Entropy of DNA sequences and leukemia patients mortality Martynenko, Oleksandr; Pastor, Xavier Duran; Frid, Santiago Andres ...
The Journal of V.N. Karazin Kharkiv National University. Series "Medicine" (Online),
11/2022, Volume:
45, Issue:
45
Journal Article
Peer reviewed
Open access
Introduction. Deoxyribonucleic acid (DNA) is not a random sequence of four nucleotides combinations: comprehensive reviews 1, 2 persuasively shows long- and short-range correlations in DNA, periodic ...properties and correlations structure of sequences. Information theory methods, like Entropy, imply quantifying the amount of information contained in sequences. the relationship between entropy and patient survival is widespread in some branches of medicine and medical researches: cardiology, neurology, surgery, trauma. Therefore, it appears there is a necessity for implementing advantages of information theory methods for exploration of relationship between mortality of some category of patients and entropy of their DNA sequences. Aim of the research. The goal of this paper is to provide a reliable formula for calculating entropy accurately for short DNA sequences and to show how to use existing entropy analysis to examine the mortality of leukemia patients. Materials and Methods. We used University of Barcelona (UB) leukemia patient’s data base (DB) with 117 anonymized records that consists: Date of patient’s diagnosis, Date of patient’s death, Leukemia diagnoses, Patient’s DNA sequence. Average time for patient death after diagnoses: 99 ± 77 months. The formal characteristics of DNA sequences in UB leukemia patient’s DB are: average number of bases N = 496 ± 69; min (N) = 297 bases; max(N) = 745 bases. The generalized form of the Robust Entropy Estimator (EnRE) for short DNA sequences was proposed and key EnRE futures was showed. The Survival Analysis has been done using statistical package IBM SPSS 27 by Kaplan-Meier survival analysis and Cox Regressions survival modelling. Results. The accuracy of the proposed EnRE for calculating entropy was proved for various lengths of time series and various types of random distributions. It was shown, that in all cases for N = 500, relative error in calculating the precise value of entropy does not exceed 1 %, while the magnitude of correlation is no worse than 0.995. In order to yield the minimum EnRE standard deviation and coefficient of variation, an initial DNA sequence's alphabet code was converted into an integer code of bases using an optimization rule for only one minimal numerical decoding around zero. Entropy EnRE were calculated for leukemia patients for two samples: 2 groups divided by median EnRE = 1.47 and 2 groups of patients were formed according to their belonging to 1st (EnRE ≤ 1.448) and 4th (EnRE ≥ 1.490) quartiles. The result of Kaplan-Meier survival analysis and Cox Regressions survival modelling are statistically significant: p < 0,05 for median groups and p < 0,005 for patient’s groups formed of 1st and 4th quartiles. The death hazard for a patient with EnRE below median is 1.556 times that of a patient with EnRE over median and that the death hazard for a patient of 1st entropy quartile (lowest EnRE) is 2.143 times that of a patient of 4th entropy quartile (highest EnRE). Conclusions. The transition from widen (median) to smaller (quartile) patients’ groups with more EnRE differentiation confirmed the unique significance of the entropy of DNA sequences for leukemia patient’s mortality. This significance is proved statistically by increasing hazard and decreasing of average time of death after diagnoses for leukemia patients with lower entropy of DNA sequences.
Pregnancy is a natural process that poses an immunological challenge because non-self fetus must be accepted. During the pregnancy period, the fetus as 'allograft' inherits maternal and also paternal ...antigens. For successful and term pregnancy, the fetus is tolerated and nurtured enjoying immune privileges that minimize the risk of being rejected by maternal immune system. Multiple mechanisms contribute to tolerate the semi-allogeneic fetus. Here, we summarize the recent progresses on how the maternal immune system actively collaborates to maintain the immune balance and maternal-fetal tolerance.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Rak dojk je heterogena bolezen, ki jo lahko zdravimo kirurško, s sistemsko terapijo in z obsevanjem. Dopolnilno obsevanje bolnic z rakom dojk pomembno vpliva na preživetje, a povzroča tudi neželene ...učinke zdravljenja. V obsevalno polje namreč ne moremo zajeti zgolj tumorskih celic, temveč zajamemo tudi celice zdravih tkiv. Neželeni učinki zdravljenja z obsevanjem so pri bolnikih z enako shemo zdravljenja različni, eden od vzrokov za ta pojav pa je tudi genetska variabilnost. Obsevanje povzroča napake na DNK tumorskih celic in vodi v celično smrt tumorskih celic. Najnevarnejša poškodba DNK, ki nastane ob izpostavitvi sevanju, je dvojni prelom. Popravi se lahko s homologno rekombinacijo. Kadar je zaradi spremenjenega genskega zapisa za proteine, ki sodelujejo v poteh popravljanja DNK, spremenjeno izražanje gena ali delovanje proteina, se to lahko kaže v različni stopnji uspešnega popravljanja napak DNK, slednje pa v različnem odgovoru na zdravljenje. V prispevku je podrobneje opisana povezava med polimorfizmi v genih, ki sodelujejo v poteh homologne rekombinacije: RAD51 rs1801320 ter rs1801321 in XRCC3 rs861539 ter rs1799794, in odgovorom na zdravljenje z obsevanjem pri raku dojk.
