Expression and DNA methylation profiles of EZH2-target genes in plasma exosomes and matched primary tumor tissues of the patients with diffuse large B-cell lymphoma

Aims Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoma. This study was designed to compare epigenetic alterations observed in Enhancer of Zeste Homolog 2 (EZH2)-target genes between plasma-derived exosomes and primary tumors in DLBCL patients. Main methods Exosomes were isolated from plasma of 21 DLBCL patients and 21 controls. We analyzed the methylation status of the target genes using methylation-specific PCR. We also examined whether the exosomes and the tumor samples contained transcripts of the target genes. Key findings We found that CDKN2A and CDKN2B were methylated in both plasma exosomes and primary tumor tissue samples. None of the transcripts were found in the exosomes except CDKN1B which was expressed in 8 (38%) of the exosome samples. Significance This study showed that plasma exosomes might preferably package certain target molecules from primary tumors and the exosomes containing dual methylated DNAs of CDKN2A and CDKN2B, or CDKN1B transcript may contribute to DLBCL pathogenesis (AU)

Expression and DNA methylation profiles of EZH2-target genes in plasma exosomes and matched primary tumor tissues of the patients with diffuse large B-cell lymphoma.

AIMS: Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoma. This study was designed to compare epigenetic alterations observed in Enhancer of Zeste Homolog 2 (EZH2)-target genes between plasma-derived exosomes and primary tumors in DLBCL patients. MAIN METHODS: Exosomes were isolated from plasma of 21 DLBCL patients and 21 controls. We analyzed the methylation status of the target genes using methylation-specific PCR. We also examined whether the exosomes and the tumor samples contained transcripts of the target genes. KEY FINDINGS: We found that CDKN2A and CDKN2B were methylated in both plasma exosomes and primary tumor tissue samples. None of the transcripts were found in the exosomes except CDKN1B which was expressed in 8 (38%) of the exosome samples. SIGNIFICANCE: This study showed that plasma exosomes might preferably package certain target molecules from primary tumors and the exosomes containing dual methylated DNAs of CDKN2A and CDKN2B, or CDKN1B transcript may contribute to DLBCL pathogenesis.

Reply to "Comment on 'Rényi entropy yields artificial biases not in the data and incorrect updating due to the finite-size data' ".

We reply to the preceding Comment by Jizba and Korbel [Jizba and Korbel, Phys. Rev. E 100, 026101 (2019)10.1103/PhysRevE.100.026101] by first pointing out that the Schur concavity proposed by them falls short of identifying the correct intervals of normalization for the optimum probability distribution even though normalization is a necessary ingredient in the entropy maximization procedure. Second, their treatment of the subset independence axiom requires a modification of the Lagrange multipliers one begins with, thereby rendering the optimization less trustworthy. We also explicitly demonstrate that the Rényi entropy violates the subset independence axiom and compare it with the Shannon entropy. Third, the composition rule offered by Jizba and Korbel is shown to yield probability distributions even without a need for the entropy maximization procedure at the expense of creating artificial bias in the data.

Increased Expression of Pentraxin 3 in Placental Tissues from Patients with Unexplained Recurrent Pregnancy Loss.

Pentraxin 3 (PTX3), a prototypical member of the long pentraxin subfamily, is a evolutionarily conserved multimeric pattern recognition receptor involved in the humoral component of the innate immune system. Pentraxin 3 is released when tissue is stressed or damaged, and interacts with many different ligands. Pentraxin 3 exerts a pivotal role both as a regulator and as an indicator of inflammatory response in the pathogenesis of many diseases such as sepsis, vasculitis and preeclampsia. Uncontrolled inflammatory response is considered a major cause of unexplained recurrent pregnancy loss (URPL). We determined the PTX3 messenger ribonucleic acid (mRNA) and protein expression levels in placentai tissues from 50 women with URPL, and made comparison with those in 50 age-matched control subjects. In quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry analyses, PTX3 mRNA and protein levels, respectively, were significantly increased in URPL patients compared with their respective controls (p = 0.0001). Although no significant correlations were identified between PTX3 expression levels and clinical parameters such as maternal age, numbers of previous pregnancy losses, and gestational age at miscarriage, PTX3 mRNA expression was significantly higher in patients with no live births than in women with previous live births (p = 0.0001). Our study suggests that tissue-specific expression of PTX3 is associated with URPL. Further larger studies are required to determine whether PTX3 expression can be used as a biomarker to manage URPL in routine clinical practice.

