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BACKGROUND:Diabetes mellitus is unfavorably associated with cancer risk. The purpose of this multidisciplinary project was to evaluate a possible association of diabetes mellitus and other comorbidities and their treatment with progression of colorectal cancer. PATIENTS AND METHODS:We investigated the correlation between pathological characteristics and clinical course, including comorbidities in 1004 Czech patients diagnosed and surgically treated for colorectal adenocarcinoma (CRC) between 1999 and 2016. RESULTS:In our data set, CRC patients treated with metformin due to coexisting diabetes mellitus type 2 (T2DM) developed fewer distant metastases which clinically correlates with slower CRC progression. Survival in metformin subgroup was longer, particularly in men with CRC. Osteoporosis may be a negative factor of survival in CRC patients. CONCLUSIONS:Our findings also indicate that aging, higher tumor grade and TNM stage, coexistence of selected endocrine disorders, and metabolic abnormalities may change the tumor microenvironment and impact survival in colorectal cancer, although mechanism of these observations yet to be explained. Patients with diabetes mellitus type 2 treated with metformin may represent the altered microenvironment with specifically tuned metabolic molecular responses and with various epigenetic characteristics. More awareness and increased understanding of the mechanisms underlying the positive effect of metformin on patients' survival could offer insight into new treatment methods and permit more individualized treatment plans.

The functional relevance of microbiota is a key aspect for understanding host–microbiota interactions. Mammalian skin harbours a complex consortium of beneficial microorganisms known to provide health and immune-boosting advantages. As yet, however, little is known about functional microbial communities on avian feathers, including their co-evolution with the host and factors determining feather microbiota (FM) diversity. Using 16S rRNA profiling, we investigated how host species identity, phylogeny and geographic origin determine FM in free-living passerine birds. Moreover, we estimated the relative abundance of bacteriocin-producing bacteria (BPB) and keratinolytic feather damaging bacteria (FDB) and evaluated the ability of BPB to affect FM diversity and relative abundance of FDB. Host species identity was associated with feather bacterial communities more strongly than host geographic origin. FM functional properties differed in terms of estimated BPB and FDB relative abundance, with both showing interspecific variation. FM diversity was negatively associated with BPB relative abundance across species, whereas BPB and FDB relative abundance was positively correlated. This study provides the first thorough evaluation of antimicrobial peptides-producing bacterial communities inhabiting the feather integument, including their likely potential to mediate niche-competition and to be associated with functional species-specific feather microbiota in avian hosts.

The functional relevance of microbiota is a key aspect for understanding host–microbiota interactions. Mammalian skin harbours a complex consortium of beneficial microorganisms known to provide health and immune-boosting advantages. As yet, however, little is known about functional microbial communities on avian feathers, including their co-evolution with the host and factors determining feather microbiota (FM) diversity. Using 16S rRNA profiling, we investigated how host species identity, phylogeny and geographic origin determine FM in free-living passerine birds. Moreover, we estimated the relative abundance of bacteriocin-producing bacteria (BPB) and keratinolytic feather damaging bacteria (FDB) and evaluated the ability of BPB to affect FM diversity and relative abundance of FDB. Host species identity was associated with feather bacterial communities more strongly than host geographic origin. FM functional properties differed in terms of estimated BPB and FDB relative abundance, with both showing interspecific variation. FM diversity was negatively associated with BPB relative abundance across species, whereas BPB and FDB relative abundance was positively correlated. This study provides the first thorough evaluation of antimicrobial peptides-producing bacterial communities inhabiting the feather integument, including their likely potential to mediate niche-competition and to be associated with functional species-specific feather microbiota in avian hosts.

•The tick Ixodes lividuscontains Rickettsia viniwith 100% prevalence.•Rickettsia viniand its most closely related organism infect nidicolous ticks.•The variability among Rickettsia vinifrom the Czech Republic and Belgium is low.

