Models of cuspy triaxial stellar systems. III: The effect of velocity anisotropy on chaoticity

In several previous investigations we presented models of triaxial stellar systems, both cuspy and non cuspy, that were highly stable and harboured large fractions of chaotic orbits. All our models had been obtained through cold collapses of initially spherical $N$--body systems, a method that necessarily results in models with strongly radial velocity distributions. Here we investigate a different method that was reported to yield cuspy triaxial models with virtually no chaos. We show that such result was probably due to the use of an inadequate chaos detection technique and that, in fact, models with significant fractions of chaotic orbits result also from that method. Besides, starting with one of the models from the first paper in this series, we obtained three different models by rendering its velocity distribution much less radially biased (i.e., more isotropic) and by modifying its axial ratios through adiabatic compression. All three models yielded much higher fractions of regular orbits than most of those from our previous work. We conclude that it is possible to obtain stable cuspy triaxial models of stellar systems whose velocity distribution is more isotropic than that of the models obtained from cold collapses. Those models still harbour large fractions of chaotic orbits and, although it is difficult to compare the results from different models, we can tentatively conclude that chaoticity is reduced by velocity isotropy.Comment: 11 pages, 14 figures. Accepted for publication in MNRA

Models of cuspy triaxial stellar systems. II. Regular orbits

In the first paper of this series we used the N--body method to build a dozen cuspy (gamma ~ 1) triaxial models of stellar systems, and we showed that they were highly stable over time intervals of the order of a Hubble time, even though they had very large fractions of chaotic orbits (more than 85 per cent in some cases). The models were grouped in four sets, each one comprising models morphologically resembling E2, E3, E4 and E5 galaxies, respectively. The three models within each set, although different, had the same global properties and were statistically equivalent. In the present paper we use frequency analysis to classify the regular orbits of those models. The bulk of those orbits are short axis tubes (SATs), with a significant fraction of long axis tubes (LATs) in the E2 models that decreases in the E3 and E4 models to become negligibly small in the E5 models. Most of the LATs in the E2 and E3 models are outer LATs, but the situation reverses in the E4 and E5 models where the few LATs are mainly inner LATs. As could be expected for cuspy models, most of the boxes are resonant orbits, i.e., boxlets. Nevertheless, only the (x, y) fishes of models E3 and E4 amount to about 10 per cent of the regular orbits, with most of the fractions of the other boxlets being of the order of 1 per cent or less.Comment: Accepted for publication in the Monthly Notices of the Royal Astronomical Societ

An analysis of the most distant catalogued open clusters -- Re-assessing fundamental parameters with Gaia EDR3 and ASteCA\texttt{ASteCA}

Several studies have been presented in the last few years applying some kind of automatic processing of data to estimate the fundamental parameters of open clusters. These parameters are later on employed in larger scale analyses, for example the structure of the Galaxy's spiral arms. The distance is one of the more straightforward parameters to estimate, yet enormous differences can still be found among published data. This is particularly true for open clusters located more than a few kpc away. We cross-matched several published catalogues and selected the twenty-five most distant open clusters ($>$9000 pc). We then performed a detailed analysis of their fundamental parameters, with emphasis on their distances, to determine the agreement between catalogues and our estimates.} Photometric and astrometric data from the Gaia EDR3 survey was employed. The data was processed with our own membership analysis code (pyUPMASK), and our package for automatic fundamental cluster's parameters estimation ($\texttt{ASteCA}$). We find differences in the estimated distances of up to several kpc between our results and those catalogued, even for the catalogues that show the best matches with $\texttt{ASteCA}$ values. Large differences are also found for the age estimates. As a by-product of the analysis we find that vd Bergh-Hagen 176 could be the open cluster with the largest heliocentric distance catalogued to date. Caution is thus strongly recommended when using catalogued parameters of open clusters to infer large-scale properties of the Galaxy, particularly for those located more than a few kpc away.Comment: Accepted for publication in A&

BRAF Activation Initiates but Does Not Maintain Invasive Prostate Adenocarcinoma

Prostate cancer is the second leading cause of cancer-related deaths in men. Activation of MAP kinase signaling pathway has been implicated in advanced and androgen-independent prostate cancers, although formal genetic proof has been lacking. In the course of modeling malignant melanoma in a tyrosinase promoter transgenic system, we developed a genetically-engineered mouse (GEM) model of invasive prostate cancers, whereby an activating mutation of BRAFV600E–a mutation found in ∼10% of human prostate tumors–was targeted to the epithelial compartment of the prostate gland on the background of Ink4a/Arf deficiency. These GEM mice developed prostate gland hyperplasia with progression to rapidly growing invasive adenocarcinoma without evidence of AKT activation, providing genetic proof that activation of MAP kinase signaling is sufficient to drive prostate tumorigenesis. Importantly, genetic extinction of BRAFV600E in established prostate tumors did not lead to tumor regression, indicating that while sufficient to initiate development of invasive prostate adenocarcinoma, BRAFV600E is not required for its maintenance

Comparative effect of ALA derivatives on protoporphyrin IX production in human and rat skin organ cultures

