METHOD: Cell viability and colony formation assays were used to determine the 50% inhibitory concentration (IC50) of Et. O.s, rosmarinic acid, and gemcitabine. Different doses of gemcitabine in combination with Et. O.s or rosmarinic acid were tested against Panc-1 to select the best concentrations which possessed synergistic effects. Elucidation of molecular mechanisms responsible for mediating chemo-sensitivity in Panc-1 was performed using Quantitative Real-time PCR (QPCR), flow cytometry and immunohistochemistry.
RESULTS: Et. O.s was found to significantly sensitise Panc-1 towards gemcitabine by reducing the gene expression of multidrug-resistant protein family (MDR) (MDR-1, MRP-4, and MRP-5) and molecules related to epithelial-mesenchymal transition (ZEB-1 and Snail-1). An induction of the human equilibrate nucleoside transporter-1 (hENT-1) gene was also found in cells treated with Et. O.s-gemcitabine. The Et. O.s-gemcitabine combination induced cellular senescence, cell death and cell cycle arrest in Panc-1. In addition, the inhibition of Notch signalling was demonstrated through the downregulation of Notch 1 intracellular domain in this treatment group. In contrast, rosmarinic acid-gemcitabine combination showed no additional effects on cellular senescence, apoptosis, epithelial mesenchymal transition (EMT) markers, the MRP-4 and MRP-5 multi-drug resistance protein family, hENT-1, and the Notch pathway through Notch 1 intracellular domain.
CONCLUSION: This study provides valuable insights on the use of Et. O.s to complement gemcitabine in targeting pancreatic cancer in vitro, suggesting its potential use as a novel complementary treatment in pancreatic cancer patients.
EXPERIMENTAL PROCEDURE: The effects of C5EOSEW5050ESA treatment on cell viability, multidrug-resistant genes, epithelial-mesenchymal transition, cellular senescence, cell death, and Notch signalling pathway were evaluated in gemcitabine-resistant Panc-1 cells.
RESULTS AND CONCLUSION: C5EOSEW5050ESA sensitised gemcitabine resistant cells towards C5EOSEW5050ESA-gemcitabine combination treatment by reducing the expression of multidrug-resistant genes and epithelial-mesenchymal transition markers in gemcitabine-resistant cells compared to the control group, possibly through the inhibition of Notch signalling. This study provides valuable insight into using C5EOSEW5050ESA as a potential complementary treatment for resistant pancreatic cancer.
MATERIALS AND METHODS: The courses of the mandibular canal in 202 cone-beam computed tomography scanned images of healthy Malaysians were evaluated, and trifid mandibular canal (TMC) when present, were recorded and studied in detail by categorizing them to a new classification (comprising of 12 types). The diameter and length of canals were also measured, and their shape determined.
RESULTS: Trifid mandibular canals were observed in 12 (5.9%) subjects or 16 (4.0%) hemi-mandibles. There were 10 obvious categories out the 12 types of TMCs listed. All TMCs (except one) were observed in patients older than 30 years. The prevalence according to ethnicity was 6 in Malays, 5 in Chinese and 1 in Indian. Four (33.3%) patients had bilateral TMCs, which was not seen in the Indian subject. More than half (56.3%) of the accessory canals were located above the main mandibular canal. Their mean diameter was 1.32 mm and 1.26 mm for the first and second accessory canal, and the corresponding lengths were 20.42 mm and 21.60 mm, respectively. Most (62.5%) canals had irregularly shaped lumen; there were more irregularly shaped canals in the second accessory canal than the first branch. None of the second accessory canal was oval (in shape).
CONCLUSIONS: This new classification can be applied for the variations in the branching pattern, length and shape of TMCs for better clinical description.
AIM: To evaluate the anti-tumour activity and toxicological effects of Orthosiphon stamineus extract formulation (ID: C5EOSEW5050ESA trademarked as Nuva-staticTM), and gemcitabine combination on pancreatic xenograft model.
METHODS: Mice were randomly divided into six groups of 6 mice each (n = 6) and given different treatments for 28 d. The study design consisted of a 2 x 3 factorial treatment structure, with gemcitabine (yes/no) by oral (at 1200 and 400 mg/kg per day). Human pancreatic cancer cells were injected subcutaneously into the flanks of athymic nude mice. C5EOSEW5050ESA (200 or 400 mg/kg per day) was administered orally, while gemcitabine (10 mg/kg per 3 d) was given intraperitoneally either alone or in combination treatment. Histopathological analyses of vital organs, tumour tissues, and incidence of lethality were analysed. Analyses of tumour necrosis and proliferation were determined by haematoxylin-eosin staining and immunohistochemistry for Ki-67, respectively.
RESULTS: No signs of toxicity or damage to vital organs were observed in all treatment groups compared to the untreated group. C5EOSEW5050ESA at 200 mg/kg and gemcitabine combination had no additive antitumor effects compared to a single treatment. Remarkably, a comparably greater response in a reduction in tumour growth, Ki-67 protein expression, and necrosis was demonstrated by 400 mg/kg of C5EOSEW5050ESA and gemcitabine combination than that of the individual agents.
CONCLUSION: These results highlighted the synergistic activity of C5EOSEW5050ESA with gemcitabine to reduce pancreatic tumour growth in mice compared to a single treatment. Thus, this study provides valuable insights into using C5EOSEW5050ESA as a complementary treatment with gemcitabine for pancreatic cancer.
METHODOLOGY: To achieve the aim of the study, four proxies of innovation (resident patent applications, nonresident patent applications, scientific and technical journal articles, and research and development expenditures) are used to establish a robust relationship between innovation activities and trade openness in BRICS economies. Panel data from 2000 to 2020 is obtained from World Development Indicators and Penn World Tables. Econometric techniques of panel data such as fixed effect and generalized least squares are employed to extract results from the specified models.
FINDINGS: The findings of the study revealed that three proxies of innovation (i.e., resident patent applications, nonresident patent applications, scientific and technical journal articles) have a significant positive role in improving trade openness in the BRICS economies. However, the fourth proxy of innovation i.e., research and development expenditures had a negative impact on the degree of trade openness. Besides, innovation activities such as inflation rate and foreign direct investment have also influenced the degree of trade openness positively and significantly. Conversely, GDP per capita had a negative relationship with trade openness. Moreover, domestic investments showed a positive influence on the degree of trade openness while employment had a negative and insignificant influence on the degree of trade openness. Finally, the causality analysis revealed a one-way relationship running from innovations to trade openness.
IMPLICATIONS: In view of the results obtained, the policymakers of the BRICS economies might focus on encouraging innovation activities to enhance the degree of trade openness. Increased trade openness will consequently contribute to economic growth enormously and thus the attainment of sustainable development goals (SDG-8). Policymakers are also suggested to encourage FDI inflows and further ensure a moderate inflation rate to improve the degree of trade openness and hence accelerate economic growth.
ORIGINALITY: This study focused on examining the nexus between innovation activities and trade openness in emerging economies, which is indeed an interesting but rarely explored area of research. The findings of the study might help the policymakers of the BRICS economies in formulating policies regarding trade openness and innovation activities.