The role of multiparametric magnetic resonance in active surveillance of a low-risk prostate cancer cohort from clinical practice.

INTRODUCTION: Active surveillance (AS) is considered a suitable management practice for those patients with low-risk prostate cancer (PCa). At present, however, the role of multiparametric magnetic resonance imaging (mpMRI) in AS protocols has not yet been clearly established. OUTCOMES: To determine the role of mpMRI and its ability to detect significant prostate cancer (SigPCa) in PCa patients enrolled in AS protocols. MATERIALS AND METHODS: There were 229 patients enrolled in an AS protocol between 2011 and 2020 at Reina Sofía University Hospital. MRI interpretation was based on PIRADS v.1 or v.2/2.1 classification. Demographics, clinical, and analytical data were collected and analyzed. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for mpMRI in different scenarios. We defined SigPCa and reclassification/progression as a Gleason score (GS) ≥ 3 + 4, a clinical stage ≥T2b, or an increase in PCa volume. Kaplan-Meier and log-rank tests were used to estimate progression-free survival time. RESULTS: Median age was 69.02 (±7.73) at diagnosis, with a 0.15 (±0.08) PSA density (PSAD). Eighty-six patients were reclassified after confirmatory biopsy, with a suspicious mpMRI an indication for a clear reclassification and risk-predictor factor in disease progression (p < 0.05). During follow-up, 46 patients were changed from AS to active treatment mainly due to disease progression. Ninety patients underwent ≥2mpMRI during follow-up, with a median follow-up of 29 (15-49) months. Thirty-four patients had a baseline suspicious mpMRI (at diagnostic or confirmatory biopsy): 14 patients with a PIRADS 3 and 20 patients with ≥PIRADS 4. From 14 patients with a PIRADS 3 baseline mpMRI, 29% progressed radiologically, with a 50% progression rate versus 10% (1/10 patients) for those with similar or decreased mpMRI risk. Of the 56 patients with a non-suspicious baseline mpMRI (PIRADS < 2), 14 patients (25%) had an increased degree of radiological suspicion, with a detection rate of SigPCa of 29%. The mpMRI NPV during follow-up was 0.91. CONCLUSION: A suspicious mpMRI increases the reclassification and disease progression risk during follow-up and plays an important role in monitoring biopsies. In addition, a high NPV at mpMRI follow-up can help to decrease the need to monitor biopsies during AS.

Five-year airborne pollen calendar for a Sonoran Desert city and the relationships with meteorological variability.

Aerobiological studies are still scarce in northwestern Mexico where allergenic pollen have great impacts on health. Current global pollution and climate change problems are closely related to many allergic diseases, enhancing the need to continue researching these issues and improve life quality. This study provides the first Pollen Calendar for Hermosillo, Sonora, México. Airborne pollen were continuously collected for 5 years (2015-2019). The standardized methodology with a Hirst-type spore trap proposed for global aerobiological studies was used. Weather data were also taken from a station located in the city and used to explore correlations between climate and airborne pollen concentrations in different seasons. The most important pollen taxa recorded in air belongs to herbaceous pollen, such as Poaceae, Ambrosia, Asteraceae, Chenopodiaceae-Amaranthaceae, and some shrub trees typical of this arid region, such as Nyctaginaceae, Prosopis, Parkinsonia, and Fabaceae. The most critical herbaceous pollen related to allergies have a long mean pollen season throughout the years, and the most critical periods with high pollen concentration in air occur in two seasons, spring (March-April) and summer-fall (August-October). In these 5 years, the correlation analyses for these two peaks indicate that a link exists between pollen in the air and decreases in precipitation and temperatures, and an increase in relative humidity. An inter-annual variability in pollen concentrations was recorded related to different weather conditions. Although pollen calendars are location-specific, they are useful for future research on biological air quality scenarios in different cities. Using this standardized method for other regions can provide pollen calendars that have been proven clinically important in allergic disease management worldwide.

The cyto-protective effects of LH on ovarian reserve and female fertility during exposure to gonadotoxic alkylating agents in an adult mouse model.

