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1.
Purinergic Signal ; 20(1): 73-82, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37055675

RESUMO

Plasmacytoid dendritic cells (pDCs) are a specialized DC subset mainly associated with sensing viral pathogens and high-type I interferon (IFN-I) release in response to toll-like receptor (TLR)-7 and TLR-9 signaling. Currently, pDC contribution to inflammatory responses is extensively described; nevertheless, their regulatory mechanisms require further investigation. CD39 and CD73 are ectoenzymes driving a shift from an ATP-proinflammatory milieu to an anti-inflammatory environment by converting ATP to adenosine. Although the regulatory function of the purinergic halo CD39/CD73 has been reported in some immune cells like regulatory T cells and conventional DCs, its presence in pDCs has not been examined. In this study, we uncover for the first time the expression and functionality of the purinergic halo in human blood pDCs. In healthy donors, CD39 was expressed in the cell surface of 14.0 ± 12.5% pDCs under steady-state conditions, while CD73 showed an intracellular location and was only expressed in 8.0 ± 2.2% of pDCs. Nevertheless, pDCs stimulation with a TLR-7 agonist (R848) induced increased surface expression of both molecules (43.3 ± 23.7% and 18.6 ± 9.3%, respectively), as well as high IFN-α secretion. Furthermore, exogenous ATP addition to R848-activated pDCs significantly increased adenosine generation. This effect was attributable to the superior CD73 expression and activity because blocking CD73 reduced adenosine production and improved pDC allostimulatory capabilities on CD4 + T cells. The functional expression of the purinergic halo in human pDCs described in this work opens new areas to investigate its participation in the regulatory pDC mechanisms in health and disease.


Assuntos
Adenosina , Linfócitos T CD4-Positivos , Humanos , Adenosina/metabolismo , Transdução de Sinais , Trifosfato de Adenosina/metabolismo , Células Dendríticas/metabolismo
2.
Res Sq ; 2023 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-37292678

RESUMO

The ancestral gamete fusion protein, HAP2, catalyzes sperm-egg fusion in a broad range of taxa dating to the last eukaryotic common ancestor. Remarkably, HAP2 orthologs are structurally related to the class II fusogens of modern-day viruses, and recent studies make clear that these proteins utilize similar mechanisms to achieve membrane merger. To identify factors that may regulate HAP2 activity, we screened mutants of the ciliate Tetrahymena thermophila for behaviors that mimic Δhap2 knockout phenotypes in this species. Using this approach, we identified two new genes, GFU1 and GFU2, whose products are necessary for the formation of membrane pores during fertilization and show that the product of a third gene, namely ZFR1, may be involved in pore maintenance and/or expansion. Finally, we propose a model that explains cooperativity between the fusion machinery on apposed membranes of mating cells and accounts for successful fertilization in T. thermophila's multiple mating type system.

3.
Entropy (Basel) ; 23(6)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34071912

RESUMO

Despite that many image encryption systems based on chaotic or hyperchaotic systems have been proposed to protect different kinds of information, it has been crucial to achieve as much security as possible in such systems. In this sense, we numerically implement a known image encryption system with some variants, making special emphasis when two operations are considered in the scrambling stage. The variants of such an encryption system are based on some hyperchaotic systems, which generated some substitution boxes and the keys of the system. With the aim to have a more complete evaluation, some internal stages of the image encryption scheme have been evaluated by using common statistical tests, and also the scaling behavior of the encrypted images has been calculated by means of a two-dimensional detrended fluctuation analysis (2D-DFA). Our results show that the image encryption systems that include two operations or transformations in the scrambling stage present a better performance than those encryption systems that consider just one operation. In fact, the 2D-DFA approach was more sensitive than some common statistical tests to determine more clearly the impact of multiple operations in the scrambling process, confirming that this scaling method can be used as a perceptual security metric, and it may contribute to having better image encryption systems.

