Traditionally, anticancer therapies focus on restraining uncontrolled proliferation. However, these cytotoxic therapies expose cancer cells to direct killing, instigating the process of natural selection favoring survival of resistant cells that become the foundation for tumor progression and therapy failure. Recognizing this phenomenon has prompted the development of alternative therapeutic strategies. Here we propose strategies targeting cancer hallmarks beyond proliferation, aiming at re-educating cancer cells towards a less malignant phenotype. These strategies include controlling cell dormancy, transdifferentiation therapy, normalizing the cancer microenvironment, and using migrastatic therapy. Adaptive resistance to these educative strategies does not confer a direct proliferative advantage to resistant cells, as non-resistant cells are not subject to eradication, thereby delaying or preventing the development of therapy-resistant tumors.

• MeSH
• chemorezistence MeSH
• lidé MeSH
• nádorové mikroprostředí * MeSH
• nádory * terapie   MeSH
• proliferace buněk MeSH
• protinádorové látky terapeutické užití   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Prey selection is a key factor shaping animal populations and evolutionary dynamics. An optimal forager should target prey that offers the highest benefits in terms of energy content at the lowest costs. Predators are therefore expected to select for prey of optimal size. Stalking predators do not pursue their prey long, which may lead to a more random choice of prey individuals. Due to difficulties in assessing the composition of available prey populations, data on prey selection of stalking carnivores are still scarce. We show how the stalking predator Eurasian lynx (Lynx lynx) selects prey individuals based on species identity, age, sex and individual behaviour. To address the difficulties in assessing prey population structure, we confirm inferred selection patterns by using two independent data sets: (1) data of 387 documented kills of radio-collared lynx were compared to the prey population structure retrieved from systematic camera trapping using Manly's standardized selection ratio alpha and (2) data on 120 radio-collared roe deer were analysed using a Cox proportional hazards model. Among the larger red deer prey, lynx selected against adult males-the largest and potentially most dangerous prey individuals. In roe deer lynx preyed selectively on males and did not select for a specific age class. Activity during high risk periods reduced the risk of falling victim to a lynx attack. Our results suggest that the stalking predator lynx actively selects for size, while prey behaviour induces selection by encounter and stalking success rates.

• MeSH
• ekosystém MeSH
• Lynx fyziologie   psychologie   MeSH
• populační dynamika MeSH
• potravní řetězec * MeSH
• predátorské chování fyziologie   MeSH
• proporcionální rizikové modely MeSH
• roční období MeSH
• sexuální faktory MeSH
• stalking psychologie   MeSH
• věkové faktory MeSH
• velikost těla MeSH
• výběrové chování fyziologie   MeSH
• vysoká zvěř fyziologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Caenorhabditis elegans has been increasingly used to study the innate immunity and for the screening of microbe/host-specific pathogenic factors. Staphylococcus aureus-mediated infections with live C. elegans were performed on solid (full-lawn) and liquid assays. S. aureus required 90 ± 10 h for the complete killing of C. elegans, but the infection was started only after 32 h of exposure with 20% inoculum of S. aureus. The short time exposure studies revealed that, in 20% of inoculum, continuous exposure to the pathogen was required for the killing of nematode. In 100% of inoculum, only 8 h of exposure was sufficient to kill the C. elegans. To evaluate kinetically at the innate immune level, the regulation of representative candidate antimicrobial genes was investigated. Both semi-quantitative reverse transcriptase polymerase chain reaction (PCR) and real-time PCR analyses indicated the regulation of candidate immune regulatory genes of lysozyme (lys-7), cysteine protease (cpr-2), and C-type lectin (clec-60 and clec-87) family members during the course of S. aureus infections, indicating the possible contribution of the above players during the host immune response against S. aureus exposures.

• MeSH
• bakteriální léková rezistence MeSH
• Caenorhabditis elegans genetika   imunologie   metabolismus   MeSH
• cysteinové proteasy genetika   imunologie   metabolismus   MeSH
• exprese genu MeSH
• interakce hostitele a patogenu MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• lektiny typu C genetika   imunologie   metabolismus   MeSH
• muramidasa genetika   imunologie   metabolismus   MeSH
• počet mikrobiálních kolonií MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• přirozená imunita MeSH
• proteiny Caenorhabditis elegans genetika   imunologie   metabolismus   MeSH
• stafylokokové infekce genetika   imunologie   mikrobiologie   MeSH
• Staphylococcus aureus fyziologie   MeSH
• virulence MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• biomarkery farmakologické MeSH
• biotechnologie metody   MeSH
• preklinické hodnocení léčiv MeSH
• protilátky farmakologie   terapeutické užití   MeSH
• Publikační typ
• příručky MeSH

• Konspekt
• Farmacie. Farmakologie
• NLK Obory
• farmacie a farmakologie
• alergologie a imunologie
• NLK Publikační typ
• kolektivní monografie