In solid cancers, invasion and metastasis account for more than 90% of mortality. However, in the current armory of anticancer therapies, a specific category of anti-invasion and antimetastatic drugs is missing. Here, we coin the term ‘migrastatics’ for drugs interfering with all modes of cancer cell invasion and metastasis, to distinguish this class from conventional cytostatic drugs, which are mainly directed against cell proliferation. We define actin polymerization and contractility as target mechanisms for migrastatics, and review candidate migrastatic drugs. Critical assessment of these antimetastatic agents is warranted, because they may define new options for the treatment of solid cancers.

Objectives: Sulfonylurea derivatives are widely used for clinical treatment of human subjects with Maturity Onset Diabetes of the Young (MODY) caused by mutations in HNF-1 or HNF-4 despite the mechanism leading to their hypersensitivity is incompletely understood. In Hnf1a-/- mice, serum concentrations and half-life of sulfonylurea derivatives are strongly increased. We thus hypothesized that reduced sulfonylurea derivatives clearance stands behind their therapeutic potential in human HNF1A/HNF4A MODY subjects. Design and Methods: Single doses of 3 mg glipizide and 5 mg glibenclamide/glyburide were administered sequentially to seven HNF1A/HNF4A MODY subjects and six control individuals matched for their age, BMI and CYP2C9 genotype. Pharmacokinetic (plasma concentration levels, Cmax, tmax, t1/2, AUC) and pharmacodynamic parameters (glycemia, C-peptide and insulin plasma levels) were followed for 24 hours after drug administration. Results: We provide the first evidence on the pharmacokinetics and pharmacodynamics of sulfonylurea derivatives in human MODY subjects. The half-life of glipizide did not change, and reached 3.8±0.7 and 3.7±1.8 h in the MODY and control subjects, respectively. The half-life of glibenclamide was increased only in some MODY subjects (t1/2 9.5±6.7 and 5.0±1.4 h, respectively). Importantly, the intra- individual responses of MODY (but control) subjects to glipizide and glibenclamide treatment were highly correlated. With regards to pharmacodynamics, we observed a differential response of control but not MODY subjects to the doses of glipizide and glibenclamide applied. Conclusions: We rejected the hypothesis that all human MODY-associated mutations in HNF1A / HNF4A induce changes in the pharmacokinetics of sulfonylureas in humans analogically to the Hnf1a-/- mouse model.

The knowledge on spiders of the Czech Republic has substantially improved since the second version of the national Red List was published, mainly due to large-scale field records and the establishment of an extensive, searchable electronic database of both retrospective and prospective records. Meanwhile, Central European spiders have undergone substantial changes in abundance and distribution. In this report, an updated Red List is presented and compared with the previous editions from 1992 and 2002, assessing all 879 spider species known to occur in the Czech Republic. For the first time, the abundance, area of occupancy and population trends were calculated for each of the species using the data from the Czech Arachnological Society recording scheme. Twenty-seven species (3% of the total) were classified as Regionally Extinct (RE), 92 (10%) as Critically Endangered, 115 (13%) as Endangered, 155 (18%) as Vulnerable, and 121 (14%) were classified as Least Concern species. Some species listed in the previous version of the Red List were found to live also in non-endangered habitats or to be more common than previously thought, and were thus removed from the list or reclassified to the lower Red List categories. Additionally, several species with dramatically decreasing abundance were identified, among them Ozyptila rauda, Agyneta equestris, Agyneta mollis, Kishidaia conspicua, Clubiona genevensisand Centromerus semiater. The results confirm that spiders are a highly threatened group of arthropods in the Czech Republic, and the updated Red List provides an important foundation for defining conservation priorities.