Rényi entropy yields artificial biases not in the data and incorrect updating due to the finite-size data.

We show that the Rényi entropy implies artificial biases not warranted by the data and incorrect updating information due to the finite size of the data despite being additive. It is demonstrated that this is so because it does not conform to the system and subset independence axioms of Shore and Johnson [J. IEEE Trans. Inf. Theory 26, 26 (1980)IETTAW0018-944810.1109/TIT.1980.1056144]. We finally show that the escort averaged constraints do not remedy the situation.

Reply to "Comment on 'Route from discreteness to the continuum for the Tsallis q-entropy' ".

It has been known for some time that the usual q-entropy S_{q}^{(n)} cannot be shown to converge to the continuous case. In Phys. Rev. E 97, 012104 (2018)PREHBM2470-004510.1103/PhysRevE.97.012104, we have shown that the discrete q-entropy S[over ̃]_{q}^{(n)} converges to the continuous case when the total number of states are properly taken into account in terms of a convergence factor. Ou and Abe [previous Comment, Phys. Rev. E 97, 066101 (2018)10.1103/PhysRevE.97.066101] noted that this form of the discrete q-entropy does not conform to the Shannon-Khinchin expandability axiom. As a reply, we note that the fulfillment or not of the expandability property by the discrete q-entropy strongly depends on the origin of the convergence factor, presenting an example in which S[over ̃]_{q}^{(n)} is expandable.

Route from discreteness to the continuum for the Tsallis q-entropy.

The existence and exact form of the continuum expression of the discrete nonlogarithmic q-entropy is an important open problem in generalized thermostatistics, since its possible lack implies that nonlogarithmic q-entropy is irrelevant for the continuous classical systems. In this work, we show how the discrete nonlogarithmic q-entropy in fact converges in the continuous limit and the negative of the q-entropy with continuous variables is demonstrated to lead to the (Csiszár type) q-relative entropy just as the relation between the continuous Boltzmann-Gibbs expression and the Kullback-Leibler relative entropy. As a result, we conclude that there is no obstacle for the applicability of the q-entropy to the continuous classical physical systems.

Comment on "Troublesome aspects of the Renyi-MaxEnt treatment".

Plastino et al. [Plastino et al., Phys. Rev. E 94, 012145 (2016)1539-375510.1103/PhysRevE.94.012145] recently stated that the Rényi entropy is not suitable for thermodynamics by using functional calculus, since it leads to anomalous results unlike the Tsallis entropy. We first show that the Tsallis entropy also leads to such anomalous behaviors if one adopts the same functional calculus approach. Second, we note that one of the Lagrange multipliers is set in an ad hoc manner in the functional calculus approach of Plastino et al. Finally, the explanation for these anomalous behaviors is provided by observing that the generalized distributions obtained by Plastino et al. do not yield the ordinary canonical partition function in the appropriate limit and therefore cannot be considered as genuine generalized distributions.

Mutational status of EZH2 and CD79B hot spots in mature B-cell non-Hodgkin's lymphomas: novel CD79B variations have been revealed.

OBJECTIVE: We aimed to determine the hot spot mutational frequencies of Enhancer of Zeste homolog 2 (EZH2) and cluster of differentiation 79B (CD79B) genes in a cohort of mature B-cell non-Hodgkin's lymphomas. PATIENTS AND METHODS: DNA samples from formalin-fixed and paraffin embedded (FFPE) tissues from a total of 37 patients with mature B-cell non-Hodgkin lymphomas were included in the study. Molecular genetic analysis was performed by direct sequencing of the DNA samples. RESULTS: We analyzed formaldehyde fixed-paraffin embedded (FFPE) tumor tissue samples from 17 female and 20 male patients with a median age of 63.7 years at the time of diagnosis. None of the patients had previously reported hot spot mutations in EZH2 and CD79B, but previously unreported single nucleotide variations of CD79B were present in nine patients. rs779833118 was the most frequent variation (7/37 patients, 18.9%). A non-synonymous variation rs757407417, which could have a potentially damaging outcome, was detected in two patients. CONCLUSIONS: None of the patients had well-known hot spot mutations in EZH2 and CD79B. However, we detected novel CD79B variations in mature B-cell non-Hodgkin's lymphoma patients.

