RESUMO
Partially unfolded alpha-lactalbumin forms the oleic acid complex HAMLET, with potent tumoricidal activity. Here we define a peptide-based molecular approach for targeting and killing tumor cells, and evidence of its clinical potential (ClinicalTrials.gov NCT03560479). A 39-residue alpha-helical peptide from alpha-lactalbumin is shown to gain lethality for tumor cells by forming oleic acid complexes (alpha1-oleate). Nuclear magnetic resonance measurements and computational simulations reveal a lipid core surrounded by conformationally fluid, alpha-helical peptide motifs. In a single center, placebo controlled, double blinded Phase I/II interventional clinical trial of non-muscle invasive bladder cancer, all primary end points of safety and efficacy of alpha1-oleate treatment are reached, as evaluated in an interim analysis. Intra-vesical instillations of alpha1-oleate triggers massive shedding of tumor cells and the tumor size is reduced but no drug-related side effects are detected (primary endpoints). Shed cells contain alpha1-oleate, treated tumors show evidence of apoptosis and the expression of cancer-related genes is inhibited (secondary endpoints). The results are especially encouraging for bladder cancer, where therapeutic failures and high recurrence rates create a great, unmet medical need.
Assuntos
Peptídeos/química , Peptídeos/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Sequência de Aminoácidos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Endocitose/efeitos dos fármacos , Determinação de Ponto Final , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Ácidos Oleicos/química , Peptídeos/farmacologia , Placebos , Conformação Proteica , Espectroscopia de Prótons por Ressonância Magnética , Termodinâmica , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologiaRESUMO
We investigated the association of matrix metalloproteinase-9 (-1562C/T, +279R/Q) and matrix metalloproteinase-2 (-1575G/A, -1306C/T) gene polymorphisms with multiple sclerosis (MS) susceptibility, gender differences and disability in 244 patients and 132 healthy subjects. A significant decrease of the -1562T allele carriers in MS patients compared to controls (Pa=0.01, Pacorr=0.05) in -1562C/T MMP-9 gene polymorphism was found, (odds ratio (OR) -0.58, 95% confidence interval (CI):0.38-0.89). Significant differences were also demonstrated between female patients and healthy females (Pa=0.01, Pacorr=0.05), (OR-0.53, 95% CI:0.32-0.86). Other polymorphisms were not associated either with MS susceptibility or with phenotype of the disease. No association with disability was found.
Assuntos
Predisposição Genética para Doença , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Esclerose Múltipla/genética , Polimorfismo Genético/genética , Adulto , Estudos de Casos e Controles , Intervalos de Confiança , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Metaloproteinase 2 da Matriz/sangue , Pessoa de Meia-Idade , Razão de Chances , Fatores SexuaisRESUMO
UNLABELLED: The purpose of this study was to investigate and compare the specificity, sensitivity, and area under curve (AUC) of the lactulose/mannitol ratio, lactulose/creatinine ratio, and lactulose recovery and their diagnostic value for intestinal permeability assessment within the absorption lactulose/mannitol (L/M) test. RESULTS: The value of the lactulose/mannitol ratio, lactulose/creatinine ratio, and the percentage of lactulose recovery in Crohn's disease (0.0763 +/- 0.0369; 99.62 +/- 67.87; 1.0478 +/- 0.6148) and in liver cirrhosis (0.0517 +/- 0.0365; 54.65 +/- 53.26; 0.838 +/- 0.929) were significantly different from the values measured in the control group (0.0123 +/- 0.0081; 10.95 +/- 7.07; 0.2438 +/- 0.1568), P < 0.0001-0.002). In Crohn's disease, specificity, sensitivity, and AUC were 100%, 89.5%, and 0.987, respectively, of the lactulose/mannitol ratio at a cut-off level of 0.022. In liver cirrhosis, the test characteristics were 88.5%, 84.2%, and 0.910 at a cut-off level of 0.018. CONCLUSION: The lactulose/mannitol ratio was evaluated to have the highest diagnostic value to assess intestinal permeability.
