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1.
Biophys J ; 122(18): 3783-3797, 2023 09 19.
Article in English | MEDLINE | ID: mdl-37559362

ABSTRACT

Membrane cholesterol-rich domains have been shown to be important for regulating a range of membrane protein activities. Low-density lipoprotein receptor (LDLR)-mediated internalization of cholesterol-rich LDL particles is tightly regulated by feedback mechanisms involving intracellular sterol sensors. Since LDLR plays a role in maintaining cellular cholesterol homeostasis, we explore the role that membrane domains may have in regulating LDLR activity. We expressed a fluorescent LDLR-mEGFP construct in HEK293T cells and imaged the unligated receptor or bound to an LDL/DiI fluorescent ligand using total internal reflection fluorescence microscopy. We studied the receptor's spatiotemporal dynamics using fluorescence fluctuation analysis methods. Image cross correlation spectroscopy reveals a lower LDL-to-LDLR binding fraction when membrane cholesterol concentrations are augmented using cholesterol esterase, and a higher binding fraction when the cells are treated with methyl-ß-cyclodextrin) to lower membrane cholesterol. This suggests that LDLR's ability to metabolize LDL particles is negatively correlated to membrane cholesterol concentrations. We then tested if a change in activity is accompanied by a change in membrane localization. Image mean-square displacement analysis reveals that unligated LDLR-mEGFP and ligated LDLR-mEGFP/LDL-DiI constructs are transiently confined on the cell membrane, and the size of their confinement domains increases with augmented cholesterol concentrations. Receptor diffusion within the domains and their domain-escape probabilities decrease upon treatment with methyl-ß-cyclodextrin, consistent with a change in receptor populations to more confined domains, likely clathrin-coated pits. We propose a feedback model to account for regulation of LDLR within the cell membrane: when membrane cholesterol concentrations are high, LDLR is sequestered in cholesterol-rich domains. These LDLR populations are attenuated in their efficacy to bind and internalize LDL. However, when membrane cholesterol levels drop, LDL has a higher binding affinity to its receptor and the LDLR transits to nascent clathrin-coated domains, where it diffuses at a slower rate while awaiting internalization.


Subject(s)
Cholesterol , Receptors, LDL , Humans , Cholesterol/metabolism , Clathrin/metabolism , Fluorescence , HEK293 Cells , Lipoproteins, LDL/metabolism , Receptors, LDL/metabolism
2.
Anal Chem ; 95(2): 730-738, 2023 01 17.
Article in English | MEDLINE | ID: mdl-36574961

ABSTRACT

The mechanisms by which angiotensin II type 1 receptor is distributed and the diffusional pattern in the plasma membrane (PM) remain unclear, despite their crucial role in cardiovascular homeostasis. In this work, we obtained quantitative information of angiotensin II type 1 receptor (AT1R) lateral dynamics as well as changes in the diffusion properties after stimulation with ligands in living cells using photoactivated localization microscopy (PALM) combined with image spatial-temporal correlation analysis. To study the organization of the receptor at the nanoscale, expansion microscopy (ExM) combined with PALM was performed. This study revealed that AT1R lateral diffusion increased after binding to angiotensin II (Ang II) and the receptor diffusion was transiently confined in the PM. In addition, ExM revealed that AT1R formed nanoclusters at the PM and the cluster size significantly decreased after Ang II treatment. Taking these results together suggest that Ang II binding and activation cause reorganization and changes in the dynamics of AT1R at the PM.


Subject(s)
Angiotensin II , Receptor, Angiotensin, Type 1 , Receptor, Angiotensin, Type 1/metabolism , Angiotensin II/pharmacology , Angiotensin II/metabolism , Microscopy , Cell Membrane/metabolism
3.
J Clin Monit Comput ; 37(3): 839-845, 2023 06.
Article in English | MEDLINE | ID: mdl-36495360