STUDY QUESTION: Does LH protect mouse oocytes and female fertility from alkylating chemotherapy? SUMMARY ANSWER: LH treatment before and during chemotherapy prevents detrimental effects on follicles and reproductive lifespan. WHAT IS KNOWN ALREADY: Chemotherapies can damage the ovary, resulting in premature ovarian failure and reduced fertility in cancer survivors. LH was recently suggested to protect prepubertal mouse follicles from chemotoxic effects of cisplatin treatment. STUDY DESIGN, SIZE, DURATION: This experimental study investigated LH effects on primordial follicles exposed to chemotherapy. Seven-week-old CD-1 female mice were randomly allocated to four experimental groups: Control (n = 13), chemotherapy (ChT, n = 15), ChT+LH-1x (n = 15), and ChT+LH-5x (n = 8). To induce primary ovarian insufficiency (POI), animals in the ChT and ChT+LH groups were intraperitoneally injected with 120 mg/kg of cyclophosphamide and 12 mg/kg of busulfan, while control mice received vehicle. For LH treatment, the ChT+LH-1x and ChT+LH-5x animals received a 1 or 5 IU LH dose, respectively, before chemotherapy, then a second LH injection administered with chemotherapy 24 h later. Then, two animals/group were euthanized at 12 and 24 h to investigate the early ovarian response to LH, while remaining mice were housed for 30 days to evaluate short- and long-term reproductive outcomes. The effects of LH and chemotherapy on growing-stage follicles were analyzed in a parallel experiment. Seven-week-old NOD-SCID female mice were allocated to control (n = 5), ChT (n = 5), and ChT+LH-1x (n = 6) groups. Animals were treated as described above, but maintained for 7 days before reproductive assessment. PARTICIPANTS/MATERIALS, SETTING, METHODS: In the first experiment, follicular damage (phosphorylated H2AX histone (γH2AX) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay), apoptotic biomarkers (western blot), and DNA repair pathways (western blot and RT-qPCR) were assessed in ovaries collected at 12 and 24 h to determine early ovarian responses to LH. Thirty days after treatments, remaining mice were stimulated (10 IU of pregnant mare serum gonadotropin (PMSG) and 10 IU of hCG) and mated to collect ovaries, oocytes, and embryos. Histological analysis was performed on ovarian samples to investigate follicular populations and stromal status, and meiotic spindle and chromosome alignment was measured in oocytes by confocal microscopy. Long-term effects were monitored by assessing pregnancy rate and litter size during six consecutive breeding attempts. In the second experiment, mice were stimulated and mated 7 days after treatments and ovaries, oocytes, and embryos were collected. Follicular numbers, follicular protection (DNA damage and apoptosis by H2AX staining and TUNEL assay, respectively), and ovarian stroma were assessed. Oocyte quality was determined by confocal analysis. MAIN RESULTS AND THE ROLE OF CHANCE: LH treatment was sufficient to preserve ovarian reserve and follicular development, avoid atresia, and restore ovulation and meiotic spindle configuration in mature oocytes exposed at the primordial stage. LH improved the cumulative pregnancy rate and litter size in six consecutive breeding rounds, confirming the potential of LH treatment to preserve fertility. This protective effect appeared to be mediated by an enhanced early DNA repair response, via homologous recombination, and generation of anti-apoptotic signals in the ovary a few hours after injury with chemotherapy. This response ameliorated the chemotherapy-induced increase in DNA-damaged oocytes and apoptotic granulosa cells. LH treatment also protected growing follicles from chemotherapy. LH reversed the chemotherapy-induced depletion of primordial and primary follicular subpopulations, reduced oocyte DNA damage and granulosa cell apoptosis, restored mature oocyte cohort size, and improved meiotic spindle properties. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: This was a preliminary study performed with mouse ovarian samples. Therefore, preclinical research with human samples is required for validation. WIDER IMPLICATIONS OF THE FINDINGS: The current study tested if LH could protect the adult mouse ovarian reserve and reproductive lifespan from alkylating chemotherapy. These findings highlight the therapeutic potential of LH as a complementary non-surgical strategy for preserving fertility in female cancer patients. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from the Regional Valencian Ministry of Education (PROMETEO/2018/137), the Spanish Ministry of Science and Innovation (CP19/00141), and the Spanish Ministry of Education, Culture and Sports (FPU16/05264). The authors declare no conflict of interest.