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• alergologie a imunologie

An infecting and propagating parasite relies on its innate defense system to evade the host's immune response and to survive challenges from commensal bacteria. More so for the nematode Anisakis, a marine parasite that during its life cycle encounters both vertebrate and invertebrate hosts and their highly diverse microbiotas. Although much is still unknown about how the nematode mitigates the effects of these microbiota, its antimicrobial peptides likely play an important role in its survival. We identified anisaxins, the first cecropin-like helical antimicrobial peptides originating from a marine parasite, by mining available genomic and transcriptomic data for Anisakis spp. These peptides are potent bactericidal agents in vitro, selectively active against Gram-negative bacteria, including multi-drug resistant strains, at sub-micromolar concentrations. Their interaction with bacterial membranes was confirmed by solid state NMR (ssNMR) and is highly dependent on the peptide concentration as well as peptide to lipid ratio, as evidenced by molecular dynamics (MD) simulations. MD results indicated that an initial step in the membranolytic mode of action involves membrane bulging and lipid extraction; a novel mechanism which may underline the peptides' potency. Subsequent steps include membrane permeabilization leading to leakage of molecules and eventually cell death, but without visible macroscopic damage, as shown by atomic force microscopy and flow cytometry. This membranolytic antibacterial activity does not translate to cytotoxicity towards human peripheral blood mononuclear cells (HPBMCs), which was minimal at well above bactericidal concentrations, making anisaxins promising candidates for further drug development. STATEMENT OF SIGNIFICANCE: Witnessing the rapid spread of antibiotic resistance resulting in millions of infected and dozens of thousands dying worldwide every year, we identified anisaxins, antimicrobial peptides (AMPs) from marine parasites, Anisakis spp., with potent bactericidal activity and selectivity towards multi-drug resistant Gram-negative bacteria. Anisaxins are membrane-active peptides, whose activity, very sensitive to local peptide concentrations, involves membrane bulging and lipid extraction, leading to membrane permeabilization and bacterial cell death. At the same time, their toxicity towards host cells is negligible, which is often not the case for membrane-active AMPs, therefore making them suitable drug candidates. Membrane bulging and lipid extraction are novel concepts that broaden our understanding of peptide interactions with bacterial functional structures, essential for future design of such biomaterials.

• MeSH
• antibakteriální látky farmakologie   MeSH
• antimikrobiální peptidy MeSH
• Bacteria MeSH
• kationické antimikrobiální peptidy chemie   farmakologie   MeSH
• leukocyty mononukleární MeSH
• lidé MeSH
• lipidy farmakologie   MeSH
• mikrobiální testy citlivosti MeSH
• paraziti * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

This paper describes the preparation and use of conjugates of porphyrins and bile acids as ligands to bind to tumor expressed saccharides. Bile acid-porphyrin conjugates were tested for recognition of saccharides that are typically present on malignant tumor cells. Fluorescence microscopy, in vitro PDT cell killing, and PDT of subcutaneous 4T1 mouse tumors is reported. High selectivity for saccharide cancer markers and cancer cells was observed. This in vivo and in vitro study demonstrated high potential use for these compounds in targeted photodynamic therapy.

• MeSH
• apoptóza účinky léků   MeSH
• buněčné linie MeSH
• buňky 3T3 MeSH
• financování organizované MeSH
• fluorescenční mikroskopie metody   MeSH
• fotochemoterapie metody   MeSH
• fragmentace DNA účinky léků   MeSH
• glykosylace MeSH
• HeLa buňky MeSH
• lidé MeSH
• ligandy MeSH
• molekulární struktura MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nádorové biomarkery analýza   MeSH
• nádory diagnóza   farmakoterapie   MeSH
• porfyriny farmakologie   chemie   MeSH
• proliferace buněk účinky léků   MeSH
• roztoky chemie   MeSH
• sacharidy chemie   MeSH
• screeningové testy protinádorových léčiv MeSH
• senzitivita a specificita MeSH
• transformované buněčné linie MeSH
• vazebná místa MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• žlučové kyseliny a soli farmakologie   chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH

When considering a mosquito release programme, one of the first issues to be addressed is how to eliminate/separate the females. The greatest number of options might eventually be available for those who can use transgenic mosquitoes, but the inherent characteristics of the target species may also provide possibilities for interim measures until more efficient methods can be developed. Differences in intrinsic size, in behaviour and in development rate between females and males are often available and useful for sexing. Efficient species-specific systems for eliminating females at the embryo stage have been developed, but most have since been discarded due to lack of use. Ideal systems specifically kill female embryos using some treatment that can be manipulated during production. Such killing systems are far more efficient than using intrinsic sexual differences, but they systems require selectable genetic markers and sex-linkage created by rare random chromosomal rearrangements. While intrinsic sexual differences should not be considered as long-term candidates for the development of robust and efficient sexing approaches, in the absence of these, the accessibility and integration of less efficient systems can provide a stop-gap measure that allows rapid start up with a minimum of investment. The International Atomic Energy Agency is funding over a 5 year period (2013-2018) a new Coordinated Research Project on "Exploring Genetic, Molecular, Mechanical and Behavioural Methods of Sex Separation in Mosquitoes" to network researchers and to address the critical need of genetic sexing strains for the implementation of the sterile insect technique (using radiation-sterilised or transgenic male mosquitoes) and for insect incompatibility technique programmes against disease-transmitting mosquitoes.