Rak pljuč je ena najbolj pogostih in smrtonosnih rakavih bolezni na svetu. V zadnjih 10 letih je z odkritjem vodilnih mutacij prišlo do velikega napredka pri zdravljenju. Zdravljenje postaja vse bolj ...prilagojeno bolniku oz. biološkim lastnostim raka, proti katerim so usmerjena tarčna onkološka zdravila, ki so bolnikom z napredovalo rakavo boleznijo pomembno podaljšala preživetje. Med tarčnim zdravljenjem se v tumorju razvijajo nove genetske spremembe, ki vodijo v odpornost tarč v rakavem tkivu, s čimer dolgoročno omejujejo uspešnost zdravljenja. Tekočinska biopsija (angl. liquid biopsy) je metoda, ki se je v zadnjih letih uveljavila kot manj invazivni diagnostični postopek, ki omogoča spremljanje odziva na zdravljenje in prepoznavanje mehanizmov odpornosti. Pri raku pljuč se najbolj uveljavlja vloga cirkulirajoče tumorske DNK (ctDNK), aktivne pa so raziskave tudi drugih bioloških označevalcev. V preglednem članku predstavljamo uporabo tekočinske biopsije pri klinični obravnavi bolnikov z nedrobnoceličnim rakom pljuč, ki se kaže v možnosti zgodnjega odkrivanja raka pljuč, identifikaciji vodilnih in odpornih mutacij, potencialni oceni bremena bolezni ter dolgoročnega spremljanja bolnika.
This comparative analysis of Scandinavian social democracies argues that the fate of socialist parties is decided, to a significant degree, by their own policies and reforms_not solely by the changes ...in social structure emphasized in previous studies. Combining quantitative analysis and historical case studies to demonstrate the electoral effects of party policy, Gosta Esping-Andersen formulates a theory that is applicable not only to Scandinavia but to Western Europe as a whole. In addition, he explains why the support basis of social democracy has deteriorated so much more in Denmark than in Sweden and Norway
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•Improved pregnancy outcomes were observed after TGF-β1 treatment following T. gondii infection.•TGF-β1 could down-regulate the expression of NKG2D/DAP10 of dNK cells induced by T. gondii ...infection.•TGF-β1 could down-regulate the ratio of killer subset of dNK cells induced by T. gondii infection.•TGF-β1 could decrease the cytotoxicity of dNK cells caused by T. gondii infection.
Our current aim was to investigate whether injection of TGF-β1 played an important role in improving abnormal pregnancy outcomes with T. gondii infection and how the TGF-β1 regulated. Results showed that TGF-β1 exhibited improved pregnancy outcomes induced by T. gondii infection. dNK cytotoxicity was increased with T. gondii infection while decreased with TGF-β1 treatment. dNK cytotoxicity related NKG2D/DAP10 expression, perforin, granzyme, IFN-γ and killer subsets were all increased with T. gondii infection while decreased after TGF-β1 treatment. In addition, anti-TGF-β1 antibodies could aggregate the cytotoxicity of dNK cells and the levels of molecules above. These results indicated that TGF-β1 treatment could improve the abnormal pregnancy outcomes with T. gondii infection by decreasing the cytotoxicity of dNK cells mediated by NKG2D/DAP10 pathway and killer subset. These results suggested that TGF-β1 might be a potential immunoprotective method for the treatment of abnormal pregnancy outcomes following T. gondii infection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Toxoplasma gondii infection causes adverse pregnancy outcomes by affecting the expression of immunotolerant molecules in decidual immune cells. Galectin-9 (Gal-9) is widely expressed in decidual ...macrophages (dMphi) and is crucial for maintaining normal pregnancy by interacting with the immunomodulatory protein T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3). However, the effects of T. gondii infection on Gal-9 expression in dMphi, and the impact of altered Gal-9 expression levels on the maternal-fetal tolerance function of decidual natural killer (dNK) cells, are still unknown. Pregnancy outcomes of T. gondii-infected C57BL/6 and Lgals9.sup.