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CAR T cell therapies face challenges in combating solid tumors due to their single-target approach, which becomes ineffective if the targeted antigen is absent or lost. Universal CAR T cells (UniCAR Ts) provide a promising solution by utilizing molecular tags (linkers), such as biotin conjugated to monoclonal antibodies, enabling them to target a variety of tumor antigens. Recently, we showed that conventional CAR T cells could penetrate the extracellular matrix (ECM) of ADCC-resistant tumors, which forms a barrier to therapeutic antibodies. This finding led us to investigate whether UniCAR T cells, targeted by soluble antibody-derived linkers, could similarly tackle ADCC-resistant tumors where ECM restricts antibody penetration. We engineered UniCAR T cells by incorporating a biotin-binding monomeric streptavidin 2 (mSA2) domain for targeting HER2 via biotinylated trastuzumab (BT). The activation and cytotoxicity of UniCAR T cells in the presence or absence of BT were evaluated in conventional immunoassays. A 3D spheroid coculture was set up to test the capability of UniCAR Ts to access ECM-masked HER2 + cells. For in vivo analysis, we utilized a HER2 + xenograft model in which intravenously administered UniCAR T cells were supplemented with intraperitoneal BT treatments. In vitro , BT-guided UniCAR T cells showed effective activation and distinct anti-tumor response. Upon target recognition, IFNγ secretion correlated with BT concentration. In the presence of BT, UniCAR T cells effectively penetrated HER2 + spheroids and induced cell death in their core regions. In vivo , upon intravenous administration of UniCAR Ts, circulating BT linkers immediately engaged the mSA2 domain and directed effector cells to the HER2 + tumors. However, these co-treated mice died early, possibly due to the lung infiltration of UniCAR T cells that could recognize both native biotin and HER2. Our results suggest that UniCAR T cells guided with soluble linkers present a viable alternative to conventional CAR T cells, especially for patients resistant to antibody therapy and those with solid tumors exhibiting high antigenic variability. Critical to their success, however, is the choice of an appropriate binding domain for the CAR and the corresponding soluble linker, ensuring both efficacy and safety in therapeutic applications.

HGFR activation drives the malignant progression of colorectal cancer, and its inhibition displays anti-autophagic activity. The interrelated role of HGFR inhibition and TLR9/autophagy signaling in HT29 cancer cells subjected to modified self-DNA treatments has not been clarified. We analyzed this complex interplay with cell metabolism and proliferation measurements, TLR9, HGFR and autophagy inhibitory assays and WES Simple Western blot-based autophagy flux measurements, gene expression analyses, immunocytochemistry, and transmission electron microscopy. The overexpression of MyD88 and caspase-3 was associated with enhanced HT29 cell proliferation, suggesting that incubation with self-DNAs could suppress the apoptosis-induced compensatory cell proliferation. HGFR inhibition blocked the proliferation-reducing effect of genomic and hypermethylated, but not that of fragmented DNA. Lowest cell proliferation was achieved with the concomitant use of genomic DNA, HGFR inhibitor, and chloroquine, when the proliferation stimulating effect of STAT3 overexpression could be outweighed by the inhibitory effect of LC3B, indicating the putative involvement of HGFR-mTOR-ULK1 molecular cascade in HGFR inhibitor-mediated autophagy. The most intense cell proliferation was caused by the co-administration of hypermethylated DNA, TLR9 and HGFR inhibitors, when decreased expression of both canonical and non-canonical HGFR signaling pathways and autophagy-related genes was present. The observed ultrastructural changes also support the context-dependent role of HGFR inhibition and autophagy on cell survival and proliferation. Further investigation of the influence of the studied signaling pathways and cellular processes can provide a basis for novel, individualized anti-cancer therapies.