4.
Semergen ; 47(5): 295-304, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33359383

RESUMO

OBJECTIVE: We aim to determine the effect of a fixed-dose combination (FDC) of tiotropium/olodaterol on Physical activity (PA) in patients with chronic obstructive pulmonary disease (COPD) in a real world setting. METHODS: COPD patients were prospectively enrolled to evaluate the effect of a FDC of tiotropium/olodaterol inhaler therapy via the Respimat® Soft Mist™ inhaler (SMI) on the physical functioning scale (PF-10), and the general condition of the patient as assessed by the physician (Physician's Global Evaluation, PGE), and the patient's satisfaction after 6 weeks of treatment. The primary end-point was the percentage of patients with therapeutic success at 6th week follow-up, defined as a ≥10-points increase in the standardised PF-10 score from baseline. RESULTS: A total of 257 patients from 57 sites were enrolled, and 234 completed the follow up. After 6 weeks of treatment, 155 out of 234 patients (66.2%) showed therapeutic success in the physical functioning score, coupled with significant improvement in PGE score: 78 (33.3%) patients with good/excellent PGE score at baseline, increasing to 172 (73.5%) at 6th week (p<0.0001). The patient's satisfaction was excellent: 77.2% reporting to be satisfied/very satisfied with the treatment, 79.9% with inhaling and 79.0% with the handling of SMI device. 1.6% of patients reported an investigator-defined drug-related adverse event. CONCLUSION: Treatment of COPD patients with a FDC of tiotropium/olodaterol SMI for 6 weeks resulted in significant improvements in the patients' condition as assessed by patients and physicians, with no new safety findings.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2 , Broncodilatadores/uso terapêutico , Combinação de Medicamentos , Exercício Físico , Volume Expiratório Forçado , Humanos , Nebulizadores e Vaporizadores , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Resultado do Tratamento
5.
Obes Surg ; 30(12): 5026-5032, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32880049

RESUMO

BACKGROUND: Roux-en-Y gastric bypass (RYGB) is often the preferred conversion procedure for laparoscopic adjustable gastric banding (LAGB) poor responders. However, there is controversy whether it is better to convert in one or two stages. This study aims to compare the outcomes of one and two-stage conversions of LAGB to RYGB. METHODS: Retrospective review of a multicenter prospectively collected database. Data on conversion in one and two stages was compared. RESULTS: Eight hundred thirty-two patients underwent LAGB conversion to RYGB in seven specialized bariatric centers. Six hundred seventy-three (81%) were converted in one-stage. Patients in the two-stage group were more likely to have experienced technical complications, such as slippage or erosions (86% vs. 37%, p = 0.0001) and to have had a higher body mass index (BMI) (41.6 vs. 39.9 Kg/m2, p = 0.005). There were no differences in postoperative complications and mortality rates between the one-stage and two-stage groups (13.5% vs. 10.8%, and 0.7% vs. 0.0% respectively, p = ns). Mean final BMI and %total weight loss (%TWL) for the one-stage and the two-stage groups were 31.6 vs. 32.4 Kg/m2 (p = ns) and 30.4 vs. 26.8 (p = 0.017) after a mean follow-up of 33 months. Follow-up at 1, 3, and 5 years was 98%, 75%, and 54%, respectively. CONCLUSIONS: One-stage conversion of LAGB to RYGB is safe and effective. Two-stage conversion carries low morbidity and mortality in the case of band slippage, erosion, or higher BMI patients. These findings suggest the importance of patient selection when choosing the appropriate conversion approach.


Assuntos
Derivação Gástrica , Gastroplastia , Laparoscopia , Obesidade Mórbida , Humanos , Obesidade Mórbida/cirurgia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/cirurgia , Reoperação , Estudos Retrospectivos , Resultado do Tratamento
6.
Naunyn Schmiedebergs Arch Pharmacol ; 392(12): 1503-1513, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31312848

RESUMO

Pulmonary fibrosis is an emerging disease with a poor prognosis and high mortality rate that is even surpassing some types of cancer. This disease has been linked to the concomitant appearance of liver cirrhosis. Bleomycin-induced pulmonary fibrosis is a widely used mouse model that mimics the histopathological and biochemical features of human systemic sclerosis, an autoimmune disease that is associated with inflammation and expressed in several corporal systems as fibrosis or other alterations. To determine the effects on proliferation, redox and inflammation protein expression markers were analyzed by immunohistochemistry. Analyses showed a significant increase in protein oxidation levels by lipoperoxidation bio-products and in proliferation and inflammation processes. These phenomena were associated with the induction of the redox status in mice subjected to 100 U/kg bleomycin. These findings clearly show that the bleomycin model induces histopathological alterations in the liver and partially reproduces the complexity of systemic sclerosis. Our results using the bleomycin-induced pulmonary fibrosis model provide a protocol to investigate the mechanism underlying the molecular alteration found in the liver linked to systemic sclerosis.