-/- pregnant mice models were recorded. Expression of Gal-9, c-Jun N-terminal kinase (JNK), phosphorylated JNK (p-JNK), and Forkhead box protein O1 (FOXO1) was detected by western blotting, flow cytometry or immunofluorescence. The binding of FOXO1 to the promoter of Lgals9 was determined by chromatin immunoprecipitation-polymerase chain reaction (ChIP-PCR). The expression of extracellular signal-regulated kinase (ERK), phosphorylated ERK (p-ERK), cAMP-response element binding protein (CREB), phosphorylated CREB (p-CREB), T-box expressed in T cells (T-bet), interleukin 10 (IL-10), and interferon gamma (IFN-gamma) in dNK cells was assayed by western blotting. Toxoplasma gondii infection increased the expression of p-JNK and FOXO1 in dMphi, resulting in a reduction in Gal-9 due to the elevated binding of FOXO1 with Lgals9 promoter. Downregulation of Gal-9 enhanced the phosphorylation of ERK, inhibited the expression of p-CREB and IL-10, and promoted the expression of T-bet and IFN-gamma in dNK cells. In the mice model, knockout of Lgals9 aggravated adverse pregnancy outcomes caused by T. gondii infection during pregnancy. Toxoplasma gondii infection suppressed Gal-9 expression in dMphi by activating the JNK/FOXO1 signaling pathway, and reduction of Gal-9 contributed to dysfunction of dNK via Gal-9/Tim-3 interaction. This study provides new insights for the molecular mechanisms of the adverse pregnancy outcomes caused by T. gondii.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Decidual natural killer (dNK) cells are the predominant lymphocytes accumulated at the maternal-fetal interface. Regulatory mechanism of dNK cells in preeclampsia, a gestational complication ...characterized by high blood pressure and increased proteinuria occurring after 20 weeks pregnancy, is not completely understood.
Multi-parameter flow cytometry is applied to investigate the phenotype and function of dNK cells freshly isolated from decidual samples or conditionally cultured by TGFb stimulation.
In preeclampsia, we documented elevated numbers of CD56+ CD3- dNK cells in close proximity to Foxp3+ regulatory T (Treg) cells within the decidua. In vitro experiments using dNK cells from early gestation showed that dNK activation (IFNG, IL-8 and CD107a) can be downregulated by Treg cells. The expression of these markers by dNK cells was significantly lower in preeclampsia. We also observed a positive correlation between the expression of dNK activation receptors (NKp30 and NKG2D) and the expression of IFNG in specific dNK subsets. TGFb levels are increased in the decidua of preeclamptic pregnancies. We analyzed co-expression of activation (IFNG/IL-8/CD107a) and angiogenic (VEGF) markers in dNK cells. TGFb treatment reduced while blockade of TGFb increased co-expression of these markers.
Our findings suggest that elevated decidual TGFb1 supresses the activation of specific subsets of dNK which in turn contributes to the uteroplacental pathology associated with the onset of preeclampsia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Plasticity of NK cells in Cancer Corvino, Dillon; Kumar, Ananthi; Bald, Tobias
Frontiers in immunology,
05/2022, Volume:
13
Journal Article
Peer reviewed
Open access
Natural killer (NK) cells are crucial to various facets of human immunity and function through direct cytotoxicity or
orchestration of the broader immune response. NK cells exist across a wide range ...of functional and phenotypic identities. Murine and human studies have revealed that NK cells possess substantial plasticity and can alter their function and phenotype in response to external signals. NK cells also play a critical role in tumor immunity and form the basis for many emerging immunotherapeutic approaches. NK cells can directly target and lyse malignant cells with their inherent cytotoxic capabilities. In addition to direct targeting of malignant cells, certain subsets of NK cells can mediate antibody-dependent cellular cytotoxicity (ADCC) which is integral to some forms of immune checkpoint-blockade immunotherapy. Another important feature of various NK cell subsets is to co-ordinate anti-tumor immune responses by recruiting adaptive and innate leukocytes. However, given the diverse range of NK cell identities it is unsurprising that both pro-tumoral and anti-tumoral NK cell subsets have been described. Here, NK cell subsets have been shown to promote angiogenesis, drive inflammation and immune evasion in the tumor microenvironment. To date, the signals that drive tumor-infiltrating NK cells towards the acquisition of a pro- or anti-tumoral function are poorly understood. The notion of tumor microenvironment-driven NK cell plasticity has substantial implications for the development of NK-based immunotherapeutics. This review will highlight the current knowledge of NK cell plasticity pertaining to the tumor microenvironment. Additionally, this review will pose critical and relevant questions that need to be addressed by the field in coming years.
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