cells is an inhibitory mechanism that negatively regulates TCR-induced IL-2 gene transcription, T cell maturation and proliferation. Inhibiting kinase activity of HPK1 results in activation of antigen presenting properties of dendritic cells and stimulates maturation and proliferation of T cells. Therefore, small molecule inhibitors of HPK1 could serve as a novel agent to transform cold, resistant tumors into sensitive hot cancers and provide additional benefit in combination with existing immunotherapies. Methods: Inhibition of HPK1 was assessed by biochemical assay with recombinant human and mouse protein. Small molecule inhibitors were tested in biochemical assay on other MAP4Ks and in addition profiled against broad kinase panel. Phosphorylation of Serine 376 and Tyrosine 128 of SLP-76 adaptor protein upon HPK1 inhibition was monitored by Western Blotting in human and murine T-cells. IL-2 release was monitored in total human PBMC, human CD3+ T cells and mouse CD3+ splenocytes. Human CD3+ T cells were isolated from PBMC, activated with plate-bound anti-CD3/anti-CD28 and exposed to compounds in the presence of PGE-2, followed by IL-2 release measurement, viability and proliferation assessment using flow cytometry. Mouse CD3+ splenocytes were isolated from Balb/c mice, activated with plate-bound anti-CD3/anti-CD28 and exposed to compounds in the presence of PGE-2, followed by IL-2 release assessment. Results: Small molecule Ryvu HPK1 inhibitors block kinase activity of recombinant mouse and human protein with nanomolar IC50 values. Ryvu compounds show broad kinome selectivity. Ryvu HPK1 inhibitors selectively engage downstream biomarkers in human and murine T cells. While inhibiting phosphorylation of Serine 376, Ryvu compounds do not affect activatory phosphorylation of Tyrosine 128 of SLP-76 in human or mouse CD3+ T cells. Ryvu HPK1 inhibitors overcome PGE-2 induced resistance following TCR activation in human PBMCs, CD3+ T-cells and mouse CD3+ T cells, inducing IL-2 release. Compounds have good druglike physicochemical properties. Conclusion: Ryvu HPK1 inhibitors promote activation of in-vitro immunostimulatory properties of both mouse and human immune cells, overcoming immunosuppression. The chemical series has the potential to show anti-tumor efficacy in syngeneic animal models as a single agent or in combination with checkpoint inhibitors. Citation Format: Stefan Chmielewski, Maciej Kujawa, Eliza Zimoląg, Paweł Guzik, Agata Dudek, Grzegorz Topolnicki, Sylwia Sudoł, Agnieszka Gibas, Marta Bugaj, Kostiantyn Krolenko, Marcin Nowogródzki, Anita Janiga, Przemysław Wyrębek, Jakub Pięta, Aleksandra Brzdonkiewicz, Grzegorz Wilkowski, Marcin Walczak, Katarzyna Maciejewska, Adam Radzimierski, Wojciech Jasnosz, Tushar Mahajan, Roberta Bartolotta, Karolina Gluza, Patryk Kret, Ewelina Rutkowska, Kinga Michalik, Katarzyna Banaszak, Adrian Podkowa, Aniela Gołas, Katarzyna Wnuk-Lipińska, Charles Fabritius, Luigi Stasi, Peter Littlewood, Krzysztof Brzózka, Anna Bartosik, Monika Dobrzańska. Development and characterization of small molecule HPK1 inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1947.

This paper presents a comparison of the impact of milling technology in the computer numerically controlled (CNC) machining centre and selective laser sintering (SLS) and on the structure and properties of solid Ti6Al4V alloy. It has been shown that even small changes in technological conditions in the SLS manufacturing variant significantly affect changes from two to nearly two and a half times in tensile and bending strengths. Both the tensile and bending strength obtained in the most favourable manufacturing variant by the SLS method is over 25% higher than in the case of cast materials subsequently processed by milling. Plug-and-play SLS conditions provide about 60% of the possibilities. Structural, tribological and electrochemical tests were carried out. In vitro biological tests using osteoblasts confirm the good tendency for the proliferation of live cells on the substrate manufactured under the most favourable SLS conditions. The use of SLS additive technology for the manufacturing of dental implants and abutments made of Ti6Al4V alloy in combination with the digitisation of dental diagnostics and computer-aided design and manufacture of computer-aided design/manufacturing (CAD/CAM) following the idea of Dentistry 4.0 is the best choice of technology for manufacturing of prosthetic and implant devices used in dentistry.

