Prostate-Specific Antigen testing in men between 40 and 70 years in Brazil: database from a check-up program

Objectives To evaluate the PSA in a large population of Brazilian men undergone to check up, and correlate the PSA cutoffs with prostate size and urinary symptoms. Materials and Methods This is a cross sectional study performed with men between 40 and 70 years undergone to check-up. All men were undergone to urological evaluation, digital rectal examination, prostate-specific antigen, and ultrasonography The exclusion criteria were men who used testosterone in the last six months, or who were using 5 alpha-reductase inhibitors. Results A total of 5015 men with an average age of 49.0 years completed the study. Most men were white and asymptomatic. The PSA in the three different aging groups were 0.9 ± 0.7ng/dL for men between 40 and 50; 1.2 ± 0.5ng/dL for men between 50 and 60; and 1.7 ± 1.5ng/dL for men greater than 60 years (p=0.001). A total of 192 men had PSA between 2.5 and 4ng/ml. From these men 130 were undergone to prostate biopsy. The predictive positive value of biopsy was 25% (32/130). In the same way, 100 patients had PSA >4ng/mL. From these men, 80 were undergone to prostate biopsy. In this group, the predictive positive value of biopsy was 40% (32/100). The Gleason score was 6 in 19 men (60%), 7 in 10 men (31%) and 8 in 3 men (9%). Conclusions The PSA level of Brazilian men undergone to check up was low. There was a positive correlation with aging, IPSS and prostate size.Universidade Federal de São Paulo (UNIFESP) Department of UrologyHospital Israelita Albert EinsteinWake Forest UniversityUNIFESP, Department of UrologySciEL

Thrombospondin modulates melanoma--platelet interactions and melanoma tumour cell growth in vivo.

In this study we have investigated the role of thrombospondin (TSP) as a possible ligand playing a key role in human M3Da. melanoma cell interaction with platelets and in tumour growth. TSP is secreted (80 +/- 6 ng TSP 10(-6) cells) and bound to the surface of M3Da. cells via receptors different from CD36, as shown by biosynthetic labelling and immunofluorescence studies. The levels of TSP binding to M3Da. cells evaluated by binding studies, using an anti-TSP monoclonal antibody (MAb) (LYP8), shows 367,000 +/- 58,000 (mean +/- s.d.) LYP8 binding sites per cell with a dissociation constant (Kd) of 67 nM. TSP binding to M3Da. cells shows 400,000 +/- 50,000 TSP binding sites per cell with a Kd of 10 nM. The capacity of anti-TSP MAb (LYP8) to inhibit M3Da.-platelet interactions was followed on an aggregometer and evaluated by electron microscopy studies. The biological role of TSP binding to M3Da. cells was investigated by implanting subcutaneously the M3Da. cell line in nude mice and following the size and time of in vivo tumour growth. Reducing the availability or the functional level of TSP by using an anti-TSP MAb (LYP8) resulted in a significant decrease in platelet aggregates interacting with M3Da. melanoma cells. Using an enzyme-linked immunosorbent assay, purified alpha nu beta 3 was shown to bind TSP. Moreover, LYP8-coated M3Da. cells showed a reduced capacity to form tumours in vivo. M3Da. cells were observed to attach and spread on human platelet TSP-coated plastic wells. This attachment by M3Da. cells was inhibited in a similar way by LYP8 and an anti-alpha nu beta 3 MAb (LYP18). The results obtained in this study show that TSP secreted and bound to the surface of a human melanoma cell line (M3Da.) acts as a link between aggregated platelets and the M3Da. cell surface. Moreover, these results shows that TSP can modulate tumour growth in vivo. Reagents such as MAbs directed against TSP and peptides derived from TSP could not only be used as a new therapeutic approach in the control of tumour metastasis of melanoma, but may also contribute to elucidation of the role of TSP in cancer biology

RNA-seq transcriptome analysis reveals long terminal repeat retrotransposon modulation in human peripheral blood mononuclear cells after in vivo lipopolysaccharide injection

