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1.
Sci Rep ; 14(1): 2951, 2024 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-38316831

RESUMO

Robertsonian translocations, specifically rob(1;29) translocation, have reportedly been the most prevalent chromosomal abnormalities in cattle, affecting various breeds and leading to a decrease in fertility and reproductive value. Currently, the identification of rob(1;29) carriers relies on cytogenetic analysis that has limitations in terms of accessibility, cost, and sample requirements. To address these limitations, a novel genomic biomarker was developed in this study for the rapid and precise identification of rob(1;29) carriers. Using q-PCR, a specific copy number variation associated with translocation was targeted, which effectively distinguished between wild-type, homozygous and heterozygous carriers. Crucially, the biomarker can be applied to DNA extracted from various biological matrices, such as semen, embryos, oocytes, milk, saliva, coat, and muscle, and it is compatible with fresh, refrigerated, or frozen samples. Furthermore, this approach offers significant reductions in cost compared to those associated with traditional cytogenetic analysis and provides results within a short turnaround time. The successful development of this genomic biomarker has considerable potential for widespread adoption in screening programs. It facilitates timely identification and management of rob(1;29) carriers while mitigating economic losses and preserving genetic integrity in bovine populations.


Assuntos
Variações do Número de Cópias de DNA , Translocação Genética , Bovinos/genética , Animais , Aberrações Cromossômicas , Análise Citogenética , Genômica
2.
ALTEX ; 40(4): 635-648, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37422923

RESUMO

Since Russell and Burch introduced and defined the 3Rs, i.e., the replacement, reduction, and refinement of animal use in research, in 1959, different definitions have emerged and been implemented in guidelines and policies. Switzerland is known for having some of the most restrictive legislation regarding the use of animals, in which the 3Rs are also defined and implemented. To our knowledge, the purpose and definitions of the 3Rs used in the Swiss Animal Welfare Act, Animal Protection Ordinance, and Animal Experimentation Ordinance have never been compared with Russell and Burch's original purpose and definitions. In this paper we make this comparison with two aims: to reveal ethically relevant departures from the original purpose and definitions, and to provide an ethical evaluation of the current Swiss law regarding the 3Rs. In doing so, we first expose the similarity of purposes. We then identify one risky departure from the original definition of replacement in Swiss law, which shows a problematic focus on species. Finally, we address Swiss law's failure to apply the 3Rs in the most effective way. With respect to this last point, we discuss the need for 3R conflict resolution, the timing of application of the 3Rs, problematic prioritizations and choices of convenience as well as a solution to apply the 3Rs more effectively using Russell and Burch's concept of total sum of distress.


Assuntos
Experimentação Animal , Alternativas aos Testes com Animais , Animais , Bem-Estar do Animal , Suíça
3.
J Clin Med ; 12(13)2023 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-37445539

RESUMO

Chronic kidney disease-associated pruritus is itching directly related to kidney disease that cannot be explained by any other condition. Despite technological advances in the different aspects of dialysis sessions and the best treatment for chronic kidney disease patients, it is still a common problem in our patients. The many complex physiological mechanisms involved, the different hypotheses made over the years on the aetiology of the condition, and the great clinical variability may partially explain the limited knowledge about this problem and the difficulties in treating it. The presence of all these factors leads to the persistence of unpleasant symptoms, which must affect the disease burden and quality of life of kidney patients. Through the presentation of an illustrative clinical case, the aim of this review article is to highlight the need for adequate diagnosis and an improved approach to all aspects of chronic kidney disease-associated pruritus, in view of the heavy burden of the disease and the huge impact on the patient's quality of life.

5.
Nefrologia (Engl Ed) ; 43(1): 48-62, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37173258

RESUMO

Defined as the unpleasant sensation that causes the desire to scratch, pruritus is the most common skin symptom associated with uremia and appears in almost half of patients with advanced chronic kidney disease (CKD). Beyond its direct impact on quality of life, CKD-associated pruritus (CKD-aP) is an independent predictor of mortality that also has a synergistic effect with other quality of life-related symptoms, such as insomnia, depression, and anxiety. Although different mechanisms have been proposed to explain the origin of Pa-ERC, its etiopathogenesis is still not fully understood. Since new therapeutic targets have been identified and several clinical trials have recently shown promising results, our current understanding of the interrelationships has expanded significantly and the pathophysiological mechanisms underlying CKD-aP are now considered to be multifactorial. The potential triggers of pruritus in patients with CKD are discussed in this review, including hypotheses about skin xerosis, accumulation of uremic toxins, dysregulation of the immune system and systemic inflammation, uremic neuropathy, and imbalances in the endogenous opioid system. Other non-uremic causes of pruritus are also discussed, with the aim of guiding the physicians to apply an adequate aetiopathogenic approach to CKD-aP in their day-to-day clinical practice.