The paper discusses problems related to the functioning of passenger transport in Rzeszow. The dynamic development of the city and the increase in the income of its inhabitants have led to significantly increased traffic within the city, which is detrimental both to the environment and the city&rsquo, s inhabitants. It limits the quality of life in the city and in the end generates additional costs for businesses and people in urban areas due to the congestion. In compliance with the policies of the European Union, this harmful tendency needs to be limited. Developing sustainable transportation should largely contribute to this objective. With the city of Rzeszow as example, this article discusses selected actions and measures taken as part of the development of sustainable transportation and demonstrates changes in the functioning of public transport based on the author&rsquo, s own research as well as data provided by the city&rsquo, s authorities. The analyses show that the actions taken so far have had a positive impact.

Przedmiotem niniejszego artykułu jest przybliżenie relacji jaka zachodzi między obowiązywaniem w polskim procesie karnym zasady prawdy materialnej a ochroną prawa do prywatności jego uczestników. Konieczność poczynienia przez organy procesowe prawdziwych ustaleń faktycznych rodzi bowiem ryzyko ingerencji w sferę prywatną jednostek, które w różnych rolach, biorą udział w postępowaniu karnym. Instytucjami istotnymi, z punktu widzenia realizacji dyrektyw wynikających z zasady prawdy materialnej, dla ochrony prawa do prywatności, są przede wszystkim przesłuchanie świadka, przeszukanie oraz oględziny i to ich szersza analiza, w kontekście potencjalnych ograniczeń, jakich doznaje zasada prawdy materialnej, z uwagi na obowiązek poszanowania prawa do prywatności, stanowi przedmiot rozważań niniejszego artykułu. The subject matter of this article is to present the relationship between the validity of the principle of material truth in the Polish criminal proceedings and the protection of the right to privacy of their participants. The necessity for real procedural arrangements to be made by judicial bodies creates a risk of interference in the private sphere of individuals who take part in criminal proceedings playing various roles in the same time. In terms of implementation of directives resulting from the principle of substantive truth in order to protect the right to privacy, the essential institutions are as follows: hearing a witness, search and inspection, and its broader analysis, within the context of potential limitations of the principle of material truth, due to the obligation to respect the right to privacy, which in general are the subject matter of this article.

The purpose of this paper is to compare the impact of selective laser-sintering (SLS) technology and computer numerical control (CNC) machining methods on the structure and properties of solid Co-Cr-W-Mo-Si alloys. Structural tests were carried out using x-ray structural analysis; energy-dispersive x-ray spectroscopy chemical composition analysis; metallographic investigations using stereoscopic, light, and scanning electron microscopes using computerized methods of quantitative metallography; and tests of tensile, bending, and compression strength. Individually designed microsamples were used, and the results were statistically processed. It was shown that if optimal conditions of SLS technology are used, it is possible to obtain a structure with a pore content of 0.1 % smaller than in the case of solid cast materials. This ensures better mechanical properties than cast materials. At the same time, it was pointed out that even minor technological errors associated with SLS technology caused a lowering of all strength properties associated with a significant increase in porosity by up to 10 %. Allowing small changes in technological conditions, including the width of the laser spot, the width of the laser beam, the allowance associated with the overlap of the laser beam, disturbances in the flow of inert gas, and uncontrolled changes in the laser power, can cause a significant reduction in strength. A plug and play approach is unacceptable. If even one layer with a thickness of 25 μm is produced in suboptimal conditions, the manufactured element cannot meet the assumed requirements. The use of SLS additive technology for the production of prosthetic components made of Co-Cr alloys is the best choice among the methods currently used in dentistry. The use of SLS technology together with the digitization of design and manufacturing processes is an important element in implementing the Dentistry 4.0 approach as part of the Industry 4.0 stage of the industrial revolution.