Brusatol attenuated proliferation and invasion induced by KRAS in differentiated thyroid cancer through inhibiting Nrf2.

BACKGROUND: Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) can be developed from differentiated thyroid cancer, and this dedifferentiated transformation leads to poor prognosis and high mortality. The role of Nrf2 in the dedifferentiation of differentiated thyroid cancer (DTC) induced by KRAS remains unclear. METHODS AND MATERIALS: In this study, two DTC cell lines, BCPAP and WRO, were used to evaluate the function of Nrf2 in the dedifferentiation caused by wild-type KRAS (KRAS-WT) and G12V point mutation KRAS (KRAS-G12V). RESULTS: The overexpression of KRAS-WT and KRAS-G12V increased the proliferative and invasive ability of BCPAP and WRO cells. Aggressive morphology was observed in KRAS-WT and KRAS-G12V overexpressed WRO cells. These results suggested that overexpression of KRAS-WT or KRAS-G12V may induce dedifferentiation in DTC cells. The expression of Nrf2 was increased by KRAS-WT and KRAS-G12V in DTC cells. In addition, compared with normal thyroid tissues, the expression of Nrf2 protein was considerably higher in thyroid cancer tissues on immunohistochemistry (IHC) staining, and the increased expression of Nrf2 indicated a poor prognosis of thyroid cancer. These results indicated that Nrf2 is the KRAS downstream molecule in thyroid cancer. Functional studies showed that the Nrf2 inhibitor Brusatol counteracted the proliferative and invasive abilities induced by KRAS-WT and KRAS-G12V in BCPAP and WRO cells. In addition, the xenograft assay further confirmed that Brusatol inhibits tumor growth induced by KRAS-WT and KRAS-G12V. CONCLUSION: Collectively, this study suggests that Nrf2 could be a promising therapeutic target in KRAS-mediated dedifferentiation of thyroid cancer.

Lexical tone perception in native speakers of Cantonese.

PURPOSE: This study aimed at investigating (1) tone perception development among typically-developing Cantonese speakers and (2) the hierarchy of tone perception difficulty among the 15 tone contrasts. METHOD: Two-hundred typically-developing children aged 3-10 and a group of 25 normal hearing adults were recruited. They were tested on a pool of 75-item calibrated recorded speech signals. Participants responded to each stimulus by pointing at the corresponding picture displayed on a computer screen from a choice of four. RESULT: There was a gradual increase in tone perception accuracy from children aged 3-6. After age 6, tone perception accuracy was similar to adults with an average error rate of 3-8%. The two tone contrasts that listeners consistently found difficult to distinguish were T2T5 (high-rising vs low-rising) and T3T6 (mid-level vs low-level). In addition, all children groups also showed difficulty in T4T6 identification (low-falling vs low-level). CONCLUSION: Tone perception is not error-free even among native Cantonese-speaking adults. Overall tone identification performance improved steadily from age 3 to age 6. Based on the participants' performance, a three-tier set of tone groups, with an increasing level of difficulty for identification, is proposed for rehabilitation purposes. These tone groups are (1) Easy: T1T2, T1T3, T1T4, T1T5, T1T6, and T2T3, (2) Medium: T2T4, T2T6, T3T4, and T4T5, and (3) Hard: T2T5, T3T5, T3T6, T4T6, and T5T6.

Aspergillus pachymeningitis mimicking nasopharyngeal carcinoma.

OBJECTIVES: We report a case of otogenic fungal pachymeningitis in a diabetic patient who presented with multiple cranial nerve palsies and nasopharyngeal swelling. METHODS: We present a case report, we describe the investigations, management and clinical course of fungal pachymeningitis, and we present a review of the world literature on fungal and non-fungal pachymeningitis. RESULTS: To our knowledge, this is the first report of fungal pachymeningitis with magnetic resonance imaging features suggestive of nasopharyngeal carcinoma. It is also the first reported case with aspergillus cultured from both a dural biopsy and the ear canal. CONCLUSION: Fungal pachymeningitis is a rare condition which may present to otorhinolaryngologists. Its clinical and radiological findings can be confused with those of nasopharyngeal carcinoma; fungal pachymeningitis should thus be included in the differential diagnosis of nasopharyngeal carcinoma.

Spontaneous tonsillar haemorrhage due to von Willebrand's disease.