Assuntos
Bleomicina , Modelos Animais de Doenças , Hepatopatias/etiologia , Fibrose Pulmonar/complicações , Actinas/metabolismo , Animais , Antígenos CD1/metabolismo , Colágeno/metabolismo , Antígeno Ki-67/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Antígeno Nuclear de Célula em Proliferação/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Escleroderma Sistêmico , Pele/efeitos dos fármacos , Pele/patologia
7.
Hum Immunol ; 80(3): 157-162, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30708029

RESUMO

The Mestizos of Oaxaca resulted from the admixture of Zapotecan Natives with Spaniards and Africans. We selected 112 donors from Oaxaca and applied next-generation sequencing to characterize exon and intron variants in complete or extended HLA genes. Some alleles found, are unique to Mexican Natives and most likely will be absent in most major ethnicities, namely: Caucasians, Africans or Asians. Among these are HLA-A*68:03:01, HLA-A*68:05:01, HLA-C*03:04:01:02, HLA-C*15:09, HLA-C*3:05, HLA-C*03:06:01, HLA-B*39:05:01, HLA-B*35:14:01, HLA-B*35:12:01, HLA-B*35:43:01, HLA-B*40:05, HLA-B:40:08, HLA-B*51:02:01, HLA-B*35:24:01 and HLA-B*39:08. HLA-DQA1*05:05:01:05 and some HLA-DRB1 alleles were only present in Amerindians/Mestizos. Three haplotypes are unique to Mexican Natives, five to Middle-Eastern and Sephardi-Jews. We detected a novel HLA-DQA1*04:01:01 exon 4 variant. Any novel allele may have been positively selected to enlarge the peptide-binding repertoire, and some, like HLA-B*39:02:02 and HLA-B*39:05:01 were found with unique haplotype associations, suggesting convergent evolution events and/or allele lineage diversification. The allele frequencies were fairly evenly distributed in most HLA loci with the exception of HLA-DPB1. The application of NGS in Oaxaca is novel and will lead to better use in the clinical setting. It offers deep knowledge on the population structure, origins, migration, and discovery of new alleles and haplotypes that other techniques did not achieve.


Assuntos
Alelos , Etnicidade/genética , Genética Populacional , Antígenos HLA/genética , Adulto , Feminino , Frequência do Gene , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala , Teste de Histocompatibilidade , Humanos , Masculino , México , Análise de Sequência de DNA
8.
Hum Immunol ; 79(12): 834-838, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30365992

RESUMO

Killer cell immunoglobulin-like receptors (KIRs), expressed on Natural Killer (NK) cells, activate/inhibit NK cell function through interactions with their HLA-A, B and C ligands. KIR3DL1 is one of the most polymorphic genes and its effect varies depending on the interaction of the specific allotype with its Bw4 ligand. We investigated the allelic diversity of KIR3DL1/S1 using sequence based typing and we typed as well, their Bw4 ligands in Mexican Mestizos of Mexico City. The results showed that this population has a great KIR3DL1 allelic diversity with ∗01502 (19.9%), ∗00101 (13.2%) and ∗00501 (12.8%) being the most common alleles, while KIR3DS1 showed predominance of ∗01301 (86%); these data agree with the diversity found in most populations studied. At least one KIR3DL1-HIGH surface expression allele was present in 67.5% of the subjects. Phylogenetic comparisons between Mestizos and 28 different populations showed that allelic diversity of KIR3DL1/S1 was similar in Mexican Mestizos from Mexico and in Hispanics from USA. Knowledge of KIR and MHC diversity worldwide is fundamental for understanding the impact of KIR and KIR-ligand polymorphism on NK cell effector functions and is relevant in genetic anthropology, disease association and transplantation.


