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Therapy-related acute promyelocytic leukemia (t-APL) is relatively rare, with limited data on outcome after treatment with arsenic trioxide (ATO) compared to standard intensive chemotherapy (CTX). We evaluated 103 adult t-APL patients undergoing treatment with all-trans retinoic acid (ATRA) alone (n=7) or in combination with ATO (n=24), CTX (n=53), or both (n=19). Complete remissions were achieved after induction therapy in 57% with ATRA, 100% with ATO/ATRA, 78% with CTX/ATRA, and 95% with CTX/ATO/ATRA. Early death rates were 43% for ATRA, 0% for ATO/ATRA, 12% for CTX/ATRA and 5% for CTX/ATO/ATRA. Three patients relapsed, two developed therapy-related acute myeloid leukemia and 13 died in remission including seven patients with recurrence of the prior malignancy. Median follow-up for survival was 3.7 years. None of the patients treated with ATRA alone survived beyond one year. Event-free survival was significantly higher after ATO-based therapy (95%, 95% CI, 82–99%) as compared to CTX/ATRA (78%, 95% CI, 64–87%; P=0.042), if deaths due to recurrence of the prior malignancy were censored. The estimated 2-year overall survival in intensively treated patients was 88% (95% CI, 80–93%) without difference according to treatment (P=0.47). ATO when added to ATRA or CTX/ATRA is feasible and leads to better outcomes as compared to CTX/ATRA in t-APL.

Core-binding factor acute myeloid leukemia (CBF-AML) is defined by the presence of either t(8;21)(q22;q22)/RUNX1-RUNX1T1or inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFB-MYH11. The resulting fusion genes require a ‘second hit’ to initiate leukemogenesis. Mutation assessment of 177 adults with CBF-AML, including 68 with t(8;21) and 109 with inv(16)/t(16;16), identified not only mutations well known in CBF-AML but also mutations in the CCND1and CCND2genes, which represent novel frequent molecular alterations in AML with t(8;21). Altogether, CCND1(n=2) and CCND2(n=8) mutations were detected in 10 (15%) patients with t(8;21) in our cohort. A single CCND2mutation was also found in 1 (0.9%) patient with inv(16). In contrast, CCND1and CCND2mutations were detected in only 11 (0.77%) of 1426 non-CBF-AML patients. All CCND2mutations cluster around the highly conserved amino-acid residue threonine 280 (Thr280). We show that Thr280Ala-mutated CCND2 leads to increased phosphorylation of the retinoblastoma protein, thereby causing significant cell cycle changes and increased proliferation of AML cell lines. The identification of CCND1and CCND2mutations as frequent mutational events in t(8;21) AML may provide further justification for cell cycle-directed therapy in this disease.

In this prospective phase 2 clinical trial conducted by Cancer and Leukemia Group B (CALGB, now the Alliance), we studied decitabine as maintenance therapy for younger adults with acute myeloid leukemia (AML) who remained in first complete remission (CR1) following intensive induction and consolidation. Given that decitabine is clinically active in AML and with hypomethylating activity distinct from cytotoxic chemotherapy, we hypothesized that 1 year of maintenance therapy would improve disease-free survival (DFS) for AML patients <60 years, who did not receive allogeneic stem cell transplantation in CR1. After blood count recovery from final consolidation, patients received decitabine at 20 mg/m2intravenously daily for 4–5 days, every 6 weeks for eight cycles. One hundred and thirty-four patients received decitabine and 85 (63%) had favorable risk AML. The median number of cycles received was 7 (range: 1–8) and the primary reason for discontinuation was relapse. DFS at 1 year and 3 years was 79% and 54%, respectively. These results are similar to the outcomes in the historical control comprising similar patients treated on recent CALGB trials. Thus, maintenance with decitabine provided no benefit overall. Standard use of decitabine maintenance in younger AML patients in CR1 is not warranted. This trial was registered at www.clinicaltrials.govas NCT00416598.

Le développement du secourisme sur le lieu de travail est devenu important au vu de différents éléments : la fréquence des accidents cardiovasculaires graves, la pression croissante médicolégale et l’accès facilité aux défibrillateurs. L’objectif de notre étude est de réaliser une revue systématique de la littérature pour évaluer les connaissances actuelles sur le secourisme en milieu du travail.

