Innate immunity conferred by the type I interferon is critical for antiviral defense. To date only a limited number of tripartite motif (TRIM) proteins have been implicated in modulation of innate ...immunity and anti-microbial activity. Here we report the complementary DNA cloning and systematic analysis of all known 75 human TRIMs. We demonstrate that roughly half of the 75 TRIM-family members enhanced the innate immune response and that they do this at multiple levels in signaling pathways. Moreover, messenger RNA levels and localization of most of these TRIMs were found to be altered during viral infection, suggesting that their regulatory activities are highly controlled at both pre- and posttranscriptional levels. Taken together, our data demonstrate a very considerable dedication of this large protein family to the positive regulation of the antiviral response, which supports the notion that this family of proteins evolved as a component of innate immunity.
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▸ Nearly half of all 75 TRIM protein family members are innate immune enhancers ▸ TRIM mRNA expression and protein localization are complexly regulated during infection ▸ TRIMs confer differential regulation in distinct innate immune signaling pathways
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Poor diet quality and obesity, especially abdominal obesity, have been associated with systemic inflammation. The neutrophil-to-lymphocyte Ratio (NLR) is an available and inexpensive inflammation ...biomarker. The aim of the present study was to determine the association of dietary patterns and obesity with an inflammatory state. A group of 1747 Spanish noninstitutionalized older adults individuals were included, and a food-frequency questionnaire was applied. The Global Food Score (GFS) and Healthy Eating Index for Spanish population (SHEI) were calculated. Weight, height and waist (WC) and hip circumferences were measured, and BMI, waist-to-height ratio (WHtR), and waist-to-hip ratio (WHR) determined. In addition, body-fat percentage was measured by bioimpedance. NLR was calculated (NLR ≥ p80: 2.6; 2.8 and 2.4 as inflammatory status in the entire population, men and women, respectively). The men with inflammatory status presented significative higher values of WC, WHtR, WHR, and body-fat percentage (101.82 ± 10.34 cm, 0.61 ± 0.06, 0.98 ± 0.06, and 31.68 ± 5.94%, respectively) than those with better inflammatory status (100.18 ± 10.22 cm, 0.59 ± 0.06, 0.97 ± 0.07, and 30.31 ± 6.16%, respectively). Those males with worse inflammatory state had lower scores for protein foods (OR = 0.898 (0.812-0.993);
= 0.037). The women with NLR ≥ 2.4 had higher WHtR and WHR (0.62 ± 0.09 and 0.91 ± 0.09) than those with NLR < 2.4 (0.60 ± 0.08 and 0.90 ± 0.08). In multiple linear regression analysis, NLR was positively related with WHtR and negatively related with SHEI score (β = 0.224 ± 0.094;
= 0.060;
< 0.05 and β = -0.218 ± 0.101;
= 0.061;
< 0.05), adjusting by sex, age, marital status, education level, smoking, hours of sleeping and inflammatory diseases. In women, the higher the SHEI and GFS scores were and the better meeting the aims of cereal and vegetable servings, the less the odds of inflammatory status (OR = 0.970 (0.948-0.992);
= 0.008; OR = 0.963 (0.932-0.995);
= 0.024; OR = 0.818 (0.688-0.974);
= 0.024 and OR = 0.829 (0.730-0.942);
= 0.004, respectively). WHtR and quality of diet is related to the inflammation status in older adults regardless to the sex.
Fipronil is an insecticide that is not approved in the European Union in food. In 2017, fipronil was involved in a European health alert due to its presence in fresh hen eggs because of an illicit ...use in poultry farms, so reliable methods are needed to determine fipronil and its main metabolites in these matrixes. In this work, we report the first approach to the study of fipronil and two metabolites, fipronil‐sulfone and fipronil‐sulfide by CE. MEKC mode was employed using a solution of 50 mM ammonium perfluorooctanoate pH 9.0 with 10% (v/v) methanol as background electrolyte. The proposed method was combined with a simple sample treatment based on salting‐out assisted LLE (SALLE) using acetonitrile as extraction solvent and ammonium sulfate as salt. The SALLE–MEKC–UV method allowed the simultaneous quantification of fipronil and fipronil‐sulfone. Validation parameters yielded satisfactory results, with precision, expressed as relative SD, below 14% and recoveries higher than 83%. Limits of detection were 90 µg/kg for fipronil and 150 µg/kg for fipronil‐sulfone, so in terms of sensitivity further studies of sample treatments allowing extra preconcentration or the use of more sensitive detection, such as MS, would be needed.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Advances in prostate cancer lag behind other tumor types partly due to the paucity of models reflecting key milestones in prostate cancer progression. Therefore, we develop clinically relevant ...prostate cancer models.
