The Blackholic energy and the canonical Gamma-Ray Burst

We outline the main results of our GRB model, based on the three interpretation paradigms we proposed in July 2001, comparing and contrasting them with the ones in the current literature. Thanks to the observations by Swift and by VLT, this analysis points to a "canonical GRB" originating from markedly different astrophysical scenarios. The communality is that they are all emitted in the formation of a black hole with small or null angular momentum. The following sequence appears to be canonical: the vacuum polarization process creating an optically thick self accelerating electron-positron plasma; the engulfment of baryonic mass during the plasma expansion; the adiabatic expansion of the optically thick "fireshell" up to the transparency; the interaction of the remaining accelerated baryons with the interstellar medium (ISM). This leads to the canonical GRB composed of a proper GRB (P-GRB), emitted at the moment of transparency, followed by an extended afterglow. The parameters are the plasma total energy, the fireshell baryon loading and the ISM filamentary distribution around the source. In the limit of no baryon loading the total energy is radiated in the P-GRB. In this limit, the canonical GRBs explain as well the short GRBs.Comment: 163 pages, 89 figures, to appear on the "Proceedings of the XIIth Brazilian School of Cosmology and Gravitation", M. Novello, S.E. Perez-Bergliaffa (editors), AIP, in pres

The Blackholic energy: long and short Gamma-Ray Bursts (New perspectives in physics and astrophysics from the theoretical understanding of Gamma-Ray Bursts, II)

[...] We turn then to the theoretical developments in the short GRBs: we first report some progress in the understanding the dynamical phase of collapse, the mass-energy formula and the extraction of blackholic energy which have been motivated by the analysis of the short GRBs. In this context progress has also been accomplished on establishing an absolute lower limit to the irreducible mass of the black hole as well as on some critical considerations about the relations of general relativity and the second law of thermodynamics. We recall how this last issue has been one of the most debated in theoretical physics in the past thirty years due to the work of Bekenstein and Hawking. Following these conceptual progresses we analyze the vacuum polarization process around an overcritical collapsing shell. We evidence the existence of a separatrix and a dyadosphere trapping surface in the dynamics of the electron-positron plasma generated during the process of gravitational collapse. We then analyze, using recent progress in the solution of the Vlasov-Boltzmann-Maxwell system, the oscillation regime in the created electron-positron plasma and their rapid convergence to a thermalized spectrum. We conclude by making precise predictions for the spectra, the energy fluxes and characteristic time-scales of the radiation for short-bursts. If the precise luminosity variation and spectral hardening of the radiation we have predicted will be confirmed by observations of short-bursts, these systems will play a major role as standard candles in cosmology. These considerations will also be relevant for the analysis of the long-bursts when the baryonic matter contribution will be taken into account.Comment: 86 pages, 50 figures, to appear on the "Proceedings of the XIth Brazilian School of Cosmology and Gravitation", AIP, in pres

Extracting energy from black holes: "long" and "short" GRBs and their astrophysical settings

The introduction of the three interpretational paradigms for Gamma-Ray Bursts (GRBs) and recent progress in understanding the X- and gamma ray luminosity in the afterglow allow us to make assessments about the astrophysical settings of GRBs. In particular, we evidence the distinct possibility that some GRBs occur in a binary system. This subclass of GRBs manifests itself in a "tryptich": one component formed by the collapse of a massive star to a black hole, which originates the GRB; a second component by a supernova and a third one by a young neutron star born in the supernova event. Similarly, the understanding of the physics of quantum relativistic processes during the gravitational collapse makes possible precise predictions about the structure of short GRBs.Comment: 8 pages, 2 figures, to appear in the Proceedings of "Gamma-Ray Burst in the Afterglow Era: 4th Workshop", held in Rome, October 18-22, 2004, L. Piro, L. Amati, S. Covino, B. Gendre (eds.), Il Nuovo Cimento C, in pres

HDAC class I inhibitor domatinostat sensitizes pancreatic cancer to chemotherapy by targeting cancer stem cell compartment via FOXM1 modulation

