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An interacting-pair model is considered to attain a new natural orbital functional (NOF). The new approach, which will be termed PNOF6, belongs to the JKL-only family of NOFs known in the literature as PNOFi. Accordingly, the approximated two-particle reduced density matrix (RDM) is reconstructed from the one-particle RDM, considering an explicit form of the two-particle cumulant in terms of the occupation numbers, and enforcing (2,2)-positivity conditions for the N-representability of the 2-RDM. PNOF6 is superior to its predecessor, PNOF5, which is an independent-pair approach. The functional is able to treat both dynamic and static correlations, thereby putting together the advantages of the other members of this series. The theory is applied to the dissociation of selected diatomic molecules. The equilibrium distances, dipole moments, harmonic frequencies, anharmonicity constants, and binding energies of the considered molecules are presented. Comparative potential energy curves for the deformation of benzene are given at the PNOF5 and PNOF6 levels of theory. In benzene, PNOF5 breaks the symmetry by about 1.5°, with an energy lowering of almost 3 kcal/mol, whereas PNOF6 provides the correct D6h symmetry [ABSTRACT FROM AUTHOR]

A previously proposed [M. Piris, X. Lopez, F. Ruipérez, J. M. Matxain, and J. M. Ugalde, J. Chem. Phys. 134, 164102 (2011)] formulation of the two-particle cumulant, based on an orbital-pairing scheme, is extended here for including more than two natural orbitals. This new approximation is used to reconstruct the two-particle reduced density matrix (2-RDM) constrained to the D, Q, and G positivity necessary conditions of the N-representable 2-RDM. In this way, we have derived an extended version of the Piris natural orbital functional 5 (PNOF5e). An antisymmetrized product of strongly orthogonal geminals with the expansion coefficients explicitly expressed by the occupation numbers is also used to generate the PNOF5e. The theory is applied to the homolytic dissociation of selected diatomic molecules: H2, LiH, and Li2. The Bader's theory of atoms in molecules is used to analyze the electron density and the presence of non-nuclear maxima in the case of a set of light atomic clusters: Li2, Li+3, Li2 + 4, and H+3 . The improvement of PNOF5e over PNOF5 was observed by visualizing the electron densities. [ABSTRACT FROM AUTHOR]

An antisymmetrized product of strongly orthogonal geminals with the expansion coefficients explicitly expressed by the occupation numbers is used to generate the Piris natural orbital functional 5 (PNOF5). Second-order corrections to PNOF5 are derived and implemented using the multiconfigurational perturbation theory size consistent at second-order (SC2-MCPT). A modified version of the SC2-MCPT including only doubly excited determinants from different geminals is proposed to describe the dispersion interaction in the helium dimer, and to avoid the breakdown of curves in homolytic dissociations of FH, CO, and N2. Comparisons of calculated properties to experimental data are included to verify the accuracy of the formulation. [ABSTRACT FROM AUTHOR]

An explicit formulation of the Piris cumulant [formula] matrix is described herein, and used to reconstruct the two-particle reduced density matrix (2-RDM). Then, we have derived a natural orbital functional, the Piris Natural Orbital Functional 5, PNOF5, constrained to fulfill the D, Q, and G positivity necessary conditions of the N-representable 2-RDM. This functional yields a remarkable accurate description of systems bearing substantial (near)degeneracy of one-particle states. The theory is applied to the homolitic dissociation of selected diatomic molecules and to the rotation barrier of ethylene, both paradigmatic cases of near-degeneracy effects. It is found that the method describes correctly the dissociation limit yielding an integer number of electrons on the dissociated atoms. PNOF5 predicts a barrier of 65.6 kcal/mol for the ethylene torsion in an outstanding agreement with Complete Active Space Second-order Perturbation Theory (CASPT2). The obtained occupation numbers and pseudo one-particle energies at the ethylene transition state account for fully degenerate π orbitals. The calculated equilibrium distances, dipole moments, and binding energies of the considered molecules are presented. The values obtained are accurate comparing those obtained by the complete active space self-consistent field method and the experimental data. [ABSTRACT FROM AUTHOR]

The positivity conditions for the N-representability of the reduced density matrices are considered to propose a new natural orbital functional. The Piris reconstruction functional, which is based on an explicit form of the two-particle cumulant λ(Δ,Π) is used to reconstruct the two-particle reduced density matrix. A new approach for Π matrix, satisfying rigorously D, Q, and G necessary conditions, leads to Piris Natural Orbital Functional 4 (PNOF4). The theory is applied to the dissociation of selected diatomic molecules. The equilibrium distances, dipole moments, harmonic frequencies, anharmonicity constants, and binding energies of the considered molecules are presented. The values we have obtained are very accurate results comparing with the experimental data. [ABSTRACT FROM AUTHOR]