Since 1996, we have generated clinically annotated patient-derived xenografts (PDXs; the MDA PCa PDX series) linked to specific phenotypes reflecting all aspects of clinical prostate cancer.
We studied two cell line-derived xenografts and the first 80 PDXs derived from 47 human prostate cancer donors. Of these, 47 PDXs derived from 22 donors are working models and can be expanded either as cell lines (MDA PCa 2a and 2b) or PDXs. The histopathologic, genomic, and molecular characteristics (androgen receptor, ERG, and
loss) maintain fidelity with the human tumor and correlate with published findings. PDX growth response to mouse castration and targeted therapy illustrate their clinical utility. Comparative genomic hybridization and sequencing show significant differences in oncogenic pathways in pairs of PDXs derived from different areas of the same tumor. We also identified a recurrent focal deletion in an area that includes the speckle-type POZ protein-like (
) gene in PDXs derived from seven human donors of 28 studied (25%).
is a
paralog, and
mutations define a molecular subclass of prostate cancer.
deletions are found in 7% of The Cancer Genome Atlas prostate cancers, which suggests that our cohort is a reliable platform for targeted drug development.
The MDA PCa PDX series is a dynamic resource that captures the molecular landscape of prostate cancers progressing under novel treatments and enables optimization of prostate cancer-specific, marker-driven therapy.
SummaryBackgroundTaxane–platinum combinations have shown promising activity in metastatic castration-resistant prostate cancers in single-group clinical studies but not in randomised trials. Distinct ...biological subsets of the disease might derive the greatest benefit from the addition of platinum. We aimed to determine whether adding carboplatin to cabazitaxel would improve the outcomes of men with metastatic castration-resistant prostate cancer. MethodsWe did a phase 1–2, open label, randomised study at two centres in men with progressive metastatic castration-resistant prostate cancer. In phase 1, patients received intravenous cabazitaxel 20–25 mg/m 2 and intravenous carboplatin area under the curve (AUC) 3–4 mg/mL per min every 21 days. The maximum tolerated dose was defined as the highest dose cohort studied in which one of six or fewer patients experienced a dose-limiting toxicity. In phase 2, patients were randomly assigned (1:1) centrally by a computerised algorithm to intravenous cabazitaxel 25 mg/m 2 with or without intravenous carboplatin AUC 4 mg/mL per min. All patients received growth factor support and oral prednisone 10 mg daily. The primary endpoints were the maximum tolerated dose of the combination in phase 1 and investigator-assessed progression-free survival in phase 2. This trial is registered at ClinicalTrials.gov, number NCT01505868. FindingsBetween Aug 17, 2012, and May 11, 2015, nine patients completed phase 1 as planned, and 160 were randomly assigned to cabazitaxel (n=79) or cabazitaxel plus carboplatin (n=81) in phase 2. During phase I, grade 3 adverse events were anaemia (n=2), fatigue (n=1), thrombocytopenia (n=1), hypomagnesaemia (n=1), diarrhoea (n=1), hypokalaemia (n=1), anorexia (n=1), and dehydration (n=1), and no grade 4 adverse events occurred. No dose-limiting toxicities were observed, therefore, a maximum tolerated dose of cabazitaxel of 25 mg/m 2 and carboplatin of AUC 4 mg/mL per min was selected for phase 2. At a median follow-up of 31·0 months (IQR 20·5–37·1), the combination improved the median progression-free survival from 4·5 months (95% CI 3·5–5·7) to 7·3 months (95% CI 5·5–8·2; hazard ratio 0·69, 95% CI 0·50–0·95, p=0·018). In the phase 2 study, the most common grade 3–5 adverse events were fatigue (7 9% of 79 in the cabazitaxel group vs 16 20% of 81 in the combination group), anaemia (3 4% vs 19 23%), neutropenia (3 4% vs 13 16%), and thrombocytopenia (1 1% vs 11 14%). There were no treatment-related deaths. InterpretationCarboplatin added to cabazitaxel showed improved clinical efficacy compared with cabazitaxel alone for men with metastatic castration-resistant prostate cancer. Although adverse events were more common with the combination, the treatment was safe and generally well tolerated. Our data suggest that taxane–platinum combinations have a clinically beneficial role in advanced prostate cancer and a randomised phase 3 study is planned. FundingSanofi Genzyme, University of Texas MD Anderson Cancer Center Prostate Cancer Moon Shot Program, and Solon Scott III Prostate Cancer Research Fund.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Morphologically heterogeneous prostate cancers that behave clinically like small-cell prostate cancers (SCPC) share their chemotherapy responsiveness. We asked whether these clinically defined, ...morphologically diverse, "aggressive variant prostate cancer (AVPC)" also share molecular features with SCPC.