Pancreatic ductal adenocarcinoma (PDAC) represents an unmet clinical need due to the very poor prognosis and the lack of effective therapy. Here we investigated the potential of domatinostat (4SC-202), a new class I histone deacetylase (HDAC) inhibitor, currently in clinical development, to sensitize PDAC to first line standard gemcitabine (G)/taxol (T) doublet chemotherapy treatment. Methods: Synergistic anti-tumor effect of the combined treatment was assessed in PANC1, ASPC1 and PANC28 PDAC cell lines in vitro as well as on tumor spheroids and microtissues, by evaluating combination index (CI), apoptosis, clonogenic capability. The data were confirmed in vivo xenograft models of PANC28 and PANC1 cells in athymic mice. Cancer stem cells (CSC) targeting was studied by mRNA and protein expression of CSC markers, by limiting dilution assay, and by flow cytometric and immunofluorescent evaluation of CSC mitochondrial and cellular oxidative stress. Mechanistic role of forkhead box M1 (FOXM1) and downstream targets was evaluated in FOXM1-overexpressing PDAC cells. Results: We showed that domatinostat sensitized in vitro and in vivo models of PDAC to chemotherapeutics commonly used in PDAC patients management and particularly to GT doublet, by targeting CSC compartment through the induction of mitochondrial and cellular oxidative stress. Mechanistically, we showed that domatinostat hampers the expression and function of FOXM1, a transcription factor playing a crucial role in stemness, oxidative stress modulation and DNA repair. Domatinostat reduced FOXM1 protein levels by downregulating mRNA expression and inducing proteasome-mediated protein degradation thus preventing nuclear translocation correlated with a reduction of FOXM1 target genes. Furthermore, by overexpressing FOXM1 in PDAC cells we significantly reduced domatinostatinducing oxidative mitochondrial and cellular stress and abolished GT sensitization, both in adherent and spheroid cells, confirming FOXM1 crucial role in the mechanisms described. Finally, we found a correlation of FOXM1 expression with poor progression free survival in PDAC chemotherapy-treated patients

Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of Resistance

Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is a devastating malignancy with a poor prognosis. The combination of cisplatin (CDDP) plus cetuximab (CX) is one of the standard first-line treatments in this disease. However, this therapeutic regimen is often associated with high toxicity and resistance, suggesting that new combinatorial strategies are needed to improve its therapeutic index. In our study, we evaluated the antitumor effects of valproic acid (VPA), a well-known antiepileptic agent with histone deacetylase inhibitory activity, in combination with CDDP/CX doublet in head and neck squamous cell carcinoma (HNSCC) models. We demonstrated, in HNSCC cell lines, but not in normal human fibroblasts, that simultaneous exposure to equitoxic doses of VPA plus CDDP/CX resulted in a clear synergistic antiproliferative and pro-apoptotic effects. The synergistic antitumor effect was confirmed in four different 3D-self-assembled spheroid models, suggesting the ability of the combined approach to affect also the cancer stem cells compartment. Mechanistically, VPA enhanced DNA damage in combination treatment by reducing the mRNA expression of ERCC Excision Repair 1, a critical player in DNA repair, and by increasing CDDP intracellular concentration via upregulation at transcriptional level of CDDP influx channel copper transporter 1 and downregulation of the ATPAse ATP7B involved in CDDP-export. Valproic acid also induced a dose-dependent downregulation of epidermal growth factor receptor (EGFR) expression and of MAPK and AKT downstream signaling pathways and prevent CDDP- and/or CX-induced EGFR nuclear translocation, a well-known mechanism of resistance to chemotherapy. Indeed, VPA impaired the transcription of genes induced by non-canonical activity of nuclear EGFR, such as cyclin D1 and thymidylate synthase. Finally, we confirmed the synergistic antitumor effect also in vivo in both heterotopic and orthotopic models, demonstrating that the combined treatment completely blocked HNSCC xenograft tumors growth in nude mice. Overall, the introduction of a safe and generic drug such as VPA into the conventional treatment for R/M HNSCC represents an innovative and feasible antitumor strategy that warrants further clinical evaluation. A phase II clinical trial exploring the combination of VPA and CDDP/CX in R/M HNSCC patients is currently ongoing in our institute

