82 research outputs found
High dosage thermoluminescence diamond dosimeters
Diamond thin films have been irradiated with high doses (up to 12.8 kGy) of ⁹⁰Sr beta particles. The diamond thin films have been synthesized from commercial Tequila as a precursor using pulsed liquid injection by chemical vapor deposition technique reported recently. Thermoluminescence phenomena at these doses exhibit peak curve shift to higher temperatures (from 370 to 440 K) in the glow curve and the integrated thermoluminescence curve show a linear behavior. Therefore, it has been considered that diamond thin films could be used as high doses dosimeters.Алмазні тонкі плівки, які було синтезовано хімічним осадженням парів з промислово виробленої Текіли в якості прекурсору з використанням методу імпульсного упорскування рідини, про який було нещодавно повідомлено, опромінювали високими (до 12,8 кГр) дозами бета-частинок ⁹⁰Sr. При таких дозах опромінення максимум кривої термолюмінесценції зсувається до більш високих (від 370 до 440 K) температур і залежність інтегрованої термолюмінесценції від дози опромінювання є лінійною. Тому алмазні тонкі плівки можуть бути використані як дозиметри при високих дозах опромінювання.Алмазные тонкие пленки, которые были синтезированы химическим осаждением паров из промышленно произведенной Текилы в качестве прекурсора при использовании метода импульсного впрыскивания жидкости, о котором недавно было сообщено, облучали высокими (до 12,8 кГр) дозами бета-частиц ⁹⁰Sr. При таких дозах облучения максимум кривой термолюминесценции сдвигается в область более высоких (от 370 до 440 K) температур и зависимость интегрированной термолюминесценции от дозы облучения является линейной. Поєтому алмазные тонкие пленки могут быть использованы как дозиметры при высоких дозах облучения
A Novel Human Ghrelin Variant (In1-Ghrelin) and Ghrelin-O-Acyltransferase Are Overexpressed in Breast Cancer: Potential Pathophysiological Relevance
The human ghrelin gene, which encodes the ghrelin and obestatin peptides, contains 5 exons (Ex), with Ex1-Ex4 encoding a
117 amino-acid (aa) preproprotein that is known to be processed to yield a 28-aa (ghrelin) and/or a 23-aa (obestatin) mature
peptides, which possess biological activities in multiple tissues. However, the ghrelin gene also encodes additional peptides
through alternative splicing or post-translational modifications. Indeed, we previously identified a spliced mRNA ghrelin
variant in mouse (In2-ghrelin-variant), which is regulated in a tissue-dependent manner by metabolic status and may thus
be of biological relevance. Here, we have characterized a new human ghrelin variant that contains Ex0-1, intron (In) 1, and
Ex2 and lacks Ex3-4. This human In1-ghrelin variant would encode a new prepropeptide that conserves the first 12aa of
native-ghrelin (including the Ser3-potential octanoylation site) but has a different C-terminal tail. Expression of In1-variant
was detected in 22 human tissues and its levels were positively correlated with those of ghrelin-O-acyltransferase (GOAT;
p = 0.0001) but not with native-ghrelin expression, suggesting that In1-ghrelin could be a primary substrate for GOAT in
human tissues. Interestingly, levels of In1-ghrelin variant expression in breast cancer samples were 8-times higher than
those of normal mammary tissue, and showed a strong correlation in breast tumors with GOAT (p = 0.0001), ghrelin
receptor-type 1b (GHSR1b; p = 0.049) and cyclin-D3 (a cell-cycle inducer/proliferation marker; p = 0.009), but not with nativeghrelin
or GHSR1a expression. Interestingly, In1-ghrelin variant overexpression increased basal proliferation of MDA-MB-231
breast cancer cells. Taken together, our results provide evidence that In1-ghrelin is a novel element of the ghrelin family
with a potential pathophysiological role in breast cance
Ghrelin-O-Acyltransferase (GOAT) Enzyme as a Novel Potential Biomarker in Gastroenteropancreatic Neuroendocrine Tumors
Objectives: The association between the presence and alterations of the components of the ghrelin system and the
development and progression of neuroendocrine tumors (NETs) is still controversial and remains unclear.