OBJECTIVE: We report a case of spontaneous tonsillar haemorrhage due to underlying von Willebrand's disease, without symptoms or signs of infection. METHOD: Case report and literature review of reported causes of spontaneous tonsillar haemorrhage. CASE REPORT: Spontaneous tonsillar haemorrhage is uncommon. Acute bacterial tonsillitis, peri-tonsillar abscess, infectious mononucleosis and idiopathic causes have been reported. Two cases of tonsillitis with underlying bleeding disorders have been reported. We present the first reported case of spontaneous tonsillar haemorrhage secondary to von Willebrand's disease, without evidence of tonsillitis. CONCLUSION: Spontaneous tonsillar haemorrhage is usually related to infection of the tonsils or peri-tonsillar space. An underlying bleeding disorder should be suspected if no evidence of infection is found.

Contributors to surgical in-patient satisfaction--development and reliability of a targeted instrument.

OBJECTIVE: Patient satisfaction is an important indicator of healthcare system performance. High patient satisfaction is associated with greater trust in caregivers, improved compliance with treatment recommendations and a better quality of life (QOL). There are few validated instruments to measure surgical patients satisfaction. The aim of this study was to develop a culturally-specific patient satisfaction instrument, for use as an outcome measure in evaluating surgical services. DESIGN: Patient focus groups were convened to explore dimensions of the peri operative hospital experience. Forums uncovered pertinent domains of interest and identified terminology understood by patients. A preliminary set of items reflecting patient satisfaction was developed. Test-retest reliability of a new surgical patient satisfaction instrument was assessed in 42 subjects at hospital discharge. RESULTS: Domains that emerged included; admission processes and hospital environment, information provision, nursing care, doctor and nurse interaction, and ancillary staff services. Staff attitudes and human qualities were highly valued, as was prompt attention to requests for assistance. Clarity or quality of medical information did not appear to influence in-patient satisfaction. A new measure of surgical patient satisfaction, Hong Kong Index of Inpatient Happiness (HK2Happ), was developed from focus group consultation. Test-retest generated an Intra Class Correlation of 0.868-0.935, indicating a highly stable tool. CONCLUSION: The initial version of HK2Happ was reliable in assessing surgical patient satisfaction. The measure is now undergoing validity testing across different surgical patient populations for generalization and generation of a short form of discriminant items.

Psychometric properties of the Chinese (Cantonese) Tinnitus Handicap Inventory.

OBJECTIVES: To establish the reliability and validity of the Chinese (Cantonese) version of the Tinnitus Handicap Inventory to measure the self-perceived handicapping effect and severity of the condition in patients with chronic tinnitus. DESIGN: Cross-sectional psychometric validation study. SETTING: Audiology clinics in a hospital setting. PARTICIPANTS: Subjects were 114 adult Chinese who attended the audiology clinics with a complaint of tinnitus. MAIN OUTCOME MEASURES: Test-retest and internal consistency reliability; construct validity. RESULTS: The Chinese version of the Tinnitus Handicap Inventory and its subscales showed good internal consistency reliabilities (alpha = 0.72-0.94) that are comparable to those of the original version. High correlations were observed between the Tinnitus Handicap Inventory and psychological distress, tinnitus-related problem ratings and severity ratings. Factor analysis showed that the Chinese version of the Tinnitus Handicap Inventory has a unifactorial structure. A high degree of test-retest reliability was observed (intraclass correlation coefficient = 0.88). CONCLUSIONS: The results suggest that the Chinese (Cantonese) version of the Tinnitus Handicap Inventory is a reliable and valid measure of general tinnitus-related distress that can be used in clinical settings to quantify the impact of tinnitus on daily life.

The accuracy of parent and teacher reports in assessing the vocabulary knowledge of Chinese children with hearing impairment.

PURPOSE: This study aimed to investigate (a) the accuracy of adult reports in assessing the vocabulary knowledge of Cantonese-speaking children with hearing impairment (HI) and (b) the factors that are associated with the accuracy of those reports. METHOD: The first participant group consisted of 47 children and their mothers. The second group consisted of 47 children and 21 teachers. All of the children had profound HI, with a mean age of 57 months. The ratings of the adults were compared with the children's test scores in a standardized test. RESULTS: Both adult groups reported children's performance with satisfactory accuracy. Mother and teacher ratings showed fair to good agreement with each other. Two factors significantly associated with the accuracy of the report were (a) the difficulty of the vocabulary and (b) the child's vocabulary ability as determined by the standardized norm-referenced receptive vocabulary test. The mothers' education level, occupation, and socioeconomic status, and the teachers' teaching experience and length of time they had trained the child, were not significant factors. CONCLUSION: The results suggest that employing adult reports to collect data on the word knowledge of children with HI is applicable to a broad spectrum of the Cantonese-speaking Chinese population.