The spin-conserving density matrix functional theory is used to propose an improved natural orbital functional. The Piris reconstruction functional, PNOF, which is based on an explicit form of the two-particle cumulant λ(Δ,Λ) satisfying necessary positivity conditions for the two-particle reduced density matrix, is used to reconstruct the latter. A new approach Λ(3), as well as an extension of the known Δαβ to spin-uncompensated systems lead to PNOF3. The theory is applied to the calculation of the total energies of the first- and second-row atoms (H–Ne) and a number of selected small molecules. The energy differences between the ground state and the lowest-lying excited state with different spin for these atoms, and the atomization energies of the considered molecules are also presented. The obtained values agree remarkably well with their corresponding both CCSD(T, full) and experimental values. [ABSTRACT FROM AUTHOR]

The natural orbital functional theory is considered for spin uncompensated systems, i.e., systems that have one or more unpaired electrons. The well-known cumulant expansion is used to reconstruct the two-particle reduced density matrix. A new condition to ensure the conservation of the total spin is obtained for the two-particle cumulant matrix. An extension of the Piris natural orbital functional 1 (PNOF1), based on an explicit form for the cumulant, to spin uncompensated systems is also considered. The theory is applied to the calculation of energy differences between the ground state and the lowest lying excited state with different spins for first-row atoms (Li, Be, B, C, N, O, and F) and diatomic oxygen molecule (O2). The values we obtained are very accurate results as compared to the CCSD(T) method and the experimental data. [ABSTRACT FROM AUTHOR]

We have investigated the dissociation behavior of the radical helium dimer He2+ using the Piris natural orbital functional (PNOF). This system is particularly challenging to be described by standard density functionals. The restricted open formulation of the PNOF-2, as well as the PNOF-2 energy plus the extended Koopmans’ vertical ionization potential calculations of the neutral helium dimer, have been tested for calculating the ground-state energies of He2+ as a function of the internuclear distance. For comparison, we present the dissociation curve obtained with the diffusion Monte Carlo method. The dissociation energies, equilibrium bond lengths, and rovibrational levels are reported. The obtained potential energy curves indicate that PNOF-2 yields a correct and accurate dissociation behavior for the helium radical dimer. [ABSTRACT FROM AUTHOR]

We have investigated the radial electron pair probability distributions (REPPDs) of the helium dimer within the Piris natural orbital functional (PNOF) theory. The analytical formulas to evaluate intracule densities, Fermi, Coulomb, and total correlation holes using our reconstruction functional PNOF-2 [J. Chem. Phys. 126, 214103 (2007)] are derived. The Löwdin’s Coulomb holes from PNOF-2 and full configuration interaction calculations are analyzed showing a very similar behavior. New definitions of the Coulomb and Fermi holes based on the cumulant expansion of the two-particle reduced density matrix are presented. The holes are defined in terms of the exact one-particle reduced density matrix and the two-particle cumulant without any reference to the Hartree–Fock state. Through these definitions, we analyze separately the contribution of each component to the total REPPD at several values of the internuclear distance. A straight connection between the Coulomb hole and dispersion interactions is observed. [ABSTRACT FROM AUTHOR]

The authors have investigated the description of the dispersion interaction within the Piris natural orbital functional (PNOF) theory. The PNOF arises from an explicit antisymmetric approach for the two-particle cumulant in terms of two symmetric matrices, Δ and Λ. The functional forms of these matrices are obtained from the generalization of the two-particle system expressions, except for the off-diagonal elements of Δ. The mean value theorem and the partial sum rule obtained for the off-diagonal elements of Δ provide a prescription for deriving practical functionals. In particular, the previous employed approximation {Jpp/2} for the mean values {Jp*} affords several molecular properties but it is incapable to account for dispersion effects. In this work, the authors analyze a new approach for Jp* obtained by factorization of the matrix Δ within the bounds on its off-diagonal elements imposed by the positivity conditions of the two-particle reduced density matrix. Additional terms for the matrix elements of Λ proportional to the square root of the holes are again introduced to describe properly the occupation numbers of the lowest occupied levels. The authors have found that the cross products between weakly occupied orbitals must be removed from the functional form of Λ to obtain a correct long-range asymptotic behavior. The PNOF is used to predict the binding energy as well as the equilibrium distance of the helium dimer. The results are compared with the full configuration-interaction calculations and the corresponding experimental data. [ABSTRACT FROM AUTHOR]