Human endogenous retroviruses (HERVs) and mammalian apparent long terminal repeat (LTR) retrotransposons (MaLRs) are retroviral sequences that integrated into germ line cells millions of years ago. Transcripts of these LTR retrotransposons are present in several tissues, and their expression is modulated in pathological conditions, although their function remains often far from being understood. Here, we focused on the HERV/MaLR expression and modulation in a scenario of immune system activation. We used a public data set of human peripheral blood mononuclear cells (PBMCs) RNA-Seq from 15 healthy participants to a clinical trial before and after exposure to lipopolysaccharide (LPS), for which we established an RNA-Seq workflow for the identification of expressed and modulated cellular genes and LTR retrotransposon elements. IMPORTANCE We described the HERV and MaLR transcriptome in PBMCs, finding that about 8.4% of the LTR retrotransposon loci were expressed and identifying the betaretrovirus-like HERVs as those with the highest percentage of expressed loci. We found 4,607 HERV and MaLR loci that were modulated as a result of in vivo stimulation with LPS. The HERV-H group showed the highest number of differentially expressed most intact proviruses. We characterized the HERV and MaLR loci as differentially expressed, checking their genomic context of insertion and observing a general colocalization with genes that are involved and modulated in the immune response, as a consequence of LPS stimulation. The analyses of HERV and MaLR expression and modulation show that these LTR retrotransposons are expressed in PBMCs and regulated in inflammatory settings. The similar regulation of HERVs/MaLRs and genes after LPS stimulation suggests possible interactions of LTR retrotransposons and the immune host response

Inactivation of wild-type p53 by a dominant negative mutant renders MCF-7 cells resistant to tubulin-binding agent cytotoxicity

The present study was performed to gain insight into the role of p53 on the cytotoxicity of tubulin-binding agents (TBA) on cancer cells. Drug sensitivity, cell cycle distribution and drug-induced apoptosis were compared in 2 lines derived from the mammary adenocarcinoma MCF-7: the MN-1 cell line containing wild-type p53 (wt-p53) and the MDD2 line, containing a dominant negative variant of the p53 protein (mut-p53). The MDD2 cell line was significantly more resistant to the cytotoxic effects of vinblastine and paclitaxel than the MN1 cell line. MN1 cells, but not MDD2 cells, displayed wt-p53 protein accumulation as well as p21/WAF1 and cyclin G1 induction after exposure to TBA. Both cell lines arrested at G2/M after drug treatment. However exposure of MN1 cells to TBA resulted in a stronger variation in mitochondrial membrane potential, associated with cleavage of PARP, and more apoptosis, as measured by annexin V expression. After exposure to vinblastine, Raf 1 kinase activity was reduced in MDD2 cells but not in MN1 cells. Addition of flavopiridol to vinblastine- and paclitaxel-treated cells reversed the MDD2-resistant phenotype by inducing G1 cell cycle arrest and inhibiting endoreduplication. We conclude that the p53 status of cancer cells influences their sensitivity to TBA cytotoxicity. This effect is likely to involve differences in the apoptotic cascade. © 2001 Cancer Research Campaignhttp://www.bjcancer.co

Complex organic molecules in low-mass protostars on Solar System scales -- II. Nitrogen-bearing species

The chemical inventory of planets is determined by the physical and chemical processes that govern the early phases of star formation. The aim is to investigate N-bearing complex organic molecules towards two Class 0 protostars (B1-c and S68N) at millimetre wavelengths with ALMA. Next, the results of the detected N-bearing species are compared with those of O-bearing species for the same and other sources. ALMA observations in Band 6 ($\sim$ 1 mm) and Band 5 ($\sim$ 2 mm) are studied at $\sim$ 0.5" resolution, complemented by Band 3 ($\sim$ 3 mm) data in a $\sim$ 2.5" beam. NH2CHO, C2H5CN, HNCO, HN13CO, DNCO, CH3CN, CH2DCN, and CHD2CN are identified towards the investigated sources. Their abundances relative to CH3OH and HNCO are similar for the two sources, with column densities that are typically an order of magnitude lower than those of O-bearing species. The largest variations, of an order of magnitude, are seen for NH2CHO abundance ratios with respect to HNCO and CH3OH and do not correlate with the protostellar luminosity. In addition, within uncertainties, the N-bearing species have similar excitation temperatures to those of O-bearing species ($\sim$ 100 $\sim$ 300 K). The similarity of most abundances with respect to HNCO, including those of CH2DCN and CHD2CN, hints at a shared chemical history, especially the high D/H ratio in cold regions prior to star formation. However, some of the variations in abundances may reflect the sensitivity of the chemistry to local conditions such as temperature (e.g. NH2CHO), while others may arise from differences in the emitting areas of the molecules linked to their different binding energies in the ice. The two sources discussed here add to the small number of sources with such a detailed chemical analysis on Solar System scales. Future JWST data will allow a direct comparison between the ice and gas abundances of N-bearing species.Comment: Accepted to A&A, 41 pages, 37 figure

Mouse transcriptome reveals potential signatures of protection and pathogenesis in human tuberculosis

