RESUMO
Early detection of developmental dysplasia of the hip (DDH) is associated with improved outcomes of conservative treatment. Therefore, we aimed to evaluate a novel screening programme that included both the primary risk factors of breech presentation and family history, and the secondary risk factors of oligohydramnios and foot deformities. A five-year prospective registry study investigating every live birth in the study's catchment area (n = 27,731), all of whom underwent screening for risk factors and examination at the newborn and six- to eight-week neonatal examination and review. DDH was diagnosed using ultrasonography and the Graf classification system, defined as grade IIb or above or rapidly regressing IIa disease (≥4o at four weeks follow-up). Multivariate odds ratios were calculated to establish significant association, and risk differences were calculated to provide quantifiable risk increase with DDH, positive predictive value was used as a measure of predictive efficacy. The cost-effectiveness of using these risk factors to predict DDH was evaluated using NHS tariffs (January 2021). The prevalence of DDH that required treatment within our population was 5/1,000 live births. The rate of missed presentation of DDH was 0.43/1000 live births. Breech position, family history, oligohydramnios, and foot deformities demonstrated significant association with DDH (p < 0.0001). The presence of breech presentation increased the risk of DDH by 1.69% (95% confidence interval (CI) 0.93% to 2.45%), family history by 3.57% (95% CI 2.06% to 5.09%), foot deformities by 8.95% (95% CI 4.81% to 13.1%), and oligohydramnios nby 11.6% (95 % CI 3.0% to 19.0%). Primary risk factors family history and breech presentation demonstrated an estimated cost-per-case detection of £6,276 and £11,409, respectively. Oligohydramnios and foot deformities demonstrated a cost-per-case detected less than the cost of primary risk factors of £2,260 and £2,670, respectively. The inclusion of secondary risk factors within a national screening programme was clinically successful as they were more cost and resource-efficient predictors of DDH than primary risk factors, suggesting they should be considered in the national guidance.
RESUMO
Human pancreatic cancer is currently one of the fourth leading causes of cancer-related mortality with a 5-year survival rate of less than 5 %. Since pancreatic carcinoma is largely refractory to conventional therapies, there is a strong medical need for the development of novel and innovative cancer preventive strategies. The forkhead transcription factors of the O class (FOXO) play a major role in cell proliferation, angiogenesis, metastasis, and tumorigenesis. The objectives of this study were to examine whether FKHRL1/FOXO3a modulates antitumor activity of (-)-epigallocatechin-3-gallate (EGCG), an active ingredient in green tea, in pancreatic cancer model in vivo. PANC-1 cells were orthotopically implanted into Balb c nude mice and gavaged with EGCG after tumor formation. Cell proliferation and apoptosis were measured by Ki67 and TUNEL staining, respectively. The expression of PI3K, AKT, ERK, and FOXO3a/FKHRL1 and its target genes were measured by the western blot analysis and/or q-RT-PCR. FOXO-DNA binding was measured by gel shift assay. EGCG-treated mice showed significant inhibition in tumor growth which was associated with reduced phosphorylation of ERK, PI3K, AKT, and FKHRL1/FOXO3a, and modulation of FOXO target genes. EGCG induced apoptosis by upregulating Bim and activating caspase-3. EGCG modulated markers of cell cycle (p27/KIP1), angiogenesis (CD31, VEGF, IL-6, IL-8, SEMA3F, and HIF1α), and metastasis (MMP2 and MMP7). The inhibition of VEGF by EGCG was associated with suppression of neuropilin. EGCG inhibited epithelial-mesenchymal transition by upregulating the expression of E-cadherin and inhibiting the expression of N-cadherin and Zeb1. These data suggest that EGCG inhibits pancreatic cancer orthotopic tumor growth, angiogenesis, and metastasis which are associated with inhibition of PI3K/AKT and ERK pathways and activation of FKHRL1/FOXO3a. As a conclusion, EGCG can be used for the prevention and/or treatment of pancreatic cancer.