Deep photothermal effect induced by stereotactic laser beams in highly scattering media.

Plasmonic photothermal therapy (PPTT), as an increasingly studied treatment alternative, has been widely regarded mostly as a surface tissue treatment choice. Although some techniques have been implemented for interstitial tumors, these involve some grade of invasiveness, as the outer skin is usually broken to introduce light-delivering optical fibers or even catheters. In this work, we present a potential non-invasive strategy using the stereotactic approach, long employed in radiosurgery, by converging multiple near infrared laser beams for PPTT in tissue-equivalent optical phantoms that enclose small gel spheres and simulate interstitial tissue impregnated with plasmonic nanoparticles. The real-time in-depth monitoring of temperature increase is realized by an infrared camera face-on mounted over the phantom. Our results show that a significant reduction in the surface heating can be achieved with this configuration while remarkably increasing the interstitial reach of PPTT, assuring a ∼6∘C temperature increase for the simulated tumors at 10 mm depth and ∼4∘C at 15 mm depth and opening up new possibilities for future clinical applications.

Correction: Temperature dependence of anomalous protonic and superprotonic transport properties in mixed salts based on CsH2PO4.

Correction for 'Temperature dependence of anomalous protonic and superprotonic transport properties in mixed salts based on CsH2PO4' by Andreu Andrio et al., Phys. Chem. Chem. Phys., 2019, 21, 12948-12960, DOI: 10.1039/C8CP07472K.

Merging Mie solutions and the radiative transport equation to measure optical properties of scattering particles in optical phantoms.

We present a new method to calculate the complex refractive index of spherical scatterers in a novel optical phantom developed by using homemade monodisperse silica nanospheres embedded into a polyester resin matrix and an ethanol-water mixture for applications in diffuse imaging. The spherical geometry of these nanoparticles makes them suitable for direct comparison between the values of the absorption and reduced scattering coefficients (µa and µs', respectively) obtained by the diffusion approximation solution to the transport equation from scattering measurements and those obtained by the Mie solution to Maxwell's equations. The values of the optical properties can be obtained by measuring, using an ultrafast detector, the time-resolved intensity distribution profiles of diffuse light transmitted through a thick slab of the silica nanosphere phantom, and by fitting them to the time-dependent diffusion approximation solution to the transport equation. These values can also be obtained by Mie solutions for spherical particles when their physical properties and size are known. By using scanning electron microscopy, we measured the size of these nanospheres, and the numerical results of µa and µs' can then be inferred by calculating the absorption and scattering efficiencies. Then we propose a numerical interval for the imaginary part of the complex refractive index of SiO2 nanospheres, ns, which is estimated by fixing the fitted values of µa and µs', using the known value of the real part of ns, and finding the corresponding value of Im(ns) that matches the optical parameters obtained by both methods finding values close to those reported for silica glass. This opens the possibility of producing optical phantoms with scattering and absorption properties that can be predicted and designed from precise knowledge of the physical characteristics of their constituents from a microscopic point of view.

Neutral high-generation phosphorus dendrimers inhibit macrophage-mediated inflammatory response in vitro and in vivo.