ABSTRACT

Capillary refill time (CRT), a costless and widely available tool, has emerged as a promising target to guide septic shock resuscitation. However, it has yet to gain universal acceptance due to its potential inter-observer variability. Standardization of CRT assessment may minimize this problem, but few studies have compared this approach with techniques that directly assess skin blood flow (SBF). Our objective was to determine if an abnormal CRT is associated with impaired SBF and microvascular reactivity in early septic shock patients. Twelve septic shock patients were subjected to multimodal perfusion and hemodynamic monitoring for 24 h. Three time-points (0, 1, and 24 h) were registered for each patient. SBF was measured by laser doppler. We performed a baseline SBF measurement and two microvascular reactivity tests: one with a thermal challenge at 44 °C and other with a vascular occlusion test. Ten healthy volunteers were evaluated to obtain reference values. The patients (median age 70 years) exhibited a 28-day mortality of 50%. Baseline CRT was 3.3 [2.7-7.3] seconds. In pooled data analysis, abnormal CRT presented a significantly lower SBF when compared to normal CRT [44 (13.3-80.3) vs 193.2 (99.4-285) APU, p = 0.0001]. CRT was strongly associated with SBF (R2 0.76, p < 0.0001). An abnormal CRT also was associated with impaired thermal challenge and vascular occlusion tests. Abnormal CRT values observed during early septic shock resuscitation are associated with impaired skin blood flow, and abnormal skin microvascular reactivity. Future studies should confirm these results.


Subject(s)
Shock, Septic , Humans , Aged , Microcirculation , Pilot Projects , Hemodynamics/physiology , Resuscitation/methods
4.
Oxid Med Cell Longev ; 2020: 8867701, 2020.
Article in English | MEDLINE | ID: mdl-33376582

ABSTRACT

Chagas disease is a neglected tropical disease, which affects an estimate of 6-7 million people worldwide. Chagas disease is caused by Trypanosoma cruzi, which is a eukaryotic flagellate unicellular organism. At the primary infection sites, these parasites are phagocytized by macrophages, which produce reactive oxygen species (ROS) in response to the infection with T. cruzi. The ROS produce damage to the host tissues; however, macrophage-produced ROS is also used as a signal for T. cruzi proliferation. At the later stages of infection, mitochondrial ROS is produced by the infected cardiomyocytes that contribute to the oxidative damage, which persists at the chronic stage of the disease. The oxidative damage leads to a functional impairment of the heart. In this review article, we will discuss the mechanisms by which T. cruzi is able to deal with the oxidative stress and how this helps the parasite growth at the acute phase of infection and how the oxidative stress affects the cardiomyopathy at the chronic stage of the Chagas disease. We will describe the mechanisms used by the parasite to deal with ROS and reactive nitrogen species (RNS) through the trypanothione and the mechanisms used to repair the damaged DNA. Also, a description of the events produced by ROS at the acute and chronic stages of the disease is presented. Lastly, we discuss the benefits of ROS for T. cruzi growth and proliferation and the possible mechanisms involved in this phenomenon. Hypothesis is put forward to explain the molecular mechanisms by which ROS triggers parasite growth and proliferation and how ROS is able to produce a long persisting damage on cardiomyocytes even in the absence of the parasite.


Subject(s)
Chagas Disease/metabolism , Macrophages/metabolism , Myocytes, Cardiac/metabolism , Reactive Nitrogen Species/metabolism , Reactive Oxygen Species/metabolism , Trypanosoma cruzi/metabolism , Animals , Chagas Disease/pathology , Chronic Disease , Humans , Macrophages/parasitology , Macrophages/pathology , Myocytes, Cardiac/parasitology , Myocytes, Cardiac/pathology , Oxidation-Reduction
5.
J Chem Ecol ; 46(9): 820-829, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32770448

ABSTRACT

Leucoptera sinuella is a leaf-miner moth present in several regions in the world, which has been recently introduced into Chile. The larvae feed exclusively on the leaves of poplar and willow trees, and the damage caused by the feeding behavior poses a threat to the wood-producing industry. Besides, L. sinuella larvae invade nearby orchards for pupation, causing rejections in Chilean fresh fruit for export. Here we report the identification of the female-produced sex pheromone of L. sinuella as a first step towards the development of pheromone-based methods for pest management of this species. First, we analyzed hexane extracts of the abdominal glands of virgin females by gas chromatography coupled with mass spectrometry and identified the major compound in these extracts to be 3,7-dimethylpentadecane, while minor compounds in the extracts proved to be 3,7-dimethyltetradecane and 7-methylpentadecane. Structure assignments were carried out by comparison of retention times and mass spectra of the natural products with those of authentic reference samples. Second, we conducted field tests, which showed that traps baited with synthetic 3,7-dimethylpentadecane were significantly attractive to males in a dose-dependent response. Our results also showed that a mixture of 3,7-dimethylpentadecane, 3,7-dimethyltetradecane, and 7-methylpentadecane in proportions similar to those found in gland extracts was the most attractive lure.


