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In the geobotanical division of Poland, Pomerania was treated as a separate subdivision, divided into “coastal plains” and the “Pomeranian uplands” or, in the newest regionalization, the “Pomeranian division”. The goal of this paper is to determine how well the distinctiveness of Pomerania is floristically justified. A total of 1,467 native species occur within the area of Pomerania, representing 57.5% of the native flora of Poland. Fifty-seven species distinguishing Pomerania were selected and their phytogeographic features were discussed and compared to the Polish vascular flora. The distribution of 32 species (56.1%) is characterized as (sub)Atlantic/oceanic. Of the taxa that characterize Pomerania, 47.45% represent the northern element of the Polish flora and 7.01% the western element; species of the eastern element do not exist in Pomerania. The maximum entropy (MaxEnt) method was used for collective distribution analysis of the 57 selected taxa. The analyzes were performed using 41 environmental variables. All the species analyzed are strictly linked to the western and the North Atlantic part of Europe. Statistical evaluation of the MaxEnt model yielded an AUC value of 0.75 for both training and test. The most important environmental variables are minimum high (min_h), temperature annual range (bio07), and mean temperature of driest quarter (bio09). The results of the MaxEnt analysis allowed us also to verify the boundaries of the region and suggest new criteria for them. The southern limit of Pomerania should run along the northern boundary of the terminal moraine belt. Also, the area east of the Vistula does not contain abundant representatives of the flora characteristic for Pomerania. The results of the present study may be used for a broader discussion on the revision of the geobotanical division of Poland, at least in its northern part.

Artykuł stanowi próbę charakterystyki eksplicytnych wykładników relacji nadawczo-odbiorczych w dawnych językoznawczych tekstach naukowych (z przełomu XIX i XX w.) i wskazania ich funkcji w analizowanych tekstach. Jako materiał badawczy posłużyły cztery dawne publikacje naukowe (Antoniego Kaliny, Jana Łosia, Aleksandra Brücknera i Zenona Klemensiewicza). Opisano specyfikę procesu komunikacji naukowej (z uwzględnieniem wszystkich komponentów aktu komunikacji), zastosowano metodę próbki 100-wyrazowej (analizy wszystkich predykatów występujących we fragmencie w środkowej partii tekstu) i na tej podstawie skonstruowano wnioski dotyczące częstotliwości ich występowania w dawnych tekstach.

Abstract Small-cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. The dismal prognosis in SCLC is in part associated with an upregulation of BCL-2 family anti-apoptotic proteins, including BCL-XL and MCL-1. Unfortunately, the currently available inhibitors of BCL-2 family anti-apoptotic proteins, except BCL-2 inhibitors, are not clinically relevant because of various on-target toxicities. We, therefore, aimed to develop an effective and safe strategy targeting these anti-apoptotic proteins with DT2216 (our platelet-sparing BCL-XL degrader) and AZD8055 (an mTOR inhibitor) to avoid associated on-target toxicities while synergistically optimizing tumor response. Through BH3 mimetic screening, we identified a subset of SCLC cell lines that is co-dependent on BCL-XL and MCL-1. After screening inhibitors of selected tumorigenic pathways, we found that AZD8055 selectively downregulates MCL-1 in SCLC cells and its combination with DT2216 synergistically killed BCL-XL/MCL-1 co-dependent SCLC cells, but not normal cells. Mechanistically, the combination caused BCL-XL degradation and suppression of MCL-1 expression, and thus disrupted MCL-1 interaction with BIM leading to an enhanced apoptotic induction. In vivo, the DT2216 + AZD8055 combination significantly inhibited the growth of cell line-derived and patient-derived xenografts and reduced tumor burden accompanied by increased survival in a genetically engineered mouse model of SCLC without causing appreciable thrombocytopenia or other normal tissue injuries. Thus, these preclinical findings lay a strong foundation for future clinical studies to test DT2216 + mTOR inhibitor combinations in a subset of SCLC patients whose tumors are co-driven by BCL-XL and MCL-1.

