RESUMO
BACKGROUND: Abdomen-based free flaps represent the gold standard option in the armamentarium of breast reconstruction. The natural evolution to more preservation with less invasive forms of these flaps has been driven by both patient and surgeon satisfaction. Nevertheless, obese patients are challenging due to the increased risk of compromised flap perfusion and donor site morbidity. This challenge is compounded by the prevalence of obesity worldwide, resulting in more free abdominal flaps being performed for breast reconstruction in obese patients. The authors present the outcomes of a modified supra-arcuate fascial muscle-sparing transverse rectus abdominus myocutaneous (FMS-TRAM) technique compared to standard muscle-sparing transverse rectus abdominus myocutaneous (MS-TRAM) technique to reduce the donor site morbidity while providing a well-vascularized large volume of autologous tissue. METHODS: A retrospective comparative data analysis was conducted at two centers: Cairo University Hospitals, Egypt, and University Hospitals Birmingham, United Kingdom. Standard MS-TRAM was performed in 65 patients between 2008 and 2011 (Group 1) versus 275 patients between 2011 and 2020 (Group 2) who underwent FMS-TRAM. The modified technique involved limiting the fascial incision to above or at the level of the arcuate line to preserve the integrity of the anterior rectus sheath caudally. All patients included were of the obese population (BMI≥30 kg/m2 ) and underwent unilateral post-mastectomy reconstruction. Patient demographics, comorbidities, operative details, and outcomes focusing on donor site morbidity and flap complications were recorded and compared between the two groups. RESULTS: The median age and BMI for Group 1 were 43 and 32, respectively. While for Group 2, they were 47 and 33, respectively. Flap weight ranged from 560 to 1470 g (Mean 705) for Group 1, while Group 2 ranged from 510 to 1560 (mean 715). The majority (280/340 [82%]) of the patients in both groups received radiotherapy. 7.7% of Group 1 were smokers, while in Group 2 it was 4.7%. The percentage of delayed versus immediate reconstruction in Group 1 was 60%/40%, while in Group 2, it was 43%/56%. The incidence of fat necrosis, partial necrosis, and total necrosis was 7.6%.1.5%, and 3%, respectively, for Group 1 and 8%, 1.4%, and 2.6%, respectively, for Group 2. The two-tailed p-value demonstrated a significant statistical difference (p < 0.00001) in donor site morbidity between both groups, with more bulge 20% (13/65) and hernia 1.5% (2/65) occurrence in Group 1 versus 1.9% (5/275) and 0.7% (2/275) in Group 2 respectively, over a follow-up period ranging from 24 to 60 months (mean 32). CONCLUSION: FMS-TRAM flaps are safe, robust, and reliable with less donor site morbidity while maintaining optimal flap perfusion for large volume flaps in obese patients with excellent, durable outcomes. It should be considered a valuable tool in the reconstructive armamentarium of breast reconstruction.
Assuntos
Parede Abdominal , Neoplasias da Mama , Retalhos de Tecido Biológico , Mamoplastia , Humanos , Feminino , Estudos Retrospectivos , Neoplasias da Mama/cirurgia , Mastectomia/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Obesidade/complicações , Obesidade/cirurgia , Retalhos de Tecido Biológico/cirurgia , Mamoplastia/métodos , Parede Abdominal/cirurgia , Necrose/etiologia , Incidência , Reto do Abdome/transplanteRESUMO
Several natural products recovered from a marine-derived Aspergillus niger were tested for their inhibitory activity against SARS CoV-2 in vitro. Aurasperone A (3) was found to inhibit SARS CoV-2 efficiently (IC50 = 12.25 µM) with comparable activity with the positive control remdesivir (IC50 = 10.11 µM). Aurasperone A exerted minimal cytotoxicity on Vero E6 cells (CC50 = 32.36 mM, SI = 2641.5) and it was found to be much safer than remdesivir (CC50 = 415.22 µM, SI = 41.07). To putatively highlight its molecular target, aurasperone A was subjected to molecular docking against several key-viral protein targets followed by a series of molecular dynamics-based in silico experiments that suggested Mpro to be its primary viral protein target. More potent anti-SARS CoV-2 Mpro inhibitors can be developed according to our findings presented in the present investigation.
