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Abstract The heterogenous treatment response of tumor cells limits the effectiveness of cancer therapy. While this heterogeneity has been linked to cell-to-cell variability within the complex tumor microenvironment, a quantitative biomarker that identifies and characterizes treatment-resistant cell populations is still missing. Herein, we use chromatin organization as a cost-efficient readout of the cells’ states to identify subpopulations that exhibit distinct responses to radiotherapy. To this end, we developed a 3D co-culture model of cancer spheroids and patient-derived fibroblasts treated with radiotherapy. Using the model we identified treatment-resistant cells that bypassed DNA damage checkpoints and exhibited an aggressive growth phenotype. Importantly, these cells featured more condensed chromatin which primed them for treatment evasion, as inhibiting chromatin condensation and DNA damage repair mechanisms improved the efficacy of not only radio- but also chemotherapy. Collectively, our work shows the potential of using chromatin organization to cost-effectively study the heterogeneous treatment susceptibility of cells and guide therapeutic design.

Abstract The vast majority of our knowledge regarding cancer radiobiology and the activation of radioresistance mechanisms emerged from studies using external beam radiation therapy (EBRT). Yet, less is known about the cancer response to internal targeted radionuclide therapy (TRT). Our comparative phosphoproteomics analyzed cellular responses to TRT with lutetium-177-labeled minigastrin analogue [177Lu]Lu-PP-F11N (β-emitter) and EBRT (ɣ-rays) in CCKBR-positive cancer cells. Activation of DNA damage response by p53 was induced by both types of radiotherapy, whereas TRT robustly increased activation of signaling pathways including epidermal growth factor receptor (EGFR), mitogen-activated protein kinases (MAPKs) or integrin receptor. Inhibition of EGFR or integrin signaling sensitized cancer cells to radiolabeled minigastrin. In vivo, EGFR inhibitor erlotinib increased therapeutic response to [177Lu]Lu-PP-F11N and median survival of A431/CCKBR-tumor bearing nude mice. In summary, our study explores a complex scenario of cancer responses to different types of irradiation and pinpoints the radiosensitizing strategy, based on the targeting survival pathways, which are activated by TRT.

Eisenia fetida and Eisenia andrei are closely related earthworm species that play a crucial part in soil and influence its structure and organic matter cycling. Due to their essential environmental role, they are widely used as model organisms in a vast spectrum of research areas. In this work, we partially sequenced genomes of E. fetida and E. andrei, using Illumina technology (Nano 2 × 250 v2 - MiSeq) and de novo assembly strategy. A total of 3785 and 4258 microsatellite or Simple Sequence Repeat (SSR) markers were identified within E. fetida and E. andrei genomic DNA, respectively. The microsatellite markers will facilitate the analyses of genetic diversity and population genetics studies for the two selected earthworm species and their interspecific hybrids.

The lumbricid earthworms Eisenia andrei (Ea) and E. fetida (Ef) have been used as model organisms for studies on hybridization. Previously they have been identified by species specific sequences of the mitochondrial COI gene of maternal origin (‘a’ or ‘f’) and the nuclear 28S gene of maternal/paternal origin (‘A’ or ‘F’). In experimental crosses, these hermaphroditic species produce progeny of genotypes Ea (aAA), Ef (fFF) and hybrids (aAF and fFA) originating by self-fertilization or cross-fertilization. To facilitate studies on new aspects of the breeding biology and hybridization of earthworms, polymorphic microsatellite markers were developed based on 12 Ea and 12 Ef specimens and validated on DNA samples extracted from 24 genotyped specimens (aAA, fFF, aAF and fFA) from three laboratory-raised families and 10 of them were applied in the present study. The results indicate that microsatellite markers are valuable tools for tracking interspecific gene flow between these species.

Anticorrosive epoxy and polyurethane coatings were compounded using zinc-free nanosized phosphates of strontium (SP) or strontium and aluminum (SAP). For comparison, a nanosized calcium aluminum ammonium phosphate (CAP) and a microsized zinc phosphate (ZP) were tested. Results of salts spray and cyclic corrosion tests revealed better anticorrosive properties of the SAP-based coatings in relation to the samples with the other Zn-free fillers or ZP. Electrochemical noise tests of uncoated steel in aqueous suspensions of the phosphates exhibited similar corrosion inhibition efficiency of the Sr-based phosphates and ZP, and worse anticorrosive features of CAP. Electrochemical impedance spectroscopy did not show better protective properties of ZP-based coatings than the samples with the Zn-free fillers.