Endometrial scratch injury before intrauterine insemination: is it time to re-evaluate its value? Evidence from a systematic review and meta-analysis of randomized controlled trials

OBJECTIVE: To assess the impact of endometrial scratch injury (ESI) on the outcomes of intrauterine insemination (IUI) stimulated cycles. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Infertile women undergoing one or more IUI stimulated cycles. INTERVENTION(S): Randomized controlled trials (RCTs) were identified by searching electronic databases. We included RCTs comparing ESI (i.e., intervention group) during the course of IUI stimulated cycle (C-ESI) or during the menstrual cycle preceding IUI treatment (P-ESI) with controls (no endometrial scratch). The summary measures were reported as odds ratio (OR) with 95% confidence-interval (CI). MAIN OUTCOME MEASURE(S): Clinical pregnancy rate, ongoing pregnancy rate, multiple pregnancy rate, ectopic pregnancy rate, miscarriage rate. RESULT(S): Eight trials were included in the meta-analysis, comprising a total of 1,871 IUI cycles. Endometrial scratch injury was associated with a higher clinical pregnancy rate (OR 2.27) and ongoing pregnancy rate (OR 2.04) in comparison with the controls. No higher risk of multiple pregnancy (OR 1.09), miscarriage (OR 0.80), or ectopic pregnancy (OR 0.82) was observed in patients receiving ESI. Subgroup analysis based on ESI timing showed higher clinical pregnancy rate (OR 2.57) and ongoing pregnancy rate (OR 2.27) in patients receiving C-ESI and no advantage in patients receiving P-ESI. CONCLUSION(S): Available data suggest that ESI performed once, preferably during the follicular phase of the same cycle of IUI with flexible aspiration catheters, may improve clinical pregnancy and ongoing pregnancy rates in IUI cycles. Endometrial scratch injury does not appear to increase the risk of multiple pregnancy, miscarriage, or ectopic pregnancy

Bladder endometriosis: A summary of current evidence

Bladder endometriosis is a specific form of endometriosis characterized by the presence of endometrial glands and stroma in the detrusor muscle. Such disease may involve different sites of the bladder, most frequently the base and the dome, with various grade of infiltration. Bladder nodules typically coexists with other localizations of deep pelvic endometriosis, resulting in a wide variety of abdominal and urinary symptoms that may be overlooked by clinicians. In spite of advances in understanding the genetic and molecular development of endometriosis, the clinical approach to bladder lesions is very challenging and may require the use of different diagnostic tools in order to set up a comprehensive diagnostic workup and direct towards the most appropriate treatment. The aim of this paper was to portray the state of art of diagnosis and management of bladder endometriosis, starting from the current evidence about epidemiology, pathophysiology, clinical signs and providing all the available strategies for medical and surgical treatmen

Structure, dynamics, and stability of assemblies of the human prion fragment SNQNNF

Misfolding of the prion protein (PrP) is associated with the development of Transmissible Spongiform Encephalopathies. The recent crystal structure of 'steric zipper' aggregates of the peptide SNQNNF (human PrP fragment 170-175) has highlighted its potential involvement in the misfolding process. A detailed molecular dynamics investigation on SNQNNF aggregates has been performed to analyze the behavior of the assemblies in a non-crystalline context. Stability, dynamics, and structural features suggest that SNQNNF assemblies are very good candidates to be involved in the structure of PrP fibrils. In addition, the analysis of small aggregates shows that steric zipper interfaces are able to stabilize assemblies composed of four strands per sheet. Altogether, the present findings indicate that steric zipper may play a key role in prion diseases. This suggestion is also corroborated by MD analyses of point mutations within the region 170-175