Assuntos
Etnicidade/genética , Variação Genética , Antígenos HLA/genética , Receptores KIR3DL1/genética , Receptores KIR3DS1/genética , Adulto , Alelos , Feminino , Frequência do Gene , Humanos , Masculino , México , Pessoa de Meia-Idade , Filogenia , Receptores KIR3DL1/classificação , Receptores KIR3DS1/classificação , Adulto Jovem
9.
Allergol Immunopathol (Madr) ; 46(3): 291-303, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29288048

RESUMO

BACKGROUND: With the availability of high-quality asthma guidelines worldwide, one possible approach of developing a valid guideline, without re-working the evidence, already analysed by major guidelines, is the ADAPTE approach, as was used for the development of National Guidelines on asthma. METHODS: The guidelines development group (GDG) covered a broad range of experts from medical specialities, primary care physicians and methodologists. The core group of the GDG searched the literature for asthma guidelines 2005 onward, and analysed the 11 best guidelines with AGREE-II to select three mother guidelines. Key clinical questions were formulated covering each step of the asthma management. RESULTS: The selected mother guidelines are British Thoracic Society (BTS), GINA and GEMA 2015. Responses to the questions were formulated according to the evidence in the mother guidelines. Recommendations or suggestions were made for asthma treatment in Mexico by the core group, and adjusted during several rounds of a Delphi process, taking into account: 1. Evidence; 2. Safety; 3. Cost; 4. Patient preference - all these set against the background of the local reality. Here the detailed analysis of the evidence present in BTS/GINA/GEMA sections on prevention and diagnosis in paediatric asthma are presented for three age-groups: children with asthma ≤5 years, 6-11 years and ≥12 years. CONCLUSIONS: For the prevention and diagnosis sections, applying the AGREE-II method is useful to develop a scientifically-sustained document, adjusted to the local reality per country, as is the Mexican Guideline on Asthma.


Assuntos
Asma/diagnóstico , Asma/prevenção & controle , Criança , Pré-Escolar , Feminino , Humanos , Masculino , México
10.
Oncogene ; 36(19): 2737-2749, 2017 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-27991928

RESUMO

Inhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure.


Assuntos
Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Neoplasias Pulmonares/genética , Proto-Oncogenes/genética , Fatores de Transcrição SOX9/genética , Serina-Treonina Quinases TOR/genética , Fatores de Transcrição/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Neoplasias da Mama/patologia , Proteínas de Transporte/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Células MCF-7 , Proteína do Locus do Complexo MDS1 e EVI1 , Proteínas dos Microfilamentos/genética , Pessoa de Meia-Idade , Metástase Neoplásica , Osteonectina/genética , Proteína Regulatória Associada a mTOR , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Rev. chil. pediatr ; 84(4): 409-416, jul. 2013. ilus, tab
Artigo em Espanhol | LILACS | ID: lil-690544

RESUMO

Introducción: Entre los efectos de la fiebre está el incremento de la frecuencia respiratoria (FR) hasta alcanzar rangos de generar taquipnea. El diagnóstico de neumonía según la OMS basado en la presencia de taquipnea puede sobreestimarse durante la fiebre. El objetivo de este estudio fue determinar la correlación entre fiebre y FR en niños febriles menores de 5 años. Pacientes y Método: Estudio prospectivo de correlación en niños entre 2 y 60 meses. Se midió FR y temperatura corporal al ingreso a Servicio de Urgencia y luego de recibir acetaminofén. Se calculó la correlación entre el cambio de temperatura y el cambio en la FR. Se determinó la frecuencia de taquipnea al ingreso y al normalizar la temperatura. Resultados: 362 pacientes fueron incluidos, media 23,7 meses (DE 16,1). La FR en menores de un año disminuyó 12,9 respiraciones por minuto (DE 6,7) al normalizar temperatura; en mayores, disminuyó 10,7 respiraciones por minuto (DE 5,2). El coeficiente r² entre temperatura y FR fue 0,08 para menores de un año y 0,11 para mayores. De los niños que estaban taquipneicos, 57 por ciento no lo estaban al normalizar la temperatura. Conclusiones: Se recomienda reevaluar la FR de todo niño febril luego de normalizar su temperatura antes de definir taquipnea.