The Piris natural orbital functional (PNOF) based on a new approach for the two-electron cumulant has been used to predict adiabatic ionization potentials, equilibrium bond distances, and harmonic vibrational frequencies of 18 diatomic molecules. Vertical ionization potentials have been calculated for the same set of diatomic molecules and another set of 20 polyatomic molecules using energy-difference methods as well as the extended Koopman theorem. The PNOF properties compare favorably with the coupled-cluster-doubles results. The calculated PNOF values are in good agreement with the corresponding experimental data, considering the basis sets used (6-31G**). [ABSTRACT FROM AUTHOR]

Defines first and second order electron correlation in reduced density matrices. Examination of the Bardeen-Cooper-Schrieffer ground state for molecules with an even number of electrons; Formalism extended to molecules with an odd number of electrons.

The potential energy curves of P2 and P2+ have been calculated using an approximate, albeit strictly N-representable, energy functional of the one-particle reduced density matrix: PNOF5. Quite satisfactory accord is found for the equilibrium bond lengths and dissociation energies for both species. The predicted vertical ionisation energy for P2 by means of the extended Koopmans' theorem is 10.57 eV, in good agreement with the experimental data. Comparison of the vibrational energies and anharmonicities with their corresponding experimental values supports the quality of the resultant potential energy curves. [ABSTRACT FROM AUTHOR]

Hartree-Fock (HF) theory makes the prediction that for neutral atoms the chemical potential ( μ) is equal to minus the ionization potential ( I). This has led us to inquire whether this intimate relation is sensitive to electron correlation. We present here therefore some discussion of the predictions for neutral atoms and atomic ions, and some homonuclear diatomic molecules. An account of fairly recent progress in obtaining the HF ionization potentials for the isoelectronic series of He, Be, Ne, Mg, and Ar-like atomic ions is first considered. The [ABSTRACT FROM AUTHOR]

Numerical estimates of the chemical (µ) and ionisation (I) potentials from natural orbital functional (NOF) theory of one of us are presented for neutral atoms ranging from H to Kr, and compared with the corresponding experimental ionisation energies. The semi-empirical treatment by Velaet al.relatesµapproximately to the measuredI. By a physical argument based on the concept of the Pauli potential, we thereby derivein the fully correlated ground states of atoms. The predicted verticalIby means of the extended Koopmans' theorem is in good agreement with the corresponding experimental data. However, the NOF theory ofµlowers the experimental values considerably though oscillatory behaviour is again in evidence. This comparison has prompted us to reopen the Hartree-Fock prediction by Alonso and March that. [ABSTRACT FROM AUTHOR]

A natural orbital functional theory for non-relativistic quantum chemistry due to one of us [MP] is here utilised to calculate the von Weizsäcker inhomogeneity kinetic energyat the equilibrium bond length (Re) for some 30 homonuclear diatomic molecules.Tw/N2, whereNis the total number of electrons in the molecule considered, behaves remarkably simply and tends to a value very near to 1/2 for the Ge2molecule whenN = 64. This is in spite of the irregular variation ofRewithN, which is inputted here from the experiment. It is then proposed that the dissociation energyDeshould be a functional ofTwto be sought. A start is made via thepower law proposed earlier by one of us [NHM]. [ABSTRACT FROM PUBLISHER]

Follicular lymphoma (FL) is characterized besides the t(14;18)(q32;q21), by recurrent chromosomal alterations and somatic mutations. In this study, we analyzed cases of FL in situ (FLIS) without manifest FL (mFL), partial involvement by FL (PFL) and paired cases of FLIS and mFL to detect possible early chromosomal imbalances, mutations, as well as DNA-methylation patterns of genomic regions of selected genes. We demonstrate that all paired FLIS and mFL cases were clonally related, based on IGH rearrangement patterns and BCL2 breakpoint sequences. FLIS and PFL had no or few secondary chromosomal imbalances detectable by array comparative genomic hybridization (FLIS 0.8 copy number alterations (CNA)/case; PFL 2.0 CNA/case; mFL 6.3 CNA/case) and a lower level of DNA methylation of genes recurrently de novo methylated in lymphomas, as compared with mFL. EZH2 Tyr641 mutations were detected in a subset of both FLIS (2/9) and PFL (1/3) cases. In conclusion, these findings provide evidence that FLIS represents a FL precursor lesion of long-lived clonal B cells carrying the t(14;18) with no or few secondary genetic changes. Our data suggest that there may be more than one distinct lesion driving the progression from FLIS to manifest lymphoma. [ABSTRACT FROM AUTHOR]