Although mouse infection models have been extensively used to study the host response to Mycobacterium tuberculosis, their validity in revealing determinants of human tuberculosis (TB) resistance and disease progression has been heavily debated. Here, we show that the modular transcriptional signature in the blood of susceptible mice infected with a clinical isolate of M. tuberculosis resembles that of active human TB disease, with dominance of a type I interferon response and neutrophil activation and recruitment, together with a loss in B lymphocyte, natural killer and T cell effector responses. In addition, resistant but not susceptible strains of mice show increased lung B cell, natural killer and T cell effector responses in the lung upon infection. Notably, the blood signature of active disease shared by mice and humans is also evident in latent TB progressors before diagnosis, suggesting that these responses both predict and contribute to the pathogenesis of progressive M. tuberculosis infection

Co expression of SCF and KIT in gastrointestinal stromal tumours (GISTs) suggests an autocrine/paracrine mechanism

KIT is a tyrosine kinase receptor expressed by several tumours, which has for specific ligand the stem cell factor (SCF). KIT is the main oncogene in gastrointestinal stromal tumours (GISTs), and gain-of-function KIT mutations are present in 70% of these tumours. The aim of the study was to measure and investigate the mechanisms of KIT activation in 80 KIT-positive GIST patients. KIT activation was quantified by detecting phosphotyrosine residues in Western blotting. SCF production was determined by reverse transcriptase–PCR, ELISA and/or immunohistochemistry. Primary cultures established from three GISTs were also analysed. The results show that KIT activation was detected in all cases, even in absence of KIT mutations. The fraction of activated KIT was not correlated with the mutational status of GISTs. Membrane and soluble isoforms of SCF mRNA were present in all GISTs analysed. Additionally, SCF was also detected in up to 93% of GISTs, and seen to be present within GIST cells. Likewise, the two SCF mRNA isoforms were found to be expressed in GIST-derived primary cultures. Thus, KIT activation in GISTs may in part result from the presence of SCF within the tumours

MINDS. Hydrocarbons detected by JWST/MIRI in the inner disk of Sz28 consistent with a high C/O gas-phase chemistry

Context. With the advent of JWST, we are acquiring unprecedented insights into the physical and chemical structure of the inner regions of planet-forming disks where terrestrial planet formation occurs. Very low-mass stars (VLMSs) are known to have a high occurrence of the terrestrial planets orbiting them. Exploring the chemical composition of the gas in these inner disk regions can help us better understand the connection between planet-forming disks and planets. Aims. The MIRI mid-Infrared Disk Survey (MINDS) project is a large JWST guaranteed time program whose aim is to characterise the chemistry and physical state of planet-forming and debris disks. We used the JWST-MIRI/MRS spectrum to investigate the gas and dust composition of the planet-forming disk around the VLMS Sz28 (M5.5, 0.12 M⊙). Methods. We used the dust-fitting tool DuCK to determine the dust continuum and to place constraints on the dust composition and grain sizes. We used 0D slab models to identify and fit the molecular spectral features, which yielded estimates on the temperature, column density, and emitting area. To test our understanding of the chemistry in the disks around VLMSs, we employed the thermochemical disk model PRODIMO and investigated the reservoirs of the detected hydrocarbons. We explored how the C/O ratio affects the inner disk chemistry. Results. JWST reveals a plethora of hydrocarbons, including CH3, CH4, C2H2 13CCH2, C2H6, C3H4, C4H2 and C6H6 which suggests a disk with a gaseous C/O &gt; 1. Additionally, we detect CO2 13CO2, HCN, and HC3N. H2O and OH are absent from the spectrum. We do not detect polycyclic aromatic hydrocarbons. Photospheric stellar absorption lines of H2O and CO are identified. Notably, our radiation thermo-chemical disk models are able to produce these detected hydrocarbons in the surface layers of the disk when C/O &gt; 1. The presence of C, C+, H, and H2 is crucial for the formation of hydrocarbons in the surface layers, and a C/O ratio larger than 1 ensures the surplus of C needed to drive this chemistry. Based on this, we predict a list of additional hydrocarbons that should also be detectable. Both amorphous and crystalline silicates (enstatite and forsterite) are present in the disk and we find grain sizes of 2 and 5 μm. Conclusions. The disk around Sz28 is rich in hydrocarbons, and its inner regions have a high gaseous C/O ratio. In contrast, it is the first VLMS disk in the MINDS sample to show both distinctive dust features and a rich hydrocarbon chemistry. The presence of large grains indicates dust growth and evolution. Thermo-chemical disk models that employ an extended hydrocarbon chemical network together with C/O &gt;1 are able to explain the hydrocarbon species detected in the spectrum.</p

MINDS. Hydrocarbons detected by JWST/MIRI in the inner disk of Sz28 consistent with a high C/O gas-phase chemistry