Subject(s)
Lepidoptera/physiology , Populus/parasitology , Salix/parasitology , Sex Attractants/chemistry , Animals , Female , Plant Leaves/parasitology
6.
Obes Surg ; 30(12): 4724-4731, 2020 Dec.
Article in English | MEDLINE | ID: mdl-32808168

ABSTRACT

INTRODUCTION: Laparoscopic bariatric surgery (LBS) in liver end-stage organ disease has been proven to improve organ function and patients' symptoms. A series of LBS in patients with cirrhosis have shown good results in weight loss, but increased risk of complications. Current literature is based on clinical series. This paper aims to compare LBS (69% gastric bypass) between patients with cirrhosis and without cirrhosis. METHODS: We conducted a retrospective 1:3 matched case-control study including bariatric patients with cirrhosis and without cirrhosis. Demographics, operative variables, postoperative complications, long-term weight loss, and comorbidity resolution were compared between groups. RESULTS: Sixteen Child A patients were included in the patients with cirrhosis (PC) group and 48 in patients without cirrhosis (control) group. Mean age was 50 years; preoperative BMI was 39 ± 6.8 kg/m2. Laparoscopic gastric bypass and laparoscopic sleeve gastrectomy were performed in 69% and 31%, respectively. Follow-up was 81% at 2 years for both groups. PC group had a higher rate of overall (31% vs. 6%; p < 0.05) and severe (Clavien-Dindo ≥ III; 13% vs. 0%; p = 0.013) complications than that of the control group. Mean %EWL of PC at 2 years of follow-up was 84.9%, without differences compared with that of the control group (83.1%). Comorbidity remission in PC was 14%, 50%, and 85% for hypertension, type 2 diabetes, and dyslipidemia, respectively. Patients without cirrhosis had a higher resolution rate of hypertension (65% vs. 14%, p = 0.03). CONCLUSION: LBS is effective for weight loss and comorbidity resolution in patients with obesity and Child A liver cirrhosis. However, these results are accompanied by significantly increased risk of complications.


Subject(s)
Bariatric Surgery , Diabetes Mellitus, Type 2 , Gastric Bypass , Laparoscopy , Obesity, Morbid , Case-Control Studies , Child , Diabetes Mellitus, Type 2/complications , Gastrectomy , Humans , Liver Cirrhosis/epidemiology , Middle Aged , Obesity, Morbid/surgery , Retrospective Studies , Treatment Outcome
7.
Cancers (Basel) ; 12(1)2020 Jan 20.
Article in English | MEDLINE | ID: mdl-31968594

ABSTRACT

The genetic variations responsible for tumorigenesis are called driver mutations. In breast cancer (BC), two studies have demonstrated that germline mutations in driver genes linked to sporadic tumors may also influence BC risk. The present study evaluates the association between SNPs and SNP-SNP interaction in driver genes TTN (rs10497520), TBX3 (rs2242442), KMT2D (rs11168827), and MAP3K1 (rs702688 and rs702689) with BC risk in BRCA1/2-negative Chilean families. The SNPs were genotyped in 489 BC cases and 1078 controls by TaqMan Assay. Our data do not support an association between rs702688: A>G or rs702689: G>A and BC risk. The rs10497520-T allele was associated with a decreased risk in patients with family history of BC or early-onset BC (OR = 0.6, p < 0.0001 and OR = 0.7, p = 0.05, respectively). rs2242442-G was associated with a protective effect and rs11168827-C was associated with increased BC risk in families with a strong history of BC (OR = 0.6, p = 0.02 and OR = 1.4, p = 0.05, respectively). As rs10497520-T and rs2242442-G seemed to protect against BC risk, we then evaluated their combined effect. Familial BC risk decreased in a dose-dependent manner with the protective allele count, reflecting an additive effect (p-trend < 10-4). To our knowledge, this is the first association study of BC driver gene germline variations in a Chilean population.