Methods: Here, we systematically evaluated the expression levels (by quantitative-PCR) of key ghrelin system
components of in gastroenteropancreatic (GEP)-NETs, as compared to non-tumor adjacent (NTA; n = 42) and normal
tissues (NT; n = 14). Then, we analyzed their putative associations with clinical-histological characteristics.
Results: The results indicate that ghrelin and its receptor GHSR1a are present in a high proportion of normal tissues,
while the enzyme ghrelin-O-acyltransferase (GOAT) and the splicing variants In1-ghrelin and GHSR1b were present in a
lower proportion of normal tissues. In contrast, all ghrelin system components were present in a high proportion of
tumor and NTA tissues. GOAT was significantly overexpressed (by quantitative-PCR (qPCR)) in tumor samples
compared to NTA, while a trend was found for ghrelin, In1-ghrelin and GHSR1a. In addition, expression of these
components displayed significant correlations with key clinical parameters. The marked overexpression of GOAT in
tumor samples compared to NTA regions was confirmed by IHC, revealing that this enzyme is particularly
overexpressed in gastrointestinal NETs, where it is directly correlated with tumor diameter.
Conclusions: These results provide novel information on the presence and potential pathophysiological implications
of the ghrelin system components in GEP-NETs, wherein GOAT might represent a novel diagnostic biomarker
Comparative Cytotoxic Activity of Hydroxytyrosol and Its Semisynthetic Lipophilic Derivatives in Prostate Cancer Cells
A high adherence to a Mediterranean diet has been related to numerous beneficial effects in human health, including a lower incidence and mortality of prostate cancer (PCa). Olive oil is an important source of phenolic bioactive compounds, mainly hydroxytyrosol (HT), of this diet. Because of the growing interest of this compound and its derivatives as a cancer chemopreventive agent, we aimed to compare the in vitro effect of HT isolated from olive mill wastewaters and five semisynthetic alkyl ether, ester, and nitro-derivatives against prostate cancer (PCa) cell lines. The effect in cell proliferation was determined in RWPE-1, LNCaP, 22Rv1, and PC-3 cells by resazurin assay, the effect in cell migration by wound healing assay, and tumorsphere and colony formation were evaluated. The changes in key signaling pathways involved in carcinogenesis were assessed by using a phosphorylation pathway profiling array and by Western blotting. Antiproliferative effects of HT and two lipophilic derivatives [hydroxytyrosyl acetate (HT-Ac)/ethyl hydroxytyrosyl ether (HT-Et)] were significantly higher in cancerous PC-3 and 22Rv1 cells than in non-malignant RWPE-1 cells. HT/HT-Ac/HT-Et significantly reduced migration capacity in RWPE-1 and PC-3 and prostatosphere size and colony formation in 22Rv1, whereas only HT-Ac and HT-Et reduced these functional parameters in PC-3. The cytotoxic effect in 22Rv1 cells was correlated with modifications in the phosphorylation pattern of key proteins, including ERK1/2 and AKT. Consistently, HT-Ac and HT-Et decreased p-AKT levels in PC-3. In sum, our results suggest that HT and its lipophilic derivatives could be considered as potential therapeutic tools in PCa
Unleashing the Diagnostic, Prognostic and Therapeutic Potential of the Neuronostatin/GPR107 System in Prostate Cancer
Certain components of the somatostatin-system play relevant roles in Prostate Cancer (PCa), whose most aggressive phenotype (Castration-Resistant-PCa (CRPC)) remains lethal nowadays. However, neuronostatin and the G protein-coupled receptor 107 (GPR107), two novel members of the somatostatin-system, have not been explored yet in PCa. Consequently, we investigated the pathophysiological role of NST/GPR107-system in PCa. GPR107 expression was analyzed in well-characterized PCa patient′s cohorts, and functional/mechanistic assays were performed in response to GPR107-silencing and NST-treatment in PCa cells (androgen-dependent (AD: LNCaP) and androgen-independent (AI: 22Rv1/PC-3), which are cell models of hormone-sensitive and CRPC, respectively), and normal prostate cells (RWPE-1 cell-line). GPR107 was overexpressed in PCa and associated with key clinical parameters (e.g., advance stage of PCa, presence of vascular invasion and metastasis). Furthermore, GPR107-silencing