Many studies have been carried out in the direction of improvement of the effectiveness of commonly utilized phosphate corrosion inhibitors. For this purpose various types of modifications are realized, e.g. introduction of different cations to the pigment composition or replacement of phosphate anions with others. In the presented work, anticorrosive pigments containing calcium hydrogen phosphate, and/or calcium hydroxyphosphate, and calcium molybdate were obtained. The phase and chemical composition and the oil absorption number of those materials were determined. The anticorrosive properties were investigated by an electrochemical noise method. The obtained results were compared with previously published studies concerning pigments containing (NH4)3Al2(PO4)3 and/or AlPO4, and CaMoO4. It was found that the pigment containing only calcium molybdate(VI) is not an effective corrosion inhibitor. However, the pigments comprising a mixture of CaHPO4 and CaMoO4 exhibited good anticorrosive properties and they were characterized by higher effectiveness in the corrosion protection than compared materials.

Eisenia andrei (Ea) and E. fetida (Ef) lumbricid earthworms are simultaneous hermaphrodites potentially capable of self-fertilization and hybridization. We have shown previously that reproductive isolation in these species is incomplete in Ea and Ef earthworms of French provenance, as viable offspring appeared in inter-specific pairs. Fertile asymmetric hybrids developed from Ea-derived ova fertilized by Ef-derived spermatozoa, as well as Ea or Ef specimens derived after self-fertilization (resulting from admixture of endogenously produced spermatozoa with sperm from a partner), but never Ef-hybrids from Ef-ova fertilized by Ea-spermatozoa. The latter appeared only in backcrosses of Ea-hybrids with the Ef. Here we show that these phenomena are not unique for French Ea/Ef earthworms, but are shared by earthworms from French, Hungarian, and Polish laboratory cultures. Semi-quantitative studies on fertility of Ea-derived hybrids revealed gradually decreasing numbers of offspring in three successive generations, more rapid in backcrosses with Ef than with Ea, and the absence of progeny in pairs of hybrids, despite the presence of cocoons in almost all pairs. Based on species specific mitochondrial and nuclear DNA sequences, we provide the first examples of two unique sterile hybrids with mitonuclear mismatch and potential mitonuclear incompatibility among offspring of one of the hybrid+Ef pairs. Earthworms from the investigated populations did not reproduce when kept from hatching in isolation or with representatives of Dendrobaena veneta but started reproducing upon recognition of a related partner, such as Ea, Ef or their hybrids. The existence of Ea or Ef specimens among offspring of hybrid+Ea/Ef pairs might be explained either by partner-induced self-fertilization of Ea/Ef or hybrid-derived ova, or by cross-fertilization of Ea/Ef /hybrid ova by partner-derived spermatozoa; the latter might contribute to interspecific gene introgression.

The inhibition of the mammalian target of rapamycin complex 1 (mTORC1) by everolimus (RAD001) was recently shown to enhance the tumor uptake of radiolabeled minigastrin. In this paper, we investigate if this finding can improve the in vivo therapeutic response to [177Lu]Lu-PP-F11N treatment. The N-terminal DOTA-conjugated gastrin analogue PP-F11N (DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Nle-Asp-Phe) was used to evaluate treatment efficacy in the human A431/CCKBR xenograft nude mouse model in combination with RAD001. Both RAD001 and [177Lu]Lu-PP-F11N single treatments as well as their combination inhibited tumor growth and increased survival. In concomitantly treated mice, the average tumor size and median survival time were significantly reduced and extended, respectively, as compared to the monotherapies. The histological analysis of kidney and stomach dissected after treatment with RAD001 and [177Lu]Lu-PP-F11N did not indicate significant adverse effects. In conclusion, our study data demonstrate the potential of mTORC1 inhibition to substantially improve the therapeutic efficacy of radiolabeled minigastrin analogues in CCKBR-positive cancers.