8.
Genes (Basel) ; 9(9)2018 Aug 22.
Article in English | MEDLINE | ID: mdl-30135399

ABSTRACT

Breast cancer (BC) is one of the most frequent tumors affecting women worldwide. microRNAs (miRNAs) single-nucleotide polymorphisms (SNPs) likely contribute to BC susceptibility. We evaluated the association of five SNPs with BC risk in non-carriers of the BRCA1/2-mutation from a South American population. The SNPs were genotyped in 440 Chilean BRCA1/2-negative BC cases and 1048 controls. Our data do not support an association between rs2910164:G>C or rs3746444:A>G and BC risk. The rs12975333:G>T is monomorphic in the Chilean population. The pre-miR-605 rs2043556-C allele was associated with a decreased risk of BC, both in patients with a strong family history of BC and in early-onset non-familial BC (Odds ratio (OR) = 0.5 [95% confidence interval (CI) 0.4⁻0.9] p = 0.006 and OR = 0.6 [95% CI 0.5⁻0.9] p = 0.02, respectively). The rs4541843-T allele is associated with increased risk of familial BC. This is the first association study on rs4541843 and BC risk. Previously, we showed that the TOX3-rs3803662:C>T was significantly associated with increased risk of familial BC. Given that TOX3 mRNA is a target of miR-182, and that both the TOX3 rs3803662-T and pri-miR-182 rs4541843-T alleles are associated with increased BC risk, we evaluated their combined effect. Risk of familial BC increased in a dose-dependent manner with the number of risk alleles (p-trend = 0.0005), indicating an additive effect.

9.
Proc Natl Acad Sci U S A ; 115(10): E2202-E2209, 2018 03 06.
Article in English | MEDLINE | ID: mdl-29463754

ABSTRACT

The translation of mRNAs into proteins serves as a critical regulatory event in gene expression. In the context of cancer, deregulated translation is a hallmark of transformation, promoting the proliferation, survival, and metastatic capabilities of cancer cells. The best-studied factor involved in the translational control of cancer is the eukaryotic translation initiation factor 4E (eIF4E). We and others have shown that eIF4E availability and phosphorylation promote metastasis in mouse models of breast cancer by selectively augmenting the translation of mRNAs involved in invasion and metastasis. However, the impact of translational control in cell types within the tumor microenvironment (TME) is unknown. Here, we demonstrate that regulatory events affecting translation in cells of the TME impact cancer progression. Mice bearing a mutation in the phosphorylation site of eIF4E (S209A) in cells comprising the TME are resistant to the formation of lung metastases in a syngeneic mammary tumor model. This is associated with reduced survival of prometastatic neutrophils due to decreased expression of the antiapoptotic proteins BCL2 and MCL1. Furthermore, we demonstrate that pharmacological inhibition of eIF4E phosphorylation prevents metastatic progression in vivo, supporting the development of phosphorylation inhibitors for clinical use.


Subject(s)
Breast Neoplasms/pathology , Eukaryotic Initiation Factor-4E/genetics , Eukaryotic Initiation Factor-4E/metabolism , Lung Neoplasms/metabolism , Lung Neoplasms/secondary , Neutrophils/metabolism , Protein Biosynthesis , Tumor Microenvironment , Amino Acid Motifs , Animals , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Line, Tumor , Eukaryotic Initiation Factor-4E/chemistry , Female , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mice , Mice, Inbred BALB C , Mice, SCID , Myeloid Cell Leukemia Sequence 1 Protein/genetics , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Neoplasm Metastasis , Phosphorylation , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism
10.
Int J Mol Sci ; 19(1)2018 Jan 22.
Article in English | MEDLINE | ID: mdl-29361751