Quality of life in head and neck cancer patients after surgical resection: translation into Cantonese and validation of the EORTC QLQ-H&N35.

CONCLUSION: High convergent and discriminant validity between subscales was achieved after the translation of EORTC QLQ-H&N35 into Cantonese. Most subscales were assessing distinct components of quality of life (QoL). OBJECTIVES: The study aimed to translate the EORTC QLQ-H&N35 cancer module into Cantonese and to confirm validity and reliability for use in a Hong Kong head and neck (H&N) cancer population. SUBJECTS AND METHODS: An ethnocentric forward-backward translation of EORTC QLQ-H&N35 was conducted by bilingual head and neck health professionals. Discrepancies were identified and problematic wording and concepts revised. Further review preceded pilot testing in 119 postoperative H&N cancer patients. Internal consistency within each subscale, convergent and discriminant validity to check the item relevance and item representativeness within and between subscales were examined. Mean and standard deviations of each subscale and single item and Cronbach's alpha coefficients for subscales were calculated. RESULTS: Six of seven subscales achieved standard reliability (Cronbach's alpha coefficient >0.7). Correlation coefficients between an item and its own subscale were significantly higher than the coefficients with other subscales. Scaling success was found in all subscales. Pearson's correlation coefficient between subscales was <0.70, except between the subscales swallowing and trouble with social eating (r = 0.795), and speech problems and social contact (r = 0.754).

The choice of chromogen and reliability of contact rhinoscopy in the irradiated nasopharynx.

A cross-sectional randomised single blind study was conducted to assess how concentrations of chromogen (vital stain) and the characteristics of the assessors affect the assessment of contact rhinoscopy. Twenty-eight patients who had undergone external radiotherapy for nasopharyngeal carcinoma were assessed by contact rhinoscopy using 0.5 per cent and 1 per cent methylene blue stain on opposite sides of the nasopharynx. Three independent observers assessed the visual clarity of the 45 contact endoscopic images showing squamous metaplasia according to a visual analogue scale. The intraclass correlation coefficients were 0.916 to 0.957 and 0.839 to 0.964 for intra-observer reliability of assessors in the groups of 0.5 per cent and 1 per cent stains, respectively. The intraclass correlation coefficients for inter-observer reliability of assessors were 0.884 and 0.885 in the groups of 0.5 per cent and 1 per cent stains, respectively. The mean scores of clarity of the cellular details were statistically higher in the group of 1 per cent stain among all assessors. These results showed that the assessment of squamous metaplasia by contact endoscopy is highly reliable irrespective of the clinical experience and knowledge of histopathology of the assessors. One per cent methylene blue should be the vital stain of choice in contact endoscopy.

Oestrogen mediates the growth of human thyroid carcinoma cells via an oestrogen receptor-ERK pathway.

OBJECTIVES: Although thyroid cancer occurs much more frequently in females, the role of sex hormones in thyroid carcinogenesis is unknown. In this study, it has been investigated how 17beta-oestradiol (E2) influenced proliferation and growth of thyroid cancer cells. MATERIALS AND METHODS: Cell proliferation and its related molecules were examined in thyroid papillary carcinoma cells (KAT5), follicular thyroid carcinoma cells (FRO) and anaplastic carcinoma cells (ARO). Levels of oestrogen receptor (ER) alpha and beta were regulated by their agonists (PPT and DPN), antagonists and siRNA. RESULTS: E2 promoted cell proliferation. Such an effect was positively related to ERalpha but negatively to ERbeta; PPT enhanced cell proliferation while DPN inhibited it. PPT increased Bcl-2 expression while DPN decreased it. DPN also elevated Bax expression. PPT elevated the level of phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), suggesting a positive role of ERK1/2 in E2-induced cell proliferation. Knockdown of ERalpha significantly attenuated E2-mediated Bcl-2 and pERK1/2 expression. In contrast, knockdown of ERbeta markedly enhanced them. CONCLUSIONS: Oestrogen stimulates proliferation of thyroid cancer cells, associated with increase in Bcl-2 and decrease in Bax levels in an ERK1/2-related pathway. Imbalance between ERalpha and ERbeta may contribute to thyroid carcinogenesis.