Assuntos
Antivirais/farmacologia , Cromonas/farmacologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Proteases/farmacologia , SARS-CoV-2/efeitos dos fármacos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Animais , Antivirais/isolamento & purificação , Aspergillus niger/química , Chlorocebus aethiops , Cromonas/isolamento & purificação , Proteases 3C de Coronavírus/metabolismo , Proteases Semelhantes à Papaína de Coronavírus/metabolismo , RNA-Polimerase RNA-Dependente de Coronavírus/metabolismo , Simulação de Acoplamento Molecular , Inibidores de Proteases/isolamento & purificação , RNA Helicases/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Células VeroRESUMO
Natural chalcones possess antitumor properties and play a role as inducers of apoptosis, antioxidants and cytotoxic compounds. We recently reported that novel nitrogen chalcone-based compounds, which were generated in our lab, have specific effects on triple-negative breast cancer cells. However, the outcome of these two new compounds on human epidermal growth factor receptor 2 (HER2)-positive breast cancer remains nascent. Thus, we herein investigated the effects of these compounds (DK-13 and DK-14) on two HER2-positive breast cancer cell lines, SKBR3 and ZR75. Our data revealed that these compounds inhibit cell proliferation, deregulate cell-cycle progression and significantly induce cell apoptosis in both cell lines. Furthermore, the two chalcone compounds cause a significant reduction in the cell invasion ability of SKBR3 and ZR75 cancer cells. In parallel, we found that DK-13 and DK-14 inhibit colony formation of both cell lines in comparison to their matched controls. On the other hand, we noticed that these two compounds can inhibit angiogenesis in the chorioallantoic membrane model. The molecular pathway analysis of chalcone compounds exposed cells revealed that these compounds inhibit the expression of both JNK1/2/3 and ERK1/2, the major plausible molecular pathways behind these events. Our findings implicate that DK-13 and DK-14 possess effective chemotherapeutic outcomes against HER2-positive breast cancer via the ERK1/2 and JNK1/2/3 signaling pathways.
Assuntos
Apoptose/efeitos dos fármacos , Chalconas/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Receptor ErbB-2/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Chalconas/química , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Nitrogênio/químicaRESUMO
RATIONALE: Possible beneficial effects of GDF11 (growth differentiation factor 11) on the normal, diseased, and aging heart have been reported, including reversing aging-induced hypertrophy. These effects have not been well validated. High levels of GDF11 have also been shown to cause cardiac and skeletal muscle wasting. These controversies could be resolved if dose-dependent effects of GDF11 were defined in normal and aged animals as well as in pressure overload-induced pathological hypertrophy. OBJECTIVE: To determine dose-dependent effects of GDF11 on normal hearts and those with pressure overload-induced cardiac hypertrophy. METHODS AND RESULTS: Twelve- to 13-week-old C57BL/6 mice underwent transverse aortic constriction (TAC) surgery. One-week post-TAC, these mice received rGDF11 (recombinant GDF11) at 1 of 3 doses: 0.5, 1.0, or 5.0 mg/kg for up to 14 days. Treatment with GDF11 increased plasma concentrations of GDF11 and p-SMAD2 in the heart. There were no significant differences in the peak pressure gradients across the aortic constriction between treatment groups at 1 week post-TAC. Two weeks of GDF11 treatment caused dose-dependent decreases in cardiac hypertrophy as measured by heart weight/tibia length ratio, myocyte cross-sectional area, and left ventricular mass. GDF11 improved cardiac pump function while preventing TAC-induced ventricular dilation and caused a dose-dependent decrease in interstitial fibrosis (in vivo), despite increasing markers of fibroblast activation and myofibroblast transdifferentiation (in vitro). Treatment with the highest dose (5.0 mg/kg) of GDF11 caused severe body weight loss, with significant decreases in both muscle and organ weights and death in both sham and TAC mice. CONCLUSIONS: Although GDF11 treatment can reduce pathological cardiac hypertrophy and associated fibrosis while improving cardiac pump function in pressure overload, high doses of GDF11 cause severe cachexia and death. Use of GDF11 as a therapy could have potentially devastating actions on the heart and other tissues.