ABSTRACT

Micro-RNAs (miRNAs) have emerged as novel gene expression regulators. Recent evidence strongly suggests a role for miRNAs in a large variety of cancer-related pathways. Different studies have shown that 18.7 to 37% of all human miRNA genes are clustered. miR-17-92 polycistronic cluster overexpression is associated with human hematolymphoid and solid malignancies including breast cancer (BC). Here, we report the identification of rs770419845, a rare 6 bp deletion located within the polycistronic miR-17-92 cluster, in two first-degree relatives from a Chilean family with familial BC and negative for point mutations in BRCA 1/2 genes. The deletion was identified by Sanger sequencing when 99 BRCA1/2 mutation-negative BC cases with a strong family history were initially screened. In silico analysis predicts that rs770419845 affects the secondary structure and stability of the pre-miR-17-pre-miR-18 region and the entire 17-92 cluster. The deletion was screened in 458 high-risk BRCA1/2-negative Chilean families and 480 controls. rs770419845 was not detected in any control but identified in a single family with two cases of BC and other cancers. Both BC cases, the mother and her daughter, carried the deletion. Based on bioinformatic analyses, the location of the deletion and its low frequency, we presume rs770419845 may be a pathogenic variant. Functional studies are needed to support this hypothesis.


Subject(s)
Breast Neoplasms/diagnosis , Breast Neoplasms/genetics , Germ-Line Mutation , Heterozygote , MicroRNAs/genetics , Multigene Family , Sequence Deletion , Adult , Aged , Base Sequence , Chile , Family , Female , Humans , Middle Aged , Nucleic Acid Conformation , Pedigree , RNA, Long Noncoding , Sequence Analysis, DNA
11.
Int J Antimicrob Agents ; 51(2): 190-196, 2018 Feb.
Article in English | MEDLINE | ID: mdl-29032112

ABSTRACT

Studies have demonstrated the efficacy of pyrazinamide (PZA) against stages of the Leishmania parasite that causes cutaneous leishmaniasis. Although PZA is widely distributed in most body fluids and tissues, the amount of drug reaching the skin is unknown. This study aimed to investigate the pharmacokinetics of PZA in rat dermal tissue by dermal microdialysis. Skin pharmacokinetics was assessed by implanting a linear microdialysis probe in the dermis of ten rats. In addition, blood samples were collected to assess plasma pharmacokinetics. Unbound microdialysate (N = 280) and plasma (N = 120) concentrations following single intravenous doses of 25 mg/kg or 50 mg/kg PZA were quantified by a validated HPLC method. Probe calibration was performed by retrodialysis. Non-compartmental analysis and non-linear mixed-effects modelling were performed using WinNonlin and NONMEM v.7.3. PZA rapidly permeated into the dermis and reached high levels, with mean maximum concentrations (Cmax) of 22.4 ± 7.1 µg/mL and 48.6 ± 17.3 µg/mL for the two doses studied. PZA showed significant distribution to the skin (fAUCdermal/fAUCplasma = 0.82 ± 0.31 and 0.84 ± 0.25 for 25 mg/kg and 50 mg/kg doses, respectively). Active unbound concentrations in dermal tissue reached lower levels than free plasma concentrations, indicating that free PZA levels in plasma were in equilibrium with tissue levels. These results showed equivalent unbound drug tissue concentrations and corresponding unbound plasma levels. This study shows that PZA distributes rapidly into dermal interstitial fluid space in rats and therefore may be a potential agent in the treatment of cutaneous leishmaniasis.


Subject(s)
Antiparasitic Agents/blood , Antiparasitic Agents/pharmacokinetics , Leishmaniasis, Cutaneous/drug therapy , Microdialysis/methods , Pyrazinamide/blood , Pyrazinamide/pharmacokinetics , Skin/chemistry , Animals , Leishmania/drug effects , Leishmaniasis, Cutaneous/parasitology , Male , Rats , Rats, Wistar , Skin/drug effects , Skin/parasitology
12.
Biol Res ; 50(1): 35, 2017 Oct 06.
Article in English | MEDLINE | ID: mdl-28985766