Assuntos
Insuficiência Renal Crônica , Uremia , Humanos , Qualidade de Vida , Prurido/etiologia , Insuficiência Renal Crônica/complicações , Uremia/complicações , Uremia/terapia
6.
Nefrologia (Engl Ed) ; 43(1): 102-110, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37069038

RESUMO

INTRODUCTION: Pruritus associated with chronic kidney disease is defined as the sensation of itching, in people with chronic kidney disease, in a one area or all over the body that causes the need to scratch, after having ruled out other dermatological or systemic causes. It is an old and known problem whose prevalence has been able to decrease with the improvement of dialytic techniques but which still persists and is underdiagnosed. OBJECTIVES: The objective of this study was to analyse the current perception of nephrologists about this problem that influences the quality of life of people with chronic kidney disease through a survey. RESULTS: 135 nephrologists, most of them engaged in haemodialysis, participated. 86% considered that pruritus associated with chronic kidney disease is still a problem today that affects the quality of life. Most nephrologists believe that the main pathophysiological cause is uremic toxins (60%) and only 16% believe that it is due to the dysregulation of the opioid system/endorphins-dynorphins. Only 16% comment that the prevalence of pruritus in their centre is greater than 20%. 40% believe that the diagnosis is made because it is manifested by the patient and only 27% because it is asked by the doctor. Moreover, it is not usual to use scales to measure it or the codification in the medical records. The main treatment used is antihistamines (96%), followed by moisturizers/anaesthetics (93%) and modification of the dialysis regimen (70%). CONCLUSIONS: Pruritus associated with chronic kidney disease is still a current problem, it is underdiagnosed, not codified and with a lack of indicated, effective and safe treatments. Nephrologists do not know its real prevalence and the different pathophysiological mechanisms involved in its development. Many therapeutic options are used with very variable results, ignoring their efficacy and applicability at the present time. The new emerging kappa-opioid-receptor agonist agents offer us an opportunity to reevaluate this age-old problem and improve the quality of life for our patients with chronic kidney disease.


Assuntos
Nefrologistas , Insuficiência Renal Crônica , Humanos , Qualidade de Vida , Analgésicos Opioides/uso terapêutico , Insuficiência Renal Crônica/complicações , Prurido/etiologia , Percepção
7.
Animals (Basel) ; 13(3)2023 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-36766391

RESUMO

In this study, we analyzed the variation of reproductive efficiency, estimated as the deviation between the optimal and real parity number of females at each stage of the cow's life, in 12,554 cows belonging to the Retinta Spanish cattle breed, using classical repeatability and random regression models. The results of the analyses using repeatability model and the random regression model suggest that reproductive efficiency is not homogeneous throughout the cow's life. The h2 estimate for this model was 0.30, while for the random regression model it increased across the parities, from 0.24 at the first calving to 0.51 at calving number 9. Additionally, we performed a preliminary genome-wide association study for this trait in a population of 252 Retinta cows genotyped using the Axiom Bovine Genotyping v3 Array. The results showed 5 SNPs significantly associated with reproductive efficiency, located in two genomic regions (BTA4 and BTA28). The functional analysis revealed the presence of 5 candidate genes located within these regions, which were previously involved in different aspects related to fertility in cattle and mice models. This new information could give us a better understanding of the genetic architecture of reproductive traits in this species, as well as allow us to accurately select more fertile cows.