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a very rare disease that currently lacks genomic and genetic biomarkers to assist in its clinical management. We performed whole-exome sequencing (WES) of three BPDCN cases. Based on these data, we designed a resequencing approach to identify mutations in 38 selected genes in 25 BPDCN samples. WES revealed 37-99 deleterious gene mutations per exome with no common affected genes between patients, but with clear overlap in terms of molecular and disease pathways (hematological and dermatological disease). We identified for the first time deleterious mutations in IKZF3, HOXB9, UBE2G2 and ZEB2 in human leukemia. Target sequencing identified 29 recurring genes, ranging in prevalence from 36% for previously known genes, such as TET2, to 12-16% for newly identified genes, such as IKZF3 or ZEB2. Half of the tumors had mutations affecting either the DNA methylation or chromatin remodeling pathways. The clinical analysis revealed that patients with mutations in DNA methylation pathway had a significantly reduced overall survival (P=0.047). We provide the first mutational profiling of BPDCN. The data support the current WHO classification of the disease as a myeloid disorder and provide a biological rationale for the incorporation of epigenetic therapies for its treatment. [ABSTRACT FROM AUTHOR]

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a very rare disease that currently lacks genomic and genetic biomarkers to assist in its clinical management. We performed whole-exome sequencing (WES) of three BPDCN cases. Based on these data, we designed a resequencing approach to identify mutations in 38 selected genes in 25 BPDCN samples. WES revealed 37-99 deleterious gene mutations per exome with no common affected genes between patients, but with clear overlap in terms of molecular and disease pathways (hematological and dermatological disease). We identified for the first time deleterious mutations in IKZF3, HOXB9, UBE2G2 and ZEB2 in human leukemia. Target sequencing identified 29 recurring genes, ranging in prevalence from 36% for previously known genes, such as TET2, to 12-16% for newly identified genes, such as IKZF3 or ZEB2. Half of the tumors had mutations affecting either the DNA methylation or chromatin remodeling pathways. The clinical analysis revealed that patients with mutations in DNA methylation pathway had a significantly reduced overall survival (P=0.047). We provide the first mutational profiling of BPDCN. The data support the current WHO classification of the disease as a myeloid disorder and provide a biological rationale for the incorporation of epigenetic therapies for its treatment. [ABSTRACT FROM AUTHOR]

In a recent paper (J. Chem. Phys. 139, 064111, 2013), an antisymmetrised product of strongly orthogonal geminals with the expansion coefficients explicitly expressed by means of the occupation numbers was used to generate the Piris natural orbital functional 5 (PNOF5). This functional describes most of the non-dynamical effects, but also an important part of the intrapair (intrageminal) electron correlation. Second-order corrections to the generating PNOF5 wave function were derived using the multiconfigurational perturbation theory size consistent at the second order (SC2-MCPT) to include the missing interpair (intergeminal) electron correlation. A modified version of the SC2-MCPT involving double excitations only from different geminals was introduced and denoted as PNOF5-PT2. In this paper, the ground-state energies of 36 closed-shell species belonging to the G2/97 test set of molecules are studied by the PNOF5-PT2 and PNOF5-SC2-MCPT methods. The numerical performance of both methods on eight dimers, with different strength of hydrogen bonds, and 13 isogyric reactions is also assessed. The results are in reasonable agreement with those obtained using the complete active space second-order perturbation theory and coupled-cluster method with singles, doubles, and noniterative triples corrections. [ABSTRACT FROM AUTHOR]

Background High levels of cyclin E (CCNE) are accompanied by shorter survival in cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone (CHOP)- treated diffuse large B-cell lymphomas (DLBCL), independent of the international prognostic index (IPI). Data on the prognostic role of CCNE in the 'rituximab (R)-era' are lacking. Methods To test reproducibility and applicability of observations from the 'pre-R era' to the 'R era', we examined the prognostic role of CCNE expression by immunohistochemistry in 1579 DLBCL on tissue microarrays (TMA); 339 patients were treated by CHOP and 635 by R-CHOP. Results 1209 samples (77%) were evaluable; failures were due to missing TMA punches and fixation artefacts. Mean expression of CCNE was 13% (0-85%); applying a cut-off of >16%, 382 DLBCL (31%) were positive. CCNE did not correlate with any of the known variables (IPI, primary site, cell of origin, proliferation, and BCL2- or C-MYC rearrangements). We were able to reproduce data suggesting an IPI- and response to therapy independent, negative prognostic impact of CCNE in CHOP-treated DLBCL patients: CCNE-positive cases had a median survival of 16 months compared with 57 months in negative ones (p=0.012). In R-CHOP-treated patients the prognostic impact of CCNE was abrogated and only IPI, cell of origin and response to therapy had a prognostic significance. Conclusions Addition of R to CHOP overcomes the negative prognostic impact of CCNE in DLBCL. Thus, R not only prolongs survival in DLBCL but also serves a cautionary note that prognostic factors should not be transferred into the 'R era' without proper scientific studies. [ABSTRACT FROM AUTHOR]