BCL-xL and BCL-2 are validated therapeutic targets in small-cell lung cancer (SCLC). Targeting these proteins with navitoclax (formerly ABT263, a dual BCL-xL/2 inhibitor) induces dose-limiting thrombocytopenia through on-target BCL-xL inhibition in platelets. Therefore, platelet toxicity poses a barrier in advancing the clinical translation of navitoclax. We have developed a strategy to selectively target BCL-xL in tumors, while sparing platelets, by utilizing proteolysis-targeting chimeras (PROTACs) that hijack the cellular ubiquitin proteasome system for target ubiquitination and subsequent degradation. In our previous study, the first-in-class BCL-xL PROTAC, called DT2216, was shown to have synergistic antitumor activities when combined with venetoclax (formerly ABT199, BCL-2-selective inhibitor) in a BCL-xL/2 co-dependent SCLC cell line, NCI-H146 (hereafter referred to as H146), in vitro and in a xenograft model. Guided by these findings, we evaluated our newly developed BCL-xL/2 dual degrader, called 753b, in three BCL-xL/2 co-dependent SCLC cell lines and the H146 xenograft models. 753b was found to degrade both BCL-xL and BCL-2 in these cell lines. Importantly, it was considerably more potent than DT2216, navitoclax, or DT2216 + venetoclax in reducing the viability of BCL-xL/2 co-dependent SCLC cell lines in cell culture. In vivo, 5 mg/kg weekly dosing of 753b was found to lead to significant tumor growth delay, similar to the DT2216 + venetoclax combination in H146 xenografts, by degrading both BCL-xL and BCL-2. Additionally, 753b administration at 5 mg/kg every four days induced tumor regressions. At this dosage, 753b was well tolerated in mice, without observable induction of severe thrombocytopenia as seen with navitoclax, and no evidence of significant changes in mouse body weights. These results suggest that the BCL-xL/2 dual degrader could be an effective and safe therapeutic for a subset of SCLC patients, warranting clinical trials in future.

Although thymidylate synthase (TYMS) inhibitors have served as components of chemotherapy regimens, the currently available inhibitors induce TYMS overexpression or alter folate transport/metabolism feedback pathways that tumor cells exploit for drug resistance, limiting overall benefit. Here we report a small molecule TYMS inhibitor that i) exhibited enhanced antitumor activity as compared with current fluoropyrimidines and antifolates without inducing TYMS overexpression, ii) is structurally distinct from classical antifolates, iii) extended survival in both pancreatic xenograft tumor models and an hTS/Ink4a/Arf null genetically engineered mouse tumor model, and iv) is well tolerated with equal efficacy using either intraperitoneal or oral administration. Mechanistically, we verify the compound is a multifunctional nonclassical antifolate, and using a series of analogs, we identify structural features allowing direct TYMS inhibition while maintaining the ability to inhibit dihydrofolate reductase. Collectively, this work identifies nonclassical antifolate inhibitors that optimize inhibition of thymidylate biosynthesis with a favorable safety profile, highlighting the potential for enhanced cancer therapy.

Abstract KRAS mutations are the most common oncogenic drivers. Sotorasib (AMG510), a covalent inhibitor of KRASG12C, was recently approved for the treatment of KRASG12C-mutated non-small cell lung cancer (NSCLC). However, the efficacy of sotorasib and other KRASG12C inhibitors is limited by intrinsic resistance in colorectal cancer (CRC) and by the rapid emergence of acquired resistance in all treated tumors. Therefore, there is an urgent need to develop novel combination therapies to overcome sotorasib resistance and to maximize its efficacy. We assessed the effect of sotorasib alone or in combination with DT2216 (a clinical-stage BCL-XL proteolysis targeting chimera [PROTAC]) on KRASG12C-mutated NSCLC, CRC and pancreatic cancer (PC) cell lines using MTS cell viability, colony formation and Annexin-V/PI apoptosis assays. Furthermore, the therapeutic efficacy of sotorasib alone and in combination with DT2216 was evaluated in vivo using different tumor xenograft models. We observed heterogeneous responses to sotorasib alone, whereas its combination with DT2216 strongly inhibited viability of KRASG12C tumor cell lines that partially responded to sotorasib treatment. Mechanistically, sotorasib treatment led to stabilization of BIM and co-treatment with DT2216 inhibited sotorasib-induced BCL-XL/BIM interaction leading to enhanced apoptosis in KRASG12C tumor cell lines. Furthermore, DT2216 co-treatment significantly improved the antitumor efficacy of sotorasib in vivo. Collectively, our findings suggest that due to cytostatic activity, the efficacy of sotorasib is limited, and therefore, its combination with a pro-apoptotic agent, i.e., DT2216, shows synergistic responses and can potentially overcome resistance.