Assuntos
Caquexia/etiologia , Cardiomegalia/tratamento farmacológico , Fatores de Diferenciação de Crescimento/uso terapêutico , Animais , Fatores de Diferenciação de Crescimento/administração & dosagem , Fatores de Diferenciação de Crescimento/efeitos adversos , Fatores de Diferenciação de Crescimento/farmacologia , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismoRESUMO
To simulate transient B cell activation that is the likely initiator of T-dependent responses, we examined the molecular and functional consequences of a single round of immunoglobulin M (IgM) signaling. This form of activation triggered early cytosolic signaling and the transcription factor NF-kappaB activation indistinguishably from conventional continuous IgM crosslinking but did not induce G1 progression. However, single round IgM signaling changed the expression of chemokine and chemokine receptor genes implicated in initiating T-dependent responses, as well as accentuated responsiveness to CD40 signaling. Several features of single-round IgM signaling in vitro were recapitulated in B cells after short-term exposure to antigen in vivo. We propose that transient BCR signals prime B cells to receive T cell help by increasing the probability of B-T encounter and creating a cellular environment that is hyper-responsive to CD40 signaling.
Assuntos
Imunidade Adaptativa , Linfócitos B/imunologia , Imunidade Inata , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais , Linfócitos T/imunologia , Animais , Linfócitos B/citologia , Linfócitos B/metabolismo , Antígenos CD40/imunologia , Antígenos CD40/metabolismo , Fase G1 , Regulação da Expressão Gênica , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/metabolismoRESUMO
The present study describes the synthesis of a series of 22 chalcone analogs. These compounds were evaluated as potential human MAO-A and MAO-B inhibitors. The compounds showed varied selectivity against the two isoforms. The IC50 values were found to be in the micromolar to submicromolar range. The Ki values of compound 16 were determined to be 0.047 and 0.020 µM for the inhibition of MAO-A and MAO-B, respectively. Dialysis of enzyme-inhibitor mixtures indicated a reversible competitive mode of inhibition. Most of the synthesized chalcone analogs showed a better selectivity toward MAO-B. However, introducing of 2,4,6-trimethoxy substituents on ring B shifted the selectivity toward MAO-A. In addition, we investigated the molecular mechanism of MAO-B inhibition by selected chalcone analogs. Our results revealed that these selected chalcone analogs increased dopamine levels in the rat hepatoma (H4IIE) cells and decreased the relative mRNA expression of the MAO-B enzyme.
Assuntos
Chalcona/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Chalcona/síntese química , Chalcona/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Relação Estrutura-AtividadeRESUMO
Toxoplasmosis is a worldwide parasitic disease responsible for serious health problems to human. The currently available drugs used for toxoplasmosis treatment showed a limited efficacy and cause serious host toxicity. The in vitro screening for toxoplasmicidal activity of Araucaria heterophylla resin (AHR) extract and its major component 13-epi-cupressic acid (CUP) showed that both AHR (EC50â¯=â¯3.90) and CUP (EC50â¯=â¯3.69) have high toxoplasmicidal activity in comparison with standard cotrimoxazole (EC50â¯=â¯4.28). The antiprotozoal effects of AHR and CUP were investigated against acute and chronic toxoplasmosis using mice models. Two groups of Swiss albino mice were infected by RH Toxoplasma strain intraperitoneally and by Me49 strain orally. Both groups were treated with AHR and CUP in different doses. Their effects were evaluated by survival rate, peritoneal, spleen and liver parasite burdens, brain cyst burden, NO serum level and histopathological lesions. The ultrastructural changes of tachyzoites of acutely infected mice were studied using scanning electron microscopy (SEM). There is an evidence of toxoplasmicidal activity of AHR and CUP in acute and chronic experimental toxoplasmosis. In the acute model, mice treated with AHR and CUP showed prolonged survival rates, a significant decrease in the parasite density in peritoneal lavage and pathological insult in both liver and spleen compared with that of untreated ones. SEM results denote evident morphological alterations of treated tachyzoites. In chronic experimental toxoplasmosis, AHR and CUP treated groups could significantly reduce brain cyst burden by 96.05% and 98.02% respectively. This study indicates that AHR and CUP showed potent toxoplasmicidal activities experimentally and could be used as a potential natural nontoxic agent for treatment of toxoplasmosis.
