Effects of palbociclib in oral squamous cell carcinoma and the role of PIK3CA in conferring resistance

Objective: Lack of effective therapies remains a problem in the treatment of oral squamous cell carcinoma (OSCC), especially in patients with advanced tumors. OSCC development is driven by multiple aberrancies within the cell cycle pathway, including amplification of cyclin D1 and loss of p16. Hence, cell cycle inhibitors of the CDK4/6-cyclin D axis are appealing targets for OSCC treatment. Here, we determined the potency of palbociclib and identified genetic features that are associated with the response of palbociclib in OSCC. Methods: The effect of palbociclib was evaluated in a panel of well-characterized OSCC cell lines by cell proliferation assays and further confirmed by in vivo evaluation in xenograft models. PIK3CA-mutant isogenic cell lines were used to investigate the effect of PIK3CA mutation towards palbociclib response. Results: We demonstrated that 80% of OSCC cell lines are sensitive to palbociclib at sub-micromolar concentrations. Consistently, palbociclib was effective in controlling tumor growth in mice. We identified that palbociclib-resistant cells harbored mutations in PIK3CA. Using isogenic cell lines, we showed that PIK3CA mutant cells are less responsive to palbociclib as compared to wild-type cells with concurrent upregulation of CDK2 and cyclin El protein levels. We further demonstrated that the combination of a PI3K/mTOR inhibitor (PF-04691502) and palbociclib completely controlled tumor growth in mice. Conclusions: This study demonstrated the potency of palbociclib in OSCC models and provides a rationale for the inclusion of PIK3CA testing in the clinical evaluation of CDK4/6 inhibitors and suggests combination approaches for further clinical studies

Effects of Titration Parameters on the Synthesis of Molybdenum Oxides Based Catalyst

Molybdenum oxides catalysts are extensively used in various selective oxidation reactions. In this work, controlled precipitation method was used to synthesise molybdenum oxides. The effects of various titration parameters on the precipitate growth rate and structure throughout catalyst synthesis were investigated. The titration parameters varied for this study were molybdates (ammonium heptamolybdate) concentration, precipitation agent (HNO3) concentration, precipitating agent rate of addition and temperature of synthesis. X-Ray diffraction (XRD) and Field Emission Scanning Electron Microscope (FESEM) were used to characterize the catalysts. This study highlights the significant effects of the titration parameters varied on the supersaturation of the solution therefore yielding precipitate with different morphology. It was observed that the temperature played the major role followed by molybdate concentration in the formation of the bulk catalyst. Supramolecular structure (Mo36O112) was observed at lower temperature (30ºC) and lower molybdate concentration (0.07 M, 0.10 M) while at higher temperature (50ºC) and higher molybdate concentration(0.14 M) hexagonal (h-MoO3) phase structure was formed. Fast rate of addition and high concentration of precipitating agent affected the solution equilibrium leading to unclear inflection point (supersaturation point) at the titration curve

Prevalence, Extent and Severity of the Psychosocial Impact of Dental Aesthetics among Malaysian Adolescents

This study aimed to assess the prevalence, extent and severity of the psychosocial impact of dental aesthetics (PIDA) among Malaysian adolescents especially those with self-perceived malocclusion, and to determine if age and gender affected their PIDA. A cross-sectional study using a self-administered questionnaire was conducted on 12-17 year old schoolchildren from schools across Malaysia selected via a multi-stage sampling method. The questionnaire included the Malaysian Psychosocial Impact of Dental Aesthetics (Malaysian PIDA) questionnaire and the Aesthetic Component of the Index of Orthodontic Treatment Need (IOTN-AC). The Malaysian PIDA measured four domains: (Dental Self Confidence, 6 items; Social Impact, 8 items; Psychological Impact, 6 items; and Aesthetic Concern, 2 items) to assess impacts on the oral health-related quality of life specific to malocclusion. While the IOTN-AC comprised a 10-point photographic scale to assess self-perceived malocclusion. Data analysis using SPSS version 20 was involved using complete data on 901 participants. The prevalence of Pion was 90.0% while prevalence associated with self-perceived malocclusion was 96.0%. Impact of dental aesthetics was highest on the psychological wellbeing of the adolescents, followed by their self-confidence. In terms of the extent of impact, 14.0% reported significant impact on all four domains and 192% were associated with self-perceived malocclusion. The prevalence of impacts was higher in younger adolescents and females. In terms of the extent and severity of impacts, younger adolescents reported higher impacts but with small effect sizes, while differences between boys and girls were not significant

The 4717C > G polymorphism in periplakin modulates sensitivity to EGFR inhibitors

The use of EGFR inhibitors on oral squamous cell carcinoma (OSCC) as monotherapy yielded modest clinical outcomes and therefore would benefit from biomarkers that could predict which patient subsets are likely to respond. Here, we determined the efficacy of erlotinib in OSCC cell lines, and by comparing sensitive and resistant lines to identify potential biomarkers. We focused on the 4717C > G polymorphism in periplakin (PPL) where the CC genotype was associated with erlotinib resistance. To validate this, erlotinib-resistant cell lines harbouring CC genotype were engineered to overexpress the GG genotype and vice versa. Isogenic cell lines were then studied for their response to erlotinib treatment. We demonstrated that overexpression of the GG genotype in erlotinib-resistant lines sensitized them to erlotinib and inhibition of AKT phosphorylation. Similarly, the expression of the CC genotype conferred resistance to erlotinib with a concomitant increase in AKT phosphorylation. We also demonstrated that cell lines with the CC genotype generally are more resistant to other EGFR inhibitors than those with the GG genotype. Overall, we showed that a specific polymorphism in the PPL gene could confer resistance to erlotinib and other EGFR inhibitors and further work to evaluate these as biomarkers of response is warranted