Inflammation is part of the physiological response of the organism to infectious diseases caused by organisms such as bacteria, viruses, fungi, or parasites. Innate immunity, mediated by mononuclear phagocytes, including monocytes and macrophages, is a first line of defense against infectious diseases and plays a key role triggering the delayed adaptive response that ensures an efficient defense against pathogens. Monocytes and macrophages stimulation by pathogen antigens results in activation of different signaling pathways leading to the release of proinflammatory cytokines. However, inflammation can also participate in the pathogenesis of several diseases, the autoimmune diseases that represent a relevant burden for human health. Dendrimers are branched, multivalent nanoparticles with a well-defined structure that have a high potential for biomedical applications. To explore new approaches to fight against the negative aspects of inflammation, we have used neutral high-generation phosphorus dendrimers bearing 48 (G3) or 96 (G4) bisphosphonate groups on their surface. These dendrimers show no toxicity and have good solubility and chemical stability in aqueous solutions. Here, we present data indicating that neutral phosphorus dendrimers show impressive antiinflammatory activities both in vitro and in vivo. In vitro, these dendrimers reduced the secretion of proinflammatory cytokines from mice and human monocyte-derived macrophages. In addition, these molecules present efficient antiinflammatory activity in vivo in a mouse model of subchronic inflammation. Taken together, these data suggest that neutral G3-G4 phosphorus dendrimers have strong potential applications in the therapy of inflammation and, likely, of autoimmune diseases.

Temperature dependence of anomalous protonic and superprotonic transport properties in mixed salts based on CsH2PO4.

We present an experimental study and a theoretical interpretation of the temperature dependence of the transport properties of doped CsH2PO4 salts in both protonic and superprotonic phases. Cesium phosphate based solid electrolytes are technologically relevant because their operational temperature range is about 100 to 300 °C in which a superprotonic transition may manifest depending on its mixed composition. The experimental study was carried out using impedance spectroscopy at the temperature range of 150-230 °C, and the protonic and superprotonic transport properties and proton concentrations were calculated and analyzed by using the electrode polarization, and the Debye and Cole-Cole models for the dielectric constant. We have shown that the transport properties predicted by the Cole-Cole model are consistent with the conductivity measurements whereas the Debye model shows some inconsistencies. We attribute this to the fact that the Cole-Cole model incorporates the effects of interactions among charge carriers better than the more commonly used Debye model. In this way, our work shows a more consistent approach to determine the transport properties of solid electrolytes and, therefore, provides a more reliable tool to analyze the transport properties of heterogeneous solid electrolytes that can be used in electrochemical devices, including fuel cells and supercapacitors.

Utilization of naproxen by Amycolatopsis sp. Poz 14 and detection of the enzymes involved in the degradation metabolic pathway.

The pollution of aquatic environments by drugs is a problem for which scarce research has been conducted in regards of their removal. Amycolatopsis sp. Poz 14 presents the ability to biotransformation naphthalene at high efficiency, therefore, in this work this bacterium was proposed as an assimilator of naproxen and carbamazepine. Growth curves at different concentrations of naproxen and carbamazepine showed that Amycolatopsis sp. Poz 14 is able to utilize these drugs at a concentration of 50 mg L-1 as a source of carbon and energy. At higher concentrations, the bacterial growth was inhibited. The transformation kinetics of naproxen showed the total elimination of the compound in 18 days, but carbamazepine was only eliminated in 19.9%. The supplementation with cometabolites such as yeast extract and naphthalene (structure similar to naproxen) at 50 mg L-1, showed that the yeast extract shortened the naproxen elimination to 6 days and reached a higher global consumption rate compared to the naphthalene cometabolite. The biotransformation of carbamazepine was not improved by the addition of cometabolites. The partial sequencing of the genome of Amycolatopsis sp. Poz 14 detected genes encoding putative enzymes for the degradation of cyclic aromatic compounds and the activities of aromatic monooxygenase, catechol 1,2-dioxygenase and gentisate 1,2-dioxygenase exhibited their involving in the naproxen biodegradation. The HPLC-MS analysis detected the 5-methoxysalicylic acid at the end of the biotransformation kinetics. This work demonstrates that Amycolatopsis sp. Poz 14 utilizes naproxen and transforms it to 5-methoxysalicylic acid which is the initial compound for the catechol and gentisic acid metabolic pathway.

Cervical cancer cells suppress effector functions of cytotoxic T cells through the adenosinergic pathway.