Assuntos
Extratos Vegetais/uso terapêutico , Resinas Vegetais/química , Toxoplasmose Animal/tratamento farmacológico , Traqueófitas/química , Doença Aguda , Animais , Líquido Ascítico/parasitologia , Encéfalo/parasitologia , Encéfalo/patologia , Doença Crônica , Modelos Animais de Doenças , Diterpenos/química , Diterpenos/farmacologia , Diterpenos/toxicidade , Feminino , Fígado/parasitologia , Fígado/patologia , Camundongos , Microscopia Eletrônica de Varredura , Óxido Nítrico/sangue , Lavagem Peritoneal , Extratos Vegetais/farmacologia , Extratos Vegetais/toxicidade , Caules de Planta/química , Distribuição Aleatória , Resinas Vegetais/farmacologia , Resinas Vegetais/toxicidade , Espectrofotometria Infravermelho , Baço/parasitologia , Baço/patologia , Taxa de Sobrevida , Toxoplasma/efeitos dos fármacos , Toxoplasma/crescimento & desenvolvimento , Toxoplasma/ultraestrutura , Toxoplasmose Animal/mortalidadeRESUMO
RATIONALE: Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor-ß super family of secreted factors. A recent study showed that reduced GDF11 blood levels with aging was associated with pathological cardiac hypertrophy (PCH) and restoring GDF11 to normal levels in old mice rescued PCH. OBJECTIVE: To determine whether and by what mechanism GDF11 rescues aging dependent PCH. METHODS AND RESULTS: Twenty-four-month-old C57BL/6 mice were given a daily injection of either recombinant (r) GDF11 at 0.1 mg/kg or vehicle for 28 days. rGDF11 bioactivity was confirmed in vitro. After treatment, rGDF11 levels were significantly increased, but there was no significant effect on either heart weight or body weight. Heart weight/body weight ratios of old mice were not different from 8- or 12-week-old animals, and the PCH marker atrial natriuretic peptide was not different in young versus old mice. Ejection fraction, internal ventricular dimension, and septal wall thickness were not significantly different between rGDF11 and vehicle-treated animals at baseline and remained unchanged at 1, 2, and 4 weeks of treatment. There was no difference in myocyte cross-sectional area rGDF11 versus vehicle-treated old animals. In vitro studies using phenylephrine-treated neonatal rat ventricular myocytes, to explore the putative antihypertrophic effects of GDF11, showed that GDF11 did not reduce neonatal rat ventricular myocytes hypertrophy, but instead induced hypertrophy. CONCLUSIONS: Our studies show that there is no age-related PCH in disease-free 24-month-old C57BL/6 mice and that restoring GDF11 in old mice has no effect on cardiac structure or function.
Assuntos
Envelhecimento/patologia , Proteínas Morfogenéticas Ósseas/farmacologia , Cardiomegalia/prevenção & controle , Fatores de Diferenciação de Crescimento/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos alfa 1/farmacologia , Fatores Etários , Envelhecimento/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/administração & dosagem , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Células Cultivadas , Esquema de Medicação , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Fatores de Diferenciação de Crescimento/administração & dosagem , Injeções Intraperitoneais , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteínas Recombinantes/farmacologia , Fatores de Tempo , Função Ventricular Esquerda/efeitos dos fármacos , Pressão Ventricular/efeitos dos fármacosRESUMO
BACKGROUND: Several different methods have been proposed for treatment of gynecomastia, depending on the amount of breast enlargement and skin redundancy. The liposuction pull-through technique has been proposed as an efficacious treatment for many gynecomastia cases. This work aims to study the outcome of this technique when applied as an outpatient procedure, without the use of drains and through a single incision. METHODS: Fifty-two patients with bilateral gynecomastia without significant skin excess were included in this study. The liposuction pull-through technique was performed through a single incision just above the inframammary fold and without the use of drains. Patients were followed up for 6 months. RESULTS: The proposed technique was able to treat the gynecomastia in all patients, with a revision rate of 1.9% to remove residual glandular tissues. There were no seromas, hematomas, nipple distortion, permanent affection of nipple sensation or wound healing problems. CONCLUSION: The liposuction pull-through technique is an effective treatment for gynecomastia without significant skin redundancy. It combines the benefits of the direct excision of glandular tissues, with the minimally invasive nature of liposuction. Performing the procedure through a single incision without the use of drains and without general anesthesia is a safe alternative. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266 .