8.
Cell Death Differ ; 30(4): 906-921, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36693903

RESUMO

Non-melanoma skin cancer (NMSC) has risen dramatically as a result of chronic exposure to sunlight ultraviolet (UV) radiation, climatic changes and clinical conditions associated with immunosuppression. In spite of considerable progress, our understanding of the mechanisms that control NMSC development and their associated molecular and immunological landscapes is still limited. Here we demonstrated a critical role for galectin-7 (Gal-7), a ß-galactoside-binding protein preferentially expressed in skin tissue, during NMSC development. Transgenic mice (Tg46) overexpressing Gal-7 in keratinocytes showed higher number of papillomas compared to WT mice or mice lacking Gal-7 (Lgals7-/-) when subjected to a skin carcinogenesis protocol, in which tumor initiator 7,12-dimethylbenz[a]anthracene (DMBA) and tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) were sequentially administered. RNAseq analysis of Tg46 tumor lesions revealed a unique profile compatible with cells of the myelomonocytic lineage infiltrating these tumors, an effect that was substantiated by a higher number of CD11b+Gr1+ cells in tumor-draining lymph nodes. Heightened c-Met activation and Cxcl-1 expression in Tg46 lesions suggested a contribution of this pathway to the recruitment of these cells. Remarkably, Gal-7 bound to the surface of CD11b+Ly6ChiLy6Glo monocytic myeloid cells and enhanced their immunosuppressive activity, as evidenced by increased IL-10 and TGF-ß1 secretion, and higher T-cell inhibitory activity. In vivo, carcinogen-treated Lgals7-/- animals adoptively transferred with Gal-7-conditioned monocytic myeloid cells developed higher number of papillomas, whereas depletion of these cells in Tg46-treated mice led to reduction in the number of tumors. Finally, human NMSC biopsies showed increased LGALS7 mRNA and Gal-7 protein expression and displayed transcriptional profiles associated with myeloid programs, accompanied by elevated CXCL1 expression and c-Met activation. Thus, Gal-7 emerges as a critical mediator of skin carcinogenesis and a potential therapeutic target in human NMSC.


Assuntos
Papiloma , Neoplasias Cutâneas , Camundongos , Animais , Humanos , Carcinógenos , Neoplasias Cutâneas/patologia , Papiloma/patologia , Carcinogênese/genética , Camundongos Transgênicos , Galectinas/genética , Pele/metabolismo , Imunidade Inata
9.
Rheumatology (Oxford) ; 62(4): 1621-1626, 2023 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-36124987

RESUMO

OBJECTIVE: To describe obstetric outcomes based on COVID-19 vaccination status, in women with rheumatic and musculoskeletal diseases (RMDs) who developed COVID-19 during pregnancy. METHODS: Data regarding pregnant women entered into the COVID-19 Global Rheumatology Alliance registry from 24 March 2020-25 February 2022 were analysed. Obstetric outcomes were stratified by number of COVID-19 vaccine doses received prior to COVID-19 infection in pregnancy. Descriptive differences between groups were tested using the chi-squared or Fisher's exact test. RESULTS: There were 73 pregnancies in 73 women with RMD and COVID-19. Overall, 24.7% (18) of pregnancies were ongoing, while of the 55 completed pregnancies, 90.9% (50) of pregnancies resulted in livebirths. At the time of COVID-19 diagnosis, 60.3% (n = 44) of women were unvaccinated, 4.1% (n = 3) had received one vaccine dose while 35.6% (n = 26) had two or more doses. Although 83.6% (n = 61) of women required no treatment for COVID-19, 20.5% (n = 15) required hospital admission. COVID-19 resulted in delivery in 6.8% (n = 3) of unvaccinated women and 3.8% (n = 1) of fully vaccinated women. There was a greater number of preterm births (PTB) in unvaccinated women compared with fully vaccinated 29.5% (n = 13) vs 18.2% (n = 2). CONCLUSIONS: In this descriptive study, unvaccinated pregnant women with RMD and COVID-19 had a greater number of PTB compared with those fully vaccinated against COVID-19. Additionally, the need for COVID-19 pharmacological treatment was uncommon in pregnant women with RMD regardless of vaccination status. These results support active promotion of COVID-19 vaccination in women with RMD who are pregnant or planning a pregnancy.