The paper tackles the problem of the role and importance of media in the lives of elderly people. It takes into account the concept of media, both traditional ones like radio and television from the sociological point of view, and modern ones like the Internet as a universal tool. Media have been noticed in the lives of seniors as a past memory and a link to modern times. The research conducted on a small group showed resources of technical media in seniors’ households and presented the seniors’ attitudes to the information and pictures of reality provided by the media. New media are on the border of habits and everyday routines of these people and completely new technologies which are brought about by modern times. In the context of so many economic, civilizational, political and social transformations as well as a dynamic development of media, their deep embedment in the lives of elderly people is shown. There is no doubt that irrespective of age, there is a strong need for lifelong learning in the process of forming awareness of the contents provided by communicators and widely understood media. A very important thing is to show possibilities of the used media to promote education at different levels and in different forms. It should be noted that this type of research is still a challenge for today’s researchers and a task which, despite numerous difficulties, is worthwhile. The problems raised in this paper are a starting point for further research which is particularly interesting and important in the context of changes within broadly understood culture, media technology and media convergence. The demographic trend entails certain economic consequences, and with them social ones, because it requires the adoption of radical actions in public policy, especially in the field of health or education.

Synthesis and characterization of the aluminum phosphates modified with ammonium, calcium and molybdenum were conducted. The influence of process parameters (reactive pressure and molar ratios) in the reaction mixture were studied. The contents of the individual components in the products were in the range of: 10.97–17.31 wt% Al, 2.65–13.32 wt% Ca, 0.70–3.11 wt% Mo, 4.36–8.38 wt% NH3, and 35.12–50.54 wt% P2O5. The materials obtained in the experiments were characterized by various physicochemical parameters. The absorption oil number was in the range from 67 to 89 of oil/100 g of product, the surface area was within the range of 4–76 m2/g, whereas the average particle size of products reached 282–370 nm. The Tafel tests revealed comparable anticorrosive properties of aluminum phosphates modified with ammonium, calcium, molybdenum in comparison with commercial phosphate.

The overexpression of cholecystokinin B receptor (CCKBR) in human cancers led to the development of radiolabeled minigastrin analogues for targeted radionuclide therapy, which aims to deliver cytotoxic radiation specifically to cancer cells. Alpha emitters (e.g., actinium-225) possess high potency in cancer cell-killing and hold promise for the treatment of malignant tumors. In these preclinical studies, we developed and evaluated CCKBR-targeted alpha particle therapy. The cellular uptake and cytotoxic effect of actinium-225 labeled and HPLC-purified minigastrin analogue [225Ac]Ac-PP-F11N were characterized in the human squamous cancer A431 cells transfected with CCKBR. Nude mice bearing A431/CCKBR tumors were used for biodistribution and therapy studies followed by histological analysis and SPECT/CT imaging. In vitro, [225Ac]Ac-PP-F11N showed CCKBR-specific and efficient internalization rate and potent cytotoxicity. The biodistribution studies of [225Ac]Ac-PP-F11N revealed CCKBR-specific uptake in tumors, whereas the therapeutic studies demonstrated dose-dependent inhibition of tumor growth and extended mean survival time, without apparent toxicity. The histological analysis of kidney and stomach indicated no severe adverse effects after [225Ac]Ac-PP-F11N administration. The post-therapy SPECT-CT images with [111In]In-PP-F11N confirmed no CCKBR-positive tumor left in the mice with complete remission. In conclusion, our study demonstrates therapeutic efficacy of [225Ac]Ac-PP-F11N without acute radiotoxicity in CCKBR-positive cancer model.

NWC is an uncharacterised protein containing three strongly conserved domains not found in any other known protein. Previously, we reported that the NWC protein is detected in cells in the germinal layer in murine testes (strain: C57BL/6), and its knockout results in no obvious phenotype. We determined the NWC expression pattern during spermatogenesis, and found this protein in spermatocytes and round spermatids, but not in epididymal sperm. Although NWC knockout males are fertile, we further characterised their reproductive potential employing non-standard mating that better simulates the natural conditions by including sperm competition. Such an approach revealed that the sperm of knockout males fail to successfully compete with control sperm. After analysing selected characteristics of the male reproductive system, we found that NWC knockout sperm had a reduced ability to fertilize cumulus-intact eggs during IVF. This is the first report describing a subtle phenotype of NWC knockout mice that could be detected under non-standard mating conditions. Our results indicate that NWC plays an important role in spermatogenesis and its deficiency results in the production of functionally impaired sperm.