Assuntos
Ginecomastia/cirurgia , Lipectomia/métodos , Adulto , Procedimentos Cirúrgicos Ambulatórios , Drenagem/instrumentação , Humanos , Masculino , Ferida CirúrgicaRESUMO
Growth differentiation factor-11 (GDF11) and myostatin (MSTN) are highly related transforming growth factor-ß (TGF-ß) ligands with 89% amino acid sequence homology. They have different biologic activities and diverse tissue distribution patterns. However, the activities of these ligands are indistinguishable in in vitro assays. SMAD2/3 signaling has been identified as the canonical pathway for GDF11 and MSTN, However, it remains unclear which receptor heterodimer and which antagonists preferentially mediate and regulate signaling. In this study, we investigated the initiation and regulation of GDF11 and MSTN signaling at the receptor level using a novel receptor dimerization detection technology. We used the dimerization platform to link early receptor binding events to intracellular downstream signaling. This approach was instrumental in revealing differential receptor binding activity within the TGF-ß family. We verified the ActR2b/ALK5 heterodimer as the predominant receptor for GDF11- and MSTN-induced SMAD2/3 signaling. We also showed ALK7 specifically mediates activin-B signaling. We verified follistatin as a potent antagonist to neutralize both SMAD2/3 signaling and receptor dimerization. More remarkably, we showed that the two related antagonists, growth and differentiation factor-associated serum protein (GASP)-1 and GASP2, differentially regulate GDF11 (and MSTN) signaling. GASP1 blocks both receptor dimerization and downstream signaling. However, GASP2 blocks only downstream signaling without interference from receptor dimerization. Our data strongly suggest that physical binding of GDF11 (and MSTN) to both ActR2b and ALK5 receptors is required for initiation of signaling.
Assuntos
Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Proteína 2 Relacionada a Actina/química , Proteína 2 Relacionada a Actina/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Fatores de Diferenciação de Crescimento/metabolismo , Células Hep G2 , Humanos , Miostatina/metabolismo , Ligação Proteica , Multimerização Proteica , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Quaternária de Proteína , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/química , Transdução de Sinais , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Especificidade por SubstratoRESUMO
Therapeutic agents antagonizing B-cell-activating factor/B-lymphocyte stimulator (BAFF/BLyS) are currently in clinical development for autoimmune diseases; belimumab is the first Food and Drug Administration-approved drug in more than 50 years for the treatment of lupus. As a member of the tumor necrosis factor superfamily, BAFF promotes B-cell survival and homeostasis and is overexpressed in patients with systemic lupus erythematosus and other autoimmune diseases. BAFF exists in three recognized forms: membrane-bound and two secreted, soluble forms of either trimeric or 60-mer oligomeric states. To date, most in vitro pharmacology studies of BAFF neglect one or more of these forms. Here, we report a comprehensive in vitro cell-based analysis of BAFF in assay systems that measure all forms of BAFF-mediated activation. We demonstrate the effects of these BAFF forms in both a primary human B-cell proliferation assay and in nuclear factor κB reporter assay systems in Chinese hamster ovary cells expressing BAFF receptors and transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI). In contrast to the mouse system, we find that BAFF trimer activates the human TACI receptor. Further, we profiled the activities of two clinically advanced BAFF antagonist antibodies, belimumab and tabalumab. Unexpectedly, we revealed differences in inhibitory potencies against the various BAFF forms, in particular that belimumab does not potently inhibit BAFF 60-mer. Through this increased understanding of the activity of BAFF antagonists against different forms of BAFF, we hope to influence the discovery of BAFF antagonist antibodies with distinct therapeutic mechanisms for improvement in the treatment of lupus or other related autoimmune pathologies.
Assuntos
Anticorpos Monoclonais Humanizados/imunologia , Fator Ativador de Células B/química , Fator Ativador de Células B/metabolismo , Membrana Celular/metabolismo , Multimerização Proteica , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Fator Ativador de Células B/imunologia , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Células CHO , Proliferação de Células/efeitos dos fármacos , Cricetinae , Cricetulus , Humanos , Camundongos , NF-kappa B/metabolismo , Estrutura Quaternária de Proteína , SolubilidadeRESUMO
Aberrant targeting of the enzyme activation-induced cytidine deaminase (AID) results in the accumulation of somatic mutations in ≈ 25% of expressed genes in germinal center B cells. Observations in Ung(-/-) Msh2(-/-) mice suggest that many other genes efficiently repair AID-induced lesions, so that up to 45% of genes may actually be targeted by AID. It is important to understand the mechanisms that recruit AID to certain genes, because this mistargeting represents an important risk for genome instability. We hypothesize that several mechanisms combine to target AID to each locus. To resolve which mechanisms affect AID targeting, we analyzed 7.3 Mb of sequence data, along with the regulatory context, from 83 genes in Ung(-/-) Msh2(-/-) mice to identify common properties of AID targets. This analysis identifies three transcription factor binding sites (E-box motifs, along with YY1 and C/EBP-ß binding sites) that may work together to recruit AID. Based on previous knowledge and these newly discovered features, a classification tree model was built to predict genome-wide AID targeting. Using this predictive model, we were able to identify a set of 101 high-interest genes that are likely targets of AID.