BACKGROUND: The expression of CD73 in tumor cells plays a significant role in the production of adenosine (Ado) that suppresses antitumor effector cells. METHODS: In this study we analyzed the capability of HPV-positive (HPV+) cervical cancer (CeCa) cell lines CaSki, SiHa, HeLa, and RoVa; and HPV-negative (HPV-) cell lines C33A and ViBo to produce Ado and inhibit effector functions of CD8+ T cells. RESULTS: HPV+ CeCa cells expressed significantly higher levels of CD73 in the membrane (p<0.01) than HPV- CeCa cells and this expression was associated with the production of larger amounts of Ado (>400µM) compared to HPV-CeCa cells (<200µM) in the presence of AMP, as well asa stronger inhibition of (>50%) proliferation, activation, and cytotoxic activity of CD8+ T cells via interaction with A2A adenosine receptor. We also provide evidence that silenced E6/E7 expression in CeCa cells, strongly reduced its CD73 expression level and its capability to generate Ado. CONCLUSION: This results suggest that HPV infection, which is associated with more than 99% of CeCa cases, may present an increased constitutive expression of CD73 in cervical neoplasia to contribute to the suppression of the immune response mediated by the production of large amounts of Ado.

The Direct Referral to Endovascular Center criteria: a proposal for pre-hospital evaluation of acute stroke in the Madrid Stroke Network.

BACKGROUND AND PURPOSE: For patients with acute ischaemic stroke due to large-vessel occlusion, it has recently been shown that mechanical thrombectomy (MT) with stent retrievers is better than medical treatment alone. However, few hospitals can provide MT 24 h/day 365 days/year, and it remains unclear whether selected patients with acute stroke should be directly transferred to the nearest MT-providing hospital to prevent treatment delays. Clinical scales such as Rapid Arterial Occlusion Evaluation (RACE) have been developed to predict large-vessel occlusion at a pre-hospital level, but their predictive value for MT is low. We propose new criteria to identify patients eligible for MT, with higher accuracy. METHODS: The Direct Referral to Endovascular Center criteria were defined based on a retrospective cohort of 317 patients admitted to a stroke center. The association of age, sex, RACE scale score and blood pressure with the likelihood of receiving MT were analyzed. Cut-off points with the highest association were thereafter evaluated in a prospective cohort of 153 patients from nine stroke units comprising the Madrid Stroke Network. RESULTS: Patients with a RACE scale score ≥ 5, systolic blood pressure <190 mmHg and age <81 years showed a significantly higher probability of undergoing MT (odds ratio, 33.38; 95% confidence interval, 12-92.9). This outcome was confirmed in the prospective cohort, with 68% sensitivity, 84% specificity, 42% positive and 94% negative predictive values for MT, ruling out 83% of hemorrhagic strokes. CONCLUSIONS: The Direct Referral to Endovascular Center criteria could be useful for identifying patients suitable for MT.

Identification of fungi isolated from banana rachis and characterization of their surface activity.

Filamentous fungi are an unexplored source for the production of biosurfactants, but over a decade one of the most surface active molecules called hydrophobins was discovered. There are few techniques to determine the surface activity of fungi without any kind of manipulation that can affect the final results. In this work, we identified 33 strains of filamentous fungi isolated from banana rachis which may have potential in producing biosurfactants. Further, the production of surface active compounds by the strains was measured by two techniques. First, the surface tension of supernatants was evaluated in liquid cultures of the strains. We found that three strains belonging to the genus Fusarium, Penicillium and Trichoderma showed activity in the reduction of surface tension, which indicate a putative production of biosurfactants. Second, we measured the contact angle between the drop of water and the solid culture of strains to determine the surface activity of cells, classifying the strains as hydrophilic or hydrophobic. These techniques can be used as a quantitative measurement of the surface activity of fungi without cell manipulation. SIGNIFICANCE AND IMPACT OF THE STUDY: Biosurfactants are an alternative to petrochemical derivatives, and filamentous fungi are a promising source of these molecules. This work identified 33 strains of filamentous fungi in agroindustrial wastes. This is important because these results open the opportunity of finding new biosurfactants (hydrophobins) with unique properties. We propose the evaluation of surface tension in the supernatant as a quantitative screening to determine the production of biosurfactants from the strains of fungi.