The cumulant expansion gives rise to an useful decomposition of the two-matrix in which the pair correlated matrix (cumulant) is disconnected from the antisymmetric product of the one-matrices. The cumulant can be approximated in terms of two matrices, Δ and Π, which are explicit functions of the occupation numbers of the natural orbitals. It produces a natural orbital functional (NOF) that reduces to the exact expression for the total energy in two-electron systems. The N-representability positivity necessary conditions of the two-matrix impose several bounds on the matrices Δ and Π. Appropriate forms of these matrices lead to different implementations of the NOF known in the literature as PNOFi ( i = 1-5). The basic features of these functionals are reviewed here. The strengths and weaknesses of the different PNOFs are assessed. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Sporadic Burkitt lymphoma (sBL) is a rapidly growing B-cell non-Hodgkin's lymphoma whose treatment requires highly aggressive therapies that often result severely toxic. Identification of proteins whose expression or function is deregulated in sBL and play a role in its formation could facilitate development of less toxic therapies. We have previously shown that E2F1 expression is deregulated in sBL. We have now investigated the mechanisms underlying E2F1 deregulation and found that the E2F sites in its promoter fail to repress its transcriptional activity in BL cells and that the transcriptional repressor E2F4 barely interacts with these sites. We also have found that E2F4 protein levels, but not those of its mRNA, are reduced in sBL cell lines relative to immortal B-cell lines. E2F4 protein expression is also decreased in 24 of 26 sBL tumor samples from patients compared with control tissues. Our data demonstrate that enforced E2F4 expression in BL cells not only diminishes E2F1 levels, but also reduces selectively the tumorigenic properties and proliferation of BL cells, while increasing their accumulation in G2/M. Our results therefore point to E2F4 as a target for developing novel and less toxic treatments for sBL. [ABSTRACT FROM AUTHOR]

A letter to the editor on the presence of Epstein-Barr virus with diffuse large B-cell lymphoma (DLBCL), is presented.

The dissociation of diatomic molecules of the 14-electron isoelectronic series N2, O2+2, CO, CN−and NO+is examined using the Piris natural orbital functional. It is found that the method describes correctly the dissociation limit yielding an integer number of electrons on the dissociated atoms, in contrast to the fractional charges obtained when using the variational two-particle reduced density matrix method under the D, Q and G positivity necessary N-representability conditions. The chemistry of the considered systems is discussed in terms of their dipole moments, natural orbital occupations and bond orders as well as atomic Mulliken populations at the dissociation limit. The values obtained agree well with accurate multiconfigurational wave function based CASSCF results and the available experimental data. [ABSTRACT FROM AUTHOR]

Natural Orbital Functional Theory in its PNOF3 implementation is used to investigate the potential energy surfaces of four isomerization reactions: (i) BOH to HBO; (ii) BOLi to LiBO; (iii) CNH to HCN; and (iv) CNLi to LiCN. These reactions are taken as a case study to illustrate the potentiality of PNOF3 to yield the correct topology for reactions sensible to electron correlation. The perfomance of PNOF3 to yield accurate reaction barriers and isomerization energies is also discussed. We have found that PNOF3 shows promising behaviour in the description of these delicate PESs, and yield the correct trends in isomerization energies and reaction barriers, although the latter trends tend to be somewhat lower than the ones calculated at highly correlated levels of theory. The present results show that PNOF3 can give a balanced description of electron correlation in both equilibrium and non-equilibrium structures. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) pathogenesis is still partially unexplained. We investigate the importance of microRNA (miRNA) expression as an additional feature that influences MCL pathway deregulation and may be useful for predicting patient outcome. Twenty-three MCL samples, eight cell lines and appropriate controls were screened for their miRNAs and gene expression profiles and DNA copy-number changes. MCL patients exhibit a characteristic signature that includes 117 miRNA (false discovery rate <0.05). Combined analysis of miRNAs and the gene expression profile, paired with bioinformatics target prediction (miRBase and TargetScan), revealed a series of genes and pathways potentially targeted by a small number of miRNAs, including essential pathways for lymphoma survival such as CD40, mitogen-activated protein kinase and NF-kappaB. Functional validation in MCL cell lines demonstrated NF-kappaB subunit nuclear translocation to be regulated by the expression of miR-26a. The expression of 12 selected miRNAs was studied by quantitative PCR in an additional series of 54 MCL cases. Univariate analysis identified a single miRNA, miR-20b, whose lack of expression distinguished cases with a survival probability of 56% at 60 months. In summary, using a novel bioinformatics approach, this study identified miRNA changes that contribute to MCL pathogenesis and markers of potential utility in MCL diagnosis and clinical prognostication. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented related to the activation of NF-KB in chronic lymphocytic leukemia.