Assuntos
Citidina Desaminase/metabolismo , Hipermutação Somática de Imunoglobulina , Fatores de Transcrição/metabolismo , Animais , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Sítios de Ligação/genética , Sítios de Ligação/imunologia , Citidina Desaminase/genética , Elementos E-Box/genética , Genes de Imunoglobulinas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos Transgênicos , Valor Preditivo dos Testes , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: Despite numerous reports outlining technical modifications in rhinoplasty, few publications discuss the importance of the perioperative assessment and surgical management of the nasal airway. This study's objective is to increase awareness regarding the functional aspects of rhinoplasty surgery and to encourage surgeons to incorporate functional airway management into their rhinoplasty practice. METHODS: A web-based survey was given to all members of the American Society of Plastic Surgeons (ASPS). Survey results were analysed to determine if surgeons' experience, annual rhinoplasty volume, or postgraduate training affected their results. The relationship between surgeon satisfaction with the outcome of the airway management and the frequency of performing an inferior turbinate reduction was investigated. RESULTS: Of the 4,383 listed ASPS members, 671 (21%) completed the web-based survey. Surgeons who performed a preoperative internal nasal exam were more satisfied with their results (p = 0.016) and report lower rates of postoperative nasal airway obstruction (p = 0.054). Inferior turbinate reduction did correlate to postoperative satisfaction with the nasal airway (p < 0.001). Overall, 85% of respondents were satisfied with their management of the nasal airway and 87% of respondents agreed that there is a need for more instructional courses on this topic. CONCLUSION: There is considerable variation in the results and techniques of assessment and treatment of the nasal airway. Rhinoplasty volume and inferior turbinate reduction are associated with surgeon satisfaction of management of the nasal airway. Functional airway considerations should be incorporated into routine rhinoplasty training, assessment, and treatment. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.
Assuntos
Rinoplastia/métodos , Conchas Nasais/cirurgia , Competência Clínica , Pesquisas sobre Atenção à Saúde , Humanos , Obstrução Nasal/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Período Pré-Operatório , Rinoplastia/efeitos adversos , Cirurgia Plástica/educaçãoRESUMO
Zein constitutes about half of the endosperm proteins in corn. Recently, attempts have been made to utilize zein for food coatings and biodegradable materials, which require better physical properties, using chemical modification of zein. In this study, zein proteins were modified using citric acid, succinic anhydride, and eugenol as natural cross-linking agents in the wet state. The cross-linkers were added either separately or combined in increment concentrations (0.1, 0.2, 0.3, and 0.4%). The effects of those agents on the mechanical properties, microstructure, optical properties, infrared (IR) spectroscopy, and antibacterial activities of zein were investigated. The addition of cross-linking agents promoted changes in the arrangement of groups in zein film-forming particles. Regarding the film properties, incorporation of cross-linking agents into zein films prepared in ethanol resulted in two- to three-fold increases in tensile strength (TS) values. According to the Fourier-transform infrared (FTIR) spectra and Hunter parameters there were no remarkable changes in the structure and color of zein films. Transparency of zein films was decreased differentially according to the type and cross-linker concentration. The mechanical and optical properties of zein films were closely related to their microstructure. All cross-linked films showed remarkable antibacterial activities against Bacillus cereus ATCC 49064 and Salmonella enterica ATCC 25566. Food spoilage and pathogenic bacteria were affected in a film-dependent manner. Our experimental results show that even with partial cross-linking the mechanical properties and antipathogen activities of zein films were significantly improved, which would be useful for various industrial applications.
