Analysis of charged particle emission sources and coalescence in E/A = 61 MeV 36^{36}Ar + 27^{27}Al, 112^{112}Sn and 124^{124}Sn collisions

Single-particle kinetic energy spectra and two-particle small angle correlations of protons ($p$), deuterons ($d$) and tritons ($t$) have been measured simultaneously in 61A MeV $^{36}$Ar + $^{27}$Al, $^{112}$Sn and $^{124}$Sn collisions. Characteristics of the emission sources have been derived from a ``source identification plot'' ($\beta_{source}$--$E_{CM}$ plot), constructed from the single-particle invariant spectra, and compared to the complementary results from two-particle correlation functions. Furthermore, the source identification plot has been used to determine the conditions when the coalescence mechanism can be applied for composite particles. In our data, this is the case only for the Ar + Al reaction, where $p$, $d$ and $t$ are found to originate from a common source of emission (from the overlap region between target and projectile). In this case, the coalescence model parameter, $\tilde{p}_0$ -- the radius of the complex particle emission source in momentum space, has been analyzed.Comment: 20 pages, 5 figures, submitted to Nuclear Physics

Quantum corrections for pion correlations involving resonance decays

A method is presented to include quantum corrections into the calculation of two-pion correlations for the case where particles originate from resonance decays. The technique uses classical information regarding the space-time points at which resonances are created. By evaluating a simple thermal model, the method is compared to semiclassical techniques that assume exponential decaying resonances moving along classical trajectories. Significant improvements are noted when the resonance widths are broad as compared to the temperature.Comment: 9 pages, 4 figure

po 237 the pro oncogenic transcription factor stat3 regulates ca2 release and apoptosis from the endoplasmic reticulum via interaction with the ca2 channel ip3r3

Introduction Signal Transducer and Activator of Transcription (STAT) 3 is an oncogenic transcription factor found constitutively activated in several tumours, where it exerts its functions both as a canonical transcription factor and as a non-canonical regulator of energy metabolism and mitochondrial functions. These two activities rely on different post-translational activating events; the phosphorylation on Y705 is involved in nuclear activities, while that on S727 is relevant for mitochondrial functions. Mitochondrial STAT3 increases aerobic glycolysis and decreases ROS production, partly by interacting with the Electron Transfer Complexes (ETC). Material and methods By means of cell fractionations, we tested STAT3 localization to the Endoplasmic Reticulum (ER) in breast cancer cell lines dependent or not on STAT3 activity. We then measured Ca2+ release and apoptotic response in the same cells. The physical interaction between inositol 1,4,5-trisphosphate receptor type 3 (IP3R3) and STAT3 was demonstrated by co-IP either of the endogenous proteins or of their truncated/mutated forms, while STAT3 role in the degradation of IP3R3 was tested by serum starvation and refeeding experiments, followed by WB. Results and discussions We describe here the previously undetected abundant localization of STAT3 also to the ER. In this cellular compartment IP3R3, a Ca2+ channel that allows Ca2+ release from the ER and the mitochondrial associated membranes (MAMs) in response to IP3, regulates the balance between mitochondrial activation and Ca2+-triggered apoptosis. We observed that STAT3 within the ER physically interacts with IP3R3 and, via its phosphorylation on S727, it down-regulates Ca2+ release and apoptosis. Indeed, STAT3 silencing enhances both ER Ca2+ release and sensitivity to apoptosis following oxidative stress in STAT3-dependent mammary tumour cells, correlating with increased IP3R3 levels. In line with this, basal-like breast tumours, which frequently display constitutively active STAT3, show an inverse correlation between IP3R3 and STAT3 protein levels. Conclusion Our results indicate that S727-phosphorylated STAT3 contribute to mammary tumour aggressiveness, also by localising to the ER and regulating Ca2+ fluxes. STAT3-mediated enhanced IP3R3 degradation leads to decreased Ca2+ release and thus to resistance to apoptosis. This new non-canonical STAT3 role appears to be particularly relevant in basal-like breast cancers, adding a new mechanisms through which STAT3 exerts its well established pro-oncogenic anti-apoptotic role

Multi-imaging investigation to evaluate the relationship between serum cystatin c and features of atherosclerosis in Non-ST-Segment elevation acute coronary syndrome