A challenging task in natural orbital functional theory is to find an efficient procedure for doing orbital optimization. Procedures based on diagonalization techniques have confirmed its practical value since the resulting orbitals are automatically orthogonal. In this work, a new procedure is introduced, which yields the natural orbitals by iterative diagonalization of a Hermitian matrix F. The off-diagonal elements of the latter are determined explicitly from the hermiticity of the matrix of the Lagrange multipliers. An expression for diagonal elements is absent so a generalized Fockian is undefined in the conventional sense, nevertheless, they may be determined from an aufbau principle. Thus, the diagonal elements are obtained iteratively considering as starting values those coming from a single diagonalization of the matrix of the Lagrange multipliers calculated with the Hartree-Fock orbitals after the occupation numbers have been optimized. The method has been tested on the G2/97 set of molecules for the Piris natural orbital functional. To help the convergence, we have implemented a variable scaling factor which avoids large values of the off-diagonal elements of F. The elapsed times of the computations required by the proposed procedure are compared with a full sequential quadratic programming optimization, so that the efficiency of the method presented here is demonstrated. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009 [ABSTRACT FROM AUTHOR]

Clinical and biological studies on nodal marginal zone lymphoma (NMZL) are hampered by the lack of specific diagnostic markers and the low reproducibility of this diagnosis. A comparative expression-profiling study has shown a set of markers to be differentially expressed in NMZL compared with follicular lymphoma (FL), including myeloid cell nuclear differentiation antigen (MNDA), a nuclear protein expressed by myeloid cells and a subset of B-cells. The aim of this study was to characterize the expression of MNDA in normal and reactive human tissue, and in a large series of non-Hodgkin's B-cell lymphomas, with particular emphasis on NMZL and FL. Our results showed that MNDA is expressed in normal tissue by a subset of the marginal zone B cells. They also showed MNDA expression in subgroups of chronic lymphocytic leukemia, mantle-cell lymphoma, and diffuse large B-cell lymphoma, but MNDA was especially expressed by lymphomas derived from the marginal zone, such as mucosa-associated lymphoid-tissue lymphoma, splenic marginal-zone lymphoma and NMZL. MNDA expression was rarely observed in FL, a characteristic that is of potential value in distinguishing between NMZL and FL. MNDA expression is thus a useful tool for the recognition of NMZL. [ABSTRACT FROM AUTHOR]

Background Interferon (IFN)-α is widely used in the treatment of mycosis fungoides (MF) and when used in combination with photochemotherapy (psoralen plus ultraviolet A, PUVA) both improved response and duration of complete remission have been reported. However, in spite of encouraging results of the initial studies, currently there is no information available on specific prognostic factors enabling prediction of patients’ resistance to PUVA ± IFN-α treatment. Objectives To identify factors responsible for resistance to PUVA ± IFN-α treatment in MF patients. Patients/methods The gene expression profiling of pretreatment samples from 29 patients diagnosed as IA, IB or IIA stage of MF enrolled in a randomized PUVA vs. PUVA + IFN-α clinical trial was analysed using cDNA microarrays. A Cox model (SAM) and gene set enrichment analysis (GSEA) were used for identification of genes and biologically significant pathways related to resistance to treatment. Results Genes involved in NF-κB signalling, T-cell receptor (TCR) signalling, cytokine signalling and proliferation were differentially expressed between responders and nonresponders. Interestingly, expression of markers representative of those pathways was found not only in the tumoral cells, but also in specific subpopulations of macrophages, dendritic cells and other non-neoplastic cell types constituting the tumour microenvironment, likely involved in the promotion of survival and proliferation of cutaneous T-cell lymphoma. Conclusions Gene expression changes in both the tumour and the tumour microenvironment are an important determinant of treatment outcome in early-stage MF patients. Some proinflammatory factors such as NF-κB, inflammatory cytokines and their receptors in addition to TCR-associated molecules could be promising targets for MF treatment. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "The Prevalence of IG Translocations and 7q32 Deletions in Splenic Marginal Zone Lymphoma," in the November 8, 2007 issue.

