Nasopharyngeal carcinoma (NPC) is an Asian-prevalent head and neck cancer with high invasiveness. Although several important risk factors for NPC development have been identified, there is currently ...no preventive strategy for NPC, even in endemic regions. Signal transducer and activator of transcription 3 (STAT3) has been implicated in NPC carcinogenesis, which may serve as a potential target for cancer prevention. Here, we examined the chemopreventive potential of Cucurbitacin I, a natural-occurring selective inhibitor of JAK/STAT3, in NPC models. We hypothesized that Cucurbitacin I would prevent NPC invasion and tumor formation. Our data demonstrated that brief exposure of NPC cells to Cucurbitacin I was sufficient to significantly reduce the in vitro clonogenicity and in vivo tumorigenicity of NPC cells. The chemopreventive potential of Cucurbitacin I was further demonstrated by pre-dosing of the animals with Cucurbitacin I prior to tumor inoculation, which was found to be able to suppress tumor growth up to 7 days post-inoculation. The anti-proliferation activity of Cucurbitacin I was accompanied by downregulation of phospho-STAT3 and STAT3 target gene expression (e.g. cyclin D1 and Mcl-1). Cucurbitacin I also reduced the invasiveness of invasive NPC cell lines with elevated STAT3 activation. Furthermore, our data demonstrated for the first time that Cucurbitacin I harbored potent anoikis-sensitization activity (i.e. sensitizing cancer cells to detachment-induced cell death) against human cancer. Taken together, our results suggested that Cucurbitacin I may be a potent chemopreventive agent for NPC with anti-invasion and anoikis-sensitizing activities.
Impaired sensorimotor control, as a common feature of autism spectrum disorder (ASD), could be a driving factor to handwriting problems. This study examined the Chinese and English handwriting and ...sensorimotor skills of 15 ASD and 174 typically developing Chinese adolescents. Participants with ASD had lower writing speed and poor manual dexterity (MD) than the typically developing participants. MD was a significant mediator between ASD and handwriting speed. Ground time and airtime represent the length of time when the pen touches the paper and is held in air, respectively. Participants with ASD who had better performance in MD showed shorter ground time in Chinese handwriting and shorter airtime in English handwriting. Training for adolescents with ASD on their MD may improve their handwriting performance.
Summary
Nasopharyngeal carcinoma (NPC) is endemic to Asia and over 40 % of NPC tissues harbor PIK3CA amplifications. This study characterized the preclinical activity of MK-2206, an oral allosteric ...inhibitor of AKT in 6 NPC cell lines: C666-1, HK1, HONE-1-EBV, HONE-1, CNE-2 and HNE-1. Exposure to increasing concentrations of MK-2206 resulted in over 95 % of growth inhibition in all NPC cell lines with IC
50
values in the low micromolar range. Further experiments were performed in 3 representative NPC cell lines: CNE-2 (harbor
PIK3CA
mutation and most sensitive to MK-2206), C666-1 (carries PIK3CA amplification), and HONE-1-EBV (least sensitive to MK-2206). MK-2206 induced G
0
/G
1
cycle arrest in all 3 cell lines, but could induce apoptosis only in CNE-2 cells. MK-2206 significantly abrogated AKT signaling in all 3 cell lines by inhibiting the activation of AKT and its downstream effectors (FKHR, GSK3β and BAD). MK-2206 also reduced mTOR signaling by reducing activation of mTOR and its downstream 4E-BP1 and p70S6 kinase. MAPK activation was observed in HONE-1 and C666-1 cells, but not in CNE-2 cells following exposure to MK-2206. The addition of MK-2206 to cisplatin (but not with paclitaxel) has a supra-additive inhibitory effect on growth in vitro. In summary, MK-2206 can inhibit growth and abrogate AKT and mTOR signaling in NPC cell lines. This agent is currently being evaluated in a phase II study in metastatic NPC.
