RESULTS: Twenty-five hydrocarbons, common in air pollution with carcinogenicity classification of 1 A/B or 2 (known/presumed or suspected human carcinogen), were divided into three groups: alkanes and alkenes, halogenated hydrocarbons, and polyaromatic hydrocarbons. The in silico data-mining revealed 87 and 44 genes commonly interacted with most of the investigated hydrocarbons are linked to breast and lung cancer, respectively. The dominant interactions among the common genes are co-expression, physical interaction, genetic interaction, co-localization, and interaction in shared protein domains. Among these genes, only 16 are common in the development of both cancers. Benzo(a)pyrene and tetrachlorodibenzodioxin interacted with all 16 genes. The molecular pathways potentially affected by the investigated hydrocarbons include aryl hydrocarbon receptor, chemical carcinogenesis, ferroptosis, fluid shear stress and atherosclerosis, interleukin 17 signaling pathway, lipid and atherosclerosis, NRF2 pathway, and oxidative stress response.
CONCLUSIONS: Within the inherent limitations of in silico toxicogenomics tools, we elucidated the molecular pathways associated with breast and lung cancer development potentially affected by hydrocarbons mixture. Our findings indicate adaptive responses to oxidative stress and inflammatory damages are instrumental in the development of both cancers. Additionally, ferroptosis-a non-apoptotic programmed cell death driven by lipid peroxidation and iron homeostasis-was identified as a new player in these responses. Finally, AHR potential involvement in modulating IL-8, a critical gene that mediates breast cancer invasion and metastasis to the lungs, was also highlighted. A deeper understanding of the interplay between genes associated with these pathways, and other survival signaling pathways identified in this study, will provide invaluable knowledge in assessing the risk of inhalation exposure to hydrocarbons mixture. The findings offer insights into future in vivo and in vitro laboratory investigations that focus on inhalation exposure to the hydrocarbons mixture.
METHOD: For designing and modeling the DSPN severity grading systems for MNSI, 19 years of data from Epidemiology of Diabetes Interventions and Complications (EDIC) clinical trials were used. Different Machine learning-based feature ranking techniques were investigated to identify the important MNSI features associated with DSPN diagnosis. A multivariable logistic regression-based nomogram was generated and validated for DSPN severity grading using the best performing top-ranked MNSI features.
RESULTS: Top-10 ranked features from MNSI features: Appearance of Feet (R), Ankle Reflexes (R), Vibration perception (L), Vibration perception (R), Appearance of Feet (L), 10-gm filament (L), Ankle Reflexes (L), 10-gm filament (R), Bed Cover Touch, and Ulceration (R) were identified as important features for identifying DSPN by Multi-Tree Extreme Gradient Boost model. The nomogram-based prediction model exhibited an accuracy of 97.95% and 98.84% for the EDIC test set and an independent test set, respectively. A DSPN severity score technique was generated for MNSI from the DSPN severity prediction model. DSPN patients were stratified into four severity levels: absent, mild, moderate, and severe using the cut-off values of 17.6, 19.1, 20.5 for the DSPN probability less than 50%, 75%-90%, and above 90%, respectively.
CONCLUSIONS: The findings of this work provide a machine learning-based MNSI severity grading system which has the potential to be used as a secondary decision support system by health professionals in clinical applications and large clinical trials to identify high-risk DSPN patients.
METHODS: This study uses a mixed methods design. It focuses primarily on qualitative data to understand processes and strategies and to identify specific areas that can be improved through stakeholder engagement in the screening program. Quantitative data play a dual role in supporting the selection of participants for the qualitative study based on program monitoring data and assessing inequalities in screening and program implementation in healthcare facilities in Malaysia. Meanwhile, literature review identifies existing strategies to improve colorectal cancer screening. Additionally, the knowledge-to-action framework is integrated to ensure that the research findings lead to practical improvements to the colorectal cancer screening program.
DISCUSSION: Through this complex mix of qualitative and quantitative methods, this study will explore the complex interplay of population- and systems-level factors that influence screening rates. It involves identifying barriers to effective colorectal cancer screening in Malaysia, comparing current strategies with international best practices, and providing evidence-based recommendations to improve the local screening program.
Objective: To evaluate the efficacy of oral mixed tocotrienols for patients with diabetic peripheral neuropathy.
Design, Setting, and Participants: The Vitamin E in Neuroprotection Study (VENUS) was a parallel, double-blind, placebo-controlled trial that recruited participants from January 30, 2011, to December 7, 2014, with 12 months of follow-up. This trial screened 14 289 patients with diabetes from 6 health clinics and ambulatory care units from 5 public hospitals in Malaysia. A total of 391 patients who reported neuropathic symptoms were further assessed with Total Symptom Score (TSS) and Neuropathy Impairment Score (NIS). Patients 20 years or older with a TSS of 3 or higher and an NIS of 2 or higher were recruited.
Interventions: Patients were randomized to receive 200 mg of mixed tocotrienols twice daily or matching placebo for 12 months. Patients with hyperhomocysteinemia (homocysteine level ≥2.03 mg/L) received oral folic acid, 5 mg once daily, and methylcobalamin, 500 μg thrice daily, in both groups.
Main Outcomes and Measures: The primary outcome was patient-reported neuropathy TSS (lancinating pain, burning pain, paresthesia, and asleep numbness) changes at 12 months. The secondary outcomes were NIS and sensory nerve conduction test result.
Results: Of 391 eligible patients, 300 were recruited (130 [43.3%] male; mean [SD] age, 57.6 [8.9] years; mean [SD] duration of diabetes, 11.4 [7.8] years) and 229 (76.3%) completed the trial. The TSS changes between the tocotrienols and placebo groups at 12 months (-0.30; 95% CI, -1.16 to 0.56; P = .49) were similar. No significant differences in NIS (0.60; 95% CI, -1.37 to 2.65; P = .53) and sensory nerve conduction test assessments were found between both groups. In post hoc subgroup analyses, tocotrienols reduced lancinating pain among patients with hemoglobin A1C levels greater than 8% (P = .03) and normohomocysteinemia (homocysteine level <2.03 mg/L; P = .008) at 1 year. Serious adverse events in both groups were similar, except more infections were observed in the tocotrienols group (6.7% vs 0.7%, P = .04). Results reported were of modified intention-to-treat analyses.
Conclusions and Relevance: Supplementation of oral mixed tocotrienols, 400 mg/d for 1 year, did not improve overall neuropathic symptoms. The preliminary observations on lancinating pain among subsets of patients require further exploration.
Trial Registration: National Medical Research Registry Identifier: NMRR-10-948-7327 and clinicaltrials.gov Identifier: NCT01973400.