Introduction We sought to identify symptoms predictive of hospitalisation of patients having the acute allergic reactions managed by an Emergency Medical Dispatch Centre in France.Methods A prospective study was conducted from 20th August 2006 to 5th November 2006 on incoming calls to the Emergency Medical Dispatch Centre for the Hauts de Seineprovince, France. Statistical analyses were used to identify hospitalisation predictors. The validity of predictors identified was tested. We calculated equivalents of sensitivity (probability of presence of the sign when the reaction is severe), specificity (probability of absence of sign when the reaction is not severe), positive predictive value (probability of severe reaction when the sign is present) and negative predictive value (probability of non-severe reaction when the sign is not present).Results A total of 210 calls were included. The following clinical hospitalisation predictors identified had very good specificity and good positive predictive value: facial oedema, sense of choking, respiratory distress, cough, difficulty speaking, dysphagia, abdominal pain, dizziness, collapse, and chest pain. However, none of the selected predictors had a safe negative predictive value (and sensitivity).Conclusion This study has identified positive clinical predictors of hospitalisation for acute allergic reactions patients managed by a Medical Emergency Dispatch Centre. The next step will be a multicentre study in order to develop a severity score or a decision-making algorithm. (Hong Kong j.emerg.med. 2014;21:80-87)

We sought to identify symptoms predictive of hospitalisation of patients having the acute allergic reactions managed by an Emergency Medical Dispatch Centre in France. A prospective study was conducted from 20th August 2006 to 5th November 2006 on incoming calls to the Emergency Medical Dispatch Centre for the Hauts de Seineprovince, France. Statistical analyses were used to identify hospitalisation predictors. The validity of predictors identified was tested. We calculated equivalents of sensitivity (probability of presence of the sign when the reaction is severe), specificity (probability of absence of sign when the reaction is not severe), positive predictive value (probability of severe reaction when the sign is present) and negative predictive value (probability of non-severe reaction when the sign is not present). A total of 210 calls were included. The following clinical hospitalisation predictors identified had very good specificity and good positive predictive value: facial oedema, sense of choking, respiratory distress, cough, difficulty speaking, dysphagia, abdominal pain, dizziness, collapse, and chest pain. However, none of the selected predictors had a safe negative predictive value (and sensitivity). This study has identified positive clinical predictors of hospitalisation for acute allergic reactions patients managed by a Medical Emergency Dispatch Centre. The next step will be a multicentre study in order to develop a severity score or a decision-making algorithm. (Hong Kong j.emerg.med. 2014;21:80-87)

A series of novel taxane-based multidrug resistance (MDR) reversal agents (TRAs) has been designed and synthesized. Structure−activity relationship (SAR) study clearly indicates that modification of the C-7 position with hydrophobic arenecarbonylcinnamoyl groups brings about high potency against drug efflux mediated by P-glycoprotein (P-gp). Six TRAs exhibit ability to modulate a wide range of ATP-binding cassette (ABC) transporters, such as P-gp, multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein (BCRP), which may serve as novel broad-spectrum modulators of ABC transporters.

In this paper, we study the implementation of the Berry approach as expressed in his seminal publication (1984 Proc. R. Soc. Lond.A 39245) within Born-Oppenheimer molecular systems (1927 Ann. Phys., Lpz.84457). This was done with the purpose of revealing the relation between the various time-dependent magnitudes in the adiabatic limit and their time-independent counterparts. The two main results are: (1) in the adiabatic limit, a single Born-Oppenheimer state becomes an eigenstate of the system during the excursion of a system along a given contour, and (2) at the end of a closed contour, the topological phases associated with the states that moved adiabatically along a closed contour are well presented by the diagonal D-matrix as obtained from the time-independent treatment. The theoretical study is supported by a detailed numerical study carried out for two ab initiomolecular systems, namely the (Na, H2) and the (H, H2) systems.