Aims: Light-chain-restricted germinal centres are generally associated with the existence of a neoplastic lymphoproliferative disorder. The aim was to present a series of cases with persistent lymph node enlargement that featured some germinal centres showing light chain immunoglobulin restriction. Methods and results: A series of six reactive lymphadenitis and two Castleman’s disease cases was analysed by immunohistochemistry, IgH-polymerase chain reaction (PCR) and microdissected PCR. In all cases some germinal centres contained a population of plasma cells and plasmacytoid germinal centre cells showing light chain immunoglobulin restriction. In three cases the monotypic cells also showed distinct Bcl-2 expression. Two of the cases showed a predominant IgH rearrangement on a florid polyclonal background and one had an IgH monoclonal rearrangement, as revealed by PCR. Microdissected germinal centre PCR revealed a dominant repeated band in one of three cases and in another case a non-repeated clonal peak was observed. One of the patients developed a follicular lymphoma, which became evident from a subsequent biopsy. Conclusions: These findings may be a manifestation of an underlying disorder in the regulation of the immune response, or an exaggeration of the germinal centre oligoclonal nature. This should be taken into account in the differential diagnosis of follicular hyperplasia. [ABSTRACT FROM AUTHOR]

Since the initial description of splenic marginal zone lymphoma (SMZL) in 1992, an increasing number of publications have dealt with multiple aspects of SMZL diagnosis, molecular pathogenesis and treatment. This process has identified multiple inconsistencies in the diagnostic criteria and lack of clear guidelines for the staging and treatment. The authors of this review have held several meetings and exchanged series of cases with the objective of agreeing on the main diagnostic, staging and therapeutic guidelines for patients with this condition. Specific working groups were created for diagnostic criteria, immunophenotype, staging and treatment. As results of this work, guidelines are proposed for diagnosis, differential diagnosis, staging, prognostic factors, treatment and response criteria. The guidelines proposed here are intended to contribute to the standardization of the diagnosis and treatment of these patients, and should facilitate the future development of clinical trials that could define more precisely predictive markers for histological progression or lack of response, and evaluate new drugs or treatments.Leukemia (2008) 22, 487–495; doi:10.1038/sj.leu.2405068; published online 20 December 2007 [ABSTRACT FROM AUTHOR]

Snai2-deficient cells are radiosensitive to DNA damage. The function of Snai2 in response to DNA damage seems to be critical for its function in normal development and cancer. Here, we applied a functional genomics approach that combined gene-expression profiling and computational molecular network analysis to obtain global dissection of the Snai2-dependent transcriptional response to DNA damage in primary mouse embryonic fibroblasts (MEFs), which undergo p53-dependent growth arrest in response to DNA damage. Although examination of the response showed that overall expression of p53 target gene expression patterns was similarly altered in both control and Snai2-deficient cells, we have identified and validated candidate Snai2 target genes linked to Snai2 gene function in response to DNA damage. This work defines for the first time the effect of Snai2 on p53 target genes in cells undergoing growth arrest, elucidates the Snai2-dependent molecular network induced by DNA damage, points to novel putative Snai2 targets, and suggest a mechanistic model, which has implications for cancer management. [ABSTRACT FROM AUTHOR]

Studies are revealing that lymphoid neoplasms are characterized by well-defined chromosome translocations and by the accumulation of subsequent molecular alterations involving mainly the cell cycle and/or apoptotic pathways. However, survival of B and T tumor cells is also dependent on the interactions with the accompanying cells that comprise the lymphoma microenvironment. Although non-tumor cells can contribute both positive and negative signals to the lymphoma cells, in this review we present compelling evidence of the essential influence of the tumor microenvironment on the initiation and progression of specific lymphoma types, highlighting some new therapeutic approaches that target the lymphoma microenvironment.Leukemia (2008) 22, 49–58; doi:10.1038/sj.leu.2404970; published online 4 October 2007 [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL), the most frequent form of adult leukemia in Western countries, is characterized by a highly variable clinical course. Expression profiling of a series of 160 CLL patients allowed interrogating the genes presumably playing a role in pathogenesis, relating the expression of functionally relevant signatures with the time to treatment. First, we identified genes relevant to the biology and prognosis of CLL to build a CLL disease-specific oligonucleotide microarray. Second, we hybridized a training series on the CLL-specific chip, generating a biology-based predictive model. Finally, this model was validated in a new CLL series. Clinical variability in CLL is related with the expression of two gene clusters, associated with B-cell receptor (BCR) signaling and mitogen-activated protein kinase (MAPK) activation, including nuclear factor-κB1 (NF-κB1). The expression of these clusters identifies three risk-score groups with treatment-free survival probabilities at 5 years of 83, 50 and 17%. This molecular predictor can be applied to early clinical stages of CLL. This signature is related to immunoglobulin variable region somatic hypermutation and surrogate markers. There is a molecular heterogeneity in CLL, dependent on the expression of genes defining BCR and MAPK/NF-κB clusters, which can be used to predict time to treatment in early clinical stages.Leukemia (2007) 21, 1984–1991; doi:10.1038/sj.leu.2404831; published online 5 July 2007 [ABSTRACT FROM AUTHOR]

