128 research outputs found
D3-D7 Quark-Gluon Plasmas at Finite Baryon Density
We present the string dual to SU(Nc) N=4 SYM, coupled to Nf massless
fundamental flavors, at finite temperature and baryon density. The solution is
determined by two dimensionless parameters, both depending on the 't Hooft
coupling at the scale set by the temperature T:
, weighting the backreaction of the flavor
fields and , where is the
baryon density. For small values of these two parameters the solution is given
analytically up to second order. We study the thermodynamics of the system in
the canonical and grand-canonical ensembles. We then analyze the energy loss of
partons moving through the plasma, computing the jet quenching parameter and
studying its dependence on the baryon density. Finally, we analyze certain
"optical" properties of the plasma. The whole setup is generalized to non
abelian strongly coupled plasmas engineered on D3-D7 systems with D3-branes
placed at the tip of a generic singular Calabi-Yau cone. In all the cases,
fundamental matter fields are introduced by means of homogeneously smeared
D7-branes and the flavor symmetry group is thus a product of abelian factors.Comment: 27 pages; v2: 29 pages, 1 (new) figure, new section 4.4 on optical
properties, references, comments added; v3: eq. (3.19), comments and a
reference adde
Chemotherapy Synergizes with Radioimmunotherapy Targeting La Autoantigen in Tumors
To date, inefficient delivery of therapeutic doses of radionuclides to solid tumors limits the clinical utility of radioimmunotherapy. We aim to test the therapeutic utility of Yttrium-90 (90Y)-radio-conjugates of a monoclonal antibody, which we showed previously to bind specifically to the abundant intracellular La ribonucleoprotein revealed in dead tumor cells after DNA-damaging treatment. Methodology/Principal Findings: Immunoconjugates of the DAB4 clone of the La-specific monoclonal antibody, APOMAB®, were prepared using the metal chelator, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and then radiolabeled with 90Y. Mice bearing established subcutaneous tumors were treated with 90Y-DOTA-DAB4 alone or after chemotherapy. Non-radiosensitizing cyclophosphamide/etoposide chemotherapy was used for the syngeneic EL4 lymphoma model. Radiosensitizing cisplatin/gemcitabine chemotherapy was used for the syngeneic Lewis Lung carcinoma (LL2) model, and for the xenograft models of LNCaP prostatic carcinoma and Panc-1 pancreatic carcinoma. We demonstrate the safety, specificity, and efficacy of 90Y-DOTA-DAB4-radioimmunotherapy alone or combined with chemotherapy. EL4 lymphoma-bearing mice either were cured at higher doses of radioimmunotherapy alone or lower doses of radioimmunotherapy in synergy with chemotherapy. Radioimmunotherapy alone was less effective in chemo- and radio-resistant carcinoma models. However, radioimmunotherapy synergized with radiosensitizing chemotherapy to retard significantly tumor regrowth and so prolong the survival of mice bearing LL2, LNCaP, or Panc-1 subcutaneous tumor implants. Conclusions/Significance: We report proof-of-concept data supporting a unique form of radioimmunotherapy, which delivers bystander killing to viable cancer cells after targeting the universal cancer antigen, La, created by DNA-damaging treatment in neighboring dead cancer cells. Subsequently we propose that DAB4-targeted ionizing radiation induces additional cycles of tumor cell death, which further augments DAB4 binding to produce a tumor-lethal ‘genotoxic chain reaction’. Clinically, this approach may be useful as consolidation treatment after a drug-induced cell death among (small-volume) metastatic deposits, the commonest cause of cancer death. This article is part II of a two-part series providing proof-of-concept for the diagnostic and therapeutic use of the DAB4 clone of the La-specific monoclonal antibody, APOMAB®.Fares Al-Ejeh, Jocelyn M. Darby and Michael P. Brow
Progressive GAA·TTC Repeat Expansion in Human Cell Lines
Trinucleotide repeat expansion is the genetic basis for a sizeable group of inherited neurological and neuromuscular disorders. Friedreich ataxia (FRDA) is a relentlessly progressive neurodegenerative disorder caused by GAA·TTC repeat expansion in the first intron of the FXN gene. The expanded repeat reduces FXN mRNA expression and the length of the repeat tract is proportional to disease severity. Somatic expansion of the GAA·TTC repeat sequence in disease-relevant tissues is thought to contribute to the progression of disease severity during patient aging. Previous models of GAA·TTC instability have not been able to produce substantial levels of expansion within an experimentally useful time frame, which has limited our understanding of the molecular basis for this expansion. Here, we present a novel model for studying GAA·TTC expansion in human cells. In our model system, uninterrupted GAA·TTC repeat sequences display high levels of genomic instability, with an overall tendency towards progressive expansion. Using this model, we characterize the relationship between repeat length and expansion. We identify the interval between 88 and 176 repeats as being an important length threshold where expansion rates dramatically increase. We show that expansion levels are affected by both the purity and orientation of the repeat tract within the genomic context. We further demonstrate that GAA·TTC expansion in our model is independent of cell division. Using unique reporter constructs, we identify transcription through the repeat tract as a major contributor to GAA·TTC expansion. Our findings provide novel insight into the mechanisms responsible for GAA·TTC expansion in human cells