inhibited proliferation/migration rates in AI-PCa-cells and altered key genes and oncogenic signaling-pathways involved in PCa aggressiveness (i.e., KI67/CDKN2D/MMP9/PRPF40A, SST5TMD4/AR-v7/In1-ghrelin/EZH2 splicing-variants and AKT-signaling). Interestingly, NST treatment inhibited proliferation/migration only in AI-PCa cells and evoked an identical molecular response than GPR107-silencing. Finally, NST decreased GPR107 expression exclusively in AI-PCa-cells, suggesting that part of the specific antitumor effects of NST could be mediated through a GPR107-downregulation. Altogether, NST/GPR107-system could represent a valuable diagnostic and prognostic tool and a promising novel therapeutic target for PCa and CRPC
Oncogenic Role of Secreted Engrailed Homeobox 2 (EN2) in Prostate Cancer
Engrailed variant-2 (EN2) has been suggested as a potential diagnostic biomarker; however, its presence and functional role in prostate cancer (PCa) cells is still controversial or unknown. Here, we analyzed 1) the expression/secretion profile of EN2 in five independent samples cohorts from PCa patients and controls (prostate tissues and/or urine) to determine its utility as a PCa biomarker; and 2) the functional role of EN2 in normal (RWPE1) and tumor (LNCaP/22Rv1/PC3) prostate cells to explore its potential value as therapeutic target. EN2 was overexpressed in our two cohorts of PCa tissues compared to control and in tumor cell lines compared with normal-like prostate cells. This profile was corroborated in silico in three independent data sets [The Cancer Genome Atlas(TCGA)/Memorial Sloan Kettering Cancer Center (MSKCC)/Grasso]. Consistently, urine EN2 levels were elevated and enabled discrimination between PCa and control patients. EN2 treatment increased cell proliferation in LNCaP/22Rv1/PC3 cells, migration in RWPE1/PC3 cells, and PSA secretion in LNCaP cells. These effects were associated, at least in the androgen-sensitive LNCaP cells, with increased AKT and androgen-receptor phosphorylation levels and with modulation of key cancer-associated genes. Consistently, EN2 treatment also regulated androgen-receptor activity (full-length and splicing variants) in androgen-sensitive 22Rv1 cells. Altogether, this study demonstrates the potential utility of EN2 as a non-invasive diagnostic biomarker for PCa and provides novel and valuable information to further investigate its putative utility to develop new therapeutic tools in PCa
Clinical Utility of Ghrelin-O-Acyltransferase (GOAT) Enzyme as a Diagnostic Tool and Potential Therapeutic Target in Prostate Cancer
Recent data suggested that plasma Ghrelin O-Acyl Transferase enzyme (GOAT) levels could represent a new diagnostic biomarker for prostate cancer (PCa). In this study, we aimed to explore the diagnostic and prognostic/aggressiveness capacity of GOAT in urine, as well as to interrogate its putative pathophysiological role in PCa. We analysed urine/plasma levels of GOAT in a cohort of 993 patients. In vitro (i.e., cell-proliferation) and in vivo (tumor-growth in a xenograft-model) approaches were performed in response to the modulation of GOAT expression/activity in PCa cells. Our results demonstrate that plasma and urine GOAT levels were significantly elevated in PCa patients compared to controls. Remarkably, GOAT significantly outperformed PSA in the diagnosis of PCa and significant PCa in patients with PSA levels ranging from 3 to 10 ng/mL (the so-called PSA grey-zone). Additionally, urine GOAT levels were associated to clinical (e.g., Gleason-score, PSA levels) and molecular (e.g., CDK2/CDK6/CDKN2A expression) aggressiveness parameters. Indeed, GOAT overexpression increased, while its silencing/blockade decreased cell-proliferation in PCa cells. Moreover, xenograft tumors derived from GOAT-overexpressing PCa (DU145) cells were significantly higher than those derived from the mock-overexpressing cells. Altogether, our results demonstrate that GOAT could be used as a diagnostic and aggressiveness marker in urine and a therapeutic target in PCa
Central blood pressure and pulse wave velocity: relationship to target organ damage and cardiovascular morbidity-mortality in diabetic patients or metabolic syndrome. An observational prospective study. LOD-DIABETES study protocol
