Phenomenological study of hadron interaction models

We present a phenomenological study of three models with different effective degrees of freedom: a Goldstone Boson Exchange (GBE) model which is based on quark-meson couplings, the quark delocalization, color screening model (QDCSM) which is based on quark-gluon couplings with delocalized quark wavefunctions, and the Fujiwara-Nijmegen (FN) mixed model which includes both quark-meson and quark-gluon couplings. We find that for roughly two-thirds of 64 states consisting of pairs of octet and decuplet baryons, the three models predict similar effective baryon-baryon interactions. This suggests that the three very different models, based on different effective degrees of freedom, are nonetheless all compatible with respect to baryon spectra and baryon-baryon interactions. We also discuss the differences between the three models and their separate characteristics.Comment: 30 pages latex, 7 tables, 12 figs; submitted to Phys. Rev.

Response of nucleons to external probes in hedgehog models: II. General formalism

Linear response theory for SU(2) hedgehog soliton models is developed.Comment: 25 pages, DOE/ER/40322-163, U. of MD PP \#92-225, (ReVTeX

RB but not R-HCVAD is a feasible induction regimen prior to auto-HCT in frontline MCL: results of SWOG Study S1106

Aggressive induction chemotherapy followed by autologous haematopoietic stem cell transplant (auto-HCT) is effective for younger patients with mantle cell lymphoma (MCL). However, the optimal induction regimen is widely debated. The Southwesterm Oncology Group S1106 trial was designed to assess rituximab plushyperCVAD/MTX/ARAC (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone, alternating with high dose cytarabine and methotrexate) (RH) versus rituximab plus bendamustine (RB) in a randomized phase II trial to select a pre-transplant induction regimen for future development. Patients had previously untreated stage III, IV, or bulky stage II MCL and received either 4 cycles of RH or 6 cycles of RB, followed by auto-HCT. Fifty-three of a planned 160 patients were accrued; an unacceptably high mobilization failure rate (29%) on the RH arm prompted premature study closure. The estimated 2-year progression-free survival (PFS) was 81% vs. 82% and overall survival (OS) was 87% vs. 88% for RB and RH, respectively. RH is not an ideal platform for future multi-centre transplant trials in MCL. RB achieved a 2-year PFS of 81% and a 78% MRD negative rate. Premature closure of the study limited the sample size and the precision of PFS estimates and MRD rates. However, RB can achieve a deep remission and could be a platform for future trials in MCL

RB but not R‐HCVAD is a feasible induction regimen prior to auto‐HCT in frontline MCL: results of SWOG Study S1106

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136294/1/bjh14480_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136294/2/bjh14480.pd

REAL-TIME DESCRIPTION OF PARTON-HADRON CONVERSION AND CONFINEMENT DYNAMICS

We propose a new and universal approach to the hadronization problem that incorporates both partonic and hadronic degrees of freedom in their respective domains of relevance, and that describes the conversion between them within a kinetic field theory formulation in real time and full 7-dimensional phase space. We construct a scale-dependent effective theory that reduces to perturbative QCD with its scale and chiral symmetry properties at short space-time distances, but at large distances (r > 1 fm) yields symmetry breaking gluon and quark condensates plus hadronic excitations. The approach is applied to the evolution of fragmenting qq~ and gg jet pairs as the system evolves from the initial 2-jet configuration, via parton showering and cluster formation, to the final yield of hadrons. The phenomenological implications for e+e- -> hadrons are investigated, such as the time scale of the transition, and its energy dependence, cluster size and mass distributions. We compare our results for particle production and Bose-Einstein correlations with experimental data, and find an interesting possibility of extracting the basic parameters of the space-time evolution of the system from Bose enhancement measurements.Comment: 51 pages, latex, 14 figures as uu-encoded postscript file

Local Function Conservation in Sequence and Structure Space

We assess the variability of protein function in protein sequence and structure space. Various regions in this space exhibit considerable difference in the local conservation of molecular function. We analyze and capture local function conservation by means of logistic curves. Based on this analysis, we propose a method for predicting molecular function of a query protein with known structure but unknown function. The prediction method is rigorously assessed and compared with a previously published function predictor. Furthermore, we apply the method to 500 functionally unannotated PDB structures and discuss selected examples. The proposed approach provides a simple yet consistent statistical model for the complex relations between protein sequence, structure, and function. The GOdot method is available online (http://godot.bioinf.mpi-inf.mpg.de)

A Collaborative Filtering Approach for Protein-Protein Docking Scoring Functions

A protein-protein docking procedure traditionally consists in two successive tasks: a search algorithm generates a large number of candidate conformations mimicking the complex existing in vivo between two proteins, and a scoring function is used to rank them in order to extract a native-like one. We have already shown that using Voronoi constructions and a well chosen set of parameters, an accurate scoring function could be designed and optimized. However to be able to perform large-scale in silico exploration of the interactome, a near-native solution has to be found in the ten best-ranked solutions. This cannot yet be guaranteed by any of the existing scoring functions