ABSTRACT

Breast cancer (BC) is the most common malignancy among women worldwide. A major advance in the understanding of the genetic etiology of BC was the discovery of BRCA1 and BRCA2 (BRCA1/2) genes, which are considered high-penetrance BC genes. In non-carriers of BRCA1/2 mutations, disease susceptibility may be explained of a small number of mutations in BRCA1/2 and a much higher proportion of mutations in ethnicity-specific moderate- and/or low-penetrance genes. In Central and South American populations, studied have focused on analyzing the distribution and prevalence of BRCA1/2 mutations and other susceptibility genes that are scarce in Latin America as compared to North America, Europe, Australia, and Israel. Thus, the aim of this review is to present the current state of knowledge regarding pathogenic BRCA variants and other BC susceptibility genes. We conducted a comprehensive review of 47 studies from 12 countries in Central and South America published between 2002 and 2017 reporting the prevalence and/or spectrum of mutations and pathogenic variants in BRCA1/2 and other BC susceptibility genes. The studies on BRCA1/2 mutations screened a total of 5956 individuals, and studies on susceptibility genes analyzed a combined sample size of 11,578 individuals. To date, a total of 190 different BRCA1/2 pathogenic mutations in Central and South American populations have been reported in the literature. Pathogenic mutations or variants that increase BC risk have been reported in the following genes or genomic regions: ATM, BARD1, CHECK2, FGFR2, GSTM1, MAP3K1, MTHFR, PALB2, RAD51, TOX3, TP53, XRCC1, and 2q35.


Subject(s)
Breast Neoplasms/genetics , Genes, BRCA1 , Genes, BRCA2 , Genetic Predisposition to Disease/genetics , Mutation , Ovarian Neoplasms/genetics , Central America , Female , Humans , South America
13.
Biol. Res ; 50: 35, 2017. tab, graf
Article in English | LILACS | ID: biblio-950894

ABSTRACT

Breast cancer (BC) is the most common malignancy among women worldwide. A major advance in the understanding of the genetic etiology of BC was the discovery of BRCA1 and BRCA2 (BRCA1/2) genes, which are considered high-penetrance BC genes. In non-carriers of BRCA1/2 mutations, disease susceptibility may be explained of a small number of mutations in BRCA1/2 and a much higher proportion of mutations in ethnicity-specific moderate- and/or low-penetrance genes. In Central and South American populations, studied have focused on analyzing the distribution and prevalence of BRCA1/2 mutations and other susceptibility genes that are scarce in Latin America as compared to North America, Europe, Australia, and Israel. Thus, the aim of this review is to present the current state of knowledge regarding pathogenic BRCA variants and other BC susceptibility genes. We conducted a comprehensive review of 47 studies from 12 countries in Central and South America published between 2002 and 2017 reporting the prevalence and/or spectrum of mutations and pathogenic variants in BRCA1/2 and other BC susceptibility genes. The studies on BRCA1/2 mutations screened a total of 5956 individuals, and studies on susceptibility genes analyzed a combined sample size of 11,578 individuals. To date, a total of 190 different BRCA1/2 pathogenic mutations in Central and South American populations have been reported in the literature. Pathogenic mutations or variants that increase BC risk have been reported in the following genes or genomic regions: ATM, BARD1, CHECK2, FGFR2, GSTM1, MAP3K1, MTHFR, PALB2, RAD51, TOX3, TP53, XRCC1, and 2q35.


Subject(s)
Humans , Female , Ovarian Neoplasms/genetics , Breast Neoplasms/genetics , Genes, BRCA1 , Genetic Predisposition to Disease/genetics , Genes, BRCA2 , Mutation , South America , Central America
14.
BMC Genet ; 17(1): 109, 2016 07 15.
Article in English | MEDLINE | ID: mdl-27421647

ABSTRACT

BACKGROUND: MicroRNAs (miRNAs) are a novel class of endogenous, non-coding, single-stranded RNAs capable of regulating gene expression by suppressing translation or degrading mRNAs. Single nucleotide polymorphisms (SNP) can alter miRNA expression, resulting in diverse functional consequences. Previous studies have examined the association of miRNA SNPs with breast cancer (BC) susceptibility. The contribution of miRNA gene variants to BC susceptibility in South American women had been unexplored. Our study evaluated the association of the SNPs rs895819 in pre-miR27a, rs11614913 in pre-miR-196a2, rs6505162 in pre-miR-423, rs4919510 in miR-608, and rs2682818 in pre-mir-618 with familial BC and early-onset non-familial BC in non-carriers of BRCA1/2 mutations from a South American population. RESULTS: We evaluated the association of five SNPs with BC risk in 440 cases and 807 controls. Our data do not support an association of rs11614913:C > T and rs4919510:C > G with BC risk. The rs6505162:C > A was significantly associated with increased risk of familial BC in persons with a strong family history of BC (OR = 1.7 [95 % CI 1.0-2.0] p = 0.05). The rs2682818:C > A genotype C/A is associated with an increased BC risk in non-familial early-onset BC. For the rs895819:A > G polymorphism, the genotype G/G is significantly associated with reduced BC risk in families with a moderate history of BC (OR = 0.3 [95 % CI 0.1-0.8] p = 0.01). CONCLUSIONS: The contribution of variant miRNA genes to BC in South American women had been unexplored. Our findings support the following conclusions: a) rs6505162:C > A in pre-miR-423 increases risk of familial BC in families with a strong history of BC; b) the C/A genotype at rs2682818:C > A (pre-miR-618) increases BC risk in non-familial early-onset BC; and c) the G/G genotype at rs895819:A > G (miR-27a) reduces BC risk in families with a moderate history of BC.