Potential antioxidants from crude extracts of roselle seeds and cashew nut shells for biodiesel storage stability improvement

Biodiesel or fatty acid methyl ester (FAME) is a green alternative fuel that degrades under long-term storage. Antioxidants are utilized in maintaining the oxidation stability of biodiesel by inhibiting the propagation of free radicals resulting in prolonged shelf life. Usage of natural antioxidants from renewable resources is preferred to sustain a green economy and potentially match synthetic antioxidants without being hazardous to the environment. In this study, the potential of antioxidants from crude extracts of Roselle seeds (Hibiscus sabdariffa) and cashew nut shells (Anacardium occidentale) which are agricultural residues that are commonly left unconsumed has been tested for biodiesel storage stability improvement. ABTS antioxidation test on both plant parts showed significant results for all samples regardless of their polarity while β-Carotene test favored polar samples. Positive correlation of DPPH test and total phenolic content (TPC) test confirmed the antioxidant activity of phenolic compounds in all samples. Total flavonoid content (TFC) test also showed positive results for all samples. GC-MS and LC-MS profiling of both plant parts revealed that all samples contained phenolic compounds with the exception of roselle seeds extracted with hexane (RH), which contained mostly fatty acids. Oxidative stability test using Rancimat test showed that polar samples have superior performance than nonpolar samples whereas 3-pentadecyl phenol showed a poor performance in improving biodiesel storage stability

The Role of Transient Receptor Potential (TRP) Channels in the Transduction of Dental Pain

Dental pain is a common health problem that negatively impacts the activities of daily living. Dentine hypersensitivity and pulpitis-associated pain are among the most common types of dental pain. Patients with these conditions feel pain upon exposure of the affected tooth to various external stimuli. However, the molecular mechanisms underlying dental pain, especially the transduction of external stimuli to electrical signals in the nerve, remain unclear. Numerous ion channels and receptors localized in the dental primary afferent neurons (DPAs) and odontoblasts have been implicated in the transduction of dental pain, and functional expression of various polymodal transient receptor potential (TRP) channels has been detected in DPAs and odontoblasts. External stimuli-induced dentinal tubular fluid movement can activate TRP channels on DPAs and odontoblasts. The odontoblasts can in turn activate the DPAs by paracrine signaling through ATP and glutamate release. In pulpitis, inflammatory mediators may sensitize the DPAs. They could also induce post-translational modifications of TRP channels, increase trafficking of these channels to nerve terminals, and increase the sensitivity of these channels to stimuli. Additionally, in caries-induced pulpitis, bacterial products can directly activate TRP channels on DPAs. In this review, we provide an overview of the TRP channels expressed in the various tooth structures, and we discuss their involvement in the development of dental pain

Preparation and characterization of cellulose and microcrystalline cellulose isolated from waste Leucaena leucocephala seeds

Cellulose and microcrystalline cellulose (MCC) were isolated from waste Leucaena leucocephala seeds (LLS) by using acid hydrolysis method. Waste LLS are unused residues after extraction of oil for conversion to biodiesel. Cellulose from LLS (LLS-cellulose) has been isolated by using 80% acetic acid and 65% nitric acid to yield 33% cellulose. MCC was further prepared from the LLS-cellulose via the acid hydrolysis method and yield 71%. The obtained LLS-cellulose and LLS-MCC samples were comparatively investigated by Fourier transform infrared spectroscopy (FTIR), Thermogravimetric analysis (TGA), X-ray diffraction (XRD) and Field Emission Scanning Electron Microscopy technique (FESEM). FTIR second derivative showed the presence of minor amounts of bound hemicellulose and relatively free of lignin compound. The crystallinity index of LLS-cellulose is higher than LLS-MCC, indicating higher crystallize size and thermal decomposition. FESEM image also showed that there is smooth surface of raw LLS after hot boiling extraction for 2 hours. Thus, this study revealed that the lignin and hemicelluloses can be removed efficiently by using hot water treatment. In addition, cellulose components produced from waste LLS could be used as precursors of other industrial applications

A Critical Outlook on the Role of Research Practices in Laboratory towards Student Skills Development in Malaysian and Japanese Public Universities

Developing talented graduates to fulfil market challenges is a formidable task for higher education today. By using qualitative method, Malaysian and Japanese professors in selected public universities were interviewed in order to investigate how research practices in laboratory contribute towards student skills development. The result shows that laboratory practices such as group work, mentoring and closed monitoring in organization enhance student employability skills. It is suggested that chain mentoring system from professors to junior researchers to be practiced as a succession planning in developing potential leaders. Closed monitoring between principal investigator, senior and junior researchers is also significant to support not only for professional skills, but also for personality growth and emotional support

Collagen Induces a More Proliferative, Migratory and Chemoresistant Phenotype in Head and Neck Cancer via DDR1

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and includes squamous cell carcinomas of the oropharynx and oral cavity. Patient prognosis has remained poor for decades and molecular targeted therapies are not in routine use. Here we showed that the overall expression of collagen subunit genes was higher in cancer-associated fibroblasts (CAFs) than normal fibroblasts. Focusing on collagen8A1 and collagen11A1, we showed that collagen is produced by both CAFs and tumour cells, indicating that HNSCCs are collagen-rich environments. We then focused on discoidin domain receptor 1 (DDR1), a collagen-activated receptor tyrosine kinase, and showed that it is over-expressed in HNSCC tissues. Further, we demonstrated that collagen promoted the proliferation and migration of HNSCC cells and attenuated the apoptotic response to cisplatin. Knockdown of DDR1 in HNSCC cells demonstrated that these tumour-promoting effects of collagen are mediated by DDR1. Our data suggest that specific inhibitors of DDR1 might provide novel therapeutic opportunities to treat HNSCC