Assuntos
Fenômenos Fisiológicos Bacterianos/efeitos dos fármacos , Ácido Cítrico/química , Eugenol/química , Membranas Artificiais , Anidridos Succínicos/química , Zeína/química , Zeína/farmacologia , Antibacterianos/síntese química , Antibacterianos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Reagentes de Ligações Cruzadas/química , Módulo de Elasticidade , Teste de Materiais , Propriedades de Superfície , Resistência à Tração , Zeína/ultraestruturaRESUMO
The genus Fusarium, especially F. verticillioides and F. proliferatum, has been found in several agricultural products worldwide, especially in maize. Regardless the occurrence of symptoms, the presence of Fusarium in maize constitutes an imminent risk due to its ability to produce fumonisins, mycotoxins with proven carcinogenic effect on rats, swine, and equines and already classified as possible carcinogens to humans. The toxicity of incremental levels of fumonisin B1 (FB1), that is, 50, 100, and 200 mg FB1/kg diet, and the role of Lactobacillus delbrueckii subsp. lactis DSM 20076 (LL) and Pediococcus acidilactici NNRL B-5627 (PA) supplementation in counteracting the FB1 effects in intoxicated rats were monitored over a period of 4 weeks. Effects on the feed intake and body weight gain were noticed. A significant (p ≤ 0.05) increase in the level of liver and kidney functions markers and DNA fragmentation was also noticed in rat groups T100 and T200. The lactic acid bacteria (LAB) supplementation could bring back the normal serum biochemical parameters in rats fed on fumonisin B1-contaminated diets (T50 and T100) compared to FB1-treated groups. In rats of high-dosage dietary groups supplemented with LAB (T200-LL and T200-PA), the supplementation reduced the serum activity levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and creatinine by 11.3, 11.9, 32, and 20%, respectively. DNA fragmentations were observed in the rat group treated with 200 mg FB1 after 3 weeks, while fragmentation was noticed in treated groups with 100 and 200 mg FB1 after 4 weeks. No DNA fragmentation was apparent in FB1-treated rats co-administered the LL or PA strain. These results suggest that in male rats consuming diets containing FB1, there is a time- and dose-dependent increase in serum enzyme activities and DNA lesions. Moreover, Lb. delbrueckii subsp. lactis (LL) and P. acidilactici (PA) strains have a protective effect against antigenotoxicity and precancerous lesions.
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Doença Hepática Induzida por Substâncias e Drogas/microbiologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Dano ao DNA/genética , Fragmentação do DNA/efeitos dos fármacos , Fumonisinas/toxicidade , Lactobacillus/fisiologia , Probióticos/uso terapêutico , Administração Oral , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Dano ao DNA/efeitos dos fármacos , Contaminação de Alimentos , Fumonisinas/administração & dosagem , Masculino , Ratos , Ratos Sprague-Dawley , Teratogênicos/toxicidade , Resultado do TratamentoRESUMO
Several Buddleja species were the target of phytochemical and biological studies; however, nothing was reported concerning the chemistry of Buddleja polystachya Fresen. growing in Saudi Arabia. Sixteen constituents were isolated from the aerial parts of B. polystachya using various chromatographic techniques and were identified by the help of different spectral techniques including 1D, 2D NMR and mass spectrometry. Moreover, the different fractions were evaluated for their anti-inflammatory and hypoglycemic activities. The isobenzofuranone derivative (4-hydroxy-7-methylisobenzofuranone) (4), has been isolated for the first time from this natural source, B. polystachya, along with fifteen known compounds namely; phenolic fatty acid ester, 1'(4-hydroxyphenyl) ethanol ester of docosanoic (1), uvaol (2), sakuranetin (3), kumatakenin (5), cirsimaritin (6), 5-hydroxy-3,7,4'-trimethoxyflavone (7), oleanolic acid (8), herbacetin 3,7,8-trimethyl ether (9), ursolic acid (10), verbascoside (11), linarin (12), luteolin 7-O-ß-D-glucoside (13), luteolin 7-(6"-caffeoyl)-O-ß-D-glucopyranoside (14), luteolin (15), and 6-O-α-L-(4''-O-trans-cinnamoyl) rhamnopyranosylcatalpol (16). Regarding the biological activities investigated, the ethyl acetate fraction showed the most significant anti-inflammatory activity, followed by the n-butanol and the aqueous fractions. As for the petroleum ether and dichloromethane fractions, their anti-inflammatory effects were moderate. The highest hypoglycemic activity was possessed by the ethyl acetate fraction, followed by the dichloromethane fraction and the n-butanol fraction showed the weakest activity.
Assuntos
Buddleja/química , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Buddleja/crescimento & desenvolvimento , Hipoglicemiantes/farmacologia , Espectroscopia de Ressonância Magnética , Masculino , Ratos , Ratos Wistar , Arábia SauditaRESUMO
Assistive technology (AT) represents one way to improve access and participation in the school and home environments of people with disabilities (PWDs). This study analyzed the obstacles to AT acquisition, knowledge, use, recommendation, and training in special needs centers in the United Arab Emirates (UAE) from the perspective of professionals (teachers and therapists). A questionnaire was developed and its validity and reliability were confirmed. The questionnaire was distributed to all special-needs centers in the UAE via Survey Monkey, and 78 responses were received. The results indicate the nature of obstacles to AT use in special education centers in the UAE, with obstacles related to parents having the highest mean. The results also indicated a statistically significant difference in professionals' perception of obstacles to using AT based on experience level, center location, and level of education. Implications for further research and recommendations for policy and practice are provided.