AbstractIn the family Canidae a wide range of the diploid chromosome numbers is observed, from 34 + B in the red fox to 78 in the dog and the wolf. Moreover, extensive chromosome polymorphisms were described in some species. In the red fox and raccoon dog a variable number of B chromosomes exist, while in the arctic fox such variability is caused by the widely spread Robertsonian translocation. Also size polymorphism of heterochromatic arms appears in the arctic fox. During the last ten years very rapid progress has been achieved in the mapping of the dog genome and it has facilitated the construction of genome maps of other canids, as well. The application of the comparative chromosome painting approach and the analysis of the chromosome localisation of marker loci have facilitated detailed studies on chromosome rearrangements which occurred during the karyotype evolution. It is foreseen that the extended knowledge on the canine genome organisation will be useful not only in the detection of gene mutations causing hereditary diseases in the dog, but also will facilitate the identification of genes responsible for the great phenotypic and behavioural variability of the dog breeds. Potentially this knowledge may also be useful in fur animal breeding.

In this article, one of the more important dilemmas in molecular physics is considered:  given a matrix of the nonadiabatic coupling terms of any desired dimension, what is the minimal sub-Hilbert space for which diabatization is still valid. This problem was addressed by one of us before (Baer, M. Chem. Phys. Lett. 2000, 329, 450), but it was recently established that the suggested criteria therein lead to subspaces that are too large to be of any use. In this article, we discuss the conditions that have to be satisfied to reach the minimal subspace. We have found that these conditions are related to the spatial distribution of the various nonadiabatic coupling terms. Thus, if nonadiabatic coupling terms for the relevant states overlap only slightly in configuration space, the required size of the subspace for diabatization can be reduced significantly. As an example, we consider the C2H molecule.

An extension is given for the standard two component model of adiabatic, Born–Oppenheimer (BO) electronic states in a polyatonic molecule, by use of Mathieu functions of arbitrary order. The curl or compatibility conditions for the construction of a diabatic set of states based on a finite-dimensional subset of BO states are not satisfied exactly. It is shown, however, that, by successively adding higher order Mathieu functions to the BO set, the compatibility conditions are satisfied with increasingly better accuracy. We then generalize to situations in which the nonadiabatic couplings (the dynamic corrections to the BO approximation) are small (though not necessarily zero) between a finite-dimensional BO subset and the rest of the BO states. We prove that approximate diabatic sets exist, with an error that is of the order of the square of the neglected nonadiabatic couplings. © 2001 John Wiley & Sons, Inc. Int J Quantum Chem, 2001

In this paper are discussed the quantum mechanical connection and its classical counterpart, as well as the quantum and classical topological angles. The two were calculated for a model system to see whether they show any resemblance. The most interesting result we found is that the quantum and the classical topological phases are each formed due to a single discontinuous jump that occurs at some time during the external cycle. However, whereas the quantum mechanical topological phase is formed in the usual adiabatic limit, we had to establish a new parameter which, by allowing it to approach its limiting value, forms the classical topological phase.

In this article we discuss new ideas regarding the effect of conical intersections on a multielectronic adiabatic manifold of eigenfunctions:  (a) The conical intersections are used to break up the Hilbert space into sub-Hilbert spaces by demanding that these subspaces do not have common conical intersections with each other (in other words electronic states belonging to different subspaces do not form conical intersections). (b) A new concept, the topological spin, is introduced; it is shown that its value is closely related to the number of (Jahn−Teller) conical intersections in a given sub-Hilbert-space and that the values of the components are related to the possible number of electronic eigenfunctions that flip sign while surrounding the conical intersections. (c) A geometrical description for the above-mentioned sign conversions is introduced, and it is, also, shown that this description agrees nicely with the results obtained from the topological matrix D. This geometrical, qualitative-type picture is supported by a quantitative analysis based again on the line integral.