Assuntos
COVID-19 , Nascimento Prematuro , Doenças Reumáticas , Gravidez , Recém-Nascido , Feminino , Humanos , Vacinas contra COVID-19 , COVID-19/epidemiologia , COVID-19/prevenção & controle , Teste para COVID-19 , Doenças Reumáticas/tratamento farmacológico , Vacinação
10.
Emerg Infect Dis ; 28(13): S191-S196, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36502384

RESUMO

The US Centers for Disease Control and Prevention, with funding from the US President's Plan for Emergency Relief, implements a virtual model for clinical mentorship, Project Extension for Community Healthcare Outcomes (ECHO), worldwide to connect multidisciplinary teams of healthcare workers (HCWs) with specialists to build capacity to respond to the HIV epidemic. The emergence of and quick evolution of the COVID-19 pandemic created the need and opportunity for the use of the Project ECHO model to help address the knowledge requirements of HCW responding to COVID-19 while maintaining HCW safety through social distancing. We describe the implementation experiences of Project ECHO in 5 Centers for Disease Control and Prevention programs as part of their COVID-19 response, in which existing platforms were used to rapidly disseminate relevant, up-to-date COVID-19-related clinical information to a large, multidisciplinary audience of stakeholders within their healthcare systems.


Assuntos
Síndrome da Imunodeficiência Adquirida , COVID-19 , Infecções por HIV , Humanos , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , COVID-19/prevenção & controle , COVID-19/epidemiologia , Pandemias/prevenção & controle , Cooperação Internacional , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Infecções por HIV/tratamento farmacológico
11.
Sci Rep ; 12(1): 9865, 2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35701652

RESUMO

Intra- and inter-layer integrity of components fabricated with advanced manufacturing techniques, such as laser powder bed fusion, is dependent upon rapid heating, melting, and solidification processes. There is a need for new techniques to provide in situ feedback of these processes. Here a laser-based ultrasonic technique to probe thermal effects induced by a high-power continuous wave laser in titanium samples is described. Numerical simulations were performed to show that, for a spatially uniform heating beam, laser-induced surface acoustic waves are strongly influenced by surface heating conditions, are dispersive in the case of rapid heating, and that an abrupt velocity reduction happens upon the onset of surface melting. Furthermore, laser-based ultrasound experimental results which monitor the transient change of surface wave travel time associated with high power laser surface heating are provided. A pulsed laser is used to generate high frequency surface acoustic waves that propagate through the laser-heated region and are detected using a photorefractive crystal-based interferometer. Qualitative agreement is observed between theory and experiment with both showing a rapid reduction in the surface wave velocity at the onset of illumination and further decrease in surface wave velocity associated with melting. It is demonstrated that changes in the surface wave velocity can be used to track local heating and detect the onset of surface melting in real time.

12.
J Clin Med ; 11(3)2022 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-35160312

RESUMO

The success of hemodialysis (HD) treatments has been evaluated using objective measures of analytical parameters, or machine-measured parameters, despite having available validated instruments that assess patient perspective. There is an emerging interest regarding the use and relevance of patient-related outcomes (PROs). Electronic PROs (ePROs) involve the use of electronic technology, provide rapid access to this information, and are becoming more widely used in clinical trials and studies to evaluate efficacy and safety. Despite the scarce literature, this review suggests that ePROs are useful in providing a more customized and multidimensional approach to patient management and in making better clinical decisions in relevant aspects such as vascular access, duration and frequency of dialysis sessions, treatment of anemia, mental health, fatigue, and quality of life. The purpose of this review is to raise interest in the systematic use of ePROs in HD and to promote the development of studies in this field, which can respond to the gaps in knowledge and contribute to the implementation of the use of ePROs through new technologies, helping to improve the quality of health care.

13.
Reprod Domest Anim ; 57(4): 349-356, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34958697

RESUMO

The Robertsonian translocation 1/29 (rob(1;29)) is the most worldwide widespread chromosomal abnormality in domestic animals. Previous studies have demonstrated its negative effect on fertility in dairy herds, but not in beef cattle extensively bred. In this study, we analysed the effect of rob(1;29) in a Retinta cattle breed data set gathered during the last 30 years. The data presented herein include rob(1;29) analysis of 11,505 cows from 251 herds, pedigree information of 24,790 animals and 67,457 calving records. Fertility was evaluated using estimated breeding values for the reproductive efficiency (Re), calculated as the percentage ratio between the number of calvings of an individual and the number expected in an optimal situation. Our results showed that cows carrying the heterozygote genotype showed a significant decrease in their Re (-5.10%, p < .001). No decrease was detected in free rob(1;29) animals and homozygous carriers. In addition, the incidence of rob(1;29) in the breed fertility was decreased to very low values after 30 years of avoiding selection of bulls' carrier as stallions. The effect of rob(1;29) on cattle fertility is only significant when the prevalence of carrier individuals is high. Selecting against the disease only by the paternal side reduced the incidence to negligible values.