Clinical studies of cancer patients have shown that overexpression or amplification of thymidylate synthase (TS) correlates with a worse clinical outcome. We previously showed that elevated TS exhibits properties of an oncogene and promotes pancreatic neuroendocrine tumors (PanNETs) with a long latency. To study the causal impact of elevated TS levels in PanNETs, we generated a mouse model with elevated human TS (hTS) and conditional inactivation of the Men1 gene in pancreatic islet cells (hTS/Men1–/–). We demonstrated that increased hTS expression was associated with earlier tumor onset and accelerated PanNET development in comparison with control Men1–/– and Men1+/ΔN3-8 mice. We also observed a decrease in overall survival of hTS/Men1+/– and hTS/Men1–/– mice as compared with control mice. We showed that elevated hTS in Men1-deleted tumor cells enhanced cell proliferation, deregulated cell cycle kinetics, and was associated with a higher frequency of somatic mutations, DNA damage, and genomic instability. In addition, we analyzed the survival of 88 patients with PanNETs and observed that high TS protein expression independently predicted worse clinical outcomes. In summary, elevated hTS directly participates in promoting PanNET tumorigenesis with reduced survival in Men1-mutant background. This work will refocus attention on new strategies to inhibit TS activity for PanNET treatment.

BackgroundThe ongoing treatment modalities for breast cancer (BC) primarily rely on the expression status of ER, PR and HER-2 receptors in BC tissues. Our strategy of chemosensitization provides new insights to counter chemoresistance, a major obstacle that limits the benefits of chemotherapy of mammary cancers.MethodsBy utilizing a murine breast cancer model employing NSG mice bearing orthotopic triple-negative breast cancer (TNBC) xenografts, we have evaluated the ability of phytochemical curcumin in chemosensitizing BC to 5-Fluorouracil (5-FU) chemotherapy and the differential modulations of cellular events in response to this strategy, independent of their receptor status.ResultsA significant synergistic antitumor potential was observed in the murine model with a sub-optimal dose treatment of 5-FU plus curcumin, as evaluated by a reduction in the tumor-related parameters. We authenticated the pivotal role of thymidylate synthase (TS) in regulating the 5-FU–curcumin synergism using the TNBC pre-clinical model. Our study also confirmed the pharmacological safety of this chemotherapeutic plus phytoactive combination using acute and chronic toxicity studies in Swiss albino mice. Subsequently, the molecular docking analysis of curcumin binding to TS demonstrated the affinity of curcumin towards the cofactor-binding site of TS, rather than the substrate-binding site, where 5-FU binds. Our concomitant in vivo and in silico evidence substantiates the superior therapeutic index of this combination.ConclusionThis is the first-ever pre-clinical study portraying TS as the critical target of combinatorial therapy for mammary carcinomas and therefore we recommend its clinical validation, especially in TNBC patients, who currently have limited therapeutic options.

[b]Introduction[i][/i][/b][i]. Borrelia burgdorferi [/i]sensu lato (s.l.) and Anaplasma phagocytophilum are well known zoonotic pathogens, whereas[i] Ehrlichia canis[/i] is usually considered to be of veterinary concern, although on the basis of recent reports it also seems to be able to infect humans. [b]objective[/b]. The aim of the study was to determine the seroprevalence of [i]B. burgdorferi [/i]s.l., A. phagocytophilum and [i]E. canis[/i] in an Italian canine population, and to verify if there are differences between dogs living in urban areas and those from a rural environment. [b]materials and method.[/b] Blood sera of 1,965 dogs, 1,235 from cities and 730 from rural areas, were tested by indirect immunofluorescent assay (IFAT). [b]results[/b]. The overall seroprevalence was highest for E. canis (7.07%), followed by [i]A. phagocytophilum[/i] (4.68%), and [i]B. burgdorferi[/i] s.l. (1.47%). Rural dogs showed the highest seroprevalence to [i]B. burgdorferi[/i] s.l. and [i]A. phagocytophilum[/i]. No significant differences were observed between rural and urban [i]E. canis[/i]-positive dogs. A low percentage (1.32%) of dogs with dual seropositivity was detected, and no triple positive reactions were observed. No significant differences were detected in the seroprevalence of the three agents in relationship to the age and gender of the dogs. Seroprevalence in the five years considered were not statistically different, except for the lowest rate for [i]E. canis[/i] observed in 2012. [b]conclusions[/b]. The results confirm the presence of [i]B. burgdorferi[/i] s.l., [i]A. phagocytophilum[/i] and [i]E. canis[/i] in Italian dogs in both urban and rural areas. Monitoring pet dogs, which share the same environment with their owners, is useful for identifying the presence of tick-borne disease agents of both veterinary and public health significance

[b]introduction and objective.[/b] Chronic kidney disease (CKD) in children burdens life of patients and their families. Little is known about parents` assessment of families’ social situation. However, the knowledge of the details of a patient’s and his family’s life standards might influence modification and optimization of applied therapy. Therefore, the main goal of the present study was to explore the selected elements of life situation of patients suffering with CKD as well as their parents, depending on the CKD stage and appropriate treatment. [b]materials and methods[/b]. Cross-sectional national study was conducted. A total of 203 children with CKD and 388 their parent-proxies (196 women and 192 men) were enrolled into this study. Patient data and questionnaires filled by both parents, concerning social-demographic parameters and assessment of changes in families after CKD diagnosis in the child, were analysed. [b]results[/b]. CKD children are being brought up in proper families whose financial situation is not good. Children need help in process of education. Perception of current situation differed between both parents in the change of the income source, taking care of CKD child, change in social relations and evaluating relations with medical staff. Parents do not obtain proper support from social workers. [b]conclusion.[/b] Families of CKD children require support in area of financial and educational help for school children. The discrepancies in evaluation of family situation between mothers and fathers of ill children might be the source of conflicts possibly resulting in worsening the outcome for CKD children.