Systemic sclerosis (SSc) is a complex autoimmune disease characterized by fibrosis, immune dysregulation, and vascular dysfunction, yet its pathogenesis remains incompletely understood. This study compares two widely used animal models of SSc—the bleomycin-induced fibrosis model and the collagen-V-induced autoimmune model—to evaluate their ability to replicate key disease features. In the bleomycin model, consistent cardiac fibrosis was observed across treatment groups despite variability in fibrosis in the skin and lungs, suggesting organ-specific differences in susceptibility. The collagen-V model demonstrated robust autoantibody production against collagen-V, confirming its utility in studying immune activation, though fibrosis was largely confined to the heart. While the bleomycin model excels at mimicking rapid fibrosis and is suitable for testing antifibrotic therapies, the collagen-V model provides insights into antigen-specific autoimmunity. Both models highlight the dynamic nature of fibrosis, where ECM deposition and degradation occur concurrently, complicating its use as a quantitative disease marker. Cardiac fibrosis emerged as a consistent feature in both models, emphasizing its relevance in SSc pathophysiology. Combining these models or refining their design through hybrid approaches, extended timelines, or sex and age adjustments could enhance their translational utility. These findings advance understanding of SSc mechanisms and inform therapeutic development for this challenging disease.

Purpose: In HT29 colon cancer cells, a close interplay between self-DNA-induced TLR9 signaling and autophagy response was found, with remarkable effects on cell survival and differentiation. IGF1R activation drives the development and malignant progression of colorectal cancer. IGF1R inhibition displays a controversial effect on autophagy. The interrelated roles of IGF1R inhibition and TLR9/autophagy signaling in HT29 cancer cells have not yet been clarified. In our study, we aimed to investigate the complex interplay of IGF1R inhibition and TLR9/autophagy signaling in HT29 cells.Methods: HT29 cells were incubated with tumor-originated self-DNA with or without inhibitors of IGF1R (picropodophyllin), autophagy (chloroquine), and TLR9 (ODN2088), respectively. Cell proliferation and metabolic activity measurements, direct cell counting, NanoString and Taqman gene expression analyses, immunocytochemistry, WES Simple Western blot, and transmission electron microscopy investigations were performed.Results: The concomitant use of tumor-derived self-DNA and IGF1R inhibitors displays anti-proliferative potential, which can be reversed by parallel TLR9 signaling inhibition. The distinct effects of picropodophyllin, ODN2088, and chloroquine per se or in combination on HT29 cell proliferation and autophagy suggest that either the IGF1R-associated or non-associated autophagy machinery is “Janus-faced” regarding its actions on cell proliferation. Autophagy, induced by different combinations of self-DNA and inhibitors is not sufficient to rescue HT29 cells from death but results in the survival of some CD133-positive stem-like HT29 cells.Conclusion: The creation of new types of combined IGF1R, autophagy, and/or TLR9 signaling inhibitors would play a significant role in the development of more personalized anti-tumor therapies for colorectal cancer.

HGFR activation drives the malignant progression of colorectal cancer, and its inhibition displays anti-autophagic activity. The interrelated role of HGFR inhibition and TLR9/autophagy signaling in HT29 cancer cells subjected to modified self-DNA treatments has not been clarified. We analyzed this complex interplay with cell metabolism and proliferation measurements, TLR9, HGFR and autophagy inhibitory assays and WES Simple Western blot-based autophagy flux measurements, gene expression analyses, immunocytochemistry, and transmission electron microscopy. The overexpression of MyD88 and caspase-3 was associated with enhanced HT29 cell proliferation, suggesting that incubation with self-DNAs could suppress the apoptosis-induced compensatory cell proliferation. HGFR inhibition blocked the proliferation-reducing effect of genomic and hypermethylated, but not that of fragmented DNA. Lowest cell proliferation was achieved with the concomitant use of genomic DNA, HGFR inhibitor, and chloroquine, when the proliferation stimulating effect of STAT3 overexpression could be outweighed by the inhibitory effect of LC3B, indicating the putative involvement of HGFR-mTOR-ULK1 molecular cascade in HGFR inhibitor-mediated autophagy. The most intense cell proliferation was caused by the co-administration of hypermethylated DNA, TLR9 and HGFR inhibitors, when decreased expression of both canonical and non-canonical HGFR signaling pathways and autophagy-related genes was present. The observed ultrastructural changes also support the context-dependent role of HGFR inhibition and autophagy on cell survival and proliferation. Further investigation of the influence of the studied signaling pathways and cellular processes can provide a basis for novel, individualized anti-cancer therapies.