Multiple forms of the transcriptional regulator CCAAT/enhancer-binding protein beta (C/EBPbeta) with molecular masses of approximately 38, 34, 20, and 14 kDa have been observed in cell extracts. It has been proposed that these proteins arise by alternative initiation at in-frame AUG codons. The truncated C/EBPbeta isoforms (p14 and p20/LIP) lack transactivation domains but retain DNA-binding and dimerization sequences and are therefore assumed to function as competitive inhibitors of C/EBP-mediated transcription in vivo. By comparing various extraction procedures to analyze endogenous and overexpressed C/EBPbeta proteins, we determined that p20-C/EBPbeta is generated predominantly by in vitro proteolytic cleavage during isolation from cells and that p14-C/EBPbeta is produced exclusively by this mechanism. In transfected cells, the full-length (p34 and p38) isoforms but not the truncated proteins were detectable in the cytoplasm, indicating that the latter are not primary translation products. In addition, the C/EBPbeta leucine zipper dimerization domain was essential for the appearance of the truncated species, demonstrating that protein folding or dimerization are critical determinants of proteolytic sensitivity. Our findings suggest that the presence of truncated C/EBPbeta proteins in cell extracts must be interpreted with caution and that assumptions about the in vivo relevance of these isoforms should be re-evaluated.

In this work are considered nonadiabatic matrices which were not derived from first principles. For this type of nonadiabatic matrices we derived the conditions for such an N × N matrix to yield an N × N diabatic potential matrix which is continuous throughout configuration space. It is shown that these conditions are very close to being quantization type conditions which select from all possible matrices only a certain group. The final theoretical results are supported by examples (a) for the N = 2 case and (b) for the N = 3 case.

In this work, we consider a diabatic 3 × 3 potential matrix which is used to study the three adiabatic−diabatic transformation angles that form the corresponding 3 × 3 adiabatic−diabatic transformation matrix. The three angles are known to be solutions of three coupled first-order differential equations (Top, Z. H.; Baer, M. J. Chem. Phys. 1977, 66, 1363). These equations are solved here for the first time and are shown to be stable and to yield meaningful solutions. Since many sets of equations can be formed for this purpose efforts were made to classify the various sets of equations, with the aim of gaining more physical content for the calculated angles. The numerical treatment was applied to a three-state diabatic potential matrix devised for the Na3 excited states (Cocchini, F.; Upton, T. H.; Andreoni, W. J. Chem. Phys. 1988, 88, 6068). A comparison between two-state and three-state angles reveals that, in certain cases, the two-state angles contain information regarding the interaction of the lower state with the upper states. However in general the two-state treatment may fail in yielding the correct topological features of the system. One of the main results of this study is that the adiabatic−diabatic transformation matrix, upon completion of a cycle, becomes diagonal again with the numbers ±1 in its diagonal.

We calculate the open path phase in a two state model with a slowly (nearly adiabatically) varying time-periodic Hamiltonian and trace its continuous development during a period. We show that the topological (Berry) phase attains πor 2πdepending on whether there is or is not a degeneracy in the part of the parameter space enclosed by the trajectory. Oscillations are found in the phase. As adiabaticity is approached, these become both more frequent and less pronounced and the phase jump becomes increasingly more steep. Integral relations between the phase and the amplitude modulus (having the form of Kramers-Kronig relations, but in the time domain) are used as an alternative way to calculate open path phases. These relations attest to the observable nature of the open path phase.

Two members of the C/EBP family of basic region‐leucine zipper proteins enriched in the liver, C/EBP (C/EBP alpha) and CRP2 (C/EBP beta), were previously shown to transactivate the albumin promoter in a cell type‐dependent manner. These proteins function efficiently in HepG2 hepatoma cells, but inefficiently in HeLa (epithelial) and L (fibroblastic) cells. Here we have investigated the mechanism for cell‐specific control of CRP2 activity. We show that CRP2 contains a negative regulatory region composed of two elements, RD1 and RD2. Deletions of RD2 relieve the inhibition of CRP2 activity in L cells, but do not affect CRP2 function in HepG2 cells. These deletions also increase the DNA binding activity of CRP2 approximately 3‐fold, suggesting that RD2‐mediated repression of DNA binding activity is responsible for CRP2 inhibition in L cells. The adjacent RD1 element functions independently of RD2 and modulates the CRP2 activation domain, which we show to be composed of three subdomains that are conserved within the C/EBP protein family. RD1 does not affect cell type specificity, but inhibits the transactivation potential of GAL4‐CRP2 hybrid proteins by 50‐fold. These findings suggest that CRP2 assumes a tightly folded conformation in which the DNA binding and activation domains are masked by interactions with the regulatory domain and that to function efficiently in HepG2 cells the protein must undergo an activation step. We propose that relief of inhibition conferred by the regulatory domains also accounts for CRP2 activation in response to extracellular signals.