<p>Abstract</p> <p>Background</p> <p>Diabetic patients show an increased prevalence of non-dipping arterial pressure pattern, target organ damage and elevated arterial stiffness. These alterations are associated with increased cardiovascular risk.</p> <p>The objectives of this study are the following: to evaluate the prognostic value of central arterial pressure and pulse wave velocity in relation to the incidence and outcome of target organ damage and the appearance of cardiovascular episodes (cardiovascular mortality, myocardial infarction, chest pain and stroke) in patients with type 2 diabetes mellitus or metabolic syndrome.</p> <p>Methods/Design</p> <p><b>Design</b>: This is an observational prospective study with 5 years duration, of which the first year corresponds to patient inclusion and initial evaluation, and the remaining four years to follow-up.</p> <p><b>Setting</b>: The study will be carried out in the urban primary care setting.</p> <p><b>Study population</b>: Consecutive sampling will be used to include patients diagnosed with type 2 diabetes between 20-80 years of age. A total of 110 patients meeting all the inclusion criteria and none of the exclusion criteria will be included.</p> <p><b>Measurements</b>: Patient age and sex, family and personal history of cardiovascular disease, and cardiovascular risk factors. Height, weight, heart rate and abdominal circumference. Laboratory tests: hemoglobin, lipid profile, creatinine, microalbuminuria, glomerular filtration rate, blood glucose, glycosylated hemoglobin, blood insulin, fibrinogen and high sensitivity C-reactive protein. Clinical and 24-hour ambulatory (home) blood pressure monitoring and self-measured blood pressure. Common carotid artery ultrasound for the determination of mean carotid intima-media thickness. Electrocardiogram for assessing left ventricular hypertrophy. Ankle-brachial index. Retinal vascular study based on funduscopy with non-mydriatic retinography and evaluation of pulse wave morphology and pulse wave velocity using the SphygmoCor system. The medication used for diabetes, arterial hypertension and hyperlipidemia will be registered, together with antiplatelet drugs.</p> <p>Discussion</p> <p>The results of this study will help to know and quantify the prognostic value of central arterial pressure and pulse wave velocity in relation to the evolution of the subclinical target organ damage markers and the possible incidence of cardiovascular events in patients with type 2 diabetes mellitus.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier: NCT01065155</p
Incidence, clinical characteristics and management of inflammatory bowel disease in Spain: large-scale epidemiological study
(1) Aims: To assess the incidence of inflammatory bowel disease (IBD) in Spain, to describe the main epidemiological and clinical characteristics at diagnosis and the evolution of the disease, and to explore the use of drug treatments. (2) Methods: Prospective, population-based nationwide registry. Adult patients diagnosed with IBD—Crohn’s disease (CD), ulcerative colitis (UC) or IBD unclassified (IBD-U)—during 2017 in Spain were included and were followed-up for 1 year. (3) Results: We identified 3611 incident cases of IBD diagnosed during 2017 in 108 hospitals covering over 22 million inhabitants. The overall incidence (cases/100, 000 person-years) was 16 for IBD, 7.5 for CD, 8 for UC, and 0.5 for IBD-U; 53% of patients were male and median age was 43 years (interquartile range = 31–56 years). During a median 12-month follow-up, 34% of patients were treated with systemic steroids, 25% with immunomodulators, 15% with biologics and 5.6% underwent surgery. The percentage of patients under these treatments was significantly higher in CD than UC and IBD-U. Use of systemic steroids and biologics was significantly higher in hospitals with high resources. In total, 28% of patients were hospitalized (35% CD and 22% UC patients, p < 0.01). (4) Conclusion: The incidence of IBD in Spain is rather high and similar to that reported in Northern Europe. IBD patients require substantial therapeutic resources, which are greater in CD and in hospitals with high resources, and much higher than previously reported. One third of patients are hospitalized in the first year after diagnosis and a relevant proportion undergo surgery. © 2021 by the authors. Licensee MDPI, Basel, Switzerland
- …