Uniformly pigmented Eisenia andrei (Ea) and striped E. fetida (Ef) lumbricid earthworms are hermaphrodites capable of self-fertilization, cross-fertilization, and asymmetrical hybridization. The latter was detected by genotyping of F1 and F2 progeny of the controlled Ea+Ef pairs by species-specific sequences of maternal mitochondrial COI genes and maternal/paternal nuclear S28 rRNA genes. Among F1offspring there were self-fertilized Ea (aAA), Ef (fFF), and cross-fertilized fertile Ea-derived hybrids (aAF); the latter mated with Ea and gave new generation of Ea and hybrids, while mated with Ef gave Ea, Ef, Ea-derived hybrids and sterile Ef-derived hybrids (fFA). Coelomic fluid of Ea exhibits unique fluorescence spectra called here the M-fluorescence considered as a molecular biomarker of this species. Since similar fluorescence was detected also in some Ef (hypothetical hybrids?), the aim of present investigations was to identify the M-positive earthworms among families genotyped previously. It was assumed that factor/s responsible for metabolic pathways leading to production of undefined yet M-fluorophore might be encoded/controlled by alleles of hypothetical nuclear gene of Eisenia sp. segregating independently from species-specific S28 rRNA nuclear genes, where 'MM' or 'Mm' alleles determine M-positivity while 'mm' alleles determine M-negative phenotypes. Spectra of M-fluorescence were detected in all 10 Ea (aAAMM) and 19 Ea-derived hybrids (aAFMm), three of four Ef-derived hybrids (fFAMm) and one 'atypical' Ef (fFFMm) among 13 Ef earthworms. Among progeny of 'atypical' M-positive Ef (fFFMm) reappeared 'typical' M-negative Ef (fFFmm), confirming such hypothesis. Alternatively, the M-fluorescence might be dependent on unknown gene products of vertically-transmitted Ea-specific symbiotic bacteria sexually transferred to the Ef partner. Hypotheses of intrinsic and external origin of M-fluorescence might complement each other. The presence/absence of M-fluorophore does not correspond with body pigmentation patterns; Ef-characteristic banding appeared in posterior parts of hybrids body. In conclusion, Ea/Ef hybridization may serve for further studies on bi-directional gene flow.

Lumbricid earthworms Eisenia andrei (Ea) and E. fetida (Ef) are simultaneous hermaphrodites with reciprocal insemination capable of self-fertilization while the existence of hybridization of these two species was still debatable. During the present investigation fertile hybrids of Ea and Ef were detected. Virgin specimens of Ea and Ef were laboratory crossed (Ea+Ef) and their progeny was doubly identified. 1 -identified by species-specific maternally derived haploid mitochondrial DNA sequences of the COI gene being either 'a' for worms hatched from Ea ova or 'f' for worms hatched from Ef ova. 2 -identified by the diploid maternal/paternal nuclear DNA sequences of 28s rRNA gene being either 'AA' for Ea, 'FF' for Ef, or AF/FA for their hybrids derived either from the 'aA' or 'fF' ova, respectively. Among offspring of Ea+Ef pairs in F1 generation there were mainly aAA and fFF earthworms resulted from the facilitated self-fertilization and some aAF hybrids from aA ova but none fFA hybrids from fF ova. In F2 generation resulting from aAF hybrids mated with aAA a new generations of aAA and aAF hybrids were noticed, while aAF hybrids mated with fFF gave fFF and both aAF and fFA hybrids. Hybrids intercrossed together produced plenty of cocoons but no hatchlings independently whether aAF+aAF or aAF+fFA were mated. These results indicated that Ea and Ef species, easy to maintain in laboratory and commonly used as convenient models in biomedicine and ecotoxicology, may also serve in studies on molecular basis of interspecific barriers and mechanisms of introgression and speciation. Hypothetically, their asymmetrical hybridization can be modified by some external factors.

This article presents the performance analysis of a cross-platform mobile application implemented with Xamarin and two native applications for Android and iOS platforms. The results concerning the time analysis for selected activities were compared in order to determine whether cross-platform tools are worth using in mobile application development. Native applications achieved better performance, however in some cases the cross-platform approach allows for significant development time reduction without deterioration in user experience.

The paper presents the results of the research aimed at assessing the condition of reinforcement and concrete cover in selected elements of the structure of the most recognizable structure in Kielce, i.e. PKS station, located at Czarnowska Street. Currently, demolition works are underway resulting from the planned modernization. The assessment of the corrosion risk of the reinforcement in the construction elements was carried out with the use of a semi-non-destructive electrochemical method. The use of this method made it possible to determine the probability of reinforcement corrosion in the selected areas and to estimate its rate. The protective properties of concrete cover were checked by the carbonation test (test using a 1% phenolphthalein solution) and phase composition analysis (X-ray diffraction analysis). In order to determine the position of the reinforcing bars and to estimate the concrete cover thickness distribution in the areas corresponding to the aforementioned measurements, ferromagnetic detection system was used.