Introduction: Increased body temperature results in raised respiratory rate (RR) leading to tachypnea. According to World Health Organization (WHO), the diagnosis of pneumonia based on the presence of tachypnea can be overestimated during fever. The aim of this study is to determine the correlation between fever and RR in febrile children under five years of age. Patients and Method: A prospective study of correlation in children between 2 and 60 months was performed. RR and body temperature were measured on Emergency Room admission and after receiving acetaminophen. The correlation between the temperature change and the change in the RR was calculated. The frequency of tachypnea at admission and after normalizing the temperature was determined. Results: 362 patients were included, mean age 23.7 months old. RR in children under one year of age decreased 12.9 breaths per minute after normalizing the temperature, in older than one year of age, it decreased 10.7 breaths per minute. The r² coefficient between temperature and RR was 0.08 for children under one year and 0.11 for older. Among the children who were tachypneic, 57 percent did not present this condition after normalizing the temperature. Conclusions: It is recommended to reevaluate RR in all febrile children after normalizing the temperature and before diagnosing tachypnea.


Assuntos
Humanos , Lactente , Pré-Escolar , Febre , Taxa Respiratória/fisiologia , Pneumonia/diagnóstico , Taquipneia , Temperatura Corporal , Estudos Transversais , Serviços Médicos de Emergência , Estudos Prospectivos
14.
Facts Views Vis Obgyn ; 5(1): 72-81, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24753931

RESUMO

Preterm birth (PTB) remains the most common cause of neonatal morbidity and mortality as well as long-term disability. Current strategies to prevent or arrest spontaneous preterm labor (SPTL) have limited success. For almost three decades, there have been no novel pharmacological agents used clinically to address this important obstetrical complication. In this review, we focus on the uterine myocyte as a target for prevention of spontaneous PTB. After presenting an overview of intracellular signaling pathways that are important in regulation of smooth muscle contractility, we discuss previous and current pharmacological approaches to manage SPTL. We also present recent evidence from our own laboratories suggesting a potentially novel and uterine-specific approach to maintain or impose uterine relaxation. Finally, we briefly discuss extrinsic systems that might affect uterine activity and reinforce the concept that SPTL represents a syndrome that is the end result of a variety of pathophysiologic etiologies leading to PTB. We conclude by emphasizing the need for much more research to provide sufficient understanding of the mechanisms of SPTL and to make inroads towards reducing the incidence and adverse consequences of this common and serious syndrome.

15.
Phys Rev E Stat Nonlin Soft Matter Phys ; 86(3 Pt 1): 031138, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23030897

RESUMO

We study heat conduction in a billiard channel formed by two sinusoidal walls and the diffusion of particles in the corresponding channel of infinite length; the latter system has an infinite horizon, i.e., a particle can travel an arbitrary distance without colliding with the rippled walls. For small ripple amplitudes, the dynamics of the heat carriers is regular and analytical results for the temperature profile and heat flux are obtained using an effective potential. The study also proposes a formula for the temperature profile that is valid for any ripple amplitude. When the dynamics is regular, ballistic conductance and ballistic diffusion are present. The Poincaré plots of the associated dynamical system (the infinitely long channel) exhibit the generic transition to chaos as ripple amplitude is increased. When no Kolmogorov-Arnold-Moser (KAM) curves are present to forbid the connection of all chaotic regions, the mean square displacement grows asymptotically with time t as tln(t).

16.
Transplant Proc ; 43(3): 749-50, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21486590

RESUMO

INTRODUCTION: Vascular complications show an 8%-15% incidence after liver transplantation and represent an important cause of mortality. An aggressive policy is necessary for an early diagnosis and treatment. PATIENTS AND METHODS: From 2001 to 2009, we performed 240 liver transplantations in 232 patients. We employed Doppler ultrasonography on days 1 and 4 as well as before hospital discharge and always try a radiological approach. RESULTS: The incidence of vascular complications was 7.2% (n = 18) including arterial (n = 12, 4.8%) of early thrombosis (n = 4), late thrombosis (n = 4), and stenosis (n = 4) or portal (n = 3; 1.2%) of thrombosis (n = 2) or stenosis (n = 1); or caval complications (n = 3, 1.2%). Radiologic therapy was effective in 1 patient with arterial stenosis, in the 3 patients with portal complications, and in 2 patients with caval complications. All patients with early thrombosis and 2/4 with late thrombosis required retransplantation. Surgical treatment was effective in 1 patient with late thrombosis, 3 with stenosis, and 2 with caval complications. The overall mortality rate was 16.6%; 2 patients with arterial complications and 1 with a caval complications. CONCLUSION: Vascular complications, mainly artery complications, represent serious problem after liver transplantation, which often requires retransplantation. With an aggressive policy of diagnosis and treatment, we can decrease the mortality rate from these adverse events.