Context. With the advent of JWST, we are acquiring unprecedented insights into the physical and chemical structure of the inner regions of planet-forming disks where terrestrial planet formation occurs. Very low-mass stars (VLMSs) are known to have a high occurrence of the terrestrial planets orbiting them. Exploring the chemical composition of the gas in these inner disk regions can help us better understand the connection between planet-forming disks and planets. Aims. The MIRI mid-Infrared Disk Survey (MINDS) project is a large JWST guaranteed time program whose aim is to characterise the chemistry and physical state of planet-forming and debris disks. We used the JWST-MIRI/MRS spectrum to investigate the gas and dust composition of the planet-forming disk around the VLMS Sz28 (M5.5, 0.12 M⊙). Methods. We used the dust-fitting tool DuCK to determine the dust continuum and to place constraints on the dust composition and grain sizes. We used 0D slab models to identify and fit the molecular spectral features, which yielded estimates on the temperature, column density, and emitting area. To test our understanding of the chemistry in the disks around VLMSs, we employed the thermochemical disk model PRODIMO and investigated the reservoirs of the detected hydrocarbons. We explored how the C/O ratio affects the inner disk chemistry. Results. JWST reveals a plethora of hydrocarbons, including CH3, CH4, C2H2 13CCH2, C2H6, C3H4, C4H2 and C6H6 which suggests a disk with a gaseous C/O &gt; 1. Additionally, we detect CO2 13CO2, HCN, and HC3N. H2O and OH are absent from the spectrum. We do not detect polycyclic aromatic hydrocarbons. Photospheric stellar absorption lines of H2O and CO are identified. Notably, our radiation thermo-chemical disk models are able to produce these detected hydrocarbons in the surface layers of the disk when C/O &gt; 1. The presence of C, C+, H, and H2 is crucial for the formation of hydrocarbons in the surface layers, and a C/O ratio larger than 1 ensures the surplus of C needed to drive this chemistry. Based on this, we predict a list of additional hydrocarbons that should also be detectable. Both amorphous and crystalline silicates (enstatite and forsterite) are present in the disk and we find grain sizes of 2 and 5 μm. Conclusions. The disk around Sz28 is rich in hydrocarbons, and its inner regions have a high gaseous C/O ratio. In contrast, it is the first VLMS disk in the MINDS sample to show both distinctive dust features and a rich hydrocarbon chemistry. The presence of large grains indicates dust growth and evolution. Thermo-chemical disk models that employ an extended hydrocarbon chemical network together with C/O &gt;1 are able to explain the hydrocarbon species detected in the spectrum.</p

JOYS+: mid-infrared detection of gas-phase SO2_2 emission in a low-mass protostar. The case of NGC 1333 IRAS2A: hot core or accretion shock?

JWST/MIRI has sharpened our infrared eyes toward the star formation process. This paper presents the first mid-infrared detection of gaseous SO$_2$ emission in an embedded low-mass protostellar system. MIRI-MRS observations of the low-mass protostellar binary NGC 1333 IRAS2A are presented from the JWST Observations of Young protoStars (JOYS+) program, revealing emission from the SO$_2~\nu_3$ asymmetric stretching mode at 7.35 micron. The results are compared to those derived from high-angular resolution SO$_2$ data obtained with ALMA. The SO$_2$ emission from the $\nu_3$ band is predominantly located on $\sim50-100$ au scales around the main component of the binary, IRAS2A1. A rotational temperature of $92\pm8$ K is derived from the $\nu_3$ lines. This is in good agreement with the rotational temperature derived from pure rotational lines in the vibrational ground state (i.e., $\nu=0$) with ALMA ($104\pm5$ K). However, the emission of the $\nu_3$ lines is not in LTE given that the total number of molecules predicted by a LTE model is found to be a factor $2\times10^4$ higher than what is derived for the $\nu=0$ state. This difference can be explained by a vibrational temperature that is $\sim100$ K higher than the derived rotational temperature of the $\nu=0$ state. The brightness temperature derived from the continuum around the $\nu_3$ band of SO$_2$ is $\sim180$ K, which confirms that the $\nu_3=1$ level is not collisionally populated but rather infrared pumped by scattered radiation. This is also consistent with the non-detection of the $\nu_2$ bending mode at 18-20 micron. Given the rotational temperature, the extent of the emission ($\sim100$ au in radius), and the narrow line widths in the ALMA data (3.5 km/s), the SO$_2$ in IRAS2A likely originates from ice sublimation in the central hot core around the protostar rather than from an accretion shock at the disk-envelope boundary.Comment: 19 pages, 17 figures, accepted for publication in A&A, abstract abbreviate