The knowledge on spiders of the Czech Republic has substantially improved since the second version of the national Red List was published, mainly due to large-scale field records and the establishment of an extensive, searchable electronic database of both retrospective and prospective records. Meanwhile, Central European spiders have undergone substantial changes in abundance and distribution. In this report, an updated Red List is presented and compared with the previous editions from 1992 and 2002, assessing all 879 spider species known to occur in the Czech Republic. For the first time, the abundance, area of occupancy and population trends were calculated for each of the species using the data from the Czech Arachnological Society recording scheme. Twenty-seven species (3% of the total) were classified as Regionally Extinct (RE), 92 (10%) as Critically Endangered, 115 (13%) as Endangered, 155 (18%) as Vulnerable, and 121 (14%) were classified as Least Concern species. Some species listed in the previous version of the Red List were found to live also in non-endangered habitats or to be more common than previously thought, and were thus removed from the list or reclassified to the lower Red List categories. Additionally, several species with dramatically decreasing abundance were identified, among them Ozyptila rauda, Agyneta equestris, Agyneta mollis, Kishidaia conspicua, Clubiona genevensis and Centromerus semiater. The results confirm that spiders are a highly threatened group of arthropods in the Czech Republic, and the updated Red List provides an important foundation for defining conservation priorities

Protein tyrosine phosphatases (PTPs) are increasingly recognized as important effectors of host-pathogen interactions. Since Guan and Dixon reported in 1990 that phosphatase YopH serves as an essential virulence determinant of Yersinia, the field shifted significantly forward, and dozens of PTPs were identified in various microorganisms and even in viruses. The discovery of extensive tyrosine signaling networks in non-metazoan organisms refuted the moth-eaten paradigm claiming that these organisms rely exclusively on phosphoserine/phosphothreonine signaling. Similarly to humans, phosphotyrosine signaling is thought to comprise a small fraction of total protein phosphorylation, but plays a disproportionately important role in cell-cycle control, differentiation, and invasiveness. Here we summarize the state-of-art knowledge on PTPs of important non-metazoan pathogens (Listeria monocytogenes, Staphylococcus aureus, Porphyromonas gingivalis, Caulobacter crescentus, Yersinia, Synechocystis, Leishmania, Plasmodium falciparum, Entamoeba histolytica, etc.), and focus also at the microbial proteins affecting directly or indirectly the PTPs of the host (Mycobacterium tuberculosis MTSA-10, Bacillus anthracis anthrax toxin, streptococcal protein, Helicobacter pylori CagA and VacA, Leishmania GP63 and EF-1α, Plasmodium hemozoin, etc.). This is the first review summarizing the knowledge on biological activity and pharmacological inhibition of non-metazoan PTPs, with the emphasis of those important in host-pathogen interactions. Targeting of numerous non-metazoan PTPs is simplified by the fact that they act either as ectophosphatases or are secreted outside of the pathogen. Interfering with tyrosine phosphorylation represents a powerful pharmacologic approach, and even though the PTP inhibitors are difficult to develop, lifting the fog of phosphatase inhibition is of the great market potential and further clinical impact.

Cancer microenvironment is increasingly recognized as an important factor affecting cancer onset and progression. Since Wirchow reported in 1863 that tumors contain inflammatory cells, the field shifted significantly forward, and immune cells residing in tumors appear to be attractive targets of cancer therapies. For some methods, such as stem/progenitor cell isolation from both cancer and healthy tissues, removal of contaminating immune cells is crucial to achieve consistent, reproducible and accurate results. Despite current methods of lineage negative selection accounts for removal of over 99 of immune cells from stem/progenitor cell isolates, the vast majority of lineage antibody cocktails retain basophils, dendritic cells, and mast cells. Here we discuss the ability of the most commonly used lineage markers to bind to the plasma membrane of mast cells and/or basophils, and suggest alternatives, which may be used for negative selection of these cellular populations. Both, mast cells and basophils, were shown to participate actively in cancer-associated angiogenesis, tissue remodeling and recruitment of other immune cell types, including eosinophils, B cells, memory T cells and Treg cells. In turn, tumor-derived peptides and chemotactic factors are known to recruit and activate mast cells in neoplasias, resulting in altered tumor progression. Repeated findings of CD34 populations of mast cells and basophils further highlight necessity of their separation from stem/progenitor cell isolates in both, preclinical experiments and clinical praxis