Systems biological and mechanistic modelling of radiation-induced cancer

This paper summarises the five presentations at the First International Workshop on Systems Radiation Biology that were concerned with mechanistic models for carcinogenesis. The mathematical description of various hypotheses about the carcinogenic process, and its comparison with available data is an example of systems biology. It promises better understanding of effects at the whole body level based on properties of cells and signalling mechanisms between them. Of these five presentations, three dealt with multistage carcinogenesis within the framework of stochastic multistage clonal expansion models, another presented a deterministic multistage model incorporating chromosomal aberrations and neoplastic transformation, and the last presented a model of DNA double-strand break repair pathways for second breast cancers following radiation therapy

STAT1-dependent expression of energy metabolic pathways links tumour growth and radioresistance to the Warburg effect

<p>Abstract</p> <p>Background</p> <p>The Signal Transducer and Activator of Transcription 1 (STAT1) has traditionally been regarded as a transmitter of interferon signaling and a pro-apoptotic tumour suppressor. Recent data have identified new functions of STAT1 associated with tumourigenesis and resistance to genotoxic stress, including ionizing radiation (IR) and chemotherapy. To investigate the mechanisms contributing to the tumourigenic functions of STAT1, we performed a combined transcriptomic-proteomic expressional analysis and found that STAT1 is associated with regulation of energy metabolism with potential implication in the Warburg effect.</p> <p>Methods</p> <p>We generated a stable knockdown of STAT1 in the SCC61 human squamous cell carcinoma cell line, established tumour xenografts in athymic mice, and compared transcriptomic and proteomic profiles of STAT1 wild-type (WT) and knockdown (KD) untreated or irradiated (IR) tumours. Transcriptional profiling was based on Affymetrix Human GeneChip^®Gene 1.0 ST microarrays. Proteomes were determined from the tandem mass spectrometry (MS/MS) data by searching against the human subset of the UniProt database. Data were analysed using Significance Analysis of Microarrays for ribonucleic acid and Visualize software for proteins. Functional analysis was performed with Ingenuity Pathway Analysis with statistical significance measured by Fisher's exact test.</p> <p>Results</p> <p>Knockdown of STAT1 led to significant growth suppression in untreated tumours and radio sensitization of irradiated tumours. These changes were accompanied by alterations in the expression of genes and proteins of glycolysis/gluconeogenesis (GG), the citrate cycle (CC) and oxidative phosphorylation (OP). Of these pathways, GG had the most concordant changes in gene and protein expression and demonstrated a STAT1-dependent expression of genes and proteins consistent with tumour-specific glycolysis. In addition, IR drastically suppressed the GG pathway in STAT1 KD tumours without significant change in STAT1 WT tumours.</p> <p>Conclusion</p> <p>Our results identify a previously uncharacterized function of STAT1 in tumours: expressional regulation of genes encoding proteins involved in glycolysis, the citrate cycle and mitochondrial oxidative phosphorylation, with predominant regulation of glycolytic genes. STAT1-dependent expressional regulation of glycolysis suggests a potential role for STAT1 as a transcriptional modulator of genes responsible for the Warburg effect.</p

The Role of DNA Double-Strand Breaks in Spontaneous Homologous Recombination in S. cerevisiae

Homologous recombination (HR) is a source of genomic instability and the loss of heterozygosity in mitotic cells. Since these events pose a severe health risk, it is important to understand the molecular events that cause spontaneous HR. In eukaryotes, high levels of HR are a normal feature of meiosis and result from the induction of a large number of DNA double-strand breaks (DSBs). By analogy, it is generally believed that the rare spontaneous mitotic HR events are due to repair of DNA DSBs that accidentally occur during mitotic growth. Here we provide the first direct evidence that most spontaneous mitotic HR in Saccharomyces cerevisiae is initiated by DNA lesions other than DSBs. Specifically, we describe a class of rad52 mutants that are fully proficient in inter- and intra-chromosomal mitotic HR, yet at the same time fail to repair DNA DSBs. The conclusions are drawn from genetic analyses, evaluation of the consequences of DSB repair failure at the DNA level, and examination of the cellular re-localization of Rad51 and mutant Rad52 proteins after introduction of specific DSBs. In further support of our conclusions, we show that, as in wild-type strains, UV-irradiation induces HR in these rad52 mutants, supporting the view that DNA nicks and single-stranded gaps, rather than DSBs, are major sources of spontaneous HR in mitotic yeast cells