Fifty-nine prostate cancer samples from 40 clinical trial participants meeting AVPC criteria, and 8 patient-tumor derived xenografts (PDX) from 6 of them, were stained for markers aberrantly expressed in SCPC. DNA from 36 and 8 PDX was analyzed by Oncoscan for copy number gains (CNG) and losses (CNL). We used the AVPC PDX to expand observations and referenced publicly available datasets to arrive at a candidate molecular signature for the AVPC.
Irrespective of morphology, Ki67 and Tp53 stained ≥10% cells in 80% and 41% of samples, respectively. RB1 stained <10% cells in 61% of samples and AR in 36%. MYC (surrogate for 8q) CNG and RB1 CNL showed in 54% of 44 samples each and PTEN CNL in 48%. All but 1 of 8 PDX bore Tp53 missense mutations. RB1 CNL was the strongest discriminator between unselected castration-resistant prostate cancer (CRPC) and the AVPC. Combined alterations in RB1, Tp53, and/or PTEN were more frequent in the AVPC than in unselected CRPC and in The Cancer Genome Atlas samples.
Clinically defined AVPC share molecular features with SCPC and are characterized by combined alterations in RB1, Tp53, and/or PTEN.
Background: Mineral intake may protect against cognitive impairment (CI) and all-cause dementia, which affects a large number of adults worldwide. The aim of this study was to investigate the ...association between mineral intake and Montreal Cognitive Assessment (MoCA), which is a sensitive and specific test. Methods: In total, 201 adults were included in a cross-sectional study. They completed a three-day dietary record to estimate their average daily intake of minerals. Contributions to dietary reference intakes (DRIs) were also calculated. The participants were divided into tertiles according to their mineral intake. CI classifications were determined via the MoCA (score < 26). Apolipoprotein E (APOE) genotyping was carried out, and the patients’ anthropometric measurements and physical activity, health and personal data were collected. Results: The prevalence of CI in this selective sample was 54.2% (34.3% females and 19.9% males). In women, being in the third tertiles of iron and manganese intake was associated with lower odds of having CI (OR 95% CI: 0.32 0.11 ± 0.93; 0.33 0.12 ± 0.93, p < 0.05). No significant differences were observed for any of the nutrients studied in men. Conclusions: These findings suggest that a low mineral intake, especially low iron and manganese intake in women, is associated with a worse cognition as assessed by MoCA.
