METHODS: Data collection was carried out from November 2017 until May 2018 among 211 Orang Asli respondents aged 18 years old and above, who lived in five villages in Tasik Chini, Pahang. All respondents who fulfilled the inclusion criteria were recruited in this study. Interview-guided questionnaire was administered, and spirometry test that include Forced Expiratory Volume in one second (FEV1), Forced Vital Capacity (FVC), and Peak Expiratory Flow Rate (PEFR) was carried out. Data were analyzed using SPSS software version 23.0. In the first stage, descriptive analysis was done to describe the characteristics of the respondents. In the second stage, bivariable analysis was carried out to compare proportions. Finally, multiple logistic regression was performed to assess the effects of various independent predictors on spirometry parameters.
RESULTS: The respondents' age ranged from 18 to 71 years old in which 50.2% of them were female. The majority ethnicity in Tasik Chini was Jakun tribe (94.3%). More than half of the respondents (52.1%) were current smoker, 5.2% were ex-smoker and 41.7% were non-smoker. More than half of them (62.1%) used woodstove for cooking, compared to only 37.9% used cleaner fuel like Liquefied Petroleum Gas (LPG) as a fuel for everyday cooking activity. The lung function parameters (FEV1 and FVC) were lower than the predictive value, whereas the ratio of Forced Expiratory Volume in one second and Forced Vital Capacity (FEV1/FVC) (%) and PEFR were within the predictive value. The FEV1 levels were significantly associated with age group (18-39 years old) (p = 0.002) and presence of woodstove in the house (p = 0.004). FVC levels were significantly associated with presence of woodstove in the house (p = 0.004), whereas there were no significant associations between all factors and FEV1/FVC levels.
CONCLUSIONS: FEV1 levels were significantly associated with age group 18-39 years old, whereas FVC levels were significantly associated with the presence of woodstove in the house. Thus, environmental interventions such as replacing the use of woodstove with LPG, need to be carried out to prevent further worsening of respiratory health among Orang Asli who lived far from health facilities. Moreover, closer health monitoring is crucial especially among the younger and productive age group.
METHODS: Data from 43 lung transplant recipients (1021 tacrolimus concentrations) administered an immediate-release oral formulation of tacrolimus were used to evaluate the predictive performance of 17 published population pharmacokinetic models for tacrolimus. Data were collected from immediately after transplantation up to 90 days after transplantation. Model performance was evaluated using (1) prediction-based assessments (bias and imprecision) of individual predicted tacrolimus concentrations at the fourth dosing based on 1 to 3 previous dosings and (2) simulation-based assessment (prediction-corrected visual predictive check; pcVPC). Both assessments were stratified based on concomitant azole antifungal use. Model performance was clinically acceptable if the bias was within ±20%, imprecision was ≤20%, and the 95% confidence interval of bias crossed zero.
RESULTS: In the presence of concomitant antifungal therapy, no model showed acceptable performance in predicting tacrolimus concentrations at the fourth dosing (n = 33), and pcVPC plots displayed poor model fit to the data set. However, this fit slightly improved in the absence of azole antifungal use, where 4 models showed acceptable performance in predicting tacrolimus concentrations at the fourth dosing (n = 33).
CONCLUSIONS: Although none of the evaluated models were appropriate in guiding tacrolimus dosing in lung transplant recipients receiving concomitant azole antifungal therapy, 4 of these models displayed potential applicability in guiding dosing in recipients not receiving concomitant azole antifungal therapy. However, further model refinement is required before the widespread implementation of such models in clinical practice.
METHODS: We performed targeted capture and next-generation sequencing of 85 cancer susceptibility genes on germline DNA from 198 patients with pleural, peritoneal, and tunica vaginalis MM.
RESULTS: Twenty-four germline mutations were identified in 13 genes in 23 (12%) of 198 patients. BAP1 mutations were the most common (n = 6; 25%). The remaining were in genes involved in DNA damage sensing and repair (n = 14), oxygen sensing (n = 2), endosome trafficking (n = 1), and cell growth (n = 1). Pleural site (odds ratio [OR], 0.23; 95% CI, 0.10 to 0.58; P < .01), asbestos exposure (OR, 0.28; 95% CI, 0.11 to 0.72; P < .01), and older age (OR, 0.95; 95% CI, 0.92 to 0.99; P = .01) were associated with decreased odds of carrying a germline mutation, whereas having a second cancer diagnosis (OR, 3.33; 95% CI, 1.22 to 9.07; P = .02) significantly increased the odds. The odds of carrying a mutation in BAP1 (OR, 1,658; 95% CI, 199 to 76,224; P < .001), BRCA2 (OR, 5; 95% CI, 1.0 to 14.7; P = .03), CDKN2A (OR, 53; 95% CI, 6 to 249; P < .001), TMEM127 (OR, 88; 95% CI, 1.7 to 1,105; P = .01), VHL (OR, 51; 95% CI, 1.1 to 453; P = .02), and WT1 (OR, 20; 95% CI, 0.5 to 135; P = .049) were significantly higher in MM cases than in a noncancer control population. Tumor sequencing identified mutations in a homologous recombination pathway gene in 52% (n = 29 of 54).
CONCLUSION: A significant proportion of patients with MM carry germline mutations in cancer susceptibility genes, especially those with peritoneal MM, minimal asbestos exposure, young age, and a second cancer diagnosis. These data support clinical germline genetic testing for patients with MM and provide a rationale for additional investigation of the homologous recombination pathway in MM.
METHODS: Cancer 10-pathway reporter array was performed to screen the pathways affected by Phyllanthus in lung carcinoma cell line (A549) to exert its antimetastatic effects. Results from this array were then confirmed with western blotting, cell cycle analysis, zymography technique, and cell based ELISA assay for human total iNOS. Two-dimensional gel electrophoresis was subsequently carried out to study the differential protein expressions in A549 after treatment with Phyllanthus.
RESULTS: Phyllanthus was observed to cause antimetastatic activities by inhibiting ERK1/2 pathway via suppression of Raf protein. Inhibition of this pathway resulted in the suppression of MMP2, MMP7, and MMP9 expression to stop A549 metastasis. Phyllanthus also inhibits hypoxia pathway via inhibition of HIF-1α that led to reduced VEGF and iNOS expressions. Proteomic analysis revealed a number of proteins downregulated by Phyllanthus that were involved in metastatic processes, including invasion and mobility proteins (cytoskeletal proteins), transcriptional proteins (proliferating cell nuclear antigen; zinc finger protein), antiapoptotic protein (Bcl2) and various glycolytic enzymes. Among the four Phyllanthus species tested, P. urinaria showed the greatest antimetastatic activity.
CONCLUSIONS: Phyllanthus inhibits A549 metastasis by suppressing ERK1/2 and hypoxia pathways that led to suppression of various critical proteins for A549 invasion and migration.