Effects of feeding ground pods of Enterolobium cyclocarpum Jacq. Griseb on dry matter intake, rumen fermentation, and enteric methane production by Pelibuey sheep fed tropical grass.

An experiment was carried out to determine the effect of supplementing ground pods of Enterolobium cyclocarpum in a basal ration of Pennisetum purpureum grass on feed intake, rumen volatile fatty acids (VFAs), and protozoa and methane (CH4) production by hair sheep. Four male sheep (Pelibuey × Katahdin) with a mean live weight of 27.0 kg (SD ± 0.5) were supplemented with 0.00, 0.15, 0.30, and 0.45 kg of dry matter (DM) of E. cyclocarpum pods daily; equivalent to 0.00, 4.35, 8.70, and 13.05 g of crude saponins, respectively. Dry matter intake (DMI), organic matter intake (OMI), and molar proportions of propionic acid increased linearly (P < 0.05) as pods of E. cyclocarpum in the ration were increased. Higher intakes of DM and OM were found when lambs were fed 0.45 kg DM per day of E. cyclocarpum, and the highest proportion of propionic acid (0.21 and 0.22, respectively) was obtained with 0.15 and 0.30 kg of DM per lamb of E. cyclocarpum, while apparent digestibility of neutral detergent fiber (NDF) and molar proportion of acetic acid were reduced (P < 0.05). Rumen CH4 production decreased (P < 0.05) when 0.30 and 0.45 kg of DM/lamb/day of E. cyclocarpum were fed (21.8 and 25.3 L CH4/lamb/day, respectively). These results suggest that to improve the feeding of sheep fed tropical grass, it is advisable to supplement the basal ration with up to 0.30 kg DM of E. cyclocarpum pods.

Microstructure of a granular amorphous silica ceramic synthesized by spark plasma sintering.

We study the microstructure of a granular amorphous silica ceramic material synthesized by spark plasma sintering. Using monodisperse spherical silica particles as precursor, spark plasma sintering yields a dense granular material with distinct granule boundaries. We use selective etching to obtain nanoscopic pores along the granule borders. We interrogate this highly interesting material structure by combining scanning electron microscopy, X-ray computed nanotomography and simulations based on random close packed spherical particles. We determine the degree of anisotropy caused by the uni-axial force applied during sintering, and our analysis shows that our synthesis method provides a means to avoid significant granule growth and to fabricate a material with well-controlled microstructure.

Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer.

BACKGROUND: Docetaxel improves symptoms and survival in metastatic castration-resistant prostate cancer (CRPC). However, ∼50% of patients are chemoresistant. This study examined whether changes in cytokine levels predict for docetaxel resistance in vitro and in a clinical cohort. METHODS: PC3 cells or their docetaxel-resistant subline (PC3Rx) were co-cultured with U937 monocytes, with and without docetaxel treatment, and cytokine levels were measured. The circulating levels of 28 cytokines were measured pre-/post cycle 1 of docetaxel from 55 men with CRPC, and compared with prostate-specific antigen (PSA) response. RESULTS: PC3Rx-U937 co-culture expressed more cytokines, chiefly markers of alternative macrophage differentiation, compared with PC3-U937 co-culture. Docetaxel treatment enhanced cytokine production by PC3Rx-U937 co-culture, while reducing cytokine levels in PC3-U937. In patients, changes in the levels of seven circulating cytokines (macrophage inhibitory cytokine 1 (MIC1), interleukin (IL)-1ra, IL-1ß, IL-4, IL-6, IL-12 and IFNγ) after cycle 1 of docetaxel were associated with progressive disease (all P<0.05). The combination of changes in MIC1, IL-4 and IL-6 most strongly predicted PSA response (P=0.002). CONCLUSIONS: In vitro studies suggest docetaxel resistance is mediated, at least in part, by cytokines induced by the interaction between the docetaxel-resistant tumour cells and macrophages. Early changes in circulating cytokine levels were associated with docetaxel resistance in CRPC patients. When considered together, these data suggest a significant role for the inflammatory response and macrophages in the development of docetaxel resistance in CRPC.