In Hungary, the pandemic waves in late 2021 and early 2022 were dominated by the Delta and Omicron SARS-CoV-2 variants, respectively. Booster vaccines were offered with one or two doses for the vulnerable population during these periods. The nationwide HUN-VE 2 study examined the effectiveness of primary immunization, single booster, and double booster vaccination in the prevention of Covid-19 related mortality during the Delta and Omicron waves, compared to an unvaccinated control population without prior SARS-CoV-2 infection during the same study periods. The risk of Covid-19 related death was 55% lower during the Omicron vs. Delta wave in the whole study population (n=9,569,648 and n=9,581,927, respectively; rate ratio [RR]: 0.45, 95% confidence interval [CI]: 0.44-0.48). During the Delta wave, the risk of Covid-19 related death was 74% lower in the primary immunized population (RR: 0.26; 95% CI: 0.25-0.28) and 96% lower in the booster immunized population (RR: 0.04; 95% CI: 0.04-0.05), vs. the unvaccinated control group. During the Omicron wave, the risk of Covid-19 related death was 40% lower in the primary immunized population (RR: 0.60; 95% CI: 0.55-0.65) and 82% lower in the booster immunized population (RR: 0.18; 95% CI: 0.16-0.2) vs. the unvaccinated control group. The double booster immunized population had a 93% lower risk of Covid-19 related death compared to those with only one booster dose (RR: 0.07; 95% CI. 0.01-0.46). The benefit of the second booster was slightly more pronounced in older age groups. The HUN-VE 2 study demonstrated the significantly lower risk of Covid-19 related mortality associated with the Omicron vs. Delta variant and confirmed the benefit of single and double booster vaccination against Covid-19 related death. Furthermore, the results showed the additional benefit of a second booster dose in terms of SARS-CoV-2 infection and Covid-19 related mortality.

In late 2021, the pandemic wave was dominated by the Delta SARS-CoV-2 variant in Hungary. Booster vaccines were offered for the vulnerable population starting from August 2021. The nationwide HUN-VE 3 study examined the effectiveness and durability of primary immunization and single booster vaccinations in the prevention of SARS-CoV-2 infection, Covid-19 related hospitalization and mortality during the Delta wave, compared to an unvaccinated control population without prior SARS-CoV-2 infection. The study population included 8,087,988 individuals who were 18-100 years old at the beginning of the pandemic. During the Delta wave, after adjusting for age, sex, calendar day, and chronic diseases, vaccine effectiveness (VE) of primary vaccination against registered SARS-CoV-2 infection was between 11% to 77% and 18% to 79% 14-120 days after primary immunization in the 16-64 and 65-100 years age cohort respectively, while it decreased to close to zero in the younger age group and around 40% or somewhat less in the elderly after 6 months for almost all vaccine types. In the population aged 65-100 years, we found high, 88.1%-92.5% adjusted effectiveness against Covid-19 infection after the Pfizer-BioNTech, and 92.2%-95.6% after the Moderna booster dose, while Sinopharm and Janssen booster doses provided 26.5%-75.3% and 72.9%-100.0% adjusted VE, respectively. Adjusted VE against Covid-19 related hospitalization was high within 14-120 days for Pfizer-BioNTech: 76.6%, Moderna: 83.8%, Sputnik-V: 78.3%, AstraZeneca: 73.8%, while modest for Sinopharm: 45.7% and Janssen: 26.4%. The waning of protection against Covid-19 related hospitalization was modest and booster vaccination with mRNA vaccines or the Janssen vaccine increased adjusted VE up to almost 100%, while the Sinopharm booster dose proved to be less effective. VE against Covid-19 related death after primary immunization was high or moderate: for Pfizer-BioNTech: 81.5%, Moderna: 93.2%, Sputnik-V: 100.0%, AstraZeneca: 84.8%, Sinopharm: 58.6%, Janssen: 53.3%). VE against this outcome also showed a moderate decline over time, while booster vaccine types restored effectiveness up to almost 100%, except for the Sinopharm booster. The HUN-VE 3 study demonstrated waning VE with all vaccine types for all examined outcomes during the Delta wave and confirmed the outstanding benefit of booster vaccination with the mRNA or Janssen vaccines, and this is the first study to provide clear and comparable effectiveness results for six different vaccine types after primary immunization against severe during the Delta pandemic wave.