Assuntos
Transplante de Fígado/efeitos adversos , Doenças Vasculares/etiologia , Humanos , Incidência , Ultrassonografia Doppler , Doenças Vasculares/diagnóstico por imagem
17.
Oncogene ; 29(45): 6071-83, 2010 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-20711236

RESUMO

Endocrine therapies targeting the proliferative effect of 17ß-estradiol through estrogen receptor α (ERα) are the most effective systemic treatment of ERα-positive breast cancer. However, most breast tumors initially responsive to these therapies develop resistance through molecular mechanisms that are not yet fully understood. The long-term estrogen-deprived (LTED) MCF7 cell model has been proposed to recapitulate acquired resistance to aromatase inhibitors in postmenopausal women. To elucidate this resistance, genomic, transcriptomic and molecular data were integrated into the time course of MCF7-LTED adaptation. Dynamic and widespread genomic changes were observed, including amplification of the ESR1 locus consequently linked to an increase in ERα. Dynamic transcriptomic profiles were also observed that correlated significantly with genomic changes and were predicted to be influenced by transcription factors known to be involved in acquired resistance or cell proliferation (for example, interferon regulatory transcription factor 1 and E2F1, respectively) but, notably, not by canonical ERα transcriptional function. Consistently, at the molecular level, activation of growth factor signaling pathways by EGFR/ERBB/AKT and a switch from phospho-Ser118 (pS118)- to pS167-ERα were observed during MCF7-LTED adaptation. Evaluation of relevant clinical settings identified significant associations between MCF7-LTED and breast tumor transcriptome profiles that characterize ERα-negative status, early response to letrozole and tamoxifen, and recurrence after tamoxifen treatment. In accordance with these profiles, MCF7-LTED cells showed increased sensitivity to inhibition of FGFR-mediated signaling with PD173074. This study provides mechanistic insight into acquired resistance to endocrine therapies of breast cancer and highlights a potential therapeutic strategy.


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Tamoxifeno/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Transdução de Sinais
18.
Parasite Immunol ; 32(6): 440-9, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20500675

RESUMO

Leishmania are protozoan parasites that infect macrophages and their survival is partially achieved through inhibition of the cellular oxidative burst by parasite lipophosphoglycan (LPG). PKCalpha is the predominant PKC isoenzyme required for macrophage oxidative burst, yet it is not known if different susceptibility of BALB/c and C57BL/6 mice to Leishmania mexicana could be related to PKCalpha. We analysed the effect of L. mexicana promastigotes and parasite LPG on expression of PKCalpha and on its activity in macrophages of both mouse strains. Our data show that expression of the isoenzyme was not altered either by LPG or by L. mexicana promastigotes. Yet LPG exerted opposing effects on PKCalpha activity of macrophages between both strains: in susceptible BALB/c cells, it inhibited PKCalpha activity, whereas in the more resistant strain it augmented enzymatic activity 2.8 times. In addition, LPG inhibited oxidative burst only in susceptible BALB/c macrophages and the degree of inhibition correlated with parasite survival. Promastigotes also inhibited PKCalpha activity and oxidative burst in macrophages of BALB/c mice, whereas in C57BL/6, they enhanced PKCalpha activity and oxidative burst inhibition was less severe. Our data indicate that control of PKCalpha-induced oxidative burst by L. mexicana LPG relates with its success to infect murine macrophages.