Rhinitis symptoms and quality of life in patients with chronic perennial rhinitis treated with desloratadine.

OBJECTIVE: To evaluate the outcome and the change in quality of life of patients with chronic rhinitis after treatment with desloratadine. STUDY DESIGN: A prospective, open-label, non-blinded, non-randomised study of patients in a secondary and tertiary ENT referral centre. METHODS: Chinese patients with chronic rhinitis were recruited. The patients were assessed by a questionnaire that included rhinitis symptoms score and SF-36 health survey components. Endoscopic assessment was performed with a rigid nasoendoscope and scored according to the modified endoscopic appearance score of Lund and Kennedy. A 12-week course of desloratadine 5 mg daily was prescribed. Patients were re-evaluated after treatment. A total of 47 subjects completed the study. RESULTS: There were significant reductions in median rhinitis symptoms score, from six to five (p < 0.001), and in median endoscopic appearance score, from five to three (p < 0.001). Patients' general health perception was also improved after treatment (p == 0.022). CONCLUSION: Desloratadine may be an effective treatment which provides symptomatic relief and improves the quality of life in patients with chronic rhinitis.

Calcium-mediated activation of PI3K and p53 leads to apoptosis in thyroid carcinoma cells.

The molecular mechanism responsible for cadmium-induced cell death in thyroid cancer cells (FRO) is unknown. We demonstrated that apoptosis of FRO cells induced by cadmium was concentration and time dependent. Cadmium caused the rapid elevation of intracellular calcium and induced phosphorylation of Akt, p53, JNK, ERK and p38. Inhibition of PI3K/Akt attenuated the cadmium-induced apoptosis, but the inhibition of JNK inhibitor, ERK or p38 aggravated it, indicating that activation of PI3K/Akt was a pro-apoptosis signal in response to cadmium treatment, whereas the activation of stress-activated protein kinase JNK, ERK and p38 functioned as survival signals to counteract the cadmium-induced apoptosis. Buffering of the calcium response attenuated mitochondrial impairment, recovered the cadmium-activated Akt, p53, JNK, ERK and p38, and subsequently blocked the apoptosis. These results suggested that apoptosis induced by cadmium in FRO cells was initiated by the rapid elevation of intracellular calcium, followed by calcium-mediated activation of PI3K/Akt and mitochondrial impairment.

Increase in circulating Foxp3+CD4+CD25(high) regulatory T cells in nasopharyngeal carcinoma patients.

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated disease with high prevalence in Southern Chinese. Using multiparametric flow cytometry, we identified significant expansions of circulating naïve and memory CD4+CD25(high) T cells in 56 NPC patients compared with healthy age- and sex-matched controls. These were regulatory T cells (Treg), as they overexpressed Foxp3 and GITR, and demonstrated enhanced suppressive activities against autologous CD4+CD25- T-cell proliferation in functional studies on five patients. Abundant intraepithelial infiltrations of Treg with very high levels of Foxp3 expression and absence of CCR7 expression were also detected in five primary tumours. Our current study is the first to demonstrate an expansion of functional Treg in the circulation of NPC patients and the presence of infiltrating Treg in the tumour microenvironment. As Treg may play an important role in suppressing antitumour immunity, our findings provide critical insights for clinical management of NPC.

Cell death induced by ent-11alpha-hydroxy-15-oxo-kaur-16-en-19-oic-acid in anaplastic thyroid carcinoma cells is via a mitochondrial-mediated pathway.

The chemical compound ent-11alpha-hydroxy-15-oxo-kaur-16-en-19-oic-acid (5F), isolated from the Chinese herbal medicine plant Pteris semipinnata L, has been known to exert antitumor activity. However, the molecular mechanism of the action is not understood. In this study we demonstrated that apoptotic cell death induced by 5F in FRO cells was concentration- and time-dependent. The rapid increase in intracellular reactive oxygen species (ROS) levels was involved in the mechanism of cell death. c-Jun N-terminal kinase (JNK) activation and G2 block were related to cell death induced by 5F. Extracellular signal-related kinase (ERK) and p38 were also activated, but as survival signals in response to 5F treatment to counteract the induction of cell death. In the process of the induction of apoptotic cell death, Bax translocated into mitochondria, a reduction in Delta psi(m) was observed and a release of cytochrome c and apoptosis inducing factor (AIF) from mitochondria into the cytosol occurred, indicating that cell death induced by 5F was through a mitochondrial-mediated pathway.