In order to examine the application of the Landau-Zener (LZ) approximation to atom-diatom collisions, the electronic transition induced by a strong laser field is considered for the F(2P3/2), F(2P1/2) + H2 + hθ systems. Comparison between the LZ transition probabilities and those obtained by numerical solution of the exact semiclassical (SC) equations demonstrates significant differences, the most important being found in the case of the F(2P1/2) + H2 + hθ, hθ = 0·117 eV system, where the LZ probability changes smoothly with translation energy, while the SC probability has deep minima.

In this paper, we study the mathematical structure of a continuum reactive mixture model of the combustion of granular energetic materials. We obtain and classify the wave fields associated with this description. This analysis shows that this system of hyperbolic equations becomes degenerate when the relative flow is locally sonic. We derive the corresponding Riemann invariants and construct simple wave solutions. We also discuss special discontinuous solutions of the system of equations. For fixed upstream conditions, different downstream states are possible when the relative velocities exceed the speed of the sound gas.

The specific binding of alfalfa mosaic virus coat protein to viral RNA requires determinants in the 3' untranslated region (UTR). Coat protein and peptide binding sites in the 3' UTR of alfalfa mosaic virus RNA 4 have been analyzed by hydroxyl radical footprinting, deletion mapping, and site-directed mutagenesis experiments. The 3' UTR has several stable hairpins that are flanked by single-stranded (A/U)UGC sequences. Hydroxyl radical footprinting data show that five sites in the 3' UTR of alfalfa mosaic virus RNA 4 are protected by coat protein, and four of the five protected regions contain AUGC or UUGC. Electrophoretic mobility band shift results suggest four coat protein binding sites in the 3' UTR. A 3'-terminal 39-nucleotide RNA fragment containing four AUGC repeats bound coat protein and coat protein peptides with high affinity; however, coat protein bound poorly to antisense 3' UTR transcripts and poly(AUGC)10. Site-directed mutagenesis of AUGC865-868 resulted in a loss of coat protein binding and peptide binding by the RNA fragment. Alignment of alfalfa mosaic RNA sequences with those from several closely related ilarviruses demonstrates that AUGC865-868 is perfectly conserved; moreover, the RNAs are predicted to form similar 3'-terminal secondary structures. The data strongly suggest that alfalfa mosaic virus coat protein and ilavirus coat proteins recognize invariant AUGC sequences in the context of conserved structural elements.

DNA photolyases catalyze the light-dependent repair of pyrimidine dimers in DNA. The results of nucleotide sequence analysis and spectroscopic studies demonstrated that photolyases from Saccharomyces cerevisiae and Escherichia coli share 37% amino acid sequence homology and contain identical chromophores. Do the similarities between these two enzymes extend to their interactions with DNA containing pyrimidine dimers, or does the organization of DNA into nucleosomes in S. cerevisiae necessitate alternative or additional recognition determinants? To answer this question, we used chemical and enzymatic techniques to identify the contacts made on DNA by S. cerevisiae photolyase when it is bound to a pyrimidine dimer and compared these contacts with those made by E. coli photolyase and by a truncated derivative of the yeast enzyme when bound to the same substrate. We found evidence for a common set of interactions between the photolyases and specific phosphates in the backbones of both strands as well as for interactions with bases in both the major and minor grooves of dimer-containing DNA. Superimposed on this common pattern were significant differences in the contributions of specific contacts to the overall binding energy, in the interactions of the enzymes with groups on the complementary strand, and in the extent to which other DNA-binding proteins were excluded from the region around the dimer. These results provide strong evidence both for a conserved dimer-binding motif and for the evolution of new interactions that permit photolyases to also act as accessory proteins in nucleotide excision repair. The locations of the specific contacts made by the yeast enzyme indicate that the mechanism of nucleotide excision repair in this organism involves incision(s) at a distance from the pyrimidine dimer.