Validity of the third law of thermodynamics for the Tsallis entropy.

Bento et al. [Phys. Rev. E 91, 022105 (2015)] recently stated that the Tsallis entropy violates the third law of thermodynamics for 01 is already inherent in the fundamental incomplete structure of the deformed logarithms and exponentials underlying the Tsallis entropy. Then, we provide the complete deformed functions and show that the Tsallis entropy conforms to the third law of thermodynamics for both superadditive q<1 and subadditive q>1 regimes. Finally, we remark that the Tsallis entropy does not require the use of an escort-averaging scheme once it is expressed in terms of the complete deformed functions.

Comment on "Third law of thermodynamics as a key test of generalized entropies".

Bento et al. [Phys. Rev. E 91, 022105 (2015)] state that the Tsallis entropy violates the third law of thermodynamics for q≤0 and 0

Transformation-cost time-series method for analyzing irregularly sampled data.

Irregular sampling of data sets is one of the challenges often encountered in time-series analysis, since traditional methods cannot be applied and the frequently used interpolation approach can corrupt the data and bias the subsequence analysis. Here we present the TrAnsformation-Cost Time-Series (TACTS) method, which allows us to analyze irregularly sampled data sets without degenerating the quality of the data set. Instead of using interpolation we consider time-series segments and determine how close they are to each other by determining the cost needed to transform one segment into the following one. Using a limited set of operations-with associated costs-to transform the time series segments, we determine a new time series, that is our transformation-cost time series. This cost time series is regularly sampled and can be analyzed using standard methods. While our main interest is the analysis of paleoclimate data, we develop our method using numerical examples like the logistic map and the Rössler oscillator. The numerical data allows us to test the stability of our method against noise and for different irregular samplings. In addition we provide guidance on how to choose the associated costs based on the time series at hand. The usefulness of the TACTS method is demonstrated using speleothem data from the Secret Cave in Borneo that is a good proxy for paleoclimatic variability in the monsoon activity around the maritime continent.

Tsallis power laws and finite baths with negative heat capacity.

It is often stated that heat baths with finite degrees of freedom i.e., finite baths, are sources of Tsallis distributions for classical Hamiltonian systems. By using well-known fundamental statistical mechanics expressions, we rigorously show that Tsallis distributions with fat tails are possible only for finite baths with constant negative heat capacity, while constant positive heat capacity finite baths yield decays with sharp cutoff with no fat tails. However, the correspondence between Tsallis distributions and finite baths holds at the expense of violating the equipartition theorem for finite classical systems at equilibrium. We comment on the implications of the finite bath for the recent attempts towards a q-generalized central limit theorem.

Finite-time erasing of information stored in fermionic bits.

We address the issue of minimizing the heat generated when erasing the information stored in an array of quantum dots in finite time. We identify the fundamental limitations and trade-offs involved in this process and analyze how a feedback operation can help improve it.

Connectivity-driven coherence in complex networks.

We study the emergence of coherence in complex networks of mutually coupled nonidentical elements. We uncover the precise dependence of the dynamical coherence on the network connectivity, the isolated dynamics of the elements, and the coupling function. These findings predict that in random graphs the enhancement of coherence is proportional to the mean degree. In locally connected networks, coherence is no longer controlled by the mean degree but rather by how the mean degree scales with the network size. In these networks, even when the coherence is absent, adding a fraction s of random connections leads to an enhancement of coherence proportional to s. Our results provide a way to control the emergent properties by the manipulation of the dynamics of the elements and the network connectivity.

Self-organization in dissipative optical lattices.

We show that the transition from Gaussian to the q-Gaussian distributions occurring in atomic transport in dissipative optical lattices can be interpreted as self-organization by recourse to a modified version of Klimontovich's S-theorem. As a result, we find that self-organization is possible in the transition regime, only where the second moment (p(2)) is finite. Therefore, the nonadditivity parameter q is confined within the range 1

M-FISH applications in clinical genetics.