[The effect of desloratadine on the TXB2 and leukotrienes levels in the nasal lavage fluid of allergic rhinitis animal model].

OBJECTIVE: To observe the thromboxane (TX)B2 and cysteinyl leukotrienes (LTs) levels in the nasal lavage fluid of allergic rhinitis model and to observe the effect of desloratadine on the mediators. METHOD: In the positive control group, 8-12 week old male or female guinea pigs were intranasal sensitized and challenged with ovalbumin solution. The antihistamine treatment group was treated with desloratadine and the negative control group was sham-sensitized and sham-challenged. The nasal lavage fluid of each group was collected 5 hours after challenge and the levels of TXB2 and LTs in the nasal lavage fluid were measured. RESULT: In the positive control group, the TXB2 and LTs levels were the highest of the three groups and the desloratadine treated group had lower level (P < 0.05 and P < 0.01). The negative control showed the lowest level. CONCLUSION: Our study demonstrated that in this model of allergic rhinitis, the levels of TXB2 and LTs in nasal lavage fluid increased dominantly after allergen challenge and desloratadine could inhibit the release of TXB2 and LTs, which implied that the therapeutic mechanism of desloratadine might contribute to the inhibitory effect on TXB2 and LTs production or release in allergic rhinitis subjects.

[The immunohistochemical observations of NOS in the nasal mucosa of allergic rhinitis animal model of guinea pigs].

OBJECTIVE: To study the immunoreactivity and distribution of both iNOS and eNOS isoforms, and observe the effect of desloratadine on them. METHOD: The guinea pigs were sensitized and challenged followed by harvest of their nasal tissue for immunohistochemical staining. The slides images were semiquantitatively analyzed and compared with the desloratadine treated group and negative control group. RESULT: Both iNOS and eNOS were positively stained in each group. The immunoreactivity of iNOS had no significant difference between groups (P > 0.05), but eNOS had stronger immunoreactivity in the model group and the desloratadine treated group when compared with the negative control group (P < 0.01 and P < 0.05). In addition to the distribution area of iNOS, eNOS was also positive stained in the goblet cells. Desloratadine had no influence on iNOS and eNOS immunoreactivity. CONCLUSION: eNOS might play a more important role than iNOS in regulating the NO level of the nasal tissue of the guinea pigs suffered from allergic rhinitis, and desloratadine had no involvement in regulating the expression of iNOS and eNOS.

Induction of thyroid papillary carcinoma cell proliferation by estrogen is associated with an altered expression of Bcl-xL.

PURPOSE: One of the features of thyroid carcinoma is its predilection for women of reproductive age relative to men. An increased risk has also been documented in women who have used estrogens for gynecologic reasons. The aim of this study was to explore the mechanism by which sex hormones contribute to the development of thyroid carcinoma, which is not well understood at present. MATERIALS AND METHODS: In this study, we investigated the effects of estradiol and testosterone on cell proliferation in a human thyroid papillary carcinoma cell line (KAT5) by MTT assay. We also studied the expression of estrogen receptors and the levels of anti-apoptotic Bcl-xL protein, pro-apoptotic Bax protein, and messenger RNA in the cells by Western blot and reverse transcriptase polymerase chain reaction analysis. RESULTS: The results showed that estradiol promotes cell proliferation when compared with cells treated with testosterone and untreated cells, and that the growth-promoting effect of estradiol was attenuated by tamoxifen. The expression of Bcl-xL was markedly increased in a dose-dependent manner, resulting in an elevated ratio of Bcl-xL to Bax. DISCUSSION: We conclude that estradiol promotes KAT5 cell proliferation and that the underlying mechanism may be associated with up-regulation of Bcl-xL expression. The data provide insight into the molecular mechanism underlying the epidemiologic data that shows a two- to threefold increased prevalence of thyroid carcinoma in women relative to men. From the therapeutic point of view, the finding that estradiol enhances anti-apoptotic signaling pathways may be significant in the search for novel prevention and treatment strategies of thyroid carcinomas.