Objectives: High cystatin C(CysC) levels are associated with impaired cardiovascular outcome. Whether CysC levels are independently related to the atherosclerosis burden is still controversial. Methods: We enrolled 31 non-ST-segment elevation acute coronary syndrome patients undergoing percutaneous coronary intervention. Patients were divided into 2 groups on the basis of median value of serum CysC. Using the high CysC group as a dependent variable, univariable and multivariable analyses were used to evaluate the association between CysC and three different features of atherosclerosis: 1) coronary plaque vulnerability as assessed by optical coherence tomography (OCT), 2) coronary artery calcium (CAC) by means of computed tomography scan, and 3) aortic wall metabolic activity, as assessed using 18 F-Fluorodeoxyglucose-positron emission tomography ( 18 F-FDG-PET). Results: After univariable and multivariable analyses, 18 F-FDG uptake in the descending aorta (DA) was independently associated with a low level of CysC [(Odds Ratio = 0.02; 95%CI 0.0004-0.89; p = 0.044; 18 F-FDG uptake measured as averaged maximum target to blood ratio); (Odds Ratio = 0.89; 95%CI 0.82-0.98, p = 0.025; 18 F-FDG uptake measured as number of active slices)]. No trend was found for the association between CysC and characteristics of OCT-assessed coronary plaque vulnerability or CAC score. Conclusions: In patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS), 18 F-FDG uptake in the DA was associated with a low level of serum CysC. There was no relation between CysC levels and OCT-assessed coronary plaque vulnerability or CAC score. These findings suggest that high levels of CysC may not be considered as independent markers of atherosclerosis

Prion protein amyloidosis with divergent phenotype associated with two novel nonsense mutations in PRNP

Stop codon mutations in the gene encoding the prion protein (PRNP) are very rare and have thus far only been described in two patients with prion protein cerebral amyloid angiopathy (PrP-CAA). In this report, we describe the clinical, histopathological and pathological prion protein (PrPSc) characteristics of two Dutch patients carrying novel adjacent stop codon mutations in the C-terminal part of PRNP, resulting in either case in hereditary prion protein amyloidoses, but with strikingly different clinicopathological phenotypes. The patient with the shortest disease duration (27 months) carried a Y226X mutation and showed PrP-CAA without any neurofibrillary lesions, whereas the patient with the longest disease duration (72 months) had a Q227X mutation and showed an unusual Gerstmann-Sträussler-Scheinker disease phenotype with numerous cerebral multicentric amyloid plaques and severe neurofibrillary lesions without PrP-CAA. Western blot analysis in the patient with the Q227X mutation demonstrated the presence of a 7 kDa unglycosylated PrPSc fragment truncated at both the N- and C-terminal ends. Our observations expand the spectrum of clinicopathological phenotypes associated with PRNP mutations and show that a single tyrosine residue difference in the PrP C-terminus may significantly affect the site of amyloid deposition and the overall phenotypic expression of the prion disease. Furthermore, it confirms that the absence of the glycosylphosphatidylinositol anchor in PrP predisposes to amyloid plaque formation

Muon `Depth -- Intensity' Relation Measured by LVD Underground Experiment and Cosmic-Ray Muon Spectrum at Sea Level

We present the analysis of the muon events with all muon multiplicities collected during 21804 hours of operation of the first LVD tower. The measured angular distribution of muon intensity has been converted to the `depth -- vertical intensity' relation in the depth range from 3 to 12 km w.e.. The analysis of this relation allowed to derive the power index, $\gamma$, of the primary all-nucleon spectrum: $\gamma=2.78 \pm 0.05$. The `depth -- vertical intensity' relation has been converted to standard rock and the comparison with the data of other experiments has been done. We present also the derived vertical muon spectrum at sea level.Comment: 7 pages, 3 figures, to be published on Phys. Rev.

Upper Limit on the Prompt Muon Flux Derived from the LVD Underground Experiment

We present the analysis of the muon events with all muon multiplicities collected during 21804 hours of operation of the first LVD tower. The measured depth-angular distribution of muon intensities has been used to obtain the normalization factor, A, the power index, gamma, of the primary all-nucleon spectrum and the ratio, R_c, of prompt muon flux to that of pi-mesons - the main parameters which determine the spectrum of cosmic ray muons at the sea level. The value of gamma = 2.77 +/- 0.05 (68% C.L.) and R_c < 2.0 x 10^-3 (95% C.L.) have been obtained. The upper limit to the prompt muon flux favours the models of charm production based on QGSM and the dual parton model.Comment: 10 pages, 4 figures, RevTex. To appear in Phys. Rev.