Use of assistive technology (AT) enhances accessibility for students with disabilities. Therefore, it is imperative for centers and schools to actively seek access to AT tools and services to meet the needs of students with disabilities.Educational institutions must establish clear AT policies and legislation to provide AT tools for students with disabilities and address barriers to their implementation.Qualitative studies should be conducted to better understand the obstacles perceived by students with disabilities, teachers, principals, other staff, and parents as well as to gather recommendations for improvement.
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In colorectal cancer (CRC), aberrations in KRAS are associated with aggressive tumorigenesis and an overall low survival rate because of chemoresistance and adverse effects. Ergo, complementary, and integrative medicines are being considered for CRC treatment. Among which is the use of natural chalcones that are known to exhibit anti-tumor activities in KRAS mutant CRC subtypes treatment regimens. Consequently, we examine the effect of two novel compounds (DK13 and DK14) having chalcones with nitrogen mustard moiety on CRC cell lines (HCT-116 and LoVo) with KRAS mutation. These compounds were synthesized in our lab and previously reported to exhibit potent activity against breast cancer cells. Our data revealed that DK13 and DK14 treatment suppress cell growth, disturb the progression of cell cycle, and trigger apoptosis in CRC cell lines. Besides, treatment with both compounds impedes cell invasion and colony formation in both cell lines as compared to 5-FU; this is accompanied by up and down regulations of E-cadherin and Vimentin, respectively. At the molecular level, both compounds deregulate the expression and phosphorylation of ß-catenin, Akt and mTOR, which are the main likely molecular mechanisms underlying these biological occurrences. Our findings present DK13 and DK14 as novel chemotherapies against CRC, through ß-catenin/Akt/mTOR signaling pathways.
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Wilms tumor (WT), or nephroblastoma, is the predominant renal malignancy in the pediatric population. This narrative review explores the evolution of personalized care strategies for WT, synthesizing critical developments in molecular diagnostics and treatment approaches to enhance patient-specific outcomes. We surveyed recent literature from the last five years, focusing on high-impact research across major databases such as PubMed, Scopus, and Web of Science. Diagnostic advancements, including liquid biopsies and diffusion-weighted MRI, have improved early detection precision. The prognostic significance of genetic markers, particularly WT1 mutations and miRNA profiles, is discussed. Novel predictive tools integrating genetic and clinical data to anticipate disease trajectory and therapy response are explored. Progressive treatment strategies, particularly immunotherapy and targeted agents such as HIF-2α inhibitors and GD2-targeted immunotherapy, are highlighted for their role in personalized treatment protocols, especially for refractory or recurrent WT. This review underscores the necessity for personalized management supported by genetic insights, with improved survival rates for localized disease exceeding 90%. However, knowledge gaps persist in therapies for high-risk patients and strategies to reduce long-term treatment-related morbidity. In conclusion, this narrative review highlights the need for ongoing research, particularly on the long-term outcomes of emerging therapies and integrating multi-omic data to inform clinical decision-making, paving the way for more individualized treatment pathways.
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Path planning is a crucial element of mobile robotics applications, attracting considerable interest from academics. This paper presents a path-planning approach that utilises the Enhanced Firefly Algorithm (EFA), a new meta-heuristic technique. The Enhanced Firefly Algorithm (FA) differs from the ordinary FA by incorporating a linear reduction in the α parameter. This modification successfully resolves the constraints of the normal FA. The research involves experiments on three separate maps, using the regular FA and the suggested Enhanced FA in 20 different runs for each map. The evaluation criteria encompass the algorithms' ability to move from the initial location to the final position without experiencing any collisions. The assessment of path quality relies on elements such as the distance of the path and the algorithms' ability to converge and discover optimum solutions. The results demonstrate significant improvements made by the Enhanced FA, with a 10.270% increase in the shortest collision-free path for Map 1, a 0.371% increase for Map 2, and a 0.163% increase for Map 3, compared to the regular FA. This work highlights the effectiveness of the Enhanced Firefly Algorithm in optimising path planning for mobile robotics applications, providing potential improvements in navigation efficiency and collision avoidance.