• MeSH
• biologická kontrola škůdců metody   MeSH
• Culicidae genetika   růst a vývoj   MeSH
• hmyz - vektory * MeSH
• molekulární biologie MeSH
• moskyti - kontrola metody   MeSH
• pohlavní dimorfismus MeSH
• sterilizace metody   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

SOT101 is a superagonist fusion protein of interleukin (IL)-15 and the IL-15 receptor α (IL-15Rα) sushi+ domain, representing a promising clinical candidate for the treatment of cancer. SOT101 among other immune cells specifically stimulates natural killer (NK) cells and memory CD8+ T cells with no significant expansion or activation of the regulatory T cell compartment. In this study, we showed that SOT101 induced expression of cytotoxic receptors NKp30, DNAM-1 and NKG2D on human NK cells. SOT101 stimulated dose-dependent proliferation and the relative expansion of both major subsets of human NK cells, CD56brightCD16- and CD56dimCD16+, and these displayed an enhanced cytotoxicity in vitro. Using human PBMCs and isolated NK cells, we showed that SOT101 added concomitantly or used for immune cell pre-stimulation potentiated clinically approved monoclonal antibodies Cetuximab, Daratumumab and Obinutuzumab in killing of tumor cells in vitro. The anti-tumor efficacy of SOT101 in combination with Daratumumab was assessed in a solid multiple myeloma xenograft in CB17 SCID mouse model testing several combination schedules of administration in the early and late therapeutic setting of established tumors in vivo. SOT101 and Daratumumab monotherapies decreased with various efficacy tumor growth in vivo in dependence on the advancement of the tumor development. The combination of both drugs showed the strongest anti-tumor efficacy. Specifically, the sequencing of both drugs did not matter in the early therapeutic setting where a complete tumor regression was observed in all animals. In the late therapeutic treatment of established tumors Daratumumab followed by SOT101 administration or a concomitant administration of both drugs showed a significant anti-tumor efficacy over the respective monotherapies. These results suggest that SOT101 might significantly augment the anti-tumor activity of therapeutic antibodies by increasing NK cell-mediated activity in patients. These results support the evaluation of SOT101 in combination with Daratumumab in clinical studies and present a rationale for an optimal clinical dosing schedule selection.

• MeSH
• buněčná cytotoxicita závislá na protilátkách MeSH
• buňky NK MeSH
• CD8-pozitivní T-lymfocyty patologie   MeSH
• cetuximab metabolismus   MeSH
• lektinové receptory NK-buněk - podrodina K * metabolismus   MeSH
• lidé MeSH
• mnohočetný myelom * patologie   MeSH
• monoklonální protilátky farmakologie   metabolismus   MeSH
• myši SCID MeSH
• myši MeSH
• receptor interleukinu-15 - alfa-podjednotka metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Cellular senescence is a form of cell cycle arrest that limits the proliferative potential of cells, including tumour cells. However, inability of immune cells to subsequently eliminate senescent cells from the organism may lead to tissue damage, inflammation, enhanced carcinogenesis and development of age-related diseases. We found that the anticancer agent mitochondria-targeted tamoxifen (MitoTam), unlike conventional anticancer agents, kills cancer cells without inducing senescence in vitro and in vivo. Surprisingly, it also selectively eliminates both malignant and non-cancerous senescent cells. In naturally aged mice treated with MitoTam for 4 weeks, we observed a significant decrease of senescence markers in all tested organs compared to non-treated animals. Mechanistically, we found that the susceptibility of senescent cells to MitoTam is linked to a very low expression level of adenine nucleotide translocase-2 (ANT2), inherent to the senescent phenotype. Restoration of ANT2 in senescent cells resulted in resistance to MitoTam, while its downregulation in non-senescent cells promoted their MitoTam-triggered elimination. Our study documents a novel, translationally intriguing role for an anticancer agent targeting mitochondria, that may result in a new strategy for the treatment of age-related diseases and senescence-associated pathologies.

• MeSH
• apoptóza účinky léků   genetika   MeSH
• genový knockdown MeSH
• hormonální protinádorové látky farmakologie   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• myši inbrední NOD MeSH
• myši SCID MeSH
• myši transgenní MeSH
• myši MeSH
• proliferace buněk účinky léků   MeSH
• stárnutí buněk účinky léků   MeSH
• tamoxifen farmakologie   MeSH
• transfekce MeSH
• translokátor adeninových nukleotidů 2 genetika   metabolismus   MeSH
• viabilita buněk účinky léků   genetika   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH