RESUMO
The balance between the CO2 entry for photosynthesis and transpiration water loss is crucial for plant growth, and ABA signaling can affect this equilibrium. To test how ABA balances plant growth and environmental adaptation, we performed molecular genetics studies in the biotech crop Nicotiana benthamiana under well-watered or drought conditions. Studies on ABA signaling in crops are complicated by the multigenic nature of the PYR/PYL/RCAR ABA receptor family and its functional redundancy, which is particularly challenging in polyploid plants. We have generated a pentuple pyl mutant in the allotetraploid Nicotiana benthamiana through CRISPR/Cas9 gene editing. The pentuple mutant is impaired in 2 NbPYL1-like and 3 NbPYL8-like receptors, affecting the regulation of transpiration and several ABA-dependent transcriptional processes. RNA-seq and metabolite analysis revealed that the synthesis of galactinol, an essential precursor for the osmoprotective raffinose family of oligosaccharides, is ABA-dependent and impaired in the mutant under osmotic stress. In contrast, our results show that, under well-watered conditions, partial inactivation of ABA signaling leads to higher CO2 entry and photosynthesis in the mutant than in WT. Photosynthesis analyses revealed an increased CO2 diffusion capacity mediated by higher stomatal and mesophyll conductances, and higher substomatal CO2 concentration in the pentuple mutant. RNA-seq analyses revealed that genes associated with cell wall loosening (e.g., expansins) and porosity were strongly downregulated by ABA in WT. In summary, a partial relief of the ABA control on transpiration mediated by ABA receptors positively affects photosynthesis when water is not limited, at the expense of reduced water use efficiency.
Assuntos
Ácido Abscísico , Nicotiana , Fotossíntese , Transpiração Vegetal , Transdução de Sinais , Ácido Abscísico/metabolismo , Transpiração Vegetal/fisiologia , Nicotiana/genética , Nicotiana/fisiologia , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Dióxido de Carbono/metabolismo , MutaçãoRESUMO
Objetivos: Determinar los cambios de frecuentación de consultas presenciales (CP) y telemáticas (CT) a su médico de familia en pacientes con diabetes tipo 2 (DM2) durante la pandemia de COVID-19 y su relación con el control de su enfermedad. Diseño: Estudio multicéntrico de seguimiento retrospectivo. Emplazamiento: Siete centros de salud en Tenerife, España. Participantes: Un total de 3.543 pacientes con DM2. Mediciones: Sexo, edad, CP, CT y control de DM2 mediante hemoglobina glicosilada (A1c) durante el periodo 2019-2021. Se ajustaron modelos de regresión logística con el control de DM2 como efecto, y con las demás mediciones como variables independientes. Resultados: El 50% eran mujeres. El 38% tenía 65 años o menos. Se midió la A1c al 84% de los pacientes en 2019, 68% en 2020, y 77% en 2021. Presentaron buen control el 58,4% en 2019, 46,1% en 2020 y 50,3% en 2021. Las CP fueron 7 en 2019, 4 en 2020 y 5 en 2021 (p<0,001). Las razones de ventaja (IC95%) de buen control en 2019 fueron 1,04 (1,04-1,05) por cada año más de edad y 1,03 (1,01-1,04) por cada CP más; en 2020 fueron 1,04 (1,03-1,05) por cada año más de edad, 1,05 (1,04-1,07) por cada CP más y 1,04 (1,02-1,07) por cada CT más; en 2021 fueron 1,04 (1,04-1,05) por cada año más de edad, 1,05 (1,03-1,06) por cada CP más y 1,02 (1,00-1,04) por cada CT más. Conclusiones: El control de pacientes con DM2 durante 2019-2021 tuvo una relación directa con el cambio de frecuentación al centro de salud, con diferencias según el tipo de consulta y la edad.(AU)
Objectives: To determine whether in patients with type 2 diabetes (DM2) the changes in their relationship with family doctors during the COVID-19 pandemic, in-person (iPC) and telematic (TC) consultations, were associated with control of their disease. Design: Multicentric study of retrospective follow-up. Setting: Seven health centers in Tenerife, Spain. Participants: 3543 patients with DM2. Main measurements: Sex, age, iPC, TC and DM2 control using glycosylated hemoglobin (A1c) during the period 2019-2021. Logistic regression models were fitted with DM2 control as an effect, and with the other measurements as independent variables. Results: 50% were women. 38% were less than 65 years old. A1c was measured in 84% of patients in 2019, 68% in 2020, and 77% in 2021. 58.4% had good control in 2019, 46.1% in 2020, and 50.3% in 2021. Median iPC were 7 in 2019, 4 in 2020 and 5 in 2021 (p<0.001). The OR(95%CI) of good control in 2019 were 1.04(1.04-1.05) per year of age and 1.03(1.01-1.04) for each iPC; In 2020 they were 1.04 (1.03-1.05) per year of age, 1.05 (1.04-1.07) for each iPC and 1.04 (1.02-1.07) for each TC; in 2021 they were 1.04 (1.04-1.05) per year of age, 1.05 (1.03-1.06) for each iPC and 1.02 (1.00-1.04) for each TC. Conclusions: The control of patients with DM2 during the period 2019-2021 had a direct relationship with the change in the frequency of consultations at the health center, with differences depending on the type of consultation and the age of the patient.(AU)
Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Médicos de Família , Atenção Primária à Saúde , /epidemiologia , Diabetes Mellitus Tipo 2 , Consulta Remota , Espanha , Assistência ao Paciente , Telemedicina , Estudos RetrospectivosRESUMO
OBJECTIVE: The aim of this study was to compare patient survival using sentinel lymph node (SLN) procedure and pelvic lymphadenectomy for stating early-stage high risk endometrial cancer. METHODS: Patients who underwent surgery for early-stage high risk endometrial cancer between 2010 and 2017 were extracted from the incidence registry of the SEER program. We identified patients who underwent SLN mapping. Patients who initially underwent pelvic lymphadenectomy were selected as the comparison group. One-to-one matching was performed according to age, ethnicity, histology, extension and grade. The primary outcome was disease-specific survival. The secondary outcome was overall survival. RESULTS: A total of 326 patients who underwent SLN mapping and 326 who underwent pelvic lymphadenectomy initially were included in the study. The three-year analysis did not find a significant difference between the SLN and lymphadenectomy groups on disease-specific survival probability (88.2% vs 82.7, P = 0.07) and on overall survival probability (82.7% vs 78.2%, P = 0.57). Patients who underwent SLN mapping had a lower mean number of lymph nodes removed (mean 3 vs 16, P < 0.001) and there was a higher rate of patients with positive pelvic lymph nodes (18% vs 14%, P = 0.04). Following adjustment for confounding factors, disease-specific survival did not vary according to the lymph node intervention performed (P = 0.056), but the SLN group had better overall survival than those in the lymphadenectomy group (P = 0.047). CONCLUSION: The SLN technique was not associated with poorer disease-specific survival than pelvic lymphadenectomy even after adjustment. These results suggest that SLN is an acceptable and safe procedure in surgical staging for early-stage high-risk endometrial cancer.
Assuntos
Neoplasias do Endométrio , Linfonodo Sentinela , Feminino , Humanos , Linfonodo Sentinela/cirurgia , Linfonodo Sentinela/patologia , Biópsia de Linfonodo Sentinela/métodos , Estudos de Coortes , Metástase Linfática/patologia , Neoplasias do Endométrio/cirurgia , Neoplasias do Endométrio/patologia , Estadiamento de Neoplasias , Linfonodos/cirurgia , Linfonodos/patologia , Excisão de Linfonodo/métodos , Estudos RetrospectivosRESUMO
OBJECTIVES: To determine whether in patients with type 2 diabetes (DM2) the changes in their relationship with family doctors during the COVID-19 pandemic, in-person (iPC) and telematic (TC) consultations, were associated with control of their disease. DESIGN: Multicentric study of retrospective follow-up. SETTING: Seven health centers in Tenerife, Spain. PARTICIPANTS: 3543 patients with DM2. MAIN MEASUREMENTS: Sex, age, iPC, TC and DM2 control using glycosylated hemoglobin (A1c) during the period 2019-2021. Logistic regression models were fitted with DM2 control as an effect, and with the other measurements as independent variables. RESULTS: 50% were women. 38% were less than 65 years old. A1c was measured in 84% of patients in 2019, 68% in 2020, and 77% in 2021. 58.4% had good control in 2019, 46.1% in 2020, and 50.3% in 2021. Median iPC were 7 in 2019, 4 in 2020 and 5 in 2021 (p<0.001). The OR(95%CI) of good control in 2019 were 1.04(1.04-1.05) per year of age and 1.03(1.01-1.04) for each iPC; In 2020 they were 1.04 (1.03-1.05) per year of age, 1.05 (1.04-1.07) for each iPC and 1.04 (1.02-1.07) for each TC; in 2021 they were 1.04 (1.04-1.05) per year of age, 1.05 (1.03-1.06) for each iPC and 1.02 (1.00-1.04) for each TC. CONCLUSIONS: The control of patients with DM2 during the period 2019-2021 had a direct relationship with the change in the frequency of consultations at the health center, with differences depending on the type of consultation and the age of the patient.
Assuntos
COVID-19 , Diabetes Mellitus Tipo 2 , Idoso , Feminino , Humanos , Masculino , COVID-19/epidemiologia , COVID-19/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/terapia , Diabetes Mellitus Tipo 2/complicações , Hemoglobinas Glicadas , Pandemias , Atenção Primária à Saúde , Estudos Retrospectivos , Pessoa de Meia-IdadeRESUMO
We describe the synthesis of trihydroxylated cyclohexane ß-amino acids from (-)-shikimic acid, in their cis and trans configuration, and the incorporation of the trans isomer into a trans-2-aminocyclohexanecarboxylic acid peptide chain. Subsequently, the hydroxyl groups were partially or totally deprotected. The structural study of the new peptides by FTIR, CD, solution NMR and DFT calculations revealed that they all fold into a 14-helix secondary structure, similarly to the homooligomer of trans-2-aminocyclohexanecarboxylic acid. This means that the high degree of substitution of the cyclohexane ring of the new residue is compatible with the adoption of a stable helical secondary structure and opens opportunities for the design of more elaborate peptidic foldamers with oriented polar substituents at selected positions of the cycloalkane residues.
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Aminoácidos , Ácidos Cicloexanocarboxílicos , Aminoácidos/química , Peptídeos/química , Estrutura Secundária de ProteínaRESUMO
Tappeh Sang-e Chakhmaq is the only Neolithic site in Northeastern Iran, characterised by aceramic and ceramic levels corresponding to an occupation of 1500 years from the eighth to the end of the sixth millennium BCE. The Western and Eastern Mounds represent the oldest and longest occupation among the sites identified East of the Zagros, providing a unique context to explore the origin and spread of farming outside the core area of the Eastern Fertile Crescent. We present data about the first harvesting activities in the Northeastern Iranian Central Plateau by applying usewear and microtexture analysis through confocal microscopy on sickle gloss blades. Our results indicate a community of pioneer farmers who settled down in the area carrying with them both domestic cereals as well as advanced techniques of cereal cultivation. We demonstrate that most of the tools were used for harvesting cereals in a fully ripened state collected near the ground, indicating a well-established cereal cultivation strategy. The use of straight shafts with parallel inserts in Tappeh Sang-e Chakhmaq, as known in some sites in the Zagros, suggests the dispersal of farming practices and technologies from the Eastern Fertile Crescent north-eastward across Iran. We observe an evolution in the degree of ripeness of harvested cereals along the first four levels of occupation of the Western Mound, where semi-ripe harvesting is relatively important, suggesting that domestic cereals to be harvested before full maturity were introduced into the village. From the topmost of the Western Mound and along the occupation of the Eastern Mound, ripe harvesting is dominant, showing a well-established cultivation strategy of fully mature cereal. This shift could indicate an in-situ evolution towards a better-established agricultural technology, including harvesting riper crops, that would have resulted in higher yields, as cereals were collected when the grain was fully formed.
Assuntos
Agricultura , Grão Comestível , Irã (Geográfico) , Fazendas , TecnologiaRESUMO
Water deficit represents a serious limitation for agriculture and both genetic and chemical approaches are being used to cope with this stress and maintain plant yield. Next-generation agrochemicals that control stomatal aperture are promising for controlling water use efficiency. For example, chemical control of abscisic acid (ABA) signaling through ABA-receptor agonists is a powerful method to activate plant adaptation to water deficit. Such agonists are molecules able to bind and activate ABA receptors and, although their development has experienced significant advances in the last decade, few translational studies have been performed in crops. Here, we describe protection by the ABA mimic-fluorine derivative 4 (AMF4) agonist of the vegetative growth in tomato plants subjected to water restriction. Photosynthesis in mock-treated plants is markedly impaired under water deficit conditions, whereas AMF4 treatment notably improves CO2 assimilation, the relative plant water content and growth. As expected for an antitranspirant molecule, AMF4 treatment diminishes stomatal conductance and transpiration in the first phase of the experiment; however, when photosynthesis declines in mock-treated plants as stress persists, higher photosynthetic and transpiration parameters are recorded in agonist-treated plants. Additionally, AMF4 increases proline levels over those achieved in mock-treated plants in response to water deficit. Thus water deficit and AMF4 cooperate to upregulate P5CS1 through both ABA-independent and ABA-dependent pathways, and therefore, higher proline levels are produced Finally, analysis of macronutrients reveals higher levels of Ca, K and Mg in AMF4- compared to mock-treated plants subjected to water deficit. Overall, these physiological analyses reveal a protective effect of AMF4 over photosynthesis under water deficit and enhanced water use efficiency after agonist treatment. In summary, AMF4 treatment is a promising approach for farmers to protect the vegetative growth of tomatoes under water deficit stress.
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The modulation of the A2B adenosine receptor is a promising strategy in cancer (immuno) therapy, with A2BAR antagonists emerging as immune checkpoint inhibitors. Herein, we report a systematic assessment of the impact of (di- and mono-)halogenation at positions 7 and/or 8 on both A2BAR affinity and pharmacokinetic properties of a collection of A2BAR antagonists and its study with structure-based free energy perturbation simulations. Monohalogenation at position 8 produced potent A2BAR ligands irrespective of the nature of the halogen. In contrast, halogenation at position 7 and dihalogenation produced a halogen-size-dependent decay in affinity. Eight novel A2BAR ligands exhibited remarkable affinity (Ki < 10 nM), exquisite subtype selectivity, and enantioselective recognition, with some eutomers eliciting sub-nanomolar affinity. The pharmacokinetic profile of representative derivatives showed enhanced solubility and microsomal stability. Finally, two compounds showed the capacity of reversing the antiproliferative effect of adenosine in activated primary human peripheral blood mononuclear cells.
Assuntos
Halogenação , Antagonistas de Receptores Purinérgicos P1 , Cricetinae , Animais , Humanos , Células CHO , Leucócitos Mononucleares/metabolismo , Antagonistas do Receptor A2 de Adenosina/farmacologia , Receptor A2B de Adenosina/metabolismo , Ligantes , HalogêniosRESUMO
Double nucleophilic displacement of D-xylo-ditriflate by amines, water and alkyl cyanoacetates, respectively, gave a series of bicyclic divergent intermediates for the synthesis of a wide range of highly functionalized targets, including hydroxylated prolines, pyrrolidines, furanoic acids, and cyclopentanes.
Assuntos
Prolina , Pirrolidinas , Xilose , Ácidos CarboxílicosRESUMO
To face the challenges of climate change and sustainable food production, it is essential to develop crop genome editing techniques to pinpoint key genes involved in abiotic stress signaling. The identification of those prevailing abscisic acid (ABA) receptors that mediate plant-environment interactions is quite challenging in polyploid plants because of the high number of genes in the PYR/PYL/RCAR ABA receptor family. Nicotiana benthamiana is a biotechnological crop amenable to genome editing, and given the importance of ABA signaling in coping with drought stress, we initiated the analysis of its 23-member family of ABA receptors through multiplex CRISPR/Cas9-mediated editing. We generated several high-order mutants impaired in NbPYL1-like and NbPYL8-like receptors, which showed certain insensitivity to ABA for inhibition of seedling establishment, growth, and development of shoot and lateral roots as well as reduced sensitivity to the PYL1-agonist cyanabactin (CB). However, in these high-order mutants, regulation of transpiration was not affected and was responsive to ABA treatment. This reveals a robust and redundant control of transpiration in this allotetraploid plant that probably reflects its origin from the extreme habitat of central Australia.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Ácido Abscísico/farmacologia , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Proteínas de Transporte/genética , Regulação da Expressão Gênica de Plantas , Sementes/metabolismo , Nicotiana/genética , Nicotiana/metabolismoRESUMO
BACKGROUND DATA: Vulvar carcinoma is a rare disease accounting for 3%-5% of all gynaecological cancers. Although surgery is the standard treatment at an early stage, the outcomes are highly correlated with clear resection margins. Therefore, surgical defects can be important and require reconstruction. The aim of this study was to evaluate vulvar reconstructions using a previously validated nomogram predicting the risk of local recurrence at 2 years. METHODS: Patients who underwent surgery for vulvar cancer between 1998 and 2017 were extracted from eight FRANCOGYN centres. We estimated the probability of local recurrence at 2 years using a previously validated nomogram and compared it with actual relapse in patients with or without vulvar reconstruction. Patients were clustered into tiertiles according to their nomogram score: low-, intermediate-, and high-risk for local relapse probability. RESULTS: We reviewed 254 patients, of whom 49 underwent immediate vulvar reconstruction. The predicted and actual probability of two-year local relapse were 20.1% and 15.7%, respectively, with a concordance index of 0.75. In the low- and intermediate-risk groups, the difference between predicted and observed recurrence was less than 10% in patients with or without vulvar reconstruction. For the high-risk group, the difference reached 25% and observed recurrence probability was lower in patients who underwent vulvar plasty compared with those who did not (20.0% vs. 36.2%, respectively). Local recurrence-free survival rates following vulvar reconstruction were comparable at two years (82.1% vs. 84.8%, respectively, p = 0.26). CONCLUSION: Vulvar reconstruction after surgical resection for vulvar cancer is safe. Vulvar reconstruction should be considered in aggressive cases to decrease local recurrence.
Assuntos
Procedimentos de Cirurgia Plástica , Neoplasias Vulvares , Feminino , Humanos , Recidiva Local de Neoplasia/cirurgia , Nomogramas , Prognóstico , Estudos Retrospectivos , Vulva/cirurgia , Neoplasias Vulvares/patologiaRESUMO
A stereoselective synthesis of polyhydroxylated cyclopentane ß-amino acids from hexoses is reported. The reaction sequence comprises, as key steps, ring-closing metathesis of a polysubstituted diene intermediate followed by the stereoselective aza-Michael functionalization of the resulting cyclopent-1-ene-1-carboxylic acid ester. Examples of synthesis of polysubstituted 2-aminocyclopentanecarboxylic acid derivatives starting from protected d-mannose and d-galactose are presented. A general protocol for the incorporation of these highly functionalized alicyclic ß-amino acids into peptides is also reported.
RESUMO
We herein document a large collection of 108 2-amino-4,6-disubstituted-pyrimidine derivatives as potent, structurally simple, and highly selective A1AR ligands. The most attractive ligands were confirmed as antagonists of the canonical cyclic adenosine monophosphate pathway, and some pharmacokinetic parameters were preliminarilly evaluated. The library, built through a reliable and efficient three-component reaction, comprehensively explored the chemical space allowing the identification of the most prominent features of the structure-activity and structure-selectivity relationships around this scaffold. These included the influence on the selectivity profile of the aromatic residues at positions R4 and R6 of the pyrimidine core but most importantly the prominent role to the unprecedented A1AR selectivity profile exerted by the methyl group introduced at the exocyclic amino group. The structure-activity relationship trends on both A1 and A2AARs were conveniently interpreted with rigorous free energy perturbation simulations, which started from the receptor-driven docking model that guided the design of these series.
Assuntos
Antagonistas do Receptor A1 de Adenosina/química , Pirimidinas/química , Antagonistas do Receptor A1 de Adenosina/metabolismo , Antagonistas do Receptor A1 de Adenosina/farmacocinética , Sítios de Ligação , Linhagem Celular , Desenho de Fármacos , Estabilidade de Medicamentos , Humanos , Cinética , Simulação de Acoplamento Molecular , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Receptor A1 de Adenosina/química , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/química , Receptor A2A de Adenosina/metabolismo , Relação Estrutura-AtividadeRESUMO
Mice that lack the gene for expression of cytochrome P450 8B1 (P450 8B1) resist weight gain and improve glucose tolerance when fed a high-fat diet. Thus, the inhibition of P450 8B1 is a target to treat obesity-associated metabolic disorders. P450 8B1 is the enzyme that hydroxylates its substrate, 7α-hydroxy-cholest-4-en-3-one to 7α-,12α-dihydroxycholest-4-en-3-one, which ultimately results in the formation of cholic acid. Cholic acid is the 12α-hydroxylated bile acid implicated in enhanced absorption of cholesterol. The synthesis of a rationally designed inhibitor for P450 8B1 was achieved through the incorporation of a C12-pyridine in the C-ring of a steroid molecule. Seven days of new inhibitor treatment showed attenuation of glucose intolerance in mice that were fed a high fat and a high sucrose diet (HFHS) without affecting body weight. Taken together, these promising results will lead to a P450 8B1 inhibitor as a potential therapeutic strategy to treat obesity-associated insulin resistance.
Assuntos
Obesidade , Esteroide 12-alfa-Hidroxilase , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/uso terapêutico , Colesterol/metabolismo , Ácido Cólico/metabolismo , Camundongos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Esteroide 12-alfa-Hidroxilase/antagonistas & inibidores , Esteroide 12-alfa-Hidroxilase/metabolismoRESUMO
Human mobility and migration are thought to have played essential roles in the consolidation and expansion of sedentary villages, long-distance exchanges and transmission of ideas and practices during the Neolithic transition of the Near East. Few isotopic studies of human remains dating to this early complex transition offer direct evidence of mobility and migration. The aim of this study is to identify first-generation non-local individuals from Natufian to Pre-Pottery Neolithic C periods to explore the scope of human mobility and migration during the Neolithic transition in the Southern Levant, an area that is central to this historical process. The study adopted a multi-approach resorting to strontium (87Sr/86Sr), oxygen (δ18OVSMOW) and carbon (δ13C) isotope ratio analyses of tooth enamel of 67 human individuals from five sites in Jordan, Syria, and Israel. The isotope ratios point both to a significant level of human migration and/or mobility in the Final Natufian which is compatible with early sedentarism and seasonal mobility and with population aggregation in early sedentary hamlets. The current findings, in turn, offer evidence that most individuals dating to the Pre-Pottery Neolithic were local to their respective settlements despite certain evidence of non-locals. Interestingly, isotopic data suggest that two possible non-local individuals benefitted from particular burial practices. The results underscore a decrease in human mobility and migration as farming became increasingly dominant among the subsistence strategies throughout the Neolithic transition of the Southern Levant.
Assuntos
Sepultamento/história , Migração Humana/história , Isótopos/análise , Agricultura/história , Isótopos de Carbono/análise , Cultura , Esmalte Dentário , Geografia , História Antiga , Humanos , Israel , Jordânia , Oriente Médio , Isótopos de Oxigênio/análise , Paleontologia/métodos , Meio Social , Isótopos de Estrôncio/análise , Síria , DenteRESUMO
We present the synthesis and structural study of a new peptidomimetic of morphiceptin, which can formally be considered as the result of the replacement of the central proline residue of this natural analgesic drug with a subunit of (1S,2R,3S,4S,5R)-2-amino-3,4,5-trihydroxycyclopentane-1-carboxylic acid, previously obtained from L-idose. An optimized synthesis of this trihydroxylated cispentacin derivative is also reported. Molecular docking calculations on the target receptor support a favorable role of the hydroxy substituents of the non-natural ß-amino acid incorporated into the peptidomimetic.
Assuntos
Analgésicos/química , Ácidos Carboxílicos/química , Técnicas de Química Sintética/métodos , Endorfinas/química , Peptidomiméticos/química , Algoritmos , Sítios de Ligação , Química Farmacêutica/métodos , Simulação por Computador , Desenho de Fármacos , Ligantes , Espectroscopia de Ressonância Magnética , Simulação de Acoplamento Molecular , Peptídeos/química , Prolina/química , Açúcares/química , TemperaturaRESUMO
Here, the synthesis and glycosidase inhibition properties of the two first known 3-ethyloctahydro-1H-indole-4,5,6-triols are reported. This study shows the transformation of d-glucose into polyhydroxylated 1-(2-nitrocyclohexane) acetaldehydes, followed by a protocol involving the formation of the azacyclopentane ring. Results of inhibitory potency assays and docking calculations show that at least one of them could be a lead for optimization in the search for compounds that behave like folding chaperones in lysosomal storage diseases.
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OBJECTIVE: The role of lymphadenectomy in intermediate risk endometrial cancer remains uncertain. We evaluated the impact of lymphadenectomy on overall survival and relapse-free survival for patients with intermediate risk endometrial cancer. METHODS: We retrospectively reviewed patients from the FRANCOGYN database with intermediate risk endometrial cancer, based on pre-operative and post-operative criteria (type 1, grade 1-2 tumors with deep (> 50%) myometrial invasion and no lymphovascular space invasion), who received primary surgical treatment between November 2002 and August 2013. We compared overall survival and relapse-free survival between staged and unstaged patients. RESULTS: From 1235 screened patients, we selected 108 patients with intermediate risk endometrial cancer. Eighty-two (75.9%) patients underwent nodal staging (consisting of pelvic +/- para-aortic lymphadenectomy). Among them, 35 (32.4%) had lymph node disease. The median follow-up was 25 months (range 0.4 to 155.0). The overall survival rates were 82.5% for patients staged (CI 64.2 to 91.9) vs 77.9 % for unstaged patients (CI 35.4 to 94.2) (P = 0.73). The relapse-free survival rates were 68.9% for staged patients (CI 51.2 to 81.3) vs 68.8% for unstaged patients (CI 29.1 to 89.3) (P=0.67). CONCLUSION: Systematic nodal staging does not appear to improve overall survival and relapse-free survival for patients with IR EC but could provide information to tailor adjuvant therapy. Sentinel lymph node dissection may be an effective and less invasive alternative staging technique and should provide a future alternative for this population.
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Neoplasias do Endométrio/mortalidade , Excisão de Linfonodo/mortalidade , Recidiva Local de Neoplasia/mortalidade , Idoso , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/cirurgia , Feminino , Seguimentos , Humanos , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
New enantiomerically pure C16-alkyl diamides derived from trihydroxy cyclohexane-1,2-dicarboxylic acid have been synthesized from (-)-shikimic acid. The hydroxyl groups in these compounds are free or, alternatively, they present full or partial protection. Their gelling abilities towards several solvents have been tested and rationalized by means of the combined use of Hansen solubility parameters, scanning electron microscopy (SEM), and circular dichroism (CD), as well as computational calculations. All the results allowed us to account for the capability of each type of organogelator to interact with different solvents and for the main mode of aggregation. Thus, compounds with fully protected hydroxyl groups are good organogelators for methanol and ethanol. In contrast, a related compound bearing three free hydroxyl groups is insoluble in water and polar solvents including alcohols but it is able to gelate some low-polarity solvents. This last behavior can be justified by strong hydrogen bonding between molecules of organogelator, which competes advantageously with polar solvent interactions. As an intermediate case, an organogelator with two free hydroxyl groups presents an ambivalent ability to gelate both apolar and polar solvents by means of two aggregation patterns. These involve hydrogen bonding interactions of the unprotected hydroxyl groups in apolar solvents and intermolecular interactions between amide groups in polar ones.
Assuntos
Ácidos Cicloexanocarboxílicos/química , Ácidos Dicarboxílicos/química , Furanos/química , Géis/química , Ligação de Hidrogênio , Modelos Moleculares , Solubilidade , Solventes/química , Estereoisomerismo , Água/químicaRESUMO
BACKGROUND: Spigelian hernia is a ventral hernia in the anterior abdominal wall extremely rare in children. CLINIC CASE: A 13 years old patient is presented with a Spigelian hernia. A surgical repair was successfully performed through a laparoscopic transperitoneal approach without prosthetic reinforcement. A review of 35 pediatric patients published on PubMed between 2000 and 2015 was performed and different therapeutic approaches in pediatric patients were analyzed. Only one patient, and the case reported on this paper, was entirely treated with a laparoscopic approach. CONCLUSIONS: Spigelian hernias in childhood can be securely closured with laparoscopic transperitoneal approach.
ANTECEDENTES: La hernia de Spiegel es una hernia ventral de la pared abdominal infrecuente en niños. CASO CLÍNICO: Se presenta el caso de un paciente de 13 años con una hernia de Spiegel que se reparó mediante abordaje laparoscópico transperitoneal con éxito sin refuerzo protésico. Se realizó una revisión de 35 casos en edad pediátrica publicados en PubMed entre los años 2000 y 2015, y se analizaron los diferentes abordajes terapéuticos. Solo un paciente, además del presentado en este trabajo, fue tratado íntegramente mediante abordaje laparoscópico. CONCLUSIONES: Las hernias de Spiegel en edad pediátrica podrían tratarse quirúrgicamente con seguridad mediante una herniorrafia laparoscópica transabdominal.