Maintenance of genomic stability is a critical determinant of cell survival and is necessary for growth and progression of malignant cells. Interstrand crosslinking (ICL) agents, including ...platinum-based agents, are first-line chemotherapy treatment for many solid human cancers. In malignant cells, ICL triggers the DNA damage response (DDR). When the damage burden is high and lesions cannot be repaired, malignant cells are unable to divide and ultimately undergo cell death either through mitotic catastrophe or apoptosis. The activities of ICL agents, in particular platinum-based therapies, establish a "molecular landscape," i.e., a pattern of DNA damage that can potentially be further exploited therapeutically with DDR-targeting agents. If the molecular landscape created by platinum-based agents could be better defined at the molecular level, a systematic, mechanistic rationale(s) could be developed for the use of DDR-targeting therapies in combination/maintenance protocols for specific, clinically advanced malignancies. New therapeutic drugs such as poly(ADP-ribose) polymerase (PARP) inhibitors are examples of DDR-targeting therapies that could potentially increase the DNA damage and replication stress imposed by platinum-based agents in tumor cells and provide therapeutic benefit for patients with advanced malignancies. Recent studies have shown that the use of PARP inhibitors together with platinum-based agents is a promising therapy strategy for ovarian cancer patients with "BRCAness", i.e., a phenotypic characteristic of tumors that not only can involve loss-of-function mutations in either BRCA1 or BRCA2, but also encompasses the molecular features of BRCA-mutant tumors. On the basis of these promising results, additional mechanism-based studies focused on the use of various DDR-targeting therapies in combination with platinum-based agents should be considered. This review discusses, in general, (1) ICL agents, primarily platinum-based agents, that establish a molecular landscape that can be further exploited therapeutically; (2) multiple points of potential intervention after ICL agent-induced crosslinking that further predispose to cell death and can be incorporated into a systematic, therapeutic rationale for combination/ maintenance therapy using DDR-targeting agents; and (3) available agents that can be considered for use in combination/maintenance clinical protocols with platinum-based agents for patients with advanced malignancies.
Clinical features characteristic of small-cell prostate carcinoma (SCPC), "anaplastic," often emerge during the progression of prostate cancer. We sought to determine the efficacy of platinum-based ...chemotherapy in patients meeting at least one of seven prospectively defined "anaplastic" clinical criteria, including exclusive visceral or predominantly lytic bone metastases, bulky tumor masses, low prostate-specific antigen levels relative to tumor burden, or short response to androgen deprivation therapy.
A 120-patient phase II trial of first-line carboplatin and docetaxel (CD) and second-line etoposide and cisplatin (EP) was designed to provide reliable clinical response estimates under a Bayesian probability model with early stopping rules in place for futility and toxicity.
Seventy-four of 113 (65.4%) and 24 of 71 (33.8%) were progression free after four cycles of CD and EP, respectively. Median overall survival (OS) was 16 months 95% confidence interval (CI), 13.6-19.0 months. Of the seven "anaplastic" criteria, bulky tumor mass was significantly associated with poor outcome. Lactic acid dehydrogenase strongly predicted for OS and rapid progression. Serum carcinoembryonic antigen (CEA) concentration strongly predicted OS but not rapid progression. Neuroendocrine markers did not predict outcome or response to therapy.
Our findings support the hypothesis that patients with "anaplastic" prostate cancer are a recognizable subset characterized by a high response rate of short duration to platinum-containing chemotherapies, similar to SCPC. Our results suggest that CEA is useful for selecting therapy in men with castration-resistant prostate cancer and consolidative therapies to bulky high-grade tumor masses should be considered in this patient population.
The present study reports the Na intake of a representative sample of Spanish young and middle-aged adults aged 18–60 years (n 418, 53·1 % women, selected from the capitals of fifteen provinces and ...the surrounding semi-urban/rural area), measured with a 24 h urinary Na excretion method. To validate the paper collection of 24 h urine, the correlation between fat-free mass determined by electrical bioimpedance (50·8 (sd 11·3) kg) and that determined via urinary creatinine excretion (51·5 (sd 18·8) kg) was calculated (r 0·633, P < 0·001). Urinary Na excretion correlated with systolic and dyastolic blood pressure data (r 0·243 and 0·153, respectively). Assuming that all urinary Na (168·0 (sd 78·6) mmol/d) comes from the diet, Na excretion would correspond with a dietary salt intake of 9·8 (sd 4·6) g/d, and it would mean that 88·2 % of the subjects had salt intakes above the recommended 5 g/d. Logistic regression analysis, adjusted for sex, age and BMI, showed male sex (OR 3·678, 95 % CI 2·336, 5·791) and increasing BMI (OR 1·069, 95 % CI 1·009, 1·132) (P < 0·001) to be associated with excreting >200 mmol/d urinary Na – a consequence of the higher salt intake in men and in participants with higher BMI. The present results help us to know the baseline salt intake in the Spanish young and middle-aged adult population, and can be used as the baseline to design policies to reduce salt consumption.
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