Spatial economic analysis, including research on regional development and competitiveness, has long been a high priority area in the social sciences, both domestically and globally. Several dominant international models relate changes in regional competitiveness to the volume of investment, physical capital and improvements in the income situation of citizens. This suggests that the promotion and implementation of investment has the greatest impact on regional development, as it generates technological innovation and innovation in order to raise the skills of the available labour force, employ human resources at higher wages and thus raise living standards. On the basis of these findings, our study examines the level of development of the domestic LAU1 districts on the basis of their complex (social, economic and infrastructural) level of development, their income situation and their economic competitiveness.

The clonal composition of a malignant tumor strongly depends on cellular dynamics influenced by the asynchronized loss of DNA repair mechanisms. Here, our aim was to identify founder mutations leading to subsequent boosts in mutation load. The overall mutation burden in 591 colorectal cancer tumors was analyzed, including the mutation status of DNA-repair genes. The number of mutations was first determined across all patients and the proportion of genes having mutation in each percentile was ranked. Early mutations in DNA repair genes preceding a mutational expansion were designated as founder mutations. Survival analysis for gene expression was performed using microarray data with available relapse-free survival. Of the 180 genes involved in DNA repair, the top five founder mutations were in PRKDC (n = 31), ATM (n = 26), POLE (n = 18), SRCAP (n = 18), and BRCA2 (n = 15). PRKDC expression was 6.4-fold higher in tumors compared to normal samples, and higher expression led to longer relapse-free survival in 1211 patients (HR = 0.72, p = 4.4 × 10−3). In an experimental setting, the mutational load resulting from UV radiation combined with inhibition of PRKDC was analyzed. Upon treatments, the mutational load exposed a significant two-fold increase. Our results suggest PRKDC as a new key gene driving tumor heterogeneity.

Diagnosing interstitial lung disease (ILD) can be a challenging process. New biomarkers may support diagnostic decisions. Elevated serum progranulin (PGRN) levels have been reported in liver fibrosis and dermatomyositis-associated acute interstitial pneumonia. Our aim was to assess the role of PGRN in the differential diagnosis of idiopathic pulmonary fibrosis (IPF) and other ILDs. Serum levels of PGRN were measured by enzyme-linked immunosorbent assay in stable IPF (n = 40), non-IPF ILD (n = 48) and healthy controls (n = 17). Patient characteristics, lung function, CO diffusion (DLCO), arterial blood gases, 6-min walk test, laboratory parameters and high-resolution (HR)CT pattern were assessed. In stable IPF, PGRN levels did not differ from healthy controls; however, serum PGRN levels were significantly higher in non-IPF ILD patients compared to healthy subjects and IPF (53.47 ± 15.38 vs. 40.99 ± 5.33 vs. 44.66 ± 7.77 ng/mL respectively; p < 0.01). The HRCT pattern of usual interstitial pneumonia (UIP) was associated with normal PGRN level, while for non-UIP patterns, significantly elevated PGRN level was measured. Elevated serum PGRN levels may be associated with non-IPF ILD, especially non-UIP patterns and might be helpful in cases of unclear radiological patterns in the differentiation between IPF and other ILDs.