Assuntos
Doenças dos Bovinos , Doenças dos Cavalos , Animais , Bovinos/genética , Doenças dos Bovinos/genética , Aberrações Cromossômicas/veterinária , Feminino , Fertilidade/genética , Doenças dos Cavalos/genética , Cavalos , Masculino , Reprodução , Estudos Retrospectivos , Translocação Genética
14.
Molecules ; 26(24)2021 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-34946715

RESUMO

The green synthesis of iron oxide nanoparticles (FeO NP) has been investigated using the extract in absolute ethanolic and alcoholic solvents 96% from the peel of the mango fruit (Mangifera indica), thus evaluating the influence of the type of solvent on the extraction of reducing metabolites. A broad approach to characterization initially controlled by UV-vis spectrophotometry has been directed, the formation mechanism was evaluated by Fourier transform infrared spectroscopy (FTIR), the magnetic properties by characterization by Physical Property Measurement System (PPSM), in addition to a large number of techniques such as X-ray energy dispersive spectroscopy (EDS), X-ray diffraction (DRX), transmission electron microscopy (TEM/STEM), electron energy loss spectroscopy (EELS), and Z potential to confirm the formation of FeO NP. The results suggest better characteristics for FeO NP synthesized using 96% alcoholic solvent extract. The successful synthesis was directly proven in the removal of metals (Cr-VI, Cd, and Pb) as a potential alternative in the remediation of agricultural soils.


Assuntos
Compostos Férricos/química , Química Verde , Mangifera/química , Nanopartículas/química , Extratos Vegetais/química , Solo/química , Produção Agrícola
15.
Sci Adv ; 7(25)2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34144987

RESUMO

Diverse immunoregulatory circuits operate to preserve intestinal homeostasis and prevent inflammation. Galectin-1 (Gal1), a ß-galactoside-binding protein, promotes homeostasis by reprogramming innate and adaptive immunity. Here, we identify a glycosylation-dependent "on-off" circuit driven by Gal1 and its glycosylated ligands that controls intestinal immunopathology by targeting activated CD8+ T cells and shaping the cytokine profile. In patients with inflammatory bowel disease (IBD), augmented Gal1 was associated with dysregulated expression of core 2 ß6-N-acetylglucosaminyltransferase 1 (C2GNT1) and α(2,6)-sialyltransferase 1 (ST6GAL1), glycosyltransferases responsible for creating or masking Gal1 ligands. Mice lacking Gal1 exhibited exacerbated colitis and augmented mucosal CD8+ T cell activation in response to 2,4,6-trinitrobenzenesulfonic acid; this phenotype was partially ameliorated by treatment with recombinant Gal1. While C2gnt1-/- mice exhibited aggravated colitis, St6gal1-/- mice showed attenuated inflammation. These effects were associated with intrinsic T cell glycosylation. Thus, Gal1 and its glycosylated ligands act to preserve intestinal homeostasis by recalibrating T cell immunity.