The concrete cover has significant impact on the intensity of reinforcement corrosion process in reinforced concrete elements. Depending on the type of corrosion risk different types of cement are recommended for concrete. In conditions of chloride corrosion, due to, for example, the use of de-icing agents in winter, it is recommended to use concrete with cement containing granulated blast-furnace slag. The risk of chloride corrosion due to the use of de-icing agents is often additionally associated with the frost and repeated freezing and thawing actions of structural elements. The liquid freezing in the pores of concrete increases its volume, which causes the increase of internal stresses and leads to cracks in the concrete cover increasing the diffusion of chlorides. In order to reduce this phenomenon the introduction of air-entraining admixture is beneficial. The paper presents the experimental results that allow to determinate the effect of the air-entraining admixture addition on the intensity of reinforcement corrosion in concrete with blast-furnace slag cement. The tests were carried out on two groups of reinforced concrete specimens subjected to freezing and thawing cycles in 3% NaCl solution. One group of specimens was prepared with the airentraining admixture addition and the other without it. The electrochemical tests of the reinforcement corrosion activity, based on the measurements of the corrosion current density were curried. The phase composition by X-ray diffraction and microstructure of concrete under the scanning electron microscope (SEM) coupled with the X-ray microanalyser (EDS) were examined. The results allowed to comprehensively assess the effect of airentrained concrete with blast-furnace slag cement on the degree of reinforcement corrosion risk in concrete caused by the simultaneous action of chlorides and frost.

The biological interaction between copper and iron is best exemplified by the decreased activity of multicopper ferroxidases under conditions of copper deficiency that limits the availability of iron for erythropoiesis. However, little is known about how copper deficiency affects iron homeostasis through alteration of the activity of other copper-containing proteins, not directly connected with iron metabolism, such as superoxide dismutase 1 (SOD1). This antioxidant enzyme scavenges the superoxide anion, a reactive oxygen species contributing to the toxicity of iron via the Fenton reaction. Here, we analyzed changes in the systemic iron metabolism using an animal model of Menkes disease: copper-deficient mosaic mutant mice with dysfunction of the ATP7A copper transporter. We found that the erythrocytes of these mutants are copper-deficient, display decreased SOD1 activity/expression and have cell membrane abnormalities. In consequence, the mosaic mice show evidence of haemolysis accompanied by haptoglobin-dependent elimination of haemoglobin (Hb) from the circulation, as well as the induction of haem oxygenase 1 (HO1) in the liver and kidney. Moreover, the hepcidin-ferroportin regulatory axis is strongly affected in mosaic mice. These findings indicate that haemolysis is an additional pathogenic factor in a mouse model of Menkes diseases and provides evidence of a new indirect connection between copper deficiency and iron metabolism.

BACKGROUND:Int-6 (integration site 6) was identified as an oncogene in a screen of tumorigenic mouse mammary tumor virus (MMTV) insertions. INT6 expression is altered in human cancers, but the precise role of disrupted INT6 in tumorigenesis remains unclear, and an animal model to study Int-6 physiological function has been lacking. PRINCIPAL FINDINGS:Here, we create an in vivo model of Int6 function in zebrafish, and through genetic and chemical-genetic approaches implicate Int6 as a tissue-specific modulator of MEK-ERK signaling. We find that Int6 is required for normal expression of MEK1 protein in human cells, and for Erk signaling in zebrafish embryos. Loss of either Int6 or Mek signaling causes defects in craniofacial development, and Int6 and Erk-signaling have overlapping domains of tissue expression. SIGNIFICANCE:Our results provide new insight into the physiological role of vertebrate Int6, and have implications for the treatment of human tumors displaying altered INT6 expression.

Two kinds of titanium dioxide were used as starting materials for thermal modification: Tytanpol A11 supplied by Chemical Factory “Police” S.A. (Poland) and Degussa P25 supplied by Degussa AG (Germany). The photocatalytic activity of titania materials modified by thermal treatment was tested in the reaction of photocatalytic oxidation of phenol. It was found that the highest activity in the reaction of photocatalytic decomposition of phenol, in case of Tytanpol A11, shows the samples of material modified at temperatures of 700 and 750°C. These catalysts were more active than untreated A11, whereas materials modified at higher temperatures show lower activity. In the case of P25, all thermally treated materials were less active than the unmodified material. The photocatalyst samples were characterized by UV-Vis/DR, FTIR/DRS, and XRD methods.