Protein tyrosine phosphatases (PTPs) are considered to be involved in the etiology of diabetes mellitus, neural diseases such as Alzheimers and Parkinsons disease, regulation of allergy and inflammation, or they are even considered to be responsible for the pathogens` virulence in vivo. Since discovery of first PTP inhibitors such as dephostatin in early 90th years, the research moved on toward search for inhibitors specific for the individual PTP molecules. Currently, dozens of new PTP inhibitors are reported each year, ranging from natural products, natural product analogs, peptides, phosphonates, nonpeptidic inhibitors, mimotopes, metalcontaining inhibitors, redox inhibitors, to simply silencing RNAs as widely used inhibitors of PTP expression. Several currently used drugs also show PTP inhibitory activity. Among them are sodium stibogluconate, phenylarsine oxide, alendronate, etidronate, vanadate, gallium nitrate, suramin, or aplidin. However, the market is still waiting for the first clinically approved selective PTP inhibitor. Here in this review are described inhibitors of activity or expression of the particular classical PTPs, with emphasis on specific inhibition of the respective PTP over the others. The inhibitors are not classified according to their chemical composition, but according to their biological activity, which should help to simplify search for inhibitors of particular classical PTPs. Even though PTP inhibitors are difficult to develop, lifting the fog of phosphatase inhibition is of the great market potential and further clinical impact.

Activation of mast cells and basophils is accompanied by the production of reactive oxygen and nitrogen species that regulate diverse signaling pathways leading to the release of inflammatory mediators and production of a variety of cytokines. Although the functional pathways of reactive oxygen and nitrogen species in vivo are not completely understood, some novel metabolic pathways can be envisioned based on recent findings that protein tyrosine phosphatases can be regulated by reversible oxidation. In this review, we describe major sources and targets of reactive oxide and nitrogen species in mast cells and basophils. Direct and indirect regulations of class I and II Cys-based protein tyrosine phosphatases (LMW-PTP, PTEN, PTPPEST, SHP-2, PTP1B, PTP, PTP, DEP-1, TC45, SHP-1, HePTP and LAR) are discussed. The combined data highlight the role of redox-regulated protein tyrosine phosphatases as targets in the development of new ways of therapeutic intervention in allergies and inflammatory diseases.

Engagement of the Fcε receptor I (FcεRI) on mast cells and basophils initiates signaling pathways leading to degranulation. Early activation events include tyrosine phosphorylation of two transmembrane adaptor proteins, linker for activation of T cells (LAT) and non–T cell activation linker (NTAL; also called LAB; a product of Wbscr5 gene). Previous studies showed that the secretory response was partially inhibited in bone marrow–derived mast cells (BMMCs) from LAT-deficient mice. To clarify the role of NTAL in mast cell degranulation, we compared FcεRI-mediated signaling events in BMMCs from NTAL-deficient and wild-type mice. Although NTAL is structurally similar to LAT, antigen-mediated degranulation responses were unexpectedly increased in NTAL-deficient mast cells. The earliest event affected was enhanced tyrosine phosphorylation of LAT in antigen-activated cells. This was accompanied by enhanced tyrosine phosphorylation and enzymatic activity of phospholipase C γ1 and phospholipase C γ2, resulting in elevated levels of inositol 1,4,5-trisphosphate and free intracellular Ca2+. NTAL-deficient BMMCs also exhibited an enhanced activity of phosphatidylinositol 3-OH kinase and Src homology 2 domain–containing protein tyrosine phosphatase-2. Although both LAT and NTAL are considered to be localized in membrane rafts, immunogold electron microscopy on isolated membrane sheets demonstrated their independent clustering. The combined data show that NTAL is functionally and topographically different from LAT.

Lycium barbarumpolysaccharides offsets LPS-induced inflammation through a MAPK/NFKB/PPARɣ pathway.

Although the parasitology belongs to one of the longest established disciplines, the recent methodical advances led to the substantial broadening of the possibilities for the detection and treatment of parasitic diseases. However, the exact mechanisms involved in the parasite establishment and survival are frequently unclear and only recently uncovered. At the cellular level, the emerging mechanisms, discussed in this journal issue, include the newly recognized role of mast cells in the host defense against bacterial pathogens, and the role of granulocytes in the host defense against helminths. At the protein level, we discuss here the emerging role of protein tyrosine phosphatases as both targets and tools of nonmetazoan pathogens and viruses. At the level of small signaling molecules, we attempt here to highlight the role of reactive oxygen species as molecules involved both in the host defense, but also produced by some human pathogens and commensals. Scientometric analysis of the fields covered by this journal issue is provided.