16.
Glycobiology ; 31(8): 908-915, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-33978732

RESUMO

Type-2 diabetes mellitus (T2DM) is an expanding global health problem, involving defective insulin secretion by pancreatic ß-cells and peripheral insulin resistance, leading to impaired glucose regulation. Galectin-1-an endogenous lectin with affinity for N-acetyllactosamine (LacNAc)-containing glycans-has emerged as a regulator of inflammatory and metabolic disorders. However, the role of galectin-1 in glucose homeostasis and pancreatic ß-cell function, independently of hypercaloric diets, has not been explored. Here, we identified a phenotype compatible with T2DM, involving alterations in glucose metabolism and pancreatic insulin release, in female but not male mice lacking galectin-1 (Lgals1-/-). Compared with age-matched controls, Lgals1-/- female mice exhibited higher body weight and increased food intake ad libitum as well as after fasting and acute re-feeding. Although fasted serum insulin levels and insulin sensitivity were similar in both genotypes, Lgals1-/- female mice presented altered glucose tolerance and higher basal glucose levels depending on the fasting period. Insulin response to glucose overload was impaired, while pancreatic insulin content was enhanced in the absence of galectin-1. Accordingly, recombinant galectin-1 enhanced glucose-stimulated insulin release in vitro. Our study identifies a role for galectin-1 in regulating glucose metabolism through modulation of pancreatic insulin secretion, highlighting novel opportunities to control T2DM.


Assuntos
Resistência à Insulina , Insulina , Animais , Feminino , Galectina 1/genética , Galectina 1/metabolismo , Glucose/metabolismo , Homeostase , Insulina/metabolismo , Secreção de Insulina , Masculino , Camundongos
17.
Ren Fail ; 43(1): 821-829, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33966595

RESUMO

BACKGROUND: Overhydration is a predictor of mortality in hemodialysis (HD) patients. Bioimpedance spectroscopy (BIS) is used to determine the body composition. Extracellular Water/Total Body Water (ECW/TBW) ratio has been proposed to predict mortality. METHODS: Multicenter, prospective, observational, proof-of-concept study to estimate the impact of ECW/TBW in global and cardiovascular mortality and the relationship with cardiovascular biomarkers. The study included 60 patients (mean age, 71.8 ± 11.4 years; mean time on HD, 52.3 ± 30.8 months) with a median follow-up of 30.5 months (IQ range, 17.2-34 months). RESULTS: Post-dialysis ECW/TBW was directly associated with NT-proBNP and cTnT. During the study 28 patients died, most of them (43%) due to cardiovascular events. Compared to the survivors, these subjects had a higher post-dialysis ECW/TBW ratio (p = 0.006), while for cardiovascular mortality the only significant difference was a higher pre-dialysis ECW/TBW. The ability of post-dialysis ECW/TBW ratio to predict all-cause mortality had an area under the ROC curve (AUC) of 0.71 (CI 95%, 0.57-0.81; p = 0.002), with a cutoff point of 0.5023. For cardiovascular mortality the AUC was 0.66 (CI 95%, 0.52-0.77; p = 0.045), with a cutoff point of 0.4713. CONCLUSIONS: The post-dialysis ECW/TBW ratio measured by BIS can be a predictor of all-cause and cardiovascular mortality.


Assuntos
Água Corporal/fisiologia , Doenças Cardiovasculares/mortalidade , Impedância Elétrica , Espaço Extracelular/fisiologia , Diálise Renal , Desequilíbrio Hidroeletrolítico/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudo de Prova de Conceito , Estudos Prospectivos , Desequilíbrio Hidroeletrolítico/fisiopatologia
18.
Proc Natl Acad Sci U S A ; 118(21)2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34006646

RESUMO

Colorectal cancer (CRC) represents the third most common malignancy and the second leading cause of cancer-related deaths worldwide. Although immunotherapy has taken center stage in mainstream oncology, it has shown limited clinical efficacy in CRC, generating an urgent need for discovery of new biomarkers and potential therapeutic targets. Galectin-1 (Gal-1), an endogenous glycan-binding protein, induces tolerogenic programs and contributes to tumor cell evasion of immune responses. Here, we investigated the relevance of Gal-1 in CRC and explored its modulatory activity within the CD8+ regulatory T cell (Treg) compartment. Mice lacking Gal-1 (Lgals1-/- ) developed a lower number of tumors and showed a decreased frequency of a particular population of CD8+CD122+PD-1+ Tregs in the azoxymethane-dextran sodium sulfate model of colitis-associated CRC. Moreover, silencing of tumor-derived Gal-1 in the syngeneic CT26 CRC model resulted in reduced number and attenuated immunosuppressive capacity of CD8+CD122+PD-1+ Tregs, leading to slower tumor growth. Moreover, stromal Gal-1 also influenced the fitness of CD8+ Tregs, highlighting the contribution of both tumor and stromal-derived Gal-1 to this immunoregulatory effect. Finally, bioinformatic analysis of a colorectal adenocarcinoma from The Cancer Genome Atlas dataset revealed a particular signature characterized by high CD8+ Treg score and elevated Gal-1 expression, which delineates poor prognosis in human CRC. Our findings identify CD8+CD122+PD-1+ Tregs as a target of the immunoregulatory activity of Gal-1, suggesting a potential immunotherapeutic strategy for the treatment of CRC.