Samples of human and rat skin in short-term organ culture exposed to ALA or a range of hydrophobic derivatives were examined for their effect on the accumulation of protoporphyrin IX (PpIX) measured using fluorescence spectroscopy. With the exception of carbobenzoyloxy-D-phenylalanyl-5-ALA-ethyl ester the data presented indicate that, in normal tissues, ALA derivatives generate protoporphyrin IX more slowly than ALA, suggesting that they are less rapidly taken up and/or converted to free ALA. However, the resultant depot effect may lead to the enhanced accumulation of porphyrin over long exposure periods, particularly in the case of ALA-methyl ester or ALA-hexyl ester, depending on the applied concentration and the exposed tissue. Addition of the iron chelator, CP94, greatly increased PpIX accumulation in human skin exposed to ALA, ALA-methyl ester and ALA-hexyl ester. The effect in rat skin was less marked.</p

Targeted molecular-genetic imaging and ligand-directed therapy in aggressive variant prostate cancer

Aggressive variant prostate cancers (AVPC) are a clinically defined group of tumors of heterogeneous morphologies, characterized by poor patient survival and for which limited diagnostic and treatment options are currently available. We show that the cell surface 78-kDa glucose-regulated protein (GRP78), a receptor that binds to phage-display-selected ligands, such as the SNTRVAP motif, is a candidate target in AVPC. We report the presence and accessibility of this receptor in clinical specimens from index patients. We also demonstrate that human AVPC cells displaying GRP78 on their surface could be effectively targeted both in vitro and in vivo by SNTRVAP, which also enabled specific delivery of siRNA species to tumor xenografts in mice. Finally, we evaluated ligand-directed strategies based on SNTRVAP-displaying adeno-associated virus/phage (AAVP) particles in mice bearing MDA-PCa-118b, a patient-derived xenograft (PDX) of castration-resistant prostate cancer bone metastasis that we exploited as a model of AVPC. For theranostic (a merging of the terms therapeutic and diagnostic) studies, GRP78-targeting AAVP particles served to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) gene, which has a dual function as a molecular-genetic sensor/reporter and a cell suicide-inducing transgene. We observed specific and simultaneous PET imaging and treatment of tumors in this preclinical model of AVPC. Our findings demonstrate the feasibility of GPR78-targeting, ligand-directed theranostics for translational applications in AVPC

Early neoplastic and metastatic mammary tumours of transgenic mice detected by 5-aminolevulinic acid-stimulated protoporphyrin IX accumulation

A photodynamic technique for human breast cancer detection founded upon the ability of tumour cells to rapidly accumulate the fluorescent product protoporphyrin IX (PpIX) has been applied to transgenic mouse models of mammary tumorigenesis. A major goal of this investigation was to determine whether mouse mammary tumours are reliable models of human disease in terms of PpIX accumulation, for future mechanistic and therapeutic studies. The haeme substrate 5-aminolevulinic acid (5-ALA) (200 mg kg−1) was administered to mouse strains that develop mammary tumours of various histological subtypes upon expression of the transgenic oncogenes HRAS, Polyoma Virus middle T antigen, or Simian Virus 40 large T antigen in the mammary gland. Early neoplastic lesions, primary tumours and metastases showed consistent and rapid PpIX accumulation compared to the normal surrounding tissues, as evidenced by red fluorescence (635 nm) when the tumours were directly illuminated with blue light (380–440 nm). Detection of mouse mammary tumours at the stage of ductal carcinoma in situ by red fluorescence emissions suggests that enhanced PpIX synthesis is a good marker for early tumorigenic processes in the mammary gland. We propose the mouse models provide an ideal experimental system for further investigation of the early diagnostic and therapeutic potential of 5-ALA-stimulated PpIX accumulation in human breast cancer patients

Nuclear translocation of haeme oxygenase-1 is associated to prostate cancer

The role of oxidative stress in prostate cancer has been increasingly recognised. Acute and chronic inflammations generate reactive oxygen species that result in damage to cellular structures. Haeme oxygenase-1 (HO-1) has cytoprotective effects against oxidative damage. We hypothesise that modulation of HO-1 expression may be involved in the process of prostate carcinogenesis and prostate cancer progression. We thus studied HO-1 expression and localisation in 85 samples of organ-confined primary prostate cancer obtained via radical prostatectomy (Gleason grades 4–9) and in 39 specimens of benign prostatic hyperplasia (BPH). We assessed HO-1 expression by immunohistochemical staining. No significant difference was observed in the cytoplasmic positive reactivity among tumours (84%), non-neoplastic surrounding parenchyma (89%), or BPH samples (87%) (P=0.53). Haeme oxygenase-1 immunostaining was detected in the nuclei of prostate cancer cells in 55 of 85 (65%) patients but less often in non-neoplastic surrounding parenchyma (30 of 85, 35%) or in BPH (9 of 39, 23%) (P<0.0001). Immunocytochemical and western blot analysis showed HO-1 only in the cytoplasmic compartment of PC3 and LNCaP prostate cancer cell lines. Treatment with hemin, a well-known specific inducer of HO-1, led to clear nuclear localisation of HO-1 in both cell lines and highly induced HO-1 expression in both cellular compartments. These findings have demonstrated, for the first time, that HO-1 expression and nuclear localisation can define a new subgroup of prostate cancer primary tumours and that the modulation of HO-1 expression and its nuclear translocation could represent new avenues for therapy