The Piris natural orbital functional (PNOF) based on a new approach for the two-electron cumulant is considered for the case of high-spin restricted open-shell systems. The theory is applied to the calculation of molecular energies, dipole moments, vertical ionization potentials (IP), and electron affinities (EA) of 10 open-shell molecules. Vertical values of IP and EA were used to evaluate the hardness. It was observed that the results obtained using the PNOF method are comparable to the corresponding results obtained using CCSD(T) in the case of energies and dipole moments. Best agreement between theory and experiment is achieved by PNOF for EA and hardness values. The calculated PNOF values for the mentioned properties are in good agreement with the available experimental data, considering the basis sets used (6–31 ++G**). © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007 [ABSTRACT FROM AUTHOR]

The use of the tyrosine kinase inhibitor imatinib, which blocks the enzymatic action of the BCR–ABL fusion protein, has represented a critical advance in chronic myeloid leukemia (CML) treatment. However, a subset of patients initially fails to respond to this treatment. Use of complementary DNA (cDNA) microarray expression profiling allows the identification of genes whose expression is associated with imatinib resistance. Thirty-two CML bone marrow samples, collected before imatinib treatment, were hybridized to a cDNA microarray containing 6500 cancer genes, and analyzed using bootstrap statistics. Patients refractory to interferon-α treatment were evaluated for cytogenetic and molecular responses for a minimum of 12 months. A set of 46 genes was differentially expressed in imatinib responders and non-responders. This set includes genes involved in cell adhesion (TNC and SCAM-1), drug metabolism (cyclooxygenase 1), protein tyrosine kinases and phosphatases (BTK and PTPN22). A six-gene prediction model was constructed, which was capable of distinguishing cytogenetic response with an accuracy of 80%. This study identifies a set of genes that may be involved in primary resistance to imatinib, suggesting BCR–ABL-independent mechanisms.Leukemia (2006) 20, 1047–1054. doi:10.1038/sj.leu.2404197; published online 6 April 2006 [ABSTRACT FROM AUTHOR]

The HDM2 oncoprotein is a cellular inhibitor of p53 and is frequently deregulated in human cancer. However, the HDM2 gene encodes alternatively spliced variants whose functional significance is poorly understood. We had previously reported the detection of alternative HDM2 forms in Hodgkin's lymphoma (HL)-derived cell lines. Here, we have cloned several of these transcripts, including the previously described HDM2-A, -B and -C (which encode the COOH terminus of HDM2), and two novel variants (HDM2-HL1 and -HL2) containing a complete p53 interaction domain. Real-time PCR assays demonstrated that HDM2-A and -B were selectively expressed by HL cell lines and primary tumors, compared with their non-neoplastic counterparts. In transient transfection experiments, alternatively spliced HDM2 isoforms were partially or totally localized within the cytoplasm. HDM2-HL2 was able to inhibit transactivation of a p53-inducible reporter construct and induced a partial relocalization of p53 to the cytoplasm. Expression of HDM2-A and -B caused the activation of p53/p21 and induced growth arrest in primary cells, but also increased the expression levels of cyclins D1 and E. Other possible genes regulated by HDM2-A and -B were identified using cDNA microarray technology. These results imply that HDM2 isoforms may have multiple effects on cell cycle control, and provide insight into the mechanisms through which these molecules contribute to tumorigenesis.Oncogene (2006) 25, 2565–2574. doi:10.1038/sj.onc.1209282; published online 5 December 2005 [ABSTRACT FROM AUTHOR]

Classification and proper treatment of extranodal lymphoma is hindered by the diversity of lymphoma types and the relative rarity of many of these tumour types. In order to review controversial issues in extranodal lymphoma diagnosis, a joint Workshop of the European Haematopathology Association (EAHP) and the Society for Hematopathology (SH) was held, where 99 selected cases were reviewed and discussed. This Workshop summary is focused on the most controversial aspect of cutaneous B-cell lymphoma, other extranodal B-cell lymphomas, plasmablastic lymphoma and anaplastic large-cell lymphoma in extranodal sites, and makes practical recommendations about diagnosis and therapeutic approaches. [ABSTRACT FROM AUTHOR]