Synergism through WEE1 and CHK1 inhibition in acute lymphoblastic leukemia

Introduction: Screening for synthetic lethality markers has demonstrated that the inhibition of the cell cycle checkpoint kinases WEE1 together with CHK1 drastically affects stability of the cell cycle and induces cell death in rapidly proliferating cells. Exploiting this finding for a possible therapeutic approach has showed efficacy in various solid and hematologic tumors, though not specifically tested in acute lymphoblastic leukemia. Methods: The efficacy of the combination between WEE1 and CHK1 inhibitors in B and T cell precursor acute lymphoblastic leukemia (B/T-ALL) was evaluated in vitro and ex vivo studies. The efficacy of the therapeutic strategy was tested in terms of cytotoxicity, induction of apoptosis, and changes in cell cycle profile and protein expression using B/T-ALL cell lines. In addition, the efficacy of the drug combination was studied in primary B-ALL blasts using clonogenic assays. Results: This study reports, for the first time, the efficacy of the concomitant inhibition of CHK1/CHK2 and WEE1 in ALL cell lines and primary leukemic B-ALL cells using two selective inhibitors: PF-0047736 (CHK1/CHK2 inhibitor) and AZD-1775 (WEE1 inhibitor). We showed strong synergism in the reduction of cell viability, proliferation and induction of apoptosis. The efficacy of the combination was related to the induction of early S-phase arrest and to the induction of DNA damage, ultimately triggering cell death. We reported evidence that the efficacy of the combination treatment is independent from the activation of the p53-p21 pathway. Moreover, gene expression analysis on B-ALL primary samples showed that Chek1 and Wee1 are significantly co-expressed in samples at diagnosis (Pearson r = 0.5770, p = 0.0001) and relapse (Pearson r= 0.8919; p = 0.0001). Finally, the efficacy of the combination was confirmed by the reduction in clonogenic survival of primary leukemic B-ALL cells. Conclusion: Our findings suggest that the combination of CHK1 and WEE1 inhibitors may be a promising therapeutic strategy to be tested in clinical trials for adult ALL

Novel and rare fusion transcripts involving transcription factors and tumor suppressor genes in acute myeloid leukemia

Approximately 18% of acute myeloid leukemia (AML) cases express a fusion transcript. However, few fusions are recurrent across AML and the identification of these rare chimeras is of interest to characterize AML patients. Here, we studied the transcriptome of 8 adult AML patients with poorly described chromosomal translocation(s), with the aim of identifying novel and rare fusion transcripts. We integrated RNA-sequencing data with multiple approaches including computational analysis, Sanger sequencing, fluorescence in situ hybridization and in vitro studies to assess the oncogenic potential of the ZEB2-BCL11B chimera. We detected 7 different fusions with partner genes involving transcription factors (OAZ-MAFK, ZEB2-BCL11B), tumor suppressors (SAV1-GYPB, PUF60-TYW1, CNOT2-WT1) and rearrangements associated with the loss of NF1 (CPD-PXT1, UTP6-CRLF3). Notably, ZEB2-BCL11B rearrangements co-occurred with FLT3 mutations and were associated with a poorly differentiated or mixed phenotype leukemia. Although the fusion alone did not transform murine c-Kit+ bone marrow cells, 45.4% of 14q32 non-rearranged AML cases were also BCL11B-positive, suggesting a more general and complex mechanism of leukemogenesis associated with BCL11B expression. Overall, by combining different approaches, we described rare fusion events contributing to the complexity of AML and we linked the expression of some chimeras to genomic alterations hitting known genes in AML

Mapping interactions with the chaperone network reveals factors that protect against tau aggregation.

A network of molecular chaperones is known to bind proteins ('clients') and balance their folding, function and turnover. However, it is often unclear which chaperones are critical for selective recognition of individual clients. It is also not clear why these key chaperones might fail in protein-aggregation diseases. Here, we utilized human microtubule-associated protein tau (MAPT or tau) as a model client to survey interactions between ~30 purified chaperones and ~20 disease-associated tau variants (~600 combinations). From this large-scale analysis, we identified human DnaJA2 as an unexpected, but potent, inhibitor of tau aggregation. DnaJA2 levels were correlated with tau pathology in human brains, supporting the idea that it is an important regulator of tau homeostasis. Of note, we found that some disease-associated tau variants were relatively immune to interactions with chaperones, suggesting a model in which avoiding physical recognition by chaperone networks may contribute to disease