A genome-wide association study of rheumatoid arthritis without antibodies against citrullinated peptides.

INTRODUCTION: Rheumatoid arthritis (RA) patients can be classified based on presence or absence of anticitrullinated peptide antibodies (ACPA) in their serum. This heterogeneity among patients may reflect important biological differences underlying the disease process. To date, the majority of genetic studies have focused on the ACPA-positive group. Therefore, our goal was to analyse the genetic risk factors that contribute to ACPA-negative RA. METHODS: We performed a large-scale genome-wide association study (GWAS) in three Caucasian European cohorts comprising 1148 ACPA-negative RA patients and 6008 controls. All patients were screened using the Illumina Human Cyto-12 chip, and controls were genotyped using different genome-wide platforms. Population-independent analyses were carried out by means of logistic regression. Meta-analysis with previously published data was performed as follow-up for selected signals (reaching a total of 1922 ACPA-negative RA patients and 7087 controls). Imputation of classical HLA alleles, amino acid residues and single nucleotide polymorphisms was undertaken. RESULTS: The combined analysis of the studied cohorts resulted in identification of a peak of association in the HLA-region and several suggestive non-HLA associations. Meta-analysis with previous reports confirmed the association of the HLA region with this subset and an observed association in the CLYBL locus remained suggestive. The imputation and deep interrogation of the HLA region led to identification of a two amino acid model (HLA-B at position 9 and HLA-DRB1 at position 11) that accounted for the observed genome-wide associations in this region. CONCLUSIONS: Our study shed light on the influence of the HLA region in ACPA-negative RA and identified a suggestive risk locus for this condition.

High levels of CC-chemokine expression and downregulated levels of CCR5 during HIV-1/HTLV-1 and HIV-1/HTLV-2 coinfections.

The human T-cell lymphotropic virus type 1 (HTLV-1) and HTLV-2 are common copathogens among Human Immunodeficiency Virus (HIV)-infected individuals. HTLV-2 may confer a survival benefit among patients with HIV-1/HTLV-2 coinfections, along with lower plasma HIV-1 levels and delayed rates of CD4(+) T-cell decline. These effects have been attributed to the ability of the HTLV-2 viral transactivating Tax2 protein to induce the production of high levels of antiviral CC-chemokines and to downregulate expression of the CCR5 receptor, resulting in impaired entry of HIV-1 into CD4(+) T-cells. This study investigated the innate immunity of coinfected HIV/HTLV individuals by testing the ability of patient PBMCs to produce CC-chemokines in association CCR5 receptor modulation. The cellular proliferative responses of HIV/HTLV coinfected versus HIV monoinfected individuals were also evaluated. Higher levels of MIP-1α, MIP-1ß, and RANTES (P < 0.05) were found in HIV-1/HTLV-2 coinfected group compared to HIV-1 monoinfected population. Upregulated levels of RANTES were shown in HIV-1/HTLV-1 after 1 and 3 days of culture (P < 0.05). Lymphocytes from HIV-1/HTLV-2 coinfected individuals showed significant CCR5 downregulation after 1 and 3 days of culture compared to lymphocytes from HIV-1 and uninfected groups (P < 0.05). Lower percentages of CCR5-positive cells were found in HIV-1/HTLV-1 coinfected after 3 days of incubation (P < 0.05). Levels of proliferation were significantly higher in the HIV-1/HTLV-1 group compared to HIV-1 alone (P < 0.05). HTLV-2 and HTLV-1 infections may induce the involvement of innate immunity against HIV-1 via stimulation of CC-chemokines and receptors, potentially modifying CCR5/HIV-1 binding and HIV-1 progression in coinfected individuals.

Information search behaviour, understanding and use of nutrition labeling by residents of Madrid, Spain.