Summary
Nasopharyngeal carcinoma (NPC) is common in Southeast Asia and over 40 % of NPC tissues have PIK3CA amplification. This study characterized the preclinical activity of a novel potent dual ...PI3K/mTOR inhibitor, PF-04691502, in five NPC cell lines: CNE-1, HK1, CNE-2, HONE-1 and C666-1, in which all of the cell lines possessed basal and activated expression of Akt and p70S6K. Over 80 % inhibition of cell growth in all of these cell lines were achieved after 72 h of PF-04691502 incubation and their IC
50
were in hundred nanomolar range. CNE-2, HK1 and HONE-1 were selected to further evaluate the effect of PF-04691502 on cell cycle, apoptosis and Akt downstream signaling. PF-04691502 induced G
0
/G
1
cell cycle arrest and apoptosis at 24 h incubation and it significantly abrogated Akt and its downstream signaling by suppressing the expression of p-mTOR, p-p70S6K, p-Akt(S473, T308), p-S6 and p-4E-BP1, suggesting its effectiveness in inhibition of translation and protein synthesis. Anti-proliferation was also observed in 3D culture system and spheroids formation of NPC cell line HONE-1-EBV was strongly inhibited by PF-04691502. Antitumor activity was observed in CNE-2 xenograft in 2 weeks of 10 mg/kg PF-09641502 treatment to tumor bearing athymic nude mice. Both tumor volume and weight in treatment group were significantly lower than those in vehicle group while no obvious body weight decrease was found, suggesting this working dose was effective and well-tolerated. Additive effects were observed in combination of PF-09641502 with either cisplatin or paclitaxel. There were no synergistic effect observed in drug combination but PF-09641502 alone was effective in treating cisplatin resistant cell lines as compared to its parental control. The beneficial effects of PF-09641502 in both in vitro and in vivo studies for NPC warrant a further investigation.
Abstract The dual PI3K–mTOR inhibitor BEZ235 was evaluated in preclinical models of nasopharyngeal carcinoma (NPC). The IC50 value of BEZ235 for growth was in the nanomolar range in vitro , induce G1 ...cycle arrest and apoptosis, and inhibited AKT and mTOR signaling in most NPC cell lines. No synergistic effect was observed when BEZ235 was combined with chemotherapy. BEZ235 increased MAPK activation in vitro but not in vivo . A daily schedule was more effective than a weekly schedule on tumor growth and inhibition of downstream mTOR signaling in vivo . The activity of BEZ235 maybe independent of the PIK3CA amplification and mutation status.
Summary
Phosphorylated (pi-) protein kinase B (AKT) is commonly expressed in nasopharyngeal carcinoma (NPC) cell lines and tissues, suggesting the involvement of AKT-mammalian target of rapamycin ...(mTOR) signaling in NPC carcinogenesis. This study evaluated the activity of an mTOR inhibitor, RAD001 (Everolimus, Novartis Pharma AG, Switzerland), in 5 NPC cell lines (HK1, HONE-1, CNE-1, CNE-2, C666-1), 2 cisplatin-resistant NPC cell lines and their respective parental cell lines (HK1-LMP1, HONE-1-EBV). RAD001 inhibited cell growth in a dose-dependent manner at nanomolar concentrations in all cell lines. HONE-1 was most sensitive to RAD001 (IC
50
= 0.63 nM, 60% maximal inhibition), while Het-1A (a normal esophageal epithelial cell line) was relatively resistant. No consistent relationship between sensitivity to RAD001 and basal expression of pi-mTOR and pi-p70S6 Kinase-1 (p70S6K) was found. Exposure to RAD001 at picomolar concentrations for 48 h resulted in reduction of pi-mTOR and pi-p70S6K1 expression, but increase in pi-AKT (Ser473) expression in HONE-1 and CNE-1 cell lines. RAD001 significantly induced apoptosis in HONE-1 cells, but has no effect on cell cycle progression. RAD001 exerted an additive to synergistic effect on cisplatin-induced growth inhibition in CNE-1 and HONE-1 cells, and could inhibit the growth of both cisplatin-resistant and cisplatin-sensitive NPC cell lines. In summary, combination of RAD001 and cisplatin maybe a useful therapeutic strategy in NPC. AKT upregulation following RAD001 treatment suggests the presence of a feedback loop on AKT signaling in NPC which warrants further investigation.
Objectives
Attention deficit hyperactivity disorder (ADHD) and learning difficulties (LDs) are proposed as 2 overlapping disorders. The objective of this study was to investigate the handwriting ...performance in ADHD and comorbid ADHD‐LD adolescents.
Methods
The study examined the Chinese and English handwriting performance and sensorimotor skills of 32 ADHD, 12 ADHD‐LD, and their matched controls.
Results
Participants with ADHD had comparable writing time and speed, but the readability was lower than their controls. Participants with ADHD‐LD had lower writing speeds in both Chinese and English handwriting than their controls. The ADHD and ADHD‐LD groups also showed larger variations in either speed or pen pressure than their controls. Chinese handwriting assessment effectively classified ADHD and ADHD‐LD with good sensitivity and positive predictive value.