Since the times of P. Ehrlich, F. D. von Recklinghausen, and O.Westphal, the research on mast cells and basophils made significant progression towards the recognition of their involvement in antimicrobial functions and of their role in mobilizing inflammation in wound healing, allergy, and autoimmunity. However, the role of mast cells in normal physiology is still poorly understood. Only in recent years, these cells are increasingly recognized as important effectors in number of pathways related mostly to tissue remodeling. The mast cells are capable to orchestrate inflammatory reactions and angiogenesis, they are frequently present near pre-neoplastic epithelial cells, etc. Absolute mast cell deficiency, as in the cross of Min mice to the C57BL/6-KitWsh/Wsh mice, can have overreaching immunological consequences.

Signal transduction pathways play crucial role in number of cellular processes including proliferation, differentiation, adhesion, apoptosis, and metabolic homeostasis. Among the major regulatory mechanisms controlling signal transduction is reversible phosphorylation, which employs multiple kinases and phosphatases. Contrary to kinases, which are now among classic therapeutic targets of carcinogenesis regulation, the field of phosphatase research is still young and the roles of individual phosphatases are only recently recognized in detail. Here we focus on novel aspects of signalling, detection, and targeting of both protein serine/threonine (PPs) and tyrosine (PTPs) phosphatases. The research on PPs is somewhat more advanced since the first discoveries of PPs in mid-60th years [1], whereas identification of the first genuine PTP was reported only as late as in 1988 by Nicholas Tonks and his colleagues [2]. The structures and functions of many PPs and PTPs and their mechanisms of regulation have already been defined. Some are specific for a particular substrate, while others are capable to dephosphorylate vast array of cellular proteins [3]. But only recently, the PPs and PTPs are recognized as not less important components of the same pathways that involve tyrosine or serine/threonine kinases. Even though we are still plagued by the problems of specificity and selectivity, the field significantly advanced forward and the PPs and PTPs holds much promise as future targets of anti-cancer agents. Here we focus on various areas of phosphatase research, which already uncovered findings with potential to improve patient care in terms of improved cancer diagnosis, prognosis, and treatment. Firstly, we focus on microcystins, potent PP inhibitors of growing interest (Fig. 1A). These toxins are produced naturally by blue-green algae (cyanobacteria), a diverse group of photosynthetic bacteria inhabiting wide range of aquatic and terrestrial environments, including drinking water reservoirs, recreational lakes, or coastal waters. H. Fujiki & M. Suganuma focus on the state-of-art knowledge about microcystins and their influence on carcinogenesis in humans, starting with their seminal discovery of tumor promoter function of microcystins in 1992 [4], and discussing the advances in the field until recent days. Despite the acute microcystin intoxication has only rarely fatal consequences, the reverse is true for the chronic exposures, and thus removal of microcystins is particularly important in water treatment plants utilizing water from surface water bodies. Thus, microcystin degradation and removal is subject of complementing paper by D. D. Dionysiou and his colleagues. The techniques described in their study have a potential to completely remove the contaminating microcystins from water even in turbid conditions. These techniques include biodegradation, photochemical degradation including titanium dioxide photocatalysis, sulphate-radical-based oxidation, sonolysis, ozonisation, and chlorination. Current WHO guidelines and local laws in most industrialized countries take in account the most widespread microcystin (microcystin-LR), however the other > 80 microcystin species are left aside without any limits even though they have comparable toxicity to microcystin-LR. Focus on other microcystins, verification of currently applied maximal acceptable limits, and improvement of both detection and elimination of microcystins in water treatment plants is highly desirable. Closely related to the above mentioned topics is review written by P. Kalev & A. A. Sablina, who explore the family of heterotrimeric serine-threonine phosphatases PP2A. This phosphatase family is responsible for the majority of serine/threonine phosphatase activity in