OBJETIVES: To describe the information search behaviour, comprehension level, and use of nutritional labeling by consumers according to sociodemographic characteristics. STUDY DESIGN: Cross-sectional study of consumers recruited in five stores of the main supermarket chains in Madrid: a random sample of 299 consumers (response rate: 80.6%). METHODS: Interviewers collected information about the information search behaviour, comprehension, and use of nutritional labeling using a questionnaire designed for this purpose. Analyses examined the frequency of the variables of interest. Differences were tested using the Chi-square statistic. RESULTS: In this sample, 38.8% of consumers regularly read the nutritional labeling before making a purchase (45% of women vs 30% in men; P = 0.03) and the most common reason reported was choosing healthier products (81.3%). The proportion of people who were interested in additives and fats was the higher, (55% and 50%, respectively). Lack of time (38.9%), lack of interest (27.1%), and reading difficulties (18.1%) were the most common reasons given for not reading labels. Over half (52.4%) of consumers reported completely understanding the nutritional information on labels and 20.5% reported using such information for dietary planning. CONCLUSIONS: Reported information search behaviour, comprehension, and use of nutritional labeling were relatively high among consumers of the study, and their main goal was picking healthier products. However, not only are there still barriers to reading the information, but also the information most relevant to health is not always read or understood. Thus, interventions to increase nutritional labeling comprehension and use are required in order to facilitate the making of healthier choices by consumers.

Circulating microRNAs are associated with docetaxel chemotherapy outcome in castration-resistant prostate cancer.

BACKGROUND: Docetaxel is the first-line chemotherapy for castration-resistant prostate cancer (CRPC). However, response rates are ∼50% and determined quite late in the treatment schedule, thus non-responders are subjected to unnecessary toxicity. The potential of circulating microRNAs as early biomarkers of docetaxel response in CRPC patients was investigated in this study. METHODS: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. RESULTS: Fourteen microRNAs were associated with serum prostate-specific antigen (PSA) response or overall survival, according to Mann-Whitney U or log-rank tests. Non-responders to docetaxel and patients with shorter survival generally had high pre-docetaxel levels of miR-200 family members or decreased/unchanged post-docetaxel levels of miR-17 family members. Multivariate Cox regression with bootstrapping validation showed that pre-docetaxel miR-200b levels, post-docetaxel change in miR-20a levels, pre-docetaxel haemoglobin levels and visceral metastasis were independent predictors of overall survival when modelled together. CONCLUSIONS: Our study suggests that circulating microRNAs are potential early predictors of docetaxel chemotherapy outcome, and warrant further investigation in clinical trials.

Methylated Glutathione S-transferase 1 (mGSTP1) is a potential plasma free DNA epigenetic marker of prognosis and response to chemotherapy in castrate-resistant prostate cancer.

BACKGROUND: Glutathione S-transferase 1 (GSTP1) inactivation is associated with CpG island promoter hypermethylation in the majority of prostate cancers (PCs). This study assessed whether the level of circulating methylated GSTP1 (mGSTP1) in plasma DNA is associated with chemotherapy response and overall survival (OS). METHODS: Plasma samples were collected prospectively from a Phase I exploratory cohort of 75 men with castrate-resistant PC (CRPC) and a Phase II independent validation cohort (n=51). mGSTP1 levels in free DNA were measured using a sensitive methylation-specific PCR assay. RESULTS: The Phase I cohort identified that detectable baseline mGSTP1 DNA was associated with poorer OS (HR, 4.2 95% CI 2.1-8.2; P<0.0001). A decrease in mGSTP1 DNA levels after cycle 1 was associated with a PSA response (P=0.008). In the Phase II cohort, baseline mGSTP1 DNA was a stronger predictor of OS than PSA change after 3 months (P=0.02). Undetectable plasma mGSTP1 after one cycle of chemotherapy was associated with PSA response (P=0.007). CONCLUSIONS: We identified plasma mGSTP1 DNA as a potential prognostic marker in men with CRPC as well as a potential surrogate therapeutic efficacy marker for chemotherapy and corroborated these findings in an independent Phase II cohort. Prospective Phase III assessment of mGSTP1 levels in plasma DNA is now warranted.