Correlation of Inter-Locus Polyglutamine Toxicity with CAG•CTG Triplet Repeat Expandability and Flanking Genomic DNA GC Content
Dynamic expansions of toxic polyglutamine (polyQ)-encoding CAG repeats in ubiquitously expressed, but otherwise unrelated, genes cause a number of late-onset progressive neurodegenerative disorders, including Huntington disease and the spinocerebellar ataxias. As polyQ toxicity in these disorders increases with repeat length, the intergenerational expansion of unstable CAG repeats leads to anticipation, an earlier age-at-onset in successive generations. Crucially, disease associated alleles are also somatically unstable and continue to expand throughout the lifetime of the individual. Interestingly, the inherited polyQ length mediating a specific age-at-onset of symptoms varies markedly between disorders. It is widely assumed that these inter-locus differences in polyQ toxicity are mediated by protein context effects. Previously, we demonstrated that the tendency of expanded CAG•CTG repeats to undergo further intergenerational expansion (their ‘expandability’) also differs between disorders and these effects are strongly correlated with the GC content of the genomic flanking DNA. Here we show that the inter-locus toxicity of the expanded polyQ tracts of these disorders also correlates with both the expandability of the underlying CAG repeat and the GC content of the genomic DNA flanking sequences. Inter-locus polyQ toxicity does not correlate with properties of the mRNA or protein sequences, with polyQ location within the gene or protein, or steady state transcript levels in the brain. These data suggest that the observed inter-locus differences in polyQ toxicity are not mediated solely by protein context effects, but that genomic context is also important, an effect that may be mediated by modifying the rate at which somatic expansion of the DNA delivers proteins to their cytotoxic state
DNA Dynamics Is Likely to Be a Factor in the Genomic Nucleotide Repeats Expansions Related to Diseases
Trinucleotide repeats sequences (TRS) represent a common type of genomic DNA
motif whose expansion is associated with a large number of human diseases. The
driving molecular mechanisms of the TRS ongoing dynamic expansion across
generations and within tissues and its influence on genomic DNA functions are
not well understood. Here we report results for a novel and notable collective
breathing behavior of genomic DNA of tandem TRS, leading to propensity for large
local DNA transient openings at physiological temperature. Our Langevin
molecular dynamics (LMD) and Markov Chain Monte Carlo (MCMC) simulations
demonstrate that the patterns of openings of various TRSs depend specifically on
their length. The collective propensity for DNA strand separation of repeated
sequences serves as a precursor for outsized intermediate bubble states
independently of the G/C-content. We report that repeats have the potential to
interfere with the binding of transcription factors to their consensus sequence
by altered DNA breathing dynamics in proximity of the binding sites. These
observations might influence ongoing attempts to use LMD and MCMC simulations
for TRS–related modeling of genomic DNA functionality in elucidating the
common denominators of the dynamic TRS expansion mutation with potential
therapeutic applications
The molecular and cellular origin of human prostate cancer
Prostate cancer is the most commonly diagnosed male malignancy. Despite compelling epidemiology, there are no definitive aetiological clues linking development to frequency. Pre-malignancies such as proliferative inflammatory atrophy (PIA) and prostatic intraepithelial neoplasia (PIN) yield insights into the initiating events of prostate cancer, as they supply a background "field" for further transformation. An inflammatory aetiology, linked to recurrent prostatitis, and heterologous signalling from reactive stroma and infiltrating immune cells may result in cytokine addiction of cancer cells, including a tumour-initiating population also known as cancer stem cells (CSCs). In prostate tumours, the background mutational rate is rarely exceeded, but genetic change via profound sporadic chromosomal rearrangements results in copy number variations and aberrant gene expression. In cancer, dysfunctional differentiation is imposed upon the normal epithelial lineage, with disruption/disappearance of the basement membrane, loss of the contiguous basal cell layer and expansion of the luminal population. An initiating role for androgen receptor (AR) is attractive, due to the luminal phenotype of the tumours, but alternatively a pool of CSCs, which express little or no AR, has also been demonstrated. Indolent and aggressive tumours may also arise from different stem or progenitor cells. Castrate resistant prostate cancer (CRPC) remains the inevitable final stage of disease following treatment. Time-limited effectiveness of second-generation anti-androgens, and the appearance of an AR-neuroendocrine phenotype imply that metastatic disease is reliant upon the plasticity of the CSC population, and indeed CSC gene expression profiles are most closely related to those identified in CRPCs
- …