Subject(s)
Breast Neoplasms/genetics , Genetic Predisposition to Disease/genetics , MicroRNAs/genetics , Polymorphism, Single Nucleotide , RNA Precursors/genetics , Female , Gene Frequency , Humans , Middle Aged , Mutation , South America
15.
BMC Cancer ; 15: 30, 2015 Jan 31.
Article in English | MEDLINE | ID: mdl-25636233

ABSTRACT

BACKGROUND: Germline mutations in PALB2 have been identified in approximately 1% of familial breast cancer (BC) in several populations. Nevertheless its contribution in the South-American population is unknown. The goal of this study was to determine the prevalence of PALB2 mutations in the Chilean population. METHODS: 100 Chilean BRCA1/2-negatives familial BC cases were included for the PALB2 mutation analysis. We use conformational sensitive gel electrophoresis and direct sequencing. Using a case-control design, we studied the identified variants in 436 BC cases and 809 controls to evaluate their possible association with BC risk. RESULTS: No pathogenic mutations were detected. We identified three variants, the variant c.1861C > A not previously described was found in one of the 436 cases and none of the 809 controls. The bioinformatic analyses indicate that this variant probably is not pathogenic. PALB2 c.1676A > G (rs152451A/G) and c.2993C > T (rs45551636C/T) variants were significantly associated with increased BC risk only in cases with a strong family history of BC (OR = 1.9 [CI 95% 1.3-2.8] p < 0.01 and OR = 3.3 [CI 95% 1.4-7.3] p < 0.01, respectively). The rs152451A/G-rs45551636C/T composite genotype produce increase of the BC risk in cases with a strong family history of BC (OR = 3.6 [CI 95% 1.7-8.0] p = 0.003). The rs152451-G/rs45551636-C and rs152451-G/rs45551636-T haplotypes were associated with an increased BC risk only in cases with a strong family history of BC (OR = 1.6 [CI 95% 1.0-2.5] p = 0.05 and OR = 3.7 [CI 95% 1.8-7.5] p < 0.001, respectively). CONCLUSION: Our results suggest that PALB2 c.1676A > G and c.2993C > T play roles in BC risk in women with a strong family history of BC.


Subject(s)
Genetic Predisposition to Disease , Genetic Variation , Nuclear Proteins/genetics , Tumor Suppressor Proteins/genetics , Adult , Age of Onset , Alleles , Breast Neoplasms/epidemiology , Breast Neoplasms/genetics , Case-Control Studies , Chile/epidemiology , Computational Biology , DNA Mutational Analysis , Fanconi Anemia Complementation Group N Protein , Female , Gene Frequency , Genotype , Haplotypes , Humans , Middle Aged , Mutation , Population Surveillance , Prevalence , Risk , Young Adult
16.
Curr Pharm Biotechnol ; 15(9): 864-79, 2014.
Article in English | MEDLINE | ID: mdl-25213311

ABSTRACT

Recent advances in nanotechnology and nanobiotechnology have contributed to the development of nanomaterials, able to be used as drug carriers, probes, targets or cytostatic drugs by itself. Nanomedicine is now the leading area in nanotechnology where a large number and types of nanoparticles (NPs) has been developed and several are already in the clinical practice. Chemotherapy is one of the most widely used strategies to treat cancer. Most chemotherapeutic agents have poor solubility, low bioavailability, and are formulated with toxic solvents. NPs have been designed to overcome the lack of specificity of chemotherapeutic agents as well to improve circulation time in blood, taking advantages on tumor cells characteristics. In immunology, recent advances regarding the activation of the innate immune system artificially enhanced by NPs functionalized with immune-stimulators open a new window as novel methods in vaccines. Also, viruses and virus-like particles (VLPs) engineered to stimulate immune response against their similar virus or as molecular platforms for the presentation of foreign epitopes have been described. In this review we focused in the use of different types of NPs in oncology and immunology, pinpointing the main novelties regarding their development and use of nanotechnology in a broad array of applications, ranging from tumor diagnostics, immune-modulation up to cancer therapeutics.