Conclusions
Clinicians should be aware of the fundamental difference between the 2 disorders and make good use of handwriting assessment as a reference to deliver effective therapies and trainings.
Purpose
RAD001 targets at the mammalian target of rapamycin (mTOR), while TKI-258 is a potent tyrosine kinase inhibitor targeting at fibroblast growth factor receptor, vascular endothelial growth ...factor receptor, platelet-derived growth factor receptor and c-kit. We aim to study the activity of combined RAD001 and TKI-258 in cell lines and xenograft model of hepatocellular carcinoma (HCC), with reference to the parallel and upstream pathways of Akt–mTOR axis.
Methods
A panel of 4 human HCC cell lines HepG2, Hep3B, PLC/PRF/5 and Huh7 and the Hep3B-derived xenograft were treated with TKI-258 or/and RAD001, respectively. Related mechanistic studies (including apoptosis and angiogenesis) were conducted.
Results
There was an enhanced increase in suppression of cell proliferation with combined TKI-258 and RAD001 compared with either drug alone. The combination could significantly suppress the phosphorylation of mTOR, MEK1/2 and p38 MAPK. Although the addition of the TKI258 only slightly suppressed the phosphorylation of AKT induced by RAD001, the pi-mTOR and its downstream signaling pathways including pi-p70S6K, pi-S6 and pi-4EBP1 were lowered in the combination. In Hep3B-derived xenograft, TKI-258 and RAD001 had shown an enhanced inhibition of tumor growth without impact on the weight of animals. There was a reduction in microvessel density in the xenograft with the combination, which indicated an enhanced inhibition on angiogenesis. Pro-caspases-3 and PARP cleavage were slightly detected at 48 h after treatment, suggesting that the combination mainly increased the cytostatic arrest ability.
Conclusions
The combination of RAD001 and TKI-258 was active in HCC via inhibition of both mTOR-mediated signaling and its parallel pathways.
Background/aim
Handwriting difficulties can be detrimental to students’ performance in school tests and even in public examinations. It is crucial for school‐based occupational therapists to identify ...students with handwriting difficulties and support them with appropriate adaptive strategies. The purpose of this study is to validate a computerised assessment – the Computerised Handwriting Speed Test System (CHSTS) of both Chinese and English handwriting for Chinese secondary students and provide an objective reference for extra time allowance in paper‐based examinations.
Methods
The internal consistency, test–retest reliability, convergent and discriminant validity of CHSTS were examined using the data from 512 typically developing students and 64 students with special educational needs (SEN) in Hong Kong mainstream secondary schools.
Results
Handwriting performance of senior students was better than that of junior students. High internal consistency was shown by over 0.80 Cronbach's α in all measurement items and over 0.90 item‐total correlations in temporal domain items. Intra‐class correlation indicated good to excellent test–retest reliability of CHSTS (all P < 0.0001). Principal Component Analysis revealed that four components in CHSTS accounted for over 80% of the variance. Handwriting performance was positively associated with manual coordination, automaticity and oculomotor control (all P < 0.05) in linear regression analyses. Students with SEN could be effectively differentiated from typically developing students (over 75% sensitivity and specificity) based on the CHSTS items.
Conclusion
Validation of CHSTS is the groundwork for identifying students with handwriting difficulties and providing adaptive strategies including fair special examination arrangements for these students.
This study aimed to determine the efficacy of silicone gel (Cica-Care) on severe post-traumatic hypertophic scars among the Chinese population.
A randomized clinical trial (RCT) was conducted on 45 ...Chinese patients with post-traumatic hypertrophic scars. Twenty-two subjects were placed in the experimental group with silicone gel sheeting (SGS) applied 24
h per day for 6 months while all subjects were taught to massage the scar daily for 15
min serving as the control intervention. Scar assessments were conducted regularly to measure the changes in thickness, pigmentation, vascularity, pliability, itchiness and pain.
Two-way repeated ANOVA showed a significant difference between MT group and SGS group on scar thickness. The post hoc comparison analysis showed that the difference was significant at the post-2-month (
p
=
0.008) and post-6-month (
p
<
0.001) intervention. The SGS group also showed changes in pigmentation which resembled normal skin but no statistical significance was found. Pain, itchiness and pliability were also improved after intervention.
This study indicated that silicone gel sheeting (Cica-Care) was effective to reduce thickness, pain, itchiness and pliability of the severe hypertrophic scar among the Chinese population. The moisturization effect of the tough and hard scar might contribute to the reduction of the skin thickness after 6 month's intervention.
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