Background/Aims: Chronic medical illness is a significant risk factor for the development of psychiatric disorders. The aims of the study were: to investigate the level of anxiety in children with chronic kidney disease (CKD) and to identify factors associated with the presence of that emotional problem. Methods: CKD children on hemodialysis (HD, n=22), peritoneal dialysis (PD, n=20,) and on conservative treatment (CT, n=95) were enrolled in the study. We used State-Trait Anxiety Inventory (STAI) for adolescents and STAI-C for children. Socio-demographic and physical factors were assessed. Results: There was a significantly higher level of anxiety-state among HD children (8-12 years) compared with other groups of participants of the same age and Polish population norms. The level of anxiety among adolescents (13-18 years), both anxiety-state and anxiety-trait, was significantly higher in the HD group compared with other groups, which did not differ among themselves. In the HD adolescents, there was a correlation between the anxiety-state and the duration of the disease as well as with the number of hospitalizations. PD adolescents in the mainstream education had higher levels of anxiety-state and anxiety-trait compared with home schooled patients. Conclusions: Even though children and adolescents with CKD are at risk of developing a variety of emotional disorders, the level of anxiety among the researched group, with the exception of HD patients, was not significantly different than the level of anxiety among healthy subjects. Adolescents on HD who present a high level of anxiety should undergo long-term psychological treatment.

Among the myriad challenges confronting contemporary medicine, the obesity epidemic stands out as one of the most critical, warranting special attention due to its association with numerous severe comorbidities and its significant consumption of both human lives and financial resource. This review presents recent clinical trials addressing the issue of the effects of Glucagon-Like Peptide 1 Receptor Agonists (GLP-1 RAs) in the management of overweight and obesity in non-diabetic patients and identifies areas requiring further investigation. GLP-1 RAs, initially used in the treatment of type II diabetes, represent some of the most promising pharmacotherapeutic agents for obesity. Their mechanism of action involves lowering glucose levels by stimulating insulin secretion, inhibiting glucagon secretion, and delaying gastric emptying. They also affect the centres of hunger and satiety, contributing to a reduction in food intake, including food cravings. In clinical studies, GLP-1 RAs have demonstrated effectiveness in reducing body weight in both diabetic and non-diabetic patients with fairly good tolerance. The discussion is grounded in three clinical studies that examine the use of liraglutide and semaglutide, and the development of a novel GLP-1 RA, ecnoglutide. The use of semaglutide and liraglutide is associated with significant weight reduction and a decrease in cardiovascular risk in non-diabetic patients, while ecnoglutide represents a promising new GLP-1 RA that requires further investigation.

While the spread of Salmonella enterica serotype Kentucky resistant to ciprofloxacin across Africa and the Middle-East has been described recently, the presence of this strain in humans, food, various animal species (livestock, pets, and wildlife) and in environment is suspected in other countries of different continents. Here, we report results of an in-depth molecular epidemiological study on a global human and non-human collection of S. Kentucky (n=70).We performed XbaI-pulsed field gel electrophoresis and multilocus sequence typing, assessed mutations in the quinolone resistance-determining regions, detected β-lactam resistance mechanisms, and screened the presence of the Salmonella genomic island 1 (SGI1). In this study, we highlight the rapid and extensive worldwide dissemination of the ciprofloxacin-resistant S. Kentucky ST198-X1-SGI1 strain since the mid-2000s in an increasingly large number of contaminated sources, including the environment. This strain has accumulated an increasing number of chromosomal and plasmid resistance determinants and has been identified in the Indian subcontinent, Southeast Asia and Europe since 2010. The second substitution at position 87 in GyrA (replacing the amino acid Asp) appeared helpful for epidemiological studies to track the origin of contamination.This global study provides evidence leading to the conclusion that high-level resistance to ciprofloxacin in S. Kentucky is a simple microbiological trait that facilitates the identification of the epidemic clone of interest, ST198-X1-SGI1. Taking this into account is essential in order to detect and monitor it easily and to take rapid measures in livestock to ensure control of this infection.