Assuntos
Adenocarcinoma/genética , Linfócitos T CD8-Positivos/imunologia , Colite/genética , Neoplasias Colorretais/genética , Galectina 1/genética , Linfócitos T Reguladores/imunologia , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Animais , Atlas como Assunto , Azoximetano/administração & dosagem , Linfócitos T CD8-Positivos/patologia , Linhagem Celular Tumoral , Colite/induzido quimicamente , Colite/imunologia , Colite/mortalidade , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Biologia Computacional , Sulfato de Dextrana/administração & dosagem , Modelos Animais de Doenças , Galectina 1/deficiência , Galectina 1/imunologia , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade beta de Receptor de Interleucina-2/genética , Subunidade beta de Receptor de Interleucina-2/imunologia , Camundongos , Camundongos Knockout , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais , Análise de Sobrevida , Linfócitos T Reguladores/patologia , Carga Tumoral
19.
Lupus ; : 961203320988586, 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33509067

RESUMO

Introduction: After more than 20 years of sustained work, the Latin American Group for the Study of Lupus (GLADEL) has made a significant number of contributions to the field of lupus, not only in the differential role that race/ethnicity plays in its course and outcome but also in several other studies including the beneficial effects of using antimalarials in lupus patients and the development of consensus guidelines for the treatment of lupus in our region. Methods: A new generation of "Lupus Investigators" in more than 40 centers throughout Latin America has been constituted in order to continue the legacy of the investigators of the original cohort and to launch a novel study of serum and urinary biomarkers in patients with systemic lupus erythematosus. Results: So far, we have recruited 807 patients and 631 controls from 42 Latin-American centers including 339 patients with SLE without renal involvement, 202 patients with SLE with prevalent but inactive renal disease, 176 patients with prevalent and active renal disease and 90 patients with incident lupus nephritis. Conclusions: The different methodological aspects of the GLADEL 2.0 cohort are discussed in this manuscript, including the challenges and difficulties of conducting such an ambitious project.

20.
RMD Open ; 6(3)2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33310863

RESUMO

AIM: A decrease in proteinuria has been considered protective from renal damage in lupus nephritis (LN), but a cut-off point has yet to be established. The aim of this study was to identify the predictors of renal damage in patients with LN and to determine the best cut-off point for a decrease in proteinuria. METHODS: We included patients with LN defined clinically or histologically. Possible predictors of renal damage at the time of LN diagnosis were examined: proteinuria, low complement, anti-double-stranded DNA antibodies, red cell casts, creatinine level, hypertension, renal activity (assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)), prednisone dose, immunosuppressive drugs and antimalarial use. Sociodemographic variables were included at baseline. Proteinuria was assessed at baseline and at 12 months, to determine if early response (proteinuria <0.8 g/day within 12 months since LN diagnosis) is protective of renal damage occurrence. Renal damage was defined as an increase of one or more points in the renal domain of The Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SDI). Cox regression models using a backward selection method were performed. RESULTS: Five hundred and two patients with systemic lupus erythematosus patients were included; 120 patients (23.9%) accrued renal damage during their follow-up. Early response to treatment (HR=0.58), antimalarial use (HR=0.54) and a high SES (HR=0.25) were protective of renal damage occurrence, whereas male gender (HR=1.83), hypertension (HR=1.86) and the renal component of the SLEDAI (HR=2.02) were risk factors for its occurrence. CONCLUSIONS: Early response, antimalarial use and high SES were protective of renal damage, while male gender, hypertension and higher renal activity were risk factors for its occurrence in patients with LN.


Assuntos
Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Estudos de Coortes , Humanos , América Latina/epidemiologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/epidemiologia , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/epidemiologia , Masculino , Prednisona/uso terapêutico
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