mammalian cells, and is among major targets of the above mentioned microcystins. In their paper, they describe current approaches to modulate PP2A signalling in cancer, which includes both activation of PP2A activity, which downregulates major cancer-associated signalling pathways, and inhibition of PP2A activity, which was shown to support the effects of currently used chemotherapeutics due to abrogation cell cycle checkpoints and promotion of premature entry into mitosis. Next we focus on advances in detection of PPs and PTPs. Improved detection methods are crucial to determine the spatiotemporal localization and activity of individual molecules of interest. In first of the two papers, A. Ishida & I. Kameshita explore the current advances in the field of in-gel phosphatase assays. These methods are of great potential in basic and preclinical research as they allow detecting and discriminating between activity of several PPs or PTPs within each sample by incorporation of various substrates to the conventional SDSPAGE gel. Employment of fluorogenic instead of radioactive substrates makes them now more user-friendly and facilitates their wider use. However, compared to in-tube methods, the in-gel assays are still limited due to the necessary ability of the enzyme to renaturate after SDSPAGE, and are efficient only when used to detect the changes caused by covalent modifications (such as phosphorylation or oxidation). In the second paper on PTP detection, S. J. Chung and his colleagues focus on recent advances in development of chemical probes for PTPs, with focus on general and selective fluorescent activity probes. Some of these probes have high potential to be used in either screens for PTP inhibitors or activators, and as diagnostic and prognostic tools. Examples of their current use in basic and preclinical science are discussed. In the next review, K. V. S. Rao and his colleagues deal with interesting emerging phenomenon, regulatory cascades of PPs and PTPs. Broadly defined, these cascades comprise of a series of successive dephosphorylation reactions occurring within a cell and are catalyzed by sequentially activated phosphatases. Despite they closely resemble the very well-known cascades, such as MAPK/Erk pathway, their existence was recognized only recently. As there is frequent crosstalk between the already known phosphatase and kinase cascades, their targeting should definitely be among the major interests of future pharmaceutical research. Several papers in this issue focus in mechanisms of action of emerging cancer-associated PTPs, and evaluate their potential to serve as potential targets for anti-cancer therapy. Our knowledge about the role of PTPs in cancer shifted significantly forward during recent years [5]. Apart of classical target of PTP pharmacological research, PTP1B [6, 7], numerous inhibitors of various PTPs were recently described [8], allowing specific and selective modulation of PTP signaling in basic and preclinical research. However, since the termination of phase II clinical trial of ertiprotafib (Wyeth Research) due to unsatisfactory efficacy, dose-limiting site effects and inconsistency of data from in vivo treatments with the expected outcomes, the market is still waiting for its first clinically approved specific PTP inhibitor, despite several currently used drugs show some degree of PTP inhibitory activity. Among the recently emerging cancer-associated PTPs are PTPN13 / PTPBAS (Fig. 1B; reviewed here by G. Freiss & D. Chalbos), PTPN6 / SHP-1 (reviewed here by B. Colas and her colleagues), emerging marker of metastasis PRL-3 / PTP4A3 (Fig. 1C; reviewed here by K. Guzinska-Ustymowicz), and various MAPK phosphatases (Fig. 1D; reviewed here by R. Pulido and his colleagues). Some PTPs and their fragments may serve as important cancer diagnostic tools. In this regard, S. E. L. Craig and S. M. Brady-Kalnay elucidate here the very interesting phenomenon of shedding of extracellular domains of some receptor PTPs. These shed extracellular domains have a great potential to be used in non-invasive molecular imaging strategies to detect the main tumor. They may be used to mark the tumor margins, and possibly for molecular targeting of tumor cells to deliver therapeutics. Extracellular domain cleavage observed for receptor PTPs resembles those of Notch, where three proteases sequentially digest Notch to release biologically active protein fragments. S. M. Brady-Kalnay pioneered this area of research [9, 10] and offers here exciting state-of-art view of this important emerging subject of cancer research..........