Subject(s)
Antineoplastic Agents , Immunologic Factors , Nanoparticles , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Dendrimers/chemistry , Graphite/chemistry , Humans , Immunologic Factors/administration & dosage , Immunologic Factors/chemistry , Immunologic Factors/therapeutic use , Liposomes , Nanomedicine , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Nanoparticles/therapeutic use , Nanotubes, Carbon/chemistry , Neoplasms/drug therapy , Silicon Dioxide/chemistry
17.
Cuad. psicol. deporte ; 14(1): 23-28, ene. 2014. tab
Article in Spanish | IBECS | ID: ibc-120715

ABSTRACT

El presente artículo muestra cuál es la percepción que tienen los estudiantes de la carrera de educación física de la UISEK de Chile hacia los profesores de distintas áreas de su carrera. En la muestra participaron 195 alumnos, 58 cursan primer año, 57 segundo, 57 tercer y 23 cuarto año. Se les aplicó una modificación del Cuestionario de actitudes de los escolares hacia la Educación Física (Cárcamo, 2012). Los resultados, revelan que los estudiantes de cuarto año, poseen una percepción menos positiva en comparación con los demás cursos, lo que podría deberse a la mayor actitud crítica que presentan los estudiantes universitarios en los últimos años de carrera. Por otra parte, los estudiantes de primer y segundo año, poseen una percepción más negativa en comparación a los demás cursos encuestados, lo que se atribuye al cambio entre la docencia de colegio y la universitaria. En relación a la percepción de los profesores por áreas de estudio y sexo de la muestra no se encontraron diferencias significativas. Se hace necesario nuevos estudios para ahondar en estas similitudes y diferencias en la percepción de los estudiantes sobre sus profesores universitarios (AU)


The present article shows which is the perception that there have the students of the career of physical education of the UISEK of Chile towards the teachers of different areas of his degree. In the sample 195 students took part, 58 deals the first year, 57 second, 57 third and 23 fourth years. There was applied to them a modification of the questionnaire of attitudes of the students towards the Physical Education (Cárcamo, 2012). The results, they reveal that the students of fourth year possess a less positive perception in comparison with other courses, which might owe to the major critical attitude that the university students present in the last years of career. On the other hand, the students of the first and second year possess a more negative perception in comparison to other polled courses, which assumes to the change between the teaching college and the university student. In relation to the perception of the teachers for areas of study and sex of the sample they did not find significant differences. It becomes new studies necessary to go deeply into these similarities and differences into the perception of the students on his university teachers (AU)


O presente artigo mostra que é a percepção de que há que os alunos da carreira de educação física da UISEK do Chile para os professores de diferentes áreas do seu diploma. Na amostra 195 estudantes participaram, 58 ofertas no primeiro ano, de 57 segundo, 57 terceiro e quarto anos 23. Foi aplicada uma adaptaçao do questionário de atitudes dos estudantes em relação à Educação Física (Cárcamo, 2012) Os resultados, revelam que os alunos do quarto ano possuem uma percepção menos positiva em comparação com outros cursos, que pode dever à grande atitude crítica que os estudantes universitários presentes em seus últimos anos de carreira. Por outro lado, os alunos do primeiro e segundo ano possuem uma percepção mais negativa em comparação com outros cursos consultados, o que pressupõe a mudança entre a faculdade eo ensino universitário. Em relação à percepção dos professores para as áreas de estudo e sexo da amostra não encontraram diferenças significativas. Torna-se novos estudos necessários para aprofundar essas semelhanças e diferenças na percepção dos alunos sobre os professores universitários (AU)


Subject(s)
Humans , Social Perception , Physical Education and Training , Students/statistics & numerical data , Faculty/statistics & numerical data , Learning , Surveys and Questionnaires
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