Assuntos
Glicoesfingolipídeos/metabolismo , Leishmania mexicana/patogenicidade , Macrófagos/imunologia , Macrófagos/parasitologia , Proteína Quinase C-alfa/antagonistas & inibidores , Proteína Quinase C-alfa/biossíntese , Explosão Respiratória , Animais , Suscetibilidade a Doenças/imunologia , Perfilação da Expressão Gênica , Leishmaniose Tegumentar Difusa/imunologia , Leishmaniose Tegumentar Difusa/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Análise de Sobrevida
19.
PLoS Negl Trop Dis ; 4(3): e620, 2010 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-20209149

RESUMO

BACKGROUND: Failure to detect a disease agent or vector where it actually occurs constitutes a serious drawback in epidemiology. In the pervasive situation where no sampling technique is perfect, the explicit analytical treatment of detection failure becomes a key step in the estimation of epidemiological parameters. We illustrate this approach with a study of Attalea palm tree infestation by Rhodnius spp. (Triatominae), the most important vectors of Chagas disease (CD) in northern South America. METHODOLOGY/PRINCIPAL FINDINGS: The probability of detecting triatomines in infested palms is estimated by repeatedly sampling each palm. This knowledge is used to derive an unbiased estimate of the biologically relevant probability of palm infestation. We combine maximum-likelihood analysis and information-theoretic model selection to test the relationships between environmental covariates and infestation of 298 Amazonian palm trees over three spatial scales: region within Amazonia, landscape, and individual palm. Palm infestation estimates are high (40-60%) across regions, and well above the observed infestation rate (24%). Detection probability is higher ( approximately 0.55 on average) in the richest-soil region than elsewhere ( approximately 0.08). Infestation estimates are similar in forest and rural areas, but lower in urban landscapes. Finally, individual palm covariates (accumulated organic matter and stem height) explain most of infestation rate variation. CONCLUSIONS/SIGNIFICANCE: Individual palm attributes appear as key drivers of infestation, suggesting that CD surveillance must incorporate local-scale knowledge and that peridomestic palm tree management might help lower transmission risk. Vector populations are probably denser in rich-soil sub-regions, where CD prevalence tends to be higher; this suggests a target for research on broad-scale risk mapping. Landscape-scale effects indicate that palm triatomine populations can endure deforestation in rural areas, but become rarer in heavily disturbed urban settings. Our methodological approach has wide application in infectious disease research; by improving eco-epidemiological parameter estimation, it can also significantly strengthen vector surveillance-control strategies.


Assuntos
Arecaceae/parasitologia , Vetores de Doenças , Ectoparasitoses/parasitologia , Doenças das Plantas/parasitologia , Rhodnius/crescimento & desenvolvimento , Animais , Humanos , Modelos Estatísticos , América do Sul
20.
Trop Med Int Health ; 10(12): 1258-66, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16359406

RESUMO

Most Rhodnius species (Triatominae) are primarily associated with palm trees. They maintain enzootic Trypanosoma cruzi transmission and are responsible for human infection (causing Chagas disease) through the Neotropics. Assessing whether individual palm traits (ecological and/or botanical) may increase the risk of palm infestation by triatomines is relevant in areas where bugs invade houses flying from peridomestic palms. We developed a novel fieldwork approach with that objective, and applied it to study infestation by sylvatic Rhodnius ecuadoriensis in 110 tagua palms (Phytelephas aequatorialis). Palm infestation (23% overall) was non-randomly distributed in our sample. Palms located in anthropic landscapes were frequently infested (>27%, n=92), whereas no bugs were collected from palms surveyed within forest remnants (n=18; P=0.01). The presence of abundant decaying vegetable matter (P=0.001) and (to a lesser extent) epiphytic plants (P=0.049) on palm crowns and stems increased the probability of infestation and was positively correlated with the apparent density of bug colonies (R2=0.68). A trend towards higher infestation rates in male palms (34% vs. 18%) could relate to female palm management (removal of infrutescences and vegetable debris) in areas where palm seeds are harvested. An outline of 'risk palm ecotopes' and environmental management-based strategies for the control of peridomestic, palm tree-living vector populations are proposed.


Assuntos
Ecossistema , Insetos Vetores/fisiologia , Doenças das Plantas/parasitologia , Rhodnius/fisiologia , Árvores/parasitologia , Animais , Doença de Chagas/epidemiologia , Doença de Chagas/transmissão , Equador/epidemiologia , Humanos , Fatores de Risco
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