Until recently, presence of de novo marker or derivative chromosomes was quite problematic for genetic counseling especially in prenatal diagnosis, because characterization of marker and derivative chromosomes by conventional cytogenetic techniques was nearly impossible. However, recently developed molecular cytogenetic technique named Multicolor Fluorescence in Situ Hybridization (M-FISH) which paints all human chromosomes in 24 different colors allows us to characterize marker and derivative chromosomes in a single hybridization. In this study, we applied M-FISH to determine the origin of 3 marker and 3 derivative chromosomes. Marker chromosomes were found to originate from chromosome 15 in two postnatal and one prenatal case. Of these, one of the postnatal cases displayed clinical findings of inv dup (115) syndrome and the other of infertility, and the prenatal case went through amniocentesis due to the triple test results. Karyotypes of the patients with derivative chromosomes were designated as 46,XY,der (21)t(1;21)(q32;p11), 46,XX,der(8)t(8;9)(p23;p22) and 46,XX,der(18)t(18;20)(q32;p11.2) according to cytogenetic and M-FISH studies. All of the M-FISH results were confirmed with locus specific or whole chromosome painting probes. The case with der (8)t(8;9) had trisomy 9(p22-pter) and monosomy 8(p23-pter) due to this derivative chromosome. The case with der(18)t(18;20) had trisomy 20(p11.2-pter) and monosomy 18(q32-qter). Parental origins of the derivative chromosomes were analyzed using microsatellite markers located in the trisomic chromosomal segments. Patients' clinical findings were compared with the literature.

Necessity of q-expectation value in nonextensive statistical mechanics.

In nonextensive statistical mechanics, two kinds of definitions have been considered for expectation value of a physical quantity: one is the ordinary definition and the other is the normalized q-expectation value employing the escort distribution. Since both of them lead to the maximum-Tsallis-entropy distributions of a similar type, it is of crucial importance to determine which the correct physical one is. A point is that the definition of expectation value is indivisibly connected to the form of generalized relative entropy. Studying the properties of the relative entropies associated with these two definitions, it is shown how the use of the escort distribution is essential. In particular, the Shore-Johnson theorem for consistent minimum cross-entropy (i.e., relative-entropy) principle is found to select the formalism with the normalized q-expectation value and to exclude the possibility of using the ordinary expectation value from nonextensive statistical mechanics.

Different chromosome Y abnormalities in Turner syndrome.

A 17-year-old phenotypically female girl was referred for evaluation because of short stature and primary amenorrhea. Cytogenetic analysis showed a mosaic 46,XY/45,X/47,XYY/46,X,idic(Yq)/47,XY,idic(Yq)/48,XXY,idic(Yq)/46,X,t(C;Y) karyotype. Conventional cytogenetic results were supplemented with fluorescence in situ hybridization (FISH) techniques to ensure a better characterization of abnormalities. By using FISH, a supernumerary marker chromosome derived from chromosome Y which could not be detected by conventional cytogenetics was revealed. Furthermore, additional abnormalities and their frequencies were highlighted by the application of DNA probes specific for X and Y chromosomes. Thus, FISH proved useful in determining low frequency cell lines which would need analysis of a large number of good quality metaphase spreads by conventional cytogenetic techniques: it helped in identifying the nature and the origin of unknown markers and rearrangements which have important implication in sexual differentiation and development of gonadal tumours.

Parental origin and mechanisms of formation of cytogenetically recognisable de novo direct and inverted duplications.

Cytogenetic, FISH, and molecular results of 20 cases with de novo tandem duplications of 18 different autosomal chromosome segments are reported. There were 12 cases with direct duplications, three cases with inverted duplications, and five in whom determination of direction was not possible. In seven cases a rearrangement between non-sister chromatids (N-SCR) was found, whereas in the remaining 13 cases sister chromatids (SCR) were involved. Paternal and maternal origin (7:7) was found almost equally in cases with SCR (3:4) and N-SCR (4:3). In the cases with proven inversion, there was maternal and paternal origin in one case each. Twenty three out of 43 cytogenetically determined breakpoints correlated with common or rare fragile sites. In five cases, including all those with proven inverse orientation, all breakpoints corresponded to common or rare fragile sites. In at least two cases, one with an interstitial duplication (dup(19)(q11q13)) and one with a terminal duplication (dup(8) (p10p23)), concomitant deletions (del(8) (p23p23.3) and del(19)(q13q13)) were found.